Department of Radiation Oncology, Shuang Ho Hospital Yu Jen Wang MD Role of Salvage Intensity Modulated Radiation Therapy for Biochemical Failure after Radical Prostatectomy 加IIMRT 前面減少 後面加入oncotarget Department of Radiation Oncology, Shuang Ho Hospital Yu Jen Wang MD

In 1853 Emperor Xian Feng of the Ching Dynasty About prostate ca Was a Very Rare Disease Prostate cancer… Rare disease… 1853清咸豐三年 太平天國 臺灣天地會 Queen Victoria https://ourworldindata.org/life-expectancy/ 40 VS. 80 In 1853 Emperor Xian Feng of the Ching Dynasty

Introduction Epidemiology: Primary treatment: 46% OP, 30% RT, 60% ADT US in 2014: 233,000 new cases / 29,480 patients death from prostate cancer Taiwan: in 2013: 4,804 in 2013, 1207 dying of the disease. More advanced disease, higher PSA Primary treatment: Life expectancy/Risk Groups (T stage, Gleason Score, PSA) Active Surveillance Radical prostatectomy (RP) Radiotherapy Young, Hugh H. "THE CURE OF CANCER OF THE PROSTATE BY RADICAL PERINEAL PROSTATECTOMY (PROSTATO-SEMINAL VESICULECTOMY)-HISTORY, LITERATURE AND STATISTICS OF YOUNG OPERATION." Journal of Urology 53.1 (1945): 188-262. 46% OP, 30% RT, 60% ADT Taiwan Cancer Registry United States Cancer Statistics

Surgery technique Traditional radical prostatectomy Localized patients Life expectancy ≥10 years No serious comorbidity Laparoscopic radical prostatectomy Robotic radical prostatectomy Adverse effects Blood loss Erectile dysfunction Urine incontinence . "Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study." A multinational, multi-institutional study comparing positive surgical margin rates among 22393 open, laparoscopic, and robot-assisted radical prostatectomy patients." Nam, Robert K., et al. The lancet oncology 15.2 (2014): 223-231. Sooriakumaran, Prasanna, et al. European urology 66.3 (2014): 450-456.

After Radical prostatectomy (RP) Overall survival Disease free survival Biochemical failure rate 15-30% Risk factors: positive surgical margins, seminal vesicle invasion (SVI), extraprostatic extension (EPE) and higher Gleason scores AUA/ASTRO Guideline 2013 Stephenson AJ, et al. Postoperative radiation therapy for pathologically advanced prostate cancer after radical prostatectomy. European urology 2012;61:443-451.

Adjuvant RT vs. Postop surveillance  Decreases the risk of biochemical relapse  Administering RT to some patients who would otherwise never require treatment SWOG 8794 (1988-1997) 425 patients EORTC 22911 (1992-2001) 1005 patients ARO 9602 (1997-2004) 268 patients Pathological risk factors Extraprostatic disease S.V.+ Margin+ AUA/ASTRO Guideline 2013

Adjuvant Radiation Therapy Results Freedom Biochemical from Relapse Local Control RP RP+RT Actuarial Endpoint ARO 54 72* NS 5 yrs EORTC 53 74* 85 95* SWOG 44 78 92* 25 51* 10 yrs *Statistically significant with RT All numbers are in percentages

Adjuvant Radiation Therapy Results Clinical Free Disease Survival Metastasis Survival Overall RP RP+RT Actuarial Endpoint ARO NS 95 97 5 yrs EORTC 81 91* 94 93 92 SWOG 70 84* 82 87 90 91 49 70* 61 71* 66 74* 10 yrs *Statistically significant with RT All numbers are in percentages

Salvage treatment Salvage RP Salvage RT Cryotherapy HIFU ADT The 2017 NCCN® clinical practice guidelines in oncology on prostate cancer.

Biochemical Relapse: Salvage Prostate Bed Radiation Therapy Results Author Pt., No. Salvage RT Dose Median (Gy) Biochemical Response % BCR-free% Endpoint actuarial Neuhof 171 63.0 83 35 5-yr Ward 211 64.0 90 48-66 5-yr. Brooks 114 69 33 6-yr. Stephenson 1540 64.8 59 32 Maier 170 68.0 - 44 7-yr. Buskirk 368 30 8-yr. Pazona 223 73 25 10-yr. Update一下

RTOG 9601

Rtog 9601 1998-2003, 760 pts Post prostatectomy with a lymphadenectomy T2 margin+, T3 RT+ADT (24 months bicalutamide) vs. RT (64.8Gy, 2D or 3DRT) Median f/u: 12 years OS: 76.3% vs. 71.3% (p=0.04) Death from prostate cancer: 5.8% vs. 13.4% (p<0.001) Metastatic prostate cancer: 14.5% vs. 23% (p=0.005) Toxicity: Gynecomastia 69.7% vs. 10.9% Shipley, William U., et al. New England Journal of Medicine 376.5 (2017): 417-428.

Shipley, William U. , et al. New England Journal of Medicine 376

GETUG-AFU 16 2006-2010 743 pts, pT2, pT3, and pT4a RT (66Gy, 3D or IMRT)+ goserelin (6m) vs. RT free of biochemical progression: 80% vs. 62% (p<0.0001) Toxicity: hot flushes, sweating Carrie, Christian, et al. The Lancet Oncology 17.6 (2016): 747-756.

Nomogram

Biochemical failure 2460 pts Median f/u : 5 yrs 24% GS≤6, 56% GS=7, 56% pT3a, 58% margin+ 16% with ADT 5-yr FFBF rate was 56% Concordance index, 0.68 "Contemporary update of a multi-institutional predictive nomogram for salvage radiotherapy after radical prostatectomy." Tendulkar, Rahul D., et al. Journal of Clinical Oncology 34.30 (2016): 3648-3654.

estimating 5- and 10-year rates of distant metastases after salvage radiotherapy Concordance index, 0.74 Tendulkar, Rahul D., et al. Journal of Clinical Oncology 34.30 (2016): 3648-3654.

Our study IMRT: Definitive IMRT in localized Pca results in lower acute and late toxicities compared with conventional conformal RT techniques Prostate cancer (PCa) patients undergoing salvage intensity modulated radiation therapy (IMRT) for post-radical prostatectomy (RP) biochemical failure Prognostic factors in IMRT era? Goenka A, Magsanoc JM, Pei X, Schechter M, Kollmeier M, Cox B, Scardino PT, Eastham JA and Zelefsky MJ. Improved toxicity profile following highdose postprostatectomy salvage radiation therapy with www.impactjournals.com/oncotarget 44235 Oncotarget intensity-modulated radiation therapy. European urology. 2011; 60:1142-1148. Goenka A,.et al European urology. 2011; 60:1142-1148. The 2017 NCCN® clinical practice guidelines in oncology on prostate cancer.

Methods Inclusion criteria From 2004 to 2012 Exclusion Criteria Patients underwent post-RP IMRT at NTUH: 69 Prostate adenocarcinoma Received salvage RT Exclusion Criteria Adjuvant intent: 16 LN+: 3 Total 50 patients enrolled Update: Inclusion criteria From 2004 to 2016: n=111, without HT: 44

methods Definition for post-RP biochemical failure PSA level of >0.20 ng/ml by two consecutive measurements. PSADT and PSA velocity (PSAV) between the post-RP PSA nadir and the initiation of salvage RT were calculated using at least two PSA measurements with a 3-month interval and log calculations on the website of the Memorial Sloan Kettering Cancer Center

RT technique All IMRT Dose: Median 70 Gy, range: 63-74 Gy CTV: prostatic and seminal vesicle bed plus periprostatic tissues as the EORTC guideline PTV: expansions were 6 mm posteriorly (rectum), 6 mm inferiorly, 10 mm anteriorly, bilaterally, and superiorly from CTV 60-ml air-filled endorectal balloon was placed 100% of prescribed radiation dose covering >95% of the PTV, with the maximum not exceeding 110% Constraint . "Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group." Poortmans, Philip, et al Radiotherapy and Oncology 84.2 (2007): 121-127.

Initial clinical T stage before RP P staging   T1 2 4 T2 22 44 T3 25 50 T4 1 Initial Gleason score 6 10 20 7 24 48 8 9 12 Total Age at IMRT 50 100 < 65 15 30 65-75 28 56 >75 7 14 Initial clinical T stage before RP   T1 18 36 T2 T3 4 8 Wang et al. 2016

PSA before RP <10 ng/ml 19 38 10-20 ng/ml 16 32 >20 ng/ml 15 30   <10 ng/ml 19 38 10-20 ng/ml 16 32 >20 ng/ml 15 30 Surgical type Open RP 76 Laparoscopic RP 12 24 PSA doubling time <3 months 21 42 3-6 months 14 28 6-12 months 10 20 ≥12 months 5 Nadir PSA after RP <0.1 ng/ml 0.1-0.2 ng/ml 0.2-0.5 ng/ml >0.5 ng/ml 6 PSA velocity   0.1-0.2 ng/ml/year 11 22 0.2-0.5 18 36 0.5-1.0 9 >1.0 12 24 PSA before IMRT <0.2 ng/ml 0.2-0.5 ng/ml 15 30 >0.5 ng/ml 23 46 IMRT dose 60-63.9 Gy 64-67.9 Gy 68-69.9 Gy 1 2 70-74 Gy 26 52 Wang et al. 2016

ADT at biochemical failure   Yes 36 72 No 14 28 ADT duration ≤ 6 months 11 22 6-12 months 5 10 12-24 months 24-36 months 6 12 Wang et al. 2016

Median BFFS time: 70 months survival 5 y/o OS: 91% 5 y/o DFS: 88% 5 y/o BFFS: 60% Median BFFS time: 70 months Wang et al. 2016

toxicity GI toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Acute 25 (50%) 20 (40%) 5 (10%) Late 42 (84%) 1 (2%) 2 (4%) GU toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Acute 31 (62%) 14 (28%) 5 (10%) Late 35 (70%) Wang et al. 2016

Prognostic factors PSA at salvage IMRT Initial PSA before RP PSA nadir after RT PSA doubling time PSA velocity Pathological T stage Gleason score Initial PSA before RP ADT at BCF Salvage IMRT dose Surgical margin on RP ADT duration

Univariate and Multivariate analysis Variable Five-year BFFS p value HR (95% CI) PSA at salvage IMRT   >0.5 ng/ml 37.0% 0.003 0.340 (0.141-0.817) 0.016 ≤0.5 ng/ml 78.3% PSA nadir after RP >0.1 ng/ml 44.4% 0.346 (0.143-0.832) 0.018 ≤0.1 ng/ml 74.0% Wang et al. 2016

Univariate and Multivariate analysis PSA doubling time   ≥6 months 75.9% 0.211 <6 months 50.8% PSA velocity <0.5 ng/ml/year 54.5% 0.358 >0.5/ng/ml/year 68.4% Pathological T stage T3-T4 58.4% 0.844 T1-T2 63.6% Wang et al. 2016

Univariate and Multivariate analysis Gleason score   8-10 58.3% 0.931 ≤7 61.3% Initial PSA before RP ≥20 ng/ml 67% 0.831 <20 ng/ml 56% ADT use at BCF Yes 65.5% 0.267 No 50.0% Salvage IMRT dose <70 Gy 67.0% 0.245 ≥70 Gy 52.4% Wang et al. 2016

Univariate and Multivariate analysis Surgical margin on RP   Positive 62.3% 0.261 Negative 56.6% ADT duration ≦6 months 72.9 0.451 > 6 months 61.9 Wang et al. 2016

Multivariate analysis PSA nadir< 0.1 5 y/o BFFS 74% vs. 44% Wang et al. 2016

PSA level at salvage RT<0.5 5 y/o BFFS 78% vs. 37% Wang et al. 2016

Favorable Group 5 y/o BFFS 83% vs. 43% Wang et al. 2016

Patients characteristics (without Ht) Median age at RP: 62 years Median age at RT: 66 years Pathological T stage: 45% T2, 50% T3 Median RT dose: 70Gy (63-73Gy) Gleason score=7: 50% Median f/u: 24 months

survival 3 y/o MFS: 95% 3 y/o BFFS: 69%

toxicity GI toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Late 40 (91%) 3 (7%) 1 (2%) GU toxicity Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Late 37 (84%) 4 (16%) 2 (4%) 1 (2%)

Comparison of Late GI Toxicity Pro/Retrospective Adjuvant/Salvage Trials # pts. F/U mths. Grade 2 Grade 3 Grade 4 Our results 44 24 2% 0% Bolla et al. EORTC 22911 1005 45 2.5% Thompson et al. SWOG 8794 214 127 3.3% Feng et al. 959 55 4% 0.4% 0.3% Zelefsky et al. 42 5% Choo et al. 98 50 Forman et al. 16 -

Conclusion Biochemical failure rate 15-30% after RP consider adjuvant RT or salvage RT (risk factors: Extraprostatic disease, S.V.+, Margin+), early salvage? Prediction factors: ADT, GS, Margin, pT3a or pT3b, pre-RT PSA, RT dose<6600cGy GETUG 16/RTOG 9601: ADT+RT better than RT, early salvage ADT? Standard of care for all men with BCR undergoing sRT? Salvage IMRT for PCa patients with post-RP biochemical failure: good outcome (5 yr BFFS after SRT: 50-60%) and low toxicity The patients with post-RP PSA nadir ≤0.1 ng/ml and PSA ≤0.5 ng/ml at salvage IMRT could be benefited the most by salvage IMRT http://www.sciencedirect.com/science/article/pii/S0302283817301793

Thank you for your attention John of Arderne https://link.springer.com/article/10.1007/BF01656167