Department of Surgery, University of Western Australia, Nedlands 6009, Australia (E-mail: bjiac@cyllene.uwa.edu.au)
Shortly after the publication of results showing a survival benefit from adjuvant therapy with 5-fluorouracil (5-FU) and levamisole [1], an NIH consensus meeting recommended this as standard treatment for stage III colon cancer. However, for patients diagnosed with stage II disease the benefits of chemotherapy are more controversial [2, 3]. The relatively good prognosis of these patients (7080% at 5 years) and the high frequency of non-cancer related deaths in this population, mean that very large clinical trials are required in order to demonstrate a significant improvement in survival following treatment. Any possible benefit for a small proportion of patients needs to be weighed against the toxicity and expense of treatment. As a consequence, routine adjuvant therapy of stage II patients does not occur in most countries. Population-based data from the USA indicate that between 30% and 50% of stage II colon and 60% and 80% of stage II rectal cancer patients aged <75 years received adjuvant chemotherapy in the mid-1990s [4]. Anecdotal evidence from Europe and Australia suggests that the proportion of stage II patients being treated with adjuvant therapy is much lower than these values.
Despite numerous studies in the literature showing important biological differences between proximal and distal tumours, including one review as early as 1990 [5], the anatomical site of tumour origin has only recently been considered as a possible predictive factor for the response to 5-FU. Data from a retrospective non-randomized study suggests that Dukes C patients with proximal tumours derive a significant survival benefit from chemotherapy, but those with distal colon or rectal tumours do not [6]. Female patients in this study also appeared to gain more benefit than males. Similar results were recently reported in a prospective trial of 5-FU/levamisole in stage II and III colorectal cancer patients [7]. Almost the entire survival benefit from treatment was found in the colon cancer subgroup, with rectal cancer patients gaining no significant benefit. Interestingly, female patients in the trial again showed a greater degree of survival benefit compared with males. As with some earlier studies [2], patients with stage II and III disease showed a similar relative benefit from adjuvant therapy.
Together, the above studies [6, 7] suggest that some stage III patients, notably males with rectal cancer, derive no survival benefit from 5-FU-based adjuvant therapy. Further trials that use alternate first-line treatments should be considered for these patients. Of more immediate concern, however, is the possibility that large numbers of stage II patients who might benefit from 5-FU are not currently receiving this treatment, especially in countries other than the USA. If the apparently non-responsive subgroup of patients (males with rectal cancers) is excluded, worldwide data on the incidence of colorectal cancer [8] indicate there are 200 000 cases annually of stage II disease that could potentially benefit from 5-FU therapy. Although additional data on the survival benefits derived from 5-FU in various stage II patient subgroups are required, it would seem prudent in the light of available evidence to recommend adjuvant therapy at least to females with proximal tumours.
B. Iacopetta
Department of Surgery, University of Western Australia, Nedlands 6009, Australia (E-mail: bjiac{at}cyllene.uwa.edu.au)
REFERENCES
1. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352358.[Abstract]
2. Mamounas E, Wieand H, Wolmark N et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes B versus Dukes C colon cancer: results from four National Surgical Adjuvant Breast and Bowel Project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999; 17: 13491355.
3. Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. International Multicentre Pooled Analysis of B2 Colon Cancer Trials (IMPACT B2) Investigators. J Clin Oncol 1999; 17: 13561363.
4. Potosky AL, Harlan LC, Kaplan RS et al. Age, sex, and racial differences in the use of standard adjuvant therapy for colorectal cancer. J Clin Oncol 2002; 20: 11921202.
5. Bufill JA. Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location. Ann Intern Med 1990; 113: 779788.[ISI][Medline]
6. Elsaleh H, Joseph D, Grieu F et al. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000; 355: 17451750.[ISI][Medline]
7. Taal BG, Van Tinteren H, Zoetmulder FA. Adjuvant 5-FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III. Br J Cancer 2001; 85: 14371443.[ISI][Medline]
8. Parkin DM. Global cancer statistics in the year 2000. Lancet Oncol 2001; 2: 533543.[Medline]