2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Stage III Colon Cancer: What Works, What
Doesn’t and Why, and What’s Next
By Thierry André, MD, Bert H. O’Neil, MD, and Jeffrey A. Meyerhardt, MD, MPH
Overview: Adjuvant treatment for patients with stage III
colon cancer, one of the most common malignancies, is an
important issue in oncology. The use of adjuvant chemotherapy
in this setting has undoubtedly improved prognosis. This
article describes the development of adjuvant therapy and
COLORECTAL CANCER is the third most common
cancer in both men and women, and the fourth leading
cause of cancer deaths in the world. 1 The estimated worldwide
incidence of colorectal cancer is 1.2 million per year. 1
In Western countries, the median age at diagnosis is 71, and
nearly 25% of all colon cancers are diagnosed at stage III. 2
The main prognostic factor for estimating survival or relapse
after surgery for localized disease is the tumor, node, and
metastasis staging system. 3 The 3-year disease-free survival
(DFS) for patients with stage III colon cancer without
any postoperative chemotherapy ranges between 44% and
52%. 4,5
This review focuses on adjuvant therapy for patients with
stage III colon cancer. The goal is to illustrate how adjuvant
therapy has improved survival 3-fold in patients with stage
III colon cancer and to acknowledge those who contributed
to this achievement. We will also review efforts that have
not succeeded and discuss next steps.
Early Chemotherapy and 5-Fluorouracil/Levamisole
The first drugs evaluated in colon cancer trials were the
alkylating agent thiotepa and the antimetabolites fluorodeoxyuridine
and 5-fluorouracil (5-FU), which was discovered
by Charles Heidelberger in 1957. 6 The first adjuvant trials
using various routes of administration were performed in
the late 1960s and early 1970s. However, all proved unsuccessful
except for trials using 5-FU. According to the criteria
of that time, positive results were reported with intraluminal
or intravenous administration of 5-FU, but the small
number of undersized randomized studies failed to show any
statistical significance. 7 In 1988, Buyse and colleagues carried
out a meta-analysis of 17 trials involving 6,791 patients
with colorectal cancer (mean of 400 patients per trial), and
found a small benefit in overall survival (OS) with the
5-FU–based regimens (hazard ratio [HR] � 0.83). 8 They also
concluded that much larger trials were needed.
Adjuvant Therapy for Patients with Colon Cancer: the
First Step (1990)
The first study demonstrating the value of adjuvant chemotherapy
in patients with stage III colon cancer (TX, N1 or
N2, M0) was published by Moertel in 1990. 4 This study
showed an increase in OS and DFS in patients receiving
5-FU/levamisole chemotherapy during 1 year compared with
patients treated with levamisole alone or not receiving
any treatment. After a mean follow-up of 6.5 years, patients
treated with 5-FU/levamisole showed a 40% reduction
in their recurrence rate and an estimated 33% reduction
in overall death rate. 4 The 3-year DFS and 5-year
OS estimated from the survival curves were 64% and 63%,
progress in the past decade as well as failures in multiple
agents that have demonstrated efficacy in the metastatic
setting. Finally, the current clinical trials will be reviewed, as
well as complementary therapies including diet and exercise
for survivors of colorectal cancer.
respectively. 4,5 These results constituted an impressive
therapeutic advance, and 5-FU/levamisole adjuvant chemotherapy
became the standard of care for patients with stage
III colon cancer.
Two other studies demonstrated the benefit of adjuvant
chemotherapy with 5-FU and leucovorin (LV) compared
with no treatment for patients with colon cancer. 9,10 The
International Multicenter Pooled Analysis of colorectal cancer
Trials (IMPACT) showed a 22% relative risk reduction in
mortality with 5-FU/LV. 9
Modulation of 5-FU with Levamisole or Leucovorin
After the publication of NSABP C-04 study results in
1999, 11 which showed a small DFS advantage of 5-FU/LV
compared with FU/levamisole in patients with high-risk
stage II and III colon cancer, the addition of levamisole to
5-FU was withdrawn. The combination of 5-FU (bolus or
short infusion) and LV, administered either daily for 5 days
per month (according to the Mayo Clinic regimen) or weekly
for 6 months (according to the Roswell Park regimen),
became the new standard treatments for patients with stage
III colon cancer. 11,12 In fact, the Intergroup study 0089
(INT-0089) showed that the Roswell Park regimen, the
Mayo Clinic regimen, 5-FU/LV/levamisole, and 5-FU/levamisole
(control arm) treatments were equivalent. In this
four-arm study, the authors concluded that 5-FU/LV (either
the Roswell Park or the Mayo Clinic regimens) could replace
5-FU/levamisole. 12 Interestingly, the biweekly LV5FU2 regimen
(LV followed by both a bolus and a 22-hour infusion of
5-FU for 2 consecutive days) was also compared with
monthly 5-FU/LV (a modified Mayo Clinic regimen) in the
GERCOR C96-1 trial, which included patients with stage II
and III colon cancer. 13 There was no significant improvement
found in DFS, but the LV5FU2 regimen became
another accepted standard because of its improved safety
profile. Finally, the ACCENT (Adjuvant Colon Cancer
ENdpoinTs) meta-analysis, which included individual data
from more than 20,000 patients followed for more than 8
years, confirmed a 10% absolute improvement in OS for
patients with stage III colon cancer who received adjuvant
From the Service d’Oncologie Médicale, Hôpital Saint-Antoine, Assistance Publique des
Hôpitaux de Paris, Paris, France and Université Pierre et Marie Curie (Paris 6); University
of North Carolina, Chapel Hill, NC; Dana-Farber Cancer Institute, Harvard Medical
School, Boston, MA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Jeffrey A. Meyerhardt, MD, MPH, Dana-Farber Cancer
Institute, 44 Binney Street, Boston, MA 02215; email: Jeffrey_Meyerhardt@dfci.harvard.
edu.
© 2012 by American Society of Clinical Oncology.
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