Clinical Oncology News Hemotology Digital Edition - April 2012

Hematology/Oncology Edition

Independent News on Advances in Cancer Care ClINICAloNColoGy.CoM • April 2012 • Vol. 7, No. 4

SOLID TUMORS

8 20 27

Fulvestrant plus anastrozole for metastatic breast cancer.

Predicting nonadherence with aromatase inhibitors.

Aggressive prostate cancer treatments compared.

PRN

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Clinical Conundrums: A quiz on recent American Society of Hematology data for the practicing hematologist/ oncologist.

EXPERT COMMENTARIES FROM JOHNS HOPKINS

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Adjuvant radiation for lymphoma.

Satish Shanbhag, MBBS, MPH

21

F ludarabine plus rituximab for hairy cell leukemia.

Nilanjan Ghosh, MD, PhD

EDUCATIONAL REVIEW

Treatment Options for Metastatic Renal Cell Carcinoma Access at clinicaloncology.com

Ruxolitinib Related To Survival Benefit in Myelofibrosis

New Options for Pretreated Multiple Myeloma

San Diego—Updated data from regulatory approval studies has confirmed the efficacy of ruxolitinib for myelofibrosis as well as provided proof of concept that JAK inhibition is effective in myeloproliferative diseases, according to research presented at the 2011 annual meeting of the American Society of Hematology (ASH).

Ruxolitinib (Jakafi, Incyte), an inhibitor of the Janus-associated kinase (JAK) pathway, is the first drug granted an indication for the treatment of myelofibrosis (MF) by the FDA. Two simultaneous trials were conducted for regulatory approval, each with the goal of demonstrating a reduction in

San Diego—Emerging data suggests that a range of new treatment options may be coming for patients with refractory multiple myeloma (MM) that has progressed after exposure to bortezomib, lenalidomide and other modern therapies for this disease.

Several new agents have shown promise in studies with clinically meaningful end points. Vorinostat, a histone deacetylase (HDAC) inhibitor, significantly improved progression-free survival (PFS) in a Phase III study, while pomalidomide, a derivative of thalidomide, demonstrated substantial activity in a Phase II study.

Outcomes in the treatment of MM

see RUXOLITINIB, page 4

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Prognostication and Prediction for ERPositive Breast Ca

see MYELOMA, page 6

A breakdown of tests available in 2012

I

nduction hormone therapy sparked a lot of discussion and interest at the 2011 San Antonio Breast Cancer Symposium (SABCS). This attractive idea uses dynamic effects of hormone therapy on tumor proliferation and estrogen receptor (ER) content during the first 2 to 12 weeks of initial hormone therapy to generate improved estimates of prognosis compared with single pretreatment studies of the tumor. A reduction in tumor cell proliferation as measured by a drop in Ki67 immunostaining and persistent see PROGNOSTICATION, page 12

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Industry-Sponsored Studies More Likely To Generate Positive Results San Diego—Randomized controlled trials sponsored by a pharmaceutical company for cancer treatments were more likely to generate positive results than trials generated by a public agency, according to a recent analysis.

Trials performed by the two different funding sources tended to have different emphases, which could explain the differences between the two.

Two concepts are useful when considering the differences between the results in randomized controlled trials

(RCTs). The first is the “equipoise principle” in which investigators cannot predict the effects of treatments in advance.

As a result, based on the fact that the new treatment will sometimes be superior to the standard, sometimes inferior and sometimes comparable, the overall success of discovery of new treatments should be around 50%. The second concept is known as “design bias,” which postulates that trials are undertaken only if there is high likelihood of detecting see STUDIES, page 5

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McMahonMedicalBooks.com To order cancer therapeutic regimens or agents pocket guides, go to http://www. clinicaloncology.com/ PocketGuides.

Counseling About Cancer: Strategies for Genetic Counseling, Third Edition Katherine Schneider See page 31.

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CLINICAL ONCOLOGY NEWS

CliniCal OnCOlOgy news • april 2012

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Susan K. Seo, MD

AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Joseph P. DeMarco, PhD

Memorial Sloan-Kettering Cancer Center New York, NY

Cleveland State University Cleveland, OH

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Maura N. Dickler, MD

Harry Erba, MD, PhD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

University of Michigan Ann Arbor, MI

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

leonard Saltz, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Shaji Kumar, MD

Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

Gynecologic Cancer

Lung, and Head and Neck Cancers Edward S. Kim, MD University of Texas MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Physician Assistant University of Texas MD Anderson Cancer Center Houston, TX

Policy and Management Mary lou Bowers, MBA The Pritchard Group Rockville, MD

Pharmacy Cindy o’Bryant, PharmD University of Colorado Cancer Center Denver, CO

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Richard Stone, MD Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

®

Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD Medical Oncologist New York, NY

Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Mayo Clinic Rochester, MN

Genitourinary Cancer Ronald M. Bukowski, MD

Oncology Nursing

Hematologic Malignancies

Andrew Seidman, MD

Edward Chu, MD

Bioethics

Michael A. Carducci, MD

Jennifer R. Brown, MD, PhD

Gastrointestinal Cancer

Infection Control

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

Charles F. von Gunten, MD University of California, San Diego, CA

Mission Statement

T

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. we strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Editorial Philosophy The editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. a significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. prior to these meetings such as the asCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published.

Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. additionally, all news articles that appear in Clinical Oncology News are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

CLINICAL ONCOLOGY NEWS

CliniCal OnCOlOgy news • april 2012

Letter to the Editor To the editor:

i

read the articles “applying Clinical Trials to ‘real-world’ Care” and “less surgery is Better for some Breast Cancer patients” (Clinical Oncology News, Feb 2012; Vol 7:2) with great interest.

The information contained in the articles is not new. The articles concisely summarize changes being seen in breast cancer management and reasons—clinical trials—for the changes. Below is a synopsis i developed for surgeons and oncologists at our institution, dovetailing use of sentinel lymph node biopsy (slnD) and nodal radiation for breast cancer patients.

The summary of the various trials regarding axillary lymph node dissection (alnD) was helpful regarding the use of alnD after slnD. The author concluded: “Doctors now have additional evidence that axillary lymph node dissection does not add benefit to sentinel node resection and clinically node negative breast cancer patients with minimal sentinel node involvement.”

+

nodal information is needed for prognosis and decisions regarding systemic therapy.

Use of slnD has significantly reduced the risk for lymphedema and sensory neuropathy of the arm and the breast compared with routine alnD. The issue now is management of involved axillary lymph nodes. in addition to the recent trials, there are older trials, specifically nsaBp BO-4, which has a 30-plus-year follow-up, which showed no survival advantage with alnD compared with no alnD. review of the radiation therapy literature would suggest the following blend regarding the use of surgery and radiation in the management of pn+ disease.

Clinically involved pn+ nodes need alnD as a therapeutic measure. These patients additionally need radiation therapy to the axilla and supraclavicular (sCF) region. Undoubtedly, this combined treatment increases risk for lymphedema. But patients with clinical palpable axillary nodes are at high risk

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for locoregional failure. Benefits of combined treatment outweigh the side effects. patients with pn+ nodes that are not clinically palpable can be well managed with slnD and radiation therapy to the axilla with or without the sCF region. The following trend can be seen in the radiation therapy literature: if the primary tumor is small with low-risk features, treating the breast with high tangents to include the level i and ii axillary nodes is adequate therapy based on the Massachusetts general Hospital series.1 if the breast primary has high-risk features—size, receptor status, lympho-vascular invasion, grade—then it would behoove [the physician] to treat the axilla and sCF region as a separate field to the breast tangents. This is based on the recent Canadian Ma.20 trial, which compared breast radiation alone with breast plus nodal radiation in patients with one to three pn+ nodes.2 addition of nodal radiation improved locoregional and systemic control, and

improves disease-free survival with a trend toward improved overall survival. in the absence of alnD, radiation to the regional nodes is well tolerated with less than 5% risk for lymphedema in the upper extremity. patients with pn0 disease generally do not need treatment to the nodes. i hope this information is useful in coordinating the locoregional care with systemic therapy. gilbert lawrence, MD radiation Oncologist Faxton st. luke’s Hospital Utica, ny

References 1.

Macdonald sM, abi-raad rF, alm el-Din Ma, et al. Chest wall radiotherapy: middle ground for treatment of patients with one to three positive lymph nodes after mastectomy. Int J Radiat Oncol Biol Phys. 2009;75:1297-1303.

2. whelan TJ, Olivotto i, ackerman, et al. nCiCCTg Ma.20: an intergroup trial of regional nodal irradiation in early breast cancer. J Clin Oncol. 2011;29(suppl; abstr lBa1003).

New Editorial Board Member: Michele Neskey, PA-C Clinical Oncology News is pleased to announce that oncology physician assistant Michele neskey, MMsc, pa-C, has joined the magazine’s editorial board.

Ms. neskey received her master of medical science degree from yale University in 2005 and currently practices in the Department of Thoracic/Head & neck Medical Oncology at the University of Texas MD anderson Cancer Center in Houston. she previously worked at yale-new Haven Hospital, new Haven, Conn., the University of Miami/Jackson Memorial Hospital and aptium Oncology/Mount sinai Comprehensive Cancer Center in Miami Beach, Fla. she is a member of the american society of Clinical Oncology, the american academy of physician assistants and the association of physician assistants in Oncology. Ms. neskey has been published in Cancer Research, the Journal of Thoracic Oncology and the Journal of the American Academy of Physician Assistants.

Ms. neskey will provide guidance to the magazine in our coverage of midlevel providers and the role of physician assistants and nurse practitioners in oncology and hematology. we welcome her to our board.

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If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

4

HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • april 2012

Myeloproliferative Diseases

RUXOLITINIB continued from page 1 

splenomegaly; however, one of the studies also showed a survival benefit in secondary analysis.

“The reduction in the spleen volume was dramatic in many patients, but we were particularly impressed with the symptomatic response. Patients with quite debilitating symptoms achieved substantial relief of their symptoms, and this has not been seen with other therapies,” said Claire N. Harrison, MD, a hematologist at Guy’s and St. Thomas National Health Service Foundation Trust in London. Presenting the results of COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy), a European study conducted independently but simultaneously with COMFORT-I, a North American study, Dr. Harrison reported that benefits were consistent across the subtypes of MF, including primary MF, postpolycythemia vera (PV) MF and postessential thrombocythemia (ET) MF. COMFORT-I (ASH, abstract 278), presented by Srdan Verstovsek, MD, PhD, an associate professor in the Leukemia Department at the University of Texas MD Anderson Cancer Center in Houston, and COMFORT-II had similar designs. In COMFORT-I, 309 patients with MF were randomized to an oral dose of ruxolitinib (15 mg if the platelet count was 100 to 200 × 109/L or 20 mg if higher) or placebo. In COMFORTII (ASH, abstract 279), which enrolled 219 patients, the randomization was to the same doses of ruxolitinib or best available therapy (BAT) at the investigator’s discretion. BAT consisted largely of off-label therapies such as steroids, hydroxyurea, erythropoiesis-stimulating agents or androgens.

The primary end point for both studies was a reduction in spleen volume of at least 35% as assessed with magnetic resonance imaging (MRI) after 24 weeks of therapy and the two studies produced nearly identical results.

In COMFORT-I, the 35% reduction in spleen volume at 24 weeks was achieved by 42% of those taking ruxolitinib compared with 1% of those taking placebo (P<0.001; Table 1). In COMFORT-II, the percentages meeting this end point were 31.9% for ruxolitinib and 0% for BAT (P<0.0001).

The proportion of patients achieving a 50% reduction at 24 weeks in total symptom score (TSS), comprised of abdominal discomfort, pain under the ribs on the left side of the abdomen, early satiety, itching, night sweats and bone or muscle pain, was a secondary end point in COMFORT-I. This was met by 45.9% of those taking ruxolitinib compared with 5.3% of those taking placebo (P<0.0001).

Table 1. Mean Percent Change in Spleen Volume And Symptom Score From Baseline to Week 24 Subgroup

SV, Mean % Change

TSS, Mean % Change

Ruxolitinib

Placebo

Ruxolitinib

Primary MF

–29.9 ± 17.5

8.5 ± 16.7

–38.5 ± 54.3

41.7 ± 92.0

Postpolycythemia vera MF

–37.3 ± 20.9

5.9 ± 14.5

–54.9 ± 41.5

27.2 ± 105

Postessential –27.0 ± 17.4 thrombocythemia MF

11.1 ± 11.2

–49.9 ± 45.1

73.7 ± 112

High risk

–30.9 ± 19.5

7.7 ± 15.8

–41.5 ± 52.2

48.7 ± 94.8

Intermediate-2 risk

–32.8 ± 18.4

9.1 ± 14.5

–53.5 ± 43.2

28.8 ± 107

Placebo

MF, myelofibrosis; SD, standard deviation; SV, spleen volume; TSS, total symptom score

‘Ruxolitinib is now clearly front-line therapy for myelofibrosis patients.’

—Ruben Mesa, MD

Table 2. Change in Quality-of-Life Scores at Week 24 In the Placebo and BAT Arms (Observed Cases)a Placebo n

BAT Mean Change From Baseline at Week 24 (SD)

n

Mean Change From Baseline at Week 24 (SD) 5.2 (23.76)

Global health status/Qol

104

-3.4 (21.53)

37

Fatigue

107

1.8 (24.71)

39

–1 (23.57)

Pain

104

8.3 (27.47)

39

3 (28.06)

BAT, best available therapy; SD, standard deviation; QoL, quality of life a

For patients with measurements at both baseline and week 24.

COMFORT-I also included a survival analysis as a secondary end point. After a median follow-up of approximately 12 months, only 13 of those randomized to ruxolitinib had died compared with 24 of those randomized to placebo, producing a 50% reduction in risk (hazard ratio, 0.499; 95% confidence interval, 0.2540.98; P=0.0395).

In COMFORT-II, the reduction in symptoms was marked although the TSS metric was not used. COMFORT-II also was not designed to evaluate survival.

In both studies, ruxolitinib was well tolerated. In COMFORT-II, for example, both diarrhea rates (23% ruxolitinib vs. 11% BAT) and headache (10% ruxolitinib vs. 4% BAT) were higher with ruxolitinib than BAT, but the rates of discontinuation for adverse events (8% ruxolitinib vs. 5% BAT) were only slightly elevated and discontinuations for any reason favored ruxolitinib (18% ruxolitinib vs. 33% BAT).

In the COMFORT-I study, the same percentage of patients stopped therapy due to side effects for both ruxolitinib and placebo (11%).

However, the importance of the new therapy is perhaps best illustrated by

a separate, combined post hoc analysis done to compare the benefit of BAT in COMFORT-II with placebo in COMFORT-I. According to Ruben Mesa, MD, a professor of medicine and chair of hematology at Mayo Clinic in Scottsdale, Ariz., who presented this analysis in a poster (ASH, abstract 1753), BAT did not appear to provide any advantage in spleen size, symptoms or quality of life (Table 2).

The benefit of a JAK inhibitor in MF is predicted by the role of JAK signaling in hematopoiesis. In particular, the JAK2V617F mutation, which can accelerate hematopoeisis and lead to fibrosis in the bone marrow, red blood cell overproduction and dysfunctional platelets, is observed in up to 50% of patients with ET and MF and up to 90% of patients with PV. However, when the benefit from ruxolitinib was compared between those with or without the JAK2V617F mutation, the advantage of ruxolitinib over the comparator was similar, indicating that this mutation need not be present for the agent to work.

In fact, patients receiving ruxolitinib “had higher response rates than placebo regardless of baseline subgroup, including MF disease subtype, age [<65

vs. >65], IPSS [International Prognostic Scoring System] risk group, presence or absence of JAK2V617F mutation, hemoglobin level [<10 or >10 g/dL], palpable spleen length [<10 or >10 cm] and symptom severity,” Dr. Verstovsek said.

The activity of ruxolitinib, although clinically important, provides a proof of concept that JAK inhibition is effective in myeloproliferative diseases. Reflecting the intensified interest in this target, new data were presented at ASH on several other JAK2 inhibitors at early stages of development.

For example, Phase II data from a 34-patient study was reported for pacritinib (S*Bio, SB1518). According to the lead author, Rami Komrokji, MD, the clinical director of the Department of Hematologic Malignancies at Moffitt Cancer Center in Tampa, Fla., the reduction in splenomegaly—which was more than 50% in 44% of treated patients— correlated with an improvement in MF symptoms, including reductions in abdominal pain, bone pain and fatigue.

Similarly, LY2784544 (Eli Lilly), another JAK2 inhibitor, reduced spleen length in all but four of 17 patients participating in a Phase I study, according to Dr. Verstovsek, who led this study.

The results of COMFORT-I and II have already led to regulatory approval of the agent but Dr. Harrison, noting the absence of alternatives, suggested that the data supports an immediate change in practice.

“At this point, I would put all my patients with myelofibrosis on ruxolitinib, particularly if they have symptomatic splenomegaly,” reported Dr. Harrison. She suggested that the major symptomatic benefits are not now achievable with any other therapy.

Asked to comment on the significance of these results, Dr. Mesa told Clinical Oncology News that “ruxolitinib is now clearly front-line therapy for myelofibrosis patients, in particular for those deemed not to need immediate stem cell transplant or those whose primary MF morbidity is anemia.”

From another perspective, Dr. Komrokji provided a very similar comment.

“At this point, JAK inhibitors are the best option for patients with symptomatic splenomegaly and/or myelofibrosis-related constitutional symptoms, especially if they were treated with hydroxurea before,” he said. In particular, Dr. Komrokji called the overall survival data “very encouraging.”

—Ted Bosworth Dr. Harrison reported that she has received honoraria and/or research funding from Celgene, Incyte, Novartis, S*Bio and SanofiAventis. Dr. Verstovsek reported receiving research funding from Incyte. Dr. Mesa reported receiving research funding from Incyte and S*Bio. Dr. Komrokji had nothing to disclose.

5

CLINICAL TRIALS

CliniCal OnCOlOgy news • april 2012

Evidence-based Medicine

‘The differences in the results clearly point to differences

STUDIES

in research agendas between publicly versus industry-

continued from page 1 

therapeutic success in favor of sponsor’s treatment.

Speaking at the 2011 annual meeting of the American Society of Hematology, Benjamin Djulbegovic, MD, PhD, reported that the equipoise hypothesis appears to drive the results observed in publicly sponsored trials, whereas the design-bias hypothesis can explain the outcomes obtained in the industrysponsored trials.

This conclusion was based on a retrospective analysis of the results of all Phase III studies sponsored by GlaxoSmithKline (GSK) or the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) from 1980 through June 2010. Using three metrics to assess treatment success in clinical trials, Dr. Djulbegovic, of the Center for Evidence-Based Medicine and Health Outcomes Research, University of South Florida and H. Lee Moffitt Cancer Center & Research Institute in Tampa, and colleagues found that new treatments are favored over standard treatments in industry-sponsored trials in comparison with trials funded by the public funder for each metric used.

Of the 40 trials funded by industry (19,889 patients) and the 77 trials funded

by NCIC CTG (33,260 patients), 42% of the industry-sponsored studies and 25% (P=0.04) of the public sector–sponsored studies showed a statistically significant superiority of experimental treatment over the control arm for the primary end point. Investigators themselves concluded that new treatments were superior to standard treatments in 80% of GSK versus 44% of NCIC CTG trials (relative risk, 1.81; P<0.001).

Pooled quantitative analysis for the primary outcome indicated higher success rate in GSK trials (odds ratio [OR], 0.61; 99% confidence interval [CI], 0.47-0.78] versus OR, 0.86; CI, 0.741.00; P=0.003). However, testing for the effect of treatment over time indicated that treatment success has become similar in the last decade.

In addition to equipoise versus design bias as the main explanation of the results, a number of other explanations are possible. They include a possibility that the results can be explained by the larger proportion of industry-sponsored trials relying on the use of placebo as a comparator, as well as differences in mix between the proportion of explanatory and pragmatic trials in industry versus publicly sponsored trials. Pragmatic trials are rarely done by industry and the effect sizes are expected to be larger in explanatory trials, which can explain the differences in the results.

Overall, Dr. Djulbegovic concluded, “the differences in the results clearly point to differences in research agendas

sponsored trials.’

industry-sponbetween publicly versus industry-spon sored trials.”

Asked to comment on these results, Smita Bhatia, MD, director of outcomes research at City of Hope in Duarte, Calif., called this a “a well-conducted study” that generated “intriguing

—Benjamin Djulbegovic, MD, PhD

findings,” but she considers the conclusions to be preliminary and awaits a study with a larger scope.

“While the findings provide food for thought, they need to be confirmed in future studies that include representation by more than one pharmaceutical company, unlike the current study that relied on

data from only one,” Dr. Bhatia said. The findings may be useful when considering differences between industry- and publicfunded studies.

—Ted Bosworth Dr. Djulbegovic reported receiving research funding from Millennium; Dr. Bhatia reported no relevant disclosures.

Op en En For rol lme n

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ore m rn e a e L t th at u l abo 3 tria .org 0 b 104 .calg w ww

Clinical Trial developed as a collaborative project by:

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6

HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • april 2012

Multiple Myeloma

MYELOMA continued from page 1 

have improved with the introduction of immunomodulating agents, such as lenalidomide, and the proteasome inhibitor bortezomib, but the prognosis remains poor when patients become refractory. Until recently, reported median survival for these patients has been less than six months.

However, recent data reflects the promise of these newer therapies: 60% of patients in both arms of a Phase III study with vorinostat were alive at two years; however, the patients in the arm with the experimental agent had a significantly longer PFS. In this study, presented at the 2011 annual meeting of the American Society of Hematology (ASH, abstract 811), vorinostat combined with bortezomib was compared with bortezomib alone in 637 patients. The schedule for bortezomib in both arms was 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day schedule. Those in the experimental arm also received 400 mg of oral vorinostat on days 1 to 14.

The median age in the study was 61 years and the median number of prior treatment regimens was two. Approximately 80% of patients had received a prior alkylating agent, 60% had received a prior immunomodulating agent and 25% had received bortezomib. Almost half were nonresponsive to their last regimen.

After a median follow-up of 25 months, the median PFS was 7.63 months in the arm that received vorinostat plus bortezomib versus 6.38 months in the arm receiving bortezomib alone. This translated into a 23% reduction in the hazard ratio (HR) of progression (HR, 0.77; 95% confidence interval [CI], 0.64-0.94; P=0.01). According to senior investigator Meletios Dimopoulos, MD, a professor of clinical therapeutics at the University of Athens in Athens, Greece, the improvement in the primary end point was consistent with the greater activity provided by vorinostat, which boosted the objective response rate from 41% to 56% (P<0.001) as well as the rate of clinical benefit, a designation that also includes stable disease, from 54% to 71% (P<0.0001).

Although not yet mature, the data for

‘That patients were all required to be refractory to bortezomib at study entry makes the response rate all the more remarkable.’

—Paul G. Richardson, MD overall survival (OS) moved in a favorable direction (HR, 0.86; 95% CI, 0.621.18; P=0.32).

The PFS advantage was consistent when patients were stratified by age, type of melanoma and lines of prior therapy. The advantage also was consistent whether or not patients had received prior immunomodulating therapies, although the benefit appeared to be lost among patients who had been previously exposed to bortezomib. The addition of vorinostat was characterized as well tolerated with both the rate of serious side effects (41% vs. 43%) and discontinuations due to serious adverse events (7% vs. 10%), both numerically lower in the vorinostat arm.

Grade 3 or 4 side effects that occurred with notably greater frequency in the vorinostat arm included thrombocytopenia (45% vs. 24%), diarrhea (17% vs. 9%) and fatigue (17% vs. 7%).

Asked whether an additional five or six weeks of PFS could be considered clinically significant, Dr. Dimopoulos maintained that for a reasonably well-tolerated therapy, this advantage is meaningful

to patients, and he expects that efforts to improve response rates by manipulating the dose or schedule of vorinostat, like successful efforts to improve the efficacy and safety of bortezomib, will likely build on the advantages demonstrated in this Phase III study.

At the same time, Phase II data with pomalidomide, an immunomodulating agent that is chemically related to lenalidomide, and panobinostat, another HDAC inhibitor, also have suggested promise for patients with heavily pretreated MM. In the study with pomalidomide (ASH, abstract 812), 84 patients were evaluated in two groups. Both received 4 mg of oral pomalidomide daily plus 40 mg dexamethasone weekly. In one group, the pomalidomide was administered only on days 1 to 21 of the 28-day cycle. In the other arm, patients received pomalidomide on all 28 days.

According to the investigator who presented the data, Xavier Leleu, MD, PhD, an associate professor of hematology at the Centre Hospitalier Régional Universitaire in Lille, France, “the data were impressive” with objective

responses in approximately 34% of patients in either group. The median PFS in those with an objective response was almost 12 months even though 69% were refractory to both bortezomib and lenalidomide and had progressed on their last line of therapy.

The Phase II study with panobinostat (ASH, abstract 814), called PANORAMA 2 (PANobinostat ORAl in Multiple myelomA), was an extension of a Phase I study conducted in patients with a median prior exposure to four regimens. All patients had progressed within 60 days of a prior bortezomib regimen. In the Phase I and II studies, the patients were restarted on bortezomib along with 20 mg of oral panobinostat on days 1, 3, 5, 8, 10 and 12 of a 21-day cycle plus 20 mg of dexamethasone on the day of and the day after bortezomib. Again, the rate of objective responses has been substantial with the length of PFS correlating with the degree of response, according to Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, the study’s lead author.

At the time of analysis, nine patients had achieved at least a partial response and an additional seven achieved a minimal response, the investigators reported.

Like vorinostat and pomalidomide, the advantages of panobinostat include oral administration and an acceptable tolerability profile. Most of the grade 3 and 4 adverse events have been hematologic, which impose a smaller adverse effect on quality of life than neuropathy or gastrointestinal complaints, which were infrequent in higher grades. According to Dr. Richardson, the fact “that the patients were all required to be refractory to bortezomib at study entry makes the response rate all the more remarkable.” He believes the level of activity with panobinostat supports a Phase III trial, which is currently under way.

—Ted Bosworth Dr. Dimopoulos reported an honorary and/ or a consultancy relationship with Celgene and Ortho-Biotech. Dr. Lelu reported honoraria and/or research funding from Amgen, Celgene, Janssen Cilag, Novartis and Roche. Dr. Richardson reported an advisory relationship with Celgene, Johnson & Johnson, Keryx Biopharmaceuticals, Millennium and Novartis.

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CliniCal OnCOlOgy news • april 2012

Patient Care

Should It Ever Happen?

Re-examining a ‘Discarded’ Antineoplastic Strategy Is it ever appropriate for the oncology community to legitimately decide to re-examine a previously discarded management strategy? And if the answer to this question is possibly yes, then what level of evidence—for example, epidemiological, preclinical or limited clinical considerations—should be required to justify such a decision?

The history of thalidomide provides a poignant example of the potential that new knowledge about disease pathogenesis and drug pharmacology has to dramatically alter the medical and societal view of a pharmaceutical agent.1 Consider the issue of high-dose chemotherapy and bone marrow/precursor cell “rescue” in the management of breast cancer and other solid tumors. While these approaches are occasionally employed— for example, with recurrent chemotherapy-sensitive metastatic germ cell tumors— rather definitive data in breast cancer in both the adjuvant and metastatic settings has revealed the lack of a major impact on overall survival and led to the abandonment of this strategy by the large majority of the oncology community.2,3 But suppose, for example, that a group of clinical investigators used a retrospective analysis of clinical data to propose a novel approach to “safely and effectively purge viable cancer from the population of precursor cells” to be re-infused back into the patient following a high-dose chemotherapy program.4 And suppose the approach progressed to the point at which the actual procedure was able to be conducted in a cost-effective manner—that is, entirely in the outpatient setting with few complications requiring hospitalization— and the treatment-related mortality using standard supportive care was anticipated to be very low, less than 0.5%.

In this scenario, what data should be required before an investigator proposes, an institutional review board approves and a third-party payer accepts responsibility for “standard-of-care” charges associated with the “performance of

another trial of high-dose chemotherapy in breast cancer”?

Or consider a long-standing issue in the realm of gynecologic oncology: Second-look surgical reassessment was long considered a standard component of the management of women with advanced ovarian cancer who had achieved a clinically defined complete response to primary cytotoxic chemotherapy.5 However,

intraperitoneal disease? Would it be reasonable to require a surgical assessment to evaluate the extent of disease, possibly with subsequent removal of residual cancer, despite the fact that this approach is no longer “routine”?

Finally, we come to the elephant in the room, and specifically the two therapeutic concepts discussed above: Will any third-party payer agree to pay for a high-

EDITORIAL BOARD COMMENTARY Maurie Markman, MD senior Vice president of Clinical affairs and national Director for Medical Oncology, Cancer Treatment Centers of america, philadelphia

of the potential that new knowledge about disease patho-

something critically relevant to the use of high-dose chemotherapy in the treatment of solid tumors, or develop a novel strategy for the management of small-volume residual ovarian cancer that will require a thorough assessment of the peritoneal cavity. Will we be willing as a clinical research community, and as a society, to re-examine these discarded approaches if they were brought forward?

genesis and drug pharmacology has to dramatically alter

References

The history of thalidomide provides a poignant example

the medical and societal view of a pharmaceutical agent. during the past decade this approach has been much less frequently used because there is no evidence that any unique diagnostic information generated through a second-look translates into a specific treatment plan that will improve the patient’s outcome. Simply stated, the performance of a second-look surgical assessment may be of prognostic value, but there is no documented predictive utility—that is, the selection of a superior management strategy associated with the procedure.

But what if a novel antineoplastic approach were developed in ovarian cancer whose use was demonstrated to be dependent on detailed knowledge of the size and location of any residual cancer within the peritoneal cavity? Or what if there was a highly rational hypothesis, or even actual clinical data, to suggest the approach could be quite effective, but only in the absence of any macroscopic

dose chemotherapy regimen in metastatic breast cancer—even if it actually costs no more and is possibly considerably less expensive than several current management strategies—or for the performance of a surgical re-assessment in a clinically disease-free ovarian cancer patient when the “existing established experience” can be used to show the “absence of clinical utility” for these approaches?

It is certainly not unreasonable to propose that a past strategy, examined under quite different circumstances and with insufficient knowledge, produced a less than optimal picture of its clinical utility.

Consider, for a moment, where we would be today in our use of tyrosine kinase inhibitors in the management of lung cancer if we did not understand the relevance of specific mutations in the epidermal growth factor receptor pathway.

Perhaps tomorrow we will learn

1. Stephens T, Brynner R. Dark Remedy: The impact of thalidomide and its revival as a vital medicine. Cambridge, MA: Perseus Publishing; 2001.

2. Berry DA, Ueno NT, Johnson MM, et al.

High-dose chemotherapy with autologous hematopoietic stem-cell transplantation in metastatic breast cancer: overview of six randomized trials. J Clin Oncol.

2011;29:3224-3231, PMID: 21768471.

3. Berry DA, Ueno NT, Johnson MM, et al.

High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol. 2011;29:3214-3223, PMID: 21768471.

4. Muller AMS, Kohrt HEK, Cha S, et al. Longterm outcome of patients with metastatic breast cancer treated with high-dose chemotherapy and transplantation of purified autologous hematopoietic stem cells. Biol Blood Marrow Transplant.

2012;18:125-133, PMID: 21767515.

5. Greer BE, Bundy BN, Ozols RF, et al. Implications of second-look laparotomy in the context of optimally resected stage III ovarian cancer: a non-randomized comparison using an explanatory analysis: a Gynecologic Oncology Group study. Gynecol Oncol.

2005;99:71-79, PMID: 16039699.

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SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Breast

Fulvestrant-Anastrozole Combo Improves Survival Study conflicts with prior clinical trial results San Antonio—Adding fulvestrant to anastrozole in first-line therapy of hormone receptor–positive metastatic breast cancer (MBC) in postmenopausal women improved progression-free survival (PFS) by 1.5 months and overall survival (OS) by 6 months, according to final results of the S0226 trial.

The findings, presented at the recent San Antonio Breast Cancer Symposium (SABCS, abstract S1-1), conflict with results from FACT (Fulvestrant and Anastrozole in Combination Trial) presented at the 2009 SABCS. FACT concluded that there was no benefit to adding fulvestrant (Faslodex, AstraZeneca) to anastrozole (Arimidex, AstraZeneca) therapy in patients with hormone receptor–positive breast cancer after first relapse.

“The combination of anastrozole plus fulvestrant cannot be recommended as a new standard in women with metastatic breast cancer,” said James Ingle, MD, a professor of oncology at Mayo Clinic who served as the discussant for the S0226 trial at SABCS. “The lack of any benefit seen in the FACT trial, a well-conducted study, is not consistent with the positive findings from S0226.”

The investigators who conducted the trial, however, said that the study populations of the two trials are different.

“S0226 stands on its own merit,” said Rita Mehta, MD, an associate health science professor at the University of California, Irvine, who led the Phase III study.

Because anastrozole lowers estrogen levels and fulvestrant downregulates the estrogen receptor, researchers thought the combination of the two could act as a one-two punch on breast cancer cells, a hypothesis supported by in vivo studies. Over the past four decades, however, a number of studies

have combined different endocrine therapies without success, including the recent FACT trial.

Southwest Oncology Group study S0226 enrolled postmenopausal women with estrogen and/or progesterone receptor–positive, measurable or nonmeasurable MBC. Exclusion criteria included adjuvant or neoadjuvant chemotherapy or therapy with an aromatase inhibitor in the last 12 months. Individuals were stratified by whether or not

The median age in both arms was 65 and roughly 40% of patients had prior tamoxifen in both arms. Roughly one-third had prior chemotherapy and almost 40% had de novo metastatic disease.

Median PFS, the primary end point, was 15.0 months in patients receiving anastrozole and fulvestrant and 13.5 months in patients receiving anastrozole alone (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.94; P=0.007). Median OS was 47.7 months in

‘The combination of anastrozole plus fulvestrant cannot be recommended as a new standard in women with metastatic breast cancer.’

—James Ingle, MD they had received adjuvant tamoxifen.

Patients were then randomized to receive anastrozole either alone or in combination with fulvestrant; 41% of patients in the single-therapy arm crossed over to receive fulvestrant after disease progression. During the trial, after other studies showed that a 500mg dose of fulvestrant was superior to 250 mg, patients were allowed to cross over to the higher dose. Nine of the 349 patients on the combination arm and five patients who crossed over received the 500-mg dose.

At SABCS, researchers presented the final analysis of 694 eligible patients.

the combination arm and 41.3 months in the anastrozole-alone arm (HR, 0.81; 95% CI, 0.65-1.00; P=0.049).

Adverse events were similar in the two treatment groups. Thirteen percent of patients in the combination arm experienced grade 3 toxicities compared with 11% in the single arm. In the combination arm, three patients had grade 5 toxicities and two had grade 4 toxicities.

Four patients in the single-agent arm had grade 4 toxicities.

In an unplanned analysis, patients who had not received prior adjuvant tamoxifen had a median PFS of 17.0 months compared with 12.6 (P=0.0055)

Table. Comparison of the S0226 and FACT Trial S0226 (n=694)

FACT (n=350)

Eligibility

HR+ metastatic breast cancer; postmenopausal

HR+ breast cancer after first relapse; postmenopausal or premenopausal

Progression-free survival

15.0 vs. 13.5 months favoring fulvestrant arm (HR, 0.80; P=0.0070)

10.8 vs. 10.2 months; no difference (HR, 0.99; P=0.91)

overall survival

47.7 vs. 41.3 months favoring fulvestrant (HR, 0.81; P=0.049)

37.8 vs. 37.2 months; no difference (HR, 1.0; P=1.00).

Prior adjuvant chemotherapy

33%

46%

No prior adjuvant endocrine therapy

60%

33%

Prior tamoxifen

40% (% relapsed unknown on tamoxifen)

65% (27% relapsed on tamoxifen)

Prior aromatase inhibitor

2%

1%

FACT, Fulvestrant and anastrozole in Combination Trial; HR, hazard ratio; HR+, hormone receptor–positive

in those who had, and the median OS was 47.7 months compared with 39.7 months (P=0.0362). In patients who had received prior adjuvant tamoxifen, the differences in OS (49.6 months vs. 44.5 months; P=0.59) and PFS (14.1 vs. 13.5 months; P=0.37) were not statistically significant.

It is not clear whether prior tamoxifen is predictive of efficacy with the combination. “We need to better understand other possible predictive factors, since the prior tamoxifen factor could be a false lead from an unplanned analysis,” Dr. Mehta said.

Dr. Ingle agreed. “The finding of no benefit in prior [tamoxifen] patients should be interpreted with caution,” he said, noting that a study in the Lancet showed that in 41% to 66% of simulated subgroups, simulations can falsely indicate that there is no treatment effect in a particular subgroup when the trial shows overall benefit (Lancet 2005;365:176-186, PMID: 15639301).

Overall, Dr. Mehta concluded that “the combination of anastrozole and fulvestrant improves PFS and OS, the primary and secondary end points, in the first-line therapy of hormone receptor–positive breast cancer in postmenopausal women.”

The results disagree sharply with results from the FACT study. In that study, the PFS HR was 0.99 (P=0.91) and the OS HR was 1.0 (P=1.00).

“Eligibility criteria, regimens and measurable/evaluable proportions were similar,” said Dr. Ingle (Table). “There are some differences, but no glaring differences.” He pointed out, however, that 38.9% of patients in S0226 had de novo metastatic disease, and this seemed “a remarkably high figure.”

According to Dr. Mehta, one of many

SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Breast

differences is that FACT had patients with locally recurrent disease and S0226 specified only metastatic disease. “S0226 had [patients with] endocrine-sensitive disease with high survival, despite not including patients with locally recurrent disease,” said Dr. Mehta. “Patients with locally recurrent disease can be cured again with a combination of local and systemic therapy.”

She pointed out that 32% of the 512 patients recruited for FACT were ineligible, leaving 350 patients, a smallersized trial.

Andy Seidman, MD, an attending

physician in the Breast Cancer MedCurrent file: MN113_A_ad.indd icine Service at Memorial-Sloan Kettering Cancer Center in New York City, Full name of said the results ofproject S0226 won’t spur him to make any broad changes in his practice. “It isProject hard to understand how the no. overall survival analysis could not be Revision # rev 1 confounded by post-protocol treatment, date/time April 11, 2012improve4:41 PM especiallyLayout with such a modest ment in PFS,” Dr. Seidman said. “I will Editorial date/time consider the combination for the fortuTrim size nately few patients who present to me Color specs with de novo, untreated metastatic dispath MN113_A_ad.indd ease. ThisFilesubset seemed to derive the largest incremental benefit.”

FILE SLUG When asked about the difference in PROOF APPROVED OK that PFS1ST and OSLAYOUT benefit, Dr. MehtaFINAL said INITIALS AND DATE INITIALS AND DATE hazard ratios are a better gauge of beneSenior editor fit than median values and that the HRs for PFS Editor and OS are similar. The OS benefit “follows exactly as expected,” said Dr. Copy editor Mehta.

Sales According to Dr. Ingle, “median outProduction comes may not tell the entire story, and subsequent MAX sign-off therapies usually balance out in aCOMMENTS: large randomized trial.” Clarity will come from future randomized clinical trials in the neoadjuvant setting, he said.

Unfortunately, any clarity is unlikely to come from the ongoing Phase III trial

STATUS &of HISTORY of fulvestrant (SoFEA [Study FasloPICKED UP FROM: ArimPROOF or 1: 1/17 dex with without concomitant APPLIED TO: 1: idex REV following progression on AromaREV 2: AD LAYOUT EXPT’D: tase inhibitors).

The trial hasRECEIVED: completed REV 3 AD LAYOUT REV 4 accrual of 700 patients and analysis is EDIT LAYOUT EXPT’D: REV 5 EDIT LAYOUT RECEIVED: under way, but the trial involves women REV 6 7 with REV disease progression a nonsteEDITOR: on Jen Kulpa ART DIRECTOR: Blake REV 8 roidal aromatase inhibitor, which was REV 9 not the case with either S0226 or FACT. REV 10 REV 11 KEYWORDS:

—Kate O’Rourke

Dr. Mehta disclosed receiving grant/research support from AstraZeneca. Dr. Ingle and Dr. Seidman had no relevant disclosures.

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Tailoring Therapy in Metastatic Breast Cancer Novel Clinical Approaches

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN113” Release Date: October 1, 2011

Expiration Date: October 1, 2012

This activity is based on a live educational symposium held May 21, 2011, in Philadelphia, Pennsylvania.

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Co-Chairs

Tessa Cigler, MD, MPH

Assistant Professor of Medicine, Weill Cornell Medical Center Attending Physician, NewYork-Presbyterian Hospital New York, New York

Paula D. Ryan, MD, PhD

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Associate Professor, Clinical Investigator, Section of Breast Oncology Medical Oncology, Fox Chase Cancer Center Philadelphia, Pennsylvania

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Oncologists, physicians, physician assistants, and other health care professionals involved in the treatment of patients with metastatic breast cancer (MBC). There are no prerequisites or fees.

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Upon completion of this activity, participants will be better prepared to:

1 Review recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or MBC. 2 Describe a treatment algorithm that reflects evidence-based management of advanced human epidermal growth factor receptor 2 (HER2)-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

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9

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SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Ovarian

Pegylated Doxorubicin Aids Survival in Recurrent Ovarian Cancer From Gynecologic Oncology

C

ytoxic therapy with pegylated liposomal doxorubicin (PL-DOX; Doxil, Janssen) may be more effective in the treatment of women with BRCA-associated recurrent epithelial ovarian cancer (EOC) than in those with a “sporadic” form of the disease, a new study has found.

Published in the December 2011 issue of the journal Gynecologic Oncology (2011;123:486-491; PMID: 21945552), the study of 64 patients was designed to compare the response rate, progressionfree survival (PFS) and overall survival (OS) among women with either sporadic ovarian cancer or ovarian cancer associated with mutations of the BRCA1 or BRCA2 genes. Patient data for the retrospective cohort study was obtained

EXPERT INSIGHT Danijela Jelovac, MD Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

T

hese cancers have been shown to have higher sensitivity to platinum-based chemotherapy compared with patients with the wildtype BRCA gene. Like platinum

from a pharmacy database at the University of Pennsylvania Hospitals. Most of the patients included in the study were treated with PLDOX between 2001 and 2007 at the hospitals’ Division of Gynecologic Oncology. Their genetic information was cross-referenced against data from the Cancer Genetics Program at the Abramson Cancer Center. Additionally, patients at two affiliated centers—the Fox Chase Cancer Center and Cedars-Sinai Medical Center—who had undergone BRCA testing and been diagnosed with ovarian cancer were included in the study.

In all, 23 women with EOC and BRCA1 or BRCA2 gene mutations who received therapy with PL-DOX were identified and were compared with 41 patients with sporadic disease. Of this latter group, 31 had no personal or family history of hereditary cancers and 10 had no documented BRCA gene mutations following genetic testing.

The researchers found that 56.5% of the patients with BRCA gene mutations responded to treatment with PL-DOX, compared with only 19.5% among those with sporadic disease (P=0.004). Median PFS with PL-DOX (from the date of the first cycle) among those with BRCA gene

mutations was 27.1 weeks; it was 17 weeks among women with sporadic disease (P=0.109). Finally, median OS (for the date of the first cycle) was 89.1 weeks among women with BRCAassociated ovarian cancer treated with PL-DOX and 48.3 weeks among those with sporadic disease who underwent the same treatment (P=0.002). Interestingly, the patients with BRCA-associated disease included in the analysis had received more chemotherapy cycles prior to starting treatment with PL-DOX than those with sporadic cancer (mean number of cycles was 3.4 and 2.3, respectively).

While noting the small sample size and retrospective design, the authors conclude that their findings “support a wider role” for PL-DOX in the treatment of advanced ovarian cancer.

drugs, anthracyclines cause direct DNA damage. Doxorubicin has been shown to cause single- and doublestrand DNA damage. PL-DOX has been used as a single agent for treatment of platinum-resistant recurrent EOC, with a response rate around 20%.

Because BRCA mutations disable double-stranded DNA repair, BRCA-associated cancers would be expected to have higher sensitivity to any DNA-damaging agents, including PL-DOX. In the present retrospective cohort study, Adams et al compared response rates and PFS and OS among patients with BRCA-associated and sporadic EOC (23 and 41 patients, respectively) who

were treated with PL-DOX. The majority of patients were platinum-resistant prior to starting PL-DOX (74% of BRCA-associated cases and 83% of sporadic cases).

The investigators noted a significantly improved response to PL-DOX in patients with BRCA mutations compared with patients with nonhereditary cancers: 56.5% versus 19.5%, respectively. This was associated with improved PFS (27 vs. 17 weeks) and OS (89 vs. 48 weeks) for patients with BRCA mutations. Response rates to PL-DOX for patients with wildtype BRCA were consistent with previously reported rates. These findings are important and indicate that PL-DOX may prolong PFS and OS in patients with

BRCA-associated EOC. As noted by the authors, the study has limitations that include small sample size and retrospective design.

Recently, another retrospective study

by Safra et al1 (Mol Cancer Ther 2011;10:2000-2007; PMID: 21835933) showed longer median time to failure, OS and response rate for patients with EOC and BRCA mutations treated with PL-DOX compared with patients with wild-type BRCA. Results of an ongoing prospective Phase II study comparing PL-DOX with poly(ADP) ribose inhibitors will further elucidate the role of PL-DOX in treatment of BRCA-associated EOC.

Neuroendocrine

Everolimus Plus Octreotide LAR Combo Ups Neuroendocrine PFS From The Lancet

T

he mammalian target of rapamycin (mTOR) inhibitor everolimus (Afinitor, Novartis), administered in combination with octreotide long-acting repeatable (Sandostatin, Novartis), has been found to improve progression-free survival (PFS) in patients with advanced neuroendocrine tumors associated with carcinoid syndrome.

The randomized, placebo-controlled RADIANT-2 trial, published in the December 10, 2011, issue of the journal Lancet (2011;378:2005-2012; PMID: 22119496), compared a regimen of everolimus at a dose of 10 mg per day plus 30 mg intramuscular octreotide long-acting repeatable (LAR) every 28

days to placebo plus 30 mg intramuscular octreotide LAR every 28 days in 429 adult patients with low- or intermediategrade advanced neuroendocrine tumors (i.e., unresectable locally advanced or distant metastatic), and disease progression established by radiological assessment within the past 12 months. PFS was the primary end point. This Phase III study was performed by an international team of researchers and funded by Novartis, which manufactures both the study drug and octreotide LAR. Median follow-up was 28 months and median duration of treatment was 37 months in the everolimus group and 36.6 months in the placebo group. According to the authors, 140 patients in the everolimus group (65%) and 74 in the placebo

group (35%) required dose reductions or temporary interruptions.

In the final analysis, median PFS was 16.4 months in the everolimus group compared with 11.3 months in the placebo group (P=0.026). Reported drugrelated adverse events (AEs) were mostly grade 1 or 2; however, there were significantly more incidents of AEs such as stomatitis, rash, fatigue and diarrhea in the study drug group compared with placebo. The most common grade 3 or 4 drug-related AEs during the trial were stomatitis, fatigue, diarrhea, hyperglycemia, thrombocytopenia and infection. Additionally, 18 incidents of pneumonitis in the everolimus group were reported; however, there were none in the placebo group. The authors note

that there were imbalances in baseline demographic and disease characteristics favoring the placebo group, such as the lung being the primary tumor site.

The authors write that their results, coupled with the findings of the recently completed RADIANT-3 trial, “support the efficacy of everolimus in a broad spectrum of advanced neuroendocrine tumors.” They add that, given the clinical challenges posed by neuroendocrine tumors and the lack of viable therapeutic options available, their results potentially position everolimus as an important addition to the treatment armamentarium, although they acknowledge that further study of the drug’s safety and efficacy in this patient population is necessary.

SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Kidney

In Study of Clear Cell Carcinoma, Axitinib Edges Sorafenib From The Lancet

T

he targeted agent axitinib (Inlyta, Pfizer) has demonstrated superior efficacy to sorafenib (Nexavar, Bayer/ Onyx) in the first published Phase III trial to compare two inhibitors of the vascular endothelial growth factor receptor (VEGFR) for second-line therapy in the treatment of advanced metastatic renal clear cell carcinoma.

Results of the international, multicenter trial were published in the December 3 issue of the journal Lancet (2011;378:1931-1939; PMID: 22056247).

The project was funded by Pfizer, which manufactures axitinib. Progression-free survival (PFS; assessed by a masked independent radiology review

EXPERT INSIGHT Hans Hammers, MD, PhD

I

Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

n patients with advanced and metastatic kidney cancer, the tyrosine

and analyzed by intention-to-treat) was the primary end point. The trial was designed to compare the agent against what was considered standard of care at the time research began; the mTOR inhibitor everolimus (Afinitor, Novartis) has since received FDA approval for the treatment of renal cell carcinoma after failure with sunitinib (Sutent, Pfizer) or sorafenib.

Researchers enrolled 723 adult patients from 175 centers in 22 countries. All the enrolled participants had been diagnosed with progressive metastatic disease despite first-line therapy consisting of sunitinib, bevacizumab (Avastin, Genentech) plus interferon-alfa, temsirolimus (Torisel, Pfizer) or cytokines. Patients were stratified

according to Eastern Cooperative Oncology Group performance status and type of previous treatment, and randomized (on a 1-to-1 ratio) to receive either axitinib 5 mg twice daily or sorafenib 400 mg twice daily.

Patients without hypertension or serious adverse events (AEs; ≥grade 2) were allowed to receive higher doses of the study drug—first to 7 mg twice daily and then to 10 mg twice daily.

Median PFS among the 361 patients given axitinib was 6.7 months compared with 4.7 months for the 362 patients who received sorafenib (P<0.0001).

Among patients who received cytokines, these figures were considerably higher (12.1 and 6.5 months, respectively). In all, 4% of the patients in

kinase inhibitor (TKI) axitinib shows a significant improvement in median PFS in second-line therapy when compared with the older-generation TKI sorafenib (6.7 vs. 4.7 months; hazard ratio, 0.665).

This is notable because this is the first trial directly comparing a new agent with another active, targeted agent, rather than using placebo.

The results also support the hypothesis that more potent inhibition of the VEGF pathway can result in a superior clinical benefit. However, the

difference in PFS is more modest than most of us would have hoped for.

Although a preplanned subgroup analysis showed a significant superiority of axitinib over sorafenib in both previous sunitinib and previous cytokine treatment subgroups, the difference in PFS for the population pretreated with the TKI was less than the overall difference in PFS. Patients pretreated with cytokines had a PFS of 12.1 months (6.5 months on sorafenib) and patients pretreated with sunitinib had a PFS of 4.8

months (3.4 months on sorafenib).

Since the standard of care for firstline treatment of advanced kidney carcinoma in 2012 is TKIs such as sunitinib and pazopanib, the data most pertinent to current clinical practice is indeed the additional 1.4 months in PFS for patients treated with axitinib. While this trial constitutes a new benchmark for the development of other agents, this gain is rather modest and should encourage further clinical investigations.

advanced pancreatic neuroendocrine tumors (pNETs).

The RADIANT-2 and RADIANT-3 studies were similarly designed. Patients in both studies had low-grade or intermediate-grade NETs and must have had progressive disease before study enrollment. PFS was the primary end point for both studies. Both studies showed everolimus improves PFS. RADIANT-3 met the primary end point, but RADIANT-2 (hazard ratio, 0.77; P=0.026) fell just short of the prespecified boundary of statistical significance (P=0.0246).

The patient population in RADIANT-3 was individuals with pNETs exclusively, but the patient population in RADIANT-2 includes those primarily with non-pancreatic, gastrointestinal NETs and a history of carcinoid syndrome.

The latter was historically referred to as carcinoid tumor. In the RADIANT-2 study, 5% and 7% of patients in each treatment group, respectively, had NETs from a pancreatic origin. pNETs and carcinoid tumors share similar pathobiologic features. The mTOR pathway is aberrantly activated in both types of

NETs. The RADIANT-2 study, however, did not meet the primary end point.

This could be explained by imbalances between the two treatment groups in baseline factors, including primary tumor site, World Health Organization performance status and previous use of chemotherapy. Therefore, the study team is proposing to confirm the benefit of everolimus on PFS in non-pancreatic NETs in a future study with a better design. When such a new study is designed, radiological challenges that were faced by both the RADIANT-2 and -3 studies associated with the assessment of advanced NETs and the clinical diversity of the patient population seen in RADIANT-2 may also need to be addressed.

Everolimus offers limited objective tumor response in both pNET and carcinoid tumors, according to both RADIANT studies. Disease stabilization appears to contribute to the benefit of everolimus on PFS. Neither RADIANT study supported the benefit of everolimus on overall survival, possibly due to the crossover design. Considering the

slow progressive nature of low- or intermediate-grade NETs, one should carefully choose the timing of initiating the everolimus treatment. It is generally recommended to wait until there is evidence of recent disease progression before starting everolimus or sunitinib, which was also recently approved for the treatment of advanced pNET. Carcinoid has a much higher prevalence than we had thought in the past.

There is definitely an unmet need for effective treatments for this disease.

With its associated secretory symptoms, carcinoid is particularly a challenge for management. The results of the RADIANT-2 study showing a significant reduction in circulating hormonal products of carcinoid tumor cells in patients in the everolimus group are encouraging. The potential role of everolimus itself or in combination with local therapies such as chemo- or radioembolization on the symptomatic management of carcinoid syndrome deserves our attention in future studies.

the axitinib group discontinued therapy due to AEs, the most common of which were diarrhea, hypertension and fatigue. In the sorafenib group, 8% of the patients discontinued treatment as a result of AEs such as diarrhea, palmar-plantar erythrodysesthesia and alopecia. Although these differences are significant, the authors acknowledge that the open-label design of the study could result in bias in the assessment of toxic effects. The authors also note that overall survival figures will be provided separately when data mature.

Axitinib is a more potent inhibitor of VEGFR than is sorafenib and these results, according to the authors, “support the hypothesis” that this “produces a more robust clinical effect.”

Neuroendocrine

EXPERT INSIGHT Lei Zheng, MD Assistant Professor of Oncology and Surgery Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

T

he RADIANT-2 study demonstrated that adding everolimus to octreotide LAR improves PFS by 5.1 months, compared with octreotide LAR alone, in patients with progressive advanced neuroendocrine tumors (NETs) and a history of carcinoid syndrome. Everolimus is an mTOR inhibitor that already has been approved by the FDA for the treatment of advanced renal cell carcinoma. After the RADIANT-3 study showed improved PFS with everolimus in patients with NETs from a pancreatic origin, in May 2011, it also was approved for the treatment of

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PROGNOSTICATION continued from page 1 

ER expression is more predictive of a favorable long-term prognosis than tumor shrinkage. This testing is simple, easy to perform and relatively inexpensive. It would not interfere with the usual course of needle biopsy for diagnosis followed by surgical excision of the cancerous mass and sentinel node identification and excision a few weeks later. Giving two weeks of hormone therapy with tamoxifen or an aromatase inhibitor (AI) is both easy and safe.

according to Table 1 and are added to estimate prognosis according to Table 2.

Failure to achieve a low Ki67 score and loss of ER were bad prognostic signs. In contrast, there were no relapses and only one death among 28 women with pT1N0 tumors. Clinical response and post-treatment tumor grade were prognostic in univariate analysis but fell out as nonsignificant in multivariate analysis.

The loss of ER expression during neoadjuvant therapy noted in the

Table 1. PEPI Score Based on 158 Patients Patients (n)

Adverse Points

Pathologic stage (p-stage) T3 or T4

33

3

Positive nodes on path exam

90

3

Allred score 0-2 at resection

16

3

Ki67 staining at resection <2.8%

0

2.8%-7.3%

1

7.4%-19.7%

2

>19.7%

3

PEPI, preoperative endocrine prognostic index

In reviewing the literature behind this concept, limitations of all the studies emerge. Rather than dwell only on induction hormone therapy, I offer a useful perspective on the range of predictive and prognostic tests for ER–positive breast cancer available in 2012.

There is no optimal test to decide which women have such a good prognosis that they do not need chemotherapy, nor to discover characteristics that assure their physicians that chemotherapy would be of no value. Instead, there is a range of available tests in varying stages of development, each with somewhat limited supporting data. It pays to review the advantages and disadvantages of each test, as well as the shortcomings of the data underpinning each one.

PEPI Score—Prognostic At SABCS, Matthew Ellis, MB, PhD, director of the Breast Cancer Program at Washington University School of Medicine in St. Louis, discussed an index he developed called the preoperative endocrine prognostic index (PEPI). This test evolved from a randomized preoperative study (P024 Trial) of 16 weeks of tamoxifen versus letrozole (Femara, Novartis Oncology) for women with stage II or III breast cancer.1 Of the 337 women in the study, only 158 could be fully profiled to develop the PEPI. Median follow-up was 62 months, a short time period for ER– positive breast cancer.

Prognosis worsens with a higher score on the PEPI. The points accrue

PEPI analysis is a reproducible phenomenon—it was seen in 6.7% of women in an American College of Surgeons Oncology Group (ACOSOG) trial of four months of preoperative AI therapy.2,3 In the IMPACT (Immediate Preoperative Anastrozole Tamoxifen or Combined with Tamoxifen) trial of 12 weeks of neoadjuvant tamoxifen versus anastrozole, total loss of ER expression during anastrozole therapy was not seen, and only three of 54 tamoxifen-treated patients had even transient loss of ER staining.4 However, in IMPACT, a drop in ER level was deleterious in terms of overall recurrence rate.5 Issues that will need to be formally addressed before reduction or loss in ER expression can be used reliably for prognostication and choice of therapy include the following: • How to reliably identify and quantify reduction and loss of ER expression (including initial false-positives, intra-tumoral heterogeneity, the use of different antibodies in different laboratories and perhaps in the same laboratory at different times).

• Knowledge of proper specimen handling.

• Analysis of cores for the initial measurement and larger tumor masses for the second measurement.

• Determining variable lengths of induction hormone therapy.

• Setting cut points for ER positivity and degree of ER loss.

Reproducibility of the Allred score

measuring in a continuous scale both the frequency and intensity of ER staining also is limited. In ACOSOG Z1031, entry was restricted to women with tumoral Allred scores of 6 to 8. On central testing, 20.3% had scores of 5 or lower and 2% were ER–negative with scores of 0 or 2.6 The PEPI model proved valid in an independent, 203-patient cohort in the IMPACT trial of neoadjuvant tamoxifen versus anastrozole, with no relapses for p-stage 0 to 1 patients with a PEPI score of 0.

Limitations of the PEPI Score 1. The PEPI score is based on a small number of patients in both development and validation sets. This led to lumping all node-positive patients together, rather than dividing them by numbers of involved nodes, and using tumor size as a discontinuous variable rather than a continuous one.

2. All patients in the development set had relatively advanced tumors; therefore, the score is not readily applicable to women with node-negative tumors less than 2 cm in diameter. Although loss of ER and high levels of Ki67 may prove negatively prognostic in women with smaller tumors, the weight of these factors may change, and tumor size may prove more important.

3. The development set had only about 50% of the patients entered in the study, and biases that the exclusions introduce cannot be estimated.

4. Also, 63 of 205 patients in the PEPI data set with full clinical information at diagnosis had chemotherapy, which was much more common in women with larger tumors at excision. Although this had little influence on the prognosis of the better-risk tumors, the numbers are far too small to correct for whatever effect this chemotherapy had on the outcome of the poorer-risk patients; and the chemotherapy regimen used, as well as its quality—dose, density and duration— were not analyzed.

5. Preoperative hormone therapy may affect the Oncotype DX recurrence score (RS) determined at surgery. Many physicians rely on the Oncotype DX performed prior to treatment to decide whether or not to give chemotherapy to women with negative nodes. The

Table 2. PEPI Score And Five-Year Prognosis PEPI Score

Relapse, Breast Cancer % Death Rate, %

0

10

2

1-3

23

11

>3

48

17

PEPI, preoperative endocrine prognostic index

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, new york City

expected drop in proliferation from preoperative hormone therapy could lead either to a drop in RS reflecting true improvement in distant relapse–free survival (DRFS), or a drop in RS reflecting decrease in proliferation with no change in outcome years later. Mitchell Dowsett, PhD, head of Breast Cancer Translational Research at the Royal Marsden Hospital and Institute of Cancer Research in London, pointed out that AIs reduce progesterone receptor (PgR) in most but not all patients. A low PgR after AI treatment in a patient who initially had a high PgR is a good sign, but remains negatively prognostic in women whose tumors started with low PgR levels.7 Tamoxifen, in contrast, increases PgR in most patients and this increase is associated with a favorable prognosis.8 Interpretation of the 16 mRNA levels that make up the Oncotype DX after induction hormone therapy thus depends on the initial level of proliferation, the initial PgR mRNA level and which hormone is administered in the interval. Thus, the RS calculation is valid only on samples taken before therapy.

6. A Japanese study, presented as a poster at the 2011 American Society of Clinical Oncology meeting, reported early outcomes among 52 women given neoadjuvant exemestane who had their RS determined at diagnosis and again at resection 24 weeks later.9 Clinical response was greater if the initial RS was low. No data on the effect of exemestane on the RS and its individual components (ER, PgR, proliferation and HER2) were given in the poster. It will be interesting to see if this study using Oncotype DX confirms the prior observations. The number of women in this trial likely will prove too small to demonstrate whether changes in proliferation, ESR1 mRNA and PgR mRNA have the prognostic implications we expect.

Day 14 Ki67 Expression Prognostic in the IMPACT Trial The IMPACT trial of neoadjuvant anastrozole versus tamoxifen versus a combination of both had 260 evaluable patients, 159 of whom had paired biopsy specimens available.10 In this trial, Ki67 expression after 14 days was much more prognostic of RFS than Ki67 at diagnosis. Those patients in the highest third of Ki67 expression had an estimated five-year RFS of 60% compared with 75% for the middle third and 85% for the lowest tertile.

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In multivariate analysis, baseline tumor size and two-week level of ER also were important in predicting RFS. Again, T1 tumors with low Ki67, preserved ER expression and negative nodes had no relapses.

Limitations of this analysis include the following: 1. The analysis was based on a small number of patients, and again, not all patients had enough information for analysis.

2. The report had a short median follow-up of only 37 months with a shorter 30-month median duration of therapy, suggesting high rates of noncompliance with adjuvant endocrine therapy. This is very short follow-up for an ER-positive population.

3. The argument that low Ki67 expression at two weeks is always favorable is undermined by the later observation in the same group that 16 of the 95 tumors that dropped their Ki67 by at least 50% within two weeks increased it again by 12 weeks, and this increase was associated with a poor prognosis—about 40% RFS at five years, the same as that of women whose tumors did not drop their Ki67 at two weeks.11

IHC4 as Prognostic Index The same group used data from the ATAC (Arimidex, Tamoxifen Alone or in Combination) study to develop a simple and cheap prognostic test for ER-positive breast cancer called the IHC4 (four immunohistochemical markers), which proved equally prognostic in the hormone-treated population as the much more expensive Oncotype DX.12 The IHC4 prognostic index uses the sum of weighted semiquantitative estimates of ER and PgR, HER2 and Ki67, to which may be added a clinical score incorporating primary tumor size, number of involved nodes, grade and age of patient that further improves the prognostic power of the index. With or without the clinical information, the IHC4 seemed equal in prognostic power to the Oncotype DX RS (recurrence score). The latter also proved stronger when clinical data were included.13 The IHC4 was validated in a separate cohort from Nottingham, England, which used a different measure of proliferation based on levels of staining with MIB1 monoclonal antibody that had to be converted to Ki67 equivalents.

Limitations of the studies of the IHC4 include the following: 1. The development set of 1,125 is only about 20% of the entire TransATAC population of 5,580 women. Although the general conclusions on prognosis will probably stand, one wonders if the likely preferential exclusion of patients from lower-quality centers—those with poorer patients and lower-quality surgeons and pathology departments— might change the quantitative estimates

of prognosis to some degree.

2. The inclusion of HER2-positive tumors is probably no longer appropriate—all of us now consider these separately. The relevant model would then be an IHC3 using only ER, PgR and HER2 IHC. Apparently this is achieved by inputting “0” for HER2 into the IHC4.

3. The use of two weeks of neoadjuvant hormone therapy followed by ER and Ki67 measurement would allow the use of the more prognostic two-week Ki67. This clearly would require another large development set followed by independent validation. The resulting index

could be called IHC3’ and might contain some measure of the change in Ki67 as well as the second Ki67 determination. In the 158-patient analysis of impact, however, the two-week level of Ki67 expression was the best metric for prognosis.14 4. The calculation of the IHC4, IHC3 and RS plus age, grade and tumor size (RSPC) are beyond the abilities of all but the most mathematical oncologist—we need either a complicated nomogram to allow the rest of us to calculate each of them or a Web-based calculator. Genomic Health, which reports the RS, is now planning a Web-based calculator for

the RSPC. No calculator is available for IHC3 or IHC4.15 5. The Ki67 measurement is not standardized and is not clearly reproducible from one lab to another. Experts in the field recently addressed this issue, as well as those of specimen handling and scoring, and note the lack of agreement on cut points for favorable and unfavorable levels.16 One could make similar arguments for the now widely used ER and PgR values. That we have accepted poor reproducibility and large technique variations for hormone receptor see PROGNOSTICATION, page 14 

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Oncotype DX Recurrence Score And Chemotherapy Benefit

PROGNOSTICATION continued from page 13 

measurements does not solve the problems with Ki67, however.

Oncotype DX Recurrence Score The Oncotype DX was developed as a unique prognostic tool for women with node-negative, ER-positive tumors treated with tamoxifen that could be determined on formalin-fixed, paraffinembedded tumor tissue. It began with the selection of 250 candidate genes from the literature, as well as laboratory studies that test designers thought might be important for tamoxifentreated women with breast cancer. Levels of mRNA for these genes were measured in 447 tumors from three studies of tamoxifen-alone adjuvant therapy— including some women from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B20 trial where another group was randomized to tamoxifen plus chemotherapy—to determine each gene’s effect on distant relapse at 10 years from diagnosis. Based not only on the predictive power of each gene for distant relapse, but also on reproducibility in all three studies and also on consistency of primer and probe performance in the lab, 16 genes in five groups were selected for inclusion in the test and their expression compared with five reference genes that are not prognostic and do not figure into the final calculation except as reference points. This is really a 16-gene test and two of the genes included refer mainly to HER2-overexpressing tumors.

Thus, for most of our patients, this is a 14-gene test. The observed mRNA levels are combined through a very complicated, weighted calculation into a single RS that ranges from 0 to 100.

Blocks with interpretable mRNA levels were available for 668 tamoxifen-treated patients in NSABP B14 from the following two populations: 1,450 randomized to tamoxifen versus observation and another 1,235 assigned to tamoxifen without randomization. These patients were the basis of the first Oncotype DX paper.17 The initial argument was that the 93% DRFS of the low-risk patients

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was so high that adjuvant chemotherapy was unnecessary.

Although the Oncotype DX RS was designed to be prognostic in a tamoxifen-treated population, the outcomes measured were determined both by the intrinsic characteristics of the tumor— prognosis of untreated patients—as well as by the ability of tamoxifen to improve or not to improve the outcomes. When the Oncotype DX RS was determined in NSABP B14 among node-negative women randomized to observation compared with those randomized to tamoxifen, these two effects could be separated (Table 3).18

First Look: Tamoxifen Benefits Only Low- And Intermediaterisk Oncotype DX Patients As is clear from Table 1, the relative benefit of tamoxifen in the low-risk group is 51%, about the same as the 46% relative benefit in the intermediate-risk group. The absolute benefit is much higher for intermediate-risk patients because their risk of distant relapse if untreated is much higher. One could argue that tamoxifen has no benefit in the high-risk group, although the numbers are relatively small to be able to say this with great confidence.

Lack of Tamoxifen Benefit Best Predicted by Low ESR1 mRNA Levels A careful reanalysis of this data has just been published in which levels of ESR1 mRNA—one of the four ER-related genes measured in the Oncotype DX RS—are better in terms of statistical power than the total RS for discriminating women who benefit from tamoxifen treatment from those who do not.19 The lowest tertile of tumors for ESR1 mRNA levels had a slightly higher 10-year distant recurrence rate with tamoxifen than with no adjuvant hormone therapy. ESR1 mRNA was a far superior determinant of tamoxifen efficacy than ER protein by ligand-binding assay. ESR1 mRNA was not a very good prognostic test, however; 10-year DRFS was about 80% in all three tertiles of ESR1 mRNA level.

Based on Dr. Dowsett’s analysis of the Oncotype DX RS in the ATAC trial, it seems likely that the same group of women with a high RS and low ESR1 mRNA levels do not fare much better on anastrozole than on tamoxifen. There are two urgent clinical research tasks: confirming that tamoxifen and AIs do not benefit these women with detectable ER protein but low levels of ESR1 mRNA, and searching for treatments— hormonal, chemotherapeutic or “targeted”—that do benefit them.

In this regard, the Oncotype DX test was applied to NSABP B20, in which women were randomized to tamoxifen or tamoxifen started with six months of cyclophosphamide, methotrexate and fluorouracil (5-FU; CMF) chemotherapy. Obvious chemotherapy benefit was restricted to the high-RS patients (a 74% relative decrease in 10-year rate of distant recurrence), although the number of events was too small in the intermediate- and low-risk groups in my opinion to exclude a modest absolute benefit in 10-year DRFS.20 Women with a high RS are a substantially different population from those with low levels of ESR1 mRNA, who benefit little or not at all from tamoxifen, although they do overlap to some extent.

One could argue that Oncotype DX “low-risk” women who are node-negative have such a good prognosis that chemotherapy should be avoided. In an analysis of the Oncotype DX test in 872 node-negative and 306 node-positive patients enrolled in the ATAC trial, the nine-year distant recurrence rates— not the same as DRFS—was only 4% for the node-negative women, leaving little room for improvement. In contrast, the nine-year distant relapse rate was 17% for the node-positive women, leaving considerable room for improvement.

Some women will be satisfied with only a 4% distant relapse rate; others might want to aggressively try to improve on it. I will be more comfortable having this discussion with my patients when we have more information on a larger number of low- and intermediate-risk patients randomized to chemotherapy or none in TAILOR-Rx (Trial Assigning IndividuaLized Options for Treatment [Rx]).

The Oncotype DX is the only technique that used randomized prospective trials of treatment versus no treatment to look at the predictive value for benefit of hormone therapy or chemotherapy added to hormone therapy, as well as prognosis. This is a major achievement. Other advantages: results usually are available within one week of specimen submission and the test is done in a single lab with very high levels of quality control. Expert and articulate lab staff also are available to help with interpretation of the results.

Limitations of the Oncotype DX As a Predictor of Chemotherapy Benefit There are several limitations of the Oncotype DX when used to predict the effect of chemotherapy: 1. All the data analyzed are based on a portion of the patients entered in each randomized trial. Although the characteristics of the tested patients were similar to those of patients across the entire

trial, one cannot be certain that the tumors with blocks available that had good mRNA were fair representatives of the entire population. These exclusions could change the extent of benefit from adding chemotherapy to tamoxifen.

2. The genes chosen for the Oncotype DX were selected from a limited pool after thoughtful consideration, rather than a formal and reproducible selection process. There is no data to show that these are the best genes, although they are clearly useful.

3. The weights used to calculate RS were optimized for prognosis on tamoxifen and clearly are not very good for predicting prognosis without hormone therapy (Table 3). Intelligent design would consider looking at expression of different genes to examine the likelihood of chemotherapy benefit, including chemotherapy targets, proteins for DNA repair like PARP and ERCC1, target enzymes like thymidylate synthetase, topoisomerase II, dihydrofolate reductase and levels of drug efflux pumps like ATP-binding cassettes. Even if all 14 genes relevant to HER2-negative tumors in the Oncotype DX do have some value for predicting sensitivity to chemotherapy, it seems unlikely that their weights would be the same as the weights for predicting prognosis with tamoxifen without chemotherapy. Sensitivity, or lack thereof, to chemotherapy is an important issue that deserves specially designed tools that are distinct from tools to measure prognosis on hormone therapy. Soonmyong Paik, MD, NSABP’s pathology director, on the other hand, points out that such reasoned approaches to predicting chemotherapy sensitivity have been tried in multiple human tumor systems and largely failed, whereas the Oncotype DX seems to work, and the Oncotype DX was developed in the hope that it would predict chemotherapy sensitivity.

4. Using the Oncotype DX to predict the benefit of chemotherapy for women with node-positive tumors is based on tiny amounts of data with very wide confidence limits. A study by Kathy Albain, MD, of Loyola University in Maywood, Ill., identified no truly low-risk group of women.21 Some argue that breast cancer–specific survival was very high in the “low-risk” population and lower for those who had CAF (cyclophosphamide, adriamycin, 5-FU) chemotherapy in addition to tamoxifen. It is not clear from the paper how much care went into defining a breast cancer death, and the number of patients with recurring disease and dying remains small, with large and overlapping confidence limits. There is no doubt that the Oncotype DX can offer prognostic information in node-positive patients.21,22 In 2012, it is still not clear how to use this information. Other trials suggest that a low-risk group of women does exist, because the prognosis of ER-positive women with

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one to three positive nodes within the past 15 years has been very good when treated with doxorubicin and cyclophosphamide (AC), doxorubicin and paclitaxel or docetaxel (AT), or docetaxel and cyclophosphamide (TC), with estimated five-year distant relapse rates of less than 10%.

5. The inclusion of HER2-positive patients in these studies and HER2 genes in the RS is probably not needed and perhaps misleading, although some argue that low-level HER2 expression may be prognostic even in non-amplified tumor patients. This has not been tested. In 2012, most experts agree that the Oncotype DX should not be used in HER2-positive tumors. I believe we need a recurrence score for small HER2positive tumors to decide which women need adjuvant systemic treatment and which of these treatments they need.

This is an unmet need. Although this prognostic index would be important, the studies to create it will prove difficult because (a) only 20% of breast cancers are HER2-positive, (b) many physicians have made up their minds, (c) many patients have made up their minds and (d) treatments are likely to keep changing with the availability of dual HER2 blockade with trastuzumab and pertuzumab.

6. Data already have been published showing that adding clinical information to mRNA levels improves the prognostic power of the RS score. Genomic Health has not yet made available this calculator in print or online, although it plans to do so.

7. The Oncotype DX offers no information on which hormone therapy or which chemotherapy to use—it was not designed or tested for either purpose.

8. Because it is a patented test done in a single lab, it also is quite expensive.

PAM50 May Be Superior To Oncotype DX as a Prognosticator Two larger tests based on tumor tissue mRNA levels are available commercially in the United States—the MammaPrint using 70 genes and the PAM50 using 50 genes. Each test can be done on formalin-fixed, paraffin-embedded tumor tissue. The PAM50 (PAM stands for prediction analysis of microarray, a mathematical means of fitting the result into predetermined categories such as luminal A and luminal B) is prognostic in ER-positive tumors.23 Dr. Dowsett determined both Oncotype DX RS and PAM50 risk of relapse (ROR) scores based on mRNA extracted from 1,007 women in the TransATAC population and compared both prognostic models with an end point of 10-year DRFS.24 The PAM50 seemed more informative not because it identified more patients as lower risk (an equal percentage of lowrisk patients was identified and did well

Table 3. NSABP B-14: 10-Year DRFS Results of 645 Randomized, Evaluable Patients Among 2,817 Entrants 10-Year DRFS

RS

Patients (n)

Placebo, %

Tamoxifen for 5 y, %

Absolute Difference, % (P Value)

1-17

338

86

93

7 (P=0.04)

18-30

149

62

79

17 (P=0.02)

>30

181

69

70

1

DRFS, distant recurrence–free survival; RS, recurrence score

with either test), but because it moved some of the intermediate-risk patients from the Oncotype DX analysis into the high-risk group, where apparently they belonged. In Dr. Dowsett’s analysis, very little prognostic information was added to clinical parameters and PAM50 results by then using the Oncotype DX RS. In contrast, the PAM50 ROR added substantially to clinical parameters and the Oncotype DX RS measurement.

Recently published data suggest that PAM50’s determination that a cancer is of the luminal A or basal-like subtype predicts no benefit for giving adjuvant epirubicin compared with methotrexate.25 Whether PAM50 will be superior to the Oncotype DX for identifying groups more or less likely to benefit from adjuvant chemotherapy—a separate predictive effect—is not yet clear.

References

What To Do in 2012

5. Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after shortterm presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst.

2007;99:167-170, PMID: 17228000.

For women with smaller, clinically node-negative, HER2-negative tumors, in whom I think it may be reasonable to avoid chemotherapy, I start the appropriate hormone once the ER is shown positive on needle biopsy. I measure Ki67 on the biopsy core and again at lumpectomy or mastectomy. If the ER staining stays positive and high, if Ki67 falls, if the final pathologic characteristics are not ominous and if HER2 is non-amplified, I comfortably recommend hormone therapy only without expensive tests of RNA levels. Once a calculator based on semiquantitative IHC expression of Ki67, ER and PgR is available, I will then calculate IHC3 and IHC3' as an adjunct to the fall in Ki67 and use this as well. I would be most comfortable if data were available for the prognostic value of an IHC3' that incorporates changes in Ki67 at two to four weeks, the usual interval between core biopsy and total excision of the primary.

For women who do not clearly have what the patient and I consider a very good prognosis after these IHC tests, I still would use the Oncotype DX—preferably on the initial biopsy until we have data on how to interpret a test done after a few weeks of hormonal intervention— to make sure I do not miss giving chemotherapy to patients with high RS, and use the ESR1 mRNA level now reported as part of the test to decide how much reliance to place on adjuvant hormone therapy to prevent distant relapse and death.

1. Ellis MJ, Tao Y, Luo J, et al. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008;100:1380-1388, PMID: 18812550.

2. Ellis MJ. Personal communication.

3. Ellis MJ, Suman VJ, Hoog J, et al. Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype-ACOSOG Z1031. J Clin Oncol. 2011;29:2342-2349, PMID: 21555689.

4. Dowsett M, Ebbs SR, Dixon JM, et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005;23:2477-2492, PMID: 15767642.

6. Luo J. Personal communication.

7. Dowsett M, Ebbs SR, Dixon JM, et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. J Clin Oncol. 2005;23:2477-2492, PMID: 15767642.

8. Dowsett M. Personal communication.

9. Masuda N, Toi M, UenoT, et al. A study of the recurrence score by the 21-gene signature assay as a predictor of clinical response to neoadjuvant exemestane for 24 weeks in estrogen-receptor-positive breast cancer.

J Clin Oncol. 2011:29(suppl; abstr 558).

10. Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after shortterm presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst.

2007;99:167-170, PMID: 17228000.

11. Generali D, Symmans WF, Berruti A, Fox SB. Predictive immunohistochemical biomarkers in the context of neoadjuvant therapy for breast cancer. J Natl Cancer Inst Monogr. 2011;2011:99-102, PMID: 22043052.

12. Cuzick J, Dowsett M, Pineda S, et al. Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. J Clin Oncol.

2011;29:4273-4278, PMID: 21990413.

13. Tang G, Cuzick J, Costantino JP, et al. Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with

Breast pathologic and clinical factors. J Clin Oncol.

2011;29:4365-4372, PMID: 22010013.

14. Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after shortterm presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst.

2007;99:167-170, PMID: 17228000.

15. A’Hern R. Personal communication.

16. Dowsett M, Nielsen TO, A’Hern R, et al.

Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103:1656-1664, PMID: 21960707.

17. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifentreated, node-negative breast cancer.

N Engl J Med. 2004;351:2817-2826, PMID: 15591335.

18. Paik S, Shak S, Tang G, et al. Expression of the 21 genes in the Recurrence Score assay and tamoxifen clinical benefit in the NSABP study B-14 of node negative, estrogen receptor positive breast cancer. J Clin Oncol.

2005;23, No. 16S, Part I of II (June 1 Supplement), 2005:510.

19. Kim C, Tang G, Pogue-Geile KL, Costantino JP, et al. Estrogen receptor (ESR1) mRNA expression and benefit from tamoxifen in the treatment and prevention of estrogen receptor-positive breast cancer. J Clin Oncol. 2011;29:4160-4167, PMID: 21947828.

20. 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;24:3726-3734, PMID: 16720680.

21. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogenreceptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. 2010;11:5565, PMID: 20005174.

22. 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;26:40634071, PMID: 18678838.

23. Parker JS, Mullins M, Cheang MC, et al.

Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol.

2009;27:1160-1167, PMID: 19204204.

24. Dowsett M, Lopez-Knowles E, Sidhu K, et al. Comparison of PAM50 Risk of Recurrence (ROR) score with OncotypeDx and IHC4 for predicting residual risk of RFS and Distant-(D)RFS after endocrine therapy: a TransATAC Study. Presented at the CTRC-AACR San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, Texas. Abstract S4-5.

25. Cheang MC, Voduc KD, Tu D, et al. Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC. CTG MA.5 randomized trial. Clin Cancer Res. 2012 Feb 20. [Epub ahead of print], PMID: 22351696.

Dr. Vogl would welcome precise modern data on the prognosis of women with ER-positive, HER2negative tumors and 1-3 involved axillary nodes after treatment with 2-3 chemotherapy drugs and 5 years of tamoxifen or an AI. Please write to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com if you have them.

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SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Breast

Lapatinib and Trastuzumab Effective in HER2-Positive Breast Cancer From The Lancet

T

he results of an international, multicenter, intention-to-treat Phase III trial of combination therapy with lapatinib (Tykerb, GlaxoSmithKline) and trastuzumab (Herceptin, Genentech) in HER2-positive early breast cancer indicate that the combination is both safe and effective, and that dual inhibition of HER2 may be a valid therapeutic approach for the disease. The study findings were published in the February issue of Lancet (2012;379:633640, PMID: 22257673).

With funding from GlaxoSmithKline, manufacturers of the brandname form of lapatinib, researchers designed the NeALTTO (NeoAdjuvant EXPERT INSIGHT Roisin Connolly, MBBS Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The management of HER2-positive breast cancer has been revolutionized by the development of antiHER2 therapies such as trastuzumab.

A number of recent studies, including the Phase III NeoALTTO study published in the Lancet earlier this year, suggest that dual anti-HER2 therapy is

Lapatinib and/or Trastuzumab Treatment Optimization) trial to prove their hypothesis that two anti-HER2 agents administered simultaneously would be more effective than a single agent administered alone. To do so, they randomized more than 450 patients from 23 countries to receive either oral lapatinib (1,500 mg), IV trastuzumab (loading dose 4 mg/kg, subsequent doses 2 mg/kg) or lapatinib (1,000 mg) plus trastuzumab for a period of six weeks; weekly paclitaxel (80 mg/m2) was then added to the regimen for 12 weeks prior to surgery (the lapatinib dose was reduced to 750 mg).

Following surgery, patients received adjuvant chemotherapy and then 52 weeks of targeted therapy as before.

All the women in the study had been

diagnosed with HER2-positive breast cancer, and had tumors larger than 2 cm in diameter. The study’s primary end point was pathologic complete response (pCR).

Of the 152 patients in the combination therapy group, 51.3% achieved pCR compared with 29.5% in the group (149 patients) receiving trastuzumab alone (P=0.0001). Only 24.7% of those in the lapatinib monotherapy group (154 patients) achieved pCR (P=0.34). However, after the six-week initial treatment period, researchers observed a higher objective response rate in the lapatinib monotherapy (52.6%) and combination therapy (67.1%) groups than in the trastuzumab monotherapy (30.2%) group.

With regard to adverse events,

more efficacious than single anti-HER2 therapy. The primary end point of the NeoALTTO study was the rate of pCR obtained in each arm, with the trastuzumab plus paclitaxel arm being compared formally with each investigational arm (trastuzumab, lapatinib plus paclitaxel/lapatinib plus paclitaxel). The rate of pCR is a potential surrogate end point for survival that is commonly used in neoadjuvant studies. The high pCR rate obtained with paclitaxel plus dual anti-HER2 therapy of approximately 50% compares favorably with studies of combination chemotherapy and trastuzumab alone. The overall pCR rate was higher in women with estrogen receptor (ER)–negative (61.3%) than ER-positive (41.6%) disease, although whether pCR rate accurately predicts outcome

in women with ER-positive disease is debatable.

Although the therapy was relatively well tolerated, it must be noted that there was increased toxicity such as diarrhea and liver enzyme alterations in the lapatinib arms. An amendment reducing the dose of lapatinib from 1,000 mg per day to 750 mg per day concurrent with paclitaxel in order to reduce the incidence of diarrhea was deemed necessary. In addition, the fact that only twothirds of patients in the lapatinib arms were able to complete protocol therapy as planned is notable.

Clearly, dual anti-HER2 therapy appears to be associated with improved outcomes for breast cancer patients. Ideally, combinations of agents that minimize toxicity alongside maximizing

incidence of grade 3 diarrhea was significantly higher in the lapatinib monotherapy (23.4%) and combination therapy (21.1%) groups than in the trastuzumab monotherapy group (2%). Incidence of grade 3 liver enzyme alterations was also higher in the lapatinib monotherapy (17.5%) and combination therapy (9.9%) groups than in the trastuzumab monotherapy group (7.4%). No incidents of cardiac dysfunction were reported over the course of the trial. Only 60.5% of the patients in the combination therapy group were able to complete treatment as planned because of adverse events (liver dysfunction, diarrhea, etc), compared with 66.2% in the lapatinib monotherapy and 91.9% in the trastuzumab monotherapy groups. efficacy will be most appealing in the clinic. Practitioners treating patients with lapatinib, as with any agent which targets the EGFR pathway, must be aggressive in their management of these side effects in order to minimize impact on patients’ safety and quality of life. Finally, it has been noted in recently presented neoadjuvant studies, such as the NeoSPHERE study, that a significant proportion of women treated with biologic therapy alone (pertuzumab and trastuzumab in this case) can obtain a pCR; and this has caused great excitement in the breast oncology community. There is a clear need to determine who these patients are upfront as they could potentially be spared the added toxicity of chemotherapy.

Kidney

Sunitinib Promising for Non–Clear Cell Renal Cell Carcinoma From Annals of Oncology

A

recently completed Phase II trial has demonstrated the safety and efficacy of sunitinib (Sutent, Pfizer) in patients with non–clear cell renal cell carcinoma (RCC). The results of the trial, which was led by a team of researchers from Seoul, South Korea, were published online in January by Annals of Oncology (2012 Jan 6. [Epub ahead of print], PMID: 22228449).

Sunitinib, a vascular endothelial growth factor (VEGF) pathway inhibitor, has already received FDA approval for advanced or metastatic clear cell RCC, as well as other cancers. The Phase II prospective, multicenter trial

was designed to assess the drug’s viability for a new indication. Non–clear cell RCC is not the most common form of the disease; however, historically, it has been associated with the poorest treatment outcomes. Another VEGF pathway inhibitor, sorafenib (Nexavar, Bayer/Onyx) also has demonstrated efficacy in the treatment of this challenging disease during expanded-access trials.

For the trial, the preliminary results of which were initially presented at the American Society for Clinical Oncology’s 2011 Genitourinary Cancers Symposium, researchers enrolled 31 patients with advanced non–clear cell RCC (those with collecting duct carcinoma and sarcomatoid carcinoma without identifiable RCC subtypes were

ineligible), 24 of whom had undergone nephrectomy prior to the study. The authors noted that 22 of the patients in the study population had papillary RCC and three had chromophobe RCC. All patients were treated with oral sunitinib 50 mg per day for four weeks, followed by two weeks of rest. The study’s primary end point was overall response rate.

At the conclusion of the trial, 11 patients (36%) had partial response and 17 (55%) had stable disease. Only one patient had progressive disease.

Median duration of response was 12.7 months. After a median follow-up period of 18.7 months, 21 patients had disease progression and 13 patients (42%) had died. Median overall survival (OS) was, therefore, 25.6 months and

median progression-free survival was 6.4 months. Median OS was not reached.

The disease control rate was 86%.

High rates of grade 3 or higher adverse events such as hand–foot syndrome, neutropenia and thrombocytopenia were reported during the trial and resulted in higher rates of dose reduction and treatment interruption than those reported during the Phase III and expanded-access trials for sunitinib. In addition, one patient had an acute fatal congestive cardiomyopathy during treatment, despite having no known risk factors. After this incident, the researchers performed pretreatment cardiac screening as well as blood pressure control and cardiac monitoring during treatment.

SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Melanoma

Abscopal Effect Maximizes Potential of Ipilimumab Plus Radiation From The New England Journal of Medicine

I

n a single-patient case study, researchers from Memorial SloanKettering’s Ludwig Center for Cancer Immunotherapy found that combination therapy with ipilimumab (Yervoy, Bristol-Myers Squibb) and radiotherapy may be a promising approach in patients with advanced metastatic melanoma. The results of the study were published in the March 8 issue of The New England Journal of Medicine (2012;366:925-931, PMID: 22397654).

The authors attribute the success of the combination of ipilimumab and radiotherapy in this patient case to the abscopal effect, a rare phenomenon in localized radiotherapy that is, as the authors wrote, “associated with

EXPERT INSIGHT Evan Lipson, MD Instructor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

This report by Postow, Callahan and colleagues of the abscopal effect in a patient with melanoma is an important step in our understanding of how

EXPERT INSIGHT Hans Hammers, MD, PhD Assistant Professor of Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

In this study, the authors report on the results of a multicenter, single-arm, Phase II study of sunitinib in Korean

the regression of metastatic cancer at a distance from the irradiated site” and may be “mediated by activation of the immune system.” The monoclonal antibody ipilimumab is known to inhibit cytotoxic T lymphocyte–associated antigen 4 (CTL-4), an immunologic checkpoint on T cells, and to enhance immunity to NY-ESO-1, an antigen expressed in 30% to 40% of patients with metastatic melanoma.

NY-ESO-1 expression was confirmed in the case patient—a 33-yearold woman—via immunohistochemical analysis and reverse transcriptase polymerase chain reaction assay. Prior to treatment with the study approach, the patient was seropositive for the whole NY-ESO-1 protein. During treatment, however, the authors observed “a trend toward lower titers

as disease burden decreased.” Following radiotherapy, they noted that the patient “had an increase by a factor of more than 30 of antibodies against an epitope or epitopes within the central portion of the protein.”

As expected, during ipilimumab administration in the study patient, there was a marked increase in CD4positive inducible T cell costimulator (ICOS) cells, which have been found to improve clinical benefit and overall survival in patients with advanced metastatic melanoma. However, interestingly, the patient’s CD4-positive ICOS count also showed a modest increase following radiotherapy, suggesting that the latter may play an immunomodulatory role. Indeed, tumor regression was seen only after radiotherapy, indicating that the case

patient’s tumor was resistant to T cell–mediated antitumor effects until the administration of radiotherapy.

Seromic analysis detected 10 antigenic targets with enhanced antibody responses after radiotherapy.

In all, the authors noted that the case study, which was funded in part by the National Institutes of Health (among other not-for-profit entities), revealed that treatment with ipilimumab and radiotherapy resulted in “tumor shrinkage with antibody responses to the cancer-testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibody responses to other antigens after radiotherapy.” Clinical trials designed to assess the benefit of the approach used in the case study are ongoing.

to reorient the immune system toward tumor elimination. As the authors pointed out, ipilimumab monotherapy is effective in only 10% to 15% of patients with melanoma. Overcoming immune tolerance, then, may require combinatorial treatment regimens that build upon one or more of the immunologic components examined in this study. First, the temporal relationship between disease response and treatments administered suggests a rationale for investigating various schedules of timed sequential therapy. Second, further investigation into host development of increased humoral responses,

including increases in antibody titers against the cancer testis antigen NYESO-1, may suggest antigenic targets that play a critical role in immunemediated tumor destruction. Finally, conversion from immune tolerance to immune attack almost certainly involves a shift in immune cell subpopulations. Characterizing the effects that particular therapies have on the immune cell landscape may help investigators rationally combine treatments for maximum anti-tumor impact.

The applicability of immune-based therapies like ipilimumab is expanding. For example, blockade of the PD-1/

PD-L1 immune checkpoint pathway has produced tumor regressions in malignancies not traditionally considered immunogenic, such as non–small cell lung and colorectal cancers. This report, though it is based on only one patient, not only suggests an approach to maximizing the anti-melanoma potential of ipilimumab, it also raises the possibility that combining multimodality approaches (eg, radiotherapy, chemotherapy, signal transduction pathway blockade, surgery or cryotherapy) with immunotherapies may provide the required framework for destruction of a wider array of tumor types.

patients with non–clear cell RCC. The optimal treatment for non-clear cell RCC remains poorly defined. Pivotal Phase III studies with tyrosine kinase inhibitors excluded non–clear cell histologies, leaving us with retrospective analyses or small Phase II studies. The evidence thus far suggests rather modest activity, mostly resulting in disease stabilization rather than significant tumor shrinkage.

The majority of patients treated in this prospective Phase II study had RCCs of the papillary subtype.

Interestingly, the partial response rate of 36%, which also was the primary end point, was rather impressive and is comparable to response rates seen typically in the clear cell population. However, this came at the price of increased grade 3/4 toxicities (neutropenia, thrombocytopenia, hand–foot syndrome) requiring higher rates of dose reduction and dose delays than were seen in the pivotal studies. This finding falls in line with a previous report of this group suggesting a higher incidence and severity of treatment-related

adverse events in Asian patients.

It is tempting to hypothesize that either pharmacogenomic differences or a smaller body habitus could have resulted in increased drug exposure of the Asian patients when compared with their Caucasian counterparts. While the findings of this study are mostly applicable to the Asian patient population, it makes us hopeful that VEGF pathway inhibition with more potent and selective agents might improve the outcome for patients with non–clear cell RCC in the future.

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PRN

CliniCal OnCOlOgy news • april 2012

Community Oncology

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD assistant Director Hematology & stem Cell Transplantation program Cancer Treatment Centers of america Zion, illinois

Highlights of American Society of Hematology 2011 Annual Meeting—Malignant Hematology Part 1: Multiple Myeloma, Myelodysplastic Syndrome and Acute Leukemias

QUESTIONS

1.

True or False: Final results 10. True or False: Treatment of 15. from the Phase II continuation study

True or False: Early treatment of patients defined as high risk for progression to multiple myeloma (MM) from smoldering multiple myeloma (SMM) with lenalidomide (Revlimid, Celgene) and dexamethasone exhibited a trend toward improvement in overall survival (OS).

thrombocytopenia in low- or intermediate–1-risk MDS patients with romiplostim (Nplate, Amgen) resulted in a decreased requirement for platelet transfusions, fewer clinically significant bleeding events but significantly higher rates of AML transformation.

2. True or False: The combination

of carfilzomib (Onyx Pharmaceuticals), lenalidomide and low-dose dexamethsone (CRd) regimen has very high and stable response rates with fewer dose modifications due to peripheral neuropathy in contrast to bortezomib (Velcade, Millennium Pharmaceuticals) combinations with similar agents.

3.

11. True or False: The retrospective

6. True or False: Pomalidomide (Cel-

gene) with or without dexamethasone is active in heavily pretreated patients with MM, including those refractory to bortezomib but not to lenalidomide.

7.

True or False: In a Phase I trial with marizomib (Nereus Pharmaceuticals), a highly potent proteasome inhibitor, once-a-week dosing of 0.4 to 0.5 mg/m2 appears to be the optimal dosing schedule for relapsed/refractory MM.

True or False: Elotuzumab (Abbott Laboratories) in combination with lenalidomide and low-dose dexamethasone exhibited 92% ORR in relapsed/ refractory patients with MM.

4. True or False: In patients with

True or False: Low-dose clofarabine (Clolar, Genzyme) has significant activity in high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia post-MDS (sAML) following azacitidine (Vidaza, Celegene) failure.

MM, the Phase II study of bortezomib in combination with panobinostat (Novartis) demonstrated activity in approximately one-third of patients who were truly refractory to bortezomib.

5. True or False: Perifosine (Keryx

Biopharmaceuticals) and bortezomib with or without dexamethasone demonstrated encouraging activity with an overall response rate (ORR; defined as minimal response or better) of 41% in 73 evaluable patients, including an ORR of 65% and 32% in bortezomib-relapsed and bortezomib-refractory patients, respectively.

8.

9.

True or False: The study by Emilio Paolo Alessandrino, MD, and colleagues at the University of Pavia in Pavia, Italy, suggests that in eligible patients with low- or intermediate-risk MDS according to the World Health Organization’s Classification-Based Prognostic Scoring System (WPSS) there is no clear benefit in adopting a delayed transplantation strategy.

data on 2,283 patients with MM suggest that observed and expected secondary primary malignancy (SPM) rates are higher with induction with both an alkylating agent and an immunomodulatory agent.

12. True or False: The combina-

tion of MLN9708 (Millennium), lenalidomide, dexamethasone in patients with MM who were not previously treated demonstrated 100% (n=15) partial or better response, including four complete responses and five very good partial responses.

13. True or False: A Phase II study

of azacitidine and vorinostat (Zolinza, Merck) in patients with newly diagnosed MDS or AML who were not eligible for clinical trials because of poor performance status and the presence of other comorbidities was closed early due to marked treatment-related toxicity.

of lenalidomide combined with azacitidine in patients with higher-risk MDS demonstrated an ORR of 71% in 35 evaluable patients.

16. True or False: A randomized

controlled Phase II/III trial demonstrated improved outcomes in younger adult patients (18-60 years) with mutated NPM1 AML with the addition of alltrans retinoic acid (ATRA; Vesanoid, Roche) to standard chemotherapy.

17. True or False: In MM, prediction of complete response by gene expression profiling (GEP) is likely to be an important goal for prospectively selecting those patients who are more likely to benefit from a given therapy.

18.

True or False: In front-line AML and higher-risk MDS a Phase II trial of vorinostat in combination with idarubicin (Idamycin, Pfizer) and cytarabine demonstrated high induction response rates with an acceptable safety profile.

19.

True or False: Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody that has activity in relapsed/ refractory acute lymphocytic leukemia (ALL).

14. True or False: Persistent min- 20. True imal residual disease by multiparameter flow cytometry at day 60+ predicted unsustained complete response (CR) after autologous stem cell transplantation (ASCT) in MM.

or False: Quizartinib monotherapy produces responses in patients with relapsed or refractory AML with mutated NPM1. for answers see CONUNDRUMS, page 22 

Let Us Visit Your Practice Please consider inviting the staff of Clinical Oncology News to visit your practice. We want to meet you and your colleagues, listen to your concerns, and observe the physical site of your practice.

You can help us improve Clinical Oncology News and fulfill our mission—to provide evidencebased, clinically relevant information that you can use to benefit your patients and practice.

If you are interested, please contact Gabriel Miller, managing editor, at (212) 957-5300 ext. 265 or via e-mail at gmiller@mcmahonmed.com

PRN

CliniCal OnCOlOgy news • april 2012

19

Patient Care

Second Primary Cancer Likely To Be Same Type as First A population-based, case–control study has found a 2.16-fold higher risk for a second primary cancer that is the same type as the first, than for not having a second primary cancer (CMAJ 2012;184:E57-E69).

Current file:

MN112Kingad.indd

Full name of project

The investigators also found a 1.13fold higher probability of the second primary being a different type from the first cancer.

An accompanying commentary noted that the study was methodologically sound, but that it is difficult to know how, if at all, the results apply to clinical practice (CMAJ 2012;184:19-20). This uncertainty exists because of the significant heterogeneity in risks of different types of second primary cancers.

different from the first was 1.13 (95% Project no.

CI, 1.12-1.15).

Revision # Rev 2 Prostate cancer wasLayoutassociated date/time April 11,with 2012 4:41 PM the lowest likelihood, Editorial by far, date/timeof a subsequent primary cancer. Trim The size HR for developing any second primary cancer after a Color specs File path

primary prostate cancer was 0.80 (95% absolute five-year risk for people with a CI, 0.77-0.83), while the HR for develop- primary tumor to later develop a second FILE SLUG STATUS low. & HISTORY ing a second primary cancer of the same cancer was quite PICKED UP FROM: 1ST PROOF LAYOUT APPROVED FINAL OK PROOF 1: 6/6 patients who have had a type as INITIALS theAND first was 0.01 (95% CI, 0.00- REV 1: 6/6“For cancer APPLIED TO: DATE INITIALS AND DATE 2: tumor, 0.02) and for developing a second pri- REV primary AD LAYOUT[we EXPT’D: found] the absolute Senior editor REV 3 AD LAYOUT RECEIVED: risk of getting a second cancer REV five-year 4 mary cancer different from the first was Editor EDIT LAYOUT EXPT’D: REV 5 EDIT LAYOUT RECEIVED: is on average far below 5% on average,” 0.79 (95% CI, 0.77-0.82).

REV 6 Copy editor REV 7 EDITOR: Jen Kulpa said Dr. Bojesen.

In addition, primary cancers not ART DIRECTOR: Blake Sales REV 8 9 —Rosemary Frei, MSc relatedProduction to tobacco use were associated REV REV 10 with a significantly lower chance of any REV 11 MAX sign-off type of COMMENTS: second primary cancer.

KEYWORDS:Drs. Winget, Yasui and Bojesen reported no conflicts of interest.

The study also showed that the

MN112Kingad.indd

®

Now Available...

Pancreatic Exocrine Insufficiency Diagnosis and Treatment in Chronic Pancreatitis and Pancreatic Cancer

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN112” “Thus, [there is] the need for separate evaluation and discussion of risk by specific type of first–second cancer pair rather than overall risk,” observed Mary Winget, PhD, and Yutaka Yasui, PhD. Stig E. Bojesen, MD, PhD, DMSc, of Copenhagen University Hospital and his two co-investigators extracted data from 1980 to 2007 from three national databases in Denmark, including the Danish Civil Registration System. This resulted in a cohort of 7,493,705 people, of whom 765,255 were diagnosed with one or more cancers, for a total of 843,118 cancer diagnoses. The investigators matched each of these individuals with up to five randomly selected people from the databases who did not have the examined cancer at the time of the subject’s diagnosis.

The investigators analyzed the associations between 27 types of cancer and the increased risks for any second primary cancer. They found that after a person had any type of first cancer, he or she had a 1.25 aggregated hazard ratio (aHR) for developing any type of second primary cancer (95% confidence interval [CI], 1.24-1.26), although there is significant variation between cancer types. The investigators also found that the aHR for developing a second primary cancer of the same type as the first was 2.16 (95% CI, 1.98-2.34) and the aHR for a second primary cancer

Release Date: May 1, 2011

Expiration Date: May 1, 2012

Chair

Accreditation Statement

Peter D. Stevens, MD

Director of Endoscopy NewYork-Presbyterian Hospital/Columbia University Medical Center Columbia University College of Physicians and Surgeons New York, New York

Faculty

Jerome H. Siegel, MD, RPh, MACG, FASGE, AGAF Co-Director Therapeutic Endoscopy Beth Israel Medical Center New York, New York Clinical Professor of Medicine Albert Einstein College of Medicine Bronx, New York

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Columbia University College of Physicians and Surgeons and Applied Clinical Education (ACE). Columbia University College of Physicians and Surgeons is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement

Columbia University College of Physicians and Surgeons designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™.

Physicians should only claim credit commensurate with the extent of their participation in the activity.

Goal

The goal of this activity is to educate oncologists, gastroenterologists, and other health care professionals in the latest evidence regarding the diagnosis and management of pancreatic exocrine insufficiency (PEI).

Learning Objectives

At the completion of this activity, participants should be better prepared to:

Medical Writer

Oren Traub, MD, PhD

1 Delineate the epidemiology and pathophysiology of chronic pancreatitis (CP) and pancreatic cancer (PC), including how these conditions can lead to PEI and the significance of PEI for nutritional health.

2 Use current techniques to assess and diagnose CP and PC, with attention to the presence of PEI. 3 Evaluate therapies for PEI in CP and PC, including the role of pancreatic enzyme supplementation (PES) in improving nutritional health.

4 Identify appropriate dosing of PES for PEI in CP, PC, and pancreatectomy.

Sponsored by

Supported by an educational grant from

Distributed via

gastroendonews.com

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN112”

20

HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • april 2012

Lymphoma

Adjuvant Radiation After R-CHOP-14 Increases Lymphoma Survival From International Journal of Radiation Oncology

A

small clinical trial has concluded that adjuvant involved-field radiotherapy (IFRT) appears still to be the best option for patients with mediastinal B-cell lymphoma who have achieved complete response (CR) with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (Rituxan, Genentech), the regimen known as R-CHOP-14.

This study, published online in December by the International Journal of Radiation Oncology (2011; Dec 13. [Epub ahead of print], PMID: 22172907), was performed at the National Medical Center of Mexico and

EXPERT INSIGHT Satish Shanbhag, MBBS, MPH Assistant Professor of Medicine and Oncology Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

There is no clear consensus on the optimal approach to treating patients with primary mediastinal large B-cell lymphoma (PMLBCL). While the addition of rituximab had clearly

was funded by the Mexican Institute of Social Security, a government agency that oversees public health and pensions in Mexico.

To date, there has been no widely accepted standard treatment approach for mediastinal B-cell lymphoma, despite the existence of data supporting the use and efficacy (as measured by CR) of R-CHOP-14; this is in large part because overall survival (OS) among patients treated with R-CHOP-14 in multiple studies has ranged from only 40% to 60%. Historically, clinicians have been hesitant to use IFRT in mediastinal B-cell lymphoma because several small, noncontrolled studies have found that the approach fails to improve outcomes in this patient population.

There also is concern regarding the cardiac and lung toxicities that have been associated with IFRT in previous studies. However, as the authors of the present trial note, a study published by Pugh et al in 2010 (Int J Radiat Oncol Biol Phys 2010;76:845-849, PMID: 19515509) revealed that cardiac mortality among patients with mediastinal B-cell lymphoma actually may be associated with anthracycline use in this patient population.

For the Mexican trial, the researchers randomized 124 consecutive patients who achieved CR following R-CHOP-14 between January 2001 and June 2004.

In all, 63 received IFRT (30 Gy) and 61 were assigned to the control group.

Originally, the researchers had planned

to enroll 182 patients in each arm; however, the study was “closed prematurely” after a security analysis revealed that disease progression and early relapse were more frequent in patients who did not receive IFRT. The 124 patients ultimately enrolled in the trial were monitored until March 2009.

At the conclusion of the follow-up period, actuarial curves at 10 years demonstrated that progression-free survival (PFS) was significantly higher (72%) in the IFRT group than in the control group (20%; P<0.001). OS also was significantly higher in the IFRT group (72%) than in the control group (31%; P<0.001). Patients in the IFRT group reported only mild toxicities, and the therapy was generally well tolerated.

contributed to increased response rates, event-free survival and OS in PMLBCL, the role of radiotherapy in the rituximab era has been controversial, with some small nonrandomized studies suggesting that the addition of rituximab to CHOP-like cytotoxic chemotherapy obviates the need for adjuvant radiation.

Agustin Avilés et al have published a randomized clinical trial evaluating adjuvant IFRT in patients who achieved a CR to 6 cycles of R-CHOP-14. The trial had to be stopped early after interim analysis on the enrolled 124 patients revealed a clear survival advantage in patients on the radiotherapy arm.

The actuarial PFS at 10 years showed a dramatic difference of 72% for the radiation therapy compared with 20% for the control arm, and OS of 72% and 31%, respectively. CR was defined by computed tomography along with gallium scans, which was standard for the institution at that time (study stopped enrollment in 2004).

The authors must be commended for conducting a randomized trial in this disease, a rarity given the relatively low incidence of this distinct clinico-pathologic entity. A clear pitfall is the dismal results in the control group, quite different from prior published experiences with R-CHOP–like or more intensive

regimens. The Cancer and Leukemia Group B is conducting a trial of R-CHOP versus dose-adjusted EPOCH-R (etoposide, adriamycin, vincristine, cyclophosphamide, prednisone and rituximab; the etoposide, adriamycin and vincristine are given as a continuous infusion) in untreated patients with diffuse large B-cell lymphoma (including PMLBCL), which should definitively prove (or disprove) the benefit of the multiday infusional regimen. Until the results from CALGB 50303—with a significant population of PMLBCL patients being treated with R-CHOP—are available, this study helps establish the role of adjuvant radiation.

SOLID TUMORS Breast

‘Bothered’ Feeling Predicts Nonadherence Substudy finding in breast cancer patients could aid in symptom management San Antonio—A trial comparing exemestane and anastrozole for early breast cancer has uncovered a finding that may be surprising to some clinicians: Nonadherence to therapy with aromatase inhibitors (AIs) is predicted by “feeling bothered by treatment side effects” that patients experience before AI therapy rather than the emergence of symptoms after treatment starts.

The finding comes from a substudy of the NCIC Clinical Trials Group (NCIC CTG) MA.27 trial. The results were reported at the recent San Antonio Breast Cancer Symposium (SABCS, S6-2).

Oncologists should be aware that when a postmenopausal patient with breast cancer starts taking an AI and then reports being bothered by side effects, she is at an increased risk for quitting

early, said Lynne Wagner, PhD, an associate professor in the Department of Medical Social Sciences at Northwestern University Feinberg School of Medicine, in Chicago, who led the study. “These patients could benefit from close monitoring of adherence, help with managing side effects and counseling on the benefits of AI therapy,” she said.

MA.27 was a Phase III trial that

randomized 7,576 postmenopausal, estrogen receptor–positive patients with early breast cancer to five years of either anastrozole or exemestane. The study showed the two treatments had nearly identical efficacy and a similar safety profile.

The E1Z03 substudy was the quality-oflife (QoL) correlative trial that assessed patient-reported outcomes among a subgroup of participants in the MA.27 trial

and focused on predictors of early treatment discontinuation. Patient-reported outcomes were measured before AI initiation (baseline) and then at three, six, 12 and 24 months after initiation. The study included information on 686 patients who provided feedback through the 46-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES).

This tool assesses physical, functional, social and emotional well-being, as well as breast cancer–specific concerns and endocrine symptoms.

The substudy did not identify any significant differences between the two treatment arms with regard to treatment-related QoL or symptoms. As suspected, symptoms such as weight

HEMATOLOGIC DISEASE

CliniCal OnCOlOgy news • april 2012

Leukemia

Fludarabine Plus Rituximab Assessed in Relapsed/Refractory HCL From Blood

A

team of researchers from Vancouver, British Columbia, has found that treatment with combination therapy of fludarabine (Fludara, Genzyme; various) and rituximab (Rituxan, Genentech) produces positive outcomes—as measured by progression-free survival (PFS) and overall survival (OS)—in relapsed/refractory hairy cell leukemia (HCL). Their report, published in the March 1 issue of the journal Blood (2012;119:1988-1991; PMID: 22223825), confirms earlier findings originally presented in 2010 at the 52nd annual meeting of the American Society of Hematology.

Despite significant advances in the

EXPERT INSIGHT Nilanjan Ghosh, MD, PhD Assistant Professor of Oncology The Johns Hopkins University School of Medicine The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

FR therapy was administered to 15 patients with relapsed/refractory HCL. Clinical responses were observed in 13 evaluable patients. In this retrospective analysis, FR showed clinical efficacy in

gain, decreased libido, feeling bloated, breast sensitivity, mood swings, irritability, joint pain and nausea had a negative impact on health-related QoL, and these symptoms increased after the start of AI therapy.

Of the entire sample of patients, 32% had no joint pain at baseline, and by month 3 of treatment, 55% of these patients reported new joint pain. New weight gain was reported by 40% of patients; 39% reported new hot flashes; 30% to 34% reported [new] decreased libido, breast sensitivity and night sweats; and 25% reported mood swings as new symptoms, reported Dr. Wagner, who is also a clinical psychologist at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, also in Chicago.

Surprisingly, however, the emergence of new symptoms at three months was not a statistically significant factor in predicting early treatment discontinuation

treatment of HCL, an estimated 30% to 40% of patients relapse. The authors reviewed the cases of 15 such patients, culled from the British Columbia Cancer Agency’s Lymphoid Cancer Database, who were treated with fludarabinerituximab (FR) between 2004 and 2010. Two of the patients included in the study had undergone first-line therapy with cladribine; the remaining patients had undergone “multiple lines of therapy” (the authors did not elaborate).

At the time the Blood article was published, 14 of the 15 patients remained

progression-free—one patient developed progressive leukemia and died—after a median followup of 35 months. According to the authors, five-year PFS and OS among the 15 patients with relapsed/refractory HCL who received FR therapy were 89% and 83%, respectively. FR therapy was started a median of 12.8 years after initial diagnosis of HCL and a median of 60 months after the discontinuation of prior therapy. The regimen consisted of 40 mg/m2 per day of fludarabine orally on days 1 to 5 (adjusted for renal function) and 375 mg/m2 of rituximab IV administered every 28

days (starting on day 1 of treatment) for four cycles. Median age of the patients receiving the combination regimen was 59 years at the start of treatment.

Patients underwent a median of four cycles of treatment.

The authors report the regimen was largely well tolerated. No patients required the IV formulation of fludarabine. Treatment was discontinued in one patient after two cycles as the result of a hypersensitivity reaction to rituximab; fludarabine was discontinued in one patient after three cycles following the development of interstitial lung disease. Herpes zoster was reported in two patients, one during treatment and one six months after receiving the last cycle. No patients required hospitalization during treatment.

relapsed or refractory HCL. In this report from British Columbia, 15 patients with relapsed/refractory HCL received a median of four cycles of FR (range, two to four cycles).

Patients had received a median of two prior systemic treatments. All patients had received a purine analog before FR. Thirteen patients (87%) had previously received cladribine and two patients (13%) had previously received fludarabine. Five-year PFS and OS for the cohort were 89% and 83%, respectively.

The authors conclude that FR has clinical efficacy in relapsed/refractory HCL and is safe and well tolerated.

Although cladribine and pentostatin have been shown to have a very high response rate (75%-90%) in the primary treatment of HCL, long-term followup shows that the relapse rate can be as high has 30% to 40%. Retreatment with purine analogs such as pentostatin or cladribine can produce high response rates and durable remissions. In this study, the authors report a high complete response rate and durable response, which provide an alternate treatment option for relapsed/refractory HCL. The treatment of this condition often is associated with a significant infection rate.

Although the authors stated that the

treatment was safe and well tolerated, the adverse effects from treatment were not reported in the paper.

In this disease, there are multiple choices of treatment in the relapsed/ refractory setting, all of which have been shown to yield clinically meaningful responses. However, there is little data suggesting the choice and sequence of therapy. The discovery of the BRAF V600E mutation in 100% of HCL makes this mutation a potential target for the treatment of this condition. Prospective clinical trials should be conducted to better guide the management of relapsed/refractory HCL.

Prior chemotherapy, prior radiation and the number of current daily medications all were found to be statistically significant predictors of patients reporting bothersome symptoms at baseline. (hazard ratio [HR], 1.11; P=0.107). Rather, being bothered by treatment side effects before initiating an AI was a risk factor for this end point (HR, 1.29; P=0.006).

Prior chemotherapy, prior radiation and the number of current daily medications all were found to be statistically significant predictors of patients reporting bothersome symptoms at baseline.

“It is possible that women who struggled with side effects during previous cancer treatments are vulnerable to AI side effects and discontinue treatment early [or] women who feel beaten up by their prior treatments may have difficulty facing five more years of treatment

side effects and end treatment early,” said Dr. Wagner, offering possible explanations. “It may be that these women are telling us they are the type of people who are likely to be bothered by treatment side effects. Regardless of the reason, these results tell us how we can identify women who are at risk for early treatment discontinuation.”

Patricia Ganz, MD, director of the Division of Cancer Prevention & Control Research at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles, served as the trial discussant at SABCS. She said that understanding the biology of post-treatment symptoms

in breast cancer may lead to innovations in management, and enhanced survival through improved adherence. “Effective symptom management strategies should be a priority,” she said.

Dr. Ganz has conducted studies showing that host factors, particularly single nucleotide polymorphisms in interleukin (IL)-1, IL-6 and tumor necrosis factor promoters, may make certain patients more vulnerable to ongoing and persistent inflammation after the primary treatment of breast cancer. “Cancer and its treatment may in fact exacerbate the immune status of patients and lead to inflammation and the treatments that do this are not just chemotherapy, but also surgery and radiation,” Dr. Ganz said.

—Kate O’Rourke Drs. Wagner and Ganz reported no relevant disclosures.

21

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CliniCal OnCOlOgy news • april 2012

Community Oncology

CONUNDRUMS continued from page 18 

ANSWERS

1. True.

Higher three-year (from study inclusion) and five-year (from diagnosis) OS rates compared with observation (hazard ratio [HR] for fiveyear OS from diagnosis: 5.01; 95% confidence interval [CI], 1-22; P=0.03) were observed. Similar to this Spanish trial, the ECOG (Eastern Cooperative Oncology Group) trial involved accrual of patients with high-risk SMM for randomization to either single-agent lenalidomide or observation (ClinicalTrials.gov identifier: NCT01169337).

Mateos MV, López-Corral L, Hernández M, et al. Smoldering multiple myeloma (SMM) at high-risk of progression to symptomatic disease: a phase III, randomized, multicenter trial based on lenalidomide-dexamethasone (Len-Dex) as induction therapy followed by maintenance therapy with Len alone vs no treatment. ASH Annual Meeting Abstracts. 2011;118(21):991.

2.

True. The majority of patients did not require dose modifications, either in the initial or in the maintenance phase of the treatment.

Jakubowiak AJ, Dytfeld D, Jagannath S, et al.

Final results of a frontline Phase 1/2 study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in multiple myeloma (MM).

ASH Annual Meeting Abstracts. 2011;118(21):631.

3.

False. Marizomib in combination with dexamethsone demonstrated encouraging responses of 15% to 20% in heavily pretreated patients. Marizomib 0.4 to 0.5 mg/m2 twice weekly appears to be the optimal dosing schedule without reports of significant peripheral neuropathy.

Richardson PG, Spencer A, Cannell P, et al.

Phase I clinical evaluation of twice-weekly marizomib (NPI-0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts.

2011;118(21):302.

4. True. The combination of pan-

obinostat and bortezomib seems to be promising for patients with bortezomibrefractory MM. A Phase III Spanish trial with panobinostat/placebo plus bortezomib plus dexamethasone in patients with relapsed MM (PANORAMA 1) will further define the potential role of panobinostat in the treatment of patients with MM.

Richardson PG, Alsina M, Weber DM, et al.

Phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib refractory multiple myeloma (PANORAMA 2).

ASH Annual Meeting Abstracts. 2011;118(21):814.

San-Miguel JF, de Moraes Hungria VT, Yoon SS, et al. Update on a Phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORAMA 1.

ASH Annual Meeting Abstracts. 2011;118(21):3976.

5.

True. Perifosine, an orally bioavailable, novel signal transduction modulator has multiple pathway effects including inhibition of Akt, NFkB and activation of JNK. A Phase III trial is under way comparing perifosine with bortezomib plus dexamethasone with bortezomib plus dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.

Richardson PG, Wolf JL, Jakubowiak AJ, et al.

Perifosine plus bortezomib and dexamethasone in relapsed/refractory multiple myeloma patients previously treated with bortezomib: final results of a Phase I/II trial. ASH Annual Meeting Abstracts.

2011;118(21):815.

6. False. In a Phase II study with

221 MM patients who had previously received a median of five prior therapies including lenalidomide and bortezomib, pomalidomide was administered at 4 mg for 21 days of a 28-day cycle.

For patients refractory to both lenalidomide and bortezomib, median progression-free survival was two months for pomalidomide alone and 3.9 months for pomalidomide and low-dose dexamethasone. The regimen is now being investigated in combination with pegylated liposomal doxorubicin (ClinicalTrials. gov identifier: NCT01541332) and bortezomib (NCT01497093).

Richardson PG, Siegel DS, Vij R, et al. Randomized, open label Phase 1/2 study of pomalidomide (POM) alone or in combination with lowdose dexamethasone (LoDex) in patients (pts) with relapsed and refractory multiple myeloma who have received prior treatment that includes lenalidomide (LEN) and bortezomib (BORT): Phase 2 results. ASH Annual Meeting Abstracts.

2011;118(21):634.

7.

True. Elotuzumab is a humanized monoclonal immunoglobulin G1 antibody directed against the cell surface glycoprotein CS1, which is highly expressed on tumor cells in more than 95% of MM patients. Phase III clinical trials with similar combinations are ongoing—ELOQUENT2 trial—for relapsed/ refractory MM (NCT01239797) and the ELOQUENT1 trial for front-line MM (NCT01335399).

Lonial S, Jakubowiak AJ, Jagannath S, et al.

A Phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma. ASH Annual Meeting Abstracts.

2011;118(21):303.

8.

True. The interim results of the GFM Clo08 Dose-escalating Phase I/II Study are reassuring for patients who have limited therapeutic options. Nineteen patients with a median age of 72 years have been enrolled in this trial.

The extended alternate-day (day 1-10) schedule seems to be better tolerated and at least as efficient as the standard day 1 to 5 schedule, although a greater number of patients are required to confirm these findings. Dose escalation in the trial is ongoing (NCT0106325).

Braun T, Raffoux E, Prebet T, et al. Low-dose

clofarabine has significant activity in high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia post-MDS (sAML) after azacitidine (AZA) failure: interim results of the GFM Clo08 dose escalating Phase I/II Study (NCT0106325). ASH Annual Meeting Abstracts.

2011;118(21):609.

9. True. Uncertainty exists about the

optimal timing of allogeneic hematopoietic stem cell transplantation (HSCT) in the low- or intermediate-risk WPSS MDS groups and to address this issue Dr. Alessandrino and colleagues performed an ad hoc decision analysis. The risk for progression abolishes the expected gain in survival resulting from postponing the procedure in this group of patients.

This is at variance with a previous decision analysis based on the International Prognostic Scoring System (IPSS) (Blood 2004;104:579-585, PMID: 15039286), which concluded that for low- and intermediate-1 IPSS-risk MDS, delayed HSCT was associated with maximal life expectancy.

Alessandrino EP, Della Porta MG, Malcovati L, et al. Decision analysis of allogeneic stem cell transplantation in patients with myelodysplastic syndrome stratified according to the WHO Classification-Based Prognostic Scoring System (WPSS).

ASH Annual Meeting Abstracts. 2011;118(21):116.

rapid responses, with 14 of 15 patients achieving at least 50% reduction in M-protein in cycle 1. Two patients discontinued the therapy following cycle 6 to undergo transplantation (one in very good partial remission and one in complete remission [CR]).

Berdeja JG, Richardson PG, Lonial S, et al.

Phase 1/2 study of oral MLN9708, a novel, investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118 (21):479.

13.

False. The combination of azacitidine and vorinostat is safe and active in this poor-prognosis population resulting in levels of activity and safety similar to those observed in populations eligible for clinical trials. These results support treatment of this poor-risk population and question current eligibility criteria for Phase I/II trials.

Garcia-Manero G, Estey EH, Jabbour E, et al.

Final report of a Phase II study of 5-azacitidine and vorinostat in patients (pts) with newly diagnosed myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) not eligible for clinical trials because of poor performance and presence of other comorbidities. ASH Annual Meeting Abstracts. 2011;118 (21):608.

False. Dr. Bruno and colleagues 10. False. Increases in peripheral 14. investigated which prognostic markers blasts of greater than 10% occurred more frequently with romiplostim than with placebo, but generally resolved after romiplostim was discontinued. The clinical significance of this finding remains to be further investigated. OS and AMLfree survival rates were similar in both arms. There was a trend for more clinically significant bleeding events with placebo (26.5%) compared with romiplostim (18.6%).

Giagounidis A, Mufti GJ, Kantarjian HM, et al. Treatment with the thrombopoietin (TPO)receptor agonist romiplostim in thrombocytopenic patients (Pts) with low or intermediate-1 (Int1) risk myelodysplastic syndrome (MDS): results of a randomized, double-blind, placebo (PBO)controlled study. ASH Annual Meeting Abstracts.

2011;118(21):117.

11.

False. The observed and expected SPM rates are similar, even for treatment that includes induction with both an alkylating agent and an immunomodulatory agent. For all patients, the rate of SPM was 2.1% (n=48); it was 0.6% (n=2) with lenalidomide and dexamethasone or cyclophosphamide, 2.4% (n=23) with lenalidomide and melphalan, 3.1% (n=17) with melphalan and thalidomide, and 1.4% (n=6) with melphalan and no immunomodulatory agent.

Palumbo A, Larocca A, Zweegman S, et al. Second primary malignancies in newly diagnosed multiple myeloma patients treated with lenalidomide: analysis of pooled data in 2459 patients.

ASH Annual Meeting Abstracts. 2011;118 (21):996.

12. True. MLN9708 is an oral, spe-

cific, reversible inhibitor of the 20S proteasome. The combination with lenalidomide and dexamethasone yielded

can predict unsustained CR in a series of 241 patients in CR at day 100+ after high-dose therapy (HDT)/ASCT who were enrolled in the Spanish GEM2000 (n=140) and GEM2005 (<65 years old, n=101) trials. Twenty-nine (12%) of the 241 patients showed unsustained CR and a dismal outcome (median OS, 39 months). The presence of baseline highrisk cytogenetics by fluorescence in situ hybridization (HR, 17.3; P=0.002) and persistent minimal residual disease by multiparameter flow cytometry at day 100+ after HDT/ASCT (HR, 8.0; P=.005) were the only independent factors that predicted unsustained CR. Paiva B, Gutierrez NC, Rosiñol L, et al. Highrisk cytogenetics and persistent minimal residual disease (MRD) by multiparameter flow cytometry (MFC) predict unsustained complete response (CR) after autologous stem cell transplantation (ASCT) in multiple myeloma (MM). ASH Annual Meeting Abstracts. 2011;118 (21):630.

15. True.

The combination of lenalidomide and azacitidine is well tolerated and highly active in treating higher-risk MDS. The ORR seen in the Phase I study was supported by Phase II data, with good OS, even among highly refractory patients. Subsequent randomized studies will compare the lenalidomide plus azacitidine combination to azacitidine monotherapy and other azacitidine-based combinations.

Sekeres MA, Komrokji RS, Lancet JE, et al.

Final results from the Phase 2 continuation study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes (MDS). ASH Annual Meeting Abstracts.

2011;118 (21):607.

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CliniCal OnCOlOgy news • april 2012

23

Community Oncology

16.

True. NPM1 mutational status was prospectively confirmed as predictive for response to all-trans retinoic acid plus conventional chemotherapy.

Schlenk RF, Döhner K, Krauter J, et al. All-trans retinoic acid improves outcome in younger adult patients with nucleophosmin-1 mutated acute myeloid leukemia–results of the AMLSG 07-04 randomized treatment trial. ASH Annual Meeting Abstracts. 2011;118(21):80.

17. True. GEP analysis of a subgroup

of patients who received bortezomib, thalidomide and dexamethasone (VTD) induction therapy provided a 41-gene signature that was able to predict attainment of CR/near complete remission (nCR) and, conversely, failure to achieve

at least nCR in 91% and 95% of cases, respectively.

Terragna C, Remondini D, Durante S, et al. A 41-gene signature predicts complete response (CR) to bortezomib-thalidomide-dexamethasone (VTD) as induction therapy prior to autologous stem-cell transplantation (ASCT) in multiple myeloma (MM). ASH Annual Meeting Abstracts.

2011;118(21):805.

18.

66 (six to 134) weeks. There was a trend toward better survival in the Flt3/ITD patients compared with the unmutated group (P=0.067). The authors concluded that further studies comparing the experimental treatment to standard IA or “7+3” induction chemotherapy with cytarabine and an anthracycline and in patients with FLT3/ITD mutations should be considered.

True. Responses were significantly higher than with standard idaGarcia-Manero G, Tambaro FP, Bekele N, et al. rubicin and high-dose cytarabine (IA) Final report of a Phase II trial of vorinostat with therapy without additional toxicity. idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia With a median follow-up of 82 weeks, (AML) or myelodysplastic syndrome (MDS). ASH the median OS and event-free surviv- Annual Meeting Abstracts. 2011;118(21):763. al (EFS) for the whole group (n=75) was 82 and 47 weeks, respectively. Median FILE SLUG True. Inotuzumab ozogamicin OS and EFS for patients with Flt3/ITD Current file: CMEzone qtrpg.indd 1ST PROOF LAYOUT APPROVED mutations were 91 (range, six to 134) and is highly active in relapsed/refractory INITIALS AND DATE

19.

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ALL. Overall, CR plus marrow CR plus CR without complete platelet recovery was 57% in 49 patients.

O’Brien S, Thomas DA, Ohanian M, et al. Inotuzumab ozogamycin (I0), a CD22 monoclonal antibody conjugated to calecheamicin, is active in refractory-relapse acute lymphocytic leukemia (R-R ALL). ASH Annual Meeting Abstracts.

2011;118(21):875.

20.

False. Quizartinib monotherapy produced a clinically meaningful response in both relapsed and refractory FLT3/ITD-positive AML. Cortes JE, Perl AE, Smith CC, et al. A phase II open-label, AC220 monotherapy efficacy study in patients with refractory/relapsed FLT3ITD positive acute myeloid leukemia: updated interim results.

Abstracts.

PROOF 1 12/10 FINAL OK ASH Annual Meeting 2011;118(21):2576.

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CliniCal OnCOlOgy news • april 2012

Breast

Adverse Effects Hinder Extended Aromatase Inhibitor Therapy From European Journal of Surgical Oncology

D

rug toxicities are the primary cause of the high rates of treatment noncompliance associated with long-term adjuvant endocrine therapy, according to results from a prospective, open-label Phase III clinical trial published in the February issue of the European Journal of Surgical Oncology (2012;38:110-117, PMID: 22172646).

The IDEAL (Investigation on the Duration of Extended Adjuvant Letrozole) trial was designed by a team of researchers from the Netherlands to identify the factors associated with treatment discontinuation among patients with hormone receptor (HR)– positive postmenopausal early breast

EXPERT INSIGHT Robert S. Miller, MD Clinical Associate, Breast Cancer Program Oncology Medical Information Officer Johns Hopkins University School of Medicine Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Landmark trials conducted over the past 10 years have demonstrated the value of AIs in the adjuvant treatment of postmenopausal women with HRpositive, early stage breast cancer.

One strategy endorsed by the American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines, and supported by clinical trial evidence, most notably the National Cancer Institute of Canada (NCIC) study MA.17 (J Clin Oncol 2012;30:718-721, PMID: 22042967), is extended adjuvant endocrine therapy, or the use of an AI following completion of a standard five-year course of adjuvant endocrine therapy, typically tamoxifen.

Several studies have shown that patient compliance within an initial five years of hormonal therapy is suboptimal, with adherence rates as low as 40% to 50% in some reports.

This paper, by Fontein et al, evaluates patient compliance with extended

cancer undergoing therapy with aromatase inhibitors (AIs) such as letrozole (Femara, Novartis). The goal of the study was to assess noncompliance in the first 2.5 years of extended adjuvant therapy. The authors defined noncompliance as “early discontinuation of letrozole for all reasons, excluding death or recurrence.” The research was supported by an educational grant from Novartis Oncology.

Researchers randomized 1,262 patients to receive either 2.5 or five years of adjuvant therapy with letrozole. In all, 1,215 of the patients in the study population had at least one dose of the study drug during the followup period, and most (1,069 patients) started treatment within six months of the discontinuation of prior adjuvant endocrine therapy, with tamoxifen,

AIs or a sequence of both.

Within the 2.5-year follow-up period, the overall noncompliance probability was 18.4%. Median followup time was 1.88 years for compliant patients and 1.11 years for noncompliant patients, respectively (P=0.003).

The highest discontinuation rates were reported during the first six months of therapy with letrozole (49.7%). The vast majority of patients (85.1%) discontinued treatment due to adverse events (AEs), the most common of which included musculoskeletal, neurologic and dermatologic disorders. Other reasons for treatment discontinuation included treatment refusal (18 patients).

Further analysis of the study population revealed that patients previously treated with tamoxifen/AI

adjuvant letrozole in the Dutch IDEAL trial. In this prospective, Phase III, randomized, nonblinded study, postmenopausal women who had completed five years of adjuvant endocrine therapy (either tamoxifen for five years, an AI for five years, or a combined five years of the sequence of tamoxifen and an AI) were randomized to 2.5 versus five years of letrozole. This report looks at the incidence of and risk factors associated with noncompliance with letrozole after 2.5 years of follow-up, in a total of 1,215 randomized patients.

The authors found an 18.4% discontinuation rate, which was highest in the first six months of treatment. Patients discontinued letrozole because of toxicity in 85.1% of cases. A number of interesting correlations were identified. Patients whose prior endocrine therapy was the sequence of tamoxifen and an AI, particularly if that AI had been letrozole, were least likely to be noncompliant compared with patients who had previously been treated with monotherapy. Not surprisingly, longer intervals between the completion of primary endocrine therapy and the start of extended adjuvant therapy also predicted for higher rates of noncompliance. Factors not predictive of early discontinuation included age, T stage, type of surgery and prior chemotherapy or radiotherapy.

This study makes a valuable contribution to the literature since it looks at the important topic of treatment discontinuation in a population of patients not

fully characterized to date, as the larger MA.17 trial has not yet reported on letrozole adherence rates and reasons for noncompliance. Table 2 in the Fontein paper lists the reason for treatment discontinuation by AE, and musculoskeletal/soft tissue AEs were most common at 18.8%; presumably AI-induced arthralgias and/or osteopenia/osteoporosis. It would have been helpful to have more detail as to the reasons for discontinuation for each category listed, as it is unclear what toxicities were experienced under “dermatologic/skin” (11%) or “neurologic” (14.9%). Also, reasons for noncompliance due to sexual/ reproductive factors seem surprisingly low at 3.2%; perhaps there was some underreporting. It also was notable that certain patient factors such as age and tumor size seemed not to influence compliance. However, sample size may have contributed to this, as only 7.5% of patients were older than 75 years of age and nearly 90% of patients had a T1 or T2 tumor.

Most treatment guidelines appropriately note that the optimal duration of adjuvant hormonal therapy for early stage breast cancer has not been determined. However, it is increasingly being recognized that HR-positive breast cancer has a long natural history, and late recurrences after 10 years or more are not rare. Until the results of trials such as NSABP (National Surgical Adjuvant Breast and Bowel Project) B-42, which closed to accrual in 2010, are available, clinicians will not have evidence-based

sequential therapy had “the lowest probability” of treatment discontinuation at 2.5 years of follow-up compared with those whose prior endocrine therapy entailed tamoxifen or AIs alone (P=0.004). According to the authors, those patients with longer treatment-free intervals (between initial endocrine therapy and adjuvant endocrine therapy) also were more likely to be noncompliant during adjuvant therapy with letrozole (P=0.011). Interestingly, prior surgery (mastectomy or breast-conserving surgery)—both with and without radiotherapy and or chemotherapy— as well as patient age, tumor type and prior locoregional treatment were not factors associated with early treatment discontinuation among patients included in the IDEAL trial. guidelines to inform this important clinical issue of whether to continue an AI past five years of initial therapy.

Some physicians and patients, particularly those with higher-risk disease, will choose not to stop the AI at the five-year mark, a decision that is easier to make when the patient has not been experiencing any dose-limiting toxicity. However, that decision can be very challenging for the woman experiencing daily joint aches, hot flashes and vaginal dryness, particularly when the magnitude of the survival benefit, if any, is speculative.

However, if B-42 and other trials suggest that the optimal duration of an adjuvant AI is protracted and more like the use of imatinib for chronic myelogenous leukemia or trastuzumab for HER2-positive metastatic breast cancer (i.e., continuation until treatment failure or unacceptable toxicity), then oncologists must expect that noncompliance— a term that is inaccurate at best and paternalistic at worst—in a substantial majority of patients will be the norm, not the exception. In the conclusion of their paper, Fontein et al wisely noted the importance of studying the reason that some patients are at a higher risk for premature treatment discontinuation based on individual metabolic or other factors. It seems likely that a tailored approach to extended adjuvant endocrine therapy with AIs will be the most successful strategy.

SUPPORTIVE CARE

CliniCal OnCOlOgy news • april 2012

25

Breast

Quality of Life Unharmed by Exemestane in Prevention Trial File slUg

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senior editor

San Antonio—Using exemestane for breast cancer prevention does not decrease a woman’s quality of life, according to new results from the MAP.3 trial.

“These quality-of-life results provide essential information for informed decision-making by women considering breast cancer chemoprevention and for their physicians,” said Harriet Richardson, PhD, from the NCIC Clinical Trials Group and Department of Community Health and Epidemiology at Queen’s University, in Kingston, Ontario, Canada. She presented the study at the San Antonio Breast Cancer Symposium (SABCS, abstract S6-1) on behalf of the MAP.3 investigators.

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time that would exacerbate symptoms of compared with placebo. Short Form-36 editorial date/ Circulation menopause, and when you look at the bodily pain scores increased for exemestime tane compared with placebo, while no Patricia Ganz, MD, director of the questionnaire for the physical summaTrim size COMMenTs: KeywOrDs: Division of Cancer Prevention & Control ry scale, there are 15 items on that scale difference between tamoxifen and plaColor specs File path Comprehenapp@itunes.indd and only three of them ask vaguely about cebo was seen in P-1.

Research at the Jonsson —Kate O’Rourke sive Cancer Center, University of Cali- aches and pains,” she said. fornia, Los Angeles, noted that although Comparing the MAP.3 and the P-1 trithe Short Form-36 is an excellent vali- al that tested tamoxifen for chemopreDrs. Richardson and Ganz reported no relevant disclosures. dated questionnaire, the MENQOL was vention, Dr. Ganz noted that exemestane

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Vasomotor symptoms were more severe in patients receiving exemestane than in patients on placebo, and bodily pain was slightly higher.

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The Phase III MAP.3 trial was a randomized, placebo-controlled study that demonstrated that in postmenopausal women at moderately increased risk for invasive breast cancer, exemestane reduced this risk by 65% without an increase in serious adverse side effects.

These results were previously reported

by Goss et al. in The New England Journal of Medicine (2011;364:2381-2391, PMID: 21639806).

As part of that study, researchers collected data on quality of life (QOL) using the Menopause Specific QOL (MENQOL) survey and the Short Form-36. At SABCS, the researchers reported that they found no clinically meaningful changes in QOL as measured by these instruments, which were completed by more than 90% of women at scheduled visits while the women were on study medications. The proportion of women on exemestane who discontinued the therapy early was greatest at six months.

Vasomotor symptoms were more severe in patients receiving exemestane than in patients on placebo (P<0.01), and bodily pain also was slightly higher.

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SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Breast

MUGA Cardiac Function Scans Unnecessary in Most Young Women From Clinical Breast Cancer

T

he results of multigated acquisition (MUGA) scans, typically used to evaluate routine cardiac function prior to the initiation of anthracycline-based adjuvant chemotherapy, rarely influence treatment decisions in breast cancer, according to a population-based cohort study recently published in the journal Clinical Breast Cancer (2012;12:4-9, PMID: 22154116).

The study, by researchers from Halifax, Nova Scotia, Canada, enrolled 593 patients who underwent curative-intent surgery for stage I, II or III breast cancer between October 2005 and September 2006. The researchers performed a retrospective chart review for all relevant clinical-pathologic variables, including baseline cardiac risk factors.

The goals of the study were to measure current MUGA scan usage patterns among this patient population and to determine what role scan results played in treatment decisions. Anthracyclinebased treatments have been associated with rare, dose-dependent, cardiovascular-related adverse events, although

these largely have been mitigated in recent years through the use of strict patient selection criteria.

Within the study population, 238 (40%) of the patients received adjuvant chemotherapy; 94% of these patients received anthracycline-based therapy with doxorubicin, cyclophosphamide or combination therapy, among other options. Among those who received adjuvant chemotherapy, 80% underwent MUGA scans prior to the initiation of therapy. The percentage was higher among patients who ultimately received anthracycline-based regimens during treatment, and among those diagnosed EXPERT INSIGHT Lillie D. Shockney, RN, BS, MAS University Distinguished Associate Professor of Breast Cancer Associate Professor, Johns Hopkins University School of Medicine Johns Hopkins Avon Foundation Breast Center

with HER2-positive breast cancer.

Only 5% of patients who underwent MUGA scans received abnormal results, and all were smokers. Scan results influenced treatment decisions in only 2% of patients, all of whom were aged 65 years or older. None of these patients received anthracycline-based chemotherapy; in fact, one did not receive adjuvant chemotherapy at all.

The authors reported that routine MUGA scans obtained before the initiation of anthracycline-based adjuvant chemotherapy without trastuzumab “did not influence [treatment] decisions for younger patients” except in the It has kind of been surprising that this recommendation—not to perform cardiac evaluation testing of young women before receiving an anthracycline— hasn’t happened several years ago. It makes perfect sense that young women without any prior medical evidence or cardiac symptoms would not be required to have MUGA scans prior to starting adjuvant chemotherapy that includes an anthracycline, which carries a risk, however low, of causing cardiotoxicity.

presence of “underlying cardiac risk factors.” They suggest that prechemotherapy MUGA scans may not be required except in special populations, in particular older women and those with other cardiac-related risk factors.

Noting that their findings echo those of Sabel et al (Am J Clin Oncol 2001;24:425-428, PMID: 11474280), the authors concluded, “There is no current evidence to support routine baseline multigated acquisition scan testing for younger, perhaps premenopausal, women without underlying cardiac risk factors who are not candidates for adjuvant trastuzumab.”

In the thousands of women I have personally been involved with during their treatments, I have never seen a young woman with an abnormal cardiac functioning test result. This research study confirms nicely that healthy young women have a very low incidence of cardiac problems, so testing all young women prior to getting their chemotherapy under way is not a wise use of medical resources, and it also creates anxiety for some.

Anti-EGFR Agents Incur Increased Risk for Thromboembolic Events From Annals of Oncology

A

meta-analysis of randomized clinical trials involving anti-epidermal growth factor receptor (EGFR) agents in the treatment of advanced cancers has confirmed that the monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs)—in particular, cetuximab (Erbitux, Bristol-Myers Squibb/ Lilly) and panitumumab (Vectibix, Amgen)—that make up the class are associated with an increased risk for venous thromboembolic events (VTEs; excluding catheter-related events) when compared with controls.

EXPERT INSIGHT David Cosgrove, MBBCh Assistant Professor of Oncology The Johns Hopkins University School of Medicine The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Although research has indicated that these agents may lead to the development of arterial thromboembolic events (ATEs) and VTEs in some patients, the incidence and level of risk associated with their use has remained unknown.

The study (Annals of Oncology 2012 Jan 11. [Epub ahead of print], PMID: 22241897), performed by researchers in the medical oncology unit at the Azienda Ospedaliera Treviglio-Caravaggio in Italy, analyzed 13 studies encompassing 7,611 patients undergoing therapy with anti-EGFR agents, including bevacizumab (Avastin, Genentech),

cetuximab, erlotinib (Tarceva, Genentech), gefitinib (Iressa, AstraZeneca), sorafenib (Nexavar, Bayer/Onyx), panitumumab and sunitinib (Sutent, Pfizer).

In 11 studies including 7,073 patients, the relative risk for VTEs in patients treated with the study drug was 1.32 compared with control patients (P=0.01).

The incidence of VTEs across all studies was 5%. In five studies that included 3,030 patients, the relative risk for ATEs in patients treated with the study drug was 1.34, compared with control patients (P=0.11). Across all studies, the incidence of ATEs was 4.5%.

Additionally, the authors found that

the relative risk for VTEs was higher among mAbs (1.34; P=0.01) than oral TKIs (1.16; P=0.65). Whereas cetuximab and panitumumab carried the highest risk for ATEs and VTEs (1.61; P=0.006) within the anti-EGFR class in settings for which they are currently approved, erlotinib and gefitinib did not carry an increased risk for thrombotic events. Overall, the use of antiEGFR agents increases the risk for VTEs by 32% in patients with advanced solid tumors.The authors note that thrombotic risk is “likely not correlated to the longer duration of therapy in experimental arms.”

In a recent Annals of Oncology article, Petrelli et al report on the relative risk for venous and arterial thromboembolic events in patients receiving anti-EGFR therapy, both mAbs and TKIs. This meta-analysis included 13 randomized studies that incorporated an anti-EGFR agent in one of the treatment arms, usually in conjunction with chemotherapy. Results suggest a slightly increased risk for VTE with the use of anti-EGFR agents, mostly

with the mAbs, although no difference in arterial or cardiac events.

While there are limitations to the ability of this kind of analysis to control for potential confounders, especially individual patient characteristics, and the absolute increased risk for VTE with anti-EGFR therapy is small (<2% in this meta-analysis), this article represents an interesting initial foray into a clinically significant arena. VTE is a major problem in patients with cancer, and it is

incumbent upon practitioners to recognize factors that increase that risk.

Of course, any potential increased risk must be considered alongside the benefit afforded to patients by these agents, in terms of disease control and prolonged survival. For now, I do not feel that these data will significantly alter practice patterns in terms of anti-EGFR therapy prescribing in patients for whom a clinical benefit can be expected. Future study is warranted.

SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Prostate

EBRT: More Toxic, More Expensive Among three common aggressive treatments for prostate cancer, EBRT produces higher costs and related toxicities San Francisco—External beam radiation therapy (EBRT) results in higher long-term toxicities and treatment-related costs than prostatectomy and brachytherapy, two other common treatments for the disease, according to an analysis of 137,427 prostate cancer patients.

“Research to date has not given us a clear picture of how each prostate cancer therapy affects men over the long run,” said lead author Jay Ciezki, MD, staff physician at the Cleveland Clinic in Ohio. “Our analysis is one of the first to examine the quality-of-life and financial costs of these three very common prostate cancer treatment strategies for more than five years after treatment. We found that external beam radiotherapy had higher toxicity rates and was the most costly therapy per patient-year.”

Dr. Ciezki, who presented the study findings at the American Society of Clinical Oncology 2012 Genitourinary Cancers Symposium (abstract 4), said there clearly are still some high-risk prostate cancer patients who will benefit from external beam radiotherapy. However, for the approximately 80% or more

of prostate cancer patients diagnosed with low- and intermediate-risk disease, brachytherapy or prostatectomy may be even more preferable options than had previously been assumed, he said.

The researchers analyzed data in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database collected between 1991 and 2007.

The median follow-up was 71 months.

They compared treatment-related toxicities and related outcomes among men who received EBRT, prostatectomy or brachytherapy.

Because the SEER-Medicare database provides information on cancer diagnoses and outcomes, along with individual patient costs, it allowed the investigators to obtain Medicare reimbursement data for both the initial treatment and any subsequent treatments related to the

by the

numbers

Cost per patient-year of common aggressive prostate cancer treatments

$2,557.36| Brachytherapy $3,205.71| Prostatectomy $6,412.29| External beam radiation therapy Toxicity-related medical interventions required

3.7%| Brachytherapy 6.9%| Prostatectomy 8.8%| External beam radiation therapy

‘External beam radiotherapy had higher toxicity rates and was the most costly therapy per patient-year.’

toxicities, which was used to calculate the total cost per patient-year for each of the three therapies over time. “We were able to get a good picture of the longterm costs of patient care and were surprised to see such dramatic differences among the three treatment strategies,” said Dr. Ciezki.

A total of 137,427 patients were examined, including 59,559 (43.3%) treated with prostatectomy, 60,806 (44.2%) who received EBRT and 17,062 (12.4%) who were treated by brachytherapy.

Overall, 10,585 (7.3%) needed some type of treatment intervention for a therapyrelated effect.

The investigators were not able to determine the stage of prostate cancer in individual patients included in the study. Additionally, the study was limited to patients older than age 65 years with prostate cancer as their only cancer diagnosis.

The investigators found that brachytherapy had the lowest cost per patientyear: $2,557.36. Prostatectomy came in slightly more expensive at $3,205.71, followed by EBRT at $6,412.29. EBRT also resulted in the most treatment-related toxicities. Within treatment modalities, the percentages of patients requiring a toxicity-related intervention were 6.9% for radical prostatectomy, 8.8% for EBRT and 3.7% for brachytherapy.

The investigators found that 7.1% of patients who received EBRT experienced genitourinary toxicities such as urethral strictures and bladder bleeding compared with 6.7% of those treated with prostatectomy and 3.4% of those treated with brachytherapy. Similarly,

—Jay Ciezki, MD

1.7% of EBRT patients had gastrointestinal effects compared with only 0.1% of prostatectomy patients and 0.3% of those in the brachytherapy group.

The researchers caution that the study findings are preliminary and they plan to more closely examine the data and the differences they observed, including differences in toxicities found between older and newer techniques, and whether certain types of patients might be predisposed to long-term effects from particular therapies.

“This is a fascinating piece of work.

It begs the question why brachytherapy is less used. I am surprised we don’t see more use of this modality,” said medical oncologist Nicholas Vogelzang, MD, head of the Genitourinary Cancer Program at the University of Nevada School of Medicine in Las Vegas. He told Clinical Oncology News that these new findings are very important because the study included so many patients and had such a long follow-up. Studies like this one will help ensure that more prostate cancer patients receive the best possible therapies while avoiding unnecessary side effects and costs, he added.

—John Schieszer Dr. Ciezki reported that he has no relevant relationships to disclose. Dr. Vogelzang reported an employment or leadership position with US Oncology and has served as a consultant or advisor or has received honoraria from Amgen, Bayer, Boehringer Ingelheim, Celgene, Clinical Care Options, Cougar Biotechnology, Dendreon, Eisai, Genentech, GlaxoSmithKline, Johnson & Johnson/Centocor, Novartis, Pfizer, Takeda/ Millennium, US Oncology and Veridex.

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SOLID TUMORS

CliniCal OnCOlOgy news • april 2012

Prostate

Optimizing Radiation for Prostate Cancer Newer techniques challenge standard schedules and ADT use San Francisco—The optimal radiation schedule for the curative treatment of prostate cancer today remains largely unknown. It is believed that using fewer fractions with a larger dose per fraction may result in an improved therapeutic ratio; however, there is little strong evidence to support this theory, according to W. Robert Lee, MD, professor of radiation oncology at Duke University in Durham, N.C. During an oral presentation on hypofractionation for prostate cancer at the American Society of Clinical Oncology’s 2012 Genitourinary Cancers Symposium (ASCO-GU), Dr. Lee said that in the United States, patients with prostate cancer are typically treated with external beam radiation therapy (EBRT) for five days per week for eight to nine weeks. The most common dose per fraction is 1.8 to 2 Gy; however, in the past 10 years a number of reports have suggested that the fractionation sensitivity of prostate cancer may favor hypofractionated schedules.

“There is some preclinical evidence to suggest that using fewer, larger doses would be beneficial,” said Dr. Lee. “However, if you are going to give fewer treatments, then you have to give higher doses. So the issue is how few doses should you give and how large a dose should you give.”

There are currently only two mature randomized trials comparing different fractionation schedules, Dr. Lee said. One study was performed in Canada and the other in Australia. Both studies compared the two fractionation schedules commonly used in each country. The problem with both trials is that they were designed many years ago and the doses and techniques studied are far from the standard of care in 2012.

The Canadian study was a noninferiority trial including 936 men (J Clin Oncol 2005;23:6132-6138, PMID: 16135479).

There were two treatment arms: One included men treated with 66 Gy in 2-Gy fractions and the second with men treated with 52.5 Gy in 2.625-Gy fractions.

After a five-year follow-up, the men in the second arm had a higher biochemical/clinical failure rate (hazard ratio, 1.18; 95% confidence interval, 0.99-1.41). The authors concluded that the hypofractionated arm was inferior.

The Australian study included 217 patients with a primary end point of late gastrointestinal/genitourinary toxicity (Int J Radiat Oncol Biol Phys 2011;81:1271-1278, PMID: 20934277).

The trial compared 64 Gy in 2-Gy fractions to 55 Gy in 2.75-Gy fractions. To date, the researchers have found no differences in biochemical recurrence rates when using the American Society of Radiation Oncology (ASTRO) definition. However, there was a difference favoring the 2.75-Gy fractionation arm

if the Phoenix definition (nadir + 2 ng/ mL) was used.

Dr. Lee said three other randomized trials have compared different fractionation schedules using more contemporary methods. In an Italian study with 168 patients comparing 80 Gy in 2-Gy fractions with 62 Gy in 3.1-Gy fractions, investigators found there were no observed differences in late rectal toxicity (Int J Radiat Oncol Biol Phys 2010;78:1118, PMID: 20047800). However, the risk for biochemical recurrence was lower in the hypofractionated arm. Two American studies also have analyzed the issue but neither reported a difference in biochemical recurrence.

“Considering all five studies published or reported to date, no consistent effect was observed,” said Dr. Lee. “Given the lack of consistency, the eight- or nineweek regimens are likely to remain the standard in the United States. There are three very large noninferiority trials that have completed accrual totaling more than 5,000 patients. The results of these studies will determine if shorter courses of four to five weeks should be adopted.”

He noted that the inconsistency might be the result of different eligibility

criteria. The use of androgen deprivation therapy (ADT) also varied greatly across the studies. It is well established that hypofractionation schedules provide patients with convenience and lower costs. However, Dr. Lee said it is still unknown whether conventional (1.8-2 Gy) or moderate (2.4-4 Gy) or extreme hypofractionation (6.5-10 Gy) is optimal in men with prostate cancer.

“The evidence is stronger for the moderate schedules. There are rigorous comparisons but most of the comparison studies are relatively small and the study design was analyzing for superiority,” Dr. Lee said in an interview with Clinical Oncology News. “The results of large noninferiority trials are eagerly anticipated. If we can determine that similar results are achievable with fewer fractions, external radiotherapy will be more convenient for patients at a lower cost.”

Modern Radiotherapy Techniques: Do More Accurate Doses Replace ADT? ADT has been shown to improve survival for men with intermediate-risk prostate cancer as well as for men with high-risk prostate cancer treated with

‘Intermediate-risk patients are a large percentage of new diagnoses and we need to know what the best approach is and whether radiation therapy by itself is all that is necessary.’

–Daniel Krauss, MD

radiation therapy with doses in the range of 65 to 70 Gy delivered without image guidance. Yet, no single multicenter, Phase III study of dose-escalated radiotherapy demonstrating a benefit with the addition of ADT exists, according to Daniel Krauss, MD, an associate professor of radiation oncology at Oakland University William Beaumont School of Medicine in Royal Oak, Mich.

At an oral presentation at ASCO-GU on dose escalation and supplemental androgen deprivation, Dr. Krauss told oncologists that to date retrospective analyses have suggested that ADT offers little to no benefit for patients treated locally with brachytherapy (Int J Radiat Oncol Biol Phys 2006;65:669-677, PMID: 16682149). He added that the same is true for dose-escalated EBRT (Int J Radiat Oncol Biol Phys 2011;80:10641071, PMID: 20584576). “[Luteinizing hormone-releasing hormone agonists] have proven to be very active against prostate cancer. But they have a lot of side effects and so if you don’t need to give them you want to avoid it,” said Dr. Krauss. “There are a lot of prospective randomized trials and they are large and well done, but the problem is that they were done in the 1980s and 1990s.”

It has created a conundrum for clinicians, he added. The radiation techniques used in the 1980s and 1990s are inferior to what are used today. The unanswered question is whether the hormones compensated for what was less-than-optimal radiation treatment. Dr. Krauss said the very nature of prostate cancer as an indolent malignancy with a protracted natural history is part of the problem when studying this issue. Today, new technologies have outpaced the clinical outcomes that objectively demonstrate their effectiveness. This appears to clearly be the case when it comes to the development of intensity-modulated radiotherapy and image-guided radiation therapy (IGRT).

“We know the prostate moves around a bit and that target motion is now dealt with, but that was not the case when the studies were conducted,” Dr. Krauss said in an interview with Clinical Oncology News. “Clinical oncologists should care about this because this diagnosis is so common and it affects so many men.

Intermediate-risk patients are a large percentage of new diagnoses and we need to know what the best approach is and whether radiation therapy by itself is all that is necessary.”

Quality-of-life issues are paramount for many men with intermediate-risk and high-risk prostate cancer. The common acute toxicities from ADT include hot flashes and sexual side effects.

PRN

CliniCal OnCOlOgy news • april 2012

Patient Care

Cancer Deaths Down, But With a Few Aberrations CRC mortality continues to decline, reflecting better screening, treatments In the past two decades, the overall death rate from cancer decreased by 22.9% in men and 15.3% in women, according to the most recent annual report on cancer incidence from the American Cancer Society (ACS; Siegel R et al. CA Cancer J Clin 2012;62:10-29, PMID: 22237781).

‘Decreases in prostate, female breast and colorectal

More than 1 million cancer deaths were avoided from 1990 through 2008, the report’s authors estimated. For 10 years with available data (1998-2008), death rates continued to decrease for all four major cancer sites—lung, colorectum, breast and prostate, with colorectal cancer accounting for much of the decline in both men and women.

“Among men, 78% of the [overall] decline is due to decreases in the top three cancer sites—lung, prostate and colorectal cancers; while among women, 56% of the decline is due to decreases in death rates for breast and colorectal cancers,” said lead author Rebecca Siegel, MPH, an ACS epidemiologist based in Atlanta.

“Lung cancer death rates have been declining among men since 1990, due to the reduction in tobacco use over the past 50 years,” she said, noting that the mortality decline has been smaller for women than for men because of the lag in decline in the lung cancer death rate among women. Smoking prevalence among women peaked 20 years later than among men.

“Decreases in prostate, female breast and colorectal cancer death rates largely reflect improvements in early detection and/or treatment,” Ms. Siegel added.

In an interview, Howard Sandler, MD, chair of radiation oncology and Ronald H. Bloom Family Chair in Cancer Therapeutics at Cedars-Sinai Medical Center in Los Angeles, attributed the long decline in cancer death rates to a “combination of factors,” including a declining number of smokers, effective methods of early cancer detection and better treatments.

Dr. Sandler did not believe that the novel, targeted cancer therapies had a great effect on cancer mortality rates, in

part because those therapies are usually administered to patients who have “not only cancer, but fatal cancer.” Such drugs are more important for increasing survival time than for changing the death rate, explained Dr. Sandler, who is an executive

editor of the American Society of Clinical Oncology Web site CancerProgress.net.

Despite the decline in overall cancer mortality, incidence rates of some less common cancers have been increasing, according to a second article from the

Additionally, the use of ADT is associated with increased risks for developing or exacerbating cardiovascular disease, osteoporosis and diabetes. Dr. Krauss said eliminating the need for ADT could mean a better quality of life for many men. “You don’t want to subject these folks to more side effects unless there is a clear clinical advantage to administering the treatment.”

Multiple large, Phase III trials have shown that there is a clinical advantage, including an improvement in overall survival, when using ADT with radiotherapy for prostate cancer patients with

intermediate- and high-risk disease, Dr. Krauss said. Additionally, studies have shown that more ADT is better than less in these patient populations.

However, Dr. Krauss added that doseescalated radiotherapy has been shown in multiple prospective randomized trials to be superior to less—that is, to standard radiotherapy doses. So, it may be possible that ADT is not as important as it once was in the management of men with intermediate-risk prostate cancer.

Clinicians know that the prostate is not a static target and they now factor in the interfraction and intrafraction position

changes when delivering radiotherapy.

Yet, today there is a lack of data showing significant clinical benefits when IGRT is combined with ADT. “One thought is that if ADT works in low-dose radiation then it should work even better with highdose. However, I don’t think we know that, and it may be that the hormones, in those prior studies, were simply masking what was suboptimal radiation therapy,” said Dr. Krauss.

He said the Radiation Therapy Oncology Group (RTOG) is currently investigating the issue in a large randomized trial (RTOG 0815). It is designed to show a

cancer death rates largely reflect improvements in early detection and/or treatment.’

—Rebecca Siegel, MPH

‘To survive [as oncologists], we have to be optimistic. Yes, the trend [in cancer mortality rates] is going to continue to go down.’

—Howard Sandler, MD

ACS (Simard EP et al. CA Cancer J Clin 2012 Jan 4. [Epub ahead of print], PMID: 22281605). Authors of that study documented increases in cancers of the pancreas, liver, thyroid and kidney, as well as increases in esophageal adenocarcinoma, melanoma and some kinds of throat cancer associated with human papillomavirus (HPV) infection.

“The reason for the increasing rates is unknown, but the obesity epidemic is probably associated with increases for some of these cancers,” Ms. Siegel said.

“Increases in early detection practices are a likely contributor as well.”

Dr. Sandler described several factors that may account for the observed increases in cancer incidence rates: gastroesophageal reflux associated with obesity for esophageal adenocarcinoma, hepatitis C and B virus infections for liver cancer, increased sun exposure for melanoma of the skin and increased prevalence of HPV infection for throat cancer associated with HPV. The increase in the incidence of melanoma was particularly sharp, he noted.

Ms. Siegel added that the increase in the incidence of thyroid cancer was the largest, and that the increase in kidney cancer incidence was an unexpected finding.

“Although most of the increases were confined to whites, rates of kidney cancer increased among both men and women of every racial/ethnic group, although the increase was not statistically significant among American Indian/Alaska Native men.”

Regarding mortality rates, Dr. Sandler expressed hope that the downward trend in deaths from cancer will continue.

“To survive [as oncologists], we have to be optimistic,” he said. “Yes, the trend is going to continue to go down.”

—George Ochoa Ms. Siegel and Dr. Sandler reported no relevant conflicts of interest.

survival advantage with the addition of short-term, six-month ADT to dose-escalated radiotherapy in men with intermediate-risk prostate cancer. A previous study (RTOG 9408) was able to demonstrate a survival advantage for men with early-stage prostate cancer with the addition of a course of four-month ADT to radiotherapy (66.6 Gy).

—John Schieszer Dr. Lee reported an employment or leadership position with Practical Radiation Oncology. Dr. Krauss reported that he has no relevant relationships to disclose.

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CliniCal OnCOlOgy news • april 2012

Breast

Partial Breast Radiation Study Sparks Debate A new study has spurred some doctors to urge caution in selecting patients for accelerated partial breast irradiation (APBI) and angered others who say the study is flawed and could derail a Phase III clinical trial testing APBI. The retrospective study, presented at the recent San Antonio Breast Cancer Symposium (SABCS), concluded that APBI with brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation (WBI) in older patients (abstract S2-1).

“From 2000 through 2007, older women in the United States treated with brachytherapy experienced higher risk for losing the breast, postoperative infection, postoperative wound complications, breast pain and fat necrosis,” said Benjamin Smith, MD, an assistant professor in the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston, who presented the study. He pointed out that the study results do not apply to APBI delivered by external beam.

Press headlines following SABCS included “Quicker Radiation Therapy Doubles Mastectomy Risk” (Reuters) and “Mastectomy Risk High With Brachytherapy for Breast Cancer” (Medscape). These articles infuriated some APBI investigators, including Robert Kuske, MD, a radiation oncologist at Arizona Breast Cancer Specialists-Scottsdale, who says that the treatment’s effectiveness is measured by recurrence rates and survival after treatment, not future mastectomies.

“The consequences of this information out of the MD Anderson analysis are potentially damaging. If the randomized NSABP [National Surgical Adjuvant Breast and Bowel Project-39] clinical trial fails to reach its goal of 4,300 patients because of this misinformation, this would be a tragedy because real answers to all of our questions will come out of this scientifically pure study,” said Dr. Kuske, a principal investigator of this ongoing randomized Phase III trial, which is expected to provide a rigorous comparison of APBI and WBI. In the SABCS study, researchers analyzed Medicare records of 130,535 women diagnosed with invasive breast cancer between 2000 and 2007 who were treated with lumpectomy followed by either WBI (n=123,244) or APBI with brachytherapy (n=7,291). To assess safety and effectiveness, Dr. Smith and his colleagues compared overall survival, the risk for subsequent mastectomy, postoperative complications and postradiation toxicities.

The investigators did not identify any difference in survival, but brachytherapy was associated with

an increased risk for mastectomy (4% vs. 2.2%; P<0.001). Patients undergoing brachytherapy had a higher rate for infectious postoperative complications (16% vs. 10%; P<0.001) and noninfectious postoperative complications (16% vs. 8%; P<0.001), such as a surgical wound breakdown, postoperative bleeding or seroma formation. Complications occurring within five years after the start of radiation therapy that also increased with brachytherapy included breast pain (15% vs. 12%; P<0.001) and fat necrosis (9% vs. 4%; P<0.001).

“Fat necrosis may not have much clinical significance, but generally is considered a marker of tissue injury from either surgery and/or radiation therapy,” said Dr. Smith. Radiation pneumonitis, however, was more common in patients receiving WBI (0.1% vs. 0.8%; P<0.001).

Study Under a Scope Critics say the study has many limitations. First, it is a retrospective analysis examining Medicare patients who were treated at the discretion of thousands of physicians, said Dr. Kuske. As such, it could not take into account tumor characteristics, margin status or a patient’s general medical condition. “We do know that women received more chemotherapy in the whole breast irradiation group of patients,” Dr. Kuske said.

“This, by itself, could account for the small 1.8% difference in mastectomy rates between the two groups.”

He added that factors such as diabetes, obesity or smoking history were not taken into account and could have contributed to the higher complication rates. Potentially significant factors, he said, are controlled and recorded in greater detail in randomized trials such as the NSABP-39 trial. Dr. Kuske also pointed out that the rate of biopsy-proven breast cancer recurrence in the two groups was not stated, and there are many noncancer reasons for subsequent mastectomy, such as testing positive for the BRCA gene or a falsepositive magnetic resonance imaging.

Another limitation is that the SABCS trial analyzed procedures that used early-generation brachytherapy techniques and not the more advanced techniques used today.

In response to the study, the American Society for Radiation Oncology (ASTRO) issued a statement saying it was concerned about the potential misinterpretation of the data. “There are limitations to the interpretation of the data, given that it was drawn from records of

patients [with] varying risk factors and stage treated between 2000 and 2007,” the statement reads. “Since that time, technology has dramatically improved, including the use of newer multichannel applicators with tighter dose constraints.” The statement also noted that although statistically significant, the rate of mastectomy is very low in either treatment group. Many patients, said Dr. Kuske, would accept a 1.8% difference in order to have a shorter treatment that exposes less normal tissue to ionizing radiation.

According to Peter Beitsch, MD, numerous retrospective studies and two prospective randomized studies have shown no difference in survival, locoregional cancer recurrence rates and complications between APBI and WBI. Dr. Beitsch is co-principal investigator of the American Society of Breast Surgeons (ASBS) MammoSite Registry, which includes information on 1,440 patients who were given APBI brachytherapy with the MammoSite balloon catheter device through 2004. Information gleaned from this registry shows a low rate of complications and a five-year local recurrence rate of less than 5%, which is comparable to that of WBI. Several single-institution randomized and nonrandomized studies using another APBI technique, multiple interstitial catheters, also report rates of local recurrence comparable to WBI. Dr. Beitsch also took issue with a study end point. “The study stated that subsequent mastectomy is a validated surrogate for local failure. However, I am unaware of any literature that states this,” he argued, adding that APBI often is used in older, sicker patients who may not be candidates for the six to seven weeks of WBI. This factor could introduce bias into the MD Anderson study results.

In response, Dr. Smith said the twofold increased risk for subsequent mastectomy was found “even after adjusting for patient age, race, comorbidity, treatment with chemotherapy, surgical assessment of the axilla and axillary lymph node involvement.”

Nevertheless, he added, “the absolute risk for subsequent mastectomy in patients treated with brachytherapy was still quite small at only 4%, and was consistent with the risks for subsequent mastectomy reported by the ASBS MammoSite Registry Study.”

According to Bruce Haffty, MD, a professor and chairman of radiation oncology at the University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medical School in New Brunswick, the SABCS study should provide an additional incentive for physicians to adhere to ASTRO’s APBI consensus statement. This 2009 statement, which he and Dr. Smith helped author, outlines criteria for selecting patients to be treated with APBI outside of a clinical trial.

While awaiting results from the NSABP-39 trial and six other ongoing randomized trials comparing APBI and WBI, oncologists may find themselves inundated by questions from patients who have heard about the retrospective study. They can point patients to the statements issued by ASTRO and ASBS. According to ASBS, “The evidence in the MD Anderson study should be considered in presurgical counseling, but is not strong enough to preclude the use of PBI in properly selected patients.”

—Kate O’Rourke

Dr. Beitsch has received lecture fees from companies making brachytherapy equipment. Dr. Kuske disclosed receiving teaching and lecture fees from companies making both external beam and brachytherapy equipment. Dr. Smith disclosed research funding from Varian Medical Systems, which makes a variety of radiation equipment, including WBI and APBI instruments. Dr. Haffty reported no relevant disclosures.

Spotlight On Our Very Best As 2011 drew to a close, the McMahon Group bestowed honors on several employees within its talented workforce. Throughout the year, McMahon’s portfolio of clinical news magazines maintained readership numbers that solidified their best-read status, and sales revenues increased despite a challenging economic climate. The diverse talents and collaborations among McMahon’s staff allowed the company to maintain its position as a trusted source of news and educational initiatives. McMahon’s publishing success was on display both in print and on the Web sites of its publications and custom media platforms.

2011

Here is a look at those recognized for their unique contributions during 2011.

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

GRAPHIC DESIGNER OF THE YEAR:

employees were asked to select the two most outstanding members from these departments. The fi rst winner was JOHN CABA, software developer, for his tireless devotion toward improving the company’s digital platforms.

The second winner was ROSA DIMICCO, accounting associate, for diligently ensuring that freelance writers and key opinion leaders are paid in a timely manner for their exceptional work.

JEANETTE MOONEY won the award in recognition of her creative talents as art director for Pain Medicine News, along with her superb layout designs for a host of special reports and custom newsletters.

MOST IMPROVED SALESPERSON OF THE YEAR:

SPECIAL PROJECTS EDITOR OF THE YEAR:

NEWSMAGAZINE EDITOR OF THE YEAR:

each member of the sales staff seeks to improve throughout the year; however, one inevita- bly displays accelerated growth. DAVID NATHANSON, account manager, managed to do just that across several publications in 2011.

SETH KANDEL was voted best projects editor for his exemplary work on numerous custom media programs for medical industry clients as well as his management of the editorial in Infectious Disease Special Edition.

DONALD PIZZI, managing editor of Pain Medicine News, was recognized for the excellence of his news coverage throughout 2011. Under Don’s discerning eye, the magazine offers a comprehensive resource for clinicians involved in the management of pain.

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

DAVE KAPLAN, publication director of Pharmacy Practice News, was the 2011 winner in this category. Dave has proven himself to be an innovator among his peers by championing exciting new platforms and marketing opportunities for his many clients.

whereas the other awards are decided by a jury of one’s peers, this honor is bestowed on the one salesperson who brings in the most revenue. For a record-breaking sixth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News. richard’s dedication to his clients’ marketing needs and intimate knowledge of their products enable him to reach the zenith of sales profi ciency year after year.

PERSON OF THE YEAR

PARTNERS AWARD

PERSON OF THE YEAR 2011:

PARTNERS SPECIAL RECOGNITION AWARD 2011:

This award recognizes the cream of the crop, and MARY LOU CAMPANELLA, chief fi nancial offi cer, was the 2011 person of the year. Mary lou has been able to streamline the company’s fi nances by thwarting ineffi ciencies and highlighting excess expenditures. Her constant professionalism, hard work and keen eye for detail have proven to be invaluable commodities that are greatly appreciated by her peers.

The partners of McMahon publishing occasionally present an award to someone who has contributed to the success of the company over many years of service. This year’s winner was URBAN S. MULVEHILL, who has provided legal services to the company since 1983. He became a partner at his law fi rm, O’neill DiManno and Kelly, in 1980 after having served as a trial lawyer for several years at the U.s. Department of Justice. Urban’s relaxed demeanor and sage advice over the past three decades have been greatly appreciated.

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Atlas of Diagnostic Oncology: Expert Consult— Online and Print: Fourth Edition

Arthur T. Skarin Elsevier/Mosby, December 23, 2009 This atlas provides the guidance you need to diagnose a full range of neoplastic conditions with greater accuracy for better patient outcomes.

More than 2,500 images and drawings—combined with succinct, clinically focused text—equips you with essential information on pathology, diagnostic studies, staging and clinical manifestations.

Scan here for our complete catalog of medical books.

ORDER ONLiNE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com.

We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com.

If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

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Cancer Metastasis: Biologic Basis and Therapeutics

David Lyden; Danny R. Welch; Bethan Psaila Cambridge University Press, April 25, 2011 This groundbreaking text comprehensively covers the processes underlying cancer metastasis and the clinical treatment of metastatic disease.

The internationally renowned authors of this volume have summarized the state-of-the-art research in the metastasis field.

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Counseling About Cancer: Strategies for Genetic Counseling, Third Edition

Katherine Schneider John Wiley, December 6, 2011 This edition features five new chapters on breast cancer, colon cancer, other solid tumors, clients and families, and genetic test results and follow-up. This is the only reference and clinical book on the market for cancer genetics counselors who must quickly assimilate complex and ever-changing data on the hereditary risk for cancer.

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DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology: Ninth Edition

Vincent DeVita, Ronald A. DePinho; Theodore S. Lawrence; Steven A. Rosenberg; Robert A. Weinberg Lippincott Williams & Wilkins, May 16, 2011 The primary goal of this book is to present the practicing oncologist with the practical as well as cutting-edge information needed to ensure the best possible care for each individual patient.

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Leibel and Phillips Textbook of Radiation Oncology: Expert Consult—Online and Print

Theodore L. Phillips; Richard Hoppe, MD Elsevier/Saunders, September 23, 2010 This textbook offers a multidisciplinary look at the presentation of uniform treatment philosophies for cancer patients emphasizing the “treat for cure” philosophy. You can also explore the implementation of new imaging techniques to locate and treat tumors, new molecularly targeted therapies and new types of treatment delivery.

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MD Anderson Manual of Medical Oncology, Second Edition

Hagop M. Kantarjian; Robert A. Wolff; Charles A. Koller McGraw-Hill, April 22, 2011 A hands-on desk reference for the practicing oncologist—from the leader in the field of cancer management. This text details the personalized multidisciplinary approach to cancer management pioneered by The University of Texas MD Anderson Cancer Center. It is intended to bring a pragmatic approach to cancer management that can serve as a guide for oncologists around the world.

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MD Anderson Manual of Psychosocial Oncology

James D. Duffy; Alan Valentine McGraw-Hill, November 23, 2010 Reflecting the collective expertise of more than 40 contributors, most from MD Anderson Cancer Center, this manual addresses key psychological and behavioral issues that should be considered when treating cancer patients, including special populations such as children and the elderly.

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Understanding Skin Cancer Anatomical Chart

Anatomical Chart Company Lippincott Williams & Wilkins, February 8, 2011 Defines skin cancer and provides detailed illustrations of how it develops from sun exposure. Shows and discusses various types of ultraviolet radiation and how each kind penetrates the skin layers. Illustrates and shows photos of various types of precancer and cancer.

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