© 2005 Foundation for Promotion of Cancer Research
Phase II Study of Irinotecan, 5-Fluorouracil and Leucovorin as First-line Therapy for Advanced Colorectal Cancer
Division of Hematology-Oncology. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
For reprints and all correspondence: Young Suk Park, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong Kangnam-Ku, Seoul, 135-710, Korea. E-mail: pys27hmo{at}smc.samsung.co.kr
Received August 20, 2004; accepted February 24, 2005
 |
Abstract |
|---|
 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Background: We evaluated the efficacy and tolerability of a modified biweekly irinotecan, 5-fluorouracil and leucovorin regimen (modified Douillard regimen) as the first-line therapy in patients with advanced colorectal cancer.
Methods: A total of 80 patients (41 male, 39 female) with recurrent or metastatic colorectal cancer were enrolled between April 2001 and December 2003. The treatment cycle consisted of irinotecan 150 mg/m2 as a 90 min infusion on day 1, leucovorin 20 mg/m2 intravenous bolus, immediately followed by a 48 h continuous infusion of 5-fluorouracil 3000 mg/m2 on day 1. The primary end-point was response rate, and the secondary end-points were time to progression and toxicity profile.
Results: An overall objective response rate of 38.7% [95% confidence interval (CI) 27.84–49.66%] was achieved. The median time to progression was 6.1 months (95% CI 4.63–7.57 months) and the median overall survival time was 20.2 months (95% CI 15.50–24.90 months). The median duration of follow-up for patients was 16.9 months. The toxicity profile was more favorable than for the conventional Douillard regimen.
Conclusion: We conclude that the modified Douillard regimen may be a practical and more tolerable treatment option in patients with advanced colorectal cancer.
Key Words: colorectal cancer • chemotherapy • irinotecan • 5-fluorouracil • leucovorin
|
INTRODUCTION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Colorectal cancer accounts for 10–15% of all cancers and is the second leading cause of cancer deaths in Western countries (1) and the fourth most common cancer in Korea (2). Although surgery is potentially curative, about one-third of all newly diagnosed patients present with inoperable metastatic disease. Palliative chemotherapy is more effective than the best supportive care in improving survival as well as the quality of life in advanced colorectal cancer (3). The treatment options for advanced colorectal cancer have been almost exclusively based on 5-fluorouracil (5-FU) and leucovorin (LV) for more than three decades (4–6). However, the overall treatment results remain unsatisfactory. Most recently, combination regimens with irinotecan, 5-FU and LV have produced survival benefits superior to 5-FU and LV. In Europe, irinotecan is most frequently combined with an infusional regimen of 5-FU, whereas in the USA bolus 5-FU has been favored until recently. In both regimens, diarrhea and neutropenia were the most common significant adverse events. To reduce diarrhea and neutropenia, we modified the Douillard regimen, and evaluated the efficacy and tolerability of this regimen as the first-line therapy in advanced colorectal cancer patients.
|
PATIENTS AND METHODS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
ELIGIBILITY CRITERIA
To be eligible, patients had to have histologically documented colorectal cancer and at least one measurable lesion according to the World Health Organization (WHO) response criteria; an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2; and adequate bone marrow, hepatic and renal functions. All patients had to be older than 18 years. Prior chemotherapy or radiotherapy for metastatic disease was not permitted; patients who had received adjuvant chemotherapy or concurrent chemoradiotherapy were eligible if they had remained free of disease for at least 6 months after the completion of adjuvant therapy. Written informed consent was required before the start of the chemotherapy.
TREATMENT REGIMEN
On day 1, irinotecan (150 mg/m2) was infused over 90 min, then LV (20 mg/m2) was administered as an intravenous bolus, immediately followed by 5-FU (3000 mg/m2) given as a continuous 48 h infusion. The regimen was repeated every 2 weeks until disease progression or intolerable toxicity was seen or the patient refused further chemotherapy. Toxicities were recorded before each subsequent course was started and graded according to the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) version 2.0. Any grade 3 or 4 toxic effect resulted in an 20% dose reduction of 5-FU for subsequent cycles. Therapy was delayed in the event of neutrophils <1500/µl, platelets <100 000/µl or persistent diarrhea. Other non-hematological toxicity had to return to at least grade 1 before resuming the next cycle of treatment. Patients were evaluated every 8 weeks (after the completion of four cycles) by computed tomography (CT) scanning for measurable lesions. To prevent nausea and vomiting, a serotonin receptor antagonist was administrated intravenously before chemotherapy and given orally at standard doses after chemotherapy. Atropine was injected subcutaneously before irinotecan administration for the prophylaxis of cholinergic syndrome in all patients. For treatment of delayed diarrhea, loperamide was prescribed after the first loose stool.
RESPONSE AND PROGRESSION CRITERIA
A complete response required that all disease disappeared without new lesions. A partial response required at least a 50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions. Progressive disease required 
25% increase in measurable lesions or appearance of any new measurable or non-measurable lesion. Patients who did not meet the definitions of response or progression were classified as having stable disease. Time to progression (TTP) was calculated from the first day of the chemotherapy of this study to the date of disease progression. Overall survival (OS) was calculated from the first day of the chemotherapy of this study to the date of death or last contact.
|
RESULTS |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
PATIENT CHARACTERISTICS
Eighty patients were enrolled from April 2001 to December 2003. One patient was lost to follow-up, and 79 patients were evaluable for response and toxicity. Patient characteristics are provided in Table 1. The median age was 60 years (range 18–81 years). Fifty-five patients (67.5%) had their primary disease in the colon and 26 (32.5%) in the rectum. Thirty-four patients (42.5%) had received previous adjuvant chemotherapy or chemoradiation therapy. The most common sites of metastasis were liver, lung and lymph nodes.
|
RESPONSE TO THERAPY
Among the eighty patients, five patients (6.3%) attained a complete response, and 26 patients (32.5%) achieved a partial response. The overall response rate was 38.7% [31 patients, 95% confidence interval (CI) 25–47%]. Thirty one patients (38.8%) showed stable disease and 17 patients (21.3%) showed progressive disease. Response rates are summarized in Table 2. A total of 500 courses of chemotherapy were administrated in 80 patients. The median number of cycles was six, ranging from one to 15 cycles. The median follow-up duration was 16.9 months, range 7.9–41.8 months. The median TTP was 6.1 months (95% CI 4.63–7.57 months) and the median OS was 20.2 months (95% CI 15.50–24.90 months).
|
TOXICITY
The incidence of grade 3–4 toxicities is outlined in Table 3. Grade 3–4 leukopenia was observed in 17 patients (21.3%), but there was no significant thrombocytopenia and one patient showed anemia of grade 3. Among the non-hematological adverse events, grade 3–4 nausea and vomiting were frequently observed (18.8 and 10%, respectively). A few patients experienced significant diarrhea (grade 3, only 3.8%; grade 4, none), which was easily manageable with loperamide. Dose reduction was needed in 18 patients (22.5%), and there was no treatment-related death in this study.
|
|
DISCUSSION |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
Irinotecan (CPT-11; 7-ethyl-10-[4(-1-piperidino)-1-piperidino] carbonyloxy camptothecin) is a synthetic derivative of the drug camptothecin that was extracted from the leaves of the Camptotheca accuminata tree. It was developed for clinical use during the 1990s because it was more soluble and less toxic than camptothecin. Irinotecan binds and stabilizes topoisomerase I. The stabilized complex of inhibitor–enzyme–DNA halts advancing replication forks, resulting in double-stranded DNA breaks and, consequently, apoptosis (7). Irinotecan alone has been shown to be active against both chemotherapy-naïve and 5-FU-refractory patients with advanced colorectal cancer. Data from multicenter studies suggested the survival benefit of irinotecan in patients with 5-FU-refractory metastatic cancer of the colon or rectum (8,9). Several phase II studies have shown the survival benefit from the use of irinotecan as a single agent in patients with no prior therapy for advanced colorectal cancer (10,11). Many preclinical studies have been performed to explore the possibility of synergistic interactions between 5-FU and irinotecan, and several of the studies confirmed the synergy of this combination in vitro (11–13). The mechanism of action of irinotecan generally does not manifest cross-resistance with 5-FU when used serially, and the synergistic effect was the rationale for combining irinotecan with 5-FU and LV as a first-line therapy for the disease. Several combination regimens of irinotecan, 5-FU and LV were developed and showed higher rates of tumor regression, progression-free survival and OS without significant toxicity (16–19). In Europe, irinotecan is most frequently combined with an infusional regimen of 5-FU, whereas in the USA bolus 5-FU has been favored until recently. No phase III trials directly compared these two regimens, although some reports suggested the equivalent efficacy of the infusional 5-FU and bolus 5-FU, with a lesser toxicity profile in the infusional 5-FU arm (20). Since the Saltz regimen (5-FU bolus regimen) showed unexpectedly high early death rates, because of gastrointestinal toxicity and thromboembolic events, its safety became the subject of considerable debate (21,22). In our dose-modified study, a biweekly infusional schedule was well tolerated and adverse reactions were relatively less than for the conventional infusional schedule. Gastrointestinal toxicity or other adverse reactions were not fatal and grade 3–4 diarrhea was observed in only three patients (3.8%). This result was perhaps due to the low dose of irinotecan (150 mg/m2). The response rate (38.7%) and median TTP (6.1 months) of our study were slightly lower than those of recent studies (18,19,23–25). Most patients with progressive disease received the second line therapy of oxaliplatin, 5-FU and LV in our study. The median overall survival was 20.2 months, which was comparable with the report of Tournigand et al. (21.5 months) (23). Fifty-nine patients (73.8%) in our study received the second line chemotherapy of oxaliplatin, 5-FU and LV. The long survival of our patients was probably due to good initial performance status and low initial carcinoembryonic antigen (CEA) level. The comparison of the current study and other randomized phase III studies is summarized in Table 4.
|
In conclusion, this phase II study showed that the modified Douillard regimen may be a practical and more tolerable treatment option in patients with advanced colorectal cancer.
|
References |
|---|
|
TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
|---|
1 Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26.
2 Shin HR, Ahn YO, Bae JM, Shin MH, Lee DH, Lee CW, et al. Cancer incidence in Korea. Cancer Res Treat 2002;34:405–8.
3 Glimelius B, Hoffman K, Graf W, Pahlman L, Sjoden PO. Quality of life during chemotherapy in patients with symptomatic advanced colorectal cancer. The Nordic Gastrointestinal Tumor Adjuvant Therapy Group. Cancer 1994;73:556–62.[CrossRef][Web of Science][Medline]
4 Machover D. A comprehensive review of 5-fluorouracil and leucovorin in patients with metastatic colorectal carcinoma. Cancer 1997;80:1179–87.[CrossRef][Web of Science][Medline]
5 Rustum YM, Harstrick A, Cao S, Vanhoefer U, Yin MB, Wilke H, et al. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J Clin Oncol 1997;15:389–400.
6 Meta-analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998;16:301–8.
7 Hsiang YH, Hertzberg R, Hecht S, Liu LF. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985;260:14873–8.
8 Rothenberg ML, Eckardt JR, Kuhn JG, Burris HA 3rd, Nelson J, Hilsenbeck SG, et al. Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 1996;14:1128–35.
9 Von Hoff DD, Rotheberg ML, Pitot HC, Elfring GL, Mohrland JS, Schaaf LJ, 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 1997;16:228a (abstract 803).
10 Conti JA, Kemeny NE, Saltz LB, Huang Y, Tong WP, Chou TC, et al. Irinotecan (CPT-11) is an active agent in untreated patients with metastatic colorectal cancer. J Clin Oncol 1995;14:709–18.
11 Cunningham D, Pyrhönen S, James RD, Punt CJA, Hickish TF, Heikkila R, et al. Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413–8.[CrossRef][Web of Science][Medline]
12 Pitot HC, Wender DB, O'Connell MJ, Schroeder G, Goldberg, Rubin RMJ, et al. A phase II trial of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma. J Clin Oncol 1997;15:2910–9.[Abstract]
13 Mullany S, Svingen PA, Kaufmann SH, Erlichmanet C. Effect of adding the topoisomerase I poison 7-ethyl-10-hydroxycamptothecin (SN-38) to 5-fluorouracil and folinic acid in HCT-8 cells: elevated dTTP pools and enhanced cytotoxicity. Cancer Chemother Pharmacol 1998;42:391–9.[CrossRef][Web of Science][Medline]
14 Guichard S, Hennebelle I, Bugat R, Canal P. Cellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line. Biochem Pharmacol 1998;55:667–76.
15 Mans DR, Grivicich I, Peters GJ, Schwartsmann G. Sequence-dependent growth inhibition and DNA damage formation by the irinotecan–5-fluorouracil combination in human colon carcinoma cell lines. Eur J Cancer 1999;35:1851–61.[CrossRef][Web of Science][Medline]
16 Ducreux M, Ychou M, Seitz JF, Bonnay M, Bexon A, Armand JP, et al. 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 cancer. J Clin Oncol 1999;17:2901–8.
17 Vanhoefer U, Harstrick A, Kohne CH, Achterrath W, Rustum YM, Seeber S, 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 1999;17:907–13.
18 Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–14.
19 Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041–7.[CrossRef][Web of Science][Medline]
20 Benson AB III, Goldberg RM. Optimal use of the combination of irinotecan and 5-fluorouracil. Semin Oncol 2003;30:68–77.[Web of Science][Medline]
21 Rothenberg ML, Meropol NJ, Poplin EA, Van Cutsem E, Wadler S. Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel. J Clin Oncol 2001;19:3801–7.
22 Sargent DJ, Niedzwiecki D, O'Connell MJ, Schilsky RL. Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 2001;345:144–5.
23 Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–37.
24 Koehne CH, Van Cutsem E, Wils JA, Bokemeyer C, El-Serafi M, Lutz M, et al. Irinotecan improves the activity of the AIO regimen in metastatic colorectal cancer: results of EOTC GI Group study 40986. Proc Am Soc Clin Oncol 2003;22:254A.
25 Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||