Prognostic significance of proliferation associated antigens (PCNA, Ki-67) and p53-expression in inoperable head and neck cancer after accelerated split-course radiation therapy

Purpose: To determine whether the immunohistochemical (IHC) expression of proliferation associated antigens (Proliferating Cell Nuclear Antigen [PCNA], Ki-67) and the nuclear p53 reactivity are predictive for overall-survival (OS) and relapse-free-survival (RFS) in patients (pts) with inoperable squamous cell carcinoma of the head and neck region (SCC H and N) after accelerated split-course radiation therapy (RT) with and without chemotherapy (ChT). Materials and Methods: Between 10/89 and 9/93, 87 pts with biopsy proven SCC H and N (80 male, 7 female, median age 52 years [range, 23-65 years]) were randomly allocated to RT alone or simultaneous RT/ChT as part of a multicenter trial. All pts had inoperable lesions in AJCC (1988) stage III (7 pts, 8%) and IV (80 pts, 92%). Primaries were located in the oral cavity (19 pts, 22%), oropharynx (38 pts, 44%) and hypopharynx (30 pts, 34%). RT consisted of 3 cycles of accelerated fractionation (180 cGy bid, total dose 7020 cGy/51 days). Scheduled split between cycles was 10 days. ChT consisted of cis-DDP, 60 mg/m2, 5-FU, 350 mg/m2, Leucovorin (LV) 50 mg/m2 iv bolus on day 2 and 5-FU, 350 mg/m2/24 h and LV 100 mg/m2/24 h ci on days 3-5. ChT was repeated on days 22 and 44. Routinely processed paraffin embedded sections were IHC-stained using the monoclonal antibodies PC 10, MIB1 and DO7 for detection of PCNA, Ki-67 antigen and p53 oncoprotein. Percentage of positive nuclei per 1000 tumor cells were given as Labeling Index (LI). In addition, tumor volume (TV) and percentage of necrosis were measured using CT-data. Median follow-up was 3.5 years (range 1.5-5 years). Results: OS and RFS were 39% and 44% after 3 years, respectively. In univariate analysis TV (>125 ml: 5% OS vs. ≤125 ml: 54% OS, p<.0001), age (>55years: 66% OS vs. ≤55years: 23% OS, p=.0025), PCNA-LI (LI>20%: 50% OS vs. LI≤20%: 31% OS, p=.0146),MIB1-LI (LI>20%: 55% OS vs. LI≤20%: 23% OS, p=.0344) and additional ChT (RT/ChT: 41% OS vs. RT: 27% OS, p=.0258) had a significant impact on OS. However, in multivariate analysis, only TV (p=.003), age (p=.0015) and ChT (p=.0024) were independent prognostic factors for OS and only the TV (p=.0013) for RFS. IHC expression of the p53 oncoprotein was not found to have any predictive value (p53-LI≤10%: 41% OS vs. LI>10%: 22%, n.s.). Conclusion: In addition to clinical factors both PCNA- and MIB1-expression may help to identify pts with inoperable SCC H and N in whom accelerated RT/ChT is potentially curative. Abnormalities of the p53 oncoprotein are of little clinical significance