Optimum duration of oral adjuvant chemotherapy of HCFU for colorectal cancer; review of 5-year follow-up. The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. Randomised controlled trial of adjuvant chemotherapy by portal-vein perfusion after curative resection for colorectal adenocarcinoma.
To investigate the optimal duration of oral HCFU administration for minimization of side effects induced by long-term administration.
                In total, 155 patients allocated to two groups of different duration of the therapy were reviewed: twice or three times per day doses of oral HCFU (8 mg/Kg body weight/day) for 3 months vs. 12 months.
                Though statistically significant difference was not found in cumulative survival and disease-free rates between the groups due to so many violations of duration of therapy, when reanalyzing the variables in order of real duration of therapy, those rates were significantly higher in patients treated for 300 and more days than less than 300 days (g-Wilcoxon test: p < 0.04). No significant difference was observed in the background factors between the groups.
                At least 300 days is suggested to be necessary to obtain the optimal effectiveness of adjuvant chemotherapy for curatively resected colorectal cancer. 204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0-1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%, 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months-8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72-151 weeks), combination arm 125 weeks (95% CI 79-170 weeks). The estimated death ratio is 0.79 (P = 0.19, 95% CI 0.56-1.12). The estimated 3-year survival is 40% (95% CI 30-50%) RT only compared with 47% (95% CI 37-57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy. This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy.
                Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups.
                Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01).
                There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective. About half the patients treated with curative resection for colorectal cancer do not survive long-term. Adjuvant chemotherapy given during and after surgery may prevent hepatic metastases and improve patient survival. In patients with colorectal cancer, we have done a multicentre, randomised controlled trial comparing five-year survival after intraportal infusion of fluorouracil (1 g per day) plus heparin (10,000 U per day) (130 patients) or heparin alone (123) during curative resection and for 7 days thereafter, or after resection alone (145). There was no reduction in liver metastasis or increased overall survival advantage in either active-treatment arm of the study. However, patients who had stage III, Dukes' C (lymph-node-positive) tumours resected and were treated with fluorouracil plus heparin had a significant (p less than 0.03) survival advantage of about 16% compared with surgery-only controls. Further study of intraportal infusion of chemotherapeutic agent as adjuvant treatment to surgery in patients with colorectal cancer appears worthwhile.
The present meta-analysis confirmed that adjuvant chemotherapy of CRC should not last for more than 6 months. Prolonged duration would result in lower benefit to risk ratio. However, the results do not make it possible to favour either 3 or 6 month durations. They should help design a future RCT comparing different durations of continuous treatment.