Weekly low-dose carboplatin and paclitaxel in the treatment of recurrent ovarian and peritoneal cancer

OBJECTIVES: Weekly paclitaxel alone has moderate activity in the salvage treatment of recurrent ovarian cancer and is associated with a favorable toxicity profile. Combination paclitaxel and carboplatin is a well-established first-line regimen for ovarian cancer. The purpose of this study was to evaluate weekly low-dose paclitaxel and carboplatin in recurrent ovarian or peritoneal cancer. METHODS: Patients with recurrent ovarian or peritoneal cancer previously treated with between one and four chemotherapeutic regimens were eligible. Patients had measurable or assessable disease defined by clinical exam, radiographic studies, or serum CA-125 greater than 75 U/ml. One cycle of treatment consisted of carboplatin at an area under the curve of 2 and paclitaxel at 80 mg/m(2) on days 1, 8, and 15 on a 28-day cycle. Clinical responses were defined by established criteria. RESULTS: Twenty-nine patients were included in this intent-to-treat study. The median number of prior treatment regimens was 2 (range 1 to 4). The overall response rate was 82.8% (16 complete clinical responses, 8 partial responses). Among 8 platinum-refractory patients, the response rate was 37.5%, while 21 platinum-sensitive patients had a 100% response rate. Median time to progression was 13.7 months among platinum-sensitive patients and 3.2 months among platinum-refractory patients. Overall median time to progression was 11.5 months and median-duration of response was 9.9 months. Hematologic toxicity was common (32% grade 3 neutropenia, no grade 4 neutropenia, 14.2% grade 3 or 4 thrombocytopenia) and managed by treatment delay, dose reduction of paclitaxel, or discontinuation of carboplatin. CONCLUSION: Weekly low-dose carboplatin and paclitaxel has significant activity in both platinum-sensitive and platinum-resistant recurrent ovarian cancer with acceptable toxicity that is easily managed by dose adjustment.     

A phase II trial of oral capecitabine in patients with platinum--and taxane--refractory ovarian, fallopian tube, or peritoneal cancer

PURPOSE: To determine the efficacy, toxicity, and quality of life of capecitabine (Xeloda), an oral 5-fluorouracil derivative, in patients with chemorefractory recurrent mullerian cancers. PATIENTS AND METHODS: Patients with chemorefractory persistent or recurrent ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled. Capecitabine was administered beginning at 2000 mg/m2/day orally in two divided doses with meals on a 21-day cycle: 14 days of capecitabine followed by a 7-day rest period. One dose escalation or reduction was allowed. Response was assessed after cycle 2 and cycle 4 and every third cycle thereafter. Standard evaluation included two-dimensional measurement of evaluable disease. Standard criteria for response were used. Therapy was discontinued if progression occurred after at least two cycles of therapy. Quality of life and symptoms were assessed. RESULTS: Forty-one patients were enrolled. Ninety-two percent of patients had >2 previous chemotherapy regimens. All patients had platinum- and taxane-resistant disease. Thirty-six patients were evaluable for response. Three patients had a partial response, with a median response duration of five cycles. Twenty-two patients had stable disease for 3 to 11 cycles (median, 6 cycles). Eleven had progressive disease. The only grade 4 toxicity was abdominal pain (n = 2). The most common grade 3 toxicities were fatigue (n = 19), hand-foot syndrome (n = 11), abdominal pain (n = 7), and diarrhea (n = 4). One patient had a grade 3 hematologic toxicity (anemia). CONCLUSION: Capecitabine at the dosages used in this study is well tolerated and has minimal hematologic toxicity.     

A Phase 2 Trial of Flavopiridol (Alvocidib) and Cisplatin in Platin-Resistant Ovarian and Primary Peritoneal Carcinoma: MC0261

PURPOSE: Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers. METHODS: A two cohort phase 2 trial of cisplatin (60mg/m(2) IV) immediately followed by flavopiridol (100mg/m(2) IV, 24h infusion; 21day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ≤6months following prior platin-based therapy). Measurable disease (RECIST) - or evaluable disease plus CA125 >2X post-treatment nadir - and ECOG performance ≤2 were required. RESULTS: Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3months; overall survival was 16.1months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8months and median overall survival 20.6months) the cohort was closed due to poor accrual. CONCLUSIONS: The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.     

Efficacy and tolerability of lower-dose topotecan in recurrent ovarian cancer: a retrospective case review

Topotecan (1.5 mg/m(2)/day for 5 consecutive days of a 21-day cycle) is an established recurrent ovarian cancer treatment, but myelosuppression can be dose limiting. This study evaluates the activity and tolerability of low-dose topotecan in our clinical experience. Case records were reviewed for patients with recurrent ovarian cancer in first through third relapse. Eligible patients had received > or =2 cycles of < or =1.25 mg/m(2) topotecan. Adverse events were evaluated using laboratory and clinical evaluation data. Twenty-seven eligible patients, most with advanced disease, received a total of 209 cycles (median, six cycles). Grade 3 or 4 hematologic toxicities during 184 cycles in 24 assessed patients were neutropenia, leukopenia, thrombocytopenia, and anemia in 35%, 28%, 36%, and 11% of cycles, and 21, 19, 16, and 10 patients, respectively. Only four grade 4 toxicities occurred: anemia (one) and thrombocytopenia (three). Myelosuppression was reversible, noncumulative, and manageable. Moreover, nonhematologic toxicity was generally mild to moderate, and the only two grade 3 events were constipation and deep vein thrombosis. Low-dose topotecan was active in this setting. Lower-dose topotecan is generally well tolerated and active in patients with pretreated ovarian cancer. Prospective clinical trials of low-dose topotecan in recurrent ovarian cancer are warranted.     

A phase II study of gemcitabine plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma

OBJECTIVES: Gemcitabine and carboplatin each have demonstrated effectiveness without increased neurotoxicity in pretreated patients with ovarian cancer. We evaluated the efficacy and safety of gemcitabine plus carboplatin in patients with recurrent ovarian cancer in a multicenter phase II study. METHODS: Women with histologically proven measurable or evaluable epithelial ovarian cancer (any FIGO) who relapsed > or =6 months after discontinuation of first-line, platinum-containing therapy received gemcitabine 1000 mg/m(2) on days 1 and 8 and carboplatin AUC 4 on day 1 (after gemcitabine) every 21 days for up to six cycles. RESULTS: Of the 40 enrolled/evaluable patients, 6 (15%) had complete response and 19 (47.5%) had partial response (PR), including one patient with PR in nonmeasurable disease (PRNM), for an overall response rate of 62.5% (95% CI, 45.8-77.3%). The median duration of response was 7.8 months (95% CI, 6.7-10.0), the median time to progressive disease was 9.6 months (95% CI, 8.5-11.0), and the median time to treatment failure was 9.3 months (95% CI, 8.2-10.4). The main grade 3/4 toxicities were neutropenia (78% of patients), leukopenia (30%), thrombocytopenia (18%), and anemia (15%); no grade 4 nonhematologic toxicities occurred, and grade 3 nonhematologic toxicities were mild. CONCLUSIONS: The combination of gemcitabine and carboplatin is active and feasible in platinum-sensitive patients with recurrent ovarian cancer. This regimen is undergoing further evaluation in a large phase III trial.     

Combination gemcitabine, platinum, and bevacizumab for the treatment of recurrent ovarian cancer

ObjectiveTo describe the response rate (RR), progression-free survival (PFS), and toxicity profile of combination gemcitabine, platinum, and bevacizumab (GPB) for the treatment of recurrent epithelial ovarian cancer (EOC).MethodsA chart review of all patients with recurrent EOC who were treated with D1, D15 GPB in a 28-day cycle at a single institution was performed. Standard doses were gemcitabine 1000 mg/m², cisplatin 30 mg/m² or carboplatin AUC 3, and bevacizumab 10 mg/kg. All patients were analyzed for toxicity. RR and PFS were assessed in all patients who received at least 2 cycles of GPB.ResultsThirty-five patients were identified, and 33 received at least 2 cycles of GPB. The majority of patients (80%) were platinum sensitive. Patients received a median of 6 cycles of GPB (range 1–24). Sixteen patients (48%) had a complete response (CR), and 10 patients (30%) had a partial response (PR), for a total RR of 78%. An additional 5 patients (15%) had stable disease, and only 2 (6%) patients had progressive disease. The median overall PFS was 12 months (95% CI 7–15), with a median follow-up time of 10 months (2–22). Two patients (6%) had bowel perforations, and both survived. Hematologic toxicities were most common, with 29% and 14% of patients experiencing grade 3 or 4 neutropenia and thrombocytopenia respectively.ConclusionsThe combination of GPB demonstrated excellent efficacy for the treatment of recurrent EOC. However, serious toxicities occurred, and the safety profile of this combination requires further study.     

Triplet combination of gemcitabine, carboplatin, and paclitaxel in previously treated, relapsed ovarian and peritoneal carcinoma: an experience in Taiwan

OBJECTIVE: The aim of this phase II study was to evaluate the efficacy and toxicity of gemcitabine, carboplatin, and paclitaxel (GCP) combination as salvage therapy in patients with relapsed ovarian or peritoneal cancer who had previously received platinum-based chemotherapy. PATIENTS AND METHODS: Patients with progressive ovarian or peritoneal carcinoma who had previously received platinum-based chemotherapy were enrolled. Gemcitabine was administered at 800 mg/m(2) as a 30-min intravenous infusion on days 1 and 8; carboplatin (AUC of 5) and paclitaxel (175 mg/m(2)) were administered as 60-min and 3-h intravenous infusions, respectively, on day 1. Treatment cycles were repeated every 3 weeks for a maximum of nine cycles. RESULTS: Twenty patients (ovarian carcinoma, 19; peritoneal carcinoma, 1) received this triplet regimen as salvage therapy. All the patients had previously received at least one platinum-based regimen for chemotherapy and 17 of them had received platinum plus paclitaxel. The median number of previous regimens was 2 (range, 1-4), and the median platinum-free interval was 9 months (range, 1-18). A total of 130 cycles were administered with a median of six cycles per patient (range, 3-9). The overall response rate was 75%, including 12 complete responses (60%; 95% confidence interval [CI], 36.1-80.9) and three partial responses (15%; 95% CI, 3.2-37.9). The other five patients showed stable disease (25%; 95% CI, 8.7-49.1). The median duration of the progression-free survival was 6.5 months (range, 3-20). Myelosuppression was the main toxicity, with leukopenia being the most prominent (grade 3/4 toxicity in 35% patients), followed by thrombocytopenia in 20% patients. In addition, 35% patients had grade 3 anemia. All the toxicities were manageable and the patients recovered fully. Among non-hematological toxicities, the only notable one was grades 2 and 3 hepatic toxicity seen in two and one patients, respectively, necessitating a decrease in the paclitaxel dose in two patients. CONCLUSIONS: GCP combination is an effective salvage chemotherapy in patients with heavily pretreated and relapsed ovarian and peritoneal cancer. The significant side effects of myelosuppression and hepatic toxicity were of moderate severity and manageable.     

A pilot study of weekly docetaxel therapy for recurrent ovarian cancer, tubal cancer, and primary peritoneal cancer

We investigated the efficacy and toxicity of salvage chemotherapy with weekly docetaxel for recurrent ovarian cancer, tubal cancer, and primary peritoneal cancer after treatment with regimens containing platinum or paclitaxel. The 15 subjects were managed as outpatients and received at least two courses of docetaxel therapy (35 mg/m2 on days 1, 8 and 15). Antitumour activity was assessed radiologically and from the CA-125 level. Among five patients with measurable lesions, one showed partial remission and three showed stable disease. Based on CA-125 levels, there were three partial remissions and five patients with stable disease (progression-free survival was 7.5 months and 7.6 months, respectively). During 61 courses, the severe toxicities were grade 3 leukopaenia/neutropaenia (6.7%) or grade 2 oedema and pleural effusion (13.3%). Weekly docetaxel may be useful salvage chemotherapy for recurrent ovarian cancer, tubal cancer, and peritoneal cancer, especially as tumour dormancy therapy.     

Weekly topotecan in heavily pretreated patients with recurrent epithelial ovarian carcinoma

OBJECTIVE: To investigate weekly topotecan in heavily pretreated patients with recurrent ovarian cancer. METHODS: The records of patients with recurrent epithelial ovarian cancer who were treated with weekly topotecan after failure of > or =1 prior regimen were reviewed. Patients received topotecan (median starting dose approximately 2.5 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Antitumor response was assessed after 2 cycles by serial CA-125 levels. RESULTS: Thirty-five heavily pretreated patients received a mean of 5 cycles of topotecan (range, 1-13 cycles). Thirty-two patients had definable platinum sensitivity (16 sensitive, 8 resistant, 8 refractory). Median age was 56 years. A total of 177 cycles (534 weeks) of topotecan was administered. Hematologic toxicity was generally mild, and no grade 4 toxicities were observed. Grade 3 hematologic toxicity, including leukopenia, neutropenia, thrombocytopenia, and anemia, was observed in 2, 2, 1, and 0 patients, respectively. No patients experienced grade 3 or 4 nonhematologic toxicity. Based on serial CA-125 measurements, there were 1 (3%) complete and 5 (15%) partial responses, with 1 of the partial responses in a patient with platinum-refractory disease. Stable disease was reported in 13 (38%) patients, including 5 patients with platinum-resistant/refractory disease. CONCLUSION: Weekly topotecan demonstrates activity and is well tolerated compared with historical data with the standard 5-day schedule. Higher doses may be warranted because of the high tolerability shown for weekly topotecan. Weekly topotecan may be an appropriate treatment option for patients with recurrent ovarian cancer, especially heavily pretreated patients who might require dosing schedules with improved tolerability.     

Abdominal carcinomatosis in women with a history of breast cancer

OBJECTIVES: The goals of this study were to: (1) characterize the etiology of abdominal carcinomatosis, (2) identify clinical features predictive of primary ovarian/peritoneal cancer, and (3) evaluate the survival impact of cytoreductive surgery among patients with advanced ovarian/peritoneal cancer and a history of breast cancer. METHODS: Patients with a history of prior breast cancer undergoing surgical exploration for abdominal carcinomatosis between 1/1/88 and 12/31/02 were retrospectively identified from tumor registry databases. Logistic regression analysis was used to explore clinical characteristics predictive of primary ovarian/peritoneal cancer versus recurrent breast cancer. Survival analyses and comparisons were performed using the Kaplan-Meier and Cox proportional hazard models. RESULTS: Seventy-nine patients underwent surgery for abdominal carcinomatosis a median of 5.39 years after initial breast cancer diagnosis. Abdominal carcinomatosis was due to primary ovarian/primary peritoneal cancer in 74.7% of cases. A history of Stage I breast cancer [OR = 10.73, 95%CI = 2.6-43.7, P < 0.001] and the lack of a prior breast cancer recurrence [OR = 10.60, 95%CI = 2.5-45.2, P < 0.001] were independently predictive of primary ovarian/peritoneal cancer. Among patients with primary ovarian/peritoneal cancer, optimal (< or =1 cm) cytoreductive surgery was associated with a median survival of 44.0 months compared to 18.0 months for patients with suboptimal residual disease [HR = 6.81, 95%CI = 3.37-13.77, P < 0.0001]. Recurrent breast cancer was associated with a median survival time of 6.4 months. CONCLUSIONS: Among patients with prior breast cancer presenting with abdominal carcinomatosis, early-stage disease and the absence of a prior recurrence were predictive of primary ovarian/peritoneal cancer. Optimal cytoreductive surgery was associated with a significant survival advantage for patients with primary ovarian/peritoneal cancer.     

Phase 2 trial of carboplatin, paclitaxel, and irinotecan in ovarian, fallopian tube, and primary peritoneal cancers

OBJECTIVE: Our goal in this nonrandomized phase 2 trial was to evaluate the toxicity and obtain preliminary data on the potential efficacy of a novel three-drug combination regimen (carboplatin-paclitaxel-irinotecan) when employed as initial therapy of advanced ovarian cancer or as second-line treatment in the setting of a prolonged (>or=12 months) treatment-free interval. METHODS: Patients with a histologically confirmed diagnosis of advanced ovarian cancer, primary adenocarcinoma of the peritoneum, or fallopian tube cancer were enrolled in the study. Patients received carboplatin (AUC 5), paclitaxel (150 mg/m(2) over 3 h), and irinotecan (100 mg/m(2) over 90 min). The three-drug combination was initially administered on an every 21-day schedule, but due to toxicity was subsequently changed to a 28-day program. RESULTS: A total of 30 patients were enrolled into this phase 2 trial. Twenty-three patients were chemotherapy naive, while 7 had received prior chemotherapy. Seventeen patients completed all six cycles of treatment. Eight patients (27%) were removed from the study after a median of three cycles due to toxicities. Seventeen patients (57%) experienced grade 4 neutropenia, with three individuals requiring hospitalization for neutropenic fever and dehydration. Grades 3 and 4 thrombocytopenia were experienced by three patients each. The principal nonhematologic toxicities were diarrhea (grade 3: three patients) and fatigue. The overall objective clinical response rate was 83%. CONCLUSIONS: The combination of carboplatin-paclitaxel-irinotecan can be administered to women with advanced ovarian cancer with significant, but overall acceptable toxicity. Modification of the regimen from a 3-week to a 4-week schedule permits a greater percentage of patients to complete the program without experiencing excessive toxicity. The overall objective response rate observed in this trial is comparable to other combination regimens employed in this setting. Defining a place for this three-drug program in the standard management of ovarian cancer will require the conduct of an appropriately designed randomized trial.     

Prospective evaluations of continuous weekly paclitaxel regimen in recurrent platinum-resistant epithelial ovarian cancer

BACKGROUND: Paclitaxel administered on a weekly basis has been reported to possess both anti-angiogenic and apoptotic-inducing effects. We investigated the activity of a weekly continuous paclitaxel regimen in patients with recurrent platinum-resistant ovarian cancer. METHODS: Patients with recurrent ovarian cancer and documented platinum-resistant disease were treated with weekly intravenous paclitaxel (60-80 mg/m(2)) continuously for up to 24 weeks over an 18-month period. Prospective data collection included: information on patients' demographics together with disease- and treatment-related toxicities. Response was evaluated using radiographic and Ca125 criteria. Chi-square tests were used to test for significant associations between categorical variables. Progression-free survival and overall survival time from commencement of weekly treatment were estimated using the Kaplan-Meier method. All P values less than 0.05 were considered to be statistically significant. RESULTS: Thirty-four patients were treated on protocol. Five patients (15%) reported grade 3/4 neurotoxicity at the end of 12 weeks. No dose reduction or treatment delay was required. No significant hematologic toxicity was observed. Responses were evaluable in thirty-two patients. Complete response was observed in three patients (9%), and another 14 patients showed a partial response (44%). Seven patients (22%) had disease stabilization. The estimated median progression-free survival and overall survival were 6.10 months (95% CI:3.81-8.39) and 10.43 months (95% CI: 8.49-12.38) respectively from the start of the regimen. CONCLUSION: Continuous weekly paclitaxel is a well-tolerated and active regimen in patients with recurrent platinum-resistant ovarian cancer.     

Phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer: an Australian and New Zealand Gynaecological Oncology Group study

Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory/platinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37-78), were enrolled. A median of six cycles (range, 1-8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6-9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9-21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.     

Treatment of relapsed carcinoma of the ovary with single-agent paclitaxel following exposure to paclitaxel and platinum employed as initial therapy

OBJECTIVES: The aim of this study was to evaluate the ability of paclitaxel to achieve a second clinical response in patients with recurrent epithelial ovarian carcinoma who responded to standard therapy with platinum and paclitaxel in the initial setting. METHODS: Thirty-four patients with epithelial ovarian who demonstrated a complete response to paclitaxel and platinum in the initial treatment setting were retreated with paclitaxel as a single agent for relapse of their disease. Paclitaxel was given at a dose of 135-175 mg/m(2) over 3 h at 21-day intervals. Fifteen patients had platinum-resistant disease and 19 had potentially platinum-sensitive disease. Response was documented by physical examination, serial serum CA125 measurement, or radiologic evaluation. RESULTS: An objective response to paclitaxel retreatment was demonstrated in 15 patients (44%), with a median progression-free interval (PFI) of 8.6 months (range 4-17 months). An additional 14 patients (41%) demonstrated disease stabilization, with a median PFI of 7.4 months (range 3-13 months). Overall, retreatment with paclitaxel was well tolerated, with minimal cumulative toxicities, despite repetitive dosing. CONCLUSION: These results demonstrate that patients with ovarian cancer who relapse after initial treatment with paclitaxel often have disease that is still responsive to the agent. Given its relative lack of cumulative toxicity, retreatment with paclitaxel as a single agent is a reasonable therapeutic option for patients with recurrent ovarian cancer.     

Phase II evaluation of 24-h continuous infusion topotecan in recurrent, potentially platinum-sensitive ovarian cancer: A Gynecologic Oncology Group study

OBJECTIVES: The aim of this study was to develop an alternative effective and more convenient administration schedule for intravenous topotecan when used as palliative treatment in ovarian cancer. METHODS: The Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional topotecan (8.5 mg/m(2)) with treatment repeated every 3 weeks in 29 patients with platinum-sensitive recurrent ovarian cancer (prior response to platinum-based chemotherapy with a minimum treatment-free interval >/=6 months). RESULTS: The major toxicities of therapy were grade 4 neutropenia and thrombocytopenia which developed in 86 and 14% of patients, respectively. Other severe side effects were uncommon. Only 2 partial responses (7%) were observed in the 28 patients evaluable for response. CONCLUSIONS: Despite the relatively favorable ovarian cancer patient population treated in this trial (platinum-sensitive recurrent disease), the response rate was disappointingly low. Considering the three- to fivefold higher objective response rates observed in other trials employing topotecan in individuals with platinum-sensitive ovarian cancer utilizing a 5-day treatment program (delivered every 3 weeks), the results of the current study provide strong support for the conclusion that clinically relevant antineoplastic activity of this agent is highly schedule dependent.     

A phase I trial of oxaliplatin and topotecan in recurrent ovarian carcinoma

OBJECTIVE: Oxaliplatin and topotecan have demonstrated activity as single agents against recurrent platinum-sensitive and -resistant ovarian cancer, as well as synergy in vitro. This was a dose-finding study of combination therapy with weekly topotecan and alternating-week oxaliplatin in patients with recurrent epithelial ovarian cancer. METHODS: Eligible patients had a diagnosis of recurrent ovarian or primary peritoneal carcinoma, a performance status of 0-2, and normal bone marrow, renal, and hepatic function. On days 1 and 15 of a 28-day cycle, patients received a fixed dose of oxaliplatin (85 mg/m2) via intravenous infusion. On days 1, 8, and 15, patients received an escalating dose of intravenous topotecan (2.0-4.0 mg/m2). Five dose levels were planned with a minimum cohort of 3 patients at each level. RESULTS: Thirteen patients were enrolled and received a total of 50 cycles of chemotherapy. The maximum tolerated dose was 85 mg/m2 of oxaliplatin and 3.0 mg/m2 of topotecan, and grade 3 neutropenia was the dose-limiting toxicity. Four of nine (44%) evaluable patients had stable disease or a partial response to the drug combination as assessed by cancer antigen-125 levels. CONCLUSIONS: A 28-day schedule of oxaliplatin and topotecan is safe and well tolerated. Because of the in vitro synergy observed between topoisomerase I inhibitors and platinum derivatives and the tolerability reported in the current study, this regimen warrants further investigation.     

Phase II study of gemcitabine and weekly paclitaxel in recurrent platinum-resistant ovarian cancer

OBJECTIVE: The purpose of this study is to evaluate the activity of gemcitabine and weekly paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Thirty-five patients with platinum-resistant disease and prior treatment with paclitaxel received treatment with paclitaxel 80 mg/m(2) IV over 60 min, followed by gemcitabine 1000 mg/m(2) IV administered on days 1, 8, and 15. Cycles were repeated every 4 weeks. RESULTS: All patients had platinum-resistant disease and all had received prior treatment with paclitaxel. Patients were heavily pretreated as the median number of chemotherapy regimens for recurrent disease was 2 (0-3). The overall response rate was 40% (95% confidence intervals (24%, 58%) and 37% of patients achieved stable disease. The median time to progression was 5.7 months (95% CI, 4.6, 8.5) and median overall survival 13.1 months (95% CI, 10.6, 15.9). More than 50% of patients were alive at 12 months, including six patients (17%) who were alive at 24 months. Treatment was well tolerated. Grades 3-4 neutropenia occurred in 17 patients (48.5%), grade 3 thrombocytopenia in 7 (20%), grade 3 anemia in 3 (8.5%). The most common serious non-hematological toxicities were nausea (14%), vomiting (14%), and fatigue (34%). CONCLUSIONS: The regimen of weekly paclitaxel and gemcitabine exhibits significant activity in heavily pretreated patients, is well tolerated, and is associated with encouraging survival. This regimen should be considered as a treatment option in patients with chemotherapy-resistant ovarian cancer.     

Preoperative detection of peripherally circulating cancer cells and its prognostic significance in ovarian cancer

OBJECTIVES: Studies in several solid tumors have shown that the presence of occult metastasis in the bone marrow or peripheral blood is highly predictive of decreased disease-free and overall survival. Our objective was to determine the incidence of circulating ovarian or primary peritoneal cancer cells in the peripheral blood at the time of disease diagnosis, or recurrence, and to determine the prognostic significance of these occult metastasis. METHODS: Peripheral blood was drawn preoperatively from 91 women thought to have newly diagnosed or recurrent epithelial ovarian or primary peritoneal carcinoma. All samples underwent a tumor-enriched immunocytochemical assay. RESULTS: Sixty-four women were found to have epithelial ovarian or primary peritoneal cancer. Of the 64 women with cancer, 12 had evidence of circulating cancer cells in their peripheral blood (18.7%). Characteristics were compared between those with circulating cancer cells and those without, using Fisher's exact test or the Wilcoxon-Mann-Whitney test, as appropriate. Women with circulating cancer cells had statistically more grade 3 tumors than women without. At a mean follow-up of 18.7 months (SD 6.7 months), analysis using Kaplan-Meier estimation and the log-rank test indicated that survival curves did not differ between patients with and without circulating cancer cells. CONCLUSIONS: Ovarian and primary peritoneal cancer, which historically has been thought to spread primarily by direct cell seeding throughout the abdominal cavity, can have circulating cancer cells in the peripheral blood. The clinical utility of identifying circulating cancer cells is yet to be defined.     

联合应用沙利度胺和脂质体阿霉素治疗复发性卵巢上皮性癌和腹膜癌的初步研究

目的:评价联合应用沙利度胺与脂质体阿霉素治疗复发性卵巢上皮性癌和腹膜癌的疗效和毒副作用。方法:将9例经手术和术后泰素+卡铂化疗后复发患者纳入本研究。每4周予以脂质体阿霉素30~50mg/m2化疗,共3~8个疗程;同时每日予以沙利度胺100~300mg,其剂量从100mg/d开始,此后每2周增加50~100mg。通过体检、影像学检查和测定CA125水平评价治疗效果。结果:9例患者的中位年龄为56岁(35~81岁),FIGO分期为ⅢB~Ⅳ期。本次化疗的中位疗程数是6个疗程。中位随访时间为18.5个月。最常见的不良反应为疲劳(55.6%)和神经系统症状(55.6%)。3例患者出现Ⅲ度副反应,1例为无力、1例过敏性皮疹和1例末梢神经感觉异常。根据RECIST标准评价有病灶的6例患者疗效,2例部分缓解,2例治疗中疾病无进展,1例病情进展,1例失访。另有2例CA125升高的患者,在联合化疗3~4个疗程后CA125水平降低50%以上。1例二次肿瘤细胞减灭术后化疗的患者治疗后随访36个月无肿瘤复发迹象。在随访的8例患者中,中位疾病无进展时间为6.5个月(0~36个月);中位总的生存时间为20.5个月(8~36个月)。结论:联合应用沙利度胺与脂质体阿霉素治疗复发性卵巢上皮性癌具有可接受的毒副作用,同时具有一定的治疗效果。     

Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer

OBJECTIVE: Docetaxel and carboplatin are active in relapsed ovarian, peritoneal and tubal cancer. Recently, two prospective-randomized trials showed an advantage of carboplatin combination regimen with paclitaxel or gemcitabine over carboplatinum alone in platinum-sensitive cases. The question on the most effective combination with the best tolerable side effects still needs to be answered. METHODS: Eligible patients had recurrent ovarian, peritoneal or tubal cancer (platinum-free interval >6 months), performance status 0-2 and normal bone marrow, renal and hepatic function. 25 patients (age 18-75 years) were enrolled into this phase II trial. Patients with debulking operation of recurrence were excluded from this study. Docetaxel 75 mg/m(2) via 30-min infusion was given on day 1 followed by carboplatin (area under curve [AUC] 5) on day 1. The administration was repeated every 3 weeks over 6 courses. Primary endpoint of this trial was the response rate; secondary endpoints were progression-free survival, overall survival and toxicity. RESULTS: In the intent-to-treat population, there were 16 (64.0%) complete and 2 (8.0%) partial responses resulting in an overall response rate of 72.0%. Three patients (12.0%) showed a stable disease and other 2 patients (8.0%) a progression of cancer. Two patients (8.0%) were not evaluable for response. Neutropenia was the most frequent G3/G4 hematologic toxicity in 15/25 patients (60.0%); but no neutropenic fever occurred in this trial. Diarrhea G3 was the most frequent G3/G4 non-hematologic toxicity in only 3/25 patients (12.0%). Dose-limiting toxicities were hypersensitivity reaction in one and depressive mood alteration requiring therapy in another case. CONCLUSION: Carboplatin in combination with docetaxel is highly active and well tolerated in patients with recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Prospective-randomized trials comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer are a possible option for the future to answer the question on the best combination regimen.