Early PSA decrease is an independent predictive factor of clinical failure and specific survival in patients with localized prostate cancer treated with radiotherapy combined or not with androgen deprivation therapy

Abstract

It is generally accepted that external beam radiotherapy (EBRT) and brachytherapy (BT) work via a relatively slow process of tumor-cell killing, producing a gradual decrease in prostate-specific antigen (PSA) to an eventual nadir in 2–5 years. The importance of the interesting study reported by De Crevoisier et al [1.de Crevoisier R. Slimane K. Messai T. et al.Early PSA decrease is an independent predictive factor of clinical failure and specific survival in patients with localized prostate cancer treated by radiotherapy with or without androgen deprivation therapy.Ann Oncol. 2010; 21: 808-814Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. is that it is the first to show that a rapid fall of PSA after only 6 weeks of EBRT alone is a significant independent prognostic factor for biochemical failure (BF), clinical failure (CF) and prostate cancer-specific survival (PCSS). The authors postulate that a rapid fall in PSA within 6 weeks after the start of EBRT indicates that (i) the tumor is extremely radiosensitive and/or (ii) all the disease is within the radiation field. In this study (as in others), the D’Amico risk groups were prognostic with regard to BF, CF and PCSS. It is probable that the differences in post-therapy outcome between the risk groups are largely due to a greater proportion of cases with unrecognized extraprostatic or systemic dissemination of cancer in the higher risk groups. This indicates that postulate (ii) above is probably not correct, i.e. there was more disease outside the radiation field in the high-risk group in this study. It is interesting to note that in group 1, the percentage of patients with a decrease in PSA within 6 weeks of initiating EBRT alone did not differ much between the risk groups since the PSA decreased in 77% of the low-risk group, 83% of the intermediate-risk group and 81% of the high-risk group. If the authors’ postulates above are correct, this means that there was extremely radiosensitive and localized cancer in ∼80% of all three risk groups. However, this raises the question why there was a difference between the risk groups with regard to long-term outcome but not with respect to early PSA response. In high-risk group 1 patients with PSA6wRT (PSA assessed during the 6th week of the external beam radiotherapy course)/PSApreRT [baseline PSA (before the start of radiotherapy)] >1, the estimated PCSS at 12 years was zero. This indicates that patients whose PSA increased during 6 weeks of EBRT alone invariably died of prostate cancer indicating that they had (i) micrometastatic disease outside the field of radiation or (ii) radioresistant and aggressive localized cancer. This paper (like most other reports on EBRT for prostate cancer) does not provide data on the management of study patients after the development of BF or CF. Presumably, most of them would have received androgen deprivation therapy (ADT), raising the question whether the higher PCSS in low-risk patients was due to a better response to ADT compared with high-risk patients. In group 2 patients who received ADT plus EBRT, the median (range) PSA before ADT was 18.2 ng/ml (1.6–148.0 ng/ml) and after 3 months of ADT, it was 1.3 ng/ml (0.01–31 ng/ml). This shows a quite rapid and dramatic overall PSA response to just 3 months of ADT, before the initiation of EBRT. The authors found an ‘undetectable’ PSA (≤0.2 ng/ml) in 12% of patients, and in this group, the 5-year BF-free rate was 87%, while the 10-year PCSS rate was 100%. The authors postulate that an undetectable PSA after 3 months of ADT (i) may indicate extremely hormone-sensitive prostate cancer, where most cancer cells have been killed by ADT or (ii) it may indicate high radiosensitivity to the subsequent EBRT. It is generally accepted that an undetectable PSA (<0.1 ng/ml) 3 months after radical prostatectomy (RP) indicates that all cancer cells have been eradicated. The findings in this study indicate that in some patients, 3 months of ADT may be ‘as effective as RP’ in eradicating prostate cancer. This raises the question whether EBRT is necessary in patients with PSA ≤0.2 ng/ml after 3 months of ADT and whether it achieves anything in those with PSA >0.2 ng/ml after ADT. It is interesting that a lower dose of EBRT (65 Gy) was used in more group 2 than group 1 patients (81% versus 36%), although high-risk cancer was present in more group 2 than group 1 patients (63% versus 40%). This raises the question whether reliance was placed on the neoadjuvant ADT to ‘take care’ of the higher risk disease in group 2 patients. Interestingly, EBRT included the pelvis in more of the group 2 patients (53% versus 22%) probably in an attempt to address the greater risk of pelvic node metastases in the higher risk patients in group 2. It remains an enigma why in several previous studies, RP after neoadjuvant short-term ADT compared with RP alone showed no benefit with regard to BF or CF (even though the positive surgical margin rates were decreased) whereas EBRT with short-term ADT was found to have better outcomes than EBRT alone. It is also interesting to note that the duration of ADT before and after EBRT has progressively increased from ∼3 months in earlier studies to 3 years in more recent studies. This raises the question whether increasingly greater reliance is placed on ADT to ensure ‘satisfactory’ outcomes after EBRT or BT. The findings in this study confirm the urgent necessity for prospective, randomized clinical trials comparing ADT alone versus ADT plus EBRT or BT in men with prostate cancer (especially high-risk cancer) to define the contribution (if any) of EBRT or BT.