Abstract
After many years, during which the assumption prevailed that adjuvant chemotherapy was of no benefit in patients with resectable adenocarcinoma of the colon, findings of several large USA studies published from the late 1980s have caused a marked shift in surgical and medical opinion. Although results in patients with Dukes' B disease have not shown any clear benefit, the efficacy of adjuvant chemotherapy has nevertheless been shown in those with Dukes' C colon cancer. As a result, the Mayo regimen of 5-fluorouracil (5-FU) with low-dose leucovorin (LV) has become accepted as standard adjuvant therapy in these patients. However, the disadvantages associated with standard 5-FU-based treatment, particularly those relating to its toxicity and inconvenience of administration, have generated interest in other regimens and agents. The novel direct and specific thymidylate synthase inhibitor raltitrexed ('Tomudex') has been associated with similar objective response rates to standard therapy with 5-FU plus LV in patients with advanced colorectal cancer. In addition, raltitrexed has an attractive tolerability profile compared with that of 5-FU plus LV (specifically with respect to lower incidences of mucositis and leucopenia), and the simple 3-weekly administration schedule may be considered more convenient by many patients and may reduce healthcare resource consumption. To investigate alternatives to the Mayo regimen in the adjuvant treatment of Dukes' C adenocarcinoma of the colon, two large European trials have been set up: (1) PETACC-1 (first Pan-European Trial for Adjuvant Treatment of Colon Cancer), to compare raltitrexed with the Mayo regimen of 5-FU and low-dose LV; (2) PETACC-2 (second Pan-European Trial), to compare the Mayo regimen with three regimens in which 5-FU is given by prolonged infusion. These trials will provide valuable international data to add to those from the USA and will assess the place of raltitrexed in the adjuvant treatment of Dukes' C colon cancer. They will also compare directly for the first time infusional and bolus 5-FU regimens in the adjuvant setting.
Highlights
ADJUVANT CHEMOTHERAPY IN COLON CANCERAdjuvant treatment may be defined as treatment given in an attempt to eradicate clinically undetectable metastases, and to prevent local lymphatic spread and recurrence after potentially curative surgical resection of the primary tumour
In a trial with 401 patients with surgically treated Dukes' B2 or C disease, the North Central Cancer Treatment Group (NCCTG) showed a significant (P = 0.003) reduction in recurrence rate when the anthelmintic drug levamisole was given as adjuvant therapy in combination with 5-fluorouracil (5-FU)
Results from a joint trial of the NCCTG and the National Cancer Institute of Canada (NCIC), in which 6- and 12-month regimens of 5-FU and LV were compared with 5-FU, LV and levamisole, showed that 12 months' chemotherapy offers no advantage over 6 months' treatment and that 5-FU plus levamisole for 6 months is inferior to 5-FU plus levamisole and LV for 6 months (Figure 3) (O'Connell et al, 1996)
Summary
Adjuvant treatment may be defined as treatment given in an attempt to eradicate clinically undetectable metastases, and to prevent local lymphatic spread and recurrence after potentially curative surgical resection of the primary tumour. In a trial with 401 patients with surgically treated Dukes' B2 or C disease, the North Central Cancer Treatment Group (NCCTG) showed a significant (P = 0.003) reduction in recurrence rate when the anthelmintic drug levamisole was given as adjuvant therapy in combination with 5-fluorouracil (5-FU). No statistically significant overall survival advantage was conferred by adjuvant treatment, but a retrospective subset analysis showed a significant survival advantage for levamisole plus 5-FU in patients with Dukes' C disease. In the Moertel study, 315 of the 929 patients with Dukes' C disease were randomized to a control group (surgery only with no further planned treatment), 310 to levamisole and 304 to levamisole plus 5-FU (same regimens as in the NCCTG study) (Laurie et al, 1989). After a median 3-year follow-up, therapy with levamisole plus 5-FU reduced the risk of recurrence of cancer by 'Tomudex' is a trademark, the property of Zeneca
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