The role of topotecan as second-line therapy in patients with recurrent ovarian cancer

INTRODUCTION: Up to 80% of patients with advanced ovarian cancer will recur following first-line platinum containing chemotherapy. Topotecan has recently been used as a second-line agent in treatment of advanced ovarian disease. The aim of the study was to evaluate the effect of topotecan on response rate and progression-free interval on patients with recurrent ovarian cancer who had been treated with platinum-containing first-line chemotherapy. METHODS: A retrospective review of all cases of recurrent ovarian cancer treated with topotecan was done. Response was determined using radiologic reports (CT scans, ultrasound scans), CA-125 level and the clinical evaluation. Response type was determined using World Health Organization (WHO) criteria. RESULTS: Between 1998-2000, a total of 43 patients were treated with topotecan. Median age was 57 (range 41-80), 40/43 patients had stage III and IV, 37/43 patients had Grade 3 tumors. Seventeen of 43 patients (39.5%) demonstrated stable disease and 9/43 (21%) patients demonstrated partial response. Median time to response was eight weeks, median progression-free interval was 31 weeks and median time of follow-up and survival was 48 weeks. CONCLUSION: Topotecan is considered a reasonable option for treatment of patients with recurrent ovarian cancer that have failed previous treatment with platinum-containing chemotherapy.     

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.     

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 II trial of topotecan in patients with advanced,persistent, or recurrent endometrial carcinoma: a gynecologic oncology group study

OBJECTIVE: To estimate the antitumor activity of topotecan in women with advanced, persistent, or recurrent endometrial carcinoma previously treated with chemotherapy, and to determine the nature and degree of toxicity of topotecan in this cohort of patients. MATERIALS AND METHODS: Eligible patients were those who had failed one prior chemotherapy regimen. Topotecan 0.5 to 1.5 mg/m(2) was administered iv daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. RESULTS: Of 29 patients entered, 28 were evaluable for toxicity and 22 were evaluable for response. Patient characteristics included a median age of 65, with 41% having prior radiation and 14% having prior hormonal therapy. Nine patients (41%) had a performance status (PS) of 0, 11 (50%) had a PS of 1, and 2 (9%) had a PS of 2. Patients received from 2 to 11 (with a median of 4) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 17 (61%) patients, leukopenia in 11 (39%), and thrombocytopenia in 7 (25%). Two deaths were considered potentially related to treatment. There was one (4.5%) complete and one (4.5%) partial response; 12 (55%) patients maintained stable disease and eight (36%) experienced increasing tumor. CONCLUSION: Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent endometrial carcinoma previously treated with chemotherapy.     

Weekly topotecan in a heavily pretreated patient with peritoneal papillary serous adenocarcinoma.

Peritoneal papillary serous adenocarcinoma is a rare müllerian tumor type that is histologically similar to ovarian serous carcinoma. The low incidence of peritoneal papillary serous adenocarcinoma has hindered the establishment of a standard of care for this disease. A 56-year-old woman, who had undergone an abdominal hysterectomy 25 years earlier, presented with a vaginal nodule and palpable pelvic mass. She underwent debulking surgery and was diagnosed with stage IIIC peritoneal papillary serous adenocarcinoma. After 6 cycles of paclitaxel/carboplatin and 10 cycles of liposomal doxorubicin/cyclophosphamide, laparotomy revealed microscopic disease. This heavily pretreated patient then started topotecan therapy (1.0 mg/m(2)/day, x 5 days). After several dosing adjustments because of fatigue and malaise, weekly topotecan 4.0 mg/m(2) was determined to be the best-tolerated dosage. The patient ultimately received 14 weekly cycles of topotecan. After 12 weekly cycles, she achieved a complete response, which was maintained for 25 weeks with weekly topotecan therapy with a subsequent recurrence. Topotecan was reinstated. She maintains a disease-free interval of 58 weeks. Weekly topotecan demonstrated antitumor activity and was well tolerated in a patient with recurrent peritoneal papillary serous adenocarcinoma.     

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.     

Three-consecutive-day topotecan is an active regimen for recurrent epithelial ovarian cancer

OBJECTIVE: The aim was to determine the response rate and toxicity of topotecan administered Days 1-3 every 21 days for recurrent epithelial cancers of the ovary, peritoneum, or fallopian tube. A 3-day regimen may be more convenient and less expensive than a 5-day schedule. METHODS: Patients with recurrent epithelial cancer of the ovary, peritoneum, or fallopian tube who had adequate hepatic, renal, and hematologic function were eligible for participation. Topotecan (2 mg/m(2)) was administered for 3 consecutive days every 21 days. Response was measured clinically and serologically. Granulocyte colony stimulating factors (GCSF) were not utilized prophylactically, but could be added under specific conditions. RESULTS: Thirty-one patients with recurrent ovarian cancer whose median age was 63 (range 32-84) received 165 cycles of topotecan (median = 6; range 2-8) and are evaluable for toxicity. The median number of prior regimens was 1. Topotecan was administered on schedule in 96.6% of cycles. Grade 3/4 neutropenia was seen in 29.1 and 23.6% of courses, respectively; but only 3.4% of cycles required GCSF support (6 cycles for 2 patients). Grade 4 thrombocytopenia was rare (1% of cycles). Nonhematologic toxicity was mild. The response rate for 28 evaluable patients was 32.1% (10.7% complete response (CR) and 21.4% partial response (PR)); stable disease was seen in 17.9% of patients. The median progression-free interval (PFI) for all patients was 15.5 weeks (range 5-40). Eighteen platinum-sensitive patients demonstrated a 43.4% response rate (12.5% CR and 31.3% PR); stable disease was documented in 18.8%. The median PFI for platinum-sensitive patients was 18.5 weeks (range 5-40). CONCLUSION: Topotecan is an effective regimen with acceptable toxicity for recurrent ovarian cancer when administered for 3 consecutive days (2 mg/m(2)) every 21 days. It can be delivered on schedule without GCSF support in the vast majority of patients.     

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.     

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.     

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 II evaluation of topotecan in carcinosarcoma of the uterus: a Gynecologic Oncology Group study

OBJECTIVES: To estimate the antitumor activity of topotecan in patients with persistent or recurrent carcinosarcoma (malignant mixed mullerian tumors) of the uterus and to determine the nature and degree of toxicity of topotecan in this cohort of patients. MATERIALS AND METHODS: Eligible patients had measurable advanced or recurrent carcinosarcoma of the uterus. Topotecan at a target dose of 1.5 mg/m(2) was administered IV daily for 5 days, every 3 weeks, until progression of disease or adverse affects prohibited further therapy. RESULTS: Twenty-seven member institutions entered 51 patients. Of the patients entered, 48 were eligible. Patient characteristics included a median age of 65, with 33% having prior radiation and 92% having prior chemotherapy. Twenty-six patients (54%) had a performance status (PS) of 0, 18 (38%) had a PS of 1, and four (8%) had a PS of 2. Patients received from 1 to 21 (with a median of 2) courses of treatment. The most frequently observed grade 4 toxicities were neutropenia seen in 35 (73%) patients, leukopenia in 14 (29%), and thrombocytopenia in 10 (21%). Three (6%) patients developed neutropenic sepsis and died shortly after their first treatment cycle. There were five (10%) complete responses; 13 (27%) patients maintained stable disease, 26 (54%) experienced increasing disease, and reassessment did not occur in four (8%). CONCLUSION: Topotecan at this dose and schedule does not appear to have major activity in patients with advanced or recurrent uterine carcinosarcoma previously treated with chemotherapy.     

A phase II trial of weekly topotecan for patients with secondary platinum-resistant recurrent epithelial ovarian carcinoma following the failure of second-line therapy

OBJECTIVE: To determine the response rate, progression-free survival and toxicity associated with weekly topotecan administered to patients with platinum-sensitive recurrent epithelial ovarian (EOC) in the third-line setting. METHODS: Patients with measurable platinum-sensitive EOC following failure of second-line chemotherapy were eligible for this phase II study. All patients were initially treated with cytoreductive surgery and platinum/paclitaxel-based chemotherapy. Continuous, weekly topotecan was administered at a starting dose of 4 mg/m(2). Toxicity and efficacy were assessed at various time points after initiation of therapy. RESULTS: Twenty nine patients were enrolled in this prospective study. Toxicity was acceptable with grade 1/2 nausea being the most commonly experienced side effect (52%). Nine patients (31%) had grade 3/4 leukopenia; however, only 3 patients had febrile neutropenia. Thirteen patients had a treatment delay and six required dose reductions. Twenty two patients were evaluable for efficacy. The overall response rate for weekly topotecan was 13.6% [95% CI; -0.7-27.9%] with 1 complete response, and 2 partial responses. Twelve patients (54.5%), including 2 with minor responses, had stable disease for a median duration of 18 weeks. CONCLUSIONS: Weekly topotecan at the current schedule in the third-line setting in patients with platinum-sensitive recurrent EOC has modest clinical activity. Toxicity associated with this regimen is acceptable but growth factor support, dose reductions, or schedule alterations may need to be considered in many of these patients.     

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.     

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.     

Preliminary experience with salvage weekly paclitaxel in women with advanced recurrent ovarian carcinoma

PURPOSE OF INVESTIGATION: To assess the role of palliative chemotherapy with weekly paclitaxel in patients with recurrent ovarian cancer. METHODS: Thirty-two patients with paclitaxel- and platinum-resistant ovarian cancer were treated with weekly paclitaxel at 80 mg/m2 as a 1-hour intravenous infusion weekly for six weeks every eight weeks (1 cycle). This schedule was considered to be given for three cycles. Evaluation of radiographically measurable disease was used in the assessment of response. CA-125 was used to classify responses only in the absence of a measurable lesion. RESULTS: Thirty-two patients were all assessable for response. Of these, nine patients (28.1%) achieved a partial response and one patient achieved a complete response, leading to an overall response rate of 31.2%. Stable disease occurred in six patients (18.8%), and 16 patients (50%) had progressive disease. Nine patients died of progressive disease while on treatment. The median survival for the entire group was 10.5 months (range 2.5-22 months). Grade 3 or 4 leukopenia and neutropenia occurred in eight and six patients, respectively. Four of these patients developed febrile neutropenia without infection. Grade 1 and 2 peripheral neuropathies were observed in 50% of the patients without causing any premature drop out. Severe (grade 3 or 4) peripheral neuropathy was not observed. There were 11 patients with grade 1 or 2 myalgias. CONCLUSION: Weekly paclitaxel regimen is well tolerated with acceptable toxicity. The favorable toxicity profile and the encouraging antitumor activity observed in this study makes this regimen an option for the salvage treatment of patients with recurrent ovarian cancer.     

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 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.     

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.     

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.     

The safety and efficacy of the weekly dosing of irinotecan for platinum- and taxanes-resistant epithelial ovarian cancer

OBJECTIVE: Irinotecan is one of the drugs that might be effective against platinum- and taxanes-resistant epithelial ovarian cancer. We investigated efficacy and safety of the weekly dosing schedule of irinotecan. METHODS: From September 2001 to March 2003, 28 eligible patients who have histologically confirmed epithelial ovarian cancer, which was resistant or refractory to both platinum and taxanes, were consecutively treated at the National Cancer Center Hospital. Irinotecan (100 mg/m(2)) was administered intravenously over 90 min on days 1, 8, and 15. The chemotherapy was repeated every 4 weeks, up to 6 cycles. RESULTS: A total of 107 treatment cycles of irinotecan were administered to 28 patients. The median number of prior chemotherapy regimen was 3. Among 28 patients, 8 (29%) responded to irinotecan (2 complete responses and 6 partial responses). The median time to progression was 17 weeks. Three patients experienced hematological toxicities of Grade 4. Five patients experienced non-hematological toxicities Grade 3 or 4. No treatment-related death occurred. CONCLUSION: The weekly dosing schedule of irinotecan seems to be effective and safe salvage chemotherapy regimen for platinum- and taxanes-resistant or refractory epithelial ovarian cancer. Gastrointestinal toxicities, especially diarrhea, were moderate and manageable in an outpatient setting.