A phase II study of liposomal doxorubicin in recurrent epithelial ovarian carcinoma

BACKGROUND: We conducted a phase II trial to evaluate the efficacy and safety of liposomal formulation of doxorubicin in recurrent ovarian carcinoma patients. METHODS: Thirty patients were included in the study after having obtained an informed consent. Their main characteristics were: median age, 64 years (range, 45-80), ECOG performance status 0 in 17 patients (56%), 1 in 11 patients (36%) and 2 in 2 patients (6.6%). Eighteen patients had metastatic disease and 12 locally advanced disease. All patients were pretreated with a platinum-based chemotherapy: 3 were considered refractory to platinum (progression or stable disease), 2 were platinum resistant (relapse < 12 months), and 7 were platinum sensitive (relapse > or = 12 months). Treatment consisted of liposomal doxorubicin, 50 mg/m2 every 4 weeks. RESULTS: The overall response rate was 26.6%, with 2 complete responses and 6 partial responses lasting 3.5 months. The incidence of grade 3-4 toxicity was 23.3% for neutropenia, 10% for mucositis and 10% for plantar-palmar erythrodysesthesia. Median survival was 12+ months (range, 2-26+). CONCLUSIONS: Liposomal doxorubicin appears to be a moderately active drug in pretreated patients, and its activity seems to be similar to that reported for other active regimens in terms of response rate. The toxicological profile of liposomal doxorubicin suggests that it may be combined with other drugs in the treatment of patients with ovarian cancer.     

A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer

BACKGROUND: The primary objective of this study was to evaluate the biochemical effects of gefitinib on its target signal-transduction pathways in patients with recurrent epithelial ovarian cancer (EOC). The secondary objectives included assessing clinical activity and toxicity and determining the association between biochemical and clinical outcomes. METHODS: Twenty-four heavily pretreated patients with EOC who had good end-organ function and performance status and who had measurable disease received gefitinib 500 mg daily. Prospectively planned core-needle tumor biopsies were obtained before treatment and after 4 weeks. Protein expression of total and phosphorylated (p) epidermal growth factor receptor (EGFR), protein kinase B (AKT), and extracellular regulated kinase (ERK) was quantified in microdissected tumor cells using tissue lysate array proteomics. RESULTS: All tumor samples had detectable levels of EGFR and p-EGFR. A decrease in the quantity of both EGFR and p-EGFR was observed with gefitinib therapy in >50% of patients. This was not associated with clinical benefit, nor were responses observed. However, trends for increased gastrointestinal and skin toxicity were observed with greater phosphorylation or quantities of EGFR, ERK, and AKT in tumor samples (P 相似文献   

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

BackgroundLenalidomide 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 methodsPatients 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.ResultsMost 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.ConclusionsLenalidomide 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.Clinicaltrials.govNCT01111903.     

Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study

AIMS AND BACKGROUND: The optimal salvage therapy for recurrent ovarian carcinoma has not been clearly established. Response to second-line chemotherapy is low, with a short median survival (8.8-15 months). We investigated the effect of an aggressive approach consisting of surgery followed by intraperitoneal drug delivery and local hyperthermia. PATIENTS AND METHODS: In a phase II clinical study, 27 patients with advanced/recurrent ovarian carcinoma were treated with cytoreductive surgery and intraperitoneal hyperthermic perfusion. Median patient age was 53 years (range, 30-67) and mean follow-up was 17.4 months (range, 0.3-36.0). Patients had been surgically staged and heavily pretreated with cisplatin-based, taxol-based or taxol/platinum-containing regimens. Nineteen (70%) patients were cytoreduced to minimal residual disease <2.5 mm. The intraperitoneal hyperthermic perfusion was performed with the closed abdomen technique, using a preheated polysaline perfusate containing cisplatin (25 mg/m2/L) + mitomycin C (3.3 mg/m2/L) through a heart-lung pump (mean flow of 700 mL/min) for 60 min in the hyperthermic phase (42.5 degrees C). RESULTS: Two-year overall survival was 55%. Median times to overall progression and local progression were 16 months and 21.8 months, respectively. Variables that affected the overall survival or time to progression were as follows: residual disease (P = 0.00025), patient age (P = 0.04), and lag time between diagnosis and cytoreductive surgery + intraperitoneal hyperthermic perfusion (P = 0.04). Treatment-related morbidity, mortality and acute toxicity (grade II-III) rates were 11%, 4% and 11%, respectively. Eight (89%) of 9 patients had ascites resolution. CONCLUSION: Our results suggest that cytoreductive surgery + intraperitoneal hyperthermic perfusion is a well-tolerated, feasible and promising alternative in the management of selected patients with recurrent ovarian cancer, but further randomized controlled studies are needed in order to confirm our findings.     

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer

Background: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer.Patients and methods: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle.Results: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%–29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3–4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity.Conclusion: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.     

A phase II study of tamoxifen in ovarian cancer

A phase II study of tamoxifen was conducted in 22 patients with stage III and IV ovarian cancer who had failed chemotherapy and who had evaluable disease. Tamoxifen was administered at a dose of 20 mg twice daily continuously until evidence of progression. Twenty-one patients had progression of disease within 3 months and one patient had stable disease for 6 months. There were no objective responses to this treatment.     

A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients.

PURPOSE: A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: Patients received 175 mg/m(2) paclitaxel (over 3 h) followed by 130 mg/m(2) oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval > or =6 months. RESULTS: Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2-64.2) the median progression-free survival was 10.2 months (range 0.3-21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3-4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3-4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity. CONCLUSIONS: The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.     

Tomudex (ZD1694, NSC 639186) in platinum-pretreated recurrent epithelial ovarian cancer: a phase II study by the Gynecologic Oncology Group

Purpose: Tomudex is a second-generation folate analogue that when polyglutamated is a potent inhibitor of thymidylate synthase (TS). Methods: Based on indications of antitumor activity in phase I trials, the Gynecologic Oncology Group initiated a phase II study of Tomudex 3 mg/m² intravenously every 3 weeks in patients with epithelial ovarian cancer, who had been pretreated with platinum drugs, and had subsequently recurred more than 6 months following such treatment. Results: Of 30 patients entered into the trial, 2 were pathologically ineligible, leaving 28 fully evaluable. In this patient population, Tomudex was generally well tolerated, but only three objective (partial) responses were documented. Conclusions: With the level of activity seen, the drug was not considered for further clinical development in ovarian cancer by the Gynecologic Oncology Group. However, it may be worthwhile to explore whether quantitation of TS could lead to selection of patients more likely to respond to this TS inhibitor. Received: 22 May 1997 / Accepted: 8 October 1997     

A phase I/II study of carboplatin and paclitaxel in patients with epithelial ovarian cancer

BACKGROUND: This study was conducted to investigate the recommended dose of paclitaxel for use in combination with a fixed dose of carboplatin and to evaluate the toxicity and efficacy of carboplatin-paclitaxel combination chemotherapy in patients with epithelial ovarian cancer. METHODS: One hundred and ten patients were enrolled in the Phase I/II study and 97 patients were evaluated for further analysis, excluding 13 ineligible patients or patients with infringement of protocol: 15 patients for the Phase I and 82 for the Phase II study. In the Phase I trial, we studied dose escalation using a carboplatin dose of AUC 5 and paclitaxel levels of 150, 175 and 200 mg/m(2). The grades of toxicity of the regimen of all patients enrolled in the Phase II study (n = 82), the progression-free survival time (PFS) of optimal-debulked patients and complete responders (n = 62) and the response rate of suboptimal-debulked patients (n = 39) were investigated. RESULTS: After observing grade 4 neutropenia in four of six patients in the paclitaxel 200 mg/m(2) administration group, we chose 175 mg/m(2) as the recommended dose of paclitaxel in this regimen. At this dose, the median of PFS and response rate were 432 days (range, 19-907 days) and 66.7%, respectively. CONCLUSION: Combination chemotherapy using paclitaxel 175 mg/m(2) and carboplatin AUC 5 is very well tolerated and highly effective for the treatment of ovarian cancer.     

A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer

Oral capecitabine is a highly active, well-tolerated and convenient treatment for breast and colorectal cancer. This trial assessed the efficacy and safety of single-agent capecitabine in patients with previously treated ovarian cancer. A total of 29 patients with platinum-pretreated relapsed ovarian cancer were enrolled in this prospective, open-label, single-centre, phase II study. Patients received oral capecitabine 1250 mg m(-2) twice daily on days 1-14 of a 21-day cycle. Tumour response was evaluated using serum CA125. Out of 29 enrolled patients, 28 were evaluable, and a response was observed in eight patients (29%, 95% confidence interval (CI), 13-49%). Median progression-free and overall survivals were 3.7 (95% CI, 2.8-4.6) and 8.0 (95% CI, 4.1-11.8) months, respectively. After 6 months of treatment, 28% (95% CI, 13-48%) of patients remained progression-free and 62% (95% CI, 42-79%) were still alive. The most common clinical adverse events were hand-foot syndrome (HFS), nausea and diarrhoea. Grade 3 HFS occurred in 14% of patients, grade 3 vomiting in 10%. Efficacy and safety of capecitabine compare favourably with other monotherapies in platinum-refractory epithelial ovarian cancer. The convenience and improved safety profile of capecitabine compared with intravenous. regimens make it an ideal agent for administration in the outpatient setting.     

复发性卵巢癌的研究进展

复发性卵巢上皮癌的检测和诊断方法有多种,较为常用的有体格检查、血清CA125测定和影像学检查.针对患者的不同情况,可以选择性地给予手术治疗,并辅以合适的化疗,尽可能改善患者的生存质量,延长生存时间.现就复发性卵巢癌的监测、诊断和治疗的研究近况作一简要综述.     

Phase II trial of tamoxifen and goserelin in recurrent epithelial ovarian cancer

Endocrine therapy is a recognised option in the treatment of chemo-resistant ovarian cancer. We conducted a nonrandomised phase II evaluation of combination endocrine therapy with tamoxifen and goserelin in patients with advanced ovarian cancer that had recurred following chemotherapy. In total, 26 patients entered the study, of which 17 had platinum-resistant disease. The median age was 63 years and enrolled patients had received a median of three chemotherapy regimens prior to trial entry. Patients were given oral tamoxifen 20 mg twice daily on a continuous basis and subcutaneous goserelin 3.6 mg once a month until disease progression. Using the definition of endocrine response that included patients with stable disease (SD) of 6 months or greater, the overall response rate (clinical benefit rate) was 50%. This included one complete response (CR) (3.8%), two partial responses (PR) (7.7%) and 10 patients with SD (38.5%). The median progression-free interval (PFI) was 4 months (95% CI 2.4-9.6) while the median overall survival (OS) was 13.6 months (95% CI 5.5-30.6). Four patients received treatment for more than 2 years (range 1-31) and one of them is still on treatment. In none of the four patients was there any evidence of recurrent or cumulative treatment related toxicity. Treatment-limiting toxicity was not seen in any of the study population. Endocrine data demonstrated a marked suppression of luteinising hormone (LH) and follicle-stimulating hormone (FSH) to less than 4% of baseline values. No consistent correlation could be established between LH/FSH suppression and tumour response. Likewise no relationship was observed between Inhibin A/B and pro-alpha C levels and tumour response. Inhibin is unlikely to be a useful surrogate marker for response in locally advanced or metastatic ovarian cancer. Combination endocrine therapy with tamoxifen and goserelin is an active regimen in platinum-resistant ovarian cancer patients. Hormonal therapy is advantageous in its relative lack of toxicity, ease of administration and tolerability, thus making it suitable for patients with heavily pretreated disease, compromised bone marrow function and other comorbid conditions that contraindicate cytotoxic therapy as well as in patients with indolent disease.     

Phase II study of combination 4′-epidoxorubicin and mitomycin C in recurrent epithelial ovarian cancer

Summary Thirty-three evaluable patients who had epithelial ovarian cancer that had not responded to treatment were entered into a phase II study of combination epirubicin and mitomycin C. Epirubicin (65 mg/m²) and mitomycin C (4 mg/m²) were administered separately, each as an i.v. bolus every 4 weeks. Ten patients (30%) had a complete or partial responses. The median duration of response was 20 weeks (range, 9–53). The regimen was well tolerated. Myelotoxicity occurred in four patients requiring hospitalization for septicaemia. Eleven patients had a blood transfusion. Alopecia was common, and nausea and vomiting, though frequent, usually mild. Cardiological toxicity was observed in one patient only. She developed congestive cardiac failure after an acute myocardial infarction. This regimen is active in advanced ovarian cancer that has not responded to prior treatment and warrants further study combination with other active drugs as a first-line regimen for ovarian cancer.     

复发上皮性卵巢癌的化学药物治疗

再次化学药物治疗是复发上皮性卵巢癌重要治疗手段之一,但仍存在诸多尚未解决的难题.现就近年来有关复发上皮性卵巢癌化疗的目标和价值、分型、化疗时机、化疗原则及化疗常用药物疗效的研究进展作一综述.     

Optimizing treatment in recurrent epithelial ovarian cancer

Introduction: Optimal management of recurrent ovarian cancer (ROC) remains an area of uncertainty. An estimated 85% of patients with epithelial ovarian cancer who achieve a full remission following first-line therapy will develop recurrent disease and median survival for these patients’ ranges from 12 months to 24 months. Many patients receive several lines of treatment following recurrence and, although each subsequent line of therapy is characterized by shorter disease-free intervals, decisions about the most appropriate treatment is complex.

Areas covered: This review focuses on chemotherapy, surgery and emerging biologic agents that present a therapeutic option for patients with ROC.

Expert commentary: Recurrent ovarian cancer is not curable. The goals of therapy should focus on palliation of cancer-related symptoms, extension of life, and maintenance of quality of life. Patients with platinum-sensitive ovarian cancer should have their recurrence treated with a platinum-based agent. For patients whose cancer progresses after platinum retreatment and for those with platinum-resistant disease, numerous other non-platinum combination and targeted therapies have been shown to be effective in palliating cancer-related symptoms and extending life.     

Epirubicin: A phase II study in recurrent small-cell lung cancer

Summary Epirubicin (4-epidoxorubicin), an analogue of doxorubicin (Adriamycin), has established activity in the treatment of small-cell lung cancer (SCLC) when used at doses of 75 to 120 mg/m² in previously untreated patients. We completed a phase II study of epirubicin (85 mg/m² given intravenously at 3-week intervals) in 20 patients with recurrent SCLC, all of whom had received prior combination chemotherapy. Of 19 patients who were assessable for response, 2 achieved a complete response and 2 a partial response, for an overall response rate of 4/19 (21%); 95% confidence interval, 8%–43%). Myelosuppression and alopecia were the most frequent toxicities; epirubicin was otherwise well tolerated, with other toxicities such as nausea and vomiting being infrequent or mild. Epirubicin at a dose of 85 mg/m² exhibits modest singleagent activity in previously treated SCLC and is generally well tolerated. Given as a single agent or in combination with other well-tolerated drugs, epirubicin would be suitable in cases in which palliation of symptoms without undue toxicity is required in the management of previously treated SCLC.     

Phase II trial of the novel sulphonylurea sulofenur in advanced breast cancer

Summary A total of 18 women with advanced breast cancer were treated with sulofenur [LY186641;N-(5-indanylsulfonyl)-N-(4-chlorophenyl)-urea], a diarylsulfonylurea that has broad-spectrum activity against a number of murine mammary tumour xenografts. The dosage chosen on the basis of pre-clinical and phase I studies was 700 mg/m² given orally once daily for 14 days, with treatments being repeated every 3 weeks. There was no response. All patients experienced at least grade 1 anaemia, and two patients developed symptomatic methaemoglobinaemia. Two patients developed grade 4 rises in serum liver-function values along with histological changes consistent with drug-induced toxicity. The mean plasma concentrations of 176 g/ml were lower than the levels required to exert anti-tumour effect in the mouse model.     

Docetaxel and oxaliplatin in the second-line treatment of platinum-sensitive recurrent ovarian cancer: a phase II study.

BACKGROUND: A prospective phase II study was conducted to evaluate the efficacy and toxicity of the combination docetaxel (Taxotere) (DTX) and oxaliplatin (OXA) in ovarian cancer patients recurring after a platinum-free interval (PFI) >12 months. PATIENTS AND METHODS: DTX, 75 mg/m(2), was administered by 60 min i.v. infusion, followed by OXA, 100 mg/m(2), given by a 2 h i.v., on day 1 every 21 days. RESULTS: From October 2003 to June 2006, 43 ovarian cancer patients were enrolled. Median PFI was 26 months. All patients were available for response evaluation: 17 complete responses and 12 partial responses were registered, for an overall response rate of 67.4%. The median response duration was 10 months. Stable disease was documented in 11 patients (median duration = 5.5 months). The median time to progression and overall survival were 14 and 28 months. A total of 259 courses were administered. Grade 3-4 leukopenia was documented in 32.5% of the patients, while no case of severe anemia and thrombocytopenia was observed. Grade 3-4 neurotoxicity and grade 2 alopecia were observed in 9.3% and 34.9% of cases, respectively. CONCLUSION: DTX/OXA combination is an active regimen with a favorable toxicity profile, for treatment of recurrent platinum-sensitive ovarian cancer patients.     

A phase II study of oral idarubicin in advanced recurrent or refractory ovarian carcinoma

Summary Oral idarubicin (40 mg/m² in 3–4 divided doses over 24 h every 21 days) was tested in a group of patients with drug-resistant ovarian carcinoma. None of 13 patients responded and the study was discontinued. Toxicity was acceptable, with neutropaenia being doselimiting. It seems unlikely that idarubicin has significant activity in this disease although phase II studies should ideally be conducted in less heavily pretreated patients.     

Hormonal therapy with letrozole for relapsed epithelial ovarian cancer. Long-term results of a phase II study

OBJECTIVE: We conducted a phase II trial to evaluate the activity of oral letrozole in women with relapsed or recurrent epithelial ovarian cancer. METHODS: Twenty-seven patients were treated with letrozole at a dose of 2.5 mg once a day. Patients with measurable or evaluable disease (n = 21) and those with only increasing CA 125 serum levels (n = 6) were eligible. Paraffin-fixed histological sections from tumor specimens resected at the initial laparotomy were assessed for the presence of estrogen, and progesterone receptors. RESULTS: Among the 21 patients with measurable or evaluable disease who were evaluated for response by WHO criteria, we observed one complete and two partial responses for an objective response rate of 15%. Using criteria for CA 125 response we obtained a marker response in 4 of 27 patients (15%), and the marker remained stable in 5 additional patients (18%). Letrozole treatment was generally well tolerated. No correlation was observed between tumor marker response or stabilization and either estrogen or progesterone receptor expression. CONCLUSION: The results of our study suggest that the aromatase inhibitor letrozole is an agent with some activity and limited toxicity for relapsed ovarian cancer. As we could not find any association between response and hormonal receptor expression, the underlying mechanisms of letrozole action have to be elucidated.