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 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.     

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.     

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.     

A Phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a gynecologic oncology group study

OBJECTIVE: The toxicity and activity of intravenous topotecan were assessed in a multicenter Phase II study (GOG 76-U) in patients with advanced, recurrent, or persistent squamous cell carcinoma of the uterine cervix. METHODS: Intravenous topotecan was administered at 1.5 mg/m2 per day for 5 consecutive days every 4 weeks in patients without prior chemotherapy, aside from chemosensitizing agents used in conjunction with radiotherapy. The study required histologic confirmation of primary diagnosis, adequate performance status, and measurable disease to assess response. A two-stage design for accrual was used to allow for early termination of the study should inadequate response or excessive toxicity be an issue. Modifications of dose were based on hematologic toxicity. Treatment was continued until progression of disease was documented or adverse effects prohibited further therapy. RESULTS: A total of 49 patients were entered on study: of these 5 were never treated, and 1 was not evaluable for response. More than 88% (38 of 43 patients) had received prior radiotherapy. A median of two courses were administered per patient with a range of 1 to 14 cycles. Grade 4 neutropenia occurred in 68% and grade 4 thrombocytopenia in 18% of patients. Nonhematologic toxic effects were infrequent and not dose-limiting. The overall response rate (complete and partial) was 18.6%. The median progression-free survival was 2.4 months. CONCLUSIONS: Topotecan administered at this dose and schedule demonstrated moderate activity albeit at a cost of substantial hematologic toxicity in patients with advanced, recurrent, or persistent squamous cell carcinoma of the cervix.     

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.     

Topotecan in heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma

Abstract.   Piura B, Rabinovich A. Topotecan in heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma. Int J Gynecol Cancer 2005; 15: 612–617.
Topotecan has demonstrated antitumor activity in heavily pretreated patients with ovarian carcinoma. This report examines the activity and toxicity of topotecan in 29 heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma. Topotecan 1.5 mg/m² was administered intravenously on days 1–5, every 21 days. It was second-line chemotherapy in 6 (20.7%) patients, third-line in 15 (51.7%), fourth-line in 4 (13.8%), fifth-line in 3 (10.3%), and seventh-line in 1 (3.4%). Median dose intensity was 1.667 mg/m²/week, and median relative dose intensity was 0.67. Disease complete response was observed in 5 (17.2%) patients, partial response in 1 (3.4%), stable disease in 12 (41.4%), and progressive disease in 11 (37.9%). CA-125 complete response was observed in 3 (10.3%) patients, partial response in 11 (37.9%), stable level in 5 (17.2%), and progressive level in 9 (31%), and no data were available in 1 (3.4%) patient. Toxicity was mainly hematologic: grade 3–4 neutropenia was observed in 20 (69%) patients, grade 3–4 leukopenia in 12 (41.4%), grade 3–4 thrombocytopenia in 9 (31%), and grade 3–4 anemia in 2 (6.9%). It is concluded that topotecan has considerable activity and noncumulative hematologic toxicity in heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma.     

Phase II evaluation of topotecan and navelbine in patients with recurrent ovarian, fallopian tube or primary peritoneal cancer

ObjectiveTo assess the efficacy and toxicity profile in patients with recurrent ovarian or primary peritoneal cancer treated with topotecan at 2.5 mg/m² days 1 and 8 plus vinorelbine at 25 mg/m² days 1 and 8 every 3 weeks.Materials and methodsEligibility criteria included patients with recurrent primary peritoneal or epithelial ovarian cancer with either platinum-resistant or platinum-sensitive disease. Patients were required to have a performance status of ≤ 2 and normal hepatic and renal function. Response to therapy and toxicity were assessed using standard criteria. Chi square and Student's t-tests were used as appropriate. Survival was assessed with Kaplan–Meier method.ResultsAll 40 patients enrolled were assessable for response. The median age of the patients was 58 years (range 30–82). Median treatment-free interval was 4.0 months. A total of 216 cycles of chemotherapy were administered with a median of 5.0 cycles per patient. Overall median TTP with this treatment regimen was 19 weeks (range 2–136 weeks). The response rate was 30% overall, and the response for platinum-sensitive and platinum-resistant patients was 44% (95% CI:22–69%) and 18% (95% CI:5–40%) respectively. Median progression-free survival was 3.0 months (range 1–9 months). Median overall survival was 16.4 months (range 1.5–51.7 months). Assessment of toxicity by patient showed 58% demonstrating grade 3/4 neutropenia with the vast majority being uncomplicated. No severe non-hematological toxicity was observed.ConclusionAdministration of topotecan and navelbine is feasible with demonstrable activity and tolerable toxicity. This regimen may be considered especially in platinum-sensitive patients if a non-platinum based doublet is desired.     

Ethnicity is a factor to be considered before dose planning in ovarian cancer patients to be treated with topotecan

The objective of this study was to determine the efficacy and toxicity of topotecan in Chinese patients with ovarian cancer. A retrospective analysis on recurrent ovarian cancer patients receiving topotecan 1.25 mg/m(2) daily for 5 consecutive days on a 21-day cycle from 1997 to 2002 was conducted. The patients included were all treated with at least two cycles of topotecan. The patient characteristics were compared in relation to their toxicity profile and their response to treatment. Response was evaluated by physical findings, imaging techniques, and serum CA125 level. A total of 60 patients were included in the study. All patients were evaluable for response and toxicities. A total of 361 cycles were given (median, 5 per patient; range 2-15). The major toxicity was neutropenia, which was grade 4 in 45.0% of the patients and 10.2% of the cycles. Age was the only covariate predicting the occurrence of grade 4 neutropenia (logistic regression P= 0.046, CI 1.01-1.12). Neutropenic fever occurred in 8.3% of the patients. Eighteen (30%) patients were required to delay their chemotherapy and 11 (18.3%) required dose reduction. Nonhematologic toxicities were mild. The overall response rate was 21.6%, with eight (13.3%) complete responses and five (8.3%) partial responses. The median duration of response and median time to progression were 11 and 5 months, respectively. The median survival was 14 months. Topotecan 1.25 mg/m(2) in a five-times-daily schedule was well tolerated in a cohort of Chinese patients. Myelotoxicity was the most important side effect in our study, but the incidence is much lower than that reported in other studies. Age was an independent factor predicting the occurrence of grade 4 neutropenia.     

Phase I trial of escalating doses of topotecan in combination with a fixed dose of pegylated liposomal doxorubicin in women with müllerian malignancies

BACKGROUND: Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity. OBJECTIVES: Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m(2)) in a cohort of women with recurrent müllerian malignancies. METHODS: Topotecan dose was escalated from 0.5 mg/m(2)/day for 3 days in 0.2 mg/m(2)/day increments with treatment repeated every 21 days. Eligibility criteria required ECOG < or = 2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity. RESULTS: Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40-71) years. Patients received a median 1 (1-6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses. CONCLUSIONS: Doxil 30 mg/m(2) and topotecan 0.5 mg/m(2)/day by 72-h infusion (total dose 1.5 mg/m(2)), although a rational combination of cytotoxic therapies, have limited clinical activity.     

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.     

Weekly single-agent carboplatin in heavily pretreated patients with recurrent ovarian, peritoneal and fallopian tube carcinoma

PURPOSE OF INVESTIGATION: To report the experience of a single institution in the south of Israel with weekly carboplatin in heavily pretreated patients with platinum-sensitive recurrent ovarian, peritoneal and fallopian tube carcinoma. METHODS: The hospital records of ten patients with platinum-sensitive recurrent ovarian, peritoneal and fallopian tube carcinoma who had 2nd-line or later chemotherapy with weekly carboplatin between January 2003 and December 2004 were retrospectively reviewed. Weekly carboplatin, at a dose calculated with use of the Hilary Calvert's formula at AUC = 2, was given intravenously in 500 ml dextrose 5% over 30 minutes on day 1 of every seven days. Response was determined using clinical evaluation, radiological reports and CA-125 level. Toxicity was graded using the National Cancer Institute (NCI) criteria. RESULTS: Overall, 155 courses of weekly carboplatin were given. The median number of courses per patient was 14 (range, 2-37) and median duration of treatment was 22.5 (range, 2-40) weeks. Four patients (40%) had complete response lasting for 8-20 (median, 12) weeks, two (20%) had partial response lasting for five and 14 weeks, respectively, one (10%) had stable disease lasting for 23 weeks and three (30%) had progressive disease. Toxicity was mainly hematological with only grade 1-2 hematological toxicity as follows: anemia--four patients (40%), leukopenia--three (30%), neutropenia--three (30%) and thrombocytopenia--two (20%). CONCLUSION: Weekly carboplatin has considerable activity and low and well tolerated toxicity in heavily pretreated patients with platinum-sensitive recurrent ovarian, peritoneal and fallopian tube carcinoma.     

Topotecan for recurrent cervical cancer after platinum-based therapy

Abstract. Abu-Rustum NR, Lee S, Massad LS. Topotecan for recurrent cervical cancer after platinum-based therapy.
The activity and toxicity of topotecan in women with recurrent cervical cancer are described from a case series of women with recurrent cervical cancer who had measurable disease and were not amenable to cure by surgery or radiation. All patients had prior platinum-based chemotherapy and developed progressive disease. Topotecan was given as 1 mg/m²/day over 30 min for 5 days every 3 weeks until progression of disease or prohibitive toxicity. Between July 1998 and July 1999, 12 patients received a total of 20 cycles of topotecan. Median age was 41 years (range 21–62), and 11 (92%) patients had prior whole pelvic radiation. The mean number of topotecan cycles was 1.5 (median 1, range 1–3). There were two partial responses (16.7%; 95% CI, 2% to 48%), both in prior radiation fields. Five patients required red blood cell transfusions, four had grade II nausea and vomiting, two developed sepsis (one with neutropenia), one developed fever, and one reported hyperpigmentation. There were no treatment-related mortalities. Although topotecan appears to exhibit modest activity in recurrent cervical cancer after radiation and platinum-based therapy, bone marrow toxicity may limit the utility of this regimen without hematopoietic growth factor support.     

Amifostine pretreatment for protection against topotecan-induced hematologic toxicity: results of a multicenter phase III trial in patients with advanced gynecologic malignancies

OBJECTIVE: To determine if amifostine could reduce the hematologic toxicity associated with topotecan. METHODS: Thirty patients with recurrent/refractory gynecologic malignancies were randomized to receive topotecan (TOPO) (1.5 mg/m(2)/day days 1-5) with or without amifostine (AMI/TOPO) (500 mg/m(2)/day days 1-5) every 3 weeks for six cycles. The primary study endpoints were the incidence of grade 3 and 4 neutropenia. RESULTS: Fifteen patients were randomized to each arm for a total of 49 TOPO and 53 AMI/TOPO cycles. Patient characteristics and pretreatment ANC were similar between groups. Topotecan 1.5 mg/m(2)/day days 1-5 was initially administered to seven patients. Five developed neutropenic fevers, one an uncomplicated grade 4 neutropenia, and the other an uncomplicated grade 3 neutropenia. There were two treatment-related deaths due to sepsis (one in each treatment arm). The starting dose was thereafter reduced to 1.25 mg/m(2)/day days 1-5 every 21 days. No treatment related deaths occurred after this dose reduction. The incidence of combined grade 3/4 neutropenia was reduced from 67% (33/49 cycles) to 38% (20/53 cycles) with the addition of amifostine (P = 0.003; OR 0.29; 95% CI 0.12-0.71). CONCLUSIONS: Topotecan at 1.5 mg/m(2)/day days 1-5 in heavily pretreated patients resulted in excessive toxicity not manageable with amifostine. At the reduced topotecan dose (1.25 mg/m(2) x 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.     

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.     

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.     

Evaluation of weekly low-dose paclitaxel and carboplatin treatment for patients with platinum-sensitive relapsed ovarian cancer

OBJECTIVE: Although paclitaxel and carboplatin therapy (TC) is an established effective standard regimen for patients with ovarian cancer, both treatment delay for hematologic toxicity and discontinuation of treatment due to neurotoxicity have occasionally been reported. To achieve therapeutic density, we evaluated the usefulness of weekly low-dose TC therapy (WTC) in patients with platinum-sensitive (median PFI was 11.4 +/- 2.7 months) recurrent epithelial ovarian cancer. METHODS: A total of 25 patients were treated with paclitaxel at 60 mg/m(2) and carboplatin at AUC = 2 using 3 weekly courses with a 1-week break schedule. Eighteen patients had assessable tumors for response, and the other seven patients were evaluated by CA-125-based response. All of the patients were assessable for toxicity. RESULTS: The overall response rate (OR) based on WHO criteria was 84.2% (95% CI; 0.65-0.98), including nine complete responses (CR); OR based on CA-125 was 85.7% (95% CI; 0.42-0.99), including 3 CR. The total response rate was 88.0% (95% C.I.; 0.68-0.97). The median progression-free survival of the patients was 13.5 months during the mean follow-up period of 21.9 +/- 9.2 months. No patients had grade 1 or higher thrombocytopenia, and although 44% of the patients developed neurotoxicity, all cases remained grade 1. Treatment delay of over 7 days due to toxicity was observed in only two patients (16.0%) and in six cycles (1.3%) in a total of 451 cycles. CONCLUSION: WTC combination, as used in this study, produced a high response rate with acceptable toxicity, and the optimal combination in a weekly regimen remains to be determined.     

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.     

Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer

OBJECTIVES: We assessed the efficacy and toxicity of once-weekly topotecan (Hycamtin; GlaxoSmithKline) for relapsed or persistent epithelial ovarian cancer (EOC) and primary peritoneal carcinoma (PPC). METHODS: Patients with recurrent or persistent EOC and PPC previously treated with > or = 1 course of platinum-based chemotherapy were treated with weekly topotecan 4.0 mg/m2 on days 1, 8, and 15 of a 28-day cycle in this prospective open-label, single-arm, phase II study. RESULTS: The median age of the 63 study patients was 63 years (range, 36-88); patients had been previously exposed to a median of 1 course (range, 1-4) of chemotherapy. A median of 5 courses (range, 1-16) were administered. Median follow-up time was 13. 2 month s (range, 1.5-39.0). The overall response rate (RR) was 23.8%, of which 17.5% (11 patients) represented a complete response and 6.3% (4 patients) a partial response. Patients with platinum-sensitive disease had a RR of 20%, whereas patients with platinum-resistant disease had a RR of 28.6%. Median time to progression was 6.2 months (95% confidence interval: 4.43, 7.97), and median survival from initiation of topotecan therapy was 22.3 months (95% confidence interval: 14.56, 30.04). Hematologic toxicities included grade 3 anemia in 3 (4.8%) patients, grade 3 thrombocytopenia in 3 (4.8%) patients, and grades 3-4 neutropenia in 5 (7.9%) patients. Dose reductions, granulocyte colony-stimulating factor, and erythropoietin support were required by 10 (15.9%), 6 (9.5%), and 16 (25.4%) patients, respectively. The most frequent nonhematologic toxicities were grades 2-3 fatigue in 10 (15.9%) patients and grades 2-3 nausea/vomiting in 3 (4.7%) patients. CONCLUSION: Weekly administration of topotecan 4.0 mg/m2 is active and well tolerated by patients with recurrent or persistent EOC and PPC.     

Phase I trial of escalating doses of topotecan in combination with a fixed dose of pegylated liposomal doxorubicin in women with müllerian malignancies

Background. Topotecan and pegylated liposomal doxorubicin (Doxil) interact with topoisomerase I and II (topo I and II), respectively, with schedule dependent, and potentially synergistic cytotoxicity.Objectives. Define dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) of topotecan delivered by 72-h infusion administered immediately after Doxil delivered at a fixed dose (30 mg/m²) in a cohort of women with recurrent müllerian malignancies.Methods. Topotecan dose was escalated from 0.5 mg/m²/day for 3 days in 0.2 mg/m²/day increments with treatment repeated every 21 days. Eligibility criteria required ECOG ≤2 and no more than four prior lines of chemotherapy. No dose reductions were allowed in the first two cycles to allow evaluation of cutaneous toxicity.Results. Between November 2000 and August 2002, 18 patients were enrolled. Median age 59 (40–71) years. Patients received a median 1 (1–6) cycles of chemotherapy, with 39 cycles of treatment delivered at DL 1. All patients were evaluable for toxicity and 12 for response. At dose level 2, dose-limiting toxicity consisted of nausea and vomiting, mucositis, cutaneous toxicity, and neutropenia. There was no clinically significant cardiac toxicity. There were no radiologically confirmed partial responses.Conclusions. Doxil 30 mg/m² and topotecan 0.5 mg/m²/day by 72-h infusion (total dose 1.5 mg/m²), although a rational combination of cytotoxic therapies, have limited clinical activity.