CARCINOMA OF THE RECTUM - POSSIBLE CELLULAR PREDICTORS OF METASTATIC POTENTIAL AND RESPONSE TO RADIATION-THERAPY

BACKGROUND: Preoperative radiation therapy can markedly improve local control of rectal carcinoma. However, some tumors do not respond well to moderate doses of preoperative radiation and would be better served by more aggressive preoperative treatment (e.g., chemoradiotherapy). Cellular predictors of responsiveness to radiation can help to select lesions for more aggressive treatment. In addition, there is a need fo r cellular predictors of metastatic potential. This is particularly im portant in the setting of preoperative radiation-downstaging by preope rative treatment can obscure the true pathologic stage of a tumor and confound the usual selection criteria for postoperative chemotherapy. PURPOSE: This study was undertaken to determine if proliferating cell nuclear antigen (PCNA), p53, DNA ploidy, and S-phase fraction are asso ciated with response to radiation and/or risk for distant metastatic d isease and to determine if these cellular markers are best evaluated f rom preradiation biopsy specimen or the larger (but possibly altered) final surgical specimen. MATERIALS AND METHODS: Archival specimens fro m 23 cases of ultrasound T3 or T4 rectal carcinoma treated preoperativ ely with radiation therapy were reviewed. Eligible lesions had preradi ation biopsy specimens of sufficient site for flow cytometric review o f archival tissue. Factors considered included PCNA positivity, presen ce of mutant nuclear p53, more than 30 percent tumor cells in S-phase, and presence of aneuploidy. RESULTS: With a median follow-up of three years, overall freedom from relapse was 83 percent, with all but one failure being extrapelvic. PCNA positivity in the preradiation specime n was significantly (P = 0.025) associated with a greater risk of tumo r recurrence. In addition, there was a trend to greater likelihood of ''probable downstaging'' (defined as surgical T stage less than prerad iation ultrasound T stage) for lesions that were PCNA-negative or lesi ons with normal p53. Biomarkers measured in the postradiation surgical specimen were not associated with either freedom from relapse or resp onse to radiation. Radiation treatment appeared to produce false-negat ives in the final specimen. Thus, there were significantly more specim ens converting from PCNA-positive to PCNA-negative after preoperative radiation than would be expected solely on thr basis of sampling error s (P = 0.004). Similar results were found for abnormal p53 findings (P = 0.02). CONCLUSIONS: Prospective studies of biomarkers should be bas ed on pretreatment specimens if preoperative radiation is given. For c arcinoma of the rectum, PCNA and p53 may be useful predictors of both metastatic potential and responsiveness to radiation.