In this RTOG 9202 study, we verified the significance of p53 as a prognostic factor in Pca. The abnormal expression of p53 was related to about a 2× increased risk of death from Pca and the development of distant metastasis at 5 years. To our knowledge, this is the largest analysis of p53 ever performed in men with Pca and the first in men treated with RT + LTAD.
Although there is little doubt concerning the relationships between p53 immunoreactivity and unfavorable histology or advanced disease in Pca, the prognostic value has been uncertain. Shurbaji et al.
) evaluated 109 patients who received curative radiotherapy, hormonal therapy, or watchful waiting with a mean follow-up of 3.8 years. Multivariate analyses showed p53 reactivity was significant with Wilcoxon test only but not with log–rank and Cox tests. Similarly, in a study of 186 Pca patients treated with transurethral resection and subsequent surveillance, Stattin et al.
) demonstrated a significant correlation between p53 staining and shorter survival only with univariate, but not with multivariate analyses. More recently, Quinn et al.
studied p53 in 263 men with localized Pca treated uniformly with radical prostatectomy and found that the p53 status was an independent predictor for relapse in multivariate analysis (24
Only a few studies have focused on the prognostic value of detecting abnormal p53 in Pca treated with radiation therapy. As mentioned previously, in the study of RTOG 8610, Grignon et al.
demonstrated that p53 status was a significant independent prognostic indicator for time to distant metastases, progression-free survival and overall survival (17
). However, Stattin et al.
), who studied 60 patients with Pca treated with definitive external beam therapy, found that p53 did not correlate with tumor grade or cancer-specific survival. Other studies, which analyzed p53 as well as bcl-2 in Pca treated with radiation therapy, showed conflicting results also (15
). Recently, Ritter et al.
) investigated p53 expression in favorable-to-intermediate-risk Pca treated with radiotherapy. Abnormal p53 was found to be strongly and independently correlated with the actuarial biochemical failure at 5 years with a hazard ratio of 2.3.
Several issues should be considered in the interpretation of these results. A major concern is the statistical power of the studies for detecting a survival difference between the patients with an abnormal p53 status and those with a normal one. Other issues that need to be considered are the cutoff point for p53 positivity, patient characteristics, treatment, and follow-up. Visakopi showed that only high-level p53 accumulation with staining in more than 20% of tumor cells was associated with a poor outcome (27
). Quinn et al.
also demonstrated that a stratum of 20% was an effective cutoff point in predicting cancer specific death for patients underwent radical prostatectomy (24
). Grignon et al.
further demonstrated that among three cutoff points studied, including (1)
presence of any detectable cells, (2)
more than 1%, and (3)
20% or more, the last cutoff point (≥20%) was the best one for assessing prognostic value of p53 in Pca (17
). In this study, using the 20% cut point, p53 was confirmed to be an independent predictor for distant metastasis and cause-specific mortality.
In addition, a possible interaction between p53 and hormone therapy was observed in this study. In the analysis of RTOG 8610, which also included men treated with STAD + RT, p53 status was significantly associated with a poor prognosis, with respect to time to distant metastases (17
). In this study, we confirmed that for patients treated with STAD + RT, p53 was significantly associated with cause-specific mortality. There is a borderline significant relationship of p53 status with distant metastasis (p
= 0.06) and a more significant relationship to cause specific mortality. A possible explanation of this difference is that after distant metastasis occurs, progression to death from prostate cancer is more rapid when p53 is abnormal. An example of this phenomenon is seen in an analysis of DNA-ploidy, wherein non-diploid tumors treated with STAD + RT (28
) had a reduced survival, but no difference in metastasis; these tumors were less responsive to salvage androgen deprivation.
Furthermore, our results showed that the improved efficacy of LTAD + RT with respect to cause-specific mortality was much more significant in the patients with abnormal p53 status. These results indicate a possible mechanism of long term hormone therapy in reversing or bypassing the p53-dependent pathway in prostate cancer. However, these findings require further confirmation by prospective studies.
In summary, our results indicate that patients with abnormal p53 who undergo STAD and RT are associated with poor prognosis; long-term androgen deprivation appears to improve outcome. Our study provides strong evidence for using p53 as a marker stratifying patients in future trials aimed at evaluation of androgen deprivation adjuvant to RT.