A prospective phase I dose-escalation trial of stereotactic ablative radiotherapy (SABR) as an alternative to cytoreductive nephrectomy for inoperable patients with metastatic renal cell carcinoma

Rohann J M Correa, Belal Ahmad, Andrew Warner, Craig Johnson, Mary J MacKenzie, Stephen E Pautler, Glenn S Bauman, George B Rodrigues, Alexander V Louie, Rohann J M Correa, Belal Ahmad, Andrew Warner, Craig Johnson, Mary J MacKenzie, Stephen E Pautler, Glenn S Bauman, George B Rodrigues, Alexander V Louie

Abstract

Background: Cytoreductive nephrectomy is thought to improve survival in metastatic renal cell carcinoma (mRCC). As many patients are ineligible for major surgery, we hypothesized that SABR could be a safe alternative.

Methods: In this dose-escalation trial, inoperable mRCC patients underwent SABR targeting the entire affected kidney. Toxicity (CTCAE v3.0), quality of life (QoL), renal function, and tumour response (RECIST v1.0) were assessed.

Results: Twelve patients of mostly intermediate (67%) or poor (25%) International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic class, median KPS of 70%, and median tumour size of 8.7 cm (range: 4.8-13.8) were enrolled in successive dose cohorts of 25 (n = 3), 30 (n = 6), and 35 Gy (n = 3) in 5 fractions. SABR was well tolerated with 3 grade 3 events: fatigue (2) and bone pain (1). QoL decreased for physical well-being (p = 0.016), but remained unchanged in other domains. SABR achieved a median tumour size reduction of - 17.3% (range: + 5.3 to - 54.4) at 5.3 months. All patients progressed systemically and median OS was 6.7 months. Crude median follow-up was 5.8 months.

Conclusions: In non-operable mRCC patients, renal-ablative SABR to 35 Gy in 5 fractions yielded acceptable toxicity, renal function preservation, and stable QoL. SABR merits further prospective investigation as an alternative to cytoreductive nephrectomy.

Trial registration: ClinicalTrials.gov NCT02264548. Registered July 22 2014 - Retrospectively registered: https://ichgcp.net/clinical-trials-registry/NCT02264548.

Keywords: Metastatic; Primary tumour; Renal cell; Stereotactic ablative radiotherapy.

Conflict of interest statement

Ethics approval and consent to participate

Ethics approval for this study was provided by the Western University Human Studies Research Ethics Board (REB# 15680). All study participants provided written consent to participate in this trial.

Consent for publication

All study participants provided written consent which included consent for the publication of trial results.

Competing interests

Dr. Louie has received speaker’s honoraria from Varian Medical Systems, Inc.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study Design. DLT – dose limiting toxicity; MTD – maximum tolerated dose
Fig. 2
Fig. 2
Renal Function. a Functional contribution of both kidneys pre- and 12 weeks post-SABR with corresponding measured GFR values listed above each bar. Numbered bars indicate % contribution from ipsilateral kidney. b Comparison of creatinine clearance (CrCl) calculated using the Cockroft-Gault equation before and after stereotactic ablative radiotherapy (SABR) for patients with available pre- and post-SABR data (n = 9). P-value reported from the Wilcoxon signed-rank test
Fig. 3
Fig. 3
Treatment Response and Survival. a Abdominal and b thoracic coronal CT slices from patient 11 pre-SABR (left) and 7 months post-SABR (right). c Tumour size expressed as percent change in longest tumour dimension. Horizontal dotted lines mark a 20% increase and 30% decrease in size. Patient 9 (dotted/dashed line) also underwent renal embolization for refractory hematuria on day 27 post-SABR. d Kaplan-Meier plot of overall survival with 95% confidence bands (n = 12)

References

    1. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004;171:1071–1076. doi: 10.1097/.
    1. Hanna N, Sun M, Meyer CP, et al. Survival Analyses of Patients With Metastatic Renal Cancer Treated With Targeted Therapy With or Without Cytoreductive Nephrectomy: A National Cancer Data Base Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2016;34:3267–3275. doi: 10.1200/JCO.2016.66.7931.
    1. Petrelli F, Coinu A, Vavassori I, et al. Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma Treated With Targeted Therapies: A Systematic Review With a Meta-Analysis. Clin Genitourin Cancer. 2016;14:465–472. doi: 10.1016/j.clgc.2016.04.001.
    1. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011;185:60–66. doi: 10.1016/j.juro.2010.09.012.
    1. Bex A. Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME) Madrid: ESMO 2017 Congress; 2017.
    1. Tsao CK, Small AC, Moshier EL, et al. Trends in the use of cytoreductive nephrectomy in the United States. Clin Genitourin Cancer. 2012;10:159–163. doi: 10.1016/j.clgc.2012.03.008.
    1. Conti SL, Thomas IC, Hagedorn JC, et al. Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. International journal of cancer Journal international du cancer. 2014;134:2245–2252. doi: 10.1002/ijc.28553.
    1. Abdollah F, Sun M, Thuret R, et al. Mortality and morbidity after cytoreductive nephrectomy for metastatic renal cell carcinoma: a population-based study. Ann Surg Oncol. 2011;18:2988–2996. doi: 10.1245/s10434-011-1715-2.
    1. Ning S, Trisler K, Wessels BW, Knox SJ. Radiobiologic studies of radioimmunotherapy and external beam radiotherapy in vitro and in vivo in human renal cell carcinoma xenografts. Cancer. 1997;80:2519–2528. doi: 10.1002/(SICI)1097-0142(19971215)80:12+<2519::AID-CNCR26>;2-E.
    1. Ponsky LE, Crownover RL, Rosen MJ, et al. Initial evaluation of Cyberknife technology for extracorporeal renal tissue ablation. Urology. 2003;61:498–501. doi: 10.1016/S0090-4295(02)02442-1.
    1. Walsh L, Stanfield JL, Cho LC, et al. Efficacy of ablative high-dose-per-fraction radiation for implanted human renal cell cancer in a nude mouse model. Eur Urol. 2006;50:795–800. doi: 10.1016/j.eururo.2006.03.021.
    1. Kothari G, Foroudi F, Gill S, Corcoran NM, Siva S. Outcomes of stereotactic radiotherapy for cranial and extracranial metastatic renal cell carcinoma: a systematic review. Acta Oncol. 2015;54:148–157. doi: 10.3109/0284186X.2014.939298.
    1. Alongi F, Arcangeli S, Triggiani L, et al. Stereotactic ablative radiation therapy in renal cell carcinoma: From oligometastatic to localized disease. Crit Rev Oncol Hematol. 2017;117:48–56. doi: 10.1016/j.critrevonc.2017.07.004.
    1. Siva S, Pham D, Gill S, Corcoran NM, Foroudi F. A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma. BJU Int. 2012;110:E737–E743. doi: 10.1111/j.1464-410X.2012.11550.x.
    1. Siva S, Kothari G, Muacevic A, et al. Radiotherapy for renal cell carcinoma: renaissance of an overlooked approach. Nature reviews. Urology. 2017;14:549-563.
    1. Siva S, Muacevic A, Staehler M, et al. Individual Patient Data Meta-analysis of SBRT Kidney: A Report From the International Radiosurgery Oncology Consortium for Kidney (IROCK) International Journal of Radiation Oncology*Biology*Physics. 2017;99:S153–S1S4. doi: 10.1016/j.ijrobp.2017.06.355.
    1. Shin BJ, Chick JF, Stavropoulos SW. Contemporary Status of Percutaneous Ablation for the Small Renal Mass. Curr Urol Rep. 2016;17:23. doi: 10.1007/s11934-016-0581-7.
    1. Kurup AN. Percutaneous ablation for small renal masses-complications. Semin Interv Radiol. 2014;31:42–49. doi: 10.1055/s-0033-1363842.
    1. Demaria S, Ng B, Devitt ML, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004;58:862–870. doi: 10.1016/j.ijrobp.2003.09.012.
    1. Park SS, Dong H, Liu X, et al. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer immunology research. 2015;3:610–619. doi: 10.1158/2326-6066.CIR-14-0138.
    1. Brooks ED, Schoenhals JE, Tang C, et al. Stereotactic Ablative Radiation Therapy Combined With Immunotherapy for Solid Tumors. Cancer J. 2016;22:257–266. doi: 10.1097/PPO.0000000000000210.
    1. Correa RJ, Rodrigues GB, Chen H, Warner A, Ahmad B, Louie AV. Stereotactic Ablative Radiotherapy (SABR) for Large Renal Tumors: A Retrospective Case Series Evaluating Clinical Outcomes, Toxicity, and Technical Considerations. Am J Clin Oncol. 2016. Epub ahead of print.
    1. Siva S, Ellis RJ, Ponsky L, et al. Consensus statement from the International Radiosurgery Oncology Consortium for Kidney for primary renal cell carcinoma. Future Oncol. 2016;12:637–645. doi: 10.2217/fon.16.2.
    1. Timmerman RD. An overview of hypofractionation and introduction to this issue of seminars in radiation oncology. Semin Radiat Oncol. 2008;18:215–222. doi: 10.1016/j.semradonc.2008.04.001.
    1. Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27:5794–5799. doi: 10.1200/JCO.2008.21.4809.
    1. Patel HD, Pierorazio PM, Johnson MH, et al. Renal Functional Outcomes after Surgery, Ablation, and Active Surveillance of Localized Renal Tumors: A Systematic Review and Meta-Analysis. Clin J Am Soc Nephrol. 2017;12:1057-1069.
    1. De Wolf K, Rottey S, Vermaelen K, et al. Combined high dose radiation and tyrosine kinase inhibitors in renal cell carcinoma: a phase I trial. ESTRO Annual Meeting. Vienna, Austria. Radiother Oncol. 2017;12:157.
    1. Demaria S, Coleman CN, Formenti SC. Radiotherapy: Changing the Game in Immunotherapy. Trends Cancer. 2016;2:286–294. doi: 10.1016/j.trecan.2016.05.002.
    1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:1803–1813. doi: 10.1056/NEJMoa1510665.
    1. Lugade AA, Moran JP, Gerber SA, Rose RC, Frelinger JG, Lord EM. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol. 2005;174:7516–7523. doi: 10.4049/jimmunol.174.12.7516.
    1. Kim MS, Kim W, Park IH, et al. Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery. Radiation oncology journal. 2015;33:265–275. doi: 10.3857/roj.2015.33.4.265.
    1. Wersall PJ, Blomgren H, Pisa P, Lax I, Kalkner KM, Svedman C. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45:493–497. doi: 10.1080/02841860600604611.
    1. Siva S, MacManus MP, Martin RF, Martin OA. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett. 2015;356:82–90. doi: 10.1016/j.canlet.2013.09.018.
    1. Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer immunology research. 2013;1:365–372. doi: 10.1158/2326-6066.CIR-13-0115.
    1. Hiniker SM, Chen DS, Reddy S, et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 2012;5:404–407. doi: 10.1593/tlo.12280.
    1. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–931. doi: 10.1056/NEJMoa1112824.
    1. Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev. 2015;41:503–510. doi: 10.1016/j.ctrv.2015.03.011.
    1. Singh AK, Winslow TB, Kermany MH, et al. A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma. Clin Cancer Res. 2017;23:5055-5065.

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