Phase 2 Trial of Stereotactic Ablative Radiotherapy for Patients with Primary Renal Cancer

Abstract

Background: Most renal cell carcinomas (RCCs) are localized and managed by active surveillance, surgery, or minimally invasive techniques. Stereotactic ablative radiation (SAbR) may provide an innovative non-invasive alternative although prospective data are limited.

Objective: To investigate whether SAbR is effective in the management of primary RCCs.

Design, setting, and participants: Patients with biopsy-confirmed radiographically enlarging primary RCC (≤5 cm) were enrolled. SAbR was delivered in either three (12 Gy) or five (8 Gy) fractions.

Outcome measurements and statistical analysis: The primary endpoint was local control (LC) defined as a reduction in tumor growth rate (compared with a benchmark of 4 mm/yr on active surveillance) and pathologic evidence of tumor response at 1 yr. Secondary endpoints included LC by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), safety, and preservation of kidney function. Exploratory tumor cell-enriched spatial protein and gene expression analysis were conducted on pre- and post-treatment biopsy samples.

Results and limitations: Target accrual was reached with the enrollment of 16 ethnically diverse patients. Radiographic LC at 1 yr was observed in 94% of patients (15/16; 95% confidence interval: 70, 100), and this was accompanied by pathologic evidence of tumor response (hyalinization, necrosis, and reduced tumor cellularity) in all patients. By RECIST, 100% of the sites remained without progression at 1 yr. The median pretreatment growth rate was 0.8 cm/yr (interquartile range [IQR]: 0.3, 1.4), and the median post-treatment growth rate was 0.0 cm/yr (IQR: -0.4, 0.1, p < 0.002). Tumor cell viability decreased from 4.6% to 0.7% at 1 yr (p = 0.004). With a median follow-up of 36 mo for censored patients, the disease control rate was 94%. SAbR was well tolerated with no grade ≥2 (acute or late) toxicities. The average glomerular filtration rate declined from a baseline of 65.6 to 55.4 ml/min at 1 yr (p = 0.003). Spatial protein and gene expression analyses were consistent with the induction of cellular senescence by radiation.

Conclusions: This clinical trial adds to the growing body of evidence suggesting that SAbR is effective for primary RCC supporting its evaluation in comparative phase 3 clinical trials.

Patient summary: In this clinical trial, we investigated a noninvasive treatment option of stereotactic radiation therapy for the treatment of primary kidney cancer and found that it was safe and effective.

Keywords: Primary renal cell carcinoma; Renal cell carcinoma; Senescence; Stereotactic ablative radiotherapy.

Fig. 1 –

Representative patient treatment plan depicting axial (top left), coronal (bottom left), and sagittal (bottom right) views, along with a dose volume histogram. The 40 Gy in five fractions PTV is shown in red, kidney in blue, small bowel in cyan, stomach in orange, and liver in magenta. Dose color wash values are 40 Gy (red), 35 Gy (cyan), 30 Gy (blue), and 25 Gy (yellow). PTV = planning treatment volume.

Fig. 2 –

Tumor response and overall survival. (A) Tumor response to SAbR at 1 year. Blue bars represent patients treated with 40 Gy in five fractions, while gold bars represent patients treated with 36 Gy in three fractions. (B) Patient tumor growth kinetics over time. Failure by per-protocol criteria is shown in red (n = 2), while partial responses by RECIST are shown in green (n = 3). (C) LC over time per protocol (blue line) and by RECIST criteria (green line). One patient failed by protocol analysis at 6 mo and by RECIST criteria at 36 mo, while another failed by protocol alone after 18 mo. (D) Overall survival is shown, with five patients dying of noncancer causes during the follow-up period. LC = local control; RECIST = Response Evaluation Criteria in Solid Tumors; SAbR = stereotactic ablative radiotherapy.

Fig. 2 –

Tumor response and overall survival. (A) Tumor response to SAbR at 1 year. Blue bars represent patients treated with 40 Gy in five fractions, while gold bars represent patients treated with 36 Gy in three fractions. (B) Patient tumor growth kinetics over time. Failure by per-protocol criteria is shown in red (n = 2), while partial responses by RECIST are shown in green (n = 3). (C) LC over time per protocol (blue line) and by RECIST criteria (green line). One patient failed by protocol analysis at 6 mo and by RECIST criteria at 36 mo, while another failed by protocol alone after 18 mo. (D) Overall survival is shown, with five patients dying of noncancer causes during the follow-up period. LC = local control; RECIST = Response Evaluation Criteria in Solid Tumors; SAbR = stereotactic ablative radiotherapy.

Fig. 3 –

Initial computed tomography (CT) obtained 11 mo prior to SAbR, magnetic resonance imaging (MRI) obtained 3 wk prior to SAbR, and surveillance MRI at 6 mo and 5 yr after SAbR of a patient with a single functional kidney (ie, congenital atrophic right kidney; open arrow on baseline CT) and a left renal mass (solid arrow). Percutaneous biopsy confirmed grade 3 clear cell renal cell carcinoma. The renal mass exhibited growth from 2.5 cm (11 mo prior to SAbR) to 2.7 cm (baseline, 3 wk prior to SAbR). The patient was treated with 36 Gy in five fractions. Follow-up MRI showed a decrease in size on initial follow-up to 2.3 cm (6 mo after SAbR) and subsequently to 1.9 cm (5 yr after SAbR). T1-weighted fat-saturated gradient-echo contrast-enhanced images obtained during the delayed nephrographic phase (top row) show progressively increased enhancement after SAbR, while T2-weighted images (bottom row) show increased signal intensity after treatment suggestive of treatment-induced fibrosis in the renal mass. SAbR = stereotactic ablative radiotherapy.

Fig. 4 –

Representative pre- and post-treatment histologic images for three patients. (A) Pretreatment staining for patient 109 shows tumor cells with minimal hyalinization. (B) After treatment, the same patient had significant hyalinization (99%, top right) and reduction in the number of tumor cells. Similarly, (C and D) tumor tissue taken from patient 112 (lower and higher magnification panels) shows Ki-67 (brown nuclear staining) in tumor cells (E) stained with membranous CAIX (magenta stain; orange arrow). (F) Post-treatment tissue from the same patient shows significant reduction in the number of tumor cells with Ki-67 expression limited to endothelial cells (black arrow). For patient 110, (G) the post-treatment staining shows significant p16 expression (bottom right) by tumor cells as compared with (H) pretreatment staining (bottom left) where p16 is not seen. H&E = hematoxylin and eosin.

Fig. 5 –

GSEA of whole transcriptomic data for enriched tumor cells using NanoString GeoMx DSP comparing pre- and post-SAbR treatment biopsy samples focusing on (A) apoptosis and (B) senescence. GSEA = gene set enrichment analysis; SAbR = stereotactic ablative radiotherapy.