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.     

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.     

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.     

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.     

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.     

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.     

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.     

Retrospective analysis of weekly topotecan as salvage therapy in relapsed ovarian cancer

OBJECTIVE: To retrospectively investigate the safety and efficacy of weekly topotecan in heavily pretreated patients with ovarian cancer. METHODS: Data were collected by retrospective review of patient records. Eligible patients had received > or =2 prior regimens for ovarian cancer before treatment with weekly topotecan. Efficacy was determined by measurable disease or CA 125 levels. Adverse event and growth factor support data were also collected. RESULTS: Fifty patients (median age, 61 years) were evaluable for safety and received a total of 244 4-week cycles of therapy (median, 3; range, 1-21 cycles). Most patients (84%) had measurable disease, and 30% had performance status of > or =2. Patients had received two to six prior treatments for ovarian cancer. Median weekly dose per patient was topotecan 3.7 mg/m(2). Grade 4 hematologic toxicities (generally manageable) occurred in 4% of patients. One patient had febrile neutropenia. Grade 3/4 nonhematologic toxicities were fatigue in two (4%) patients. Forty-two patients were evaluable for response. Of 35 evaluable patients with measurable disease, 11 (31%) had a partial response (median duration, 3 months), and 15 (43%) patients had stable disease (median duration, 3.5 months). Of 41 evaluable patients with elevated CA 125 (median, 154 U/l; range, 47-7200 U/l), 11 (27%) had > or =50% decreases or normalization of CA 125 levels. Median time to progression in all patients with stable disease has not been reached (follow-up range, 1.5-17.3 months). CONCLUSIONS: Weekly topotecan is active and well tolerated in heavily pretreated patients with relapsed ovarian cancer. Prospective studies of this regimen are warranted.     

Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical carcinoma

OBJECTIVE: This trial investigated the safety and efficacy of paclitaxel and topotecan combination chemotherapy for patients with advanced cervical cancer (ACC). METHODS: Patients with recurrent, persistent, or metastatic ACC and an ECOG performance status < or =2 were treated with 175 mg/m(2) paclitaxel on Day 1 and 1 mg/m(2) topotecan on Days 1-5 of a 21-day cycle with G-CSF support and the standard pretreatment regimen for paclitaxel. Patients were treated until disease progression or unacceptable toxicity. RESULTS: Fifteen patients were enrolled, and 86 cycles of therapy (median, 5; range, 1-14) were administered. Grade 3/4 toxicities included anemia (47%), leukopenia (27%), neurotoxicity (13%), thrombocytopenia (13%), and diarrhea (13%). Among 13 evaluable patients, 7 (54%) responded (1 complete and 6 partial; 95% confidence interval = 29.2%, 76.8%). Three (23%) patients experienced stable disease. Progression-free and overall survival were 3.77 and 8.62 months, respectively. CONCLUSION: The combination of paclitaxel/topotecan was generally well tolerated and active in the relapsed, recurrent, or metastatic ACC setting, with response rates comparable with those of other current ACC systemic therapies.     

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.     

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 phase II clinical trial of topotecan and carboplatin in patients with newly diagnosed advanced epithelial ovarian cancer

A phase II clinical trial conducted to evaluate the efficacy and tolerability of topotecan and carboplatin as first-line therapy for women with advanced epithelial ovarian cancer was the objective of this study. Patients had histologically confirmed ovarian epithelial cancer with at least one measurable lesion. Patients received topotecan 1.5 mg/m(2) on days 1-3 and carboplatin at an area under the curve (AUC) of 5 on day 3 every 21 days for six cycles. All 42 patients enrolled were evaluable for response and toxicity. Median number of cycles delivered was six. Overall response rate was 71%, with 19 clinical complete responses (45%) and 11 clinical partial responses (26%). Median survival time was 47 months and 5-year survival was 42%. Myelosuppression was the predominant toxicity, with grade 3 or 4 neutropenia occurring in 100% of patients. However, this toxicity was transient and easily manageable; no patients experienced febrile neutropenia. The combination of topotecan and carboplatin is active in advanced epithelial ovarian cancer. Delay of therapy by 1 week or topotecan dose reduction to 1.25 mg/m(2) is the first-choice option to reduce topotecan toxicity without affecting the efficacy. Moreover, a chemotherapy regimen using weekly topotecan, which is currently being tested, should be considered.     

Topotecan in squamous cell carcinoma of the cervix: A Phase II study of the Gynecologic Oncology Group

PURPOSE: The activity and toxicity of topotecan were evaluated in a multicenter Phase II study for patients with previously treated squamous cell carcinoma of the uterine cervix. PATIENTS AND METHODS: Histologic confirmation of the primary diagnosis was required, as well as adequate performance status and vital organ function and the presence of measurable disease. Patients were allowed one prior regimen of systemic therapy, usually platinum-based. A two-stage accrual design was utilized with early stopping criteria and monitoring of toxicity. Topotecan was administered at 1.5 mg/m(2) per day for 5 consecutive days on a 21-day cycle with modifications based on hematologic toxicity. RESULTS: Forty-five patients were entered. Two patients were ineligible (incorrect tumor type) and 2 were inevaluable (never received therapy). One additional patient was not evaluable for response (nonmeasurable disease). A median of 2 cycles was administered to each patient (range: 1-17 cycles) with grade 4 neutropenia in 68% and grade 4 thrombocytopenia in 39% of patients, but without treatment-related deaths. Nonhematologic toxicity was generally mild and not dose-limiting. The overall (complete and partial) response rate among evaluable patients with measurable disease was 12.5% with stable disease in an additional 37. 5%. Median progression-free survival was 2.1 months. CONCLUSIONS: As a single agent topotecan shows modest antitumor activity, with manageable hematologic and nonhematologic toxicity, in patients with previously treated squamous cell carcinoma of the cervix. Further evaluation in chemotherapy-naive patients or in combination with cisplatin and/or radiation may be indicated.     

Phase II study of sequential doublets: topotecan and carboplatin, followed by paclitaxel and carboplatin, in patients with newly diagnosed advanced ovarian cancer

OBJECTIVE: Incorporating topotecan into standard platinum/taxane chemotherapy for advanced ovarian cancer has been complicated by myelosuppression. This study evaluated sequential doublets of topotecan and carboplatin, followed by paclitaxel and carboplatin, in newly diagnosed advanced ovarian cancer patients. METHODS: Forty-five patients (median age, 56 years; range, 38-77 years) with stage III/IV disease and GOG performance status <2 were enrolled and received four cycles of topotecan (1.0 mg/m(2)/day on days 1 to 3) and carboplatin (AUC 4 on day 1), followed by four cycles of paclitaxel (175 mg/m(2) via 3-h IV infusion on day 1) and carboplatin (AUC 5 on day 1). All cycles were 21 days. Antitumor response was assessed after four and eight cycles; patients with clinical complete response (CR) underwent second-look laparotomy for determination of pathologic CR (PCR). Dose reductions were instituted for grade 4 neutropenia and thrombocytopenia, and for grade 3/4 nonhematologic toxicity. RESULTS: Among 41 CA-125 evaluable patients, complete and partial responses were observed in 29 (70.7%) and 11 (26.8%) patients, respectively. Of the 12 clinical CRs (43%) in 28 evaluable patients, 10 patients underwent second-look laparotomy, with 3 PCRs (30%). Median time to progression was 14 months and actuarial survival was 23 months. Neutropenia was the primary toxicity and cause of dose adjustments and delays, including two deaths. CONCLUSION: The antitumor activity observed is comparable with other series, although neutropenic complications were increased. Progression-free and actuarial survivals were slightly inferior. A Phase III trial (GOG 182) of sequential doublets in the reverse sequence is ongoing.     

Paclitaxel and carboplatin with amifostine in advanced, recurrent, or refractory endometrial adenocarcinoma: a phase II study of the Southwest Oncology Group

OBJECTIVES: To evaluate the response rate and progression free and overall survival of patients with advanced endometrial cancer treated with paclitaxel, carboplatin and amifostine. To evaluate the toxicity of amifostine when used in combination with carboplatin and paclitaxel. METHODS: Forty-seven eligible patients (median age: 66; range 45-82) with bidimensionally measurable advanced, recurrent, or refractory endometrial cancer were treated with carboplatin (AUC = 6), paclitaxel (175 mg/M2) and amifostine (740 mg/M2) every 4 weeks for 6 cycles or until disease progression or unacceptable toxicity. RESULTS: There were 4 CRs (8%) (2 confirmed, 2 unconfirmed) and 15 PRs (32%) (9 confirmed, 6 unconfirmed) for a total response rate of 40% (95% confidence interval [CI], 26% to 56%). The median progression-free survival (PFS) was 7 months (95% CI, 6-9 months) and a 6-month PFS rate of 64% (95% CI, 50% to 78%). The median overall survival was 14 months (95% CI, 12 to 17 months). Toxicity was tolerable. While 79% of patients developed Grade 3/4 neutropenia (30% Grade 3, 49% Grade 4), there were no episodes of Grade 4 febrile neutropenia and one episode of infection with grades 3-4 neutropenia. CONCLUSION: The combination of paclitaxel and carboplatin with amifostine was well reasonably tolerated in this cohort. The regimen demonstrated significant activity in endometrial cancer, comparable to other multi-agent chemotherapy programs in terms of response rate and survival, and with a favorable toxicity profile.     

Daily low-dose oral etoposide for recurrent epithelial ovarian cancer after platinum-based therapy.

The activity and toxicity of oral etoposide in women with recurrent ovarian cancer are described from a case series of women who had measurable disease. All patients had had previous platinum-based chemotherapy. Etoposide was given as 50 mg/day for 21 days every 4 weeks until there was progression of the disease or prohibitive toxicity. Twelve patients were enrolled into this study. Ten patients received a total of 48 cycles of etoposide; the median number of cycles was 4 (range 1-11). There were two partial responses (20%; 95% CI, 0-45%). The responses lasted 3.5 and 6 months. Median progression-free interval (PFI) was 7.5 months (range 5.5-11), and median survival time was 8.5 months (range 1.2-21.5). The main haematological toxicity was leukopenia and no treatment-related death occurred. Although etoposide appears to exhibit activity in recurrent ovarian cancer, response and survival durations are short, with a high rate of complications.     

Prolonged topotecan infusion with cisplatin in the first-line treatment of ovarian cancer: an NYGOG and ECOG study

OBJECTIVE: To determine the toxicity and efficacy of combined therapy with cisplatin and prolonged infusion topotecan as front line therapy in women with epithelial ovarian cancer. PATIENTS AND METHODS: Women with previously untreated, measurable and non-measurable epithelial ovarian cancer, stages Ic-IV were eligible. Patients were treated with cisplatin 75 mg/m(2) on day 1, followed by topotecan 0.3 to 0.4 mg/m(2)/day given as a continuous infusion over 14-21 days, every 28 days. Dose levels and duration of infusion were adjusted for toxicity as appropriate. Patients were evaluated for response to treatment and treatment toxicity by standard NYGOG criteria. RESULTS: Sixty patients were enrolled. Among the 20 patients with post-surgical residual disease >2 cm, 80% [95% CI (56.3%, 94.3%)] demonstrated an objective response to therapy. The median progression-free survival for all 60 patients enrolled was 19.3 months with a median overall survival of 45.6 months given the median follow-up of 55 months (range 6-81 months). Five year survival is estimated to be 41%. Toxicity was observed in the first four patients treated with topotecan (0.4 mg/m(2)/day x 21 days) and dosing was continued at 0.3 mg/m(2)/day x 14 days thereafter. Of the 56 patients treated at the amended dose level, marrow suppression continued to be dose-limiting, with 86% of patients experiencing grade 3 or 4 neutropenia, 55% experiencing grade 3 or 4 thrombocytopenia and 50% of patients experiencing grade 3 or 4 anemia. Nonetheless, only 11/245 cycles administered were associated with febrile neutropenia and/or infection (8 port-related). Other non-hematologic toxicity was as expected. There were no treatment-related deaths. CONCLUSION: This large, multicenter phase II study of prolonged infusion topotecan in combination with cisplatin demonstrated similar response, time to progression and survival compared with reported results of taxane and platinum combinations. Hematologic toxicity was greater but tolerated. Further studies investigating topotecan in combination with platinum therapy as a first line agent are warranted.     

Paclitaxel and carboplatin in the treatment of advanced or recurrent endometrial cancer: a large retrospective study

The aim of this study was to assess the efficacy and tolerability of paclitaxel and carboplatin (TC) in the treatment of patients with advanced or recurrent endometrial cancer. Patients eligible for this retrospective analysis had endometrial cancer with either advanced or recurrent measurable disease (untreated primary stage III/IV or stage III/IV patients with persistent, measurable disease [> or =2 cm] after surgery), Eastern Cooperative Oncology Group (ECOG) performance status > or =3, and received at least one cycle of TC. Response rates were determined using Response Evaluation Criteria in Solid Tumors criteria. Institutional Review Board approval was obtained prior to the initiation of this study. Eighty-five eligible patients, with a median age of 62 years (range 36-80) were identified. Fifty-seven (67%) of patients were treated at the time of recurrence. Prior radiation therapy had been used in the treatment of 36 (42%) patients, while 13 (15%) patients had received prior chemotherapy. Median follow-up time was 11.7 months (range 1.1-96.7 months), and the median number of cycles of therapy received was six (range 1-18). The overall response rate (ORR) was 43%, with a complete response rate of 5% and a partial response rate of 38%. Chemotherapy-naive patients had an ORR of 47%. Only seven (8%) patients had to discontinue therapy due to toxicity. Median progression-free survival was 5.3 months (95% CI, 4.6-7.4), with a median overall survival of 13.2 months (95% CI, 11.7-18.2). We conclude that TC is an active and tolerable regimen in the treatment of patients with advanced or recurrent endometrial cancer.     

Costs of treatment and outcomes associated with second-line therapy and greater for relapsed ovarian cancer

OBJECTIVES: Most women with epithelial ovarian cancer (EOC) will develop disease progression or recurrence with resistance to platinum therapy. We report overall costs and treatment outcomes associated with topotecan or gemcitabine administration in platinum- and paclitaxel-resistant EOC patients. METHODS: Patients who received topotecan (n = 51) or gemcitabine (n = 56) as second-line therapy or greater for platinum- and paclitaxel-resistant EOC were retrospectively identified. Per patient costs for each regimen were determined and compared. RESULTS: The mean total direct cost per cycle per patient of gemcitabine was $2732.28, with a median total direct cost per cycle of $1382.73. The mean total direct cost per cycle per patient of topotecan was $7832.07, with a median total direct cost per cycle of $4219.02. By comparison of the means, total direct cost per cycle per patient was significantly more expensive for topotecan (P = 0.001). Fifty-six patients received a total of 415 cycles of gemcitabine, median 5 cycles per patient (range, 1-59). Thirteen (23.2%; 95% CI, 11.9-34.5%) of 56 patients displayed clinical benefit, with median PFS of 1.8 months and median overall survival (OS) of 8.2 months. Fifty-one patients received topotecan, for a total of 264 cycles, median 4 cycles per patient (range, 1-42). Twenty-eight (56%; 95% CI, 42.0-70.0%) of 50 patients achieved clinical benefit, with PFS and OS medians of 3.6 and 16.8 months, respectively. CONCLUSIONS: Gemcitabine and topotecan are active agents in heavily pretreated, platinum- and paclitaxel-resistant EOC patients. Topotecan was more costly to deliver. Although a larger percentage of patients received clinical benefit with topotecan use, this likely reflects physician selection for use of topotecan earlier in the course of disease.     

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

OBJECTIVE: To determine the activity and tolerability of gemcitabine in the palliative treatment of ovarian cancer. METHODS: Patients affected by ovarian cancer, and with progressive disease after treatment with platinum/paclitaxel-based chemotherapy, were enrolled into this phase II study. Gemcitabine, 1000 mg/m(2), was administered on days 1, 8, and 15, by 30-min intravenous infusion. Cycles were repeated every 28 days. RESULTS: Fifty patients were enrolled. All the patients were platinum and/or paclitaxel resistant (median number of previous regimens, 2; range, 1-5). Median platinum-free interval was 3 (range, 1-11) months and median paclitaxel-free interval was 6 (range, 1-36) months. A total of 210 courses were evaluable for toxicity, with a median number of four cycles administered per patient (range, 1-10). A grade 3 or 4 hematological toxicity was observed in 27 patients (54%) (anemia grade 3, 16%; grade 4, 2%; neutropenia grade 3, 24%; grade 4, 18%; thrombocytopenia grade 3, 8%; grade 4, 0%). A 20-50% dose reduction was required for 36 patients (72%, 55% of cycles). Blood transfusions were necessary for 15 patients (30%), while 2 (4%) were treated with erythropoetin. Granulocyte colony-stimulating factor was necessary in 4 patients (8%). Nonhematological toxicity was mild and manageable. Only 4 patients (8%) experienced a grade 3 hepatic toxicity (elevated liver enzymes). Forty-one patients (82%) are, so far, evaluable for response. Among them, 7 partial responses (17%; 95% confidence interval [CI], 6-29), 15 disease stabilizations (>16 weeks) (36.6%; 95% CI, 21.9-51.3), and 19 progressions (46.3%; 95% CI, 31.0-61.6) have been registered. An overall clinical benefit was observed in 53.7% of patients. Thirteen patients (31.7%) had a time-to-progression exceeding 24 weeks. CONCLUSIONS: This study confirms the activity and safety of gemcitabine in heavily pretreated patients with recurrent ovarian cancer.