Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1-5) plus either oral sorafenib 400 mg or placebo twice daily on days 6-15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01047891. FINDINGS: Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). INTERPRETATION: Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. FUNDING: Bayer, Amgen, and GlaxoSmithKline.

[Expectation about maintenance therapy among the GINECO French ovarian cancer cohort from the European NOGGO/ENGOT-ov22 Expression IV survey]. / Attentes des patientes suivies pour un cancer de l'ovaire concernant les traitements d'entretien : résultats de la cohorte française GINECO de l'enquête européenne NOGGO/ENGOT-ov22 (Expression IV).

BACKGROUND: Expression IV survey evaluated the patients' expectations to a maintenance therapy. METHODS: From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines. RESULTS: Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission. CONCLUSION: This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations.

Health-related quality of life during sequential chemotherapy with carboplatin followed by weekly paclitaxel in advanced ovarian cancer: a multicenter phase ii study of the North Eastern German Society of Gynecological Oncology.

AIM: We describe the impact of a sequential dose-dense schedule of carboplatin and paclitaxel on the quality of life (QoL) of patients with ovarian cancer. PATIENTS AND METHODS: In this multicenter phase II trial, four cycles of carboplatin followed by 12 cycles of weekly paclitaxel were applied after cytoreductive surgery. QoL was assessed using the QoL questionnaires EORTC QLQ-C30 and QLQ-OV28 before chemotherapy (baseline), after four cycles of carboplatin, at the end of treatment (EOT), and after 6, 12, and 24 months. RESULTS: Out of 104 eligible patients 87 (84%) participated in at least one QoL assessment. At baseline, all QLQ-C30 scales and symptoms were significantly worse than age-adjusted values for the general population. Subsequently QoL improved in general. During chemotherapy with paclitaxel, most functioning scales and symptoms worsened slightly (not significantly). However, peripheral neuropathy and chemotherapy-related side-effects increased to clinically important levels. At the end of treatment, most QoL scores were similar to those of the general population, but physical functioning and fatigue were worse. Sexual functioning and peripheral neuropathy remained problematic. CONCLUSION: QoL was affected mainly by the weekly paclitaxel schedule, but effects were in most cases only temporary. A dose-dense regimen using a sequential protocol may be favourable in terms of QoL.

Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer: a randomized multicenter phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group.

PURPOSE: Weekly administration of topotecan (Tw) is less toxic and widely considered a better treatment option than conventional 5-day therapy (Tc) in women with platinum-resistant recurrent ovarian cancer. We conducted a randomized phase II trial (TOWER [Topotecan Weekly Versus Conventional 5-Day Schedule in Patients With Platinum-Resistant Ovarian Cancer]) to better define the ratio between benefits and risks with either treatment approach. PATIENTS AND METHODS: Patients were randomly assigned to two independent two-stage protocols of Tw (4 mg/m(2)/wk administered on days 1, 8, and 15) or Tc (1.25 mg/m(2)/d on days 1 to 5). We evaluated risk ratios (RRs) for the primary end point of clinical benefit (complete response, partial response, and stable disease), the duration of progression-free survival (PFS) and overall survival (OS), associated hazard ratios (HRs), and RRs of toxicity with 95% CIs. RESULTS: In total, 194 patients were randomly assigned at 54 centers to Tw (n = 97) or Tc (n = 97). Clinical benefit was observed in 36 of 76 (47%; 95% CI, 36% to 59%) Tw and 46 of 80 (58%; 95% CI, 46% to 68%) Tc patients (RR, 1.21; 95% CI, 0.90 to 1.64; P = .205). Patients in the Tw group had a slightly shorter PFS (HR, 1.29; 95% CI, 0.96 to 1.76) but similar OS (HR, 1.04; 95% CI, 0.74 to 1.45) compared with Tc. Tw was associated with significantly lower risks of anemia (RR, 0.35; 95% CI, 0.16 to 0.79), neutropenia (RR, 0.38; 95% CI, 0.23 to 0.65), and thrombocytopenia (RR, 0.23; 95% CI, 0.09 to 0.57). CONCLUSION: With regard to effectiveness in terms of response and PFS, Tc remains the standard of care in patients with platinum-resistant recurrent ovarian cancer. However, comparable OS rates and a favorable toxicity profile make Tw another viable treatment option in this setting.

Clinical management of borderline tumours of the ovary - experience from the "Berlin online tumour conference for gynaecological malignancies".

Borderline ovarian tumour (BOT) represents a rare and special tumour entity. Despite a generally favourable prognosis for patients with BOT, the presence of invasive peritoneal implants decreases the survival rate to 30-50%. In contrast to ovarian cancer, only few data exist concerning the current clinical management of patients with BOT. For this reason, the present analyses were performed for patients with BOT who were admitted into our online tumor conference for patients with gynaecological malignancies. Based on the results discussed in this article, the current aspects and problems regarding the diagnostic, surgical and conservative treatment and aftercare management of patients with BOT are considered.

A phase-I trial of pemetrexed plus carboplatin in recurrent ovarian cancer.

BACKGROUND: Carboplatin-based combinations are established in platinum-sensitive recurrent ovarian cancer. To improve the therapeutic index, new platinum-based combinations are required. Pemetrexed is a multi-targeted antifolate inhibiting thymidylate synthase. The aim of this study was to determine the maximally tolerated dose (MTD) and dose-limiting toxicity (DLT) and to characterize toxicities of the combination of pemetrexed (Pem) and carboplatin (Cb). DESIGN: A standard three-patient cohort dose escalation was performed starting at Cb AUC-5 and Pem 500 mg/m(2). Patients with platinum-sensitive recurrent ovarian cancer were eligible. Two levels of Cb (AUC-5, 6) and five levels of Pem (500, 600, 700, 800, and 900 mg/m(2)) were evaluated. DLTs were based on cycle 1. RESULTS: Twenty patients were enrolled. The median age was 57.4 years (37.3-75.3) and the median platinum-free interval was 26.2 months (7.2-124.4). There was one DLT at dose level 3 in cycle one. No serious adverse events related to the study therapy were observed. The 20 patients completed 112 cycles of Cb (104 were planned) and 115 cycles of Pem (112 were planned). The maximum dose level of Cb AUC-6 and Pem 900 mg/m(2) was well tolerated. Response rates in 19 patients were: CR: 63.2%; PR: 21.1%; SD; 5.3%, PD: 10.5%. CONCLUSIONS: The combination carboplatin and pemetrexed is safe and well tolerated. A multicenter phase-II trial is currently underway.

Development of the Berlin Symptom Checklist Ovary (BSCL-O) for the measurement of quality of life of patients with primary and recurrent ovarian cancer: results of a phase I and II study.

GOALS OF WORK: Quality of life (Qol) represents a relevant end point in the clinical management of advanced ovarian cancer (AOC). However, there exist only a few specific instruments which have been designed for patients with ovarian cancer. The aim of this study was to develop a systematic checklist (Berlin Symptom Checklist Ovary (BSCL-O)) as an instrument of Qol for patients with AOC and to discriminate between the frequency and the importance of symptoms. PATIENTS AND METHODS: The main symptoms were identified in a phase I study via free interviews of five patients with ovarian cancer (OC) as well as five medical doctors, family dependent, and care workers. In the phase II study, the capability of BSCL-O was evaluated by questionnaire-guided interviews of 200 patients with primary OC, recurrent OC, metastasized breast cancer, and benign ovarian tumors. MAIN RESULTS: In phase I, 36 main symptoms were identified. In phase II, 7,200 answers from 98.5% of all patients were evaluable. Of the 36 symptoms of the BSCL-O, 23 revealed clinical relevance. There was a correlation of frequency and importance of symptoms (p < 0.05). The symptoms of the BSCL-O were deemed twice as strenuous in patients with recurrent OC. CONCLUSIONS: The BSCL-O can measure Qol of patients with OC. The BSCL-O is being validated in a phase III study.

Brain metastases from epithelial ovarian cancer: overview and optimal management.

Central nervous system involvement is a rare finding in the management of epithelial ovarian cancer with an incidence between 1-2%. A sharp rise in the incidence has been widely and repeatedly proclaimed for nearly two decades now, but has to be treated with scepticism after a careful review of the current literature. Brain metastases from ovarian cancer are known to be related to a very poor prognosis. Since brain imaging is not part of the routine follow-up care for ovarian cancer patients, and since CA-125--one of the standard tools--cannot be relied upon to detect central nervous system relapse, brain lesions are mostly traced by unspecific neurological symptoms only. Several prognostic factors are still being discussed today. But only a high performance status and the absence of an extra cranial disease at the time of CNS relapse have been accepted throughout the current literature as having a highly significant positive impact on survival. In the past, therapeutic efforts have focused on symptom palliation with corticosteroids and whole-brain radiation therapy (WBRT). During the last years several other therapy options have evolved from encouraging efforts made by several study groups, including chemotherapy, neurosurgery and radiosurgery. It has been shown that a multi-modal approach, combining these strategies, promises the best prolongation of survival and in some cases even resulted in long-term remissions. The present article gives an overview of brain metastases in epithelial ovarian cancer and discusses the current treatment options.

Tumor- and stromal cell-specific expression of topoisomerase IIα and HER-2/neu in primary and recurrent ovarian cancer: Results of a prospective study.

The aim of the present study was to evaluate the expression of topoisomerase IIα (TOP2A) and HER-2 in tumor epithelial and adjacent stromal cells in ovarian cancer (OvCa). Immunohistochemistry for TOP2A and HER-2 was performed on 50 OvCa specimens from the Tumor Bank of Ovarian Cancer, and was correlated to established clinicopathological parameters. TOP2A was expressed in 98% and HER-2 in 52% of the OvCa specimens. Moderate expression of TOP2A was detected in 72% of the adjacent stromal cells. TOP2A and HER-2 were strongly expressed in the tumor epithelial cells of primary OvCa, but reduced in recurrent OvCa. Stromal expression of TOP2A increased in recurrent OvCa after platinum-based chemotherapy. In conclusion, distinct epithelial and stromal cell expression of TOP2A and HER-2 is a novel feature in the tumor biology of OvCa. Differential cellular expression of TOP2A in relation to previous chemotherapy probably reflects a modified activity of the 'stromal compartment' in drug resistance. Thus, analysis of TOP2A expression in tumor and stromal OvCa cells can aid in identifying subgroups of patients who may have a more favorable response to chemotherapy.

Nonplatinum topotecan combinations versus topotecan alone for recurrent ovarian cancer: results of a phase III study of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group.

PURPOSE: The management of recurrent ovarian cancer remains controversial. Single-agent topotecan is an established treatment option, and preliminary evidence suggests improved tumor control by combining topotecan with etoposide or gemcitabine. PATIENTS AND METHODS: Women with relapsed ovarian cancer after primary surgery and platinum-based chemotherapy were randomly assigned to topotecan monotherapy 1.25 mg/m(2)/d, topotecan 1.0 mg/m(2) plus oral etoposide 50 mg/d, or topotecan 0.5 mg/m(2)/d plus gemcitabine 800 mg/m(2) on day 1 and 600 mg/m(2) on day 8 every 3 weeks. Patients were stratified for platinum-refractory and platinum-sensitive disease according to a recurrence-free interval of less or more than 12 months, respectively. The primary end point was overall survival. Secondary end points included progression-free survival, objective response rates, toxicity, and quality of life (as measured by the European Organisation for Research and Treatment of Cancer [EORTC] 30-item Quality-of-Life Questionnaire). RESULTS: The trial enrolled 502 patients with a mean age of 60.5 years (+/- 10.2 years), 208 of whom were platinum resistant. Median overall survival was 17.2 months (95% CI, 13.5 to 21.9 months) with topotecan, 17.8 months (95% CI, 13.7 to 20.0 months) with topotecan plus etoposide (log-rank P = .7647), and 15.2 months (95% CI, 11.3 to 20.9 months) with topotecan plus gemcitabine (log-rank P = .2344). Platinum-sensitive patients lived significantly longer than platinum-refractory patients (21.9 v 10.6 months). The median progression-free survival was 7.0, 7.8, and 6.3 months, respectively. Objective response rates were 27.8%, 36.1%, and 31.6%, respectively. Patients under combined treatment were at higher risk of severe thrombocytopenia. CONCLUSION: Nonplatinum topotecan combinations do not provide a survival advantage over topotecan alone in women with relapsed ovarian cancer.

Biweekly pegylated liposomal doxorubicin as second-line treatment in patients with relapsed ovarian cancer after failure of platinum and paclitaxel: results from a multi-center phase II study of the NOGGO.

BACKGROUND: Pegylated liposomal doxorubicin (PLD) is one of the most effective cytotoxic agents in recurrent ovarian cancer. Palmar-plantar erythrodysesthesia (PPE) is a typical and commonly noted adverse event and often represents the dose-limiting toxicity. The purpose of this multicenter study was to determine the efficacy of this regimen as second-line therapy for patients with recurrent ovarian cancer. PATIENTS AND METHODS: Patients with recurrent epithelial ovarian cancer after surgery and initial treatment with carboplatin and paclitaxel were enrolled. Eligible patients were required to have an ECOG performance status of < or =2, and sufficient organ function. PLD was administered at a dose of 20 mg/m2 every two weeks. RESULTS: Twenty patients were recruited into this trial. Overall, 155 cycles of chemotherapy with a median of six courses (range 4-24) were administered. The median patient age was 64 years (range, 41-77 years). The hematological and non-hematological toxicity profile was favorable. No grade IV toxicity was observed. PPE grade III toxicity was noted in only one patient. Median overall survival was 19.2 months (range 1.8 to 39 months; 95% confidence interval (CI) 14.2-29.7 months) Progression-free survival was 3.3 months (range 1.38 to 36.4 months; 95% CI 1.84-13.4 months). CONCLUSION: Biweekly PLD is an effective second-line treatment for patients with relapsed ovarian cancer. Toxicity incidence with this treatment schedule does not appear to be associated with the number of previous chemotherapies. Our data supports the need for a randomized study comparing biweekly with conventional monthly administration of 40 mg/m2 or 50 mg/m2 PLD to determine the best therapeutic index for PLD.

Topotecan and carboplatin in patients with platinum-sensitive recurrent ovarian cancer. Results of a multicenter NOGGO: phase I/II study.

OBJECTIVE: Second-line treatment with paclitaxel and carboplatin enhances survival of women with platinum-sensitive recurrent ovarian cancer (ROC). However, because of its cumulative neurotoxicity, there is a strong demand for platinum-combinations with better therapeutic index. Because of its pharmacological properties, topotecan is a good adjunct to carboplatin in this setting, but its safety and efficacy remains to be defined. METHODS: Patients with platinum-sensitive ROC were eligible in this multicenter phase I/II study, stratified according to treatment-free interval (TFI). Dose level 0 consisted of topotecan 1 mg/m(2)/d1-3/q21d plus carboplatin AUC5/d3/q21d. DLT was defined as grade > or =3 neutropenia or thrombocytopenia or grade > or =3 non-hematological toxicity excluding alopecia, nausea and vomiting, accompanied by a treatment delay >1 week. RESULTS: From June 2004 to August 2005, 26 patients were enrolled, receiving a total of 145 cycles of chemotherapy. MTD was reached at topotecan 0.75 mg/m(2) and carboplatin AUC5. We observed a single grade 4 leucopenia. There were 3 (12%), 15 (58%) and 8 (31%) events of grade 3/4 hematological anaemia, leucopenia, and thrombocytopenia. Response rate was 67% (95% CI 43-85), median progression-free survival 9.5 months (95% CI 7.3-12.0), median overall survival 19.4 months (95% CI 12.3-26.9). None of the toxicity or efficacy endpoints were associated with TFI. CONCLUSION: Topotecan and carboplatin is a well tolerated novel doublet option for women with platinum sensitive ROC. We encourage further studies on this approach, but to limit the doses of topotecan to 0.75 mg/m(2)/d1-3 and carboplatin AUC 5/d3.