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Editor's Comment: - Although there is considerable evidence of a protective effect of calcium and vitamin D against development of colorectal cancer in animals, the results of dietary studies in humans have been inconsistent. One limitation of the present study was the small number of cases; many more would be needed to confirm the relatively weak association with calcium that was found. Another problem is the undoubted drift toward higher calcium intake over time in response to reports of health benefits in osteoporosis, etc. This cannot be completely allowed for despite exclusion of those nurses who reported a change in milk consumption. There clearly needs to more investigation of vitamin D which has been less studied than calcium. The association reported here looks more convincing.
A Phase II trial of 5-FU at medium dose (2 g/m2) by weekly 48-hour continuous infusion, with oral leucovorin (60 mg every 6 hours) produced a response rate of 37.5% and median survival of 14.5 months, results no better than those achieved with the maximum tolerated dose of 5-FU at 3.5 mg/m2 under the same dosing conditions (Aranda, Ann Oncol 7:581, 1996).
The second study in Annals of Oncology examined the combination with alpha-interferon, which tripled the response rate seen with 5-FU alone (19.6% versus 6.1%), and increased event-free survival from 2 to 6 months, however, there was no significant effect on overall survival, and toxicity was significantly greater (Dufour, Ann Oncol 7:575, 1996).
The 5-FU - interferon alpha combination was covered in more depth in the October, 1996 issue of the Journal of Clinical Oncology, with two articles and an editorial on this combination. The upshot of the two studies, a large Phase III trial of 245 advanced colorectal cancer patients in France, and a smaller one (106 patients) in Greece, was clear. Interferon alpha added either to 5-fluorouracil (French study) or to a 5-fluorouracil - leucovorin combination (Greek study) provided no additional benefit as regards tumor effect in these patients with advanced colorectal cancer, but did increase the frequency or severity of toxicity. (Greco, J Clin Oncol 14:2674, 1996; Kosmidis, J Clin Oncol 14:2682, 1996)
Editor's Comment: - One of the oldest cancer chemotherapy drugs, 5-FU is still a mainstay in the treatment of advanced colorectal cancer, although when used alone by rapid injection response rates have been only in the 10-20% range. Weekly 48-hour infusions may give a response rate of over 30%. Furthermore, there is no proof that survival is increased significantly. Other drugs used as single agents have fared no better in larger trials, although they had looked more promising in Phase II studies. In response to the failure to find more active drugs, various combinations intended to to modulate 5-FU action have been tried, of which the most successful have been those with leucovorin and with levamisole (as an adjuvant to surgery). The history of the 5-FU - interferon combination in clinical application for advanced colorectal cancer, the main thrust of these selected articles, has been one of steadily diminishing response rates since the initial rate of 76% claimed for the first Phase II study. There would appear to be no future for this combination, this is certainly the stated message of the two Journal of Clinical Oncology articles. However, the Dufour report (Dufour, Ann Oncol 7:575, 1996) did show enhanced response, as have some other earlier ones. There is a question of whether pharmacological information about 5-FU has been effectively applied in some of the studies. The preclinical results clearly show that the timing of treatment is critical - interferons must be present at the time 5-FU is being metabolized to its nucleotides, which means it should be given just before or together with 5-FU. This has not been true of many clinical trials of the combination, but was true of the early Phase II studies. Much also needs to be learned of the mechanisms whereby interferon, as a biological modulator of many systems, produces its multiple side-effects, and how to minimize them.
Editor's Comment: - Although p53 is not yet recommended as a marker to be used in the management of colorectal cancer, there is increasing evidence that it does provide significant prognostic information, and will in time assume official recognition. An article in the October, 1996 issue of the Journal of Clinical Oncology by researchers at the Memorial Sloan-Kettering Cancer Center in New York underlines this. There was p53 reactivity in 72% of cases with advanced colorectal cancer with hepatic metastases, together with significantly decreased survival in this group of patients, 21 months versus 53 months for those with tumor negative for p53. (Belluco, J Clin Oncol 14:2696, 1996)