Through the years, the National Cancer Institute (NCI) Gastrointestinal Intergroup has designed a series of sequential clinical trials to explore chemotherapy and radiation regimens for patients with stage II and III rectal cancer. Intergroup participants have included Cancer and Leukemia Group B (CALGB), the Eastern Cooperative Oncology Group (ECOG), the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG), the National Surgical Adjuvant Breast and Bowel Project (NSABP), the North Central Cancer Treatment Group (NCCTG), the Radiation Therapy Oncology Group (RTOG), and the Southwest Oncology Group (SWOG). Most recently, the American College of Surgery Oncology Group (ACOSOG) has joined the Intergroup network. This article summarizes the Gastrointestinal Intergroup continuum of rectal cancer trials, with an outline of current or planned future trials.
The first Intergroup trial of adjuvant therapy for rectal cancer, initiated in 1986, was coordinated by NCCTG and included CALGB, ECOG, RTOG, and SWOG. A total of 660 patients with stage II or III rectal cancer were randomly assigned to receive bolus 5-FU with or without semustine (methyl-CCNU) for two cycles prior to radiation treatment. Protracted venous infusion 5-FU or bolus 5-FU was combined with radiation. After radiation, two additional 5-FU cycles with or without semustine were administered (Table 1). Results showed significantly improved relapse-free survival (63% vs 53%, P =.01) among 328 patients who received protracted venous infusion 5-FU with radiation compared with 332 patients who received bolus 5-FU (Figure 1). Overall survival also favored the protracted venous infusion fluorouracil(Drug information on fluorouracil) regimen (70% vs 60%, P = .005). The addition of semustine did not improve relapse-free or overall survival (P = .33, P = .61, respectively). The regimens were well tolerated, although diarrhea occurred more often in patients receiving protracted venous infusion fluorouracil with radiation and leukopenia was more predominant with the bolus regimen.
Multiple analyses of results of the second Intergroup rectal cancer adjuvant therapy trial have been published (INT 0114). This study included the same cooperative group participants as the first, plus the NCIC-CTG.[2-4] It was designed to assess the role of biochemical modulation of 5-FU and that of levamisole(Drug information on levamisole) (Ergamisol) in postoperative rectal cancer patients, building upon colon cancer adjuvant therapy data. Because the first Intergroup trial results were unavailable at the time of initiation, INT 0114 did not incorporate protracted venous 5-FU infusion during radiation. The same "sandwich" approach was taken, incorporating two cycles of chemotherapy prior to combined chemotherapy and radiation followed by two additional chemotherapy cycles. The four regimens tested included bolus 5-FU with or without leucovorin or levamisole vs the three drugs given as concomitant therapy (see Table 1).
Levamisole was not administered during radiation treatment, but 5-FU with or without leucovorin was. Accrual of 1,792 patients was completed in 1992, and 1,695 were evaluable. Patients had pathologically confirmed stage II or III rectal cancer (T3/4, N0-3, M0). With a median follow-up of 7.4 years, overall disease-free survival was not statistically significantly different among the four treatment groups; however, there were significant differences by stage. High-risk (T3, N+; T4) and low-risk (T1/2, N+; T3, N0) groups of patients were identified, who also had significant differences in 5- and 7-year survival rates (P < .0001). For example, 5- and 7-year survival rates were 76% vs 70% in the low-risk group, and 55% vs 45% in the high-risk group, respectively.
Results also showed a significant difference in risk of local failure in the low- and high-risk groups (9% vs 18%, respectively; P < .0001) (Table 2). The overall local failure rate increased over time (14% at 5 years vs 17% at 7 years). Patients with T4 disease had the highest risk of local failure, a 24% local failure rate at 5 years. This rate is of concern because it is significantly higher than reported in other studies (eg, study R-02).
Toxicities occurred significantly more frequently and were more severe in females than in males (P < .001). Grade 3 to 5 toxicity was noted in 81% of females and 69% of males, suggesting that females received a biologically higher dose. There was a nonsignificant trend to improved outcome in males who received 5-FU and leucovorin regimens; however, disease-free survival and local recurrence rates were not significantly different by gender. Overall survival was worse for males (P = .03).
Pathologic assessment of lymph nodes in the surgical specimens yielded important results. While no differences were noted among lymph node-positive patients, relapse-free and overall survival differed significantly among lymph node-negative patients as determined by the number of lymph nodes examined. For example, 5-year survival rate was 68% for patients with mire than 0 but under 5 lymph nodes analyzed, compared with 82% for patients with > 14 lymph nodes analyzed (Table 3).