Curative approach for prostate cancer with 1-2 Bone Metastases

Curative approach for prostate cancer with 1-2 Bone Metastases Mack Roach III, MD Professor of Radiation Oncology & Urology UCSF Helen-Diller Family Comprehensive Cancer Center Department of Radiation Oncology, Mt Zion Hospital, San Francisco, CA

Disclosure Potential conflicts of interest: Employment: University of California San Francisco, The National Cancer Institute (Funding & Board Member of the National Cancer Advisory Board (NCAB)) Consulting: Ferring, Johnson & Johnson (Janssen) Pharmaceuticals and the International Atomic Energy Agency (IAEA) (consultant) Speaker Support: An honorarium is provided by Accuray for this presentation Leadership: American Cancer Society (ACS), NCAB, NRG (NSABP/RTOG/GOG)

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Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. Lerner et al. J Urol 156: 137-43, 1996 All 904 men treated with curative intent: If you don t treat for cure, you wont cure those you treated Ted Phillips Kaplan-Meir progression-free (PSA> 0.2 ng/ml) survival estimates for 904 patients with pathologically organ confined prostate cancer (pt2 or less)

Roach et al. IJROBP 2015 Figures1b: Graphical summary of the median difference in the estimated 10 year CSS (b) by the dichotomized reliability score (RS) (< to 12 vs. >12). Above 0 indicates benefit for RP, at 0 no differences between treatments and below 0 a benefit to RT +/- androgen deprivation therapy (ADT). Broken lines (---) indicate the pointwise 95% CI based on bootstrap estimation of 100,000 replicates, and the black dotted line indicates the overall differences.

Acta Oncologica, 2015; 54:875-881 ORIGINAL ARTICLE Radical prostatectomy versus high-dose irradiation in localized/locally advanced prostate cancer: A Swedish multicenter randomized trial with patient-reported outcomes. Lennermas et al. RP vs HDR+EBRT + 6 mo. ADT in PC pts in Sweden 1996-2001 M & M: T1b-T3a, N0, M0 and PSA</=50 ng/ml RESULTS: survival rate ~ 76%. Only eight pts (9%) died of PC. CONCLUSION: RP and HDR + EBRT appeared to be comparable...

Selected Papers on Non-classic Radiation and ADT 2/1/2018 7 Modified from Corso Ali and Diaz Am J Cancer Res 2011; 1(3):390-412

Non-classic Radiation Effects Zhang et al. JEM 204:49-55, 2007 * *C3H Rag2-/- mice have stroma incapable of cross-presenting tumor antigens

Selected Papers on Non-classic Radiation and ADT Antigens No. of models Type of Model P-Selectin / E-Selectin 11 In Vivo & Vitro ICAM-1 (CD54)/ NCAM (CD56) / V-CAM 16 In Vivo & Vitro PECAM-1 (CD31) 5 In Vivo & Vitro α2β3 Integrin / B1 Integrin 3 In Vitro E-Cadherin (CD324) 2 In Vivo & Vitro MHC Class 1 10 In Vitro CD80(B7.1) / CD20 7 In Vitro NKG2D Ligand (MICA, MICB, ULBP1,2,3) / Fas (CD95/Apo-1) 6 In Vivo & Vitro FasL / Trail-R1 &Trail-R2 (DR4 & DR5) / GRP78 (BiP) 7 In Vivo & Vitro Calreticulin / 2 In Vitro ERp57 (grp58 / PDIA3) 1 In Vitro CEA 5 In Vitro TIP-1 1 In Vivo & Vitro Modified from Corso Ali and Diaz Am J Cancer Res 2011; 1(3):390-412

Consolidative Radiotherapy for Limited Metastatic Non-Small Cell Lung Cancer (NSCLC): A Randomized Phase II Trial P. Iyengar, V. Tumati, D. Gerber, Z. Wardak, C. Ahn, R. Hughes, J. Dowell, N. Cheedella, L. A. Nedzi, K. D. Westover, S. Pulipparacharuvil, H. Choy and R. D. Timmerman University of Texas Southwestern Medical Center, Dallas, TX

Harris et al. Prostate 68: 1319-29, 2008

Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, Lambert B, Delrue L, Bultijnck R, Claeys T, Goetghebeur E, Villeirs G, De Man K, Ameye F, Billiet I, Joniau S, Vanhaverbeke F, De Meerleer G. J Clin Oncol. 2017 Dec 14:JCO2017754853. Multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline PET/CT, and serum testosterone levels > 50 ng/ml. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or SBRT). Surveillance was performed with PSA follow-up Q 3 months, with repeated imaging at PSA progression or clinical suspicion for progression. Random assignment was balanced dynamically on the basis of two factors: PSA doubling time (</= 3 v > 3 months) and nodal versus non-nodal mets. The primary end point was ADT-free survival. ADT was started at symptomatic progression, progression to more than 3 mets, or local progression of known mets.

Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, De Bruycker A, Lambert B, Delrue L, Bultijnck R, Claeys T, Goetghebeur E, Villeirs G, De Man K, Ameye F, Billiet I, Joniau S, Vanhaverbeke F, De Meerleer G. Results Between August 2012 and August 2015, 62 patients were enrolled. At a median follow-up time of 3 years, the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P =.11). QOL was similar between arms at baseline and remained comparable at 3-month and 1-year fu. Six pts developed grade 1 toxicity in the MDT arm. No grade 2 to 5 toxicity was observed. Conclusion ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials.

Contemporary Phase III Prostate Cancer Trials (ADT +/- RT) Widmark et al. (2009) Warde et al. (2011) Conclusion: Better survival with ADT (mostly antiandrogens) + RT. Median-Follow Up: 7.6; NNT: 10.2; Curves separate beyond 5 years Conclusion: Better survival with RT+ADT (LHRH drug used) Median-Follow Up: 6; NNT: 9.9; Curves separate beyond 5 years

The Concept of Bone Mets Spawn More Bone Mets 1 Recently Demonstrated The bone matrix is fertile soil that stimulates growth of tumor cells 2 The same tumor cells travel from site to site and establish additional metastatic lesions 1 Supports seed and soil theory where subclones develop the potential to metastasize on their own and spread, rather than being a property of the primary tumor 1 Gundem G et al. Nature. 2015;520(7547):353-357. 2.Yin JJ et al. Cell Res. 2005;15(1):57-62.

Major Take Home Message: Curative approach for Prostate Cancer with 1-2 Bone Metastases 1. We have NO level I evidence that patients are curable when treated for 1-2 bone metastases. They live longer, but: a. There are suggestive data and a plausible biologic rationale b. Radiotherapy may be uniquely suited to combine with immunotherapy and may enhance control systemic disease! c. Bone to bone mets a real problem? d. Much work remains to be done!!!!!!!!

Palliation of urinary obstruction from advanced prostate cancer with SBRT. Lauren Boreta, David Ronan Raleigh, Mack Roach III; University of California San Francisco, San Francisco, CA ASCO PALLIATIVE & SUPPORTIVE CARE ONCOLOGY SYMPOSIUM 2017 Background: In patients with advanced prostate cancer (PCa), urinary obstruction (UO) can lead to urinary retention requiring indwelling or suprapubic catheterization, which negatively impacts quality of life. Palliative options for UO from advanced PCa include surgical and medical treatment. Surgical intervention, including prostatectomy, pelvic exenteration and TURP, may confer undue risk to patients... Medical palliation may require months to take effect. Stereotactic Body Radiotherapy (SBRT) is a non-invasive technique that delivers high-dose and highly conformal radiation in 5 fractions... Methods: A retrospective review of patients undergoing SBRT for UO was completed at a single institution between 2011 and 2017. Stage, PSA at diagnosis and time of treatment were recorded. Assessment of urinary function by IPSS/SHIM and documentation of catheterization were reviewed at consultation and subsequent follow-up. Results: A total of 3 patients were treated with SBRT to the prostate for the palliation of urinary obstruction. Patient ages were 67, 57 and 52 years, and all had high risk, stage IV disease, Gleason 4+4 or 4+5, T3 or T4, with regional nodal, bony or visceral metastases. All patients required indwelling catheterization for an average 4 months prior to SBRT. Two patients were treated with whole pelvis irradiation after SBRT. In those who received subsequent pelvic irradiation, the SBRT doses to the prostate were 19 Gy in 2 fractions. The patient treated with SBRT monotherapy received 38 Gy in 4 fractions. Catheters were successfully removed in all 3 patients, one at the completion of radiation, and the others within 4 weeks of completion. With fu (1.2 to 6 yrs), no patients required re-catheterization, and there were no reports of grade 3 acute or long-term toxicity. Conclusions: SBRT is an effective treatment to palliate UO from locally advanced PCa, leading to removal of urinary catheters and presumed improved in quality of life. Further investigation is required to establish the optimal dose and fractionation of palliative SBRT for UO from PCa