Controlled outcome assessment of radiotherapy for primary renal cell carcinoma (RCC) remains limited, particularly regarding its impact on ipsilateral renal function and predictors of response. We evaluated oncological and renal function outcomes of stereotactic body radiation therapy (SBRT) for RCC and identified genomic predictors of response. Our study cohort comprised 83 surgically unfit patients with cT1a RCC who were prospectively enrolled to receive SBRT of 42 Gy in three fractions between 2016 and 2022. The median tumor size was 2.3 cm and local control was achieved in 78 patients, including eight with a complete response. The 3-yr survival rates were 96% (95% confidence interval [CI] 89.8–99.9) for progression-free survival and 96% (95% CI 89.4–99.9%) for cancer-specific survival. The glomerular filtration rate of the treated kidney decreased up to 12–18 mo (−9.8 ml/min/1.73 m2) but stabilized thereafter. Transcriptome sequencing conducted on biopsy specimens from five responders and eight nonresponders showed enrichment of apical surface/junction pathways among responders, and enrichment of cell cycle, DNA repair, oxidative phosphorylation, and hypoxia pathways among nonresponders. A machine learning model based on gene expression demonstrated good predictive performance, with a cross-validated area under the receiver operating characteristic curve of 0.9. SBRT for T1a RCC was acceptable in terms of intermediate-term cancer control and preservation of renal function. Distinctive genomic profiles may aid in identifying optimal candidates pending external validation.
This prospective phase 2 trial by Song et al. represents a significant advancement in the field of non-surgical management of localised renal cell carcinoma (RCC), particularly in frail or surgically unfit patients. The study evaluates the efficacy and safety of stereotactic body radiation therapy (SBRT) in 83 patients with cT1a RCC, using a regimen of 42 Gy delivered in three fractions. While the oncologic and functional outcomes are promising in themselves, the most novel and potentially transformative contribution of this study lies in its exploration of genomic predictors of treatment response, a step toward personalised radiotherapeutic strategies in urologic oncology.
The study achieved high local control (94%) with excellent 3-year progression-free survival (96%) and cancer-specific survival (96%) rates, indicating that SBRT could be an effective treatment option in this population. Importantly, the functional safety profile is also reassuring: although there was an initial decline in estimated glomerular filtration rate (eGFR) in the irradiated kidney (median reduction of 9.8 ml/min/1.73 m² at 12–18 months), renal function stabilised thereafter. These results position SBRT as an alternative to surgery or ablation in patients with high operative risk.
Perhaps the most innovative element of the study is the transcriptomic analysis conducted on tumour biopsy samples from a subset of responders (n=5) and non-responders (n=8). This analysis revealed distinct gene expression profiles: responders exhibited enrichment of apical junction and surface pathways, whereas non-responders showed upregulation in oxidative phosphorylation, hypoxia, DNA repair, and cell cycle–related pathways: such biological processes are commonly associated with radio-resistance.
Of note is the identification of gene sets and pathways (such as SSBP1, RFC1, RFC4, and MBD4) involved in DNA repair and genomic stability, and GATA3, a gene previously implicated in radiation response in epithelial tissues. Using a machine learning approach, the authors developed a predictive model with excellent discrimination (AUC 0.9). That said, external validation is warranted.
These findings are important because they suggest that molecular profiling may help identify patients more likely to benefit from SBRT, facilitating a precision medicine approach in RCC management. While the sample size for transcriptomic analysis is very small and lacks normal tissue controls, this work sets the foundation for future studies aimed at integrating radio-genomic biomarkers into clinical decision-making.
In conclusion, this trial represents a commendable integration of clinical oncology, radiotherapy, and translational genomics. By combining robust prospective data with exploratory genomic analysis, Song et al. pave the way for biologically informed selection criteria for SBRT in renal cancer. The study not only confirms the therapeutic potential of SBRT in selected patients but also introduces the exciting prospect of personalised radiotherapy guided by gene expression profiles. However, the work also raises key research questions: Can the genomic markers identified be validated in larger cohorts? How do these findings compare with molecular signatures of response to other ablative modalities? And critically, can a biomarker-driven approach be operationalised in routine clinical practice?