A systematic overview of chemotherapy effects in colorectal cancer

A systematic review of chemotherapy trials in several tumour types was perf ormed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are describ ed separately (Acta Oncol 2001: 40: 155-65). This synthesis of the literatu re on adjuvant and palliative therapy with cytostatics for colorectal cance r is based on 208 scientific articles, including eight meta-analyses and 16 2 randomised studies. These studies involve approximately 126800 patients. The conclusions reached can be summarized into the following points: The benefit of postoperative adjuvant chemotherapy with fluorouracil and le vamisole in patients with colon cancer stage Dukes' C was demonstrated more than ten years ago in two phase III trials. There was a reduction of recur rence from 56% to 39% and reduction of death from 51% to 40% after more tha n five years of follow-up. Although this combination has been widely accept ed as standard adjuvant treatments for stage Dukes' C colon cancer, there i s still debate on whether adjuvant treatment with fluorouracil alone would be equally efficacious. Several phase III trials with postoperative adjuvant chemotherapy with fluo rouracil and leucovorin in patients with colon cancer stage Dukes' C have d emonstrated a similar statistically significant improvement in disease-free and overall survival in comparison with a control arm. Six months of treat ment with fluorouracil and leucovorin is as efficient as twelve months of f luorouracil and levamisole. This treatment is. thus. recommended for routin e use. No convincing benefit from adjuvant chemotherapy is proven in colon cancer stage Dukes' B although some randomised trials have shown the same relative survival gain as seen in stage Dukes' C. There is less knowledge on survival benefits from adjuvant chemotherapy for Dukes' stage B and C rectal cancer. In small randomised trials. postoperat ive radiochemotherapy has, however. improved survival to the same extent as chemotherapy in colon cancer Dukes' stage C. A meta-analysis of nine randomised trials revealed a small but statisticall y significant benefit in five-year survival and a reduction in the risk of death for the patients receiving immediate postoperative portal vein infusi on compared with controls. At present, however, the use of portal vein infu sion or intraperitoneal therapy outside of a research trial cannot be recom mended in the light of the limited effects. This conclusion is Further supp orted by similarly limited effects in two recently reported very large Euro pean multicentre trials. In advanced colorectal cancer, chemotherapy may prolong survival, decrease tumour-related symptoms. improve general well-being or maintain it at a hig h level for a longer time period compared with best supportive care. These effects have been seen using systemic chemotherapy and using regional chemo therapy in patients with metastases limited to the liver. Subjective respon ses and quality of life improvements are seen more frequently than objectiv e tumour remissions. Although the impact on overall survival is modest, i.e . an improvement in median survival of five to six months, treatment is rec ommended also outside clinical trials. High-dose infusional regimens with modulated fluorouracil may turn out to b e superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression and possibly longer survi val. A plateau seems, however, to have been reached with fluorouracil, givi ng objective response rates of up to 30% to 40% with a variety of modulator s. Randomised studies of regional therapy, mostly hepatic arterial infusions, of liver metastases in colorectal patients have demonstrated significantly higher response rates than systemic fluorouracil therapy alone without impa ct on overall survival. The importance of the higher response rates for pat ient benefit in the predominantly asymptomatic patients with isolated liver metastasis remains to be elucidated. Regional therapy in advanced disease cannot be recommended outside of clinical trials. New cytotoxic agents are emerging with antitumour activity similar to fluor ouracil-based chemotherapy. The addition of oxaliplatin or irinotecan to ex isting fluorouracil regimens improves response rates and duration of respon se, and possibly overall survival. Based upon the results of two randomised studies. there is a role for irinotecan as second line therapy for selecte d patients who have failed first-line therapy with fluorouracil plus leucov orin. The role of these agents, alone or in combinations, in clinical routi ne remains, however, to be determined due to more pronounced toxicity than caused by fluorouracil-based regimens.