W.W. ten Bokkel Huinink

Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer.

PURPOSE Topotecan and paclitaxel were evaluated in a randomized, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen. PATIENTS AND METHODS Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 112) or paclitaxel (175 mg/m2) infused over 3 hours every 21 days (n = 114). Patients had bidimensionally measurable disease and were assessed for efficacy and toxicity. RESULTS Response rate was 23 of 112 (20.5%) in topotecan-treated patients and 15 of 114 (13.2%) in paclitaxel-treated patients (P = .138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (P = .222) and median times to progression were 23 and 14 weeks, respectively (P = .002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (P = .515). Response rates for topotecan and paclitaxel were 13.3% versus 6.7% (P = .303) in resistant patients (not responded to prior platinum-based therapy or progressed within 6 months of an initial response) and 28.8% versus 20.0% (P = .213) in sensitive patients (progressed > 6 months after response). Neutropenia was significantly more frequent on the topotecan arm 79% versus paclitaxel arm 23% (P < .01). It was short-lasting and noncumulative in both arms. Nonhematologic toxicities were generally mild (grades 1 to 2) for both agents. CONCLUSION Topotecan has efficacy at least equivalent to paclitaxel manifested by the higher response rate and significantly longer time to progression.

European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion.

PURPOSE Taxol (paclitaxel; Bristol-Myers Squibb, Wallingford, CT) is a new anticancer agent with activity in a number of human tumors, including epithelial ovarian cancer. In nonrandomized trials, doses studied have ranged from 135 mg/m2 to 250 mg/m2 administered over 24 hours with premedication to avoid hypersensitivity reactions (HSRs). This study addressed two questions: the dose-response relationship of Taxol in relapsed ovarian cancer and the safety of a short infusion given with premedication. METHODS Women with platinum-pretreated epithelial ovarian cancer and measurable recurrent disease were randomized in a bifactorial design to receive either 175 or 135 mg/m2 of Taxol over either 24 or 3 hours. Major end points were the frequency of significant HSRs and objective response rate. Secondary end points were progression-free and overall survival. RESULTS Of 407 patients randomized, 391 were eligible and 382 assessable for response. Analysis was performed according to the bifactorial design. Severe HSRs were rare (1.5% patients) and were not affected by either dose or schedule. Response was slightly higher at the 175-mg/m2 dose (20%) than at 135 mg/m2 (15%), but this was not statistically significant (P = .2). However, progression-free survival was significantly longer in the high-dose group (19 v 14 weeks; P = .02). Significantly more neutropenia was seen when Taxol was administered as a 24-hour infusion. Response rates were similar in the 24- and 3-hour groups (19% and 16%, respectively; P = .6). No survival differences were noted. CONCLUSION The 3-hour infusion of Taxol is safe when given with premedication and is associated with less neutropenia. There is a modest dose effect with longer time to progression at 175 mg/m2. The observation that longer infusion produces more myelosuppression but does not yield higher response rates should lead to further studies to determine the optimal dose and schedule of this interesting new agent.

Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918

PURPOSE We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate-binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. PATIENTS AND METHODS In cohort A, eight patients received 1.0 mg/m(2) oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day 1 or day 8). In cohort B, eight other patients received 1.0 mg/m(2) intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. RESULTS After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 +/- 9.6 microg.h/L without GF120918 to 78.7 +/- 20.6 microg.h/L when GF120918 was coadministered (P =.008). The mean maximum plasma concentration of total topotecan increased from 4.1 +/- 1.5 microg/L without GF120918 to 11.5 +/- 2.4 microg/L with GF120918 (P =.008). The apparent bioavailability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P =.008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecan, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. CONCLUSION Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF120918.

Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients.

PURPOSE To investigate the pharmacokinetics and pharmacodynamics of paclitaxel in a randomized comparative study with four different treatment arms in patients with platinum-pretreated ovarian carcinoma. PATIENTS AND METHODS Eighteen patients were entered onto this study in which paclitaxel was administered at a high dose of 175 mg/m2 versus a low dose of 135 mg/m2 on a 3- or 24-hour infusion schedule. A solid-phase extraction technique for sample pretreatment followed by a reverse-phase high-performance liquid chromatographic (HPLC) assay was used for analysis of plasma. RESULTS Grade 3 neutropenia occurred in all four treatment arms. However, it was more severe on the 24-hour infusion schedule. Paclitaxel concentrations as low as 0.012 mumol/L were measured with the HPLC assay. With this low quantitation threshold, we found the plasma disappearance of paclitaxel to be triphasic, with half-lives t1/2(alpha), t1/2(beta), and t1/2(gamma) mean values for the different treatment arms of 0.19 hours (range, 0.01 to 0.4), 1.9 hours (range, 0.5 to 2.8), and 20.7 hours (range, 4 to 65), respectively. Eleven possible metabolites were found, of which three were identified as taxanes by on-line HPLC-photodiode array (PDA) detection. Investigation of pharmacodynamics shows no clear relationship between the pharmacokinetic parameters area under the plasma concentration time curve (AUC), area under the plasma concentration moment curve (AUMC), maximal plasma concentration (Cmax), clearance, and toxicity. However, a relationship was found between the duration of plasma concentrations above a threshold of 0.1 mumol/L with absolute neutrophil count (ANC) and white blood cell count (WBC). CONCLUSION Paclitaxel is metabolized, and putative metabolic products can be found in plasma of patients treated with the drug. Our results indicate that myelosuppression can be predicted by the measurement of the duration of plasma concentrations above the threshold of 0.1 mumol/L.

Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Taxanes: A New Class of Antitumor Agents

Taxanes belong to a new group of antineoplastic agents with a novel mechanism of action for a cytotoxic drug. They promote microtubule assembly and stabilize the microtubules. Paclitaxel, the first agent in this group to become available, was isolated from the Pacific yew, Taxus brevifolia, in 1971. In preclinical and clinical studies, paclitaxel and its semisynthetic analog docetaxel exhibit significant antitumor activity. This review deals with the physicochemical properties, pharmacology, and results of preclinical and clinical trials of the taxanes.

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.

Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group.

PURPOSE This prospective randomized trial was designed to compare the efficacy of etoposide plus cisplatin (EP) versus bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with good-prognosis metastatic nonseminomatous testicular cancer. PATIENTS AND METHODS Four hundred nineteen patients with good-prognosis nonseminomatous testicular cancer were randomized to receive four cycles of cisplatin 20 mg/m2 on days 1 to 5 plus etoposide 120 mg/m2 on days 1, 3, and 5 with or without bleomycin 30 mg weekly. RESULTS Of 395 eligible patients, 169 of 195 patients allocated to EP (87%) and 189 of 200 patients allocated to BEP (95%) achieved a complete response with chemotherapy alone or after postchemotherapy surgery. These results are significantly different (P = .0075). After a median follow-up duration of 7.3 years, eight patients (4%) on each treatment arm relapsed. In view of the low number of unfavorable treatment outcomes (11%), no significant differences were detected in time to progression (P = .136) and survival (P = .262). Both the acute and late pulmonary toxicity and neurotoxicity were significantly greater in patients who received BEP, whereas Raynauds phenomenon occurred exclusively in patients who received BEP (P < .001). Two patients treated with BEP died of bleomycin pulmonary toxicity. CONCLUSION BEP is the most effective combination regimen in the treatment of disseminated nonseminomatous germ cell cancer. In this particular BEP regimen with etoposide at a dose of 360 mg/m2 per cycle, even in good-prognosis patients, bleomycin cannot be deleted without compromising treatment efficacy, but its use is associated with more toxicity (particularly pulmonary) and efforts to reduce this merit further exploration.

LONG-TERM SURVIVAL IN OVARIAN-CANCER - MATURE DATA FROM THE NETHERLANDS JOINT STUDY-GROUP FOR OVARIAN-CANCER

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

Randomised Trial Comparing Two Combination Chemotherapy Regimens (HEXA-CAF VS CHAP-5) In Advanced Ovarian Carcinoma

186 patients with advanced epithelial ovarian carcinoma were treated with either a combination of hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexa-CAF) or cyclophosphamide and hexamethylmelamine alternating with doxorubicin and a 5-day course of cisplatin (CHAP-5). Treatment with CHAP-5 resulted in more complete remissions as determined by laparatomy or peritoneoscopy (p = 0.004), better overall response (p = 0.0001), and longer overall survival and progression-free survival (p less than 0.002). Therapy, histological grade, and Karnofsky index were reliable predictors of overall response, whereas therapy, FIGO-stage, and size of residual tumour before chemotherapy were independent predictors for complete remission and for prolonged survival. Peripheral neurotoxicity was a major problem in patients assigned to the CHAP-5-group and was likely to be due to the simultaneous administration of hexamethylmelamine and cisplatin. The CHAP-5 regimen is one of the most effective regimens for the initial treatment of ovarian cancer.