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-transcriptase–polymerase 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 1990—The 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 1).
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 Recommendations—In 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.
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