5-Year Outcomes After Ablative Radiotherapy for Primary RCC

What can we offer patients with primary renal cell carcinoma (RCC) who are unable to undergo surgery? According to a recent study published in The Lancet Oncology, radiation may be an answer offering safety and long-term efficacy.¹ This report has particular relevance for elderly patients. The authors begin by noting that the incidence of RCC is rising especially in patients older than 70 years. These patients typically have more comorbidities, putting them at increased risk for surgical intervention. Current guidelines recommend that for these patients, thermal ablation, and stereotactic ablative body radiotherapy (SABR) are potential options.²

The Use of SABR for RCC

The utilization of SABR has been increasing,³ and support for its use include efficacy and safety results in in several studies^4,5,6; however, long-term follow-up data have been lacking. This is what propelled the authors of the current study to assess the long-term data for use of SABR in patients with primary RCC from the International Radiosurgery Oncology Consortium of the Kidney (IROCK). The population included patients with long-term follow-up and additional patients registered from contributing institutions.

The study included patients from 5 countries including the United States at 12 international institutions over an 11- year period between 2007 and 2018. Patients were included only if they were followed for r2 years, were diagnosed with nonmetastatic RCC at the time of diagnosis, were adults with any performance status, and had no contraindications for receiving SABR. Specific excluded patients were those with previous abdominal radiation or a previous diagnosis of upper tract urothelial carcinoma. All patients were considered inoperable by the referring urologist.

Patients were followed every 3 to 4 months in year 1, every 3 to 6 months in years 2 and 3, and every 6 to 12 months after year 3 using computed tomography imaging and serum creatinine. According to the authors, “The primary objective of this study was to assess the local efficacy of SABR for primary renal cell carcinoma and secondary objectives were to evaluate treatment related toxic effects, patterns of failure, survival, and renal function outcomes.”¹ Survival endpoints included progression-free survival (PFS), cancer-specific survival (CSS), local failure, distant failure, and any failure.

Nearly 200 patients were included in the study with a median age of 73.6 years; the median follow-up time was 5 years. A total of 73% of patients were men and 27% were women. Overall, 88% of patients had good performance status measured by an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1, or a Karnofsky performance status score of ≥70%. 83% of patients had biopsy confirmed RCC. Baseline tumor complexity was moderate as measured by the R.E.N.A.L. nephrometry score (R=radius [tumor size as maximal diameter], E=exophytic/ endophytic properties of the tumor, N=nearness of tumor deepest portion to the collecting system or sinus, A=anterior [a]/posterior [p] descriptor, L=location relative to the polar line). Nearly 30% of patients had only 1 kidney.

Of note, no patients included in the study received adjuvant or concurrent systemic therapy. Local failure was 5.5% at 3 years, 5.5% at 5 years, and 8.4% at 7 years; 86% of patients did not have a recorded failure. A total of 35% of patients died during the follow-up period. In 15% of those patients, deaths were attributed to cancer-related causes and 77% were attributed to nonmalignant causes, including cardiovascular causes (18%).

Other causes of death included sepsis, renal failure, respiratory failure, acute subdural hemorrhage, liver disease, lung disease, and pneumonitis. There were 5 patients who died from other malignancies. CSS was 95.5% at 3 years, 92% at 5 years, and 92% at 7 year and the progression free survival at 3 years, 5 years and 7 years was 72.1%, 63.6%, and 48.5% respectively. Median PFS was 6.7 years (95% CI, 5.5-7.5). The 3-year, 5-year, and 7-year estimates from local failure were 93.7%, 93.7%, and 89.4% respectively, while the 3-year, 5-year and 7-year estimates of freedom from distant failure was 90.5%, 87.3%, and 81%, respectively, indicating that the dominant pattern of progression was distant failure. The endpoint of median times to any failure was not reached. The authors note that “1 of 4 patients with local progression underwent successful salvage with radical nephrectomy, whereas the remaining 3 were not considered for surgery due to either pre-existing medical inoperability or T4 disease, which was surgically inoperable.”¹

The Effects of SABR on Renal Function

The authors then evaluated the effects of SABR on renal function. Chronic kidney disease (CKD) classification before and after SABR remained stable in nearly half the patients and worsened in 47%; 7% declined to end-stage renal failure and renal function improved in 5%. For almost all patients, the median baseline estimated glomerular filtration rate (eGFR) was 60 mL/min per 1.73 m². Median eGFR was reduced by 5.5 at 1 year, 10.3 3 years, and 14.2 at 5 years. A similar trend seen for creatinine, with results showing an inverse steady increase in creatinine. A total of 4% of patients underwent dialysis after receiving SABR.

In all, 50% of patients had tumors 4 cm (median 4.9 cm). The authors noted that patients with tumors ≥4 cm were more likely to be older, with worse performance status, and underwent less total radiation dosing. Importantly, there was no difference in CSS, PFS, or local or distant failure between patients with tumors 4 cm. The cumulative incidences of local failure were 4.2 versus 6.7% in the 4 cm groups, and the corresponding 5-year estimates of freedom from local failure were 95.4% versus 92%. The authors then investigated whether tumor complexity is associated with treatment-related toxic effects, worsening eGFR, and local failure. They found an association with tumor complexity as measured by the R.E.N.A.L. nephrometry score and treatment-related toxic effects, as well as large declines in renal function (at 3 and 5 years, but not at 1 year), while there was no association appreciated with local failure.

When comparing patients with 1 kidney as compared to those with 2 kidneys, patients had better performance status, were younger, had a higher proportion of clear cell histology, and received lower total radiation in fewer fractions. Of the patients with 1 kidney, 75% underwent single-fraction SABR and 2 patients required dialysis. No significant difference in decline in eGFR was observed when compared patients with 1 versus 2 kidneys. There also was no difference in CSS, PFS, or local or distant failure.

Single-fraction SABR was delivered in 43% of patients at a median dose of 25 Gy, while multifraction SABR was administered in the other 57% of patients at a median dose of 42 Gy in 2 to 10 fractions over a median of 7 days. No significant difference in the incidence of toxicity events was seen. Patients who underwent single-fraction SABR were younger, had better performance status, and were more likely to have clear cell histology and a solitary kidney. Patients who underwent single-fraction SABR had reduced rates of local failure and experienced improvement in PFS but not CSS. Multivariable analysis showed a significantly higher risk of local failure for patients who received multifraction SABR (hazard ratio [HR], 6.10; 95% CI, 1.02-36.66; P=0.048) but not distant failure. Grade 1 to 2 toxicities were seen in 37% of patients, but there were no grade 3 events. One patient had a grade 4 duodenal ulcer and late grade 4 gastritis.

Long-Term Outcomes of SABR in RCC

This study is the first to describe long-term outcomes with a median of 5 years for use of SABR in patients with primary RCC. This study showed a 5.5% 5-year local failure rate and a 5-year CSS rate of 92% in a population that was considered to be inoperable. The authors observed a significant difference in PFS and local failure between single-fraction and multifraction SABR, and on multivariable analysis, there was still a significantly higher risk of local failure for multifraction SABR compared with single-fraction SABR. The authors also found no difference in long-term renal function outcomes in the single fraction versus multifraction cohorts. The authors note that these results comparing single fraction and multifraction SABR should be interpreted with caution and are not definitive, but should be treated as hypothesis generating. They noted that these findings will be evaluated in a “prospective randomized registry trial, with the infrastructure for the IROCK registry under development.”¹

The finding in this study that patients with smaller renal masses had a 95.4% 5-year survival with freedom from local failure is consistent with other studies.⁷ Limitations of the study included possible underreporting of treatment-related toxic effects. Nevertheless, the authors concluded that “this analysis provides mature outcome and safety data for SABR in primary renal cell carcinoma. Single fraction SABR yielded fewer local failures than multifraction SABR. This observation should be tested in a prospective randomized trial.¹

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology.

References

1. Siva S, Ali M, Correa RJM, et al. 5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney). Lancet Oncol. 2022;23(12):1508-1516. doi: 10.1016/S1470-2045(22)00656-8
2. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Kidney Cancer. Version 3.023. Published September 22, 2022. Accessed December 1, 2022. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf
3. Haque W, Verma V, Lewis GD, Lo SS, Butler EB, Teh BS. Utilization of radiotherapy and stereotactic body radiation therapy for renal cell cancer in the USA. Future Oncol. 2018; 14: 819-827. doi: 10.2217/fon-2017-0536
4. Siva S, Louie AV, Warner A, et al. Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: a report from the International Radiosurgery Oncology Consortium for Kidney (IROCK). Cancer. 2018; 124:934-942. doi: 10.1002/cncr.31156
5. Siva S, Correa RJM, Warner A, et al. Stereotactic ablative radiotherapy for ≥T1b primary renal cell carcinoma: a report from the International Radiosurgery Oncology Consortium for Kidney (IROCK). Int J Radiat Oncol Biol Phys. 2020; 108:941-949. doi: 10.1016/j.ijrobp.2020.06.014
6. Correa RJM, Louie AV, Staehler M, et al. Stereotactic radiotherapy as a treatment option for renal tumors in the solitary kidney: a multicenter analysis from the IROCK. J Urol. 2019; 201:1097-1104. doi: 10.1097/JU.0000000000000111
7. Andrews JR, Atwell T, Schmit G, et al. Oncologic outcomes following partial nephrectomy and percutaneous ablation for cT1 renal masses. Eur Urol. 2019; 76:244-251. doi: 10.1016/ j.eururo.2019.04.026