Node + Prostate Cancer (N1/M0), Mack Roach III, MD Professor Radiation Radiation Options (and Evidence): Oncology & Urology, Where are we Now? UCSF APCCC Basel Switzerland 8/29/19; 11:15 – 12:45; 12 minutes
Goal: Discuss Management of N1/M0 Prostate Cancer & the Role of Radiation Therapy 1. Who are we talking about here? a. Clinically node + (e.g. imaging) vs path node +? b. Definitive vs post Op? c. High risk for occult node + Dz? 2. Endpoints? a. Overall Survival , Cause Specific Survival, Mets … b. PSA control c. Biopsies d. QoL? Node-Positive 3. Level of evidence? Prostate Cancer (N1/M0): 4. Technical RT Details? Radiotherapeutic a. SBRT vs ENRT Approaches b. Prophylactic Irradiation
eau European Association of Urology Identifying the Optimal Candidate for Salvage Lymph Node Dissection for Nodal Recurrence of Prostate Cancer: Results from a Large, Multi- institutional Analysis. Fossati et al. Eur Urol. 2019 (176 – 183) PSA (SLND) = 2.1 No. PET +nodes n=1 (51%) n=2 (23%) n=3 (17%) n>4 (9%) No. +nodes PO n=0 (9%) n=1 (33%) Node-Positive n=2 (14%) Prostate Cancer n>3 (54%) (N1/M0): Radiotherapeutic 70% PSA > 0.1 Approaches ng/ml PO Analysis based on 654 pts … PSA rise and nodal recurrence after RP and … SLND ... Lymph node recurrence was documented by PET/CT using (11)C-choline or (68)Ga-labeled PSMA.
Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome & Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. De Bleser, Jereczek-Fossa … Ost. EU 2019 BACKGROUND: … SBRT vs ENRT … mets-directed txs in oligorecur. CAP. OBJECTIVE: … Primary endpoint was metastasis-free survival … toxicity PARTICIPANTS: … multi-instit. … SBRT: 309, ENRT: 197 hormone- sensitive nodal oligorecur. (< 5 nodes (LNs; N1/M1a) (2004-2017. Med fu 36 mo. INTERVENTION: SBRT > 5Gy per fraction (max n=10 fxs). ENRT min. dose of > 45Gy in up to 25 fxs at the discretion of the physician. OUTCOME MEASUREMENTS & STATISTICAL ANALYSIS: … 506 pts … 15 Node-Positive centers. Primary tx RP, RT, or their combination. Nodal recurrences … by PET/CT (97%) or conventional imaging (3%). Prostate Cancer (N1/M0): RESULTS … : ENRT assoc. with fewer nodal recur. vs SBRT (p<0.001). Radiotherapeutic MVA, pts with 1 LN at recur. … longer aMFS after ENRT (HR: 0.50, p=0.009). Late toxi was higher after ENRT VS SBRT (16% vs. 5%, p<0.01). Approaches Hypothesize that ENRT should be preferred to SBRT in the treatment of nodal oligorecurrences … needs to be evaluated in a randomized trial.
Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome & Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. De Bleser, Jereczek-Fossa … Ost. EU 2019 Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches Figure. 1 – Cox model plots showing the diff. in adjusted metastasis-free survival following SBRT vs ENRT. … treated by RP at Dx and presenting with N1 at recurrence and no ADT & PSA < 4.0 at recurrence … (modified)
Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome & Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. De Bleser, Jereczek-Fossa … Ost. EU 2019 Table 2 (modified Pattern of Progression following SBRT or ENRT) SBRT ENRT Metastatic Location (n=309,61%) (N=197,39%) p Value Node 131 40 <0.001 Pelvic 55 3 Extrapelvic 34 32 Pelvic+extra-pelvic 42 5 Bone 35 26 0.6 Node-Positive Prostate bed 1 2 0.6 Prostate Cancer Visceral 10 6 >0.9 (N1/M0): Radiotherapeutic Approaches Total 177 74 <0.001
Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome & Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. De Bleser, Jereczek-Fossa … Ost. EU 2019 Key points: 1. Single node + benefitted more from ENRT? a) field size issue? – i. diff. between SBRT vs ENRT smaller if > 1 node? ii. ENRT field not big enough if > 1 node? 2. MFS vs PSA failure? Node-Positive 3. Increased toxicity with ENRT (RTOG 9413 vs 0924)? Prostate Cancer 4. Role of ADT? (N1/M0): Radiotherapeutic Approaches
Salvage extended field or involved field nodal irradiation in (18)F-fluorocholine (FCH) PET/CT oligorecurrent nodal failures from prostate cancer. Lépinoy … Créhange. Eur J Nucl Med Mol Imaging (2019) 46:40-48 Pts treated with salvage Involved field radiotherapy (s-IFRT) … with salvage extended field radiotherapy (s-EFRT). RESULTS: … 62 pts + nodes only FCH PET/CT after RP/RT. Of these pts, 35 had s-IFRT and 27 had s-EFRT. Med fu of 42 mo., no diff. in acute/late GI/ GI tox. of > grade 2. 3-yr failure rates … 55% vs 88% … s-IFRT vs s-EFRT (p= 0.01). Node-Positive … strong trend toward better outcomes with s-EFRT … after Prostate Cancer adjusting for concomitant ADT (HR = 0.38, p = 0.116 ). (N1/M0): Radiotherapeutic CONCLUSION: FCH PET+ node-targeted s-EFRT is feasible Approaches with low … toxicity and longer TTF.
RTOG 9413 Progression-Free Survival: Protocol Definition 100 Whole Pelvis Progression Free Survival (%) Prostate Only Mini-Pelvis 80 60 Table 3a Progression-Free Survival by Median Field-Size per Protocol Definition of Biochemical Failure 40 Field-Size Comparisons Median PFS P value* Time (yrs) Node-Positive Whole Pelvis vs. Prostate Only 4.9 vs. 2.6 0.001 Prostate Cancer 20 Whole Pelvis vs. Mini-Pelvis 4.9 vs. 3.4 0.015 (N1/M0): Mini-Pelvis vs. Prostate Only 3.4 vs. 2.6 0.7697 Radiotherapeutic *Pair-Wise Log-Rank test Approaches 0 0 1 2 3 4 Time (Years)
The Template of the Primary Lymphatic Landing Sites of the Prostate Should be Revisited: Results of a Multimodality Mapping Study. Mattei … Studer. EAU 53:118-125, 2008 RTOG 0924 (WPRT) RTOG 9413 (WPRT) GETUG-01 RTOG 9413 (PO) RTOG 0924 (PO)
Long-Term Follow-up of a Randomized Study of Locally Advanced Prostate Cancer Treated with Combined Orchiectomy and External Radiotherapy Versus Radiotherapy Alone. Granfors et al. J of Urol 176, 544-547, 2006 Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches
Completed Contemporary Phase III Prostate Cancer Trials (ADT +/- RT) Widmark et al. (2009) Warde et al. (2011) A 100 ADT ADT and RT 80 Survival (%) 60 40 Survival at 7 years (95% CI) ADT: 66% (60–70) 20 ADT and RT: 74% (70–78) Log-rank p=0·03 0 0 2 4 6 8 10 Number at risk ADT 602 564 419 213 89 40 ADT and RT 603 552 419 232 99 39 Conclusion: Better survival with Conclusion: Better survival with ADT (mostly anti-androgens) + RT RT+ADT (LHRH drug used) Median-Follow Up: 7.6; NNT: 10.2; Median-Follow Up: 6; NNT: 9.9; Curves Curves separate beyond 5 years separate beyond 5 years
Prophylactic Post Op Pelvic RT in the “Salvage” Setting
Prophylactic Post Op Pelvic RT in the “Salvage” Setting 100 100 + Censored + Censored p=0.002 (two-sided log-rank) p=0.002 (two-sided log-rank) Progression-Free Survival (%) Progression-Free Survival (%) 75 75 50 50 25 25 NHT+WPRT NHT+WPRT NHT+PORT NHT+PORT WPRT+AHT WPRT+AHT PORT+AHT PORT+AHT 0 0 NHT+WPRT NHT+WPRT 318 318 159 159 78 78 29 29 NHT+PORT NHT+PORT 316 316 132 132 62 62 21 21 WPRT+AHT WPRT+AHT 319 319 139 139 53 53 21 21 PORT+AHT PORT+AHT 317 317 157 157 86 86 40 40 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 15 15 Time Since Randomization (Years) Time Since Randomization (Years) # of Patients Dead Censored NHT+WPRT 318 274 44 NHT+PORT 316 278 38 WPRT+AHT 319 286 33 PORT+AHT 317 265 52
Progression-Free Survival: RTOG 9413 1.0 0.8 0.6 Nonfailure Rate 0.4 NHT + WP RT 0.2 NHT + PO RT Node-Positive WP RT + AHT PO RT + AHT Prostate Cancer 0.0 (N1/M0): 0 1 2 3 4 5 Years since Randomization Radiotherapeutic P =.008 Approaches NHT=neoadjuvant hormonal therapy; AHT=adjuvant hormonal therapy JCO 2003 Roach, et al.
Sequence of Hormonal Therapy and Radiotherapy Field Size in Unfavorable Localized Prostate Cancer: Long Term Results of a Phase III Randomized Trial NRG Oncology / RTOG 9413. Roach et al. (Lancet Oncol 2018) 100 100 NHT+WPRT NHT+WPRT p=0.01 (two-sided Gray's test) p=0.01 (two-sided Gray's test) NHT+PORT NHT+PORT WPRT+AHT WPRT+AHT PORT+AHT PORT+AHT Biochemical Failure (%) Biochemical Failure (%) 75 75 50 50 25 25 0 0 NHT+WPRT NHT+WPRT 318 318 160 160 80 80 32 32 NHT+PORT NHT+PORT 316 316 138 138 66 66 23 23 WPRT+AHT WPRT+AHT 319 319 146 146 56 56 22 22 PORT+AHT PORT+AHT 317 317 165 165 88 88 41 41 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 15 15 Time Since Randomization (Years) Time Since Randomization (Years) # of Patients Failure Alive, No Failure Dead, No Failure NHT+WPRT 318 144 47 127 NHT+PORT 316 177 43 96 WPRT+AHT 319 156 37 126 PORT+AHT 317 143 53 121 Interaction of Sequence of Hormones and Radiation Therapy on Progression-Free Survival
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