It has been shown that more than 80% of advanced colorectal carcinomas harbor mutations in the p53 tumor suppressor, and are associated with lymphatic dissemination and a poorer prognosis 17,18. We previously found that patients with irradiated rectal carcinomas with p53 overexpression had poor prognosis after radical resection. In 1998 , PMC improved the prognosis of rectal carcinoma with P53 overexpression after radical resection. Forty-two of 107 patients examined between January 1992 and December 1997 with irradiated rectal carcinomas (39%) showed positive immunohistochemical staining for p53. Among them, 14 patients received adjuvant chemotherapy. This study showed a lower local recurrence rate (0% in PMC vs. 28.6% in non-PMC), a lower distant recurrence rate (7.1% in PMC vs. 42.9%in non-PMC) , and a higher 3-year survival rate (100% in PMC vs. 64.3% in non-PMC)14. These results suggested that the antitumor property of 5-FU, enhanced by pharmacokinetic modulation, might have a lethal effect on rectal tumors with a loss of the p53-related apoptosis pathway.
Subsequently, a prospective study using PMC for unresectable colorectal carcinoma was reported in 1999 as a treatment for inoperable and metastatic colorectal carcinoma, but remained unsatisfactory despite the aviability of many anti-cancer agents. The subjects were 120 patients who were prospectively selected for study between November 1989 and July 1998. The patients selected PMC or alternative treatment. Fifty-six patients recieved PMC. PMC markdly improved the median survival period (26.6 months vs. 9.2 months P<0.000001). This significant improvement was observed in unresectable primary colorectal carcinoma (P=0.0003), recurrent tumors (P<0.00001), local extension (P=0.01), lung metastasis (P=0.03), liver metastasis (P=0.0001), and peritoneal seedings (P=0.02). One of 56 patients who recieved PMC developed grade 4 toxicity15. PMC significantly improved the prognosis of unresectable colorectal carcinoma, which has a low survival rate.
Hepatic metastases are a major cause of mortality in patients with colorectal carcinomas. We also reported our experiences with arterial 5-FU infusion and UFT after resection of hepatic colorectal secondaries in 2000. Fifty-eight patients were divided into two groups after hepatectomy. Group A, 30 patients, underwent hepatic arterial infusion (HAI) via an implantable port system with perfusion 5-FU for 2 consective days per week at 600 mg/m2/day, and oral administration of UFT at 400 mg/day for 5-7 days per week, repeated 10 times, while Group B, 28 patients, underwent oral administration of UFT at 400 mg/day for 6 months. Plasma 5-FU concentrations during chemotherapy were detected using high performance liquid chromatography. Maximum plasma concentrations 5-FU in Group A reached 144.0 ng/mL and Group B 58.7 ng/mL. The cumulative 5-year survival rate after hepatectomy in group A was 59% and in group B was 27%(p=0.00001). HAI-PMC drastically decreased hepatic recurrence after curative resection (median hepatic recurrence free times were 34.2 months in Group A vs.18.4 months in Group B ; p=0.00002). Group 3 toxicity in Group A was found in 3 patients 23.
However, extrahepatic recurrence could not be reduced by HAI-PMC. Despite adequate response in the liver using HAI, systemic failure has been reported in > 50% of patients, most commonly in the lung. Systemic concentration of 5-FU during HAI-PMC (60-150 ng/mL) might not be enough to prevent other distant metastasis. This data suggests that systemic chemotherapy, such as continuous venous infusion (CVI)-PMC , which was previously used in the treatment of colorectal metastasis, might be essential after HAI-PMC is completed.
Thus, PMC significantly improved the prognosis of advanced colorectal carcinoma and also indicated tolerable compliance and cost effectiveness. Therefore, Professor M.Kusunoki acquired an American patent of PMC in 2001. Now, a randomised study comparing 6 month's bolus 5-FU / leucovorin with PMC as adjuvant chemotherapy for patients with Dukes' C colorectal carcinma is ongoing .
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