COMBINED INTRAVENOUS AND INTRAPERITONEAL CHEMOTHERAPY WITH FLUOROURACIL PLUS LEUCOVORIN VS FLUOROURACIL PLUS LEVAMISOLE FOR ADJUVANT THERAPY OF RESECTED COLON-CARCINOMA

Adjuvant chemotherapy with fluorouracil (FU) and levamisole or FU/leuc ovorin (LV) has been established as effective adjuvant treatment for p atients with stage III colon cancer. Among several other promising tre atment strategies in resected colon cancer, intraperitoneal anti-cance r drug administration with its appealing rationale of counteracting mi croscopic residual disease on peritoneal surfaces and occult metachron ous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation. To determine wh ether a combination of this locoregional therapeutic concept with syst emic intravenous administration of FU/LV would yield better results th an conventional adjuvant chemoimmunotherapy with FU/levamisole, the pr esent randomized study was initiated. A total of 241 patients with res ected stage III or high-risk stage II (T4N0M0) colon cancer were rando mly assigned to 'standard therapy' with FU and levamisole, given for a duration of 6 months, or to an investigational arm, consisting of LV 200 mg m(-2) plus FU 350 mg m(-2), both administered intravenously (da ys 1-4) and intraperitoneally (days 1 and 3) every 4 weeks for a total of six courses. In patients with stage II disease, no significant dif ference was noted between the two arms after a median follow-up time o f 4 years (range 2.5-6 years). Among 196 eligible patients with stage III disease, however, a comparative analysis of the two treatment grou ps suggested both an improvement in disease-free survival (P = 0.0014) and a survival advantage (P = 0.0005), with an estimated 43% reductio n in mortality rate (95% confidence interval 26-70%) in favour of the investigational arm. In agreement with its theoretical rationale, comb ined intraperitoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or o ther organ site involvement (9 vs 25 patients in the FU/levamisole arm ; P = 0.005). Treatment-associated side-effects were infrequent and ge nerally mild in both arms, although a lower rate of severe (WHO grade 3) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy (3% vs 12%; P = 0.01). The results of this t rial suggest that combined intraperitoneal plus systemic intravenous c hemotherapy with FU/LV is a promising adjuvant treatment strategy in p atients with surgically resected stage III colon carcinoma.