P53 overexpression predicts poor chemosensitivity to high‐dose 5‐fluorouracil plus leucovorin chemotherapy for stage IV colorectal cancers after palliative bowel resection

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Abstract
Our study aims to further clarify the prognostic significance of p53 overexpression in stage IV colorectal cancer. Between January 1994 and June 1997, we recruited 144 patients with stage IV colorectal cancers for our study, based on appropriate eligibility criteria. The patients were nonrandomly allocated to 2 treatment groups of either with or without high‐dose 5‐fluorouracil plus leucovorin chemotherapy (HDFL: 5‐Fu: 2,600 mg/m2 leucovorin 300 mg/m maximum 500 mg). Each treatment group was further divided into 2 subgroups according to the status of p53 overexpression. Therefore, 4 subgroups were allocated in our study and were designated as p53 (overexpression) HDFL (+), n = 65; p53 (normal) HDFL (+), n = 37; p53 (overexpression) HDFL (−), n = 27; and p53 (normal) HDFL (−), n = 15, respectively. All patients were prospectively followed until April 2001. There was no significant difference of the background clinicopathologic data of these 4 allocated subgroups of patients (p > 0.05). Multivariate analysis of various clinicopathologic factors of the whole group of patients indicated that age ≥60 years, poor differentiation, mucin production, CEA >100 ng/ml, p53 overexpression and without chemotherapy were the significant independent poor prognostic factors (p < 0.05). Survival analyses indicated that the patients of subgroup p53 (normal) HDFL (+) survived significantly longer than those of subgroup p53 (overexpression) HDFL (+), with mean survival time (95% confidence interval [CI]) of 20.24 (16.24–24.25) and 13.29 (10.98–15.60) months, respectively (p = 0.0043, log‐rank test). In contrast, in patients without chemotherapy, the prognosis was poor regardless of their p53 status, with mean survival time (95% CI) of 6.85 (5.47–8.23) and 5.87 (4.48–7.26) months in p53 (overexpression) HDFL (−) and p53 (normal) HDFL (−) subgroups of patients, respectively (p = 0.2820, log‐rank test). Cancers of normal p53 expression responded significantly better to HDFL (p < 0.05), with mean response rate (95% CI) being 65.57% (52.18–82.96%) in subgroup p53 (normal) HDFL (+) as compared to 35.38% (23.52–47.24%) in subgroup p53 (overexpression) HDFL (+). The toxicity to HDFL was similarly minimal between p53‐normal and p53‐overexpression patients (p > 0.05). We thus concluded that the poorer prognosis of stage IV colorectal cancers with p53 overexpression was associated with their poorer chemosensitivity rather than the more biologic aggressiveness.