Our main findings were that HDR (N=131 men) and SBRT boost (N=101 men) resulted in what appears to be similar rates of biochemical control and metastasis freedom, both before and after propensity matching, and with a median follow up of 73 and 186 months, respectively. At 10 years, biochemical control was 85.3% (95% confidence interval [CI] 77.9-93.5%) for SBRT and 74.6% (95% CI 65.3-85.2%) for HDR boost (P=0.3, Log-rank); metastasis freedom was 84.3% versus 82%, respectively. Almost all patients received androgen deprivation therapy, which remains the standard of care for unfavorable and high-risk patients. Remarkably, after testosterone recovery, the median latest PSA reached by men treated with SBRT boost was 0.088, nearly identical to the PSA nadir reported in ASCENDE-RT.6 Serious urinary/gastrointestinal toxicity was rare (4.6%/1.5% for SBRT and 3.0%/0.0% for HDR). Thus, SBRT boost appears safe and may provide similar outcomes to HDR boost for men with unfavorable and high-risk prostate cancer, and we await the results of ongoing trials comparing these modalities.
Several additional observations we make in our study are of note and may shed further light on the management of high-risk prostate cancer in a broader context. First, our study reports remarkably long follow up in a group of patients receiving “ultra-dose-escalation” to the prostate. Indeed, the biologically effective dose of boost therapy exceeds that of SBRT monotherapy or dose-escalated conventionally fractionated radiation. This additional dose-escalation to the prostate may be reflected in the lower PSA nadirs/plateaus achieved by boost therapy -- 0.088 in our study, 0.08 in ASCENDE-RT, as compared to 0.20 for SBRT monotherapy series, and perhaps also in the very low rate of local recurrence we identified (2% overall). A prior dose escalation trial established a dose-response for prostate radiation and biopsy positivity at 2-years post-treatment;7 remarkably, in this study, even at the highest SBRT dose level of 40Gy in 5 fractions, the rate of biopsy positivity at 2-years was 7.7%, perhaps suggesting room for further dose escalation or addition of concurrent hormone therapy if local eradication of disease is of concern.
For low or favorable intermediate risk patients, such an aggressive approach of further dose-escalation may not be clinically prudent. Rather, the optimal dose and fractionation for low to intermediate risk prostate cancer with SBRT, hypo-fractionation, or conventional fractionation, is now well established based upon excellent biochemical control, survival, and low toxicity rates in multiple prospective trials. The same perhaps cannot be said with confidence as of yet for unfavorable to high risk disease. Whether strategies for “ultra-dose-escalation” to the whole gland or more focused dose escalation to MRI-defined intra-prostatic lesions as per the recently published FLAME trial,8 could result in improvement in clinically meaningful endpoints such as metastasis freedom or prostate cancer specific survival in some patients will require further study. Nevertheless, the results of our study seem to suggest that SBRT or HDR boost can safely provide excellent intra-prostatic disease control, even among patients with high and very-high risk disease.
Men with unfavorable and high-risk prostate cancer do not only relapse in the prostate, however, but often experience nodal and distant bone or visceral metastatic relapse. Indeed, the majority of recurrences in our study were distant (non-pelvic) nodal or osseous relapses. Remarkably, among men with long follow up, the recurrence rate slowed but did not appear to plateau, and relapses as late as 180 months post-treatment were observed.
Men treated at our institution with HDR or SBRT boost also receive pelvic nodal radiation extending to a superior border of the L4/L5 or L5/S1 interface, corresponding to the level of the common iliac vessels. In comparison to distant and non-regional nodal sites, in-field pelvic nodal relapse in our cohort was rare (5.3% of relapses), suggesting that pelvic nodal radiation is indeed effective in addressing microscopic pelvic nodal spread. This observation is concordant with the recently published POP-RT trial which found both a disease-freedom and metastasis-freedom benefit to pelvic nodal radiation in men with high nodal metastasis risk.9 In our study, men with nodal relapses largely failed in para-aortic, peri-rectal, and inguinal locations, areas not included in typical pelvic radiation fields. In addition, men often failed at distant sites alone (50% of relapses), suggesting either existence of occult distant micro-metastases prior to treatment which escaped detection during staging, or spread from occult residual loco-regional disease resistant to combined radiation and androgen deprivation, although we would favor the former explanation.
Taken together, our findings suggest that combined prostate “ultra” dose escalation with SBRT or HDR boost, pelvic nodal radiation, and androgen deprivation, is safe, and resulted in remarkably low rates of prostate and pelvic nodal relapse among high and very-high risk patients. Yet, over the course of 10-15 years of follow up, a sizeable subset of men still experienced relapse at distant and non-regional sites. There remains substantial room for improvement for this patient population. Future endeavors to identify and target pre-existing occult sites of metastatic disease with additional focal or expanded radiation fields, to better risk-stratify patients prior to treatment for the purposes of treatment escalation as well as de-escalation, and to further investigate the role, if any, of the addition of systemic therapy such as next-generation anti-androgen drugs or chemotherapies,10 are needed in order to move the dial forward and improve outcomes among our patients with the highest risk of prostate cancer metastasis and mortality.
Written by: William Chen, MD, & Mack Roach III, MD, Department of Radiation Oncology, University of California San Francisco, California
References:
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