Early hematological toxicity of adjuvant perioperative intraportal and intravenous chemotherapy with fluorouracil, mitomycin and heparin in colorectal cancer. Swiss Group for Clinical Cancer Research.

BACKGROUND: From 1987 to 1993 the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III adjuvant trial in patients with colorectal adenocarcinoma with the objective of comparing intraportal versus intravenous perioperative chemotherapy. PATIENTS AND METHODS: Patients younger than 75 years had a curative en bloc resection of their cancer and were then randomized into three arms: 1. adjuvant perioperative portal liver infusion with fluorouracil, mitomycin and heparin, 2. adjuvant subclavian intravenous infusion with the same regimen and 3. no adjuvant treatment. The hematological toxicity was evaluated by hemoglobin determination and leucocyte and thrombocyte counting before and during ten days after surgery. RESULTS: Hemoglobin showed a median decrease of 22% in the control group. This decrease is aggravated significantly by 3% through the chemotherapy. Leucocytes showed a median decrease of 7% in the control group. Perioperative chemotherapy caused a significantly higher median drop; 23% when given into the liver through the portal vein and 34% when given systemically through a subclavian catheter. Thrombocytes revealed a median decrease of 25% in the control group. Chemotherapy was not associated with a significant additional drop. CONCLUSIONS: Adjuvant perioperative chemotherapy with fluorouracil, mitomycin and Heparin as given in this study is associated with a significant mild drop in hemoglobin and leucocytes during the first 10 postoperative days. If drug dose increases are planned in future trials the addition of hematopoietic growth factors might be considered.

[Status of portal perfusion in colorectal cancer. Swiss Study Group for Clinical Cancer Research]. / Stellenwert der portalen Perfusion beim colorectalen Carcinom. Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK).

533 patients with diagnosis of operable colorectal carcinoma were randomized to receive either a single course of portal infusion with Mitomycin-C (MMC) and 5-Fluorouracil (5-FU) starting immediately after operation, or no adjuvant treatment. Of these, 505 (94%) were evaluable. Over the median follow-up of 8 years, the adjuvant therapy reduced the risk of recurrence by 22% (Hazard ratio = 0.78%, 95% CI 0.61-0.99; P = 0.045). The relative reduction of relapse on death was similar in all subgroups (i.e. nodal status, localization). However, adjuvant portal chemotherapy proved to be most efficient in the subgroups of patients with tumor involvement of the regional lymph nodes (Dukes C) and of patients with colon cancer. Analysis of the pattern of relapse showed that most of the difference in overall and disease-free survival is to be attributed to a consistent reduction of all kinds of tumor recurrences (i.e. local relapses, liver metastases and/or other distant metastases) in the treated group, rather than to liver relapses alone. We conclude therefore, that part of significant benefit obtained for patients with operable colorectal carcinoma treated with a single course of adjuvant chemotherapy via the portal vein might be due to the additional systemic effects of the portal chemotherapy and further study of perioperative treatment with and without prolonged chemotherapy appears worthwhile.

[Final evaluation of the randomized multicenter study SAKK 40/81: adjuvant portal chemotherapy of curatively resected colorectal cancer]. / Endauswertung der randomisierten Multizenter-Studie SAKK 40/81: Adjuvante portale Chemotherapie beim kurativ resezierten kolorektalen Karzinom.

Between 1981 and 1987, 533 patients from 9 institutions have been entered in a randomized trial to assess the value of adjuvant portal infusion (5-Fluorouracil, Mitomycin C) compared to radical surgery alone. Analysis of 469 evaluable patients at a median follow-up of 5.8 years revealed 110 recurrences in the control and 94 recurrences in the infusion group. Estimated 5-year disease-free survival was 52% and 61% respectively (hazard ratio 1:0.75; 95% confidence interval 0.57-0.99; p = 0.046). Overall survival was 59% in the control and 69 in the infusion group (p = 0.048). Adjuvant portal infusion did not influence the occurrence of liver metastases but reduced the overall recurrence rate.

Hematological toxicity of adjuvant portal liver infusion with fluorouracil, mitomycin and heparin.

Adjuvant perioperative liver infusion chemotherapy with fluorouracil, mitomycin and heparin caused mild but significant myelosuppression in the first two postoperative weeks. This was associated with a slightly increased bleeding tendency. Mortality was not increased. Future trials might combine chemotherapy with hematopoietic growth factors in order to minimize myelosuppression.

Randomized multicenter trial of adjuvant intraportal chemotherapy for colorectal cancer (SAKK 40/81). An interim report.

A prospective, randomized trial of adjuvant portal infusion of 5-fluorouracil in combination with mitomycin C was conducted on 469 patients with operable colorectal cancer. A single postoperative course of the cytotoxic agents was compared with radical surgery alone. The actuarial 5-year survival (median follow-up 48 months) was 70 +/- 3% in the chemotherapy group and 57 +/- 4% in the control group (p = 0.10). The respective figures for disease-free survival were 62 +/- 4% and 53 +/- 4% (p = 0.09). Among the 195 cases with strict adherence to the protocol for adjuvant chemotherapy there were 59 recurrences and 44 deaths in the follow-up period, whereas in the 274 with no or incomplete chemotherapy there were 120 recurrences and 99 deaths (p less than 0.05). Perioperative adjuvant chemotherapy via portal infusion proved to be feasible in a multicenter setting. Follow-up will be continued, in order to provide definitive information on survival according to randomization.

[Initial results of adjuvant portal liver infusion following radical surgery of colorectal cancer (Swiss Study Group for Epidemiologic and Clinical Cancer Research Study 40/81)]. / Erste Ergebnisse der adjuvanten portalen Leberinfusion nach Radikaloperation von Kolorektalkarzinomen (SAKK-Studie 40/81).

Between July 1981 and June 1987, 533 patients from 7 participating institutions have been entered in a prospective randomized trial to assess the value of adjuvant portal infusion (5-Fluorouracil 500 mg/m2/d x 7 continuous infusion + Mitomycin-C 10 mg/m2 on day 1 as a bolus injection through portal venous catheter) compared to radical surgery alone. The portal venous catheter was placed through any side-branch of the mesenteric venous system during laparotomy for the primary tumour. Using the transabdominal route, there have been no catheter-related complications. Overall hospital mortality in the study was 1.75% and was not influenced by adjuvant treatment. Analysis of 469 eligible patients at a median follow-up of 48 months revealed 39.1% recurrencies in the control group and 31.8% in the infusion group (p = 0.09, logrank). Median survival of control patients is 72 months, of chemotherapy treated patients not yet reached. Significant survival advantages have been detected for those 195 (85%) patients who received full-dose adjuvant chemotherapy (67% versus 53% 5-year survival). Due to the low number of deaths in this trial, prolonged follow-up is needed for definitive survival conclusions.