AbstractPurpose

Oligoprogression, defined as limited sites of progression on systemic therapy, in patients with metastatic renal cell carcinoma (mRCC) is not uncommon, possibly because of inter- and intratumoral heterogeneity. We evaluated the effect of stereotactic ablative radiation therapy (SAbR) for longitudinal control of oligoprogressive mRCC.

Methods and Materials

Patients with extracranial mRCC were included in this retrospective analysis if they progressed in ≤3 sites on systemic therapy while demonstrating response/stability at other sites and received SAbR to all progressing sites without switching systemic therapy. Our primary endpoint was modified progression-free survival (mPFS), which we calculated from the start of SAbR to the start of a subsequent systemic therapy, death, or loss to follow-up.

Results

We identified 36 patients with a median follow-up of 20.4 months (interquartile range, 10.9-29.4). Forty-three sites were treated with SAbR with a median dose of 36 Gy (range, 18-50) in 3 fractions (range, 1-5). Median time to SAbR from the start of systemic therapy was 11.4 months (interquartile range, 6.1-17.1). Median mPFS was 9.2 months (95% confidence interval [CI], 5.9-13.2). Patients receiving SAbR while on immunotherapy exhibited a longer median mPFS (>28.4 months, log-rank P = .0001) than patients not on immunotherapy (9.2 months). Median overall survival from SAbR administration was 43.4 months (95% CI, 21.5-not Reached). The 1-year local control rate was 93% (95% CI, 78.7-97.5). Most SAbR-related toxicities were grade 1 to 2 (33% of patients), with one grade 5 hemoptysis event possibly related to SAbR or disease progression.

Conclusions

SAbR has the potential to extend the the duration of current systemic therapy for selected patients with mRCC, preserving subsequent therapies for later administration possibly enabling longer treatment duration.

IntroductionOver one-third of patients with renal cell carcinoma (RCC) develop metastasis (mRCC) and their outcome remains poor.1Noone AM HN Krapcho M Miller D et al.SEER Cancer StatisticsReview, 1975-2015. The standard of care for patients with mRCC is systemic therapy.2Systemic therapy for metastatic renal-cell carcinoma. Combination frontline therapy yields a median progression-free survival (PFS) of over 1 year,3Rini BI Plimack ER Stus V et al.Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.,4Motzer RJ Tannir NM McDermott DF et al.Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. but complete responses are few, and most patients develop resistance. Upon progression, the standard of care is to switch systemic therapies, but each subsequent line typically yields a shorter PFS.2Systemic therapy for metastatic renal-cell carcinoma.,5Motzer RJ Escudier B Tomczak P et al.Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: Overall survival analysis and updated results from a randomised phase 3 trial.The causes of resistance are not fully understood. In many tumors, resistance to targeted therapies results from mutations in the target. Bypass pathways and cell plasticity also drive resistance. In RCC, an example has been reported of a mutation in hypoxia-inducible factor 2α rendering resistance to its inhibitor.6Courtney KD Ma Y Diaz de Leon A et al.HIF-2 complex dissociation, target inhibition, and acquired resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with clear cell renal cell carcinoma. RCC is considered a paradigm for both histologic7Cai Q Christie A Rajaram S et al.Ontological analyses reveal clinically-significant clear cell renal cell carcinoma subtypes with convergent evolutionary trajectories into an aggressive type. and molecular tumor heterogeneity. Genomic studies of multiple regions of primary and matched metastases show inter- and intratumoral mutational heterogeneity.8Gerlinger M Rowan AJ Horswell S et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. Both branched and parallel evolution of clonally accumulated mutational drivers have been reported.8Gerlinger M Rowan AJ Horswell S et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing., 9Turajlic S Xu H Litchfield K et al.Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal., 10Turajlic S Xu H Litchfield K et al.Deterministic evolutionary trajectories influence primary tumor growth: TRACERx renal., 11Mitchell TJ Turajlic S Rowan A et al.Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. This reveals Darwinian selection of the fittest clones.8Gerlinger M Rowan AJ Horswell S et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.,9Turajlic S Xu H Litchfield K et al.Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. The tumor microenvironment may also influence resistance.12Microenvironmental regulation of tumor progression and metastasis.Resistance to systemic therapy manifests as generalized or focal disease progression. The underlying mechanisms probably differ. In some patients, resistance involves limited sites of metastases. This suggests that changes at those sites likely drove their progression. When systemic therapy is well tolerated, targeting those sites with focal therapies may be reasonable. Herein, we retrospectively report our institutional experience using stereotactic ablative radiation therapy (SAbR), which has shown excellent disease control rates with minimal toxicity in mRCC,13Franzese C Franceschini D Di Brina L et al.Role of stereotactic body radiation therapy in the management of oligometastatic renal cell carcinoma., 14Meyer E Pasquier D Bernadou G et al.Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group., 15Stenman M Sinclair G Paavola P Wersall P Harmenberg U Lindskog M Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014., 16Wersall PJ Blomgren H Lax I et al.Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma., 17Zelefsky MJ Greco C Motzer R et al.Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma., 18Svedman C Sandstrom P Pisa P et al.A prospective phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma., 19Kothari G Foroudi F Gill S Corcoran NM Siva S Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: A systematic review., 20Wang CJ Christie A Lin MH et al.Safety and efficacy of stereotactic ablative radiation therapy for renal cell carcinoma extracranial metastases., 21Zhang Y Schoenhals J Christie A et al.Stereotactic ablative radiation therapy (SABR) used to defer systemic therapy in oligometastatic renal cell cancer. to eradicate limited sites of progressing metastases and delay switching systemic therapy.Discussion

mRCC remains largely incurable, and as RCC progresses, systemic therapy is re-evaluated and changed as necessary. Widespread disease progression, especially soon after initiating systemic therapy, suggests innate resistance. In contrast, limited progression after a prolonged period on systemic therapy suggests focally acquired resistance. Using a local therapy like SAbR is an attractive option to eradicate the few progressing sites while patients remain on the same systemic therapy, particularly if the systemic therapy is active overall and well tolerated. Our study shows that, in patients with oligoprogressive mRCC, SAbR may increase the PFS from the time of radiation to the next systemic therapy by a median of 9.2 months.

SAbR is increasingly being used to treat mRCC beyond intracranial and bone metastases.20Wang CJ Christie A Lin MH et al.Safety and efficacy of stereotactic ablative radiation therapy for renal cell carcinoma extracranial metastases.,21Zhang Y Schoenhals J Christie A et al.Stereotactic ablative radiation therapy (SABR) used to defer systemic therapy in oligometastatic renal cell cancer. Multiple studies have evaluated its use in various settings, including oligometastasis and oligoprogression.13Franzese C Franceschini D Di Brina L et al.Role of stereotactic body radiation therapy in the management of oligometastatic renal cell carcinoma., 14Meyer E Pasquier D Bernadou G et al.Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group., 15Stenman M Sinclair G Paavola P Wersall P Harmenberg U Lindskog M Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005-2014., 16Wersall PJ Blomgren H Lax I et al.Extracranial stereotactic radiotherapy for primary and metastatic renal cell carcinoma., 17Zelefsky MJ Greco C Motzer R et al.Tumor control outcomes after hypofractionated and single-dose stereotactic image-guided intensity-modulated radiotherapy for extracranial metastases from renal cell carcinoma., 18Svedman C Sandstrom P Pisa P et al.A prospective phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma., 19Kothari G Foroudi F Gill S Corcoran NM Siva S Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: A systematic review., 20Wang CJ Christie A Lin MH et al.Safety and efficacy of stereotactic ablative radiation therapy for renal cell carcinoma extracranial metastases., 21Zhang Y Schoenhals J Christie A et al.Stereotactic ablative radiation therapy (SABR) used to defer systemic therapy in oligometastatic renal cell cancer.,26Survival outcomes after adding stereotactic body radiotherapy to metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors., 27Zaorsky NG Lehrer EJ Kothari G Louie AV Siva S Stereotactic ablative radiation therapy for oligometastatic renal cell carcinoma (SABR ORCA): A meta-analysis of 28 studies., 28Correa RJM Louie AV Zaorsky NG et al.The emerging role of stereotactic ablative radiotherapy for primary renal cell carcinoma: A systematic review and meta-analysis. Although most of these studies are retrospective and limited by patient numbers, a heterogeneous patient population, and short follow-up, local control of irradiated lesions is typically 78% to 98% at 1-3 years, and grade 3 to 4 adverse events after SAbR are generally 14Meyer E Pasquier D Bernadou G et al.Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the Getug group. They had 101 patients with oligoprogressive disease, but only 7 of them were treated with SAbR after partial response to systemic therapy. More recently, a meta-analysis of the safety and survival of patients with oligometastatic cancer treated with SAbR revealed 1.2% acute grade 3 to 5 toxicity, 1.7% late grade 3 to 5 toxicity, and 94.7% 1-year local control,29Lehrer EJ Singh R Wang M et al.Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: A systematic review and meta-analysis. consistent with our findings. Our study extends this body of literature by focusing on SAbR's effects in a select group of patients with RCC who demonstrated some response to systemic therapy with limited oligoprogressive disease, and it shows that SAbR can control the progressing sites while delaying changes in systemic therapy. For some patients, SAbR can also be considered as a longitudinal strategy, with several rounds of SAbR administered over time if only a few sites progress and the disease appears to remain sensitive to the ongoing systemic therapy. Using SAbR for longitudinal disease control is similar to what we reported recently for patients with oligometastatic RCC.21Zhang Y Schoenhals J Christie A et al.Stereotactic ablative radiation therapy (SABR) used to defer systemic therapy in oligometastatic renal cell cancer. A prospective phase II study investigating SAbR treatment of 37 patients with oligoprogressive RCC was recently reported, and revealed a 9.6 months mPFS, which is comparable to our findings (NCT02019576).30A phase II multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy.One challenge to deploying SAbR for oligoprogression is identifying the patient population most likely to benefit. In our study, oligoprogressive patients treated with SAbR while on an ICI-containing regimen appeared to have better mPFS than those receiving either vascular endothelial growth factor or mTOR inhibitors. These patients may have received additional synergistic benefits from SAbR's antigen presenting properties and immune cell recruitment.31Marciscano AE Haimovitz-Friedman A Lee P et al.Immunomodulatory effects of stereotactic body radiation therapy (SBRT): Preclinical insights and clinical opportunities. Several trials are investigating the combination of ICI and radiation in kidney cancer (including NCT03065179, NCT02781506, and NCT03115801). In addition to therapy before SAbR, sites of metastatic disease may inform about the aggressiveness of the cancer.32Ryan C Stoltzfus KC Horn S et al.Epidemiology of bone metastases., 33Horn SR Stoltzfus KC Lehrer EJ et al.Epidemiology of liver metastases., 34Singh R Stoltzfus KC Chen H et al.Epidemiology of synchronous brain metastases. RCC commonly metastasizes to the lung, lymph nodes, bone, liver, and brain.35Dudani S de Velasco G Wells JC et al.Evaluation of clear cell, papillary, and chromophobe renal cell carcinoma metastasis sites and association with survival. Tumors that metastasize to the bone, liver, and brain have been shown to be associated with worse OS.35Dudani S de Velasco G Wells JC et al.Evaluation of clear cell, papillary, and chromophobe renal cell carcinoma metastasis sites and association with survival. In our study, we determined that patients with metastases to the bone or lung did not exhibit a different mPFS or PFS. However, this may be due to the limited number of patients in this study. RCC that metastasize to the pancreas may have a more indolent course,35Dudani S de Velasco G Wells JC et al.Evaluation of clear cell, papillary, and chromophobe renal cell carcinoma metastasis sites and association with survival.,36Singla N Xie Z Zhang Z et al.Pancreatic tropism of metastatic renal cell carcinoma. but with only one patient with a pancreatic lesion treated, we were unable to assess whether this patient population may benefit from SAbR to oligoprogressive disease.SAbR was generally well tolerated, with 33% of patients experiencing grade 1 to 2 adverse events, one patient hospitalized for a gastric ulcer (no operative or endoscopic intervention), and one patient who developed fatal hemoptysis 8 months after lung SAbR, where SAbR's contribution was unclear. How SAbR should be optimally integrated with systemic therapy remains uncertain. Several studies retrospectively evaluated treatment-related toxicities in patients receiving TKI therapy and SAbR. One study that investigated toxicity rates in patients on TKI therapy undergoing SAbR to spinal metastases showed no grade 3 or greater toxicities.37Miller JA Balagamwala EH Angelov L et al.Spine stereotactic radiosurgery with concurrent tyrosine kinase inhibitors for metastatic renal cell carcinoma. Another study showed that 4 of 56 patients receiving SAbR to oligoprogressive lesions while on TKI therapy experienced grade 3 toxicities, including radiation dermatitis, neuropathy, and anemia.26Survival outcomes after adding stereotactic body radiotherapy to metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors. Given these limited data, caution should be exercised when combining SAbR with TKI and mTOR inhibitors, particularly when radiosensitive structures are close to the targeted lesion. In such instances, holding systemic therapy is reasonable. Holding ICI during SAbR is unlikely to affect toxicity given the long half-life of antibodies. Concurrent administration of SAbR and ICI may be safe, as reported previously.38Mohamad O Diaz de Leon A Schroeder S et al.Safety and efficacy of concurrent immune checkpoint inhibitors and hypofractionated body radiotherapy., 39Tang C Welsh JW de Groot P et al.Ipilimumab with stereotactic ablative radiation therapy: Phase I results and immunologic correlates from peripheral t cells., 40Sha CM Lehrer EJ Hwang C et al.Toxicity in combination immune checkpoint inhibitor and radiation therapy: A systematic review and meta-analysis.

Our study has several limitations. First, it is a retrospective study from a single institution, and it involves a cohort of highly selected patients. Patient selection for this report was based on specific, objective criteria (including number of progressive sites, SAbR treatment to all, and continuation of existing systemic therapy) and did not necessarily include provider intent to use SAbR for oligoprogression. This merits consideration, as nearly 50% of the SAbR-treated lesions were in bone, where SAbR is standard of care. Second, the absence of a control group precludes determining SAbR's specific contribution to extending systemic therapy . Third, although it makes sense that extending the duration of systemic therapy and overall disease control should benefit patients, this lacks formal evaluation. Fourth, some of the patients may have had more indolent cancer given prolonged disease control before SAbR, which may have led to longer PFS and/or mPFS in the cohort. Also, our patient population was treated between 2007 and 2017, during which time immunotherapy became approved in the front line. Lastly, the median follow-up of 20 months is still too short to assess the long-term control of SAbR-treated metastases.

Article InfoPublication History

Published online: May 25, 2021

Accepted: March 11, 2021

Received in revised form: February 9, 2021

Received: January 5, 2021

Publication stageIn Press Journal Pre-ProofFootnotes

Sources of support: J.B. and A.C. are funded by P50CA196516 . R.H. is funded by American Cancer Society RSG-16-004-01-CCE .

Disclosures: none.

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

Identification

DOI: https://doi.org/10.1016/j.adro.2021.100692

Copyright

© 2021 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

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