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 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
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 (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
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
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).
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fluorouracil-modulated chemotherapy combined with pelvic radiation therapy for
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