Recent combinations of chemotherapy have significantly improved the response rate and survival time for patients with metastatic colorectal cancer.
Recent combinations of chemotherapy have significantly improved the responserate and survival time for patients with metastatic colorectal cancer. Thisimprovement has been initially demonstrated with the combination of fluorouracil(5-FU)/leucovorin and irinotecan (CPT-11, Camptosar), which now is consideredand recommended as first-line treatment. The combination of improved efficacywith survival benefit should translate into a better cure rate in patients withresected, locally advanced, nonmetastatic colorectal cancer for whom adjuvantchemotherapy with 5-FU/leucovorin is of proven benefit. Several randomized phaseIII trials are ongoing in Europe or would begin shortly to assess the potentialbenefit of a 5-FU/leucovorin-irinotecan combination in the adjuvant settingfor patients with stage II or III colorectal cancer. This article will reviewthe inclusion criteria and goal of these European trials. An update on accrualand on tolerance will also be provided. [ONCOLOGY 16(Suppl 3):13-15, 2002]
In industrialized countries,colorectal cancer is the most frequently occurring cancer in adults. A positive effect on cure rate has been seen overthe past decade with the use of adjuvant therapy, but about 50% of patientsdiagnosed with colorectal cancer still will die eventually from metastaticdisease. An estimated 30% of patients probably have overt metastatic disease atthe time of surgical resection.
In patients whose tumors extend through the bowel wall to regional lymphnodes (International Union Against Cancer stage III), adjuvant therapyconsisting of a leucovorin-biomodulated fluorouracil (5-FU) regimen improvessurvival time. The role of adjuvant therapy in the treatment of stage IIcolorectal cancer in which lymph nodes are not affected is not yet defined andremains under investigation.
The combination of irinotecan (CPT-11, Camptosar), a topoisomerase Iinhibitor, with the standard 5-FU/leucovorin regimen has been shown to improveboth response rate and survival in previously untreated patients with advancedcolorectal cancer as compared with that achieved with 5-FU/leucovorinalone.[1,2] This improved efficacy in first-line therapy of metastaticcolorectal cancer should translate into a better control of micrometastases andimprovement of 5-year survival rate. Ongoing trials in Europe that are assessingthe use of irinotecan in combination therapy for adjuvant treatment ofcolorectal cancer are presented in this article, with an update on the status ofeach.
Five randomized trials of irinotecan in the adjuvant setting are eitherplanned or ongoingfour in colon cancer and one in rectal cancer patients (Table1). These trials aim to evaluate the effects of adding irinotecan to5-FU/leucovorin on survival in patients receiving adjuvant treatment.
Aventis V307 (PETTAC 3)
V307, the Aventis-sponsored trial, started in September 1999. This study,chaired by E. van Cutsem, is designed mainly to assess the role of irinotecan inaddition to infusional 5-FU/leucovorin in patients with stage III colon cancer.Stage II patients are also eligible for the study at the physician’sdiscretion. Patients are assigned randomly to receive 5-FU/leucovorin alone or5-FU/leucovorin plus 80 mg/m² of irinotecan weekly or 180 mg/m² of irinotecangiven every 2 weeks.
5-FU/leucovorin may be administered according to either the de Gramontregimen as reported by Douillard et al (200 mg/m² of leucovorin IV for 2hours and 400 mg/m² of 5-FU via bolus injection, followed by 600 mg/m² of 5-FU given IVover 22 hours on days 1 and 2 and repeated every 2 weeks) or the AIO regimen(500 mg/m² of leucovorin with 2.6 g/m² of 5-FU IV, administered over 24 hoursevery week; when given in combination with irinotecan, the 5-FU dose is reducedto 2 g/m²), which has been used in the pivotal European phase III trial offirst-line 5-FU/leucovorin plus irinotecan. The accrual goals are 1,800patients with stage III colorectal cancer to assess 3-year disease-free survivaland approximately 630 stage II patients to assess disease-free survival at 3 and5 years and overall survival at 7 years. The comparative safety profile,quality-adjusted survival, putative markers (thymidylate synthase [TS],telomerase, and topoisomerase I) and socioeconomic analyses of the two regimensare secondary objectives. As of December 2001, 1,799 stage III and 738 stage IIpatients were accrued. The initial disease-free survival data will probably bereported in March 2004, with final survival results expected in March 2006 andMarch 2008 to reflect the respective 3- and 5-year follow-up. Data available ontolerability show comparable results in the two arms and no major toxic events,confirming the safety of the infusional 5-FU/leucovorin regimen with and withoutirinotecan.
The ACCORD 2 trial is being conducted by the French Federation of CancerCenters (FNCLCC) in conjunction with the French Foundation of Digestive Oncology(FFCD). Eligible patients have high-risk stage III colon cancer, defined as anyT with at least four positive lymph nodes or any N1 or N2 with perforation orobstruction. Patients are stratified by institution, disease type (more thanfour involved lymph nodes or any number of positive nodes with perforation orobstruction), time between surgery and chemotherapy (> 28 days vs 28days or less), and age (< 65 years vs 65 years or more). Patients are randomly assigned to receiveadjuvant therapy with 5-FU/leucovorin (de Gramont regimen) or 5-FU/leucovorinplus irinotecan (180 mg/m² every 2 weeks) as in the Douillard et al study.The primary trial end point is event-free survival rate at 3 years; secondaryend points include overall survival time and quality of life. The accrual goalis 400 patients, of which 352 patients have been enrolled as of March 2002.Enrollment should be completed by the end of 2002. As in the Aventis V307 study,no unexpected toxicities have been observed so far in either treatment arm ofthe ACCORD 2 trial.
The third ongoing European trial (AERO R98) involves patients with stages IIand III rectal cancer. Patients are randomly assigned to receive the Mayo Clinicbolus 5-FU/leucovorin regimen (425 mg/m²/d of 5-FU × 5 days, plus 20 mg/m²/d ofleucovorin × 5 days, both every 4 weeks) or the de Gramont infusional regimenas control arms; the experimental arm is the de Gramont regimen plus 180 mg/m²of irinotecan as reported by Douillard et al. Preoperative radiation isallowed and generally is administered to most patients in Europe. Of 600patients to be recruited into this trial, 150 had been enrolled as of December2001. The primary end point is recurrence-free survival rate at 3 years.Patients are stratified based on institution, age, sex, involvement of upper orlower rectum, sphincter-preserving surgery or not, stage II vs III, N less thanor greater than 3, any T or T4, and delay between surgery and randomization.
European Organization for Research and Treatment of Cancer (EORTC) (PETTAC 4)
The EORTC is initiating an international randomized study (PETTAC 4)comparing surgery alone vs surgery followed by irinotecan (80 mg/m² weekly or180 mg/m² every 2 weeks) in combination with 5-FU/leucovorin (de Gramont or AIOregimen). Accrual was started in late 2001 and will continue until 1,960patients are enrolled.
In the United Kingdom, patients with stage III colorectal cancer will berandomly assigned to receive irinotecan plus bolus 5-FU/leucovorin orcapecitabine (Xeloda) plus irinotecan in the QUASAR (Quick and Simple andReliable) trial. This study, coordinated through the CRC Institute for CancerStudies in Birmingham, is scheduled to begin in spring 2002, with an accrualgoal of 4,000 patients.
Adjuvant therapy reduces the risk of death in patients with resectedcolorectal cancer with lymph node involvement (stage III). The use of regimenswith improved efficacy against metastatic disease potentially could improveefficacy further. One such regimen currently being assessed is the combinationof irinotecan with 5-FU/leucovorin. Further development of other new agents,such as combinations incorporating irinotecan or oxaliplatin and also oralfluoropyrimidines (uracil/tegafur [UFT], capecitabine) with 5-FU/leucovorin arewarranted.
1. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined withfluorouracil compared with fluorouracil alone as first-line treatment formetastatic colorectal cancer:A multicentre randomized trial. Lancet 355:1041-1047, 2000.
2. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil andleucovorin for metastatic colorectal cancer. New Engl J Med 343:905-914, 2000.