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© 2003 American Society for Clinical Oncology Phase III Comparison of Two Irinotecan Dosing Regimens in Second-Line Therapy of Metastatic Colorectal Cancer
From the Dana-Farber Cancer Institute, Boston, MA; Georgia Cancer Research Center, Decatur, GA; Intermountain Hematology/Oncology Associates, PC, Salt Lake City, UT; Oncology Radiation Associates, PC, Mercy Hospital, Miami, FL; Louisiana Oncology Associates, Lafayette, LA; and UCLA Medical Center, Los Angeles, CA. Address reprint requests to Charles S. Fuchs, MD, Dana-Farber Cancer Institute, 44 Binney Street, Office Dana 1232, Boston, MA 02115; email: charles_fuchs{at}dfci.harvard.edu.
Purpose: Randomized trials in fluorouracil (FU)-refractory colorectal cancer demonstrate significant survival advantages for patients receiving irinotecan. We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients.
Patients and Methods: This multicenter, open-label, phase III study randomly assigned patients in a 1:2 ratio to irinotecan given either weekly (125 mg/m2) or once every 3 weeks (350 mg/m2, or 300 mg/m2 in patients who were Results: With median follow-up of 15.8 months, there was no significant difference in 1-year survival (46% v 41%, respectively; P = .42), median survival (9.9 v 9.9 months, respectively; P = .43), or median time to progression (4.0 v 3.0 months, respectively; P = .54) between the two regimens. Grade 3/4 diarrhea occurred in 36% of patients treated weekly and in 19% of those treated once every 3 weeks (P = .002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34% of those treated once every 3 weeks (P = .35). Treatment-related mortality occurred in five patients (5.3%) receiving irinotecan weekly and three patients (1.6%) given therapy once every 3 weeks (P = .12). Global quality of life was not statistically different between treatment groups. Conclusion: Irinotecan schedules of weekly and of once every 3 weeks demonstrated similar efficacy and quality of life in patients with FU-refractory, metastatic colorectal cancer. The regimen of once every 3 weeks was associated with a significantly lower incidence of severe diarrhea.
THE CAMPTOTHECIN derivative, irinotecan (CPT-11), is a topoisomerase I inhibitor with single-agent activity in advanced colorectal cancer as well as in other solid tumors.1–3 SN-38, the active metabolite of irinotecan, binds to and stabilizes the topoisomerase I-DNA complex, preventing the religation of DNA during replication and transcription.4 Subsequent collision between this stable complex and an advancing replication fork results in double-stranded DNA breaks and apoptosis. In single-agent phase I and II trials, several irinotecan schedules were evaluated. In North America, Rothenberg et al5 administered the drug as a 90-minute intravenous infusion weekly for 4 consecutive weeks, followed by a 2-week rest period (hereafter known as "weekly"). Diarrhea and neutropenia were the principal toxicities, and the recommended dose for subsequent study was 125 mg/m2. At the same time, investigators in Europe administered the drug once every 3 weeks with intensive loperamide therapy to ameliorate diarrhea.6,7 Neutropenia and diarrhea also were the dose-limiting toxicities, and the recommended phase III dose was 350 mg/m2. In patients with fluorouracil (FU)-refractory colorectal cancer, phase II trials of both irinotecan schedules demonstrated objective response rates of 12% to 15% and median survivals of 8 to 9 months.8–10 Once again, diarrhea and neutropenia were the principal adverse events. Subsequently, two phase III trials demonstrated statistically significant survival advantages for patients randomly assigned to irinotecan compared with patients given either best supportive care or second-line infusional FU.1,3 In both trials, irinotecan was delivered in the every-3-weeks schedule. Although phase II efficacy and safety results with the weekly and every-3-weeks regimens seemed to be equivalent, no formal comparison of these regimens has been performed. We therefore conducted a randomized phase III trial to compare the efficacy, safety, and effect on patient quality of life of these two schedules of irinotecan.
Study Design and Patient Selection This was a multicenter, open-label, randomized study comparing two irinotecan (CPT-11, Camptosar; Pharmacia Corporation, Peapack, NJ) dosing regimens in patients with metastatic colorectal cancer whose disease had recurred or progressed after FU-based therapy. The study was conducted at 29 centers across the United States.
Patients were required to have bidimensionally measurable, histologically proven, metastatic colorectal cancer. Disease progression had to have occurred during or within 6 months after FU-based chemotherapy for metastatic disease or relapse had to have occurred during or within 12 months after adjuvant FU-based chemotherapy. Patients had to be at least 18 years old and ambulatory with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) Patients who had received prior irinotecan or topotecan were excluded. We also excluded individuals who had a seizure disorder, were receiving antiepileptic prophylaxis, or had a history of Gilbert’s syndrome. Also, patients with metastatic involvement of the CNS, a psychiatric disorder that could interfere with treatment compliance, significant concurrent infection, or significant cardiac disease were excluded. This study was performed in accordance with precepts established by the Helsinki Declaration, and the protocol was approved by the institutional review board of each study center. All patients gave written informed consent to participate.
Stratification, Random Assignment, and Treatment Patients were treated with standard regimens of antiemetics, atropine, and intensive loperamide; however, prophylactic use of atropine was not allowed for the first study infusion. Irinotecan dosage was modified based on the intensity of adverse events that occurred in the preceding course, according to product labeling. Treatment continued until the scheduled evaluation at 12 months, disease progression, unacceptable toxicity, patient refusal, or death. In responding patients or those with stable disease, treatment could be extended beyond 12 months at the investigator’s discretion.
Efficacy and Tolerability Assessments
Quality of Life
Study End Points and Statistical Analysis
Survival curves for the randomly assigned population were estimated with the Kaplan-Meier13 method and compared by a two-tailed log-rank test. With a two-sided alpha of 0.05, a power of 0.80, and a dropout rate of
Analysis of all efficacy and quality-of-life end points was by intention to treat. To examine the joint influence of stratification factors and other baseline characteristics on patient outcomes, we conducted Cox regression models or stratified log-rank tests.14 Variables that were considered included PS (0 or 1 v 2), age (< 70 years v Dose-intensity was defined as the amount of irinotecan delivered per unit of time (expressed in mg/m2/wk) over the entire period of therapy for each patient. Dose intensity was calculated as the ratio of the total dose (expressed in mg/m2) actually received by the patient divided by the actual total treatment duration expressed in weeks. The relative dose intensity was calculated as the ratio of the actual delivered dose intensity to the dose intensity planned by the protocol.
The QLQ-C30 was analyzed with the Global Health Status/Quality of Life subscale as the primary end point and the other 14 scales as secondary end points. Quality-of-life variables were compared by univariate and multivariate analyses of variance of values at baseline and during study, of score changes from baseline, and of worst postbaseline scores. Percentages were rounded to the nearest whole number and, as a result, may not add up to 100% in some instances (Table 1
Patients and Treatment A total of 291 patients were enrolled between August 1998 and January 2001. Ninety-five of these patients were randomly assigned to the weekly schedule, and 196 patients to the every-3-weeks schedule. Although efficacy analyses were conducted on an intent-to-treat basis, a total of seven patients, one on the weekly schedule and six on the every-3-weeks regimen, received no irinotecan and were excluded from the tolerability analysis. Individuals did not receive irinotecan because of withdrawal of consent in three patients, discovery of study ineligibility in two patients, withdrawal of an investigator from the study in one patient, and election of surgery instead of chemotherapy in one patient. Among patients in the every-3-weeks group who received treatment (n = 190), 105 patients (55%) were defined by the protocol as compromised (age  70 years, ECOG PS of 2, or prior pelvic irradiation) and began irinotecan at 300 mg/m2. For the overall study population, median follow-up was 15.8 months. Last survival data were accrued in January 2002.
No significant differences in baseline clinical characteristics existed between patients on weekly therapy and those assigned to every-3-weeks treatment (Table 1 Median duration of treatment was 2.8 months (range, 1.4 to 12.5 months) for patients receiving weekly therapy compared with 2.8 months (range, 0.7 to 14.4 months) for those given every-3-weeks treatment (P = .75). The most frequent reasons for treatment discontinuation were progressive disease (67% in the weekly group v 70% in the every-3-weeks group), adverse reactions (15% in the weekly group v 9% in the every-3-weeks group), and treatment refusal (10% in the weekly group v 6% in the every-3-weeks group); no significant differences existed between the study groups in the rate of discontinuation for any of these reasons. The median irinotecan dose intensity administered was 63 mg/m2/wk for the weekly group and 100 mg/m2/wk for the every-3-weeks group (P < .0001). Among the every-3-weeks group, median dose intensity was 96 mg/m2/wk for the subgroup that started on 300 mg/m2 and 114 mg/m2/wk for the subgroup that started on 350 mg/m2 (P < .0001). Median relative irinotecan dose intensities administered were 75% of the dose planned for the weekly arm and 97% of the dose planned for the every-3-weeks arm (P < .0001).
Efficacy
Time to progression was similar between treatment arms (P, log-rank = 0.54). Median time to progression was 4.0 months (95% CI, 2.6 to 5.0 months) for patients who received weekly irinotecan and 3.0 months (95% CI, 2.7 to 4.0 months) for patients who received every-3-weeks therapy (Fig 2  ).
For both overall survival and time to progression, we used stepwise Cox multivariate analysis to examine the joint influence of stratification factors and other predefined baseline clinical characteristics (Table 2 ). Factors adversely influencing survival were ECOG PS of 2, baseline WBC more than 8 x 103/mm3, baseline hemoglobin less than 11 g/dL, and metastatic involvement of more than one organ. When the irinotecan schedule was added to these variables in the model, the effect of the irinotecan regimen remained nonsignificant (P = .93). Factors adversely influencing time to progression were ECOG PS of 2, baseline hemoglobin less than 11 g/dL, and metastatic involvement of the lung plus other organs. When the treatment group was added to these variables in the model of time to progression, the effect of the irinotecan regimen remained nonsignificant (P = .70).
Among patients randomly assigned to every-3-weeks irinotecan, individuals who were 70 years or older, had an ECOG PS of 2, or had had prior pelvic irradiation received a lower starting dose (300 mg/m2), as defined by the protocol. We repeated our analyses after excluding patients who started at 300 mg/m2. Nonetheless, there remained no significant difference in either overall survival (P = .44) or time to progression (P = .37) between the weekly (125 mg/m2) and every-3-weeks (350 mg/m2) schedules.
Tolerability
No other chemotherapy-related toxicity differed significantly between the treatment groups. Grade 3/4 neutropenia and grade 3/4 nausea were somewhat more common in the every-3-weeks group than in the weekly arm, although these differences did not reach statistical significance.
We conducted a stepwise logistic regression analysis to examine the joint influence of stratification factors and other predefined baseline clinical characteristics on the risks of grade 3/4 neutropenia or of grade 3/4 diarrhea (Table 4
Rates of any hospitalization during therapy were similar for both treatment groups (26% for weekly v 30% for every 3 weeks; P = .55). Median duration of hospitalization also was similar between the two regimens (11 v 9 days, respectively; P = .92). During treatment, five patients (5.3%) receiving weekly and three patients (1.6%) given every-3-weeks therapy died of causes considered by the investigator to be possibly related to the study drug (P = .12). Of the five deaths on the weekly arm, three were attributable to a combination of diarrhea, neutropenia, and probable sepsis; one to aspiration pneumonia; and one to unknown causes. Of the three deaths on the every-3-weeks arm, two were attributable to a combination of diarrhea, neutropenia, and probable sepsis, and one was classified as sudden death.
A significantly higher proportion of patients on the weekly schedule (61%) than on the every-3-weeks schedule (41%) required dose reduction (P < .0001). We examined the proportion of patients who received full doses of irinotecan during the first 4 weeks of therapy (Fig 3
Quality of Life The global rates of compliance with the quality-of-life questionnaires were similar in the two treatment arms: 81% in the weekly group and 86% in the every-3-weeks group (P = .11). Analyses of mean changes from baseline in the scores on the Global Health Status/Quality of Life subscale of the quality-of-life questionnaire demonstrated no significant differences between patients given irinotecan in the weekly or every-3-weeks schedules (Fig 4 ). Univariate and multivariate analyses of variance revealed no significant difference between the dosage arms in quality-of-life scores at baseline or during the study, or in worst postbaseline scores, in any of the EORTC QLQ-C30 symptoms, or in item or function scales.
This prospective, randomized, multicenter trial provides comparative data on the efficacy, tolerability, and effect on patient quality of life between the weekly versus the every-3-weeks schedules of irinotecan in 291 patients with FU-refractory colorectal cancer. The study found no significant differences in efficacy between the schedules in this population. Both schedules offered similar survival and time to tumor progression. The study was statistically powered to detect a 15% difference in 1-year survival; a smaller difference is unlikely to be clinically meaningful in the second-line treatment of colorectal cancer. Toxicity patterns of the two schedules were somewhat distinctive. Severe (grade 3/4) diarrhea was significantly more common with the weekly schedule than with the every-3-weeks regimen. In contrast, grade 3/4 neutropenia was slightly more frequent in the every-3-weeks group, although this difference was not statistically significant. However, the rates of fever with neutropenia were virtually identical between the two treatment schedules, and the rates of hospitalization did not differ between the groups. Acute cholinergic symptoms during the first dose of irinotecan were significantly more common with the every-3-weeks schedule, presumably as a result of the higher dose of drug administered. Nonetheless, this toxicity can be abrogated by the administration of prophylactic atropine, which was not permitted during the first dose in this study. Severe (grade 3/4) nausea was relatively uncommon in our patients, although the rate of severe nausea was marginally higher with the every-3-weeks regimen. Despite the apparent disparities in toxicity, quality-of-life scores did not differ significantly between the two irinotecan dosage groups. A higher treatment-related mortality rate was noted among patients receiving weekly irinotecan (5.3%) than among those given the every-3-weeks schedule (1.6%), although this difference was not statistically significant. In the weekly group, at least three of five treatment-related deaths were caused by diarrhea and dehydration. Although the event rate in the weekly irinotecan group appears high, early experience with the weekly (Roswell Park) schedule of FU and high-dose leucovorin indicated a 6.4% mortality rate attributable to severe diarrhea and dehydration.15 Clearly, patients treated with weekly irinotecan require close monitoring, rapid institution of antidiarrheal therapy, and administration of parenteral fluids should significant diarrhea persist.
Patients enrolled onto this study appear to be representative of the general population of patients with colorectal cancer who receive second-line irinotecan.1,3,5,9,10 The median survival ( During the conduct of this study, two randomized trials reported that the combination of irinotecan with FU and leucovorin prolonged survival in patients with previously untreated metastatic colorectal cancer.16,17 The schedules used in those trials differ considerably; whereas Saltz et al17 delivered bolus FU, leucovorin, and irinotecan weekly for 4 weeks every 6 weeks, Douillard et al16 principally delivered higher doses of irinotecan with infusional FU and leucovorin every 2 weeks. Of note, the rate of grade 3/4 diarrhea was 23% for the weekly three-drug combination compared with 13% for the every-2-weeks schedule of Douillard et al. Although no formal comparison of the weekly and every 2-weeks schedules of irinotecan, FU, and leucovorin has been reported, these findings are consistent with the higher rate of grade 3/4 diarrhea observed with weekly irinotecan alone in our trial. Such observations could suggest that regimens using less frequent irinotecan dosing may be associated with less severe treatment-related diarrhea. As an additional consideration, future studies may examine whether weekly schedules that deliver irinotecan for 2 consecutive weeks followed by a 1-week rest, rather than for 4 consecutive weeks followed by a 2-week rest, could offer a means for improving patient tolerability.
The following investigators participated in the study: F. Ahmed, MD, HemOnc Care, Brooklyn, NY; N. Anderson, MD, Cancer Center of Boston, Boston, MA; R. Carroll, MD, Maine Center for Cancer Medicine, Scarborough, ME; L. Drinkard, MD, Arlington Cancer Center, Arlington, TX; P. Gilman, MD, The Lakenau Hospital, Cancer Treatment Center, Wynnewood, PA; R. Gousse, MD, Florida Hematology and Oncology Specialists, Alamonte Springs, FL; D. Headley, MD, The Oncology Clinic PC, Colorado Springs, CO; L. Holt, MD, Coastal Cancer Center, Myrtle Beach, SC; B. Kim, MD, Florida Cancer Specialists, Fort Myers, FL; J. Kugler, MD, Oncology Hematology Associates of Central Illinois, Peoria, IL; R. Lemon, MD, The Desert Hospital, Comprehensive Cancer Center, Palm Springs, CA; W. Lipera, MD, North Shore Oncology, East Setauket, NY; S. Malamud, MD, Continuum-Clinical Studies, Beth Israel Medical Center, New York, NY; M. Mession, MD, Cancer Care of West North Carolina, Asheville, NC; T. O’Rourke, MD, Cancer &Hematology Center of WMichigan, Grand Rapids, MI; G. Sarna, MD, The Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA; F. Schnell, MD, Central Georgia Hematology Oncology, Macon, GA; S. Shambaugh, MD, Comprehensive Blood &Cancer Center, Bakersfield, CA; T. Terjanian, MD, Staten Island University Hospital, Staten Island, NY; S. Watkins, MD, Annapolis Medical Specialists, Annapolis, MD; S. Williamson, MD., The University of Kansas Cancer Center, Kansas City, KS; S. Yandel, MD, Clinical Studies, Melbourne, Melbourne, FL;and K.-Y. Yeung, MD, Oncology Hematology Associates, Clinton, MD.
We acknowledge the contributions of the patients, our fellow investigators, the nurses and other caregivers in this study, and James P. McGovren, PhD, Ambrose Kwok, MSc, and Robert Marlowe, BA.
Supported by Pharmacia Corporation, Peapack, NJ.
1. Cunningham D, Pyrhönen S, James RD: Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 352:1413–1418, 1998[CrossRef][Medline] 2. Rosen LS: Irinotecan in lymphoma, leukemia, and breast, pancreatic, ovarian, and small-cell lung cancers. Oncology (Huntingt) 12:S103–S109, 1998 (suppl 6)[CrossRef] 3. 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[CrossRef][Medline] 4. Pommier Y, Tanizawa A, Kohn KW: Mechanisms of topoisomerase I inhibition by anticancer drugs, in Liu LF (ed): Advances in Pharmacology. New York, NY, Academic Press, 1994, pp 73–92
5. 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
6. Abigerges D, Armand JP, Chabot GG, et al: Irinotecan (CPT 11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 86:446–449, 1994
7. Catimel G, Chabot GG, Guastalla JP, et al: Phase I and pharmacokinetic study of irinotecan (CPT 11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors. Ann Oncol 6:133–140, 1995
8. Armand JP, Abigerges D, Chabot GG, et al: High dose intensity of CPT-11 administered as single dose every 3 weeks: The Institut Gustave Roussy experience. Ann Oncol 5:189, 1994 (suppl 5, abstr) 9. 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] 10. Rothenberg ML, Cox JV, De Vore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786–795, 1999[CrossRef][Medline] 11. National Cancer Institute: Guidelines for the Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1999, pp 1–80
12. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365–376, 1993 13. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 14. Lininger L, Gail M, Green S, et al: Comparison of four tests for quality of survival curves in the presence of stratification and censoring. Biometrika 3:419–428, 1979[CrossRef]
15. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 5:1559–1565, 1987 16. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041–1047, 2000[CrossRef][Medline]
17. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914, 2000 Submitted August 8, 2002; accepted November 14, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2. The study included only patients with a life expectancy of at least 12 weeks and adequate hematologic reserve and hepatic and renal function, documented by WBC 
10 months) in this study appears comparable to the findings in other phase II and III trials of irinotecan in similar populations.
