UCSF APCCC Basel Switzerland 8/29/19; 11:15 12:45; 12 minutes - - PowerPoint PPT Presentation

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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

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Node + Prostate Cancer (N1/M0), Radiation Options (and Evidence): Where are we Now?

Mack Roach III, MD

Professor Radiation Oncology & Urology,

UCSF

APCCC Basel Switzerland 8/29/19; 11:15 – 12:45; 12 minutes

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

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? 3. Level of evidence? 4. Technical RT Details? a. SBRT vs ENRT b. Prophylactic Irradiation

Goal: Discuss Management of N1/M0 Prostate Cancer & the Role of Radiation Therapy

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

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)

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.

n=1 (51%) n=2 (23%) n=3 (17%) n>4 (9%)

No. PET +nodes

PSA (SLND) = 2.1

n=0 (9%) n=1 (33%) n=2 (14%) n>3 (54%)

No. +nodes PO

70% PSA > 0.1 ng/ml PO

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

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

centers. Primary tx RP, RT, or their combination. Nodal recurrences … by

PET/CT (97%) or conventional imaging (3%). RESULTS … : ENRT assoc. with fewer nodal recur. vs SBRT (p<0.001). 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). Hypothesize that ENRT should be preferred to SBRT in the treatment of nodal oligorecurrences … needs to be evaluated in a randomized trial.

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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

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

Metastatic Location SBRT (n=309,61%) ENRT (N=197,39%) p Value Node Pelvic Extrapelvic Pelvic+extra-pelvic 131 55 34 42 40 3 32 5 <0.001 Bone 35 26 0.6 Prostate bed 1 2 0.6 Visceral 10 6 >0.9 Total 177 74 <0.001

Table 2 (modified Pattern of Progression following SBRT or ENRT) 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

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

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? 3. Increased toxicity with ENRT (RTOG 9413 vs 0924)? 4. Role of ADT?

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

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Node-Positive Prostate Cancer (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). … strong trend toward better outcomes with s-EFRT … after adjusting for concomitant ADT (HR = 0.38, p = 0.116). CONCLUSION: FCH PET+ node-targeted s-EFRT is feasible with low … toxicity and longer TTF.

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

20 40 60 80 100 Time (Years) 1 2 3 4 Whole Pelvis Prostate Only Mini-Pelvis

Progression-Free Survival: Protocol Definition

RTOG 9413

Progression Free Survival (%)

Table 3a Progression-Free Survival by Median Field-Size per Protocol Definition of Biochemical Failure Field-Size Comparisons Median PFS Time (yrs) P value* Whole Pelvis vs. Prostate Only 4.9 vs. 2.6 0.001 Whole Pelvis vs. Mini-Pelvis 4.9 vs. 3.4 0.015 Mini-Pelvis vs. Prostate Only 3.4 vs. 2.6 0.7697 *Pair-Wise Log-Rank test

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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 9413 (WPRT) RTOG 9413 (PO) RTOG 0924 (WPRT) RTOG 0924 (PO)

GETUG-01

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

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

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Completed Contemporary Phase III Prostate Cancer Trials (ADT +/- RT)

Widmark et al. (2009)

Number at risk ADT ADT and RT 602 603 2 564 552 4 419 419 6 213 232 8 89 99 10 40 39 20 40 60 80 100

Survival (%) Survival at 7 years (95% CI) ADT: 66% (60–70) ADT and RT: 74% (70–78) Log-rank p=0·03 ADT ADT and RT

Conclusion: Better survival with ADT (mostly anti-androgens) + RT Median-Follow Up: 7.6; NNT: 10.2; Curves separate beyond 5 years

Warde et al. (2011)

Conclusion: Better survival with RT+ADT (LHRH drug used) Median-Follow Up: 6; NNT: 9.9; Curves separate beyond 5 years

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Prophylactic Post Op Pelvic RT in the “Salvage” Setting

SLIDE 14 52 265 317 PORT+AHT 33 286 319 WPRT+AHT 38 278 316 NHT+PORT 44 274 318 NHT+WPRT Censored Dead # of Patients 318 159 78 29 316 132 62 21 319 139 53 21 317 157 86 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time Since Randomization (Years) 25 50 75 100 Progression-Free Survival (%) NHT+WPRT NHT+PORT WPRT+AHT PORT+AHT p=0.002 (two-sided log-rank) + Censored PORT+AHT WPRT+AHT NHT+PORT NHT+WPRT 318 159 78 29 316 132 62 21 319 139 53 21 317 157 86 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time Since Randomization (Years) 25 50 75 100 Progression-Free Survival (%) NHT+WPRT NHT+PORT WPRT+AHT PORT+AHT p=0.002 (two-sided log-rank) + Censored PORT+AHT WPRT+AHT NHT+PORT NHT+WPRT

Prophylactic Post Op Pelvic RT in the “Salvage” Setting

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

Progression-Free Survival: RTOG 9413

P=.008

Nonfailure Rate

NHT=neoadjuvant hormonal therapy; AHT=adjuvant hormonal therapy JCO 2003 Roach, et al.

Years since Randomization 0.0 0.2 0.4 0.6 0.8 1.0 1 2 3 4 5 NHT + WP RT NHT + PO RT WP RT + AHT PO RT + AHT

SLIDE 16 121 53 143 317 PORT+AHT 126 37 156 319 WPRT+AHT 96 43 177 316 NHT+PORT 127 47 144 318 NHT+WPRT Dead, No Failure Alive, No Failure Failure # of Patients 318 160 80 32 316 138 66 23 319 146 56 22 317 165 88 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time Since Randomization (Years) 25 50 75 100 Biochemical Failure (%) NHT+WPRT NHT+PORT WPRT+AHT PORT+AHT p=0.01 (two-sided Gray's test) PORT+AHT WPRT+AHT NHT+PORT NHT+WPRT 318 160 80 32 316 138 66 23 319 146 56 22 317 165 88 41 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time Since Randomization (Years) 25 50 75 100 Biochemical Failure (%) NHT+WPRT NHT+PORT WPRT+AHT PORT+AHT p=0.01 (two-sided Gray's test) PORT+AHT WPRT+AHT NHT+PORT NHT+WPRT

Interaction of Sequence of Hormones and Radiation Therapy on Progression-Free Survival

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)

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

Outcome Stratified variables Variable categories HR* 95% CI p-value† Progression-Free Survival (Phoenix) Treatment NHT+WPRT RL

NHT+PORT

1.21 (1.02,1.43) 0.027 WPRT+AHT 1.21 (1.03,1.43) 0.025 PORT+AHT 0.93 (0.78,1.10) 0.39 Gleason 2-6 RL

7-10

1.27 (1.11,1.45) 0.0006 PSA ≤ 30 RL

> 30

1.43 (1.26,1.63) <0.0001 Phoenix Biochemical Failure Treatment NHT+WPRT RL

NHT+PORT

1.38 (1.11, 1.72) 0.0045 WPRT+AHT 1.11 (0.89, 1.40) 0.35 PORT+AHT 1.00 (0.9, 1.27) 0.97 Gleason 2-6 RL

7-10

1.42 (1.18, 1.71) 0.0002 PSA ≤ 30 RL

> 30

1.59 (1.33, 1.89) < 0.0001 T-Stage T1c,T2a RL

T1b, T2b

1.23 (0.92, 1.64) 0.15 T2c-T4 1.22 (0.998, 1.49) 0.052 Multivariable Analysis: *HR: hazard ratio, a risk ratio of 1 indicates no difference between subgroups. † p-values are from the chi-square test using the Cox proportional hazards model for progression-free survival and the p-values are from the Fine-Gray regression model for Phoenix biochemical failure 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. (In Press, Lancet Oncol 2018)

SLIDE 18

Basis of study design for RTOG 0924?

SLIDE 19

RTOG 0924

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

“If you want to prove something doesn’t work, design an underpowered study”

Mack Roach III, MD

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

WPRT for Prostate Cancer: Important & Challenging

Practical issues:

– Small field vs Big Field? – Potential Morbidity – Cost (time and money)?

Challenge – tough to prove:

– e.g. 1200 pts with 1/3rd (33%) having + nodes

… then study really based on n=400 pts
… if disease beyond pelvis in 25% down to n=300 pts
… and local failures 1/3rd to n=200 pts
… competing causes of death (e.g. 50%) n=100
… improved “salvage” treatments, delaying deaths
… “study too small?”

Thus, RTOG 0924: n=2580 (@2592 pts ()!

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

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Node-Positive Prostate Cancer (N1/M0): Radiotherapeutic Approaches

1. Composite endpoints might be necessary? :

a) MFS, QoL, freedom from ADT … b) Phase I-II PSA based evidence?:

1. Nadir promising?
2. Complicated by a direct impact on ADT?
3. Stratification variables?
2. Prepare for unanticipated findings (e.g. sequence,

volume interactions (e.g. RTOG 9413).

3. Doses and techniques and drugs probably matter!
4. Underpowered/poorly designed trial worse than none!

Conclusions Concerning the Trial Design for Clinically Localized but N1 prostate cancer: