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- Publisher
- Pubmed Central
- Copyright
- Copyright 2020 Phillips R et al. JAMA Oncology.
- ISSN
- 2374-2437
- eISSN
- 2374-2445
- DOI
- 10.1001/jamaoncol.2020.0147
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- See Article on Publisher Site
Abstract
IMPORTANCE Complete metastatic ablation of oligometastatic prostate cancer may provide Invited Commentary an alternative to early initiation of androgen deprivation therapy (ADT). page 659 OBJECTIVE To determine if stereotactic ablative radiotherapy (SABR) improves oncologic Supplemental content outcomes in men with oligometastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized. INTERVENTIONS Patients were randomized in a 2:1 ratio to receive SABR or observation. MAIN OUTCOMES AND MEASURES The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)–measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)–targeted positron emission tomography in the identification of metastatic disease. RESULTS In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03). CONCLUSIONS AND RELEVANCE Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, Author Affiliations: Author and baseline immune phenotype and tumor mutation status may predict the benefit from affiliations are listed at the end of this SABR. These results underline the importance of prospective randomized investigation of article. the oligometastatic state with integrated imaging and biological correlates. Corresponding Author: Phuoc T. Tran, MD, PhD, Department of TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02680587 Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, 1500 Orleans St, CRB2 Room 406, JAMA Oncol. 2020;6(5):650-659. doi:10.1001/jamaoncol.2020.0147 Baltimore, MD 21231 Published online March 26, 2020. (tranp@jhmi.edu). 650 (Reprinted) jamaoncology.com Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Original Investigation Research n the US, prostate cancer is the third most common cancer overall and the most common in men, accounting Key Points I for approximately 30 000 deaths per year. Metastatic Question How effectively does stereotactic ablative radiotherapy prostate cancer remains incurable despite advances in sys- prevent progression of disease compared with observation in temic management for hormone-sensitive and castration- men with recurrent hormone-sensitive prostate cancer with 1 to resistant disease. 3 metastases? The oligometastatic state described by Hellman and Findings In this phase 2 randomized clinical trial of 54 men, Weichselbaum may benefit from localized therapies, and progression of disease at 6 months occurred in 7 of 36 participants mounting prospective evidence supports the inclusion of (19%) treated with stereotactic ablative radiotherapy and in 11 of 5,6 radiotherapy in the metastatic paradigm. Two trials 18 participants (61%) undergoing observation, a statistically significant difference. have shown that stereotactic ablative radiotherapy (SABR) significantly improves progression-free survival (PFS) and Meaning Stereotactic ablative radiotherapy is a promising overall survival in patients with oligometastatic non–small treatment approach for men with recurrent hormone-sensitive cell lung cancer when added to maintenance systemic oligometastatic prostate cancer who wish to delay initiation of androgen deprivation therapy. therapy, and the Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastases (SABR- COMET) trial reported an overall survival benefit with SABR in patients with oligometastases when used in addition to standard-of-care systemic therapy across histologies. Methods In the treatment of prostate cancer, radiotherapy has demonstrated clinical benefits in both de novo and meta- Study Design and Participants chronous low-volume metastatic disease. Parker et al The Observation vs Stereotactic Ablative Radiation for Oligo- showed that the addition of prostate radiotherapy to stan- metastatic Prostate Cancer (ORIOLE) 2-arm, phase 2 random- dard systemic treatment improves overall survival for men ized clinical trial was approved by the Johns Hopkins Univer- with de novo metastatic prostate cancer with low metastatic sity Institutional Review Board and performed across 3 burden. In the Surveillance or Metastasis-Directed Therapy affiliated centers in the US. Patients eligible for enrollment had for Oligometastatic Prostate Cancer Recurrence (STOMP) 1 to 3 asymptomatic metastases that had arisen within the prior trial, to our knowledge the first phase 2 randomized clinical 6 months and were no larger than 5.0 cm in the largest axis or trial of SABR vs observation in oligometastatic prostate can- 250 cm . The number of metastases was assessed by com- cer (OMPC), Ost et al found significantly longer time to ini- puted tomography (CT), magnetic resonance imaging, and/or tiation of androgen deprivation therapy (ADT) in men radionuclide bone scan. All patients had histologic confirma- treated with SABR. Although the approach is controversial, tion of prostate cancer and prior definitive treatment of the pri- many men are interested in avoiding the unpleasant adverse mary tumor with surgery or radiotherapy. Salvage radio- effects and potential health risks of ADT for as long as is rea- therapy to the prostate bed or pelvis was allowed. Patients were sonable. With early clinical data suggesting the existence allowed to have received ADT or other systemic therapy dur- of an oligometastatic state and the importance of local ing initial management or salvage treatment but not within therapies in management, strategies are now needed to 6 months of enrollment. The trial protocol is available in define who may benefit most from metastasis-directed Supplement 1. Additional inclusion criteria and full exclusion therapy (MDT). criteria are available in eMethods in Supplement 2. All study This question is multifaceted, but 2 key components are participants provided written informed consent approved (1) determining which patients truly have oligometastatic dis- by the institutional review board. This study followed the ease and (2) ascertaining who is most likely to experience a Consolidated Standards of Reporting Trials (CONSORT) meaningful response to local consolidation. To answer the reporting guideline. former, advanced imaging and circulating biomarkers, such 11-14 15-17 as microRNA and circulating tumor DNA (ctDNA), Randomization and Blinding may improve our ability to characterize disease burden and Participants were randomized to the SABR or observation arm behavior. To address the latter requires a more complete in a 2:1 ratio using an interactive web response system. 18 21 understanding of response to radiotherapy and the comple- Minimization was applied to balance assignment based on 19,20 mentary role of the immune system. stratification by initial treatment (surgery or radiotherapy), This study reports the findings of a phase 2 randomized history of prior ADT or lack thereof, and prostate-specific clinical trial of observation vs SABR in men with hormone- antigen (PSA) doubling time (<6 months vs 6-14.9 months) sensitive OMPC, to our knowledge the first in the western (eMethods in Supplement 2). Neither the treating physician, hemisphere. The study also shows the value of the prostate- the participants, nor the personnel responsible for data analy- specific membrane antigen (PSMA)–targeted positron emis- sis were blinded to assignment. The trial radiologist assess- 18 18 sion tomography (PET) radiotracer F-DCFPyL and liquid ing response by CT size criteria and by F-DCFPyL uptake was biopsy correlatives in defining patients with oligometastasis blinded to the participant treatment arm and to the treat- who would benefit the most from MDT. ment fields used (eMethods in Supplement 2). jamaoncology.com (Reprinted) JAMA Oncology May 2020 Volume 6, Number 5 651 Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Procedures Statistical Analysis For assessment of eligibility, patients provided a comprehen- Briefly, comparisons of progression at 6 months and pres- sive medical history, underwent a physical examination, and ence of new metastases at 6 months were performed using the had blood drawn for analysis of complete blood count, serum 2-sided Fisher exact test. PFS curves were generated using chemistry measurements, and PSA level. Radiographic stud- the Kaplan-Meier method, and P values were calculated using ies were performed as necessary to complete staging. After the log-rank test. Brief Pain Inventory responses were com- randomization, participants underwent routine laboratory test- pared between and within arms across time using the Holm- ing on days 1, 90, and 180 as well as collection of blood for cor- Sidak method for multiple t tests. Differential clonotype abun- relative studies and PSMA-targeted PET-CT (performed at base- dance and ctDNA allele fraction comparisons between arms line and day 180 for patients randomized to SABR) (eMethods were performed using 2-tailed Mann-Whitney tests. Statisti- in Supplement 2). cal significance was defined as P < .05. Statistical analysis was Participants underwent CT-based simulation with cus- performed using Prism version 8 (GraphPad Software) and tomized immobilization. Magnetic resonance imaging–based Rstudio version 1.2.5 (Rstudio Inc). All analysis was per- simulation and 4-dimensional CT were performed at the dis- formed on an intention-to-treat basis, and further details are cretion of the treating physician. Gross tumor volume delin- available in eMethods in Supplement 2. eation was performed by the treating radiation oncologist with the addition of a variable expansion of up to 5 mm to gener- ate the planning target volume. Adjacent organs at risk were Results delineated by the treating radiation oncologist. A stereotactic body radiotherapy plan was then generated with dose and Between May 25, 2016, and March 5, 2018, a total of 80 men fractionation determined based on the size and location of each were screened and 54 were randomized in a 2:1 ratio to SABR lesion, with prescription doses ranging from 19.5 to 48.0 Gy or observation (Figure 1). Of the 54 men randomized, the me- in 3 to 5 fractions (eTable 1 in Supplement 2) and normal dian (range) age was 68 (61-70) years for patients allocated to tissue constraints per American Association of Physicists in SABR and 68 (64-76) years for those allocated to observation. Medicine Task Group 101 recommendations. Treatment The follow-up period for each participant extended from the was initiated within 3 weeks of simulation. Image guidance date of randomization to the most recent clinical contact as of with daily cone beam CT prior to treatment was used for all May 20, 2019 (median [range] follow-up of 18.8 [5.8-35.0] participants. months), and the trial was completed 6 months after random- ization of the final participant. The Table and eTable 2 in Outcomes Supplement 2 summarize participant and lesion characteris- The primary outcome was the proportion of men in each arm tics, respectively. Gleason grade was higher in the observa- with disease progression at 6 months. Progression was a com- tion arm than in the SABR arm with mean values of 8 and 7, posite end point that included any of the following: a PSA rise respectively. The arms were otherwise well balanced. of at least 2 ng/dL (to convert to micrograms per liter, multi- The proportion of men with disease progression by com- ply by 0.01) and 25% above nadir; concern for radiologic pro- posite end point at 6 months was 7 of 36 patients (19%; 95% gression by CT, magnetic resonance imaging, or bone scan CI, 9.6-35.4) treated with SABR and 11 of 18 patients (61%; 95% as determined by the reading radiologist; symptomatic pro- CI, 38.5-79.6) in the observation arm (P = .005). The propor- gression of disease; initiation of ADT for any reason; or death. tion of participants with disease progression by PSA level at Withdrawal from the study after randomization was consid- 6 months was 4 of 36 patients (11%; 95% CI, 3.9-26.1) treated ered progression. with SABR and 9 of 18 patients (50%; 95% CI, 29.1-70.9) in the Predefined secondary outcomes included the adverse ef- observation arm (P = .005). The median PFS for participants fects of SABR as defined by the Common Terminology Crite- treated with SABR was not reached compared with 5.8 months ria for Adverse Events (version 4.0), local control at 6 months for those undergoing observation (hazard ratio [HR], 0.30; for lesions treated with SABR, PFS, quality of life as measured 95% CI, 0.11-0.81; P = .002) (Figure 2A). Median biochemical by the Brief Pain Inventory (Short Form), the concordance be- PFS was not reached for patients treated with SABR and was tween conventional imaging and PSMA-targeted PET in the 6.4 months for those undergoing observation (HR, 0.31; 95% identification of metastatic disease, and sequencing of T-cell CI, 0.13-0.75; P = .002) (Figure 2B). Local control was excel- receptor repertoires from peripheral blood mononuclear cells lent as expected (98.9%) at 6 months (eResults, eFigure 1, and using ImmunoSEQ (Adaptive Biotechnologies). eTable 1 in Supplement 2). For radiologic evaluation of lesions that did not meet for- Because of blinding of the investigative team to the PSMA- mal Response Evaluation Criteria in Solid Tumors (RECIST) ver- targeted PET data during treatment planning, 16 of 36 partici- sion 1.1 criteria, progression by imaging was assessed based on pants treated with SABR had baseline PET-avid lesions that the blinded professional assessment of the primary radiolo- were not included in the treatment fields. The proportion of gist reading the images combined with application of the men with no untreated lesions with progression at 6 months RECIST version 1.1 size criteria to all measurable lesions, was 1 of 19 (5%; 95% CI, 0-26.8) compared with 6 of 16 (38%; including those not meeting formal size criteria. To minimize 95% CI, 18.5-61.5) for those with any untreated lesions (P = .03). the risk of underestimating local progression, any evidence of The median PFS was unreached among participants with no progression by size was counted as a progression. untreated lesions vs 11.8 months among participants with any 652 JAMA Oncology May 2020 Volume 6, Number 5 (Reprinted) jamaoncology.com Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Original Investigation Research Figure 1. CONSORT Diagram 80 Patients assessed for eligibility 26 Excluded 19 Did not meet inclusion criteria 5 Declined to participate 2 Insurance denied 54 Randomized 36 Randomized to treatment arm 18 Randomized to observation arm 36 Received allocated intervention 17 Received allocated intervention 1 Withdrew and did not receive allocated intervention 0 Lost to follow-up 0 Lost to follow-up 0 Discontinued intervention 7 Discontinued intervention because of progression prior to 180 days 36 Analyzed 18 Analyzed 23-25 untreated lesions (HR, 0.26; 95% CI, 0.09-0.76; P = .006) Based on prior sequencing studies that identified mu- (Figure 2C). The proportion of men who developed new meta- tations associated with outcomes in metastatic prostate can- static lesions at 180 days was 3 of 19 (15.8%; 95% CI, 4.9-38.6) cer, we defined a high-risk mutation signature with truncating/ with no untreated lesions and 10 of 16 (62.5%; 95% CI, 38.5- pathogenic germline mutations identified via a Color Genomics 81.5) with any untreated lesions (P = .006). Median distant assay and confirmed by CAPP-Seq (Figure 4A; eTables 5 and 6 metastasis–free survival was 29.0 months in men with no in Supplement 2). To avoid false negatives owing to undetect- untreated lesions at baseline and 6.0 months in men with any able ctDNA, we limited our analyses to participants with de- untreated lesions at baseline (HR, 0.19; 95% CI, 0.07-0.54; tectable ctDNA or truncating/pathogenic germline mutations P < .001) (Figure 2D; eResults in Supplement 2). in high-risk genes (n = 22). PFS was significantly longer among No grade 3 or higher adverse events were identified participants receiving SABR than among those in the obser- (eTables 3 and 4 in Supplement 2). No differences in Brief Pain vation arm in the high-risk mutation–negative subgroup Inventory (Short Form) scores were observed between arms (Figure 4B) but not in the high-risk mutation–positive sub- or within either arm across time. group (Figure 4C). Peripheral blood mononuclear cells were collected at base- line and day 90 from participants in both arms for deep se- quencing of T-cell receptor DNA. Differential clonotype abun- Discussion dance appeared more pronounced in the SABR arm (Figure 3A), with significantly more expanded clones and a nonsignifi- This phase 2 randomized clinical trial showed that among men cantly greater amount of contracted clones at 90 days com- with OMPC, those treated with SABR were significantly less pared with observation. Greater peripheral baseline clonality likely to have disease progression than those undergoing ob- was associated with composite end point progression at 180 servation alone. Local control for SABR-treated lesions was ex- days in participants receiving SABR (0.082085 vs 0.026051; cellent, and the adverse effects associated with SABR were mild P = .03) but not with observation (0.084299 vs 0.060002; and did not appear to affect quality of life. These results are P = .68) (Figure 3B). At baseline, no participant had clusters of consistent with prior reports validating the existence of the similar expanded T-cell receptors within their repertoire, but oligometastatic state in prostate cancer and the utility of SABR at day 90, clusters of similar expanded T-cell receptors were as MDT in this condition. identified in 3 participants, all in the SABR arm (Figure 3C). With a median (interquartile range) follow-up of 3.0 (2.3- Plasma and matched leukocyte DNA samples collected at 3.8) years, Ost et al reported a median ADT-free survival of baseline from 54 participants were profiled by the CAPP-Seq 21 months (80% CI, 14-29 months) with SABR compared with (cancer personalized profiling by deep sequencing) method for 13 months (80% CI, 12-17 months) with observation (HR, 0.60; analysis of ctDNA. Nonsynonymous mutations were present 80% CI, 0.40-0.90; log-rank P = .11). Criteria for initiation of in 20 participants (37%) with a mean of 1.3 mutations per par- ADT were defined as “symptomatic progression, progression ticipant and a median allele fraction of 0.25%. No significant to more than three metastases, or local progression of baseline- 9(p448) differences in ctDNA concentration were noted between par- detected metastases.” Importantly, progression by PSA ticipants whose disease did or did not progress in either the increase alone was not an indication to start ADT, nor was de- SABR or observation arm (eFigure 2 in Supplement 2). velopment of additional metastases amenable to MDT as long jamaoncology.com (Reprinted) JAMA Oncology May 2020 Volume 6, Number 5 653 Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer analysis of PFS based on extent of disease appreciable by Table. Baseline Patient Characteristics PSMA-targeted PET-CT found significant PFS and distant me- No. (%) tastasis–free survival advantages among men who received SABR Observation consolidation of all detectable disease. These data support Characteristic (n = 36) (n = 18) the use of molecular imaging in conjunction with MDT for Age, median (range), y 68 (61-70) 68 (64-76) patients with OMPC. Initial T stage The key question that remains incompletely answered is cT1c 3 (8) 1 (6) whether we can alter the natural history of OMPC with MDT. cT2a 2 (6) 0 Clearly, SABR is a safe and effective way to forestall progres- cT2b 0 1 (6) sion of treated metastases and improves oncologic outcomes cT3a 1 (3) 1 (6) 6,7 in certain patients. Furthermore, complete consolidation of pT2 12 (33) 6 (33) detectable metastases improves time to progression. Most men pT3a 10 (28) 8 (44) with oligometastatic disease do not experience a complete PSA pT3b 8 (22) 1 (6) response after SABR, which suggests that residual microme- Initial N stage tastases are present but undetectable. The consolidation of N0 31 (86) 16 (89) macroscopic disease may simply reset the clock on time to de- N1 2 (6) 1 (6) tectable metastases, and micrometastatic disease may con- NX 3 (8) 1 (6) tinue to grow unchecked until it reaches sufficient size to be- Margin status come clinically actionable. Alternatively, consolidation of R0 20 (56) 10 (56) macroscopic metastases may remove or significantly affect sig- R1 10 (28) 5 (28) nals that promote the development of remaining microme- Gleason grade tastases. Our finding that total consolidation of disease de- 3+3=6 3 (8) 0 tectable by PSMA-targeted PET-CT was associated with lower 3+4=7 8 (22) 4 (22) risk of new metastases at 6 months is consistent with this lat- 4+3=7 14 (39) 4 (22) ter explanation, as is the recent overall survival improve- 4+4=8 4 (11) 1 (6) ment observed in the SABR-COMET trial. A deeper under- 4+5=9 4 (11) 8 (44) standing of this process may be obtained through sequencing 5+4=9 3 (8) 0 of biopsy or liquid biopsy specimens to explore the relation- 5+5=10 0 1 (6) 14,26 ships and lineages of specific metastases in these patients Initial management or through advances in analysis of circulating readouts, such Surgery 30 (83) 15 (83) as circulating tumor cells, ctDNA, and exosomes. Radiotherapy 6 (17) 3 (17) Our analysis of ctDNA revealed several key findings. Time to first recurrence, 22 (9-42) 22 (9-51) First, ctDNA concentrations in patients with OMPC were median (range), mo 17,27 significantly lower than those reported in prior studies of Had received prior ADT 15 (42) 5 (28) more advanced metastatic castration-resistant or hormone- Baseline, median (range) sensitive prostate cancer. This suggests that ultrasensitive strat- PSA, ng/dL 6 (2-13) 7 (3-17) egies, such as tumor-informed ctDNA monitoring, will be re- PSADT, mo 8 (4-11) 6 (4-11) quired for reliable detection and monitoring of ctDNA in Abbreviations: ADT, androgen deprivation therapy; PSA, prostate-specific patients with OMPC. Second, we did not find an association antigen; PSADT, prostate-specific antigen doubling time; SABR, stereotactic ablative radiotherapy. of baseline ctDNA concentration with outcome. However, our SI conversion factor: To convert PSA to μg/L, multiply by 0.01. analysis was limited by the small fraction of participants with detectable ctDNA, so further exploration in future cohorts using as the patient still had 3 or fewer total metastases. In the pre- tumor-informed monitoring or alternative methods is war- sent cohort, 2 of 7 men with disease progression in the SABR ranted. Third, the results of the study suggest that the pres- arm and 7 of 11 men with disease progression in the observa- ence of mutations associated with worse prognosis may iden- tion arm experienced biochemical progression alone. Further- tify a subset of patients who do not benefit from MDT. If these more, additional SABR was the next intervention in 14 of 15 findings are confirmed in independent cohorts, the absence men in the observation arm who ultimately received subse- of high-risk mutations could potentially serve as a predictive quent treatment and 6 of 14 men in the SABR arm. These biomarker for benefit from MDT. differences inform the limitations of direct comparison of The benefit of early ADT initiation remains a controver- 28-30 these trials. sial question, and rigorous evaluation of men who un- Another important consideration is that SABR in the dergo multiple rounds of MDT rather than proceeding to sys- temic therapy at first progression may shed light on the effect STOMP trial included all concerning lesions identified by cho- line PET-CT. The ORIOLE trial enrolled participants with less- of SABR on the natural history of this disease. If a single round of MDT arrests the progression of some but not all lesions, sub- sensitive conventional imaging and still demonstrated a posi- tive benefit for MDT, suggesting that the oligometastatic state sequent rounds of MDT might salvage the remaining disease until what remains is inadequate to support a metastatic phe- is heterogeneous and that better biomarkers are needed to de- fine participants who would benefit most from MDT. Post hoc notype. The utility of repeated MDT may also vary by patient 654 JAMA Oncology May 2020 Volume 6, Number 5 (Reprinted) jamaoncology.com Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Original Investigation Research Figure 2. Clinical Outcomes of Stereotactic Ablative Radiotherapy (SABR) Compared With Observation and Benefit of Total Consolidation of Prostate-Specific Membrane Antigen Radiotracer-Avid Lesions A Composite PFS stratified by study arm B Biochemical PFS stratified by study arm 100 100 80 80 SABR SABR 60 60 Observation 40 40 Observation 20 20 HR, 0.30; 95% CI, 0.11-0.81; P = .002 HR, 0.31; 95% CI, 0.13-0.75; P = .002 0 0 0 6 12 18 24 0 6 12 18 24 Time from randomization, mo Time from randomization, mo No. at risk No. at risk SABR 36 26 13 7 2 SABR 36 28 20 10 4 Observation 18 8 1 1 0 Observation 18 9 7 4 1 C PFS stratified by presence of untreated lesions D DMFS stratified by presence of untreated lesions 100 100 No untreated lesions 80 80 60 60 No untreated lesions 40 40 Any untreated lesions Any untreated lesions 20 20 HR, 0.26; 95% CI, 0.09-0.76; P = .006 HR, 0.19; 95% CI, 0.07-0.54; P < .001 0 0 0 6 12 18 24 0 6 12 18 24 Time from randomization, mo Time from randomization, mo No. at risk No. at risk No untreated 19 14 10 6 2 No untreated 19 14 12 8 4 Any untreated 16 7 1 1 0 Any untreated 16 6 2 2 0 A, Composite progression-free survival (PFS) stratified by study arm. presence of untreated lesions detected by prostate-specific membrane B, Biochemical PFS stratified by study arm. C, Composite PFS and (D) distant antigen–positron emission tomography. metastasis–free survival (DMFS) for patients treated by SABR stratified by and the response of individual; therefore, well-selected pa- tate Cancers (RAVENS) trial (ClinicalTrials.gov identifier: tients for MDT may have intrinsic predictive value for guid- NCT04037358). Soldatov et al also found that 17% of recur- ing subsequent management. rences after MDT were in pelvic nodes. The best manage- The effect of radiotherapy on the immune system is also an ment approach for pelvic recurrences is currently being stud- area of interest with the promise of using SABR to induce an in ied in the Salvage Treatment of Oligorecurrent Nodal Prostate 20,31 situ vaccine response. We observed enhanced differential Cancer Metastases (STORM) trial (ClinicalTrials.gov identi- clonotype expansion, clusters of similar expanded T-cell recep- fier: NCT03569241). tors, and a clinical benefit to greater baseline clonality seen only in participants treated with SABR. Future studies assessing the Limitations association of these findings with T-cell characteristics or re- While these results are promising, this trial is limited by its rela- latedness to tumor-infiltrating lymphocytes may help further tively small sample size; subsequent phase 3 validation would characterize this systemic immune response. strengthen the argument in favor of this approach. Addition- Soldatov et al described patterns of failure following ally, our ability to study the long-term implications of this treat- PSMA-ligand–based, conventionally fractionated radio- ment approach was limited by high rates of crossover occur- therapy for OMPC and found that recurrences are bone tro- ring after the predefined 6-month primary end point, with 15 phic. This suggests a role for aggressive management of mi- of 18 men randomized to observation ultimately seeking SABR. crometastatic osseous disease with ADT and/or radium 223, It should also be noted that the correlative data pre- the latter of which will be the center of investigation for sented herein are hypothesis generating and require further the Radium-223 and SABR vs SABR for Oligometastatic Pros- prospective validation. Although we have identified a sys- jamaoncology.com (Reprinted) JAMA Oncology May 2020 Volume 6, Number 5 655 Progression-free survival, % Progression-free survival, % Distant metastasis-free survival, % Biochemical progression-free survival, % Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Figure 3. Baseline and Dynamic Immunologic Features Suggesting Interplay Between Stereotactic Ablative Radiotherapy (SABR) and the Immune System A T-cell clonotype abundance Control patients Expanded clones Contracted clones –50 –100 1 2 10141822242933363843474852 53 Patient Patients in SABR group Expanded clones Contracted clones –50 –100 35 6 7 8 911 12 13 16 17 19 20 21 23 25 26 27 28 31 32 34 35 37 39 40 41 42 44 45 46 50 51 54 55 Patient B C Baseline Simpson clonality T-cell receptor sequences Control SABR Patient Amino acid sequence Progression at 180 days 0.4 CASSPRLYEQYF 13 Yes CASSPRLNEQYF CASSYSTTGSSYEQYF 0.3 40 No CASSYSTRGSSYEQYF CASSLVPAGTNTGELFF 0.2 50 No CASSLLPAGTNTGELFF 0.1 No progression Progression No progression Progression Patient A, Changes in T-cell clonotype abundance at day 90 from baseline. B, Baseline Simpson clonality stratified by progression at 180 days. C, Clustered T-cell receptor sequences identified at day 90 in 3 patients treated with SABR. temic immune response to SABR, we do not yet understand analysis was the lack of available biopsy specimens to con- the nature of this response, and additional studies are needed firm the presence or absence of mutations. Thus, although we to better characterize the interactions between immune cells, sequenced matched leukocyte DNA to identify mutations tumor, and the microenvironment. A limitation of our ctDNA owing to clonal hematopoiesis, it is possible that some of the 656 JAMA Oncology May 2020 Volume 6, Number 5 (Reprinted) jamaoncology.com Clones, No. Clones, No. Baseline Simpson clonality Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Original Investigation Research Figure 4. Association of High-Risk Mutation Status With Progression-Free Survival (PFS) After Stereotactic Ablative Radiotherapy (SABR) A Patient and tumor characteristics High-risk mutation positive High-risk mutation negative Treatment arm Treatment arm Progression Observation Yes Progression SABR No TP53 Mutation type Missense ATM Missense-near-splice BRCA2 Nonsense BRCA1 Germline truncating/pathogenic RB1 None Other mutations B C PFS for patients without high-risk mutations PFS for patients with high-risk mutations 1.0 1.0 SABR 0.8 0.8 SABR 0.6 0.6 Observation Observation 0.4 0.4 0.2 0.2 Log-rank P = .01 Log-rank P = .62 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Time from randomization, mo Time from randomization, mo No. at risk No. at risk Observation 6 2 00 0 0 Observation 2 1 00 0 0 SABR 9 8 63 2 0 SABR 5 3 00 0 0 A, Patient characteristics and tumor mutations for patients with detectable circulating tumor DNA via CAPP-Seq or pathogenic germline mutations. B, PFS stratified by treatment arm for patients without high-risk mutations (n = 15). C, PFS stratified by treatment arm for patients with high-risk mutations (n = 7). mutations we detected did not originate from tumor cells. Fu- in a systemic adaptive immune response. Complete consolida- ture studies in this area should prioritize acquisition of tissue tion of metastatic disease detectable by molecular imaging de- samples for molecular analysis. creases the risk of subsequent metastases, suggesting an altera- tion in the natural history. Finally, baseline immune phenotype and a tumor mutation signature may predict clinical response to SABR, pending validation in independent cohorts. Although Conclusions SABR alone may or may not be sufficient as curative manage- In conclusion, SABR is a safe and effective modality for MDT in ment, the combination of SABR with systemic therapies may OMPC that improves PFS compared with observation and results provide the multipronged attack required to cure this disease. ARTICLE INFORMATION Maryland (Phillips, Deek, Radwan, Deville, Greco, School of Medicine, Baltimore, Maryland (Rowe, H. Wang, Dipasquale, DeWeese, Song, Tran); Gorin, Pomper); The James Buchanan Brady Accepted for Publication: January 21, 2020. Stanford Cancer Institute, Department of Radiation Urological Institute and Department of Urology, Published Online: March 26, 2020. Oncology, School of Medicine, Stanford University, Johns Hopkins University School of Medicine, doi:10.1001/jamaoncol.2020.0147 Stanford, California (Shi, Diehn); Department of Baltimore, Maryland (Rowe, Ross, Gorin, DeWeese, Open Access: This is an open access article Medical Oncology, Johns Hopkins University School Song, Pienta, Pomper, Tran); Sidney Kimmel Cancer distributed under the terms of the CC-BY License. of Medicine, Baltimore, Maryland (Lim, Center, Department of Radiation Oncology, Thomas © 2020 Phillips R et al. JAMA Oncology. Antonarakis, Denmeade, Paller, DeWeese, Song, Jefferson University, Philadelphia, Pennsylvania H. Wang, Carducci, Pienta, Eisenberger, Tran); The (Dicker); Stanford Cancer Institute, Division of Author Affiliations: Department of Radiation Russell H. Morgan Department of Radiology and Oncology, Department of Medicine, School of Oncology and Molecular Radiation Sciences, Johns Radiological Science, Johns Hopkins University Hopkins University School of Medicine, Baltimore, jamaoncology.com (Reprinted) JAMA Oncology May 2020 Volume 6, Number 5 657 PFS, % High-risk mutations PFS, mo PFS, % Research Original Investigation Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer Medicine, Stanford University, Stanford, California expert testimony on intellectual property for 3. Nuhn P, De Bono JS, Fizazi K, et al. Update on (Alizadeh). Wilson Sonsini; and serving as an unpaid advisor for systemic prostate cancer therapies: management of Google LaunchPad Accelerator, Dreamit Ventures, metastatic castration-resistant prostate cancer in Author Contributions: Drs Phillips and Tran had and Evolution Road outside the submitted work. the era of precision oncology. Eur Urol. 2019;75(1): full access to all of the data in the study and take Dr Alizadeh reported receiving consulting fees from 88-99. doi:10.1016/j.eururo.2018.03.028 responsibility for the integrity of the data and the Roche, Genentech, Chugai Pharmaceutical Co, and accuracy of the data analysis. 4. Hellman S, Weichselbaum RR. Oligometastases. Pharmacyclics outside the submitted work; having Study concept and design: Rowe, Hao Wang, J Clin Oncol. 1995;13(1):8-10. doi:10.1200/JCO.1995. equity in Forty Seven and CiberMed; and being a Carducci, Pienta, Pomper, Dicker, Eisenberger, 13.1.8 coinventor on patent applications related to Diehn, Tran. 5. Iyengar P, Wardak Z, Gerber DE, et al. CAPP-Seq. Dr Diehn reported receiving grants and Acquisition, analysis, or interpretation of data: Consolidative radiotherapy for limited metastatic personal fees from Illumina; receiving consulting Phillips, Shi, Deek, Radwan, Lim, Antonarakis, non–small-cell lung cancer: a phase 2 randomized fees from Roche, AstraZeneca, BioNTech, Novartis, Rowe, Ross, Gorin, Deville, Greco, Hailun Wang, clinical trial. JAMA Oncol. 2018;4(1):e173501. doi:10. Varian Medical Systems, and Quanticel Denmeade, Paller, Dipasquale, DeWeese, Song, 1001/jamaoncol.2017.3501 Pharmaceuticals; receiving honoraria from Hao Wang, Carducci, Dicker, Eisenberger, Alizadeh, RefleXion Medical; and having equity in CiberMed 6. Gomez DR, Tang C, Zhang J, et al. Local Diehn, Tran. outside the submitted work, as well as being a consolidative therapy vs maintenance therapy or Drafting of the manuscript: Phillips, Shi, Deville, coinventor and having pending and issued patents observation for patients with oligometastatic Hailun Wang, Dipasquale, Carducci, Pienta, Pomper, related to CAPP-Seq. Dr Tran reported receiving non–small-cell lung cancer: long-term results of Dicker, Diehn, Tran. grants from RefleXion Medical, the Prostate Cancer a multi-institutional, phase II, randomized study. Critical revision of the manuscript for important Foundation, and Movember Foundation during the J Clin Oncol. 2019;37(18):1558-1565. doi:10.1200/ intellectual content: Shi, Deek, Radwan, Lim, conduct of the study; receiving grants from Astellas JCO.19.00201 Antonarakis, Rowe, Ross, Gorin, Deville, Greco, Pharma and Bayer and personal fees from Denmeade, Paller, DeWeese, Song, Hao Wang, 7. Palma DA, Olson R, Harrow S, et al. Stereotactic Noxopharm and RefleXion Medical outside the Carducci, Pienta, Dicker, Eisenberger, Alizadeh, ablative radiotherapy versus standard of care submitted work; and holding a licensed patent Diehn, Tran. palliative treatment in patients with oligometastatic related to ablative radiotherapy compounds and Statistical analysis: Phillips, Shi, Deek, Lim, cancers (SABR-COMET): a randomised, phase 2, methods (Natsar Pharmaceuticals). Hao Wang, Alizadeh, Diehn. open-label trial. Lancet. 2019;393(10185):2051-2058. Obtained funding: Pomper, Diehn, Tran. Funding/Support: This work was supported by the doi:10.1016/S0140-6736(18)32487-5 Administrative, technical, or material support: Nesbitt-McMaster Foundation, Ronald Rose and 8. Parker CC, James ND, Brawley CD, et al; Phillips, Deek, Radwan, Antonarakis, Ross, Gorin, Joan Lazar, the Movember Foundation and Prostate Systemic Therapy for Advanced or Metastatic Deville, Greco, Paller, Eisenberger, Diehn, Tran. Cancer Foundation, and the National Cancer Prostate Cancer: Evaluation of Drug Efficacy Study supervision: Antonarakis, Deville, Greco, Institute (grants R01CA166348, U01CA212007, (STAMPEDE) Investigators. Radiotherapy to the Denmeade, Hao Wang, Pienta, Dicker, Alizadeh, U01CA231776, and R21CA223403) (Dr Tran); the primary tumour for newly diagnosed, metastatic Diehn, Tran. National Cancer Institute (grants R01CA188298 and prostate cancer (STAMPEDE): a randomised 1R01CA233975) (Drs Diehn and Alizadeh); Conflict of Interest Disclosures: Dr Phillips controlled phase 3 trial. Lancet. 2018;392(10162): SDW/DT and Shanahan Cancer Research Funds reported receiving consulting fees and honoraria 2353-2366. doi:10.1016/S0140-6736(18)32486-3 (Dr Alizadeh); the US National Institutes of Health from RefleXion Medical outside the submitted 9. Ost P, Reynders D, Decaestecker K, et al. Director’s New Innovator Award (grant work. Mr Shi reported receiving support from the Surveillance or metastasis-directed therapy for 1-DP2-CA186569) (Dr Diehn); the Virginia and Alpha Omega Alpha Carolyn L. Kuckein Student oligometastatic prostate cancer recurrence: D.K. Ludwig Fund for Cancer Research (Drs Diehn Research Fellowship. Dr Antonarakis reported a prospective, randomized, multicenter phase II and Alizadeh); the CRK Faculty Scholar Fund receiving research grants to his institution from trial. J Clin Oncol. 2018;36(5):446-453. doi:10. (Dr Diehn); and the Transdisciplinary Integration Dendreon, Genentech, Novartis, Janssen, Johnson 1200/JCO.2017.75.4853 of Population Science Program of Sidney Kimmel & Johnson, Sanofi, Bristol-Myers Squibb, Pfizer, Cancer Center–Jefferson Health and a Challenge 10. Loo BW Jr, Diehn M. SABR-COMET: harbinger of AstraZeneca, Celgene, Merck & Co, Bayer, and Grant from the Prostate Cancer Foundation a new cancer treatment paradigm. Lancet. 2019; Clovis; serving as a paid consultant/advisor to (Dru Dicker). 393(10185):2013-2014. doi:10.1016/S0140-6736(19) Astellas Pharma, Janssen, Pfizer, Sanofi, Dendreon, 30278-8 Bayer, Bristol-Myers Squibb, Amgen, Merck & Co, Role of the Funder/Sponsor: The funders had no AstraZeneca, and Clovis outside the submitted role in the design and conduct of the study; 11. Lussier YA, Xing HR, Salama JK, et al. MicroRNA work; and holding a patent to a biomarker collection, management, analysis, and expression characterizes oligometastasis(es). PLoS technology licensed to Qiagen. Drs Rowe and Gorin interpretation of the data; preparation, review, or One. 2011;6(12):e28650. doi:10.1371/journal.pone. reported receiving research funding and consulting approval of the manuscript; and decision to submit 0028650 fees from Progenics Pharmaceuticals, the licensee the manuscript for publication. 12. Lussier YA, Khodarev NN, Regan K, et al. of F-DCFPyL, outside the submitted work. Additional Contributions: We acknowledge Oligo- and polymetastatic progression in lung Dr Carducci reported receiving personal fees from Terrence Caldwell, BS, and Colby Yu, BS, metastasis(es) patients is associated with specific Pfizer and Roche/Genentech for serving on data Department of Radiation Oncology and Molecular microRNAs. PLoS One. 2012;7(12):e50141. doi:10. safety monitoring boards outside the submitted Radiation Sciences, Johns Hopkins University 1371/journal.pone.0050141 work. Dr Pienta reported receiving grants from School of Medicine, Baltimore, Maryland, as study 13. Uppal A, Wightman SC, Mallon S, et al. Progenics Pharmaceuticals and the Prostate Cancer coordinators. They were compensated for their 14q32-Encoded microRNAs mediate an Foundation, consulting fees and stock options from contributions. oligometastatic phenotype. Oncotarget. 2015;6(6): Cue Biopharma, and consulting fees from Data Sharing Statement: See Supplement 3. 3540-3552. doi:10.18632/oncotarget.2920 GloriousMed Technology outside the submitted work. Dr Pomper reported receiving grants and 14. Pitroda SP, Khodarev NN, Huang L, et al. REFERENCES other from Progenics Pharmaceuticals and grants Integrated molecular subtyping defines a curable from the National Institutes of Health during the 1. Surveillance, Epidemiology, and End Results oligometastatic state in colorectal liver metastasis. conduct of the study, as well as holding a patent Program. Cancer stat facts: prostate cancer. Nat Commun. 2018;9(1):1793. doi:10.1038/ (US 8,778,305 B2) covering F-DCFPyL with Accessed January 28, 2020. https://seer.cancer. s41467-018-04278-6 royalties paid (Progenics Pharmaceuticals). gov/statfacts/html/prost.html 15. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Dr Dicker reported receiving grants from the 2. Damodaran S, Lang JM, Jarrard DF. 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Med Phys. 2010;37(8):4078- 4101. doi:10.1118/1.3438081 Invited Commentary Forging New Strategies in the Cure of Human Oligometastatic Cancer Carlo Greco, MD; Zvi Fuks, MD In this issue of JAMA Oncology, Phillips et al report out- providing a window of opportunity for cancer cure if comes of the phase 2 ORIOLE (Observation vs Stereotactic equilibrium-phase lesions are ablated before polymetastatic Ablative Radiation for Oligometastatic Prostate Cancer) clini- escape occurs. cal trial in patients with hormone-sensitive oligometastatic Consideration of this hypothesis raises the question as to prostate cancer randomized the extent of the ablative approach required to optimize cure to receive stereotactic abla- of oligometastatic disease. Treatment with SABR using high- Related article page 650 tive radiotherapy (SABR) vs end dose schedules of either 3 fractions of ultra-high 18 to 20 observation alone. Data on baseline prostate-specific mem- Gy/fraction or 24-Gy single-dose radiotherapy (also referred brane antigen (PSMA)–targeted positron emission tomogra- to as SDRT), feasible when high-precision treatment plan- phy (PET) were blinded by protocol during SABR treatment ning and delivery are used, is known to confer 90% or greater planning, and 45% of patients treated with SABR were even- permanent local control regardless of oligometastatic 3 3 tually found to harbor PSMA-avid lesions undetected by the subtypes. Nonetheless, a recent phase 2 trial reported that treatment planning computed tomography (CT), which were despite 92% actuarial 5-year local relapse-free survival, the re- left untreated. Progression-free and distant metastasis–free spective polymetastasis-free survival rate was only 26%. The survival indicated adverse outcomes in these patients com- oligometastatic phenotype in this study was defined as 5 or pared with the 55% of patients in whom all detectable lesions fewer concomitant lesions. Hence, appearance of 6 or more were ablated. Notwithstanding, the SABR-treated cohort synchronous lesions was scored as polymetastatic conver- had a significant 3-fold decrease in disease progression at sion with no further ablation pursued. It is unclear how many 6 months compared with patients randomized to observation untreated patients would have ever displayed bona fide alone. One interpretation of these observations posits that polymetastatic conversion if all clinically identifiable lesions macroscopic lesion consolidation by SABR alters the natural had been ablated. Furthermore, 42% of the patients in this history of prostate oligometastatic disease by removing or study exhibited 1 to 6 sequential bouts of new oligometa- greatly affecting signals that promote further development static (≤5) lesions, subject at each such event to sequential of micrometastatic disease. This hypothesis is consistent oligometastatic ablation (SOMA) to a cumulative total of up with the oligometastatic paradigm, which postulates that to 20 progressively ablated oligometastatic lesions per pa- the oligometastatic state is a transient phase of metastato- tient. The actuarial 5-year polymetastasis-free survival of genic equilibrium with delayed clonal expansion, potentially patients treated with SOMA was 56%, compared with 20% in jamaoncology.com (Reprinted) JAMA Oncology May 2020 Volume 6, Number 5 659 © 2020 American Medical Association. All rights reserved.
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Published: Mar 26, 2020