Menopausal symptoms in epithelial ovarian cancer survivors: a GINECO VIVROVAIRE2 study.

OBJECTIVE: We have previously shown that epithelial ovarian cancer (EOC) and its treatments have negative effects on long-term quality of life (QoL) and fatigue. The present multicenter study investigated the main menopausal symptoms and gynecological management of EOC survivors (EOCS). METHODS: 166 patients with relapse-free ≥3 years after the end of treatment attended a consultation with a gynecologist, including a questionnaire related to vasomotor symptoms (VMS) and sexuality, a clinical examination, a blood sample and an osteodensitometry. QoL, fatigue, insomnia and mood disorders were measured with validated questionnaires and correlated to VMS. VMS and QoL were assessed according to natural menopause (NM) or surgical menopause (SM). RESULTS: Mean age at the survey was 62 [21-83] years and stage III/IV (48%). Mean delay since the end of treatment was 6 years. Fifty-nine patients (36%) had SM. Half of patients reported VMS. Seventy-two percent of EOCS with SM had VMS compared to 41% with NM (P < .001). VMS were not associated with poor global QoL, fatigue, insomnia or mood disorders. Two-thirds of EOCS reported a decrease in libido. Patients with SM showed a greater decrease in libido than NM (P < .02). Fourteen percent of them had osteoporosis and 50% osteopenia. Among the 85 patients with VMS, 80 did not receive HRT after cancer treatment. At the time of the survey, only 7 (4%) patients were receiving hormone replacement therapy (HRT). CONCLUSIONS: VMS and sexual disorders are frequently reported by EOCS, particularly among patients with SM. Most EOCS with menopausal symptoms could benefit from HRT to improve these symptoms.

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.

Flexor tendon rupture after volar plating of distal radius fracture: A systematic review of the literature.

Flexor tendon rupture after volar plate fixation of distal radius fracture (DRF) is rare. There is no consensus as to how to prevent them. The aim of our study was to identify the pathological mechanisms, and to establish the clinical and epidemiological profile of patients suffering from this complication. We carried out a systematic review using the PubMed, Scopus and Cochrane databases. Studies were included if they described complete or partial flexor tendon rupture following volar plate fixation of DRF. Forty-six 46 were included, for a total of 145 patients were reported: 138 from the literature, and 7 from our personal experience. Etiology was usually mechanical, by impingement with either the plate or protruding screws. Plate impingement was due to positioning beyond the watershed line, consolidation with posterior tilt, plate thickness, or low palmar cortical angle. Mean patient age was 62.4 years (range, 23-89 years). Median postoperative interval was 8 months (range, 3-120 months). Flexor pollicis longus was the most frequently injured tendon. The plate should be positioned proximally to the watershed line if possible, to ensure good initial reduction. Hardware should be removed 4 months after surgery if the plate is causing impingement according to the Soong criteria or if signs of tenosynovitis appear.

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.

Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). METHODS: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. RESULTS: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. CONCLUSION: Although pazopanib prolonged PFS, this was not associated with improvement in median OS. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov: NCT00866697.

Long-term fatigue and quality of life among epithelial ovarian cancer survivors: a GINECO case/control VIVROVAIRE I study.

BACKGROUND: Few data are available on long-term fatigue (LTF) and quality of life (QoL) among epithelial ovarian cancer survivors (EOCS). In this case-control study, we compared LTF, symptoms and several QoL domains in EOCS relapse-free ≥3 years after first-line treatment and age-matched healthy women. PATIENTS AND METHODS: EOCS were recruited from 25 cooperative GINECO centers in France. Controls were randomly selected from the electoral rolls. All participants completed validated self-reported questionnaires: fatigue (FACIT-F), QoL (FACT-G/O), neurotoxicity (FACT-Ntx), anxiety/depression (HADS), sleep disturbance (ISI), and physical activity (IPAQ). Severe LTF (SLTF) was defined as a FACIT-F score <37/52. Univariate and multivariate logistic regressions were conducted to analyze SLTF and its influencing factors in EOCS. RESULTS: A total of 318 EOCS and 318 controls were included. EOCS were 63-year-old on average, with FIGO stage I/II (50%), III/IV (48%); 99% had received platinum and taxane chemotherapy, with an average 6-year follow-up. There were no differences between the two groups in socio-demographic characteristics and global QoL. EOCS had poorer FACIT-F scores (40 versus 45, P < 0.0001), lower functional well-being scores (18 versus 20, P = 0.0002), poorer FACT-O scores (31 versus 34 P < 0.0001), and poorer FACT-Ntx scores (35 versus 39, P < 0.0001). They also reported more SLTF (26% versus 13%, P = 0.0004), poorer sleep quality (63% versus 47%, P = 0.0003), and more depression (22% versus 13%, P = 0.01). Fewer than 20% of EOCS and controls exercised regularly. In multivariate analyses, EOCS with high levels of depression, neurotoxicity, and sleep disturbance had an increased risk of developing SLTF (P < 0.01). CONCLUSION: Compared with controls, EOCS presented similar QoL but persistent LTF, EOC-related symptoms, neurotoxicity, depression, and sleep disturbance. Depression, neuropathy, and sleep disturbance are the main conditions associated with severe LTF.

Localized high grade endometrial stromal sarcoma and localized undifferentiated uterine sarcoma: a retrospective series of the French Sarcoma Group.

OBJECTIVE: High grade endometrial stromal sarcoma and undifferentiated uterine sarcomas are associated with a very poor prognosis. Although large surgical resection is the standard of care, the optimal adjuvant strategy remains unclear. METHODS: A retrospective analysis of patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas (stages I-III) treated in 10 French Sarcoma Group centers was conducted. RESULTS: 39 patients with localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas treated from 2008 to 2016 were included. 24/39 patients (61.5%) were stage I at diagnosis. 38/39 patients underwent surgical resection, with total hysterectomy and bilateral oophorectomy completed in 26/38 (68%). Surgeries were mostly resection complete (R0, 23/38, 60%) and microscopically incomplete resection (R1, 6/38, 16%). 22 patients (58%) underwent postoperative radiotherapy (including brachytherapy in 11 cases), and 11 (29%) underwent adjuvant chemotherapy. After a median follow-up of 33 months (range 2.6-112), 17/39 patients were alive and 21/39 (54%) had relapsed (9 local relapses and 16 metastases). The 3 year and 5 year overall survival rates were 49.8% and 31.1%, respectively, and 3 year and 5 year disease free survival rates were 42.7% and 16.0%, respectively. Median overall survival and disease free survival were 32.7 (95% CI 16.3-49.1) and 23 (4.4-41.6) months, respectively. Medians were, respectively, 46.7 months and 39.0 months among those who underwent adjuvant radiotherapy and 41.0 months and 10.3 months for those who underwent adjuvant chemotherapy. In multivariate analysis, adjuvant radiotherapy was an independent prognostic factor for overall survival (P=0.012) and disease free survival (P=0.036). Chemotherapy, International Federation of Gynecology and Obstetrics I-II stages, and Eastern Cooperative Oncology Group-performance status 0 correlated with improved overall survival (P=0.034, P=0.002, P=0.006), and absence of vascular invasion (P=0.014) was associated with better disease free survival. CONCLUSIONS: The standard treatment of primary localized high grade endometrial stromal sarcoma and undifferentiated uterine sarcomas is total hysterectomy and bilateral oophorectomy. The current study shows that adjuvant radiotherapy and adjuvant chemotherapy appear to improve overall survival. A prospective large study is warranted to validate this therapeutic management.

[Primary management of endometrial carcinoma. Joint recommendations of the French society of gynecologic oncology (SFOG) and of the French college of obstetricians and gynecologists (CNGOF)]. / Prise en charge primaire des cancers de l'endomètre : recommandations SFOG-CNGOF.

OBJECTIVES: The management of endometrial carcinoma is constantly evolving. The SFOG and the CNGOF decided to jointly update the previous French recommendations (Institut national du cancer 2011) and to adapt to the French practice the 2015 recommendations elaborated at the time of joint European consensus conference with the participation of the three concerned European societies (ESGO, ESTRO, ESMO). MATERIAL AND METHODS: A strict methodology was used. A steering committee was put together. A systematic review of the literature since 2011 has been carried out. A first draft of the recommendations has been elaborated, with emphasis on high level of evidence. An external review by users representing all the concerned discipines and all kinds of practice was completed. Three hundred and four comments were sent by 54 reviewers. RESULTS: The management of endometrial carcinoma requires a precise preoperative workup. A provisional estimate of the final stage is provided. This estimation impact the level of surgical staging. Surgery should use a minimal invasive approach. The final pathology is the key of the decision concerning adjuvant therapy, which involves surveillance, radiation therapy, brachytherapy, or chemotherapy. CONCLUSION: The management algorithms allow a fast, state of the art based, answer to the clinical questions raised by the management of endometrial cancer. They must be used only in the setting of a multidisciplinary team at all stages of the management.

Bevacizumab with or after chemotherapy for platinum-resistant recurrent ovarian cancer: exploratory analyses of the AURELIA trial.

BACKGROUND: In the open-label randomized phase III AURELIA trial, adding bevacizumab to chemotherapy for platinum-resistant ovarian cancer (PROC) significantly improved progression-free survival and response rate versus chemotherapy alone, but not overall survival (OS). We explored the effect of bevacizumab use after disease progression (PD) in patients randomized to chemotherapy alone. PATIENTS AND METHODS: In AURELIA, 361 women with PROC were randomized to chemotherapy alone or with bevacizumab. Patients initially randomized to chemotherapy were offered bevacizumab after PD. Post hoc analyses assessed efficacy and safety in three subgroups: chemotherapy alone, chemotherapy followed by bevacizumab after PD, and chemotherapy plus bevacizumab at randomization. RESULTS: Of the 182 patients randomized to chemotherapy alone, 72 (40%) received bevacizumab after PD and 110 (60%) never received bevacizumab. There were no significant differences in patient and disease characteristics between these subgroups at baseline or the time of PD. Compared with patients never receiving bevacizumab, the risk of death was significantly reduced in patients receiving bevacizumab either upfront with chemotherapy [hazard ratio (HR) = 0.68, 95% confidence interval (CI) 0.52-0.90] or after PD (HR = 0.60, 95% CI 0.43-0.86). The tolerability of bevacizumab was similar with administration upfront or after PD. CONCLUSIONS: Post-PD bevacizumab use may have confounded OS results in AURELIA. In these exploratory analyses of non-randomized subgroups, bevacizumab use, either with chemotherapy or after PD on chemotherapy alone, improved OS compared with no bevacizumab. Combining bevacizumab with chemotherapy at first appearance of platinum resistance maximises the likelihood of patients receiving this active treatment for PROC. ClinicalTrials.gov: NCT00976911.

Networking for ovarian rare tumors: a significant breakthrough improving disease management.

BACKGROUND: Rare ovarian tumors represent >20% of all ovarian cancers. Given the rarity of these tumors, natural history, prognostic factors are not clearly identified. The extreme variability of patients (age, histological subtypes, stage) induces multiple and complex therapeutic strategies. METHODS: Since 2011, a national network with a dedicated system for referral, up to 22 regional and three national reference centers (RC) has been supported by the French National Cancer Institute (INCa). The network aims to prospectively monitor the management of rare ovarian tumors and provide an equal access to medical expertise and innovative treatments to all French patients through a dedicated website, www.ovaire-rare.org. RESULTS: Over a 5-year activity, 4612 patients have been included. Patients' inclusions increased from 553 in 2011 to 1202 in 2015. Expert pathology review and patients' files discussion in dedicated multidisciplinary tumor boards increased from 166 cases in 2011 (25%) to 538 (45%) in 2015. Pathology review consistently modified the medical strategy in 5-9% every year. The rate of patients' files discussed in RC similarly increased from 294 (53%) to 789 (66%). An increasing number (357 in 5 years) of gynecologic (non-ovarian) rare tumors were also registered by physicians seeking for pathological or medical advice from expert tumor boards. CONCLUSION: Such a nation-wide organization for rare gynecological tumors has invaluable benefits, not only for patients, but also for epidemiological, clinical and biological research.

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.

A new approach to integrate toxicity grade and repeated treatment cycles in the analysis and reporting of phase I dose-finding trials.

BACKGROUND: Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. PATIENTS AND METHODS: Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. RESULTS: Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. CONCLUSIONS: Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.

Actinomycin D, cisplatin, and etoposide regimen is associated with almost universal cure in patients with high-risk gestational trophoblastic neoplasia.

BACKGROUND: Patients with high-risk gestational trophoblastic neoplasia (GTN) need multi-agent chemotherapy to be cured. The most common regimen is etoposide (E), methotrexate (M) and actinomycin D (A), alternating weekly with cyclophosphamide (C) plus vincristine (O) (EMA/CO). Cisplatin (P) is a very active drug, but it is usually restricted to second-line therapies. Herein, we report the results of a cisplatin-based therapy: APE (actinomycin D, cisplatin, and etoposide). PATIENTS AND METHODS: The efficacy and safety of APE for high-risk GTN (defined by Institut Gustave-Roussy (IGR) criteria and/or an International Federation of Gynaecology and Obstetrics (FIGO) score >6) are reported. Patients with brain metastasis or placental-site trophoblastic tumour were excluded. RESULTS: Between 1985 and 2013, 95 patients were treated with APE for high-risk GTN: 59 patients as first-line, 36 as ⩾ 2nd-line therapy. There was 94.7% complete remission, though five patients relapsed. One patient died from GTN after multiple lines of chemotherapy. The five-year overall survival rate (median follow-up 5.7 years) was 97% (95% confidence interval (CI): 91-99%). No death from toxicity occurred. Long-term, six grade-1 neuro-toxicities, three grade-1 and two grade-2 oto-toxicities, and one grade-1 renal toxicity were recorded. One patient developed AML-M4 after APE and EMA/CO. Thirty-four of 35 women, who wished to become pregnant, succeeded and all had at least one live birth. CONCLUSION: With a 97% long-term overall survival rate, limited long-term toxicity, and an excellent reproductive outcome, APE could be regarded as an alternative option to EMA/CO as a standard therapy for high-risk GTN.

Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a phase II trial of GINECO.

BACKGROUND: Patients with recurrent/metastatic endometrial cancer that progresses after chemotherapy have limited treatment options and poor outcomes. Preclinical data suggest the oral mammalian target of rapamycin inhibitor everolimus may provide clinical benefit in these patients. METHODS: In this multicenter, open-label, phase 2 study, patients with advanced or metastatic endometrial cancer refractory to one or two previous chemotherapy regimens received everolimus 10 mg per day until progression or unacceptable toxicity. Primary end point was the non-progressive disease rate at 3 months. Secondary end points included duration of response, progression-free, and overall survival (OS), and safety. RESULTS: Forty-four patients were enrolled (median age, 65 years); 66% received one previous chemotherapy regimen. The 3-month non-progressive disease rate was 36% (95% confidence interval 22-52%), including two patients (5%) with partial response (PR). At 6 months, two additional patients experienced PR. Median duration of response was 3.1 months. Median progression-free and OS were 2.8 months and 8.1 months, respectively. The most common adverse events were anaemia (100%), fatigue (93%), hypercholesterolaemia (81%), and lymphopenia (81%). CONCLUSION: Everolimus demonstrated efficacy and acceptable tolerability in patients with chemotherapy-refractory advanced or metastatic endometrial cancer. These results support the further development of phosphatidylinositol 3-kinase-targeted therapies in endometrial cancer.

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.

Combined oral topotecan plus carboplatin in relapsed or advanced cervical cancer: a GINECO phase I-II trial.

AIM: Combined cisplatin-topotecan therapy is standard care for advanced cervical cancer, however it is associated with haematotoxicity and nephrotoxicity. This trial was designed to assess the combination of carboplatin which is less nephrotoxic, and oral topotecan. PATIENTS AND METHODS: Patients with advanced/recurrent squamous cervical cancer received carboplatin (AUC5) on day 1, with escalating oral topotecan (3.0 mg/m(2) starting dose) on days 1, 8 and 15, every 4 weeks. Endpoints were the maximal tolerated dose for the phase I part and safety profiles and response rates for the phase II part of the study. RESULTS: Two dose levels were evaluated. A total of 18 patients (6 phase I, 12 phase II) were treated. The maximal tolerated dose was 3.0 mg/m(2) topotecan with carboplatin AUC5. Phase II accrual was interrupted following unacceptable toxicity, with 10 therapy-related related serious events in 9 out of 12 patients: grade 3-4 pancytopenia (7), febrile neutropenia (1), grade 3 haemorrhage (1) and grade 3 vomiting (1). CONCLUSION: Weekly oral topotecan combined with carboplatin is associated with unmanageable toxicity and is not recommended. Future studies are warranted to better understand the toxicity of such a combination and explore alternative combinations for advanced cervical cancer.

Ovarian cancer in elderly patients: carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in late relapse: a Gynecologic Cancer Intergroup (GCIG) CALYPSO sub-study.

BACKGROUND: CALYPSO (CAeLYx in Platinum Sensitive Ovarian) patients compared carboplatin-pegylated liposomal doxorubicin (C-PLD) with carboplatin-paclitaxel (C-P) in patients with late-relapsing recurrent ovarian cancer (ROC). We analyzed outcomes in patients ≥70 years. PATIENTS AND METHODS: Nine hundred and seventy-six patients with taxane-pretreated ROC relapsing >6 months after first- or second-line platinum-based therapy were randomly assigned to 4-weekly C area under the curve (AUC) 5 plus PLD 30 mg/m(2) or 3-weekly C AUC 5 plus P 175 mg/m(2) for six or more cycles. RESULTS: One hundred and fifty-seven (16%) patients ≥70 years (median: 74 years, C-PLD; 73 years, C-P; range 70-82 years) were included (n = 71, C-PLD; n = 86, C-P). In comparing elderly and younger, elderly patients experienced fewer grade ≥2 allergic reactions (P = 0.005) but more grade ≥2 sensory neuropathy (P = 0.007). Myelosuppression did not differ with age. Elderly patients completed planned treatment as frequently as younger (79%, C-PLD; 82%, C-P). In comparing arms within elderly patients, C-P was associated with more grade ≥2 alopecia, sensory neuropathy, arthralgia/myalgia (P < 0.001 for all), severe leukopenia plus febrile neutropenia; C-PLD was associated with more grade ≥2 hand-foot syndrome (P = 0.005). Median progression-free survival was 11.6 months (C-PLD) and 10.3 months (C-P; P = 0.44). CONCLUSIONS: Patients ≥70 years experienced more neuropathy, with a higher incidence in the C-P arm. Similar to all study patients, C-PLD provided a better therapeutic index with less toxicity than C-P in elderly women with platinum-sensitive ROC.

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.