Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the standard of care for some patients with advanced ovarian cancer. We evaluated the efficacy and safety of PARP inhibitor rechallenge. PATIENTS AND METHODS: This randomized, double-blind, multicenter trial (NCT03106987) enrolled patients with platinum-sensitive relapsed ovarian cancer who had received one prior PARP inhibitor therapy for ≥18 and ≥12 months in the BRCA-mutated and non-BRCA-mutated cohorts, respectively, following first-line chemotherapy or for ≥12 and ≥6 months, respectively, following a second or subsequent line of chemotherapy. Patients were in response following their last platinum-based chemotherapy regimen and were randomized 2 : 1 to maintenance olaparib tablets 300 mg twice daily or placebo. Investigator-assessed progression-free survival (PFS) was the primary endpoint. RESULTS: Seventy four patients in the BRCA-mutated cohort were randomized to olaparib and 38 to placebo, and 72 patients in the non-BRCA-mutated cohort were randomized to olaparib and 36 to placebo; >85% of patients in both cohorts had received ≥3 prior lines of chemotherapy. In the BRCA-mutated cohort, the median PFS was 4.3 months with olaparib versus 2.8 months with placebo [hazard ratio (HR) 0.57; 95% confidence interval (CI) 0.37-0.87; P = 0.022]; 1-year PFS rates were 19% versus 0% (Kaplan-Meier estimates). In the non-BRCA-mutated cohort, median PFS was 5.3 months for olaparib versus 2.8 months for placebo (HR 0.43; 95% CI 0.26-0.71; P = 0.0023); 1-year PFS rates were 14% versus 0% (Kaplan-Meier estimates). No new safety signals were identified with olaparib rechallenge. CONCLUSIONS: In ovarian cancer patients previously treated with one prior PARP inhibitor and at least two lines of platinum-based chemotherapy, maintenance olaparib rechallenge provided a statistically significant, albeit modest, PFS improvement over placebo in both the BRCA-mutated and non-BRCA-mutated cohorts, with a proportion of patients in the maintenance olaparib rechallenge arm of both cohorts remaining progression free at 1 year.

Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status. PATIENTS AND METHODS: Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis. RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms. CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Need for risk-adapted therapy for malignant ovarian germ cell tumors: A large multicenter analysis of germ cell tumors' patients from French TMRG network.

BACKGROUND: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients. PATIENTS AND METHODS: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients. RESULTS: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival. CONCLUSION: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.

The French national network dedicated to rare gynecological cancers diagnosis and management could improve the quality of surgery in daily practice of granulosa cell tumors. A TMRG and GINECO group Study.

OBJECTIVE: The French national rare gynecological tumor network has been established to improve the quality of care through offering expertise in double reading histological diagnosis, reviewing cases and guiding management of these tumors through specialized multidisciplinary tumor boards and online clinical guidelines (www.ovaire-rare.com). The aim of this study is to evaluate the impact of the development and implementation of this network by assessing the conformity of medical practice with the guidelines concerning the granulosa cell tumors (GCTs). METHODS: This is a French nationwide study, including 463 patients (out of the 639 identified patients) with a definitive diagnosis of GCT between 2011 and 2016. Surgical practices were analyzed for conformity with the current guidelines (www.ovaire-rare.org). Medical records, surgical and pathological reports were systematically analyzed. Total conformity was defined by a conservative (unilateral salpingo-oophorectomy) or radical surgery (hysterectomy and bilateral salpingo-oophorectomy) including surgical staging (omentectomy, peritoneal biopsies and peritoneal cytology) according to the FIGO stage. Partial conformity referred to a conservative or radical surgery without surgical staging and non-conformity was defined as a non-optimal surgery as recommended by the guidelines. RESULTS: Median age at diagnosis was 49 years old (range 10-89). The median size of tumor was 94 mm (range 5-400). Radical surgery was performed in 240 patients (52%); while a fertility-sparing surgery was performed in 98 cases (21%). A surgical staging was performed in 76 cases (16%) and an evaluation of the endometrium in 289 cases (62%). Surgery was fully compliant with the guidelines in 65 patients (14%), partially compliant in 213 patients (46%), non-compliant in 137 patients (30%) and not assessable in 48 cases (10%). A statistically significant difference for compliance was observed in restaging surgery (p < 0,001), radical surgery (p = 0,017) and the period (before or after) of the implementation of the network (p < 0,001). Survival analyses did not allow us to demonstrate a significant difference in overall survival nor in PFS although there was a trend in favor of optimal surgery compared to incomplete/non optimal surgery. CONCLUSION: Surgical management's conformity to the guidelines increases over time from 2011 to 2016. According to this study, the implementation of a national network dedicated to rare gynecologic tumors seems to significantly improve the surgical management of the patients with ovarian granulosa cell tumors.

Phase II study of the PI3K inhibitor BKM120 in patients with advanced or recurrent endometrial carcinoma: a stratified type I-type II study from the GINECO group.

Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma. METHODS: This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100 mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety. RESULTS: A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100 mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100 mg and to continue the clinical trial with a lower dose of 60 mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8-6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60 mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade ⩾3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity. CONCLUSIONS: The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.

Clinical and genetic predictors of paclitaxel neurotoxicity based on patient- versus clinician-reported incidence and severity of neurotoxicity in the ICON7 trial.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel, with no reliable method to identify at-risk patients. We investigated the incidence and risk factors including genetic polymorphisms associated with the development of CIPN based on clinician and patient reporting of neuropathic symptoms. PATIENTS AND METHODS: Risk factors for the development of CIPN were examined in 454 patients treated with paclitaxel/carboplatin from the International Collaboration on Ovarian Neoplasms 7 (ICON7) trial. Neuropathy was graded by clinicians by standard adverse event reporting and by patients utilising OV28 questionnaire. Genetic risk factors were examined by selecting six single nucleotide polymorphisms in genes associated with microtubule function. Risk factors were assessed via dose-to-event cox regression models. RESULTS: Grade >2 neuropathy was reported by clinicians in 28% of patients, while 67% of patients reported 'quite a bit' or 'very much' tingling or numbness. Agreement between clinicians and patients was poor (κ = 0.236, 95% confidence interval, 0.177-0.296, P < 0.001). Older age, bevacizumab treatment and bowel resection were associated with clinician reported CIPN, while older age and volume of residual disease were associated with patient-reported neuropathy. There were no significant associations between clinician-reported neuropathy or patient-reported neuropathy and TUBB2, CEP72 or individual MAPT or GSK3B SNPs, however MAPT additive polymorphisms were associated with patient-reported neuropathy and GSK3B additive polymorphisms were associated with clinician reported CIPN. CONCLUSIONS: There was significant discordance between patient- and clinician-reported neurotoxicity. The lack of consensus regarding optimal outcome measures and whose opinion with regard to CIPN takes precedence is a limitation in the investigation of risk factors for CIPN. Care must be taken to select and include patient-reported outcome measures in CIPN assessment to enable accurate identification of genetic and other risk factors for neuropathy.

Salvage high-dose chemotherapy in female patients with relapsed/refractory germ-cell tumors: a retrospective analysis of the European Group for Blood and Marrow Transplantation (EBMT).

BACKGROUND: High-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation. PATIENTS AND METHODS: Between 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15-48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%). RESULTS: Nine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm-), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1-219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm- following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3-219 months). CONCLUSIONS: Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.

Multidisciplinary management of advanced ovarian cancer for an optimal therapeutic strategy.

The management of advanced ovarian cancer generally requires specialist multidisciplinary teamwork to achieve optimum outcomes. Preoperative computed tomography scans are the imaging modality of choice in determining the extent of disease and aiding in surgical planning. Histological classification is crucial to define various subtypes with their different behaviour and prognosis and to plan the best therapeutic strategy. Pathological prognostic factors, such as histological type, degree of differentiation, and FIGO stage must be described. To determine the ability to optimally cytoreduce advanced ovarian cancer, an experienced gynaecological oncologist needs to explore the entire upper abdomen and the pelvic and para-aortic lymph node regions to define the peritoneal cancer index (PCI). The final assessment is the completeness of cytoreduction (CC) score which is important in predicting prognosis and decision of post-surgical surgery. Ovarian cancer is the leading cause of death from gynaecologic cancers. Initial management is best provided by a specialist multidisciplinary team, including a radiologist, a pathologist, a gynaecologic oncologist, and a medical oncologist.

A phase II study of lenalidomide in platinum-sensitive recurrent ovarian carcinoma.

BACKGROUND: Lenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated. PATIENTS AND METHODS: Patients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety. RESULTS: Most of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9-56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6-12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4-4.4). Most frequent toxicity was hematologic, notably grade 3-4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity. CONCLUSIONS: Lenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents. CLINICALTRIALSGOV: NCT01111903.

A phase II trial of high-dose chemotherapy (HDCT) supported by hematopoietic stem-cell transplantation (HSCT) in germ-cell tumors (GCTs) patients failing cisplatin-based chemotherapy: the Multicentric TAXIF II study.

BACKGROUND: High-dose chemotherapy (HDCT) is an effective salvage treatment of germ-cell tumors (GCTs) patients. In the first salvage setting, 30%-70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT. PATIENTS AND METHODS: This phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy. Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy, nonseminomatous GCT in relapse after first or second lines, partial remission after first line, primary mediastinal GCT in first relapse. Patients received two cycles combining Epirubicin and Paclitaxel (Epi-Tax), followed by three consecutive HDCT, one using a Paclitaxel/Thiotepa (Thio-Tax) association and two using the 5-day Ifosfamide-Carboplatin-Etoposide regimen. The main objective was to determine the complete response rate. RESULTS: Forty-five patients were included between September 2004 and December 2007: 44 received the first HDCT cycle, 39 two HDCT cycles, 29 could receive the whole protocol. Sixteen patients did not receive the entire protocol, including eight (17.7%) for toxic side-effects. Two patients (4.4%) died of toxicities, and 17 (37.7%) of disease progression. With a median follow-up time of 26 months (range, 4-51), the final overall response rate was 48.8% (including a complete response rate of 15.5% and a partial response/negative serum markers rate of 26.6%) in an intent-to-treat analysis. The median progression-free survival (PFS) and overall survival (OS) times were 22 months [95% confidence interval (CI) 2-not reached] and 32 months (95% CI 4-49), respectively. The 2-year PFS was a plateau setup at 50% (95% CI 32-67) and the 2-year OS was 66% (95% CI 44-81). CONCLUSION: The TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy. The toxic death rate remained acceptable in the field of HDCT regimens. TRIAL REGISTRATION NUMBER: NCT00231582.

A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide, and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). A study of the French Sarcoma Group.

BACKGROUND: There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase ≥ 20% of 3-year PFS. METHODS: Patients with FIGO stage ≤ III US, physiological age ≤ 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m² d1, ifosfamide 3 g/m²/day d1-2, cisplatin 75 mg/m² d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment. RESULTS: Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41). CONCLUSION: API adjuvant CT statistically increases the 3 year-DFS of patients with US.

A single-arm multicentre phase II trial of doxorubicin in combination with trabectedin in the first-line treatment for leiomyosarcoma with long-term follow-up and impact of cytoreductive surgery.

BACKGROUND: Uterine leiomyosarcomas (U-LMSs) and soft tissue leiomyosarcomas (ST-LMSs) are rare tumours with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with manageable toxicity. Herein, we report the updated and long-term results of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients received 60 mg/m2 intravenous doxorubicin followed by trabectedin 1.1 mg/m2 as a 3-h infusion on day 1 and pegfilgrastim on day 2, every 3 weeks, up to six cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. RESULTS: One-hundred and eight patients were enrolled, mainly with metastatic disease (85%), and 20 patients (18.5%) had surgical resection of metastases after chemotherapy. With a median follow-up of 7.2 years [95% confidence interval (CI) 6.9-8.2 years], the median PFS was 10.1 months (95% CI 8.5-12.6 months) in the whole population, and 8.3 months (95% CI 7.4-10.3 months) and 12.9 months (95% CI 9.2-14.1 months) for U-LMSs and ST-LMSs, respectively. The median OS was 34.4 months (95% CI 26.9-42.7 months), 27.5 months (95% CI 17.9-38.2 months), and 38.7 months (95% CI 31.0-52.9 months) for the whole population, U-LMSs, and ST-LMSs, respectively. The median OS of the patients with resected metastases was not reached versus 31.6 months in the overall population without surgery (95% CI 23.9-35.4 months). CONCLUSIONS: These updated results confirm the impressive efficiency of the doxorubicin plus trabectedin combination given in first-line therapy for patients with locally advanced/metastatic LMS in terms of PFS and OS. Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing the doxorubicin plus trabectedin combination versus doxorubicin alone in first-line therapy in metastatic LMSs, are pending.

Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients.

BACKGROUND: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. METHODS: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86). RESULTS: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001). CONCLUSION: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

Mucinous advanced epithelial ovarian carcinoma: clinical presentation and sensitivity to platinum-paclitaxel-based chemotherapy, the GINECO experience.

BACKGROUND: Advanced mucinous epithelial ovarian carcinoma (mEOC) has been associated with a worse prognosis than the more common serous epithelial ovarian carcinomas (sEOC), but it remains unclear whether this observation reflects a more aggressive clinical presentation and/or chemoresistance. PATIENTS AND METHODS: Data from four randomized phase III and one phase II advanced epithelial ovarian carcinoma (EOC) first-line clinical trials were retrospectively collected, yielding 1118 patients with advanced EOC (International Federation of Gynecology and Obstetrics stages IIB-IV), 85% of whom were treated with paclitaxel (Taxol)-carboplatin-based chemotherapy. RESULTS: Based on 786 patients with sEOC and 54 (5%) with mEOC, peritoneal carcinomatosis were more limited in mEOC, which was more frequently stages IIB-IIIB (32% versus 19%, P = 0.001) and had more frequently macroscopic complete resection after initial surgery (50% of stages II-III versus 30%, P = 0.02). In contrast, visceral metastases (stage IV) were more frequent in mEOC (30% versus 15%, P = 0.004). mEOC had a lower response rate to carboplatin-paclitaxel, and shorter progression-free and overall survival rates, for both stage IV and optimally debulked stages II-III patients. CONCLUSIONS: Advanced mEOC appears to be highly chemoresistant and complete resection of peritoneal metastases is unable to reverse its poor prognosis. New therapeutic options are needed.

The role of lymph node resection in ovarian cancer: analysis of the Surveillance, Epidemiology, and End Results (SEER) database.

OBJECTIVE: The therapeutic role of lymphadenectomy on the survival in patients with ovarian cancer is controversial. The aim of this study was to evaluate the survival impact of lymphadenectomy, depending on the disease stage and extent of the surgery. DESIGN: The surveillance, epidemiology, and end results (SEER) registry provided ovarian cancer data from 17 registries. SETTING: Surveillance, Epidemiology, and End Results database. POPULATION: The study population comprised 49,783 patients. METHODS: Survival was studied according to the number of lymph nodes removed, with stratifications on disease stage and extent of surgery. MAIN OUTCOME MEASURE: The 5-year cause-specific survival rate. RESULTS: The median follow up for patients alive at the last follow-up visit was 39 months. The five-year cause-specific survival rates were 37, 62, and 71% for the groups in which no lymph nodes were examined, in which between one and nine nodes were examined, and in which ten or more nodes were examined, respectively (P< 0.001). Avoiding lymphadenectomy was deleterious in all stages of the disease. It was maximal for International Federation of Gynecology and Obstetrics (FIGO) stage-II patients, but there was no significant interaction between stage and extent of lymphadenectomy. The cause-specific survival was found to significantly increase when more nodes were resected, even if the surgical procedure consisted of debulking surgery or a pelvic exenteration. CONCLUSION: Our study suggests a beneficial effect of lymphadenectomy in epithelial ovarian tumours, regardless of the stage of disease and extent of surgery. However, potential biases inherent to this retrospective methodology, such as staging migration, defining the extent of residual disease, and the possibility that thorough lymphadenectomy may reflect the quality of cytoreductive surgery, preclude any formal conclusions on the therapeutic role of lymphadenectomy.

Pulmonary morbidity of diaphragmatic surgery for stage III/IV ovarian cancer.

OBJECTIVE: To determine the morbidity of diaphragmatic peritonectomy. DESIGN: Prospective cohort study. SETTING: A Gynecology Department of a University Hospital. POPULATION: From 2005 to 2007, thirty-seven consecutive patients underwent surgery for stage IIIC or IV ovarian cancer. METHODS: Patients were separated into a diaphragmatic surgery group (n = 18) and a control group (n = 19). Diaphragmatic surgery may consist of coagulation, stripping or muscle resection. MAIN OUTCOME MEASURES: Postoperative course and outcome were analysed. RESULTS: Patients in group 1 (diaphragmatic surgery) underwent more intestinal resection (89% versus 37%, P = 0.01) and pelvic (94% versus 63%, P = 0.02) or para-aortic lymphadenectomy (94% versus 53%, P = 0.04). Neither the mean estimated blood loss (960 ml versus 909 ml) nor the rates of intra-operative blood transfusion (11 versus 9) were significantly different between the two groups. The mean operative time was higher in group 1 (480 minutes versus 316 minutes, P < 0.05). There were thirteen postoperative complications in group 1 and eight in group 2 (P = 0.065). In group 1, the main complication was pleural effusion (seven cases): four patients required secondary pleural drainage, two required only pleural puncture and one had both procedures. There were more complete cytoreduction in group 1 than in group 2 (89% versus 63%, P = 0.068). CONCLUSIONS: Diaphragm peritonectomies and resections are an effective way to cytoreduce diaphragm carcinomatosis and increase the rate of optimal debulking surgery. Such procedures frequently result in pleural effusion, but with no long-term morbidity.

[Glassy cell carcinoma of the uterine cervix: An aggressive type of cancer]. / Glassy cell carcinoma du col de l'utérus : une maladie tumorale agressive.

INTRODUCTION: Cervical cancer is the twelfth most frequent cancer in women in France. Glassy cell carcinoma is a rare histological entity, rapidly aggressive, associated with a poor prognosis. CASE REPORT: A 30-year-old woman was admitted in an internal medicine department for polyarthralgia with high grade fever, evolving for 3 weeks. There was an inflammatory syndrome. The 18-FDG-PET-scan showed inflammatory lymph nodes as well as disseminated osteolytic lesions, and a primitive pelvic tumor. A 3cm tumor of the cervix was found during the gynaecologic examination. Histological analysis elicited a high-index mitotic carcinoma, glassy cell carcinoma type. Despite chemotherapy, the outcome was poor, with early death occurring after three months of follow-up. CONCLUSION: The glassy cell carcinoma of the cervix should be considered as an aetiology of bone metastases in young female patients.

Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol.

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day x 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day x 5 days.

[The use of GnRH analogues in early and advanced breast carcinomas]. / Analogues de la LHRH: leur utilisation dans le traitement du cancer du sein en situation métastatique et adjuvante.

Breast cancer is often an estrogen-dependent disease. The primary goals of the treatment of breast carcinomas are multiple, depending on the situation in which the patients are treated. In adjuvant setting, the aims are to delete the time of relapse, to increase the overall survival, and to offer to the patients the best quality of life they may expect. Tamoxifen is the standard hormonal agent for premenopausal women with receptor-positive breast cancer. Recent data show an increasing role for aromatase inhibitors in postmenopausal women. In metastatic setting, the primary goals are improved quality of life and prolonged survival; effective therapies with minimal toxicity, such as endocrine therapy, are highly desirable and should be considered a primary option over chemotherapy for selected estrogen-receptor positive patients. Ovarian ablation has been worldwide used. Methods of irreversible ovarian ablation include surgical oophorectomy and ovarian irradiation. Potentially reversible castration can be medically accomplished using luteinizing hormone releasing hormone analogues (LHRH agonists). In the metastatic setting, ovarian ablation (induced by the use of LHRH agonists or by surgical ovarian ablation) and tamoxifen monotherapies produce comparable outcomes, and may be more effective when used together (combined estrogen blockade). In advanced breast cancer, the combination prolongs the progression-free survival and increases response rates and duration of response rate relative to the use of LHRH agonist alone. In the adjuvant setting, data suggest that ovarian ablation followed by tamoxifen produces similar results to those obtained with adjuvant chemotherapy in hormone-receptor positive breast cancer women. The value of combining these modalities remains unclear, but the addition of the LHRH analogue goserelin to standard treatment results in a significant benefit in terms of relapse-free and overall survival, especially for estrogen-receptor positive patients. Finally, considering the efficacy of the new aromatase inhibitors, the interest of combining these drugs with the LHRH analogues has yet to be defined, both for pre- and post-menopausal patients.