Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation

Abstract

Purpose/Objectives Existing definitions of high-risk prostate cancer comprise men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of NCCN high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease, and/or ≥5 biopsy cores with Gleason sum 8–10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients. Methods and Materials All men consecutively treated with definitive radiation by a single provider from 1993–2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 (34%) patients with VHR disease. Multivariable-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariable-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men. Results Men with VHR disease as compared to other NCCN high-risk men experienced higher 10-year incidences of BF (54.0% vs. 35.4%, p<0.001), DM (34.9% vs. 13.4%, p<0.001), PCSM (18.5% vs. 5.9%, p<0.001), and OM (36.4% vs. 27.0%, p=0.04). VHR men with a detectable PSA at the end-of-radiation (EOR) remained at high risk of 10-year PCSM, as compared to VHR men with an undetectable EOR PSA (31.0% vs. 13.7%, p=0.05). Conclusions NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be further explored, as should novel agents.

Classifying high-risk versus very high-risk prostate cancer: is it relevant to outcomes of conformal radiotherapy and androgen deprivation?

“…In contrast to our findings, Narang et al showed that when evaluating patients with HR disease who were treated over a 15 year interval from 1993 to 2006, the revised 2015 NCCN HR/VHR subgrouping were predictive for worse outcomes in the VHR subgroup [6]. Although the long follow-up interval is an important strength of Narang’s study, the median follow-up time of our cohort is 50 m (range: 12 m-142 m) and the median time to BF in our reports are similar at 34 m and 30 m. The difference in our findings may be better explained by the differences in treatment received by our respective cohorts.…”

“…In consideration of these findings, the 2014 NCCN guidelines were revised and added the presence of primary Gleason grade 5 or ≥5 cores with Gleason score 8–10 as new criteria for inclusion into the VHR group [1]. While relevant for surgical outcomes, the predictive value of the HR/VHR grouping has not been assessed in patients treated with current CRT techniques [6]. Recently, Narang et al showed inferior outcomes in the VHR versus HR group in a cohort of patients treated with RT and ADT from 1993 through 2006.…”

“…Recently, Narang et al showed inferior outcomes in the VHR versus HR group in a cohort of patients treated with RT and ADT from 1993 through 2006. However, this retrospective study was limited by use of radiation techniques, treatment volumes, dose, and use of ADT that do not reflect current therapeutic approaches [6]. …”

Outcomes of very high‐risk prostate cancer after radical prostatectomy: Validation study from 3 centers

“…5 Subsequently, VHR criteria were shown to also identify men with markedly higher rates of METS and PCa-specific mortality in a cohort treated with definitive radiation therapy (RT) plus androgen deprivation therapy (ADT). 11 Cancer February 1, 2019 Here we sought to determine whether VHR criteria retain prognostic significance in a validation study by pooling patients with high-risk PCa who underwent RP at 3 independent tertiary centers.…”

High-Risk Prostate Cancer: Role of Radical Prostatectomy and Radiation Therapy

“…Warde et al [10] randomized 1,205 patients between RT plus ADT and ADT only, and showed that RT plus ADT improved overall survival at 7-year follow-up compared with ADT only (74 vs. 66%). A number of retrospective studies have shown results that favor RT over RP, with Narang et al [11 ]showing lower PCSM (24 vs. 38% in a total of 214 patients) (table 1) and Stephans et al [12] indicating lower BCR rates (46 vs. 53% in a total of > 1,500 patients). Moreover, concerns about side effects, positive margins, and inadequate disease control in high-risk patients may contribute to a ‘therapeutic nihilism' that sways physicians away from recommending RP and towards RT plus ADT for patients with high-risk PC [13].…”