Therapy for Early-Stage Colorectal Cancer
Therapy for Early-Stage Colorectal Cancer
Colorectal cancer is most common in economically developed
countries, particularly in parts of Europe, North America,
Australia, and New Zealand. The annual incidence of this cancer
varies between 57.4 and 0.7 per 100,00 people, respectively, in high-
and low-risk populations. Colorectal cancer is one of the leading
causes of cancer-related deaths in the Western world. Every year,
colorectal cancer is responsible for an estimated 400,000 deaths.
Most patients (70%) who have colorectal cancer present with
apparently localized disease. The remaining 30% have advanced disease
at diagnosis, 25% of whom have distant metastatic disease and 5%,
locally advanced disease. One-quarter of colorectal cancer cases are
confined to the rectum, while the remainder are located in some part
of the colon.
Colorectal cancer is not uniformly fatal, although there are large
differences in survival depending on stage of disease. Pathologic
stage is presently the most important determinant of prognosis. The
classification system described by Cuthbert Dukes in 1930 is still
widely used. However, the original Dukes system no longer
fulfills the requirements of modern tumor staging, as it fails to
take into account distant metastasis, the number of lymph nodes
involved, and carcinomas limited to the submucosa.
Therefore, the TNM classification of the American Joint Committee on
Cancer (AJCC) is currently recommended for daily use and in clinical
trials. Each stage of this system is related to differences in 5-year
survival after surgery alone. Survival rates decrease with increasing
stage, from 90% for stage I to < 5% for stage IV.
Although the TNM classification is generally used to determine
therapy for a given patient, the other factors are thought to have an
independent influence on outcome. Risk of recurrence appears to
increase with bowel perforation, obstruction, and adherence or
invasion of the tumor to other organs. Additional determinants of
prognosis include the presence of venous, perineural, or lymphatic
invasion, and histopathologic grade.
Furthermore, a 1991 study found that DNA aneuploidy (as determined by
flow cytometry) predicted for relapse and survival in patients with
stage B2 colon cancer. A more recent study demonstrated that
detection of micro-metastases by reverse-transcriptasepolymerase
chain reaction (RT-PCR) amplification of carcinoembryonic antigen
(CEA) messenger RNA (mRNA) in lymph nodes from patients with stage II
colorectal cancer was a prognostic tool. Thymidylate synthase, the
target enzyme for fluorodeoxyuridine monophosphate, may be another
predictor of prognosis for colorectal cancer.
The large differences in survival between early- and late-stage
disease clearly indicate the advantage of detecting colorectal cancer
at an early stage. Curative resection is undertaken in 75% of cases.
Unfortunately, experience reveals that, in approximately half of
these cases, tumor recurrence can be expected. High-risk tumors, ie,
those penetrating the whole bowel wall (pT3-4 N0 M0) or invading
local lymphatics (pTx N1-2 M0), have a high risk of recurrence.
Treatment failure results from residual occult viable tumor cells,
the bulk of which are below the threshold of detection of currently
available diagnostics. They may be in the circulation system (blood,
lymph) or may indeed be aggregated microfoci of cells at either local
or distant sites.
This problem has led to the development of adjuvant cytotoxic
therapy, administered with the intent to target these low-burden,
rapidly cycling foci of cancer cells and eradicate them before they
become established and, therefore, relatively refractory to
intervention. Important considerations are the risk-benefit ratio of
such treatment and the need to achieve a balance between maximum
chance of cure/prolonged survival and tolerance of side effects.
In any discussion of adjuvant therapy modalities for colorectal
cancer, one must differentiate between colon and rectal cancer. The
latter can be defined as any tumor that is located either partly or
entirely below the peritoneal reflection. The retroperitoneal
location makes it more difficult for surgeons to obtain wide margins
at resection and is associated with a higher incidence of
locoregional failure. Adjuvant therapies in patients with high-risk
rectal cancer (stages II and III) must include an aggressive local
approach to reduce the risk of local failure and ultimately also to
influence overall survival.
The stage of disease at the time of presentation remains the most
influential factor affecting 5-year survival. The excellent survival
rates for stage I patients treated with surgery alone have excluded
this group from adjuvant therapy. Since 1990, growing evidence has
supported the role and importance of adjuvant chemotherapy or
immunotherapy in the treatment of patients with stage III (Dukes
C) colon cancer. The role of adjuvant therapy in patients with stage
II disease is less clear-cut.
Standard Adjuvant Therapy for Stage III Disease
5-FU Plus Levamisole: NCI Standard in 1990The intergroup
trial reported in 1990 by Moertel et al (INT-0035) was the first
large-scale study to demonstrate a significant survival benefit and a
reduction in recurrence risk after postoperative treatment in
patients with resected stage III colon cancer. This trial randomized
1,296 patients to one of three arms: (1) surgery alone, (2) surgery
plus 12 months of levamisole (Ergamisol), or (3) surgery plus 12
months of fluorouracil (5-FU) plus levamisole. The study showed a 15%
absolute reduction in risk of recurrence and a 33% relative reduction
in the overall death rate with the combination of surgery plus 5-FU/levamisole.
Based on these results, the National Cancer Institute (NCI)
recommended 5-FU/levamisole as the standard of care for patients with
resected Dukes stage D1 colon cancer. As a result,
essentially all adjuvant therapy studies conducted in the 1990s used
5-FU plus levamisole as the treatment against which investigational
therapies were compared.
5-FU Plus Leucovorin: New Standard in 1998-One new direction
in adjuvant therapy has been biochemical modulation of the cytotoxic
activity of 5-FU with such drugs as leucovorin (folinic acid). The
addition of folinic acid stabilizes the 5-FU/thymidylate synthase
complex, maximizing and prolonging the inhibition. A meta-analysis
published in the early 1990s showed no overall survival benefit from
5-FU/leucovorin in patients with advanced colon cancer, but the
response rate was significantly increased, as compared with that seen
with 5-FU alone (23% vs 11%).
The therapeutic efficacy of leucovorin-modulated 5-FU in the
metastatic setting resulted in several new adjuvant therapy studies
in colon cancer. The heterogeneity of the study populations (ie, the
mixture of patients with stage II and III disease), limited number of
patients randomized, and differences in dose and regimens in the
early studies made it difficult to draw final conclusions from these
studies. Moreover, most trials that did not offer 5-FU plus
levamisole as standard treatment for Dukes C disease were
closed prematurely. Nevertheless, three studies that randomized
approximately 1,500 patients with stage III colon cancer to either
surgery alone or postoperative treatment with regimens of 5-FU plus
leucovorin were published.
The International Multicentre Pooled Analyses of Colon Cancer Trials
(IMPACT) study pooled and analyzed data from three studies (Fondation
Française de Cancerologie Digestive [FFCD], NCI-Canada, and
Gruppo Interdisciplinaze Valutazione Interventi Oncologia [GIVIO]) in
which six cycles of 5-FU/folinic acid were compared with follow-up
alone. A total of 1,526 patients were randomized, 685 (45%) of whom
had stage III disease. Overall patient tolerance of and compliance
with the regimen were good; more than 80% of patients completed the
planned treatment, and the incidence of grade 4 toxicity was only 3%.
Patients who received 5-FU/folinic acid had a disease-free survival
rate of 62%, compared to a rate of 44% in the untreated group after
37 months of follow-up.
A small Italian study by Francini et al used the same treatment
arms as the previous study. However, therapy was given for 12 months
instead of 6 months. Adjuvant therapy significantly reduced the
recurrence rate compared with observation alone, and also achieved a
longer disease-free interval (66% vs 41%) and better overall survival
rate (69% vs 43%).
In the National Surgical Adjuvant Breast and Bowel Project (NSABP)
protocol C-03, the control group received a combination of
methyl-CCNU, Oncovin, and 5-FU (MOF). Comparison with weekly 5-FU
(500 mg/m²) plus leucovorin for 1 year provided clear evidence
that leucovorin-modulated 5-FU is significantly superior to MOF in
prolonging disease-free and overall survival rates.
Indirect comparison between the intergroup study of Moertel et al,
which used 5-FU and levamisole for 1 year, and IMPACT, which
studied 5-FU plus leucovorin, demonstrated similar disease-free and
overall survival rates. These encouraging results for biochemically
modulated 5-FU made direct comparison of the two regimens necessary.
The second intergroup study (INT-0089) was initiated for that purpose
in 1989. The study accrued 3,759 patients, 20% of whom had high-risk
Dukes B2 disease. These patients were randomly assigned to
receive standard 5-FU plus levamisole for 12 months, 5-FU plus
high-dose leucovorin, 5-FU plus low-dose leucovorin, or 5-FU plus
low-dose leucovorin and levamisole. The latter three regimens were
administered for approximately 6 to 7 months.
The final analysis of data after 5 years of follow-up was presented
at the 1998 American Society of Clinical Oncology (ASCO) meeting.
The results affirmed that 6 months of therapy with 5-FU plus
leucovorin should represent standard adjuvant therapy for patients
with resected high-risk colon cancer (Table
A difference in toxicity profiles was detected between the low- and
high-dose leucovorin arms. The 5-FU/low-dose leucovorin regimens
(with or without levamisole) had significantly higher incidences of
stomatitis and neutropenia than were seen with 5-FU/levamisole or
5-FU/high-dose leucovorin regimens. Conversely, grade 3 diarrhea was
more common with 5-FU/high-dose leucovorin than with 5-FU/levamisole
or 5-FU/low-dose leucovorin.
The NSABP C-04 study, which randomized a total of 2,152 patients (41%
with Dukes B colon cancer), showed similar results.
Disease-free survival rates at 5 years were 74% for 5-FU plus
leucovorin vs 69% for 5-FU plus levamisole. No significant
differences in toxicity were noted.
The last large adjuvant study, managed by the North Central Cancer
Treatment Group (NCCTG) and NCI-Canada (NCIC), compared 1 year with 6
months of treatment and addressed whether leucovorin was a useful
addition to the original levamisole-based regimen. Therapy consisted
of 5-FU plus levamisole or 5-FU plus leucovorin and levamisole.
Two conclusions can be drawn from the study: First, 12 months of
adjuvant chemotherapy offers no advantage over 6 months. Second, 6
months of triple therapy produced a significantly superior survival
rate than the combination of 5-FU plus levamisole for the same time
period (75% vs 63%).
Current RecommendationsIn 1998, every patient with stage
III colon cancer should be considered for adjuvant chemotherapy.
Based on the current data (Table 2),
therapy could consist of 1 year of 5-FU plus levamisole or, more
likely, 6 months of 5-FU plus leucovorin. The benefit of adding
levamisole to the latter regimen is uncertain but is probably marginal.