Abstract
Background
Metastasis-directed radiotherapy (MDT) is the mainstay in management of oligometastatic prostate cancer (PCa), and PSMA-PET is currently the most sensitive imaging modality for localizing PCa metastases. The efficacy of MDT guided by PSMA-PET imaging with and without androgen deprivation therapy (ADT) ± androgen-receptor pathway inhibitor (ARPI) has not yet been well characterized. We sought to evaluate the efficacy of PSMA PET-guided MDT.
Methods
This is a single-institutional retrospective study of patients diagnosed with metastatic PCa by PSMA-PET imaging who were treated with MDT. Survival analyses were performed using the Kaplan-Meier method with Cox proportional hazards testing for significance. Cumulative incidence analyses were performed with Gray’s testing for significance.
Results
One hundred and ninety-four metastatic lesions from 101 patients identified by PSMA PET were irradiated with MDT. Forty-seven of the 79 (59%) patients with hormone-sensitive PCa (HSPC) received ADT ± ARPI along with MDT. Four of 194 lesions (2.1%) demonstrated radiographic progression after MDT, with a median follow-up of 22.4 months. Two-year cumulative incidence of progression from HSPC to CRPC was 11% in patients who received ADT ± ARPI and 35% in those who did not (P = .027). Median biochemical progression free survival of patients with CRPC, HSPC treated without ADT or ARPI, and HSPC treated with ADT ± ARPI was 5.4, 7.6, and 43.9 months, respectively (P < .0001). No Grade 3-5 adverse effects were observed.
Conclusions
MDT guided by PSMA-PET imaging is well-tolerated and delays biochemical progression in patients with CRPC and HSPC, with a greater effect observed in patients also receiving ADT ± ARPI.
Introduction
Oligometastatic cancer is a disease state characterized by low metastatic tumor burden that demonstrates distinct clinical behavior from high-burden metastatic disease.1,2 Metastasis-directed radiotherapy (MDT) is increasingly prevalent in the management of oligometastatic cancer, as it has been shown to improve local control of metastatic lesions, progression-free survival (PFS), and potentially overall survival (OS) across cancer types3,4 including prostate cancer (PCa) in particular.5,6 PSMA PET is currently the most sensitive FDA-approved imaging modality for detecting PCa metastases.7-9 PSMA PET imaging enables more comprehensive and precise targeting of metastatic lesions with MDT than previously possible. The efficacy of MDT guided by PSMA PET imaging has not yet been fully characterized and may differ from that of MDT guided by conventional imaging modalities.5,6,10 Additionally, PSMA PET features such as SUVmax may inform more optimal radiotherapy target delineation or treatment planning and have not yet been investigated in this context.
Another open question pertaining to MDT in the management of oligometastatic PCa is the optimal use of concurrent or adjuvant systemic therapy. Systemic therapy in patients with metastatic hormone sensitive prostate cancer (mHSPC) typically entails administration of primary androgen deprivation therapy (ADT), sometimes “intensified” with the addition of androgen receptor pathway inhibitors (ARPIs), while systemic therapy in metastatic castration resistant prostate cancer (mCRPC) generally consists of adding or switching an ARPI. The use of concurrent or adjuvant systemic therapy with MDT remains controversial. On one hand, primary ADT has long been considered the backbone of treatment for metastatic PCa, and intensification with ARPIs has recently been shown to improve OS and PFS in select patient populations.11-14 These findings may suggest that systemic therapy should be administered concurrently or adjuvantly with MDT with the goal of prolonging patient survival. Although initiated before the era of PSMA PET, the phase II RADIOSA and EXTEND studies support this notion that combination therapy with ADT and MDT offers improved progression-free survival compared to either ADT or MDT alone.15,16 On the other hand, MDT is also sometimes delivered without systemic therapy with the alternative goal of delaying or mitigating the adverse effects of systemic therapy, as was performed in a recent clinical trial.5 Due to these competing factors and limited high-level evidence to support one treatment approach over the other, practice patterns regarding systemic therapy administration in combination with MDT vary considerably across providers.
Given our longitudinal institutional experience with PSMA PET imaging used for both PCa metastasis detection and MDT planning, we sought to assess the efficacy of PSMA PET-guided MDT in patients with metastatic PCa treated with and without systemic therapy. By comparing outcomes between these patient groups, we aimed to elucidate the outcomes of PSMA-PET guided MDT with or without systemic therapy to provide new insights into optimal treatment paradigms for patients with oligometastatic PCa.
Methods
Study population
A retrospective IRB-approved study was conducted at the University of California, San Francisco (UCSF), and the requirement for informed consent was waived. Eligibility criteria included controlled primary prostate cancer, metachronous metastases detected on PSMA PET imaging performed between February 2016 and July 2022, at least one bone or visceral organ metastasis, and MDT performed after PSMA PET imaging using stereotactic body radiotherapy (SBRT) delivered in ≤5 treatment fractions. Radiotherapy prescription dose was required to be ≥1500 cGy in 1 fraction, ≥2400 cGy in 3 fractions, or ≥3000 cGy in 5 fractions. Systemic therapy was administered per clinician discretion. Patients with de novo metastatic prostate cancer (synchronous metastases) were excluded. For patients who underwent multiple courses of MDT, only the first course of PSMA-PET directed MDT was included. Follow-up included clinical history, physical exam, and laboratory studies at 3- to 6-month intervals. Follow-up imaging studies were obtained per clinician discretion.
Variable definitions
Maximum SUV (SUVmax) was identified within MDT planning target volumes (PTVs) performed in the MIM 7.3 software planning system. In-field progression of disease (IFPD) was defined as imaging-proven increase in long-axis diameter by at least 20% of a lesion that overlapped the PTV of a prior course of MDT. Radiographic progression of disease was defined as an increase in volume of a lesion by at least 20% based on conventional CT or MRI imaging.17 Biochemical progression was defined as a PSA increase of ≥ 25% and ≥ 2 ng/mL if PSA was ≥ 2 ng/mL at the time of initiating salvage treatment, or a PSA increase of ≥ 25% if PSA was < 2 ng/mL at the time of salvage treatment, as previously defined.5 Date of castration-resistance was defined as date of first rising PSA lab value in the setting of testosterone < 50 ng/dl and a subsequent PSA value confirming a rising trend.18 Imaging features were extracted from radiology images using segmentation maps and the previously published PyRadiomics platform.19 Survival endpoints were defined from time of MDT completion.
Statistical analyses
Univariable survival analyses with respect to overall and progression-free survival were performed using the Kaplan-Meier method with Cox proportional hazards testing for significance. Multivariable survival analyses were performed using Cox proportional hazards models to account for multiple clinicopathologic and treatment factors simultaneously. Predictor variables were included if at least one event was observed in each group (stratum). Cumulative incidence analyses were performed with Gray’s testing for significance. Adverse event data were assessed per CTCAE v5 guidelines. All statistical comparisons were performed at a 2-tailed significance level of 0.05 unless otherwise stated.
Results
One hundred and ninety-four PSMA PET-avid lesions from 101 patients were irradiated with stereotactic body radiotherapy (SBRT). Median time from prior definitive locoregional therapy to MDT was 6.2 years (Table 1). The median age of the cohort at the time of MDT was 70.4 years (IQR: 67.6-to 75.3). Ninety-eight patients (97%) had tumors consistent with adenocarcinoma histology based on last known tumor pathology. Ninety-three patients (92%) had at least one osseous metastasis and neither visceral nor soft tissue metastases. Seventy-nine patients (78%) had hormone-sensitive PCa (HSPC) and 22 patients (22%) had castration-resistant PCa (CRPC) at the time of MDT. All 3 patients with treatment-emergent small-cell neuroendocrine prostate cancer had CRPC at the time of MDT. Forty-seven of 79 (59%) patients with HSPC received ADT along with MDT, and 20 of the 47 patients additionally received an ARPI. Twenty-nine of the 47 (62%) patients had undergone at least one prior course of ADT, and 36 of 47 (77%) patients received >6 months of concurrent ADT with MDT (Table 1). Twenty-five of the 32 (78%) HSPC patients receiving MDT without ADT had undergone at least one prior course of ADT, and none had castrate levels of testosterone at the time of MDT with a median testosterone level of 341 ng/dl. All 22 patients with mCRPC remained on ADT.
Table 1.
Patient demographics and clinicopathologic features.
| Characteristic | Full cohort (n = 101) | HSPC without ADT or ARPI (n = 32) |
HSPC with ADT ± ARPI (n = 47) |
CRPC (n = 22) |
|---|---|---|---|---|
| Age in years, median [IQR] | 70 [68-75] | 71 [68-75] | 69 [65-74] | 75 [70-78] |
| Sites of metastasis | ||||
| Bone without lung or soft tissue involvement | 94 (93) | 29 (91) | 44 (94) | 21 (95) |
| Lung or soft tissue involvement | 7 (7) | 3 (9) | 3 (6) | 1 (5) |
| Number of metastases irradiated | ||||
| 1 | 45 (45) | 16 (50) | 18 (38) | 11 (50) |
| 2 | 29 (29) | 10 (31) | 15 (32) | 4 (18) |
| 3 | 19 (19) | 5 (16) | 9 (19) | 5 (23) |
| 4 | 6 (6) | 1 (3) | 3 (6) | 2 (9) |
| 5 | 2 (2) | 0 (0) | 2 (4) | 0 (0) |
| Castration-resistant status | ||||
| Hormone-sensitive | 79 (78) | 100 (100) | 100 (100) | 0 (0) |
| Castration-resistant | 22 (22) | 0 (0) | 0 (0) | 100 (100) |
| Hormone therapy duration (concurrent ± adjuvant) | ||||
| None | 32 (32) | 32 (100) | 0 (0) | 0 (0) |
| 1-6 months | 11 (11) | 0 (0) | 11 (23) | 0 (0) |
| 6-18 months | 20 (20) | 0 (0) | 19 (40) | 1 (5) |
| >18 months | 38 (38) | 0 (0) | 17 (36) | 21 (95) |
| Hormone therapy modality | ||||
| ADT without ARPI | 35 (35) | 0 (0) | 27 (57) | 8 (36) |
| Intensified (ADT with ARPI) | 33 (33) | 0 (0) | 20 (43) | 13 (59) |
| Orchiectomy | 1 (1) | 0 (0) | 0 (0) | 1 (5) |
| None | 32 (32) | 32 (100) | 0 (0) | 0 (0) |
| Histology | ||||
| Adenocarcinoma | 98 (97) | 32 (100) | 47 (100) | 19 (86) |
| Treatment-emergent small cell neuroendocrine | 3 (3) | 0 (0) | 0 (0) | 3 (14) |
| Time from primary prostate treatment to MDT in years, median [IQR] | 6.2 [3.2-10.5] | 6.5 [4.0-9.9] | 4.7 [2.3-8.7] | 10 [7.0-12.2] |
| Baseline PSA prior to MDT, median [IQR] | 1.5 [0.4-4.1] | 1.7 [0.8-3.1] | 1.1 [0.3-3.3] | 1.6 [0.5-5.9] |
All values represent number of patients (%) unless otherwise noted. “ASI” status indicates whether the ASI was administered concurrently with MDT.
Abbreviations = ADT, androgen deprivation therapy; ARPI, androgen-receptor pathway inhibitor; CRPC, castration-resistant prostate cancer; HSPC, hormone-sensitive PCa; MDT, metastasis-directed radiotherapy; PSA, prostate-specific antigen.
Clinical outcomes
Median biochemical progression free survival (bPFS) of patients with CRPC, HSPC treated without systemic therapy, and HSPC treated with systemic therapy following MDT was 5.4, 7.6, and 43.9 months respectively (P < .0001; Figure 1, A). Two-year overall survival of the abovementioned groups was 72.2%, 100%, and 97.5% respectively (P < .001; Figure 1, B). On univariate analysis, use of concurrent ADT with MDT was associated with improved bPFS (P < .0001), and prior exposure to ADT was associated with poor bPFS (P < .05; Table S1). On multivariable analysis, only concurrent ADT use was significantly associated with improved bPFS (P < .0001; Table S2).
Figure 1.
Kaplan-Meier curves demonstrating (A) PFS and (B) OS stratified by hormone-sensitive disease status and receipt of systemic therapy.
Two-year cumulative incidence of progression from HSPC to CRPC was 11% in patients who received systemic therapy (ADT ± ARPI) at the time of MDT and 35% in those who did not, when considering the subset of patients with HSPC (P = .027) (Figure 2). All patients who progressed from HSPC to CRPC had prior exposure to ADT. No difference in cumulative incidence of progression from HSPC to CRPC was observed between patients who received ADT alone and those who received ADT with ARPI (Tables S3 and S4, Figure S1). On univariate analysis, PSA measured prior to MDT was associated with poor castration resistance-free survival, and use of concurrent ADT with MDT was associated with improved castration resistance-free survival (P < .05; Table S3). Both associations remained significant on multivariable analysis (P < .05; Table S4). Duration of concurrent and adjuvant ADT was not associated with time to CRPC progression (Figure S2).
Figure 2.
Cumulative incidence of disease progression from HSPC to CRPC, stratified by receipt of concurrent ADT.
Of the 22 patients with CRPC at the time of MDT, 13 were previously exposed to ARPI; 12 were maintained on their existing ADT + ARPI regimen and 1 patient was switched from abiraterone to enzalutamide at the time of MDT. No Grade 3-5 adverse effects were observed.
PSMA imaging analysis
Median SUVmax for all PET-avid lesions treated with MDT was 11.5 (IQR: 6.15-21.4). Median SUVmax of the 4 lesions that subsequently developed in-field progression was 40.3. The following imaging features were investigated on the full cohort, and none were associated with biochemical PFS on univariable analysis: SUVmax, tumor volume, flatness, elongation, sphericity, first-order entropy, or first-order energy (P > .05; Figure S3).
With a median follow-up of 22.4 months (IQR: 11.7-46.7), 4 of 194 lesions (2.1%) in 4 patients demonstrated IFPD (Figure 3). Two patients with IFPD demonstrated HSPC and 2 patients demonstrated CRPC at the time of MDT. All 4 IFPD events occurred concurrently with or after a disease progression event involving a lesion outside of a prior radiotherapy treatment field, as observed on either PSMA PET or conventional imaging obtained after radiotherapy completion.
Figure 3.
Cumulative incidence of in-field progression of disease by imaging.
Discussion
Herein, we report the results of a large retrospective study investigating long-term clinical outcomes of PSMA PET-directed MDT for the management of metachronous oligometastatic PCa. We observed overall excellent local control rates and found that MDT yielded a median biochemical PFS rate of 5.4 months for patients with CRPC and 43.9 and 7.6 months for patients with HSPC treated with and without concurrent systemic therapy, respectively. Overall, MDT was well-tolerated with no Grade 3-5 adverse events observed in our cohort, consistent with acute and late Grade 3-5 adverse event incidences of <2% for SBRT-based MDT previously reported.20
Only 4 of 194 (2%) irradiated lesions demonstrated IFPD. Moreover, these 4 IFPD events were all preceded by or accompanied by an out-of-field disease progression event, suggesting that PSMA PET-directed MDT provided acceptably durable local control in our mixed cohort of HSPC and CRPC. While clinically reassuring, the low event rate of IFPD observed in our cohort limited our ability to validate radiologic features prognostic of MDT response with respect to this endpoint. Nevertheless, our exploratory analyses revealed that the SUVmax of the lesions that demonstrated IFPD was nominally higher than most other PET-avid lesions in our cohort, suggesting that high SUVmax may be prognostic of poor response to MDT. Future larger studies are needed to validate the association between high SUVmax and increased risk of IFPD after MDT. If true, this finding would suggest a potential role for treatment intensification via radiotherapy dose escalation or larger PTV margin expansion. Alternately, intensified systemic therapy could be considered, especially considering recent studies suggesting high SUV values on PSMA PET imaging may be predictive of response to ADT ± ARPI or PSMA-directed therapies.21,22
Our observed biochemical PFS rate of 7.6 months for patients with HSPC treated with MDT alone (without systemic therapy) was comparable to the historical control rate of 10 months reported in a prior trial that used the same definition of PSA progression.5 We observed that combining MDT with ADT ± ARPI was associated with prolonged biochemical PFS in patients with HSPC. This finding is consistent with the results of the RADIOSA trial,15 which was initiated before PSMA PET-directed metastasis screening and MDT were available but demonstrated a PFS benefit with addition of 6 months of ADT to MDT. Our study suggests that the clinical benefit of concurrent ADT persists even with PSMA PET-directed MDT. Taken together with findings from the EXTEND16 and SATURN23 trials, which demonstrated improved PFS with the addition of MDT to ADT alone, our findings suggest that combination therapy with PSMA PET-directed MDT and ADT may offer optimal biochemical PFS.
We also found that inclusion of systemic therapy in our cohort of patients who received MDT was also associated with longer time to disease progression to CRPC (2-year cumulative incidence of CRPC 11% vs 35%, P = .027). On multivariable analysis including known prognostic factors such as pre-treatment PSA,24 use of concurrent ADT with MDT was associated with prolonged castration resistance-free survival. Prior studies suggested that de novo metastatic disease and high metastatic burden24-26 are prognostic of shorter time to CRPC from the mHSPC disease state. Thus, a more comprehensive and aggressive upfront treatment approach including both MDT and ADT ± ARPI may reduce disease burden and prolong time to developing CRPC. Of note, no patients who were ADT-naïve at the time of MDT progressed to CRPC on our study. This subgroup of patients was more likely to have a relatively favorable response to salvage ADT ± ARPI in the event of disease progression. Additional studies of ADT-naïve patients with longer follow-up are needed to assess optimal combination of MDT and ADT ± ARPI in this disease state.
Our observed median bPFS of 5.4 months for patients with CRPC was shorter than that reported in the ARTO trial, which reported a median PFS greater than 17 months for patients treated with MDT and abiraterone.27 The ARTO study only included patients who were ARPI-naïve, in contrast to our cohort, which largely included patients who were previously treated with an ARPI or who were not initiated on a new ARPI at time of MDT. Thus, the difference in PFS may be explained by the likely superior efficacy of ARPI treatment in the ARPI-naïve patients enrolled on the ARTO trial compared to the ARPI-exposed patients included in this study (only one of whom started a new systemic therapy regimen at the time of MDT). A distinct small retrospective study of patients with CRPC treated with MDT reported a median PFS of 16.4 months.28 However, those patients appeared to have a lower disease burden than those presented in this study: 42% of patients enrolled on that study had nodal metastases without bone or visceral metastases, and no patients had >3 treated sites. Altogether, the short bPFS observed in our subgroup of patients with CRPC can be explained by an enrichment for ARPI-refractory CRPC and the fact that most of these patients were not initiated on a new systemic therapy regimen at the time of MDT.
There are several limitations of the present study. First, its retrospective nature introduces the possibility of systematic selection and treatment bias. In particular, since the patients in this retrospective study received systemic therapy per provider discretion, selection bias should be considered likely. In addition, while our overall sample size is reasonably large (n = 101) considering the recent adoption of PSMA PET guided MDT, the patients were relatively heterogeneous with respect to disease state (including both HSPC and CRPC) and treatment history (eg, radiotherapy dose and fractionation, prior exposure to ADT with or without ARPI). Stratified analyses resulted in relatively modest group sizes, so conclusions about event frequencies should be guarded. Prospective studies are warranted to validate the prognostic potential of PSMA PET imaging features and the optimal combination of MDT and systemic therapies.
Conclusions
MDT guided by PSMA-PET imaging is well-tolerated and delays biochemical progression in patients with CRPC and HSPC. Patients with HSPC undergoing MDT may benefit from concurrent use of ADT with or without intensification with an ARPI, though confirmatory studies are needed.
Supplementary Material
Contributor Information
William S Chen, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States; Department of Urology, University of California, San Francisco, San Francisco, CA, United States.
Abuzar Moradi Tuchayi, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.
Ali Sabbagh, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States.
Inkyu Kim, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States.
Evan Porter, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States.
Amir Ashraf-Ganjouei, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States.
Yun Rose Li, Department of Radiation Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
Alon Witztum, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States.
Abhejit Rajagopal, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.
Steven N Seyedin, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States.
Roxanna Juarez, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.
Peter R Carroll, Department of Urology, University of California, San Francisco, San Francisco, CA, United States.
Felix Y Feng, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States; Department of Urology, University of California, San Francisco, San Francisco, CA, United States.
Eric J Small, Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Thomas A Hope, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.
Julian C Hong, Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, United States; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, United States; UCSF-UC Berkeley Joint Program in Computational Health, San Francisco, CA, United States.
Additional Information
Coauthor Felix Y. Feng, MD, died December 10, 2024.
Author contributions
William Chen (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Validation, Writing—original draft, Writing—review & editing), Abuzar Moradi Tuchayi (Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Writing—review & editing), Ali Sabbagh (Data curation, Formal analysis, Investigation, Methodology, Writing—review & editing), Inkyu Kim (Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Writing—review & editing), Evan Porter (Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Writing—review & editing), Amir Ashraf-Ganjouei (Data curation, Formal analysis, Investigation, Methodology, Software, Writing—review & editing), Yun Rose Li (Data curation, Formal analysis, Investigation, Writing—review & editing), Alon Witztum (Data curation, Formal analysis, Investigation, Writing—review & editing), Abhejit Rajagopal (Data curation, Formal analysis, Investigation, Software, Writing—review & editing), Steven N. Seyedin (Investigation, Methodology, Writing—review & editing), Roxanna Juarez (Data curation, Formal analysis, Investigation, Validation, Writing—review & editing), Peter R. Carroll (Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing—review & editing), Felix Y. Feng (Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing—review & editing), Eric J. Small (Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Writing—review & editing), Thomas A. Hope (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Writing—review & editing), and Julian C. Hong (Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing—review & editing)
Supplementary material
Supplementary material is available at JNCI Cancer Spectrum online.
Funding
This research was supported by an ASTRO-PCF Career Development Award to End Prostate Cancer (to J.C.H.) and a PCF Young Investigator Award (to W.S.C.). The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; or the writing of the manuscript and decision to submit it for publication.
Conflicts of interest
J.C.H., who is a JNCI Cancer Spectrum Associate Editor and co-author on this paper, was not involved in the editorial review or decision to publish the manuscript.
Data availability
Data are included within the article, tables, and figures, and additional supporting data are available on request.
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