Effectiveness of weekly topotecan in patients with recurrent epithelial ovarian cancer

The objective of this study was to investigate the effectiveness and toxicity of weekly topotecan in patients with recurrent epithelial ovarian cancer. Twenty patients were treated with topotecan at a dose of 4 mg/m(2) weekly. Efficacy was determined according to the Response Criteria in Solid Tumors (RECIST) Gynecologic Cancer Inter Group criteria. Median age was 62 years (45-78). Patients had received 1-7 (median 3) prior chemotherapy lines. A total of 203 weekly treatments were administered. In 13 patients (65%) treatment delay was necessary due to bone marrow toxicity. Grade 3/4 neutropenia occurred in 11 patients (55%) and grade 3/4 thrombocytopenia in four patients (20%). Six patients (30%) needed a dose reduction, and 42 cycles (21%) were given with dose reduction. No neutropenia, fever, or sepsis was observed. There was one complete response and one partial response (response rate 10%). All patients with response had platin-sensitive disease (three out of eight). Six patients needed blood transfusion. None of the patients required granulocyte/granulocyte-macrophage colony-stimulating factor. The median duration of response was 13 months. In addition, there were four patients (20%) with a stable disease lasting at least for 4 months. Based on the results of this Phase II study, the toxicity of weekly topotecan seems to be lower than with the 3-weekly topotecan. The response rate of 10% is low but was not expected to be higher as these patients were heavily pretreated.     

Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer

A total of 61 patients with recurrent or persistent clinically measurable platin-resistant epithelial ovarian carcinoma were treated with 260 mg/m2 oral hexamethylmelamine daily for 14 days, repeated at 4-week intervals. Platin resistance was defined as progression or stable disease during cis- or carboplatin treatment (used alone or in combination with other drugs), or relapse within 6 months after the end of that therapy. Fifty patients were evaluable for response and 57 for toxicity. The objective response rate was 14% (3 complete and 4 partial responses). The response rate was higher in patients with relapse within 6 months than in patients with progression or stable disease on platin-based therapy. This observation underscores the importance of defining response and time to progression after first-line chemotherapy. The median duration of response was 8 months and the median survival in responding patients was 9+ months versus 5 months for patients with progression on hexamethylmelamine. Nausea and vomiting requiring antiemetic treatment occurred in 8 (14%) patients and reversible peripheral neuropathy in 3 patients. Two patients developed agitation, insomnia, and depression during hexamethylmelamine therapy. In conclusion, the 14% objective response rate and the occurrence of complete responses with oral hexamethylmelamine treatment in a group of ovarian cancer patients with true platin resistance are noteworthy.     

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.     

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.     

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.     

Whole-abdomen radiation as a second-line therapy for epithelial ovarian cancer

Whole-abdomen irradiation was delivered to 11 patients with persistent epithelial ovarian cancer after chemotherapy. Ten of the eleven patients have recurred and subsequently died of disease. The median time to recurrence was 5.5 months. All 10 recurrences were within the irradiated field. All 6 patients with microscopic disease at second-look laparotomy recurred. Four of the five patients with minimal residual disease (less than or equal to 5 mm) at second-look laparotomy recurred. One patient is alive with no evidence of recurrence at 14 months. Four patients developed small bowel obstruction, three of which were associated with recurrence. During therapy, 4 patients developed significant enteritis and 5 patients developed significant bone marrow suppression. All 11 patients completed radiation therapy, although in 4 there were interruptions of 1 to 3 weeks. Whole-abdomen irradiation does not appear to be an effective second-line regimen for epithelial ovarian cancer, even in the presence of microscopic or minimal residual disease.     

The role of topotecan for extending the platinum-free interval in recurrent ovarian cancer: an in vitro model

OBJECTIVE: Topotecan, a novel topoisomerase-I inhibitor, is an active agent of second-line chemotherapy for extending the platinum-free interval (PFI) and improving the chances of a response to platinum in recurrent ovarian cancer patients. The aim of this study was to understand the molecular mechanism of topotecan-based second-line chemotherapy through an in vitro cell culture model and to gain clinical insight into sequencing issues for second-line treatment with novel agents versus retreatment with platinum. STUDY DESIGN: The human ovarian cancer cell line A2780 and the cisplatin resistance cell line A2780-CR were separately seeded in 6-well cell culture plates and then exposed to multiple concentrations of cisplatin plus paclitaxel or topotecan for 7 days. Surviving cells were recovered and cultured in drug-free media for 3 weeks and then replated in a 96-well microtiter plate. The LD(50) for these cells was determined by a cytotoxic MTT assay after exposure to multiple clinically relevant concentrations of cisplatin or topotecan. Surviving cells were cultured in drug-free media for an additional 4 weeks at which time the LD(50) was reassessed for each cell population by a second MTT assay. Using RT-PCR and Northern blot hybridization to measure mRNA expression, the molecular profile of these cells in terms of resistance was evaluated for the multidrug-resistant gene (MDR-1), multidrug-resistant protein (MRP), Topoisomerase-I, and beta-Actin. RESULTS: The LD(50) to cisplatin was unchanged in A2780-CR cells treated by topotecan. Those A2780-CR cells originally exposed to higher concentrations of cisplatin became more resistant to cisplatin in the MTT assays, while those A2780-CR cell lines treated with a combination of lower cisplatin concentrations and paclitaxel became more sensitive to cisplatin in the MTT assay (P < 0.01). The second MTT assay demonstrated that the LD(50) for cisplatin in every cell line decreased significantly after a 4-week drug-free interval (P < 0.01). There was no difference in the mRNA expression for MRP or topoisomerase-I regardless of cell line, or type or concentration of chemotherapeutic exposure. The mRNA for MDR-1 was uniquely overexpressed in the cisplatin-resistant cell line A2780-CR9 initially treated with low doses of cisplatin and paclitaxel, but was not amplified in A2780 (P < 0.01). CONCLUSIONS: The acquired resistance to cisplatin in A2780 is potentially due to P-glycoprotein-mediated multidrug resistance. This acquired resistance to cisplatin is an unstable phenotype in that some cell populations become sensitive after a drug-free interval and topotecan treatment. This reversal of resistance, however, does not appear to be simply due to loss of MDR-1 expression. While in vivo confirmation is required, agents with novel mechanisms of action offer a strategy to extend the platinum-free interval and thereby improve survival in patients with recurrent ovarian 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.     

Topotecan as a second-line therapy in patients with ovarian and primary peritoneal cancer: initial response and long-term follow-up

The purpose of this study was to evaluate the role of topotecan at a dose of 5-day standard 1.5 mg/m2/day in patients with relapsed ovarian cancer. Two different groups of patients were included. In group 1, 23 patients who had bidemensionally measurable disease were examined, and in group 2, 11 patients were given topotecan after positive second-look laparotomy (SLL) were analyzed. Total number of cycles was 190 with a median value of six cycles. In group 1, three (13%) patients had complete response (CR) and seven (30%) had partial response (PR) with a total response rate of 43%. Six patients (27%) had stable disease (SD), and seven (30%) had progressive disease (PD). Median survival durations for patients with CR, PR, SD, and PD were 35, 14, 15, and two months, respectively. In group 2, two patients had PD during treatment. The remaining nine patients had no measurable disase or marker relapse at the end of treatment period. Median survival duration was 27 months. In conclusion, topotecan had significant antitumor activity as a second-line therapy in relapsed ovarian cancer patients with measurable disease. In a subgroup of patients with positive second-look laparotomy topotecan was also associated with long median survival duration.     

Oral altretamine used as salvage therapy in recurrent ovarian cancer

BACKGROUND: Altretamine has reported efficacy in the treatment of recurrent ovarian cancer following platinum-based therapy. This report presents the cases of two long-term survivors with recurrent ovarian cancer given oral altretamine. CASES: Two patients diagnosed with stage IIIC ovarian cancer underwent optimal cytoreductive surgery. Both women were subsequently treated with platinum-based chemotherapy. One had persistent cancer documented 2 months post therapy, while the other was disease-free for 22 months before recurring. Both received altretamine in a salvage setting. Each of these women achieved a prolonged response to third-line altretamine therapy, and one of whom was disease-free for 4 years and the other remains disease-free over 7 years following initiation of salvage therapy. CONCLUSION: Outpatient-administered oral altretamine can provide a prolonged disease-free interval with minimal toxicity.     

CA-125 response in patients with recurrent ovarian or primary peritoneal cancer treated with pegylated liposomal doxorubicin or topotecan

OBJECTIVE: Recent additions of novel chemotherapeutics, such as pegylated liposomal doxorubicin (PLD) and topotecan (TPT), have provided clinicians with multiple options for treating recurrent ovarian cancer. Evaluating treatment response in patients without radiographic or physically measurable disease is problematic, thereby CA-125 values may be the only available objective criteria. It has been advocated that several cycles of novel agents are required prior to an observed CA-125 response. In this study, we sought to gain insight into response patterns regarding CA-125 in responders vs. non-responders and to determine whether specific "cut-off" values could help predict ultimate clinical response. METHODS: Patients with recurrent ovarian cancer who received either single agent PLD, TPT, or both were included. CA-125 levels were evaluated prior to initiation of chemotherapy and thereafter for each additional cycle. The Rustin criteria were utilized to evaluate CA-125 response. RESULTS: Fifty-four of 120 patients were judged to be responders. When comparing responders to non-responders, as expected, the majority of responders demonstrated a decrease after each of the first 4 cycles. However, nearly 50% of responders who received PLD demonstrated an increase in CA-125 after cycle 1. There were no responders who demonstrated two successive rises in CA-125. CONCLUSION: The majority of patients with recurrent ovarian cancer who will ultimately manifest a CA-125 response to novel agents, such as TPT or PLD, will demonstrate a decrease following each cycle. An initial increase in CA-125 should not mandate discontinuation of current therapy, but a successive rise over two or more cycles reliably predicts that a treatment response ultimately is unlikely.     

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 a 3-day infusion of topotecan in patients with recurrent ovarian or primary peritoneal cancer

OBJECTIVE: To assess the efficacy and toxicity profile in patients treated with topotecan at 2.0 mg/m2/day x 3 days every 3 weeks. MATERIALS AND METHODS: Eligibility criteria included patients with recurrent primary peritoneal or epithelial ovarian cancer with > or =6 months elapsed from time of prior platinum treatment. Patients were required to have a performance status of < or =2 and normal hepatic and renal function. Response to therapy and toxicity was assessed using standard criteria. Chi-square and Student's t tests were used as appropriate. Survival was assessed with Kaplan-Meier method. RESULTS: All 40 patients enrolled were assessable for response. The mean age of the patients was 63.2 years (range 43-85). Median time to progression from initial treatment was 11.8 months. A total of 286 cycles of chemotherapy were administered with an average of 7.1 cycles per patient. Overall median time to progression (TTP) with 3-day topotecan treatment was 21 weeks (range 6-43 weeks). Of the 33 patients with measurable disease, 24% (11-42%, 95% CI) demonstrated a response. Seven patients had CA-125 evaluable disease with a response of 43% (10-89%, 95% CI). Median progression-free survival (PFS) was 16 weeks (range 12-21 weeks, 95% CI). Median overall survival was 106 weeks (range 76-117 weeks, 95% CI). Assessment of toxicity by patient showed 90% demonstrating grade 3/4 neutropenia with the vast majority being uncomplicated. No severe non-hematological toxicity was observed. CONCLUSION: Administration of topotecan as a 3-day regimen is feasible with demonstrable activity and tolerable toxicity. Critical comparison to the 5-day regimen in a randomized fashion is warranted.     

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.