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N.º 6 - Enero 2014

EDITORES Luis Chiva Antonio González

TEMAS DE ACTUALIDAD SECONDARY DEBULKING IN OVARIAN CANCER AND BEYOND GENETIC PROFILING IN GYNECOLOGIC ONCOLOGY. WHAT CAN WE EXPECT? MATURE DATA OF INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER. STILL AN EXPERIMENTAL OPTION? CARCINOMA BORDERLINE MUCINOSO DE OVARIO CON RECURRENCIA METASTÁSICA HEPÁTICA: ¿TUMOR OVÁRICO O DIGESTIVO? DESCRIPCIÓN DE UN CASO CLÍNICO CARCINOMA DE OVARIO RECURRENTE CON SENSIBILIDAD INTERMEDIA A PLATINO


EDITORES

COMITÉ EDITORIAL

Luis Chiva Departamento de Ginecología Oncológica Hospital MD Anderson Cancer Center. Madrid

Anatomía Patológica

Antonio González Departamento de Oncología Médica Hospital MD Anderson Cancer Center. Madrid

Anais Malpica Departamento de Anatomía Patológica Sección de Ginecología Oncológica MD Anderson Cancer Center. Houston Juan F. Garcia Departamento de Anatomía Patologica Hospital MD Anderson Cancer Center. Madrid

Oncología Radioterápica Natalia Carballo Departamento de Radioterapia Hospital MD Anderson Internacional España. Madrid Anuja Jhingran Departamento de Radioterapia MD Anderson Cancer Center. Houston

Ginecología Oncológica David Cibula Departamento de Ginecología Oncológica Charles University Prague, República Checa. Robert Coleman Departamento de Ginecología Oncológica MD Anderson Cancer Center. Houston Dennis Chi Departamento de Ginecología Oncológica MSKCC. Nueva York. Javier de Santiago Departamento de Ginecología Oncológica Hospital Universitario de La Paz. Madrid Matías Jurado Departamento de Ginecología Oncológica Clínica Universitaria de Navarra. Pamplona

Salomón Menjón Departamento de Ginecología Oncológica Hospital Virgen de las Nieves. Granada Jordi Ponce Departamento de Ginecología Oncológica Hospital de Bellvitge. Barcelona Pedro Ramírez Departamento de Ginecología Oncológica MD Anderson Cancer Center. Houston Aureli Torné Departamento de Ginecología Oncológica Hospital Clínic. Barcelona Edgardo Yordan Departamento de Ginecología Oncológica Rush Presbyterian St. Luke´s Medical Center. Chicago

Oncología Médica José María del Campo Departamento de Oncología Médica Hospital Vall d´Hebron. Barcelona César Mendiola Departamento de Oncología Médica Hospital Universitario 12 de Octubre. Madrid Antonio Casado Departamento de Oncología Médica Hospital Clínico San Carlos. Madrid Andrés Poveda Departamento de Oncología Médica Instituto Valenciano de Oncología IVO. Valencia Sandro Pignata Departamento de Oncología Médica Istituto Nazionale dei Tumori. Nápoles.

Javier Magriñá Departamento de Ginecología Oncológica Mayo Clinic. Scottsdale. Arizona

Realización: LUZÁN 5, S. A. Pasaje de la Virgen de la Alegría, 14 28027 Madrid e-mail: luzan@luzan5.es http://www.luzan5.es

© 2007-2014, los autores. © 2007-2014, LUZÁN 5, S. A. de Ediciones. ISSN: 1887-4312. Depósito legal: M. 48807-2007. El contenido de esta información refleja las conclusiones y los hallazgos propios de los autores, que no son necesariamente los de los editores, y se presenta como un servicio a la profesión médica. Reservados todos los derechos. Ninguna parte de esta publicación puede ser reproducida ni transmitida en ninguna forma o medio alguno, electrónico o mecánico, incluyendo las grabaciones en cualquier sistema de recuperación de almacenamiento de información, sin el permiso escrito del titular del copyright.


MÁS QUE MIL PALABRAS Enfermedad de Paget de la vulva de larga evolución . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Luis Chiva

BIBLIOGRAFÍA COMENTADA Raúl Márquez

Índice

Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial . . . . . . . . . . . . . . . . . . 34 Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer . . . . 35

EDITORIAL . . . . . . . . . . . . . . . . . . . . . . . . . . 3 CREANDO OPINIÓN Secondary debulking in ovarian cancer and beyond . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Christina Fotopoulou

Genetic profiling in gynecologic oncology. What can we expect? . . . . . . . . . . . . . . . . . . . . . . . 13 Gema Moreno-Bueno

Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging . . . . . . . . . . . . . . . 36 BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study . . . . . . . . . . 37

Mature data of intraperitoneal chemotherapy in ovarian cancer. Still an experimental option? . . . . . . . . . . . . . . . . . 17

Type I and II endometrial cancers: have they different risk factors? . . . . . . . . . . . . . . 38

Lisa M. Landrum

OBRAS DE REFERENCIA EN NUESTRA ESPECIALIDAD

CASOS CLÍNICOS Carcinoma borderline mucinoso de ovario con recurrencia metastásica hepática: ¿tumor ovárico o digestivo? Descripción de un caso clínico. . . . . . . . . . . . . . . . 24 Teresa Castellanos, Sonsoles Alonso

Carcinoma de ovario recurrente con sensibilidad intermedia a platino . . . . . . . . . 29 Raquel Bratos

Gynecologic Cancer Surgery . . . . . . . . . . . . . . . . . . 39 Matías Jurado

IN MEMORIAN ANTONIO LÓPEZ SALVÁ . . . . . . . . . . . . . . 40 María Herrera

AGENDA DE CONGRESOS . . . . . . . . . . . . . 42


Editorial Apreciado lector o lectora: Es para nosotros un gran placer poder volver a escribir el editorial de la Revista de Ginecología Oncológica que, tras unos meses de silencio obligado por el contexto presupuestario, vuelve a editarse y a salir a la luz con el mismo afán de siempre pero con mayor ilusión si cabe. El objetivo de Revista de Ginecología Oncológica es difundir los avances en este campo de la mano de reconocidos expertos internacionales que amablemente escriben excelentes artículos de revisión, actualizar las más recientes publicaciones a través de la sección de revisión bibliográfica, y compartir algunos casos clínicos que por la singularidad de la patología o el manejo terapéutico nos permita enriquecer nuestro conocimiento para el manejo diario de nuestras pacientes. En el número que ya tienes en tus manos podrás leer tres magníficos artículos de revisión: la Dra. Cristina Fotopoulou ha realizado una excelente, rigurosa y exhaustiva revisión sobre el papel de la cirugía en la recaída del carcinoma epitelial de ovario. A falta de evidencia procedente de los ensayos clínicos aleatorizados que están en marcha (DESSKTOP III y GOG-213), la Dra. Fotopoulou nos proporciona las claves para entender el beneficio potencial de esta intervención terapéutica y qué criterios de selección de pacientes nos pueden ayudar en nuestra práctica diaria para ofrecer este procedimiento a las pacientes que más se puedan beneficiar. Por su parte, la Dra. Gema Moreno nos ha ilustrado con el papel de la caracterización genómica en cáncer de ovario y endometrio. El tratamiento del cáncer en el presente milenio no se entiende ya sin un adecuado conocimiento de la biología de las distintas enfermedades y las alteraciones moleculares subyacentes. Gracias a este esfuerzo de caracterización, empezamos a ser capaces de identificar aquellas alteraciones moleculares realmente relevantes para la progresión tumoral y, lo más importante, que pueden ser objeto de terapias dirigidas. Finalmente, la Dra. Lisa M. Landrum nos presenta un análisis de factores pronóstico realizados en los ensayos de quimioterapia intraperitoneal GOG-114 y GOG-172. El tratamiento intraperitoneal ha demostrado un claro beneficio en supervivencia global en pacientes con cáncer de ovario en estadio III con enfermedad residual menor de 1 cm tras una citorreducción inicial. Sin embargo, su uso no se ha generalizado por la complejidad técnica y el incremento de efectos adversos asociada a esta intervención. En este trabajo, la Dra. Landrum nos proporciona información sobre el beneficio del tratamiento intraperitoneal en distintos subgrupos de pacientes que puede resultar muy útil en la información inicial que realizamos a nuestras pacientes durante el planteamiento terapéutico inicial. Esperamos que en esta nueva etapa de Revista de Ginecología Oncológica podamos alcanzar nuestro objetivo de ofrecerte de manera amena aquellos contenidos que te resulten interesantes desde el punto de vista clínico y que finalmente repercutan en un beneficio para las pacientes que serán tratadas por cáncer ginecológico. Atentamente, Dr. Luis Chiva y Dr. Antonio González-Martín


CREANDO OPINIÓN

SECONDARY DEBULKING IN OVARIAN CANCER AND BEYOND Christina Fotopoulou Department of Surgery and Cancer Ovarian Cancer Action Research Centre Imperial College London. United Kingdom

E

PITHELIAL OVARIAN CANCER (EOC) IS THE SECOND MOST COMMON GENITAL MALIGNANCY AFTER UTERINE CANCER IN WOMEN AND ACCOUNTS FOR THE MAJORITY OF DEATHS FROM GYNAECOLOGIC MALIGNANCIES IN THE WESTERN COUNTRIES.1 LIFETIME RISK IS ABOUT 1.6%; THE LATEST DATA SHOW THAT 1 IN 43 WOMEN WILL DEVELOP EOC DURING THEIR LIFETIME. WOMEN WITH A MUTATED BRCA1 OR BRCA2 GENE ARE AT INCREASED RISK RANGING BETWEEN 25% AND 60% DEPENDING ON THE SPECIFIC MUTATION.1

Despite the continuous advances in diagnostics and imaging, more than 70% of the patients with newly diagnosed EOC will present with an advanced stage FIGO III and IV. This is mainly attributed to the unusual tumour biology and clinical behavior of the disease, which is typically associated with locoregional dissemination throughout the peritoneal cavity that result to symptoms until only at a later stage in a rather unspecific symptoms pattern, including abdominal bloating and distention with pain, urinary frequency, postmenopausal bleeding, loss of appetite and occasionally rectal bleeding.2 This unusual natural history has therefore generated unique therapeutic strategies that clarify the important contribution of locoregional control to survival for this disease.

4

The last decades have brought a significant advance in the treatment of EOC, both in surgical and systemic aspects, with the development and addition to standard treatment of extensive cytoreductive techniques, refinement of surgical skills in the upper abdomen, dose dense regimes and novel targeted

therapies. Nevertheless, the survival rate of women with EOC has changed little since the revolutionary platinumbased treatment that was introduced more than 30 years ago.3,4 Only in the recent years targeted therapies based on the principle of antiangiogenesis and homologous recombination repair mechanisms have brought a significant efficacy in the treatment of EOC: bevacizumab, pazopanib and olaparib have proven in a maintenance regime during and/or after successful chemotherapy their efficacy in significantly prolonging progression free survival (PFS), but failed to significantly influence the overall survival of the patients.5 Possible mechanisms discussed for this consistent discrepancy is the high rate of cross over in the subsequent lines that impurify any survival benefit attributed to each agent. Despite all the advances brought by novel targeted agents, in advanced disease, still one of the strongest predictors of survival is the residual tumor after debulking surgery.6 Therefore maximal effort surgery aiming at maximal tumour reduction, ideally without any macroscopic tumour residual disease, followed by adjuvant systemic chemotherapy typically with paclitaxel and carboplatin constitute the currently established gold-standard in the primary management of the disease.7 The hypothesis underlying the value of surgery is mainly based on the removal of “bulks” of tumor setting so EOC more responsive to systemic chemotherapy. This enhancement of response to cytotoxic treatment may theoretically be achieved through the reduction of tumor mass critical for development of second resistance by minimising tumor areas with poor perfusion and resecting of primary resistant tumor clones. These assumed mechanisms are derived on the hypothesis that platinum-resistant clones are generated by clonal diversity from the outset of the disease and co-exist in the chemonaive state, representing hence a slowly growing chemoresistant “second disease” that eventually recurs clinically well after the dominant presenting clone has Ginecología Oncológica - N.º 6


SECONDARY DEBULKING IN OVARIAN CANCER AND BEYOND

been thoroughly controlled.7 This complex interaction of tumor biology and surgical effort could be mathematically projected as a result of tumor volume x time as source of development of chemotherapy resistance. Validated data show that in the primary presentation of the disease, for each 10% increase in cytoreduction there is a direct correlation to a 5.5% increase in median survival of those patient populations.8 Increasing surgical effort, continuous education and practice and growing expertise seem to clearly be associated with improved rates of primary cytoreduction with no increase in operative morbidity. 9-12 Despite the established value of cytoreduction in the primary setting, the value of tumour debulking surgery for recurrent EOC remains highly controversial and is one of the largest debate issues currently worldwide. While many proponents of the cytoreduction at relapse advocate that complete tumour resection may result in higher survival rates, opponents of this radical approach argue instead with high complication rates and longer hospitalization times in an anyway chronic ill and not curable patients cohort with questionable and non evidence- based surgical benefit and with complete lack of any assessment on short and long term quality of life. Many authors have attempted to define a preoperative algorithm which would identify optimal candidates for secondary cytoreduction as based on well-defined selection criteria. The scene is even more vague in the tertiary tertiary setting and beyond. In this review we will summarize current evidence for cytoreduction at EOC- relapse, discuss surgical options in the palliative setting and set the entire picture under the perspective of novel targeted therapies and the new challenges that come with it.

DEFINITION OF SURGERY IN EOC The large differences in current practice nationally and internationally are also being reflected on the discrepancy in the terminology used to adequately characterize the different types of surgery at the different stages of the disease. A clarification of the various definitions used broadly is necessary before proceeding so that the context is clear. > Explorative surgery: usually laparoscopically to assess intraperitoneal dissemination patterns; value of this in assessing operability highly questionable and not standard practice, unless to set histological diagnosis or in cases of unclear ascites with absent ovarian mass or peritoneal disease at imaging. > Primary or upfront cytoreduction: Tumor debulking at initial diagnosis before any systemic treatment, aiming at maximal tumor reduction and ideally total macroscopic tumor clearance. > Intervall debulking: Cytoreductive surgery after usually 3 cycles of neoadjuvant chemotherapy. > Second look surgery: explorative laparotomy or laparoscopy after completion of systemic treatment to confirm response; this method is obsolete, since has no evidence of survival benefit. Ginecología Oncológica - N.º 6

> Secondary surgery: Surgery due to the first relapse. Here definition unclear in regards to aim; usually used to describe cytoreductive effort but can also be used for palliative surgery due to symptoms at 1st relapse > Tertiary surgery: the equivalent of secondary surgery at the second relapse > Quaternary surgery: the equivalent of secondary surgery at the third relapse > Palliative surgery: surgery aiming at palliation of tumor induced symptoms, such as bowel obstruction, intestinal perforation, where conservative management has failed.

TUMOR DISSEMINATION PATTERNS AT RELAPSE A better understanding of the tumor dissemination patterns followed in the primary and subsequently in the recurrent situation of EOC is highly essential for the better understanding of the disease and may enhance the evolution and refinement of surgical and, by extension, systemic approach. Nevertheless, data correlating the tumor dissemination pattern and surgical outcome in primary and later recurrent situation at the same patient hardly exist. We performed for the first time a systematic analysis of a prospectively maintained database evaluating the intraoperative tumor dissemination pattern and operative outcome of all women who underwent both primary and secondary tumor debulking surgery in the same institution within a 10-year period of time.13 On the basis of 79 patients it could be demonstrated that secondary cytoreduction appears to be associated with significantly lower optimal tumor-debulking rates compared to primary debulking, mainly attributed to less “accessible” recurring patterns such as gastrointestinal serosa, radix mesenterii, gastric serosa and porta hepatis. Interestingly, no significant predictors of surgical outcome or tumor-pattern, such as peritoneal carcinomatosis, intestinal tumor involvement or positive lymph nodes could be identified between primary and relapse. It appeared that a different tumor “behavior” is followed in the primary compared to recurrent situation of the disease even at the same patient, while interestingly the primary tumor patterns do not appear to have any predictive value for the tumor patterns at recurrence, apart from the predictive value of initial tumor residuals which clearly correlate with the amount of postoperative tumor residuals at relapse. Venturing even beyond surgical borders, one could say that ovarian cancer reappears under a different dissemination profile than at its initial presentation in terms of a higher “aggressivity” and higher dissemination tendency, changing so surgical outcome and required surgical effort. Any potential attempts to derive clinical relevant conclusions on the outcome of the forthcoming cytoreduction depending on the outcome and tumor dissemination at the outset of the disease would rather fail. Therefore, novel biomarkers are warranted in order to predict tumor patterns followed at recurrence and hence surgical outcome. Elusive appears also to be the role of imaging in the characterization of peritoneal carcinosis as definite basis for indication for surgery at relapse, even though PET-CT appears

5


CREANDO OPINIÓN

to have higher accuracy indices than simple CT. Results suggest that PET/CT may prove a useful tool for pre-surgical staging of ovarian cancer with a sensitivity and specificity of 78 and 68%, respectively. In a prospective trial correlating the PET-CT results with laparoscopic findings, PET/CT showed an adequate correlation between SUVmax values and laparoscopy findings of lesions>5mm, but a high rate of false negative results in lesions<5mm such as in carcinomatosis.14 Therefore clinical decision making processes should be very carefully constructed around clinical findings and symptoms and history of the disease and not on imaging alone. Interestingly, it appears that patterns of relapse also may be altered depending to the primary mode of treatment. In a retrospective evaluation of 175 stage IIIC-IV EOC- patients who were operated in an Italian gyn cancer center with a diffuse peritoneal carcinosis, patterns of relapse were stratified according to whether the patient had upfront or interval debulking surgery at initial presentation.15 Forty patients received complete primary debulking surgery, and the remaining 135 were treated with neoadjuvant chemotherapy followed by interval debulking surgery with absent residual tumor after surgery. No differences were observed in the distribution of clinical pathological characteristics at the time of diagnosis between the two groups. In a median follow-up period of 31 months (range 9-150 months) the authors observed 20 (50.0 %) recurrences in the upfront group compared to 103 (76.3 %) in the interval debulking group (p = 0.001). Duration of primary platinum-free interval was also significantly shorter in the interval debulking arm (13 vs. 21 months, respectively; p = 0.014). A significantly higher percentage of patients in the interval debulking group experienced platinum-resistant recurrences (35.9 vs. 5.0 %; p = 0.006) and carcinomatosis at the time of relapse (57.3 vs. 20.0 %; p = 0.0021). Also the platinum free interval of second relapse was significantly longer in favor of the upfront arm (p = 0.006). This documented more “favorable behavior” of recurrent disease in EOC patients with diffuse peritoneal carcinomatosis treated with complete upfront surgical approach compared to women submitted to neoadjuvant chemotherapy need to be prospectively validated in larger datasets, is giving however a clear signal about the highly significant impact of the quality of upfront treatment even in peritoneal disseminated disease.

VALUE OF SECONDARY CYTOREDUCTION

6

There is clear evidence that patients experiencing an early platinum resistant or even refractory EOC – relapse will highly unlikely benefit from secondary debulking surgery. Already older reports could demonstrate very dismal overall survival rates of a mean value of 8 months, not adequately justifying a radical surgical approach, but rather concentrating on palliation.16,17 Anecdotal and just empirical case reports may demonstrate a survival benefit in platinum resistant patients who present with early lymph node relapse which rather represents a persistent lymph node metastasis not removed through lymph node dissection at primary surgery and hence not representing a

true relapse. However the selection of these patients is very challenging and no randomized data will ever exist for this special subgroup of women. Caution should be awarded to adequately judge and evaluate situations always taking into consideration the quality of surgery at primary or interval debulk and the tumor dissemination pattern at relapse. The first systematic data analysis for secondary debulking in a platinum sensitive setting originate from the German AGO (Arbetsgemeinschaft Gynaekologische Onkologie) within the DESKTOP I trial. This was a retrospective evaluation of 267 patients which showed that patients appeared to benefit from surgery in recurrent EOC only when total macroscopic clearance was achieved.18 Complete tumor resection was associated with significantly longer survival compared with surgery leaving any postoperative residuals (median 45.2 vs. 19.7 months; HR: 3.71; 95%CI: 2.27-6.05; P < .0001). Hence, the challenge was to accurately preoperatively identify the optimal candidates for surgery, in order to avoid surgical procedures that would not have a prognosis benefit for the patients. Therefore based on a multivariate model 3 factors were identified as being independently predicting resectability building so the so called “AGO score”: good performance status, complete resection at primary surgery and absence of ascites. The value of the AGO score lies among others also on the simplicity to use based on easy to assess clinical features and not on complicated mathematic algorithms that would make its use in the daily routine very challenging. An exploratory analysis of the DESKTOP results to evaluate the role of peritoneal carcinomatosis present in recurrent EOC clearly showed that even though peritoneal carcinomatosis was a negative predictor for complete resection in the recurrent situation of the disease, it appeared to have no negative impact on survival if total macroscopic clearance could be achieved. The authors concluded that improving surgical skills might increase the patient proportion that could benefit from surgery for recurrent disease.19 Survival curves are presented in figures 1, 2 and 3. A subsequent confirmation and validation of the AGO-score followed within the prospective, multicentre DESKTOP II trial, in which the AGO score could be confirmed as a useful and reliable tool to predict complete tumour resection in more than 2/3 of patients with platinum-sensitive relapsed EOC. Participating centers prospectively enrolled patients with platinum sensitive first or second relapse. The AGO-score was then applied to all patients, but each center was free to decide the therapeutic management. A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse received a secondary tumour debulking. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in more than 2/3 patients.20 Interestingly, the authors when correlating within this prospective design the preoperative defined number of lesions by imaging with the intraoperative number of detected lesions they only found a poor correlation of imaging and intraoperative findings both in terms of number of lesions and localization of tumor (table I). Ginecología Oncológica - N.º 6


SECONDARY DEBULKING IN OVARIAN CANCER AND BEYOND

Med. OS for TR=0 (months): 45.2 (CI 38,1 – –) Med. OS for TR=1-10 mm (months): 19.6 (CI 16,1 – 25,5) Med. Os for TR> 10 mm (months): 19.7 (CI 17,8 – 26,1)

1,0

Estimated probability

0,9 0,8 0,7

Intra-OP

0,6

Pre operative imaging

0,5 0,4

TR=1-10 mm vs. TR=0 HR: 4.17 (CI 2,42 - 7,16) Log-rank p<0.001 TR>10 mm vs. TR=0 HR: 3.31 (CI 1,86 - 5,88) Log-rank p<0.001

0,3 0,2 0,1 0 0

12

TR=0

24

TR1-10

36

48

60

Months

TR>10

Figure 1. OS according to postoperative residual disease after secondary cytoreduction: DESKTOP I. TR= tumour residual.

100

Percentage survival

Table I. Correlation of intraoperative findings with preoperative imaging

50

0 mm 1-10 mm >10 mm

25

0

10

20

30

40

50

Months 0 vs. 1-10 mm: p<0.0001; HR: 0.20 (95% CI: 0.12-0.48) 0 vs. >10 mm: p<0.0021; HR: 0.27 (95% CI: 0.14-0.64) 1-10 mm vs. >10 mm: p=0.30; HR: 1.36 (95% CI: 0.76-2.44)

Figure 2. Surgical results and survival in patients with peritoneal carcionosis: DESKTOP I.

Multivariate analysis Pre-op factor

OR

(95% CI)

p-Value

Performance status (ECOG 0 vs. >0)

2.65

(1.56 - 4.52)

<0.001

Tumour residuals at primary surgery (0 vs. >0)

2.46

(1.45 - 4.20)

<0.001

or: initial FIGO (I/II vs. III/IV)

1.87

(1.04 - 3.37)

0.036

Ascites (cut-off 500 ml)*

5.08

(1.97 - 13.16)

<0.001

OR= objetive response; ECOG= Eastern Cooperative Oncology Group; FIGO=

Figure 3. Federation DESKTOP-OVAR Predictive factors for International of GynecologyI.and Obstetrics. Harter P, et al. Ann Surg Oncol 2006; 13: 1702-10. complete tumour resection. *exclusively CA125response; (correlation with ascites) OR= objetive ECOG= Eastern Cooperative Oncology Non-significant for a complete resection: Site of relapse (pelvis vs. extra-pelvis). Group; FIGO= International Federation of Gynecology and Therapy-free interval. Obstetrics. Harter P, et al. Ann Surg Oncol 2006; 13: 1702-10.

*exclusively CA125 (correlation with ascites) Non-significant for a complete resection: Site of relapse (pelvis vs. extra-pelvis). Therapy-free interval. Ginecología Oncológica - N.º 6

4-5 lesions

>5 lesions

1 lesions

39 (60%)

6 (9%)

19 (29%)

2

12 (48%)

3 (12%)

10 (40%)

3

2 (18%)

2 (18%)

7 (64%)

<3

7 (26%)

3 (11%)

17 (63%)

Perioperative morbidity and mortality appeared to be acceptable within the DESKTOP series with a mortality as low as 0.8%, an 11% relaparotomy rate mainly due to bowel leakage or fistula (7%), a 2% DVT rate, while 52% of the patients required a postoperative intensive care of a median 2 days (range: 1-20). Morbidity and mortality data of other equivalent series are in a similar level.

Median OS (months): 0 mm: nyr 1-10 mm: 17.9

75

1-3 lesions

A subsequent multicenter randomized trial, the DESKTOP III (AGO-Ovar OP.4.) commenced in June 2010, to prospectively evaluate the impact of recurrent EOC-surgery in platinumsensitive patients with positive AGO-score (tumour free initial surgery, good performance status and ascites <500ml). At the time of writing this review (October 2013) 236 patients have been recruited and randomized with a plan to recruit 385. This very important study is anticipated to finally answer the question whether surgery at the relapse situation of the disease is truly associated with a benefit on survival and quality of life of the affected patients. Study design is presented in figure 4. The equivalent American trial from the GOG (GOG 0213) has started recruiting longer period than the DESKTOP trial, however in a slower rhythm. A further difference is the additional randomization to systemic bevacizumab 15mg/m2 at maintenance. There are future plans to combine data of both trials together to achieve a larger cohort and more robust survival data. The largest retrospective multicenter and multinational analysis worldwide showed equivalent results.21,22 Of the 1075 evaluated patients, 434 (40.4%) underwent complete resection. Total macroscopic tumor clearance was associated with a significant improvement of survival, from a median OS of 57.7 months, when compared with only 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Complete secondary cytoreduction was associated with six variables: FIGO stage (OR = 1.32, 95% CI: 0.97-1.80), residual disease after primary cytoreduction (OR = 1.69, 95% CI: 1.26-2.27), PFS (OR = 2.27, 95% CI: 1.71-3.01), Eastern Cooperative Oncology Group (ECOG) performance status (OR = 2.23, 95% CI: 1.45-3.44), CA125 (OR = 1.85, 95% CI: 1.41-2.44),

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CREANDO OPINIÓN

and ascites at recurrence (OR = 2.79, 95% CI: 1.88-4.13). These variables were entered into the risk model and assigned scores ranging from 0 to 11.9. Patients with total scores of 0-4.7 were categorized as the low-risk group, in which the proportion of complete cytoreduction was 53.4% compared with 20.1% in the high-risk group (OR = 4.55, 95% CI: 3.436.04). In external validation, the sensitivity and specificity was 83.3% and 57.6%, respectively. Area under the curve of the receiver-operating characteristics for predicting complete SCR was 0.68 (95% CI: 0.60-0.79). In one systematic metaanalysis by Bristow et.al23 where forty cohorts of 2019 patients with recurrent EOC were identified over a period of 24 years, could be clearly shown that after controlling of all other disease related factors each 10% increase in the proportion of patients undergoing complete cytoreductive surgery was associated with a 3.0 month increase in median cohort survival time. Despite the very encouraging retrospective data it is still not clear if the actual tumor resection is significantly influencing survival or if it is just a surrogate marker of more “favorable” tumor biology and therefore associated with a better overall prognosis. The first two prospectively randomized surgical trials will definitely answer this question, change clinical practice worldwide and set new evidence based standards.

VALUE OF TERTIARY CYTOREDUCTION The scenery is even more vague and undefined in the second relapse of EOC. Obtaining palliation in cases of severe tumorinduced symptoms like bowel obstruction may often be the main purpose of tertiary cytoreduction (TCS); still, the potential prolongation of survival and improvement of quality of life may also constitute relevant goals even in a tertiary setting of this chronic disease. Experiences regarding TCS were up to recently only limited in six monocentric analyses including small number of patients.24-29 All conclude mainly to the fact that TCS may indeed offer a survival benefit in a highly select

group of recurrent EOC- patients and that this benefit appears to be greatest in those patients in whom a complete gross resection can be achieved. Leitao et al.24 was the first to report on 26 patients who had undergone TCS at a single institution. Treatment-free interval before TCS and current postoperative residual disease could be identified as independent prognostic factors for survival, whereas time to first recurrence failed to retain prognostic significance in the mutlivariate analysis. Interestingly, platinum-resistance failed to be identified as being significantly associated with a more dismal outcome. No independent factors predicting optimal cytoreduction could be identified among common clinical factors such as advanced age, residual disease after initial surgery, time to first recurrence, time from second cytoreduction, platinum-sensitivity as well as size and site of tumor-recurrence. A further retrospective report by Karam et al.25 evaluating the outcome of 47 EOC-patients undergoing tertiary cytoreduction confirmed the statistically significant superior overall survival in patients with microscopic versus macroscopic residual disease (24 versus 16 months, p=0.03). After controlling these analyses for age, time to progression and optimal residual disease during TCS the authors identified only the presence of diffuse peritoneal carcinosis, at tertiary exploration as significant predictor of a worse overall survival. In a subanalysis of patients with limited disease implants, multivariate analysis could indeed indicate that total macroscopic tumor clearance at TCS retains prognostic significance of overall survival, so that the authors concluded that size of disease implants on preoperative imaging may guide the selection of ideal candidates for TCS. Regarding the assessment of potential preoperative predictors of optimal TCS, the authors could identify only tumor size (<5cm) as a statistically significant predictor of complete tumor resection at TCS. Other variables like presence of ascites, initial disease-free interval, age at TCS and limited number of disease sites on preoperative imaging (i.e.<4) could not show any significant impact. In a smaller analysis including only 20 patients26, the authors concluded to opposing results, challenging the benefit of TCS in EOC. Multivariate analysis could identify neither any significant A randomized trial evaluating cytoreductive surgery in patients with platinum-sensitive recurrent ovarian cancer

Platinum-sensitive recurrent cancer of the ovaries, fallopian tubes or peritoneum PFI >6 months since last chemotherapy that was platinum-based No prior chemotherapy for this 1st relapse Complete resection seems feasible and positive AGO score: • ECOG PS 0 • No ascites >500ml • Prior complete debulking or initial FIGO I/II Post-op standard chenotherapy planned

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R A N D O M I Z E

Cytoreductive surgery Platinum-based chemotherapy* recommended

No surgery

*Recommended platinum-based chemotherapy regimens: – Carboplatin/paclitaxel – Carboplatin/gemcitabine – Carboplatin/PEG-liposomal doxorubicin

Figure 4. AGO-OVAR DESKTOP III (Protocol AGO-OVAR OP.4) PS= performance status. Ginecología Oncológica - N.º 6


SECONDARY DEBULKING IN OVARIAN CANCER AND BEYOND

predictors for optimal cytoreduction nor any significant prognostic factors for survival. Major intrinsic pitfalls of this particular analysis are though, as emphasized by the authors themselves, the small sample of patients, rendering a multivariate analysis to have to be interpreted with caution. Furthermore, the authors defined as “optimal” cytoreduction residual disease of <2cm, and not, as universally accepted, microscopic or <0.5cm tumor residuals.

Multivariate analysis identified platinum-resistance, tumor residuals at secondary-surgery and peritoneal-carcinomatosis to be of predictive significance for complete tumor resection, while tumor residuals at secondary and tertiary surgery, decreasing interval to 2nd-relapse, ascites, upper abdominal tumor involvement and non-platinum 3rd line-chemotherapy significantly affected OS.

The largest monocentric TCS- analysis evaluated 135 patients, and identified tumor involvement of the middle abdomen and peritoneal carcinomatosis as the two only parameters negatively affecting tumor resection.28

Again here, like at secondary surgery, correct selection of surgical candidates is crucial to minimize morbidity and maximizing benefit from this radical approach in a highly palliative patients´ cohort.

Ginecología Oncológica - N.º 6

BEYOND TERTIARY CYTOREDUCTION QUATERNARY SURGERY Venturing even beyond tertiary cytoreduction, the evidence is very scarce. There are only two series internationally to systematically evaluate the results of quaternary surgery in EOC. We published the largest series of 49 recurrent EOC-patients, and demonstrated that even in a quaternary setting nearly 33% complete tumour resection rates are feasible in a highly specialized gynaecologic oncologic centre, despite the fact that the majority of the patients had peritoneal-carcinomatosis (77.6%). According to a prospectively documented intraoperative tumor mapping patients presented following tumor pattern: lower-abdomen 85.7%; middle-abdomen 79.6% and upperabdomen 42.9%. Median duration of surgery was 292 minutes and hence equivalent to the duration of primary and secondary cytoreduction. Rates of major operative morbidity and 30-days Postoperative tumour residuals after tertiary surgery

1.0

no residual 0.8

Cumulative survival

Recently, we published the largest multicentric analysis on TCS worldwide including 406 patients (median age: 55y; range: 16-80) who underwent TCS between 1997 and 2011 in 12 centers across Europe, USA and Asia.30 This represents the largest series so far in the tertiary setting of the disease and considering the fact that the conduction of any prospectively randomized trial in this advanced stage will be very challenging if not impossible, this constitutes currently the most valuable source of experience. The majority of the patients had an advanced initial FIGO-stage III/IV (69%), peritoneal-carcinomatosis (51.7%) and absence of ascites (72.2%). 224 (54.1%) patients underwent complete tumor resection. The most frequent tumor dissemination site was the pelvis (73%). We could confirm the knowledge form the previous results that even in the tertiary setting complete macroscopic tumor clearance plays a significant role both on overall and progression free survival overruling the factor peritoneal carcinomatosis which failed to retain any prognostic significance on survival after controlling for tumor residual status. Median OS for patients without versus any tumor residuals was 49 (95%CI: 42.5-56.4) versus 12 months (95%CI: 9.3-14.7) (p<0.001) (figure 5). Most importantly, common clinicopathologic characteristics such as tumor stage, age and histological subtype, which have been shown to be of significant predictive value at initial presentation of the disease, did not appear to be of any prognostic significance at the tertiary stage. We identified a significant impact of 3rd line postoperative systemic chemotherapy on overall survival emphasizing so the importance of combinative systemic and surgical treatment in the fight against EOC even in this heavily pretreated patients collective. This may nevertheless constitute a selection bias since those patients who were fit enough and able to tolerate chemotherapy following radical surgery have theoretically also more favorable survival rates than patients too weak or to tolerate any systemic treatment or even so advanced and multifocal metastasized that no chemotherapy was indicated. Rates of major operative morbidity and 30-days mortality were 25.9% and 3.2%, respectively and hence slightly higher than the equivalent data of secondary patients at the DESKTOP series, however here not only platinum-sensitive patients for cytoreduction were included but also palliative symptomatic patients who underwent surgery aiming at amelioration of symptoms. The most common complication was infection/ sepsis by 13%, a 4.4% relaparotomy rate, but interestingly without any higher rates of thromboembolic events (2.5%).

residual no residual-censored residual-censored

0.6

0.4

419 pts 0.2

0.0

0

12

24

36

48 60

72 84

96 108 120 132 144 156 168 180 192

Postoperative survival (months) p<0.001 Postoperative tumour residuals after tertiary surgery

Median OS

95% CI

None

49.0

41.5-56.4

Any

12.0

9.3-14.67

Total

26.0

19.5-32.5

Figure 5. Value of tertiary cytoreductive surgery in epithelial ovarian cancer: An international multicentre evaluation

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CREANDO OPINIÓN

mortality were 28.6% and 2%, respectively. Also here we noted highly significant differences in survival between tumor free and not tumor free patients. Mean OS for patients without any tumor residuals was 43 months (95%CI: 26.4-59.5) as opposed to only 13.4 months (95%CI: 7.42-19.4) for patients with any residual disease (p=0.001). Mean OS for patients who received postoperative chemotherapy (n=18; 36.7%) was 40.5 months (95%CI: 27.4-53.6) versus 12 months (95%CI: 5.918.18) for those who did not, also highly a significant difference, corresponding so with the results of the TCS (p<0.001). Multivariate analysis indentified multifocal tumor dissemination to be of predictive significance for incomplete tumor resection, higher operative morbidity and more dismal survival. Interestingly, otherwise established prognostic factors such as ascites, platinum-resistance, high-grade histology and advanced age appeared not to carry any significant impact on survival. The second monocentric analysis includes 15 patients and originates from the Memorial Sloan-Kettering Cancer Center.31 Their findings showed remarkable equivalence to ours: the number of sites of recurrence and optimal tumor debulking were associated with a prolonged survival, especially when a total macroscopic tumor clearance could be obtained. In context with our data they also reported that all other well established predictive factors for primary ovarian cancer and first-relapse such as time to recurrence and response to platinum failed to retain any prognostic value on survival. Still, especially in this advanced situation of the disease indication for cytoreduction aiming at a putative amelioration of survival should be done only with high caution, careful patients selection and clear discussion with the patients about the chronic and palliative situation of the disease and weighing of risks and benefits.

SALVAGE SURGERY IN ACUTE SITUATIONS: BOWEL OBSTRUCTION, INTESTINAL PERFORATION IN THE ERA OF TARGETED ANTIANGIOGENETIC AGENTS

10

EOC appears to behave differently from other epithelial cancer types, since its constant, almost pathognomonic feature is its local and lymphatic dissemination to the peritoneal and pleural layers by a paucity of visceral distant metastases via hematogeneous pathways. Loco regional peritoneal disease is what most patients die from, in terms of bowel obstruction, cachexia, hypoproteinemia from ascites, organ failure and exhaustion. Attributed to this diffuse tumor dissemination pattern along the peritoneal layers, EOC-patients often present with the clinical picture of impaired intestinal passage or even bowel obstruction in the advanced primary and especially relapsed EOC.32 The newly emerging novel implementation of targeted therapies with antiangiogenetic potential may additionally favor fistula formation or intestinal perforation.33 EOC complicated by such severe and acute events constitutes a therapeutic dilemma. Massive systemic and surgical

pretreatment, extensive tumor dissemination combined by acute systemic inflammatory immunologic response make any surgical intervention in this setting highly challenging, while associated with high morbidity and mortality rates. Appropriate balancing of risks and benefits is required to design the optimal treatment options tailored around the individual needs. The patient-communication processes are currently based on rather scattered monocentric data series; since data from large multicenter analyses are broadly lacking. Surgical interventions include various surgical techniques and strategies, such as enbloc resections of the involved intestinal package and terminal proximal ileo- or jejunostomy, since due to the severe peritoneal carcinosis and inflammation no plane dissection with anastomotic and repair techniques are feasible. Short bowel syndrome with subsequent total parenteral nutrition (TPN) is therefore in some cases inevitable and require high institutional and physical resources. In cases of acute intestinal complications such as perforation and peritonitis therapeutic approaches are rather limited. The cancer induced tissue alterations and the overall low patients reserve constitute a major challenge for both the patients themselves but also the treating physician´s so that often such acute situations provoke a therapeutic nihilism and overall hesitation of active surgical measures. Retrospective analyses have shown that patients operated in acute situations had significantly higher rates of anastomotic insufficiency compared to those operated within a planned setting33, as also that the anastomotic insufficiency rate seems to be higher at primary debulking with tumor residuals compared to those without.34 For that reasons, even though no randomized trials exist to prove the safety or not of a primary anastomosis in an acute setting with peritonitis, the high probability of an intestinal stoma should be preoperatively discussed with the affected patients. EOC rarely develops true visceral metastases; organ involvement is mainly due to direct extension by continuous tumor growth of the visceral peritoneum. Based on this, tumor resection is best achieved by an extraperitoneal approach of the tumor mass and en block dissection of all the tumor involved organs together with the adjacent peritoneum, following their dissection from the ureteric and blood vessel level in the lower abdomen, and duodenum, pancreas and billiary duct in the upper abdomen. Extensive multivisceral techniques are increasingly therefore being included in the surgical armamentarium of advanced disease management. This reflects also the optimal approach in acute situations. A simple local intestinal resection with reanastomosis or barrel loop ileostomy are often not feasible, since the combination of peritoneal carcinosis and peritonitis makes a dissection in the physiological planes impossible and of high risk of further injury. A major issue is also the highly crucial role of psychosocial and nutritional support network to provide TPN at home. Therefore multidisciplinary teams consisting of nutritional specialists, dieticians, gastroenterologists and psychooncologists are indispensable for the successful outcome of such surgeries. Ginecología Oncológica - N.º 6


SECONDARY DEBULKING IN OVARIAN CANCER AND BEYOND

FUTURE PERSPECTIVES The value of radicality in surgery in EOC is currently being challenged worldwide as a result of a combination of lack of robust prospective evidence and the feared high surgical morbidity and mortality which derives from poor surgical expertise in a very challenging surgically disease. Even though in various retrospective but also prospective series the reduction of bulk of disease was clearly associated with significantly longer survival, the factor “tumor biology” is still an uncertain factor that influences survival in pathways still not well defined. Future studies should focus in the mapping of tumor heterogeneity within the abdominal cavity and prospectively correlate phenotypic tumor dissemination patterns with surgical outcome, survival and genomic profiles. Under the perspective of not sacrificing total macroscopic tumor reduction in the landscape of poor surgical quality, efforts should be focused on training and specialization, so that surgical morbidity and mortality are minimized. However, especially in relapsed disease a reflective patients´ selection and identification should be undertaken to avoid performing unnecessary procedures to patients who will hardly benefit. The results of the currently ongoing randomized trials will elucidate this area of unmet need while future studies should focus on assessing the interaction of tumor biology and surgical effort.

REFERENCES 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA: Cancer J Clin, 2007; 57(1): 43-66. 2. Goff B. Symptoms associated with ovarian cancer. Clin Obstet Gynecol. 2012; 55(1): 36-42. 3. Vaughan S, Coward JI, Bast RC Jr, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011; 11(10): 719-25. 4. Omura G, Blessing JA, Ehrlich CE, Miller A, Yordan E, Creasman WT, et al. A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A Gynecologic Oncology Group Study. Cancer. 1986; 57: 1725-30. 5. Monk BJ, Coleman RL. Changing the paradigm in the treatment of platinum-sensitive recurrent ovarian cancer: from platinum doublets to nonplatinum doublets and adding antiangiogenesis compounds. Int J Gynecol Cancer. 2009; 19(Suppl 2): S63-7. doi: 10.1111/ IGC.0b013e3181c104fa. 6. Du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer. 2009; 115(6): 1234-44. 7. Gabra H. Back to the future: Targeting molecular changes for platinum resistance reversal. Gyn Oncol. 2010; 118: 210-1. Ginecología Oncológica - N.º 6

8. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002; 20(5): 1248-59. 9. Vernooij F, Heintz P, Witteveen E, van der Graaf Y. The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review. Gynecol Oncol. 2007; 105: 801-12. 10. Eisenkop SM, Spirtos NM, Montag TW, Nalick RH, Wang HJ. The impact of subspecialty training on the management of advanced ovarian cancer. Gynecol Oncol. 1992; 47: 203-9. 11. Paulsen T, Kjaerheim K, Kaern J, Tretli S, Tropé C. Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals. Int J Gynecol Cancer. 2006; 16(Suppl 1): 11-17. 12. Colombo PE, Mourregot A, Fabbro M, Gutowski M, SaintAubert B, Quenet F, et al. Aggressive surgical strategies in advanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients. Eur J Surg Oncol. 2009; 35(2): 135-43. 13. Braicu EI, Sehouli J, Richter R, Pietzner K, Lichtenegger W, Fotopoulou C. Primary versus secondary cytoreduction for epithelial ovarian cancer: a paired analysis of tumour pattern and surgical outcome. Eur J Cancer. 2012; 48(5): 687-94. Epub 2011 Jul 13. 14. De Iaco P, Musto A, Orazi L, Zamagni C, Rosati M, Allegri V, et al. FDG-PET/CT in advanced ovarian cancer staging: value and pitfalls in detecting lesions in different abdominal and pelvic quadrants compared with laparoscopy. Eur J Radiol. 2011; 80(2): e98-103. Epub 2010 Aug 4. 15. Petrillo M, Ferrandina G, Fagotti A, Vizzielli G, Margariti PA, Pedone AL, et al. Timing and Pattern of Recurrence in Ovarian Cancer Patients with High Tumor Dissemination Treated with Primary Debulking Surgery Versus Neoadjuvant Chemotherapy. Ann Surg Oncol. 2013 Jul 10. [Epub ahead of print] 16. Morris M, Gershenson DM, Wharton JT. Secondary cytoreductive surgery in epithelial ovarian cancer: nonresponders to first-line therapy. Gynecol Oncol. 1989; 33(1): 1-5. 17. Segna RA, Dottino PR, Mandeli JP, Konsker K, Cohen CJ. Secondary cytoreduction for ovarian cancer following cisplatin therapy. J Clin Oncol. 1993; 11(3): 434-9. 18. Harter P, du Bois A, Hahmann M, Hasenburg A, Burges A, Loibl S, et al.; Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Committee; AGO Ovarian Cancer Study Group. Surgery in recurrent ovarian cancer: the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) DESKTOP OVAR trial. Ann Surg Oncol. 2006; 13(12): 1702-10. 19. Harter P, Hahmann M, Lueck HJ, Poelcher M, Wimberger P, Ortmann O, et al. Surgery for recurrent ovarian cancer: role of peritoneal carcinomatosis: exploratory analysis of the DESKTOP I Trial about risk factors, surgical implications, and prognostic value of peritoneal carcinomatosis. Ann Surg Oncol. 2009; 16(5): 1324-30.

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20. Harter P, Sehouli J, Reuss A, Hasenburg A, Scambia G, Cibula D, et al. Prospective validation study of a predictive score for operability of recurrent ovarian cancer: the Multicenter Intergroup Study DESKTOP II. A project of the AGO Kommission OVAR, AGO Study Group, NOGGO, AGO-Austria, and MITO. Int J Gynecol Cancer. 2011; 21(2): 289-95. 21. Tian WJ, Chi DS, Sehouli J, Tropé CG, Jiang R, Ayhan A, et al. A risk model for secondary cytoreductive surgery in recurrent ovarian cancer: an evidence-based proposal for patient selection. Ann Surg Oncol. 2012; 19(2): 597-604. 22. Zang RY, Harter P, Chi DS, Sehouli J, Jiang R, Tropé CG, et al. Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort. Br J Cancer. 2011; 105(7): 890-6. Epub 2011 Aug 30. 23. Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancaer: a meta- analysis. Gynecol Oncol. 2009; 112(1): 265-74. 24. Leitao Jr MM, Kardos S, Barakat RR, Chi DS. Tertiary cytoreduction in patients with recurrent ovarian carcinoma. Gynecol Oncol. 2004; 95: 181-8. 25. Karam AK, Santillan A, Bristow RE, Giuntoli R 2nd, Gardner GJ, Cass I, et al. Tertiary cytoreductive surgery in recurrent ovarian cancer: selection criteria and survival outcome. Gynecol Oncol. 2007; 104(2): 377-80. Epub 2006 Oct 2. 26. Gultekin M, Velipaşaoğlu M, Aksan G, Dursun P, Dogan NU, Yuce K, et al. A third evaluation of tertiary cytoreduction. J Surg Oncol. 2008; 98(7): 530-4. 27. Shih KK, Chi DS, Barakat RR, Leitao Jr MM. Tertiary cytoreduction in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer: an updated series. Gynecol Oncol. 2010; 117: 330-5.

28. Hızlı D, Boran N, Yılmaz S, Turan T, Altınbaş SK, Celik B, et al. Best predictors of survival outcome after tertiary cytoreduction in patients with recurrent platinum-sensitive epithelial ovarian cancer. Eur J Obstet Gynecol Reprod Biol. 2012; 163(1): 71-5. 29. Fotopoulou C, Richter R, Braicu IE, Schmidt SC, Neuhaus P, Lichtenegger W, et al. Clinical outcome of tertiary surgical cytoreduction in patients with recurrent epithelial ovarian cancer. Ann Surg Oncol. 2011; 18: 49-57. 30. Fotopoulou C, Zang R, Gultekin M, Cibula D, Ayhan A, Liu D, et al. Value of tertiary cytoreductive surgery in epithelial ovarian cancer: an international multicenter evaluation. Ann Surg Oncol. 2013; 20(4): 1348-54 Epub 2012 Oct 2. 31. Shih KK, Chi DS, Barakat RR, Leitao MM Jr. Beyond tertiary cytoreduction in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. Gynecol Oncol. 2010; 116(3): 364-9. Epub 2009 Nov 7.) 32. Janczar S, Graham JS, Paige AJW, Gabra H. Targeting locoregional peritoneal dissemination in ovarian cancer. Expert Rev Obstet. Gynecol. 2009; 4(2): 133-147. 33. Sehouli J, Papanikolaou G, Braicu EI, Pietzner K, Neuhaus P, Fotopoulou C. Feasibility of surgery after systemic treatment with the humanized recombinant antibody bevacizumab in heavily pretreated patients with advanced epithelial ovarian cancer. Ann Surg Oncol. 2012; 19(4): 1326-33.

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Ginecología Oncológica - N.º 6


GENETIC PROFILING IN GYNECOLOGIC ONCOLOGY. WHAT CAN WE EXPECT?

GENETIC PROFILING IN GYNECOLOGIC ONCOLOGY. WHAT CAN WE EXPECT? Gema Moreno-Bueno Departamento de Bioquímica. Universidad Autónoma de Madrid (UAM) Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), IdiPAZ. Madrid Fundación MD Anderson Internacional. Madrid

O

VER THE LAST TWO DECADES, THE DEVELOPMENT OF NEW STRATEGIES IN THE TRANSLATIONAL RESEARCH FIELD HAS BEEN VAST. INITIALLY, GENE EXPRESSION ANALYSIS (TRANSCRIPTOME PROFILING) EMERGED AS A PROMISING PLATFORM WITHIN BIOMEDICAL RESEARCH. THE MICROARRAYS STUDIES ALLOWED THE SIMULTANEOUS ANALYSIS OF MESSENGER RNAs OF A LARGE NUMBER OF GENES IN RELATION TO THE EXPRESSION STATUS OF THE WHOLE GENOME1,2. MICROARRAYS WERE ONE OF THE MOST POPULAR HIGH-THROUGHPUT TECHNOLOGIES USED FOR SEVERAL YEARS-. MORE RECENTLY, AFTER OBTAINING THE WHOLE HUMAN GENOME SEQUENCE, OTHER NOVEL STRATEGIES OF MASSIVE SEQUENCING EMERGED. NEXT GENERATION SEQUENCING (NGS) ALLOWS NOT ONLY SEQUENCING OF DNA BUT ALSO mRNAS AND microRNAS. This technology has revolutionized the standard translational research. Both methods, microarrays and NGS, are complementary in several aspects. However, NGS has more resolution and allows as well the identification of new variants and/or transcripts (RNAseq), the detection of expression at the gene, exon or transcript level, and the distinction of structural variants due to alternative splicing and gene fusion. On the other hand, the best advantage of NGS is its capacity to characterize in a single analysis all types of genomic alterations (base substitutions, short insertions and deletions, fusions/translocations and copy number alterations including both homozygous deletions and amplifications)2. Ginecología Oncológica - N.º 6

Some years ago, an American Consortium of around 30 research centers including the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) constituted a massive and collaborative research project. This project, named TCGA (The Cancer Genome Project), has as its main objective classifying the genomic and genetic data for more than 20 types of tumours. All the obtained genomic results have been analysed in relation to the clinical context for each type of tumour. Importantly, all data are available for the scientific community. TCGA consortium not only includes the study of several samples from each tumour type by NGS or microarrays, but also comprises the study of other important molecular events in cancer such as promoter hypermethylation, microRNA expression and genome rearrangement. In general, all the recovered information could help characterize each type of cancer and also contribute to the appropriate selection of specific treatments. Fortunately, for the first time, the TCGA data provides the opportunity to obtain an overview of the biological and molecular profile as well as the clinical behaviour of every tumour. In fact, several studies derived from TCGA have identified a great number of potential prognosis and therapeutic markers, being this considerer as “key drivers” in specific tumorigenic settings. Likewise, it is important to mention that during the last two years these global genomic and genetic studies have been also applied to the study of tumor heterogeneity. These analyses have demonstrated the high tumor diversity not only between patients but also within tumors. The identification of molecular alterations in different tumoral lesions from the same patient can be useful to clarify the sequential molecular events during tumor progression as well as the origin of clinical recurrences. This tool has emerged as a new approach to understand the clinical pattern of a given tumor and for the selection of specific treatments during the time course of the disease in order to obtain a better evolution and clinical response1. In general, the

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Table I. Selection of the representative high-throughput studies in Ovarian (OC) and Endometrial Carcinoma (EC). PubMed Reference

Samples

Approach1 Conclusion

Ovarian carcinoma data: Ross JS, et al. Gynecol Oncol. 2013; 130: 554-9. Bashashati A et al. J Pathol 2013; 231:21-34 Huang RL, et al. Epigenetics. 2013; 8: 624-34.

48 FFPE2 NGS3,4 (22 primary tumors & 26 recurrence or metastatic ovarian samples)

Focalized study in selected genes rearranged in cancer to identify novel drug targets (e.g. MET oncogene)

6 pired samples from HGSC3

NGS

Clonal diversity in OC

75 OC & 26 NT3

NGS5

OC epigenome signature

Mosig RA, et al. J Ovarian 41 OC RNASeq6 Res. 2012;5:4.

Transcripts related to metastasis and tumor progression in OC

TCGA Research Network. 316 HGSC 3 NGS7 Nature 2011; 474: 609–615.

Identification of four novel molecular signatures in OC

Endometrial carcinoma data: TCGA Research Network, et al. Nature. 2013; 497: 67-73. Kuhn E, et al. J Natl Cancer Inst. 2012;104:1503-13.

373 EC

Microarrays/ NGS

Molecular re-classification of EC

10 paired samples NGS Alterations in TP53, cyclin E-FBXW7, (NT/ EC) and PI3K pathways involved in uterine serous carcinoma.

Krakstad C, et al. PLoS One. 67 EC, 15 Metastases Microarrays 2012; 7: e52795.

FGFR2, KRAS and PIK3CA mutations in EC as novel therapeutic strategies.

Murayama-Hosokawa S, et al. 31 EC CGH-arrays Oncogene. 2010; 29: 1897-908.

Alterations in the RAS-PI3K pathway as prognosis factor in EC

1. NGS: Next generation sequencing; RNAseq: mRNA sequencing analysis; Microarrays: Analysis of the gene expression profile; CGH-arrays: Comparative genome hybridization arrays. 2. FFPE: Formalin-Fixed, Paraffin-Embedded; NoT: normal tissue 3. HGSC: High-Grade Serous Carcinoma

improvements in the genomics and related fields have created new expectations for a flood of novel health-related applications, such as specific tests and interventions which could reduce the burden of common complex diseases as cancer. However, in spite of the genomic advances from bench to bedside nowadays there are few number of commercial genetic/genomic tests adopted in clinical practice, probably due to the need of implementing specific molecular analysis in health programs2.

14

Focusing on gynecological cancer, specifically ovarian and uterine carcinomas have been prototypes of tumors used in genomic studies included in TCGA analysis [summarized in Table I]. The analysis of other gynecological malignances such as cervical squamous cell or/and adenocarcinomas of cervix are not available yet. In ovarian and endometrial TCGA studies several research groups have identified numerous novel hypothetical molecular targets opening new avenues for their potential use as therapeutic targets to prevent tumour progression. These

recent observations provide novel insights into the relationship between alterations in gynecological cancer and their usefulness in the clinical practice. This review is a summary about the use of these new technical massive approaches, specially the data contained in the TCGA, directed to understand the molecular events during ovarian and endometrial carcinogenesis.

FROM THE GENETIC AND GENOMIC FEATURES TO THE OVARIAN CARCINOMA Ovarian cancer is the fifth most common form of cancer in women and it is the responsible for 5% of all women deaths related to cancer. The majority of ovarian cancers have an epithelial origin and these tumors are mostly diagnosed in advanced disease (where metastases are present beyond the ovaries) involving high morbidity and mortality. The standard therapy for ovarian cancer includes a combination of cytoreductive Ginecología Oncológica - N.º 6


GENETIC PROFILING IN GYNECOLOGIC ONCOLOGY. WHAT CAN WE EXPECT?

surgery with chemotherapy based on platinum and taxane compounds3. The response rate of these standard regimens is higher than 80%, however, more than 70% of patients with advanced ovarian cancer suffer recurrence within five years and eventually die due to the development of chemotherapeutic resistance. Most of these patients are treated with other agents with lower overall response rates. At a clinical and molecular level, ovarian carcinomas branch into main groups based on histological grade, molecular phenotype and general genotype3,4. Type I tumors, normally diagnosed in early disease, include serous, mucinous, endometrioid and clear-cell low grade histology. The more prevalent type II cancers are high-grade tumors and comprise serous, endometrioid and undifferentiated histologies3. One of the strong bets /of the present research in the ovarian cancer field is the understanding of the molecular biology of these groups of tumors. In this sense, ovarian cancer remains a challenging condition for both clinicians and scientists. Over the last two decades the heterogeneity of ovarian cancers among and within subtypes has been illustrated by transcriptomic and genetic profiling3. The data obtained demonstrated that ovarian cancer is a spectrum of diseases and not a single disorder entity. Indeed, many molecular signatures or specific gene variations have been identified (Table I) being nowadays not a clear translation to the clinical setting. Firstly, different studies based on the transcriptome analysis of ovarian cancer have been reported. These studies have allowed the identification of new markers which are directly or indirectly related to clinical behavior of ovarian carcinomas5. Additionally, these studies have been used in the analysis of different ovarian cancer histologies including serous, high-grade endometrioid and clear cell carcinomas as well as distinct tumoral grades. Specific molecular signatures have been found including genes associated to control of cell cycle, cell proliferation, and DNA repair. In fact, a gene signature composed by 115 genes referred as Ovarian Cancer Prognostic Profile (OCPP) (reviewed in 5). The test results signature has been considered to have an independent prognosis value in multivariate analysis even though up until now it has not been cross-validated. Lately, diverse researchers have identified mainly oncogenic activities of KRAS, BRAF, and AKT and/or silencing mutations in TP53, RB and PTEN related to ovarian cancer development. However, this information has been insufficient in terms of clinical outcome for women diagnosed with ovarian cancer4. Moreover, TCGA study provided the first large scale analysis of serous ovarian tumours (around 500 specimens). This analysis included: i) the combination of targeted sequencing of hundreds of genes with multiple high-throughput techniques, ii) the analysis of mRNA and microRNA expression and the methylation status, iii) the identification of polymorphisms, and iv) the study of genome rearrangements in practically each of the analysed samples (Table I). The obtained results indicate that the molecular alterations found in serous ovarian cancer seem to be directly related to the copy number variations, showing as well that more advanced lesions have different genetic profiles than primary tumours6. All of the studies derived from TCGA mainly identified the same molecular variaGinecologĂ­a OncolĂłgica - N.Âş 6

tions mentioned above besides other new alterations found in a few number of tumour samples. Briefly, TP53 mutations have been found in around 96% of analysed samples while BRCA1/2 mutations were identified in about 20% of samples. The rest of the significant mutated genes, including ARID1A, PIK3CA, CTTNB1 and KRAS were found in lower percentages. The problem been that this type of analysis has identified several hypothetical new markers, represented in a few number of ovarian cancers (6, Table I). Unfortunately, most of them are not currently targetable by either commercially available therapies or treatments being tested in registered clinical trials. In conclusion, this approach allows the classification of ovarian adenocarcinoma into new molecular subgroups related to the clinical data but without clear impact on prognosis. Certainly, it is very difficult to summarize the high number genes with novel molecular alterations identified as new prognosis and predictive markers involved in ovarian tumorigenesis. In addition to the common molecular alterations mentioned above, other promising variations found are: the gains in 8q, 3q, 1q, 20q and the losses in 4q, 5q, 8p, 22q, 18q, 17p chromosomal regions; and the amplification and/or over-expression of MERIT40 and ANKLE1 genes which are functionally activated during ovarian tumour development. Moreover, a novel polymorphism (rs266851) located into Kallikrein 15 (KLK15) gene has been related to ovarian cancer survival. On the other hand, loss and promoter hypermethylation have been reported in MAP2K4 gene which has been considered as a new tumour suppressor gene in both high-grade serous and endometrioid ovarian carcinoma (reviewed in Table I). The next steps in the exploitation of the data regarding the genomic of ovarian cancer is directed to obtain integration networks based on bioinformatics analysis which will be able to set nodes of genetic variants or differences in gene expression applicable to the predictive clinical outcome.

UNDERSTANDING THE GENETICS AND THE GENOMICS ENDOMETRIAL CANCER IN RELATION TO THE CLINICAL PRACTICE In the western world, endometrial cancer (EC) is the most frequent gynecological malignant tumor7. Although the prognosis is favorable for patients identified with early-stage disease, the outcome for patients with metastatic or recurrent endometrial cancer remains awful, with median survival lower than one year. Two different variants have been recognized: endometrioid carcinoma (type I) related to estrogen expression, and non-endometrioid carcinoma (type II) which is non-estrogen related. Several previous reports have shown the specific molecular alterations in each type of endometrial tumors. In EC type I is very frequent to find mutation and/or deletion of PTEN as well as mutations in FGFR2, ARID1A, CTNNB1, PIK3CA, PIK3R1 and KRAS and/or microsatellite instability (MSI). In the case of type II carcinomas, around 80% of tumors (mostly in serous histology) show inactivating mutations in TP53, aside from PIK3CA and PPP2R1A mutations and chromosomal instability7. However, some non-endometrioid carcinomas probably

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arise from pre-existing endometrioid carcinomas as a result of tumor progression and, not surprisingly, some tumors exhibit combined or mixed features at the clinical, pathological, and molecular levels. In terms of clinical outcome, normally type I tumors have more favorable prognosis compared to type II carcinomas7. Furthermore, associations with genetic mutations or different expression profile analysis of endometrial cancerrelated genes have been shown. These neither provide a complete explanation of the endometrial carcinogenesis nor the clinical behavior of patients. In addition, other molecular alterations such as silencing genes by promoter hypermethylation and different expression of specific miRNAs may underlie carcinogenesis in endometrial cancer. As shown for ovarian carcinoma, an integrative study included into TCGA project has focused on the genomic and genetic analysis of more than 370 EC8. Besides to the common molecular profiles in endometrial cancer a new molecular entity has been detected. This is related to mutations in the exonuclease gene POLE (~7% of cases) mainly in type I carcinomas. According to this study, endometrioid carcinomas showed a similar molecular profile as colorectal cancer with POLE mutations and activation of the APC/WNT/CTNNB1 signaling pathway. Serous carcinoma showed a mutational profile similar to basal-breast carcinoma as well as high-grade serous ovarian cancers. Yet, frequent mutations in FBXW7, PPP2R1A and ARID1A genes were only observed in serous endometrial tumors. In addition to TP53 mutations, these tumors have also amplification of ERBB2 and mutations in PIK3CA, among other molecular variations. This integrated analysis provides key molecular insights into tumor classification, which may have a direct effect on treatment recommendations for patients, and provide opportunities for genome-guided clinical trials and drug development. These studies go beyond the simple analysis of a number of discrete markers and are needed to understand a complex biological scenario as cancer.

APPLIED STRATEGIES: DIAGNOSIS PLATFORM During the last years and according to the knowledge collected concerning tumorigenic events, several microarray-based tests have been commercialized in relation to the diagnosis and/or prognosis of endometrial and ovarian tumors9,10. As an example, Tissue Origin Endometrial Test includes the expression analysis of 316 genes, has been used to classify ovarian and endometrial cancer9. In addition, a test for the high-risk of endometrial cancer using uterine aspirates has been commercialized10.

vel chemotherapeutic agents specifically directed. Strictly related to the progress in the analysis of more number of tumors, the powerful techniques used hold the potential to unravel the genetic origins of gynecological cancers. This could be translated in earlier diagnosis and better patient outcome. Finally, a strong interaction between clinicians and scientists is necessary to drive the correct translation of the identified markers from the lab to the clinical practice. In conclusion, the genomic and genetic approaches are required to understand the complexity of a genome-based disease like cancer. Enhanced partnerships between genetic and non-genetic providers of clinical medicine and health are needed for implementing genomic medicine applications now and should be a must in the near future

REFERENCES 1. Chibon F. Cancer gene expression signatures - the rise and fall?. Eur J Cancer. 2013; 49(8): 2000-9. 2. Idris SF, Ahmad SS, Scott MA, Vassiliou GS, Hadfield J. The role of high-throughput technologies in clinical cancer genomics. Expert Rev Mol Diagn. 2013; 13(2): 167-81. 3. Farley J, Ozbun LL, Birrer MJ. Genomic analysis of epithelial ovarian cancer. Cell Res. 2008;18(5):538-48. 4. Gurung A, Hung T, Morin J, Gilks CB. Molecular abnormalities in ovarian carcinoma: clinical, morphological and therapeutic correlates. Histopathology. 2013; 62(1): 59-70. 5. Donninger H, Bonome T, Radonovich M, Pise-Masison CA, Brady J, Shih JH, et al. Whole genome expression profiling of advance stage papillary serous ovarian cancer reveals activated pathways. Oncogene. 2004; 23(49): 8065-77. 6. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474(7353): 609-15. 7. Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology. 2013; 62(1): 111-23. doi: 10.1111/his.12053. Review. 8. The Cancer Genome Atlas Research Network Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497(7447): 67-73. 9. Lal A, Panos R, Marjanovic M, Walker M, Fuentes E, Kapp DS, et al. A gene expression profile test for the differential diagnosis of ovarian versus endometrial cancers. Oncotarget. 2012; 3(2): 212-23. 10. Colas E, Pérez C, Cabrera S, Pedrola N, Monge M, Castellvi J, et al. Molecular markers of endometrial carcinoma detected in uterine aspirates. Int J Cancer. 2011; 129(10): 2435-44.

FUTURE INSIGHTS

16

Taking into account all the data disused herein, massive genetic studies will influence treatment decisions in a near future. The approaches used in the analysis of ovarian and endometrial cancers could help us select the patients whose treatment should be based on standard regimens including common chemotherapy, and those patients that would benefit from noGinecología Oncológica - N.º 6


MATURE DATA OF INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER. STILL AN EXPERIMENTAL OPTION?

MATURE DATA OF INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER. STILL AN EXPERIMENTAL OPTION? Lisa M. Landrum Section of Gynecology Oncology University of Oklahoma Health Sciences Center. United States

E

PITHELIAL OVARIAN CARCINOMA (EOC) IS THE MOST LETHAL OF GYNECOLOGIC MALIGNANCIES WITH MOST PATIENTS PRESENTING WITH ADVANCED STAGE DISEASE. DIAGNOSES OFTEN OCCUR AT LATER STAGES DUE TO THE ABSENCE OF EFFECTIVE SCREENING METHODS AND THE INHERENT BIOLOGY OF THE TUMOR. IN THE ABSENCE OF SCREENING TOOLS, THE BEST APPROACH FOR IMPROVING CLINICAL OUTCOME IS TO OPTIMIZE MANAGEMENT AFTER DIAGNOSIS. AGGRESSIVE SURGERY, FOLLOWED BY PLATINUM AND TAXANE-BASED CHEMOTHERAPY, HAS RESULTED IN IMPROVEMENTS IN OVERALL SURVIVAL, BUT THE VAST MAJORITY OF PATIENTS WILL EXPERIENCE RECURRENCE AND ULTIMATELY DIE FROM THEIR DISEASE. Epithelial ovarian carcinoma (EOC) is the most lethal of gynecologic malignancies with most patients presenting with advanced stage disease. Diagnoses often occur at later stages due to the absence of effective screening methods and the inherent biology of the tumor. In the absence of screening tools, the best approach for improving clinical outcome is to optimize management after diagnosis. Aggressive surgery, followed by platinum and taxane-based chemotherapy, has resulted in improvements in overall survival, but the vast majority of patients will experience recurrence and ultimately die from their disease. The most promising improvements in survival in recent years have been demonstrated in clinical trials for patients treated with intraperitoneal (IP) chemotherapy. Jaaback and colleagues analyzed the results from eight randomized clinical trials for 1819 women treated with IP chemotherapy as Ginecología Oncológica - N.º 6

primary management of EOC and demonstrated improved overall and progression free survival for patients receiving IP chemotherapy (HR= 0.79; CI 0.69 - 0.90)1. These encouraging results prompted the US National Cancer Institute to release a clinical announcement on January 5, 2006 concerning the use of IP chemotherapy as adjuvant treatment for advanced ovarian cancer. The rationale for giving IP chemotherapy is that it provides a pharmacokinetic advantage over intravenous (IV) therapy in patients with minimal residual disease including the ability to infuse greater concentrations of cytotoxic agents into the peritoneal cavity than would be tolerated with systemic treatment as well as providing a longer half-life for the drugs. This allows the predominant site of tumor to have sustained exposure to antitumor agents while normal tissues, such as the bone marrow, are relatively spared2. Drugs delivered by IP route penetrate only to a depth of a few millimeters beneath the tumor surface, so patients with small volume residual disease are expected to benefit the most. It is less clear whether IP chemotherapy is of benefit to patients following suboptimal cytoreduction or disease outside of the peritoneal cavity, specifically those with retroperitoneal disease. There have been three large randomized clinical trials conducted by the Gynecology Oncology Group (GOG) which have demonstrated a clinically significant survival advantage associated with IP chemotherapy compared to intravenous (IV) chemotherapy in EOC patients following optimal cytoreductive surgery3-5. Table 1 summaries patient eligibility, treatment arms, and overall survival (OS) data from the three trials. In the most recent trial (GOG 172), Armstrong et al documented the longest median survival to date at 66 months for stage III EOC patients treated with IP chemotherapy. The improvement in median overall survival was 15.9 months favoring the IP treatment arm (HR = 0.75; CI 0.58 – 0.97). Yet, despite these marked improvements in survival, there have been challenges with toxicity. Only 42%

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Table I: Summary of Gynecologic Oncology Group randomized, clinical trials comparing intraperitoneal (IP) and intravenous (IV) chemotherapy. Clinical Trial Patient Eligibility IP Arm IV Arm IP OS IV OS P value (months) (months) Alberts, 1996 Stage III EOC (GOG 104) < 1 cm residual disease

IP cisplatin (100 mg/m2) IV cyclophosphamide (600 mg/m2)

Markman, 2001 Stage III EOC (GOG 114) < 1 cm residual disease

IV carboplatin AUC 9 Q 28 days X 2 cycles IV paclitaxel 135 mg/m2 over 24 hours IP cisplatin 75 mg/m2

IV cisplatin (75 mg/m2) IV paclitaxel (135 mg/m2)

Amrstrong, 2006 Stage III EOC (GOG 172) < 1 cm residual disease

IV paclitaxel 135 mg/m2 over 24 hours IP cisplatin 100 mg/m2 IP paclitaxel 60 mg/m2

IV cisplatin (75 mg/m2) IV paclitaxel (135 mg/m2)

of patients in the IP treatment arm of GOG 172 completed six cycles of the assigned therapy. Reasons for discontinuation included port complications, chemotherapy-related side effects, and complaints related to IP infusion such as grade 3-4 abdominal pain6. Because of the technical challenges and toxicities, widespread use of IP chemotherapy has been slow to be accepted. An ancillary data analysis was undertaken to review pooled data collected from GOG trials using IP chemotherapy and identify subsets of patients within this group that had better or worse clinical outcome measures7. It was the intention of this study to identify prognostic factors which would enable clinicians to predict which subsets of patients would be most likely to benefit from IP chemotherapy and spare those who are less likely to benefit from potential toxicity of treatment.

18

IV cisplatin 49 (100 mg/m2) IV cyclophosphamide (600 mg/m2)

41

0.02

62

53

0.05

65

49

0.03

(location and size of disease) prior to and after surgery using a tumor burden index. Tumor burden was subsequently grouped into intraperitoneal, retroperitoneal (pelvic and para-aortic lymph nodes) and extraperitoneal (brain, lung, inguinal lymph nodes, bone and parenchymal liver/spleen) disease. Finally, sites of recurrence following therapy or sites of persistent disease at second look surgery were recorded. Pearson Χ2 test was used to examine relationships between categorical variables with the Wilcoxson-Mann-Whitney test for continuous variables. Differences were considered statistically significant at P = 0.05. Kaplan-Meier survival curves were calculated and compared using log-rank test. Cox proportional hazards model was used to assess the association between prognostic variables.

RESULTS

MATERIAL AND METHODS

Patient characteristics

A retrospective review was undertaken to analyze data collected from patients with stage III EOC treated with IP platinum and paclitaxel chemotherapy on the three randomized clinical trials conducted by the GOG including protocols 104, 114, and 172. Data from GOG 104 were not included in the final analysis because data collection forms were substantially different from those used for GOG 114 and 172 and did not provide detailed description of disease sites before and after surgery. The primary end points for both studies were progression free survival (PFS), OS and disease recurrence. PFS was calculated from the date of enrollment to the date of recurrence, death, or most recent follow-up visit. OS was calculated from date of enrollment to date of death or last contact.

Data from 845 patients enrolled in the IP and IV arms of GOG114 and GOG-172 were included in the analysis. For the 428 patients randomized to IP treatment, median age was 57 years (range, 49 to 64), 91% were white, and 71% had a performance status of 0. Fifty percent of all patients had poorly differentiated tumors with only 6% of all tumors representing clear cell or mucinous histology. Eighty-three percent of patients had stage IIIC disease with 91% of patients described as having a tumor burden >5 cm prior to surgical cytoreduction. After surgery, 84% of all patients had less than 0.5 cm of residual disease, with 36% having only microscopic disease or no visible residual disease. Bowel resection was completed in 29% of patients as a component of cytoreduction. Pelvic and para-aortic lymph nodes were at least sampled in 52% and 47% of all patients, respectively. Among patient treating with IP chemotherapy, 31% of patients had evidence of nodal metastasis. Forty-one percent of patients had no lymph nodes removed at the time of initial debulking.

Clinicopathologic and surgical variables were abstracted from patient research charts. This included: the type of surgical procedures involved in initial debulking, disease characteristics

Ginecología Oncológica - N.º 6


MATURE DATA OF INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER. STILL AN EXPERIMENTAL OPTION?

Survival The median PFS for the ancillary-study IP patients was 24.9 months (95% CI, 23.0-29.2 months), with median OS at 61.8 months (95% CI, 55.5-69.8 months). In comparison, the median PFS for the 415 patients treated on IV arms of GOG 114 and 172 was 20.2 months (95% CI, 17.8 -23.5 months) with median OS at 50.9 months (95% CI, 45.5-58.6 months). The p-value for differences between the survival distributions of the IP and IV treatment groups for PFS and OS was 0.018 and 0.046, respectively, favoring IP chemotherapy. The adjusted hazard ratio for PFS and OS was 0.84 and 0.85, respectively.

Multivariate Analysis All variables with potential prognostic impact were included in a Cox proportional hazards regression model to identify inde-

pendent prognostic factors for PFS and OS. Histology, surgical stage, and extent of residual disease were identified as statistically significant variables for PFS in the final multivariate analysis. Patient age, histology, and extent of residual disease were prognostic factors for OS. Table II provides a detailed analysis of each of the prognostic factors that were evaluated. Interestingly, surgical stage was predictive of disease progression but not OS. Performance status, race, lymph node status, and tumor grade were not independently associated with clinical outcomes.

Age While not a relevant variable in the PFS model for IP patients, age is noted to be significant among predictors for OS with a HR of 1.01 (P=0.019). Hence, the risk of death increases by 1.01 times for each year a patient is older, after adjustment for the effects of the other variables in the model. Age was also

Table II: Multivariate Analysis of Prognostic Factors from IP arms of GOG 114 and 172

N Nevent

Adj. HR (PFS)

P†

N event

Adj. HR (OS)

P†

Age years

428

347

0.99 1.00 1.02

0.464

308

1.00 1.02 1.03

0.012

Race/Ethnicity White Black other

390 21 17

321 18 8

referent 0.65 1.10 1.88 0.25 0.57 1.30

— 0.720 0.182

284 17 7

referent 0.74 1.29 2.24 0.30 0.70 1.61

— 0.369 0.399

Performance status 0 1 2

302 103 23

240 86 21

referent 0.81 1.15 1.62 0.77 1.34 2.35

— 0.441 0.306

211 78 19

referent 0.76 1.10 1.59 0.88 1.61 2.92

— 0.610 0.121

Histology serous adenocarcinoma endometrioid mixed epithelial clear-cell carcinoma other

298 49 35 19 27

248 31 27 18 23

referent 0.43 0.69 1.12 0.59 0.94 1.48 1.64 2.97 5.37 0.57 0.95 1.59

— 0.131 0.788 < 0.001 0.846

217 27 26 18 20

referent — 0.46 0.77 1.28 0.310 0.59 0.94 1.50 0.795 2.27 4.20 7.74 < 0.001 0.53 0.92 1.58 0.755

Surgical stage IIIA 23 12 referent — 11 referent — IIIB 46 38 1.07 2.28 4.88 0.033 31 0.75 1.71 3.91 0.200 IIIC 336 278 0.94 2.05 4.49 0.071 251 0.90 2.04 4.65 0.089 Tumor grade 1 2 3

49 164 215

33 136 178

referent 0.69 1.11 1.78 0.66 1.04 1.65

— 0.664 0.854

27 122 159

referent 0.70 1.16 1.91 0.66 1.07 1.74

— 0.565 0.787

Lymph node status negative positive unknown

121 133 174

90 106 151

referent 0.64 0.98 1.51 0.77 1.16 1.75

— 0.941 0.484

80 91 137

referent 0.58 0.90 1.38 0.64 0.97 1.48

— 0.622 0.900

Residual disease microscopic ≤ 0.5 cm > 0.5 cm

125 172 55

81 153 51

referent 1.19 1.64 2.26 1.20 1.80 2.70

— 0.002 0.005

68 143 44

referent — 1.34 1.87 2.62 < 0.001 1.31 2.03 3.15 0.001

a b c represent the lower 95% confidence limit a, the value b, and the upper 95% confidence limit c. Ginecología Oncológica - N.º 6

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1,0

serous adenocarcinoma endometrioid adenocarcinoma mixed epithelial carcinoma clear-cell carcinoma other

0,8

0,6

0,4

0,4

0,2

0,0

0,0 50

100

150

serous adenocarcinoma endometrioid adenocarcinoma mixed epithelial carcinoma clear-cell carcinoma other

0,6

0,2

0

OS

0,8

Probability

Probability

1,0

PFS

0

50

Time (months)

100

150

Time (months)

Figure 1. Progression free and overall survival curves for patients randomized to intraperitoneal chemotherapy stratified by histology. evaluated for linearity, but found not to stray significantly from it within the model.

Histology When compared to serous histology, patients with clear cell histology were associated with decreased PFS (HR=2.66; 95% CI, 1.47-4.82; P=0.001) and OS (HR=3.88; 95% CI, 2.11-7.12; P= <0.001) (Figure 1).

Residual disease

20

Using microscopic residual disease as the referent, both PFS (HR=1.71; 95% CI, 1.26–2.32; P <0.001) and OS (HR=1.89; 95% CI, 1.37–2.62; P <0.001) were decreased for patients with ≤ 0.5 cm. Likewise, PFS (HR=1.79; 95% CI, 1.20–2.68; P=0.004) and OS (HR=1.92; 95% CI, 1.25–2.96; P=0.003) were decreased for patients with residual disease from 0.6–1.0 cm in size (Figure 2). When survival data were evaluated for each study, patients with no residual disease treating with IP chemotherapy on GOG-114 had median PFS of 41.1 months (95% CI; 24.2-54.6) and OS of 83.8 months (95% CI; 60.1161.3). IP patients on GOG 172 with no residual disease had median PFS of 60.4 months (95% CI 36.9–N/A) and OS of 127.6 months (95% CI; 84.7-N/A). Not surprisingly, patients with microscopic disease also had the best survival outcomes of all patients randomized to receive IV chemotherapy with a median PFS of 33.4 months (95% CI; 26.1-44.2) and median OS of 82.4 months (65.9-111). Patients with microscopic disease treated with IP chemotherapy had median PFS and OS of 43 and 110 months, respectively, compared to 33 and 82 months for patients receiving IV chemotherapy with no gross residual. Despite this marked differences in median PFS and OS, these measures were not statistically significant for PFS (p = 0.09) or for OS (p = 0.23).

Lymph node status For patients receiving IP chemotherapy, lymph node status was not an independent predictor of PFS or OS. However, when patients from both treatment arms were evaluated, patients receiving IV chemotherapy with unknown lymph node status had a significantly poorer outcome with a PFS of 16.3 months (95% CI, 15.4-19.9, p=0.005) and OS of 39.8 months (95% CI, 34.6-49.5, p=0.013) compared to patients with negative lymph nodes that received systemic therapy with a PFS of 28.1 months (95% CI, 22.6-33.1) and OS of 72.6 months (95% CI 53.6-91.4) (Table III).

Relapse Sites Relapse of disease in the peritoneal cavity was significantly lower for patients treated with IP chemotherapy than for patients on IV treatment arms (43% versus 56%, p <0.001). Though not statistically significant, there were more recurrences noted in extraperitoneal locations such as brain, chest, inguinal lymph nodes, and bone.

DISCUSSION This study is an ancillary data analysis of a large group of stage III EOC patients who received primary surgical cytoreduction to <1 cm followed by IP platinum and paclitaxel chemotherapy during participation in cooperative group trials. A review of the similarities and differences between the experimental (IP) and control arms (IV) of these three trials as noted in Table 1 will demonstrate that it is difficult to compare studies with different cytotoxic agents and dosing schedules. Experimental and control arms for patients treated on GOG 104 were the most similar with route of administration as the only difference, however, this study was completed prior to the use paclitaxel as a standard agent in the Ginecología Oncológica - N.º 6


MATURE DATA OF INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER. STILL AN EXPERIMENTAL OPTION?

1,0

PFS microscopic < = 0.5 cm > 0.5 cm

0,8

0,6

0,4

0,0

0,0 100

microscopic < = 0.5 cm > 0.5 cm

0,4

0,2

50

P < 0.001 110 months

0,6

0,2

0

OS

0,8

Probability

Probability

1,0

P < 0.001 43 months

150

50

0

Time (months)

100

150

Time (months)

Figure 2. Progression free (PFS) and overall survival (OS) curves for patients randomized to intraperitoneal chemotherapy stratified by residual disease following primary cytoreductive surgery. Median PFS and OS for patients with microscopic residual disease was 43 months and 110 months, respectively.

Table III: Lymph Node Status and Survival

N

Median PFS (months)

HR

P value

Median OS (months)

HR

P value

IV Lymph node Negative Positive Unknown

118 125 172

28.07 22.18 16.33

referent — 1.30 0.09 1.51 0.005

72.64 56.25 39.79

referent — 1.28 0.14 1.47 0.01

IP Lymph node Negative Positive Unknown

121 133 174

30.72 27.01 21.63

0.92 0.59 1.04 0.82 1.13 0.43

75.33 63.18 54.44

0.96 0.84 1.06 0.71 1.11 0.49

treatment of advanced ovarian cancer, and as such paclitaxel was not included in this study. Patients receiving IP chemotherapy in GOG 114 were given an additional 2 cycles of IV carboplatin at an AUC of 9 prior to starting IP treatment which may have provided a survival advantage regardless of the IP treatment. Finally, patients receiving IP chemotherapy on GOG 172 were given a higher dose of cisplatin as well as an additional dose of IP paclitaxel on day 8 which may have influenced survival. While we acknowledge these differences in the treatment arms, in the final outcome, patients treated with IP chemotherapy have improved OS compared to patients treated with IV chemotherapy alone. Despite the provocative survival measures that have been demonstrated, the widespread use of IP chemotherapy has been slow to be embraced due the technical challenges and toxicities described in GOG 172. Patients randomized to the IP group in this study reported significantly worse quality of life (QOL) prior to cycle 4 (p <0.0001) and worse QOL 3-6 weeks post-treatment (p= 0.0035)8. However, at one year following treatment, there Ginecología Oncológica - N.º 6

were no significant differences in overall QOL between patients receiving IV and IP chemotherapy. It is important to note, that significant differences did exist with respect to neurotoxicity, with IP patients reporting more neurotoxicity. Since the publication of GOG 172 in 2006, a number of strategies have been explored in an effort to minimize toxicity including aggressive supportive care with pre- and post-hydration and liberal use of new and improved anti-emetics as well as standardization of surgical technique for IP port placement9. Patient and nurse education have also been important tools in reducing complications. In addition to these changes, attention has been directed at modifying the IP regimen used in GOG 172 to preserve the survival advantage but to arrive at a treatment that is tolerable for patients to receive 6 cycles of treatment without discontinuing due to distress and toxicity. These attempts are reflected in the most recent phase III trial conducted by the GOG (GOG 252) in which the following modifications were made in an effort to improve acceptance by patients and clinicians: 1) dose of IP cisplatin was reduced to 75 mg/m2; 2) IV paclitaxel at 135 mg/m2 was given over 3 hour

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CREANDO OPINIÓN

infusion; and 3) the role of IP carboplatin was investigated. Once these data are mature we will learn more about whether dose reduction or specific platinum agent improves toxicity profiles for these patients and whether modifications to improve treatment tolerability compromise survival. Our objective for the current ancillary data analysis was to identify subsets of patients treated with IP chemotherapy that may benefit most from this modality of treatment. This information may enable clinicians to prioritize these patients while sparing the toxicity for patients less likely to benefit from IP chemotherapy. We were particularly interested in evaluating the value of IP chemotherapy for patients with retroperitoneal disease. As we began to review surgical data it became apparent that our ability to answer this question would be hindered by a surprising number of patients that did not have any surgical evaluation of pelvic or para-aortic lymph node basins. Despite the fact that all patients underwent cytoreductive surgery with <1 cm of residual tumor, only 59% of patients had lymph nodes sampled or completely excised at the time of primary surgery. Of the 254 patients that underwent lymph node evaluation, metastatic disease was identified in 52%. There were no statistically significant differences in PFS or OS for IP patients that were of node positive, node negative or node unknown status which suggests that IP chemotherapy is equally effective for patients with both intraperitoneal and retroperitoneal disease. We had hoped to further stratify patients with stage IIIC disease into those who met classification by retroperitoneal disease only, in the absence of large volume intraperitoneal disease. Unfortunately, only three patients were identified and so we were unable to adequately power survival in stage IIIC patients with peritoneal verses retroperitoneal disease. Of note, patients with unknown lymph node status that randomized to IV chemotherapy had significantly poorer median PFS (16 months) and OS (40 months) than IV patients with negative lymph nodes (28 and 72 months, respectively. The significance of this finding is unclear but does bring to question the role of lymphadenectomy in primary surgical cytoreduction. Is surgical excision of lymph nodes beneficial to survival? Was lymphadenectomy omitted secondary to some poor prognostic factor perceived by the surgeon such as patient age or performance status? Does failure to complete lymphadenectomy indicate a lack of commitment by the surgeon to definitively leave “no residual disease”? While these questions cannot be answered at this time, it is clear from the findings of this study that patients with retroperitoneal disease should not be excluded from receiving IP chemotherapy.

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A number of factors have been identified as prognostic for survival in patients with EOC including age, performance status, presence of ascites, residual disease and administration of a platinum-based agent as significant predictors of survival in patients with advanced EOC. Winter and colleagues reviewed data collected from 1,895 patients with stage III EOC who had undergone primary surgical cytoreduction followed by six cycles of IV platinum and paclitaxel chemotherapy on GOG trials10. Age, performance status, tumor histology, and residual tumor were identified as independent predictors of prognosis in patients with stage III EOC. Grade of tumor and race were not associated with clinical outcomes. In a similar fashion, we have

attempted to identify prognostic factors for survival in stage III EOC patients who underwent surgical cytoreduction followed by IP chemotherapy with cisplatin and paclitaxel. Our study revealed patient age, histology, and residual disease to be predictors for OS in stage III EOC patients treated with IP chemotherapy. Performance status, race, surgical stage and tumor grade were not independent predictors of survival. Age at the time of diagnosis for patients with EOC has been consistently recognized as an independent predictor of clinical outcome. Part of this survival difference is due to the frequency of young patients with early stage disease and tumors of low grade or low malignant potential. However, when early stage EOC and low malignant potential tumors are extracted, younger women will still have significantly better survival rates than older women with stage III and IV disease. Another reason for the discrepancy in clinical outcome may be related to performance status and co-existing medical co-morbidities in an older patient population. This undoubtedly influences the decision making process of a surgeon regarding whether to undertake an aggressive cytoreductive surgery as the primary step in treatment. In the setting of adjuvant treatment, age may also influence how aggressively a patient is managed. Clinicians may also be more accepting of challenging a younger patient with fewer co-morbid conditions to the potential toxicity of IP chemotherapy. While these ideas represent plausible reasons for the age-related differences, it must be emphasized that patient age stands as a prognostic factor for survival independent of residual disease, performance status, grade, and stage. A better understanding of the changes in tumor biology or immune response in older patients may lead to new insights into the best treatment methods for this rapidly increasing population. Most studies describing the role of histology in prognosis have focused on mucinous and clear cell tumors. Because these tumors types are less common, the studies have been retrospective and comprised of small numbers of patients. In the current study, only 6% of patients had mucinous or clear cell EOC and when stratified by histology were among the poorest performers. Patients with endometrioid and serous histology had the best prognosis of the group. This is consistent with the large data analysis published by Winter et al in which patients with mucinous and clear cell histology were associated with poorer PFS and OS compared to serous histology in patients treated with IV chemotherapy10. This is not to suggest that IP chemotherapy is contraindicated in patients with mucinous or clear cell EOC, but rather that the evidence is less supportive of a role in these rare tumor types. In counseling patients regarding a therapy with a certain degree of toxicity, this should be kept in the forefront. There is overwhelming, retrospective evidence that residual tumor following surgical cytoreduction is an independent predictor of OS for patients with EOC. Our ancillary data study provides further evidence that even within a population of patients with <1 cm of residual disease, less is more. Our analysis has shown that extent of residual disease is an independent predictor of survival whereas stage of disease is not. This suggests that efforts to reduce the tumor burden to no gross residual Ginecología Oncológica - N.º 6


MATURE DATA OF INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER. STILL AN EXPERIMENTAL OPTION?

disease may mitigate the impact of stage. This is supported by survival data from the patients with no gross residual regardless of treatment arm. For example, patients that randomized to IV chemotherapy with no gross residual also had superior survival outcomes than counterparts with small volume residual disease. It should be noted that while IP patients with no gross residual demonstrated a 28 month advantage in median OS compared to IV patients with microscopic disease (110 vs. 82 months, respectively), there were no statistically significant differences in this analysis (p = 0.23). It is likely that once we had stratified by both treatment regimen and residual disease we were not powered to definitely answer this question.

chemotherapy. It is also important to note that despite concerns regarding the effectiveness of IP chemotherapy for patients with retroperitoneal disease, no significant differences in PFS or OS were noted in patients with positive, negative, or unknown lymph node status. Therefore, retroperitoneal disease should not be a contraindication for treatment with IP chemotherapy. Finally, patterns of recurrence are altered in patients treated with IP chemotherapy in that fewer intraperitoneal relapses were identified compared to patients treating with systemic therapy.

To further highlight the value of complete surgical cytoreduction, patients treated on the IP arm of GOG 172 with no gross residual disease had survival measures that are unprecedented, with a median PFS of 60 months and OS of 128 months. Regardless of difficulties in achieving no gross residual disease through aggressive surgical cytoreduction or the challenge of managing toxicity associated with IP chemotherapy, these outcome measures exceed any previously reported in a population with advanced ovarian cancer.

1. Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev. 2006, Issue 1. (cited January 25, 2006). 2. Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Inst. 1997; 89: 480-7. 3. Alberts DS, Liu PY, Hannigan EV, O’Toole R, Williams SD, Young JA, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996; 335: 1950-5. 4. Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately highdose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001; 19: 1001-7. 5. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006; 354: 34-43. 6. Walker JL, Armstrong DK, Huang HQ, Fowler J, Webster K, Burger RA, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2006; 100: 27-32. 7. Landrum LM, Java J, Mathews CA, Lanneau GS, Copeland LJ, Armstrong DK, et al. Prognostic factors for stage III epithelial ovarian cancer treated with intraperitonal chemotherapy: a Gynecologic Oncology Group Study. Gynecol Oncol. 2013; 130: 12-8. 8. Wenzel LB, Huang HQ, Armstrong DK, Walker JL, Cella D. Health-related quality of life during and after intraperitoneal versus intravenous chemotherapy for optimally debulked ovarian cancer: A Gynecologic Oncology Group Study. J Clin Oncol. 2007; 25: 437-43. 9. Markman M, Walker JL. Intraperitoneal chemotherapy of Ovarian cancer: A review, with a focus on practical aspects of treatment. J Clin Oncol. 2006; 24: 1-7. 10. Winter WE 3rd, Maxwell GL, Tian C, Carlson JW, Ozols RF, Rose PG, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007; 25: 3621-7.

A final component of our study was to determine whether the administration of IP chemotherapy would alter the pattern of recurrence sites for patients compared to those treated with systemic chemotherapy. The primary site for relapse of disease for patients with EOC after a period of clinical remission is in the abdomen or pelvis. Interestingly, significantly fewer recurrences were noted in the intraperitoneal cavity for patients that received IP chemotherapy than for patients that received systemic therapy. The clinical significance of this is not clear at this time, but provides more information for investigators designing clinical trials in the future. This should also serve to heighten the awareness of physicians that follow this population of patients in surveillance that recurrence patterns may be altered. The most recent cooperative group trial for patients with advanced EOC may further elucidate a role for dose-dense paclitaxel in combination with IP chemotherapy. GOG 252 which has recently completed accrual included an experimental arm with IP carboplatin (AUC 6) and IV paclitaxel (80 mg/m2) on day 1, 8, and 15. Perhaps additional systemic chemotherapy given in combination with IP chemotherapy may prove to have benefit in reducing extraperitoneal recurrences. In summary, our ancillary data analysis identified several factors that are independent predictors of prognosis in stage III EOC patients treated with IP chemotherapy - age at the time of diagnosis, histology, and residual disease following surgical cytoreduction. Clinicians should be mindful that younger patients with serous or endometrioid EOC that have undergone surgical resection to no residual disease are the best candidates for IP chemotherapy. The survival measures for patients with no gross residual disease treated with IP chemotherapy are unprecedented with median OS of 110 months. These are very encouraging data and should promote further investigation of novel strategies for implementing IP chemotherapy for patients with no residual disease. We should also continue to educate patients and treating physicians in an effort to promote the use of IP Ginecología Oncológica - N.º 6

REFERENCES

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CASOS CLÍNICOS

CARCINOMA BORDERLINE MUCINOSO DE OVARIO CON RECURRENCIA METASTÁSICA HEPÁTICA: ¿TUMOR OVÁRICO O DIGESTIVO? DESCRIPCIÓN DE UN CASO CLÍNICO Teresa Castellanos Sonsoles Alonso Servicio de Ginecología Oncológica MD Anderson Cancer Center. Madrid

L

OS TUMORES MUCINOSOS DE OVARIO REPRESENTAN ENTRE EL 10 Y EL 15 % DE TODOS LOS TUMORES OVÁRICOS. DE ESTOS, SE ESTIMA QUE ENTRE UN 75 Y 80 % SON BENIGNOS Y, DEL RESTO, LA MAYORÍA, APROXIMADAMENTE EL 10 %, SON DE NATURALEZA BORDERLINE1. AUNQUE TRADICIONALMENTE SE HA ESTIMADO QUE LOS CARCINOMAS MUCINOSOS DE OVARIO SUPONÍAN EL SEGUNDO GRUPO MÁS FRECUENTE DENTRO DE LOS TUMORES MALIGNOS DE OVARIO, ACTUALMENTE SE ESTIMA QUE, SI SE EXCLUYEN LAS METÁSTASIS EN OVARIO, SOBRE TODO AQUELLAS DE ORIGEN GASTROINTESTINAL, CONSTITUYEN TAN SOLO EL 3 % DE LOS MISMOS.

Los tumores mucinosos de ovario pueden presentar dos tipos de revestimiento histológico que los divide en dos categorías: tipo intestinal (85 %), con células caliciformes que se asemejan a las de la mucosa intestinal (entre el 80-90 % se encuentran en estadio I y solo el 5 % de ellos son bilaterales) o tipo endocervical o mulleriano (15 %), con células similares a las del endocérvix2.

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El pronóstico de este tipo de tumores se encuentra en relación con el estadio al diagnóstico y la estructura histológica. La gran mayoría de tumores mucinosos tipo intestinal se diagnostican en estadios I, lo que les confiere un pronóstico excelente, con tasas de metástasis entre el 0 y el 3 % y tasas de supervivencia en tumores sin microinvasión ni carcinoma invasor del 98 % a los 5 años y del 96 % a los 10 años2.

CASO CLÍNICO Paciente de 31 años de edad, diagnosticada en otro centro de carcinoma mucinoso de ovario derecho estadio IA en mayo del año 2000 (a los 17 años). Como único antecedente familiar refiere una abuela fallecida por carcinoma de ovario sin poder especificar la edad de diagnóstico ni el tipo histológico. El tratamiento inicial es quirúrgico mediante anexectomía derecha. Durante este procedimiento no se realiza biopsia de anejo contralateral. Posteriormente, realiza 6 ciclos de quimioterapia trisemanal con paclitaxel-CBDCA (con algún retraso de los ciclos por mielotoxicidad). Finaliza el tratamiento en octubre de 2000. Durante una revisión rutinaria en 2002, se evidencia una imagen sospechosa en el ovario izquierdo por la que se programa cirugía. Antes de la fecha programada para la misma, la paciente sufre un cuadro compatible con torsión ovárica por el que es intervenida de urgencia de nuevo en otro centro. Según el informe de dicha intervención, se realiza solamente quistectomía. El estudio anatomopatológico de la pieza quirúrgica informaba de un tumor mucinoso bordeline. Posteriormente, la paciente realiza seguimiento en nuestro centro (MD Anderson Cancer Center Madrid). En noviembre de 2011, acude por un cuadro de distensión abdominal y dolor epigástrico inespecífico de dos semanas de evolución, sin alteración del hábito intestinal, ni otra sintomatología. Durante la exploración ginecológica, se palpa una tumoración de 8-9 cm en Douglas, con escasa movilidad, que en la ecografía se corresponde con una tumoración sólida dependiente de ovario izquierdo de 83 x 73 mm. Se objetiva asimismo ascitis. Ante estos hallazgos, se realiza panendoscopia con toma de biopsias, que no muestran hallazgos relevantes. Dados los antecedentes de la paciente, se solicita un estudio de extensión Ginecología Oncológica - N.º 6


CARCINOMA BORDERLINE MUCINOSO DE OVARIO CON RECURRENCIA METASTÁSICA HEPÁTICA: ¿TUMOR OVÁRICO O DIGESTIVO? DESCRIPCIÓN DE UN CASO CLÍNICO

de tomografía por emisión de positrones (PET). En dicho estudio, se describe como único hallazgo una masa pélvica de 85 x 78 x 79 mm con un SUVmáx de 6,8, y no se visualizan adenopatías patológicas.

tan hiperplasia mesotelial marcada y múltiples granulomas de células gigantes de tipo cuerpo extraño y macrófagos asociados a microcalcificaciones, sin evidencia de tumor. También se observan ganglios linfáticos libres de tumor (0/55).

Tras presentar el caso al comité de tumores ginecológicos, se decide realizar laparotomía y cirugía de citorreducción. Los hallazgos de dicha intervención fueron: ascitis abundante de aspecto mucoide (5.000 cc); tumoración anexial izquierda de 10 cm aproximadamente, que parece presentar tumor en superficie y se encuentra adherida al ligamento uterosacro izquierdo. Se extirpa dicha tumoración y se remite para estudio de anatomía intraoperatoria con resultado de sospecha de malignidad, o al menos de tumor borderline; peritoneo pélvico sospechoso de malignidad; y nódulos sospechosos en cápsula de Glisson. En la intervención se realiza:

En el estudio inmunhistoquímico, el tumor expresa CK7, CK20 y CDX2 focal. Son negativos WT1, receptores de estrógeno y progesterona; P53 (+) y Ki67 del 35 %. Las células mesoteliales en las muestras peritoneales expresan calretinina, WT1 y CK7. Los marcadores de dichas células fueron CK20 y p53 negativos.

> Histerectomía radical modificada. > Anexectomía izquierda. > Peritonectomía pélvica. > Linfadenectomía radical paraórtica hasta vasos renales. > Desperitonización parcial de la cápsula de Glisson. > Omentectomía radical. Se considera la existencia de una citorreducción óptima con residuo tumoral 0. La anatomía patológica definitiva es informada como tumor mucinoso borderline de tipo intestinal de ovario izquierdo con carcinoma intraepitelial, sin afectación de superficie ovárica. Las muestras peritoneales (incluido el peritoneo de la plica vesical y la cápsula hepática estudiados intraoperatoriamente) presen-

Se realiza estudio mutacional del gen K-RAS, con resultado de mutación en G12V exón 2. Se realiza asimismo estudio de mutación BRCA 1/2 por edad muy precoz al diagnóstico, que resulta negativa. Se continúan realizando los controles periódicos de la paciente: en julio de 2012, en una ecografía abdominal de control se descubre una imagen nodular de 18 mm en la porción más caudal del lóbulo hepático derecho, de nueva aparición, por la que se realiza una resonancia magnética (RM) hepática que es informada como sospecha de depósito secundario de 17 mm en segmento VI hepático (fig. 1). Se solicita un PET y, en él, se describe posible metástasis en región caudal del segmento VI (SUVmáx de 6,4) (figs. 2 y 3). Tras presentar de nuevo el caso en la sesión de Ginecología Oncológica, debido a la localización única y resecable, se decide realizar una nueva cirugía para la resección de la lesión descrita. Durante la intervención, se describe ausencia de ascitis, múltiples adherencias de delgado a pelvis y de hígado a diafragma y nódulos sospechosos en peritoneo mesentérico, cápsula de Glisson y en cúpula vesical. Se visualiza, así mismo, un área compatible con metástasis hepática de 2 cm, intraparenquimatosa en segmento VI hepático. Se realiza una resección del nódulo hepático sospechoso, liberación de adherencias y examen meticuloso de toda la cavidad abdominal, mediante abordaje del retroperitoneo. En el estudio en diferido de la anatomía patológica, se informa de lesión hepática compatible con metástasis hepática de adenocarcinoma mucinosa de ovario moderadamente diferenciado (estudio inmunohistoquímico superponible al del tumor previo: CK7 +; CK20 +; CEA +; Ca 19.9 + ; p53 + y Ki67 elevado; mutación K-RAS +). El resto de muestras remitidas (áreas sospechosas de adherencias) muestran fibrosis cicatricial sin evidencia de invasión neoplásica. Ante estos hallazgos, tras presentar el caso en sesión, en agosto de 2012 se comienza una nueva línea de quimioterapia con FOLFOX-6: un esquema habitualmente utilizado para los tumores de origen gastrointestinal, dadas las características inmunohistoquímicas y el comportamiento de tipo digestivo que había mostrado el tumor. La paciente finaliza el tratamiento el 20 de febrero de 2013.

Figura 1. Imágenes de RM hepática. Ginecología Oncológica - N.º 6

En julio de 2013, se realiza una tomografía computarizada (TC) toracoabdominopélvica en la que se describen varias lesiones

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en la posición 524, en el 39,08 % de las secuencias analizadas y en el gen K-RAS en el 29,61 %. Ambas mutaciones se consideran variantes con repercusión clínica. Para la mutación de K-RAS, a día de hoy existen terapias en fase clínica y/o preclínica, mientras que, para la mutación de p53, existen terapias dirigidas a la vía de señalización, en la que p53 participa, que se encuentran actualmente en estudios preclínicos. Así mismo, se detectó una mutación del gen STK11 en el 3,89 % de las secuencias analizadas: esta mutación no ha sido identificada anteriormente, aunque el estudio de predicción, utilizando diversos algoritmos (incluidos dentro del software Allamut), muestra que la variante observada podría tener un efecto deletéreo sobre la proteína. El papel funcional de esta proteína ha sido estudiado en los carcinomas colorrectales. El resultado del estudio sugiere, por tanto, que el tumor podría ser sensible a fármacos cuya diana terapéutica es SKT11, para la que a día de hoy existen terapias en fase clínica y/o preclínica.

DISCUSIÓN

Figura 2. PET-TC recidiva en segmento VI hepático. en el hígado y espacio portocava que sugieren la existencia de nuevos implantes tumorales. Se realiza nuevo PET en la que se informa de nódulo hepático hipodenso hipermetabólico de 17 x 12 mm en la región caudal del segmento VI; adyacente al espacio hepatorenal y situado craneal y medialmente a la lesión conocida y operada en el segmento VI, 3 focos hipermetabólicos en el retroperitoneo, en un espacio portococava (SUVmáx 5,7), otro izquierdo caudal a la arteria mesentérica superior (SUVmáx 4,2) y otro por detrás de la arteria renal derecha (SUVmáx 4,6): todos ellos compatibles con depósitos secundarios. Tras desestimar la cirugía, se decide llevar a cabo una nueva línea de tratamiento con folfiri-bevacizumab. Solicitamos un estudio genético de mutaciones del tumor por secuenciación masiva (AmpliSeqTM Cancer Panel). En la muestra se detecta alteración en el gen TP53 (tumor protein p53)

El resultado anatomopatológico de un tumor mucinoso de ovario supone un reto, tanto para el diagnóstico del mismo y su origen, como para el abordaje clínico y terapéutico de estos tumores. El diagnóstico histológico es tan complejo que requiere de un estudio minucioso y detallado de cada caso. En este tipo de tumores es fundamental realizar un buen muestreo histológico de la pieza, puesto que al tratarse, en la mayoría de los casos, de tumores de gran diámetro es muy frecuente que coexistan en ellos áreas de apariencia benigna, borderline, no invasivas e invasivas. Aunque los tumores borderline de ovario se distinguen de los carcinomas infiltrantes en la ausencia de invasión estromal, en ocasiones esta distinción no es fácil. La complejidad glandular inherente a este tipo de tumores dificulta en gran medida el reconocimiento de la invasión estromal, por lo que determinados carcinomas mucinosos infiltrantes pueden ser muy difíciles de diferenciar de carcinomas extensos no infiltrantes2.

Tabla I. Patrones negativos.

26

CK7 CK20 CEA CA19.9 CDX20 CA125 ER DPC4 P16

Ovario tipo intestinal

D o F

F o D

F o D

D

F

N

N

D

N

Ovario tipo mulleriano

D N N N o F N D D D N

Colorrectal

N* D D D D N N D NoF

Pancreatico

D o F

N o F

D o F

D

F

F o D

N

D o N

N

Biliar

D o F

N o F

D o F

D

F

F o D

N

D o N

N

Gástrico

D o F

N o F

D o F

D

F

N

N

D

N

Cervical

D

N o F

D o F

N

N o F

D

N o F

D

D

D: difusamente positivo; ER: receptores de estrógenos; F: focalmente positivos: HPV virus del papiloma humano; N: negativo. *Los rectales puedes ser CK7 positivos5. Ginecología Oncológica - N.º 6


CARCINOMA BORDERLINE MUCINOSO DE OVARIO CON RECURRENCIA METASTÁSICA HEPÁTICA: ¿TUMOR OVÁRICO O DIGESTIVO? DESCRIPCIÓN DE UN CASO CLÍNICO

Además, existe una variante: los tumores mucinosos borderline con carcinoma intraepitelial, como es el caso de nuestra paciente, que se refiere a aquellos tumores que no presentan invasión estromal clara, pero muestran áreas menores de 10 mm2, en las que las características citológicas de las células del tumor son claramente malignas1. En el caso de nuestra paciente, el ovario izquierdo estaba ocupado por una tumoración constituida por múltiples cavidades quísticas y estructuras papilares revestidas por el epitelio mucinoso de tipo intestinal, con áreas de pseudoestratificación nuclear, atipia ligera/moderada y presencia de ocasionales figuras de mitosis. Se observaban focos con mayor estratificación de displasia de alto grado y mayor actividad mitótica, con patrón arquitectural cribiforme, pero sin evidencia de invasión estromal. Dentro del grupo de carcinomas mucinosos podemos distinguir dos categorías. Por una parte, el carcinoma mucinoso “tipo infiltrativo”, aquel en el que distinguimos áreas de clara invasión estromal frecuentemente asociada a áreas de reacción desmoplásica estromal, de peor pronóstico. Estos son más agresivos, representando la mayoría de tumores mucinosos diagnosticados en un estadio avanzado y siendo responsables de la mayoría de las muertes. Por otra parte, el carcinoma “tipo expansivo” tiene zonas de más de 10 mm2 que presentan glándulas complejas contiguas con mínima o incluso ausencia de invasión estromal3,4. Una vez superado el reto de realizar un diagnóstico correcto del tipo de tumor al que nos enfrentamos, surge la necesidad de realizar el diagnóstico diferencial con las metástasis ováricas de otro origen. Para ello, es fundamental el haber realizado, antes de la cirugía, un correcto estudio de extensión descartando la presencia de tumor primario de otro origen. A pesar de esto, y aunque en la práctica clínica el hecho de que se trate de tumores unilaterales, de gran diámetro y confinados al ovario, orienta hacia un origen primario de ovario, los tumores bilaterales y pequeños nos hacen sospechar que se trata de metástasis de otro origen. La mayoría de tumores mucinosos son de tipo intestinal, lo que implica que el diagnóstico diferencial entre tumor primario de ovario y tumor metastásico (de origen digestivo) no siempre es fácil, siendo necesario recurrir a técnicas inmunohistoquímicas y de biología molecular para un correcto diagnóstico diferencial.

la mayoría de los casos de tumores mucinosos de ovario, esta expresión suele ser focal. En cuanto a la expresión de CDX2, en los tumores de ovario es focal mientras que en los tumores colorrectales suele ser positiva (no es así en los tumores gastrobiliopancreáticos, que habitualmente muestran expresión focal) (figs. 3, 4 y 5). En cuanto a las anomalías moleculares, estudios recientes han demostrado que una no desdeñable proporción de carcinomas mucinosos primarios de ovario sobrexpresan HER26. Basándose en esto, se están realizando estudios con trastuzumab en pacientes con carcinomas mucinosos de ovario recurrente para evaluar el papel de esta línea terapéutica. Así mismo, la mutación de K-RAS es frecuente en la mayoría de los tumores mucinosos de ovario, al igual que en gran parte de los de origen gastrointestinal2,5,6. En cuanto al pronóstico de los tumores mucinosos (ya sean borderline, carcinomas no invasivos, microinvasivos o carci-

Figura 3. CK 7 positivo.

Además, el comportamiento más agresivo y la mala respuesta a los tratamientos convencionales del cáncer de ovario nos deben hacer pensar que el origen del tumor puede ser primario de otra localización diferente al ovario. En la tabla I se detallan los patrones inmunohistoquímicos de los diferentes tipos de tumor mucinoso según el órgano del que proceden. En más del 80 % de los casos de los tumores de ovario primarios, encontramos positividad para CK7, mientras que en los tumores colorrectales habitualmente son CK7 negativos, excepto los carcinomas rectales que pueden ser CK7+. Los tumores digestivos expresan CK 20 de forma difusa, mientras que en Ginecología Oncológica - N.º 6

27 Figura 4. CD 20 positivo.


CASOS CLÍNICOS

nomas invasivos con patrón de crecimiento expansivo), en la mayoría de los casos suele ser excelente con unas tasas de supervivencia a los 5 y 10 años, que superan a las de otros tipos de carcinoma epitelial de ovario como el seroso2. Sin embargo, ante el diagnóstico de carcinoma mucinoso de ovario, conviene no olvidar que existen determinados subtipos de tumor, como es el caso de la paciente presentada, cuya evolución es mucho más agresiva, con desarrollo de metástasis a distancia y, por tanto, un pronóstico nefasto. En estos casos, desgraciadamente, los tumores mucinosos no suelen responder a los esquemas de quimioterapia convencional en cáncer de ovario (carboplatino-taxano) y tanto los tiempos de supervivencia global como supervivencia libre de progresión, suelen verse acortados si los comparamos con otros tipos de carcinoma epitelial de ovario. Por ello, y dado que la gran mayoría de carcinomas de ovario mucinoso presenta diferenciación gastrointestinal (85 %), y por tanto un comportamiento similar a los tumores del tracto digestivo, debemos plantearnos el tratamiento quimioterápico con agentes utilizados en esta línea como 5-fluorouracilo y oxaliplatino (FOLFOX) o esquema basado en irinotecán (FOLFIRI).

Figura 5. CK 7 positivo.

BIBLIOGRAFÍA 1. Prat J. New Insights in to ovarian cancer pathology. Symposium article. Ann Oncol. 2012 Sep; 23(Suppl 10): X111-7. 2. Hart WR. Mucinous Tumours of the ovary: A Review. Int J Gynecol Pathol. 2005; 24 (1): 4-25. 3. Rodríguez IM, Prat J. Mucinous tumors of the ovary. A clinicopathologic analysis of 75 borderline tumors (of intestinal type) and carcinomas. Am J Surg Pathol. 2002; 26: 139-52. 4. Lee KR, Scully RE. Mucinous tumors of the ovary. A clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with “pseudomyxomaperitonei”. Am J Surg Pathol. 2000; 24: 1447-64. 5. Mc Cluggage WG. Immunohistochemistry in the distinction between primary and metastático ovarian mucinous neoplasms. J Clin Pathol 2012;65:596-600. 6. Sholi A, Martino MM, Pirigyi M, Rosenblum NG, Markman M, Peterson CS, Bradbury AR, Morris GJ. Mucinous adenocarcinoma of the ovary. Semin Oncol 2010; 37 (4): 314-20.

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Ginecología Oncológica - N.º 6


CARCINOMA DE OVARIO RECURRENTE CON SENSIBILIDAD INTERMEDIA A PLATINO

CARCINOMA DE OVARIO RECURRENTE CON SENSIBILIDAD INTERMEDIA A PLATINO Raquel Bratos Servicio de Oncología Médica. Unidad Ginecología Oncológica Hospital MD Anderson Cancer Center. Madrid

A

PESAR DEL MANEJO ÓPTIMO INICIAL DEL CÁNCER DE OVARIO AVANZADO (CITORREDUCCIÓN DE MÁXIMO ESFUERZO Y TRATAMIENTO SISTÉMICO BASADO EN CARBOPLATINO-PACLITAXEL), LA MAYORÍA DE LAS PACIENTES RECAERÁN Y MORIRÁN COMO CONSECUENCIA DE ESTA RECIDIVA TUMORAL. El manejo terapéutico en el cáncer de ovario recurrente no es estándar y se ha basado tradicionalmente en el intervalo libre de platino (ILP: inferior o superior a 6 meses), constituyendo este el factor predictor de sensibilidad a retratamiento con platino más importante. Otros factores igual de importantes a la hora de seleccionar el régimen terapéutico en segunda línea son la conveniencia del régimen, la toxicidad previa, el perfil de tolerabilidad y la calidad de vida. Aunque una combinación que incluya platino es el esquema terapéutico habitual en recaída platino-sensible (ILP > 6 meses), un doblete que no contenga platino como trabectedinadoxorrubicina liposómica pegilada debe ser considerado como opción de tratamiento en pacientes con cáncer de ovario tras fallo a régimen basado en platino, particularmente en aquéllas con ILP entre 6 y 12 meses1.

DESCRIPCIÓN DEL CASO Antecedentes clínico-patológicos La paciente tiene 66 años y diabetes mellitus controlada con antidiabético oral (metformina cada 24 horas). Ginecología Oncológica - N.º 6

En cuanto a sus antecedentes ginecorreproductivos, refirió dos partos eutócicos, siendo el primero a los 30 años y la menopausia a los 48 años. Entre sus antecedentes familiares, su madre había fallecido por carcinoma vesical.

Debut oncológico, citorreducción y tratamiento de primera línea La paciente fue diagnosticada en enero de 2011 a raíz de cuadro de distensión abdominal, plenitud posprandial, astenia y tos seca de semanas de evolución, de carcinomatosis peritoneal asociada a derrame pleural. Se realizaron las siguientes pruebas complementarias: > Analítica con marcadores: destacaba Ca 125 = 3438 UI/ml. > Exploración física: hipofonesis de hemitórax inferior derecho. > Tomografía computarizada (TC) toracoabdominopélvica: derrame pleural derecho. Ascitis. Engrosamiento difuso peritoneal. > Colonoscopia y gastroscopia: compatibles con normalidad. > Citología de líquido ascítico: sospechosa para malignidad. > Tomografía por emisión de positrones (PET): carcinomatosis peritoneal e implante en región recto sigmoidea. Con la sospecha de carcinomatosis peritoneal primaria con derrame pleural asociado, la paciente fue sometida el 31-1-2011 a tratamiento quirúrgico citorreductor primario. Se halló carcinomatosis peritoneal con afectación omental, afectación de peritoneo diafragmático y pleural (afectación miliar): pelvis congelada con afectación del recto-sigma sin adenopatías patológicas aparentes.

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CASOS CLÍNICOS

Se realizó exenteración posterior (con resección en bloque del tumor, histerectomía radical, resección del recto-sigma y peritonectomía pélvica), omentectomía radical, apertura-drenaje del derrame pleural, drenaje de ascitis, apendicectomía, exploración retroperitoneal, anastomosis colorrectal y resección de nódulos aislados en mesoíleon. La anatomía patológica informó de una extensa infiltración por adenocarcinoma seroso de alto grado en la pieza de exenteración posterior, ligamento redondo, omentectomía, apendicectomía y en múltiples biopsias peritoneales, con ovarios de aspecto involutivo, compatible con carcinomatosis peritoneal serosa primaria de alto grado con invasión vasculolinfática y el siguiente perfil de inmunohistoquimia: WT1+, p53+, Ki 67 elevado, RE < 5 % y RP-. Posteriormente, la paciente recibió terapia complementaria en el seno de un ensayo clínico en que se aleatorizaba a paclitaxel-carboplatino en pauta estándar trisemanal asociado o no al fármaco antiangiogénico nintedanib (BIBF 1120) entre el 232-2011 y el 9-6-2011 con buena tolerancia clínica. Mantuvo, posteriormente, el fármaco experimental o el placebo hasta febrero de 2012.

A

B

Figura 1. A. Adenopatía axilar, retropectoral derecha. B. Adenopatía en crura diafragmática (febrero de 2012). C. Corte coronal que muestra la topografía e intensidad de la enfermedad en febrero de 2012 (se aprecian implantes peritoneales). Evolución de Ca 125

Tratamiento de segunda línea

Con estos datos, se ofreció una segunda línea basada en trabectedina-doxorrubicina liposómica pegilada basándose en el intervalo libre de platino de 8 meses. El marcador Ca 125 ascendió en este momento a 189 UI/ml. La paciente recibió seis ciclos entre el 22-2-2012 y el 19-6-2012. Como efectos secundarios asociados, presentó astenia grado 1 que se incrementó a grado 3 tras el 5.º ciclo, mucositis grado 1 y neutropenia asintomática que requirió algún retraso terapéutico. La evolución del marcador Ca 125 se muestra en la figura 2. La PET de control mostró una excelente respuesta clínica con respuesta metabólica parcial en todos los territorios (fig. 3). Se decidió mantener la trabectedina en monoterapia con buena tolerancia hasta octubre de 2012, en que se mostró progresión bioquímica (Ca 125:489 UI/ml) y radiológica (axilar, pélvica y ganglionar retroperitoneal).

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Tratamiento de tercera y posteriores líneas terapéuticas En octubre de 2012, se inició una tercera línea con esquema carboplatino-gemcitabina-bevacizumab con excelente respues-

200 150

(UI/ml)

En este momento (febrero de 2012), se evidenció una recidiva a nivel peritoneal (región perihepática subfrénica anterior izquierda, gotiera parietocólica derecha, mesenterio e ileocecal) y adenopático supra e infradiafragmático (axilar/retropectoral derecho, gastrohepático, crura diafragmática e hiato aórtico) (fig. 1).

C

100 50 0 feb-12

mar-12

abr-12

may-12

jun-12

jul-12

ago-12

sep-12

Mes/ciclo

Figura 2. Evolución de marcador Ca 125 con tratamiento de trabectedina-DLP. ta tras 3 y 6 ciclos, continuando con terapia biológica hasta abril de 2013, en que se evidenció progresión a nivel pleural, peritoneal, perirrectal y adenopática retroperitoneal, iniciando una cuarta línea con paclitaxel semanal-bevacizumab que mantiene.

DISCUSIÓN El cáncer de ovario representa el 6 % de las muertes por cáncer en la mujer, situándolo en el cuarto tumor más letal en la población femenina (y el más letal de los tumores ginecológicos en población occidental). Hasta el 75 % de los casos son diagnosticados en etapas avanzadas, constituyendo el estado el factor más determinante en la alta tasa de mortalidad. La terapia estándar habitual en cáncer de ovario avanzado consiste en una cirugía citorreductora de máximo esfuerzo seguido de tratamiento sistémico basado en paclitaxel y carboplatino. Sin embargo, la mayoría de paGinecología Oncológica - N.º 6


CARCINOMA DE OVARIO RECURRENTE CON SENSIBILIDAD INTERMEDIA A PLATINO

A

C

primera línea con platino), existe una alta probabilidad de responder a tratamiento con platino (siendo mayor, cuanto más prolongado sea este intervalo libre de platino). En estos casos, hemos de considerar un doblete con platino (sobre todo si el ILP es superior a 12 meses); sin embargo, se dispone de combinaciones no basadas en platino que han demostrado beneficio en población platino-sensible. El estudio fase III OVA 301 se diseñó para mostrar beneficio en pacientes con recidiva de cáncer de ovario de una combinación de fármacos no basados en platino (trabectedina-DLP/ doxorrubicina liposómica pegilada) frente a DLP en monoterapia tras una primera línea que hubiera contenido platino.

B

Aproximadamente, un tercio de pacientes fueron asignadas a cada grupo determinado por el ILP (platinorresistente, parcialmente sensible a platino y platino sensibles). Figura 3. A. Adenopatía axilar tras tratamiento. B. Adenopatía crural tras 6 ciclos de tratamiento. C. Corte coronal de revaluación en junio de 2012 con menor metabolismo. cientes recaerán y fallecerán por progresión de enfermedad, puesto que, habitualmente, la recidiva del cáncer de ovario es incurable y la intención del tratamiento es mantener la calidad de vida el máximo tiempo posible2. No existe estandarización en el tratamiento de segunda línea y, salvo excepciones en que se considera la citorreducción secundaria, consistirá en quimioterapia. A la hora de seleccionar el esquema de quimioterapia más idóneo, hemos de considerar factores dependientes de la paciente y del tratamiento (tabla I). El principal factor predictor de respuesta a retratamiento con platino es el intervalo libre de platino. A mayor intervalo, mayor probabilidad de sensibilidad a platino, que se traduce en beneficio clínico. Así, en pacientes con recaída platinosensible (pacientes con respuesta y recaída tras 6 meses de finalizar el tratamiento de

Tabla I. Factores a considerar en la elección de segunda línea de cáncer de ovario Dependientes de la paciente: - Toxicidad desarrollada con tratamientos previos - Preferencia de la paciente - Comorbilidad y situación clínica de la paciente Dependientes del tratamiento: - Tiempo transcurrido y respuesta obtenida a la terapia de primera línea (intervalo libre de platino) - Actividad y perfil de efectos secundarios de las terapias disponibles - Posología y coste Ginecología Oncológica - N.º 6

Se consiguió el objetivo primario con diferencias estadísticamente significativas (supervivencia libre de progresión) con un HR: 0,79 (IC 95 %: 0,65-0,96), p = 0,0190. Este dato se tradujo en una mediana de SLP de 7,3 meses en el grupo de combinación frente a 5,8 meses en el grupo de monoterapia. Al analizar por subgrupos, las pacientes platinorresistentes no obtuvieron beneficio alguno, concentrándose la reducción del riesgo de progresión de enfermedad en las pacientes con ILP superior a 6 meses. HR: 0,73 (IC 95%: 0,56-0,95), p = 0,0170. La toxicidad de este régimen en combinación es manejable y predecible, presentando como principales efectos secundarios la neutropenia G3-4 y elevación de transaminasas (ALT) G3-4, que son reversibles y no acumulativas3. En el subanálisis realizado en las pacientes parcialmente sensibles (ILP de 6-12 meses); aquéllas tratadas con la combinación presentaron una reducción del riesgo de progresión o muerte del 35 %. HR: 0,65 (IC 95 %: 0,45-0,92), p = 0,0152. Con una supervivencia libre de progresión (SLP) de 7,4 meses en el grupo de trabectedina-doxorrubicina liposomal pegilada frente 5,5 meses en el grupo de monoterapia. Asimismo, en un análisis intermedio, en pacientes con ILP entre 6-12 meses, tratadas con la combinación, se mostró un incremento en supervivencia global estadísticamente significativo respecto a las que recibieron DLP en monoterapia. HR: 0,59 (IC 95 %: 0,42-0,82), p = 0,0015 que se tradujo en un incremento de 6 meses de supervivencia global (23 meses frente 17,1)4. Otro análisis exploratorio en el grupo parcialmente sensible a platino demostró que el intervalo hasta el siguiente tratamiento con platino (tercera línea) en pacientes tratadas con la combinación era 4 meses superior (7,5 meses en el grupo de monoterapia frente 11,5 meses en el brazo de combinación). HR: 0,61 (IC 95 % 0,40- 0,93); p = 0,0203. Así mismo, en este grupo de sensibilidad intermedia, la supervivencia global desde la reintroducción del platino como

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CASOS CLÍNICOS

primera terapia, tras el fracaso en el ensayo OVA 301, también fue mayor en las pacientes que habían recibido la doble terapia que en las que habían recibido solo DLP (9,9 meses en el grupo de DLP y 18,6 meses en el grupo de combinación). HR: 0,54 (IC 95% 0,32- 0,90); p = 0,01695. Tras una mediana de seguimiento de 47,4 meses y con 522 muertes acontecidas se analizó la supervivencia global. La mediana de SG fue de 22,2 y 18,9 meses para los grupos de trabectedina-DLP y DLP, respectivamente. HR: 0,86 (IC 95 % 0,72- 1,02); p = 0,0835. Este hallazgo no significativo estadísticamente se ha explicado por un desequilibrio en el ILP favoreciendo al grupo de monoterapia. Ante tales hallazgos, tras ajustar por factores pronóstico en un análisis no planificado, sí se mostró beneficio en SG a favor del grupo de la combinación: HR: 0,82 (IC 95 % 0,69-0,98); p = 0,0285. Al considerar por ILP, en el grupo de pacientes correspondientes a sensibilidad parcial, se detectó el mayor beneficio en SG, traduciéndose en una mediana de SG de 22,4 meses en el grupo de trabectedina-DLP y 16,4 meses en el brazo de DLP: HR: 0,64 (IC 95 % 0,47-0,86); p = 0,00276. Estos análisis sugieren que el beneficio detectado en pacientes parcialmente sensibles al platino con el esquema trabectedinaDLP podría ser debido a una extensión del ILP.

BIBLIOGRAFÍA 1. Sehouli J, Alfaro V, González-Martín A. Trabectedin plus pegylated liposomal doxorubicin in the treatment of patients with partially platinum-sensitive ovarian cancer :current evidence and future perspectivas. Ann Oncol. 2012; 23: 556-62. 2. Markman M. Optimal Management of recurrent ovarian cancer. Int J Gynecol Cancer. 2009; 19: 40-3. 3. Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol. 2010; 28: 3107-14. 4. Poveda A, Vergote I, Tjulandin S, Kong B, Roy M, Chan S, et al.Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinumsensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol. 2011; 22: 39-48. 5. Kaye SB, Colombo N, Monk BJ, Tjulandin S, Kong B, Roy M, et al. Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval. Ann Oncol. 2011; 22: 49-58. 6. Monk BJ, Herzog TJ, Kaye SB, Krasner CN, Vermorken JB, Muggia FM, et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis. Eur J Cancer. 2012; 48: 2361-8.

Una hipótesis que se plantea es la reversión de una potencial resistencia al platino, aumentando la sensibilidad a este fármaco en un tratamiento posterior que se traduce en beneficio en supervivencia global. Esta hipótesis está pendiente de evaluación en el ensayo en marcha (INOVATYON–INternational OVArian cancer patients Treated with YONdelis) en el que se compara DLP-trabectedina vs. DLP-carboplatino/CBDCA en pacientes con ILP comprendido entre 6 y 12 meses, y cuyo objetivo principal es la supervivencia global. Los pacientes de la rama de DLP-trabectedina deben recibir obligatoriamente un platino en el momento de la progresión.

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Ginecología Oncológica - N.º 6


MÁS QUE MIL PALABRAS

ENFERMEDAD DE PAGET DE LA VULVA DE LARGA EVOLUCIÓN Luis Chiva Departamento de Ginecología Oncológica MD Anderson Cancer Center. Madrid

LA IMAGEN QUE PRESENTAMOS PERTENECE A UNA PACIENTE DE 79 AÑOS DE EDAD QUE HABÍA SIDO DIAGNOSTICADA 10 AÑOS ANTES DE UNA ENFERMEDAD DE PAGET DE LA VULVA SIN INVASIÓN ASOCIADA. INICIALMENTE, EMPEZÓ A SENTIR UN PRURITO LEVE PERO, SEGÚN LA ENFERMEDAD FUE EVOLUCIONANDO, LA DOLENCIA EMPEZÓ A SER REALMENTE MOLESTA. TRAS 5 AÑOS DE EVOLUCIÓN, LA PACIENTE ACUDIÓ A LA CONSULTA DE OTRO CENTRO DONDE SE CONSIDERÓ QUE LA ENFERMEDAD REQUERÍA DE UNA CIRUGÍA EXCESIVAMENTE AGRESIVA PARA SU EDAD, POR LO QUE FUE TRATADA EN EXCLUSIVA CON RADIOTERAPIA EXTERNA. Cuando finalmente vino a nuestro centro, la enfermedad era muy sintomática: dificultaba la vida cotidiana, impedía la sedestación y obligaba a la toma de mórficos. Por lo demás, la paciente presentaba un buen estado general. Tras una valoración global de la enfermedad, descubrimos que se había convertido en un tumor invasivo en varias zonas, ocluía completamente la vagina y se acompañaba de enfermedad peritoneal vesicouterina. No se apreciaban metástasis a distancia. Curiosamente, toda la enfermedad vulvar seguía siendo intraepitelial. Tras múltiples deliberaciones, decidimos llevar a cabo con carácter paliativo una exenteración anterior elevadora más vulvectomía radical, que fue reconstruida mediante un derivación urinaria de Bricker y una colgajo musculo cutáneo de recto anterior izquierdo del abdomen. La paciente tuvo un posoperatorio sin complicaciones severas y fue dada de alta con escasa cantidad de analgésicos. Desafortunadamente falleció unas semanas después en su domicilio como consecuencia de una infección urinaria que paso asintomática y se tornó rápidamente séptica. Definitivamente, son pocas las ocasiones en que un ginecólogo oncólogo tiene que enfrentarse a una situación tan compleja como infrecuente. Ginecología Oncológica - N.º 6

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BIBLIOGRAFÍA COMENTADA Raúl Márquez Servicio de Oncología Médica MD Anderson Cancer Center. Madrid

Long-term results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled, open-label trial Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, Aoki D, Jobo T, Kodama S, Terauchi F,Sugiyama T, Ochiai K; Japanese Gynecologic Oncology Group. Lancet Oncol. 2013; 14(10): 1020-6. doi: 10.1016/S1470-2045(13)70363-2. Epub 2013 Aug 13.

BACKGROUND: The primary analysis of the JGOG 3016 trial showed that a dose-dense paclitaxel and carboplatin regimen significantly improves progression-free and overall survival compared with the conventional regimen as first-line chemotherapy for patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. We report the long-term follow-up results for survival. METHODS: This randomised controlled trial was done at 85 centres in Japan. Patients with stage II-IV ovarian cancer were randomly assigned to receive conventional treatment (carboplatin area under the curve [AUC] 6 mg/mL per min and paclitaxel 180 mg/m(2) on day 1) or dose-dense treatment (carboplatin AUC 6 mg/mL per min on day 1 and paclitaxel 80 mg/m(2) on days 1, 8, and 15). The treatments were repeated every 3 weeks for six cycles; responding patients had three additional cycles. The randomisation was done centrally by telephone or fax, stratified by residual disease, stage, and histological type. The primary endpoint was progression-free survival; overall survival was a secondary endpoint. Long-term information on adverse events was not collected. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00226915. FINDINGS: 637 patients were enrolled, of whom 631 were analysed (312 assigned to the dose-dense regimen, 319 to the conventional regimen). Median follow-up was 76·8 months (IQR 68·9-85·6). Median progression-free survival was significantly longer in the dose-dense treatment group than in the conventional treatment group (28·2 months [95% CI 22·3-33·8] vs 17·5 months [15·7-21·7]; hazard ratio [HR] 0·76, 95% CI 0·62-0·91; p=0·0037). Median overall survival was 100·5 months (95% CI 65·2-∞) in the dose-dense treatment group and 62·2 months (52·1-82·6) in the conventional treatment group (HR 0·79, 95% CI 0·63-0·99; p=0·039). INTERPRETATION: Dose-dense treatment offers better survival than conventional treatment and is a potential new standard of care for first-line chemotherapy for patients with advanced epithelial ovarian cancer.

COMENTARIO. La combinación de paclitaxel y carboplatino de forma trisemanal se considera el régimen estándar de quimioterapia de primera línea para el tratamiento del cáncer de ovario. Otras opciones recomendadas implican la quimioterapia intraperitoneal (para pacientes con residuo tumoral menor de 1 cm), así como las dosis densas de paclitaxel semanal en combinación con carboplatino trisemanal. Estas últimas recomendaciones se basaron en los resultados del estudio JGOG 3016, en el que el Grupo Oncológico Ginecológico Japonés demostró que existía una mejora significativa de la supervivencia libre de progresión (PFS) en los pacientes con dosis densas de paclitxel y carboplatino (28 meses), comparado con aquéllos de la rama convencional cada 3 semanas (17,2 meses), como primera línea para cáncer epitelial de ovario, trompa o peritoneal primerio estadios II-IV (HR 0,71 95 % IC 0,58-0,88, p = 0,0015). De esta forma, la pauta de dosis densas prolongaban la PFS en 11 meses en el análisis primario, con una mediana de seguimiento de 29 meses. En este artículo se ponen de manifiesto los resultados a largo plazo.

34

El ensayo se realizó en 85 centros japoneses. Se aleatorizó a recibir el tratamiento convencional (carboplatino AUC 6 y paclitaxel 180 mg/m2), o las dosis densas (carboplatino AUC 6 y paclitxel 80 mg/m2 días 1,8,15). Los ciclos se repetían cada 3 semanas, por una duración de 6 ciclos (los pacientes respondedores podían recibir otros 3 ciclos extras). Se estratificó por enfermedad residual, estado y subtipo histológico. Destaca

que el objetivo primario era la PFS, y secundario la OS. De esta forma, se extrajeron datos de 631 pacientes (312 en la rama densa y 319 en la convencional). La mediana de OS fue de 100,5 meses con paclitaxel a dosis densas, y de 62,2 meses en la rama estándar (HR 0,79, 95 % IC 0,63-099, p = 0,039). Hay que destacar que estos datos son concordantes con una tendencia a que las pacientes asiáticas tengan mejor supervivencia que las pacientes caucásicasno hispanas. En el análisis por subgrupos se ponía de manifiesto que aquellas pacientes en estados III-IV con enfermedad residual de 1 cm o más, o aquéllas con histología serosa u otra (que no fuera células claras o mucinosa) obtenían mayor beneficio de las dosis densas. Globalmente, podemos concluir que el uso de paclitaxel en dosis densas ofrece una alternativa de tratamiento quimioterápico de primera línea para pacientes con cáncer epitelial de ovario avanzado. Sin embargo, no se puede considerar aún un tratamiento estándar en la medida que estos datos no han sido reproducidos en población caucásica.

Ginecología Oncológica - N.º 6


BIBLIOGRAFÍA COMENTADA

Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. N Engl J Med. 2012; 366(15): 1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.

BACKGROUND: Olaparib (AZD2281) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or BRCA2 germline mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75). CONCLUSIONS: Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).

COMENTARIO. Aproximadamente, el 80 % de las pacientes con cáncer de ovario de nuevo diagnóstico responden a esquemas de quimioterapia basados en platino. Sin embargo, muchas de estas pacientes recaen, y la respuesta a posteriores tratamientos suele ser corta. Existe evidencia de que la quimioterapia de mantenimiento tras primera línea, o incluso la combinación de la quimioterapia con bevacizumab en primera línea o tras una recaída platino sensible, puede aumentar el control de la enfermedad. A pesar de lo previo, urge investigar nuevos tratamientos en este punto. En este estudio se valora el papel de olaparib (AZD2281) como terapia de mantenimiento en las pacientes con carcinoma seroso de alto grado que han recaído, y han sido sensibles a esquemas basados en platino. Como tal, olaparib es un inhibidor oral de Poly- ADP-ribose polymerase (PARP). PARP desempeña un rol esencial en la reparación de las hebras simples de ADN por excisión de bases. Basado en que, particularmente, los cánceres de ovario serosos de alto grado tienen deficiencia en la recombinación homóloga (HR) como resultado de la alteración de BRCA (adquirida o heredada), olaparib resultaría en un potente inductor letal en estas células. Se estima que el 50 % de los serosos de alto grado tienen déficit de HR. De esta forma, en este fase II, se aleatorizan 265 pacientes con cáncer de ovario seroso de alto grado que habían recibido dos o más regímenes basados en platino, es decir, que habían recaído tras al menos 6 meses del último régimen, y que habían responGinecología Oncológica - N.º 6

dido de forma completa o parcial al último. De estas, 136 recibieron olaparib (400 mg, dos veces al día), y 129 placebo. Se estratificó por el intervalo a la progresión tras el penúltimo régimen basado en platino (de 6-12 vs. > de 12 meses), la respuesta al último esquema (parcial vs. completa), y origen (judío vs. no judío, para balancear mutaciones heredadas de BRCA1/2). Los resultados son significativos respecto al objetivo primario: el intervalo libre de progresión (PFS). De esta forma, esta fue significativamente mayor en la rama de olaparib (8,4 meses) respecto a placebo (4,8 meses) (HR 0,35, IC 95 % 0,25-0,49, p < 0,001). Este beneficio se obtenía independientemente del subgrupo. Los efectos secundarios de olaparib fueron moderados (la mayoría grado 1-2) y comprendían náusea, vómitos y anemia. A pesar de ello, sin embargo, tras un análisis interino de la supervivencia global (OS) con el 38 % de eventos (el 38 % de las pacientes habían muerto), no se halla significación (HR 0,94, IC95 % 0,63-1,39, p = 0,75). Podemos concluir, pues, que olaparib aumenta de forma significativa la PFS en pacientes con cáncer de ovario de alto grado recidivado platino-sensible. Actualmente, se ha activado un estudio fase III para confirmar estos datos en una población de pacientes con mutación de BRCA y que igualmente se encuentran en respuesta tras un esquema de platino en una recaída platino-sensible.

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BIBLIOGRAFÍA COMENTADA

Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging Gouy S, Morice P, Narducci F, Uzan C, Martinez A, Rey A, Bentivegna E, Pautier P, Deandreis D, Querleu D, Haie-Meder C, Leblanc E. J Clin Oncol. 2013; 31(24): 3026-33. doi: 10.1200/JCO.2012.47.3520. Epub 2013 Jul 15.

PURPOSE: The aim of this prospective study conducted in three French comprehensive cancer centers was to evaluate the therapeutic impact on survival of laparoscopic para-aortic (PA) staging surgery in locally advancedcervical cancer (LACC) before chemoradiotherapy. PATIENTS AND METHODS: We conducted a prospective multicenter study of 237 patients treated from 2004 to 2011 for LACC with negative positron emission tomography (PET) imaging of the PA area and undergoinglaparoscopic PA lymphadenectomy. Radiation fields were extended to the PA area when PA nodes were involved. Chemoradiotherapy modalities were homogeneous across institutions. Patients with a poor prognosis histologic subtype or peritoneal carcinosis were excluded. RESULTS: Patients had clinical International Federation of Gynecology and Obstetrics stages IB2 (n = 79), IIA (n = 10), IIB (n = 121), III (n = 22), or IVA (n = 5). One hundred ninety-nine patients had squamous carcinoma, and 38 had adenocarcinoma/adenosquamous lesions. Twenty-nine patients (12%) had nodal involvement (false-negative PET-computed tomography [CT] results)-16 with a PA nodal metastasis measuring more than 5 mm and 13 with a nodal metastasis measuring ≤ 5 mm. Event-free survival rates at 3 years in patients without PA involvement or with PA metastasis measuring ≤ or more than 5 mm were 74% (SE, 4%), 69% (SE, 21%), and 17% (SE, 14%; P < .001). CONCLUSION: To our knowledge, this is the largest series of patients reported undergoing such a strategy. We obtained the same survival rate for patients with PA nodal metastasis ≤ 5 mm and patients without PA lymph node involvement, suggesting that this strategy is highly efficient in such patients. Conversely, the survival ofpatients with PA nodal involvement greater than 5 mm remained poor, despite the absence of extrapelvic disease on PET-CT imaging in this subgroup.

COMENTARIO. La incidencia de enfermedad extrapélvica al diagnóstico de los tumores localmente avanzados de cérvix es alta, variando del 10 al 30 %, particularmente en la región paraórtica y tóracica. Actualmente, la quimiorradioterapia sigue siendo el estándar para estos tumores, consiguiendo una mejoría del control local; sin embargo, la tasa de afectación ganglionar o recaída sistémica continúa siendo un problema mayor. La técnicas de imagen, así como el tomografía por emisión de positrones (PET), nos ayudan a detectarlas, a pesar de ello, puede existir enfermedad potencialmente oculta (la tasa de falsos negativos varía del 9 al 22 % en la PET). Mediante este estudio, el grupo francés, de forma multicéntrica y prospectiva, evalúa el papel de la estadificación paraórtica laparoscópica, no solo para desenmascarar falsos negativos de la PET, sino también para evaluarla como herramienta pronóstica.

Los resultados mostraron 29 pacientes con afectación ganglionar (tasa de falso negativo del 12 %), de los cuales 16 eran metástasis que medían > 5 mm, y 13 con tamaño menor o igual a 5 mm. La tasa de supervivencia libre de enfermedad a 3 años en pacientes sin afectación paraórtica, con afectación ganglionar < 5 mm o > 5 mm fue respectivamente de 74 %, 69 % y 17 % (p < 0,001).

De esta forma, 237 pacientes estadios IB2-IVA tratados de 2004 a 2011 con PET negativa (u otras pruebas de imagen negativas) en áreas paraórticas se sometieron a linfadenectomía paraórtica laparoscópica. En caso que estas áreas fueran positivas, se extendía el área de quimiorradioterapia a ellas posteriormente.

Podemos concluir que esta es la mayor serie comunicada hasta el momento, y ha podido responder a las 2 preguntas iniciales: la exactitud del PET en la detección de la enfermedad en el cáncer de cérvix, así como determinar el impacto en supervivencia de un estadiaje quirúrgico.

Si observamos los resultados, vemos que la tasa de supervicencia de las pacientes sin afectación ganglionar y aquéllas con metástasis menor de 5 mm es similar, por lo que se puede sugerir que esta estrategia es altamente efectiva para este tipo de pacientes. Además, la supervivencia en pacientes con afectación paraórtica mayor de 5 mm es pobre, a pesar de la ausencia de enfermedad extrapélvica por PET en este grupo.

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Ginecología Oncológica - N.º 6


BIBLIOGRAFÍA COMENTADA

BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study Lesnock JL, Darcy KM, Tian C, Deloia JA, Thrall MM, Zahn C, Armstrong DK, Birrer MJ, Krivak TC. Br J Cancer. 2013; 108(6): 1231-7. doi: 10.1038/bjc.2013.70. Epub 2013 Mar 5.

BACKGROUND: Breast cancer 1, early onset (BRCA1) is a tumour-suppressor gene associated with familial epithelial ovarian cancer (EOC). Reduced BRCA1 expression is associated with enhanced sensitivity to platinum-based chemotherapy. We sought to examine the prognostic relevance of BRCA1 expression in EOCpatients treated with intraperitoneal platinum/taxane. METHODS: The GOG172 was a phase III, multi-institutional randomised trial of intravenous paclitaxel and cisplatin (IV therapy) vs intravenous paclitaxel, intraperitonealcisplatin plus paclitaxel (IP therapy) in patients with optimally resected stage III EOC. The BRCA1 expressionwas assessed with immunohistochemistry (IHC) staining blinded to clinical outcome in archival tumour specimens. Slides with 10% staining were defined as aberrant and >10% as normal. Correlations betweenBRCA1 expression and progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier method and Cox regression analysis. RESULTS: Of the 393 patients, 189 tumours had aberrant expression, and 204 had normal BRCA1 expression. There was an interaction between BRCA1 expression and route of administration on OS (P=0.014) but not PFS (P=0.054). In tumours with normal BRCA1 expression, the median OS was 58 months for IP group vs 50 months for IV group (P=0.818). In tumours with aberrant BRCA1expression, the median OS was 84 vs 47 months in the IP vs IV group, respectively (P=0.0002). AberrantBRCA1 expression was an independent prognostic factor for better survival in women randomised to IP therapy (hazard ratio (HR)=0.67, 95% confidence interval (CI)=0.47-0.97, P=0.032). Similar survival was observed in the IV and IP patients with normal BRCA1 expression. Multivariate but not univariate modelling demonstrated that IVpatients with aberrant vs normal BRCA1 expression had worse survival. CONCLUSION: Decreased BRCA1expression is associated with a 36-month survival improvement in patients with EOC treated with IP chemotherapy. Although these results merit validation in future studies, the results suggest that decreasedBRCA1 expression predicts for improved response to cisplatin-based IP chemotherapy with cisplatin andpaclitaxel.

COMENTARIO. BRCA1 es un gen supresor tumoral que se asocia al cáncer de ovario epitelial familiar. La expresión reducida de BRCA1 tiene asociación con una sensibilidad aumentada a la quimioterapia basada en platino. Este estudio buscó examinar la relevancia pronóstica de la expresión de BRCA1 en pacientes con cáncer de ovario tratadas con terapia intraperitoneal. El estudio GOG-172 es un fase III, aleatorizado y multicéntrico, que comparaba el tratamiento con cisplatino y paclitaxel endovenoso (IV) vs. paclitaxel endoveoso, y cisplatino-paclitaxel intraperitoneal (IP) en pacientes sometidas a una citorreducción óptima por un cáncer de ovario epitelial estadio III. La expresión de BRCA1 se obtuvo mediante tinción inmunohistoquímica (IHQ) sobre muestras almacenadas. Se consideraba como “aberrante” a aquéllas con una tinción menor o igual del 10 %, y considerábamos como “normales” a aquéllas de más de un 10 %. La correlación entre la expresión de BRCA1 y la PFS-OS fue analizada usando el método de Kaplan-Meier y el análisis de regresión de Cox. De los 393 tumores analizados del GOG-172, 189 tumores tenían expresión aberrante, es decir, baja; y 204 tenían expresión normal de BRCA1. Existía una interacción entre la expresión de BRCA1 y la vía de administración respecto a la OS (p = Ginecología Oncológica - N.º 6

0,014), pero no respecto a la PFS (p = 0,054). En los tumores con expresión normal de BRCA1, la mediana de OS fue de 58 meses para el grupo de IP, vs. 50 meses para el grupo IV (p = 0,818). En los tumores con expresión aberrante de BRCA1, la mediana de OS fue de 84 vs. 47 meses de IP respecto a IV, con una p = 0,0002. La expresión aberrante de BRCA1 es un factor pronóstico independiente de mejoría en la supervivencia en las mujeres aleatorizadas a la rama IP (HR de 0,67 con IC 0,47-0,97, p = 0,032). Llama la atención que la OS fue similar en las ramas IV e IP con expresión normal de BRCA1. En conclusión, la expresión baja de BRCA1 se asocia con una mejoría en 36 meses en las pacientes con cáncer de ovario epitelial tratadas con terapia IP. A pesar que estos resultados deben ser validados en ensayos futuros, los resultados sugieren que la expresión baja de BRCA1 predice una mejor respuesta al tratamiento intraperitoneal con cisplatino y paclitaxel. La interpretación de estos hallazgos es que la baja expresión de BRCA1 se debe asociar a una mutación del gen y que estos pacientes tienen mejor supervivencia global cuando son tratados con cisplatino intraperitoneal. Sin embargo, sería necesario correlacionar la expresión de BRCA con la mutación del gen.

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BIBLIOGRAFÍA COMENTADA

Type I and II endometrial cancers: have they different risk factors? Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, Wolk A, Wentzensen N, Weiss NS, Webb PM, van den Brandt PA, van de Vijver K, Thompson PJ; Australian National Endometrial Cancer Study Group, Strom BL,Spurdle AB, Soslow RA, Shu XO, Schairer C, Sacerdote C, Rohan TE, Robien K, Risch HA, Ricceri F, Rebbeck TR,Rastogi R, Prescott J, Polidoro S, Park Y, Olson SH, Moysich KB, Miller AB, McCullough ML, Matsuno RK, Magliocco AM, Lurie G, Lu L, Lissowska J, Liang X, Lacey JV Jr, Kolonel LN, Henderson BE, Hankinson SE, Håkansson N,Goodman MT, Gaudet MM, Garcia-Closas M, Friedenreich CM, Freudenheim JL, Doherty J, De Vivo I, Courneya KS,Cook LS, Chen C, Cerhan JR, Cai H, Brinton LA, Bernstein L, Anderson KE, Anton-Culver H, Schouten LJ, Horn-Ross PL. J Clin Oncol. 2013; 31(20): 2607-18. doi: 10.1200/JCO.2012.48.2596. Epub 2013 Jun 3.

PURPOSE: Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type IItumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type IItumors. PATIENTS AND METHODS: Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS: Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION: The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.

COMENTARIO. Basándose en las diferencias en histología y evolución, los cánceres de endometrio se han dividido tradicionalmente en dos tipos: los de tipo I comprenden la mayor parte de los cánceres de endometrio, suelen ser endometrioides y se asocian con el estímulo estrogénico, y son precedidos con frecuencia por hiperplasia endometrial. Los de tipo II son predominantemente carcinomas serosos, y descritos como estrogenoindependientes, soliendo emerger sobre endometrios atróficos y derivados de carcinomas intrapiteliales, una lesión precancerosa. Los de tipo II son de peor diferenciación histológica, y tienen peor pronóstico que los de tipo I, y acostumbran a ser causa de muerte desproporcionada (es decir, provocan el 40 % de las muertes representando el 10-20 % de todos los casos). Además, existe disparidad respecto a las alteraciones genéticas de ambos, lo que sugiere que deben tener distintos orígenes. Son conocidos los factores etiológicos asociados al tipo I, siendo la una consecuencia del disbalance entre estrógenosprogesterona. En este estudio, se combinan datos específicos de 24 estudios epidemiológicos partícipes en el Epidemiology of Endometrial Cancer Consortium (E2C2), mediante el análisis de 854 tipo II, y 12.853 tipo I, y 35.312 controles. Se

clasificaron endometrioides (n = 7.246), adenocarcinomas sin especificar (n = 4.830) y adenocarcinomas con diferenciación escamosa (n = 777) como de tipo I, y los tumores serosos (n = 508) y mixtos (n = 346) como de tipo II. Los resultados llaman la atención: paridad, uso de contraceptivos, tabaco, edad de la menarquia y diabetes se asocian con los tipo I y II de la misma forma. Sin embargo, el índice de masa corporal tiene mayor efecto en los tipo I (un aumento del odds ratio por cada 2 kg/m2 es 1,20 (95 % IC 1,19-1,21) para el tipo I y 1,12 (95 % IC, 1,09-1,14) para el de tipo II. Los patrones de riesgo para los tumores endometrioides de alto grado y los de tipo II son similares. Concluimos pues que, basándonos en los resultados, los dos tipos de cánceres endometriales comparten muchos factores etiológicos. De esta forma, los de tipo II deben, en su trasfondo, no ser completamente estrogenoindependientes, como se pensaba.

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Ginecología Oncológica - N.º 6


OBRAS DE REFERENCIA EN NUESTRA ESPECIALIDAD

GYNECOLOGIC CANCER SURGERY Matías Jurado Departamento de Ginecología y Obstetricia Clínica Universidad de Navarra

DESDE HACE POCO, ESTÁ EN EL MERCADO LA SEGUNDA EDICIÓN DEL LIBRO DE CIRUGÍA DEL CÁNCER GINECOLÓGICO GYNECOLOGIC CANCER SURGERY DE C. PAUL MORROW, COMO ES BIEN SABIDO, UNO DE LOS MÁS DESTACADOS CIRUJANOS DEL CÁNCER GINECOLÓGICO CON PRESTIGIO MUNDIALMENTE RECONOCIDO. Su libro está basado en toda una vida de experiencia clínica personal, estudio riguroso y un juicioso espíritu crítico. Sus puntos de vista y la profundidad de los mismos no tienen precedentes en nuestra literatura. No escribe nada superfluo, cada línea refleja un equilibrio casi perfecto entre una realidad vivida y la integración de la opinión científica publicada. Desde su primera edición ha sido siempre mi referente definitivo. Sinceramente creo que la publicación de esta segunda edición ha sido largamente añorada por muchos a lo largo y ancho del mundo y finalmente ha visto la luz: el sueño se ha visto cumplido.

Naturalmente, se trata de una edición totalmente actualizada que, como la anterior, contiene una descripción escrita y ampliamente ilustrada paso a paso de todas las intervenciones quirúrgicas importantes en el campo de la ginecología oncológica. También cubre de una manera clara y concisa la anatomía quirúrgica más relevante, los cuidados pre y posoperatorios, así como el manejo de las complicaciones quirúrgicas. Contiene una amplia y exhaustiva documentación bibliográfica, propia del rigor científico de su autor. En la página web de la editorial (http://scmedicalpublishing.com/the-author/) del libro puede verse con detalle toda la información necesaria.

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Ginecología Oncológica - N.º 6


IN MEMORIAN

María Herrera Servicio de Ginecología Hospital Universitario La Paz. Madrid

Semblanza de un médico extraordinario

ANTONIO LÓPEZ SALVÁ NOTA DEL EDITOR: EN 2010, EL ÚLTIMO NÚMERO DE LA PRIMERA TEMPORADA DE ESTA REVISTA INCLUÍA UNA SEMBLANZA DE NUESTRO QUERIDO ANTONIO LÓPEZ SALVÁ TRAS SU RECIENTE FALLECIMIENTO PERO QUE NUNCA SE LLEGÓ A PUBLICAR EN PAPEL; EN ESTA NUEVA ANDADURA Y AUNQUE FUERA DE FECHA, NO QUEREMOS DEJAR DE DARLE UN ABRAZO ANTONIO EN FORMA DE RECUERDO…

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Ginecología Oncológica - N.º 6


SEMBLANZA DE UN MÉDICO EXTRAORDINARIO ANTONIO LÓPEZ SALVÁ

El pasado cinco de abril de 2010, el mundo ginecológico amaneció con una triste noticia: el fallecimiento de nuestro querido compañero Antonio López Salvá. Una corta pero implacable enfermedad ponía fin prematuramente a una carrera brillante y nos privaba para siempre de una figura indiscutible de la Ginecología, y una persona excepcional desde el punto de vista médico, científico y humano. Antonio López Salvá hizo la residencia de Ginecología y Obstetricia en La Maternidad de La Paz, tras un año “interno” en Puerta de Hierro. Cursando el cuarto año de residencia, comenzó su incursión en la laparoscopia en el John Hopkins de Baltimore. Fue adjunto en La Paz y Jefe de Servicio en Salamanca hasta 1997, año en el que volvió a Madrid como jefe de área de la entonces Fundación de Alcorcón (hoy Hospital Universitario Fundación Alcorcón). Fue autor de un gran número de trabajos científicos de la especialidad y su vocación docente le llevó a participar en una innumerable serie de cursos y reuniones nacionales e internacionales. Antonio era una Buena Persona con mayúsculas: sencillo, humilde, amable, cariñoso y de gran calidad humana. Desde la perspectiva médica, destacaban su destreza quirúrgica, su espíritu crítico, su afán de estudio y conocimiento y su avidez por experimentar y mejorar todo aquello que aprendía y en lo que confiaba. Son muchas sus aportaciones a la Ginecología, fundamentalmente en los campos de la Oncología y en el de la cirugía laparoscópica, vaginal y del suelo pélvico. Su preocupación siempre fue la búsqueda de la calidad y del bienestar de las pacientes por encima de todo resultado, lo que reflejaba su dimensión humana. Dentro de la laparoscopia, a Antonio le apasionaba especialmente la cirugía oncológica. Su conocimiento profundo de la anatomía y de los espacios le ayudaron a ser pionero en considerar la preservación nerviosa como objetivo fundamental en la cirugía radical y en llevarla a cabo en España. En lo referente a la cirugía vaginal, que Antonio dominaba y defendía a ultranza, su aportación mayor fue proclamar la utilidad de la laparoscopia para aumentar las indicaciones de la cirugía vaginal y nunca en detrimento de esta, convencido como estaba de sus ventajas. Incluso en la cirugía oncológica, donde impulsó la técnica de Schauta Celioasistido para el tratamiento del cáncer de cérvix. En el campo del suelo pélvico, trajo de Suecia las técnicas de corrección de incontinencia urinaria mediante bandas libres de tensión, y de Francia las mallas para los defectos del suelo pélvico. Son muchos los compañeros de toda España que pudieron aprender estas técnicas de su mano, ya que Antonio regalaba su conocimiento generosamente. Ginecología Oncológica - N.º 6

Otra gran aportación de Antonio a la Ginecología en general, y especialmente a la Oncología Medicoquirúrgica, fue su sentido común y su criterio, siempre contrastado con el análisis crítico de estudios y opiniones, obteniendo conclusiones sopesadas que apoyaba y compartía posteriormente con gran empeño y entusiasmo, pero siempre de una manera abierta y sin obcecación. Su participación en los foros oncológicos era solicitada por esa visión global y lógica de la conveniencia o inconveniencia de las nuevas técnicas y enfoques. Escuché hablar por primera vez de Antonio durante mi residencia en el Hospital Maternal La Paz, a mediados de los 90. Con esa admiración que ahí se guarda hacia los exrresidentes aventajados, sus amigos, antiguos compañeros y maestros, decían de él: “Lo tiene todo: es inteligente, trabajador, habilidoso, humilde, buen orador, estudioso y magnífico cirujano”. Ya siendo adjunta, atraída por su buen hacer, su carisma y su persona, me uní a su equipo y compartí profesionalmente con él los trece últimos años de su carrera en Alcorcón. Con Antonio aprendí que no hay dogmas de fe en Medicina, y que esta no tiene sentido si no colocamos a cada paciente, individualmente, en un primer plano cuando nos planteamos este u otro enfoque de curación. Sus ganas de crecer y de compartir su extenso conocimiento, su templanza y paciencia en el quirófano, su ecuanimidad como jefe, su interés por conocer a las personas y ensalzar lo mejor de ellas, su sentido del humor, su afición por el jazz y el tango… le hicieron un maestro, un compañero y un amigo inolvidable. Aceptó su implacable enfermedad y el revés que le envió la vida, pero no se resignó a perder un segundo de vitalidad. Días antes de su partida nos deleitó con una intervención de Schauta Celioasistido, bordando con maestría el tiempo vaginal a pesar de las molestias que le aquejaban. Fue su última obra quirúrgica, contemplada y admirada por cuantos ahí estábamos, su última lección humana y médica…

SON MUCHAS SUS APORTACIONES A LA GINECOLOGÍA, FUNDAMENTALMENTE EN LOS CAMPOS DE LA ONCOLOGÍA Y EN EL DE LA CIRUGÍA LAPAROSCÓPICA, VAGINAL Y DEL SUELO PÉLVICO. SU PREOCUPACIÓN SIEMPRE FUE LA BÚSQUEDA DE LA CALIDAD Y DEL BIENESTAR DE LAS PACIENTES POR ENCIMA DE TODO RESULTADO, LO QUE REFLEJABA SU DIMENSIÓN HUMANA.

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Agenda de congresos 2014

FEBRERO 2014 IV Reunión Anual Internacional MD Anderson sobre Cáncer Ginecológico February 19-21, 2014 Madrid, Spain

MARZO 2014 ECCO 2014 9th European Breast Cancer Conference (EBCC-9) March 19-21, 2014 Glasgow, Scotland

MAYO 2014 11th International Conference of the Asian Clinical Oncology Society in conjunction with The 19th Taiwan Joint Cancer Conference May 2-4, 2014 Taipei International Convention Center (TICC) Taipei, Taiwan GOC’s 14th Annual CPD Meeting May 2, 2014 Toronto, Ontari ESGO sesión en el Congreso EBCOG (ESGO tema del Cáncer en el embarazo) May 7 - 10 mayo, 2014 Glasgow, Reino Unido – Escocia 15 º Congreso Mundial de Patología Cervical y Colposcopia (IFCPC) May 26 – 30, 2014 Londres, Reino Unido

MAYO/JUNIO 2014

JULIO 2014 56th Meeting of Japan Society Of Gynecologic Oncology July 17-19, 2014 Tochigi, Japan

SEPTIEMBRE 2014 35th ESMO September 26-30, 2014 Madrid, Spain

OCTUBRE 2014 18ª SIS Congreso Mundial de Salud de Mama (SIS 2014) October 16-19, 2014 Orlando, Florida, EE.UU 32 Reunión Nacional de la Sección de Ginecología Oncológica y Patología Mamaria de la SEGO Octubre 23-25, 2014 Madrid, España

NOVIEMBRE 2014 15a Reunión Bienal de la Sociedad Internacional de Cáncer Ginecológico (IGCS 2014) 8 a 11 noviembre 2014 Melbourne, Australia

2015 ESGO19 2015 Encuentro internacional October 23-27, 2015 Niza, Francia

ASCO 50th Annual Meeting Science &Society May 30-June 3, 2014 Chicago, Illinois

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Ginecología Oncológica - N.º 6


INSTRUCCIONES PARA LOS COLABORADORES DESCRIPCIÓN Y ENVÍO DE MANUSCRITOS El comité editorial tiene previsto publicar dos números anuales de Revista de Ginecología Oncológica con diversas secciones fijas, que serán llevadas a cabo por encargo del mismo. También, a partir del presente número, se admitirán artículos originales, casos clínicos e imágenes comentadas para la sección “Más que mil palabras”, que serán revisados y considerados por el comité editorial antes de su publicación. El contenido de los artículos debe coincidir con los temas de interés de la revista (Ginecología Oncológica y Patología Mamaria). A continuación se describen brevemente las secciones en las que se admiten colaboraciones y las normas que han de seguir los autores para cada una de ellas: CREANDO OPINIÓN: esta sección constituye el núcleo científico de la revista y consistirá habitualmente en tres-cuatro artículos originales o de revisión llevados a cabo por expertos nacionales e internacionales de prestigio. Pautas: la extensión de los originales será de 8-10 páginas por artículo/revisión, incluyendo texto, tablas, figuras y bibliografía. Los artículos se estructuran de la siguiente forma: Introducción, Material y métodos, Resultados, Discusión, Bibliografía, Tablas, Pies de figura y Figuras. CASOS CLÍNICOS: breve descripción de hasta tres casos de un problema determinado, cuya publicación resulte de interés por la rareza del problema y las nuevas perspectivas diagnósticas y/o terapéuticas que aporte. Pautas: la extensión de los originales del caso será de 6-8 páginas, incluyendo texto, tablas, discusión, figuras y bibliografía. Los artículos se estructuran de la siguiente forma: Introducción, Descripción del caso(s), Discusión, Bibliografía, Tablas, Pies de figura y Figuras. MÁS QUE MIL PALABRAS: comentario a propósito de una imagen clínica, radiológica o de anatomía patológica que represente un hallazgo llamativo del que se puedan extraer conclusiones. Pauta: la extensión de los originales será de 1 página.

NORMAS GENERALES PARA LAS COLABORACIONES En la primera página se incluirán, en el orden que se cita, los siguientes datos: título del trabajo; nombre y dos apellidos de los autores; grado académico más alto o cargo que ostentan en el centro donde trabajan; nombre del centro donde se ha realizado el trabajo, dirección completa del mismo; nombre y dirección para la correspondencia relacionada con el trabajo, e-mail, número de teléfono y fax si tuviera. En la segunda y siguientes páginas se incluirán: texto; bibliografía, tablas y figuras. El texto debe estar mecanografiado en hojas de tamaño DIN A4, con tipografía Times, a cuerpo 12 e interlineado sencillo. El margen superior será de 4,5 cm y el inferior, el izquierdo y el derecho, de 2,5 cm. Las menciones a figuras y tablas (ej. figura 1, tabla I) y a la bibliografía consultada se incluirán por orden de aparición, con numeración correlativa. La bibliografía deberá aparecer siempre en el texto con la numeración de la correspondiente cita con número volado o superíndice (NO UTILIZAR la herramienta de Word “Notas a Pie” o “Notas al Final”) y para elaborarla se deben seguir las Normas de Vancouver (última edición). Se entiende como figura todo tipo de imagen, fotografía, gráfico, algoritmo, etc. Las características deben ser las siguientes: tamaño mínimo 10 x 8 cm y resolución 300 píxels por pulgada. El tipo de archivo ha de ser JPG, TIF o PSD (Photoshop). Se acompañarán de breves leyendas o pies a cada una de ellas, que es conveniente presentar en una página aparte. Si se incluyen imágenes de pacientes que puedan ser identificables (aparición del rostro o parte del mismo) se debe adjuntar un consentimiento firmado por el enfermo o tutor (en caso de menores de edad). Este es un requerimiento indispensable. Las tablas se presentarán en hojas aparte mecanografiadas a doble espacio y numeradas con números romanos. Deben incluir un enunciado (o título) conciso, significación estadística y, cuando proceda, un título explicativo de las siglas y abreviaturas a pie de página. Cada manuscrito se acompañará de una página (no computable en el número de páginas solicitado) que incluya un esquema de la estructura del trabajo y muestre claramente la jerarquía de los diferentes apartados y subapartados. Los manuscritos se enviarán a los editores (lchiva@mdanderson.es, agonzalezm@seom.org) con copia a Coordinación Editorial, LUZÁN 5 S. A. de Ediciones, Pasaje Virgen de la Alegría 14, 28027 Madrid (mfranco@luzan5.es).



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