Radiation dose and late failures in prostate cancer

Abstract

Purpose-To quantify the impact of radiotherapy (RT) dose escalation on the timing of biochemical failure (BF) and distant metastasis (DM) for prostate cancer treated with RT alone.Methods and Materials-A total of 667 men with clinically localized intermediate and high risk prostate cancer treated with 3D-conformal RT alone were retrospectively analyzed. The interval hazard rates of DM and biochemical failure (BF), using ASTRO and Phoenix (Nadir+2) definitions, were determined. Median follow-up was 77 months.Results-Multivariate analysis showed that increasing RT dose was independently associated with decreased ASTRO BF (P<.0001), Nadir+2 BF (P=.001), and DM (P=.006). The preponderance (85%) of ASTRO BF occurred at ≤4 years after RT, while Nadir+2 BF was more evenly spread over years 1-10, with 55% BF in ≤4 years. RT dose escalation caused a shift in the BF from earlier to later years. The interval hazard function for DM appeared to be biphasic (early and late peaks) overall and for the <74 Gy group. In patients receiving ≥74 Gy, there was a reduction in the risk of DM in both the early and late waves, although the late wave appears reduced to a greater degree.Conclusions-The ASTRO definition of BF systematically underestimates late BF due to backdating. RT dose escalation diminished and delayed BF; the delay suggests that there may still be local persistence in some patients. For DM, higher RT dose reduced both the early and late waves, suggesting that persistence of local disease contributes to both.

Tumor Hypoxia Predicts Biochemical Failure following Radiotherapy for Clinically Localized Prostate Cancer

“…The diminished long-term predictive power of hypoxia may reflect the fact that oxygen dynamics in tumors change over time and in response to treatment (11), so that hypoxia measured at diagnosis may not be relevant to the biologic or clinical behavior several years later. Also, there is evidence to indicate that radiotherapy dose-escalation to the levels used in this study may more effectively suppress late recurrences than early recurrences (28), consistent with the former arising from more indolent, better oxygenated, more radiosensitive disease at the time of treatment. The median follow-up of patients in this study was only 6.6 years, and a clearer picture of the relationship between pretreatment tumor hypoxia and late disease recurrence may emerge with further surveillance.…”

“…The explanation for this is unclear, but it may reflect an interaction between the effects of hypoxia on local versus metastatic recurrence in the context of modern, high-dose radiotherapy, coupled to the longer natural history of prostate cancer compared with other tumors. Several reports have described a biphasic recurrence pattern in prostate cancer patients who receive radiotherapy, with an early wave in the first 4 years mainly due to unrecognized disseminated disease at diagnosis and a late wave between 8 and 10 years thought to arise from locally persistent tumor leading to secondary metastases (26)(27)(28). Primary tumor hypoxia has been shown in laboratory and clinical studies to impair the local response to radiotherapy and increase the development of metastases (3,4).…”

Daidzein Effect on Hormone Refractory Prostate Cancer In Vitro and In Vivo Compared to Genistein and Soy Extract: Potentiation of Radiotherapy

“…The majority of cases of PCa now diagnosed in the United States present with clinically localized disease (12). Localized PCa is sensitive to conventional radiotherapy, yet this treatment was reported to be insufficient to eradicate PCa in a proportion of patients, resulting in clinical recurrence (12)(13)(14). Recurrent tumors reflect the limitations of radiotherapy and are caused by radioresistance of tumor cells, which is also partly due to focal areas of radioresistant hypoxic cells.…”

Advances in the treatment of prostate cancer with radiotherapy

“…As Milosevic et al stated, this pattern of early recurrence is compatible with the presence of hypoxia-driven radioresistant cells. Moreover, it has been shown that radiotherapy dose escalation suppresses late recurrences more effectively [52], possibly caused by more indolent and better oxygenated cells. Thus, the combination of dose escalation with hypoxia targeted therapies in intermediate-risk prostate cancer deserves further investigation [51].…”