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Stereotactic Body Radiation Therapy (SBRT) for Oligometastatic Genito-Urinary Cancers – A Review of Prospective Studies STOMPing Out Disease - Beyond the Abstract

Oligometastatic disease (OMD) has been defined as a transitional state of metastatic spread, in which localized treatment with ablative intent can translate into a prolonged state of tumor remission, and even cure. Originally proposed in 1995 by Hellman and Weichselbaum, the hypothesized OMD state has become a practical reality for clinicians to grapple with in multidisciplinary decision-making as the convergence of improved methods of detection, metastatic-directed therapy (MDT) using stereotactic body radiation therapy (SBRT), and improved systemic therapies are enabling patients to live long enough to experience both the benefits and the toxicities of pursuing a locally “curative” approach.1

A growing body of prospective randomized data has helped counteract the selection bias that historically limited the generalizability of prior reports of favorable outcomes after MDT for OMD, which has typically been defined as 1 to 5 metastatic sites. However, this numeric view of OMD is rapidly evolving. Technologically, there is no upper limit on number of sites treated as long as RT can be safely delivered with curative intent to all sites per American Society for Therapeutic Radiation Oncology (ASTRO) consensus guidelines in the context of radiotherapy.2 Biologically, tumor histology may also impact outcomes, as MDT was not associated with improved outcomes in recent randomized studies assessing the role of MDT for patients with oligometastatic breast cancer.3,4 Finally, OMD is increasingly being recognized as a dynamic state, and can be categorized as genuine or induced by systemic therapy based on presence or absence of prior polymetastases, and de novo or repeat, before further subcategorization based on timing (synchronous or metachronous) or growth pattern of lesions (recurrent, progressive, or persistent).1,5 In the absence of biomarkers, these clinical selection criteria may help refine patient selection for MDT and serve as a benchmark for evaluating clinical outcomes in comparison to alternative standards of care (SOC).2

In this critical review, we aimed to systematically review the literature combined with expert input to examine all prospective studies assessing the role of SBRT in the context of oligometastatic prostate, renal, and bladder cancers with this dynamic framework of OMD. Our hope was to illuminate the clinical scenarios where the best available evidence exists to support a comprehensive MDT approach and highlight opportunities for further study, such that treatment with MDT is not primarily based on extrapolation based on principle.6

Our findings highlight that the most commonly studied application of SBRT has been for metachronous oligorecurrent hormone-sensitive prostate cancer, which included the Phase 2 randomized controlled trials (RCT), STOMP and ORIOLE, which compared MDT vs observation.7, 8 Both identified an association of MDT with improved local control (99-100%) and PSA progression-free survival in men with 1-3 metastases on choline-PET or conventional imaging, respectively. Consistent with the OMD hypothesis, the ORIOLE study on post-hoc analysis identified complete ablation of metastases detected on PSMA-PET as being significantly associated with improved outcome.8 These results were consistent with the Phase I single arm POPSTAR trial, which reported 93% 2 year local control (LC) and 2 year ADT-free survival (ADT-FS) of 48%, and the Phase II single arm PSMA-MRgRT trial, in which median ADT-FS was 17.7 months for men with negative conventional imaging and up to 5 positive lesions on PSMA-PET treated with MDT.9,10 Bone represented the majority of sites treated on POPSTAR (61%), and 39% of lesions treated on STOMP and ORIOLE, and only 8% of lesions treated on PSMA-MRgRT, with lymph nodes compromising the remainder of the lesions, which reflects the variance in screening imaging eligibility criteria. Importantly, among a total of 127 men treated across the four trials, there were only 3 grade 3 toxicities, including 1 grade 3 vertebral body fracture in POPSTAR, 1 grade 3 ureter injury and 1 grade 3 deep vein thrombosis in the surgery MDT cohort. The MDT approach with or without combined ADT or other systemic agents is the topic of multiple ongoing studies for oligorecurrent HSPC.

There is no defined standard for the management of oligometastatic lymph nodes and a wide range of locoregional approaches, ranging from pelvic lymph node dissection and SBRT as MDT or comprehensive whole pelvic nodal irradiation, could be considered depending on the perceived risk of relapse in regional nodes or the competing risk of toxicity. The Phase II OligoPelvis trial utilized high dose pelvic IMRT + 6 months ADT for men with up to five oligorecurrent nodes detected on choline PET with median biochemical PFS 25.9 months comparable to the 17.7 months achieved with PSMA-MRgRT.10, 11 Novel approaches incorporating MR technology to adaptively treat lymph nodes is expanding the ability to deliver higher doses to tumor targets abutting bowel, and thus expanding the opportunity for hypofractionation or dose escalation while also minimizing the risk of toxicity to nearby visceral organs.12-14 The management of oligorecurrent lymph nodes is the focus of two prospective randomized trials, including OLIGOPELVIS 2 (intermittent ADT +/- salvage high-dose IMRT) and PEACE V-STORM (MDT + 6 mo ADT +/- whole pelvis RT), which will help establish the optimal approach.

Despite the theoretical benefit of SBRT in oligoprogressive castrate-resistant prostate cancer (CRPC) in potentially sterilizing resistance cancer cell clones, thereby delaying time to next therapy (TTNT), there have been no published randomized prospective studies to demonstrate such an association. A Phase II single arm trial reported a median OS of 29.3 months and 2 year PFS of 21% for 89 men with 128 lesions identified on choline-PET.15 There are currently at least five ongoing phase II/III RCTs that will assess the benefit of SBRT for oligometastatic CRPC in the background of systemic therapy, with PSA response as the primary endpoint.

The rationale for SBRT in renal cell carcinoma (RCC) stems also from the theoretical benefit of hypofractionation and dose intensification in addressing classically radio-resistant histology. Two phase II trials have studied the role of SBRT for systemic therapy-naïve (synchronous or metachronous) oligometastatic RCC among patients with a controlled primary tumor. In a study of 23 patients with up to 3 extracranial sites, Hannan and colleagues met their primary endpoint of a 1-year freedom from systemic therapy rate of 87%.16 Similarly Tang and colleagues reported a median PFS of 22.7 months in their cohort of 30 patients with up to five sites treated.17 In oligoprogressive RCC, a Phase II multicenter study of SBRT for men with up to five progressive metastases after tyrosine kinase inhibitor (TKI) was associated with median PFS 9.3 months and TTNT 12.6 months.18 Similarly, in a phase 2 trial of 20 patients with oligoprogressive RCC and up to 3 metastases, SBRT extended median TTNT by 11.1 months, with one possibly treatment-related Grade 3 gastrointestinal toxicity.19

The potential synergy of SBRT and immune checkpoint blockade in RCC has been explored in multiple trials of RCC, including the single-arm NIVES trial of nivolumab and concurrent SBRT,20 RADVAX trial of nivolumab and ipilimumab and concurrent SBRT (reported in abstract form), and was associated with overall response rate (ORR) of 17% and 56%, respectively.21 Both trials included patients with predominantly polymetastatic, intermediate, or poor IMDC risk. In contrast, the Phase I/II multi-center RAPPORT trial reported an ORR of 63% and 2 year distant PFS 52% for patients with oligometastatic clear cell RCC treated with SBRT and 6 months of anti-PD-1 monotherapy pembrolizumab, which compares favorably with results from KEYNOTE-427 of 2-yr pembrolizumab as first line therapy for advanced clear cell RCC.22,23 Within RCC, the rationale for SBRT could thus range from pure palliation of symptoms for patients with widely metastatic disease but potentially could be an attractive alternative to allow an abridged course of ICI for patients with favorable-risk oligometastatic RCC based on current data.

The role of SBRT MDT for oligometastatic urothelial cancer remains the least understood among patients with genito-urinary cancers, with data primarily from retrospective case series. A randomized phase I trial of SBRT to one metastatic lesion administered either sequentially or concomitantly with pembrolizumab for 18 patients with metastatic urothelial cancer showed an ORR of 0% in non-irradiated lesions with sequential SBRT and 44% in non-irradiated lesions with concomitant SBRT24 and intriguingly suggests that delivering RT during – and not prior to – checkpoint inhibition is required for synergy of combination immunoradiotherapy. The clinical rationale for SBRT in oligometastatic urothelial cancer remains primarily based on extrapolation from the tumor-agnostic Phase II SABR-COMET trial, which did show a PFS and OS benefit to comprehensive SBRT through the representation of patients with urothelial cancers was limited.25-27

Despite the growing application of SBRT for oligometastatic cancers, which have all demonstrated high rates of local control and limited rates of grade 3 or higher toxicities, there remain far more questions than answers regarding which patient population benefits the most from a locally ablative approach, with perhaps the exception of oligorecurrent HSPC. As the treatment landscape for patients with metastatic cancer continues to evolve, prospective evaluation of SBRT MDT compared with alternative SOC, stratifying by OMD state and tumor histology, will continue to inform clinicians and patients on how best to balance the benefits versus risk of an MDT approach in the pursuit of better outcomes and cure. In the context of metastatic disease, the role of radiation should otherwise be reserved for palliation of symptoms and will continue to require multidisciplinary decision-making in tailoring treatment to clinical intent.

Written by:

  • Mai Anh Huynh, MD, PhD, Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA
  • Phuoc Tran, MD, PhD, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD
References:

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  3. Chmura SJ WK, Woodward WA, Borges VF, Salama JK, Al-Hallaq HA, et al. . NRG-BR002: A phase IIR/III trial of standard of care systemic therapy with or without stereotactic body radiotherapy (SBRT) and/or surgical resection (SR) for newly oligometastatic breast cancer (NCT02364557). JCO. 2022;40(16_suppl):1007–.
  4. Tsai CJ YJ, Guttmann DM, Shaverdian N, Shepherd AF, Eng J, et al. Consolidative Use of Radiotherapy to Block (CURB) Oligoprogression ― Interim Analysis of the First Randomized Study of Stereotactic Body Radiotherapy in Patients With Oligoprogressive Metastatic Cancers of the Lung and Breast. Int J Radiat Oncol Biol Phys. 2021;111(5):1325-6.
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  12. Henke L, Kashani R, Robinson C, Curcuru A, DeWees T, Bradley J, et al. Phase I trial of stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of oligometastatic or unresectable primary malignancies of the abdomen. Radiother Oncol. 2018;126(3):519-26.
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