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Future Directions in Adjuvant Therapy for Rectal Cancer

Future Directions in Adjuvant Therapy for Rectal Cancer

ABSTRACT: The US National Cancer Institute Gastrointestinal Intergroup has contributed to the development of chemotherapy and radiation regimens for the treatment of stage II and III rectal cancer. The first Intergroup trial demonstrated improvement in relapse-free and overall survival for patients who received protracted venous infusion fluorouracil (5-FU) with radiation compared to those treated with bolus 5-FU. The second trial, INT 0114, demonstrated that there was no difference among four regimens, including 5-FU with or without leucovorin or levamisole (Ergamisol) vs three drugs given as concomitant therapy. High-risk (T3, N+; T4) and low-risk (T1/2, N+; T3, N0) tumor categories were identified, revealing significant differences in 5- and 7-year survival rates. Risk of local failure was also greater in the high-risk group. Pathologic assessment of lymph nodes in the surgical specimens had an important impact on these trial results. Relapse-free and overall survival were significantly different among the lymph node-negative patients, as determined by the number of lymph nodes examined. The National Surgical Adjuvant Breast and Bowel Project trials (R-01, R-02) have shown that the addition of radiation does not affect disease-free or overall survival but improves local recurrence rates. Future trials will explore use of newer agents, including capecitabine (Xeloda), irinotecan, and oxaliplatin. In addition, prospective evaluation of laboratory correlates, including molecular markers, will be integrated into trial design. [ONCOLOGY 16(Suppl 5):45-51, 2002]

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.

Improved Survival With Protracted Venous 5-FU Infusion

The first Intergroup trial of adjuvant therapy for rectal cancer, initiated
in 1986, was coordinated by NCCTG and included CALGB, ECOG, RTOG, and SWOG.[1] 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
regimen.

Identification of Tumor Risk Categories in INT 0114

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
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,[4]
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).[2]

Ongoing Trial of Postoperative Infusional 5-FU (S9304)

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