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Introducing the world’s first blood based gene expression test for breast cancer

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Available in India through SRL Diagnostics BCtect™ pending CE marking in Europe

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EDITORS AND PUBLISHERS OF THE A SIA-P ACIFIC J OURNAL OF O NCOLOGY & H EMATOLOGY THE

Owned and Published by San Lucas Medical Limited John Gault, MD, Editor-in-Chief

EDITORIAL BOARD Alan KS Chiang, Hong Kong Alexander Eggermont, Netherlands Alfredo Q.Y. Pontejos, Philippines Andrew Spencer, Australia Anthony J. Murgo, USA Aradhana Kaushal, USA Beng H Chong, Australia Bharat Agarwal, India Bogda Koczwara, Australia Catherine Shannon, Australia Chng Wee Joo, Singapore Craig Lewis, Australia Darren Lim Wan Teck, Singapore Delong Liu, USA Divye Chhabra, India Etienne GC Brain, France Eu Kong Weng, Singapore Fei Sun, China Gilbert B. Zulian, Switzerland Gurpreet Singh Ranger, United Kingdom Guy Young, USA Hari S Shukla, India Harpreet Wasan, United Kingdom Hatem Salem, Australia Helmut Friess, Germany Hildegard Greinix, Austria Hiroya Takiuchi, Japan Huyen Tran, Australia Jafri Malin Abdullah, Malaysia

Jean-Pierre Droz, France Jin-Yeong Han, Korea Kensei Tobinai, Japan Khee Chee Soo, Singapore Kok-Sun Ho, Singapore Les Bokey, Australia Li Jia PhD, United Kingdom Lim Jit Fong, Singapore Linda Mileshkin, Australia Linn Yeh Ching, Singapore Maheep Singh Gaur, India. Manjeet Chadha, USA Mark Mckeage, New Zealand Martine J. Piccart-Gebhart, Belgium Masanori Terashima, Japan Michael Anthony Quinn, Australia Michael Boyer, Australia Michael Brown, Australia Michael Michael, Australia Mickey Koh Boon Chai, Singapore Mitsugu Sekimoto, Japan Morito Monden, Japan Nagahiro Saijo, Japan Paul L.F. Giangrande, United Kingdom Peizhong Peter Wang, China Peng Huang, USA Rehan A. Kazi, India Richard Schilsky, USA Robert K. Andrews, Australia

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Ross Baker, Australia Ryo Nishikawa, Japan Sandeep Agarwal, India Satyajit Pradhan, India Saw Aik, Malaysia Scott Dunkley, Australia Shiu-Feng Huang, Taiwan Simone Schoenwaelder, Australia Soon-Beom Kang, Korea Stephen Clarke, Australia Steve You, Korea Suoqin Tang, China Su-Pin Choo, Singapore Surapol Issaragrisil, Thailand Szu-Hee Lee, Australia Takuji Okusaka, Japan Tang Choong Leong, Singapore Thomas Tursz, France Timothy Brighton, Australia Ulrich Wedding, Germany Vijay Kumar Shukla, India Wai Hoe Ng, Singapore Wan Ariffin Abdullah, Malaysia Weijing Sun, USA Winnie Yeo, Hong Kong Wong Sze Chuen Cesar, China Xue Yongquan, China Young Goo Lee, Korea

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PUBLISHING INFORMATION Asia-Pacific Journal of Oncology & Hematology (APJOH) [Print ISSN 1759-6637, Online ISSN 1759-6645] is published quarterly; February/March, July, August and November, by San Lucas Medical, Ltd. Copyright 2009 by San Lucas Medical, Ltd.

Scientific Review and Acceptance The Asia-Pacific Journal of Oncology & Hematology publishes Original Research Manuscripts, Reviews, Editorials, Correspondence and Special Articles such as treatment guidelines. Original Reports remain the focus of the Asia-Pacific Journal of Oncology & Hematology, but we also consider other high quality work which relates to cancer and hematology. The Asia-Pacific Journal of Oncology & Hematology is distributed across Asia-Pacific in print and electronic forms to thousands of physicians, researchers, academics, nurses and related care practitioners with an interest in oncology and hematology. Subscription and access are both free and there are no author fees for publication. Submitted manuscripts are reviewed by members of the APJOH or EJCMO editorial board in the double blind peer review process with the understanding that they have not been submitted for publication elsewhere. Papers are accepted for publication based on originality, quality and relevance to the audience.

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C ONTENTS

March 2009 – Vol 1, No 1

REVIEW ARTICLES The Role of HPV Testing in Diagnosis and Screening of Cervical Cancer Ashfaq M. Khan and Albert Singer........................................................................................................................................1 nab™-Paclitaxel: A Targeted Chemotherapy to Improve Outcomes in Metastatic Breast Cancer Martine Piccart........................................................................................................................................................................5 Clinical Implications of Gene Expression Profiling in Cancer James Mackay, Anna Burford, Sana Sajun, and Andrea Pithers....................................................................................13 Male Breast Cancer: A Review Kathryn M. Field and Richard H. de Boer...........................................................................................................................19 Third Line Treatment Options for Metastatic Colorectal Cancer Wei Chua, Melissa M. Moore, Philip Beale and Stephen J. Clarke..................................................................................27 Quantitative Evaluations for the Optimal Utilization of Radiotherapy in Lung Cancer Shalini K. Vinod.......................................................................................................................................................................37 Gefitinib in Asian Patients or Never Smoker Patients with Non–Small Cell Lung Cancer Luca Toschi and Federico Cappuzzo.................................................................................................................................45 New Advances in Multimodality Treatment and Biological Research of Diffuse Malignant Peritoneal Mesothelioma Marcello Deraco, Dario Baratti, Nadia Zaffaroni, Raffaella Villa, Shigeki Kusamura, Aurora Costa and Maria Grazia Daidone..........................................................................................................................55 Current Management of Malignant Pleural Mesothelioma Arman Hasani and Anna K. Nowak....................................................................................................................................65 An Australian Clinical Perspective: Management of Hormone-Refractory (Androgen-Independent) Prostate Cancer Elizabeth Hovey, Gavin Marx, Andrew Kneebone, Manish Patel and Jeremy Shapiro...............................................77 What’s New in Diagnosis of Hepatocellular Cancer? Linda L. Wong and Chet Hammill........................................................................................................................................89

CASE REPORTS Non-Hodgkin’s Lymphoma-Associated Chylothorax Rajesh Kashyap.....................................................................................................................................................................97 Rapidly Progressive Cushing’s Syndrome in a Carcinoma of Unknown Primary Origin Kathryn M. Field, Robin Cassumbhoy, Bill Murray and Linda Mileshkin.........................................................................101 Sign up for a FREE subscription............................................................................................................................................. ii

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F REE S UBSCRIPTIONS Welcome to the Asia-Pacific Journal of Oncology & Hematology, a new peer reviewed journal. To obtain your FREE subscription to the journal please complete and return the form below. With the help of the world class editorial advisory panel made of an excellent blend of oncologists and hematologists, the Asia-Pacific Journal of Oncology & Hematology aims to help bridge the gap between education and practice, improve the dissemination of important research findings. With the ultimate aim of improving patient care in Asia-Pacific. The editorial team and I are honoured to invite you to join us on a journal that will strengthen and accelerate the communication of important scientific information across Asia-pacific. We aim to provide you an excellent platform to communicate your findings to the highest number of your colleagues possible. To ensure a wide circulation of your research the journal is available free of charge, furthermore there are no charges levied on authors to submit your work. Our peer review system will also ensure your manuscript will be reviewed fairly, quickly and once accepted published rapidly. We will provide you with an indexed, impactful and informative journal discussing the latest issues and we hope you will read the Asia-Pacific Journal of Oncology & Hematology regularly. We encourage you to subscribe for your free personal copy of the journal via the website (http://www.slm-oncology.com) and ask you to recommend that your colleagues to do the same. The editorial team and I are delighted to present you a new, impactful journal which is free to access and publish. We invite you to submit your most important work to the Asia-Pacific Journal of Oncology & Hematology and share it with your colleagues across Asia. Yours sincerely, John Gault, MD, PhD Editor in Chief

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REVIEW ARTICLE

The Role of HPV Testing in the Screening and Diagnosis of Cervical Cancer Ashfaq M. Khan1 and Albert Singer2 Affiliations: 1Department of Women’s Health, Whittington Hospital NHS, London, UK and 2Whittington and Royal Northern Hospitals, London, UK Submission date: 16th January 2009, Acceptance date: 6th February 2009

ing is more sensitive but less specific than cytology at detecting high-grade CIN.7–9 HPV testing tends to be more sensitive when clinicians conduct specimen sampling from the cervix compared to self-collection by women from the vagina. Screening of women older than thirty tends to improve the specificity of HPV testing because viral infections in this group are more likely to be persistent rather than transient in nature and more directly related to the development of highgrade disease. A recent meta-analysis showed that overall sensitivity of HPV testing with Hybrid capture (HC2) for detecting high-grade intraepithelial neoplasia (CIN) was 89.3% (95%CI: 85.2% to 93.4%). The overall specificity of HC2 in excluding high-grade CIN was 87.8% (95%CI: 85.5% to 90%),6 with higher specificity in Europe and North America compared to other countries. It is difficult to explain why the sensitivity of HPV testing is decreased in African (81% in Zimbabwe) or Asian (50% to 80% in India) countries compared to Europe (97.9%),6 because epidemiological studies suggest an almost similar distribution of high-risk HPV types in these areas. The possibility of excluding important types of high-risk HPV from HC2 probes may not be a valid argument. Interestingly, when a polymerase chain reaction (PCR) system was employed to detect HPV DNA, sensitivity was reduced, but specificity improved. Meta-analysis showed the pooled sensitivity for CIN2+ was 80.9% (95% CI: 70% to 91.7%) and specificity was 94.7% (95% CI: 92.5% to 96.9%). The combination of HPV DNA testing (by HC2) and cytology improves the sensitivity of screening significantly. For detection of CIN2+, this combination increased the sensitivity to 99.2%. Several randomized, controlled trials comparing cytology alone with cytology and HPV testing combined have shown a substantially increased sensitivity with the latter approach.10,11 In general, the sensitivity of these tests is greater for CIN2+ than CIN1. The high negative predictive value of the double test could allow increased time intervals between screening tests (that is to say, up to 3 to 5 year intervals). However, its relatively low specificity still produces a high number of false positives and unnecessary referrals to colposcopy clinics. A developed country

Keywords: virus, diagnosis, cancer screening, cervical cancer, human papillomaviruses Correspondence: Mr Ashfaq M. Khan, Department of Women’s Health, Whittington Hospital NHS, London, UK. e-mail: ashfaq.khan@whittington.nhs.uk

INTRODUCTION Cervical cancer is the second most common cancer in women worldwide. Approximately 500000 women are diagnosed annually with invasive cancer of the cervix. Two reports from the 1990s detected high-risk human papilloma virus (HPV) in 99.7% of the cervical cancers analyzed, leading to the conclusion that HPV is necessary for the development, maintenance and progression of cervical intraepithelial neoplasia (CIN) to cervical cancer.1,2 There are more than 200 genotypes of HPV, of which about 40 exhibit a tropism for the mucosa of the anogenital tract. However, only 15 types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 73 and 82) of high-risk HPV are involved in cervical carcinogenesis. Other HPV genotypes rarely cause cancer. Most women are infected with this virus shortly after the commencement of their first sexual relationship,3 with the highest prevalence seen in women less than 25 years of age. However, most of these infections are transient, last an average of 6 months, and are cleared in almost 90% of women within 2 years.4 It is evident from both meta-analyses and cross-sectional studies that HPV testing has a higher sensitivity than cytology for detecting high-grade lesions and that the combination of HPV DNA testing and cytology has a high negative predictive value for the detection of CIN.5,6 At present, HPV DNA testing is useful in three clinical applications: as a primary screening test (either as an adjunct or stand alone), as a triage test to detect genuine high-risk women who are diagnosed with minor cytological abnormalities and also as a follow-up test for women with high-grade lesions who are treated with local ablation or excision.

PRIMARY SCREENING WITH HPV TESTING The use of HPV DNA testing as a potential cervical cancer screening tool emerged in the late 1980s. Several research studies have shown that HPV DNA testAPJOH 2009; 1: (1). March 2009

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Asia-Pacific Journal of Oncology & Hematology

ity was statistically very heterogeneous among groups within the analysis. Nonetheless, these data indicated that HPV testing has a higher sensitivity but similar specificity when compared to cytology in detecting residual disease.6 Other studies suggested that combined cytology and HPV DNA testing is more effective than either test alone.20–22

can support the extra costs of a double testing screening program, especially because the longer screening interval is significantly cheaper in the long run. In the developing world, it is very difficult to implement a cytology-based screening program due to a lack of highly trained personnel and specialized equipment. Moreover, multiple visits to a colposcopy unit from remote areas are a major practical problem. A compromise has been achieved by the visual inspection of the cervix with application of the acetic acid (VIA) procedure. This technique reduces the incidence of cancer in low resource settings.12 However, its sensitivity and specificity are not sufficiently high to consider it as a suitable long-term method. In such remote areas, use of the recently developed, rapid HPV DNA test (provided in 2.5 h)13 and immediate treatment by cryotherapy of high-risk disease could be an effective, alternative approach.

Therefore, it would seem reasonable to follow up posttreatment women with an HPV test after 6 months with reflex cytology reserved for those with a positive HPV DNA test. However, this proposition needs further validation with larger multi-center studies.

HPV TESTING TO TRIAGE MINOR CYTOLOGICAL LESIONS Atypical squamous cells of undetermined significance (ASCUS) remains a common cytological diagnosis and is detected in about 4% of screened women. In several countries, it is currently recommended to follow these women with a conventional (Pap) smear or liquid-based cytology (LBC) in 6 months. Women are then referred for a colposcopy if the ASCUS persists. In the Netherlands, about one-third of women with ASCUS in primary screening smears are eventually referred for colposcopy.23

HPV TEST TO FOLLOW UP AFTER TREATMENT OF CERVICAL INTRAEPITHELIAL NEOPLASIA The main purpose of a follow-up after treatment of CIN is to detect persistent or recurrent disease. Recurrence rates of 5% to 10% have been reported in various studies.14–17 In most countries, women are followed for at least 10 years after excision biopsy for high-grade lesions. The rationale behind such a long follow-up period is the increased risk of developing CIN and cancer for 10 years or more after excision of high-grade lesions compared to a normal cohort.18 The majority of treatment failures are due to residual disease and can be detected by cytology within 2 years of treatment. A recent multi-center prospective study evaluated the role of HPV testing in combination with cytology in the follow-up of treated women.19 The cumulative risk of residual disease was low after 24 months of follow-up when both HPV test and cytology were negative. Therefore, the authors suggested that a woman with negative cytology and HPV test results at 6  months could safely be recalled for follow-up at 3-year intervals rather than the currently recommended yearly cytology for 10  years. Interestingly, the negative predictive value of a double-negative test result was similar between women with incomplete and complete excision margins in their original operative specimens. This suggests that the HPV status is a more important risk factor than margin status with regard to residual disease. The high negative predictive value of HPV DNA testing has potential for use in the clinic for following patients treated for CIN. Women who are HPV-negative after treatment are at very low risk of having residual or recurrent disease. A large meta-analysis showed that the sensitivity of HPV DNA testing for predicting treatment failure is 94.4% (95%CI: 90.9% to 97.9%) and its specificity is 75% (95% CI: 68.7% to 81.4%). Unfortunately, specificAPJOH 2009; 1: (1). March 2009

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The poor cytological reproducibility of this diagnosis remains a problem, since 5% to 17% of ASCUS cases are subsequently diagnosed as cervical intraepithelial neoplasia grade 2 (CIN2) or CIN3 on cervical biopsy.24–28 This creates a significant clinical management issue as these cases require further evaluation to identify those women with high-grade diseases (CIN2+). Colposcopy and colposcopy-directed biopsy have historically been considered the gold standard to accomplish this evaluation. However, this approach is invasive, expensive and can miss up to one-third of high-grade lesions because of sampling and diagnostic errors.29 Hence, it can be difficult to identify high-grade lesions because of false positive cytology results and false negative biopsy results. The burden on women and the healthcare system could be reduced if the subgroup of patients with highgrade lesions could be more easily identified. HPV testing can be used for risk stratification of women with low-grade abnormal smears because no histological progression is seen in women who spontaneously clear their HPV infection.30 Women without a detectable HPV infection do not need further follow-up. This possibility could be the case in up to 40% to 60% of women with persistent ASCUS smears.31–37 An updated meta-analysis found better sensitivity for HPV test triage of ASCUS cases in comparison with repeat cytology for detection of high-grade CIN but similar specificity (63% versus 62% for cytology).6 Moreover, cytology triage is dependent on high patient compliance with making multiple follow-up visits for repeated smear tests to achieve this specificity and sensitivity. 2

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The Role of HPV Testing in the Screening and Diagnosis of Cervical Cancer

REFERENCES

As evidenced by this discussion, the optimal strategy and time points for incorporating HPV testing to triage women with ASCUS (or borderline nuclear abnormality) smears are yet to be determined.

1. 2.

ROLE OF TYPE SPECIFIC HPV TESTS

3.

Although cervical cancer is induced by HPV, the different HPV types are not equally carcinogenic. About 15 oncogenic or high-risk strains are involved in cervical carcinogenesis. Of these high-risk types, HPV  16, and to a lesser extent HPV  18 and 45, carry greater risk than others. HPV 16 and HPV 18 are etiologically associated with CIN3 and invasive cervical carcinomas (CIN3+) in 60% and 10% to 20% of specimens, respectively.38 Wright et al. suggested the use of combined cytology and HPV DNA testing as a primary screening tool. Women with normal cytology and a positive HPV test could be triaged with a type specific test for HPV 16. Women found to be positive would then be referred to colposcopy. Those who are found to be HPV 16 negative could be retested with liquid-based cytology or Pap smear and an HPV test after a year. This approach would improve the sensitivity of testing and reduce the number of unnecessary referrals for colposcopy.39

4. 5. 6. 7.

8. 9.

10.

Approximately 50% of ASCUS specimens demonstrate high-risk HPV infections.40 The ASCUS LSIL Triage Study Group reported that the 2-year cumulative absolute risk for CIN lesions of grade 3 or higher is 48.5% for HPV 16-positive ASCUS specimens. This study also showed that HPV 16 infected women with an initially low-grade squamous intraepithelial lesion (LSIL) cytology had a 51.6% risk of CIN2 or worse lesions (biopsy confirmed) within 2 years.41

11.

12.

13.

Moreover, the persistence of HPV infection is most often associated with HPV 16 and 18, suggesting that the identification of these two HPV types may play an important role in the risk stratification of patients with ASCUS.42–45

14.

HPV typing provides no diagnostic value for CIN3 or cervical cancer, however, it may have prognostic significance. Demonstrating the same HPV type in the posttreatment specimen and the treated CIN3 lesion may indicate recurrent HPV infection, suggesting that the patient may be unable to cope with this particular HPV type and might require more intense follow-up.46

15. 16.

17.

CONCLUSION The cytology-based cervical screening program performs best in the developed world. Unfortunately, it still has poor sensitivity and specificity and can not likely be improved by itself. It is time to replace this testing modality or at least supplement it with HPV-based tests. However, regular clinical validation is incredibly important and necessary for all HPV-based assays.

18. 19. 20.

Disclosure: The authors have no financial interests to disclose related to the contents of this article. www.slm-oncology.com

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Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55(4):244–265. Bosch FX, Manos MM, Muñoz N, et al. and The IBSCC study group. Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst. 1995;87:796–802. Collins S, Mazloomzadeh S, Winter H, et al. High incidence of cervical human papillomavirus infection in women during their first sexual relationship. BJOG. 2002;109(1):96-98. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338(7):423–428. Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer. 2006;119(5):1095–1101. Arbyn M, Sasieni P, Meijer CJ, et al. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine. 2006;24(Suppl 3):S3/78–89. Kulasingam SL, Hughes JP, Kiviat NB, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002;288(14):1749–1757. Cuzick J, Szarewski A, Cubie H, et al. Management of women who test positive for high-risk types of human papillomavirus: the HART study. Lancet. 2003;362(9399):1871–1876. Petry KU, Menton S, Menton M, et al. Inclusion of HPV testing in routine cervical cancer screening for women above 29 years in Germany: results for 8466 patients. Br J Cancer. 2003;88(10):1570–1577. Naucler P, Ryd W, Tornberg S, et al. Human papillomavirus and Papanicolau tests to screen for cervical cancer. N Engl J Med. 2007;357(16):1589–1597. Bulkmans N, Berkhof J, Rozendaal L, et al. Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and Cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet. 2007;370(9601): 1764–1772. Sankaranarayanan R, Esmy PO, Rajkumar R, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster randomized trial. Lancet. 2007;370:398–406. Qiao YL, Sellors JW, Eder PS, et al. A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China. Lancet Oncol. 2008;9(10):929–936. Alvarez RD, Helm CW, Edwards RP, et al. Prospective randomized trial of LLETZ versus laser ablation in patients with cervical intraepithelial neoplasia. Gynecol Oncol. 1994;52: 175–179. Bigrigg A, Haffenden DK, Sheehan AL, Codling BW, Read MD. Efficacy and safety of large-loop excision of the transformation zone. Lancet. 1994;343(8888):32–34. Hulman G, Pickles CJ, Gie CA, Dowling FM, Stocks PJ, Dixon R. Frequency of cervical intraepithelial neoplasia following large loop excision of the transformation zone. J Clin Pathol. 1998;51:375–377. Mitchell MF, Tortolero-Luna G, Cook E, Whittaker L, RhodesMorris H, Silva E. A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intra-epithelial lesions of the cervix. Obstet Gynecol. 1998;92:737–744. Soutter WP, de Barros LA, Fletcher A, et al. Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia. Lancet. 1997;349:978–980. Kitchener HC, Walker PG, Nelson L, et al. HPV testing as an adjunct to cytology in the follow up of women treated for cervical intraepithelial neoplasia. BJOG. 2008;115(8):1001–1007. IzumiT, Kyushima N, Genda T, et al. Margin clearance and HPV infection do not influence the cure rates of early neoplasia of the uterine cervix by laser conization. Eur J Gynaecol Oncol. 2001;21(3):251–254.

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21. Zielinski GD, Rozendaal L, Voorhorst FJ et al. HPV testing can reduce the number of follow-up visits in women treated for cervical intraepithelial neoplasia grade 3. Gynecol Oncol. 2003;91(1):67–73. 22. Nobbenhuis MA, Meijer CJ, van den Brule AJ, et al. Addition of high-risk HPV testing improves the current guidelines on follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer. 2001;84(6):796–801. 23. Rebolj M, Ballegooijen MV, Berkers LM, Habbema F. Monitoring a national cancer prevention programme: Successful changes in cervical cancer screening in the Netherlands. Int J Cancer. 2006;120:806–812. 24. Crum CP, Genest DR, Krane JF, et al. Subclassifying atypical squamous cells in thin-prep cervical cytology correlates with detection of high-risk human papillomavirus DNA. Am J Clin Pathol. 1999;112:384–390. 25. Davey DD, Neal MH, Wilbur DC, et al. Bethesda 2001 implementation and reporting rates: 2003 practices of participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology. Arch Pathol Lab Med. 2004;128:1224–1229. 26. Quddus MR, Sung CJ, Steinhoff MM, et al. Atypical squamous metaplastic cells. Cancer. 2001;93:16–22. 27. Sherman ME, Solomon D, Schiffman M. Qualification of ASCUS: a comparison of equivocal LSIL and equivocal HSIL cervical cytology in the ASCUS LSIL Triage study (ALTS). Am J Clin Pathol. 2001;116:386–394. 28. Solomon D, Schiffman M, Tarrone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance. J Natl Cancer Inst. 2001;93:293–299. 29. Gage JC, Hanson VW, Abbey K, et al. for the ASCUS LSIL Triage Study (ALTS) Group. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108:264–272. 30. Nobbenhuis MA, Helmerhorst TJ, van den Brule AJ, et al. Cytological regression and clearance of high-risk human papillomavirus in women with an abnormal cervical smear. Lancet. 2001;358:1782–1783. 31. Bais AG, Rebolj M, Snijders PJ, et al. Triage using HPVtesting in persistent borderline and mildly dyskaryotic smears: proposal for new guidelines. Int J Cancer. 2005;116:122–129. 32. Herrington CS, Evans MF, Hallam NF, et al. Human papillomavirus status in the prediction of high-grade cervical intraepithelial neoplasia in patients with persistent low-grade cervical cytological abnormalities. Br J Cancer. 1995;71:206–209. 33. Pisal N, Sindos M, Chow C, Singer A. Triage by HPV-DNA testing: is it useful in women with persistent minor smear abnormalities? Acta Obstet Gynecol Scand. 2003;82:575–577. 34. Fait G, Kupferminc MJ, Daniel Y, et al. Contribution of human papillomavirus testing by hybrid capture in the triage of

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women with repeated abnormal pap smears before colposcopy referral. Gynecol Oncol. 2000;79:177–180. Ho L, Terry G, Londesborough P, et al. Human papillomavirus DNA detection in the management of women with twice mildly abnormal cytological smears. J Med Virol. 2003;69:118–121. Zielinski GD, Snijders PJF, Rozendaal L, et al. High-risk HPV testing in women with borderline and mild dyskaryosis: long-term follow-up data and clinical relevance. J Pathol. 2001;195:300–306. Rebello G, Hallam N, Smart G, et al. Human papillomavirus testing and the management of women with mildly abnormal cervical smears: an observational study. Br Med J. 2001;322:893–894. Munoz N, Bosch FX, de Sanjose S, et al. for the International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527. Wright TC Jr, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol. 2004;103(2):304–309. Evans M, Adamson C, Papillo JL. Distribution of human papillomavirus types in thinprep Papanicolaou tests classified according to the Bethesda 2001 terminology and correlations with patient age and biopsy outcomes. Cancer. 2006;106: 1054–1064. Castle PE, Solomon D, Schiffman M, et al. for the ALTS Group. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytological abnormalities. J Natl Cancer Inst. 2005;97:1066–1071. Ho GY, Bierman L, Beardsley C, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423–428. Wallin KL, Wiklund F, Anstrom T, et al. Type specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med. 1999;341:1633-1638. Solomon D, Schiffman M, Tarrone R. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance. J Natl Cancer Inst. 2001;93:293–299. Londesborough P, Ho L, Terry G, Cuzick J, Wheeler C, Singer A. Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities. Int J Cancer. 1996;69:364–368. Carrington M, Wang S, Martin MP, et al. Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci. J Exp Med. 2005;201(7):1069–1075.

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REVIEW ARTICLE

nab™-Paclitaxel: A Targeted Chemotherapy to Improve Outcomes in Metastatic Breast Cancer Martine Piccart1 Affiliation: 1Institut Jules Bordet, Brussels, Belgium Submission date: 25th February 2009, Acceptance date: 4th March 2009

ABSTRACT

toxicities, including hypersensitivity reactions, neuropathy, and neutropenia, which can complicate treatment and diminish quality of life.2 The hydrophobic nature and poor water solubility of taxanes mandate the concomitant use of synthetic solvents for their solubilization and delivery. Paclitaxel is formulated with polyoxyethylated castor oil (Cremophor® EL), while docetaxel requires a combination of polysorbate 80 (Tween® 80) and ethanol to allow parenteral administration. These solvents may be responsible for some of the toxicities associated with taxanes, particularly hypersensitivity and neurotoxicity.3,4 Cremophor EL also leaches plasticizers from polyvinyl chloride bags and infusion sets, which can result in severe, and sometimes fatal, hypersensitivity reactions.3–6 Special intravenous tubing is therefore required for taxane administration in order to reduce the risk of hypersensitivity reactions. In addition, premedication with corticosteroids and antihistamines is also required to limit the severity of any arising hypersensitivity reactions. Solvents may also affect the efficacy of conventional taxane formulations. Cremophor EL has been shown to entrap paclitaxel through formation of micelles in plasma, preventing the drug from reaching tumor sites and resulting in reduced intratumoral concentrations of the active drug.5,7–9 Micelle formation may explain the lack of dose–response seen with solvent-based paclitaxel, as it limits the potential benefit of increased dose.7 Dose escalation of solvent-based paclitaxel does not improve outcomes, and is associated with increased toxicity.9 These limitations of solvent-based taxanes have prompted research efforts to improve their therapeutic index by creating solvent-free formulations, such as liposomal encapsulated paclitaxel, paclitaxel vitamin E emulsion and a polymer microsphere formulation of paclitaxel.10 The first successful attempt to formulate a solvent-free taxane has been the development of nanoparticle albumin-bound (nabTM)-paclitaxel (Abraxane®, Abraxis BioScience, Los Angeles, CA, USA). The nab platform exploits the natural properties of albumin to increase drug delivery to the tumor and eliminates the need for solvents.11

Nanoparticle albumin-bound (nab )-paclitaxel is a novel formulation of paclitaxel that does not require the synthetic solvent carrier used with other taxanes. It exploits the natural properties of albumin to increase uptake and accumulation of paclitaxel in the tumor through gp60-mediated endothelial transcytosis, and interaction with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine). Preclinical models have shown that nab-paclitaxel has greater antitumor activity than solvent-based paclitaxel and docetaxel, leading to the clinical testing of nab-paclitaxel. TM

A large phase III randomized controlled trial demonstrated the superior efficacy and favorable safety profile of nab-paclitaxel compared with solvent-based paclitaxel in patients with metastatic breast cancer (MBC). Based on these findings, nab-paclitaxel has now received regulatory approval in 37 countries, including Australia, China and South Korea in the Asia Pacific region. nab-Paclitaxel is currently licensed for the treatment of MBC after failure of anthracycline therapy, and is given as a 30 min intravenous infusion without corticosteroid or antihistamine premedication. Also, because it is free of solvents, there is no need for special infusion sets with nab-paclitaxel. Thus, nab-paclitaxel is not just another taxane but is a targeted chemotherapy that represents a new treatment advance for women with MBC. An extensive clinical development program is now ongoing for nabpaclitaxel in a range of tumor types, including MBC, and it is hoped that this will establish the true role of this novel anticancer therapy. Keywords: nab-paclitaxel, albumin, metastatic breast cancer, chemotherapy, solvent-based paclitaxel, targeted therapy, Cremophor EL, taxane Correspondence: Dr Martine Piccart, Institut Jules Bordet, Boulevard de Waterloo 125, B-1000 Brussels, Belgium. Tel: + 32 2 541 32 06; fax: + 32 2 538 08 58; e-mail: martine. piccart@bordet.be

INTRODUCTION The taxanes paclitaxel and docetaxel are among the most active drugs in the treatment of metastatic breast cancer (MBC), and are established as the standard of care, either as monotherapy or in combination with other cytotoxic agents.1 However, despite their clinical activity in MBC, the use of taxanes is often limited by significant APJOH 2009; 1: (1). March 2009

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nab-Paclitaxel nab-Paclitaxel is a novel formulation of paclitaxel that consists of nanometer-range particles of paclitaxel bound 5

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paclitaxel and solvent-based paclitaxel were 47 and 30 mg/kg/day, respectively. The maximum tolerated doses (MTDs) were 30 and 13.4  mg/kg/day for nabpaclitaxel and solvent-based paclitaxel, respectively11; these doses induced a 4% mortality rate in treated mice and were considered equitoxic. The possible mechanisms of increased intratumoral paclitaxel accumulation were examined in vitro using human umbilical vascular endothelial cells treated with fluorescent-labeled nab-paclitaxel and solvent-based paclitaxel.11 Endothelial binding of nab-paclitaxel was found to be 9.9-fold higher than solvent-based paclitaxel, and transcytosis across endothelial cells was 4.2fold higher with nab-paclitaxel than with solvent-based paclitaxel.11 Endothelial transcytosis of nab-paclitaxel was blocked by methyl b-cyclodextrin, a known inhibitor of caveolar-mediated transport. Cremophor EL inhibited binding of paclitaxel to the endothelial cells and to albumin in a dose-dependent manner, highlighting the negative effect this solvent may have on intratumoral delivery of paclitaxel. The absence of Cremophor EL, and the enhanced endothelial binding and transcytosis of nab-paclitaxel, may explain in part its greater antitumor activity when compared with solvent-based paclitaxel. The encouraging antitumor activity and reduced toxicity reported in preclinical studies led to the progression of nab-paclitaxel into clinical development.

Figure 1. Transmission electron microscopy (TEM) of nab-paclitaxel nanoparticles (magnification 110,000× [standard TEM]). (reprinted with permission from PharmaVentures Ltd.).10

to human serum albumin.12 The albumin-bound paclitaxel particles have an average size of 130 nm (Figure 1). nab-Paclitaxel exploits the role of albumin as the natural carrier of hydrophobic molecules in humans to increase delivery of paclitaxel to tumor cells, thereby removing the necessity for synthetic solvents.11 The albumin moiety of nab-paclitaxel binds to the specific albumin cell surface receptor (gp60) on the endothelial cell membrane.1 This   activates caveolin-1, a major component of membrane vesicles, resulting in receptor-mediated internalization of the albumin–drug complex into caveolae, with subsequent transcytosis and delivery of drug to the tumor cells. The leaky junctions associated with tumor vasculature also facilitate the entry and accumulation of nabpaclitaxel into the tumor microvessels,1 although this is now believed to be a minor component of the transport relative to the gp60-based mechanism.11

CLINICAL DEVELOPMENT OF nab-PACLITAXEL The efficacy and safety of nab-paclitaxel was established in a phase III randomized, controlled trial.18 Based on the findings from this study, nab-paclitaxel has received regulatory approval in 37  countries, including Australia, China and South Korea in the Asia Pacific region. nab-Paclitaxel is currently licensed for the treatment of MBC after failure of anthracycline therapy, and is given as a 30 min intravenous infusion without premedication.19 Also, because it is free of solvents, there is no need for special infusion sets with nab-paclitaxel. There is an extensive clinical development program ongoing for nab-paclitaxel in a range of tumor types, including MBC. This will evaluate the efficacy and safety of nab-paclitaxel as a single agent and in combination with various other agents commonly used in MBC and other tumor types.

The uptake and accumulation of nab-paclitaxel in the tumor interstitium may be enhanced through the interaction of albumin with SPARC (secreted protein, acidic and rich in cysteine).13,14 SPARC is overexpressed in many tumor types, including breast cancer, and its overexpression is associated with poorer outcomes in patients with breast cancer.15 Preclinical studies using the SPARC-positive MX-1 breast cancer xenograft model showed that nab-paclitaxel achieved a 33% higher intratumoral paclitaxel concentration compared with equivalent doses of solvent-based paclitaxel.11 Other studies in patients with head and neck cancer demonstrated a correlation between high SPARC expression and response to nab-paclitaxel,13,14 suggesting a possible role for SPARC as a biomarker for nab-paclitaxel effectiveness.14,16

Early Clinical Development of nab-Paclitaxel The toxicity profile, MTD, and pharmacokinetics of nab-paclitaxel administered every 3 weeks (q3w) were examined in a phase I study involving 19 patients with advanced solid tumors.12 nab-Paclitaxel was administered as a 30 min infusion without premedication. Doses ranged from 135 to 375 mg/m2. No hypersensitivity reactions occurred, despite the absence of premedication. The MTD was determined to be 300 mg/m2, almost

In preclinical models, nab-paclitaxel has been shown to have greater antitumor activity than solvent-based paclitaxel11 and docetaxel17 in multiple tumor types, including breast xenografts. In a dose-finding study in mice, nab-paclitaxel was significantly less toxic than solvent-based paclitaxel: the LD50 values for nabAPJOH 2009; 1: (1). March 2009

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50% higher than the recommended dose of paclitaxel (175 mg/m2 q3w). Dose-limiting toxicities included sensory neuropathy, stomatitis and superficial keratopathy. Linear pharmacokinetics were observed with nabpaclitaxel over the clinically relevant dose range of 135 to 300 mg/m2, suggesting that a dose increase over this range may improve efficacy. The MTD and pharmacokinetics of nab-paclitaxel administered weekly were also examined.20 In this phase I study, 39 patients with advanced nonhematologic malignancies received nab-paclitaxel at doses of 80 to 200 mg/m2 weekly for 3 weeks in each monthly cycle. The drug was administered as a 30  min infusion without premedication. After the first cohort was enrolled, patients at subsequent dose levels were enrolled into 1 of 2 cohorts, ‘lightly’ or ‘heavily’ pretreated, based on the extent of prior chemotherapy. MTDs were 100 and 150  mg/m2 for heavily and lightly pretreated patients, respectively. The dose-limiting toxicities were grade 4 neutropenia in heavily pretreated patients, and grade 3 peripheral neuropathy in lightly pretreated patients. Pharmacokinetics were linear over the dose range studied. These findings indicate that nab-paclitaxel could be administered weekly as a 30 min infusion without premedication. Subsequent to the Ibrahim et al.12 phase I study of nab-paclitaxel q3w, a phase II study21 was conducted in patients with MBC to evaluate the safety and antitumor activity of nab-paclitaxel at a dose of 300 mg/m2. A total of 63  patients with histologically confirmed and measurable MBC received nab-paclitaxel by intravenous infusion over 30  min q3w without premedication. Fortyeight patients had received prior chemotherapy, and 39 had no prior first-line treatment for metastatic disease. Overall response rates (ORR) were 48% for all patients, and 64% for those who received nab-paclitaxel as firstline therapy. Median time to disease progression (TTP) was 26.6 weeks, and median overall survival (OS) was 63.6  weeks. As in the phase  I study, no severe hypersensitivity reactions were observed, despite the absence of premedication. The observed toxicities were typical for paclitaxel, including grade 4 neutropenia (24%) and grade  3 sensory neuropathy (11%). The results of this study led to the initiation of a randomized phase III trial of nab-paclitaxel in patients with MBC.

Figure 2. Overall response rates, phase III comparative trial of nabpaclitaxel versus solvent-based paclitaxel.18

cation, or solvent-based paclitaxel at its licensed dose of 175 mg/m2 intravenously over 3  h with corticosteroid and antihistamine premedication. The dose of nabpaclitaxel used in this study18 was lower than the MTD used in the phase  II study, and was selected so that nab-paclitaxel would not be more toxic than solventbased paclitaxel at 175 mg/m2. Of the 460 patients enrolled, 83% were postmenopausal, 76% had more than 3 metastatic lesions, 86% had received prior chemotherapy and 59% had progressed following first-line treatment for metastatic disease. Approximately half of the patients in each treatment group received at least 6 treatment cycles. The paclitaxel dose intensity delivered was 49% higher in patients in the nab-paclitaxel group than in the solvent-based paclitaxel group (mean [standard deviation], 85.13 [3.118] mg/m2 vs 57.02 [3.008] mg/m2 per week, respectively). Solvent-based paclitaxel was administered with premedication in 99% of cycles, whereas nab-paclitaxel was administered without premedication in 95% of cycles. Treatment with nab-paclitaxel was associated with a significant improvement in response rate (primary end point) compared with solvent-based paclitaxel (33% vs 19%; P<0.001; Figure  2). The superiority of nabpaclitaxel was also observed across the subgroups analyzed, including patients who received nab-paclitaxel as first-line therapy (42% vs 27%; P=0.029), and those who received it as second-line therapy or greater (27% vs 13%; P=0.006; Figure  2). Median TTP (secondary end point) was significantly longer with nab-paclitaxel than with solvent-based paclitaxel for all patients (23.0 vs 16.9  weeks; hazard ratio [HR]=0.75; P=0.006), and

Phase III Trial of nab-Paclitaxel Versus Solvent-Based Paclitaxel An international, randomized phase III trial directly compared the antitumor activity and safety of nabpaclitaxel with solvent-based paclitaxel in patients with MBC.18 The study was conducted at 70 sites in 5 countries (Canada, Russia, Ukraine, UK, and the USA). A total of 460  patients with measurable MBC were enrolled into the study and randomly assigned (1:1) to treatment q3w with either nab-paclitaxel at a dose of 260 mg/m2 intravenously over 30 min without premediwww.slm-oncology.com

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Despite the 49% higher dose of paclitaxel administered to patients in the nab-paclitaxel group, grade 4 neutropenia was significantly less common in this group than in the solvent-based paclitaxel group (9% vs 22%, respectively; P<0.001), suggesting that the solvent (Cremophor EL) may have contributed to this toxicity. As expected with a higher dose of paclitaxel, grade  3 sensory neuropathy was more common with nabpaclitaxel (10% vs 2%; P<0.001). This was easily managed with treatment interruption and dose reduction, and rapidly improved to grade  2 or 1 in a median of 22 days (Figure 4). No severe (grade 3 or 4) hypersensitivity reactions occurred in patients treated with nabpaclitaxel, despite the absence of routine premedication and the shorter infusion time compared with solventbased paclitaxel. Conversely, 5 patients in the solventbased paclitaxel group experienced grade 3 hypersensitivity reactions, despite standard premedication. Comparable efficacy results were reported in a phase  III trial involving 210  Chinese patients with MBC.22 As in the Gradishar et al.18 study, patients were randomized 1:1 to receive either nab-paclitaxel 260  mg/m2 intravenously over 30  min q3w with no premedication, or solvent-based paclitaxel 175 mg/m2 intravenously over 3  h q3w with standard premedication. The ORR was significantly higher in the nabpaclitaxel group than in the solvent-based paclitaxel group (54% vs 29%, respectively; P<0.001). This advantage was maintained in the subgroups who received nabpaclitaxel as first-line therapy (56% vs 29%, P<0.001), and in the group with no prior anthracycline exposure (61% vs 21%, P=0.001). Median TTP (nab-paclitaxel vs solvent-based paclitaxel, 7.6 months vs 6.2 months; P=0.078) and median progression-free survival (PFS) (7.6  months vs 6.2  months; P=0.118) were higher in the nab-paclitaxel group, although the differences were not statistically significant. The most common toxicities reported were alopecia and peripheral neuropathy; both occurred with similar frequency in the 2 groups. Thus, results from phase III studies establish the efficacy and safety of nab-paclitaxel 260 mg/ m2 administered q3w in patients with MBC.

Figure 3. Patient survival over time, phase III comparative trial of nab-paclitaxel versus solvent-based paclitaxel: (A) overall patient population, and (B) in patients who received second-line or greater therapy (reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Gradishar WJ et al.: J Clin Oncol. 2005;23:7794–7803).18

among those receiving second-line therapy or greater (20.9 vs 16.1 weeks; HR=0.73; P=0.020). Although not significantly different, there was a trend for greater median overall survival (secondary end point) among all patients treated with nab-paclitaxel compared with solvent-based paclitaxel (65.0 vs 55.7 weeks; P=0.374; Figure  3A). A significant difference was observed in patients who received nab-paclitaxel as second-line or greater therapy (56.4 vs 46.7 weeks; P=0.024; Figure 3B). Treatment compliance was high in both groups, with 96% of patients in the nab-paclitaxel group receiving 90% of the protocol-specified dose, and 94% in the solvent-based paclitaxel group receiving 90% of the protocol-specified dose. Drug-related discontinuations, reductions and dose delays were also infrequent (3% to 7%) in both groups. APJOH 2009; 1: (1). March 2009

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nab-Paclitaxel Once Weekly Administration Recent data show that weekly solvent-based paclitaxel is more effective than q3w administration. 23 This finding, along with results demonstrating efficacy of nab-paclitaxel in first-line patients, 18 and superior efficacy versus docetaxel in preclinical models,17 provided the rationale for evaluating weekly nabpaclitaxel in first-line MBC. A randomized phase II study compared the efficacy and safety of 3 regimens of nab-paclitaxel with docetaxel for first-line therapy in patients with MBC.24 In this 4 arm study, 300  patients with previously untreated MBC were randomized to receive nab-paclitaxel 300  mg/m2 q3w (n=76), nab-paclitaxel 100 or 150  mg/m2 weekly 8

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Figure 4. Time to improvement of sensory neuropathy in patients treated with nab-paclitaxel and who developed grade 3 sensory neuropathy (reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Gradishar WJ et al.: J Clin Oncol. 2005;23:7794–7803).18

Figure 5. Overall response rates (investigator assessment), demonstrated in the phase II comparative trial of nab-paclitaxel weekly and q3w versus docetaxel (from Gradishar WJ et al.: Presented at the 6th European Breast Cancer Conference (EBCC); April 15–19, 2008, Berlin, Germany [Poster 409]).24 NS, not significant; qw, weekly; q3w, every 3 weeks.

for 3 of every 4 weeks (n=76 and 74, respectively), or docetaxel 100  mg/m2 q3w (n=74). nab-Paclitaxel was administered intravenously over 30  min without premedication, while docetaxel was given over 60 min after oral corticosteroids. The lower-dose nab-paclitaxel arms were compared with the higher-dose arm, and all nab-paclitaxel arms were compared with docetaxel. Most (75%) of the patients enrolled were postmenopausal, and 43% had received prior adjuvant or neoadjuvant chemotherapy. Weekly nab-paclitaxel schedules of 100 and 150  mg/m2 produced higher response rates compared with the q3w schedule. Response rates were higher in all nab-paclitaxel regimens compared with docetaxel, and these differences were significant in both weekly nab-paclitaxel groups compared with docetaxel (Figure 5). In terms of disease control (complete response + partial response + stable disease for ≥16 weeks), the rates were significantly higher in both weekly nab-paclitaxel arms compared with docetaxel (Figure 6). Median PFS was significantly longer with nab-paclitaxel 150 mg/m2 than with docetaxel (14.6 vs 7.8 months, respectively; HR=0.57; P=0.012; Figure 7). Although median PFS was also longer with nab-paclitaxel 300 mg/m2 than with docetaxel, this did not reach statistical significance. OS data were not mature at the time of data cut-off for this publication. Regarding toxicity, all nab-paclitaxel arms were associated with lower rates of grade  3/4 neutropenia, grade  3/4 fatigue, and febrile neutropenia compared with docetaxel. The incidence of grade 4 neutropenia was higher with docetaxel than with nab-paclitaxel (5%, 9%, 5%, and 75% for nab-paclitaxel 100 mg/m2 weekly, nabpaclitaxel 150 mg/m2 weekly, nab-paclitaxel 300 mg/m2 q3w, and docetaxel 100  mg/m2 q3w, respectively). Peripheral neuropathy occurred with similar frequency in www.slm-oncology.com

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Figure 6. Investigator-assessed disease control rates (complete response + partial response + stable disease for ≥16 weeks), demonstrated in the phase II comparative trial of nab-paclitaxel qw and q3w versus docetaxel (from Gradishar WJ et al.: Presented at the 6th European Breast Cancer Conference (EBCC); April 15–19, 2008, Berlin, Germany [Poster 409]).24 NS, not significant; qw, weekly; q3w, every 3 weeks.

all treatment arms. However, median time to improvement in grade 3 peripheral neuropathy was shorter with nab-paclitaxel (22, 22, and 19  days for 300  mg/ m2 q3w, 100  mg/m2 weekly, and 150  mg/m2 weekly, respectively) than with docetaxel (37  days). These results therefore strongly suggest superior efficacy and

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Figure 8. Study design, CALGB/NCCTG 40502 trial in patients with locally recurrent or metastatic breast cancer. †Days 1, 8, and 15 q28d; CEC, circulating endothelial cells; CTC, circulating tumor cells; n=900.

pared with solvent-based paclitaxel and the absence of premedication. The phase III and phase II data reported18,24 support the use of single-agent nab-paclitaxel 260 mg/m2 as a valuable treatment option for MBC. Moreover, additional medications such as corticosteroids, which may be associated with unpleasant side effects, are not needed.

Figure 7. Progression-free survival, phase II comparative trial of nab-paclitaxel weekly and q3w versus docetaxel (from Gradishar WJ et al.: Presented at the 6th European Breast Cancer Conference (EBCC); April 15–19, 2008, Berlin, Germany [Poster 409]).24 HR, hazard ratio; N/A, not applicable; NS, not significant; qw, weekly; q3w, every 3 weeks.

ONGOING CLINICAL DEVELOPMENT OF nabPACLITAXEL IN MBC AND FUTURE DIRECTION

safety of weekly nab-paclitaxel therapy over docetaxel in first-line MBC, with the nab-paclitaxel weekly dose of 150 mg/m2 appearing to be the most effective.

The positive efficacy data for nab-paclitaxel coupled with a more favorable tolerability profile compared with solvent-based taxanes has led to the initiation of an extensive clinical development program for nabpaclitaxel in various tumor types, including MBC. A key phase III study in patients with MBC is the Cancer and Leukemia Group  B/North Central Cancer Treatment Group (CALGB/NCCTG) study.

CLINICAL IMPLICATIONS OF USING nabPACLITAXEL IN MBC From the clinical studies described above, the use of the nab platform may overcome the limitations and adverse consequences of synthetic solvents, resulting in improved efficacy without increasing toxicity. Compared with solvent-based paclitaxel, higher doses of nab-paclitaxel can be administered over a shorter infusion time (30 min vs 3 h) without the need for special tubing or premedication.

The CALGB/NCCTG Study The Eastern Cooperative Oncology Group 2100 study demonstrated that adding bevacizumab to paclitaxel for the first-line treatment of MBC leads to significant improvements in response rate and PFS.25 Based on these results, the CALGB/NCCTG 40,502 randomized phase III study will compare weekly regimens of solvent-based paclitaxel, nab-paclitaxel, and ixabepilone, all combined with bevacizumab in firstline therapy for MBC (Figure  8 [ClinicalTrials. gov identifier: NCT00785291; accessed February  27, 2009]). The study will recruit 900  patients with locally recurrent or MBC. The primary outcome will be PFS; secondary outcomes will include objective tumor response, duration of tumor response, time to treatment failure, probability of being progression-free at 12  months, and OS. Serum and tumor biomarkers (caveolin-1 and SPARC), along with circulating tumor

In the pivotal phase III study, treatment with nabpaclitaxel resulted in superior efficacy in terms of response rates and TTP when compared with solventbased paclitaxel.18 A survival benefit was also seen in patients receiving second-line or greater therapy. nab-Paclitaxel treatment was also associated with an improved safety profile compared with solventbased paclitaxel, with a significantly lower incidence of hematologic toxicities despite the higher paclitaxel dose administered in nab-paclitaxel. The risk of hypersensitivity reactions was reduced with nabpaclitaxel, despite the shorter infusion times comAPJOH 2009; 1: (1). March 2009

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and endothelial cells, will be measured to assess their possible role as predictive markers of response. This will be a US-based study.

REFERENCES

nab-Paclitaxel in Triple-Negative Breast Cancer

2.

The expression of caveolin-1, a structural component of caveolae in breast cancer, is associated with triple-negative breast cancer.26 As nab-paclitaxel is transported from the circulation to the tumor site via albumin-receptor mediated transcytosis, which involves caveolin-1,1 it is possible that patients with the triplenegative phenotype may respond particularly well to this novel drug. In addition, expression of SPARC, which has been shown to correlate with tumor response to nab-paclitaxel,13,14 is higher in triple-negative breast cancer.27 However, to date, only a few nab-paclitaxel studies have included small numbers of patients with triple-negative breast cancer.28–30 As such, there are currently no data available on the correlation between the triple-negative phenotype, SPARC expression and/ or response to nab-paclitaxel, although some studies are planned.

3.

1.

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SUMMARY

10.

nab-Paclitaxel is a novel paclitaxel formulation that does not require the synthetic solvents used with other taxanes. It is approved for the treatment of MBC and is the first nanotechnology-based drug on the market. The nab platform exploits the properties of albumin to facilitate uptake of drug directly into the tumor cells via the gp60 receptor-mediated pathway, resulting in increased antitumor activity and reduced toxicity compared with solvent-based paclitaxel. The advantages of the nab platform are borne out by the results from clinical studies with nabpaclitaxel, which support the superior efficacy and safety of nab-paclitaxel compared with solvent-based paclitaxel and docetaxel. Thus, nab-paclitaxel is not just another taxane, but is a targeted chemotherapy which exploits albumin-based transport mechanisms such as gp60 transcytosis across tumor endothelial cells and binding of tumoral SPARC. This nanotechnology-based drug represents a new treatment advance for women with MBC.

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Disclosure: Dr Piccart has received honoraria from Abraxis BioScience and Sanofi-Aventis, and a research grant (to the Institute Jules Bordet) from BristolMyers Squibb.

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ACKNOWLEDGEMENTS Medical writing support was provided by Annete NjueDoswell and Angela Corstorphine at Prime Medica Ltd during the preparation of this paper, supported by Abraxis BioScience Inc. Responsibility for opinions, conclusions and interpretation of data lies with the author. www.slm-oncology.com

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Aapro MS, Minckwitz GV. Molecular basis for the development of novel taxanes in the treatment of metastatic breast cancer. Eur J Cancer Suppl. 2008;6:3–11. Harries M, Ellis P, Harper P. Nanoparticle albumin-bound paclitaxel for metastatic breast cancer. J Clin Oncol. 2005;23:7768–7771. Weiss RB, Donehower RC, Wiernik PH, et al. Hypersensitivity reactions from taxol. J Clin Oncol. 1990;8:1263–1268. Gelderblom H, Verweij J, Nooter K, Sparreboom A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur J Cancer. 2001;37:1590–1598. ten Tije AJ, Verweij J, Loos WJ, Sparreboom A. Pharmacological effects of formulation vehicles: implications for cancer chemotherapy. Clin Pharmacokinet. 2003;42:665–685. Kloover JS, den Bakker MA, Gelderblom H, van Meerbeeck JP. Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens. Br J Cancer. 2004;90:304–305. Sparreboom A, van Zuylen L, Brouwer E, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res. 1999;59:1454–1457. van Tellingen O, Huizing MT, Panday VR, Schellens JH, Nooijen WJ, Beijnen JH. Cremophor EL causes (pseudo-) nonlinear pharmacokinetics of paclitaxel in patients. Br J Cancer. 1999;81:330–335. Winer EP, Berry DA, Woolf S, et al. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342. J Clin Oncol. 2004;22:2061–2068. Desai N. Nab technology: a drug delivery platform utilising endothelial gp60 receptor-based transport and tumourderived SPARC for targeting. Drug Delivery Report. 16th ed. 2007/2008:37–41. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317–1324. Ibrahim NK, Desai N, Legha S, et al. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res. 2002;8:1038–1044. Trieu V, Damascelli B, Soon-Shiong P, Desai N. SPARC expression in head and neck cancer correlates with tumor response to nanoparticle albumin-bound paclitaxel (nab-paclitaxel, ABI-007, Abraxane). Presented at the 97th Annual Meeting of the American Association for Cancer Research (AACR); April 1–5, 2006; Washington, DC (Abstract 4477). Desai N, Trieu V, Damascelli B, Soon-Shiong P. SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl Oncol. 2009 (in press). Watkins G, Douglas-Jones A, Bryce R, Mansel RE, Jiang WG. Increased levels of SPARC (osteonectin) in human breast cancer tissues and its association with clinical outcomes. Prostaglandins Leukot Essent Fatty Acids. 2005;72:267–272. Trieu V, Frankel T, Labao E, Soon-Shiong P, Desai N. SPARC expression in breast tumors may correlate to increased tumor distribution of nanoparticle albumin-bound paclitaxel (ABI-007) vs Taxol. Presented at the 96th Annual Meeting of the American Association for Cancer Research (AACR); April 16–20, 2005; Anaheim, CA (Abstract 5584). Desai NP, Trieu V, Hwang LY, Wu R, Soon-Shiong P, Gradishar WJ. Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status. Anticancer Drugs. 2008;19:899–909. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794–7803.

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25. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676. 26. Pinilla SM, Honrado E, Hardisson D, Benítez J, Palacios J. Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat. 2006;99:85–90. 27. Gralow J, Rugo H, Gradishar W, et al. Novel taxane formulations in the treatment of breast cancer: a thought leader discussion and consensus roundtable. Clin Breast Cancer. 2008;8:33–37. 28. Bernstein JA, Schubbert T, Kong K, Mehta RS. Weekly carboplatin and nab-paclitaxel plus trastuzumab, or plus or minus bevacizumab: Clinical response in patients with breast cancer. J Clin Oncol. 2006 Part 1;24(Suppl 18S): Abstract 10699. 29. Mehta RS, Schubbert T, Jackson D, Hsiang D, John B. Pathologic complete response following paclitaxel (cremophor or albumin bound) + carboplatin ± trastuzumab ± bevacizumab sequenced after in vivo chemosensitivity-adapted dose-dense doxorubicin-cyclophosphamide in inflammatory breast cancer. Presented at the 30th San Antonio Breast Cancer Symposium; December 13–16, 2007 (Abstract 5066). 30. Yardley DA, Inhorn R, Daniel B, et al. Preliminary progression free survival and SPARC tumor correlatives from a phase II neoadjuvant trial of gemcitabine, epirubicin, and nab- paclitaxel. Presented at the 31st San Antonio Breast Cancer Symposium, December 10–14, 2008 (Abstract 5116).

19. Abraxane® Summary of Product Characteristics. Available at http://emc.medicines.org.uk/emc/assets/c/html/displaydoc. asp?documentid=21384. Document last updated on emc January 12, 2009. Accessed January 28, 2009. 20. Nyman DW, Campbell KJ, Hersh E, et al. Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J Clin Oncol. 2005;23:7785–7793. 21. Ibrahim NK, Samuels B, Page R, et al. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005;23:6019–6026. 22. Guan ZZ, Feng F, Li QL, et al. Randomized study comparing nab-paclitaxel with solvent-based paclitaxel in Chinese patients with metastatic breast cancer. J Clin Oncol. 2007 Part 1;25(Suppl 18S): Abstract 1038. 23. Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26: 1642–1649. 24. Gradishar WJ, Krasnojon D, Cheporov S, et al. Randomized comparison of nab-paclitaxel weekly or every 3 weeks compared to docetaxel every 3 weeks as first-line therapy in patients with metastatic breast cancer. Presented at the 6th European Breast Cancer Conference (EBCC); April 15–19, 2008, Berlin, Germany (Poster 409).

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REVIEW ARTICLE

Clinical Implications of Gene Expression Profiling in Cancer J. Mackay1,2, A. Burford1, S. Sajun1 and A. Pithers2 Affiliations: 1University College London, London, UK; 2Trinity Health Innovations Ltd, London, UK Submission date: 28th November 2008, Acceptance date: 3rd January 2009

Abstract

cancer care, millions of dollars have been invested across the world into molecular biology laboratories over the last few decades, and it is not unreasonable to expect a return on this investment. Gradually, exciting advances have been made in our theoretical understanding of cancer development and progression. Recent technological advances have enabled us to examine the activity of thousands of genes simultaneously within a single sample. This technique is known as gene expression profiling, and the data produced are amalgamated into a gene expression signature. Early studies looked at these expression signatures in tumor tissue from breast cancer and in cancers of unknown primary origin. This research produced prognostic and diagnostic information which may help in the choice of appropriate cancer treatment. Extending these technological developments to the examination of the genetic activity of white blood cells in peripheral blood may give us early clues to the development of disease, including breast cancer.

Clinicians everywhere wish to introduce innovations into their clinical practice that will improve patient care, but are also anxious to ensure that there is sound evidence to do so. Gene expression profiling examines the activity of many genes simultaneously. Several products are now available within the breast cancer field using this technology. Two expression arrays give information about tumor biology that may facilitate decision making in the choice of adjuvant treatment for the breast cancer patient. A third array gives information that may help determine the primary site of origin of a cancer and, therefore, may help the clinician in choosing the most appropriate regimen. Gene expression profiling in peripheral blood has been considered to provide a large amount of complex data, but an assay recently launched in India claims to identify early breast cancer. It is possible that this new assay may complement regular mammography within a breast cancer screening program. Herein, the basic epidemiology of breast cancer in Asia is considered. It is axiomatic that the introduction of a novel diagnostic will depend on the level of care already available for a particular disease. The level of evidence required to introduce such a diagnostic will vary across different demographics. A blood-based breast screening assay may well be of great importance in countries where it is not possible to provide a general program of high quality mammography. Health care systems in resource-poor countries may welcome the introduction of such a test; however, they are likely to require sound research evidence before instituting a screening program involving blood-based gene expression analysis. We welcome input from readers regarding appropriate research projects to address this problem.

Gene Expression Profiling Gene expression occurs in two major stages. The first is transcription, which is the copying of the gene to produce an RNA molecule (a primary transcript) with essentially the same sequence as the genomic transcript. The second stage is synthesis of the protein from the RNA, known as translation. A DNA microarray is a collection of hundreds to tens of thousands of DNA sequences secured to a glass slide; each spot on the slide contains a specific DNA fragment. RNA is extracted from the tumor sample and then amplified to produce complementary RNA (cRNA). The cRNA is then hybridized to the DNA sequences on the microarray and hybridization is quantified using fluorescence intensities. This technique, known as gene expression profiling, can be used to measure the expression activity of all of the sequences within a genome. The use of microarrays for gene expression profiling was first reported in 19951 and it has since been used to examine specific gene activity levels in many cancers, including the diagnosis of leukemia.2 More recently, this technology has been shown to be effective as a prognostic and diagnostic tool in assessing patients with breast cancer. Prognosis is conducted by measuring the expression levels of certain informative genes

Keywords: gene expression profiling, breast cancer, breast screening, cancer registers, blood test, cancer of unknown primary Correspondence: James Mackay, Consultant Genetic Oncologist, Research Department of Genetics, Evolution and Environment, University College London, Gower Street, London, UK. Tel: +44 (0) 20 7647 8382; fax: +44 (0) 20 7182 1744; j.mackay@ucl.ac.uk

INTRODUCTION There is an understandable conflict between our desire to introduce innovation into clinical care as quickly as possible and a moral obligation to only introduce changes that will be beneficial to patients. In APJOH 2009; 1: (1). March 2009

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within the tumor cells. The expression activity of these genes is altered in cancer cells, and the specific variation of the gene expression can be used to predict the likely progression of the tumor. The most recent development in gene expression profiling, however, is the utilization of gene expression techniques for the detection of breast cancer, possibly even before it is detected by radiological techniques.

cer recurrence in the patient was also derived. The score is a number between 0 and 100 that relates to a specific likelihood of the breast cancer returning within 10 years of the diagnosis. The Oncotype DX® test and the recurrence score have been clinically validated in an independent study.11 This study found that the score was more reliable and better at predicting cancer recurrence than using the patient’s age, tumor size or tumor grade. Oncotype DX® has also been shown to be effective in predicting the magnitude of benefit that chemotherapy would provide for the patient.12 The NSABP B-20 study has shown that women with a recurrence score in the low (0 to 17) or intermediate (18 to 30) risk groups gain little benefit from chemotherapy whereas chemotherapy would have a much greater effect on cancer from women with highrisk recurrence scores (31 to 100). The Oncotype DX® test and the recurrence score have also been proven to be effective in a wider population-based study that found that combining the predictive powers of the recurrence score, the tumor size and the tumor grade was more effective than any of these predictive factors on their own.13

Gene Expression Profiling For Breast Cancer Prognosis An example of a test that uses gene expression profiling to predict the progression of certain types of breast cancer is the MammaPrint™ test developed by Agendia BV in the Netherlands. MammaPrint™ is used to assess the risk of breast cancer metastasis in lymph nodenegative breast cancer patients who are under 61 years of age and whose tumors are less than 5 cm in diameter. It is a microarray-based test that uses the 70-gene breast cancer gene signature published by Van’t Veer et al (2002)3 to predict the clinical outcome and survival of patients with breast cancer.4 Unlike other gene expression array tests, MammaPrint™ can be used with fresh tissue which offers a higher quality read out, as the RNA is not degraded. This requires a sample taken from an unfixed tumor specimen within hours of surgery. A microarray is then used to assess the relative gene expressions of each of the 70 genes in the breast cancer gene signature. Each microarray contains three identical sets of the 70-gene signature and negative control genes, the inclusion of which improve the reliability of the test results. From the results of this test, a patient’s risk of distant breast cancer metastasis is determined as high or low. This test thus adds independent prognostic information5 and helps physicians to make decisions about adjuvant treatment following surgery. A study carried out by Bueno-de-Mesquita et al assessed the feasibility of implementing the MammaPrint™ test in a community-based setting6 and found that the use of the gene-signature was feasible in Dutch community hospitals. More recently, MammaPrint™ has been shown to be effective in predicting survival in patients with small T1 tumors, usually regarded as low-risk patients.7

Gene Expression Profiling In Cancer of Unknown Primary Origin (Cup) Gene expression profiling has also been used in the management of cancers other than breast cancer tumors. Agendia’s CUPPrint™ uses similar technology to MammaPrint™ to diagnose the most likely site of origin in patients with cancers of unknown primary origin (known as CUP). Many studies have assessed the prognosis and survival of patients with CUP, and most show that these patients have a significantly worse prognosis than patients whose primary tumor site is known14,15: the median survival of a patient with CUP is just 7 months. Traditionally, the clinical analysis of patients with CUP relied on clinical investigation (PET scans and CT scans) and immunohistochemistry (IHC) to determine the most likely cancer origin. CUPPrint™ uses gene expression microarray analysis of a tissue sample from a metastasis to determine the most likely site of the primary tumor by identifying which genes are present and active (out of hundreds of classdiscriminating gene signatures). The accuracy of the CUPPrint™ test has been validated in a recent study that suggests that gene expression microarray analysis diagnosis is useful when the primary clinical algorithm has failed to provide a diagnosis.16

Oncotype DX® from Genomic Health Inc. is another microarray test that uses gene signatures as a prognostic tool in breast cancer and that has been extensively researched and clinically validated. This array was developed for use with samples from women with early stage node-negative and estrogen receptor (ER)positive invasive breast cancer. A sample of tumor tissue is taken after surgery, fixed in formalin and then embedded in paraffin for preservation. Oncotype DX® uses a panel of 16 cancer genes and five reference genes derived from three studies of breast cancer patients.8–10 From these three studies, a recurrence score algorithm that quantifies the likelihood of breast canAPJOH 2009; 1: (1). March 2009

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Gene Expression Profiling Using Peripheral Blood The potential use of large-scale gene expression analyses for the early diagnosis of disease has been well documented. Many diseases, including breast cancer, have been studied, but almost all of the published work involves the examination of samples of the diseased 14

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tissue or samples containing circulating diseased cells. An interesting development in this field suggests that circulating leukocytes can be viewed as scouts, continuously maintaining a comprehensive surveillance of the body for signs of infection or other threats, such as cancer. An initial pilot study reported the analysis of gene expression patterns in peripheral blood cells in women with breast cancer compared with women without breast cancer. A panel of genes was identified with distinct and specific expression profiles in the breast cancer blood samples, suggesting that breast cancer causes characteristic changes in the biochemical environment of blood, even in the very early stages of breast cancer development.17 Follow-up clinical studies have been encouraging, with the most recent report presented at the San Antonio Breast Cancer Symposium in December 200829. In this Indian study, a total of 741 samples were collected, including a training set of 292 patients and a test set of 152 patients. This study reported an overall test accuracy of 77% for BCtect™ in premenopausal Indian women. These data are very similar to the results reported for a cohort of European/US patients.18 Both the informative assays and the diagnostic performance of these assays were similar in the racially diverse populations studied.

Moreover, in contrast to Western countries, breast cancer is diagnosed at a younger age in Pakistani and Indian women. The incidence of reproductive age breast cancer in women of Karachi has been reported as the highest in the world.21 The lack of national screening programs, poor detection methods, and a lack of awareness amongst the masses of these regions may explain some of these findings. India and Pakistan have a significant cancer problem, with a rising trend of risk factors. Both are in need of an improved cancer control programme.22 Assessing the magnitude of the cancer burden using cancer registries is an initial step in the development of a ‘National Cancer Control Program’ (NCCP). If a prompt and targeted NCCP was implemented today, the overall benefits may take 20 to 30 years to be fully realised. However, a positive impact may occur within 2 to 3 years through a down-staging of cancer diagnosis. In the Philippines, cancer ranks as the third leading cause of morbidity and mortality. Breast cancer has consistently been the most common cancer reported among Filipino women, with 14,043 cases recorded in 2005.23 Data derived from two population-based cancer registries in Manila and Rizal reported that breast cancer ASR was 43.2 per 100000.24 Consistent with India and Pakistan, there is a low general awareness of cancer, with most patients presenting with advanced disease. The Filipino government has appreciated the need for an aggressive information campaign and has taken a firm stance toward putting public health measures in place. The Cancer Control Program was set up in 1988, and the further establishment of ‘C-Network’— a web-based support service, has provided Filipino women with more widespread access to cancer information, statistics, resources and innovations. This has been achieved through research and community building initiatives.25

Breast Cancer in Asia Breast cancer is more common in the developed rather than in the developing world, whereas mortality rates due to breast cancer are higher in lowresource developing countries. In Asia, India, Pakistan and the Philippines have the highest breast cancer incidence rates. The escalating burden of breast cancer on these countries highlights the need for measures to control and improve breast cancer detection and management. The introduction of an effective and acceptable method to promote early diagnosis could also, potentially, be the most cost-effective way of reducing mortality. Only six population-based registries are functioning in India for a population of over one billion. Based on data obtained from these registries, the Age-Standardized Incidence Rate (ASR) for breast cancer varies between 22 and 24 per 100,000.19 In urban areas, this is increased to 28.1 per 100,000.20 Breast cancer is diagnosed at a much later stage in India, compared with the UK, with 26% of patients being diagnosed at stage 0 or I, while 74% are detected at stage II or further advanced. Data collected from the Karachi Cancer Registry in South Karachi indicate that Pakistani women demonstrate a high incidence rate of 50.1 per 100,000. This is despite their living within a similar socio-cultural background to women in India; for example, women in both societies experience their first childbirth at a young age and have similar breast-feeding practices. It is observed that one in every nine women suffer from breast cancer in Pakistan. www.slm-oncology.com

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Using Cancer Registries Cancer registries play a pivotal role in providing data to justify the implementation of cancer screening programs and in monitoring the efficacy of new therapies introduced within a population. Cancer registration is an active process involving visits by registry staff to hospitals, laboratories and death-registry offices.26 A cancer registry is a systemic data collection unit that requires cancer registrars to acquire the history, diagnosis, treatment and present status for all patients affected by the disease. Cancer registries can be ‘population-based’ or ‘hospital-based’. A population-based cancer registry measures the incidence of cancer diseases over time within a specified population and within specific regions by collecting reports from sources such as clinicians and pathologists. This type of registry accurately monitors the effectiveness of preventative measures. Comparing data 15

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India, the performance of regular mammography in asymptomatic women is poor, with 65% sensitivity and 25% specificity.18 In India and Pakistan, two-thirds of breast cancers are reproductive age malignancies. Hence, mammography from the age of 50 years would have limited effectiveness in these patients. The cost efficiency of mammographic screening is thus questionable under these conditions.

extracted from different registries can provide information on probable risk factors. A hospital-based registry, on the other hand, collects detailed data regarding diagnosis and therapy from all patients attending that hospital, holding the improvement in cancer therapy27 as its main objective. Cancer registries have now been set up in most countries across the world, and the information extracted from them has been the backbone of most cancer control programs in the West. However, the quality of data obtained from developing countries can provide an inaccurate picture of the cancer burden present. There are certain biases involved in data collection. For instance, extracting data from death-registry offices has limited application, as most deaths recorded are incomplete or inadequate. Deaths frequently occur at home, and cancer is uncommonly stated as the cause of death. Advanced malignancies are clinically diagnosed in outpatient departments or clinicians’ offices, and accurate pathological diagnosis may not be made. Records may not be available for some of these patients in hospitals or clinics. Some may not be registered at all. For countries like India and Pakistan that have a population of approximately one billion, which corresponds to 16.5% of the world’s population, a handful of cancer registries are unable to accurately assess the cancer burden.19 An inaccurate assessment of the cancer burden by the overzealous use of registry data can have severe negative repercussions on the use of limited health resources in a country. Hence, in order for effective cancer control programs to be implemented, planning must account for the limitations inherent in the political, social, economic and organizational factors of every country.21 Developing countries, in particular, must be cautious in how and where their scarce and valuable resources are spent.

Introducing a Blood Test for Early Breast Cancer The introduction of the BCtect™ blood test could prove to be cost effective in low-resource developing countries. This discrete patient-friendly test has achieved promising results after a multi-center study was conducted for detecting breast cancer in an Indian population. The evidence base is constantly increasing due to the publication of new results, but the latest report from the San Antonio Breast Cancer Symposium 2008 confirms that the performance of the BCtect was independent of menopausal status, stage of breast cancer, or type of benign disease.29 The diverse population recruited to the study confirms the broad applicability of the BCtect™ blood test in India for women of various ages and ethnic backgrounds. Introducing a diagnostic test using gene expression analysis may not only decrease mortality rates but also help promote breast cancer awareness within a population.30 It is very likely that increased breast cancer awareness in resource-poor countries will lead to earlier diagnosis, with consequent mortality reduction. A reduction in the mortality rate may take years to become evident, although there is a tremendous intellectual attraction to using data collection infrastructures, such as cancer registries, which are already in place to determine whether introducing new practices actually improves outcome. However, it is likely that the scientific rigor of these structures will not be strong enough to provide convincing evidence of mortality reduction. The most accurate measure of the success of a new diagnostic test is a fall in the breast cancer-specific mortality rate. However, in view of the time lag involved, it may be reasonable to institute a study examining surrogate end points, such as tumor size and nodal status, which can then be used to calculate the expected disease-specific mortality reduction. We are currently discussing such a study in several resource-poor countries in various parts of the world. We would welcome critical comments and offers of both clinical and academic collaborations from readers of the Asia-Pacific Journal of Oncology and Hematology.

Breast Screening with Mammography Breast cancer is one of the few malignancies where mass screening by mammography has been proven to reduce mortality in randomized clinical trials. Countries offering a regular mammography screening program have demonstrated significant mortality reduction outside clinical trials. The establishment of Cancer Control Programs in developing countries such as India, Pakistan and the Philippines is rare, despite the mass screening of women within the population. The benefits of mammographic screening are limited by geography, age, economics, social and psychological issues. According to the International Agency for Research on Cancer (IARC), the sensitivity of mammography in women aged over 50 has been estimated to range from 68% to 90%, while this is somewhat lower in women aged 40 to 49 years where the estimated range is 62% to 76%.28 Although few studies have been reported from APJOH 2009; 1: (1). March 2009

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Disclosures: Employment or Leadership Position— J. Mackay and A. Pithers are directors of Trinity Health Innovations Ltd, which is a consultant to DiaGenic ASA. 16

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15. van de Wouw AJ, Janssen-Heijnen MLG, Coebergh JW, Hillen HF. Epidemiology of unknown primary tumours; incidence and population based survival of 1285 patients in southeast Netherlands, 1984–1992. Eur J Cancer. 2002;38:409–413. 16. Bridgewater J, van Laar R, Floore A, van’t Veer L. Gene expression profiling may improve diagnosis in patients with carcinoma of unknown primary. Br J Cancer. 2008;98:1425–1430. 17. Sharma P, Sahni NS, Tibshirani R, et al. Early detection of breast cancer based on gene-expression patterns in peripheral blood cells. Breast Cancer Res. 2005;7(5):R634–R644. 18. DiaGenic. World premier of a revolutionary breast cancer test [Web page]. November 8, 2008. http://www.diagenic.no/site. php?id=pr&year=2008&id1=56031374572401. Accessed February 12, 2009 19. Chakraborti KL et al. Magnetic resonance imaging of breast masses: Comparison with mammography. Indian J Radiol Imaging. 2005;15:381–387. 20. Desai P, Cancer control efforts in the Indian subcontinent. Jpn J Clin Oncol. 2002;32(suppl 1):S13–S16. 21. Sohail S, Alam SM. Breast cancer in Pakistan—Awareness and early detection. J Coll Physicians Surg Pak. 2007;17(12): 711–712. 22. Bhurgri Y, Bhurgri A, Nishter S, et al. Pakistan—Country profile of cancer and cancer control 1995–2004. J Pak Med Assoc. 2006;56(3):124–130. 23. CNetwork. Estimated leading cancer sites in 2005, female [Web page]. http://www.cnetwork.org.ph/factsfigures. asp?cat=4&id=8. Accessed February 12, 2009. 24. Ngelangel CA, Wang EHM. Cancer and the Philippine Cancer Control Program. Jpn J Clin Oncol. 2002;32(Suppl 1):S52–S61. 25. The Manila Times. A look at cancer in the Philippines [Web page]. March 3, 2007. http://www.manilatimes.net/national/ 2007/mar/03/yehey/life/20070303lif4.html. Accessed February 12, 2009. 26. Bhurgri Y, Bhurgri A, Hassan SH, et al. Cancer incidence in Karachi, Pakistan: first results from Karachi Registry. Int J Cancer. 2000;85:325–329. 27. Jensen OM, Parkin DM, MacLennan R, Muir CS, Skeet RG, eds. Cancer Registration: Principles and Methods. IARC Scientific Publication no. 95. Lyons: IARC; 1991. 28. IARC. IARC Handbooks of Cancer Prevention: Breast Cancer Screening. Lyon: IARC; 2002. 29. Tobin D, Lindahl T, Bardsen K, et al. Development of a blood based breast cancer test in an Indian population. Poster presented at: The San Antonio Breast Cancer Conference; December 10–14, 2008; San Antonio, TX. 30. International Business Times. DiaGenic announces launch of first breast cancer gene-expression blood test [Web page]. November 10, 2008 http://www.ibtimes.com/prnews/20081110/ diagenic-and-applied.htm. Accessed February 12, 2009.

Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science. 1995;270:467–470. Golub TR, Slonim DK, Tamayo P, et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science. 1999;286:531–537. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530–536. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17):1183–1192. Bueno-de-Mesquita JM, van Harten WH, Retel VP, et al. Use of 70-gene signature to predict prognosis of patients with node-negative breast cancer: a prospective community-based feasibility study (RASTER). Lancet Oncol. 2007;8:1079-–1087. Glas AM, et al. MammaPrint predicts survival in small T1 breast tumours. Poster presented at: ESMO conference; July 3–6, 2008, Lugano, Switzerland. Esteban J, Barker J, Cronin M, et al. Tumour gene expression and prognosis in breast cancer: multi-gene RT-PCR assay of paraffin-embedded tissue. Abstract 3416. Presented at: The 39th Meeting of the American Society of Clinical Oncology; May 31–June 3, 2003; Chicago, IL. Paik S, Shak S, Tang G, et al. Multi-gene RT-PCR assay for predicting recurrence in node-negative breast cancer patients—NSABP Studies B-20 and B-14. Abstract 16. Presented at: The 26th Annual San Antonio Breast Cancer Symposium; December 3–6, 2003; San Antonio, TX. Cobleigh MA, Tabesh B, Bitterman P, et al. Tumour gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res. 2005;11 (24 Pt 1):8623–8631. Paik S, Tang G, Shak S, et al. A multi-gene assay to predict recurrence of tamoxifen-treated, node negative breast cancer. N Engl J Med. 2004;351(27):2817–2826. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor positive breast cancer. J Clin Oncol. 2006;24(23):3726–3734. Goldstein LJ, Gray R, Badve S, et al. Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol. 2008;26(25):4063–4071. Abbruzzese JL, Lenzi R, Abbruzzese MC. Analysis of a diagnostic strategy for patients with suspected tumours of unknown origin. J Clin Oncol. 1995;13:2094–2103.

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REVIEW ARTICLE

Male Breast Cancer: A Review Kathryn M. Field1 and Richard H. de Boer1 Affiliations: 1Royal Melbourne Hospital, Victoria, Australia Submission date: 30th December 2008, Acceptance date: 7th February 2009

Abstract

countries up to 15% of breast cancers are diagnosed in men.13,14 Europe and the United States, as well as Australia, have an incidence of approximately one in 100,000.15 Aside from genetic differences between populations, hypotheses as to the reasons for these large differences include, for example, hyperestrogenism in men, which could be a result of obesity in developed countries or liver disease from infection in African nations. Of note, breast cancer incidence in men appears to be increasing in some countries, including the United States and Australia.16,17 This may be due to a number of factors, including improved diagnostic techniques and the increasing incidence of obesity.

Male breast cancer is a rare entity. In Australia in 2004, just over 100 men were diagnosed with breast cancer, representing 0.2% of all cancer cases for the country (AIHW). As such, there is only limited clinical experience in managing this disease. Without the guidance of randomized clinical trials, most management decisions are based on experience and guidelines for managing breast cancer in women. Nevertheless, there is increasing awareness and understanding in the scientific literature regarding particular features of male breast cancer that may help to guide both management and prevention of this rare disease.1–9 An appreciation of risk factors and appropriate treatment modalities, as well as the psychosocial consequences of being diagnosed with breast cancer as a male, can help to guide optimal management of these patients. This review outlines the available data regarding risk factors, histopathological features, treatment options and also the psychosocial aspects of breast cancer in men.

RISK FACTORS The majority of men diagnosed with breast cancer do not have any discernible risk factors for the disease. However, as there are definite genetic associations with male breast cancer, a careful family history of malignancy should be taken for every patient, and clinicians should have a low threshold for referral to a familial cancer center for further discussion. This is clearly important not only for the patient himself, but other family members as well. Shah et al. recently presented a review of 233 male breast cancer patients seen at the MD Anderson Cancer Center between 1944 and 2008. Over 60% of these patients had a positive family history.18 Even without a family history of malignancy, breast cancer in a younger man (less than 60 years old) probably warrants referral to a familial cancer center.

Keywords: male breast cancer, risk factors, epidemiology, local therapies Correspondence: Dr Richard de Boer, Department of Medical Oncology, Royal Melbourne Hospital, Grattan Street, Parkville Victoria 3050, Australia. Tel: +61 3 9342 7560; fax: +61 3 9347 7508; e-mail: richard.deboer@wh.org.au

INCIDENCE AND EPIDEMIOLOGICAL FEATURES Breast cancer is one of the most common malignancies worldwide but is predominantly a disease occurring in women. Overall, less than 1% of all breast cancers occur in men. Stage for stage, prognosis is similar between men and women.8,9 However, breast cancer in men is generally diagnosed at a later stage; around 40% of patients present with stage III or IV disease,6 and, thus, overall survival is worse for men than for women. Nevertheless, gender itself is not thought to be a prognostic factor per se.10 In a recent presentation of a matched-pair analysis of female and male breast cancer, investigators in Germany and the Czech Republic confirmed the higher incidence of late-stage diagnosis in men, but found no significant differences in 5-year overall survival (68.1% vs. 70.4%).11

Genetic Risk Factors. The most common genetic association with male breast cancer is a BRCA2 mutation. BRCA2 is a tumor suppressor gene located on chromosome 13q12-13. The BRCA2 mutation is present in up to 15% of men with breast cancer,19 and a male carrier has a lifetime risk of breast cancer 80 to 100 times higher than the general population.20 Other malignancies associated with BRCA2 include prostate, pancreas, stomach and melanoma. In some reports, BRCA1 (also a tumor suppressor gene, located on 17q12-21) is thought to be associated with male breast cancer21–23 but not in others.9,24 A recent population-based study from Italy assessed 108 male breast cancer cases and found that 2 (1.9%) carried BRCA1 mutations and 8 (7.4%) carried BRCA2 mutations.25

Male breast cancer is associated with interesting epidemiological features. Incidence varies greatly between geographic regions of the world. Japan and Finland have a very low incidence,12 whereas in some African APJOH 2009; 1: (1). March 2009

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evated serum estrogen/androgen ratio and a hyperestrogenic state. Numerous publications report an association between cirrhosis and male breast cancer,44,45 and, as mentioned earlier, liver disease from infection is thought to be the main reason why the incidence of male breast cancer is so high in African nations.46 Other intriguing associations between a hyperestrogenic state and the development of male breast cancer include numerous case reports documenting the development of breast cancer in men receiving exogenous estrogenic or antiandrogenic treatment for conditions such as prostate cancer47,48 and transsexual men receiving estrogen therapy.49–51 There have been mixed reports from studies regarding the association between male breast cancer and smoking8,35 and alcohol consumption.35,44,52,53 Although alcohol abuse can lead to cirrhosis and secondary hyperestrogenism due to liver disease, alcohol consumption itself was not found to be related to risk in the recent NIH prospective study.35 In contrast, a European case–control study found that male breast cancer risk increased by 16% per 10 g of daily alcohol intake.52 There is differing opinion in the literature regarding the association between gynecomastia and male breast cancer. While some studies report an association,54–56 others do not,57,58 and some postulate that any association may just be by chance alone, given that up to 35% to 40% of healthy men have clinical evidence of gynecomastia.59 Other reported associations with the development of breast cancer in men include testicular damage (eg, mumps infection), radiation exposure, exposure to industrial fumes and high temperatures6,60–62; hyperthyroidism63 and exposure to hyperprolactinemia due to pituitary adenomas.64–66 One interesting association documented from case– control studies57,63 is that never-married men may be at a higher risk of developing breast cancer. Another publication reported that childless men were at a significantly higher risk of developing the disease42; however, this is probably associated with secondary infertility due to imbalances in the hormonal milieu.

Ambiguity exists in the literature regarding a possible association between male breast cancer and the presence of a CHEK2 mutation.26–28 CHEK2 is a cell cycle checkpoint kinase involved in DNA repair. Klinefelter’s syndrome is potentially related to a hyperestrogenic state; in this syndrome, phenotypic men have the karyotype XXY and have elevated serum estradiol levels. The risk of breast cancer in men with Klinefelter’s syndrome is up to 50 times that of the general population.29,30 There are case reports describing associations between mutations in the PTEN tumor suppressor gene and male breast cancer.31 There is a higher incidence of male breast cancer in certain ethnic populations such as Ashkenazi Jews and some regions in Scandinavia. This is thought to be the result of founder mutations in these populations.32–34 In a recently published prospective assessment of risk factors for male breast cancer, the presence of a firstdegree relative with breast cancer increased the relative risk of breast cancer for men (relative risk 1.92).35 Any family history of breast cancer in particular, and potentially other malignancies, should precipitate a referral to a familial cancer center for further genetic discussion and assessment.

Family History A family history of breast cancer in a female relative increases the odds of men developing breast cancer by a factor of up to 2.5.36 In fact, 15% to 20% of men with breast cancer have at least one first-degree relative (usually female) with breast cancer.37–40 A family history (in male or female relatives) of malignancies other than breast, including prostate, ovarian and pancreatic cancers, generally would indicate an underlying genetic predisposition.

Nongenetic Risk Factors Similar to women, increasing age is one of the most frequent associations with male breast cancer. The median age at diagnosis for men is around 67 to 71 years17,41 which is older than for women, who have a bimodal age distribution at diagnosis. As has been mentioned, a hyperestrogenic state can increase the risk of male breast cancer. There are multiple potential causes of hyperestrogenism (Table 1). The most common cause is obesity, which is a recognized risk for male breast cancer. The United States prospective National Institutes of Health (NIH) Diet and Health Study evaluated over 320,000 men and reported a relative risk for male breast cancer of 1.79 for men with a body mass index (BMI) greater than or equal to 30 kg/m2, compared with those with a BMI less than 25  kg/m2.35 Multiple other studies support the association between obesity and male breast cancer risk.39,40,42,43 Hepatic cirrhosis and dysfunction from various causes are commonly associated with hypogonadism, an elAPJOH 2009; 1: (1). March 2009

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Personal History of Malignancy Outside the familial cancer syndromes, where multiple primary malignancies can develop in one individual, associations between male breast cancer and other malignancies are thought to be rare. The exception is with contralateral breast cancer where the risk is significantly increased.67,68 We have noted above the relationship between prostate cancer and male breast cancer. This is thought to be more likely related to estrogen therapy for prostate cancer, rather than a biological association between the two malignancies per se. Nevertheless, the association, for whatever reason, appears to be real; one study of nearly 140,000 patients with prostate cancer found a significantly increased 20

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Table 1. Causes of Hyperestrogenic State in Men Obesity (increased aromatase enzyme in fat → peripheral aromatization of androgens) Liver disease/cirrhosis (multiple causes including infection, alcoholism) Exogenous estrogen administration (eg, prostate cancer treatment) Klinefelter’s syndrome (karyotype XXY) Familial hyperestrogenism (very rare)

risk of breast cancer in these individuals (standardized incidence ratio of 2.01).69

Figure 1. Right medial rectus muscle metastasis in a 54-year-old man with newly diagnosed metastatic breast carcinoma.

CLINICAL FEATURES The most common method of presentation, in up to 75% to 95% of men, is that of a painless breast mass.5,6 There is skin or nipple involvement in up to one-third of patients,7 partly due to the paucity of breast tissue compared with women.70 Shah et al. found that the presence of skin or nipple involvement alone did not appear to be a predictor of a poor outcome.18 Approximately 40% of men present with stage III or IV disease,6 perhaps because of lack of awareness of the significance of a breast lump. Due to the work of advocacy groups and cancer councils, there is an excellent level of awareness in women regarding the importance of early medical consultation should a lump be detected, and women also benefit from regular mammographic screening. However, the equivalent situation does not exist for men. Importantly, the risk of contralateral breast cancer in men is greatly increased, up to 30-fold,67,68 which is significantly higher than the risk for women. The site of distant metastasis is similar to that in women, with bone, lung and liver metastases being the most common.71 Occasionally, rarer sites of metastasis are seen, such as orbital metastases (Figure 1).72 Interestingly, orbital metastases from breast cancer are seen in up to 10% to 30% of autopsy reports,73 the majority being asymptomatic.

be intermediate (grade II) or high grade (grade  III); only 6% to 20% are reported to be low grade (grade I) tumors.6

Hormone Receptors Male breast cancers are significantly more likely to express hormone receptors than those from women17,76–78; 64% to 90% of cases are estrogen receptor-positive, and up to 80% to 96% are progesterone receptor-positive.6,17,79,80 This has obvious implications with regard to the importance of hormonal therapies for men with breast cancer. Androgen receptors are present in male breast cancer specimens in varying levels, between 30% and 95%.79,81,82 The clinical significance of androgen receptor positivity is currently unclear,82 but raises interesting questions as to the role of antiandrogen therapy. Prolactin receptor expression has been reported to be as high as 60% in one recent study83; again, the clinical significance of this is unknown.

HER2/neu With the advent of targeted therapies, and in particular trastuzumab (Herceptin®), which targets the HER2/neu receptor, awareness of the importance of HER2/neu status, both as a prognostic and a predictive factor, is crucial for the appropriate management of breast cancer in both male and female patients. Both immunohistochemistry and FISH (fluorescence in-situ hybridization) or CISH (chromogenic in-situ hybridization) are used to ascertain HER2 status, and these techniques have continually improved in terms of accuracy and consistency. Perhaps as a result of this, earlier studies had suggested a high rate of HER2/neu positivity in male breast cancers, but more recent studies do not support this. Rates of positivity differ significantly between publications, ranging from 1% to 30%.79,84–86 Foerster et al. found a 9% positivity

HISTOPATHOLOGICAL FEATURES Histology The majority of male breast cancers (>80%) are infiltrating ductal carcinomas.9 The second most common subtype is papillary carcinoma, occurring in approximately 5% of patients.70,74 Lobular carcinoma is very rarely seen in men.75 There are other rare subtypes including medullary, mucinous and tubular carcinomas. Occasionally different tumors may initially present with a breast mass, such as sarcomas and metastases from other sites. The grade of differentiation tends to www.slm-oncology.com

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THERAPY Figure 2 provides an overview, as flow charts, of the therapeutic options available for early stage and advanced male breast cancer. The therapeutic options are discussed in detail below.

Early stage disease (stage I, II, III)

Consider referral to familial cancer center (young patient, any family history breast/ovarian cancer)

Surgery As for women with breast cancer, surgery is the primary treatment modality for localized disease. A modified radical mastectomy with sentinel node biopsy or axillary node dissection is the most common method of surgical intervention. Although there are no prospective trials to assess the value of sentinel lymph node biopsy, emerging literature seems to support its use.88–90

Surgery

Consider adjuvant radiotherapy: large tumour size, chest wall/pectoral muscle invasion, skin involvement, positive axillary nodes

Adjuvant chemotherapy for high-risk disease

For low-risk disease: adjuvant tamoxifen for 5 years if HR +ve

Radiotherapy This is commonly utilized after mastectomy to reduce the incidence of loco-regional relapse. The primary indications for postmastectomy radiotherapy are large tumor size (>5 cm), chest wall or pectoral muscle invasion, skin involvement, or ≥4 positive axillary nodes91; although some experts recommend radiotherapy to all patients with tumors >1 cm or with any axillary nodal involvement.4,92 In a recently presented cohort study, Foerster et al. showed that radiotherapy had a significant survival benefit.11

Adjuvant tamoxifen for 5 years if HR +ve

Metastatic (stage IV) disease

Surgery If painful or fungating chest wall tumor

Radiotherapy If painful or symptomatic bony metastases

Hormonal therapy

Chemotherapy If hormonal therapy fails to control disease, or if rapid control of disease in patient is needed

Chemotherapy As with female patients, men with breast cancer should be considered for adjuvant chemotherapy if they present with higher risk disease, such as node-positive disease or high-risk node-negative disease (larger primary tumor size, hormone receptor-negative, or grade III). Without the benefit of randomized clinical studies, the chemotherapy regimens are derived from studies in female patients. Regarding efficacy of chemotherapy for reducing recurrence in male patients, retrospective studies largely support the use of adjuvant chemotherapy, with favorable survival benefits.55,93,94 The value of the newer generation of chemotherapy regimens, including the taxanes, is unknown. In reality, there will never be a large volume of literature regarding the relative efficacy of chemotherapy regimens to select from, and thus, common sense should dictate the appropriate regimen, taking into consideration a patient’s age and comorbidities. For metastatic breast cancer, chemotherapy is generally reserved for patients whose tumor has progressed despite hormonal therapies (in the situation of hormone receptor-positive disease). Again, clinical judgment comes into play in this decision; a clinician may be more likely to offer first-line chemotherapy to a younger patient with a heavy burden of disease, in an attempt to gain more rapid control. Regimen choices are similar to those for female patients. A large review of 60 years of breast cancer publications, including a

Tamoxifen first-line ?AI second-line +/– LHRH agonist Consider third-line hormonal therapy (aminoglutethimide, cyproterone acetate)

Figure 2. Flow charts for the management of breast cancer in men.

rate,11 while Rudlowski et al. detected a 6.3% positive rate in 96 male patients.87 Regardless of the incidence, it is important to determine HER2/neu status in men with breast cancer, using confirmatory FISH/CISH testing for gene amplification, as there are obvious implications regarding both prognosis and treatment recommendations. A recent Italian population-based study of 108  male breast cancer cases found statistically significant associations between BRCA2-related tumors and absence of PR expression, HER2 overexpression and high grade tumors, with all of these being associated with a worse overall prognosis.25

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variety of regimens, determined that the overall response rate for chemotherapy in men with metastatic breast cancer is around 40%.95

greater than 6 months. For letrozole, 5 cases have been described,106–108 again with most achieving stable disease. Most of these patients received aromatase inhibitors as a second-line therapy after failure of prior therapies (such as tamoxifen or chemotherapy). As the aromatase inhibitors can increase serum testosterone, agents that decrease testosterone production may potentially be of benefit. Luteinising hormone releasing hormone (LHRH) agonists inhibit the feedback loop to the hypothalamic-pituitary axis and decrease the production of testosterone and estrogen. There are two small studies (two patients each) that have combined an aromatase inhibitor with an LHRH agonist in the setting of metastatic male breast cancer.102,103 Two patients had partial responses, and two developed progressive disease. These reports are too small to make any conclusive statements regarding the use of aromatase inhibitors for male breast cancer; however, in a situation where few alternatives are available—for example, after progression on tamoxifen in a patient who would not tolerate chemotherapy—the evidence seems to support a therapeutic trial. Ablative therapies for metastatic disease such as orchidectomy, adrenalectomy and hypophysectomy have been utilized in earlier management strategies. However, as surgical techniques have significant potential complications, use of these therapies has decreased with the development of drug-based hormonal therapies.

Hormonal Therapy The majority of male breast cancers are hormone receptor-positive, and, thus, endocrine therapy is an important component of systemic management in both the adjuvant and metastatic settings. Tamoxifen is widely regarded as the most appropriate initial endocrine therapy, both in the adjuvant and metastatic disease settings. Retrospective studies demonstrate improved disease-free and overall survival in the adjuvant setting.54,96 One prospective study examined disease-free and overall survival benefits for 39 men with stage II and III breast cancer, all with node-positive disease, who were given adjuvant tamoxifen for 1 or 2 years. Compared with historical controls, overall survival at 5 years was 61% versus 44%, and disease-free survival 56% versus 28%.96 Similar to metastatic disease where hormonal therapy is indicated, varying response rates have been reported for tamoxifen, between 25% and 80% depending on the study.95,97 In recent years, the aromatase inhibitors have become a standard of care for postmenopausal women with breast cancer. However, this literature does not necessarily apply to men. It is important to be aware that in men, while the majority of circulating estrogen is derived from peripheral aromatization of androgens, approximately 20% of estrogen is produced by the testes independently of aromatase.85 Thus, there remains uncertainty whether aromatase inhibitors in men will adequately suppress estrogen concentration, and some studies do indicate that estrogen may be inadequately suppressed. An analysis of the effect of anastrozole on hormone suppression in healthy male volunteers found that estrogen concentration decreased by only 48%, in contrast to the near-complete estrogen suppression in women given aromatase inhibitors.98 Letrozole, when tested in healthy men in a separate study, decreased estrogen by up to 90% from baseline.99,100 Both of these studies also reported an increase in serum testosterone levels, which may be important when considering that androgen receptor positivity in male breast cancer cells is up to 95% in some studies. A recently published comprehensive literature review appraised evidence surrounding the use of aromatase inhibitors in men.101 To summarize, there have been only small case reports regarding the efficacy of aromatase inhibitors, the majority of which have been in the setting of metastatic disease. Specifically, for the newer ‘thirdgeneration’ aromatase inhibitors such as anastrozole, letrozole and exemestane, there have been mixed results. Exemestane has not been found to have efficacy.102,103 For anastrozole, only 8 cases are described,102,104,105 with the majority having stable disease, 4 with stable disease www.slm-oncology.com

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Trastuzumab The efficacy of trastuzumab for women in both the adjuvant and metastatic disease settings is well established.109,110 Although lacking randomized studies, there is no reason to think that trastuzumab would not have similar benefits in men. Liaison with pathology services regarding both immunohistochemistry and FISH or CISH results is important, given that HER-2 gene amplification itself may be rare.86 While there are no available data regarding efficacy of trastuzumab for men in the adjuvant disease settings, case reports support its use in metastatic disease.111,112

EMOTIONAL CONSEQUENCES The consequences of being diagnosed with what is mostly thought of as a ‘female’ disease can be particularly distressing for men. While resources exist in terms of support and advocacy for women, some of the available resources and literature do not necessarily apply to men. Not only the diagnosis, but also the treatment of male breast cancer (in particular, the potential side effects of hormonal therapies) can have adverse physical and psychological effects on patients’ sense of masculinity and sexuality. Many institutions are linked with psychology, psychiatry and specialized psychooncology clinics or specialists, and referral to such disciplines should be considered if patients are struggling 23

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to cope with their illness. This is common; nearly 25% of men in one UK study experienced traumatic stress symptoms related to their breast cancer diagnosis.113 In the era of the internet, there are increasing numbers of Web sites dedicated specifically to men with breast cancer, providing information and further contact details specifically for men with the disease.114 It is important for gender-specific information to be available, as supported by a study that found that over 50% of men felt that information generally available was inappropriate, as it was primarily directed at women.115

13. Bhagwandeen SB. Carcinoma of the male breast in Zambia. East Afr Med J. 1972;49(2):89–93. 14. Amir H, Makwaya CK, Moshiro C, Kwesigabo G. Carcinoma of the male breast: a sexually transmitted disease? East Afr Med J. 1996;73(3):187–190. 15. Ries L, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2004. Available from: http://www.seer.cancer.gov. 16. Australian Institute of Health and Welfare: Australian cancer incidence data 2006. Available from: http://www.aihw.gov.au. 17. Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men: a population-based study. Cancer. 2004;101(1):51–57. 18. Shah S, Middleton L, Yang W, et al. Male breast cancer outcomes: Validation and modification of the benchmark approach. Abstract 4131. Presented at: The 31st San Antonio Breast Cancer Symposium, Dec 2008. 19. Liede A, Karlan BY, Narod SA. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004;22(4):735–742. 20. Thompson D, Easton D. Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet. 2001;68(2):410–419. 21. Ottini L, Masala G, D’Amico C, et al. BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res. 2003;63(2):342–347. 22. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20(6):1480–1490. 23. Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94(18):1365–1372. 24. Basham VM, Lipscombe JM, Ward JM, et al. BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res. 2002;4(1):R2. 25. Ottini L, Rizzolo P, Zanna I, et al. BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy. Breast Cancer Res Treat. 2008 Sep 26. [Epub ahead of print] 26. Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31(1):55–59. 27. Syrjakoski K, Kuukasjarvi T, Auvinen A, Kallioniemi OP. CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer. 2004;108(3):475–476. 28. Ohayon T, Gal I, Baruch RG, Szabo C, Friedman E. CHEK2*1100delC and male breast cancer risk in Israel. Int J Cancer. 2004;108(3):479–480. 29. Hultborn R, Hanson C, Kopf I, Verbiene I, Warnhammar E, Weimarck A. Prevalence of Klinefelter’s syndrome in male breast cancer patients. Anticancer Res. 1997;17(6D): 4293–4297. 30. Harnden DG, Maclean N, Langlands AO. Carcinoma of the breast and Klinefelter’s syndrome. J Med Genet. 1971;8(4): 460–461. 31. Fackenthal JD, Marsh DJ, Richardson AL, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001;38(3):159–164. 32. Thorlacius S, Struewing JP, Hartge P, et al. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998;352(9137):1337–1339. 33. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996;13(1):117–119. 34. Struewing JP, Coriaty ZM, Ron E, et al. Founder BRCA1/2 mutations among male patients with breast cancer in Israel. Am J Hum Genet. 1999;65(6):1800–1802.

SUMMARY Although breast cancer in men is rare, there has been increasing study, research and interest directed toward this disease. With an increased understanding of the mechanisms and risk factors for the disease, and an increasing armamentarium of anticancer agents, gains continue to be made. Although there will never be the volume of research undertaken for male breast cancer that is possible for women, awareness of the similarities and, more importantly, differences between the genders with respect to breast cancer is crucial in terms of recommending appropriate treatments and interventions necessary to successfully manage this disease. We look forward to continued research gains that will lead to better treatment, and ultimately prevention, of male breast cancer. Disclosures: The authors have no financial interest related to the contents of this article to disclose.

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35. Brinton LA, Richesson DA, Gierach GL, et al. Prospective evaluation of risk factors for male breast cancer. J Natl Cancer Inst. 2008;100(20):1477–1481. 36. Rosenblatt KA, Thomas DB, McTiernan A, et al. Breast cancer in men: aspects of familial aggregation. J Natl Cancer Inst. 1991;83(12):849–854. 37. Friedman LS, Gayther SA, Kurosaki T, et al. Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am J Hum Genet. 1997;60(2):313–319. 38. Hill A, Yagmur Y, Tran KN, Bolton JS, Robson M, Borgen PI. Localized male breast carcinoma and family history. An analysis of 142 patients. Cancer. 1999;86(5):821–825. 39. Ewertz M, Holmberg L, Tretli S, Pedersen BV, Kristensen A. Risk factors for male breast cancer—a case-control study from Scandinavia. Acta Oncol. 2001;40(4):467–471. 40. Johnson KC, Pan S, Mao Y. Risk factors for male breast cancer in Canada, 1994–1998. Eur J Cancer Prev. 2002;11(3):253–263. 41. Anderson WF, Althuis MD, Brinton LA, Devesa SS. Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat. 2004;83(1):77–86. 42. D’Avanzo B, La Vecchia C. Risk factors for male breast cancer. Br J Cancer. 1995;71(6):1359–1362. 43. Hsing AW, McLaughlin JK, Cocco P, Co Chien HT, Fraumeni JF Jr. Risk factors for male breast cancer (United States). Cancer Causes Control. 1998;9(3):269–275. 44. Sorensen HT, Friis S, Olsen JH, et al. Risk of breast cancer in men with liver cirrhosis. Am J Gastroenterol. 1998;93(2):231–233. 45. Misra SP, Misra V, Diwivedi M. Cancer of the breast in a male cirrhotic: is there an association between the two? Am J Gastroenterol. 1996;91(2):380–382. 46. El-Gazayerli MM, Abdul-Aziz AS. On bilharziasis and male breast cancer in Egypt: A preliminary report and review of the literature. Br J Cancer. 1963;17:566–571. 47. Sobin LH, Sherif M. Relation between male breast cancer and prostate cancer. Br J Cancer. 1980;42(5):787–790. 48. Schlappack OK, Braun O, Maier U. Report of two cases of male breast cancer after prolonged estrogen treatment for prostatic carcinoma. Cancer Detect Prev. 1986;9(3-4):319–322. 49. Symmers WS. Carcinoma of breast in trans-sexual individuals after surgical and hormonal interference with the primary and secondary sex characteristics. Br Med J. 1968;2(5597):83–85. 50. Pritchard TJ, Pankowsky DA, Crowe JP, Abdul-Karim FW. Breast cancer in a male-to-female transsexual. A case report. JAMA. 1988;259(15):2278–2280. 51. Ganly I, Taylor EW. Breast cancer in a trans-sexual man receiving hormone replacement therapy. Br J Surg. 1995;82(3):341. 52. Guenel P, Cyr D, Sabroe S, et al. Alcohol drinking may increase risk of breast cancer in men: a European population-based case-control study. Cancer Causes Control. 2004;15(6):571–580. 53. Weiderpass E, Ye W, Adami HO, Vainio H, Trichopoulos D, Nyren O. Breast cancer risk in male alcoholics in Sweden. Cancer Causes Control. 2001;12(7):661–664. 54. Goss PE, Reid C, Pintilie M, Lim R, Miller N. Male breast carcinoma: a review of 229 patients who presented to the Princess Margaret Hospital during 40 years: 1955–1996. Cancer. 1999;85(3):629–639. 55. Yildirim E, Berberoglu U. Male breast cancer: a 22-year experience. Eur J Surg Oncol. 1998;24(6):548–552. 56. de Bree E, Tsagkatakis T, Kafousi M, Tsiftsis DD. Breast enlargement in young men not always gynaecomastia: breast cancer in a 22-year-old man. ANZ J Surg. 2005;75(10):914–916. 57. Sasco AJ, Lowenfels AB, Pasker-de Jong P. Review article: epidemiology of male breast cancer. A meta-analysis of published case-control studies and discussion of selected aetiological factors. Int J Cancer. 1993;53(4):538–549. 58. Carlsson G, Hafstrom L, Jonsson PE. Male breast cancer. Clin Oncol. 1981;7(2):149–155. 59. Braunstein GD. Gynecomastia. N Engl J Med. 1993;328(7): 490–495.

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84. Bloom KJ, Govil H, Gattuso P, Reddy V, Francescatti D. Status of HER-2 in male and female breast carcinoma. Am J Surg. 2001;182(4):389–392. 85. Muir D, Kanthan R, Kanthan SC. Male versus female breast cancers. A population-based comparative immunohistochemical analysis. Arch Pathol Lab Med. 2003;127(1):36–41. 86. Barlund M, Kuukasjarvi T, Syrjakoski K, Auvinen A, Kallioniemi A. Frequent amplification and overexpression of CCND1 in male breast cancer. Int J Cancer. 2004;111(6):968–971. 87. Rudlowski, Joost, Schildhaus, et al. HER2 and topoisomerase IIa gene alterations in male breast cancer. Abstract 4128. Presented at: The 31st San Antonio Breast Cancer Symposium, December 2008. 88. Albo D, Ames FC, Hunt KK, Ross MI, Singletary SE, Kuerer HM. Evaluation of lymph node status in male breast cancer patients: a role for sentinel lymph node biopsy. Breast Cancer Res Treat. 2003;77(1):9–14. 89. Goyal A, Horgan K, Kissin M, et al. Sentinel lymph node biopsy in male breast cancer patients. Eur J Surg Oncol. 2004;30(5):480–483. 90. Flynn LW, Park J, Patil SM, Cody HS 3rd, Port ER. Sentinel lymph node biopsy is successful and accurate in male breast carcinoma. J Am Coll Surg. 2008;206(4):616–621. 91. Recht A, Edge SB, Solin LJ, et al. Postmastectomy radiotherapy: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2001;19(5):1539–1569. 92. Nahleh Z, Girnius S. Male breast cancer: a gender issue. Nat Clin Pract Oncol. 2006;3(8):428–437. 93. Giordano SH, Perkins GH, Broglio K, et al. Adjuvant systemic therapy for male breast carcinoma. Cancer. 2005;104(11): 2359–2364. 94. Margaria E, Chiusa L, Ferrari L, Dal Canton O, Pich A. Therapy and survival in male breast carcinoma: A retrospective analysis of 50 cases. Oncol Rep. 2000;7(5): 1035–1039. 95. Jaiyesimi IA, Buzdar AU, Sahin AA, Ross MA. Carcinoma of the male breast. Ann Intern Med. 1992;117(9):771–777. 96. Ribeiro G, Swindell R. Adjuvant tamoxifen for male breast cancer (MBC). Br J Cancer. 1992;65(2):252–254. 97. Patterson JS, Battersby LA, Bach BK. Use of tamoxifen in advanced male breast cancer. Cancer Treat Rep. 1980;64 (6–7):801–804. 98. Mauras N, O’Brien KO, Klein KO, Hayes V. Estrogen suppression in males: metabolic effects. J Clin Endocrinol Metab. 2000;85(7):2370–2377. 99. Trunet PF, Mueller P, Bhatnagar AS, Dickes I, Monnet G, White G. Open dose-finding study of a new potent and selective nonsteroidal aromatase inhibitor, CGS 20 267, in healthy male subjects. J Clin Endocrinol Metab. 1993;77(2):319–323.

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100. Bhatnagar AS, Muller P, Schenkel L, Trunet PF, Beh I, Schieweck K. Inhibition of estrogen biosynthesis and its consequences on gonadotrophin secretion in the male. J Steroid Biochem Mol Biol. 1992;41(3-8):437–443. 101. Nordman IC, Dalley DN. Breast cancer in men: should aromatase inhibitors become first-line hormonal treatment? Breast J. 2008;14(6):562–569. 102. Giordano SH, Hortobagyi GN. Leuprolide acetate plus aromatase inhibition for male breast cancer. J Clin Oncol. 2006;24(21):e42–e43. 103. Soon Wong N, Seong Ooi W, Pritchard KI. Role of gonadotropinreleasing hormone analog in the management of male metastatic breast cancer is uncertain. J Clin Oncol. 2007;25(24):3787. 104. Giordano SH, Valero V, Buzdar AU, Hortobagyi GN. Efficacy of anastrozole in male breast cancer. Am J Clin Oncol. 2002;25(3):235–237. 105. Baumgartner A, Schnelzer A, Harbeck N, Kiechle M, Steinburg SV. Endocrine combination therapy for prostate and metastatic breast cancer in a male patient. Breast Care. 2007;2:37–39. 106. Arriola E, Hui E, Dowsett M, Smith IE. Aromatase inhibitors and male breast cancer. Clin Transl Oncol. 2007;9(3):192–194. 107. Italiano A, Largillier R, Marcy PY, et al. [Complete remission obtained with letrozole in a man with metastatic breast cancer.] Rev Med Interne. 2004;25(4):323–324. 108. Zabolotny BP, Zalai CV, Meterissian SH. Successful use of letrozole in male breast cancer: a case report and review of hormonal therapy for male breast cancer. J Surg Oncol. 2005;90(1):26–30. 109. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–1672. 110. Baselga J, Perez EA, Pienkowski T, Bell R. Adjuvant trastuzumab: a milestone in the treatment of HER-2-positive early breast cancer. Oncologist. 2006;11(Suppl 1):4–12. 111. Hayashi H, Kimura M, Yoshimoto N, et al. A case of HER2positive male breast cancer with lung metastases showing a good response to trastuzumab and paclitaxel treatment. Breast Cancer. 2008 Jun 12. [Epub ahead of print] 112. Carmona-Bayonas A. Potential benefit of maintenance trastuzumab and anastrozole therapy in male advanced breast cancer. Breast. 2007;16(3):323–325. 113. Brain K, Williams B, Iredale R, France L, Gray J. Psychological distress in men with breast cancer. J Clin Oncol. 2006;24(1):95–101. 114. National Breast Cancer Centre: Breast Cancer in Men. Available from http://www.breasthealth.com.au/men. 115. Iredale R, Brain K, Williams B, France E, Gray J. The experiences of men with breast cancer in the United Kingdom. Eur J Cancer. 2006;42(3):334–341.

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REVIEW ARTICLE

Third-Line Treatment Options for Metastatic Colorectal Cancer Wei Chua1, Melissa M. Moore1, Philip Beale1 and Stephen J. Clarke1 Affiliations: 1Department of Medical Oncology, Sydney Cancer Centre, Concord Repatriation General Hospital, Concord, NSW, Australia Submission date: 4th December 2008, Acceptance date: 5th January 2009

ABSTRACT

which includes switching chemotherapeutic agents before disease progression, the use of maintenance therapy and drug “holidays”, the surgical resection of metastatic disease in selected patients, and individually planned treatment based on molecular predictive markers of efficacy and toxicity.1 However, the current approach of continuing treatment until disease progression before switching to a new class of drug is still reasonable, as the evidence for an individually planned treatment continuum is still evolving. While physicians involved in treating patients with mCRC have significantly more options than they did a decade ago, they are also confronted by issues such as the increased toxicity and increased costs associated with use of the newer agents, as well as the need to determine the most effective method for incorporating these agents into routine clinical practice. The aim of this review is to summarize the available evidence with regard to the use of third-line treatment for fit patients with mCRC after their progression during treatment with oxaliplatin- and irinotecan-containing regimens.

Treatment for metastatic colorectal cancer has evolved significantly over the last decade to include the use of various active classes of drugs in multiple lines of therapy. These include chemotherapeutic agents, such as the fluoropyrimidines, raltitrexed, mitomycin C, oxaliplatin, and irinotecan, and monoclonal antibodies targeted against the epidermal growth factor receptor and vascular endothelial growth factor. The median survival of patients receiving treatment with combinations of these agents now approaches 2 years for those with good performance status. There is no conclusive evidence or firm recommendations for the use of third-line therapy in metastatic colorectal cancer for patients well enough to receive further treatment. The aim of this review is to summarize available evidence in regard to the use of third-line treatment for fit patients with metastatic colorectal cancer after their progression on treatment with oxaliplatin- and irinotecan-containing regimens. Keywords: colorectal cancer, metastatic, third-line, chemotherapy, monoclonal antibodies, treatment Correspondence: Wei Chua, Dept of Medical Oncology, Building 76, Concord Repatriation General Hospital, Hospital Rd., Concord, NSW 2139, Australia. Tel: +61 2 9767 5791; fax: +61 2 9767 5764; e-mail: weic@med.usyd.edu.au

FIRST- AND SECOND-LINE OPTIONS FOR METASTATIC COLORECTAL CANCER Chemotherapy with a doublet therapy using a fluoropyrimidine and either oxaliplatin or irinotecan has formed the backbone of first-line chemotherapy for mCRC, with multiple phase III trials supporting the use of such combinations over single-agent fluoropyrimidines.2–5 Tournigard et al. (2004) provided evidence that the median overall survival (OS) could be increased to >20 months when patients were exposed to the three key cytotoxic agents in either sequence (FOLFOX6 then FOLFIRI or FOLFIRI then FOLFOX6), with no difference between the two arms.6 A combined analysis of recent phase III trials of patients with mCRC receiving 5-fluorouracil (5-FU)/ leucovorin (LV), oxaliplatin, and irinotecan similarly reported a positive correlation between median OS and patients who received all three of these active cytotoxic agents.7 Recent evidence has supported the use of bevacizumab in combination with a fluoropyrimidine doublet or fluoropyrimidine alone as initial

INTRODUCTION Twenty years ago, it was common not to use any chemotherapy for patients with advanced or metastatic colorectal cancer (mCRC). However, treatment for mCRC has evolved significantly over the last decade to include the use of various active classes of drugs in multiple lines of therapy. These include chemotherapeutic agents, such as the fluoropyrimidines, raltitrexed, mitomycin-C, oxaliplatin, and irinotecan, and monoclonal antibodies targeted against the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). The median survival of patients receiving treatment with combinations of these agents has substantially improved over the last decade and now approaches 2 years for those fit enough to receive all agents. There have been suggestions of a paradigm shift in the treatment of mCRC from the simple concept of successive ‘lines’ of chemotherapy to that of a continuum of care, APJOH 2009; 1: (1). March 2009

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chemotherapy in patients with untreated mCRC.8-–12 Based on recent evidence, patients with wild-type k-ras should be considered for cetuximab treatment, either alone or in combination with irinotecan, after failure of an irinotecan-containing regimen.13–15

53% with time to progression (TTP) of 4 months.18 The authors concluded that capecitabine was a safe and cost-effective alternative to best supportive care (BSC), even in patients previously treated with 5-fluorouracil, oxaliplatin, and irinotecan. However, Gubanski and colleagues (2005), in a retrospective review of 20  patients who had progressed on combination therapy with both irinotecan and oxaliplatin, showed that there was little or no clinical benefit derived from third-line use of capecitabine.19 In this cohort, the majority of patients (17/20) showed progressive disease during treatment, with a median TTP and overall survival (OS) of 2.8 and 6.1 months, respectively.

THIRD-LINE OPTIONS FOR METASTATIC COLORECTAL CANCER There is no conclusive evidence or firm recommendation for the use of third-line therapy in mCRC for those fit enough to receive additional treatment. Although the majority of patients in the United States have received bevacizumab as a first-line chemotherapy since its approval in 2004, this is not the case in the rest of the world where the cost of bevacizumab is prohibitive. Similarly, a large proportion of patients do not have access to other targeted antibodies, such as cetuximab or panitumumab, either due to the cost of treatment or the presence of k-ras mutations which make EGFR inhibitors less effective. We discuss herein the available evidence for third-line options for both chemotherapy agents and targeted monoclonal antibodies after disease progression on both oxaliplatin- and irinotecancontaining regimens. A literature review was performed using the PubMed and Medline databases with the following terms: colorectal cancer, metastatic, third-line, salvage, and advanced. Abstracts from the American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meetings were also searched. Published articles and meeting abstracts in English that reported on patients receiving salvage chemotherapy and targeted treatment for mCRC after both oxaliplatin- and irinotecan-containing regimens were included in the review. A total of 29 articles were included in this review, nine of which were preliminary results presented in abstract form.

Mitomycin-C The use of mitomycin-C (MMC) has been reported in combination with either protracted intravenous 5-FU or oral capecitabine in both first-line and nonfirst-line settings for mCRC. Although an earlier study reported a response rate (RR) of 15% with median failure-free survival (FFS) of 5.4 months in the third-line setting with capecitabine and MMC, the majority of patients in this study had not received prior oxaliplatin and irinotecan.20 Subsequent studies of MMC combined with fluoropyrimidines in patients who progressed on both oxaliplatin and irinotecan have failed to replicate these favorable results, with a RR ranging from 0% to 10% and a median TTP or progression-free survival (PFS) of 2.0 to 3.7 months21–27 (Table 1). Furthermore, a retrospective review of 18 patients from our center enrolled in one such trial included a number of patients (one-third) who had received prior biological agents with either bevacizumab or cetuximab.25 These results indicate that combination of MMC with capecitabine/ infusional 5-FU/UFT or raltitrexed has low efficacy in the setting of heavily pretreated mCRC, even though this combination has an acceptable safety profile. A phase II study examining the safety and efficacy of irinotecan and MMC as third-line chemotherapy showed a RR of 6.5% with median survival not reached at the time of analysis.28 However, there were significant grade 3 or 4 toxicities in 37% of patients, with one toxic death reported in the preliminary report.

CHEMOTHERAPY OPTIONS AS THIRD-LINE TREATMENT Capecitabine Capecitabine, a prodrug of 5-fluorouracil (5-FU), is converted to the active fluoropyrimidine via a threestep process, the last step of which is catalyzed by intratumoral thymidine phosphorylase. There are higher levels of thymidine phosphorylase in tumors than in the equivalent normal tissue, thereby providing a selective advantage for capecitabine. There have been two large randomized phase III trials comparing singleagent capecitabine with bolus intravenous 5-FU (Mayo regimen) that demonstrated at least similar efficacy between the two regimens16,17; consequently, capecitabine is considered a safe and convenient alternative to intravenous 5-FU. A small, single center phase  II study using single-agent capecitabine in 28 heavily pretreated patients with mCRC reported a disease control rate [partial response (PR) and stable disease (SD)] of APJOH 2009; 1: (1). March 2009

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Miscellaneous The use of gemcitabine as third-line chemotherapy has been studied, and preliminary results from a phase I/II study of gemcitabine plus continuous infusion of 5-FU after failure of oxaliplatin- and irinotecan-containing regimens have been reported from a study of 18 patients.29 There were no objective responses, but 70.5% of patients had SD with a TTP of 112 days. Jeung and colleagues (2006) reported the results of S-1 monotherapy, an oral fluoropyrimidine, as third- and fourth-line chemotherapy after progression on irinotecan- and oxaliplatin-containing regimens in 28  patients, with an overall RR of 14% (95% CI 0.4 to 28.1) and a median TTP and OS of 91 and 414  days, respectively.30 28

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Table 1. Chemotherapy Trials as Third-line Treatment in mCRC Type Sample Response Reference of study size Treatment rate (%)

Median TTP or PFS (months)

Median OS (months)

Ardavanis et al. Phase II 28 Capecitabine (2006)18

4.0 (range 2.0–7.0)

5.2 (95% CI 3.1–7.3)

2.8

6.1

Gubanski et al. (2004)19

7.0 (95% CI 0.09–23.5)

Retrospective 20 Capecitabine 0 review

Harba et al. Phase II 27 (2003)21 (abstract)

Capecitabine 10.0 and MMC

3.7 (range 0.5–10)

7.8 (range 1.5–22.0)

Lim et al. Phase II 21 (2005)22

Capecitabine 4.8 and MMC

2.6 (95% CI 2.5–2.7)

6.8 (95% CI 0.9–12.7)

Scartozzi et al. Phase II 61 (2006)23

Capecitabine 8.0 and MMC

3.0 (range 2.0–10.0)

6.0 (range 1.0–13.0)

Rimassa et al. (2006)24

Capecitabine 4.0 and MMC

2.0 (range 1.0–9.0)

6.0 (range 1–29)

Chua et al. Retrospective 18 review (2008)25

Capecitabine or 0 5-FU and MMC Comments: 1/3 received prior biological agents

2.7 (range 0.5–8.8)

5.4 (range 1.3–31.2)

Vormitaag et al. (2007)26

UFT/leucovorin 7.3 and MMC

2.5 (range 1.5–13.5)

6.0 (range 1.5–26.0)

Rosati et al. Phase II 21 (2003)27

Raltitrexed 0 and MMC

2.3 (95% CI 1.7–3.0)

5.0 (95% CI 2.5–7.5)

Polus et al. Phase II 49 (2004)28 (abstract)

Irinotecan and MMC

6.5

Not reached

Not reached

Pachon et al. Phase I/II 18 (2005)29 (abstract)

Gemcitabine and infusional 5-FU

0 (SD 70.5%)

112 days (range 44–396)

296 days (range 58–569)

14.3 (95% CI 0.4–28.1)

91 days (95% CI 336–492)

414 days (95% CI 336–492)

Retrospective 28 review

Retrospective 41 review

Jeung et al. Phase II 28 S-1 (2006)30

line setting when combined with FOLFOX, XELOX, or 5-FU/LV alone, and in the second-line setting in combination with FOLFOX4.9–11,31,32 A large openlabel, multicenter, single-arm clinical trial involving 350 patients from 32 participating sites was conducted in the third-line setting for mCRC after initial results with bevacizumab were reported in 2003.33 The objective RR was 4% by investigator’s assessment and 1% based on independent review, with SD of 50%, a median PFS of 3.5 months, and a median OS of 9.0 months. The safety profile in this study was similar to that observed in previous studies in the first-line setting, with a 5% rate of grade 3 or 4 hemorrhage, including 3.8% with bleeding in the gastrointestinal tract. There have been other smaller phase  II studies evaluating

The 1-year survival rate of all patients was 60.7%, with a favorable safety profile; however, there have been no other studies performed with S-1 to confirm its utility in this population.

TARGETED MONOCLONAL ANTIBODIES AS THIRD-LINE TREATMENT Bevacizumab The use of bevacizumab, a targeted monoclonal antibody against VEGF, was reported in a pivotal randomized, phase III, multicenter study investigating the addition of bevacizumab to irinotecan, 5-FU, and leucovorin for patients with previously untreated mCRC.8 Its use has now been reported in the firstwww.slm-oncology.com

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Table 2. Targeted Monoclonal Antibody Trials as Third-Line Treatment in mCRC Reference

Type of study

Chen et al. (2006)33

Sample size

Treatment

Response rate (%)

Phase II

350

Bevacizumab and 5-FU/LV

4.0* (95% CI 1.1–9.9) (SD 50.0)

Emmanouilides et al. (2004)

Phase II

19

Bevacizumab and 5-FU/LV

0

Zoran et al. (2007) (abstract)

Phase II

28

Bevacizumab and capecitabine

14.0

Kang et al. (2008)

Retrospective review

42

Bevacizumab and FOLFOX/FOLFIRI

9.5

34

35

36

Phase II 346 Cetuximab 12.4+ (95% CI 9.1–16.4) Lenz et al. (2006)39 Mirtsching et al. (2004)40 (abstract)

Phase II

29

Cetuximab

11.0

Jonker et al. Phase III 572 Cetuximab (Cet) versus Best Cet 8.0 BSC 0 (P<0.001) (BSC) Supportive Care (2007)41 Grande et al. (2006)44 (abstract)

Phase II

40

Cetuximab and irinotecan

13.0 (95% CI 3.0–34.0)

Vincenzi et al. (2006)45

Phase II

55

Cetuximab and irinotecan

25.4

Gamucci et al. (2008)

Phase II

66

Cetuximab and irinotecan

15.7

46

Retrospective review 60 Gebbia et al. (2006)

Cetuximab 20.0 (95% CI 11.0–32.0) and irinotecan

Pfeiffer et al. (2007)48

Retrospective review

65

Cetuximab and irinotecan

20.0 (95% CI 18.0–25.0)

Berlin et al. (2006) (abstract)

Phase II

39

Panitumumab

8.0

47

49

Phase II 23 Panitumumab 13.0 Hecht et al. (2006) (abstract) 50

Phase III 463 Panitumumab (Pan) & Pan 10.0 Van Cutsem et al. (2007)51 BSC versus BSC alone BSC 0 Saltz et al. (2007)52 Randomized phase II 83

Cetuximab, Bevacizumab and Irinotecan (CBI) versus Cetuximab and Bevacizumab alone (CB)

CBI 37.0 CB 20.0

Phase II 8 Tubb et al. (2007)53 (abstract)

Cetuximab, bevacizumab and irinotecan

13.0

*RR 4% by investigator’s assessment, 1% by independent review. +RR 12.4% by investigator’s assessment, 11.6% by independent review.

Cetuximab

the use of bevacizumab in combination with 5-FU/LV and capecitabine in patients after failure of irinotecanand oxaliplatin-containing regimens34,35 (Table 2). Kang and colleagues (2008) reported the results of 42 patients treated with bevacizumab plus FOLFIRI or FOLFOX as third-line treatment (or beyond) after failure of FOLFIRI or FOLFOX.36 In this study, only four patients (9.5%) had a PR, 52.4% had SD, and the median PFS and OS were 5.3 and 9.5 months, respectively. However, there was significant grade 3 or 4 neutropenia (42.9%), including febrile neutropenia in four patients (9.5%), although toxicities related to bevacizumab, such as bleeding, thrombosis, and gastrointestinal perforation, were consistent with reports from previous studies. APJOH 2009; 1: (1). March 2009

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Cetuximab is an immunoglobulin (IgG1) monoclonal antibody that binds to the extracellular ligand-binding domain of the epidermal growth factor (EGF) receptor, therefore, blocking the binding of EGF and other ligands. Currently, the best available evidence for the use of cetuximab in mCRC is in the heavily pretreated setting used either alone or in combination with cytotoxic chemotherapy, rather than in the first-line setting.37,38 However, not all patients in the earlier studies of cetuximab received both irinotecan- and oxaliplatincontaining regimens, as these studies preceded the use of oxaliplatin in routine practice for fit patients. Lenz and colleagues (2006) reported a RR to cetuximab monotherapy of 11.6% and a median PFS and OS of 1.4 and 6.6 months, respectively in a large multicenter phase II 30

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Median TTP or PFS (months)

Median OS (months)

3.5 (95% CI 2.1–4.4)

9.0 (95% CI 7.2–10.2)

16.0 weeks

Not reached

3.0

14.0

5.3 (range 1.0–13.6)

9.5 (range 1.0–25.7)

Comments

1 year survival 60.7%

1.4 (95% CI 1.4–2.1) 6.6 (95% CI 5.6–7.6) 72 days (mean)

EGFR immunohistochemical staining (IHC), EGFR sequencing and gene copy numbers

Not reported

Cet 6.1 BSC 4.6 (Hazard ratio [HR] 0.77; 95% CI 0.64-0.92; P=0.005)

Further analysis by k-ras mutation; benefit of cetuximab only for k-ras wild-type (Karapetis et al. 2008)42

3.5 (range 1.0–10.0+)

7.3 (range 1.5–12.0+)

4.7 (95% CI 2.5–7.1) (95% CI 21.7–39.6)

9.8 (95% CI 3.9–10.1)

EGFR IHC staining >0

4.0

9.0

Predictive value of early toxicities

3.1 (range 1.2–9.0) 6.0 (range 2.0–13.0)

No EGFR testing

5.5 (95% CI 4.6–6.1)

10.4 (95% CI 7.2–13.1)

No EGFR testing

Not reported

Not reported

High EGFR IHC expression

7.9 weeks Not reported (95% CI 7.0–23.0)

Pan 8.0 weeks; BSC 7.3 weeks (P<0.0001)

Low or negative EGFR IHC expression

No difference inOS (HR 1.00; 95% CI 0.82–1.22) (HR 0.54; 95% CI 0.44–0.66, P<0.0001)

CBI 7.3 CB 4.9

CBI 14.5 CB 11.4

24.0 weeks (range 7.0–36.0+)

Not reported

Prior third-line treatment with panitumumab

study of patients refractory to irinotecan, oxaliplatin, and fluoropyrimidines.39 These responses are consistent with results from the use of cetuximab alone in irinotecanrefractory patients from earlier studies and with a small phase II trial of 29 patients receiving cetuximab alone after failure of oxaliplatin- and irinotecan-containing regimens.37,38,40

assessed in 394/572 patients (68.9%) for activating mutations in exon-2 of the k-ras gene, and patients with a colorectal tumor bearing mutated k-ras were found not to benefit from cetuximab. In contrast, in patients with wild-type k-ras tumors, treatment with cetuximab significantly improved OS compared to BSC (median 9.5 versus 4.8  months; hazard ratio for death 0.55, P<0.001). These results are consistent with findings in recent studies that the use of antiEGFR antibodies, cetuximab, and panitumumab are limited to patients with wild-type k-ras genes.13–15,43

A large, open-label randomized trial of 572 patients comparing cetuximab alone versus BSC showed that cetuximab can improve OS, PFS, and preserve quality of life measures in patients previously treated with a fluoropyrimidine, irinotecan, and oxaliplatin.41 Importantly, a recent correlative analysis of this patient cohort examined the effect of the mutation status of k-ras gene and reported its effect on overall survival and progression free survival.42 K-ras mutations were www.slm-oncology.com

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EGFR IHC stain ≥ 1%; Further analysis by k-ras mutation; benefit of panitumumab only for wild-type k-ras (Amado et al. 2008)43

Five trials examining the use of cetuximab and irinotecan in this heavily pretreated population reported a RR between 13% and 25%, a PFS between 3.5 and 5.5 months, and an OS between 7.3 and 10.4 months.44–48 These data indicate that cetuximab taken in combination 31

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at least one adverse event with skin toxicities, diarrhea and hypomagnesemia being the most common toxicities with no grade 3 or 4 infusion reactions reported. K-ras mutations were assessed retrospectively in 427 (92%) of these patients, and panitumumab efficacy was confined to patients with wild-type k-ras.43 PFS for patients in the wild-type k-ras group (hazard ratio 0.45; 95% CI 0.34 to 0.59, P<0.0001) was significantly better than in the mutant group (median PFS 12.3 weeks and 7.3  weeks, respectively). Patients with wild-type k-ras also had a longer OS (HR 0.67; 95% CI 0.55 to 0.82) compared to those with mutant k-ras.

with irinotecan has greater activity compared to cetuximab alone, even in heavily pretreated patients in the chemotherapy refractory setting. Toxicities were manageable in patients receiving either cetuximab alone or cetuximab plus irinotecan, with an incidence of grade 3 or 4 rash between 3% and 33%,39–41,44,45,47,48 grade 3 or 4 infusion reactions between 2% and 4.6%,41,47,48 and only one reported death on treatment with cetuximab and irinotecan.48 There was a higher incidence of grade 3 or 4 diarrhea (10% to 27%), neutropenia (4% to 18%), and nausea or vomiting (0% to 33%) in patients receiving the combination of cetuximab and irinotecan compared to single-agent cetuximab.44,45,47,48 One study examined the predictive value of early specific toxicities and demonstrated that the presence and severity of rash correlated strongly with both PFS (P=0.01) and OS (P=0.04), with moderate hematological and gastrointestinal toxicity correlating with PFS (P=0.03).46

Combination of Targeted Monoclonal Antibodies The use of combination monoclonal antibodies for patients with chemotherapy-refractory colorectal cancer was investigated in 83 patients in a randomized phase II trial of cetuximab, bevacizumab, and irinotecan (CBI) compared with cetuximab and bevacizumab (CB) alone (BOND-2 Study).52 The median number of prior regimens was three, and all patients had irinotecan-refractory colorectal cancer with 89% of patients having previously received oxaliplatin-containing regimens. The median TTP was higher for the CBI arm (7.3  months) than for the CB arm (4.9  months). Response rates were also higher for the CBI arm (37%) than for the CB arm (20%). The median OSs for the CBI and CB arms were 14.5 months and 11.4 months, respectively. The toxicities reported in this study were comparable to those expected from the use of the individual agents, with an incidence of grade  3 or 4 rash of 20%, grade 3 or 4 diarrhea and neutropenia of 28% and 23% in the CBI and CB arms, respectively, and no grade 3 or 4 allergic reactions. A small phase II study reported the preliminary results of 8  patients treated with cetuximab, bevacizumab, and irinotecan who had been previously treated with third-line panitumumab following disease progression on oxaliplatin and irinotecan and who had a median TTP of 24 weeks, and a RR of 13%; adverse events from this regimen were not reported.52 Although results from these phase II trials of combination monoclonal antibodies are promising, these results will need to be confirmed in large randomized ongoing phase  III trials. Preliminary results from two large phase  III studies for dual monoclonal antibodies in the first-line setting, however, have been disappointing, with inferior PFSs obtained for patients receiving two monoclonal antibodies in combination with chemotherapy.54,55

Apart from the study reported by Karapetis and colleagues,42 none of the other studies examining third-line treatment with cetuximab or cetuximab plus irinotecan in mCRC performed k-ras testing on tumor samples; however, EGFR immunohistochemical staining, EGFR gene sequencing, and gene copy number assessments were tested in a few of the studies.39,44,45,47 Based on recently available evidence regarding the predictive value of wild-type k-ras and the response to EGFR monoclonal antibodies, patients with wild-type k-ras may derive the greatest benefit from cetuximab treatment if retrospective testing of k-ras is performed.

Panitumumab Panitumumab, a fully humanized monoclonal IgG2 antibody, binds to EGFR with similar downstream effects to cetuximab. The main advantage of panitumumab over cetuximab is the lower incidence of infusion reactions and antibody formation compared to cetuximab. Two phase II studies reported preliminary results investigating the safety and efficacy of panitumumab in patients who failed prior chemotherapy with negative (<1%), low (1% to 9%) and high (≥10%) EGFR IHC tumor staining.49,50 Median RRs were 8% to 13%, and panitumumab was well tolerated. Results were recently reported from a large open-label phase III trial of panitumumab plus BSC versus BSC alone involving 463 patients with chemotherapy-refractory mCRC.51 All patients were required to have ≥1% EGFR-positive membrane staining in evaluated tumor cells by IHC and to have failed both irinotecan- and oxaliplatin-containing regimens. Panitumumab significantly prolonged PFS (hazard ratio 0.54; 95% CI 0.44 to 0.66, P<0.0001), with a median PFS of 8 weeks (95% CI 7.9 to 8.4) for panitumumab and 7.3 weeks for BSC (95% CI 7.1 to 7.7). Although there was no significant difference between the two arms in terms of overall survival, a large number (76%) of patients in the BSC group received panitumumab under the cross-over protocol. All patients on panitumumab had APJOH 2009; 1: (1). March 2009

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DISCUSSION Treatment options for patients with mCRC have undergone a significant expansion over the last decade, with the advent of both new chemotherapeutic agents as well as targeted therapies. For the first time, second and subsequent lines of treatment have become a reality 32

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for patients. This has meant that clinicians need to keep abreast of an array of new data to balance benefit and toxicity in their patients. The purpose of this review was to summarize the data available for treatment of mCRC in the third-line setting. Overall, outcomes of third-line chemotherapy have been disappointing, and targeted therapies appear to be the future of colorectal cancer treatment. There have been no randomized controlled trials of thirdline chemotherapy, and the published phase II trials all included less than 100  patients, with a RR ranging from zero to 14.3% (Table 1). Results from trials of targeted therapies, including bevacizumab, cetuximab, and panitumumab, have been more promising, with two large randomized trials showing an improvement in disease-free survival. These benefits were demonstrated in terms of OS when the results were analyzed for the presence of wild-type k-ras. It should be noted, however, that both of these studies were conducted before the use of bevacizumab in the first-line setting; so it is unclear what impact prior targeted therapy would have on these results. The updated National Comprehensive Cancer Network (NCCN) Guidelines for Colorectal Cancer recommend targeted antibody treatment with cetuximab +/– irinotecan or panitumumab for those with k-ras wild-type tumors, and recommend FOLFOX or XELOX, participation in a clinical trial, or best supportive care after second-progression, depending on prior therapy and fitness for treatment for patients without wild-type K-ras tumors.56 Toxicity is an important consideration in deciding to treat any advanced cancer. This is especially true when patients have undergone multiple lines of previous therapy. Fortunately, monoclonal antibodies have a favorable side effect profile, with acneiform rash associated with cetuximab and panitumumab being the most prevalent. The small (5%) risk of hemorrhage with bevacizumab may limit some patients’ access to this drug, depending on the location of their disease and the presence of comorbidities. It is also essential to consider quality of life measures when evaluating trials of thirdline treatment in the advanced setting when the aims of treatment are not curative, and the toxicity of more aggressive treatment should be weighed against potentially small benefits in response or survival. In conclusion, knowledge of the molecular pathophysiology of colorectal cancer has increased exponentially, and with it, the number of new therapies, both in use and in development, has increased. It is now clear that all patients should receive 5-fluorouracil in addition to oxaliplatin or irinotecan; however, the use of biological agents is not as clear-cut in routine clinical practice. It is likely that as our knowledge increases, targeted therapies will become ‘personalized’, as treatments are chosen on the basis of the molecular signature of the patient’s cancer. Ten years ago, the idea of third-line treatment for mCRC for the majority of patients was www.slm-oncology.com

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unimaginable due to poor prognosis and the paucity of available options. However, this has become a reality in recent times for a large proportion of patients, and the next decade will likely see an even greater expansion of newer and better treatment options with ‘personalized’ treatments being favored in the future. Disclosures: The authors have no financial interests to disclose related to the contents of this article.

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16. Hoff PM, Ansari R, Batist G, et al. Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J Clin Oncol. 2001;19:2282–2292. 17. van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol. 2001;19:4097–4106. 18. Ardavanis AS, Ioannidis GN, Orphanus GS, et al. Salvage treatment with single agent capecitabine in patients with heavily treated advanced colorectal cancer. Anticancer Res. 2006;26:1669–1672. 19. Gubanski M, Naucler G, Almerud A, et al. Capecitabine as third line therapy in patients with advanced colorectal cancer. Acta Oncol. 2004;44:236–239. 20. Chong G, Dickson JLB, Cunningham D, et al. Capecitabine and mitomycin C as a third line therapy in patients with metastatic colorectal cancer resistant to fluorouracil and irinotecan. Br J Cancer. 2005;93:510–514. 21. Harba A, Jordan K, Kegel T, et al. Capecitabine/mitomycin C as salvage therapy in oxaliplatin and CPT11 refractory advanced colorectal carcinoma (ACRC). Proc Am Soc Clin Oncol. 2003;22: Abstract 1335. 22. Lim DH, Park YS, Park B, et al. Mitomycin-C and capecitabine as third-line chemotherapy in patients with advanced colorectal cancer: a phase II study. Cancer Chemother Pharmacol. 2005;56:10–14. 23. Scartozzi M, Falcone A, Pucci F, et al. Capecitabine and mitomycin C may be an effective treatment option for thirdline chemotherapy in advanced colorectal cancer. Tumori. 2006;92:384–388. 24. Rimassa L, Gullo G, Carnaghi C, et al. Chemotherapy with mitomycin C and capecitabine in patients with advanced colorectal cancer pretreated with irinotecan and oxaliplatin. Tumori. 2006;92:285–289. 25. Chua W, Beale P, Leung M, Clarke S. Retrospective review of mitomycin use as third-line chemotherapy in metastatic colorectal cancer. Asia Pac J Clin Oncol. 2008;4:132–136. 26. Vormitaag L, Kornek GV, Gruhsmann B, et al. UFT/leucovorin and mitomycin C as salvage treatment in patients with advanced colorectal cancer—a retrospective analysis. Anticancer Drugs. 2007;18:709–712. 27. Rosati G, Rossi A, Germano D, et al. Raltitrexed and mitomycin-C as third-line chemotherapy for colorectal cancer after combination regimens including 5-fluorouracil, irinotecan and oxaliplatin: a phase II study. Anticancer Res. 2003;23: 2981–2985. 28. Polus M, Peeters F, Baert P, et al. CPT-11 and mitomycin-C in heavily pretreated patients with metastatic colorectal cancer: A Belgian multicentre phase II study. J Clin Oncol. 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2004;22(14s): Abstract 3716. 29. Pachon V, Garcia-Alfonso P, Iglesias L, et al. Gemcitabine plus continuous infusion of 5-FU for heavily pretreated advanced colorectal cancer patients. Phase I/II study. J Clin Oncol. 2005 ASCO Annual Meeting Proceedings. 2005;23(16s): Abstract 3735. 30. Jeung H, Rha S, Cho BC, et al. A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens. Br J Cancer. 2006;95:1637–1641. 31. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomised trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21:60–65. 32. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539–1544. 33. Chen HX, Mooney M, Boron M, et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin with advanced

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34.

35.

36.

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39.

40. 41. 42. 43. 44.

45. 46.

47.

48.

49.

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51.

34

refractory colorectal cancer: an NCI Treatment Referral Center trial TRC-0301. J Clin Oncol. 2006;24:3354–3360. Emmanouilides C, Pegram M, Robinson R, et al. Anti-VEGF antibody bevacizumab (Avastin) with 5FU/LV as third-line treatment for colorectal cancer. Tech Coloproctol. 2004;8: S–0-S52. Zoran P, Tarabar D, Doder R. A phase II trial of bevacizumab and capecitabine combination in metastatic colorectal cancer after failure of irinotecan and oxaliplatin-containing regimens. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings. 2007;25: Abstract 14555. Kang BW, Kim TW, Lee JL, et al. Bevacizumab plus FOLFIRI or FOLFOX as third-line or later treatment in patients with metastatic colorectal cancer after failure of 5-fluorouracil, irinotecan and oxaliplatin: a retrospective analysis. Med Oncol. 2008 May 2. [Epub ahead of print] Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan refractory metastatic colorectal cancer. N Engl J Med. 2004;35:337–345. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol. 2004;22:1201–1208. Lenz HJ, van Cutsem E, Khambata-Ford S, et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol. 2006;24:4914–4921. Mirtsching B, Headlee C, Beasley S, et al. Single-agent activity in refractory metastatic colorectal cancer: Single center experience. J Clin Oncol. 2004;22(14S):3703. Jonker DJ, O’Callaghan C, Karepetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;257:2040–2048. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–1765. Amado RG, Wolf M, Peeters M, et al. Wild-type k-ras is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–1634. Grande C, Mel JR, Salgado M, et al. Multicenter phase II study of cetuximab and irinotecan as third line chemotherapy in patients with metastatic colorectal cancer (MCRC) previously treated with both irinotecan and oxaliplatin regimens. J Clin Oncol. 2006;24:13351. Vincenzi B, Santini D, Rabitti C, et al. Cetuximab and irinotecan as third-line therapy in advanced colorectal cancer patients: a single center phase II trial. Br J Cancer. 2006;94:792–797. Gamucci T, Nelli F, Cianci G, et al. A phase II study of cetuximab/irinotecan in patients with heavily pretreated metastatic colorectal cancer: predictive value of early specific toxicities. Clin Colorectal Cancer. 2008;7:273–279. Gebbia V, Del Prete S, Borsellino N, et al. Efficacy and safety of cetuximab/irinotecan in chemotherapy-refractory, metastatic colorectal adenocarcinomas: a clinical practice setting, multicenter experience. Clin Colorectal Cancer. 2006;5:422–428. Pfeiffer P, Nielsen D, Yilmaz M, et al. Cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure of irinotecan, oxaliplatin and 5-fluorouracil. Acta Oncol. 2007;46:697–701. Berlin J, Neubauer M, Swanson P, et al. Panitumumab antitumour activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing >10% epidermal growth factor receptor (EGFR). J Clin Oncol. 2006 ASCO Annual Meeting Proceedings. 2006 Part 1;24(suppl 18S): Abstract 3548. Hecht JR, Mitchell E, Baranda J, et al. Panitumumab antitumour activity in patients (pts) with metastatic colorectal cancer (mCRC) expressing low (1–9%) or negative (<1%) levels of epidermal growth factor receptor (EGFR). J Clin Oncol. 2006 ASCO Annual Meeting Proceedings. 2006 Part 1;24(Suppl 18S): abstract 3547. van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus BSC compared with BSC alone in

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patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–1664. 52. Saltz L, Lenz H, Kindler H, et al. Randomised phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007;29:4557–4561. 53. Tubb E, Jacobs M, Mitchell P. Response to the combination of cetuximab, bevacizumab and irinotecan (Cetux/bev/iri) in patients (pts) previously treated with 3rd-line panitumumab, following disease progression on oxaliplatin, irinotecan and a fluoropyrimidine. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings. 2007;25: Abstract 14586.

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54. Hecht J, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin, bevacizumab +/– panitumumab for 1st line treatment of metastatic colorectal cancer (mCRC) from a randomised controlled trial (PACCE). ASCO Gastrointestinal Cancers Symposium 2008: abstract 273. 55. Punt CJ, Tol J, Rodenburg CJ, et al. Randomised phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol. 2008;26(May 20 Suppl): abstract LBA 4011. 56. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Colon Cancer, version 4 2008. National Comprehensive Cancer Network (NCCN). www.nccn.org.

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REVIEW ARTICLE

Quantitative Evaluations for the Optimal Utilization of Radiotherapy in Lung Cancer Shalini K. Vinod1,2 Affiliations: 1Collaboration for Cancer Outcomes, Research & Evaluation (CCORE), New South Wales, Australia and 2 University of New South Wales, New South Wales, Australia Submission date: 2nd December 2008, Acceptance date: 3rd January 2009

Abstract

annually and has been the most common cancer in the world since 1985 (excluding nonmelanoma skin cancers).1,2 Lung cancer is also the leading cause of cancer related mortality and is responsible for 1.18 million deaths annually, or 17.6% of all cancer deaths.2 There is a worldwide variation in the incidence of lung cancer, and fewer than half of all new cases occur in the developing countries.

Lung cancer is the leading cause of cancer mortality throughout the world. The three main modalities of treatment are surgery, radiotherapy and chemotherapy. Radiotherapy is the only treatment with a proven role in all stages of lung cancer, both small cell and non-small cell. Models have estimated that the optimal utilization of radiotherapy for lung cancer at diagnosis ranges from 45% to 68%. However, actual utilization rates range from 27% to 52%. Radiotherapy utilization for lung cancer worldwide is less than optimal, with the exception of radiotherapy for non-small cell lung cancer in the USA. The greatest shortfall in radiotherapy utilization occurs in small cell lung cancer.

In the Asia-Pacific region, lung cancer is the second most common cancer after stomach cancer but causes the greatest number of cancer deaths.3 It is responsible for 15.8% of cancer incidence and 19.9% of cancer mortality in the region.3 It is a greater health problem in Australia, New Zealand and East Asian countries such as China, Korea and Japan than in other countries in the Asia-Pacific region.

The reasons for the difference between optimal and actual radiotherapy utilization are multifactorial. Models cannot account for patient factors such as comorbidity and pulmonary function, or tumor factors such as size. All of these factors influence treatment recommendations. Additionally, health service factors, including limited resources and clinician biases such as nihilism and ageism, are also responsible for the underutilization of radiotherapy.

Lung cancer is a disease affecting the elderly and predominates in men.1,4 The median age of cancer onset is between 68 and 71 years.5 There are racial and socioeconomic differences associated with its incidence and mortality rates, with these being greater in minority populations, those with lower education levels, and those from a poorer socioeconomic background.6

Measures are required to improve the use of radiotherapy in lung cancer. These measures should, at minimum, include discussion of lung cancer patients at multidisciplinary meetings to ensure adherence to guidelinebased treatment. The optimal utilization of radiotherapy will improve survival and quality of life for lung cancer patients. Measures to increase these end points at the population level will result in improved outcomes, at a level greater than those resulting from technological or pharmaceutical advances.

The vast majority of patients present with locally advanced or metastatic disease. According to recent statistics, 74% of patients in the USA presented with stage III or IV cancers.7 In Scotland, 77% of patients presented with regional or metastatic disease.8 In New South Wales, Australia, 56% of patients had stage III or IV non-small cell lung cancer (NSCLC) or extensive stage small cell lung cancer (SCLC).9 This pattern of advanced disease at diagnosis holds true for both NSCLC and SCLC.7,9,10

Keywords: lung neoplasms, radiotherapy utilization, radiotherapy, physicians’ practice patterns, small cell lung cancer, non-small cell lung cancer

The survival rate from lung cancer is poor. In developing countries, the relative survival is 12% in men and women, while in developed countries, it is 13% in men and 20% in women.1 There has been little change in mortality rates from lung cancer over the last three decades, with a slight reduction in men and an increase in women.11 A review of clinical trials spanning two decades in advanced lung cancers also shows only a modest improvement in median survival, of up to

Correspondence: Shalini K. Vinod, Cancer Therapy Centre, c/o Liverpool Hospital, Locked Bag 7103, Liverpool BC, NSW 1871, Australia. Tel: +61 2 98285282; fax: +61 2 98285299; e-mail: Shalini.Vinod@swsahs.nsw.gov.au

INTRODUCTION Lung cancer is a global health problem. It accounts for 12.3% of all new cancer cases (1.35 million new cases) APJOH 2009; 1: (1). March 2009

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prove quality of life in lung cancer patients.25,26 There is no doubt that radiotherapy is an important therapeutic modality in the treatment of lung cancer.

Table 1. Estimated Optimal Utilization of Radiotherapy in Lung Cancer (%) Tyldesley27

Delaney28

MODELS OF RADIOTHERAPY UTILIZATION

At At Overall diagnosis Overall diagnosis SCLC

54

45

79

68

Limited stage

81

80

94

94

Extensive stage

33

20

68

49

64

46

75

68

Stage I

41

27

50

31

Stage II

55

37

50

31

Stage III

84

76

92

81

Stage IV

66

35

83

83

61

45

76

68

NSCLC

All lung cancers

There have been two published evidence-based models estimating the proportion of lung cancer patients who should receive radiotherapy.27,28 The methodology for both of these models included a review of international, evidence-based guidelines to determine all possible indications for radiotherapy in lung cancer, both at initial diagnosis and later in the course of the illness.28 Epidemiological data were then used to determine the proportion of lung cancer patients with particular attributes as an indication for radiotherapy. The epidemiological data obtained was variable; it was therefore ranked, with more emphasis given to population-based cancer registry data in order to overcome potential selection biases. The frequency of each indication for radiotherapy was calculated and added to give the optimal rate of use. Delaney et al. used predominantly Australian epidemiological data to determine the proportion of lung cancer patients with an indication for radiotherapy, based on stage, symptoms, patient performance status and natural history.28 They calculated that the ideal utilization of radiotherapy for lung cancer is 76% overall: 68% at diagnosis and 8% later in the illness (Table 1). Of these treatments, 50% would be with curative intent, 49% palliative and 1% adjuvant. The ideal utilization rates for NSCLC and SCLC were 75% and 79%, respectively. Sensitivity analysis, substituting ranges of variables where the data were uncertain, showed the range of optimal radiotherapy utilization to be between 73% and 76%.

2 months.12,13 Therefore, treatment and improvement in survival of lung cancer remain a challenge.

THE ROLE OF RADIOTHERAPY The main treatment modalities for lung cancer are surgery, radiotherapy and chemotherapy. Radiotherapy is the only treatment modality with a proven efficacy for all stages of lung cancer, both SCLC and NSCLC. The indications for radiotherapy are similar across Australian, British, Scottish and US guidelines.14–20 Radiotherapy is a potentially curative treatment in medically inoperable stage I and II NSCLC and it is the main curative treatment, in addition to chemotherapy, in stage  III NSCLC. It also has an important role in palliation of stage IV NSCLC, especially for symptoms from the primary cancer or from metastases to the brain or to bone. The role of adjuvant radiotherapy following surgery is less clear, with a meta-analysis showing it to be detrimental to survival.21 However, recent data would support its role in patients with pathological N2 disease.22,23

Another study by Tyldesley et al. used North American epidemiological data.27 The variables used in their model included pathology, stage, resection margins, performance status and history of response to treatment. There were some differences compared to the Delaney model in that patient preferences were taken into account. This was for scenarios where the indication for radiotherapy was not clearly defined but it was a possible treatment option. Recognizing that some patients may refuse radiotherapy in this setting, Tyldesely et al. incorporated this into their model. Furthermore, to define rates for adjuvant radiotherapy, actual rather than estimated rates of surgery were used. Tyldesley et al. calculated the optimal utilization of radiotherapy in lung cancer to be 61%: 45% at diagnosis and 16% later in the illness (Table 1). The respective statistics for SCLC were 54%, 45% and 8%, and for NSCLC they were 64%, 46% and 18%.

In limited stage SCLC, both thoracic radiotherapy, given in conjunction with chemotherapy, and prophylactic cranial radiotherapy increase survival. In extensive stage SCLC, palliative radiotherapy provides symptomatic benefits similar to that in stage IV NSCLC. Recent evidence shows that prophylactic cranial irradiation in patients who respond to chemotherapy improves survival.24 Although survival end points are important, quality of life is also equally important in the majority of patients who present with locally advanced or metastatic disease. Both palliative and curative radiotherapy can imAPJOH 2009; 1: (1). March 2009

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Both of these models estimate the highest utilization of radiotherapy in lung cancer to be in stage III and IV NSCLC. However, Delaney et al. also predict a high 38

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Quantitative Evaluations for the Optimal Utilization of Radiotherapy in Lung Cancer

Table 2. Actual Utilization of Radiotherapy in Lung Cancer at Diagnosis (%)

USA NCDB31

Victoria, Australia32

Ontario, Canada30

USA SEER30

USA NCDB7 Ireland33

NSW, Australia9

Scotland8

Years

1986, 1992

1993

1994–6

1994–6

1995

1994–8

2001–2

2002

n

183297

1054

30688

100385

78307

7218

1812

971

SCLC

42

28

40

42

24

36

37

Limited stage

48

46-52*

46

Extensive stage

37

37

36

54

50

40

48

37

43

53

Stage I

25

14/27/29

26

Stage II

48

47/52/51#

39

Stage III 66 — — —

IIIA 63/72/72# IIIB 52/74/67#

55

Stage IV

NSCLC

All lung cancer

#

62

56/62/61

49

52

44

33

44

49

27

39

45

#

NCDB, National Cancer Data Base; SEER, Surveillance, Epidemiology & End-Results; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer. *Range given as this reflects the radiotherapy utilization for stage I–III SCLC. # Radiotherapy utilization for adenocarcinoma, squamous cell carcinoma, large cell carcinoma, respectively.

surance scheme, all of the radiotherapy centers had multidisciplinary lung groups, and the clinicians were salaried. Counties with local radiotherapy facilities and short waiting lists did not possess the potential barriers of distance and resources. In this “ideal setting,” the utilization of radiotherapy for lung cancer at diagnosis was 33%, well below the estimated ideal of 45% for North America (Table 3). The shortfall was similar for NSCLC (40% actual versus 46% optimal) and SCLC (40% actual versus 45% optimal). These differences were statistically significant.

utilization in SCLC. This may be because, in Tyldesley’s model, the indications for radiotherapy are based on response to chemotherapy. This is dissimilar to Delaney’s model and likely limited the group of SCLC patients with an indication for radiotherapy. The 15% difference in overall utilization between the models can be partly attributed to the different epidemiological data used and the slight differences in methodology. The methodology used by Delaney et al. has been applied to Scottish epidemiological data with their estimated optimal radiotherapy utilization in lung cancer equaling 63%.29

This Canadian group also examined the radiotherapy utilization from SEER cancer registries, which collect data from 11 geographically localized population-based cancer registries in the USA, representing 14% of the US population. The radiotherapy utilization rate for all lung cancers was 44%—not statistically different from the predicted ideal of 45%. The radiotherapy utilization for NSCLC was greater than optimal (48% actual versus 46% optimal), and that for SCLC was slightly less (42% actual versus 45% optimal). The difference in utilization for NSCLC was not statistically significant, but was for SCLC, although actual P values were not provided.

No model is perfect and models simply provide an estimate of what is thought to be the ideal utilization based on the best available evidence. However, models are useful in that they provide a benchmark from which to compare the actual utilization rates of radiotherapy in lung cancer and to identify any areas of shortfall.

ACTUAL RADIOTHERAPY UTILIZATION There have been many patterns of care studies and cancer registry reports documenting the utilization of radiotherapy in lung cancer (Table 2). These show wide variation in the use of radiotherapy throughout the world. One Canadian group performed a study to examine the achievable utilization rates of radiotherapy for lung cancer in the “ideal” setting,30 whereby there is local availability of radiotherapy, no cost to the patient and no financial incentive to provide treatment. The province of Ontario satisfied most of these requirements. It had a comprehensive provincial health inwww.slm-oncology.com

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In Ontario, despite “ideal” conditions, the actual radiotherapy utilization for lung cancer was significantly lower than the evidence-based estimates. The differences between the utilization rates in Ontario and SEER were due to the greater use of initial radiotherapy in the treatment of NSCLC. In both settings, there was underutilization of radiotherapy for SCLC. 39

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Table 3. Actual Versus Optimal Radiotherapy Utilization in Lung Cancer (%) USA NCDB31

Ontario, Canada30

USA SEER30

Victoria, Australia32

NSW, Australia9

USA NCDB7

Scotland8

Optimal

45

45

45

68

68

Actual

42

40

42

28

36

Difference

-3

-5

-3

-40

-32

Optimal

46

46

46

68

68

Actual

54

40

48

50

43

Difference

8

-6

2

-18

-25

Optimal

45

45

45

68

68

45

63

Actual

52

33

44

44

39

49

45

Difference

-7

-12

-1

-24

-29

4

-18

SCLC

NSCLC

All lung cancer

NCDB, National Cancer Data Base; SEER, Surveillance, Epidemiology & End-Results; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer.

The National Cancer Database also provides information on the treatment of lung cancer in the USA.7,31 These data are from hospital cancer registries in the USA, which provide treatment details for various stages of cancer. In 1986–1987, the recorded lung cancer cases represented approximately 30% of all lung cancer cases in the USA, and in 1992, this figure had increased to 55%.31 During this period, the utilization of radiotherapy, as part of initial therapy for all lung cancer cases was 52%, and 42% and 54% for SCLC and NSCLC, respectively. Except for SCLC, these figures exceed the optimal utilization predicted by Tyldesley et al. (Table 3).

NSW and 44% in Victoria, less than two-thirds of the 68% optimal utilization estimated by Delaney et al. The greatest discrepancy was apparent in small cell lung cancer, where the actual utilization rates were 36% in NSW and 28% in Victoria, compared to the optimal of 68% (Table 3). In NSW, where utilization was available by stage, the ratio of actual to optimal utilization was lowest in limited stage SCLC, followed by stage IV and III NSCLC (Table 4).9 In New Zealand, lung cancer patterns of care were documented in 2005, in four district health boards, comprising 37% of the New Zealand population.10 Rates of radiotherapy were not reported by stage or pathology, but they do document referrals to radiation oncologists. Overall, 44% of lung cancer patients received referrals, as did 53% of NSCLC patients and 39% of SCLC patients. Of all patients referred, only 66% received radiotherapy. At best, this would give a 29% utilization of radiotherapy at diagnosis. Assuming that the proportion of patients with NSCLC and SCLC receiving radiotherapy was identical, the radiotherapy utilization would have been 34% in NSCLC and 26% in SCLC. These figures are substantially less than the optimal utilization from either model, and again the proportional difference is greater in SCLC cases.

The updated data from 1995 showed that overall radiotherapy utilization for all lung cancers in USA had fallen to 49%, although there were no direct comparisons from which to evaluate statistical significance. The utilization in SCLC was similar to the previous time period. For NSCLC, an overall utilization figure per stage was not calculated, since the results were reported by pathology, giving a wide range of variability. In stages I, II and IV disease, the actual utilization was similar to the ideal predicted (Table 4). However, for stage  III NSCLC, the actual utilization was slightly less than ideal. Of note, radiotherapy utilization in adenocarcinoma was lower than that in other NSCLC pathologies for every stage, despite the fact that pathological subtype does not influence indications for radiotherapy (Table 2).

Radiotherapy utilization in lung cancer has also been reported in Ireland, Scotland and Andalusia, Spain.8,33,34 In Ireland, during the period from 1994 to 1998, the utilization of radiotherapy at diagnosis was 27% overall; 37% in NSCLC and 24% in SCLC.33 These figures may actually be overestimates, as all patients who received combined modality treatment were assumed to receive

In Australia, patterns of care studies were conducted in the two most populous states: NSW and Victoria.9,32 The radiotherapy utilization at diagnosis was 39% in APJOH 2009; 1: (1). March 2009

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Quantitative Evaluations for the Optimal Utilization of Radiotherapy in Lung Cancer

radiotherapy. It is possible that some of the combined modality treatment referred to a combination of surgery and chemotherapy. Radiotherapy utilization varied throughout the different health boards.

Table 4. Actual Versus Optimal Radiotherapy Utilization by Stage of NSCLC and SCLC (%) NSW, Australia9

Optimal

80

80

94

Actual

48

46 to 52*

46

Difference

-32

-34 to -28

-48

Optimal

20

20

49

Actual

37

37

36

Difference

17

17

-13

Optimal

27

27

Actual

25

14 to 29

26

Difference

-2

-13 to 2

-5

Optimal

37

31

37

Actual

48

47 to 52#

39

Difference

11

-16 to 20

2

Optimal

76

76

81

Actual

66

52 to 74

55

Difference

-10

-24 to -2

-26

Optimal

35

35

83

Actual

62

56 to 61#

49

Difference

27

21 to 26

-34

Extensive stage SCLC

Stage I NSCLC

From the data presented, with the exception of the USA, it is clear that worldwide there is an underutilization of radiotherapy in the treatment of lung cancer, irrespective of the model used for comparison (Table 3). The deficit ranges from 1% to 29%, with the greatest differences seen in Australia where the optimal radiotherapy utilization is higher than that estimated in Canada. The greatest shortfall (as calculated by the lowest ratio of actual to optimal utilization) is apparent in limited stage SCLC, followed by stage  III NSCLC (Table  4). This pattern is evident even in the USA. Conversely, in North America, there is an overutilization of radiotherapy in extensive stage SCLC and stage  IV NSCLC, signifying greater use of palliative radiotherapy compared with curative radiotherapy.

31 #

Stage II NSCLC

Stage III NSCLC

#

Stage IV NSCLC

However, the available data are biased toward the UK, North America and Australasia. Unfortunately, there are a lack of population-based data from other regions with available radiotherapy utilization rates. While there are many patterns of care studies in radiotherapy for lung cancer, they are mostly surveys of radiotherapy facilities and, therefore, do not give a true denominator from which to calculate actual radiotherapy utilization.

NCDB, National Cancer Data Base; SCLC, small cell lung cancer; NSCLC, nonsmall cell lung cancer. *Range given as this reflects the radiotherapy utilization for stage I-III SCLC. # Range given as this reflects the radiotherapy utilization for adenocarcinoma, squamous cell carcinoma and large cell carcinoma.

THE DIFFERENCE BETWEEN IDEAL AND ACTUAL RADIOTHERAPY UTILIZATION

for active treatment are not easily available and could influence the results. There is also a paucity of data on attributes such as the proportion of lung cancer patients with symptomatic bony metastases or spinal cord compression. However, these attributes would only identify small groups of patients and will have less influence than the epidemiological data used for the initial grouping of patients. Delaney et al. performed a sensitivity analysis to test for the effect of uncertainties in the epidemiological data. The range of ideal radiotherapy utilization was small, ranging from 73% to 76%.

The Models Any model is only as good as the quality of data used to develop it. Much of the evidence for indications of radiotherapy has relied on Level II and III evidence, which has become the basis for guidelines. The quality of the epidemiologic data used can substantially influence the calculation of ideal utilization, and both Delaney et al. and Tyldesley et al. clearly defined a hierarchy for the epidemiological evidence used. Data on performance status and the selection of patients

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USA NCDB7

Limited stage SCLC

In Andalusia, Spain, in 2006, the utilization of radiotherapy for lung cancer was 48% of the predicted ideal in Spain.34 In contrast, the actual utilization for other cancers, such as breast and gynecological cancers, was comparable to the ideal.

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USA NCDB31

In Scotland in 2002, 45% of all lung cancer patients received radiotherapy within 6 months of diagnosis.8 This is below the predicted ideal of 63% in Scotland (Table 3).29 Curative radiotherapy was prescribed in 15% and palliative in 31% of cases. An increase in the utilization of radiotherapy from 49% to 53% in NSCLC and from 29% to 31% in SCLC, occurred between 1995 and 2002.

41

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Patient Factors

counted for in Tydesley’s model. Review of the NSW lung cancer patterns of care study showed that, in patients who did not have any treatment for their potentially curable cancer, this was due to patient refusal in 20% of cases.9 Overall, this was a minor factor in determining utilization rates of treatment.

The presence of comorbidities can affect the decision to use radiotherapy and other treatments in lung cancer patients, who have a high prevalence of comorbidity that increases with age. A population-based study from the Netherlands showed that the prevalence of comorbidity was 48% in patients less than 60 years, 68% for patients 60 to 69 years, and 86% for those 70 years and above.35 The most common comorbidities were cardiovascular disease and chronic obstructive pulmonary disease. The prevalence of comorbidity was about twice that in the general population.36 In Australia and New Zealand, 73% and 81% of lung cancer patients, respectively, had a comorbidity that could influence treatment.9,10 The presence of comorbidity resulted in less treatment utilization in lung cancer including less radiotherapy.10,37 Related to comorbidity and more relevant to lung cancer patients is adequate pulmonary function. Because there are no well-defined criteria as to what constitutes acceptable pulmonary function for radiotherapy, the decision to treat is often a subjective one. The prevalence of these factors is unknown at the population level; the demarcation between treating and not treating based on these is unclear and thus cannot be accounted for in models of utilization. Lung cancer affects an older population. The effect of age on determining utilization of treatment is well documented. In Scotland, patients aged 80  years and over were half as likely to receive radiotherapy than those aged less than 60  years.38 SEER data showed that, in patients with stage IV NSCLC, radiotherapy utilization in patients aged 80  years and greater was half of that for those aged less than 70 years, independent of comorbidities.37 In Ireland, New Zealand and NSW (Australia), increasing age can be an independent predictor of a patient being less likely to receive cancerspecific treatment.9,10,33 The use of radiotherapy decreases with increasing patient age, as has been demonstrated in Ontario, particularly in the adjuvant and palliative settings.39 This reduction in radiotherapy use exceeded the relative decline in functional status with age in the general population. The lower radiotherapy utilization was due to fewer referrals of elderly patients for radiotherapy. In lung cancer, in the oldest patients, the referral rate for palliative radiotherapy was half that of the younger patients, but the proportion of referred patients treated was relatively constant. However, treatment decisions in lung cancer should not be based on age alone. In SCLC, age does not impact the delivery, tolerance or efficacy of thoracic radiotherapy.40 Older patients who receive radiotherapy alone for their lung cancer have survival outcomes comparable to younger patients.41,42 Patient preferences may also influence radiotherapy utilization. To some extent, these preferences were acAPJOH 2009; 1: (1). March 2009

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Tumor Factors Tumor size is an important determinant of the ability to deliver radiotherapy safely. Although there is no defined upper limit of tumor size for radiotherapy administration, in a given patient, the risks of delivering radiotherapy could potentially outweigh the benefits. This is more likely to influence the intent of radiotherapy rather than overall utilization, as palliative radiotherapy is safe for patients with larger tumors. Although T stage partially accounts for tumor size, the correlation between tumor size and stage is limited.43 There is poor documentation of tumor measurement in patients undergoing nonsurgical therapies, making it impossible to incorporate this into a model of utilization.

Treatment Factors Health service factors can have a major impact on the actual rates of radiotherapy utilization. In Ireland, areas with local radiotherapy facilities have higher radiotherapy utilization rates.33 Service factors have also been implicated in the varying radiotherapy delivery throughout health boards in Scotland, although radiotherapy utilization was not directly related to resource availability.38 In NSW, Australia, rural residents who were required to travel further to access oncology services were less likely to receive treatment for their lung cancer.9 Other factors influence overall treatment utilization rates in lung cancer. These factors include treatment in the private sector and discussion at a multidisciplinary meeting in New Zealand, being diagnosed by a lung cancer specialist in Scotland, and being treated by a lung cancer specialist who sees a minimum of one lung cancer patient per month in NSW.9,10,38 None of these studies showed any influence of socioeconomic status on the utilization of radiotherapy, or any other treatment, for lung cancer.9,10,33,38 The underutilization of radiotherapy in SCLC is of concern. Most SCLC patients are treated with chemotherapy, implying referral to a medical oncologist. In NSW, chemotherapy was provided to 70% of all SCLC patients, 63% of those with limited stage disease and 64% of those with extensive stage disease. The comparable radiotherapy utilization in these groups was 36% overall, 46% in limited stage and 36% in extensive stage.9 Similarly, the Irish and Scottish studies showed a chemotherapy utilization of 58% and 68% in SCLC compared to radiotherapy utilization of 25% and 37%, respectively. Similar trends are evident in the National Cancer Database from the USA.7,31 42

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Quantitative Evaluations for the Optimal Utilization of Radiotherapy in Lung Cancer

other cancer-specific treatments) at the population level will increase quality of life and survival in lung cancer patients, more than any technological or pharmaceutical advances.

Medical and radiation oncologists usually work closely together, yet this underutilization of radiotherapy in patients with a chemosensitive tumor suggests either that medical oncologists have a bias toward their own treatment or that they are not aware of the benefits of radiotherapy in this setting. The attitude of clinicians can have a major influence on treatment recommendations and hence treatment utilization. Clinician surveys in NSCLC have shown that treatment recommendations vary amongst lung cancer specialists, with preferences significantly influenced by specialist training and personal beliefs.44,45 Professionals in different disciplines show preferences for their own treatment modalities.46 Respiratory physicians and cardiothoracic surgeons are the main sources of referrals to radiation and medical oncologists. For these specialists, length of time since speciality training and lower volume of lung cancer patients seen were associated with beliefs not supported by the literature.47

Disclosures: The author has no financial interest to disclose related to the contents of this article.

REFERENCES 1. 2. 3. 4. 5. 6.

IMPROVING THE UTILIZATION OF RADIOTHERAPY IN LUNG CANCER

7.

Many factors need addressing in order to improve the utilization of radiotherapy in lung cancer. Patient and tumor factors are not changeable. However, service delivery factors and clinician attitudes can be changed, and these variables need to be targeted. Resources are a difficult issue and are related to governmental funding. Models of optimal utilization can be used with epidemiological data to calculate resource need and aid in health planning.29 Clinician beliefs and biases can be modified by discussion of patients at multidisciplinary meetings. Discussion at such forums can be influential in changing management and can result in adherence to guideline-based treatment.48,49 Regular audits and feedback are important.

8. 9. 10. 11.

12.

13.

CONCLUSIONS Current models of ideal radiotherapy utilization in lung cancer estimate this use to be 61% in North America and 76% in Australia. Actual radiotherapy utilization from different centers throughout the world is less than ideal, with the possible exception of NSCLC in USA. This is even the case in the setting of “ideal” conditions for radiotherapy delivery. The reasons for the differences between optimal and actual radiotherapy use are multifactorial. The models are imperfect in that they cannot account for all factors that play a role in the decision making process. Nevertheless, they provide a benchmark for performance. Health service and clinician factors are influential in determining the actual rate of radiotherapy utilization. While there is much research related to technological advances in radiotherapy and new pharmaceuticals in lung cancer, their use is limited to select subpopulations. Increasing the utilization of radiotherapy (and www.slm-oncology.com

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20. National Comprehensive Cancer Network. NCCN small-cell lung cancer practice guidelines. Oncology. 1996;10(Suppl):179–194. 21. PORT meta-analysis trialists group. Postoperative radiotherapy in non-small cell lung cancer: a systematic review and meta-analysis of individual patient data from nine randomised controlled trials. Lancet. 1998;352:257–263. 22. Lally BE, Zelterman D, Colasanto JM, Haffty BG, Detterbeck FC, Wilson LD. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol. 2006;24:2998–3006. 23. Douillard JY, Rosell R, De Lena M, Riggi M, Hurteloup P, Mahe MA. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: The Adjuvant Navelbine International Trialist Association (ANITA) randomized trial. Int J Radiat Oncol Biol Phys. 2008;72:695–701. 24. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357:664–672. 25. Langendijk JA, Aaronson NK, de Jong JMA, et al. Prospective study of quality of life before and after radical radiotherapy in non-small cell lung cancer. J Clin Oncol. 2001;19:2123–2133. 26. Langendijk JA, ten Velde GPM, Aaronson NK, de Jong JMA, Muller MJ, Wouters EFM. Quality of life after palliative radiotherapy in non-small cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys. 2000;47:149–155. 27. Tyldesley S, Boyd C, Schulze K, Walker H, MacKillop WJ. Estimating the need for radiotherapy for lung cancer: an evidencebased epidemiologic approach. Int J Radiat Oncol Biol Phys. 2001;49:973–985. 28. Delaney G, Barton M, Jacob S, Jalaludin B. A model for decision making for the use of radiotherapy in lung cancer. Lancet Oncol. 2003;4:120–128. 29. Erridge SC, Featherstone C, Chalmers R, Campbell J, Stockton D, Black R. What will be the radiotherapy machine capacity required for optimal delivery of radiotherapy in Scotland in 2015? Eur J Cancer. 2007;43:1802–1809. 30. Barbera LMFM, Zhang-Salomons JM, Huang JM, Tyldesley SMFM, Mackillop WMCFF. Defining the need for radiotherapy for lung cancer in the general population: a criterionbased, benchmarking approach. Med Care 2003;41: 1074–1085. 31. Fry WA, Menck HR, Winchester D. The National Cancer Data Base Report on Lung Cancer. Cancer. 1996;77:1947–1955. 32. Richardson GE, Thursfield VJ, Giles GG. Reported management of lung cancer in Victoria in 1993: comparison with best practice. Med J Aust. 2000;172:321–324. 33. Mahmud SM, Reilly M, Comber H. Patterns of initial management of lung cancer in the Republic of Ireland. Lung Cancer. 2003;41:57–64. 34. Jaen OJ, Alonso RE, Exposito HJ, de las Penas Cabrera MD, Cabrera RP. Evidence-based estimation and radiotherapy utilisation rate in Andalusia. Clin Transl Oncol. 2007;9:789–796. 35. Janssen-Heijnen MLG, Smulders S, Lemmens VEPP, Smeenk FWJM, van Geffen HJAA, Coebergh JW. Effect of comorbidity

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on the treatment and prognosis of elderly patients with nonsmall cell lung cancer. Lung Cancer. 2004;59:602–607. Janssen-Heijnen MLG, Schipper RM, Razenberg PPA, Crommelin MA, Coebergh JW. Prevalence of co-morbidity in lung cancer patients and its relationship with treatment: A population-based study. Lung Cancer. 1998;21:105–113. Hayman JA, Abrahamse PH, Lakhani I, Earle CC, Katz SJ. Use of palliative radiotherapy among patients with metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2007;69:1001–1007. Erridge SC, Thomson CS, Davidson J, Jones RD, Price A, Scottish Cancer Trials Lung Group and The Scottish Cancer Therapy Network. Factors influencing the use of thoracic radiotherapy in lung cancer—an analysis of the 1995 Scottish Lung Cancer Audit. Clin Oncol (R Coll Radiol). 2002;14:219–227. Tyldesley S, Zhang-Salomons J, Groome PA, et al. Association between age and the utilisation of radiotherapy in Ontario. Int J Radiat Oncol Biol Phys. 2000;47:469–480. Quon H, Shepherd FA, Payne DG, et al. The influence of age on the delivery, tolerance and efficacy of thoracic irradiation in the combined modality treatment of limited stage small cell lung cancer. Int J Radiat Oncol Biol Phys. 1999;43:39–45. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol. 2007;25(35):5570-5577. Gauden SJ, Tripcony L. The curative treatment by radiation therapy alone of Stage I non-small cell lung cancer in a geriatric population. Lung Cancer. 2001;32:71–79. Ball DL, Fisher R, Burmeister B, et al. Stage is not a reliable indicator of tumor volume in non-small cell lung cancer: a preliminary analysis of the Trans-Tasman Radiation Oncology Group 99-05 database. J Thorac Oncol. 2006;1:667–672. Perez EA. Perceptions of prognosis, treatment, and treatment impact on prognosis in non-small cell lung cancer. Chest. 1998;114:593–604. Raby B, Pater J, MacKillop WJ. Does knowledge guide practice? Another look at the management of non-small cell lung cancer. J Clin Oncol. 1995;13:1904–1911. Palmer MJ, O’Sullivan B, Steele R, MacKillop WJ. Controversies in the management of non-small cell lung cancer: the results of an expert surrogate study. Radiother Oncol. 1990;19:17–28. Schroen AT, Detterbeck FC, Crawford R, Rivera MP, Socinski MA. Beliefs among pulmonologists and thoracic surgeons in the therapeutic approach to non-small cell lung cancer. Chest. 2000;118:129–137. Wright FC, De VC, Langer B, Hunter A, Expert Panel on Multidisciplinary Cancer Conference Standards. Multidisciplinary cancer conferences: a systematic review and development of practice standards. Eur J Cancer. 2007;43:1002–1010. Conron M, Phuah S, Steinfort D, Dabscheck E, Wright G, Hart D. Analysis of multidisciplinary lung cancer practice. Intern Med J. 2007;37:18–25.

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REVIEW ARTICLE

Gefitinib in Patients of Asian Ethnicity or Never Smokers Luca Toschi1 and Federico Cappuzzo2 Affiliations: 1Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; 2Istituto Clinico Humanitas IRCCS, Rozzano, Italy Submission date: 10th December 2008, Acceptance date: 5th January 2009

ABSTRACT

fering with the tyrosine kinase domain.2 Among the latter group, gefitinib (Iressa, AstraZeneca, UK) and erlotinib (Tarceva, Genentech, USA) have proven to be effective in patients with non-small cell lung cancer (NSCLC) and have received regulatory approval for the treatment of pretreated subjects with advanced disease. Initial studies with gefitinib were conducted in unselected NSCLC populations3â&#x20AC;&#x201C;7 mostly due to evidence that EGFR is commonly overexpressed in the disease.8,9 However, it soon became evident that only relatively small subsets of patients could derive a substantial benefit from this treatment, including subjects with adenocarcinoma, female gender, Asian ethnicity and those who had never smoked.3,10 This review will focus on gefitinib activity in the last two of these patient populations.

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been proven to be active in selected patients with advanced non-small cell lung cancer (NSCLC), including women, patients with adenocarcinomas, Asians and never smokers. The biological reasons underlying this spectrum of activity have been identified in the peculiar EGFR alterations observed in responders. Prospective studies have confirmed that Asian patients and never smokers can be effectively treated with gefitinib, although clinical selection of candidate subjects for gefitinib treatment might be more appropriate. Preliminary results from trials specifically aimed at comparing gefitinib with chemotherapy seem to suggest that patients that are likely to derive a benefit from gefitinib are also more sensitive to chemotherapy, an intriguing and novel observation that requires further validation. Gefitinib-induced interstitial lung disease (ILD), a potentially fatal complication, has been observed in significant fractions of Asian patients with NSCLC, suggesting that tools for the identification of patients at risk for this complication are urgently needed.

CLINICAL PREDICTORS OF GEFITINIB ACTIVITY: RETROSPECTIVE DATA Asian Ethnicity

Keywords: NSCLC, gefitinib, Asian, never-smokers, EGFR

The first evidence that gefitinib was most effective in some NSCLCs emerged from retrospective analyses of randomized phase II trials of single-agent gefitinib in chemorefractory patients, where response rates ranged from 9% to 18%.3,4 Importantly, in the IDEAL1 study, Japanese patients had a significantly higher response rate when compared with non-Japanese subjects (27.5% versus 10.4%; P=.0023), suggesting that ethnicity might be a relevant clinical predictor of response to EGFR tyrosine kinase inhibitors (TKIs).3 Similar activity findings also emerged from several retrospective reports with response rates consistently above 20% in subjects from East Asia.11â&#x20AC;&#x201C;14 A better understanding of the role of Asian ethnicity in predicting gefitinib activity came from the ISEL trial, a large randomized phase III study of gefitinib versus placebo in 1692 patients with pretreated advanced NSCLC10 (Table 1). Although the study failed to demonstrate a significant survival improvement for patients in the gefitinib arm, in Asian patients survival was significantly longer in the gefitinib group than in the placebo arm (9.5 versus 5.5 months, HR=.66, P=.01), with similar outcome for non-Asian subjects

Correspondence: Federico Cappuzzo, Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20089-Rozzano, Italy. Tel: +39 02 82244097; fax: +39 02 82244590; e-mail: federico.cappuzzo@humanitas.it

INTRODUCTION The epidermal growth factor receptor (EGFR) is a transmembrane receptor with intrinsic tyrosine kinase activity that belongs to the ErbB family, which includes three other members, ErbB2, ErbB3 and ErbB4.1 Upon ligand binding, EGFR homo- or heterodimerizes with other ErbB family members followed by subsequent activation of an intracellular tyrosine kinase domain. This event triggers a cascade of phosphorylation events with effects on cell proliferation and survival. EGFR has often been found to be aberrantly activated in human malignancies of epithelial origin, and for this reason, has represented an attractive target for pharmacological inhibition.1 Different strategies have been investigated to effectively disrupt EGFR activity, including monoclonal antibodies against the extracellular portion of the receptor or small molecules interAPJOH 2009; 1: (1). March 2009

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Table 1. Phase III Trials of Single Agent Gefitinib in Patients with Advanced NSCLC Patient Control Primary Trial N population arm end point

HR for primary end point** P

RR for gefitinib (%)

ISEL10

1692

Unselected, pretreated

Placebo

OS

0.89

0.087

8.0

V-15-3288

490

Japanese, pretreated

Docetaxel

OS*

1.12

0.33

22.5

INTEREST89

1466

Unselected, pretreated

Docetaxel

OS*

1.02

NR

9.1

Asian, never or light smokers, adenocarcinoma, untreated

Carboplatin/ paclitaxel

PFS*

0.74

<0.0001

43.0

1217 iPASS90

OS, overall survival; PFS, progression-free survival; HR, hazard ratio; NR, not reported; RR, response rate. *Non-inferiority design; **HR<1 favors gefitinib.

BIOLOGICAL PREDICTORS OF GEFITINIB ACTIVITY: RETROSPECTIVE DATA

regardless of the treatment received. Importantly, results from the BR21 trial of erlotinib versus placebo in pretreated patients were consistent with those of the ISEL study, with a larger survival benefit for Asian individuals.7

EGFR Mutations and EGFR Copy Number A milestone driving future strategies for EGFR TKI development has been the identification of mutations in the EGFR tyrosine kinase domain of patients responding to gefitinib or erlotinib.20–22 This finding has been corroborated by preclinical data indicating that EGFR mutant lung cancers require EGFR for tumor growth and are exquisitely sensitive to EGFR inhibition inflicted by EGFR TKIs.20 The two most common EGFR somatic mutations are exon 19 deletions and the L858R substitution in exon 21, which are responsible for about 85% of all EGFR somatic mutations. Importantly, the presence of EGFR mutations has been associated with clinical features predictive of response to EGFR TKIs, including Asian ethnicity and never smoking history.21,22 Notably, the exposure to tobacco smoke has recently been shown to be a sensitive predictor of the likelihood of harboring EGFR mutations,23 serving as a useful tool in clinical decision-making in the absence of information about EGFR mutational status. The reported EGFR mutation rate in Asians and those who have never smoked ranges from 30% to 50%, being significantly higher than that observed in patients from Western countries and in smokers (<10%).16,24–32 While patients with mutant EGFRs are likely to exhibit dramatic responses to gefitinib, survival data from large randomized trials of EGFR TKIs have failed to show a survival benefit for patients with mutant EGFRs receiving a TKI, suggesting a possible better natural history for these subjects.5,6,17,18 In order to investigate whether the presence of EGFR mutations represents a predictive marker for survival benefit from gefitinib or a prognostic marker in patients with advanced adenocarcinoma, Japanese investigators analyzed the outcome of patients who began first-line chemotherapy before and after gefitinib approval in Japan.33 In this study, survival was significantly longer among

Smoking Status Another clinical feature that emerged as an independent predictor for gefitinib-treated NSCLC patients was smoking status. Specifically, those who have never smoked, in which the most common histological type is adenocarcinoma, have been found to have the greatest chance of deriving a benefit from gefitinib treatment, with response rates of about 30% to 40% and increased progression-free and/or overall survival when compared to former/current smokers in most retrospective reports.15–17 In the ISEL trial, subjects with Asian ethnicity who had never smoked exhibited significantly longer survival with gefitinib treatment than those with the same ethnicity and smoking characteristics in the placebo group (8.9 versus 6.1 months, HR=.67, P =.012), while the outcome did not differ between groups for smokers.10 Similar results were observed in the BR21 trial, where those who had never smoked derived a consistent survival benefit with erlotinib.7 The relevance of smoking history in predicting a benefit from TKIs also emerged from unplanned subgroup analyses performed in large randomized trials of chemotherapy with or without erlotinib in advanced NSCLC patients.18,19 In these studies, those who had never smoked had improved survival with erlotinib compared to former/ current smokers, with no difference observed according to smoking status for patients who had received chemotherapy alone. Overall, these initial findings supported the idea that Asian patients and those who had never smoked presented peculiar biological features that could play a major role in driving gefitinib activity, prompting investigators to continue exploring EGFR biology. APJOH 2009; 1: (1). March 2009

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Gefitinib in Patients of Asian Ethnicity or Never Smokers

patients with EGFR mutations treated after gefitinib approval when compared with survival of EGFRmutant patients treated before gefitinib approval, whereas no difference was observed in patients without EGFR mutations. Importantly, among patients treated before gefitinib approval, those with EGFR mutations lived significantly longer than those without EGFR mutations. These data clearly indicate that EGFR mutations significantly predict both a survival benefit from gefitinib therapy and a favorable prognosis in patients with advanced lung adenocarcinoma. It should be noted that not all EGFR mutations have been associated with sensitivity to EGFR TKIs. In fact, it has been observed that about 50% of the EGFR mutant patients who develop acquired resistance to either gefitinib or erlotinib present a secondary EGFR mutation in exon 20 (T790M).34 Preclinical experiments have shown that this mutation induces resistance to reversible EGFR inhibitors increasing adenosine triphosphate (ATP) affinity in the EGFR tyrosine kinase domain rather than preventing drug binding, and that resistance can be overcome using irreversible EGFR inhibitors.35,36 The evidence that a significant fraction of patients with EGFR mutations (12% to 84%) do not respond to TKIs16,18,32 has prompted the assessment of other biomarkers as potential tools to predict EGFR TKI activity. While the role of EGFR protein expression assessed by immunohistochemistry has produced conflicting results,16,32,37–40 increased EGFR gene copy number seems to be a relevant biological feature associated with gefitinib sensitivity.16,32,39,41,42 Interestingly, EGFR gene gain has been found in some studies to be associated with the presence of EGFR mutations and never-smoking status. Prospective randomized trials of EGFR TKIs versus placebo, the only studies able to discriminate between predictive and prognostic value of a specific biomarker, showed that increased EGFR gene copy number is the most relevant predictive factor for survival for patients receiving gefitinib or erlotinib, with no difference in survival among patients with no gene gain, irrespective of the treatment.32,39 A recent large retrospective study confirmed that increased EGFR gene copy number has no prognostic role in NSCLC.43

in most reports, in both Western and Asian populations, irrespective of EGFR status. In particular, an Italian study performed in 101 NSCLC patients who received gefitinib for advanced disease showed that subjects who were positive for HER2 assessed by fluorescence in situ hybridization (FISH) had a significantly higher response rate (34.8% versus 6.4%; P=.001), a longer time to progression (9.1 versus 2.7 months; P=.02), and a trend toward longer survival (20.8 months versus 8.4 months; P=.056).49 HER2 gene gain is more commonly observed in patients with increased EGFR gene copy number and with EGFR mutations,40,49,55,57 while no significant association between HER2 gene gain and smoking status or ethnicity has been reported so far, suggesting that this phenomenon is not necessarily occurring only in patients with clinical predictors of response to EGFR TKIs. Few data are currently available regarding the clinical relevance of HER3 assessment for patient selection. In vitro findings clearly indicate that mutant EGFR uses HER3 for activation of downstream pathways,58 but at the same time, a cell line with acquired resistance to gefitinib has been found to signal via HER3 for cell survival,59 suggesting that the protein might be involved in either sensitivity or resistance to EGFR TKIs. In our cohort of gefitinib-treated patients, HER3 FISHpositive subjects had a significantly longer time to progression than individuals with no HER3 gene gain.60 Another recent report including patients from China indicated a trend toward better response to gefitinib for patients with HER3 overexpression assessed by immunohistochemistry, with no difference in terms of time to progression and survival between positive and negative tumors,61 suggesting that HER3 assessment does not represent a valuable tool for patient selection. Taken together, these data indicate that NSCLCs in Asian patients or in those who have never smoked have an extremely peculiar biology, with a strong dependence on EGFR signaling for cell survival. This evidence has led to a prospective evaluation of clinical and/or biological factors that are predictive for EGFR TKI activity in selected cohorts of patients.

KRAS Mutations and Gefitinib Resistance Activating mutations of the KRAS oncogene occur in about 15% to 30% of lung adenocarcinomas and have been associated with a poor prognosis.27,62–66 They are associated with tobacco smoke exposure and are described more commonly in patients from Western countries than in individuals of Asian ethnicity.32,62 Interestingly, they have been observed to be mutually exclusive with EGFR mutations,27,32 corroborating the hypothesis of a different pathogenesis of lung adenocarcinoma between smokers and those who had never smoked. The presence of KRAS mutations has been reported to be associated with a lack of benefit from treatment with EGFR TKIs in a number of studies.67–71

Other EGFR Family Members Other members of the EGFR family have been investigated as possible predictors of EGFR TKI activity, including HER2 and HER3. HER2 is the preferred partner of EGFR for receptor heterodimerization and preclinical data have suggested that HER2 expression might influence gefitinib activity.44–47 To date, several studies have assessed HER2 gene and protein status in patients who received gefitinib for advanced disease,37,48–56 and increased HER2 gene copy number has consistently been associated with an improved outcome www.slm-oncology.com

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Moreover, a detrimental effect of EGFR TKIs in patients with KRAS mutations cannot be excluded. In fact, in a large randomized trial of chemotherapy with or without erlotinib, KRAS mutant patients receiving erlotinib had a worse outcome,72 encouraging the use of KRAS testing for candidates for treatment with EGFR TKIs. The appropriateness of this approach should be reinforced by results from two recent studies that reported an unexpectedly high incidence (14% to 15%) of KRAS mutations in lung adenocarcinoma from those who had never smoked,73,74 suggesting that they are not a rare event in this patient population. Genotyping studies of tumor samples collected from gefitinib-sensitive patients obtained at the time of disease progression did not show the presence of KRAS mutations,75 indicating that they do not play a role in acquired resistance to EGFR TKIs.

study performed in those who had never smoked from Asia, these results indicate a lower activity in terms of response rate when compared to Asian patients prospectively selected for EGFR mutations, suggesting that EGFR genotyping might represent a better tool for patient selection. In the Italian trial, patients who had never smoked or patients with EGFR FISH gene gain/p-AKT activation at immunohistochemistry received gefitinib.56 The overall response rate was 47.6% and median survival was not reached at the time of study publication. It should be noted that no difference in response was observed according to smoking history, while EGFR status effectively predicted the response to gefitinib, highlighting the relevance of an appropriate target assessment for patients who were candidates for treatment with EGFR TKIs.

PROSPECTIVE VALIDATION OF PREDICTORS FOR GEFITINIB SENSITIVITY

Phase III Studies: Gefitinib or Chemotherapy? The promising results observed in these prospective studies suggest that gefitinib might represent a valid, if not better, alternative to chemotherapy for selected patients with advanced NSCLC. This hypothesis has been and is currently being tested in a number of randomized studies comparing gefitinib with chemotherapy in clinically or biologically selected populations (Table 1). In the V-15-32 trial, 490 Japanese patients with advanced NSCLC who progressed with treatment with one or two chemotherapy regimens were randomized to gefitinib or docetaxel.88 Although patients in the gefitinib arm had a significantly higher response rate (22.5% versus 12.8%; P=.009), the study failed to demonstrate the non-inferiority of gefitinib versus docetaxel in terms of overall survival according to predefined criteria. Nevertheless, it should be noted that no significant survival difference was detected between the two arms, suggesting a possible imbalance in terms of known prognostic factors favoring the docetaxel group. A limited number of samples were available for biomarker assessment, but collected data indicated that patients with EGFR mutations and increased EGFR gene copy number might be more sensitive to both docetaxel and gefitinib when compared to EGFR-negative patients. A similar finding emerged from the INTEREST trial, a large phase III study comparing gefitinib with docetaxel in unselected patients pretreated with platinum-based chemotherapy.89 The study, which showed non-inferiority of gefitinib to docetaxel in terms of overall survival, failed in the coprimary end point of superiority for gefitinib versus docetaxel among patients with increased EGFR gene copy number assessed by FISH. Moreover, in this study, response rate for docetaxel was substantially higher in EGFR mutant cancers when compared to EGFR wild-type tumors, providing the rationale for further

Phase II Studies The discovery of EGFR mutations and their association with gefitinib activity led to several phase II trials in which prospectively selected patients with EGFR mutant NSCLC were treated with EGFR TKIs.76–78 Studies conducted in Asian populations4 confirmed a high incidence of EGFR mutations in this subset of patients, with about one-third of screened individuals carrying a mutant EGFR76–79,81,83 (Table 2). The vast majority of the studies confirmed that patient selection based on EGFR mutational status represents an effective treatment approach in Asian countries, with objective responses observed in about 75% of patients. Importantly, in the vast majority of these studies, a similar efficacy was reported for patients with exon 19 deletions versus those with the L858R mutation, in contrast with previous retrospective data that suggested a more favorable outcome for individuals with deletions.40,85,86 Nevertheless, these latter retrospective reports included mostly non-Asian patients, suggesting that the impact of EGFR mutations on the outcome of TKI-treated patients might vary according to ethnicity. Another relevant factor to consider is that a significant number of patients enrolled in prospective trials of gefitinib in patients with EGFR mutations were chemonaive, offering a strong rationale for randomized trials comparing gefitinib and chemotherapy in EGFR mutant patients in the first-line setting. To the best of our knowledge, only two phase II studies have prospectively evaluated the role of neversmoking status in predicting gefitinib activity.56,87 Lee et al performed a phase II trial with the intent of assessing gefitinib as first-line treatment in Korean never smokers with lung adenocarcinoma.87 The authors observed a 55.5% response rate, with a median survival of 19.7  months. Although this was the only APJOH 2009; 1: (1). March 2009

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investigation of the drug in tumors that are dependent upon EGFR for their growth. In agreement with biological data, both gefitinib and docetaxel appeared to be more active in those who had never smoked and Asian patients, a novel finding considering that previous data indicated that docetaxel is equally active in different clinical subgroups. Multiple studies have been designed to compare gefitinib with chemotherapy in the first-line setting in selected NSCLC populations. The iPASS trial compared gefitinib with a standard carboplatin/paclitaxel regimen in 1217 Asian patients with lung adenocarcinoma who had never smoked or had been light smokers, with progression-free survival as the primary end point.90 The study succeeded in showing a significantly improved progression-free survival for patients in the gefitinib arm (HR 0.74, P<.0001). Subgroup analyses revealed that patients with mutant EGFR (~60%) derived a substantial benefit from gefitinib, while subjects with the wild-type receptor had a better outcome with chemotherapy in terms of progression-free survival. These data indicate that even in a population of Asians, those who have never smoked, or women with adenocarcinoma, when EGFR is not mutated, the expected benefit is higher with chemotherapy than with gefitinib. In other words, biomarker assessment is more useful for patient selection than clinical factors. The second important finding emerging from the iPASS trial is the possible higher sensitivity to chemotherapy of the EGFR mutated population. Despite a statistically significant difference in favor of gefitinib for EGFR mutant cancers, progression-free survival curves show that 20% of the patients with an EGFR mutation have a similar outcome, regardless of the treatment, with curve separation becoming evident after 4 months, which represents the average duration of chemotherapy. This observation seems to encourage a sequential strategy of chemotherapy followed by gefitinib in this subgroup of patients. This approach is currently being evaluated in the SATURN trial, where erlotinib is administered as a maintenance treatment after firstâ&#x20AC;&#x201C;line chemotherapy in unselected patients. In the iPASS trial, EGFR mutant cancers responded better to chemotherapy than tumors lacking EGFR mutations, and survival did not significantly differ according to mutation status irrespective of treatment. These findings, together with the V-15-32 and INTEREST results, seem to indicate that patients that are likely to respond to EGFR TKIs based on biological features might also benefit from chemotherapy. In this regard, biomarker analyses from a phase II trial of gefitinib versus vinorelbine in chemonaive elderly patients are somewhat controversial.91 In fact, outcome data of patients with EGFR gene gain surprisingly favored vinorelbine, addressing the need to perform prospective comparison trials of EGFR TKIs versus chemotherapy in biologically selected cohorts of patients. www.slm-oncology.com

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Table 2. Phase II Trials of Gefitinib in Asian Patients with EGFR Mutations Screened patients Author, year (N)

EGFR mutant patients (N/%)

Enrolled patients (N)

RR (%)

Inoue, 200676

75

25/33

16

75

Asahina, 200677

82

20/24

16

75

Sutani, 200678

100

38/38

27

74

Sunaga, 200779

33

21/64

21

76

Yoshida, 2007

66

27/41

21

90.5

Sugio, 2007

48

20/42

19

63.2

80

83

EGFR, epidermal growth factor receptor; RR, response rate.

To this end, two studies are ongoing in the first-line setting. The RANGE trial will compare gefitinib to standard cytotoxic regimens in EGFR FISH-positive patients, while the EURTAC study will be conducted in patients with EGFR mutations and will employ erlotinib in the experimental arm. Results from these studies might significantly change the treatment paradigm of large populations of advanced NSCLC patients. Nevertheless, a relevant issue for a correct interpretation of these comparative trials will be the choice of appropriate control arms. In fact, the addition of bevacizumab, an anti-VEGF antibody, to standard platinum-based regimens has been shown to significantly improve survival of patients with non-squamous NSCLC compared to chemotherapy alone. Furthermore, a recent study suggested that cisplatin/pemetrexed might be a preferred regimen for patients with adenocarcinoma, suggesting that first-line strategies for advanced NSCLC are currently evolving.

GEFITINIB TOXICITY IN ASIANS AND THOSE WHO HAVE NEVER SMOKED Early studies with gefitinib showed a good tolerability profile for the drug, with skin rash and diarrhea being the most common treatment-related adverse events.3,4 While these toxicities have been reported with similar frequency among different study populations, severe interstitial lung disease (ILD) associated with gefitinib administration has been consistently observed more frequently in Asian subjects, representing a major concern for both patients and clinicians.92 A retrospective analysis of 1976 Japanese patients treated with gefitinib reported 70 cases of treatmentrelated ILD with 30 deaths, for an overall incidence of 3.5% and a 1.6% mortality rate for gefitinib inducedILD.93 The same study attempted to identify which patients were more likely to develop ILD, and male gender, 49

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REFERENCES

smoking history and a coincidence of idiopathic pulmonary fibrosis emerged as significant risk factors both in univariate and multivariate analyses. In particular, male smokers had an approximately 20-fold increased risk of developing gefitinib-induced ILD when compared with non-smoking women, with a 6.6% versus 0.4% incidence. Similarly, in the highly selected population of the iPASS trial, gefitinib-related ILD occurred in 1.3% of patients.90 These clinical observations have been biologically confirmed by a recent pooled analysis of prospective trials of gefitinib monotherapy for EGFR-mutant NSCLC, with an overall 2% incidence of treatmentrelated ILD.94 Although age does not appear to be a risk factor for ILD under gefitinib treatment, a recent phase II study of gefitinib in chemonaive elderly patients (≥75 years old) with advanced NSCLC conducted in Japan reported 4/49 (8.2%) drug-related ILDs,95 suggesting that Asian elderly populations might require accurate pretreatment evaluation for known risk factors. Taken together, these data indicate that patients with clinical and biological predictors of gefitinib sensitivity (women, non-smokers, presence of EGFR mutations) can safely tolerate the drug, and that individuals at risk for gefitinib-induced ILD should be carefully excluded from treatment. The molecular bases underlying the development of gefitinib-related ILD are largely unknown. A recent preclinical study has evoked surfactant protein A suppression in the lung resulting from gefitinib-induced EGFR inhibition as a possible primum movens for ILD induction.96 In fact, surfactant protein A reduction might render the lung more susceptible to pathogens commonly involved in ILD pathogenesis. Additional biological data might help to identify preventive strategies to be employed in patients at increased risk of ILD development.

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CONCLUSIONS Gefitinib is highly active in selected NSCLC populations, including Asians and those who have never smoked. This activity pattern has a clear biological background, consisting of EGFR oncogene addiction which is mediated by mutations in the EGFR tyrosine kinase domain and/or EGFR gene gain. Available data from prospective trials seem to indicate that biological selection of candidate patients for EGFR TKI treatment might represent a more valuable approach compared with customizing treatment based on clinical criteria. Recent evidence from studies comparing gefitinib with chemotherapy suggest that patients who are more likely to respond to TKIs are also more sensitive to chemotherapy, which is an interesting finding that is currently being assessed further in randomized trials of TKIs versus chemotherapy in biologically selected cohorts of patients with NSCLC.

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89. 90.

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cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900–5909. Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25:5240–5247. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 2008;14:5731–5734. Kosaka T, Yatabe Y, Endoh H, et al. Analysis of epidermal growth factor receptor gene mutation in patients with nonsmall cell lung cancer and acquired resistance to gefitinib. Clin Cancer Res. 2006;12:5764–5769. Inoue A, Suzuki T, Fukuhara T, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol. 2006;24:3340–3346. Asahina H, Yamazaki K, Kinoshita I, et al. A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations. Br J Cancer. 2006;95:998–1004. Sutani A, Nagai Y, Udagawa K, et al. Gefitinib for non-smallcell lung cancer patients with epidermal growth factor receptor gene mutations screened by peptide nucleic acid-locked nucleic acid PCR clamp. Br J Cancer. 2006;95:1483–1489. Sunaga N, Tomizawa Y, Yanagitani N, et al. Phase II prospective study of the efficacy of gefitinib for the treatment of stage III/IV non-small cell lung cancer with EGFR mutations, irrespective of previous chemotherapy. Lung Cancer. 2007;56:383–389. Yoshida K, Yatabe Y, Park JY, et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol. 2007;2:22–28. Tamura K, Okamoto I, Kashii T, et al. Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403). Br J Cancer. 2008;98:907–914. Sequist LV, Martins RG, Spigel D, et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harbouring somatic EGFR mutations. J Clin Oncol. 2008;26:2442–2449. Sugio K, Uramoto H, Onitsuka T, et al. Prospective phase  II study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations. Lung Cancer. November 5, 2008. [Epub ahead of print] Porta R, Queralt C, Cardenal F, et al. Erlotinib customization based on epidermal growth factor receptor (EGFR) mutations in stage IV non-small-cell lung cancer (NSCLC) patients. Proc Am Soc Clin Oncol. 2008;26:A8038. Jackman DM, Yeap BY, Sequist LV, et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:3908–3914. Riely GJ, Pao W, Pham D, et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006;12:839–844. Lee DH, Han JY, Yu SY, et al. The role of gefitinib treatment for Korean never-smokers with advanced or metastatic adenocarcinoma of the lung: a prospective study. J Thorac Oncol. 2006;1:965–971. Maruyama R, Nishiwaki Y, Tamura T, et al. Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer. J Clin Oncol. 2008;26:4244–4252. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809–1818. Mok T, Wu YL, Thongprasert S, et al. Phase III, randomised, open-label, first-line study of gefitinib vs carboplatin/paclitaxel in clinically selected patients with advanced non-small cell

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lung cancer (IPASS). Presented at: European Society For Medical Oncology, Stockholm, 2008. 91. Crino L, Cappuzzo F, Zatloukal P, et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, phase II study. J Clin Oncol. 2008;26:4253–4260. 92. Inoue A, Saijo Y, Maemondo M, et al. Severe acute interstitial pneumonia and gefitinib. Lancet. 2003;361:137–139. 93. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumor response, and survival in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol. 2006;24:2549–2556.

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94. Costa DB, Kobayashi S, Tenen DG, et al. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer. 2007;58:95–103. 95. Ebi N, Semba H, Tokunaga SJ, et al. A phase II trial of gefitinib monotherapy in chemotherapy-naive patients of 75 years or older with advanced non-small cell lung cancer. J Thorac Oncol. 2008;3:1166–1171. 96. Inoue A, Xin H, Suzuki T, et al. Suppression of surfactant protein A by an epidermal growth factor receptor tyrosine kinase inhibitor exacerbates lung inflammation. Cancer Sci. 2008;99:1679–1684.

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REVIEW ARTICLE

New Advances in Multimodality Treatment and Biological Research on Diffuse Malignant Peritoneal Mesothelioma Marcello Deraco1, Dario Baratti1, Nadia Zaffaroni2, Raffaella Villa2, Shigeki Kusamura1, Aurora Costa2 and Maria Grazia Daidone2 Affiliations: 1Department of Surgery, National Cancer Institute of Milan, Milan, Italy and 2Department of Experimental Oncology, National Cancer Institute of Milan, Milan, Italy Submission date: 5th December 2008, Acceptance date: 22nd December 2008

Abstract

20 years.2 In the United States, about 2,500 new cases of mesothelioma are registered each year. Diffuse malignant peritoneal mesothelioma (DMPM) accounts for 10% to 30% of cases.3 DMPM has been traditionally regarded as an invariably lethal disease. An extensive literature review showed that in retrospective historical caseseries treated with palliative surgery and systemic/ intraperitoneal chemotherapy, median survival was about 1  year, ranging from 9 to 15  months.4–11 Only recently, an aggressive loco-regional treatment strategy has reportedly resulted in a relevant improvement in survival. This innovative approach involves cytoreductive surgery (CRS) and peri-operative intraperitoneal chemotherapy (PIC) in the form of hyperthermic intraperitoneal chemotherapy (HIPEC) and/ or early postoperative intraperitoneal chemotherapy (EPIC). In several independent prospective trials, median survival has reached 5  years and seems to improve with subsequent reports.12–18

Diffuse malignant peritoneal mesothelioma (DMPM) has traditionally been regarded as a rapidly lethal tumor, and its biology remains largely unknown. In recent years, understanding of the genetic and molecular mechanisms of DMPM has considerably increased, as have the treatment options. Several independent trials have reported improved survival with intensive locoregional treatment strategies including cytoreductive surgery (CRS) with peri-operative intraperitoneal chemotherapy in the form of hyperthermic intraperitoneal chemotherapy (HIPEC) and/or early postoperative intraperitoneal chemotherapy (EPIC). However, most surgical data come from mono-institutional phase I or II studies with varying inclusion criteria, cytoreductive surgical procedures, drugs, temperatures and methods of delivering heated chemotherapy. This manuscript critically analyses the clinical results of highly specialized international centers in the management of DMPM. General treatment guidelines based on the available literature and future investigational perspectives are discussed. Recent basic science investigations on cellular and molecular mechanisms responsible for proliferation and relative resistance to therapy of DMPM cells are reviewed. Novel potential prognostic factors for patient selection and possible targets for molecular therapy have been suggested by ongoing work assessing the roles of telomerase, epidermal growth factor receptors (EGFR), survivin, and other proteins involved in the regulation of apoptosis. The potential implications for clinical management are presented.

Despite these encouraging results, 50% to 70% of patients with DMPM do not benefit from treatment and die of the disease.12–18 Furthermore, the disease biology is still largely unknown, and the cellular and molecular mechanisms responsible for the proliferation and relative resistance to therapy of DMPM cells have not yet been elucidated. The purpose of the present paper is to review the current evidence in DMPM clinical management and to present an overview of recent basic science investigations on novel prognostic factors and potential molecular therapeutic targets.

Keywords: peritoneal mesothelioma, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), telomeres, survivin, apoptosis, caspase Correspondence: Marcello Deraco, MD, Istituto Nazionale Tumori Milano, Via Venezian 1, 20133 Milano, Italy. Tel: +39.02.23902362; fax: +39.02.23902404; e-mail: marcello.deraco@istitutotumori.mi.it

PREOPERATIVE ASSESSMENT AND SELECTION FOR COMBINED TREATMENT The goal of the diagnostic pathway is to start an adequate and timely treatment, thus optimizing the clinical results. Early diagnosis of DMPM is traditionally challenging.19 Due to its rare and nonspecific presentation, the disease is commonly diagnosed at an advanced stage or confused with ovarian cancer or other peritoneal carcinoma types. Since DMPM has a great propensity to implant in needle tracts, laparoscopic port sites or surgical incisions, prevention of disease

INTRODUCTION Malignant mesothelioma is an uncommon tumor arising from the serosal layer of the pleura, peritoneum, pericardium or tunica vaginalis testis.1 The incidence of the disease has been rising worldwide since 1970 due to widespread exposure to asbestos in the last few decades, and it is not expected to peak within the next APJOH 2009; 1: (1). March 2009

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tion and nodular thickening) are related to failure in adequately removing the entire macroscopic tumor. In a composite analysis, no patient with both of these radiological features showed adequate cytoreduction. Patients lacking these two preoperative CT findings had a 94% probability of adequate cytoreduction.26

dissemination resulting from inappropriate invasive procedures is of great importance.14 Pathological confirmation is always required for definitive diagnosis.19 Despite the quality of modern immunocytochemical and ultrastructural methods, cytological analyses of ascitic fluid are often inconclusive.14 Pathological differentiation from benign mesothelial proliferation or from other peritoneal malignancies can be difficult and requires appropriate immunohistochemical studies. DMPM is characterized by positive staining for calretinin, epithelial membrane antigen (EMA), Wilms tumor-1 antigen (WT1), cytokeratin 5/6, human mesothelial cell-1 (HBME-1) and mesothelin, and negative staining for carcinoembryonic antigen (CEA), B72.3, MOC-31, TTF-1 and Ber-EP4.1,2 In most cases, positive staining for calretinin and EMA with negative CEA is highly suggestive of DMPM.20 The determination of the histological subvariant can also predict the prognosis for pleural and peritoneal mesothelioma.1,2 Localized forms (adenomatoid tumors and localized fibrous mesothelioma) usually show benign clinical behavior. Patients affected by borderline mesothelioma (well-differentiated papillary and multicystic) are generally good candidates for CRS and HIPEC, since high rates of loco-regional recurrence after surgical debulking and a transition to a more malignant phenotype have been described.21,22 According to the WHO classification, DMPM can be broadly divided into epithelial, biphasic (mixed) and sarcomatoid subtypes.23,24 Biphasic and sarcomatoid histology is associated with poor prognosis.2 Since epithelial variants with intermediate prognosis represent the great majority of DMPM, the identification of additional selection factors to reliably predict prognosis and design individualized multimodality treatment plans is warranted. The combination of CRS and HIPEC is costly, requires increased operative time, and results in major morbidity.25 Therefore, the selection process is important for excluding patients who will not benefit from a potentially life-threatening procedure. Candidates have to be medically fit in order to safely undergo combined treatment. The performance status is prognostically relevant, since an Eastern Cooperative Oncology Group (ECOG) score of  0 has been demonstrated to be independently related to better progression-free survival in patients with DMPM.16 Hepatic or extra-abdominal metastases as well as peritoneal disease not amenable to macroscopically complete cytoreduction are exclusion criteria. Unnecessary laparotomy can be avoided by accurate radiological evaluation. Computed tomography (CT) is the exam of choice, as it can reliably assess the size and distribution of tumor deposits within the abdominal cavity. CT scans can also select patients unlikely to attain optimal surgical cytoreduction. Tumor mass >5  cm in the epigastric region and loss of normal architecture of the small bowel and its mesentery (segmental obstrucAPJOH 2009; 1: (1). March 2009

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In patients with suspected DMPM or peritoneal dissemination of unknown origin, laparoscopy can be a minimally invasive tool for performance of peritoneal biopsies. As it allows direct inspection of peritoneal surfaces, laparoscopy may also facilitate disease staging and the selection of surgical candidates.27 If DMPM is incidentally discovered during abdominal surgery carried out for other causes, the surgeon should only perform multiple tumor biopsies in order to preserve the integrity of the peritoneal barrier and facilitate a future multimodal approach.

OPERATIVE TREATMENT, OUTCOME RESULTS AND PROGNOSTIC FACTORS Accurate exploration of the abdominal cavity and lyses of adherences are needed to assess the extent of peritoneal disease. Surgical cytoreduction is aimed at removing the entire macroscopic tumor by means of formal diaphragmatic, parietal and pelvic peritonectomies with complete greater and lesser omentectomy. Small-volume tumor deposits on the bowel surface and mesentery can be electro-fulgurated. Conversely, the opportunity to perform multivisceral resections in cases of massive involvement should be carefully evaluated in light of the functional consequences and the individual prognosis. The HIPEC technique (open versus closed), type and dose of antiblastic drugs, duration of treatment and degree of hyperthermia vary from one series to another, as summarized in Table 1. Cisplatin has a favorable pharmacological profile for intraperitoneal administration and is likely the most active drug against both pleural and peritoneal mesothelioma.28 Theoretically, mitomycin-C is advantageous for intraperitoneal administration, since pharmacokinetic studies have demonstrated a better area-under-thecurve ratio of peritoneal fluid to plasma.28 Doxorubicin has been shown to be actively transported into mesothelioma cancer cells.29 The use of EPIC represents a major technical variation but its contribution as a therapeutic tool when combined with CRS and HIPEC is presently unknown. A comprehensive treatment plan including induction of intraperitoneal chemotherapy, second-look surgery, HIPEC and total abdomen radiation has been tested in a phase I/II trial.18 A small number of studies have reported prognostic factors for patients with DMPM treated by cytoreductive surgery and PIC, as summarized in Table 2. There is substantial agreement among different groups that incomplete surgical cytoreduction is one of the main 56

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Table 1. Technical Features of Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy Center

Pts (n)

Residual disease status

HIPEC technique

HIPEC agents

HIPEC duration

Temperature (C°)

Wake Forest Un.

12

60% <2.5 cm

Closed

Mitomycin-C

120 min

42.5

NCI Bethesda, MD 49 88% <1 cm Open

Cisplatin 5-FU + paclitaxel (EPIC)

90 min

41

Milan, Italy 49 82% <2.5 mm Closed

Cisplatin + doxorubicin

90 min

42.5

Lyon, France 15 66% <2.5 mm Closed

Cisplatin + mitomycin-C

90 min

42

Washington, DC 62 69%<2.5 cm Open

Cisplatin + doxorubicin Paclitaxel (EPIC)

90 min

42

Columbia Un. 27 NS Open

1st stage: debulking + 60 min IP cisplatin + doxorubicin + IP gamma-interferon (4 courses) 2nd stage: 2nd look surgery + HIPEC (cisplatin + mitomycin-C) + whole abdominal radiation

40

HIPEC, hyperthermic intraperitoneal chemotherapy; EPIC, early postoperative intraperitoneal chemotherapy; 5-FU, 5-fluoruracil; IP, intraperitoneal; NS, not significant.

determinants of reduced overall survival, presumably due to the limited penetration of intraperitoneal chemotherapy into the residual tumor. Incomplete cytoreduction has been correlated to worse prognosis by the Washington Cancer Institute, but only with univariate analysis; in that study, the nuclear size of the DMPM cells was the only independent prognostic factor.17 Tumor invasion of deep tissues, no history of prior surgical debulking, nonincidental diagnosis and high mitotic count can be considered markers of aggressive biological behavior. The correlation of these markers to progression-free survival was only analyzed in two studies, which used multivariate analysis to identify no prior debulking,13 deep tissue invasion,13 ECOG performance status >017 and mitotic count >5/50 HPF17 as independent predictors of adverse prognosis.

chemotherapy. Furthermore, patients not suitable for immediate cytoreduction and HIPEC may theoretically benefit from the induction of systemic chemotherapy to reduce disease extent, after which they could undergo a second comprehensive surgical evaluation. Different hypotheses of integrated treatment for each clinical setting were debated during the workshop. Adequate surgical cytoreduction and HIPEC was favored by 66.7% of experts for mesothelioma with low potential for malignancy (multicystic and papillary well-differentiated). For epithelial DMPM, 33.3% of participants voted for cytoreduction with HIPEC and adjuvant/neoadjuvant systemic chemotherapy, 41.7% for cytoreduction with HIPEC and EPIC and only 25% for cytoreduction with HIPEC. CRS with HIPEC and adjuvant/neoadjuvant systemic chemotherapy was the treatment of choice for biphasic and sarcomatoid DMPM, according to 83.3% of voters.

During the 5th International Workshop on Peritoneal Surface Malignancies (Milan, Italy, December 4–6, 2006), the hypothesis that systemic chemotherapy could be integrated with combined loco-regional treatment was discussed.30 Cisplatin has shown good activity alone and particularly in combination with gemcitabine.31 A phase III clinical trial showed that the antifolate drug pemetrexed in combination with cisplatin showed an increased response rate and overall survival when compared to cisplatin alone.32 There is little information on the effectiveness of this combination for DMPM. The preliminary results of a nonrandomized trial started in June 2002 suggest an overall objective response rate of 26% among 73 patients with DMPM.33 On these bases, patients at high risk for postoperative failure might be potential candidates for adjuvant systemic www.slm-oncology.com

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BIOLOGICAL PROGNOSTIC FACTORS One of the hallmarks of cancer cells is their limitless replicative potential.34 In many human tumors, the attainment of immortality is due to the reactivation of telomerase, an RNA-dependent DNA polymerase that stabilizes telomeres and allows tumor cells to avoid senescence.35 Some tumors, however, do not have telomerase activity (TA) and maintain their telomeres by one or more mechanisms referred to as alternative lengthening of telomeres (ALT).36 Telomere maintenance mechanisms (TMM) may therefore contribute to tumorigenesis and neoplastic progression, but no information is available thus far concerning TMM in DMPM.37 57

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95% confidence interval [CI]=1.23 to 8.86; P=0.018) and cancer-related survival (TA+ versus TA–: 32% versus 79%; HR=3.56; 95% CI=1.03 to 12.51; P=0.045). These results were also confirmed for the 29 patients who underwent CRS and HIPEC; patients with TA+ tumors (16 cases) had a significantly lower probability of being disease-free than patients with TA– tumors (13 cases) (HR=3.32; 95% CI=1.09 to 10.12; P=0.03), and showed a trend toward better overall survival (HR=3.69; 95% CI=0.79 to 17.13; P=0.09) (Figure 1). ALT did not significantly affect the clinical outcome both in the overall series and in the subset of patients undergoing CRS and HIPEC (Figure 2). It has been demonstrated that 60% to 80% of peritoneal and pleural mesotheliomas express epidermal growth factor receptors (EGFR), but the prognostic value of EGFR is still unclear.20,41 Determining the frequency of mutations in the DNA is an innovative method to assess the importance of a molecular pathway in a given tumor. In nonsmall-cell lung cancer, EGFR expression is common and EGFR mutations that predict the response to tyrosine kinase (TK) therapy have been identified. Now, these mutations play an important role in patient selection and prognostic assessment.42,43 The incidence of EGFR mutations and their predictive value in achieving optimal cytoreductive surgery were investigated in a series of 29 patients with DMPM treated at Creighton University (Omaha, NE, USA).44 EGFR expression was evaluated by immunohistochemical staining and detected in 28/29 cases (97%). Tumor samples from each patient were assessed for point mutations in the catalytic TK domain of EGFR. All specimens were examined for somatic mutations by polymerase chain reaction amplification of 7 EGFR amplicons (exons 18 to 24). All variants were confirmed by multiple independent amplifications. Mutations were found in 9/29 (31%) tumors. Nine different EGFR point mutations were identified. One of these mutations was the known L858R activating mutation described in non-small-cell lung cancer, and 7 were eight novel EGFR-TK catalytic domain point mutations. One patient had two separate point mutations, while one mutation was identified in tumors from two different patients. Twenty-five patients underwent cytoreductive surgery with or without HIPEC. Of these patients, 18 had wild-type tumors, while EGFR mutations were identified in 7. Comparison of clinical data including age, sex, cytoreductive score, mutations, and survival was performed for the two subgroups. Optimal cytoreduction (residual tumor nodules ≤5  mm) was achieved in 7 of 7 of patients with EGFR mutations and 9 of 18 patients with wild-type DMPM  (P=.026). The median followup was 14.5  months for the entire series. Among the 25 patients managed surgically, all with EGFR mutations were alive after 24  months, whereas 5/18 (28%) of the wild-type group had died from the disease with a mean survival of 7 months (P=.27). In an analysis of

Table 2. Survival Results and Prognostic Factors for Reduced Overall Survival after Cytoreductive Surgery and HIPEC in Patients with Peritoneal Mesothelioma

Center (ref.) year

Bethesda, MD13 2003

Milan, Italy16 2006

Washington, DC17 2006

Statistical analysis

Multivariate

Multivariate

Multivariate

No. of patients

49

49

62

Median follow-up (months)

28

(1)

20

37

Median overall survival (months)

92

NR

79

Median progression- free survival (months)

17

40

NS

Male sex

X

Age >60 years

X

No prior debulking

X

Deep tissue invasion

X

Nuclear size Completeness of cytoreduction Mitotic count >5/50 HPF

X (3)

X (2)

X (4)

X

HIPEC, hyperthermic intraperitoneal chemotherapy; (1)mean; (2) nuclear size: I (10–20 mm) versus II (21–30 mm) versus III (31–40 mm) versus IV (>40 mm); (3) residual disease >10 mm versus ≤10 mm; (4)completeness of cytoreduction (CC) score 2/3 (residual disease >2.5 mm) versus 0/1 (residual disease ≤2.5 mm); NS, not significant; NR, not reached.

The prevalence and prognostic role of the two known TMMs, TA and ALT, were investigated for the first time in a series of patients treated at the NCI of Milan (Italy). Forty-four samples from 38 patients undergoing CRS and HIPEC (n=29) or debulking surgery (n=9) were available.38 TA was determined using the telomeric-repeat amplification protocol (TRAP) assay39 and ALT by detecting ALT-associated promyelocytic leukemia (PML) nuclear bodies (APB). APB are subnuclear structures containing telomeric DNA, telomerespecific binding proteins and proteins involved in DNA recombination and replication.40 Thirty-eight samples (86.4%) showed at least one TMM. Specifically, 28 samples (63.6%) were TA+/ALT-, 8 (18.2%) were TA-/ALT+, and 2 (4.6%) were defined as ALT+/TA+ due to the concomitant expression of APB and TA. The remaining 6 lesions (13.6%) did not show any TMM. TA and ALT were inversely associated (P=0.002). After a median follow-up of 38 months, TA was correlated by multivariate analysis to both disease-free (TA+ versus TA–: 10% versus 64%; hazard ratio [HR]=3.30; APJOH 2009; 1: (1). March 2009

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Figure 1. Disease-free survival (A) and cancer-related survival (B) as a function of TA (telomerase activity) in 29 DMPM patients undergoing cytoreductive surgery and HIPEC.

Figure 2. Disease-free survival (A) and cancer-related survival (B) as a function of ALT (alternative lengthening of telomeres) in 29 DMPM patients undergoing cytoreductive surgery and HIPEC.

covariance model, only optimal surgical cytoreduction (P=.04) predicted survival.

HIPEC at the NCI of Milan.46 The expression of the proapoptotic protein Smac/DIABLO and of antigens associated with cell proliferation (Ki-67, assessed by MIB-1) and apoptosis (identified using the M30 antibody that specifically recognizes caspase-cleaved cytokeratin 18) were also studied. The results of the immunostaining studies are shown in Table  3. According to cut-off staining rates of 5% and 25% for nuclear and cytoplasmic immunoreactivity, respectively, survivin was expressed only in the cytoplasm in 19 of 32  DMPM samples (59%), only in the nucleus in 2  samples (6%), and in both the cytoplasm and nucleus in 5 samples (16%). In the remaining 6  cases, no survivin immunoreactivity was seen. IAP-2 and IAP-1 were expressed in 100% of samples. X-IAP was expressed in 22/32 samples (68.7%) and Smac/DIABLO in 11/32 samples (34.4%). Staining for the CK18-caspase cleavage product was positive in 0 to 5.8% of cells (median 0.45%) and Ki-67 was positive in 0 to 50% of cells (median 10%). Caspases are the mediators of apoptosis in both intrinsic and extrinsic pathways.47 Activated caspases are subject to inhibition by IAPs through direct binding.48 This inhibitory effect can be abrogated by Smac/DIABLO,

These findings indicate that EGFR-TK might be a common site for mutations in DMPM. EGFR mutations can predict optimal surgical cytoreduction and might identify a subset of patients responsive to TK-inhibitor therapy.

MOLECULAR THERAPEUTIC TARGETS Apoptotic cell death is the main mode by which chemical and physical anticancer agents kill tumor cells. Dysregulation of apoptotic pathways may play a role in the relative chemo-resistance of DMPM, as this mechanism has already been demonstrated for pleural mesothelioma.45 Better understanding of the biological mechanism underlining the apoptosis-resistant phenotype could result in novel therapeutic strategies. For this purpose, the expression of survivin and other IAP family members including IAP-1 (also known as MIHC/ cIAP2), IAP-2 (also known as MIHB/cIAP1), and X-IAP (also known as MIHA/hILP) were analyzed by immunohistochemistry in surgical specimens obtained from 32 patients with DMPM uniformly treated by CRS and www.slm-oncology.com

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Table 3. Staining Characteristics for IAP Family Members, Smac/DIABLO, Apoptotic and Proliferation Indices in Peritoneal Mesothelioma Positive cases, n (%)

Median expression, % (range, %)

Survivin, full length*

24 (75.0)

60 (0–100)

Survivin, specific nuclear form

7 (21.9)

1.5 (0–20)

IAP-2*

32 (100)

90 (30–100)

IAP-1

32 (100)

95 (40–100)

X-IAP

22 (68.7)

50 (0–100)

Smac/DIABLO

11 (34.4)

5 (0–90)

Apoptotic index (CK18-caspase cleavage product)

0.45 (0–5.8)

Proliferation index (Ki-67)

10 (0–50)

Figure 3. Representative Western blotting experiments illustrating survivin expression in STO cells exposed to oligofectamine alone or transfected with control siRNA and antisurvivin siRNA. b-actin was used as control for protein loading (A). Densitometric quantification of survivin band intensities in oligofectamine-exposed cells (unfilled column) and cells transfected with the control siRNA (gray column) or the antisurvivin siRNA (black column). Data represent mean values ± SD of 3 independent experiments (*P<0.02; **P<0.01; Student’s t-test); inhibition was highest (around 80%; P<0.01) at 48 and 72 h after transfection and still appreciable, although to a lesser extent (around 50%; P<0.02), at 96 h (B).

*cytoplasmic/nuclear subcellular distribution.

a proapoptotic factor released from mitochondria that reactivates initiator and effector caspases by binding to IAPs and relieving IAP-mediated inhibition.49 All 4 IAP family members were simultaneously overexpressed in 16/32 cases, while a lack of expression was consistently found in the normal peritoneum, suggesting that these antiapoptotic proteins are heavily dysregulated in DMPM. Furthermore, an inverse association was found between Smac/DIABLO expression and IAP coexpression. In the 16  cases overexpressing survivin, IAP-1, IAP-2 and X-IAP, the median expression rate of Smac/DIABLO protein was 0% (range, 0% to 50%); it increased to 40% (range, 0% to 90%) in the 14 cases with IAP expression, and to 60% to 70% in the 2 cases with coexpression of 2 IAPs (P=0.0032). These results provide important insights into DMPM biology. Although the cell proliferative index (MIB-1) was mostly low, antigens associated with apoptosis such as the CK-18 caspase cleavage product were expressed at low levels. Furthermore, concurrent overexpression of apoptosis inhibitors and low expression of proapoptotic factors were seen in the majority of cases. This pattern suggests that resistance to programed cell death may contribute to the chemo-insensitivity of DMPM. In recent years, considerable efforts have been made to develop strategies for modulating apoptosis in cancer.50 In this context, approaches to counteract survivin aim to inhibit tumor growth and enhance the response of tumor cells to apoptosis-inducing agents.51 An RNA interference-based strategy to down-regulate survivin expression in a human peritoneal mesothelioma cell line (STO) was recently established in our laboratory.52 Cells were transfected with survivin-targeting small interferAPJOH 2009; 1: (1). March 2009

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ing RNA (siRNA) or control siRNA. The effects of RNA interference (RNAi)-mediated survivin down-regulation were evaluated by Western blotting, flow cytometry, fluorescence microscopy, and at the molecular level. Western blotting experiments carried out in cells transfected with antisurvivin siRNA showed a significant reduction in survivin protein abundance. The specificity of the inhibitory approach was confirmed by the lack of any effect following transfection with a control siRNA (Figure 3). Silencing of the survivin gene resulted in a significant and time-dependent decline in cell proliferation (Figure 4). Flow cytometry revealed an apoptotic subG0/1 peak for cells transfected with antisurvivin siRNA but not for cells transfected with control siRNA or exposed to oligofectamine, suggesting that the cytotoxic effect was due to the induction of apoptosis by antisurvivin siRNA. To further verify that programed cell death resulted from transfection of antisurvivin siRNA, apoptotic nuclear morphology was assessed by fluorescence microscopy. The rate of apoptosis in cells transfected with antisurvivin siRNA markedly increased with time, reaching 38.5% (P<0.01) of the overall cell population at 96 h, while it was negligible (always <3%) in cells transfected with the control siRNA or exposed to oligofectamine. 60

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Figure 5. Catalytic activity of caspase-9 as determined by hydrolysis of the fluorogenic substrate LEHD-AFC in control cells exposed to oligofectamine alone (unfilled column) and transfected with the control siRNA (gray column) or the antisurvivin siRNA (black column). Data are expressed as relative fluorescence units and represent mean values ± SD of 3 independent experiments (*P<0.01; Student’s t-test).

Figure 4. Effects of RNAi-mediated survivin down-regulation on in vitro growth of STO cells. Data are expressed as percentage cell growth in cells transfected with the control siRNA (gray column) or the antisurvivin siRNA (black column) compared to control cells exposed to oligofectamine alone (unfilled column). Data represent mean values ± SD of 3 independent experiments (*P<0.05; **P<0.01; Student’s t-test).

At the molecular level, RNAi-mediated inhibition of survivin expression in STO cells coincided with significantly increased catalytic activity of caspase-9, while no appreciable difference in caspase-9 activation was found for cells transfected with the control siRNA when compared to oligofectamine-exposed cells (Figure 5). A number of in vitro and in vivo studies have indicated that survivin down-regulation is able to sensitize human tumor cells of different histologic origins to conventional chemotherapeutic drugs with distinct mechanisms of action, as well as to ionizing radiation.51–53 To test whether survivin plays a role in the in vitro sensitivity of DMPM cells to anticancer drugs, we examined the effect of survivin down‑regulation on the apoptotic response to cisplatin and doxorubicin 72 h after treatment with antisurvivin siRNA. Exposure to cisplatin resulted in a concentration-dependent increase in the percentage of apoptotic cells that was significantly (P<0.01) higher in cells exposed to antisurvivin siRNA than in those transfected with control siRNA or treated with oligofectamine, accounting for 30.5% to 85.9% of the overall cell population (Figure 6). A concentrationdependent increase in caspase-9 catalytic activity was also observed following cisplatin exposure; this enhancement was significantly (P<0.02) greater in cells transfected with antisurvivin siRNA than in those exposed to the control siRNA or oligofectamine. Results obtained after a 1 h exposure to doxorubicin showed a significantly (P<0.05) greater induction of apoptosis (ranging from 9.9% to 63.2% as a function of drug concentration) in cells transfected with the antisurvivin siRNA (Figure  6). Concentration-dependent

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Figure 6. Effects of RNAi-mediated survivin down-regulation on the apoptotic response of STO cells to cisplatin and doxorubicin. The percentage of STO cells with apoptotic morphology with respect to the overall population as assessed by fluorescence microscopy after exposure to oligofectamine alone (unfilled column) or the control siRNA (gray column) or antisurvivin siRNA (black column) in the absence or presence of different cisplatin or doxorubicin concentrations. Data represent mean values ± SD of 3 independent experiments (*P<0.05; **P<0.01; ***P<0.001; Student’s t-test).

activation of caspase-9 was also consistently observed, and the extent of this activation was significantly (P<0.02) greater in cells transfected with antisurvivin siRNA than in those exposed to the control siRNA or oligofectamine. These findings demonstrate that the level of survivin expression influences the in vitro response of DMPM cells to cisplatin and doxorubicin. Such results could

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have potential clinical implications since they could provide a rational basis for the design of combined therapies, including survivin inhibitors, to improve the responsiveness of DMPM to chemotherapy. However, considering the presence of multiple antiapoptotic factors, approaches based on the simultaneous targeting of different cytoprotective factors to obtain enhanced DMPM cell sensitivity require further investigation.

11. Eltabbakh GH, Piver MS, Hempling RE, Recio FO, Intengen ME. Clinical picture, response to therapy, and survival of women with diffuse malignant peritoneal mesothelioma. J Surg Oncol. 1999;70:6–12. 12. Loggie BW, Fleming RA, McQuellon RP, Russel GB, Geisinger KR, Levine EA. Prospective trial for the treatment of malignant peritoneal mesothelioma. Am Surg. 2001;67:999–1003. 13. Feldman AL, Libutti SK, Pingpank JF, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol. 2003;21: 4560–4567. 14. Sugarbaker PH, Welch LS, Mohamed F, Glehen O. A review of peritoneal mesothelioma at the Washington Cancer Institute. Surg Oncol Clin North Am. 2003;12:605–621. 15. Brigand C, Monneuse O, Mohamed F, Sayag-Beaujard AC, Gilly FN, Glehen O. Malignant peritoneal mesothelioma treated by cytoreductive surgery and intraperitoneal chemohyperthermia: Results of a prospective study. Ann Surg Oncol. 2006;13:405–412. 16. Deraco M, Nonaka D, Baratti D, et al. Prognostic analysis of clinicopathologic factors in 49 patients with diffuse malignant peritoneal mesothelioma treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Ann Surg Oncol. 2006;13:229–237. 17. Yan TD, Brun EA, Cerruto CA, Haveric N, Chang D, Sugarbaker PH. Prognostic indicators for patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for diffuse malignant peritoneal mesothelioma. Ann Surg Oncol. 2007;14:41–49. 18. Hesdorffer ME, Chabot JA, Keohan ML, et al. Combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for the treatment of malignant peritoneal mesothelioma. Am J Clin Oncol. 2008;31:49–54. 19. Hassan R, Alexander R, Antman K, et al. Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference. Ann Oncol. 2006;17(11):1615–1619. 20. Nonaka D, Kusamura S, Baratti D, et al. Diffuse malignant mesothelioma of the peritoneum: a clinicopathological study of 35 patients treated locoregionally at a single institution. Cancer. 2005;104:2181–2188. 21. Baratti D, Kusamura S, Nonaka D, Oliva GD, Laterza B, Deraco M. Multicystic and well-differentiated papillary peritoneal mesothelioma treated by surgical cytoreduction and hyperthermic intra-peritoneal chemotherapy (HIPEC). Ann Surg Oncol. 2007;14:2790–2797. 22. Gonzalez-Moreno S, Yan H, Alcorn KW, Sugarbaker PH. Malignant transformation of benign cystic mesothelioma of the peritoneum. J Surg Oncol. 2002;79:243–251. 23. Battifora H, McCaughey WTE. Tumors of the serosal membranes. In: Atlas of Tumor Pathology. Third series. Fascicle 15. Washington, DC: Armed Forces Institute of Pathology; 1995. 24. Weiss SW. World Health Organization, International Histological Classification of Tumours. Histological Typing of Soft Tissue Tumours. 2nd ed. Berlin: Springer-Verlag; 1994. 25. Kusamura S, Younan R, Baratti D, et al. Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of peritoneal surface malignancies: analysis of morbidity and mortality in 209 cases treated with closed abdomen technique. Cancer. 2006;106:1144–1153. 26. Yan TD, Haveric N, Carmignani CP, Chang D, Sugarbaker PH. Abdominal computed tomography scans in the selection of patients with malignant peritoneal mesothelioma for comprehensive treatment with cytoreductive surgery and perioperative intraperitoneal chemotherapy. Cancer. 2005;103:839–849. 27. Laterza B, Kusamura S, Baratti D, Oliva GD, Deraco M. Role of explorative laparoscopy to evaluate optimal candidates for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal mesothelioma. In Vivo, in press.

CONCLUSIONS Although the number of centers that have reported their experience in DMPM comprehensive treatment is relatively small, the current evidence demonstrates improved overall survival in selected patients treated with aggressive cytoreductive surgery and PIC, compared with historical controls. The clinical management of these patients, however, is still challenging and many unanswered questions remain regarding their surgical and combined management. There is still a subset of DMPM that is not suitable for aggressive local-regional treatment or has a poor prognosis after CRS and PIC. Recent biological and molecular studies have identified novel selection factors correlated to patient outcome as well as promising targets for molecular approaches. Further clinical and investigational studies are needed to integrate these recent advances into clinical practice. Disclosures: The authors have no financial interest to disclose related to the content of this article. Acknowledgements: The study was supported in part by grants from the Italian Health Ministry and the Italian Association for Cancer Research (AIRC).

REFERENCES 1.

Robinson BWS, Lake RA. Advances in malignant mesothelioma. N Engl J Med. 2005;353:1591–1603. 2. Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005;366:397–408. 3. Price B. Analysis of current trends in the United States of mesothelioma incidence. Am J Epidemiol. 1997;45:211–218. 4. Sugarbaker PH, Yan TD, Stuart OA, Yoo D. Comprehensive management of diffuse malignant peritoneal mesothelioma. Eur J Surg Oncol. 2006;32:686–691. 5. Chailleux E, Dabouis G, Pioche D, et al. Prognostic factors in diffuse malignant pleural mesothelioma. A study of 167 patients. Chest. 1988;93:159–162. 6. Antman K, Shemin R, Ryan L, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the DanaFarber Cancer Institute and Brigham and Women’s Hospital experience over two decades, 1965–1985. J Clin Oncol. 1988;6:147–153. 7. Sridhar KS, Doria R, Raub WA Jr, Thurer RJ, Saldana M. New strategies are needed in diffuse malignant mesothelioma. Cancer. 1992;70:2969–2979. 8. Markman M, Kelsen D. Efficacy of cisplatin-based intraperitoneal chemotherapy as treatment of malignant peritoneal mesothelioma. J Cancer Res Clin Oncol. 1992;118: 547–550. 9. Yates DH, Corrin B, Stidolph PN, Browne K. Malignant mesothelioma in south east England: clinicopathological experience of 272 cases. Thorax. 1997;52:507–512. 10. Neumann V, Muller KM, Fischer M. Peritoneal mesothelioma —incidence and etiology. Pathologe. 1999;20:169–176.

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28. Stewart JH 4th, Shen P, Levine EA. Intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: current status and future directions. Ann Surg Oncol. 2005;12:765–777. 29. Yan TD, Welch L, Black D, Sugarbaker PH. A systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for diffuse malignancy peritoneal mesothelioma. Ann Oncol. 2007;18:827–834. 30. Deraco M, Bartlett D, Kusamura S, Baratti D. Consensus statement on peritoneal mesothelioma. J Surg Oncol. 2008;98:268–272. 31. Garcia Carbonero R, Paz-Ares L. Systemic chemotherapy in the management of malignant peritoneal mesothelioma. Eur J Surg Oncol. 2006;32:676–681. 32. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636–2644. 33. Janne PA, Wozniak AJ, Belani CP, et al. Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program. Clin Lung Cancer. 2005;7:40–46. 34. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. 35. Shay JW, Zou Y, Hiyama E, et al. Telomerase and cancer. Hum Mol Genet. 2001;10:677–685. 36. Bryan TM, Englezou A, Dalla-Pozza L, et al. Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines. Nat Med. 1997;3:1271–1274. 37. Stewart SA, Weinberg RA. Telomerase and human tumorigenesis. Semin Cancer Biol. 2000;10:399–406. 38. Villa R, Daidone MG, Motta R, et al. Multiple mechanisms of telomere maintenance exist and differentially affect clinical outcome in diffuse malignant peritoneal mesothelioma. Clin Cancer Res. 2008;14:4134–4140. 39. Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–2015. 40. Yeager TR, Neumann AA, Englezou A, et al. Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body. Cancer Res. 1999;59:4175–4179.

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41. Trupiano JK, Geisinger KR, Willingham MC, et al. Diffuse malignant mesothelioma of the peritoneum and pleura, analysis of markers. Mod Pathol. 2004;17:476–481. 42. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123–132. 43. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139. 44. Foster JM, Gatalica Z, Lilleberg S, Haynatzki G, Loggie BW. Novel and existing mutations in the tyrosine kinase domain of the epidermal growth factor receptor are predictors of optimal resectability in malignant peritoneal mesothelioma. Ann Surg Oncol. November 8, 2008 [Epub ahead of print] 45. Xia C, Xu Z, Yuan X, et al. Induction of apoptosis in mesothelioma cells by antisurvivin oligonucleotides. Mol Cancer Ther. 2002;1:687–694. 46. Zaffaroni N, Costa A, Pennati M, et al. Survivin is highly expressed and promotes cell survival in malignant peritoneal mesothelioma. Cell Oncol. 2007;29:453–466. 47. Salvesen GS, Dixit VM. Caspase activation: the inducedproximity model. Proc Natl Acad Sci USA. 1999;96: 10964–10967. 48. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nature Rev Mol Cell Biol. 2002;3:401–410. 49. Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33-42. 50. Fischer U, Schulze-Osthoff K. New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev. 2005;57:187-215. 51. Altieri DC. Validating survivin as a cancer therapeutic target. Nat Rev Cancer. 2003;3:46–54. 52. Zaffaroni N, Costa A, Pennati M, et al. Potential of survivin as a new therapeutic target in diffuse malignant mesothelioma of the peritoneum. Abstract n° 4613. Presented at: The 97th AACR Annual Meeting; April 1–5, 2006; Washington, USA. 53. Pennati M, Binda M, Colella G, et al. Radiosensitization of human melanoma cells by ribozyme-mediated inhibition of survivin expression. J Invest Dermatol. 2003;120:648–654.

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REVIEW ARTICLE

Current Management of Malignant Pleural Mesothelioma Arman Hasani1,2, Anna K. Nowak1,2 Affiliations: 1School of Medicine and Pharmacology, University of Western Australia, Hackett Drive, Nedlands, Western Australia 6009, Australia; 2Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009, Australia Submission date: 24th December 2008, Acceptance date: 26th January 2009

Abstract

economic development and limited community understanding of its dangers.12 Thus, the global burden of MPM can be expected to continue for decades. Other rarer causes of MPM include radiation and erionite, another fibrous mineral used to build houses in central Turkey.1 Pedigree studies of affected areas in Turkey have confirmed the genetic predisposition to erionite carcinogenesis in MPM.13 SV40, a DNA virus, has also been implicated in the etiology of MPM, although its role is controversial.1 Unfortunately, there are currently limited therapeutic options for patients diagnosed with MPM. At presentation, most patients have locally advanced disease and treatment is generally considered palliative. The median survival without treatment is reported as around 6 to 9 months.3,5,14 In this review, we discuss the management of MPM with an emphasis on treatments that are currently in use. We also briefly review promising new therapies that are in the advanced stages of clinical testing, and discuss areas of current controversy.

Malignant pleural mesothelioma is increasing in importance in the Asia-Pacific region, where ongoing asbestos consumption in many countries and a long latency period will result in a rising incidence over many decades. Treatment, whether it is with palliative or curative intent, can involve several different modalities, with chemotherapy, radiotherapy, palliative care, and surgery having important roles. There is now good evidence for survival and quality of life benefits from treatment with palliative chemotherapy. Controversies surrounding “curative” treatment with trimodality therapy are discussed, including the lack of high quality evidence for this approach. The current and developing roles of different modalities in the treatment of malignant pleural mesothelioma are reviewed. Keywords: mesothelioma, trimodality, chemotherapy, radiotherapy, extrapleural pneumonectomy, pleurectomy decortication Correspondence: A/Prof Anna K. Nowak, MBBS, FRACP, Ph.D., Department of Medical Oncology, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009. Tel: +61 (0)8-93461222; fax: +61 (0)8-93461873; e-mail: anowak@cyllene.uwa.edu.au

Diagnosis and Staging The characteristic presentation of MPM is development of dyspnea, with or without chest pain, with a pleural effusion visualized on imaging.1 Presentation with weight loss, night sweats, or fatigue is less common, but these symptoms often occur during the disease course. The pleural effusion may be accompanied by localized or circumferential pleural thickening (Figure 1). This clinical picture, in association with prior asbestos exposure, is highly suspicious for MPM. However, obtaining a definitive tissue diagnosis is imperative, not only for prognostication and management, but also to allow pursuit of legal compensation. The most common alternative diagnosis is adenocarcinoma with pleural metastases, originating in the lung or metastatic from other organs; chest wall sarcomata may also mimic MPM. Diagnosis may be made from pleural fluid cytology where there is adequate expertise in this technique, however, cytological diagnosis is only possible where there is a significant epithelioid component.15 Tissue diagnosis may also be pursued by pleural biopsy, image-guided fine-needle aspiration, or core biopsy, or by thoracoscopy when less invasive techniques prove elusive. Noncytological techniques are usually

INTRODUCTION Malignant pleural mesothelioma (MPM) is an aggressive malignancy arising from the mesothelial cells of the pleura. It is almost always caused by inhalation of asbestos fibers, in particular, the amphibole asbestos crocidolite, or ‘blue asbestos’.1,2 Although considered to be a rare tumor, its incidence is increasing, and as a result of a latency period of several decades between asbestos exposure and development of MPM, the worldwide incidence will not peak for at least 10 to 20 years.1,3-7 Countries in Asia, where population exposure to asbestos occurred later than in Western countries, are consequently expected to have a delayed peak incidence of disease.1,4,5,8 Currently, most developed countries have banned or significantly restricted the use of asbestos. However, most of the world’s ongoing asbestos consumption, in the form of the less carcinogenic chrysotile or ‘white asbestos’, takes place in Russia and developing countries in Asia, including China, Indonesia, and India.9-11 Many of these countries are still importing and using asbestos as a result of rapid APJOH 2009; 1: (1). March 2009

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involvement of intercostal nerves and painful chest wall or bony infiltration. Specialty pain management teams may assist with complex interventions such as intercostal nerve blocks, intrathecal analgesics, and hemi-chordotomy.18 Symptoms such as night sweats, anorexia, and weight loss may be palliated using low dose corticosteroids in some patients. Patients may also require drainage of pleural effusions to improve dyspnea and performance status, especially before receiving chemotherapy. Management of recurrent effusions using palliative surgery is discussed below. Patients with significant effusions who are unable or unwilling to have surgical control of effusions may benefit symptomatically from talc pleurodesis. Until recently, many physicians have been nihilistic about active treatment of MPM. However, in 2009, following optimization of symptom control, function, and performance status, active treatment should be considered in fit patients. In countries with a longstanding asbestos ban, this will become more challenging as the exposed population ages and the mean age of patients with MPM increases. Active treatment includes surgical, radiotherapy, and chemotherapy options, with differing goals, toxicities, and levels of evidence to support each modality.

Figure 1. Presentation with dyspnea. Imaging shows a left pleural effusion with a contracted hemithorax and a small rind of pleural thickening.

needed to fully characterize the pathological subtype (epithelioid, sarcomatoid, biphasic, anaplastic), which can provide prognostic information since nonepithelioid disease is associated with a poorer prognosis.16,17

Palliative Surgery Outside of a role in diagnosis and staging, there is increasing evidence for the palliative benefits of surgery. Recurrent pleural effusions are a major cause of dyspnea, and repeated pleurocentesis is invasive, requires patients to tolerate worsening symptoms between drainages, and exposes them to potential local tumor seeding along needle tracks. The optimal treatment of recurrent malignant pleural effusions is surgical talc pleurodesis with video assisted thoracoscopic surgery (VATS).19 If the patient can tolerate an anesthetic, this procedure is safe, minimally morbid, and can have significant palliative benefits. For patients unable to tolerate a general anesthetic, those with a poor prognosis, or those who have entrapped lung, insertion of a longterm indwelling catheter may palliate symptoms.20,21 Pleurectomy/decortication (PD) is a further palliative surgical option in MPM. Radical PD includes removal of the visceral and parietal pleura, ipsilateral pericardium, and diaphragm through a thoracotomy or sternotomy incision. A more conservative PD uses VATS through thoracoscopic ports to remove the pleura, leaving the diaphragm and pericardium in-situ.22 Overall, PD is well tolerated, with operative mortality rates of 1% to 2% and complications including prolonged air leakage in 10% of cases, and lower rates of bleeding or infection.23 A recent retrospective review reported improvement in pain and/or dyspnea with VATS PD.19 Because PD is unlikely to achieve complete tumor resection, it should be considered a palliative debulking procedure. The use of adjuvant postoperative chemotherapy has been recommended; however, this practice is not supported

Careful staging of MPM has limited therapeutic relevance unless aggressive surgical therapy is under consideration, and will be discussed below with trimodality treatment. At present, the involvement of regional lymph nodes does not alter palliative management. Distant metastatic disease, while not uncommon later in the disease course, is often overshadowed by local thoracic symptoms. The management of symptomatic distant metastases follows similar therapeutic principles to other metastatic malignancies. Nevertheless, crosssectional imaging with thoraco-abdominal computed tomography (CT) scan allows the clinician to visualize chest wall infiltration, pleural effusion or pericardial effusion, and provides a baseline by which to measure treatment efficacy. Disease staging can also provide prognostic information in the palliative setting.16

Active Symptom Control Many patients with MPM are symptomatic at presentation, and active symptom control is paramount. In MPM, the goals of treatment include improving dyspnea, exercise tolerance, anorexia, lethargy, pain, and health-related quality of life (HRQL). Simple palliative measures such as oxygen, corticosteroids, and appropriate analgesia should be considered from the outset if appropriate, and may be the only available management options in less developed countries or in patients with poor performance status. Pain can be complex and intractable, and can include neuropathic pain from APJOH 2009; 1: (1). March 2009

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published the results of a phase III study comparing cisplatin alone with cisplatin in combination with pemetrexed.30 This trial was the first to report a survival advantage from chemotherapy in MPM, showing a statistically significant improvement in median survival from 10  months in the cisplatin arm to 13.3  months in the combination arm in patients who received supplementation with folate and vitamin B12. The objective response rate increased from 19.6% in the cisplatin arm to 45.5% in the combination arm. Grade 3/4 nausea and vomiting, stomatitis, and diarrhea were more common in the combination arm, but only affected a minority of patients, and, overall, the combination was well tolerated when patients received vitamin supplementation; both HRQL and lung function tests improved in the combination arm.31 Following this report, the combination of cisplatin and pemetrexed has become the gold standard for first-line systemic treatment of MPM. However, there are still unanswered questions about the optimal use of chemotherapy, including when to start treatment, and the optimal number of cycles to give. Table 1 summarizes the most active secondgeneration regimens reported in this disease. The most effective combinations include a platinum-based agent in combination with an antimetabolite or vinca alkaloid. Cisplatin in combination with raltitrexed has shown an improvement in survival similar to that reported by Vogelzang, but raltitrexed is no longer commercially available. For patients unable to obtain or tolerate pemetrexed, cisplatin in combination with gemcitabine or vinorelbine is an alternative, although a survival benefit has not been shown for these regimens. For patients in whom cisplatin cannot be used, carboplatin can be substituted but nonrandomized data have shown lower response rates for carboplatin-based combinations; retrospective analysis of a nonrandomized expanded access program compared those receiving cisplatin/pemetrexed with carboplatin/pemetrexed and demonstrated similar survival, but lower response rates and higher rates of hematological toxicity in the carboplatin arm.46 Carboplatin and pemetrexed is active and well tolerated in fit elderly patients.39 Survival figures from studies using oxaliplatin do not compare favorably with other platinum agents. Combination chemotherapy demonstrates higher response rates than single agent chemotherapy, and the place of single agent treatment in elderly patients or those with a poor performance status is unclear. Single agent vinorelbine or pemetrexed are both modestly active and very well tolerated, but have not shown a survival benefit over supportive care alone; however, a trend toward improved survival was demonstrated for vinorelbine in a study that was underpowered to answer this question.36 This study also failed to demonstrate any HRQL benefit within 6  months for chemotherapy compared to supportive care alone. Single agent gemcitabine does not appear to have significant activity in MPM.47,48 Other drugs

by randomized controlled trials.24 Where postoperative imaging demonstrates measurable disease, the treatment paradigm is similar to that in advanced disease. However, where imaging does not demonstrate clear measurable disease, the use of chemotherapy has been extrapolated from its use for palliation of advanced disease, and there is no guidance as to the optimal timing or duration of chemotherapy. Postoperative hemithoracic irradiation is specialized and technically challenging, as the ipsilateral lung parenchyma remains intact;25 this area is under active investigation. Given the limitations of postoperative adjuvant treatments, most recurrences occur in the ipsilateral pleura.

Palliative Radiotherapy MPM has been considered relatively radioresistant, and radiotherapy is limited by potential damage to underlying lung parenchyma. However, radiotherapy has an important role in the palliation of chest wall or mediastinal invasion and symptomatic metastases. More specific to MPM is the well described risk of malignant seeding along tracts from invasive procedures. The risk of clinically evident needle track seeding is lower for image-guided core-needle biopsies of the pleura (4%) compared with surgical biopsies (22%), and VATS (up to 50%).26 Established subcutaneous nodules can be treated with external beam radiotherapy; most patients will have an improvement in pain. However, the benefit is often transient, and most nodules will not reduce in size.26 The role of prophylactic chest wall radiotherapy to procedural sites remains controversial, despite several small randomized clinical trials. A randomized prospective study found that 21 Gy in 3 fractions using electrons prevented all tract metastases in 20 patients, compared with a 40% incidence in 20  patients in the control arm (P<0.001).27 However, a subsequent study randomized 43 patients to no prophylactic radiotherapy or 10 Gy in a single fraction and found no difference in the development of tract metastases (10% vs. 7%).28 More recently, another trial comparing no prophylactic radiotherapy (n=30) to prophylactic radiotherapy with 21 Gy in 3 fractions (n=31) found no significant difference between the study arms (seven metastases in the radiotherapy arm, three in the observation arm).29 Current practice is varied; some radiation oncologists treat only symptomatic lesions, whereas others recommend prophylactic irradiation to ‘high risk’ sites.

Palliative Chemotherapy Until recently, chemotherapy was considered to be ineffective in this disease. Although drugs such as cisplatin and the vinca alkaloids were known to have some activity, response rates were in the order of 20% and accompanied by significant toxicities. Furthermore, most studies were small, single center phase II trials, and the lack of adequately powered randomized controlled trials precluded demonstration of a survival benefit. This changed in 2003 after Vogelzang and colleagues www.slm-oncology.com

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Table 1. Results of Modern Chemotherapy Schedules for MPM Study author Chemotherapy Response rate

Median progression-free survival (months)

Median overall survival (months)

Van Meerbeeck (2005)32

Raltitrexed + cisplatin vs. Cisplatin alone

24% vs. 14% (P=0.06)

5.3 vs. 4.0 (P=0.058)

11.4 vs. 8.8 (P=0.048)

Sørensen (2008)33

Cisplatin + vinorelbine (n=54)

29.6% (3.7% CR, 25.9% PR)

7.2

16.8

Nowak (2002)34

Cisplatin + gemcitabine (n=53)

33% (all PR)

6.4

11.2

Utkan (2006)35

Cisplatin (split-dose) + gemcitabine (n=26)

23.1% (all PR)

4

19.5

ASC (n=136) vs. Not reported 5.1 vs. Muers (2008)36 ASC + vinorelbine (n=136) 6.2 (P=0.11) vs. vs. ASC + mitomycin + 5.1 (P=0.96) vinblastine + cisplatin (n=137)

7.6 vs. 9.5 months (P=0.08 cf ASC, P=0.04 cf mitomycin containing arm) vs. 7.6 (P=0.95)

Maruyama (2005)37

Cisplatin + gemcitabine + vinorelbine (n=12, n=9 for first line)

58% (67% for first line)

Not reported

11

Castagneto (2008)38

Carboplatin + pemetrexed (n=76)

25% (4% CR, 21% PR)

8

14

Ceresoli (2006)39

Carboplatin + pemetrexed (n=102)

18.6% (2% CR, 16.6% PR)

6.5

12.7

Favaretto (2003)40

Carboplatin + gemcitabine (n=50 total, n=31 for first line)

26% (all PR)

9.2

15

Portalone (2005)41

Epirubicin + gemcitabine (n=28)

14% (all PR) (high SD 69%)

14.5

15.8

Steele (2000)42

Vinorelbine (n=29)

24% (all PR)

Not reported

10.6

Scagliotti (2003)43

Pemetrexed (n=43 vitamin supplementation)

16.3% (all PR)

4.8

13.0

Fizazi (2003)44

Oxaliplatin + raltitrexed (n=55 for first line)

20% (all PR)

3.9

7.1

Fennell (2005)45

Oxaliplatin + vinorelbine (n=26)

23% (all PR)

4.7

8.8

Abbreviations: ASC, active symptom control; CR, complete response; PR, partial response; SD, stable disease

that have been tested and do not have significant activity in MPM include irinotecan, capecitabine, and the taxanes.49-53

tron emission tomography (FDG-PET) scanning.54â&#x20AC;&#x201C;56 Furthermore, the importance of radiological response is debatable and may be associated with an improvement in progression-free survival (PFS), but not necessarily in overall survival.57 Adequately powered randomized controlled trials with a survival benefit are needed to answer questions about the relative efficacy of different regimes. However, such trials are unlikely to be done comparing any of the regimens discussed above because none challenge the position of cisplatin and pemetrexed as the standard of care.

In discussing objective radiological response rates in different phase II clinical trials, it is important to understand the difficulties in assessing tumor response in this disease. Unidimensional or bidimensional response criteria have been applied in different studies and may give differing response rates. While unidimensional measurement criteria are now used increasingly in clinical trials, there may be significant interobserver variability in response assessment, and current research is focusing on improving accuracy with computer assisted measurements or using F-labeled 2-deoxyglucose posiAPJOH 2009; 1: (1). March 2009

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and parietal pleura, pericardium and diaphragm, with reconstruction of the pericardium and diaphragm using Gore-Tex grafts.61 Mortality ranges from 3.6% in experienced centers to over 10%, and morbidities include empyema, bronchopleural fistula, tamponade, pulmonary edema, pulmonary embolism, diaphragm patch rupture, cardiac herniation, and cardiac arrhythmias.62,63 Despite this being a radical operation, complete removal of all malignant cells in MPM with EPP is impossible, and so must only be considered as part of multimodality treatment.24 Trimodality therapy (TMT) gained prominence after Sugarbaker and colleagues published a retrospective analysis of 183 patients with surgically resectable MPM who underwent TMT over a 17-year period.62 Various adjuvant chemotherapy schedules were used, some using cytotoxics now considered inactive in MPM. Adjuvant radiotherapy was dosed to 30 Gy (40 Gy to the mediastinum) with boosts to 54  Gy in areas of gross residual disease, positive margins, and/or localized positive lymph nodes. Although 27% of patients were 65 years of age or older, the 30-day mortality was only 3.8%; however, 25% of patients experienced significant morbidity leading to prolonged admission. In the 176  patients who survived more than 30 days after the operation, median survival was 19 months, and 2- and 5-year survival was 38% and 15%, respectively. Improved survival was significantly associated with negative surgical resection margins, negative extrapleural lymph nodes, and epithelioid histology. In total, 31 surgical “survivors” had all 3 favorable factors, and in these patients, the median and 5-year survival periods were 51 months and 46%, respectively. When recurrence occurred, it was in the ipsilateral hemithorax (35%), or distally in the abdomen (26%), contralateral hemithorax (17%), or other sites (8%).64 Thus, TMT seems to alter the natural course of MPM because clinically relevant distant disease is otherwise uncommon. Abdominal recurrence may occur because of the continuity of the chest and peritoneal cavity after diaphragmatic removal and because the inferior chest is difficult to treat adequately with radiotherapy.24 Metastatic recurrence indicates a failure of chemotherapy to eliminate micrometastases, highlighting a need for better systemic treatment (Figure 2). Proponents of TMT argue these results indicate potential for cure, but other reported case series have been unable to replicate the impressive survival figures in the subgroup reported by Sugarbaker. Median survival for all treated patients in most TMT series ranges between 15 and 26 months.65-69 Where TMT is considered, accurate staging is vital to ensure resectable disease. Modern staging systems are detailed in Table 2. The presence of locally inoperable disease due to diffuse chest wall or mediastinal invasion, or distant metastases, is a contraindication to TMT; however, focal chest wall invasion may

survival benefit to second-line chemotherapy. Jassem and colleagues reported on 243 good performancestatus patients who had received non-pemetrexed containing first-line chemotherapy.58 Patients were randomized to receive best supportive care (BSC) alone or BSC with up to eight cycles of single agent pemetrexed with vitamin supplementation. Although PFS was significantly greater in the chemotherapy arm (3.6 vs. 1.5 months, P=0.01), there was no difference in median survival (8.4 months in chemotherapy arm vs. 9.7 months, P=0.7), or HRQL. Median survival was 20.5 months in the 19% of patients with a radiological response to chemotherapy. The HRQL and overall survival results were attributed to a high drop-out from the control arm, with more patients from the control arm (52%) than the chemotherapy arm (28%) receiving subsequent off-study chemotherapy. In a recently reported phase II study of 63 patients, weekly vinorelbine was given as second-line therapy.59 Despite a modest objective response rate of 16%, the overall survival was 9.6 months; nevertheless, these encouraging survival data may represent patient selection bias. The largest body of data on management following cisplatin and pemetrexed comes from a retrospective analysis of patients from the landmark Vogelzang study.60 Patients with a good initial baseline performance score, younger age, and epithelioid histology were more likely to receive second-line chemotherapy. In total, 37% of patients in the pemetrexed arm and 47% of patients in the cisplatin control arm received further chemotherapy, mostly as single agents, with gemcitabine, anthracyclines, or vinorelbine. Fewer patients received combination chemotherapy, but if combination therapy was given it usually consisted of gemcitabine with a platinum agent. Second-line chemotherapy was associated with improved survival (HR 0.56, CI 0.44-0.72), even when corrected for baseline prognostic factors before first-line chemotherapy and type of first-line chemotherapy. These nonrandomized data, however, simply demonstrate that an association exists between overall survival and second-line therapy. Enrolment in a clinical trial of second-line therapy remains a good option for patients who are fit for further treatment. Encouraging second-line options should be tested in a randomized setting, with best supportive care as a comparator arm, and including patient-rated end points such as HRQL and lung function, in addition to overall survival and tumor response.

Trimodality Therapy A limited group of patients with MPM may be suitable for aggressive surgical management with extrapleural pneumonectomy (EPP), adjuvant or neoadjuvant chemotherapy, and adjuvant hemithoracic radiotherapy with the aim of ‘cure’ or prolonged palliation; however, this area remains very controversial. EPP consists of en-bloc removal of the ipsilateral lung with visceral www.slm-oncology.com

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plication rates may be higher after neoadjuvant chemotherapy.68 Postoperative chemotherapy may be delayed for patient recovery, and patients may not tolerate full dose intensity. In either setting, the choice of regimen is usually one with activity in a palliative setting, such as cisplatin with pemetrexed. The optimal timing and number of treatment cycles are unclear, and these questions are unlikely to be answered in the near future. Postoperative hemithoracic irradiation is used to gain local disease control. Doses to a median of 54Â Gy are well tolerated, but limited by the spinal cord and heart (45 Gy), and contralateral lung (20 Gy) tolerance. Also, as the reconstructed diaphragm is usually placed well above the original diaphragm, there is shifting of the abdominal viscera into the hemithorax post-EPP. These abdominal organs limit the dose in the inferior hemithorax to 30 Gy, potentially resulting in inadequate treatment of the former pleural recesses.23,24 Despite appropriate planning and shielding of other organs, significant radiation-induced toxicities can still occur.77,78 Intensity modulated radiation therapy (IMRT) utilizes three-dimensional planning and may optimize treatment of the tumor bed while minimizing organ toxicity, but it requires careful placement of intraoperative marking clips to guide planning and attention to contralateral lung doses that may lead to fatal pulmonary toxicity.79,80 Results of outcomes of TMT utilizing IMRT in a small number of reported series are encouraging, and further reports are awaited.81 Several areas of controversy remain surrounding TMT of MPM, primarily the absence of any strong evidence to support this practice. Although the results of case series can appear impressive, no randomized trial data have been reported, and, thus, there are significant potential problems with reporting bias and patient selection bias. Emerging evidence indicates that TMT may not be as successful as first thought.80 Flores and colleagues have recently published the results of a retrospective review of 663 nonrandomized patients undergoing EPP or PD for MPM, and this showed that median survival in the EPP group was significantly worse than the PD group (HR 1.4, 95% CI 1.18 to 1.69).82 There was a trend for improved median survival in patients with early stage MPM who underwent PD instead of EPP (23 vs. 19 months, P=0.07), even when excluding operative deaths, of which there was a higher rate in the EPP group. Most of those in the PD group received multimodal therapy. In a retrospective review of patients at our institution who were referred for TMT, survival in patients who did or did not undergo EPP was similar in both groups (unpublished data). As part of the discussion about TMT, patients must be informed about the lack of evidence indicating a benefit and must have full disclosure of the significant mortality and morbidity associated with this procedure. Currently, a randomized controlled multinational trial, the Mesothelioma and Radical Surgery (MARS) trial, is

Figure 2. Metastatic recurrence of MPM in left (contralateral) lung following TMT (routine CT scan taken 23 months following right EPP).

be potentially resectable. Currently, there is controversy about offering EPP to patients with known N2 disease because, despite aggressive therapy, this is associated with a very poor outcome.70 Preoperative staging with FDG-PET scan may upstage nearly 30% of patients.33 The role of magnetic resonance imaging (MRI) is less clear, but it can assist with determining the extent of local invasion.70,72 Surgical staging, including bilateral thoracoscopy, mediastinoscopy, and laparoscopy with multiple biopsies can confirm histopathological subtype and help exclude occult, contralateral, or abdominal disease.73,74 Taking multiple biopsies from the ipsilateral pleura increases the likelihood of detecting nonepithelioid histology,75 where this is considered a contraindication to TMT. However, this method is controversial and current guidelines suggest that there is insufficient evidence to exclude patients with nonepithelioid MPM from surgical resection.70 During mediastinoscopy, mediastinal invasion should be assessed, and biopsies of all accessible lymph nodes obtained.70 In our experience of surgical staging, 26% of patients did not proceed to EPP based on contraindications discovered at surgical staging, either by upstaging patients or detecting nonepithelioid MPM.76 The use of adjuvant or neoadjuvant chemotherapy is not guided by high-level evidence, but is an attempt to eradicate micrometastatic disease causing distant recurrence. An advantage of neoadjuvant chemotherapy is that patients with chemoresistant disease may be selected out, thus avoiding EPP following early tumor progression. Furthermore, patients are likely to be fit for optimal treatment dosing. However, surgical comAPJOH 2009; 1: (1). March 2009

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Table 2. Current Staging Systems for Resection of Malignant Pleural Mesothelioma

Stage

Brigham and Womenâ&#x20AC;&#x2122;s I Hospital revised staging system59

Description

Comment

Disease confined to the interior parietal pleura, or chest wall limited to previous biopsy sites; no lymph node involvement

Resectable

II All of stage I with positive intrathoracic lymph nodes (N1 or N2)

Resectable but controversial (see text)

III

Local extension of disease into chest wall, mediastinum, heart, diaphragm, peritoneum; extrapleural lymph node involvement

Not resectable

Distant metastatic disease

Not resectable

International Mesothelioma T1 Interest Group staging system71

Disease limited to ipsilateral parietal pleura (T1a), or scattered tumor foci involving visceral pleura (T1b)

Resectable

T2

Disease involving diaphragmatic muscle, or confluent visceral pleural involvement (including fissures or lung parenchyma invasion)

Resectable

T3

Disease involving endothoracic fascia or mediastinal fat, or solitary focus of chest wall invasion, or nontransmural involvement of pericardium

Locally advanced but potentially resectable

T4

More advanced/diffuse chest wall involvement; or transdiaphragmatic extension; or extension to contralateral pleura, mediastinal organs, spine or internal surface of pericardium

Locally advanced and not resectable

N0

No regional lymph node metastases

Resectable

N1

Spread to ipsilateral bronchopulmonary or hilar lymph nodes

Resectable

N2

Spread to subcarinal or ipsilateral mediastinal lymph nodes (including ipsilateral internal mammary lymph nodes)

Technically resectable but controversial (see text)

N3

Spread to supraclavicular, contralateral mediastinal, or contralateral internal mammary lymph nodes

Not resectable

IV

Abbreviations: N, lymph nodes; T, tumor

assessing the efficacy of TMT.83 In this study, patients with operable MPM receive neoadjuvant chemotherapy; nonprogressing patients are then randomized to either EPP and adjuvant IMRT, or to any other treatment deemed appropriate short of EPP. Recruitment has been difficult, and it seems unlikely that this trial will be able to confirm the efficacy of this approach without strong support from patients and referrers. Other investigational approaches include intraoperative intrathoracic chemotherapy post-EPP, intraoperative hyperthermic or hypothermic intrathoracic chemotherapy, photodynamic therapy, and simultaneous intraperitoneal chemotherapy at the time of EPP.23,24

rangements reported in chromosomes 1, 3, 6, 9, and 22. Loss of the tumor suppressor gene p16 is particularly common. A good biological rationale can be identified for testing numerous novel targeted agents in this disease, including agents targeting angiogenesis, epidermal growth factor receptor pathways, c-Met and PI3K pathways, and immunological strategies. No clear leader has yet emerged, and here we briefly discuss some of the current strategies under investigation. Vascular endothelial growth factor (VEGF) appears important in MPM; many patients have high serum and pleural fluid levels of VEGF as well as VEGF overexpression on immunohistochemistry.84 In-vitro studies suggest that both VEGF and Platelet derived growth factor (PDGF) may be useful targets.85,86 However, a double-blind placebo-controlled phase II study randomizing 115 patients to receive gemcitabine and cisplatin with bevacizumab or placebo in the first-line setting showed no difference in response rates between the

Targeted Therapies MPM is a disease characterized by a clear etiology, but no single dominant genetic alteration that is readily targeted by a single therapy. It is more commonly a disease of chromosome loss, with deletions or rearwww.slm-oncology.com

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FRs, was found to have no significant activity in a small study of 11 patients, nine of whom had received previous chemotherapy.95 Mesothelin is a cell membrane protein encoded by the mesothelin gene and is expressed normally in mesothelial cells lining the pleura, pericardium and peritoneum. It is highly expressed in epithelial MPM as well as in some other cancers, but is absent in sarcomatoid MPM. The function of mesothelin is unclear, but it seems to have a role in the peritoneal spread of ovarian cancer, and mesothelin specific antibodies are detected in approximately 40% of MPM patients.96 Various therapies are in development targeting mesothelin. One of these, SS1P, is a recombinant immunotoxin directed against mesothelin and is currently in phase II trials after showing a high stable disease rate and occasional long-lived objective and clinical responses in phase I studies.97 SS1P has also shown potential synergy with radiation and various chemotherapy agents in mouse studies. The dose limiting toxicity of SS1P is self-limiting pleuritis, presumably as a result of targeting mesothelin on normal pleural mesothelial cells.96 Mesothelin is also being studied as a target for vaccine therapy, gene therapy, and radioimmunotherapy.96,98 Ranpirnase is a single-chain ribonuclease enzyme which preferentially and irreversibly degrades transfer RNA (tRNA), but not ribosomal RNA or messenger RNA, leading to inhibition of protein synthesis and caspase-dependent apoptosis.99 A phase II study of 105  patients with MPM showed a response rate of 5% and median survival of 6 months.100 The low response rate was not surprising, since ranpirnase is predominantly cytostatic, and the stable disease rate of 43% prompted further study. In the phase III study that followed, 144 patients were randomized to receive ranpirnase or doxorubicin. The median survival of just over 8 months was the same in both arms when analyzed on an intention-to-treat basis. There were, however, more poor prognosis patients in the ranpirnase arm and post-hoc analysis which excluded the poor prognosis patients showed a survival benefit for ranpirnase.99 A further phase III study, comparing doxorubicin with or without ranpirnase as first- or second-line therapy for MPM, has stratified patients based on prespecified prognostic factors and closed enrollment in early 2008. The final results of this study are awaited, but an interim analysis suggests a survival benefit in the ranpirnase group.99 Ranpirnase seems to be well tolerated, with a low rate of side effects including asthenia, flu-like symptoms, vasodilatation (flushing, hypotension, vasovagal reactions), paresthesia, and allergic reactions.100 Other potentially interesting molecular targets in mesothelioma include c-Met receptor tyrosine kinase, Insulin-like growth factor 1 receptor (IGF-1R), mammalian target of rapamycin (mTOR), and Wnt signaling.101–104 In the absence of a clear standard for

bevacizumab and placebo arms (25% vs. 22%, P=0.74), which had similar median PFS (6.9 vs. 6.0 months, P=0.88) and overall survival (15.6 vs. 14.7 months, P=0.91).87 Interestingly, patients with baseline VEGF levels above the median had a significantly shorter PFS and overall survival compared with patients with lower VEGF levels, and those with low baseline VEGF levels appeared to have improved median survival when treated with bevacizumab. Thus, serum VEGF may be a predictive biomarker for bevacizumab efficacy in MPM, as well as a prognostic marker. Further studies looking at bevacizumab in combination with cisplatin and pemetrexed are ongoing. Other agents targeting angiogenesis include sunitinib and thalidomide. Sunitinib is an oral small molecule inhibitor of several receptor tyrosine kinases (RTKs) including VEGF and PDGF receptors.88 Its current clinical uses include advanced renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. The preliminary findings of a phase II study of single-agent sunitinib in the second-line treatment of 23 patients with MPM have been reported recently, showing a partial response rate of 18% and stable disease rate of 50%, median overall survival of 8.2 months and time to progression of 3.7 months from start of treatment. Treatment was well tolerated with fatigue the most common major toxicity in 17% of patients.89 Thalidomide is believed to inhibit angiogenesis mediated by VEGF and other growth factors.86 A phase I/II study investigating single agent thalidomide in 40 patients, half of whom had received prior chemotherapy, reported stable disease of more than 6 months duration in 27% of patients and a median survival of 7.5 months.90 In a phase II study of 27 patients with MPM who were not well enough to receive chemotherapy or who had previously received chemotherapy, thalidomide resulted in a stable disease rate of 50%, with 25% having stable disease for more than 6 months, and a median survival of 11 months.91 Currently, a phase III study is investigating the benefit of maintenance thalidomide in patients with MPM who have not progressed after four cycles of platinum and pemetrexed chemotherapy.86 Other biological agents have not shown promise in this disease. Despite overexpression of epidermal growth factor receptor (EGFR) in most MPM and significant in-vitro growth inhibition of mesothelioma cell lines with EGFR tyrosine kinase inhibitors, results of first-line erlotinib and gefitinib in MPM have been disappointing, with progression-free survival of around 2  months.92,93 The combination of erlotinib and bevacizumab, a regimen that has activity in nonsmall cell lung cancer, did not produce any radiological responses as second-line treatment in 24 patients with MPM. Although the stable disease rate was 50%, median time to progression was only 2 months and median survival 6  months.94 Similarly, Imatinib, which inhibits PDGAPJOH 2009; 1: (1). March 2009

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second-line chemotherapy in this disease, clinical trials in this setting remain ethical and are a high priority to identify activity signals from novel agents.

11. Joshi T, Gupta R. Asbestos in developing countries: magnitude of risk and its practical implications. Int J Occup Med Environ Health. 2004;17(1):179–185. 12. Takahashi K, Karjalainen A. A cross-country comparative overview of the asbestos situation in ten Asian countries. Int J Occup Environ Health. 9(3):244–248. 13. Dikensoy O. Mesothelioma due to environmental exposure to erionite in Turkey. Curr Opin Pulm Med. 2008;14(4):322–325. 14. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol. 1989;7(8):1157–1168. 15. Whitaker D, Henderson D, Shilkin K. The concept of mesothelioma in situ: implications for diagnosis and histogenesis. Semin Diagn Pathol. 1992;9(2):151–161. 16. Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus P, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol. 1998;16(1):145–152. 17. Edwards J, Abrams K, Leverment J, Spyt T, Waller D, O’Byrne K. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax. 2000;55(9):731–735. 18. Murphy D. Interpleural analgesia. Br J Anaesth. 1993;71(3):426–434. 19. Shaw P, Agarwal R. Pleurodesis for malignant pleural effusions. Cochrane Database Syst Rev. 2004(1):CD002916. 20. Pien G, Gant M, Washam C, Sterman D. Use of an implantable pleural catheter for trapped lung syndrome in patients with malignant pleural effusion. Chest. 2001;119(6):1641–1646. 21. Pollak J. Malignant pleural effusions: treatment with tunneled long-term drainage catheters. Curr Opin Pulm Med. 2002;8(4):302–307. 22. Nakas A, Martin Ucar A, Edwards J, Waller D. The role of video assisted thoracoscopic pleurectomy/decortication in the therapeutic management of malignant pleural mesothelioma. Eur J Cardiothorac Surg. 2008;33(1):83–88. 23. van Ruth S, Baas P, Zoetmulder F. Surgical treatment of malignant pleural mesothelioma: a review. Chest. 2003;123(2):551–561. 24. Bueno R. Multimodality treatments in the management of malignant pleural mesothelioma: an update. Hematol Oncol Clin North Am. 2005;19(6):1089–1097, vii. 25. Gupta V, Mychalczak B, Krug L, et al. Hemithoracic radiation therapy after pleurectomy/decortication for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys. 2005;63(4):1045–1052. 26. Agarwal P, Seely J, Matzinger F, et al. Pleural mesothelioma: sensitivity and incidence of needle track seeding after image-guided biopsy versus surgical biopsy. Radiology. 2006;241(2):589–594. 27. Boutin C, Rey F, Viallat J. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest. 1995;108(3):754–758. 28. Bydder S, Phillips M, Joseph D, et al. A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. Br J Cancer. 2004;91(1):9–10. 29. O’Rourke N, Garcia J, Paul J, Lawless C, McMenemin R, Hill J. A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma. Radiother Oncol. 2007;84(1):18–22. 30. Vogelzang N, Rusthoven J, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21(14):2636–2644. 31. Gralla RJ, Hollen PJ, Liepa AM, et al. Improving quality of life in patients with malignant pleural mesothelioma: Results of the randomized pemetrexed + cisplatin vs. cisplatin trial using the LCSS-meso instrument. Proc Am Soc Clin Oncol. 2003;22: Abstract 2496. 32. van Meerbeeck J, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup

Conclusion and Recommendations The management of MPM will become more important in coming years as its incidence increases, especially in the Asia-Pacific region. Adequate palliation of symptoms is a management priority and can be achieved with active symptom control and chemotherapy, and at times the judicious use of radiotherapy or surgery. Palliative chemotherapy with cisplatin and pemetrexed (with vitamin supplementation) is now standard first-line treatment for patients with advanced disease, and has been shown to improve survival and HRQL. Carboplatin can be substituted for cisplatin, but equivalence has not been demonstrated in a randomized clinical trial. Second-line chemotherapy has not been proven to be of benefit, but can be considered in fit patients, whereas targeted therapies remain investigational. Trimodality therapy is controversial, but has been reported to result in long-term survival in selected patients. However, this approach remains unproven in prospective randomized studies, and requires thorough radiological and surgical staging to ensure localized and resectable disease. Where possible, patients should be encouraged to enter clinical trials as many questions remain in all aspects of the management of this disease. Disclosures: The authors have no financial interest related to the contents of this article to disclose.

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study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J Clin Oncol. 2005;23(28):6881–6889. Sørensen J, Frank H, Palshof T. Cisplatin and vinorelbine first-line chemotherapy in non-resectable malignant pleural mesothelioma. Br J Cancer. 2008;99(1):44–50. Nowak A, Byrne M, Williamson R, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer. 2002;87(5):491–496. Utkan G, Büyükçelik A, Yalçin B, et al. Divided dose of cisplatin combined with gemcitabine in malignant mesothelioma. Lung Cancer. 2006;53(3):367–374. Muers M, Stephens R, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial. Lancet. 2008;371(9625):1685–1694. Maruyama R, Shoji F, Okamoto T, et al. Triplet chemotherapy with cisplatin, gemcitabine and vinorelbine for malignant pleural mesothelioma. Jpn J Clin Oncol. 2005;35(8):433–438. Castagneto B, Botta M, Aitini E, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008;19(2):370–373. Ceresoli G, Zucali P, Favaretto A, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006;24(9):1443–1448. Favaretto A, Aversa S, Paccagnella A, et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study. Cancer. 2003;97(11):2791–2797. Portalone L, Antilli A, Nunziati F, et al. Epirubicin and gemcitabine as first-line treatment in malignant pleural mesothelioma. Tumori. 2005;91(1):15–18. Steele J, Shamash J, Evans M, Gower N, Tischkowitz M, Rudd R. Phase II study of vinorelbine in patients with malignant pleural mesothelioma. J Clin Oncol. 2000;18(23): 3912–3917. Scagliotti G, Shin D, Kindler H, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as frontline therapy in malignant pleural mesothelioma. J Clin Oncol. 2003;21(8):1556–1561. Fizazi K, Doubre H, Le Chevalier T, et al. Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study. J Clin Oncol. 2003;21(2):349–354. Fennell D, Steele JPC, Shamash J, et al. Phase II trial of vinorelbine and oxaliplatin as first-line therapy in malignant pleural mesothelioma. Lung Cancer. 2005;47(2):277–281. Santoro A, O’Brien M, Stahel R, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008;3(7):756–763. van Meerbeeck J, Baas P, Debruyne C, et al. A Phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. Cancer. 1999;85(12):2577–2582. Kindler H, Millard F, Herndon Jn, Vogelzang N, Suzuki Y, Green M. Gemcitabine for malignant mesothelioma: A phase II trial by the Cancer and Leukemia Group B. Lung Cancer. 31(2–3):311–317. Kindler H, Herndon J, Zhang C, Green M. Irinotecan for malignant mesothelioma. A phase II trial by the Cancer and Leukemia Group B. Lung Cancer. 2005;48(3):423–428. Otterson G, Herndon Jn, Watson D, Green M, Kindler H. Capecitabine in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (39807). Lung Cancer. 2004;44(2):251–259. Vorobiof D, Rapoport B, Chasen M, et al. Malignant pleural mesothelioma: a phase II trial with docetaxel. Ann Oncol. 2002;13(3):412–415.

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89. Nowak AK, Millward MJ, Francis R, van der Schaaf A, Musk AW, Byrne MJ. Phase II study of sunitinib as second-line therapy in malignant pleural mesothelioma (MPM). J Clin Oncol. 2008;26(15S):8063. 90. Baas P, Boogerd W, Dalesio O, Haringhuizen A, Custers F, van Zandwijk N. Thalidomide in patients with malignant pleural mesothelioma. Lung Cancer. 2005;48(2):291–296. 91. Pavlakis N, Abraham R, Harvie R, et al. Thalidomide alone or in combination with Cisplatin/Gemcitabine in malignant pleural mesothelioma (MM): Interim results from two parallel non-randomised phase II studies. Lung Cancer. 2003;41 (Suppl 2):S11. 92. Garland L, Rankin C, Gandara D, et al. Phase II study of erlotinib in patients with malignant pleural mesothelioma: a Southwest Oncology Group Study. J Clin Oncol. 2007;25(17):2406–2413. 93. Govindan R, Kratzke R, Herndon Jn, et al. Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B. Clin Cancer Res. 2005;11(6): 2300–2304. 94. Jackman D, Kindler H, Yeap B, et al. Erlotinib plus bevacizumab in previously treated patients with malignant pleural mesothelioma. Cancer. 2008;113(4):808–814. 95. Porta C, Mutti L, Tassi G. Negative results of an Italian Group for Mesothelioma (G.I.Me.) pilot study of single-agent imatinib mesylate in malignant pleural mesothelioma. Cancer Chemother Pharmacol. 2007;59(1):149–150. 96. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. Eur J Cancer. 2008;44(1):46–53. 97. Hassan R, Bullock S, Premkumar A, et al. Phase I study of SS1P, a recombinant anti-mesothelin immunotoxin given as a bolus I.V. infusion to patients with mesothelin-expressing mesothelioma, ovarian, and pancreatic cancers. Clin Cancer Res. 2007;13(17):5144–5149. 98. Yokokawa J, Palena C, Arlen P, et al. Identification of novel human CTL epitopes and their agonist epitopes of mesothelin. Clin Cancer Res. 2005;11(17):6342–6351. 99. Mutti L, Gaudino G. The therapeutic potential of the novel ribonuclease ranpirnase (Onconase) in the treatment of malignant mesothelioma. Oncol Rev. 2008;2:61–65. 100. Mikulski S, Costanzi J, Vogelzang N, et al. Phase II trial of a single weekly intravenous dose of ranpirnase in patients with unresectable malignant mesothelioma. J Clin Oncol. 2002;20(1):274–281. 101. Wilson S, Barbone D, Yang T, et al. mTOR mediates survival signals in malignant mesothelioma grown as tumor fragment spheroids. Am J Respir Cell Mol Biol. 2008;39(5):576-583. 102. Whitson B, Jacobson B, Frizelle S, et al. Effects of insulin-like growth factor-1 receptor inhibition in mesothelioma. Thoracic Surgery Directors Association Resident Research Award. Ann Thorac Surg. 2006;82(3):996–1001; discussion 2. 103. Hoang C, Zhang X, Scott P, et al. Selective activation of insulin receptor substrate-1 and -2 in pleural mesothelioma cells: association with distinct malignant phenotypes. Cancer Res. 2004;64(20):7479–7485. 104. Uematsu K, Seki N, Seto T, et al. Targeting the Wnt signaling pathway with dishevelled and cisplatin synergistically suppresses mesothelioma cell growth. Anticancer Res. 2007;27(6B):4239–4242.

71. Rusch V. A proposed new international TNM staging system for malignant pleural mesothelioma. From the International Mesothelioma Interest Group. Chest. 1995;108(4):1122–1128. 72. Entwisle J. The use of magnetic resonance imaging in malignant mesothelioma. Lung Cancer. 2004;45(Suppl 1):S69–S71. 73. Alvarez J, Ha T, Musk W, Robins P, Price R, Byrne M. Importance of mediastinoscopy, bilateral thoracoscopy, and laparoscopy in correct staging of malignant mesothelioma before extrapleural pneumonectomy. J Thorac Cardiovasc Surg. 2005;130(3):905–906. 74. Rice D, Erasmus J, Stevens C, et al. Extended surgical staging for potentially resectable malignant pleural mesothelioma. Ann Thorac Surg. 2005;80(6):1988-1992; discussion 92–93. 75. Bueno R, Reblando J, Glickman J, Jaklitsch M, Lukanich J, Sugarbaker D. Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma. Ann Thorac Surg. 2004;78(5):1774–1776. 76. Hasani A, Alvarez J, Millward M, Byrne M, Musk B, Nowak AK. Outcomes of patients referred for trimodality therapy (TMT) for epithelioid malignant pleural mesothelioma (MPM) in Western Australia—a case series. Asia-Pac J Clin Oncol. 2007;3(Suppl 2):A52–A53. 77. Senan S. Indications and limitations of radiotherapy in malignant pleural mesothelioma. Curr Opin Oncol. 2003;15(2):144–147. 78. Allen A, Den R, Wong J, et al. Influence of radiotherapy technique and dose on patterns of failure for mesothelioma patients after extrapleural pneumonectomy. Int J Radiat Oncol Biol Phys. 2007;68(5):1366–1374. 79. Rice D, Smythe W, Liao Z, et al. Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys. 2007;69(2):350–357. 80. Miles E, Larrier N, Kelsey C, et al. Intensity-modulated radiotherapy for resected mesothelioma: the Duke experience. Int J Radiat Oncol Biol Phys. 2008;71(4):1143–1150. 81. Rice D, Stevens C, Correa A, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg. 2007;84(5):1685–1692; discussion 92–93. 82. Flores R, Pass H, Seshan V, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg. 2008;135(3):620–626, 6.e1–6.e3. 83. Treasure T, Tan C, Lang-Lazdunski L, Waller D. The MARS trial: mesothelioma and radical surgery. Interact Cardiovasc Thorac Surg. 2006;5(1):58–59. 84. Lee A, Raz D, He B, Jablons D. Update on the molecular biology of malignant mesothelioma. Cancer. 2007;109(8):1454–1461. 85. Strizzi L, Catalano A, Vianale G, et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J Pathol. 2001;193(4):468–475. 86. Dowell J, Kindler H. Antiangiogenic therapies for mesothelioma. Hematol Oncol Clin North Am. 2005;19(6):1137–1145, viii. 87. Kindler HL, Karrison T, Gandara DR, et al. Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo (P) in patients with malignant mesothelioma: C5-06. J Thorac Oncol. 2007;2(8):S374. 88. Chow L, Eckhardt S. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25(7):884–896.

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REVIEW ARTICLE

An Australian Clinical Perspective: Management of Hormone Refractory (Androgen-Independent) Prostate Cancer Elizabeth Hovey1, Gavin Marx2, Andrew Kneebone3, Manish Patel4 and Jeremy Shapiro5 Affiliation: 1Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW, Australia. 2 Sydney Adventist Hospital Sydney NSW, 3Dept of Radiation Oncology, Royal North Shore Hospital, Sydney. NSW, 4Department of Urology, Westmead and Sydney Adventist Hospitals, NSW, 5Department of Medical Oncology, Cabrini Hospital, Melbourne, Victoria, Australia Submission date: 15th January 2009, Acceptance date: 10th February 2009

Abstract

early (neoadjuvant/adjuvant) and in combination with definitive radiation.7–9 Neoadjuvant ADT before prostatectomy reduces margin positivity rates but has no impact on survival.10–13 Hormones and adjuvant radiotherapy following prostatectomy are considered for patients at an intermediate or high risk for recurrence.14 The risk of recurrence can be estimated by consulting tools such as the Kattan nomogram.15 Men with newly diagnosed metastatic prostate cancer have a rapid response to ADT, with improvement in bone pain, regression of soft tissue metastases and a decline in serum prostate-specific antigen (PSA) levels.16 The duration of this response is variable, after which patients are considered to have progressed. The term ‘progressive disease’ often refers to patients with a rising PSA; however, clinical and radiological parameters can also reflect progressive disease.17 Management of hormone-refractory prostate cancer (HRPC) remains a challenge. The prognosis is often poor and, historically, median survival is less than 12 months for symptomatic patients.18–20 This is a complex problem and management needs to be individualized according to each patient’s specific needs. This should take into account their previous treatment, extent of disease, pace of disease, performance status, comorbidities and the patient’s preferences. The approaches described below combine evidencebased medicine and clinical experience of prostate cancer specialists (including urologists, radiation oncologists and medical oncologists) in the routine, day-to-day multidisciplinary management of patients with HRPC.

Hormone-refractory prostate cancer (HRPC) patients are a very heterogeneous group of patients. Management is guided by a number of patient-related factors such as previous treatment, site of disease (prostatespecific antigen only/bone only/visceral or lymph node involvement), pace of disease, performance status, comorbidities and patient choice. Treatment choices include secondary hormonal manipulations, palliative radiotherapy, first- and second-line chemotherapy, clinical trials of new agents, radioisotopes and quality supportive care. Keywords: hormone refractory prostate cancer, androgen-independent prostate cancer, prostate cancer, HRPC Correspondence: Dr Elizabeth Hovey, Department of Medical Oncology, Prince of Wales Hospital, High Street, Randwick, NSW, Australia 2031. Tel: +61 (0) 2-9382 2577; fax: +61 (0) 2-93822588; e-mail: Elizabeth. Hovey@sesiahs.health.nsw.gov.au

BACKGROUND Prostate cancer is a leading cause of morbidity and death among men in Western countries.1 In Australia, it is the most common cancer in men and the second leading cause of male cancer-related deaths after lung cancer. An estimated 18,700 new cases of prostate cancer were diagnosed in 2006, and more than 2,900 men died of prostate cancer in 2005.2 A significant proportion of patients relapse after definitive local therapy, regardless of whether the intervention was surgical- or radiation-based therapy. Approximately 38% to 52% of patients are found to have advanced disease after radical prostatectomy.3–5

DEFINING HRPC—REFRACTORY, RESISTANT, OR INDEPENDENT?

The standard, first-line therapy is androgen deprivation therapy (ADT), with a luteinizing hormone-releasing hormone (LHRH) agonist, orchidectomy and/or oral antiandrogens. Hormonal therapy is not curative and, ultimately, hormone-refractory disease will develop.6 In men with locally advanced prostate cancer, ADT results in significant improvements in survival when used APJOH 2009; 1: (1). March 2009

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Multiple phrases are used to define this entity in the literature, including hormone-refractory prostate cancer, hormone-resistant prostate cancer, androgenindependent prostate cancer and castrate-resistant prostate cancer. Hormone-refractory prostate cancer has been defined as a progressive disease with serum testosterone levels of less than 50 ng/mL.17 Some use 77

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the phrase ‘hormone-resistant disease’ (rather than refractory) as progressive cancer despite all secondary hormonal manipulations. Some patients may meet the criteria for ‘hormone-refractory’, that is to say, they have disease progression despite castrate levels of testosterone, yet this does not necessarily mean that their disease is, in fact, refractory to secondary hormonal manipulations.21 Indeed, even when a patient is clearly refractory to hormonal manipulations, it is common practice to continue therapy using an LHRH agonist, even after commencing cytotoxic chemotherapy. As implied by responses to secondary hormonal manipulations, even when the patient is clinically castrateindependent, it appears the androgen receptor remains central to prostate cancer cell growth.22 Although there is controversy regarding the definitions of hormone-refractory and hormone-resistant disease, the key driver from a clinical perspective is the appropriate management of patients on a LHRH agonist (or following orchidectomy) and usually also an antiandrogen, with a rising PSA level. This involves a multidisciplinary shared care approach with early referral to a medical oncologist. Advantages of such a referral include assessing the possible role of secondary hormonal manipulations or other systemic treatment options as well as the discussion of possible clinical trial opportunities for the patient. Assessment of burden and pace of disease (including the extent of metastases, visceral or soft tissue involvement, PSA velocity and doubling time) should direct the management plan. Options include early incorporation of chemotherapy, further use of second-line hormonal manipulations, introduction of bisphosphonates or careful follow-up and monitoring.

a trial of bicalutamide withdrawal.26 Nilutamide is also well tolerated and is given once daily, but can result in alcohol intolerance, and up to 30% of patients note difficulties with dark-to-light visual adaptation that resolves upon cessation of the drug.27 Nilutamide is usually commenced at 300 mg daily for the first 4  weeks and then maintained at 150 mg daily. Flutamide (usually given as 250 mg po tds) is another commonly used antiandrogen, but can be associated with slightly increased gastrointestinal side effects28 such as nausea and abnormal liver function tests. Most patients tolerate antiandrogens very well; however, a small minority can experience side effects such as severe fatigue, nausea, vomiting, skin reactions and hepatic toxicity. On further rise in PSA, cessation of the antiandrogen (referred to as ‘antiandrogen withdrawal’) may also be considered. It is theorized that antiandrogen withdrawal can be effective in certain scenarios because the androgen receptor becomes mutated over time and the anti-androgen then acts as an agonist rather than as an antagonist.17 Acquired mutations in the androgen receptor have been found, and there is some preclinical and clinical support for this theory.29,30 An alternative explanation is that the patient may develop hypersensitivity to low levels of the androgen, associated with a modest increase in androgen receptor mRNA.31 A reduction of PSA in 20% to 40% of patients has been described with antiandrogen withdrawal.32 In the SWOG 9426 study, 27% of the patients on flutamide withdrawal showed a >50% PSA decline compared to 7% withdrawing from bicalutamide and 38% withdrawing from nilutamide.33 Some patients have a sustained decline in PSA. Additionally, there is no evidence that antiandrogens improve survival. The disease eventually becomes androgen-independent and refractory to hormone treatment.16,34,35

Further Hormonal Manipulation Generally, clinicians do not change management based on a single PSA rise. Instead, they respond to two or three consecutive rises, particularly if the rise reflects a fast PSA doubling time (eg, 3–6 months or shorter).23,24 Different analytical methodologies between commercial laboratories can introduce variations in PSA levels, which needs to be considered before a change in therapy. The addition of an antiandrogen to LHRH agonist monotherapy (or orchidectomy) in order to achieve complete androgen blockade is a useful therapeutic intervention for rising PSA levels. Antiandrogens include agents such as bicalutamide, flutamide, nilutamide and cyproterone acetate.25 Most of these antiandrogens have similar side-effect profiles, including gynecomastia, fatigue and dry skin. Many clinicians opt for the initial use of bicalutamide due to the convenience of oncedaily dosing and a favorable toxicity profile. If the PSA rises on 50  mg daily of bicalutamide, some clinicians trial ‘high-dose’ bicalutamide at 150  mg daily, which can be associated with a further PSA response, prior to APJOH 2009; 1: (1). March 2009

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For patients who respond to secondary hormonal manipulation, additional hormonal strategies can be considered. The response duration, however, usually becomes shorter. Even if patients fail to respond to antiandrogens and antiandrogen withdrawal therapy, they may respond to further hormonal manipulation with a different antiandrogen.32 This intervention may be useful with appropriate patient selection. Other treatment options include chemotherapy, bisphosphonates, palliative radiotherapy and radioisotopes.36 Treatments such as adrenal suppression with ketoconazole are used in some countries, although it is not available in Australia for this purpose. In one phase II ketoconazole study, the PSA declined by >50% for 8 or more weeks in 62.5% of patients.37 It is thought that glucocorticoids can have indirect antiangiogenic activity via their indirect hormonal suppression effects on adrenal androgens. Prednisone monotherapy has also been found to directly benefit patients with asymptomatic HRPC.38 78

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Effect of Prolonged ADT

are limited in terms of long-term use of bisphosphonates in the Australian population. The majority of international guidelines recommend the use of the agent in conjunction with standard antineoplastic therapy. It is important to note that, in the trial by Saad et al.,47 zolendronate was not given concurrently with chemotherapy. The timing of commencement of bisphosphonate therapy remains controversial. Some clinicians are reluctant to commence bisphosphonate use with patients who are asymptomatic and have only a few metastases. Caution should also be applied when patients have impaired renal function. In this case, the dose and duration of administration of zolendronate should be modified according to the glomerular filtration rate. There is a documented increased risk of osteonecrosis of the jaw with the use of bisphosphonates, particularly with zolendronate.50 Many clinicians mandate dental review of patients before initiation of zolendronate. If a patient requires dental extraction, it is best to delay the commencement of zolendronate, as there is a potential risk of delayed healing. This risk increases with cumulative exposure and has led to recommendations to limit treatment to a 2 year maximum in patients with myeloma.51

There is increasing awareness of the long-term toxicities associated with prolonged ADT. Cardiovascular toxicity has also been documented,39 and effects on mood and energy as well as on bone density are well recognized. Despite limited data, many clinicians now assess bone mineral density at commencement of ADT. Some clinicians routinely recommend calcium and vitamin D supplements and regular weight-bearing exercise.40,41

ROLE OF BISPHOSPHONATES The most common site of metastases from HRPC is bone, with more than 80% of men with advanced prostate cancer having bone metastases.42,43 Loss of bone mineral density (BMD) as a result of previous orchidectomy or ADT may also contribute to the skeletal complications associated with prostate cancer.44,45 Adverse events associated with bone metastases are a major cause of morbidity in men with prostate cancer, causing pain, spinal cord compression, fractures and increases in serum calcium.46 Bisphosphonates have been shown to inhibit osteoclast activity, and may thus reduce skeletal complications and prevent bone loss in at-risk patients.47 Three studies investigating the use of bisphosphonates to prevent bone loss in patients treated with ADT have shown prevention of bone loss, an increase in lumbar spine BMD with pamidronate48 and a significant increase in BMD of the hip with zolendronate.49

THE ROLE OF RADIOTHERAPY Which Patients Should be Referred for Palliative Radiation? Many patients with HRPC have painful bone metastases. For limited sites of pain, single or short fractionation schedules of local radiation treatment offer pain improvement rates between 55% and 85%. No difference, however, is observed in progression-free or overall survival.52–57 In the majority of cases, retreatment with radiation is feasible and can result in decent rates of pain relief, especially if the patient responded initially with radiation.58 Palliative radiation is an excellent modality when there are minimal focal painful sites rather than multiple sites of pain, which are better managed by chemotherapy or radioisotope treatment. There is also debate as to whether single fraction radiotherapy is as effective as multi-fraction radiotherapy in the palliation of metastatic bone pain. In one systematic review of randomized trials in this area, both forms of radiotherapy were demonstrated to be as effective as the other in relieving metastatic bone pain, although the retreatment and fracture rates were higher in those who had received single fraction radiotherapy.59 Radiation can play a role in the management of pelvic symptoms. Although there is limited published evidence for the efficacy of high-dose palliative radiation therapy, it is used in many centers to relieve the local pelvic symptoms associated with HRPC, including urinary obstruction, pelvic pain, hematuria and obstructive rectal symptoms.60

Zolendronate, also known as zoledronic acid, is approved in Australia for the treatment of bone metastases in patients with HRPC. The approval was based on results from a study that investigated the effect of the agent on skeletal complications in prostate cancer patients with bone metastases.47 Patients were randomly selected to receive intravenous zolendronate at 4 mg, 8 mg (subsequently reduced to 4  mg) or placebo every 3  weeks for 15 months. Zolendronate 4 mg was associated with a reduction in skeletal-related events compared to placebo, with 33.2% and 44.2% of patients experiencing such an event (P<0.021) respectively.47 Urinary markers of bone resorption were also significantly decreased in patients who received either dose of zolendronate compared to those who received placebo (P<0.001).47 The 4 mg dose was well tolerated as an infusion over 15  minutes, although the 8 mg dose was associated with a decrease in renal function in some patients.47 The above study47 recommends the use of zolendronate every 4 weeks. Some clinicians tend to modify the frequency of administration, mindful of the concerns regarding cumulative toxicity. This is particularly the case in the second year of bisphosphonate therapy, when some clinicians administer zolendronate every 3 months or even less frequently. There are currently no data supporting this frequency modification. Data www.slm-oncology.com

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medication every 3 weeks with concomitant daily prednisone (5 mg po bd) has become the standard of care for first-line chemotherapy for patients with HRPC.34,35,65–67 There are very limited randomized trial data to support the use of other chemotherapy agents in the firstline setting, such as mitoxantrone and cyclophosphamide.34,36,64 The SWOG 9916 study16 involved docetaxel plus estramustine; however, estramustine is associated with toxicity and is not recommended as part of the standard approach. Estramustine has never been available in Australia.

Radiation oncologists are also involved in the management of spinal cord compression. Depending on the site of the cord compression and the involvement of adjacent vertebrae, up-front neurosurgical decompression is usually offered as the preferred means of treatment. In the appropriately selected patient, this treatment can be associated with better neurological outcome.61 In patients that are not deemed candidates for neurosurgical intervention (eg, those with multiple vertebral level involvement, disseminated disease or significant comorbidities), radiotherapy can minimize neurological dysfunction and local progression.62 If a patient deteriorates neurologically while receiving up-front radiation, further neurosurgical opinion should be obtained.

To date, the data do not adequately address the relevance and benefits of this treatment in particular groups, such as asymptomatic patients with indolent disease.63 Another poorly addressed issue in the existing data set is how to manage patients who are technically hormone-refractory but do not have overt metastases.

THE ROLE OF CHEMOTHERAPY Hormone-refractory prostate cancer is a heterogeneous disease with patient characteristics ranging from asymptomatic PSA increases with no, minimal or extensive metastases to symptomatic PSA increases with minimal or extensive metastases.63 Prostate cancer was considered resistant to chemotherapy up until the mid-1990s,64 when palliative benefits were observed with mitoxantrone therapy.18,34 Historically, survival for HRPC patients was 10 to 12 months.16,64 More recently, both survival and palliation benefits were demonstrated with docetaxelbased chemotherapy in two pivotal trials (TAX 327 and SWOG 9916).16,34 The TAX 327 trial compared the control arm of mitoxantrone plus prednisone to two different docetaxel arms (weekly docetaxel plus prednisone or docetaxel given every three weeks plus prednisone). There was a significant benefit in overall survival (OS) for the 3-weekly docetaxel arm compared to mitoxantrone with a hazard ratio for death of 0.76 (95% confidence interval [CI] 0.62 to 0.94, P=0.009).34 The median survival times were 19.2 months for the 3-weekly docetaxel arm, 17.8  months for the weekly docetaxel arm (which did not reach significance in terms of benefit compared to mitoxantrone and had a hazard ratio of 0.91, 95% CI 0.75 to 1.11) and 16.3 months for the patients in the mitoxantrone arm.34,64 In the TAX 327 study, in addition to survival benefits comparing the 3-weekly docetaxel group to the mitoxantrone group, there were significant improvements in the >50% PSA response (45% versus 32%, P<0.001), pain response (35% versus 22%, P=0.01) and global quality of life (22% versus 13%, P=0.009). Interestingly, though the weekly docetaxel group had the highest >50% PSA response of 48%, it did not translate into the best overall survival. A higher proportion of grade 3 or 4 adverse events was reported in the 3-weekly docetaxel arm (45.8%) compared to the mitoxantrone arm (34.6%), and the majority of these events were due to myelosuppression.34 Based on findings from the TAX 327 study, docetaxel (75  mg/m2, 1  hour infusion) and dexamethasone preAPJOH 2009; 1: (1). March 2009

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The optimal time-point to initiate a cytotoxic regimen in patients with HRPC remains to be defined.68 This is particularly so for patients with minimal or no symptoms. A general oncology review article examining this question concluded that only limited studies have examined this issue, and to date, there is little evidence of an overall survival benefit for early initiation of chemotherapy for asymptomatic patients with metastatic tumors.68 The issue of timing is further confounded in this cohort of patients, with some having indolent disease and some having significant comorbidities. Conversely, the potential advantages of early intervention include lower tumor burden and superior performance status.69 As opinions are divided and no supporting data are available, involvement of the patient is essential in these decisions. In patients with rapidly progressive disease, symptoms and/or visceral involvement, early introduction of chemotherapy is more established. Patients with HRPC who have a rising PSA and have had at least one secondary hormonal manipulation can be divided into three groups: patients who have a clear indication for chemotherapy, patients in which chemotherapy is a possible option and patients in which there is no defined indication for chemotherapy (Table 1). The optimum duration of chemotherapy is also of some debate. In a clinical trial population, a median of 9.5 cycles of docetaxel-based chemotherapy demonstrated the best outcomes and overall survival benefit34; however, in the real-world setting many patients cannot realistically tolerate this many cycles. Optimal patient care requires regular assessment of toxicity, quality of life, symptomatic benefit and clinical response to define the duration of therapy. Many patients initially receive between four and six cycles of docetaxel (given every three weeks). Some clinicians will continue treatment if a response is evident, while others reserve ongoing cycles for retreatment with docetaxel at a later date. 80

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Table 1. Patient Selection for Chemotherapy Clear indication

Possible indication

No indication

Fit patients (<75 years) with Fit asymptomatic patients (<75 years) metastatic visceral disease with progressive bone-only metastatic (such as liver metastases) or disease and short doubling time bulky lymphadenopathy (symptomatic/asymptomatic) Fit geriatric patientsb with visceral metastatic disease Fit patients (<75 years) with progressive and new multiple painful Fit geriatric patientsb with bone metastases and rising PSA despite multiple painful bone metastases secondary hormonal manipulationa Fit geriatric patientsb with asymptomatic progressive bone metastases and short PSA doubling time

Frail, geriatric patientsb with overt metastases with significant comorbidities and poor performance status due to their other comorbidities (ECOG 3 to 4).70 Any patient with biochemical progression only, that is to say, no metastatic disease documented (refer these patients for a clinical trial)

Vulnerable/frail geriatric patientsb with overt metastases and poor performance status deemed to be secondary to their prostate cancer (e.g., due to painful bone metastases) [these patients need to be discussed on a case-by-case basis] If there are only a few painful bone metastases, palliative radiation can be considered rather than moving straight to chemotherapy. For the purpose of this table, we have defined geriatric as ≥75 years old (as per the TAX-327 study).34

a b

Management of Elderly Patients

Previously, there was a suggestion that weekly docetaxel treatment was perhaps less toxic than 3-weekly docetaxel; however, this has not been borne out by the TAX 327 data.34 There is less neutropenia in the weekly setting, so if there is an episode of febrile neutropenia, a weekly approach (25 to 35 mg/m2) could be considered.

In the assessment of elderly patients, it is important to consider more than just the performance status. A variety of screening assessment tools (e.g., instrumental activities of daily living [IADLs] and activities of daily living [ADLs] scales) can divide geriatric patients into three groups: fit, vulnerable and frail.71 Fit patients should receive the same treatment approach as their younger counterparts. Vulnerable patients (e.g., patients who are functioning well but have some comorbidities and may not tolerate the toxicities of treatment very well) warrant a comprehensive geriatric team assessment and a modified and tailored approach. Frail elderly patients with poor performance status (e.g., ECOG 3 to 4)70 or significant comorbidities should not be offered chemotherapy72 but rather optimal supportive care and palliation.

Assessing Patients for Clinical Benefit At the initiation of chemotherapy, treatment goals need to be clearly defined between the medical oncologist and the patient. Treatment should be individualized and based on these agreed goals. Assessing patients for clinical benefit is complex and can involve some elements of subjective judgment. Parameters that are used include: • symptoms (eg, improvement in bone pain)

In fit, elderly patients with a possible indication for chemotherapy (Table 1), careful monitoring is required upon initiation of the docetaxel regimen. If there are concerns, options include closer hematological monitoring and clinic visits, and some clinicians suggest dose modification (eg, a dose reduction to 50  mg/m2 for the first cycle, with dose escalation to 75  mg/m2 if it is well tolerated). Granulocyte-colony stimulating factor (G-CSF) support may be considered in elderly patients (although this intervention is not reimbursed in Australia). More ‘vulnerable’72 elderly patients who require a comprehensive geriatric assessment or careful monitoring should not necessarily be excluded from docetaxel therapy.73 www.slm-oncology.com

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• PSA response • weight • patient-reported global quality of life • toxicities of treatment • other indirect parameters (eg, alkaline phosphatase level in the assessment of bone involvement) • radiological assessment (CT scans and bone scans)

Very little evidence exists for the utility of these individual parameters in assessing the HRPC patient on cytotoxic therapy. Further clinical research is needed to evaluate the complex assessment of clinical benefit. 81

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biological and/or clinical relapse showed PSA responses of 42% (docetaxel monotherapy) and 66.6% to 81.8% for two different docetaxel combination regimens.81 These results may provide a measure of confidence to patients and physicians regarding the stopping and reintroduction of docetaxel chemotherapy in carefully selected patients.84 More modest treatment goals for second-line docetaxel, however, are warranted. Mitoxantrone, the previous ‘gold-standard’ chemotherapy for HRPC, is the most commonly used secondline chemotherapy approach. Three randomized controlled trials in the first-line setting have compared mitoxantrone plus low-dose corticosteroid to low-dose corticosteroid alone.18,19,85 In all instances, PSA response rates were higher in the mitoxantrone group, and were significantly so in one.85 One of the studies evaluated pain,18 finding that a total of 29% of patients had a two-point reduction in pain intensity on the sixpoint McGill-Melzack Pain Questionnaire, maintained for 3 weeks without an increase in analgesic use, compared to 12% of patients treated with prednisone alone (P=0.01).18 In the second-line setting, sequencing mitoxantrone after a taxane, >50% PSA responses of 6% to 15% have been reported.80,86,87 Vinorelbine is a semisynthetic vinca alkaloid that is used as a monotherapy in HRPC.88 In the first-line setting, this agent was shown to increase progressionfree survival (PFS), but not OS.89 This was in a trial comparing patients treated with hydrocortisone with or without aminoglutethimide, who were then randomized to receive vinorelbine or placebo. In this same trial, vinorelbine was associated with higher PSA response rates and clinical benefit responses than the placebo arm (PSA response rate 30.1% versus 19.2%, P=0.01 and clinical benefit 30.6% versus 19.2%, P=0.008).89 There are minimal data in the second-line setting; however, one study demonstrated a >50% PSA response in 17.9% of patients receiving single-agent vinorelbine or vinorelbine plus estramustine, with a 16.1 month median survival rate in responders.82 Cyclophosphamide (an alkylating agent available in oral and intravenous forms) is used as a monotherapy as well as combination therapy, although it appears to yield better results when combined with other agents.36 When used in combination with other cytotoxic agents, it may have superior palliative activity.36 Most of the data relate to first-line use. After promising phase II data, a phase III clinical trial of the cytotoxic agent satraplatin reported disappointing results with no difference in overall survival rates between satraplatin plus prednisolone compared with prednisolone plus placebo.65 Other agents with limited data in the second-line setting either as monotherapies or in combination include carboplatin, etoposide, doxorubicin, and more recently, gemcitabine, and the epothilone-B analogues, ixabepilone and patupilone.90–94

There is some evidence that PSA response (particularly >50%) can be a surrogate marker for improved survival. In the TAX 327 study, patients with a PSA response had a 60% reduction in mortality risk compared to PSA nonresponders (P<0.001).74 The survival benefits, however, are only partially explained by PSA response.74 There is no available literature to guide clinicians on the optimal timing or utility of PSA measurements or CT scans. In patients with discordant clinical and marker responses (such as falling PSA but increased pain or increasing liver function tests), earlier radiological assessment may be prudent. In a small proportion of patients, the PSA may in fact rise before falling after the initiation of chemotherapy, and then go on to have a >50% PSA response.75 In view of this phenomenon, it is important not to prematurely cease docetaxel treatment solely because of one or two rises in PSA. It is recommended that treatment with docetaxel cease if severe adverse events occur, or in the presence of confirmed disease progression.76 Furthermore, PSA measurements can be very unreliable or not raised at all in patients with small cell prostate cancer or high-grade prostate cancer with significant neuro-endocrine differentiation.77 The complex issues surrounding the standardization of PSA assessment have been addressed in recent guidelines.78

Second-line Chemotherapy There are no randomized trials in the second-line setting that demonstrate survival or quality of life benefits. All patients will eventually relapse after first-line docetaxel chemotherapy. With HRPC now often diagnosed earlier, patients who progress on first-line therapy may still have a good performance status, and some may be eligible for consideration of second-line approaches. One US study79 evaluated subsequent treatments for 108 patients treated with first-line microtubule-targeting agents for HRPC. The study found that 83% of patients ultimately receive second-line chemotherapy (with 15% PSA response), and that 40% receive third-line chemotherapy (with a 22% PSA response). Factors that impacted the likelihood of survival in the second-line setting included the pretreatment PSA level, alkaline phosphatase (ALP) level and performance status. There are a number of chemotherapy options available, such as retreatment with docetaxel,80,81 mitoxantrone, cyclophosphamide, carboplatin and vinorelbine,79,82 which should be individualized according to patient preference. There are, however, limited data for any survival benefit with second-line treatments.83 A retrospective study supporting reintroduction with docetaxel demonstrated that patients (n=54) who initially responded to first-line chemotherapy with docetaxel that were later rechallenged with docetaxel at APJOH 2009; 1: (1). March 2009

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82

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Table 2. Key Points in the Optimal Management of HRPC

Tolerability appears to be worse than for first-line chemotherapy, with 45% to 65% of patients requiring a delay, dose reduction, or cessation of chemotherapy in the second-line setting.86 In view of such limited data and benefits, enrollment into clinical trials should be encouraged.

• Multidisciplinary discussion, including involvement of allied health teams • Early consideration of referral to a medical oncologist • Closer monitoring of patients who are deteriorating, including imaging

CLINICAL TRIALS FOR PATIENTS WITH HRPC Treatment of HRPC is an evolving area and there a number of novel agents that are available for further evaluation in the clinical trial setting. Only a limited number of patients, however, are enrolled into clinical trials for prostate cancer. In particular, for groups of patients in which there is limited evidence of treatment benefit, and outcomes are disappointing, referral to clinical trials is a very real alternative. Clinical trials are particularly important in prostate cancer, where knowledge is still limited for optimal patient management, such as second-line treatment after chemotherapy and for patients with biochemical progression only. The Australian & New Zealand Urogenital & Prostate Cancer Trials Group (ANZUP) has details of trials enrolling prostate cancer patients in Australia.95

• Management of bone health (calcium, vitamin D and exercise) • Consideration of bisphosphonates for bone metastases • Symptom management, especially for pain • Address the issue of patient anxiety and offer patient a referral to counselling services if necessary • Discussion of participation in clinical trials

receptor and binds to proangiogenic VEGFs, thereby preventing VEGFs from binding to their cell receptors. Disruption of VEGF binding to their cell receptors may result in the inhibition of tumor angiogenesis, metastasis and ultimately, tumor regression.98

There are a wide range of novel agents currently under investigation for HRPC, including antiandrogens, vaccines, targeted agents and cytotoxic agents. The following list is not exhaustive of all agents undergoing investigation. Abiraterone is an oral, selective, steroidal inhibitor of CYP17, a key enzyme in androgen synthesis. The results from a phase I clinical trial in chemotherapy-naïve patients with progressive disease, despite treatment with LHRH analogues and other hormonal therapies, demonstrated a PSA response in 57% of those treated with the agent. Radiological and symptomatic responses were also documented.96 These results have formed the basis for an ongoing international multi-centre randomized, placebocontrolled phase III trial in patients previously treated with docetaxel therapy. With the understanding of the importance of angiogenesis in the development and progression of HRPC,97 studies are under way to evaluate angiogenesis inhibitors in the first- and second-line settings using agents such as aflibercept, bevacizumab and other vascular endothelial growth factor (VEGF) inhibitors. Other studies are evaluating the role of endothelin A antagonists as single agents or in combination with docetaxel. Aflibercept (known as VEGF trap) is a fully human recombinant fusion protein comprised of segments of the extracellular domains of human vascular endothelial growth factor receptors  1 (VEGFR1) and 2 (VEGFR2) that are fused to the constant region (Fc) of human IgG1, and have potential antiangiogenic activity. Aflibercept thus functions as a soluble decoy VEGF www.slm-oncology.com

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Generally, the targeted agents have very little singleagent activity and are offered in combination with cytotoxic therapy. Improvement in the understanding of how prostate cancer evades immune detection has led to the development of several vaccine therapies.65,99–101 This approach is based on the overexpression of a variety of unique tumor-associated antigens that are potential targets for immune-based therapy. Various strategies have been considered, including autologous dendritic cells (the DC Vax prostate vaccine and sipuleucel-T, which is known as Provenge®), gene therapy and monoclonal antibodies against various antigens.99–101 An example of a monoclonal antibody is ipilumimab, which is a fully humanized antibody targeting CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) in combination with GM-CSF.102

MANAGEMENT ALGORITHMS To help decide on an appropriate treatment course, there is the benefit of multidisciplinary decisionmaking. There are multiple facets to the holistic approach to the HRPC patient, some of which are mentioned in Table 2. Optimal management of HRPC includes multidisciplinary discussion, early consideration of referral to a medical oncologist, very close monitoring of patients who are deteriorating, management of symptoms such as pain and proactive management of bone health. It is also important to discuss possible participation in clinical trials, and it is vital to address any anxiety or distress the patient may have. 83

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Evidence of visceral disease (eg, liver metastases) or bulky soft tissue disease (eg, lymphadenopathy associated with encroaching hydronephrosis) in an asymptomatic patient (Figure 1B) warrants at least discussion of early intervention with docetaxel-based chemotherapy. Some of these patients (with bone metastases) may also be concurrently offered bisphosphonates, usually intravenous zolendronate, to reduce the risk of skeletal-related events.47

A Rising PSA level, no overt metastases, asymptomatic, already had one secondary hormonal manipulation

Surveillance

Secondary hormonal manipulations

Participation in clinical trials

B

Symptomatic Patients with HRPC Short PSA doubling time, overt metastatic disease (visceral and/or bone), no symptoms (including no pain), at least one secondary hormonal manipulation

Secondary hormonal manipulation(s)*

Chemotherapy

(see Table 1 for patient selection)

Sometimes the approaches listed in Figure 1C may be performed simultaneously. For example, a patient may be referred for palliation of a specific painful bone metastasis at the same time as commencing chemotherapy. Likewise, many of these patients may also be concurrently offered bisphosphonates, usually intravenous zolendronate, to reduce the risk of skeletal-related events.47

Participation in clinical trials

C

Palliative Radioisotopes Symptomatic (eg, pain) and overt progressive metastatic disease (visceral and/or bone)

Radiotherapy • Palliative radiotherapy • Consideration of radioisotope intervention

Chemotherapy

(see Table 1 for patient selection)

Two beta-emitting radioisotopes, strontium-89 and samarium-153, can partially or completely decrease bone pain in 33% to 70% of patients63,103,104; however, they have not been shown to extend survival.

Participation in clinical trials

Radioisotopes can play an important part in the palliation of metastatic bone pain in patients with multifocal painful bone metastases whose pain is inadequately controlled with conventional analgesics and when no chemotherapy is planned.103 Radioisotopes can be associated with myelosuppression, specifically significant thrombocytopenia and leucopenia.63 Utilization of these agents must be considered with caution. Myelosuppression associated with this modality may compromise the ability to deliver chemotherapy. Due to the proven survival benefit associated with docetaxel chemotherapy, most clinicians prioritize delivery of chemotherapy, which may also provide a symptomatic benefit.

(if not fit for chemotherapy) *The asymptomatic patient may still be eligible for secondary hormonal manipulations (eg, the patient with asymptomatic bone metastases and no visceral disease or lymphadenopathy). Secondary hormonal manipulations can include the addition or withdrawal of antiandrogens.

Figure 1. Management algorithms. A) relates to asymptomatic patients with no overt metastases with a rising PSA. B) relates to asymptomatic patients with overt metastases with a rising PSA. C) relates to symptomatic patients with overt metastases with a rising PSA.

The management algorithms in the figure above review the clinical pathways available for asymptomatic and symptomatic patients with HRPC. Patient selection for each management option is discussed in the following sections. Figure 1 relates to potential management options within the above scenarios.

Clinicians need to be aware that a superscan (a bone scan in which virtually all of the radiotracer is concentrated symmetrically and intensely within bone, associated with diminished renal and soft tissue activity105) is a relative contraindication to referral for radioisotope treatment, as patients with such extensive bone involvement would be at an increased risk of significant myelosuppression. In clinical practice, however, if pain is a significant issue and the patient is otherwise fit, radioisotope treatment may still be considered.

Asymptomatic Patients with HRPC For an asymptomatic patient with no overt metastases (ie, biochemical progression only) (Figure 1A), surveillance is a reasonable option. The patient’s anxiety level and desire for active treatment may lead to active interventions, such as secondary hormonal manipulations, rather than surveillance. If a patient has significant comorbidities but no prostate cancerrelated symptoms, surveillance may be favored.

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In the palliative setting, when no further chemotherapy is planned, patients with multiple painful bone metastases may benefit from judicious use of one of these radioisotopes. 84

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LINKING THE PATIENT INTO PALLIATIVE CARE SUPPORT

pects of optimally managing a patient with HRPC. It is important that urologists and radiation oncologists consider timely referral of HRPC patients to their medical oncology colleagues to maximize treatment options.

Critical issues of palliation should be considered by all involved clinicians, including management of pain (particularly considering the need for palliative external beam radiation and analgesics), constipation, anorexia, nausea, fatigue and depression.63 The ongoing involvement of the urologists is integral in continued patient care, particularly relating to obstructive and local symptoms. Depending on the clinical status of the patient, there are also issues surrounding end-of-life management, such as accessing superannuation, encouraging patients to have their financial and business affairs in order and considering transfer of patients to appropriate care environments such as a nursing home or a palliative care unit. Social workers can provide invaluable assistance under these circumstances. Formal linkage of patients into palliative care support does not need to be deferred until the end of active treatment. Optimally, all symptomatic HRPC patients should be offered palliative care team support services. Palliative care community nurses can play a vital role in terms of assessing the patient in his home environment (including symptom control, compliance with medications, ability to manage at home) and placing patients into contact with other crucial services. For example, it may be community nurses who instigate access to home equipment for the patients via local hospital occupational therapy departments, and who arrange athome occupational therapy assessments to evaluate the need for home modifications such as shower rails, wheelchairs, and walking frames. The involvement of palliative care physicians is desirable if the treating clinicians are unable to adequately manage the patient’s pain (or other symptoms). Palliative care physicians are also involved in the decision to transfer a patient to a hospice or palliative care unit. Palliative care physicians are the lead clinicians in the management of patients in the hospice or palliative unit settings.

Disclosures: This manuscript was sponsored by sanofi-aventis Australia, including funding for the provision of a medical writer and honoraria to the authors for scientific advice on the article development. The authors maintained full editorial control and responsibility for the final article. Drs Hovey, Shapiro and Patel have disclosed that they are currently members of the sanofi-aventis Australia Prostate Advisory Board and have received honoraria in this capacity.

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CONCLUSION Hormone-refractory prostate cancer patients are a heterogeneous group of patients. Treatment choices, which can include secondary hormonal manipulations, palliative radiotherapy, first- and second-line chemotherapy, clinical trials of new agents, bisphosphonates, radioisotopes and best supportive care, need to be guided by a number of patient-related factors, such as site of disease (bone-only versus visceral or lymphadenopathy), pace of disease, performance status, comorbidities and patient choice. It is imperative that disease management be individualized to each patient’s needs. There are important roles for the medical oncologist, radiation oncologist, urologist, allied health and palliative care nursing and medical teams in the complex aswww.slm-oncology.com

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European Study Group on Neoadjuvant Treatment of Prostate Cancer. Eur Urol 2000;38(6):706–713. Corn BW, Winter K, Pilepich MV. Does androgen suppression enhance the efficacy of postoperative irradiation? A secondary analysis of RTOG 85-31. Radiation Therapy Oncology Group. Urology 1999;54(3):495–502. Kattan MW. Nomograms are superior to staging and risk grouping systems for identifying high-risk patients: preoperative application in prostate cancer. Curr Opin Urol 2003;13(2):111–116. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr., Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351(15):1513–1520. Sartor O. Hormone-Refractory Prostate Cancer: A Continuum of Diseases and Options. PCRI Insights 2005;8(4). Tannock I, Osoba D, Stockler M et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996;14(6):1756–1764. Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17(8):2506–2513. Smaletz O, Scher HI, Small EJ, Verbel DA, McMillan A, Regan K, et al. Nomogram for overall survival of patients with progressive metastatic prostate cancer after castration. J Clin Oncol 2002;20(19):3972–3982. Scher HIS, G. Kelly, W.K. Hormone-refractory (D3) prostate cancer: refining the concept. Urology 1995;46(2):142–148. Gilbert DC, Parker C. Docetaxel for the treatment of prostate cancer. Future Oncol 2005;1(3):307–314. Oudard S, Banu E, Scotte F et al. Prostate-specific antigen doubling time before onset of chemotherapy as a predictor of survival for hormone-refractory prostate cancer patients. Ann Oncol 2007;18(11):1828–1833. Arlen PM, Bianco F, Dahut WL et al. Prostate Specific Antigen Working Group guidelines on prostate specific antigen doubling time. J Urol 2008;179(6):2181-5; discussion 2185–2186. Klotz L. Maximal androgen blockade for advanced prostate cancer. Best Pract Res Clin Endocrinol Metab. 2008;22(2):331–340. Merseburger AS, Belka C, Behmenburg K, Stenzl A. Secondary hormonal manipulation. Front Radiat Ther Oncol 2008;41:93–102. Harnois C, Malenfant M, Dupont A, Labrie F. Ocular toxicity of Anandron in patients treated for prostatic cancer. Br J Ophthalmol 1986;70(6):471–473. McLeod DG. Tolerability of nonsteroidal antiandrogens in the treatment of advanced prostate cancer. Oncologist 1997;2(1):18–27. Taplin ME, Bubley GJ, Shuster TD et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med 1995;332(21):1393–1398. Taplin ME, Rajeshkumar B, Halabi S et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663. J Clin Oncol 2003;21(14):2673–2678. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10(1):33–39. Small EJ, Vogelzang NJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 1997;15(1):382–388. Sartor OT, C. Hussain, M. Eisenberger, M. Crawford, ED. Anti-androgen withdrawal in prostate cancer: results from SWOG 9426. Proc Am Soc Clin Oncol. 2002;21: abstract 785. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502–1512.

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77. Dawson N. Response criteria in prostatic carcinoma. Semin Oncol 1999;26(2):174–184. 78. Scher HI, Halabi S, Tannock I et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26(7):1148–1159. 79. Beekman KW, Fleming MT, Scher HI et al. Outcomes with second-line chemotherapy in castrate metastatic prostate cancer. J Clin Oncol (Meeting Abstracts) 2005;23(16 suppl):4659. 80. Oh WK, Manola J, Babcic V, Harnam N, Kantoff PW. Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes. Urology 2006;67(6):1235–1240. 81. Eymard J, Oudard S, Gravis G, et al. Second-line chemotherapy with docetaxel (D) in men treated with docetaxelbased regimen for metastatic hormone-refractory prostate cancer (mHRPC). ASCO Prostate Cancer Symposium 2007; Abstract 249. 82. Nakabayashi M, Ling J, Xie W, Regan MM, Oh WK. Response to vinorelbine with or without estramustine as second-line chemotherapy in patients with hormone-refractory prostate cancer. Cancer J 2007;13(2):125–129. 83. Joshua A.M., Nordman I, Venkataswaran R et al. Weekly docetaxel as second line treatment after mitozantrone for androgen-independent prostate cancer. Int Med J. 2005;35(8):468–472. 84. Beer TM, Ryan CW, Venner PM et al. Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. Cancer 2008;112(2):326–330. 85. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L. Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol 2002;168(6):2439–2443. 86. Michels J, Montemurro T, Murray N, Kollmannsberger C, Nguyen Chi K. First- and second-line chemotherapy with docetaxel or mitoxantrone in patients with hormonerefractory prostate cancer: does sequence matter? Cancer 2006;106(5):1041–1046. 87. Berthold DR, Pond GR, de Wit R, Eisenberger M, Tannock IF, On behalf of the TAX 327 investigators. Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa. Ann Oncol 2008;19(10):1749–1753. 88. Winquist E WT, Berry S, Ernst D.S., Hotte S, Lukka H. Nonhormonal systemic therapy in men with hormone-refractory prostate cancer and metastases: a systematic review from the Cancer Care Ontario Program in Evidence-based Care’s Genitourinary Cancer Disease Site Group. BMC Cancer 2006;6:112. 89. Abratt RP, Brune D, Dimopoulos MA, Kliment J, Breza J, Selvaggi FP, et al. Randomised phase III study of intravenous vinorelbine plus hormone therapy versus hormone therapy alone in hormone-refractory prostate cancer. Ann Oncol 2004;15(11):1613–1621. 90. Di Lorenzo G, Autorino R, Giuliano M, Morelli E, Giordano A, Napodano G, et al. Phase II trial of gemcitabine, prednisone, and zoledronic acid in pretreated patients with hormone refractory prostate cancer. Urology 2007;69(2):347–351. 91. Oh W.K, Tay MH, Huang J. Is there a role for platinum chemotherapy in the treatment of patients with hormone-refractory prostate cancer? Cancer 2007;109(3):477–486. 92. Harzstark AL, Weinberg VK, Sharib J et al. Second-line combination chemotherapy: A phase I study of ixabepilone, mitoxantrone, and prednisone in patients with metastatic hormone-refractory prostate cancer (HRPC) refractory to docetaxel-based therapy. J Clin Oncol 2008;26:Abstract 5151. 93. Lee D. Activity of epothilone B analogues ixabepilone and patupilone in hormone-refractory prostate cancer. Clin Prostate Cancer 2004;3(2):80–82.

57. Roos DE, Turner SL, O’Brien PC et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 2005;75(1):54–63. 58. Mithal NP, Needham PR, Hoskin PJ. Retreatment with radiotherapy for painful bone metastases. Int J Radiat Oncol Biol Phys 1994;29(5):1011–1014. 59. Sze WM, Shelley M, Held I, M. M. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy— a systematic review of the randomised trials. Cochrane Database Syst Rev. 2004;2:CD004721. 60. Hindson B, Turner S, Do V. Palliative radiation therapy for localized prostate symptoms in hormone refractory prostate cancer. Australas Radiol 2007;51(6):584–588. 61. Patchell RT, PA. Regine, WF. Payne, R. Saris, S. Kryscio, RJ. Mohiuddin, M. Young, B. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366(9486):643–648. 62. Moser L, Schubert T, Hinkelbein W. Hormone-refractory and metastatic prostate cancer - palliative radiotherapy. Front Radiat Ther Oncol 2008;41:117–125. 63. Heidenreich A AG, Abbou CC et al. Guidelines on Prostate Cancer. European Association of Urology (March 2007 Update). 64. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008;26(2):242–245. 65. Bradley DA, Hussain M. Promising novel cytotoxic agents and combinations in metastatic prostate cancer. Cancer J 2008;14(1):15–19. 66. Bhandari MS, Petrylak DP, Hussain M. Clinical trials in metastatic prostate cancer--has there been real progress in the past decade? Eur J Cancer 2005;41(6):941–953. 67. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, Prostate Cancer. V.1.2009. NCCN; 2008. 68. Carden CP, Rosenthal MA. Immediate versus delayed chemotherapy in patients with asymptomatic incurable metastatic cancer. Asia Pac J Clin Oncol 2008;3(4):187–198. 69. Berthold DR, Pond GR, Roessner M, de Wit R, Eisenberger M, Tannock AI. Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life response and survival in the TAX-327 study. Clin Cancer Res 2008;14(9):2763–2767. 70. Oken MM, Creech RH, Tormey DC, Horten J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649–655. 71. Balducci L, Yates J. General guidelines for the management of older patients with cancer. Oncology (Williston Park) 2000;14(11A):221–227. 72. Droz J-PB, L. Bolla, M. Emberton et al. International Society of Geriatric Oncology Prostate Cancer Guidelines Proposals in Senior Adult Men. Presented at: 8th Annual Meeting of the International Society of Geriatric Oncology ; 2007; Madrid. 73. Italiano A, Ortholan C, Oudard S et al. Docetaxel-based chemotherapy in elderly patients (age 75 and older) with castrationresistant prostate cancer. Eur Urol 2008. 74. Roessner M, de Wit R, Tannock I et al. Prostate-specific antigen (PSA) response as a surrogate endpoint for overall survival (OS): Analysis of the TAX 327 Study comparing docetaxel plus prednisoe with mitoxantrone plus prednisone in advanced prostate cancer. J Clin Oncol. 2005 ASCO Annual Meeting Proceedings. 2005;23(16 suppl): abstract 4554. 75. Hovey E. George, M. Shapiro, J. Chern, B. Moylan, E. Experience with docetaxel in hormone-refractory prostate cancer (HRPC) at three Australian cancer centers: a retrospective study. Asia-Pac J Clin Oncol 2007;3(3):156–162(7). 76. National Institute for Health and Clinical Excellence (NICE). Docetaxel for the Treatment of Hormone-Refractory Metastatic Prostate Cancer. Quick reference guide. London: NICE; 2006.

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94. Dawson N. Epothilones in prostate cancer: review of clinical experience. Ann Oncol 2007;18(suppl_5):v22–27. 95. Australian Prostate and Urogenital Cancer Group (APUG). Cancer cooperative research groups. 2008. http://www.cosa.org. au/Groups/Co-operativeGroups.htm 96. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol 2008;26(28):4563–45671. 97. Harris KA, Reese DM. Treatment options in hormone-refractory prostate cancer: current and future approaches. Drugs 2001;61(15):2177–21792. 98. National Cancer Institute. NCI Drug Dictionary. NCI, US National Institutes of Health. 99. Tarassoff CP, Arlen PM, Gulley JL. Therapeutic vaccines for prostate cancer. Oncologist 2006;11(5):451–462. 100. Eder JP, Kantoff PW, Roper K et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res 2000;6(5): 1632–1638.

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101. Arlen PM, Gulley JL, Parker C et al. A randomized phase II study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen-independent prostate Cancer. Clin Cancer Res 2006;12(4):1260–1269. 102. Fong L, Kwek SS, O’Brien S et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res 2009;69(2):609–615. 103. Bauman G, Charette M, Reid R, Sathya J. Radiopharmaceuticals for the palliation of painful bone metastasis-a systemic review. Radiother Oncol 2005;75(3):258–270. 104. Lewington VJ, McEwan AJ, Ackery DM et al. A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991;27(8):954–958. 105. Love C, Din AS, Tomas MB, Kalapparambath TP, Palestro CJ. Radionuclide bone imaging: an illustrative review. Radiographics 2003;23(2):341–358.

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REVIEW ARTICLE

What’s New in the Diagnosis of Hepatocellular Cancer? Linda L. Wong1 and Chet Hammill2 Affiliations: 1Department of Surgery, Hawaii Medical Center-East, The University of Hawaii, Honolulu, Hawaii, USA and 2 John A. Burns School of Medicine, Honolulu, Hawaii, USA Submission date: 20th December 2008, Acceptance date: 5th January 2009

Abstract

ity rates.2 The incidence of HCC in the USA has been increasingly steadily over the past two decades. In the late 1990s, the estimated US incidence was 2.4  per 100,000, but based on Survival, Epidemiology, End Results (SEER) data from 2000 to 2004, the overall age-adjusted incidence of these cancers is now estimated at 6.2 per 100,000.3,4 While most cancers in the USA have decreased in incidence and death rate, liver and bile duct cancers had the highest increase in death rate and the second highest increase in incidence between 1995 and 2000.4

Hepatocellular cancer (HCC) is an increasingly important cancer worldwide that accounts for a significant amount of morbidity and mortality. Viral hepatitis and alcohol abuse are etiologic factors in most cases; however, recent studies indicate that metabolic factors such as diabetes, obesity, and insulin resistance may contribute.  In Europe and Japan, where screening is widely practiced, HCC is usually identified at earlier stages, most commonly using ultrasound. However, in the United States, HCC is more likely to be found either on a CT or MRI scan that is performed for an unrelated issue or at an advanced stage in patients who present symptomatically. Newer diagnostic modalities such as contrast-enhanced ultrasonography and positron emission tomography (PET) scanning are being investigated, though their exact role is currently unclear. Several different classification systems are used for HCC, with no global consensus as to which is optimal. Unlike other cancers, the treatment and prognosis of HCC depend not only on tumor characteristics but also on the underlying organ function. It is thus difficult to develop a unified approach to the diagnosis of this heterogeneous cancer. Groups such as the European Association for the Study of the Liver, American Association for the Study of Liver Disease, and the Japanese Society of Hepatology have all issued various guidelines and recommendations. Although there are many areas of controversy, all of the societies recognize the importance of early identification in order to effectively treat HCC.

As the incidence of HCC increases, practicing physicians will more frequently encounter HCC patients in their practices. Since surgical therapies including liver transplant and resection are the optimal treatments for long-term disease-free survival, the challenge is to make every effort to identify patients at risk and diagnose HCC at an early stage while the disease is still amenable to surgical treatment. Even patients who are not surgical candidates may benefit from an earlier diagnosis, as nonoperative therapies continue to improve survival. These include ablative therapies such as radiofrequency ablation, cryotherapy, ethanol injection, and transarterial chemoembolization. In addition, newer chemotherapeutic drugs such as sorafenib, which was recently approved for HCC and other molecular-targeted therapies, show promise for treatment of advanced staged disease.

Keywords: HCC, diagnosis, screening, liver cancer Correspondence: Linda L. Wong MD, 2226 Liliha Street, Suite 402, Honolulu, Hawaii 96817, USA. Tel: +1 (808)5230166; fax: +1 (808)-5284940; e-mail: hepatoma@aol.com

CLINICAL PRESENTATION Advanced HCC usually presents with abdominal pain, an abdominal mass, fatigue, or weight loss. Early stage HCC is usually found incidentally or  by screening of patients with known risk factors. An estimated 75% to 80% of all HCC cases are seen in the setting of viral hepatitis B or C.5 Other known risk factors include chronic alcohol abuse, smoking, and taking oral contraceptives.5–7 Aflatoxins produced by fungal infestation of crops and animal feed, found mostly in underdeveloped countries, are also a risk factor for HCC, especially in hepatitis B carriers.7

INTRODUCTION Hepatocellular cancer (HCC) is the sixth most prevalent noncutaneous cancer and the third most common cause of cancer death worldwide. In 2002, there were approximately 626,000 new cases and 598,000 deaths due to HCC. Most of these cases (82%) occurred in subSaharan Africa, east and southeast Asia, and Oceania, with 55% of all cases reported in China.1 Fewer cases are reported in Europe and the developed countries, but incidence and mortality are variable. Recent data from the World Health Organization showed the highest mortality rates to be in men from France (6.8/100,000), Italy (6.7), and Switzerland (5.9), while Norway, Ireland, and Sweden had the lowest mortalAPJOH 2009; 1: (1). March 2009

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In the 15% to 50% of HCC cases in which viral hepatitis or chronic alcohol abuse is absent, other risk factors are emerging, including diabetes, insulin resistance, and metabolic syndrome.8 One proposed mechanism of hepatocarcinogenesis is chronic hyperinsulinemia, 89

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which results in the synthesis and activity of insulinlike growth factor (IGF-1). This in turn stimulates cell proliferation and inhibits apoptosis.9,10 Initial studies have shown that diabetes increases the risk of HCC in hepatitis C patients.11–13 Extreme obesity (BMI>30) was also shown to be associated with a four-fold increased risk of developing HCC in hepatitis C patients. Patients with hepatitis B or C who had both diabetes and obesity were shown to have a 100-fold increased risk of HCC.14  More recent studies suggest that diabetes and insulin resistance are also risk factors for HCC, independent of whether or not the patient has viral hepatitis. A systematic review of the association between diabetes and HCC demonstrated a pooled odds ratio of 2.5 in 13 studies. Ten of these studies showed that the risk of diabetes was independent of alcohol use or viral hepatitis.15 Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) develop in close association with insulin resistance, diabetes, and metabolic syndrome. There is indirect evidence that patients with NAFLD and NASH may eventually develop cirrhosis, end-stage liver disease, and HCC. In a study of 105 patients with HCC, Marrero et al. found that 51% had hepatitis  C cirrhosis and 29% had  cryptogenic cirrhosis. About half of the cohort with cryptogenic cirrhosis exhibited  histological or clinical features of NAFLD.16 In a case-controlled study by Bugianesi et al., patients with cryptogenic cirrhosis-related HCC (compared to HCC secondary to viral hepatitis or alcohol abuse) were more likely to be diabetic and obese. This group also had higher glucose, cholesterol, and triglyceride levels, in addition to  evidence of higher levels of insulin resistance.17 In 2005, it was estimated that 1.6 billion people in the world  were overweight and another 400  million  were obese. In addition, 171 million currently have diabetes, a figure that is expected to double by 2,030.18  In the USA, the incidence of diabetes has steadily risen from 8.3% of the population in 1988–1994 to 10.2% in 2001– 2004.19 As a result of this global increase in diabetes and the increasing evidence that obesity and metabolic syndrome are risk factors for HCC, the incidence of this malignancy will continue to escalate.

28% of patients.24,29 This is in contrast to Japan and Europe, where 50% to 60% of HCC cases are identified with screening.30 Even with the benefits of screening shown by these retrospective studies, it is not clear how it should be performed or who should be screened. The most common methods for screening are alpha-fetoprotein (AFP) and ultrasound. Marrero et al. found that AFP as a screening test has a sensitivity of 25% to 65% and specificity of 79% to 95%; however, these results are variable based on the AFP value used to indicate a positive result.31 Other tumor markers such as Prothrombin Induced by Vitamin K Absence II (PIVKA II), glycosylated AFP to total AFP ratio, alpha fucosidase, and glypican 3 have been suggested but have not been adequately investigated.32 Ultrasound has been the most widely utilized imaging modality for surveillance, and Bolondi et al.33 determined that it has a sensitivity of 65% to 80% and a specificity greater than 90%. Time intervals used for screening in these studies varied from 3 months to 1 year, but the optimal surveillance interval is unknown.25,34–37 Multiple  mathematical decision/cost-analysis models have been developed to assess screening practices. They assume that screening for HCC has been recommended for certain hepatitis B carriers, nonhepatitis B cirrhotics, and patients with autoimmune hepatitis.31 The models are based on the estimated annual incidence of HCC in hepatitis B carriers at 0.5%, in hepatitis B cirrhotic patients at 2.5%, and in chronic hepatitis  C patients at 2% to 8%.38–42  Unfortunately, the  mathematical models arrive at different conclusions, including: 1)  no benefit of biannual screening, 2)  screening only for transplant-eligible patients, or 3)  screening all high-risk patients with AFP and ultrasound every 6 months.33,35,43–45 Overall, decision models and reviews have provided some insight, but there is no consensus regarding the optimal screening protocol. A large randomized prospective, long-term study would provide the answers, but it is unlikely that such a study will ever be conducted. This is because it is generally believed that screening is helpful; therefore, withholding screening could be construed as unethical. Current recommendations of the American Association for the Study of Liver Disease regarding HCC screening and surveillance are summarized in Table 1.46

SCREENING FOR HCC Retrospective studies have demonstrated that screening for HCC allows for earlier identification of tumors, resulting in patients being more likely to qualify for surgical intervention or transplantation.21–25 Trevisani et al. found that with screening, nearly twice as many patients underwent liver transplants.27 This study, as well as others, also demonstrated an improved survival rate in patients who received surgery or transplant.20,23,26–28 Unfortunately, screening for HCC in the USA is underutilized, with several studies indicating that HCC was identified by screening in only 22% to APJOH 2009; 1: (1). March 2009

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RADIOLOGIC DIAGNOSIS Although ultrasound has been recommended for screening, CT or MRI scanning provides more detailed characterization and/or confirmation of the diagnosis of HCC. More recently, contrast-enhanced ultrasound (CEUS) has been used to aid in the diagnosis of HCC. CEUS utilizes intravenously administered microbubbles as contrast agents, which do not have the renal toxicity associated with other contrast 90

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agents. In addition, microbubbles allow for better definition of tumors and improved visualization of arterial neoangiogenesis, which is associated with malignancy. CEUS has improved the accuracy of conventional ultrasound, especially for detection of lesions smaller than 2 cm.47,48 Sensitivity of CEUS is 52% to 100%, and specificity is 90% to 100%, with overall accuracy at 85% to 97%.47,49–52 Several studies suggest that the accuracy is similar to MRI or CT,48,52–54 and Jang et al. demonstrated that CEUS could help determine the degree of tumor differentiation.55 Lanka et al. reported that CEUS decreased the need for other imaging, decreased time to diagnosis, and facilitated successful guidance for ablation.56 However, Lencioni et al. reported that CEUS is not as effective at evaluating small tumors; therefore, CT or MRI scans are still necessary for proper staging.57 More recently, targeted microbubbles have been developed, which may aid in molecular imaging as well as in drug and gene delivery.58 HCC is a hypervascular malignancy that has been shown to overexpress proangiogenic factors including vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGF), and angiopoetin-2. VEGF receptor-2 and alpha (v) beta (3) integrins have been attached to microbubbles to allow visualization of tumor angiogenesis in animal models.59 In addition to their use in imaging, angiogenesis inhibitors are under evaluation as chemotherapeutic agents for the treatment of HCC. The exact role of CEUS in HCC has not been completely defined, but targeted microbubbles have the potential to improve imaging and therapy in the future.

Table 1. Surveillance for HCC Hepatitis B carriers Asian men ≥40 years Asian women ≥50 years All chronic hepatitis B carriers Family history of HCC Africans over age 20 For noncirrhotic hepatitis B carriers, risk of HCC varies depending on severity of underlying liver disease and current/past hepatic inflammatory activity. Patients with high hepatitis B virus (HBV) DNA concentration and those with ongoing hepatic inflammatory activity remain at risk for HCC Nonhepatitis B carriers Hepatitis C Alcoholic cirrhosis Genetic hemochromatosis Primary biliary cirrhosis No definite recommendations due to lack of data for: Alpha-1-antitrypsin deficiency Nonalcoholic steatohepatitis Autoimmune hepatitis

PATHOLOGIC DIAGNOSIS

The role of PET scans in the diagnosis of HCC is also not well defined. PET scans are expensive, and the literature primarily consists of small studies with only a few series that involve more than 50 patients. Early studies suggested that the sensitivity of PET was suboptimal, with up to 50% of known HCC cases undetected by the scans.60–62 Low grade and well-differentiated tumors have much lower activity on PET scans and are frequently not visualized.63 Isolated studies have shown that PET scans may be useful for identifying recurrences at radiofrequencyablated sites64,65 and in patients who have high AFP after liver resection or transplant.66 Typically, F-18fluorodeoxyglucose is used as a tracer for PET scans, but newer agents such as 18C-choline may allow for better detection of HCC, especially those consisting of moderately differentiated lesions.67 PET currently seems to be most useful for identifying extrahepatic metastases.68–71 In the largest series of 87  patients studied by Yoon et al., PET scans identified 24  patients with extrahepatic metastases, which included four patients with nodal metastasis and six patients with bony lesions not seen on conventional imaging.68  Additional studies will be necessary to clarify the role of PET in HCC. www.slm-oncology.com

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Liver biopsy may be useful if imaging and tumor markers are equivocal. Although a biopsy can seemingly afford a rapid answer and tissue confirmation, there are risks of bleeding, pneumothorax, and tumor seeding through the needle tract. Bleeding is especially concerning in patients who usually have coagulopathy, thrombocytopenia, and ascites as a result of their liver disease. The initial case series that looked at needle-tract seeding reported an incidence of 5%; however, a recent meta-analysis of eight studies found the seeding incidence to be 2.7%, with mean time to development of tumor along the needle tract of 17 months.72,73 Although the incidence is not as high as initially reported, patients who do develop needle-tract tumor seeding are no longer candidates for liver transplant. Pathologic diagnosis of small tumors can also be difficult. Attempts are under way to identify tissue markers that can more accurately make the diagnosis. Nam et al. have identified a microarray-generated signature of 120 genes that discriminated between dysplastic nodules and HCC in hepatitis  B virus (HBV) patients.74 Glypican-3 immunostaining, or as part of a 3-gene set including LYVE1 and survivin, has also 91

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between clinicians and help unify treatment groups in large studies and multi-center trials. Unlike other cancers, the treatment and prognosis of HCC are dependent on underlying liver function in addition to tumor characteristics. Various staging systems are used for HCC, some of which incorporate liver function, but there is no global consensus regarding the best system. In the USA, most cancers are staged with the American Joint Commission on Cancer (AJCC) staging system, which is based on tumor characteristics (T), nodal status (N) and metastases (M). Although this has been used historically in HCC staging, this system is based upon pathological findings which are often not known, and it does not account for underlying liver function. Modifications have been made by the United Network for Organ Sharing (UNOS), which is the current staging system used for liver transplant allocation (Table 2).79 In Japan, the Okuda staging system was developed in the 1980s. This system accounted for liver function by including bilirubin, albumin, the presence of ascites, and tumor volume. The Okuda stage appeared to be useful for identifying patients with end-stage hepatocellular cancer.80 The Cancer of the Liver Italian Program (CLIP) staging is a system of seven stages that not only takes into account underlying liver function using Childs Class  A, B or C but also includes tumor characteristics, vascular invasion, and AFP (Table 3). This was initially developed based on a retrospective study of 435 patients and was externally validated by several other groups.81–85 The CLIP score stratifies patients by prognosis better than Okuda staging; however, CLIP is unable to divide patients into appropriate treatment groups. The Barcelona Clinic Liver Cancer (BCLC) staging system incorporates tumor size, underlying liver function, presence of portal hypertension, and physical status (Table  4). Patients are assigned a stage between A and D (early, intermediate, advanced, or end-stage), and these classifications are used for treatment planning.86 Marrero et al., through evaluation of seven different scoring systems in 239 patients, found the BCLC staging system to have the best prognostic stratification.87 This system is currently endorsed by the EASL and AASLD.46,72 More recently, the Japanese have developed the Japan Integrated Staging Score (JIS). This score involves the modified TNM system (created by the Liver Cancer Study Group of Japan) and the Childs class (Table 5). The Japan Society of Hepatology (JSH) currently endorses this staging system as it is better at discriminating between prognoses in small tumors. JSH recommends that BCLC should be used for treatment selection but that it is not appropriate for predicting survival.73 The JIS scoring system has not been validated by a Western cohort.

been shown to be highly predictive of HCC.75,76 Hopefully, once these novel markers are validated, they will provide a standardized method of differentiating HCC from dysplastic nodules.

CURRENT GUIDELINES Guidelines for the diagnosis of HCC were established by the European Association for the Study of the Liver (EASL) during a consensus conference in 2000. If a mass less than 1 cm was identified with ultrasound, EASL recommended serial ultrasound every 3 months. For nodules greater than 2 cm that were identified with ultrasound and verified with CT, MRI, angiography, or an AFP >400 ng/mL, a presumptive diagnosis of HCC could be made without biopsy.  Biopsy was recommended for nodules between 1 cm and 2 cm, as imaging techniques did not have sufficient accuracy to differentiate between HCC, dysplastic nodules, or benign lesions.77 The American Association for the Study of Liver Disease (AASLD) published its guidelines in 2005.  Like EASL, the AASLD stated that lesions less than 1  cm have a low likelihood of being HCC but recommended that they be followed carefully with ultrasound.  Lesions that do not progress in 1 to 2 years are unlikely to be HCC. Hypervascular lesions larger than 2 cm with an AFP >200 ng/mL are presumed to be HCC and do not require confirmation with biopsy. Lesions between 1 and 2 cm have a high likelihood of being HCC, and biopsy is recommended for confirmation. However, it was cautioned that biopsy may not be reliable due to the technical difficulty in accurately sampling lesions of this size. In addition, pathologists may have difficulty differentiating dysplastic nodules from welldifferentiated HCC in small lesions. Negative biopsies still require close follow-up with enhanced imaging to monitor for growth.46   Unlike the conclusions drawn by the EASL and AASLD, the consensus conference from the Japanese Society of Hepatology concluded that the diagnosis of HCC can be made from imaging regardless of size. The society suggests that the diagnosis of HCC can be made with typical vascular patterns seen on CT, dynamic MRI, CEUS, or with a combination of CT arteriogram and portagram. They also stated that AFP >200  ng/mL, PIVKA II >40  mAU/mL,  and AFP-L3 positivity are highly suggestive of HCC even without ultrasound demonstration of a nodule. Hypovascular lesions on MRI or CEUS scans are presumed to be benign and should be followed with serial imaging. In their algorithms, a liver biopsy is used liberally for confirmation of HCC.78

STAGING AND CLASSIFICATION In general, staging systems for cancer have been developed to guide treatment and to help physicians determine prognosis. Staging systems can serve as a language APJOH 2009; 1: (1). March 2009

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Table 2. American Joint Commission on Cancer (AJCC) Staging for Liver Cancer

Table 3. Cancer of the Liver Italian Program (CLIP) Scoring System

T1

Points

0

1

2

Child-Pugh

A

B

C

Tumor morphology

Uninodular, <50%

Multinodular, <50%

Massive <50%

AFP (ng/dL)

<400

>400

Portal vein thrombosis

No

Yes

Solitary tumor without vascular invasion

T2 Solitary tumor with vascular invasion or multiple tumors all <5 cm T3 Multiple tumors >5 cm or involving a major branch of portal vein or hepatic vein T4 Tumor with direct invasion of other organs other than gall bladder or perforation of visceral peritoneum

N0 no nodal involvement

N1 regional nodes are involved

M0 no evidence of distant metastasis

M1 distant metastasis

not only predicts prognosis but also guides treatment. This level of understanding has not been reached with HCC, but the recent introduction of sorafenib, a multikinase inhibitor, demonstrates a better understanding of the molecular pathways involved in HCC. Genetic aberrations, dysregulated gene expression, epigenetic alterations, and protein modifications all play a role in the pathogenesis of HCC and have been used in attempts to classify patients. The most successful classification attempts to date have used gene expression signatures based on tumor tissue. Lee et al., using genes related to cell proliferation, apoptosis, ubiquitination, and histone modification, identified a 406-gene expression signature that classified patients into two groups with significant differences in survival.88 Ye et al. developed a 153-gene expression signature that identified patients with metastatic disease.89 Two additional groups have identified two separate gene expression signatures that identify patients at high risk for recurrence.90,91 In addition to gene expression, microRNA expression is also being studied. MicroRNAs are small, noncoding RNAs that control a wide range of biological functions including cell proliferation, differentiation, and apoptosis. Comparison of microRNA expression in HCC tumors to the surrounding liver tissue has resulted in the identification of microRNA expression signatures associated with tumor status, poor survival, and metastasis.92–94 Although these findings are exciting, they need to be externally validated through further investigation before they are ready for use in the clinical setting.

Stage I

T1N0M0

II

T2N0M0

IIIA

T3N0M0

IIIB

T4N0M0

IIIC

anyTN1M0

IV

anyTanyNM1

UNOS modified TNM T1

One nodule <2.0 cm

T2

One nodule <5 cm or two or three nodules all <3.0 cm

T3

One nodule >5 cm, two or three nodules at least one >3 cm

T4a

Four or more nodules, any size

T4B T2, T3 or T4a with intrahepatic portal or hepatic vein involvement Stage I

T1

II

T2

III

T3

IVa1 T4a IVa2 T4B IVb

any N1 or M1

SUMMARY HCC can be diagnosed and staged with various imaging techniques and tumor markers. Although no staging or scoring system is universally accepted, several systems incorporate measures of underlying liver function and are more promising for stratifying prognosis and treatment. Molecular classification may one day prove to be a better method of predicting prognosis and determining treatment; however, a significant amount

Due to the difficulty in clinical classification and staging of HCC, attempts are ongoing to develop a molecular classification. The molecular pathogenesis of HCC is slowly being elucidated and has the potential to revolutionize diagnosis and treatment. The treatment of breast cancer can be taken as an example, whereby testing for hormonal receptors and HER2/NEU status www.slm-oncology.com

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Table 4. BCLC (Barcelona Clinic Liver Cancer) Staging Classification Stage

PST

Tumor status

Liver functional status

A (early HCC) A1 

0

Single < 5 cm

Normal bilirubin, no portal HTN

A2

0

Single < 5 cm

Normal bilirubin, portal HTN

A3

0

Single < 5 cm

Abnormal bilirubin and portal HTN

A4

0

3 tumors, all <3 cm

Child-Pugh A-B

B (intermediate HCC)

0

Single >5 cm or >3 tumors, ?3 cm

Child-Pugh A-B

C (advanced HCC)

1–2

Vascular invasion or extrahepatic spread

Child-Pugh A-B

D (end-stage HCC)

3–4

Any

Child-Pugh C

PST, performance status; HTN, hypertension.

Table 5. Liver Cancer Study Group of Japan TNM Staging

the importance of early diagnosis in HCC to allow patients the opportunity to receive curative treatments.

T factor

I- single tumor

II - <2 cm

Disclosures: The authors have no financial interests to disclose related to the contents of this article.

III - No vascular involvement

T1

Fulfilling 3 factors

T2

Fulfilling 2 factors

T3

Fulfilling 1 factor

T4

Fulfilling 0 factors

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73. Silva MA, Hegab B, Hyde C, Guo B, Buckels JA, Mirza DF. Needle track seeding following biopsy of liver lesions in the diagnosis of hepatocellular cancer: a systematic review and meta-analysis. Gut. 2008;57:1592–1596. 74. Nam SW, Park JY, Ramasamy A, et al. Molecular changes from dysplastic nodule to hepatocellular carcinoma through gene expression profiling. Hepatology. 2005;42:809–818. 75. Paradis V, Degos F, Dargere D, et al. Identification of a new marker of hepatocellular carcinoma by serum protein profiling of patients with chronic liver diseases. Hepatology. 2005;41:40–47. 76. Llovet JM, Chen Y, Wurmbach W, et al. A molecular signature to discriminate dysplastic nodules and early hepatocellular carcinoma in HCV-cirrhosis. Gastroenterology. 2006;131: 1758–1767. 77. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma; Conclusions of the Barcelona-2000 EASL conference. J Hepatol. 2001;35:421–430. 78. Kudo M, Okanoue T. Management of hepatocellular carcinoma in Japan: consensus-based practice manual proposed by the Japan Society of Hepatology. Oncology. 2007;72(suppl):2–15. 79. Greene FL, Page DL, Fritz A. AJCC Cancer Staging Manual. 6th ed. Philadelphia, PA: Lippincott-Raven Publishers; 2002. 80. Okuda K, Ohtsuki T, Obata H, et al. Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Cancer. 1985;56:918–928. 81. The Cancer of the Liver Italian Program (CLIP) Investigators. A new prognostic system for hepatocellular cancer: a retrospective study of 435 patients. Hepatology. 1998;28:751–755. 82. CLIP. Prospective validation of CLIP score: a new prognostic system for patients with cirrhosis and hepatocellular carcinoma. Hepatology. 2000;31:840–845. 83. Ueno S, Tanabe S, Sako K, et al. Discrimination value of the new western prognostic system (CLIP score) for hepatocellular carcinoma in 662 Japanese patients. Hepatology. 2001;34: 529–534. 84. Farinati F, Rinaldi M, Gianni S, Naccarato R. How should patients with hepatocellular carcinoma be staged? Validation of a new staging system. Cancer. 2000;89:2266–2273. 85. Takanishi DM, Severino R, Wong LL. The Cancer of the Liver Italian Program (CLIP) score: validation of a new prognostic system for hepatocellular carcinoma. Hawaii Med J. 2007;66:209–212. 86. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329–338. 87. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology. 2005;41:707–716. 88. Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–676. 89. Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus positive metastatic hepatocellular carcinomas using gene profiling and supervised machine learning. Nat Med. 2003;9:416–423. 90. Iizuka N, Oka M, Yamada-Okabe H, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361:923–929. 91. Kurokawa Y, Matoba R, Takemasa I, et al. Molecular-based prediction of early recurrence in hepatocellular carcinoma. J Hepatol. 2004;41:284–291. 92. Murakami Y, Yasuda T, Saigo K, et al. Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 2006;25:2537–2545. 93. Budhu A, Jia HL, Forgues M, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47:897–907. 94. Huang YS, Dai Y, Yu XF, et al. Microarray analysis of microRNA expression in hepatocellular carcinoma and nontumorous tissues without viral hepatitis. J Gastroenterol Hepatol. 2008;23:87–94.

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CASE REPORT

Non-Hodgkin’s Lymphoma-Associated Chylothorax: A Case Report and Literature Review Rajesh Kashyap1 Affiliation: 1Department of Haematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bariely Road, Lucknow 226014 UP, India Submission date: 3rd December 2008, Acceptance date: 31st December 2008

Abstract

Laboratory investigations showed a hemoglobin level of 10.3 g/dL, total leukocyte count of 6.8  ×  109/L and a platelet count of 132 × 109/L. The serum lactate dehydrogenase (LDH) level was elevated to 1130 U/L (normal range 85 to 450 U/L). The biochemical tests for renal and liver functions were within normal limits. Chest radiograph showed bilateral pleural effusion with mediastinal enlargement. A computed tomography (CT scan) of the thorax revealed multiple enlarged mediastinal lymph nodes with bilateral pleural effusion and a CT scan of the abdomen showed ascites with hepatosplenomegaly. The spleen had multiple hypoechoic lesions. The retroperitoneal lymph nodes were enlarged with encasement of the abdominal great vessels. There was no evidence of venous thrombosis. An ultrasound guided Tru-cut biopsy of the enlarged abdominal lymph nodes was performed. The histopathological examination showed a diffuse population of atypical lymphoid cells which had round to oval nuclei with irregular contours and scant cytoplasm. Immunohistochemistry staining showed that these tumor cells were positive for leukocyte common antigen (L-CA) and CD20 and negative for CD3, cytokeratin and nonspecific enolase. The histopathological diagnosis was diffuse large B-cell lymphoma (DLCL). The bone marrow biopsy was normal. A pleural tap revealed hemorrhagic exudative fluid. The cytological and biochemical examination of the pleural fluid showed 1,800 red cells/mL, 600 neutrophils/mL, and a protein level of 4.1 g/dL.

Chylothorax is a pathological state that occurs due to a collection of fat-rich chyle in the pleural space. It is a rare condition and occurs following trauma or in association with a malignancy. Lymphoma is the most common neoplasia associated with chylothorax. However, chylothorax accounts for less than 12% of all pleural effusions seen in non-Hodgkin’s lymphoma. Recurrence is common and is associated with significant morbidity and mortality. Keywords: chyle, pleural effusion, lymphoma Correspondence: Rajesh Kashyap, Associate Professor, Department of Haematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Rae Bariely Road, Lucknow 226014 UP, India. Fax: +91-522-2668017; e-mail: rajkashyapmd@yahoo.co.in

INTRODUCTION Chylothorax is a rare but well-recognized condition characterized by accumulation of chylous fluid in the pleural space. This chylous fluid is rich in triglycerides and chylomicrons.1 Malignancy is the most common nontraumatic cause of chylothorax and non-Hodgkin’s lymphomas (NHL) are associated with one-half to threefourths of all chylothorax cases.2,3 However, only 12% of pleural effusion cases in NHL may be chylous.4 Recurrence of chylothorax in NHL is common and is associated with significant morbidity and mortality. Here, we report a case of a 63-year-old man with NHL and recurrent chylothorax. The challenges with his diagnosis and management are discussed.

A diagnosis of NHL (DLCL) stage IIIB was made and the patient was started on combination chemotherapy, R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine and prednisolone). Three weeks after the administration of the first cycle of chemotherapy, the patient developed breathlessness, bilateral pedal edema, and abdominal distension. A repeat CT-scan of the thorax showed bilateral pleural effusion (Figure 1). A thoracocentesis was performed; 1.5 L of thick, creamy white fluid was drained (Figure 2) and an intercostal thoracic drainage tube was placed for continuous pleural drainage. Physical and biochemical examination of the pleural fluid showed 800 cells/mL, predominantly lymphocytes, with no malignant cells present. The protein level was 1.5  g/dL and the glucose level was 35  mg/dL. The pleural fluid triglycerides and cholesterol level was

CASE REPORT A 63-year-old man presented with a history of anorexia and weight loss for 3 months and breathlessness for the past 1 month. Upon physical examination, the patient had a fever of 101  °F, moderate pallor and bilateral pitting pedal edema. There was no enlargement of the peripheral lymph nodes. Examination of the respiratory system revealed dullness on both sides from the 6th intercostal space onwards, with diminished breath sounds. Abdominal examination revealed moderate ascites with hepatomegaly (2 cm below the costal margin) and splenomegaly (10 cm below the costal margin). APJOH 2009; 1: (1). March 2009

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Figure 1. CT scan of the thorax showing bilateral pleural effusion.

542 mg/dL and 65 mg/dL, respectively. The corresponding serum triglyceride and cholesterol level was 81 mg/ dL and 149  mg/dL, respectively. The ratio of pleural fluid to serum triglyceride levels was 6.69 and the ratio of pleural fluid to serum cholesterol was 0.043, which is suggestive of chylous pleural effusion. A diagnosis of chylothorax secondary to NHL was made. The patient was started on oral dietary supplementation with medium chain triglycerides (MCT). After the next two cycles of R-CHOP, there was complete resolution of chylothorax. The patient was given a total of 6 cycles of R-CHOP, followed by 2 cycles of salvage chemotherapy. He attained complete remission, was disease-free at his 6-month post chemotherapy follow-up, and has had no recurrence of chylothorax.

Figure 2. Fluid obtained after a pleural tap had a creamy yellow appearance suggestive of chylothorax.

of the thoracic duct to the spine, esophagus, and arch of the aorta makes it vulnerable to injury during surgery. Congenital heart surgery, esophagectomy, pulmonary resection, and gastric resection have also been associated with chylothorax formation. The incidence of postoperative chylothorax is less than 1%. Penetrating chest injury and spinal fracture can also produce chylothorax. Malignancy is the most common cause of nontraumatic chylothorax, and NHL accounts for 50% to 75% of all cases. Bronchogenic carcinoma is the next most common cause of chylothorax.2,3 Pleural effusions are seen in up to 20% of patients with NHL. However, in less than 12% of NHL-associated pleural effusions, the fluid is chylous.4 Chronic lymphocytic leukemia and Waldenstrom’s macroglobulinemia are other hematological conditions associated with chylothorax.6 Other causes which can produce chylothorax include lymphangiectasia, liver cirrhosis, subclavian vein thrombosis, tuberculosis, filariasis, and sarcoidosis.7

Chylothorax The term “chylothorax” is derived from the Latin words Chylus (juice) and thorax (breast) and refers to the collection of chyle-containing lymphatic fluid in the pleural space. Chyle is a lymphatic fluid rich in fat that has a white, milky, or opalescent appearance.1 The fat in chyle consists predominantly of chylomicrons and triglycerides, with lesser quantities of cholesterol and phospholipids. The concentration of fat in chyle ranges from 0.4 to 6.0 g/dL and the protein concentration ranges from 2.2 to 6.0  g/L.5 Lymphocytes are the predominant cell type in the fluid.

Pathogenesis In trauma related chylothorax, injury to the thoracic duct causes leakage of chyle into the posterior mediastinum forming a “chyloma”. If the mediastinal pleura are intact, the chyloma ruptures after a few days into the pleural space, usually on the right side at the base of the pulmonary segment producing chylothorax.

Etiology Chylothorax can occur due to a variety of causes (Table 1). Iatrogenic trauma during surgery accounts for approximately 25% of all cases. The anatomical proximity

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Non-Hodgkin’s Lymphoma-Associated Chylothorax: A Case Report and Literature Review

In neoplastic conditions, the enlarged hilar lymph nodes compress the lymphatic channels and thoracic duct, resulting in obstruction of the drainage of lymphatic fluids from the periphery of lung parenchyma and pleural surfaces. This leads to extravasation of the chyle and lymph, producing chylothorax. Another postulated mechanism for chylothorax formation is the direct infiltration of the thoracic duct by tumor cells. This infiltration by the neoplastic cells makes the duct more rigid and vulnerable to rupture following minimal or occult trauma resulting in chyle leakage and chylothorax formation.

Table 1. Etiology of Chylothorax A. Congenital Down’s syndrome

Noonan syndrome

Tracheo-esophageal fistula

Thoracic duct hypoplasia

B. Acquired Traumatic

Clinical Presentation The clinical manifestations of chylothorax are similar to other types of pleural effusion. The patient usually has signs and symptoms of the underlying disease. When the effusion is large, it produces dyspnea and chest discomfort. Fever is typically absent, as the chyle does not elicit an inflammatory response. Superadded bacterial infection is rare since the chyle is bacteriostatic. Chylothorax should be suspected in patients with lymphoma when there is persistent drainage of pleural fluid in the thoracostomy tube. The pleural fluid may not appear chylous if the pleural fluid is mixed with blood or if the patient is fasting. Following a high fat meal, the pleural fluid in patients with suspected chylothorax shows a dramatic change in its color and in its biochemical constituents. A detailed clinical evaluation provides a clue to its etiology.

Iatrogenic (surgical)

Thoracic surgery

Coronary bypass graft

Gastric resection

Blunt trauma Nontraumatic

Neoplastic

Lymphoma

Metastatic tumors

Kaposi sarcoma

Castleman’s disease

Nonneoplastic

Hepatic cirrhosis

Diagnosis

Sarcoidosis

A chest radiograph in a lateral and decubitus position helps in estimating the size of the effusion. A CT scan is useful in patients with malignancies to detect the sites and size of mediastinal lymphadenopathy. It detects any associated lung parenchymal or pleural disease. The diagnosis is confirmed by obtaining a sample of pleural fluid and estimating its triglycerides and cholesterol content with reference to the corresponding serum levels. The fluid triglyceride level is a very sensitive indicator of chylothorax, with a level greater than 110 mg/dL being strongly suggestive of the disease and a level less than 50  mg/dL eliminating the diagnosis. Chylothorax needs to be differentiated from pseudochylothorax, which is frequently seen in association with tuberculosis and rheumatoid arthritis. Pseudochylothorax is also a milky to creamy white fluid, but contains high levels of cholesterol and the characteristic chylomicrons are absent (Table 2). Romero et al.8 have proposed diagnostic criteria for chylothorax which include: i) pleural fluid triglycerides >110 mg/dL; ii) pleural fluid to serum triglycerides ratio >1; and iii) pleural fluid to serum cholesterol ratio <1.

Hypothyroidism

Lymphangiectasis

Bechet’s disease

Histoplasmosis

Tuberculosis

Sarcoidosis

Venous thrombosis

ment of the underlying cause (Table 3). Thoracocentesis and tube thoracostomy are effective in relieving the dyspnea due to pleural effusion. However, continued drainage of chyle from the body leads to loss of essential proteins, immunoglobulins, fat, vitamins, electrolytes, and water. Nutritional support is provided by giving a fat-free diet with oral medium chain triglycerides (MCT) supplementation or parenteral hyperalimentation. The MCTs are directly absorbed into the portal vein effectively supplementing the diet with lipids. In addition, MCTs reduce the quantity of chyle flow through the thoracic duct, thereby reducing the leak into the pleural cavity. If the chyle production remains unchanged, total parenteral nutrition (TPN) should be started. Parenteral

Treatment The goals of treatment are a) evacuation of the chylous fluid and facilitate re-expansion of the lung; b) reduction of chyle formation; c) nutritional support; and d) treatwww.slm-oncology.com

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Table 2. Laboratory Profile of Chylothorax versus Pseudochylothorax

Table 3. Therapeutic Options for Chylothorax A. Conservative

Parameter

Chylothorax

Pseudochylothorax

Color

Milky/ creamy white

Milky/ creamy white

Cells

Lymphocyte predominance

Variable

Cholesterol crystals

Absent

Present

Proteins (g/dL)

>3.0

>3.0

Glucose (g/dL)

>60

<60

Triglycerides (mg/dL)

>110

<50

Pleural fluid/ serum ratio

>1

<1

Cholesterol (mg/dL)

<100

<200

Pleural fluid/ serum ratio

<1

>1

B. Medical

Nutritional support Chemical Thoracocentesis pleurodesis Tube thoracostomy

C. Surgery Pleuroperitoneal shunt Thoracic duct ligation Pleurectomy

Microscopy

Malignancy associated chylothorax rarely responds to repeated thoracocentesis or intercostals tube (ICT) drainage alone.11 Treatment of the underlying condition with chemotherapy and/or radiotherapy is essential. Previously, when radiotherapy was the main therapeutic modality, mediastinal radiation was found to be effective in controlling chylothorax in 68% of patients with lymphoma and in 50% of patients with other malignancies. Recurrence of chylothorax is quite frequent and is usually due to treatment failure of the primary disease or primary disease relapse. In these patients, chemical pleurodesis with talc is highly effective. It has been observed that pleurodesis via thoracoscopy is more successful than via tube thoracostomy in chylothorax. Medication reactions, persistent drainage, empyema, and acute respiratory distress syndrome (ARDS) are reported complications of thoracoscopic talc pleurodesis.12,13

Biochemistry

hyperalimentation is a more effective method of dietary supplementation for the treatment of chylothorax. In patients with traumatic chylothorax, wherein spontaneous healing occurs over several days, chest tube drainage and nutritional support are adequate for management. Surgery is indicated when the pleural drainage is >1.5 L/ day in adults and >100 mL/per year of age/day in children for at least a period of 5 days or when the chyle flow has not decreased after at least 2 weeks of conservative management, which is an indicator that surgery must be performed.9 In patients with traumatic chylothorax, the site of the defect of the thoracic duct should be identified and repaired. In situations where the defect cannot be located, duct ligation can be performed. In patients with nontraumatic chylothorax who are not responding to conservative measures, a pleuroperitoneal shunt or thoracic duct ligation can be performed. Milson and colleagues10 have recommended that a pleuroperitoneal shunt be inserted for a short period of time before performing surgical repair or duct ligation in patients with nontraumatic chylothorax. This approach reduces the loss of chyle and improves the nutritional status of the patient before surgery. It also reduces the hospitalization cost and risk of iatrogenic complications. However, pleuroperitoneal shunt insertion is contraindicated in patients who have associated chylous ascites. Shunt occlusion is seen in up to 10% of patients and is a major problem. APJOH 2009; 1: (1). March 2009

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Disclosures: The author has no financial interest to disclose related to the contents of this article.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Valentine VG, Raffin TA. The management of chylothorax. Chest. 1992;102:586–591. Strausser JL, Flye MW. Management of non-traumatic chylothorax. Ann Thorac Surg. 1981;31:520–526. Doerr CH, Miller DL, Ryu JH. Chylothorax. Semin Respir Crit Care Med. 2001;22:617–626. Berkman N, Breuer R, Kramer MR, Polliack A. Pulmonary involvement in lymphoma. Leuk Lymphoma. 1996;20:229–237. Robinson CL. The management of chylothorax. Ann Thorac Surg. 1985;39:90–95. Anton E, Bouros D. Chylothorax in hematological malignancies. Chest. 2005;127:1866–1867. Johnstone DW, Feins RH. Chylothorax. Chest Clin N Am. 1994;3:617–628. Romero S, Martin C, Hernandez L, et al. Chylothorax in cirrhosis of the liver: analysis of its frequency and clinical characteristics. Chest. 1998;114:154–159. Selle JG, Snyder WH, Schreiber JT. Chylothorax: indication for surgery. Ann Surg. 1973;177:245–249. Milsom JW, Kron IL, Rheuban KS, Rodgers BM. Chylothorax: an assessment of current surgical management. J Thorac Cardiovasc Surg. 1985;89:221–227. Roy PD, Carr DT, Payne WS. The problem of chylothorax. Mayo Clin Proc. 1967;42:457–467. Mares DC, Mathur PN. Medical thoracoscopic talc pleurodesis for chylothorax due to lymphoma. A case series. Chest. 1998;114:731–735. Vargas FS, Milanez JR, Filomeno LT, et al. Intrapleural talc for the prevention of recurrence in benign or undiagnosed pleural effusions. Chest. 1994;106:1771–1775.

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CASE REPORT

Rapidly Progressive Cushing’s Syndrome in a Carcinoma of Unknown Primary Origin Kathryn M. Field1, Robin Cassumbhoy2, Bill Murray3 and Linda Mileshkin1 Affiliations: Departments of 1Medical Oncology, 2Radiology and 3Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia Submission date: 5th January 2009, Acceptance date: 10th January 2009

ABSTRACT This discussion highlights key investigations required when making a diagnosis of Cushing’s syndrome in cancer patients. The striking radiologic findings, together with the unusual clinical picture, will provide a valuable reminder of endocrinologic diagnoses that may overlap with oncologic investigations, in addition to a review of the methods by which Cushing’s syndrome and its source are diagnosed. Keywords: Cushing’s syndrome, neuroendocrine, ACTH, endocrine, cancer Correspondence: Dr Linda Mileshkin, Department of Medical Oncology, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, Victoria, Australia 8006. Tel: +61 3 9656 1111; fax: +61 3 9656 1408; e-mail: Linda.Mileshkin@petermac.org

CASE DISCUSSION A 47-year-old female nonsmoker presented with rapid onset of hirsutism, acneiform rash, weight gain, hyperglycemia, hypertension and dyspnea. Her symptoms developed over a period of approximately 1 month. She had been a previously well mother of three children, and there was no family history of malignancy. A few days before her presentation, her family physician prescribed prednisolone for what was thought to be asthma, but before that she had not taken steroids. She presented with worsening dyspnea to the emergency department, where her blood sugar level was measured at 23  mmol/L and serum potassium was 2.5  mmol/L. Arterial blood gases demonstrated a metabolic alkalosis and type  1 respiratory failure with pH 7.57, pCO2 36 mmHg, HCO3 34 mmHg, pO2 47 mmHg and SaO2 88% on room air. Insulin infusion and noninvasive ventilation were required. A chest X-ray and subsequent computerized tomography (CT) scan were performed, demonstrating innumerable bilateral lung lesions (Figure  1), multiple liver lesions and a mass adherent to the uterus, but no adrenal lesions were identified. The 24 h urinary free cortisol excretion was >4,750 nmol/ day (reference range 0 to 350 nmol/24 h). Low-dose and high-dose dexamethasone suppression tests failed to suppress morning cortisol of 2,994 and 3,461 nmol/L, APJOH 2009; 1: (1). March 2009

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respectively (reference range 119 to 618 nmol/L). Plasma adrenocorticotropic hormone (ACTH) was high at 29.1 pmol/L (reference range 0 to 20 pmol/L), which was consistent with ectopic ACTH secretion. Other pituitary hormones including follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin were within normal limits. Serum testosterone was elevated at 6.8 nmol/L (reference range 0.5 to 2.6  nmol/L). Serum tumor markers including a-fetoprotein, b-human chorionic gonadotropin and CA15.3 were normal. CA19.9 was slightly elevated (63 kU/L, reference range 0 to 35 kU/L), as were carcinoembryonic antigen (CEA) (12.3  mg/L, reference range 0 to 5.0 mg/L) and CA125 (44 U/mL, reference range 0 to 35 U/mL). A liver biopsy demonstrated non-small cell neuroendocrine carcinoma (Figure 2A), with diffuse strong staining for cytokeratin (CK)7, and patchy positive staining for broad spectrum CK (AE1/AE3), chromogranin (Figure 2B), neuron-specific enolase (NSE), synaptophysin and CD56. The Ki-67 proliferative index was 20% to 30% (Figure 2C). Chemotherapy (carboplatin and etoposide) was administered to the patient, but following the first cycle, clinical and radiological evidence of disease progression along with neutropenic sepsis was reported. Despite aggressive intravenous antibiotics, her respiratory status deteriorated, and she died from progressive disease leading to respiratory failure approximately 3  weeks after her diagnosis. This woman presented with classic clinical and biochemical features of Cushing’s syndrome. The hypokalemic metabolic alkalosis at presentation is related to cortisol activation of the renal mineralocorticoid receptor. Her illness resulted from a nonsmall cell carcinoma, which is atypical. Cushing’s syndrome caused by ectopic ACTH secretion1 from a non-pituitary tumor is well described in the literature. It is, however, more common in the setting of carcinoid tumors or small cell carcinomas, as neuroendocrine cells, which are most commonly associated with ectopic ACTH secretion1, are able to express the pro-opiomelanocortin (POMC) gene. Endogenous Cushing’s syndrome affects 0.7 to 2.4  people per www.slm-oncology.com

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Figure 1. Chest X-ray and computerized tomography findings at presentation.

A

B

C

Figure 2. Histopathology from liver biopsy showing non-small cell neuroendocrine carcinoma. (A) H&E stain; (B) chromogranin; (C) Ki-67 proliferative index.

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Rapidly Progressive Cushing’s Syndrome in a Carcinoma of Unknown Primary Origin

million annually2; the majority are related to an ACTH-producing pituitary tumor or, less commonly, a primary adrenal tumor.3 Only 15% to 20% of cases are due to ectopic ACTH secretion. Recently, the subject of ectopic ACTH syndrome and its potential sources has been reviewed.4 Carcinoma per se, aside from small cell carcinoma, is a very rare source of ectopic ACTH secretion and is described in a small number of case reports. The most common sources are lung carcinoids and small cell lung cancer; the syndrome rarely occurs in nonendocrine, non-pulmonary tumors. In this case, we were unable to determine the primary tumor site from either the imaging or histology results. Despite the history of non-smoking, the lung may have been the primary source, but no evident primary lesion was identified even though there was extensive involvement. This case is a useful reminder to non-endocrinologists of the investigations required to diagnose the cause of Cushing’s syndrome. The first step is to diagnose the syndrome with initial tests (24 h urinary free cortisol and dexamethasone suppression tests) to demonstrate an abnormal increase in serum cortisol. Second, a plasma ACTH will demonstrate whether the syndrome is ACTH-dependent (for example, pituitary ACTH-producing adenomas, ectopic ACTH or corticotropin-releasing hormone (CRH) production) or ACTH-independent (most commonly adrenal tumors). A high-dose dexamethasone suppression test can be performed if the syndrome appears ACTH-dependent. If cortisol suppresses the symptoms, Cushing’s disease (pituitary origin) is suspected, but if there is no suppression, then an ectopic tumor is likely. Radiological investigations, such as somatostatin receptor scintigraphy or positron emission tomography, have been employed when an ACTH-secreting tumor is occult and not visualized on CT5,6 or to provide diagnostic and functional information about the tumor, such as suitability for treatment with radio-labeled octreotide.7

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Perhaps the most striking aspect of this woman’s presentation was the rapid onset of her symptoms and the sheer volume of pulmonary involvement. Based on the clinically aggressive and histological neuroendocrine features of the malignancy, it was decided to treat in a fashion similar to small cell carcinoma in an attempt to gain control of the disease’s extent. In general, successful treatment of the tumor leads to control or resolution of Cushing’s syndrome. However, in some instances, other medical treatments, such as medical adrenal suppression with agents that inhibit steroidogenesis, for example, ketoconazole, or surgical adrenalectomy, may need to be considered. Control of the syndrome ultimately depends on controlling the underlying disease, which we unfortunately did not achieve in this case. Disclosures: The authors have no financial interests to disclose related to the content of this article. Author contributions: Drs Field and Mileshkin assisted with the intellectual planning, writing and editing of the paper. Drs Cassumbhoy and Murray assisted with the figures, as well as the writing and editing of the paper.

REFERENCES 1. 2.

3. 4. 5.

6.

7.

Penezic Z, Savic S, Vujovic S, et al. [The ectopic ACTH syndrome]. Srp Arh Celok Lek. 2004;132:28–32. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86:117–123. Pivonello R, De Martino MC, De Leo M, et al. Cushing’s syndrome. Endocrinol Metab Clin North Am. 2008;37:135–149, ix. Isidori AM, Lenzi A. Ectopic ACTH syndrome. Arq Bras Endocrinol Metab. 2007;51:1217–1225. Tsagarakis S, Christoforaki M, Giannopoulou H, et al. A reappraisal of the utility of somatostatin receptor scintigraphy in patients with ectopic adrenocorticotropin Cushing’s syndrome. J Clin Endocrinol Metab. 2003;88:4754–4758. Kumar J, Spring M, Carroll PV, Barrington SF, Powrie JK. 18Flurodeoxyglucose positron emission tomography in the localization of ectopic ACTH-secreting neuroendocrine tumours. Clin Endocrinol (Oxf). 2006;64:371–374. Rufini V, Calcagni ML, Baum RP. Imaging of neuroendocrine tumors. Semin Nucl Med. 2006;36:228–247.

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Lower fat EPA enriched * With 2 servings or more per day References: 1. Fearon K, et al. Gut. 2003;52:1479-1486. 2. Guarcello M, et al. Nutr Ther & Metab. 2006;24: 168-175. 3. Read J, et al. Support Care Cancer. 2007;15:301-307. 4. Bauer JD, et al. Support Care Cancer. 2005;13:270-274. 5. Barber M, et al. Brit J Can. 1999;81:80-86. 6. von Meyenfeldt M, et al. Proc Am Assoc Clin Oncol. 2002;21:385A. 7. Moses A, et al. Br J Can. 2004;90:996-1002. © 2008 Abbott Laboratories 5004 1108 0121 A1

…to help them stay in step with everyday life ProSure is designed to help patients with cancer enjoy the activities of everyday life, even while fighting their disease. It is the first and only therapeutic nutrition with clinically demonstrated results: • Promotes weight gain1-5 • Increases lean body mass1,4,5 and strength1,6 • Attenuates proinflammatory response2,3,5 • Improves physical activity4,7 and quality of life1-5

Begin to see results in 3 weeks* 1 Maritime Square, HarbourFront Centre #12-01 Singapore 099253

ProSure HCP Ad.indd 1

Tel: 6278 7366

Fax: 6278 6137

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www.slm-oncology.com

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Asia Pacific Journal of Oncology & Hematology  

Inaugural Issue. The Asia-Pacific Journal of Oncology & Hematology is distributed across Asia-Pacific in print and electronic forms to thous...

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