A phase I/II trial of weekly topotecan and carboplatin in potentially platinum-sensitive relapsed ovarian and peritoneal carcinoma

OBJECTIVE: Topotecan and carboplatin are active in relapsed ovarian cancer, but attempts to combine these agents are limited by myelotoxicity. This phase I/II trial combined weekly topotecan, which is less myelosuppressive than the standard 5-day regimen, with carboplatin in patients with potentially platinum-sensitive relapsed ovarian or peritoneal carcinoma (PS-OVCa/PCa). METHODS: Eligible patients had PS-OVCa/PCa, performance status 0-2, and normal bone marrow, renal, and hepatic functions. On day 1 of a 21-day cycle, patients received carboplatin (area under the curve [AUC] 5) followed by topotecan 2.0 mg/m2, both via 30-min intravenous infusion. Topotecan 2.0 mg/m2 also was administered on days 8 and 15. Treatment was withheld for neutropenia or thrombocytopenia on day 8 or 15. Dose escalation was planned. RESULTS: Seventeen patients received a total of 115 (median, 6) cycles of chemotherapy. With carboplatin AUC 4, neutropenia prevented dose escalation of topotecan; hematologic toxicity caused 34/105 (32%) weekly treatments to be withheld. However, carboplatin could be dose escalated to AUC 5 when the day 15 dose of topotecan was withheld. In the intent-to-treat population, there were 4 (24%) complete and 9 (53%) partial responses, 2 (12%) patients (at the carboplatin AUC 4 dose) with stable disease, and 2 (12%) nonevaluable patients. CONCLUSION: Carboplatin (AUC 5) on day 1 in combination with topotecan 2.0 mg/m2 on days 1 and 8 of a 21-day cycle is well tolerated and active in patients with PS-OVCa/PCa. A phase II trial comparing this with other carboplatin therapeutic doublets in patients with recurrent ovarian cancer is warranted.     

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.     

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.     

A phase I study of weekly topotecan and Paclitaxel in previously treated epithelial ovarian carcinoma patients

OBJECTIVE: We have previously reported on the feasibility of weekly topotecan as single-agent therapy in previously treated patients with ovarian cancer. The objective of this study was to assess the maximum tolerated dose (MTD) of weekly bolus intravenous (IV) topotecan combined with weekly paclitaxel in a comparable patient population. METHODS: Previously treated ovarian cancer patients with measurable disease and/or elevated cancer antigen 125 (CA-125) received (as second-line or third-line therapy) weekly 30-min bolus IV topotecan starting at 2 mg/m(2) combined with weekly paclitaxel starting at a dose of 60 mg/m(2). In this intrapatient dose-escalation study, topotecan and paclitaxel were escalated in parallel until the MTD was reached, defined as the first dose level at which >or= 2 of 6 patients experienced dose-limiting toxicity. RESULTS: Twenty-one of 26 patients were evaluable for toxicity and received a total of 306 weeks of therapy (median, 13 weeks; range, 5 to 33 weeks). No significant dose-limiting toxicity was observed up to a weekly bolus IV topotecan dose of 3 mg/m(2) and a concurrent paclitaxel dose of 80 mg/m(2). The MTD was topotecan 3.5 mg/m(2) plus 90 mg/m(2) paclitaxel. The dose-limiting toxicities included anemia and fatigue, with 10 of 21 patients receiving epoetin alfa for grade 3 or 4 anemia; only 1 patient required a blood transfusion. Two patients had a treatment delay of at least 1 week and only 1 patient required a dose reduction to maintain the weekly schedule. CONCLUSIONS: Based on the results of this study, the recommended initial dose for this novel regimen is topotecan 3 mg/m(2) and paclitaxel 80 mg/m(2). Further investigation of the efficacy of weekly topotecan plus paclitaxel in less heavily pretreated patients is warranted.     

Phase II trial of topotecan and cisplatin in persistent or recurrent squamous and nonsquamous carcinomas of the cervix

OBJECTIVE: Cisplatin is a standard treatment in advanced, recurrent cervical cancer. Because topotecan is an established treatment in gynecologic malignancies such as ovarian cancer and exhibits nonoverlapping toxicity with cisplatin, a phase II trial was conducted to evaluate the tolerability and antitumor activity of a cisplatin/topotecan doublet in persistent or recurrent cervical cancer patients. METHODS: Patients with bidimensionally measurable persistent or recurrent squamous cell and non squamous cell cervical cancer and adequate bone marrow were enrolled. Patients received 50 mg/m(2) of cisplatin intravenously over 1 h on Day 1 and 0.75 mg/m(2) of topotecan intravenously over 30 min on Days 1, 2, and 3 of 21-day cycles for six cycles or until disease progression. Tumor response and regimen toxicity were assessed using established Gynecologic Oncology Group criteria. RESULTS: Thirty-two of 35 enrolled patients were evaluable for toxicity and tumor response. All but 2 evaluable patients had received previous radiotherapy. No patient received prior chemotherapy. The cisplatin/topotecan doublet was well tolerated, with 77 and 78% of courses given without interruption or delay and at full doses, respectively. As anticipated, the most common toxicity was hematologic, with grade 3/4 neutropenia and thrombocytopenia reported in 30 and 10% of cycles, respectively. The overall response rate was 28% (9/32), with 3 complete and 6 partial responses. The antitumor response in nonirradiated fields (30%) was similar to the response observed in previously irradiated fields (33%), suggesting good drug penetration. Median duration of response was 5 months (range, 2 to 15+ months). An additional 9 (28%) patients achieved stable disease. Median survival was 10 months, with 3 patients in lasting remission. CONCLUSIONS: These results demonstrate that the cisplatin/topotecan combination is safe, well tolerated, and active in persistent or recurrent cervical cancer patients. A phase III, multicenter trial is under way (cisplatin/topotecan versus cisplatin) based on these favorable results to confirm the safety and efficacy profile in this patient population.     

A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients

OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients.     

A phase I trial of gemcitabine and topotecan in previously treated ovarian or peritoneal cancer: a Gynecologic Oncology Group study

OBJECTIVE: To determine the maximum tolerated dose (MTD) of the combination of gemcitabine and topotecan in women with previously treated epithelial ovarian, peritoneal, or fallopian tube cancer. METHODS: Patients with recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study. Initial treatment was gemcitabine at a dose of 800 mg/m(2) on days 1, 8, and 15 and topotecan at a dose of 0.5 mg/m(2) on days 2-5, with cycles repeated every 28 days. Dose escalations were planned first for topotecan (Cohort I, Dose Levels 1-5) then for gemcitabine (Cohort II, Dose Levels 6-9) until the MTD was reached. RESULTS: Ten patients received a total of 29 cycles. When none of the first four patients could complete therapy as prescribed due to toxicity, doses for each drug were reduced by 1 day. The next six patients were treated at the modified schedule of gemcitabine days 1 and 8 and topotecan days 2-4 (Dose Level -1). Despite this modification, dose-limiting toxicities including neutropenia, thrombocytopenia, and stomatitis occurred at Dose Level -1, and the study was closed early. CONCLUSIONS: At both the initial dose schedule and an attenuated schedule, the combination of gemcitabine and topotecan produced dose-limiting toxicities in women with previously treated epithelial ovarian or peritoneal cancer.     

Improved therapeutic index of lower dose topotecan chemotherapy in recurrent ovarian cancer

OBJECTIVE: Topotecan (1.5 mg/m(2)) administered daily for 5 consecutive days of a 21-day cycle is an established chemotherapeutic regimen in recurrent ovarian cancer. However, noncumulative myelosuppression has limited its use by many clinicians. We sought to determine whether a lower dose of topotecan could provide comparable tumor activity and higher tolerability in pretreated ovarian cancer patients. METHODS: A retrospective chart review was conducted on recurrent ovarian, peritoneal, or fallopian tube cancer patients with measurable disease or elevated cancer antigen 125 levels (evaluable disease). Patients were treated with topotecan (1.0 mg/m(2)) given by 30-min intravenous infusion for 5 consecutive days every 21 days until disease progression or unacceptable toxicity. RESULTS: Treatment records from 37 women who had been treated with a median of 3 courses (range, 1 to 17) of lower dose topotecan were evaluated; all were evaluable for tolerability and 36 were evaluable for response. Patients had received a median of 3 (range, 1 to 6) previous treatments. The overall response rate was 22% (8/36); the response rates for patients with evaluable disease and measurable disease were 35.7 (5/14) and 13.6% (3/22), respectively. An additional 8 patients (22%) achieved stable disease. Grade 4 neutropenia, thrombocytopenia, and anemia occurred in 48.6, 5.4, and 5.4% of patients, respectively. Granulocyte colony-stimulating factor support was used in 37% of patients, including 5 who experienced febrile neutropenia. CONCLUSION: Topotecan at 1.0 mg/m(2) x 5 days every 21 days is active in platinum- and paclitaxel-resistant ovarian cancer, with significant improvements in hematologic toxicity. In heavily pretreated patients-topotecan can be safely given at reduced doses without apparent loss of efficacy.     

Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer

PURPOSE; The aim of this study was to investigate the toxicity and efficacy of a more convenient topotecan administration schedule (in contrast to the "standard" 1.5 mg/m(2)/day x 5 days q 21 days) in the management of platinum- and paclitaxel-refractory ovarian cancer. METHODS: Patients with clinically defined platinum- and paclitaxel-refractory ovarian cancer participating in this phase 2 trial conducted by the Gynecologic Cancer Program of the Cleveland Clinic Taussig Cancer Center received topotecan at a dose of 1.5 mg/m(2)/day x 3 days on a 21-day schedule. Both dose escalations and reductions were permitted in the protocol design. RESULTS: A total of 29 patients (median age: 61; range: 43-80) were treated with this modified topotecan schedule. These individuals had received a median of two prior regimens (range: 1-4) (retreatment with a platinum agent or paclitaxel considered a single regimen). The median number of topotecan courses delivered was 3 (range: 1-7). Major toxicity included grade 4 neutropenia (24% of patients); neutropenic fever (10%); grade 3 thrombocytopenia (10%); and requirement for blood transfusion (14%). Dose escalation was possible, and dose reductions required, in 14 and 28% of patients, respectively. Two patients exhibited evidence of a clinically relevant response to treatment. CONCLUSION: This 3-day topotecan program is more convenient and less toxic than the standard 5-day regimen. The limited level of activity observed is not inconsistent with that previously reported for the 5-day topotecan infusion schedule in platinum/paclitaxel-refractory ovarian cancer. Further investigation will be required to document the clinical utility of a 3-day topotecan schedule in a less heavily pretreated and more chemosensitive patient population.     

A new therapeutical approach: topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy with paclitaxel and platinum

AIM: Topotecan and gemcitabine have demonstrated mono-activity against recurrent ovarian cancer. Both drugs affect DNA replication; in addition, topotecan inhibits DNA repair. Based on the efficacy profiles and different mechanisms of action, a phase-I study was conducted to determine the maximum tolerated dose (MTD) of topotecan (day 1-5) and the dose-limiting toxicities (DLT) in combination with gemcitabine (day 1 + 8) every 21 days. METHODS: Three to six patients were treated per dose-level. Patients with ovarian cancer who had failed a platinum and paclitaxel-containing therapy were enrolled. No individual dose escalation or use of cytokines were allowed. RESULTS: Twenty-three patients were recruited. Fifty percent of all patients were pretreated with at least two platinum-containing therapies. Eighty courses were assessable for toxicity. The MTD was reached at a dosage of 0.75 mg/m2 topotecan in combination with 800/600 mg/m2 gemcitabine. Thrombocytopenia and leucopenia were the major DLTs. The dose for phase-II trials is 0.50 mg/m2 topotecan given with 800/600 mg/m2 gemcitabine. In this dose-level only one related non-haematological adverse event > grade 2 was observed (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in six patients and stable disease in four out of 12 assessable patients. Median survival time was 15.3 (95% CI: 13.21-28.64) months. CONCLUSION: The results demonstrate feasibility and the tolerability of topotecan in combination with gemcitabine in recurrent ovarian cancer patients. Based on these results a phase-II study was conducted to evaluate the efficacy of this new combination.     

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.     

Phase I study of alternating doublets of topotecan/carboplatin and paclitaxel/carboplatin in patients with newly diagnosed, advanced ovarian cancer

OBJECTIVE: The aim of this study was to evaluate topotecan with carboplatin in an alternating doublet with carboplatin and paclitaxel in first-line ovarian cancer. METHODS: Patients with newly diagnosed stage III/IV ovarian cancer were studied. The maximum tolerated dose (MTD) of topotecan (cycles 1, 3, 5, 7) in an alternating doublet regimen was determined through standard dose escalation in cohorts of three; doses of carboplatin (area under the curve [AUC] 4 to 5) and paclitaxel (175 mg/m(2), cycles 2, 4, 6, 8) were fixed. Dose-limiting toxicity (DLT) was defined only for cycle 1 as febrile neutropenia, prolonged grade 4 granulocytopenia, grade 4 thrombocytopenia, > or =grade 3 nonhematologic toxicity, or failure to recover in < or =7 days. The use of granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was also studied. RESULTS: Thirty-seven patients received 142 cycles of topotecan/carboplatin. Hematologic DLTs included grade 4 neutropenia (59 events, 42% of cycles) and thrombocytopenia (32 events, 23% of cycles). Granulocytopenia was generally short-lived, and only 2 cases of febrile neutropenia occurred. The MTD was 1.0 mg/m(2)/day topotecan and carboplatin AUC 4, alternating with 175 mg/m(2) paclitaxel and carboplatin AUC 4. Although G-CSF effectively managed myelosuppression, thrombocytopenia developed in later cycles, limiting further topotecan dose escalation. The median progression-free survival was 20.5 months, and elevated pretreatment CA-125 levels normalized in 29 of 34 (85%) patients. CONCLUSION: The establishment of a reasonably well-tolerated alternating doublet regimen, coupled with evidence of antitumor activity, provides the basis for further investigation of topotecan in first-line therapy of ovarian cancer. Topotecan (1.0 mg/m(2) daily for 3 days) was chosen for further evaluation in a phase II study.     

Phase II evaluation of 3-day topotecan with cyclophosphamide in the treatment of recurrent ovarian cancer

OBJECTIVE: The aim of this trial was to investigate the toxicity and efficacy of a 3-day topotecan administration schedule in combination with cyclophosphamide in the management of recurrent ovarian cancer. METHODS: Patients with recurrent measurable ovarian cancer who had up to two prior chemotherapy regimens for the management of their disease participating in this phase II trial were to receive topotecan at a dose of 1.25 mg/m(2)/day x 3 days in combination with cyclophosphamide at 600 mg/m(2) on Day 1 every 21 days. Dose escalation and reductions were permitted. RESULTS: A total of 36 patients (median age = 65; range 37-84) were treated with this combination regimen. Seventeen were platinum-sensitive and 19 were platinum-resistant. A total of 169 cycles of chemotherapy was administered (median = 4; range 1-10). Major toxicity included grade 4 neutropenia (68.6%), neutropenic fever (7.1%), grade 3 thrombocytopenia (18.3%), and requirement for blood transfusion (19.5%). Dose escalation was possible in 3 (8.3%), and dose reduction was required in 14 (38.9%) patients. Overall response rate was 25 and 44.5% stable disease. Median progression-free interval and overall survival was 5.4 and 23.5 months, respectively, independent of platinum sensitivity. CONCLUSION: The 3-day topotecan schedule in combination with cyclophosphamide appears to have good activity in recurrent ovarian cancer regardless of platinum sensitivity. Neutropenia was the only severe toxicity and was less prevalent than other reported trials of topotecan. This tolerable regimen offers patients more convenience and appears to have moderate activity.     

A phase I study of paclitaxel, topotecan, cisplatin and Filgrastim in patients with newly diagnosed advanced ovarian epithelial malignancies: a Gynecologic Oncology Group study

OBJECTIVES: To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. METHODS: Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m2/3 h, followed 2 h later by cisplatin 50 mg/m2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m2 (cohort 1), or 3 days beginning at 0.5 mg/m2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. RESULTS: Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.5 mg/m2 daily x 5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m2/3 h, cisplatin 50 mg/m2 and topotecan 0.75 mg/m2 daily x 3 with Filgrastim. CONCLUSION: In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.     

Lack of efficacy of 24-h infusional topotecan in platinum-refractory ovarian cancer: A Gynecologic Oncology Group trial

BACKGROUND: The aim of this study was to evaluate the efficacy of a more convenient topotecan administration schedule in the second-line treatment of advanced platinum-refractory ovarian cancer. METHODS AND MATERIALS: The Gynecologic Oncology Group conducted a Phase II trial of 24-h infusional topotecan (8.5 mg/m(2)), repeated every 3 weeks in 26 patients with platinum-refractory ovarian cancer (failure to respond to initial platinum-based treatment or development of recurrent disease within 6 months of completion of chemotherapy). RESULTS: Grade 4 neutropenia (85% of patients) and thrombocytopenia (12%) were the major toxicities encountered. Of the 25 patients evaluable for response, only a single patient experienced an objective response (4%). CONCLUSIONS: When employed at this dose and schedule (24-h infusion every 3 weeks), topotecan has minimal second-line activity in platinum-refractory ovarian cancer.     

High-dose topotecan, melphalan, and cyclophosphamide (TMC) with stem cell support: a new regimen for the treatment of advanced ovarian cancer

OBJECTIVE: The goal of this study was to determine the optimal dose of topotecan when used in combination with high-dose melphalan and cyclophosphamide (TMC), and to assess the toxicity and efficacy of the regimen in patients with advanced ovarian cancer. METHODS: Fifty-three patients with persistent or recurrent ovarian cancer were treated. Disease status at study entry included: platinum-sensitive recurrent disease (15 patients), platinum-resistant or refractory recurrent disease (15 patients), positive second-look surgery (16 patients), failure to achieve a primary clinical complete response (CR) (7 patients). Following stem cell mobilization and collection, patients were given cyclophosphamide 1 g/m(2)/day on Days -6, -5, -4; melphalan 70 mg/m(2)/day on Days -3, -2; and topotecan at escalating doses from 1.25 to 4.0 mg/m(2)/day on Days -6 to -2. Peripheral blood stem cells were infused on Day 0. RESULTS: The optimal topotecan dose selected for future trials was 4.0 mg/m(2)/day x 5 days. The regimen had acceptable toxicity with no regimen-related death. Toxicity (Bearman toxicity criteria) was limited mostly to grade 1-2 mucositis and diarrhea. The overall response rate of patients with measurable or evaluable disease was 93%. Median survival has not yet been reached, but with a median follow up of 18 months (range: 11-37) 77% of patients are alive. CONCLUSION: With a topotecan dose of 4.0 mg/m(2)/day x 5 days, the TMC regimen has acceptable toxicity and produces high response rates. In the setting of ovarian cancer, high-dose chemotherapy should be administered only as part of well-designed clinical trials. TMC should be considered a potential regimen for future randomized trials in patients with advanced ovarian cancer.     

Weekly topotecan for recurrent endometrial cancer: a case series and review of the literature

OBJECTIVE: Topotecan, a topoisomerase 1 inhibitor, has demonstrated antitumor activity in ovarian and endometrial cancers when administered daily for 5 days every 3 weeks. Recently, topotecan has been studied on a weekly dosing schedule for the treatment of ovarian cancer and found to have efficacy with reduced toxicity. The aim of this study is to review the Memorial Sloan-Kettering Cancer Center (MSKCC) experience with weekly topotecan dosing in women with recurrent endometrial cancer. We have included a review of the literature of weekly topotecan in the treatment of patients with gynecologic cancer. METHODS: After Institutional Review Board (IRB) approval, we identified all women with recurrent endometrial cancer treated with topotecan at MSKCC from May 1996 to February 2004. Patients treated on a weekly schedule were assessed for toxicity and response. A review of the literature pertaining to weekly topotecan in the treatment of endometrial cancer was also performed. RESULTS: Eleven patients were treated with weekly topotecan during the study period, with doses ranging from 2.5-4.0 mg/m(2) on a 2- or 3-week schedule with 1 week off. The median age of the patients was 60 years old (range, 47-76 years), and the median Karnofsky performance status was 80%. Six of the 11 patients were previously treated with more than three chemotherapy regimens and eight had received prior pelvic radiation. Ninety-seven percent of treatment doses were delivered as scheduled, and only two patients required dose reductions. One patient achieved a prolonged partial response for 54 weeks, and two patients had stabilization of disease for 15 weeks each. CONCLUSIONS: Weekly topotecan has antitumor activity and is well tolerated in patients with recurrent endometrial cancer, including those patients with multiple prior treatments. Topotecan on a weekly bolus schedule should be evaluated in prospective trials to better establish its role in the treatment of recurrent endometrial cancer.     

Repetitive high-dose topotecan, carboplatin, and paclitaxel with peripheral blood progenitor cell support in previously untreated ovarian cancer: results of a Phase I study

OBJECTIVE: In view of the significant activity of topotecan in ovarian cancer with dose-limiting toxicity (DLT) of myelosuppression, we evaluated the addition of topotecan to carboplatin and paclitaxel with peripheral blood progenitor cell (PBPC) support. METHODS: Patients with previously untreated stage IIIC or IV ovarian cancer with macroscopic residual disease following primary debulking surgery were eligible. Patients received two cycles of carboplatin AUC = 5 and 175 mg/m(2) of paclitaxel with collection of PBPCs after the second cycle. Patients subsequently received three cycles of high-dose therapy (HDT) with topotecan on a daily x5 schedule, paclitaxel (250 mg/m(2) over 24 h), and carboplatin (AUC = 12-16). RESULTS: Nineteen patients with a median age of 49 years (range 21-63) were enrolled and topotecan was escalated in 6 patient cohorts up to a dose of 4.5 mg/m(2)/day. Fifty-two of the planned 57 treatment cycles were delivered with no treatment-related deaths. Neutrophil and platelet recovery was rapid and the interval between HDT was 28 days. Febrile neutropenia occurred following 57% of all HDT cycles. DLTs of mucositis and diarrhea were observed at topotecan (4.5 mg/m(2)/day), paclitaxel (250 mg/m(2)) and carboplatin (AUC = 12). The protocol was subsequently modified to administer topotecan (2.5 mg/m(2)/day) with carboplatin (AUC = 16); however, 2 patients developed grade 4 diarrhea (1 with grade 3 mucositis and 1 with grade 4 mucositis). The clinical CR rate was 73% (14/19) with an overall clinical response rate of 95% (18/19). Of the 14 patients with a CCR, 13 of these underwent a second-look laparotomy with 8 (61%) achieving a pathological CR. With a median follow-up of 28 months (range 11-40 months), the median PFS is 36 months and OS has not been reached. CONCLUSION: When combined with carboplatin (AUC = 12) and paclitaxel (250 mg/m(2)), the recommended topotecan dose is 3.5 mg/m(2)/day for 5 days. This outpatient HDT regimen combines three of the most active drugs in ovarian cancer with acceptable toxicity and promising activity.     

紫杉醇联合奥沙利铂治疗复发性或晚期宫颈癌临床疗效分析

目的：探讨分析紫杉醇联合奥沙利铂治疗复发性或晚期宫颈癌的临床疗效及不良反应。方法：选取北京同仁医院32例复发性或晚期宫颈癌,给予紫杉醇联合奥沙利铂化疗方案：第1天紫杉醇150 mg/m2静脉滴注≥3 h,第2天奥沙利铂130 mg/m2静脉滴注≥2 h,每21天为1个周期,治疗2个周期后进行评价,评估患者近远期疗效及不良反应。结果：全部患者均可参与评价疗效,总有效率为25.0%,中位无进展生存期（progression-free survival,PFS）和中位总生存期（overall survival,OS）分别为21.2周和52.1周。主要不良反应为神经毒性和骨髓抑制,非血液学不良反应较轻。结论：紫杉醇联合奥沙利铂治疗复发性或晚期宫颈癌患者疗效肯定,不良反应可以耐受,值得进一步临床研究。     

A phase I trial of a 3-day topotecan Q 21 days for recurrent epithelial cancers of the ovary, fallopian tube, and peritoneum

OBJECTIVE: This trial was undertaken to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of topotecan that can be administered for 3 days q 21 days. A 3-day schedule is more convenient and less expensive than standard 5-day dosing. METHODS: Patients with recurrent epithelial ovary, tubal, or peritoneal carcinoma were treated with escalating doses of topotecan beginning at 2.50 mg/m(2) as an outpatient days 1-3 q 21 days. Colony stimulating factors were not employed prophylactically, but could be added for grade 4 marrow toxicity. RESULTS: Twenty patients with a median age of 61 (range 46-80) and performance status of 0 or 1 were entered. All patients had received at least one prior paclitaxel/platinum regimen; 6 had received two. Ninety-one cycles were delivered (median = 6) and 98.9% were on schedule. Grade 4 neutropenia was seen in 17 of 20 patients (85%) in cycle 1 and in 38 of 91 (41.8%) total cycles. Sixteen of 20 patients (80%) started G-CSF on cycle 2. Two of 91 (2.2%) cycles had grade 4 thrombocytopenia. Four cycles (4.4%) were associated with febrile neutropenia. Two patients experienced grade 4 neurotoxicity (DLT) at 4.25 mg/m(2). Other nonhematologic toxicity was mild. CONCLUSIONS: Topotecan can be safely administered on schedule as an outpatient days 1-3 q 21 days. Neurotoxicity was the DLT when G-CSF was added; the MTD was 3.75 mg/m(2). There was minimal other nonhematologic toxicity. Neutropenia was predictable and easily managed with G-CSF. Febrile neutropenia was uncommon and thrombocytopenia was rare at the doses evaluated.