title: Classifying high-risk versus very high-risk prostate cancer: is it relevant to outcomes of conformal radiotherapy and androgen deprivation?
abstract: OBJECTIVE
  To evaluate outcomes in prostate cancer patients classified as high-risk (HR) or very high-risk (VHR) who were treated with conformal radiation therapy (CRT) and androgen deprivation therapy (ADT).
  
  
  METHODS
  Between 11/2001 and 3/2012, 203 patients with HR disease received CRT to the prostate (78-82 Gy) and pelvic lymph nodes (46-50 Gy) with ADT (6 m-2 years). Median follow-up was 50 months (12 m-142 m). Biochemical failure was defined according to Phoenix definition. Imaging studies were used to identify local, regional or metastatic failure. Four different VHR/HR groupings were formed using the 2014 and revised 2015 NCCN guidelines. Differences were examined using Kaplan Meier (KM) estimates with log rank test and uni- and multivariate Cox regression analysis (MVA).
  
  
  RESULTS
  Failure occurred in 30/203 patients (15%). Median time to failure was 30 m (4 m-76 m). KM estimate of 4 year biochemical disease free survival (b-DFS) for the entire cohort was 87% (95%CI: 82-92%). Four year KM survival estimates for b-DFS, PCSS and OS were comparable for each NCCN subgroup. On univariate analysis, the NCCN subgroups were not predictive of b-DFS at 4 years, however, DMFS was worse for both VHR subgroups (p = .03and .01) respectively. Cox univariate analysis was also significant for: PSA ≥40 ng/ml p = 0.001; clinical stages T2c p = .004, T3b p = .02 and > 4 cores with Gleason score 8-10 p < .03. On MVA, only PSA ≥ 40 ng/ml was predictive for b-DFS or MFS at 4 years (HR: 3.75 and 3.25, p < 0.005).
  
  
  CONCLUSIONS
  Patients with HR and VHR disease treated with CRT and ADT had good outcomes. Stratification into HR and VHR sub-groups provided no predictive value. Only PSA ≥40 ng/ml predicted poor outcomes on MVA. Distant failure was dominant and local recurrence rare, suggesting that improved systemic treatment rather than intensification of local therapy is needed. Patients with high-risk prostate cancer are most often treated with conformal dose escalated radiation therapy with androgen deprivation. Stratification into high versus very high-risk subgroups using 2014 or revised 2015 National Comprehensive Cancer Network (NCCN) criteria did not impact treatment outcomes. Only Prostate Serum Antigen (PSA) ≥40 ng/ml was predictive of poor prognosis. Distant failure was dominant and local recurrence uncommon which challenges the notion that intensification of local therapy will further improve outcomes in patients with high-risk disease.
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Akram
authors.initials: A
authors.lastname: Saad
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Goldstein
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Yaacov R
authors.initials: YR
authors.lastname: Lawrence
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Spieler
authors.affiliation: Medical Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel-Hashomer, 52621, Israel.
authors.forename: Raya
authors.initials: R
authors.lastname: Leibowitz-Amit
authors.affiliation: Medical Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel-Hashomer, 52621, Israel.
authors.forename: Raanan
authors.initials: R
authors.lastname: Berger
authors.affiliation: Nuclear Medicine, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel-Hashomer, 52621, Israel.
authors.forename: Tima
authors.initials: T
authors.lastname: Davidson
authors.affiliation: Medical Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel-Hashomer, 52621, Israel.
authors.forename: Damien
authors.initials: D
authors.lastname: Urban
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Lev
authors.initials: L
authors.lastname: Tsang
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Alezra
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Weiss
authors.affiliation: Departments of Radiation Oncology, Chaim Sheba Medical Center, Tel Aviv University Sackler School of Medicine, Tel Hashomer, 52621, Ramat Gan, Israel. Zvi.Symon@sheba.health.gov.il.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Symon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D059248:Chemoradiotherapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000145:classification* / Q000401:mortality / Q000628:therapy*; D020266:Radiotherapy, Conformal; D012306:Risk; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists