BERKELEY, CA (UroToday.com) - Prostate cancer is the most common form of cancer in men in the United States, with nearly 240 000 new cases occurring each year. SEER data illuminates the fact that greater than 99% of these men will be alive 5 years after the diagnosis of their disease, which is in stark contrast to most other common cancers in men (lung, colon, bladder, etc). When definitive therapy (surgery or radiotherapy) fails and the patient progresses through salvage hormonal therapy, the disease is termed castration-resistant prostate cancer (CRPC). CRPC occurs in approximately 35 000 men each year and, unlike newly diagnosed localized prostate cancer, it is nearly uniformly fatal, with a median survival of approximately 2 years.
To avoid overtreatment, it is important to identify men who are at the highest risk of progressing to CRPC, and attempt to intervene at earlier stages of the disease with curative intent. To begin to understand how to identify patients with such risk, we performed the first study to evaluate predictors for the progression to CRPC, using a large cohort of 2 478 men with localized prostate cancer undergoing definitive external beam radiation therapy. We found that 14.6% of the entire cohort progressed through definitive upfront therapy to ultimately requiring salvage androgen-deprivation therapy (ADT). However, only 9.9% ultimately progressed to CRPC. This is important, as men with prostate cancer often die from non-oncologic causes of death (i.e., heart disease) more commonly than prostate cancer itself, and that even in a very-high-risk group of men who fail upfront therapy and are on salvage ADT, only 2/3 of them will progress during their lifetimes to CRPC, the most lethal form of prostate cancer. In addition, the progression to CRPC is rare with modern dose-escalated radiotherapy combined with risk-adapted use of ADT.
We identified risk factors that would predict which men would progress to CRPC. These included a more rapid prostate-specific antigen doubling time, higher Gleason score, and an increased duration of ADT at the time of their radiotherapy. Interestingly, neither absolute prostate-specific antigen nor T-stage were independent predictors of development of CRPC, which emphasized the enormous prognostic significance of Gleason score.
As discussed in detail in the Discussion section of the paper, duration of ADT was significantly associated with progression to CRPC, even on multivariate analysis when correcting for potential confounding variables, but the reason is unknown. There are multiple potential hypotheses. To avoid possible confusion, a key point should be mentioned first: ADT with radiotherapy improves survival and outcome for men with intermediate- and high-risk prostate cancer and in and of itself does not promote men to develop lethal prostate cancer. What our results demonstrate is that if you are not cured by radiotherapy combined with ADT, then you are more likely to fail subsequent ADT, which is termed CRPC. Possible explanations for this include the following:
- Acquired resistance to ADT developed during the initial course of therapy;
- A small subset of patients and sub-clones of prostate cancer had intrinsic resistance to ADT from time of diagnosis and were simply selected for during their initial therapy; and
- ADT actually caused a select molecular subgroup of prostate cancer to become more aggressive and transform to CRPC.
This data should help identify men at highest risk for progression to CRPC, for further dedicated study in early-phase clinical trials. Future efforts should investigate new treatment approaches for these men, including novel strategies to inhibit androgen-receptor signaling, or alternative approaches independent of the androgen receptor (i.e., PI3K inhibition).
Daniel E. Spratt and Michael J. Zelefsky as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY USA