|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology Irinotecan Combined With Bolus Fluorouracil, Continuous Infusion Fluorouracil, and High-Dose Leucovorin Every Two Weeks (LV5FU2 Regimen): A Clinical Dose-Finding and Pharmacokinetic Study in Patients With Pretreated Metastatic Colorectal CancerFrom the Institut Gustave Roussy, Villejuif; Centre du Val d'Aurelle, Montpellier; Institut Paoli Calmettes, Marseille; and Laboratoires Rhône-Poulenc Rorer, Montrouge, France. Address reprint requests to M. Ducreux, MD, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France.
PURPOSE: To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT-11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC). PATIENTS AND METHODS: All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m2). LV5FU2 was started 1 hour after the end of the biweekly CPT-11 infusion and was also administered on day 2. RESULTS: Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m2, and a dose level of 300 mg/m2 was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m2. Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months. CONCLUSION: The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT-11 at 180 to 200 mg/m2 in combination with LV5FU2 has been selected as the recommended dose for further studies.
IRINOTECAN (7-ethyl-10-[4(1-piperidino)-1-piperidino] carbonyloxy camptothecin; CPT-11) is a semisynthetic derivative of the plant alkaloid camptothecin.1 Like camptothecin, CPT-11 exerts its cytotoxic activity through the inhibition of the nuclear enzyme topoisomerase I.2-4 Topoisomerase I facilitates DNA replication and transcription by causing single-strand protein-bridged breaks in DNA, permitting relief of torsional strain in the double helix ahead of the replication fork.5,6 Unlike camptothecin, CPT-11 is water-soluble, which results in more predictable and manageable toxicity than was encountered with the parent compound.7 CPT-11 has shown encouraging antitumor activity in a number of solid tumors, including colorectal cancer (CRC).8-12 In a study of its use in first-line chemotherapy, Rougier et al11 treated 48 chemotherapy-naive patients using a schedule of 350 mg/m2 of CPT-11 once every 3 weeks and reported an objective response rate of 18.8%, which was no different from the rate achieved in 165 pretreated patients, suggesting a lack of cross-resistance with fluorouracil (5-FU). In other single-agent studies, response rates of 23%,9 25%,12 27%,8 and 32%10 were reported. Recently, in two large randomized studies,13,14 CPT-11 has been shown to significantly improve the overall survival (OS) of patients with 5-FU–resistant CRC without having a negative impact on quality of life, and use of this agent is now considered to be a standard treatment after 5-FU failure. 5-FU is an antimetabolite that has been the mainstay of gastrointestinal oncology for more than 30 years.15,16 The clinical value of 5-FU–based regimens has been demonstrated in terms of survival and quality of life17,18 in front-line chemotherapy for metastatic disease. Numerous schedules and doses of 5-FU have been investigated without reaching any consensus regarding a standard. Daily-times-five bolus 5-FU plus low-dose leucovorin (LV) is one of the most widely used schedules. However, high-dose infusional 5-FU regimens, with or without LV, are becoming increasingly popular due to their higher antitumor activity19 and better safety profile,19-22 including, in particular, a low incidence or even total absence of severe neutropenia. Furthermore, preclinical data strongly suggest that infusional 5-FU acts through a different mechanism (thymidylate synthase inhibition) from that of bolus 5-FU (inhibition of RNA synthesis).23 These data are strengthened by the clinical evidence that resistance to bolus 5-FU can be overcome by infusional 5-FU.22,24-28 Thus a hybrid regimen combining bolus and infusional 5-FU is an attractive manner of 5-FU delivery and is currently under investigation.23 The LV5FU2 hybrid regimen combines bolus and infusional administration and is the only one so far that has been shown to be superior to bolus 5-FU in terms of response rate and time to tumor progression.19 Because multidrug therapy with non–cross-resistant drugs usually leads to enhanced antitumor activity when compared with single-agent therapy, combining an optimal 5-FU regimen with CPT-11 is a strategic priority for the management of patients with advanced CRC. The administration of CPT-11 every other week has been shown to be feasible and may provide the optimal balance between dose-intensity and treatment frequency29 and fits with the LV5FU2 schedule of every 2 weeks. In the present study, we assessed for the first time the combination of CPT-11 with the LV5FU2 regimen.
Patients Eligibility criteria included the following: histologic documentation of metastatic CRC, WBC count  4 x 109/L, neutrophils 2 x 109/L, platelets 100 x 109/L, hemoglobin 10 g/dL, serum creatinine 120µmol/L, total bilirubin 1.25 times the upper limit of normal (x ULN) in the absence of liver metastasis and 1.5 x ULN if hepatic metastases were present, AST and ALT 3 x ULN, alkaline phosphatase less than 2.5 x ULN, life expectancy of 3 months, age between 18 and 75 years, and World Health Organization (WHO) performance status of less than 2. Pregnant and breast-feeding women were excluded from the study, as were patients with angor or a history of myocardial infarction. All patients had to have been previously treated with at least one 5-FU–based regimen, with documented progressive disease after their last chemotherapy. Bidimensionally measurable lesions were preferred. Prior radiation therapy was permitted, except for extensive abdominopelvic irradiation. Prior chemotherapy or radiotherapy was required to have ended at least 4 weeks before study entry. Written informed consent was obtained from each patient. Pretreatment evaluation included a complete medical history and physical examination, imaging of measurable or nonmeasurable but assessable disease, chest x-ray, and ECG. A complete and differential blood cell count and biochemical profiles were obtained at baseline and were determined weekly. Tumor markers (carcinoembryonic antigen and CA19-9) were obtained at baseline and at the start of each treatment cycle. Tumor imaging was repeated after every four treatment cycles (8 weeks). Response, as determined by the investigators, was recorded according to WHO response criteria.30
Treatment Plan and Dose-Escalation Schedule
Evaluation During Treatment
Pharmacokinetics The pharmacokinetic parameters of CPT-11 were determined using a model-dependent analysis. Plasma concentrations were fitted to a two- or three-compartment open model with first-order elimination using nonlinear least-square regression analysis with APIS software (MIIPS, Marseilles, France). Concentration at the end of infusion (Cmax), area under the plasma concentration versus time curve (AUC), total body clearance, volume of distribution at steady-state (calculated according to the statistical moment method), and half-lives were calculated. A model-independent analysis was performed for the metabolite SN-38 using MicroPharm software (Loginserm, Paris, France). This included actual concentration at the end of infusion, the time required to reach it, AUC (determined using the trapezoidal method), and apparent elimination half-life (determined from the linear regression analysis of the last points of concentration versus time).
Between April 1996 and October 1997, 55 patients were entered and treated in three centers. Fifty-two patients were assessable for efficacy and 55 for safety. A summary of baseline patient characteristics is included in Table 1. All patients had advanced CRC and all had received at least one prior fluoropyrimidine-based chemotherapy regimen (median, two regimens; range, one to five regimens; one patient had received capecitabine). The response rate for the most recent palliative chemotherapy was 19.6% (nine of 46 assessable patients).
Study Treatment Exposure and Determination of MTD
Safety
Pharmacokinetics
Efficacy
The aim of this study was to define the MTD and recommended dose for CPT-11 associated with a standard, fixed-dose LV5FU2 regimen administered every 2 weeks. The first important finding is the lack of clear overlap between CPT-11 and 5-FU/LV toxicities with this regimen. The doses of 5-FU and CPT-11 that can be administered are close or equal to those of either agent used alone. Indeed, in a phase II study of CPT-11 used as a single agent given every 2 weeks, Rothenberg et al29 have recommended a dose of 250 mg/m2. This lack of overlapping toxicity may explain why a CPT-11 dose of 300 mg/m2 was used without attaining the MTD. At this dose level, only one of four patients experienced a DLT in the first treatment cycle. However, in three of the four patients treated at this dose level, the treatment could not be resumed on day 15 and the dose had to be reduced. Thus, given the desirability of repeating the treatment every 2 weeks without any delays, the 180 mg/m2 CPT-11 dose level was considered the best compromise between dose-intensity and safety for multicenter phase II/III studies. Furthermore, antitumor efficacy was observed at all dose levels, and so the determination of the highest tolerable dose-intensity did not seem necessary. Indeed, data on the dose-response relationship are scarce in the literature because they are not generally available in phase I studies, in which miscellaneous tumors are usually treated and tumor response is not assessable. Only one single-agent study has suggested such a relationship,31 and this was for CPT-11 doses greater than 350 mg/m2. Five severe diarrhea episodes occurred at the dose of 200 mg/m2, including three in the first cycle. However, the fact that diarrhea was absent at higher dose levels suggests that its occurrence was more related to patient susceptibility than dose, and that this latter dose can, therefore, also be recommended. At the 180 and 200 mg/m2 dose levels, the actual CPT-11 dose-intensities administered were, in practice, very close (median dose-intensities, 87 and 92 mg/m2/wk, respectively). The safety profile for these two dose levels was documented for 21 patients with more than 212 cycles and supports their use in further studies. Taken together, the patients entered at these two dose levels received a median of 10 cycles (range, three to 24 cycles). Seventy-one percent of patients had at least one cycle delayed, including 38% who had a cycle delayed for more than 7 days. A dose reduction was required for 33% of the patients, 5% of patients experienced febrile neutropenia, and 24% experienced dose-limiting diarrhea (either grade 3 or 4, or any grade lasting more than 7 days). As expected, the combination is not tolerated as well as the LV5FU2 regimen,19 but it is at least as well tolerated as CPT-11 used as a single agent. Severe diarrhea (grade 3 or 4) was not a concern in this study and occurred in 18% of patients, compared with 20% in the most recent single-drug trials,13,14 even when the same schedule (every 2 weeks) was used.29 Febrile neutropenia occurred at nearly all dose levels but never during the first cycle, suggesting that hematologic toxicity in this regimen may be more dependent on a cumulative effect than on dose level in some patients. On the other hand, dose reduction and/or treatment delay allowed for protracted treatment in patients who did not experience disease progression. Severe nausea and vomiting, fatigue, or alopecia seemed to occur less frequently than with single-agent CPT-11,9,11 and the overall impression is indeed one of better tolerance. This fact may be due to better management of CPT-11 toxicity with the benefit of time and experience, rather than to a lower CPT-11 dose-intensity in combination therapy. Indeed, the CPT-11 dose-intensity in this study is slightly inferior to that achieved in various single-agent schedules (350 mg/m2 every 3 weeks,11 125 mg/m2 weekly,9 and 250 mg/m2 every 2 weeks29). Although the assessment of antitumor efficacy was not the primary objective of this phase I study, the 22% response rate, 6.2-month TTP, and 15-month median OS observed seem to be clinically relevant in this heavily pretreated population of CRC patients who had received a median of two prior chemotherapy regimens (range, one to five regimens), including 18% who received oxaliplatin, the only other drug considered to be active after 5-FU failure. The efficacy is similar to that of the last chemotherapy regimen before treatment (20% response rate). The clinical value of this combination is further supported by the results of a phase III study showing that after 5-FU failure, the median OS with supportive care alone was 6.5 months.13 Similarly, the antitumor activity of this combination regimen was similar to that of single-agent CPT-11 reported for patients in three phase II studies,8,9,11 although they were pretreated with only one prior 5-FU–based regimen versus a median of two in the present study (response rates of between 17% and 23%, TTP of 4 months, and median OS of 10.4 months9 [10 months for pretreated patients and 12 months for chemotherapy-naive patients11]). Moreover, the results are better than those achieved in phase III trials using CPT-11 alone, with median OS of 9.213 and 10.8 months,14 suggesting that the present combination is superior to single-agent therapy. However, in our study, six of 12 responders had no proven 5-FU resistance (treatment-free interval > 6 months), and the LV5FU2 regimen may have contributed to the antitumor activity. Nevertheless, seven of 12 patients had been exposed to a prior 5-FU infusional regimen, so the true value of this combination still remains to be assessed in chemotherapy-naive patients. Many other phase I/II studies of the CPT-11 plus 5-FU combination have been performed using different schedules. Two studies of CPT-11 combined with concomitant bolus 5-FU have been published. In the first study, which used a daily times five 5-FU schedule,33 tolerability was found to be poor and only a low dose-intensity was achieved. In the second study, in which a weekly 5-FU schedule was used,34 both the safety and the dose-intensity were acceptable, and six of the 38 patients with heavily pretreated CRC experienced objective responses. Another way to combine CPT-11 with bolus 5-FU that has been explored is an alternating regimen in which CPT-11 and 5-FU/LV are administered every other cycle.35,36 This schedule avoids toxicity overlap but decreases the dose-intensity of both drugs. The response rate in both studies was approximately 30% in patients who were all chemotherapy-naive. Two other phase I studies using simultaneous infusional 5-FU and CPT-11, either with protracted low-dose 5-FU and CPT-11 every 3 weeks37 or with weekly 24-hour 5-FU infusion and weekly CPT-11,38 exhibit excellent safety profiles, and the recommended CPT-11 doses are close to those used in single-agent therapy. This good tolerability may be due to the very low incidence of severe neutropenia observed with infusional 5-FU regimens when compared with bolus 5-FU.21 The DLTs of infusional 5-FU regimens are hand-foot syndrome and diarrhea. Nevertheless, the incidence of severe diarrhea does not seem to be increased by the combination, probably due to different mechanisms of drug-induced diarrhea. In the first study, antitumor activity could not be assessed because patients were enrolled with miscellaneous tumor types.37 In the second study,38 a 60% response rate was observed, but in relatively young, chemotherapy-naive patients. The clinical value of many of these CPT-11/5-FU combination regimens will be determined in ongoing phase III trials. The pharmacokinetic results of this study were consistent with previous data from studies of CPT-11 administered as a single agent.39 The higher CPT-11 terminal half-life (mean, 22.5 ± 14.6 hours v 12.0 ± 7.8 hours) was probably due to the fact that blood collection was performed up to 48 hours postinfusion, which allowed the terminal phase to be more accurately explored. However, this phenomenon induced a minimal effect on the drug exposure, because clearance values were comparable to those observed in monotherapy39 (14.7 v 14.8 L/h/m2). The SN-38 terminal half-life was also comparable to that determined in 168 phase I cancer patients treated with CPT-11 alone (12.0 v 10.6 hours).39 SN-38 Cmax and AUC values were in the same range as those observed with CPT-11 single-agent therapy. For instance, at 100 mg/m2, mean values were 0.034 µg/mL and 0.298 µg·h/mL, respectively.39 Despite the administration of 5-FU, SN-38/CPT-11 AUC ratios were approximately stable over the tested dose range and were close to those observed in CPT-11 single-agent therapy (mean value of 4.1% v 3.1%). In conclusion, this phase I study has shown the feasibility of the CPT-11/LV5FU2 combination regimen every 2 weeks and the lack of overlapping toxicity. The present data suggest that this 5-FU–based regimen does not influence the pharmacokinetics of CPT-11. Although the MTD has not been clearly assessed in terms of severe toxicity, increasing the CPT-11 dose to more than 200 mg/m2 led to a high rate of treatment delay and/or dose reduction, with a subsequent effect on the dose-intensity. On the basis of the large number of patients and cycles evaluated, CPT-11 doses of 180 to 200 mg/m2 can be safely recommended for further phase II/III studies. Given the likely improved therapeutic index of this combination regimen over that of single-agent CPT-11, the authors are already using it in their everyday practice.
1. Kunimoto T, Nitta K, Kanaka T, et al: Antitumor activity of 7-ethyl-10 (4 -(1-piperidino)-1-piperidino)-1-carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res 47:5944-5947, 1987 2. Hertzberg RP, Caranfa MJ, Hecht SM: On the mechanism of topoisomerase I inhibition by camptothecin: Evidence for binding to an enzyme-DNA complex. Biochemistry 28:4629-4638, 1989[Medline]
3.
Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722-1726, 1988 4. Eng WK, Faucette L, Johnson RK, et al: Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 34:755-760, 1988[Abstract] 5. Liu LF: DNA topoisomerases: Enzymes that catalyse the breaking and rejoining of DNA. CRC Crit Rev Biochem 15:1-24, 1983[Medline] 6. Wang JC: DNA Topoisomerases. Annu Rev Biochem 54:665-697, 1985[Medline] 7. Gottlieb JA, Guarino AM, Call JB, et al: Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep 54:461-470, 1970[Medline]
8.
Shimada Y, Yoshino M, Wakui A, et al: Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. J Clin Oncol 11:909-913, 1993
9.
Rothenberg ML, Eckert JR, Kuhn JG, et al: Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14:1128-1135, 1996
10.
Conti JA, Kemeny NE, Salz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996
11.
Rougier P, Bugat R, Douillard JY, et al: Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251-260, 1997 12. Pitot HC, Wender DB, O'Connell MJ, et al: Phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910-2919, 1997[Abstract] 13. Cunningham D, Pyrhönen S, James RD, et al: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:9138 1413-1418, , 1998 14. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998[Medline] 15. Cohen AM, Minsky BD, Schilsky RL: Colon cancer, in Devita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 4). Philadelphia, PA, Lippincott, 1993, pp 929-967
16.
Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330:1136-1142, 1994 17. Nordic Gastrointestinal Tumor Adjuvant Therapy Group: Expectancy or primary chemotherapy in patients with advanced asymptomatic colorectal cancer: A randomized trial. J Clin Oncol 10:904-911, 1992[Abstract] 18. Scheitauer W, Rosen H, Kornek GV, et al: Randomized comparison of combination chemotherapy plus supportive care or supportive care alone in patients with metastatic colorectal cancer. BMJ 306:752-755, 1993
19.
De Gramont A, Bosset JF, Milan C, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: A French intergroup study. J Clin Oncol 15:808-815, 1997
20.
Aranda E, Diaz-Rubio E, Cervantes A, et al: Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous infusion fluorouracil for advanced colorectal cancer: A Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study. Ann Oncol 9:727-731, 1998 21. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group study. J Clin Oncol 13:1303-1311, 1995[Abstract] 22. Ardalan B, Chua L, Tien E, et al: A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma. J Clin Oncol 9:625-630, 1991[Abstract]
23.
Sobrero AF, Aschele C, Bertino Jr: Fluorouracil in colorectal cancer: A tale of two drugs—Implications for biochemical modulation. J Clin Oncol 15:368-381, 1997 24. Hansen R, Quebban E, Ausman R, et al: Continuous systemic 5-fluorouracil infusion in advanced colorectal cancer: Results in 91 patients. J Surg Oncol 40:177-181, 1989[Medline]
25.
Findlay M, Hill A, Cunningham D, et al: Protracted venous infusion 5-fluorouracil and interferon-alpha in advanced and refractory colorectal cancer. Ann Oncol 5:239-243, 1994 26. Jäger E, Klein O, Wächter B, et al: High dose 5-fluorouracil (5-FU) and folinic acid in advanced colorectal cancer resistant to standard dose 5-FU treatment: Results of a phase II study. Eur J Cancer 31A:1717- 1717, 1995 27. Izzo J, Fandi A, Villalobos W, et al: Low-dose protracted continuous 5-fluorouracil infusion in solid tumors. J Infus Chemother 4:135-139, 1994
28.
Weh HJ, Wilke HJ, Dielamm J, et al: Weekly therapy with folinic acid (FA) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma. Ann Oncol 5:233-237, 1994 29. Rothenberg ML, Hainsworth JD, Rosen L, et al: Phase II study of irinotecan (CPT-11) 250 mg/m2 given every other week in previously treated colorectal cancer patients. Proc Am Soc Clin Oncol 17:1092, 1998 (abstr) 30. Miller AB, Hoogstraten B, Staquet M: Reporting results of cancer treatment. Cancer 47:207-214, 1981[Medline] 31. Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13, 210-221, 1995 32. Barilero I, Gandia D, Armand JP, et al: Simultaneous determination of the camptothecin analogue CPT-11 and its active metabolite SN-38 by high-performance liquid chromatography: Application to plasma pharmacokinetic studies in cancer patients J Chromatogr 575:275-80, 1992[Medline] 33. Benhammouda A, Bastian G, Rixe O, et al: A phase I and pharmacokinetic study of CPT-11 and 5 FU combination. Proc Am Soc Clin Oncol 16:202:710, 1997 (abstr) 34. Saltz L, Kanowitz J, Kemeny N, et al: Phase I clinical and pharmacokinetic study of irinotecan, 5FU and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959-2967, 1996[Abstract] 35. Rothenberg ML, Pazdur R, Rowinsky EK, et al: A phase II multicenter of alternating cycles of irinotecan and 5FU/LV in patients with previously untreated metastatic colorectal cancer. Proc Am Soc Clin Oncol 16:944, 1997 (abstr)
36.
Van Cutsem E, Pozzo C, Starkhammar H, et al: A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer. Ann Oncol 9:1199-1204, 1998 37. Sastrey J, Paz-Ares L, Diaz-Rubio E, et al: Phase I dose finding study of irinotecan (CPT-11) over a short IV infusion combined with a fixed dose of fluorouracil (5FU) protracted continuous IV infusion in patients with advanced solid tumors. Eur J Cancer 33:1141, 1997 (suppl 8) (abstr)
38.
Vanhoefer U, Harstrick A, Müller C, et al: Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first line chemotherapy in patients with advanced colorectal cancer. J Clin Oncol 17:907-913, 1999
39.
Chabot GG, Abigerges D, Catimel G, et al: Population pharmacokinetics and pharmacodynamics of irinotecan (CPT-11) and active metabolite SN-38 during phase I trials. Ann Oncol 6:141-151, 1995 Submitted October 26, 1998; accepted May 6, 1999.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
