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© 1999 American Society for Clinical Oncology Phase I and Pharmacologic Study of the Combination of Paclitaxel, Cisplatin, and Topotecan Administered Intravenously Every 21 Days as First-Line Therapy in Patients With Advanced Ovarian CancerFrom the Departments of Medical Oncology and Gynecology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands; Department of Medical Oncology, Medical Spectrum Twente, Enschede, the Netherlands; and SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom. Address reprint requests to Virginie M.M. Herben, PhD, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email apvhe{at}slz.nl
PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma. PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m2 administered over 24 hours (day 1), followed by cisplatin 50 mg/m2 over 3 hours (day 2) and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 µg/kg of G-CSF subcutaneously starting on day 6. RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease. CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m2 (day 1), followed by cisplatin 75 mg/m2 (day 2) and topotecan 0.3 mg/m2/d (days 2 to 6) with G-CSF support repeated every 3 weeks.
OVARIAN CANCER IS one of the leading causes of death among women with gynecologic malignancies. Chemotherapy for ovarian cancer, the mainstay of treatment after maximal cytoreductive surgery in all but early-stage, well-differentiated tumors, has undergone a clear evolution over the past decade. The basic therapeutic regimen for advanced-stage epithelial ovarian cancer after surgery is systemic platinum-based cytotoxic chemotherapy. The combination of a platinum compound with the taxane derivative paclitaxel has been accepted now as first-line chemotherapy after publication of the phase III study of the Gynecologic Oncology Group.1 This study demonstrated that the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in terms of significant improvements in response rate, median survival, and disease-free survival.1 Nonetheless, even with these recent improvements in the treatment of advanced epithelial ovarian cancer, the majority of patients still face a poor prognosis. Therefore, the search for better first- and second-line treatments remains a high priority. Topotecan is a water-soluble, semisynthetic analog of the alkaloid camptothecin. It is a specific inhibitor of the nuclear enzyme topoisomerase I. Inhibition of this enzyme results in lethal DNA damage during DNA replication.2 Topotecan has proven to be active in recurrent ovarian cancer after failure of platinum therapy. A recent study3 has shown that topotecan (1.5 mg/m2 as a 30-minute infusion for 5 consecutive days) compares favorably with paclitaxel (175 mg/m2 over 3 hours) as second-line therapy, manifested by a higher response rate (20.5% v 14%) and longer time to progression (P = .072). Topotecan also seemed active in a smaller percentage of patients refractory or resistant to paclitaxel.3,4 This has encouraged the use of this new antitumor agent in combination with drugs with established activity in recurrent ovarian cancer. Several dose-finding studies have been performed with topotecan plus paclitaxel and topotecan plus cisplatin.5-9 Preclinical synergy has been reported for the three-drug combination of topotecan, paclitaxel, and cisplatin.10 The incorporation of topotecan in the established first-line regimen consisting of platinum plus paclitaxel was therefore a logical next step in the development of topotecan. The lack of significant cross-resistance of topotecan with the other agents, their distinct mechanisms of action, and their partly non-overlapping toxicities supported this rationale. Because neutropenia was anticipated to be the principal toxicity, granulocyte colony-stimulating factor (G-CSF) was added to the combination after the initial maximum-tolerated dose (MTD) was determined without G-CSF. The primary objectives of this phase I study were (1) to determine the MTD and dose-limiting toxicities (DLTs) for the combination of paclitaxel (24-hour infusion on day 1), cisplatin (3-hour infusion on day 2), followed by topotecan as a daily 30-minute infusion over 5 consecutive days without and with G-CSF support in chemotherapy-naive patients with advanced ovarian carcinoma; (2) to determine the qualitative and quantitative toxicities of this combination; (3) to describe the pharmacokinetics of paclitaxel, cisplatin, and topotecan; and (4) to seek preliminary evidence of therapeutic activity with this combination regimen.
Eligibility Criteria Patients with histologically confirmed stage III advanced epithelial ovarian carcinoma who had undergone cytoreductive surgery and were left with residual disease (> 1 cm residual mass) or stage IV disease and who had not received any previous chemotherapy, immunotherapy, or hormonal therapy for ovarian carcinoma were eligible for the study. Patients had to have measurable or assessable disease. At a later stage, patients with successfully debulked tumor status could also be entered after amendment of the protocol in agreement with the medical ethics committee. Other eligibility criteria included age at least 18 years; Eastern Cooperative Oncology Group performance status 2 or lower; estimated life expectancy at least 12 weeks; adequate bone marrow function, defined as WBC count at least 4,000/µL, absolute neutrophil count at least 1,500/µL, hemoglobin at least 6.2 mmol/L (9.0 g/dL), and platelet count at least 100,000/µL; adequate hepatic function, defined as serum bilirubin not more than 34 µmol/L (2.0 mg/dL) and AST and alkaline phosphatase not more than twice the normal upper limit or not more than three times the normal upper limit when related to liver metastases; and adequate renal function, defined as serum creatinine not more than 133 µmol/L (1.5 mg/dL) or calculated creatinine clearance at least 60 mL/min (method of Cockcroft and Gault11). Ineligibility criteria included a histologic diagnosis of borderline epithelial carcinoma, gross ascites, uncontrolled infection, concomitant ketoconazole treatment, history of allergic reactions to polyoxyethylated castor oil or compounds chemically related to topotecan, cisplatin, or paclitaxel, or pre-existing cardiac disease. The study protocol was approved by the medical ethics committee of the hospital, and all patients gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki as amended in Hong Kong in 1989.
Treatment Plan and Study Design
Drug Administration Recombinant methionyl human G-CSF (Neupogen [filgrastim]; Amgen, Inc, Thousand Oaks, CA) was supplied as a sterile solution (300 µg/mL) in 1-mL and 1.6-mL vials. At the dose levels with G-CSF support, 5 µg/kg/d of G-CSF subcutaneously was prophylactically administered on day 7 (ie, 24 hours after the last topotecan dose) through day 12 and then until the neutrophil count was above 10,000/µL.
Toxicity and Response Evaluation
Plasma Pharmacokinetics Plasma levels of paclitaxel, topotecan, and topotecan as the total of the lactone and carboxylate forms and urine levels of total topotecan were determined by validated high-performance liquid chromatographic methods, as described.14,15 Non–protein-bound platinum was determined with atomic absorption spectroscopy.16 For each drug, the maximal plasma concentration at the end of the infusion (Cmax) was generated directly from the experimental data. The mean plasma concentration of paclitaxel during infusion (Cinf) was calculated as the mean of the plasma levels at 3, 10, and 24 hours during the infusion. The area under the plasma concentration-time curve (AUC) was determined using the linear logarithmic trapezoidal method with extrapolation to infinity. The duration of paclitaxel plasma levels above a concentration of 0.1 µM was determined using linear logarithmic interpolation. Individual elimination curves of paclitaxel and unbound cisplatin were described using noncompartmental analysis. Individual plasma concentration-time curves of topotecan were described using a two-compartment linear model with first-order elimination from the central compartment. Total-body clearance from plasma, terminal half-life (t1/2), and apparent volume of distribution at steady-state (Vss) were calculated using standard equations.17 The software package MW\Pharm (Medi\Ware BV, Groningen, the Netherlands) was used for pharmacokinetic calculations. Data are represented as means ± SD.
Statistical Analysis
Twenty-one patients with advanced International Federation of Gynecology and Obstetrics stage III and IV ovarian cancer (18 patients with bulky disease) were entered into this phase I and pharmacologic study. Fifteen patients had undergone cytoreductive surgery before chemotherapy. Patient characteristics are listed in Table 1. Interventional debulking was performed in three patients after three courses of chemotherapy and in one patient after the fourth course. The following dose levels of paclitaxel/cisplatin/topotecan (in milligrams per meter squared per day) were evaluated: 110/50/0.3 without G-CSF and 110/50/0.3, 110/75/0.3, and 110/75/0.4 with G-CSF (Table 2). A total of 116 full courses of chemotherapy were administered, with a median number of administered courses of six (range, one to eight) per patient. Three patients received only one course of chemotherapy because of severe hematologic (two patients) and renal toxicity (one patient). Four patients required dose modifications owing to toxicity. The cisplatin dose was reduced from 75 to 50 mg/m2 (dose level III) in one patient in her fourth treatment course because of persistent neutropenia. One patient treated at dose level I received no cisplatin in the sixth course owing to suspected ototoxicity. Topotecan dose reductions were performed in two patients who experienced thrombocytopenia grade 4 at dose level IV. Topotecan dosage was reduced from 0.4 to 0.3 mg/m2/d in the fifth treatment course, and in one of these patients topotecan was not given at all in the sixth course because of persistent severe thrombocytopenia. Two patients treated at the first dose level received G-CSF during their sixth and subsequent courses after severe neutropenia during preceding courses without G-CSF.
Hematologic Toxicity
Table 3 lists the median and range of nadir neutrophil and platelet counts at each dose level during the first course and all courses. Myelosuppression was not cumulative, as evidenced by the similar neutrophil and platelet nadirs in later courses compared with the first course (Table 3). The neutrophil nadir occurred on day 9 (range, day 3 to 20) for the initial courses and also on day 9 for all courses (range, day 3 to 21). Of all administered courses, seven courses (6%) were delayed for 1 week because of unresolved neutropenia (five courses) and thrombocytopenia (two courses) on day 21,
Nonhematologic Toxicity Microscopic hematuria was noted in 35% of all courses and mild proteinuria in 3% of courses. Other adverse reactions that were possibly treatment-related were mild to moderate (grade 1 and 2) transient elevations in hepatic function tests, constipation (16% of courses), weight loss (21%), myalgia (18%), being severe (grade 3) in one course, malaise (12%), being severe (grade 3) in one course, bone pain (12%), flushes (11%), and dyspnea (7%). Mild hypomagnesia (65% of courses) was noted in 19 patients and was severe in five patients (grade 3 in four courses; grade 4 in three courses), requiring intravenous magnesium supplements. One episode of hypocalcemia grade 3 was observed. No cardiac toxicity was encountered. No hypersensitivity reactions were observed.
Pharmacokinetics
Antitumor Activity
The significant single-agent activity observed with topotecan both in patients with advanced ovarian carcinoma refractory or resistant to cisplatin and in patients refractory or resistant to paclitaxel has encouraged us to evaluate the feasibility of incorporating this drug into standard first-line treatment of ovarian cancer. Chou et al10 pointed to synergistic antitumor effects of two- and three-drug combinations of topotecan, cisplatin, and paclitaxel against human teratocarcinoma cells in vitro. We selected the sequence of paclitaxel preceding cisplatin followed by topotecan based on in vitro and clinical results and the mechanistic rationale for maximal interactions between cisplatin and topotecan.18,19 In a panel of human solid tumor cell lines, the combination of cisplatin with topotecan yielded schedule-dependent synergistic toxicity, with cisplatin followed by topotecan being most active.18,19 This synergy might at least partly be explained by the increased retention of platinum-DNA intrastrand cross-links in the presence of topotecan.19 Several clinical studies have been performed with cisplatin plus topotecan.7-9 Rowinsky et al8 showed that cisplatin preceding topotecan was more myelotoxic than the alternate sequence, which may be due, in part, to reduced topotecan clearance. Three clinical studies have explored the combination of topotecan with paclitaxel.5,6,20 O'Reilly et al6 investigated the effects of drug sequencing on the hematologic toxicity; no significant differences were found between the two drug sequences. In the other two studies, paclitaxel preceded topotecan.5,20 Different topotecan administration schedules have been explored; O'Reilly et al6 and Lilenbaum et al5 administered topotecan according to the United States Food and Drug Administration–approved daily times five schedule, whereas in the study of Hochster et al,20 topotecan was given as a 14-day continuous infusion. In all of these combination studies, the DLT was hematologic, and the drugs could not be administered at their individual MTDs. The present study showed that neutropenia was the DLT of the combination regimen of paclitaxel, cisplatin, and topotecan without and with growth factor support. The MTD without growth factors was reached at doses of paclitaxel 110 mg/m2 over 24 hours (day 1), cisplatin 50 mg/m2 over 3 hours (day 2), and topotecan 0.3 mg/m2/d over 30 minutes for 5 consecutive days (days 2 to 6). Grade 4 neutropenia was observed in all six patients entered on this dose level and in 39 of 40 administered courses (98%); 24 of these episodes lasted for 5 days or more. The addition of G-CSF improved the tolerance to the combination regimen. Patients receiving G-CSF had significantly fewer episodes of severe neutropenia and fewer fevers during neutropenia. Nonetheless, the impact of G-CSF on dose escalation was limited. We were unable to escalate topotecan, in combination with paclitaxel, cisplatin, and G-CSF, to a dose near the single-agent MTD of 1.5 mg/m2/d for the 5-day schedule. The addition of G-CSF allowed the dose of cisplatin to be escalated from 50 to 75 mg/m2. An increase of the topotecan dose from 0.3 to 0.4 mg/m2, however, resulted in dose-limiting febrile neutropenia and grade 4 thrombocytopenia. Whereas the feasibility of paclitaxel dose escalation with growth factors has previously been demonstrated,21 the role of growth factors in topotecan dose escalation has not been clearly defined. Saltz et al22 reported that topotecan dose escalation was not possible with growth factors, because thrombocytopenia rapidly became dose-limiting. In contrast, Rowinsky et al23 demonstrated that posttreatment G-CSF support allowed a 2.3-fold dose escalation for topotecan administered as five daily 30-minute infusions, whereas for the combination of topotecan and cisplatin, the addition of G-CSF did not improve tolerance to this regimen.8 However, Miller et al7 could escalate the cisplatin dose from 50 mg/m2 without G-CSF to 75 mg/m2 with G-CSF in combination with topotecan 1.0 mg/m2/d for 5 days. Nonhematologic toxicity was relatively mild and tolerable and included nausea/vomiting, alopecia, and fatigue. No patient had evidence of significant (> grade 2) neurologic toxicity. Only two episodes of nonhematologic DLT were observed, and they were of renal origin. Two patients had increased levels of serum creatinine and urea and were therefore taken off-study. In all but three patients who underwent pharmacokinetic monitoring during the first treatment course, paclitaxel plasma concentrations were maintained above the biologically active threshold concentration of 0.1 µM24 for more than 15 hours. The mean duration above 0.1 µM was 18 hours. Huizing et al25 demonstrated that in patients with non–small-cell lung cancer who received paclitaxel in combination with carboplatin, a time above 0.1 µM exceeding 15 hours was positively related to improved survival. Although this observation has not yet been confirmed in other combination regimens of paclitaxel and in other tumor types, these data suggest that, in the present study, a clinically relevant dose and schedule of paclitaxel was used. Previous studies suggested that in patients receiving cisplatin before topotecan, cisplatin-induced subclinical renal tubular toxicity might reduce renal clearance of topotecan.8 Their results agree with our pharmacokinetic data. Topotecan pharmacokinetic parameters obtained after the first dose (day 2) were similar to previously published values.26 Limited pharmacokinetic sampling was performed on treatment days 3 to 6. Topotecan concentrations at 2 hours postinfusion were consistently higher on days 3 to 6 compared with those on day 2. As measurement of only one timed sample at 2 hours postinfusion gives a reliable estimation of the topotecan AUC and plasma clearance,27 these data might indicate that cisplatin administered before topotecan does not immediately alter topotecan clearance but reduces the clearance 2 to 5 days after cisplatin administration.8 The differences in topotecan clearance between day 2 and days 3 to 6 could also be partly related to other factors, such as the administration of paclitaxel, other co-medication, or hydration on days 1 and 2. However, O'Reilly et al6 demonstrated that the pharmacologic behavior of topotecan and paclitaxel was not altered by drug sequencing when topotecan was administered as a 30-minute infusion daily for 5 days and paclitaxel was given as a 24-hour infusion either before topotecan on day 1 or after topotecan on day 5. The combination of paclitaxel, cisplatin, and topotecan after surgery was highly active, with an overall response rate of 86.7%. Second-look laparotomy performed in three patients with a complete response after chemotherapy revealed that these patients were pathologically free of disease. Given that the number of patients was small in this study, these data suggest that it would be helpful in future studies of new antineoplastic agents or new combinations to have more of these data available. It is pathologic complete response that would lead an investigator to accept formidable toxicity as an acceptable tradeoff for the potential for long-term disease control. In our study, the short median follow-up at the time of analysis did not allow the assessment of response duration and time to progression. In conclusion, neutropenia was the DLT of the combination of paclitaxel, cisplatin, and topotecan. The drugs could not be administered at their individual MTDs, but true synergy and pharmacokinetic interactions may obviate the need to use full single-agent dose schedules. Notwithstanding, the need for bone marrow colony-stimulating factors makes the regimes less attractive, but the observed high response rate justifies the search for other ways of combining these three drugs. With the Gynecologic Oncology Group trial1 as the basis for the combination, we chose to administer paclitaxel over 24 hours, in spite of the inconvenience and expense of the administration schedule. Reduction of the duration of the paclitaxel infusion to 3 hours might contribute to an equally effective but less myelosuppressive and more convenient treatment schedule, as has been shown for single-agent paclitaxel in previously treated ovarian cancer patients.28 A drawback of short-infusion paclitaxel is the reported higher incidence and severity of neurotoxicity when paclitaxel is administered over 3 hours compared with 24 hours in combination with cisplatin.29,30 Notwithstanding, the increased neuropathy is primarily related to higher doses, rather than the infusion duration, and it is unlikely that a full paclitaxel dose (ie, 175 mg/m2) would be administered in the combination regimen. Similarly, we evaluated only a daily times five schedule of topotecan, which prevented topotecan dose escalation, owing to excessive neutropenia and the emergence of thrombocytopenia. Shorter schedules (daily times three) are being evaluated in other disease settings. Although a shorter duration may not be ideal as a single-agent regimen, this compromise could be considered in multidrug combinations. An alternative is to use the oral formulation of topotecan. Oral topotecan was shown to have efficacy similar to that of the intravenous form in advanced ovarian cancer but was associated with less hematologic toxicity.31 Another option for a triple chemotherapeutic combination could be to substitute carboplatin for cisplatin; this might reduce emesis, nephrotoxicity, and neurotoxicity. The more frequently observed myelosuppression with carboplatin might be reduced by individualized dose calculation. A phase I trial combining topotecan with carboplatin is in preparation in our institute. Yet another—and perhaps the most challenging—approach for combining paclitaxel, cisplatin, and topotecan is to use multiple single-agent or two-drug combinations either in an alternating or a sequential regimen.32 The search for effective first-line regimens in advanced ovarian cancer remains a high priority, and several other agents that have demonstrated activity in recurrent disease, including encapsulated doxorubicin, oral etoposide, and gemcitabine, are being evaluated in combination with paclitaxel and platinum compounds in all phases of postoperative chemotherapy for ovarian cancer. Nevertheless, the toxicity of any of these platinum/taxane–based triplets is likely to be high, and it is unclear whether this degree of toxicity is essential for optimal antitumor activity. Although ovarian cancer is often initially responsive to chemotherapy, the disease remains difficult to cure. Phase II/III studies incorporating novel drugs that are active in ovarian cancer into front-line combination chemotherapy are required to demonstrate whether these drugs can meaningfully prolong survival and increase cure rates in ovarian cancer.
We thank Marianne Mahn and Marion Grob for assistance with data collection, and Desirée van Zomeren, Sindy Jansen, Ciska Koopman, and Matthijs Tibben for technical assistance with the bioanalytic assays. We also express our gratitude to the medical and nursing staffs of the Antoni van Leeuwenhoek Hospital and Medical Spectrum Twente for the care and support of the patients in this study. Supported by a grant from SmithKline Beecham Pharmaceuticals, Collegeville, PA
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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Hsiang Y-H, Liu LF, Wall ME, et al: DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogs. Cancer Res 49:4385-4389, 1989 3. Gordon A, Carmichael J, Malfetano J, et al: Final analysis of a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma: International Topotecan Study Group. Proc Am Soc Clin Oncol 17:356a, 1998 (abstr) 4. Swisher EM, Mutch DG, Rader JS, et al: Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 66:480-486, 1997[Medline]
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Miller AA, Hargis JB, Lilenbaum RC, et al: Phase I study of topotecan and cisplatin in patients with advanced solid tumors: A Cancer and Leukemia Group B study. J Clin Oncol 12:2743-2750, 1994 8. Rowinsky EK, Kaufmann SH, Baker SD, et al: Sequences of topotecan and cisplatin: Phase I, pharmacologic, and in vitro studies to examine sequence dependence. J Clin Oncol 14:3074-3084, 1996[Abstract]
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Raymond E, Burris HA, Rowinsky EK, et al: Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated non–small-cell lung carcinoma. Ann Oncol 8:1003-1008, 1997
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Chou T-C, Motzer RJ, Tong Y, et al: Computer quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: A rational approach to clinical protocol design. J Natl Cancer Inst 86:1517-1524, 1994 11. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31, 1976[Medline] 12. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988 13. World Health Organization: Handbook for Reporting Results of Cancer Treatment. WHO publication no. 48. Geneva, Switzerland, World Health Organization, 1979
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Huizing MT, Keung AC, Rosing H, et al: Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 11:2127-2135, 1993 15. Rosing H, Doyle E, Davies BE, et al: High-performance liquid chromatographic determination of the novel antitumour drug topotecan and topotecan as the total of the lactone plus carboxylate forms, in human plasma. J Chromatogr B Biomed Appl 668:107-115, 1995[Medline] 16. van Warmerdam LJC, Van Tellingen O, Maes RAA, et al: Validated method for the determination of carboplatin in biological fluids by Zeeman atomic absorption spectrometry. Fresenius J Anal Chem 351:1820-1824, 1995 17. Rowland M, Tozer TN: Clinical Pharmacokinetics: Concepts and Applications (ed 2). Philadelphia, PA, Lea and Febiger, 1989, pp 78-97 18. Cheng M-F, Chatterjee S, Berger NA: Schedule-dependent cytotoxicity of topotecan alone and in combination chemotherapy regimens. Oncol Res 6:269-279, 1994[Medline] 19. Ma J Maliepaard M, Nooter K, et al: Synergistic toxicity of cisplatin and topotecan or SN-38 in a panel of eight solid-tumor cell lines in vitro. Cancer Chemother Pharmacol 41:307-316, 1998[Medline] 20. Hochster H, Speyer J, Oratz R, et al: Phase I study of taxol with 14-day topotecan continuous low-dose infusion. Proc Am Soc Clin Oncol 14:486, 1995 (abstr) 21. Sarosy G, Kohn E, Stone DA, et al: Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J Clin Oncol 10:1165-1170, 1992[Abstract]
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Saltz L, Sirott M, Young C, et al: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Cancer Inst 85:1499-1507, 1993
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Rowinsky EK, Grochow LB, Sartorius SE, et al: Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors. J Clin Oncol 14:1224-1235, 1996
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Huizing MT, Giaccone G, van Warmerdam LJ, et al: Pharmacokinetics of paclitaxel and carboplatin in a dose-escalating and dose-sequencing study in patients with non–small-cell lung cancer: A European Cancer Centre. J Clin Oncol 15:317-329, 1997 26. Herben VM, ten Bokkel Huinink WW Beijnen JH: Clinical pharmacokinetics of topotecan. Clin Pharmacokinet 31:85-102, 1996[Medline]
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van Warmerdam LJC, Verweij J, Rosing H, et al: Limited sampling models for topotecan pharmacokinetics. Ann Oncol 5:259-264, 1994
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Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654-2666, 1994 29. Connelly E, Markman M, Kennedy A, et al: Paclitaxel delivered as a 3-hr infusion with cisplatin in patients with gynecologic cancers: Unexpected incidence of neurotoxicity. Gynecol Oncol 62:166-168, 1996[Medline] 30. Piccart MJ, Bertelsen K, Stuart G, et al: Is cisplatin-paclitaxel (P-T) the standard in first-line treatment of advanced ovarian cancer? The EORTC-GCCG, NOCOVA, NCI-C and Scottish intergroup experience. Proc Am Soc Clin Oncol 16:352a, 1997 (abstr) 31. Gore M, Rustin G, Calvert H, et al: A multicentre randomised phase III study of topotecan administered intravenously or orally for advanced epithelial ovarian carcinoma. Proc Am Soc Clin Oncol 17:349a, 1998 (abstr) 32. Markman M: Topotecan: An important new drug in the management of ovarian cancer. Semin Oncol 24:S5-S11, 1997 Submitted July 13, 1998; accepted December 28, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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TOP
ABSTRACT
INTRODUCTION
, 
) and carboxylate forms (
, 
) in patients who received 0.3 mg/m2 (square symbols) and 0.4 mg/m2 (triangles) by a 30-minute intravenous infusion.
