Randomized trial of dose-intensity with single-agent carboplatin in patients with epithelial ovarian cancer. London Gynaecological Oncology Group

PURPOSE: We have examined the role of an increase in cisplatin dose-intensity in patients with advanced epithelial ovarian cancer by means of single-agent carboplatin therapy. PATIENTS AND METHODS: Two hundred twenty-seven patients were randomized to treatment and eligible for analysis. The dose of carboplatin was calculated according to the Calvert formula. One hundred seventeen patients received carboplatin at an area under the concentration time curve (AUC) of 6 for six courses, administered every 28 days, and 110 patients received carboplatin at an AUC of 12 for four courses, administered every 28 days. Patients were eligible provided they had not received prior chemotherapy or radiotherapy and had International Federation of Gynecology and Obstetrics stages II to IV or relapsed stage I epithelial ovarian cancer. RESULTS: The planned total-dose increase was 33% for the patients treated with carboplatin AUC 12, but the received percentage total-dose increase was 20%. There were no differences in progression-free or overall survival between the two treatment arms; the overall survival rate at 5 years was 31% and 34% of patients treated at AUCs 6 and 12, respectively. There was significantly more toxicity associated with carboplatin AUC 12, which resulted in more treatment delays and/or dose reductions (52% v 18%; P < .001). CONCLUSION: We have shown that carboplatin can be delivered at an AUC of 12 for four courses without granulocyte colony-stimulating factor support, although significant hematologic toxicity occurs. Nonhematologic toxicities were not clinically significant. Carboplatin offers an opportunity to intensify cisplatin therapy, but a greater than two-fold increase in dose-intensity probably needs to be achieved before significant effects on survival will be produced and hematologic support will be required.     

Phase II study of 3-hour infusion of paclitaxel in patients with previously untreated stage III and IV non-small cell lung cancer. West Japan Lung Cancer Group

BACKGROUND AND AIMS: Hysterectomy is believed to be associated with disturbed defecation, mainly constipation. This study longitudinally describes bowel function in women submitted for hysterectomy. MATERIAL AND METHODS: Rectoanal manovolumetry, whole gut transit time and detailed interviews on bowel function and dyspareunia were performed preoperatively and at 3 and 11-18 months after hysterectomy in 42 women. Twenty healthy women matched for age and parity served as manovolumetry controls. RESULTS: No significant changes in anal sphincter pressures could be demonstrated, neither early nor late after hysterectomy. Transit time was unaffected. All but one of the patients claimed that they had been suffering from one or more of the following symptoms; abdominal pain, distension, constipation and dysparenuia. While postoperative interviews revealed a significant improvement with respect to abdominal pain and dyspareunia (P < 0.01) after 3 and 11-18 months, improvement of abdominal distension and constipation proved to be transient only. CONCLUSION: Simple abdominal hysterectomy appears not to interfere adversely with bowel function. On the contrary many patients were relieved from abdominal pain present before operation.     

The combination of paclitaxel and carboplatin as first-line chemotherapy in patients with stage III and stage IV ovarian cancer: a phase I-II study

BACKGROUND: Stool softening is a physician's first step in the management of chronic constipation. AIM: To compare stool softening (stool water content) and laxative efficacy of psyllium hydrophilic mucilloid vs. docusate sodium. METHODS: The multi-site, randomized, double-blind, parallel-design study of 170 subjects with chronic idiopathic constipation involved a 2-week baseline (placebo) phase followed by 2 weeks of treatment. The treatment phase compared psyllium (5.1 g b.d.) plus docusate placebo to docusate sodium (100 mg b.d.) plus psyllium placebo. Stools were collected and assessed. RESULTS: Compared to baseline, psyllium increased stool water content vs. docusate (psyllium 2.33% vs. docusate 0.01%, P = 0.007). Psyllium also increased stool water weight (psyllium 84.0 g/BM; docusate 71.4 g/BM; P = 0.04), total stool output (psyllium 359.9 g/week: docusate 271.9 g/week; P = 0.005), and O'Brien rank-type score combining objective measures of constipation (psyllium 475.1; docusate 403.9; P = 0.002). Bowel movement (BM) frequency was significantly greater for psyllium (3.5 BM/week) vs. docusate (2.9 BM/week) in treatment week 2 (P = 0.02), with no significant difference (P > 0.05) between treatment groups in treatment week 1 (3.3 vs. 3.1 BM/week). CONCLUSION: Psyllium is superior to docusate sodium for softening stools by increasing stool water content, and has greater overall laxative efficacy in subjects with chronic idiopathic constipation.     

Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens

PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.     

Malignant epithelial parotid gland tumours: analysis and results in 65 previously untreated patients

BACKGROUND: Optimal management of malignant epithelial parotid tumours requires knowledge of the available therapeutic modalities and the different biological characteristics. The aim of the study was to review the characteristics of patients at presentation, histological classification, disease-free and overall survival rates, and the results of the applied treatment policy regarding the facial nerve and neck. METHODS: Between 1974 and 1995 a total of 65 patients was treated with curative intent for a previously untreated malignant epithelial parotid gland tumour. All patients underwent some type of parotidectomy, 20 of whom had an en bloc radical neck dissection. In selected cases the facial nerve or its branches were peeled off the tumour thus violating the objective of tumour-free margins and relying heavily on the efficacy of postoperative radiotherapy. In total 51 patients received postoperative radiotherapy. None of the patients was lost to follow-up. RESULTS: There were 12 locoregional failures (18 per cent). In only one of these 12 patients was salvage therapy successful; the remaining 11 patients died from the tumour. All but one of the eight patients with distant metastasis only died from the tumour. The estimated 5- and 10-year disease-free rates were 68 and 59 per cent respectively. The corresponding survival rates were 75 per cent and 67 per cent. A significant relationship could be observed between tumour stage and survival. The presence of lymph node metastases proved to be the strongest single prognostic factor. CONCLUSION: In selected cases a conservative approach towards the facial nerve is justified.     

Phase I and pharmacologic study of the combination paclitaxel and carboplatin as first-line chemotherapy in stage III and IV ovarian cancer

PURPOSE: To determine the maximum-tolerated dose for the combination paclitaxel and carboplatin administered every 4 weeks and to gain more insight into the pharmacokinetics and pharmacodynamics of this combination in previously untreated ovarian cancer patients. PATIENTS AND METHODS: Thirty-five chemotherapy-naive patients with suboptimally debulked stage III (tumor masses > 3 cm) and stage IV ovarian cancer were entered onto this phase I trial in which paclitaxel was administered as a 3-hour intravenous (IV) infusion at dosages of 125 to 225 mg/m2 immediately followed by carboplatin over 30 minutes at dosages of 300 to 600 mg/m2. A total of six courses was planned, followed by a second-look laparoscopy/laparotomy. Patients with a response and/or minimal residual disease at second-look laparoscopy received three additional courses. Twenty-six patients participated in the pharmacokinetic part of the study. RESULTS: The most important hematologic toxicity encountered was neutropenia. Neutropenia was more pronounced for the higher dose levels (DLs) and was cumulative. Thrombocytopenia was mild in the first eight DLs, but increased during the treatment courses. Nonhematologic toxicities consisted mainly of vomiting, neuropathy, fatigue, rash, pruritus, myalgia, and arthralgia. Dose-limiting toxicities (DLTs) in this trial were neutropenic fever, thrombocytopenia that required platelet transfusions, and cumulative neuropathy. Of 33 patients assessable for response, 26 major responders (78%, 20 complete response [CR] and six partial response [PR]) were documented. The maximal concentration (Cmax) of paclitaxel and the area under the concentration-time curve (AUC) were not different from the historical data for paclitaxel as a single agent. Retrospective analysis using a modified Calvert formula showed that the measured carboplatin AUCs in plasma ultrafiltrate (pUF) were 30% +/- 3.4% less than the calculated carboplatin AUC. Neutropenia was more pronounced than could be expected on the basis of the historical times above a threshold concentration greater than 0.1 mumol/L (T > or = 0.1 mumol/L) or 0.05 mumol/L (T > or = 0.05 mumol/L), and thrombocytopenia was less than could be expected from historical sigmoidal Emax models. CONCLUSION: The combination of paclitaxel 200 mg/ m2 and carboplatin 550 mg/m2 every 4 weeks is a well-tolerated treatment modality. The paclitaxel-carboplatin combination is highly active in stage III (bulky) and stage IV ovarian cancer. No indications for a pharmacokinetic drug-drug interaction between carboplatin and paclitaxel were found.     

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.     

Phase II trial of paclitaxel and topotecan with granulocyte colony-stimulating factor support in stage IV breast cancer

PURPOSE: This multicenter phase II trial investigated the efficacy and safety of a combination of paclitaxel and topotecan in patients with pretreated metastatic breast cancer. Plasma levels of paclitaxel and topotecan were obtained during cycle 1 to correlate pharmacokinetic parameters with toxicity. PATIENTS AND METHODS: Paclitaxel was administered intravenously (i.v.) at 230 mg/m2 over 3 hours on day 1 followed by topotecan 1.0 mg/m2 i.v. over 30 minutes on days 1 to 5. Patients received an abbreviated premedication regimen that consisted of ranitidine 50 mg, diphenhydramine 50 mg, and a single 20-mg dose of dexamethasone, all administered i.v. 30 minutes before paclitaxel. Granulocyte colony-stimulating factor (GCSF) was administered at 5 micrograms/kg/d subcutaneously starting on day 6 and continuing until the absolute granulocyte count (AGC) was greater than 10,000/microL. Plasma paclitaxel and topotecan concentrations were assessed during the first cycle using limited-sampling strategies. RESULTS: Seventeen patients were treated. The majority had visceral metastases. Four patients experienced neutropenic fever and one had mild bronchospasm. Only one partial response (PR) was observed. Nadir AGC correlated strongly with both duration of paclitaxel levels greater than 0.05 mumol/L and maximum concentration (Cmax) of paclitaxel. CONCLUSION: This regimen does not produce a response rate superior to that expected with single-agent paclitaxel at doses that do not require growth factor support.     

Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum

PURPOSE: Lonidamine (LND) is an energolytic derivative of indazol-carboxylic acid that has been shown to enhance cisplatin (CDDP) activity in both sensitive (A2780) and resistant (A2780/Cp8) ovarian cancer cell lines. The aim of this study was to confirm the potentiating or reverting activity of LND on CDDP activity obtained in experimental models in a phase II study of advanced ovarian cancer patients previously treated with platinum-based regimens. PATIENTS AND METHODS: Twenty-seven consecutive women with histologically proven and measurable ovarian cancer previously treated with platinum compounds were treated with CDDP plus LND. CDDP was administered at 1 mg/kg intravenously (IV) once weekly for 6 weeks and every 3 weeks thereafter until disease progression or toxicity. LND was administered at 450 mg daily (1 tablet every 8 hours) for the entire period of therapy starting 3 days before the first CDDP administration. In addition, a higher LND dosage was provided on the day of CDDP administration in an attempt to maximize the synergy of this drug with CDDP. RESULTS: Ten patients achieved a complete response (CR) or partial response (PR) for an overall response rate of 37% (95% confidence interval [CI], 19% to 55%). In particular, responses were observed in five of 18 (28%) refractory or early relapsed patients (one CR and four PRs) and in five of nine patients (55%) in the late-relapsed group (two CRs and three PRs). Grade 3 or 4 anemia, leukopenia, and thrombocytopenia were observed in 19%, 15%, and 11% of patients, respectively, whereas seven of 27 patients (26%) showed LND-related myalgia. Grade 3 renal toxicity was observed in two patients (8%). Neurotoxicity, often concealed by LND-related myalgia, was recorded as grade 1 or 2 in six patients (22%) and as grade 3 in one (4%). CONCLUSION: The 37% response rate observed in this study (28% in refractory or early-relapsed patients), suggests that the synergism between CDDP and LND observed in vitro against ovarian cancer cell lines can be clinically confirmed. However, larger series and randomized studies are needed to assess definitely the revertant activity of LND on CDDP-refractory patients.     

A comparison of the costs of paclitaxel and best supportive care in stage IV non-small-cell lung cancer

PURPOSE: To compare the expenditures associated with single-agent paclitaxel (Taxol) with those of best supportive care as treatment for stage IV non-small-cell lung cancer (NSCLC). METHODS: The primary data sets of 2 phase II trials of paclitaxel in advanced NSCLC were obtained. Paclitaxel delivery costs were estimated at the Ottawa Regional Cancer Centre using the mean paclitaxel dose from the 2 phase II trials, 214 mg/m2, a 3-week schedule and a median of 3 treatment cycles. Data regarding dosage, costs and survival were incorporated into the Statistics Canada POpulation HEalth Model (POHEM), which generated hypothetical cohorts of patients treated either with best supportive care or paclitaxel. The POHEM model assigned diagnostic workup, treatment, disease progression and survival characteristics to each of these cohorts and tabulated the costs associated with each. RESULTS: The total cost of administering 3 cycles of chemotherapy was Can$8143 per patient. The strategy of treating NSCLC patients with paclitaxel cost $3375 more per patient than best supportive care. On the basis of the difference in survival duration between stage IV patients treated in the best supportive care arm of a previous National Cancer Institute of Canada trial and those represented in the pooled phase II survival results, the cost per life-year saved was $4778. For sensitivity analyses, the days of hospitalization for terminal care, number of cycles given and survival benefit produced were varied. The sensitivity analysis produced a cost per life-year saved of up to $21,377 under the least favourable assumptions. CONCLUSION: If large phase III trials confirm the survival benefits observed in the phase II trials, paclitaxel can be considered to be a cost-effective agent in the management of advanced NSCLC.     

Single agent paclitaxel in resistant and relapsed epithelial ovarian cancer after first-line platinum-based chemotherapy--experience in an Asian population

In 1997, a new GCP has taken effect by the Ministry of Health and Welfare, Japan, and will be enforced as of April, 1998. The GCP regulates the method of clinical trials in the light of ethics and science. The New GCP requires written informed consent, enforcement of the responsibility of the client and so on.     

Long-term results from a phase II study of single agent paclitaxel (Taxol) in previously platinum treated patients with advanced ovarian cancer: the Nordic experience

BACKGROUND: Owing to the wide spread perception of a possible benefit from paclitaxel in the second-line situation the Nordic Gynecologic Oncology Group (NGOG) conducted two prospective phase II studies of paclitaxel single agent treatment (175 mg/m2, three-hour i.v. infusion with standard pre-medication every third week) in patients with relapsing or progressing epithelial ovarian cancer following platinum. PATIENTS AND METHODS: Between 1992-1994 138 patients in total were enrolled of whom 136 received paclitaxel and were included in the toxicity and survival analysis, while 112 were evaluable for response. RESULTS: The overall response rate (CR + PR) was 28% with 16 patients achieving a CR (14%). The estimated median (range) time to progression was 4.1 (0.7-60.7) months. The projected four-year overall survival was 7%, with a median (range) of 9.6 (0.3-60.7) months. A multivariate logistic regression analysis showed that platinum resistance, and WHO performance status at baseline, independently correlated with survival at all three time points (median survival time 9.6, 18, and 24 months). Patients with platinum sensitive tumors and WHO performance status 0 had a median survival of 25.6 months compared to 7.0 months for the rest of the patients (P < or = 0.0001). No serious toxicity was registered. CONCLUSION: Paclitaxel could safely be administered in an outpatient setting using this schedule. Patients with platinum sensitive tumors and a good performance status were most likely to survive. However, these patients are also most likely to respond to re-treatment with a platinum compound. With reference to the reasonably good tumor control and limited toxicity observed in this study, we conclude that paclitaxel single agent therapy is a viable option in the salvage situation, which in some patients can give long-lasting responses. However, although responses can be induced in a significant number of patients, the survival figures remain poor.     

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer

BACKGROUND: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle. RESULTS: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%-29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3-4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity. CONCLUSION: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.     

Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes

Thirteen patients with epithelial ovarian cancer, who did not show any detectable lesion after cisplatin-containing chemotherapy following primary operation, were treated with adoptive transfer of tumor-infiltrating lymphocytes (TIL group). Eleven patients with almost equivalent conditions of disease, who were treated with only chemotherapy following primary operation, served as a control group. The median time of follow-up was 36 (range, 23-44) months in the TIL group and 33 (range, 14-48) months in the control group. The estimated 3-year overall survival rate of disease-free patients in the TIL group and in the control group was 100% and 67.5%, respectively. A significant difference was noticed between the overall survival rate of the TIL group and the control group (P < 0.01). Furthermore, the estimated 3-year disease-free survival rate of the patients in the TIL group and in the control group was 82.1% and 54.5%, respectively. The disease-free survival rate of patients in the TIL group and in the control group was significantly different (P < 0.05). These results suggest that the adoptive transfer of TILs after all chemotherapy has been finished might be one promising method to achieve complete cure of advanced epithelial ovarian cancer.     

High-dose busulfan, melphalan and thiotepa followed by autologous peripheral blood stem cell (PBSC) rescue in patients with advanced stage III/IV ovarian cancer

The purpose of this study was to evaluate the efficacy of high-dose chemotherapy (HDC) with busulfan, melphalan and thiotepa (BUMELTT) followed by autologous PBSC infusion in treating patients with advanced ovarian cancer. Thirty-one patients, 18 with stage III/IIIc and 13 with stage IV ovarian cancer, were treated with BU (12 mg/kg), MEL (100 mg/m2) and TT (500 mg/m2) and autologous PBSC rescue. Fifteen patients were in clinical complete remission (CR) at treatment; 11 had platinum-sensitive disease. Sixteen patients were not in CR; two had platinum-sensitive disease. The probabilities of overall survival (OS), event-free survival (EFS) and relapse (R) for all patients at 18 months were 0.57, 0.30 and 0.63; for patients in CR, the rates were 0.87, 0.44 and 0.49 and for patients not in CR, 0.38, 0.13 and 0.81. Two patients (6.5%) died of treatment-related causes. Among the 13 patients with platinum-sensitive disease, all are still alive, with seven having relapsed 129-1021 days after PBSC infusion. OS, EFS and R were 1.00, 0.52 and 0.48. Of the 18 patients with platinum-resistant disease, four remain alive (two in remission). Six patients did not respond and eight relapsed from days 104-429. The OS, EFS and R were 0.33, 0.11 and 0.78. We conclude that BUMELTT is well tolerated in patients with advanced ovarian cancer and results are equivalent to other published HDC regimens.     

Ifosfamide and etoposide in previously treated patients with advanced breast cancer

AIMS AND BACKGROUND: Ifosfamide is an active alkylating agent in the treatment of breast cancer, as a first-line therapy and in advanced disease. Since the combination of etoposide with an alkylating agent produces a synergistic and tolerable activity in various malignancies, in the present study, ifosfamide and etoposide were administered to patients with advanced breast cancer to evaluate the response characteristics and the toxicity profile. STUDY DESIGN: The combination of ifosfamide, mesna and etoposide was prospectively administered to 41 previously treated patients with stage IV breast carcinoma. The treatment schedule consisted of ifosfamide, 1500 mg/m2, infused over 24 hrs with 1500 mg/m2 mesna on days 1 to 5 and 120 mg/m2 etoposide, infused over 1 hr on days 1 to 3, to be repeated every 4th week. RESULTS: After a median follow-up of 10 months, an objective response rate of 23% (overall 2.5% complete remission and 20.5% partial remission) and a median response duration of 5.3 months were obtained in 39 assessable patients. The non-responder group consisted of 28.3% stable disease and 48.7% progressive disease. The prior status of chemotherapy was the only significant prognostic factor with an impact on the response rate. The overall toxicity was generally mild, with grade 3 myelotoxicity encountered in 25.7% of patients. CONCLUSIONS: The tolerable side effect profile of the ifosfamide and etoposide combination might be advantageous as regards the quality of life. To improve the rate and/or the duration of response and to clarify the precise role of the ifosfamide-etoposide combination in previously treated advanced breast cancer, further trials are warranted.     

Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel

PURPOSE: Topotecan, a topoisomerase I inhibitor, was evaluated in a multicenter, phase II study of women with epithelial ovarian carcinoma who relapsed after one or two prior regimens that included platinum and paclitaxel. PATIENTS AND METHODS: Topotecan 1.5 mg/m2 daily was administered as a 30-minute infusion for 5 consecutive days on a 21-day cycle. Eligibility criteria included bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of 2 or less, and adequate bone marrow, liver, and renal function. Efficacy was assessed by independent radiologic review. RESULTS: One hundred thirty-nine patients were treated; 81% were platinum resistant. Sixty-two patients had received one prior regimen and 77 patients had received two prior regimens. Nine patients were not assessable for response; however, all patients were included in the response analysis. The overall response rate was 13.7%; 12.4% in platinum-resistant and 19.2% in platinum-sensitive patients. Stable disease lasted at least 8 weeks in 27.3% of the patients. The median duration of response and time to progression were 18.1 and 12.1 weeks, respectively. The median survival was 47.0 weeks. Grade 4 neutropenia occurred in 82% of the patients (34% of the courses) and thrombocytopenia in 30% of the patients (9% of the courses). Infectious complications occurred in 6% of the courses. Nonhematologic toxicities were mild. There were no drug-related toxic deaths. CONCLUSION: As a single agent, topotecan has modest activity in women with advanced epithelial ovarian carcinoma who have progressed or not responded after one or two prior regimens with platinum and paclitaxel. Further investigation of combination regimens is indicated in the primary therapy for ovarian cancer based on the mechanism of action and tolerability.