Safety and efficacy of ET-743: the French experience

Initial evidence of clinical benefit with ecteinascidin-743 (ET-743) in patients with sarcoma was provided during a Phase I pharmacokinetic study in which 52 patients received ET-743 at doses of 50-1800 micrograms/m2 as a 24 h continuous infusion every 3 weeks. Neutropenia and thrombocytopenia were the dose-limiting toxicities; liver toxicity (a severe but transient and reversible increase in transaminase concentrations) was not treatment limiting. In conjunction with results obtained with ET-743 in a compassionate-use program, these indications of activity in heavily pretreated patients with sarcoma prompted initiation of a French multicenter Phase II study of ET-743 in this population. From February 1999 to January 2001, 54 patients with advanced anthracycline-pretreated soft-tissue sarcoma (STS) received ET-743 at a dose of 1500 micrograms/m2 every 3 weeks by continuous 24 h infusion. The main histological subtype was leiomyosarcoma (37%); the majority of primary tumors were visceral (24%) or uterine (19%) sarcomas. In this Phase II population (> or = 25% negative prognostic or predictive factors of response to chemotherapy; > or = 50% anthracycline- and ifosfamide-resistant), safety data were comparable to those obtained in the Phase I and compassionate-use studies. Asymptomatic and reversible neutropenia and transaminitis (grade 3/4) were the most frequent toxicities (approximately 60% of patients); febrile neutropenia was infrequent (< 10%). No mucositis, alopecia, cardiac or neurotoxicity was observed. Two severe cases of rhabdomyolysis occurred. Side effects were non-cumulative, reversible and manageable. Of 52 evaluable patients, three (6%) achieved a long-lasting (8-13 months) partial response, four (8%) achieved a minor response (25-50% tumor reduction) and 22 (42%) achieved disease stabilization. With a 13-month median follow-up, median survival was almost 11 months. Progression-free survival at 6 months was 26.5% and the overall survival rate at 12 months was almost 50%. The response rate was uninfluenced by tumor metastatic site, size or anthracycline sensitivity status. These results, combined with the lack of cumulative toxicity, confirm the role of ET-743 in the treatment of advanced STS.     

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m(2) intravenously days 1-4 and 15-18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-na?ve and 14 GR. The chemotherapy-na?ve patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21% (95% CI: 8-58%). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.     

Phase II study of S-1 monotherapy as a first-line treatment for elderly patients with advanced nonsmall-cell lung cancer: the Central Japan Lung Study Group trial 0404

Although S-1 has been shown to have activity against advanced nonsmall-cell lung cancer (NSCLC), its efficacy for elderly patients remains unclear. This phase II study evaluated the efficacy and safety of S-1 as a first-line treatment for elderly patients. Chemotherapy-na?ve patients aged 70 years or older with stages IIIB to IV or postoperative NSCLC and performance status 1 or lower were eligible. Patients received S-1 approximately equivalent to 80 mg/m/day for 2 weeks followed by a 1-week rest period every 3 weeks. The primary end point was the response rate. Secondary end points were toxicity, disease control rate, progression-free survival, and overall survival. Twenty-nine patients were eligible. The median age was 78 years (range, 70-85 years). The overall response rate and the disease control rate were 27.6 [95% confidence interval (CI), 11.3-43.9%] and 65.5% (95% CI: 48.2-82.8%), respectively. The median progression-free survival time was 4.0 months (95% CI: 4.0-9.8 months). The median overall survival was 12.1 months (95% CI: 13.8-25.5 months) and the 1-year survival rate was 53.6%. No grade 4 toxicities were observed. The only hematological toxicity of grade 3 was anemia in 6.9% of patients. The grade 3 nonhematological toxicities included hyponatremia, anorexia, nausea, oral mucositis, and diarrhea in 3.4% of patients and infection in 6.9% of patients. S-1 monotherapy was effective and well tolerated as a first-line treatment for elderly patients with advanced NSCLC. The results of this study warrant further investigations of this regimen, including a randomized controlled trial.     

The “old drug” dacarbazine as a second/third line chemotherapy in advanced soft tissue sarcomas

Summary The aim of this study was to evaluate retrospectively the response rate, progression-free survival and median duration of response to dacarbazine as second/third-line chemotherapy for refractory soft tissue sarcomas. We studied 40 valuable patients with refractory soft tissue sarcomas and confirmed progressive disease (median age 54 years; range 24–73) treated between May 1997 and October 2005: 30 (75%) with metastases, and 23 (57.5%) with grade 3 disease. Dacarbazine was given as second-line chemotherapy to 29 patients (72.5%) every 21 days using three different schedules: dacarbazine 800 mg/m² on day 1 (26 patients); dacarbazine 400 mg/m² on days 1 and 2 (five patients); and dacarbazine 300 mg/m² on days 1, 2 and 3 (nine patients). There were no complete responses, three (7.5%) partial responses and five (12.5%) cases of stable disease, for an overall disease control rate of 20%. Median progression-free survival was 2 months and median response duration 9 months. The 3- and 6-month progression-free rates were, respectively, 25% (SE 6.85%) and 20% (SE 6.32%). There were no cases of grade 3–4 hematological and non-hematological toxicity. In conclusion, our results suggest that second/third-line therapy with dacarbazine leads to satisfactory disease control in refractory soft tissue sarcomas; its activity seems to be comparable with other treatments, such as high dose ifosfamide or ecteinascidin-743, but it has a better toxicity profile.     

Efficacy and safety of doublet versus single agent as salvage treatment for metastatic breast cancer pretreated with anthracyclines and taxanes: a systematic review and meta-analysis

Aim: To perform a systematic review and meta-analysis of randomized controlled trials to compare the efficacy and safety of doublet versus single agent as salvage treatment for pretreated metastatic breast cancer.

Methods: A comprehensive literature search was performed to identify relevant randomized controlled trials (RCTs). All clinical studies were independently identified by two authors for inclusion. Demographic data, treatment regimens, objective response rate (ORR), and progression-free survival (PFS) and overall survival (OS) were extracted and analyzed using Comprehensive MetaAnalysis software (Version 2.0).

Results: Thirteen RCTs involving 4878 pretreated metastatic breast cancer patients were ultimately identified. The pooled results demonstrated that doublet combination therapy significantly improved ORR (RR 1.13, 95% CI: 1.01–1.27, p?<?.001) and PFS (hazard ration [HR] 0.83, 95% CI: 0.73–0.96, p?=?.011), but not OS (HR 0.93, 95% CI: 0.86–1.01, p?=?.065). Similar results were observed in sub-group analysis according to treatment regimens. Additionally, more incidences of grade 3 or 4 myelosuppression toxicities nausea and fatigue were observed in doublet combination therapy.

Conclusions: In comparison with a single agent alone, doublet combination therapy as salvage treatment for pretreated metastatic breast cancer patients significantly improves ORR and PFS, but not OS. Further studies are recommended to identify patients who will most likely benefit from the appropriate doublet combination therapy.     

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium

Background Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease. Patients and methods We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-na?ve patients with histologically-confirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m² on days 1, 8 and 15 of a 28 day cycle. Results Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%. Conclusion Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.     

Treosulfan and gemcitabine in metastatic uveal melanoma patients: results of a multicenter feasibility study

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54-133 weeks], the progression-free survival was 28.5 weeks (95% CI 13-62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.     

Clinical pharmacology of the novel marine-derived anticancer agent Ecteinascidin 743 administered as a 1- and 3-h infusion in a phase I study

Ecteinascidin 743 (ET-743) is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. In the present article, the pharmacokinetics and pharmacodynamics of ET-743 are described within a phase I study. Forty patients with solid tumors initially received ET-743 as a 1-h i.v. infusion every 21 days at nine dose levels (50-1100 microg/m(2)). The maximal tolerated dose (MTD) was 1100 microg/m(2), with thrombocytopenia and fatigue as dose-limiting toxicities (DLTs). As this MTD was substantially lower than in parallel phase I studies, dose escalation continued using a prolonged, 3-h infusion. Thirty-two patients were entered at five dose levels (1000-1800 microg/m(2)). The MTD was 1800 microg/m(2) with pancytopenia and fatigue as DLTs. The recommended phase II dose was 1650 microg/m(2) given over 3 h at which 12 patients were treated. Pharmacokinetic monitoring was performed for both treatment schedules. Non-compartmental pharmacokinetic parameters at the recommended dose with the 3-h infusion were (mean value+/-SD): clearance 87+/-30 l/h and mean elimination half-life 26+/-7 h. Pharmacokinetics were linear at the dose range tested with this schedule. The percentage decrease in platelets, white blood cells and neutrophils correlated with the area under the plasma concentration versus time curve (AUC), dose and maximal plasma concentration (C(max)). Hepatic toxicity increased with dose, AUC and C(max). Administration of 1650 microg/m(2) ET-743 over 3 h seemed clinically feasible; pharmacokinetics were linear with this schedule. Hepatic and hematological toxicities correlated with exposure to ET-743.     

Addition of vandetanib to chemotherapy in advanced solid cancers: a meta-analysis

The addition of vandetanib to chemotherapy has been shown to have a marked effect on patients with advanced cancers who had failed previous chemotherapy. We carried out a meta-analysis to determine the efficacy and safety of vandetanib compared with chemotherapy in patients with advanced cancers. For this meta-analysis, we selected randomized clinical trials that compared vandetanib-based therapy (VBT) with the matched chemotherapy or placebo alone in patients with advanced cancers. The outcomes included overall survival (OS), progression-free survival (PFS), the objective response rate, and toxicities. Hazard ratios (HRs) and odds ratios were reported with 95% confidence intervals (CIs). A total of 14 eligible trials were included for the meta-analysis, with 2995 patients in the VBT group and 2479 patients in the control group. A significant improvement was observed in PFS (HR 0.76, 95% CI 0.68-0.86 in all cancers, HR 0.80, 95% CI 0.70-0.90 in lung cancer, HR 0.54, 95% CI 0.40-0.74 in thyroid cancer) and in objective response rate (odds ratio 2.09, 95% CI 1.42-3.07) in the VBT group. However, no significant difference was found in OS (HR 0.96, 95% CI 0.90-1.03). The subgroups of patients with non-small-cell lung cancer who benefited from vandetanib therapy were identified as those with a history of smoking (HR 0.87, 95% CI 0.80-0.95) and an adenocarcinoma histology (HR 0.85, 95% CI 0.77-0.94). In addition, patients who received VBT had an increased incidence of adverse events such as rash, diarrhea, and neutropenia. The addition of vandetanib to chemotherapy significantly improves PFS in patients with locally advanced or metastatic cancers, especially lung and thyroid cancer.     

Low cytotoxicity of ecteinascidin 743 in yeast lacking the major endonucleolytic enzymes of base and nucleotide excision repair pathways

Ecteinascidin 743 (ET-743) is a promising antitumoral drug for the treatment of soft tissues sarcomas, becoming a good candidate for clinical trials. However, the molecular mechanism of how ET-743 induces cells death is poorly understood. The chemical structure of ET-743 suggests that it can form cytotoxic cross-links with proteins and DNA. Experiments with Escherichia coli and mammalian cells indicate that the nucleotide excision repair (NER) pathway promotes ET-743 cytotoxicity. We therefore analyzed cytotoxicity and tolerance to ET-743 in the yeast Saccharomyces cerevisiae, defective for NER and/or base excision repair (BER), either in single mutants or in combination with mutant alleles of genes encoding proteins involved in DNA translesion synthesis (TLS) and homologous recombination (HR). Treatment of haploid and diploid S. cerevisiae strains with ET-743 led to induced mutagenesis, mitotic gene conversion, and crossing-over. The results indicated that yeast strains lacking endonucleases of the NER and BER pathways are especially resistant for ET-743. The mutagenesis data points to a weak mutagenic activity of ET-743 in both WT and strains lacking BER/NER endonuclease, and that a mutant blocked in both BER and TLS totally lacks induced mutagenesis. The diploid strain shows an increase in the frequencies of crossing-over and mitotic recombination. These data lead us to propose a model for ET-743 action in eukaryotic cells, where the presence of BER and NER endonucleases results in cell death. However, ET-743 damage can be tolerated in BER and/or NER mutants by TLS (error-prone) or in combination with HR (error-free).     

A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma

Objective: Ipilimumab is a fully human, anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. Methods: Chemotherapy-na?ve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3 mg/kg every 4 weeks for four doses either alone or with up to six 5-day courses of DTIC at 250 mg/m²/day. The primary efficacy endpoint was objective response rate. Results: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8–30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7–18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4 months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3 months (95% CI, 10.2–18.8) and 11.4 months (95% CI, 6.1–15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. Conclusion: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.     

Phase II trial of vinorelbine tartrate in patients with treatment-naive metastatic melanoma

Metastatic melanoma carries a dismal prognosis and there is a need to develop new treatment strategies. Vinca alkaloids have shown consistent activity in melanoma patients, as monotherapy and as part of combination regimens. The current study evaluates the clinical activity and tolerability of vinorelbine as first-line monotherapy in patients with metastatic melanoma. Patients were eligible if they presented metastatic melanoma not amenable to curative resection, had received no prior systemic therapy for advanced disease and had an adequate performance status (ECOG 0-1). Patients received vinorelbine at a dose of 30 mg/m2 on days 1 and 8 of a 21-day cycle, on an outpatient basis. Thirteen patients were accrued into the study and received 64 cycles. All patients were assessable for response, toxicity and survival. No objective responses were documented, for an overall response rate of 0% [95% confidence interval (CI) 0-19%] and the trial was terminated in accordance to the predetermined early discontinuation rule. The median progression-free survival was 3.3 months (95% CI 2.3-4.3 months) and the estimated median overall survival was 8.1 months (95% CI 6.0-10.2 months). No life-threatening toxicities occurred. Neutropenia was the main hematologic toxicity, but none of the three episodes of grade 3-4 neutropenia were complicated by infection. The most common non-hematologic toxicities were asthenia, nausea, neuropathy and myalgia. We conclude that vinorelbine as a single agent on days 1 and 8 of a 21-day cycle has a favorable toxicity profile, but appears to have no relevant clinical activity in patients with metastatic melanoma.     

Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials

Background

Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown.

Methods

A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed.

Results

Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR)?1.71, 95 % CI??1.43–2.05] and PFS [hazard ratio (HR) ?0.83, 95 % CI?0.76–0.90], but not OS (HR 0.93, 95 % CI?0.83–1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR?2.78, 95 % CI? 2.37–3.26; OR?1.92, 95 % CI?1.65–2.24; OR ?2.90, 95 % CI?2.19–3.84, respectively) and less nausea and vomiting (OR?0.71, 95 % CI?0.60–0.83; OR?0.75, 95 % CI?0.61–0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups.

Conclusions

Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC.     

Systemic treatment options for patients with refractory adult-type sarcoma beyond anthracyclines

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcoma, such as Ewing/PNET, desmoplastic small round cell sarcoma and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensitive and neoadjuvant protocols regardless of size or overt metastatic disease. A limited number of effective agents available for the treatment of patients with metastatic adult soft-tissue sarcoma exists, which have failed anthracyline and ifosfamide-based chemotherapy. Most other high-grade (grading >I) so-called adult-type soft-tissue sarcomas such as fibro, lipo, pleomorphic and synovial sarcoma are treated with a anthracycline-based regimen with or without ifosfamide as front-line therapy. In this review, the therapeutic activities of drugs currently available as second-line treatment in patients with metastatic soft tissue sarcoma are summarized, providing an overview of contentious or emerging treatment issues. In relapsed 'adult-type' soft-tissue sarcomas trofosfamide, gemcitabine and ecteinascidin (ET-743) appear to be drugs associated with moderate activity and an acceptable toxicity profile. An interesting finding to be noted is that the different drugs have particular effects in distinct subtypes of soft-tissue sarcoma; however, it has to be taken into account that the number of patients included in those phase II trials are limited. The role of the newer agents (e.g. patupilone derivates, brostallicin) is currently not definable. The so-called selective therapy targeting vascular endothelial growth factor (receptor), epidermal growth factor receptor, c-kit, Raf kinase or platelet-derived growth factor receptor and bcl-2 antisensing, proteasome, protein kinase C/B, and mammalian target of rabamycin inhibition will continue to be tested in gastrointestinal stromal tumors patients refractory to imatinib mesylate as well as in selected sarcoma subtypes.     

Phase II study of high-dose megestrol acetate in platinum-refractory epithelial ovarian cancer

Our objective was to determine the efficacy of megestrol acetate in the treatment of platinum-refractory epithelial ovarian cancer (EOC), and to evaluate the toxicities and quality of life (QOL) associated with this therapy. Patients with platinum-resistant epithelial ovarian cancer were treated with megestrol acetate (800 mg/day) orally for 28 days and then 400 mg/day for a minimum of 28 days before being assessed ready for evaluation of response to therapy. Patients who demonstrated a complete response (CR), partial response (PR) or stable disease were continued in the study until there was objective evidence of disease progression. All patients who went off study were followed up at regular intervals, every 2 months, to assess overall survival. Thirty-six patients were enrolled. Response was observed in seven of 36 patients (three CR and four PR). The response rate was 19.4% (95% CI 9-36). Four of the responders had the endometrioid cell type, while two were clear cell carcinoma and one was serouscystadenocarcinoma. All three CR patients had the histology of endometrioid carcinoma with the tumors located in the pelvis. Median survival of the study population was 5.8 months. Median survival in the responders was 12 months, while median survival in the non-responders was 5.5 months. Median progression-free survival in the responders was 8.3 months, while median progression-free survival in the non-responders was only 2 months. The majority of patients gained weight and had a fair quality of life score during treatment. The only toxicity observed was alopecia (grade 1) in four patients. We conclude that megestrol acetate has modest but definite activity in patients with platinum-refractory EOC, particularly in a small subset of the endometrioid subtype with limited disease in the pelvis. Only minimal toxicity was observed and the patients had a fair QOL score during the treatment.     

Subjective well-being in schizophrenia: A randomised controlled open-label 12-month non-inferiority study comparing quetiapine XR with risperidone (RECOVER)

This randomised 12-month open study analysed the effectiveness of quetiapine XR (400–800 mg) versus risperidone (2–6 mg) on subjective well-being in schizophrenia (NCT00600756). Primary objective was to demonstrate non-inferiority of quetiapine XR to risperidone in 6-month responder rate using the Subjective Well-Being under Neuroleptics scale (SWN-K) (per-protocol at Month 6 [PP 6] population). Non-inferiority was defined as the lower limit of the 95% confidence interval (CI) greater than ?9.7% for the adjusted difference between quetiapine XR and risperidone. Secondary objectives included non-inferiority of quetiapine XR versus risperidone (lower limit of 95% CI greater than ?7.5 points) for SWN-K change from baseline to Month 12 (PP 12). 798 patients were randomised (quetiapine XR, n=395; risperidone, n=403); at Month 12, 212 (54%) and 227 (56%) patients, respectively, completed the study. At Month 6, SWN-K responder rate in the PP 6 population was 65% (136/210) with quetiapine XR and 68% (158/232) with risperidone (adjusted treatment difference: ?5.7%; 95% CI: ?15.1, 3.7); thus, non-inferiority could not be established. SWN-K change from baseline to Month 12 was 23.2 points for quetiapine XR and 21.1 points for the risperidone group; treatment difference was 2.1 (95% CI: ?0.8; 5.0); non-inferiority was established (PP 12). Conclusion: SWN-K response at 6 months was comparable between the two antipsychotics. However, with a lower than expected responder rate and a lower than expected number of evaluable patients in the PP 6 population, non-inferiority was not demonstrated. A secondary objective (SWN-K total score) established non-inferiority of quetiapine XR to risperidone at Month 12.