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© 1999 American Society for Clinical Oncology Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal CancerFrom the Department of Internal Medicine (Cancer Research), West German Cancer Center, University Medical School, Essen, Germany; Department of Hematology and Oncology, Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany; Department of Clinical Research, Oncology-New Technology, Rhône-Poulenc Rorer, Cologne, Germany; and Department of Pharmacology and Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY. Address reprint requests to U. Vanhoefer, MD, Department of Internal Medicine (Cancer Research), West German Cancer Center, University Medical School, Hufelandstr 55, 45122 Essen, Germany
PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.
FOR THE LAST three decades, fluorouracil (5-FU)–based chemotherapy has been the mainstay of treatment in advanced colorectal cancer.1-3 When given alone as an intravenous (IV) bolus once weekly or for 5 consecutive days every 4 to 5 weeks, 5-FU produces response rates from 11% to 17% and a median survival time of approximately 1 year.4-6 Although increased therapeutic efficacy of 5-FU in terms of higher response rates by the biomodulation with leucovorin (LV) has been well established, a meta-analysis of clinical studies failed to demonstrate a clear survival benefit.6,7 Recently, evidence has accumulated that a prolonged infusion of 5-FU may improve the tumor response rate and survival time when compared with 5-FU bolus regimens.8 De Gramont et al9 reported the results of a randomized study involving 448 patients with advanced colorectal cancer and comparing high-dose LV in combination with bolus plus infusional 5-FU to the standard low-dose LV-5-FU bolus schedule given according to the North Central Cancer Treatment Group (NCCTG) regimen. The infusional 5-FU arm yielded a statistically significant higher response rate (348 patients; 32.6% v 14.4%, P = .0004) and an improved progression-free survival time (27.6 v 22.0 weeks, P = .0012). Furthermore, a significant increase in the median survival time was achieved in patients with measurable disease. Additionally, the German Association of Medical Oncology (AIO), in a randomized multicenter trial in metastatic colorectal cancer, demonstrated an overall response rate of 44% and a median survival time of 16 months using a weekly-times-six schedule of high-dose LV (500 mg/m2/2-hour IV infusion) followed by infusional 5-FU (2.6 g/m2 given as a 24-hour IV infusion) (5-FU24h/LV).10 These results again indicate the superiority of LV-modulated infusional 5-FU over LV-5-FU bolus regimens given on a weekly or daily-times-five schedule. In contrast to these data, no significant differences in the overall survival time were found in a multicenter trial of the Southwest Oncology Group, which compared low-dose LV-modulated bolus 5-FU, administered according to the NCCTG regimen, with several 5-FU regimens including single-agent infusional 5-FU24h at a dose of 2.6 g/m2 on a weekly schedule.7 Thus, significant emphasis has been placed on designing more effective 5-FU–based combination protocols. Irinotecan (CPT-11; 7-ethyl-10-[4(-1-piperidino)-1-piperidino]carbonyloxy-camptothecin) is a new semisynthetic derivative of a plant alkaloid, camptothecin, with significant clinical efficacy against colorectal cancer.11,12 CPT-11 (SN 38) appears to exert its cytotoxic mechanism by binding to DNA-associated topoisomerase I, a nuclear enzyme that facilitates DNA replication and transcription by causing single-strand protein-bridged DNA breaks and preventing the enzyme from rejoining the transient DNA breaks. The collision of these drug-stabilized protein-bridged DNA breaks, referred to as cleavable complexes, with moving replication forks leads to cell death during DNA replication.13,14 As first-line chemotherapy in metastatic colorectal cancer, CPT-11 produced a cumulative response rate of 26% (95% confidence interval, 20% to 32%), a median remission duration of 8 to 9 months, and a median survival time of 12 months.15-18 Thus, CPT-11 demonstrates antitumor efficacy comparable to that achievable with LV-modulated 5-FU–based standard regimens. Furthermore, CPT-11 showed considerable antitumor activity in 5-FU–refractory colon cancer, producing response rates of 13% to 23% and a median remission duration of 6 to 8 months.11,19-21 These results suggest that CPT-11 is one of the most active single agents for chemotherapy in colorectal cancer.20-22 On the basis of the promising single-agent activity of CPT-11 in colorectal cancer, different schedules of 5-FU–based regimens (with or without LV) combined with CPT-11 have been evaluated or are currently under investigation.23-26 Preclinical data on human colon tumor cell lines and tumor xenografts suggested additive to synergistic antitumor activity for the combination of both drugs if CPT-11 preceded 5-FU.27-30 Although it was reported earlier that 5-FU may decrease the carboxylesterase-mediated conversion of CPT-11 to its active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin),31 recent data on human hepatic microsomes showed no substantial alterations of the metabolism of CPT-11 to SN-38 by 5-FU.32 Furthermore, no pharmacokinetic interactions between 5-FU and CPT-11 were observed.25 Recently, Saltz et al23 reported the results of an extended phase I study in patients with metastatic colon cancer using a weekly schedule of bolus 5-FU (500 mg/m2) plus low-dose LV (20 mg/m2), together with CPT-11. The maximum-tolerated dose (MTD) for CPT-11 in this combination was 125 mg/m2 given on a weekly-times-four schedule, with neutropenia being the dose-limiting toxicity (DLT). Furthermore, the incidences of grade 3 or higher diarrhea and neutropenia for weekly bolus LV/5-FU regimens are similar to those observed with 5-FU24h/LV, as reported previously33,34; however, the antitumor efficacy of the 5-FU24h/LV regimen appears to be higher.10 Considering the antitumor activity and safety profile of 5-FU24h/LV given on a weekly-times-six schedule10 and the data on weekly bolus LV/5-FU combined with CPT-11, as stated above,23 we designed a phase I trial of 5-FU24h/LV given together with CPT-11 on a weekly schedule as first-line chemotherapy in patients with metastatic colorectal cancer. The concept of this regimen was further supported by preclinical data demonstrating a lack of cross-resistance between CPT-11 and 5-FU based on different molecular mechanisms of cytotoxic action and the potential for synergistic antitumor activity between both drugs in vitro and in vivo.27-30
Eligibility The eligibility criteria were as follows: age between 18 and 70 years; measurable, metastatic colorectal cancer; no prior chemotherapy or radiotherapy for metastatic colorectal cancer; interval between the end of prior adjuvant radiotherapy and/or chemotherapy and study entry at least 6 months; predicted life expectancy at least 3 months; World Health Organization (WHO) performance status 2 or lower; adequate baseline organ functions, defined as neutrophil count at least 2,000/µL, platelet count at least 100,000/µL, hemoglobin at least 10.0 g/dL; serum bilirubin level 1.25 or less times the upper limit and AST and ALT 3 or less times the upper limit of the institutional reference range; serum creatinine 140 µmol/L or less or a creatinine clearance of at least 60 mL/min; no chronic diarrhea or unresolved bowel obstruction; no severe uncontrolled comorbidities or medical conditions (eg, myocardial infarction within the last 12 months); no brain metastases; no concurrent treatment with other commercial or experimental antineoplastic drugs; no second malignancies; and signed informed consent. The trial was initiated after institutional review board approval of both participating centers in July 1996.
Pretreatment Evaluation and Follow-Up
Treatment Plan All patients were instructed that, in the case of diarrhea, they had to take immediately 4 mg of loperamide orally and to continue with a dose of 2 mg every 2 hours for at least 12 hours and up to 12 hours after the last liquid stool occurred, without exceeding a total treatment duration of 48 hours. If diarrhea persisted for more than 24 hours, oral antibiotics (usually ofloxacin) were additionally administered. In the case of diarrhea, mucositis, or myelosuppression of National Cancer Institute common toxicity criteria (NCI-CTC) grade 1 or greater on the day of scheduled treatment, therapy was delayed until full recovery. For patients who experienced diarrhea or mucositis of NCI-CTC grade 3 or higher, the dose of 5-FU was reduced by 20% in the subsequent courses. For hematologic toxicities of grade 3 or higher, a dose reduction of CPT-11 by 20% was prescribed by the protocol. In the case of progressive disease, intolerable toxicity, or a treatment delay for more than 4 weeks between the cycles, the study treatment had to be discontinued. Patients with documented stable disease or objective response continued the study treatment for at least one further cycle.
Dose-Escalation Plan
Toxicity and Response Evaluation Tumor response was assessed by CT scans of the target lesion(s) before each new cycle of chemotherapy (every 4 or 6 weeks) and at the end of treatment. Complete remission, partial remission, no change, and progressive disease were defined according to the standardized response definitions of the WHO. Tumor responses were confirmed by a second evaluation at least 4 weeks later.
From July 1996 to October 1997, 26 patients with measurable metastatic colorectal cancer were entered onto this trial at the Department of Internal Medicine (Cancer Research), West German Cancer Center, University Medical School of Essen (22 patients), and at the Charité, Department of Hematology and Oncology, Robert Rössle Klinik, Humboldt University, Berlin (four patients). The patients' characteristics are listed in Table 1. Fifteen men and 11 women were treated on seven different dose levels (Table  2). The median age of the patients was 60 years (range, 42 to 70 years), and the median WHO performance status was 0 (range, 0 to 2). Twelve patients (46.2%) had prior 5-FU–based adjuvant chemotherapy, and four patients (15.4%) had adjuvant radiotherapy.
Twenty-five of 26 enrolled patients received at least one complete cycle of chemotherapy and were assessable for toxicity and tumor response. One patient experienced angina pectoris after the first administration of 5-FU and was taken off study (dose level 5).
A total of 79 cycles were administered. No DLTs were observed during the first cycle of chemotherapy at dose levels 1 to 6 (Table
With the escalation of CPT-11 to 100 mg/m2 (dose level 7), the MTD was achieved with diarrhea of NCI-CTC grade 3 or higher occurring in four of six patients during the first cycle. In addition, three of the six patients had a declining performance status and showed weight loss of more than 5% of their initial body weight during the first cycle. One patient experienced neutropenia of NCI-CTC grade 2; however, no other hematologic toxicities were observed.
Although tumor response was not the primary objective of this study, significant antitumor activity was seen at all dose levels (Table
The MTD of the investigated weekly schedule of CPT-11, high-dose LV, and infusional 5-FU given according the AIO regimen is as follows: CPT-11 100 mg/m2, LV 500 mg/m2, and 5-FU 2.6 g/m2. The DLT was diarrhea of NCI-CTC grade 3 or higher. Thus, the recommended doses for further clinical studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU 2.6 g/m2 given on a weekly-times-six schedule followed by 1 week of rest. Diarrhea has also been the main side effect at dose levels below the MTD; however, all cases of diarrhea were manageable by intensive loperamide treatment. Other nonhematologic side effects (including alopecia) were mild and did not exceed NCI-CTC grade 2. The incidence of grade 2 vomiting in 64% of patients was not expected but may be related to overlapping toxicity of both 5-FU24h/LV and CPT-11.10,21 However, CPT-11 alone at a dose of 125 mg/m2 given on a weekly-times-four schedule induced vomiting of grade 3 or 4 in 16% of patients.17,19 Furthermore, in the present study, prophylactic antiemetic treatment did not contain dexamethasone, which might have helped to reduce the incidence and severity of emesis. Of importance is the finding that multiple cycles of the investigated regimen did not produce neutropenia exceeding NCI-CTC grade 2. Therefore, the full dose of 5-FU24h/LV could be administered together with CPT-11 given at a similar dose-intensity or 20% less when administered on a weekly-times-four schedule every 6 weeks.17,19,21 These results are in accordance with those recently reported by investigators at the Institut Gustave Roussy, in which a biweekly schedule of CPT-11 in combination with LV-modulated infusional 5-FU given according to the De Gramont regimen was tolerated even at a dose of CPT-11 of 260 mg/m2 every 2 weeks, again with diarrhea being the main side effect.24 However, the recommended dose of CPT-11 given on this biweekly LV/5-FU schedule was 180 mg/m2 every 2 weeks. In contrast to the infusional LV/5-FU regimens, the DLT of a weekly schedule of bolus LV/5-FU in combination with CPT-11 was neutropenia rather than diarrhea, underlining different mechanisms of cytotoxic action of 5-FU when administered either as an IV bolus or as a prolonged IV infusion.23,35
Different schedules of 5-FU–based regimens (with or without LV) combined with CPT-11 have been evaluated or are currently under clinical investigation (Table
Although tumor response was not the primary end point of this study, the overall response rate of 58% (95% confidence interval, 35% to 80%) for patients treated at the dose levels below the MTD demonstrates significant antitumor activity for the investigated regimen. Of importance is that 5-FU24h/LV without CPT-11 produced only 10% objective remissions in patients with prior adjuvant 5-FU–based chemotherapy.10 In the present trial, the tumor response rate was comparable for patients who had been pretreated with 5-FU in an adjuvant setting and patients without prior exposure to chemotherapy. These results may be related to the different mechanisms of cytotoxic action of 5-FU and topoisomerase I interactive agents as well as the fact that infusional 5-FU may still be active in patients with resistance to bolus 5-FU.35,38 However, patient selection (eg, performance status, sites of metastases) may have contributed to the high response rate of the present phase I trial. Thus, further clinical studies will be needed to confirm the antitumor activity of the investigated schedule of 5-FU24h/LV and CPT-11. Despite these limitations, the data reported herein suggest that the addition of CPT-11 to infusional 5-FU, administered according to either the AIO regimen or the De Gramont schedule, may result in higher antitumor activity than that seen for combinations of CPT-11 with LV/5-FU bolus regimens or alternating schedules of CPT-11 and bolus 5-FU, with a manageable toxicity profile.23,24,26,36,37 In conclusion, the present study demonstrates that a weekly schedule of CPT-11 in combination with LV-modulated infusional 5-FU, given according to the AIO regimen, is feasible. Diarrhea was the DLT, whereas no significant hematologic side effects were observed. The addition of CPT-11 to the weekly schedule of 5-FU24h/LV appears to improve the therapeutic efficacy in terms of tumor response rate. Therefore, a randomized trial comparing the investigated regimen of 5-FU24h/LV and CPT-11 with 5-FU24h/LV alone as first-line chemotherapy in metastatic colorectal cancer has been initiated.
Supported by Rhône-Poulenc Rorer, Cologne, Germany
U.V. is recipient of the Bristol-Myers Squibb Young Investigator Award of the American Association for Cancer Research, New Orleans, LA, March 28, 1998. Presented in part at the 34th Annual Meeting of the American Society for Clinical Oncology, Los Angeles, CA, May 16-19, 1998, and at the 89th Annual Meeting of the American Association for Cancer Research, New Orleans, LA, March 28-April 1, 1998.
1. Moertel CG: Chemotherapy for colorectal cancer. N Engl J Med 330:1136-1142, 1994
2.
Rustum YM, Harstrick A, Cao S, et al: Thymidylate synthase inhibitors in cancer therapy: Direct and indirect inhibitors. J Clin Oncol 15:389-400, 1997 3. Machover D: A comprehensive review of 5-fluorouracil and leucovorin in patients with metastatic colorectal carcinoma. Cancer 80:1179-1187, 1997[Medline] 4. Petrelli N, Douglass HO, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase II trial. J Clin Oncol 7:1419-1426, 1989[Abstract] 5. Valone FH, Friedman MA, Wittlinger PS, et al: Treatment of patients with advanced colorectal carcinoma with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil and leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol 7:1427-1436, 1989[Abstract] 6. Advanced Colorectal Cancer Meta-Analysis Project: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. J Clin Oncol 10:896-903, 1992[Abstract] 7. 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]
8.
Meta-Analysis Group in Cancer: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 16:301-308, 1998
9.
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 10. Köhne CH, Schöffski P, Wilke H, et al: Effective biomodulation by leucovorin of high-dose infusion fluorouracil given as a weekly 24-hour infusion: Results of a randomized trial in patients with advanced colorectal cancer. J Clin Oncol 16:418-426, 1998[Abstract]
11.
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
12.
Rothenberg ML: Topoisomerase I inhibitors: Review and update. Ann Oncol 8:837-855, 1997 13. Lavelle F, Bissery MC, André S, et al: Preclinical evaluation of CPT-11 and its active metabolite SN-38. Semin Oncol 23:11-20, 1996 (suppl 3) [Medline] 14. Wiseman LR, Markham A: Irinotecan: A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer. Drugs 52:606-623, 1996[Medline]
15.
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
16.
Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 14:709-715, 1996 17. Pitot HC, Wender DB, O'Connell MJ, et al: A phase II trial of irinotecan in patients with metastatic colorectal carcinoma. J Clin Oncol 15:2910-2919, 1997[Abstract] 18. Irigoyen AL, Firvida JL, Vazquez S, et al: Phase II trial of irinotecan (CPT-11) in patients with not pretreated advanced colorectal cancer. Proc Am Soc Clin Oncol 17:279a, 1998 (abstr)
19.
Rothenberg ML, Eckardt 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 20. Van Cutsem E, Rougier P, Droz JP, et al: Clinical benefit of irinotecan (CPT-11) in metastatic colorectal cancer (CRC) resistant to 5-FU. Proc Am Soc Clin Oncol 16:268a, 1997 (abstr) 21. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irinotecan (CPT-11) therapy for patients with previously treated metastatic colorectal cancer (CRC): Overall results of FDA-reviewed pivotal US clinical trials. Proc Am Soc Clin Oncol 16:228a, 1997 (abstr) 22. Conroy T: Single-agent chemotherapy of colorectal cancer, in Bleiberg H, Rougier P, Wilke H (eds): Management of Colorectal Cancer. London, United Kingdom, Martin Dunitz, 1998, pp 211-220 23. Saltz LB, Kanowitz J, Kemeny NE, et al: Phase I clinical and pharmacokinetic study of irinotecan, fluorouracil, and leucovorin in patients with advanced solid tumors. J Clin Oncol 14:2959-2967, 1996[Abstract] 24. Seitz JF, Ducreux M, Ychou M, et al: Phase I/II study of CPT-11 in combination with LV5FU2 (De Gramont regimen) every 2 weeks for the treatment of colorectal cancer (CRC) after 5-FU failure. 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, the Netherlands, June 16-19, 1998 (abstr 261) 25. Benhammouda A, Bastian G, Rixe O, et al: A phase I and pharmacokinetic (PK) study of CPT-11 (C) and 5-FU (F) combination. Proc Am Soc Clin Oncol 16:202a, 1997 (abstr) 26. Fonseca R, Goldberg RM, Erlichman C, et al: Phase I study of the combination of CPT-11/5-FU and leucovorin (LV). Proc Am Soc Clin Oncol 17:203a, 1998 (abstr) 27. Grivicich I, Mans DRA, da Rocha AB, et al: The cytotoxicity of irinotecan (CPT-11)-5-fluorouracil (5-FU)-combination in human colon carcinoma cell lines is related to the sequence dependent introduction of DNA-lesions. Proc Am Assoc Cancer Res 38:318, 1997 (abstr) 28. Harstrick A, Vanhoefer U, Müller C, et al: Combination of CPT-11 and 5-FU in colorectal cancer: Preclinical rationale and initial phase I results. Proc Am Assoc Cancer Res 38:319, 1997 (abstr) 29. Guichard S, Cussac D, Hennebelle I, et al: Sequence-dependent activity of the irinotecan-5-FU combination in human colon-cancer model HT-29 in vitro and in vivo. Int J Cancer 73:729-734, 1997[Medline] 30. Vanhoefer U, Hapke G, Harstrick A, et al: Schedule-dependent antitumor efficacy of irinotecan and 5-fluorouracil (5-FU) in nude mice bearing colon tumor xenografts that are resistant to 5-FU. 23rd Congress of the European Society for Medical Oncology, Athens, Greece, November 6-10, 1998 (abstr 634)
31.
Sasaki Y, Ohtsu A, Shimada Y, et al: Simultaneous administration of CPT-11 and fluorouracil: Alteration of the pharmacokinetics of CPT-11 and SN-38 in patients with advanced colorectal cancer. J Natl Cancer Inst 86:1096-1098, 1994 (letter) 32. Sams JP, Su P, Slatter JG, et al: In vitro studies on the effect of co-therapy on carboxylesterase-mediated bioactivation of the anticancer agent CPT-11 (U-101440E) to its active metabolite SN-38. Proceedings of the 4th International ISSX Meeting, Seattle, WA, 1995 (abstr 129) 33. Jäger E, Heike M, Bernhard H, et al: Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: Results of a randomized multicenter trial. J Clin Oncol 14:2274-2279, 1996[Abstract]
34.
Weh HJ, Wilke H, Dierlamm J, et al: Weekly therapy with folinic acid (FA) and high dose 5-fluorouracil (5-FU) 24-hour infusion in pretreated patients with metastatic colorectal carcinoma. Ann Oncol 5:233-237, 1994
35.
Aschele C, Sobrero A, Faderan MA, et al: Novel mechanism(s) of resistance to 5-fluorouracil in human colon cancer (HCT-8) sublines following exposure to two different clinically relevant dose schedules. Cancer Res 52:1855-1864, 1992
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. Rothenberg ML, Pazdur R, Rowinsky EK, et al: A phase II multicenter trial of alternating cycles of irinotecan (CPT-11) and 5-FU/LV in patients with previously untreated metastatic colorectal cancer (CRC). Proc Am Soc Clin Oncol 16:266a, 1997 (abstr) 38. 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 31:1717, 1995 Submitted June 18, 1998; accepted November 23, 1998. This article has been cited by other articles:
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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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ABSTRACT
INTRODUCTION
