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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 2044-2051 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.3332 Open-Label, Multicenter, Randomized, Phase III Study Comparing Oral Topotecan/Cisplatin Versus Etoposide/Cisplatin As Treatment for Chemotherapy-Naive Patients With Extensive-Disease Small-Cell Lung Cancer
From The Center for Cancer Care and Research, St Louis, MO; Zentralkrankenhaus Gauting, Gauting bei Muenchen, Germany; Koranyi National Institute of Pulmonology, Budapest, Hungary; Oncology Dispensary, Plovdiv, Bulgaria; University Hospital Tzaritza Joanna, Sofia, Bulgaria; GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Harlow, United Kingdom Address reprint requests to John Eckardt, MD, The Center for Cancer Care and Research, 12855 N Outer Forty Dr, Suite 200, St Louis, MO 63141; jeckardt{at}tcccr.com
PURPOSE: This open-label, randomized, multicenter phase III study compared oral topotecan/intravenous cisplatin (TC) with intravenous (IV) etoposide/cisplatin (PE) in patients with untreated extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: A total of 784 patients were randomly assigned to either oral topotecan 1.7 mg/m2/d x 5 with IV cisplatin 60 mg/m2 on day 5 (n = 389) or IV etoposide 100 mg/m2/d x 3 with IV cisplatin 80 mg/m2 on day 1 (n = 395) every 21 days.
RESULTS: Overall survival (primary end point) was similar between groups (P = .48; median: TC, 39.3 weeks v PE, 40.3 weeks). One-year survival was 31% (95% CI, 27% to 36%) in both groups and the difference of –0.03 (95% CI, –6.53 to 6.47) met the predefined criteria of CONCLUSION: Oral topotecan with cisplatin provides similar efficacy and tolerability to the standard (etoposide with cisplatin) in untreated ED-SCLC and may provide greater patient convenience compared with intravenous etoposide and cisplatin.
The majority of patients with small-cell lung cancer (SCLC) present with extensive-stage disease (ED-SCLC).1 A current standard regimen for first-line treatment of ED-SCLC is etoposide-cisplatin (PE). Phase III trials of this regimen have demonstrated median survival times of 8.4 to 10.2 months and a 2-year survival rate of approximately 5%.2,3,5 Outcomes have improved little in the last decade and new, active therapies are urgently required for ED-SCLC. Topoisomerase-I inhibitors are active against SCLC. A randomized trial of the topoisomerase-I inhibitor irinotecan plus cisplatin versus PE in ED-SCLC was terminated early due to a survival benefit in the irinotecan plus cisplatin group.4 A confirmatory trial using a modified dosing regimen failed to demonstrate a survival benefit for the irinotecan arm; however, response rates, time to progression, and overall survival were similar between groups and less myelosuppression was observed in the irinotecan arm.5 Topotecan, a camptothecin analog and topoisomerase-I inhibitor, has demonstrated single-agent activity similar to cyclophosphamide-doxorubicin-vincristine in relapsed, chemotherapy-sensitive SCLC.6 Data from phase II studies of topotecan with cisplatin as first-line therapy for ED-SCLC indicate efficacy in this setting, with response rates of 60% to 63%7,8 and median survival of 8.0 to 9.6 months.7,8 The activity of the topotecan/cisplatin combination in ED-SCLC is supported by a phase II trial of the combination as second-line treatment of refractory or sensitive ED-SCLC.9 An oral formulation of topotecan has been developed that may offer more convenience than the intravenous (IV) formulation. The maximum-tolerated dose for single-agent oral topotecan as 5-day dosing every 21 days is 2.3 mg/m2/d.10 The dose-limiting toxicity is grade 4 neutropenia, consistent with the profile of IV topotecan. Oral topotecan is active in SCLC. In a randomized phase II study of oral or IV topotecan in relapsed, chemotherapy-sensitive SCLC, median survival times were 32 weeks for oral topotecan and 25 weeks for IV topotecan11; in a subsequent phase III study, median survival times were 33 weeks and 35 weeks, respectively.12 A phase III study of oral topotecan versus best supportive care in relapsed, resistant SCLC demonstrated prolonged survival and improved quality of life with oral topotecan.13 The current open-label, randomized, study was undertaken to compare the efficacy and safety of oral topotecan plus cisplatin against the standard first-line regimen of cisplatin plus etoposide in chemotherapy-naive ED-SCLC.
Patient Selection Patients were recruited from 176 centers in 31 countries, randomly assigned in a 1:1 ratio, and stratified according to sex, performance status (PS), serum lactate dehydrogenase, and country. Eligible patients had histologically or cytologically confirmed ED-SCLC with either measurable or nonmeasurable disease (bycomputed tomography, magnetic resonance imaging, x-ray, or physical examination) and met the following inclusion criteria: at least 18 years old, no prior chemotherapy, Eastern Cooperative Oncology Group (ECOG) PS  2, hemoglobin  9.0 g/dL, WBC count 3,500/mm3, platelets 100,000/mm3, neutrophils 1,500/mm3, serum creatinine 1.5 mg/dL and calculated creatinine clearance 60 mL/min, serum bilirubin 2.0 mg/dL, AST, ALT, and alkaline phosphatase 5x the upper limit of normal with liver metastases or 2x without liver metastases, and life expectancy of 3 months.
Previous radiotherapy was allowed if at least 24 hours had passed and no additional toxicity was expected. Disease could be in the field of radiation if Patients were excluded for symptomatic CNS metastases, concomitant or previous malignancies (except for adequately treated basal or squamous cell carcinoma of the skin, carcinoma-in-situ of the cervix, or localized low-grade prostate cancer), infection, severe comorbidities, gastrointestinal conditions affecting absorption, treatment with cyslosporine, or hypersensitivity or other contraindication to the study drugs. The protocol was approved by the institutional review board at each site. Each patient provided written informed consent.
Chemotherapy Regimens In an earlier study of 50 patients with advanced non–small-cell lung cancer (NSCLC), oral topotecan (2.0 mg/m2 daily x 5) plus IV cisplatin (75 mg/m2 on day 5) resulted in three treatment-related deaths (6%).14 Because this finding could possibly be attributed to the cisplatin dose, a reduced cisplatin dose (60 mg/m2/d) was used in the TC arm. Oral topotecan was supplied as capsules containing topotecan hydrochloride equivalent to 0.25 mg or 1.00 mg of the anhydrous free base (GlaxoSmithKline, Middlesex, United Kingdom) and compliance was documented. At study initiation, the dose of topotecan was 2.0 mg/m2/d; however, two patients died as a result of neutropenia associated with enterocolitis. Additionally, there were five other patients who died on the TC arm. Two died as a result of neutropenia after therapy, one patient had empyema with sepsis, one had respiratory failure after a viral syndrome, and one had a ruptured abdominal aortic aneurysm. The protocol was amended to reduce the starting dose of oral topotecan to 1.7 mg/m2/d and measures were put in place to exclude patients of borderline PS 2/3 or rapidly worsening PS. Of 75 enrolled patients, 40 patients had received topotecan at a dose of 2.0 mg/m2/d. All patients enrolled onto the study before the dose reduction were excluded from the intent-to-treat (ITT) population, and additional patients were recruited to meet the required sample size.
Dose Delays and Modifications Dose adjustments were prescribed by the protocol according to tolerability. Dose reductions are listed in Table 1. The minimum dose of oral topotecan was 1.1 mg/m2/d; delays of more than 2 weeks at this dose resulted in withdrawal from the study.
The dose of oral topotecan could be increased in increments of 0.3 mg/m2 up to a maximum of 2.3 mg/m2/d if no toxicity higher than grade 2 occurred during the previous course. The dose of cisplatin in the topotecan arm could be increased to 75 mg/m2 if the maximum topotecan dose was tolerated for at least two cycles (creatinine clearance 60 mL/min; neuropathy grade 1; and other toxicities grade 2).
Assessments Before each course, the following assessments were made: medical history, physical exam, LCSS (completed by patient), toxicity (graded according to the National Cancer Institute Common Toxicity Criteria version 2.0), PS, blood count, and clinical tumor assessment. During treatment, blood counts were obtained on day 8, 9, or 10 and on day 15. Blood chemistries were obtained on day 15, or earlier if indicated. The same physician was to evaluate the patient's tumor response/disease status before each course, whenever possible. Patients were assessable for response if they had received at least one full treatment course. The protocol required radiographic disease assessment after two courses of treatment and at end of therapy. Hematologic adverse events were from recorded laboratory values. All other toxicities were tabulated from investigator-reported adverse events. The primary end point was overall survival (all-cause mortality). Secondary end points were 1-year survival rate, response rate, time to response, response duration, time to progression (TTP), quality of life (QOL), and safety. All randomly assigned patients were to be observed for the full duration of survival. Those patients who progressed while on study were to be observed every 3 months. Patients who had not progressed on treatment or who subsequently received second-line therapy were assessed for disease status clinically or radiologically, PS, and QOL every 4 weeks following treatment until progression or for a maximum of 16 weeks and then once every 3 months. Suspected disease progression was confirmed radiologically.
Statistical Methods A total of 552 deaths in the ITT population were required over the duration of the study to test whether TC resulted in prolonged survival compared with PE with 90% power at a .05 significance level. A sample size of 760 patients (380 per arm) was needed, assuming an 8.6-month median survival (38% 1-year survival rate)4 for the PE arm, an 11.3-month median survival (48% 1-year median survival) for the TC arm, recruitment time of 18 months, maximum follow-up of 30 months, and an 8% dropout rate. If TC was found to be not superior to PE, noninferiority was to be judged using the associated 95% CI for the difference between the two groups in 1-year survival rates. A two-group large-sample normal approximation test of proportions was used and had 81% power to exclude an absolute 10% margin of noninferiority with a one-sided .025 significance level assuming underlying 38% 1-year survival rates for both treatment groups and 380 patients per group. One interim analysis was conducted. The final analysis was performed after all randomly assigned patients had at least 1 year of follow-up after random assignment, which occurred approximately 30 months after study start. Overall survival and other event-related data (TTP, duration of response, and time to response) were analyzed using the Kaplan-Meier method. Survival and TTP were compared using the two-sided log-rank test. Multivariate analyses were performed using a Cox proportional hazards model. Analyses of all secondary end points were descriptive. Additionally, a logistic regression model was used to evaluate overall response including, at a minimum, covariates for treatment and the stratification factors. The primary analysis of LCSS scores was conducted using area under the curve (AUC) methodology as described by Hollen et al.16 A Wilcoxon rank sum test was used to test the difference between groups. The LCSS symptom scores were reversed so that a score of 0 could be used to indicate death. Patients who did not have complete data for each visit were excluded. A random coefficient regression was also performed to estimate the rate of change in scores from baseline.
Patients From July 2001 to April 2003 a total of 784 patients were randomly assigned to TC (n = 389) or PE (n = 395). Baseline characteristics and prognostic factors were well matched between arms (Table 2).
Delivered Chemotherapy Patients were considered to have completed the study if they completed at least one full course of treatment or had withdrawn from treatment due to progressive disease or lack of efficacy (Table 3). The median number of courses administered was 5 (range, 1 to 9) in the TC arm and 6 (range 1 to 8) in the PE arm. Compliance with oral topotecan was high, with 346 patients (90.8%) taking at least 90% of their prescribed capsules.
In the TC arm, dose reductions of topotecan and cisplatin occurred in 107 courses (7.9%) and 19 courses (1.4%), respectively. In the PE arm, dose reductions of etoposide and cisplatin occurred in 122 courses (8.4%) and 45 courses (3.1%), respectively. Hematologic toxicity accounted for the majority of topotecan and etoposide dose reductions (7.1% and 6.5% of courses, respectively). Cisplatin dose reductions primarily occurred as a result of nonhematologic toxicity (0.9% and 1.7% of courses in the TC and PE arms, respectively). Dose escalation of topotecan occurred in 114 courses (8.4%). Dose delays occurred in 40.8% of TC courses and 47.3% of PE courses. A similar proportion of delays occurred due to hematologic toxicity in the TC and PE arms (23.1% and 21.2% of courses, respectively). Delays of more than 7 days due to hematologic toxicity occurred in a slightly higher proportion of TC courses (7.7% v 3.8%).
Efficacy
Toxicity In the TC arm, incidences of grade 3/4 leukopenia and neutropenia were lower, whereas incidences of grade 3/4 thrombocytopenia and anemia were higher than in the PE arm (Table 7). A higher percentage of patients in the TC group received RBCs (42.5% v 21.9%), platelets (10.2% v 3.4%), and erythropoietin (2.6% v 0.8%). The median duration of grade 4 neutropenia and thrombocytopenia was 7 days each in both arms. The percentage of patients receiving granulocyte or granulocyte-macrophage colony-stimulating factor was slightly lower in the TC arm (7.6% v 10.5%).
The incidences of febrile neutropenia and infection are listed in Table 8. Fever and infection occurring within 2 days of grade 4 neutropenia occurred in 4.2% of patients (1.1% of courses) in the TC group and 9.7% of patients (2.6% of courses) in the PE group. Nonhematologic adverse events are listed in Table 9. Overall, the most common toxicities occurring in both groups were nausea, vomiting, and anorexia. Diarrhea occurred more frequently in the TC group, 33% versus 18% in PE group. Blood creatinine increases and alopecia occurred more frequently in the PE group (12% and 40%, respectively v 5% and 24%, respectively, in TC group). The incidence of events classified as serious (ie, resulting in hospitalization or otherwise regarded as serious by the investigator) was similar between the treatment groups (TC, 33% v PE, 29%). Toxic deaths occurred in 10 patients (2.6%) in the TC arm and 7 patients (1.9%) in the PE arm.
QOL The AUC analysis demonstrated a small but statistically significant improvement with PE compared with TC (P = .049). The median AUC was 60.55 with PE and 58.68 with TC, an absolute difference of 1.87 points. In regression analysis, numerical differences for symptom scores tended to favor PE; statistical superiority for PE relative to TC was reached for severity of "Pain" and "Symptoms of Lung Cancer" as demonstrated by 95% CIs. Differences between treatments (TC –PE) in rate of change ranged from –0.17 to –3.51 points.
In the current study, the difference in overall survival between TC and PE was not statistically significant (P = .48), and the 95% CI for the difference in 1-year survival rate (–6.53 to 6.47) successfully met the predefined criteria of a 10% absolute difference to establish noninferiority of TC. The proportion of patients who received poststudy therapy was similar between the groups. The noninferiority in the 1-year survival rate end point was met, despite a reduced dose of cisplatin in the TC arm (60 mg/m2 v 80 mg/m2). There was a statistically significant difference in TTP favoring PE (log-rank P = .02). The difference in median TTP was modest (1 week) and had no effect on third-line therapy or survival. No clinically significant differences occurred in response end points. Although slightly better QOL profiles were observed with PE, the numerical differences were quite small. A correlation study in NSCLC demonstrated clinically meaningful changes for 10 mm to 25 mm changes on the LCSS.17 Thus, the clinical significance of these lesser changes is unclear. Overall, both regimens had similar tolerability with each regimen, but were associated with somewhat different toxicities. Alopecia, blood creatinine increases, grade 3/4 leukopenia, and grade 3/4 neutropenia were more frequent with PE. Diarrhea, grade 3/4 thrombocytopenia, and grade 3/4 anemia were more frequent with TC. The number of toxic deaths, however, was similar between the groups. While TC provided similar efficacy and tolerability to the current standard, it was not superior to PE. Similarly, results from the confirmatory trial comparing irinotecan/cisplatin to etoposide/cisplatin also failed to show increased survival in the irinotecan arm versus the etoposide arm.5 The lack of superiority of the topoisomerase-I inhibitor combination in these trials compared with the increased survival noted in the Noda trial may be due to pharmacogenomic differences (the Noda trial was conducted in Japanese patients)4,25,26 or to different topoisomerase-I inhibitor schedules (irinotecan and cisplatin schedules differed between the Noda and Hanna trials). The current study was one of the largest studies ever conducted in this population and was adequately powered to assess the primary end point. The overall response rates of 63% (TC) and 68.9% (PE) and median survival times of 9.2 months (TC) and 9.4 months (PE) compare equitably with other trials of IV topotecan/cisplatin and etoposide/cisplatin that have demonstrated response rates of 60% to 63% and median survival rates of 8.0 to 9.6 months in untreated ED-SCLC.2,7,8 As a topoisomerase-I inhibitor, topotecan offers a different mechanism of action than other drugs used in SCLC without overlapping subjective toxicities and is a good candidate for combination therapy in this setting. In doublets, topotecan has been combined with cisplatin, carboplatin, paclitaxel, and etoposide in phase II studies.7,8,18-24 These regimens are active, with response rates of 45% to 100%, median survival times of 8.0 to 12.6 months, and 1-year survival rates of 27% to 80%. The oral formulation may provide a more convenient schedule for some patients, particularly if alternative regimens consist solely of IV medications. In conclusion, this study confirms the efficacy of topotecan in SCLC and demonstrates that oral topotecan with cisplatin provides similar efficacy and tolerability to the standard of care (etoposide with cisplatin) in chemotherapy-naive patients with ED-SCLC.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Supported by GlaxoSmithKline, Middlesex, United Kingdom. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, and at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Murren JR, Turrisi AT, Pass HI: Small cell lung cancer, in DeVita Jr VT, Hellman S, Rosenberg SA (eds): Cancer Principles and Practice of Oncology. Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp810-843 2. Roth BJ, Johnson DH, Einhorn LH, et al: Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10:282-291, 1992[Medline] 3. Sundstrøm S, Bremnes RM, Kaasa S, et al: Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: Results from a randomized phase III trial with 5 years' follow-up. J Clin Oncol 20:4665-4672, 2002 4. Noda K, Nishiwaki Y, Kawahara S, et al: Randomized phase III study of irinotecan (CPT-11) and cisplatin versus etoposide and cisplatin in extensive disease small cell lung cancer: Japan Clinical Oncology Group Study. Proc Am Soc Clin Oncol 19:483a, 2000 (abstr 1887). 5. Hanna NH, Einhorn L, Sandler A, et al: Randomized, phase III trial comparing irinotecan/cisplatin (IP) with etoposide/cisplatin (EP) in patients (pts) with previously untreated, extensive-stage (ES) small cell lung cancer (SCLC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005 (abstr 7004) 6. von Pawel J, Schiller JH, Shepherd FA, et al: Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658-667, 1999 7. Quoix E, Breton JL, Gervais R, et al: A randomised phase II study of the efficacy and safety of intravenous topotecan in combination with either cisplatin or etoposide in patients with untreated extensive disease small-cell lung cancer. Lung Cancer 49:253-261, 2005[Medline] 8. Seifart U, Jensen K, Ukena J, et al: Randomized phase II study comparing topotecan/cisplatin administration for 5 days versus 3 days in the treatment of extensive stage small cell lung cancer (SCLC). Lung Cancer 48:415-422, 2005[CrossRef][Medline] 9. Ardizzoni A, Manegold C, Debruyne C, et al: European Organisation for Research and Treatment of Cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as second-line treatment of refractory and sensitive small cell lung cancer. Clin Cancer Res 9:143-150, 2003 10. Gerrits CJ, Burris H, Schellens JH, et al: Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours. Eur J Cancer 34:1030-1035, 1998[CrossRef][Medline] 11. von Pawel J, Gatzemeier U, Pujol JL, et al: A phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small cell lung cancer. J Clin Oncol 19:1743-1749, 2001 12. Eckardt JR, Von Pawel J, Hainsworth JD, et al: Single agent oral topotecan (PO) versus intravenous topotecan (IV) in patients (pts) with chemosensitive small cell lung cancer (SCLC): An international phase III study. Proc Am Soc Clin Oncol 22:619, 2003 (abstr 2488) 13. O'Brien MER, Ciuleanu T, Tsekov H, et al: Survival benefit of oral topotecan plus supportive care versus supportive care alone in relapsed, resistant SCLC. Presented at the 11th World Conference on Lung Cancer, Barcelona, Spain, July 3-6, 2005 (abstr O157) 14. Palshof T, Riviere A, Moreau L, et al: Phase II study of topotecan (T) with cisplatin (C) in advanced non-resectable NSCLC: A promising combination. Lung Cancer 29:36, 2000 (abstr 115) 15. Hollen PJ, Gralla RJ, Kris MG: An overview of the Lung Cancer Symptom Scale, in Gralla RJ, Moinpour CM (eds): Assessing Quality of Life in Subjects with Lung Cancer: A Guide for the Clinician. Monograph, Quality of Life Symposium, 7th World Conference on Lung Cancer, Colorado Springs, CO, June 26-July 1, 1994. New York, NY, NCM, 1995, pp 57-63 16. Hollen PJ, Gralla RJ, Cox C, et al: A dilemma in analysis: Issues in the serial measurement of quality of life in subjects with advanced lung cancer. Lung Cancer 18:119-136, 1997[Medline] 17. Hollen PJ, Gralla R: Clinical vs statistical significance: Using the LCSS quality of life instrument and Karnofsky performance status (KPS) to approach the problem in patients with non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 19:636a, 2000 (abstr 2510) 18. Treat J, Huang CH, Lane SR, et al: Topotecan in the treatment of relapsed small cell lung cancer patients with poor performance status. Oncologist 9:173-181, 2004 19. Seifart U, Fink U, Hans K, et al: Topotecan/carboplatin 5 days vs topotecan/carboplatin 3 days in patients with metastatic small cell lung cancer (SCLC). Proc Am Soc Clin Oncol 22:654, 2003 (abstr 2630) 20. Jett JR, Bernath AM Jr, Hillman SL, et al: Oral topotecan and paclitaxel with G-CSF support in patients with untreated extensive stage small cell (ED-SCLC): A phase II trial of the NCCTG. Proc Am Soc Clin Oncol 21:326a, 2002 (abstr 1301) 21. Lynch TJ Jr, Herndon JE, Lyss AP, et al: Paclitaxel (P) + topotecan (T) + GCSF for previously untreated extensive small cell lung cancer (E-SCLC): Preliminary analysis of Cancer and Leukemia Group B (CALGB) 9430. Proc Am Soc Clin Oncol 19:491a, 2000 (abstr 1922) 22. Ramalingam S, Belani CP, Day R, et al: Phase II study of topotecan and paclitaxel for patients with previously untreated extensive stage small-cell lung cancer. Ann Oncol 15:247-251, 2004 23. Schutte W, Bork I, Ohlmann K, et al: Phase II study: First line treatment of stage IV small cell lung cancer with topotecan and paclitaxel. Proc Am Soc Clin Oncol 20:283b, 2001 (abstr 2882) 24. Tweedy CR, Andrews DF, Ball T: Topotecan and paclitaxel in extensive stage small cell lung cancer as initial therapy. Proc Am Soc Clin Oncol 18:525a, 1999 (abstr 2025) 25. Jung LL, Zamboni WC: Cellular, pharmacokinetic, and pharmacodynamic aspects of response to camptothecins: Can we improve it? Drug Resistence Updates 4:273-288, 2001 26. Mathijssen RHJ, Loos WJ, Verweij J, et al: Pharmacology of topoisomerase I inhibitors Irinotecan (CPT-11) and Topotecan. Current Cancer Drug Targets 2:103-123, 2002[CrossRef][Medline] Submitted July 21, 2005; accepted January 5, 2006. Related Editorial
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
