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It has been proposed that diverse anticancer drugs and radiation therapy may induce a mode of cell death with the characteristics of apoptosis. Since apoptosis is under the control of several oncogenes, we analyzed the expression of the protein encoded by the proto-oncogenes bcl-2 and p53. Furthermore, we studied cell proliferation [using PC-10 mAb to proliferating cell nuclear antigen (PCNA)] and vascularization [using the CD-31 mAb and by counting intratumoral microvessel density (IMD)] using immunocytochemistry. A series of 73 patients with clinical stage II-IV squamous cell invasive carcinoma of the head and neck (H&N) were treated with concurrent chemoradiation therapy (cisplatin, 80 mg/m2, versus carboplatin, 375 mg/m2, three times every 3 weeks and a total dose of radiation therapy of 64 Gy in 6-8 weeks). We correlated the expression of these markers, determined prior to treatment, with response to the therapy and prognosis. Bcl-2 protein was expressed in 37.4% of the carcinomas (25/67 evaluable), and it was not significantly associated with any other feature studied. Forty (56. 4%) of the 71 carcinomas evaluable for p53 were p53 positive; the median IMD was 38 microvessels/field at the hot spot (range, 18-80), and the median percentage of nuclei labeled by the PC-10 mAb was 50% (range, 0-95%). In the univariate analysis, regional lymph node negativity (P = 0.016), good performance status (PS) (PS >/= 90; P = 0.044), bcl-2 positivity (P = 0.070), and low vascularization (P = 0. 085) were significantly associated with a higher probability of complete remission. In the multivariate analysis (final model), only IMD (continuous variable; P = 0.045) and PS (P = 0.017) retained significance. As far as prognosis is concerned, in the univariate analysis, patients with tumors with low histological grading (grades 1-2; P = 0.006), p53 negative (P = 0.09), bcl-2 positive (P = 0.08), and high PCNA labeling (P = 0.06) had a significantly better disease-free survival. In the multivariate analysis, only grading (P = 0.003) and p53 (P = 0.04) retained significance for disease-free survival. For overall survival, in the univariate analysis, the following markers were significantly prognostic when only deaths due to progression are considered: response to therapy (P = 0.00001), PS (P = 0.04), nodal status (P = 0.028), PCNA (P = 0.04), p53 (P = 0. 08), and grading (P = 0.01). In the multivariate analysis, only patients who achieved complete response (P = 0.00002), high PCNA values (P = 0.002), and low histological grading (P = 0.01) retained a statistically significant probability of better overall survival. Our results suggest that in this series of H&N cancer patients the markers capable of predicting response to therapy are distinct from those associated with prognosis, once the remission has been achieved. This information is potentially useful to the clinician for developing a more rational therapeutic approach for H&N cancer patients eligible for concurrent chemoradiation therapy.

Type

Journal article

Journal

Clin Cancer Res

Publication Date

11/1995

Volume

1

Pages

1375 - 1383

Keywords

Adult, Aged, Analysis of Variance, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Carcinoma, Squamous Cell, Cisplatin, Combined Modality Therapy, Disease-Free Survival, Follow-Up Studies, Head and Neck Neoplasms, Humans, Middle Aged, Neoplasm Proteins, Proliferating Cell Nuclear Antigen, Proto-Oncogene Proteins c-bcl-2, Tumor Suppressor Protein p53