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Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3023-3031 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.005 A Randomized Trial Comparing Defined-Duration With Continuous Irinotecan Until Disease Progression in Fluoropyrimidine and Thymidylate Synthase Inhibitor—Resistant Advanced Colorectal CancerFrom the Royal Marsden Hospital, London and Surrey; St Luke's Oncology Centre, Guildford; Kent Oncology Centre, Maidstone, United Kingdom Address reprint requests to David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey, United Kingdom SM2 5PT; e-mail: david.cunningham{at}icr.ac.uk
PURPOSE: Irinotecan given until disease progression is an accepted standard treatment for advanced colorectal cancer (CRC) resistant to fluoropyrimidines. It is not known whether a predefined period of irinotecan treatment would result in similar duration of disease control. We performed a multicenter phase III trial to compare the two policies of defined-duration versus continuous irinotecan treatment. PATIENTS AND METHODS: Three hundred thirty-three eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered. After receiving eight cycles of irinotecan given at 350 mg/m2 once every 3 weeks, 55 patients with responding or stable disease were randomly assigned to stop irinotecan (n = 30) or continue until disease progression (n = 25). Registered patients were not randomly assigned predominantly due to disease progression (n = 236) and intolerable toxicity (n = 38). RESULTS: From the time of random assignment, there were no differences in failure-free survival (P = .999) or overall survival (P = .11) between the two arms. No difference was seen in mean global health status quality-of-life score between the two arms at 12 weeks after random assignment. No grade 3 diarrhea and febrile neutropenia was seen in the continue-irinotecan arm after random assignment. CONCLUSION: For most patients, the decision to continue on irinotecan beyond 24 weeks is influenced by disease progression or treatment-related toxicity. However, for 17% of patients in whom this decision is clinically relevant, there seems to be little benefit from continuing irinotecan, though the drug was well tolerated without any deterioration in quality of life.
In advanced colorectal cancer (CRC), patients with access to fluoropyrimidines, irinotecan, and oxaliplatin can achieve a median survival of 18 to 22 months.1,2 The role of irinotecan was first established in patients with fluoropyrimidine-refractory CRC, with two randomized studies demonstrating survival benefit over best supportive care3 or alternative continuous infusion of fluorouracil (FU)4 in this group of patients. In both studies, irinotecan was given until disease progression. Subsequently, the combination of irinotecan with FU and leucovorin (LV) produced superior survival compared with FU/LV in a first-line setting,5,6 and led to irinotecan becoming the standard of care in first-line treatment of metastatic CRC. In addition, oxaliplatin/infused FU/LV (FOLFOX) has recently been shown to have a survival advantage over irinotecan/bolus FU/LV (IFL),1 and similar efficacy to irinotecan/infused FU/LV (FOLFIRI).2 Oxaliplatin combination has therefore also become standard of care in the first-line setting. Whereas the issue of treatment duration has been addressed in many adjuvant studies in CRC,7-9 only one randomized study evaluated two policies of a defined treatment period of 12 weeks, compared with treatment until disease progression in patients receiving first-line treatment.10 No studies have evaluated whether continuous treatment with irinotecan until disease progression is superior to a defined period of treatment in the second-line setting in terms of survival or quality of life (QoL). In this prospective study, we compared the two policies of continuous treatment until disease progression, with a defined duration of eight cycles of irinotecan monotherapy, given every 3 weeks.
This phase III multicenter prospective randomized controlled trial recruited patients from six oncology centers in the United Kingdom. The eligibility criteria included: locally advanced or metastatic histologically proven CRC that progressed on or within 24 weeks of FU, raltitrexed, or oral fluoropyrimidine–based chemotherapy; WHO performance status (PS)  2; bidimensionally measurable disease assessed by chest x-ray or computed tomography (CT) scan; and satisfactory hematological, renal, and liver functions. Patients who had received previous adjuvant chemotherapy and up to a maximum of three lines of palliative chemotherapy, as well as those with no measurable disease, were permitted into the study. The protocol was approved by the Scientific and Research Ethics Committee of the participating institutions as well as the London Multicenter Research Ethics Committee. Written informed consent was obtained from each patient at registration. Details of all eligible patients were forwarded to the trial office based at the Royal Marsden Hospital (Surrey, UK) to verify eligibility criteria and were prospectively registered for the trial. Patients who achieved a radiological objective response or disease stabilization after 24 weeks of irinotecan were then randomly assigned by an independent randomization office to either stop irinotecan or continue irinotecan in a 1:1 basis using random permuted blocks. Patients were stratified according to number of previous lines of treatment. Patients, who did not have measurable disease on entry into the study, were eligible for random assignment if no objective disease progression was observed after 24 weeks of irinotecan. Before treatment, the serum carcinoembryonic antigen level was measured, in addition to laboratory testing for hematological and biochemical profile. Baseline QoL assessment was made using the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 (EORTC QLQc30).
Patients were treated with irinotecan 350 mg/m2 intravenously over 30 minutes every 3 weeks for eight cycles. No reduced starting dose was recommended in the protocol for patients aged Toxicity was measured using the National Cancer Institute Common Toxicity Criteria version 2.11 Delayed diarrhea was managed with loperamide and prophylactic ciprofloxacin as per unit guideline. A dose reduction of irinotecan to 300 mg/m2 in subsequent courses was made if patients developed grade 3 or 4 diarrhea, grade 4 neutropenia, or grade 3 febrile neutropenia. A second dose reduction to 250 mg/m2 was recommended with the recurrence of these toxicities. Patients were withdrawn from the study if significant toxicity occurred at a dose level of 250 mg/m2. Dose delay for up to 2 weeks was recommended in cases of absolute neutrophil count less than 1.5 x 109/L, platelet less than 100 x 109/L on the day of treatment, or grades 2 to 3 renal and liver dysfunction during treatment.
Radiological assessments with CT scan were made after every four cycles of irinotecan. Radiological tumor response was evaluated according to WHO criteria.12 Complete response (CR) was defined as the complete disappearance of all measurable lesions, without the appearance of new lesion(s). Partial response was defined as a reduction of bidimensional lesions by
The primary end point was failure-free survival (FFS) from time of random assignment (ie, after eight cycles of irinotecan). One hundred twelve patients (56 in each arm) were required to detect a 25% difference (from 25% to 50%) in 6-month FFS following random assignment with 80% power and a 2-sided Secondary end points included QoL, overall survival (OS), and adverse events after random assignment. FFS was calculated from the date of random assignment until PD, relapse, or death from any cause. OS from registration or random assignment was calculated from the date of registration or random assignment until death from any cause or censored at last follow-up respectively. Both FFS and OS were estimated using the Kaplan-Meier method13 and were compared between the two arms using the log-rank test.14 Hazard ratios for the stop-irinotecan arm were set at 1. All analyses were performed on an intention-to-treat basis. Analyses were performed using SPSS package version 12 (SPSS Inc, Chicago, IL).
Between November 1997 and September 2002, 333 patients were prospectively registered into this study. Figure 1 shows the trial profile. Two patients were ineligible because of previous carcinoma of the prostate (n = 1) and elevated bilirubin (n = 1). Five patients were commenced with a reduced dose of 300 mg/m2 and were considered to be protocol violations, but they were included in the intention-to-treat analysis. Two hundred thirty-six patients (71%) developed PD, and 38 (11%) withdrew because of intolerable toxicity. Of the remaining 57 patients (17.1%) with responding or SD who were eligible, two refused to be randomly assigned; thus 55 patients were randomly allocated to stop irinotecan (n = 30) or continue irinotecan (n = 25).
Table 1 presents the baseline characteristics at registration for the whole group as well as those who were randomly assigned. Baseline demographics were balanced between the two treatment arms. The majority of the randomly assigned patients were still of PS 0 or 1 after eight cycles of irinotecan. Only one patient and two patients were of PS 2 at random assignment in the stop-irinotecan and continue-irinotecan arms, respectively. However, more patients had two or three organs involved by metastatic disease in the continue irinotecan arm. For 79% of all patients, trial treatment was their second-line treatment, whereas for 18%, it was their third-line therapy.
Table 2 presents the status of patients and outcome events after the first four and eight cycles of irinotecan before random assignment. Of 333 patients registered in the study, 153 (45.9%) developed PD during the first four cycles of treatment, and in total, 236 patients (70.9%) progressed after eight cycles. Twenty-nine patients withdrew from the study during the first four cycles due to intolerable toxicity, and another nine patients did so at the end of eight cycles.
Table 3 presents the objective tumor response during the first eight cycles of irinotecan. The overall response rate for the whole cohort was only 9% (95% CI, 6.2% to 12.6%). Thirty patients, including eight patients who achieved an objective response, were randomly assigned to stop irinotecan. One patient with lung metastases at registration had a CR during the first eight cycles of treatment and remains in CR. Fifteen patients in the stop-irinotecan arm had further chemotherapy on PD. Eight of these patients were rechallenged with irinotecan. The other seven patients received oxaliplatin or mitomycin C–containing regimens, usually due to short progression-free interval. It was not possible to treat 14 of 29 patients in the stop-irinotecan arm with PD due to deterioration of PS.
Twenty-five patients, including six objective responses, were randomly assigned to continue irinotecan. Two patients developed PD following random assignment before receiving any further irinotecan, and were included in analyses on an intention-to-treat basis. One hundred thirty-six further cycles of irinotecan were given to this group of patients. The median additional cycles delivered was four (range, one to 12 cycles). The total irinotecan dosage per cycle prescribed to patients after random assignment was 88% of the recommended total irinotecan dose (350 mg/m2) per cycle. There were no further responses after random assignment. Figure 2 shows the FFS for the randomly assigned patients. There were no significant differences in FFS between the two arms (hazard ratio, 1.01; 95% CI, 0.57 to 1.78; log-rank P = .999). Six-month FFS rates were 25.3% (95% CI, 11.2 to 42.2%) for stop irinotecan, and 36.4% (95% CI, 17.4 to 55.7%) for continue-irinotecan arm. At 6 months, the point difference in FFS was not significant (P = .377). Median FFS was 3.2 months (95% CI, 2.7 to 3.8) and 4.9 months (95% CI: 3.9-5.9) for stop- and continue-irinotecan arms, respectively.
Figure 3 shows the OS for the randomly assigned patients. Forty-three patients (78%) had died. There was no significant difference in OS between the two arms (hazard ratio, 1.63; 95% CI, 0.88 to 3.02; P = .109). One-year survival rates were 54.8% (95%CI, 34.2 to 71.4%) for the stop-irinotecan arm and 46.3% (95%CI, 25.1 to 65.1%) for the continue-irinotecan arm. The median survival from random assignment was 13.4 months for the stop-irinotecan arm and 12.1 months for the continue-irinotecan arm. From the time of registration, the median survival was 19 months for the stop-irinotecan arm and 17.7 months for the continue-irinotecan arm. Figure 4 shows the FFS and OS for the whole cohort of 333 patients. The median and 1-year FFS was 3.6 months and 7.7% (95% CI, 5.1% to 11.1%), respectively. The median and 1-year OS was 9.3 months and 35.6% (95% CI, 30.1 to 42.2%).
Table 4 presents the mean scores and standard deviations of QoL scores assessed at random assignment and 12 weeks after random assignment. The number of questionnaires returned was small, but there were no differences in QoL between the two arms. Table 5 shows the incidences of grade 3 or 4 toxicities occurring after random assignment. Serious adverse events were infrequent in both arms. In the continue-irinotecan arm, no patients developed grade 3 diarrhea, febrile neutropenia, or infection after random assignment. Grade 3 neutropenia occurred in two patients only. All the grade 3 or 4 hematological toxicities seen in the stop-irinotecan arm were due to subsequent chemotherapy treatment on PD.
In this article, we report that administering irinotecan for a defined duration of 24 weeks did not influence outcome compared with continuous therapy in patients with fluoropyrimidine-refractory advanced CRC. However, continuing irinotecan beyond 24 weeks did not lead to any clinically important incidences of serious adverse events, and QoL was not compromised by continuing on treatment.
Only 17% of our patients still had responding or SD after eight cycles of irinotecan—much lower than our original anticipation of 50%. This study was designed in 1997 before the results of the two pivotal studies of irinotecan in second-line treatment were known.3,4 Indeed, in these two studies, irinotecan was given for a median of 4.1 and 4.2 months.3,4 Fifty-five percent of our patients already stopped treatment after four cycles (3 months), predominantly due to disease progression. Thus our question of whether continuous treatment would lead to prolonged disease control compared with a defined duration of eight cycles was only relevant to a small proportion of patients. Our study was therefore closed early and was underpowered to show a clinically relevant survival difference between the two treatment arms. In fact, based on the actual proportion of patients who were eligible to be randomly assigned, close to 660 patients would be required to register on the study for our original sample size of 112 randomly assigned patients. Due to the prolonged period of recruitment and the inability to randomly assign 112 patients in a reasonable timeframe, the principal investigator, in conjunction with other participating centers, decided to close the study in May 2003, after 348 patients were registered. No further patients underwent random assignment. Based on 55 patients randomly assigned, a 40% difference in 6-month FFS (from 25% to 65%) could be detected with 81% power (2-sided Although the optimal duration of adjuvant chemotherapy has been addressed in colon cancer,7-9 randomized data are lacking in advanced CRC comparing the two strategies of continuous treatment until disease progression or defined treatment duration. Whereas an early study in breast cancer suggested that continuous chemotherapy resulted in longer time to disease progression, longer survival, and better QoL compared with intermittent therapy,15 more recent data in patients with non–small-cell lung cancer and breast cancer suggested no additional clinical benefit in terms of survival, QoL, and symptomatic response with prolonged treatment.16-21 The United Kingdom Medical Research Council (MRC) published a randomized study comparing intermittent and continuous palliative first-line chemotherapy for 354 patients with advanced CRC.10 In this study, patients received either infused FU/LV (LVFU2) as described by de Gramont et al,22 or protracted venous infusion FU or raltitrexed for 3 months only. Those who achieved tumor response or disease stabilization were then randomly assigned between the two treatment strategies (intermittent v continuous). No survival difference was found between the two treatment strategies, though intermittent therapy was associated with reduced toxicity. The median time to rechallenge was 4.3 months after stopping first-line chemotherapy. During rechallenge, an objective response rate of 21% was obtained, with a median survival of 10.8 months and 1-year survival of 46%. Notably, despite being a principal intention of the trial, only 66 patients (37%) randomly assigned to the intermittent group were rechallenged with the same first-line chemotherapy. To our knowledge, our study is the first evaluating the duration of second-line treatment in advanced CRC. Patients recruited into our study were representative of patients with CRC who received second-line treatment,4,23 though patients with PS 0 or 1 and solitary site of metastases in our study seemed to be fewer than in other published studies.3 The whole group's median survival of 9 months seemed to be similar to other published studies.3,4,23,24 However, the survival of randomized patients was exceptionally good (median survival of 17 to 19 months from registration). This reflects that this group of patients, who had responding or SD after 24 weeks of second-line irinotecan, was prognostically much more favorable than the average patient receiving second-line treatment. Notably, this group of patients only comprised 17% of the whole group. Despite that, the median FFS was only 3 to 4 months after random assignment, suggesting that chemoresistance was probably already emerging at the time of random assignment. Indeed no objective responses were observed with continuing irinotecan after random assignment. Only eight patients (27%) in the stop irinotecan group could be rechallenged with irinotecan on disease progression, and nearly half of the patients could not receive further treatment due to rapid deterioration of their PS. Our protocol required patients in the stop-irinotecan arm to be reviewed in clinic 3 months after random assignment without any specific repeat imaging assessment, and this period might be too long. An earlier clinic visit with imaging assessment may allow disease progression to be detected in a more timely fashion, thus allowing more patients to receive further anticancer treatment. Aside from the previously mentioned MRC study, three other studies have evaluated the value of rechallenge in the first-line setting. One study reported on 49 patients who were reinduced with same dose and schedule of FU and LV on disease progression after completing a 6-month course of first-line FU and LV in a randomized trial of 248 patients comparing two isomers of LV.25 The median time to rechallenge was 5.4 months after stopping first-line chemotherapy. During rechallenge, an objective response rate of 18% was obtained with a median OS of 8.9 months. Another study assessed FU rechallenge in 613 patients recruited within three consecutive randomized studies. Ninety-three patients were rechallenged, with a response rate of 17% and a median survival of 14.8 months.26 More recently, the OPTIMOX study reported on 623 patients randomly assigned to FOLFOX4 given till disease progression or FOLFOX7 given for 12 weeks followed by LVFU2 for 24 weeks, and then reintroduced FOLFOX7 for 12 weeks or earlier in case of progression on LVFU2 in patients having responsive or SD at the first FOLFOX7 administration. This study aimed to decrease the neurotoxicity associated with FOLFOX and to allow FOLFOX rechallenge. The response rates and time to disease control was similar in both arms, but less neurotoxicity was seen in the intermittent FOLFOX7 arm.27 However, the role of irinotecan rechallenge has been highlighted by the recent introduction of cetuximab, a monoclonal antibody against epidermal growth factor receptor. In a randomized study, patients with epidermal growth factor receptor–expressing metastatic CRC who progressed on or within 3 months of irinotecan were randomly allocated to either combination of cetuximab and irinotecan at the same dose and schedule or cetuximab monotherapy.28 The combination produced an overall response rate of 22.9% and median time to progression of 4.1 months, which were both statistically significantly better than cetuximab monotherapy. This study demonstrated that cetuximab could circumvent chemotherapy resistance allowing irinotecan rechallenge. After four cycles of irinotecan, only nine patients withdrew from our study due to intolerable toxicity, and for those randomly assigned to continuous treatment, serious adverse events were infrequent after eight cycles. No patients developed grades 3/4 diarrhea, febrile neutropenia, or infection in the continue-irinotecan arm. Indeed two patients in the continue-irinotecan arm proceeded to receive an additional 12 cycles of treatment. Our data suggest that patients who tolerate irinotecan with appropriate dose modification beyond the first four cycles are unlikely to experience further dose-limiting toxicity, and the incidence of late intolerable adverse events is low. There were no differences in QoL in all functional domains and symptom scales between the two arms at 12 weeks after random assignment. The small number of patients randomly assigned and the low number of questionnaires returned 12 weeks after random assignment precluded smaller subtle differences in QoL to be detected and firm conclusions to be made, though our data showed that QoL was maintained with continuous treatment. In conclusion, the decision to continue irinotecan beyond eight cycles in patients with fluoropyrimidine-resistant metastatic CRC is relevant in only a small proportion (17%) of patients. There were no improvements in FFS from continuing irinotecan beyond eight cycles. However, for patients randomly assigned to continue irinotecan, there was no deterioration in QoL, and treatment was well tolerated. Although no OS benefit was demonstrated from continuing irinotecan, small but clinically important differences may exist.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: David Cunningham, Aventis. Received more than $2,000 a year from a company for either of the last 2 years: David Cunningham, Aventis.
We thank all patients, their families and other investigators who took part in the study: N. Hodson (East Sussex Hospital, Brighton), F. Lofts (St George's Hospital, London), D. Pickering (Kent Oncology Centre, Maidstone), N. Stuart (Ysbyty Gwynedd Hospital, Bangor), J. Summers (Kent Oncology Centre, Maidstone).
Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Goldberg RM, Sargent DJ, Morton RF, 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 22:23-30, 2004
2. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22:229-237, 2004 3. Cunningham D, Pyrhonen 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 352:1413-1418, 1998[CrossRef][Medline] 4. 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] 5. 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]
6. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343:905-914, 2000
7. Andre T, Colin P, Louvet C, et al: Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: Results of a randomized trial. J Clin Oncol 21:2896-2903, 2003
8. O'Connell MJ, Laurie JA, Kahn M, et al: Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 16:295-300, 1998 9. Saini A, Norman AR, Cunningham D, et al: Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer. Br J Cancer 88:1859-1865, 2003[CrossRef][Medline] 10. Maughan TS, James RD, Kerr DJ, et al: Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: A multicentre randomised trial. Lancet 361:457-464, 2003[CrossRef][Medline] 11. National Cancer Institute: National Cancer Institute–Common Toxicity Criteria. Bethesda, MD, National Cancer Institute, 1998 12. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 13. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 14. Peto R, Peto J: Asymptotically efficient invariant procedures. J R Stat Soc A 135:185-206, 1972 15. Coates A, Gebski V, Bishop JF, et al: Improving the quality of life during chemotherapy for advanced breast cancer: A comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490-1495, 1987[Abstract]
16. Smith IE, O'Brien ME, Talbot DC, et al: Duration of chemotherapy in advanced non-small-cell lung cancer: A randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 19:1336-1343, 2001 17. Gregory RK, Powles TJ, Chang JC, et al: A randomised trial of six versus twelve courses of chemotherapy in metastatic carcinoma of the breast. Eur J Cancer 33:2194-2197, 1997 18. Muss HB, Case LD, Richards F, et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer: The Piedmont Oncology Association. N Engl J Med 325:1342-1348, 1991[Abstract]
19. Epirubicin-based chemotherapy in metastatic breast cancer patients: Role of dose-intensity and duration of treatment. J Clin Oncol 18:3115-3124, 2000 20. Harris AL, Cantwell BM, Carmichael J, et al: Comparison of short-term and continuous chemotherapy (mitozantrone) for advanced breast cancer. Lancet 335:186-190, 1990[CrossRef][Medline]
21. Socinski MA, Schell MJ, Peterman A, et al: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 20:1335-1343, 2002
22. 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
23. Fuchs CS, Moore MR, Harker G, et al: Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807-814, 2003 24. Tsavaris N, Ziras N, Kosmas C, et al: Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination: A randomized study. Cancer Chemother Pharmacol 52:514-519, 2003[CrossRef][Medline] 25. Hejna M, Kornek GV, Raderer M, et al: Reinduction therapy with the same cytostatic regimen in patients with advanced colorectal cancer. Br J Cancer 78:760-764, 1998[Medline] 26. Yeoh C, Chau I, Cunningham D, et al: Impact of 5-fluorouracil rechallenge on subsequent response and survival in advanced colorectal cancer: Pooled analysis from three consecutive randomized controlled trials. Clin Colorectal Cancer 3:102-107, 2003[Medline] 27. Andre T, Figer A, Cervantes A, et al: FOLFOX7 compared to FOLFOX 4: Preliminary results of the randomized OPTIMOX study. Proc Am Soc Clin Oncol 22:253, 2003 (abstr 1016) 28. Cunningham D, Humblet Y, Siena S, et al: A randomized comparison of cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med (in press) Submitted January 6, 2004; accepted May 10, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 years, those with WHO PS 2, or patients receiving previous pelvic radiotherapy. Before irinotecan, intravenous 5HT3 antagonist and dexamethasone were given. If patients developed acute cholinergic syndrome, then atropine 0.25 mg subcutaneously was given, and future courses would also be preceded by atropine, although in the latter part of the study, all patients were given prophylactic atropine before the first course of treatment. 
of 5%. It was anticipated that around 50% of prospectively registered patients would have SD or responding disease after eight cycles of treatment and were available for random assignment; therefore, 224 patients were required to be registered on the study. 
