Adjuvant Therapy for High-Risk Localized Renal Cell Carcinoma: Current Landscape and Future Direction

Figures & data

Figure 1 Schematic of RCC tumor microenvironment. Schematic depicts cell types and protein targets corresponding to therapeutics with demonstrated efficacy for advanced RCC.

Table 1 Summary of Major Randomized Controlled Trials Evaluating Adjuvant Therapy for High-Risk Renal Cell Carcinoma

Trial	First Author	Year	N	Intervention (vs Placebo*)	Primary Outcome(s)	Results of Primary Outcome
ASSURE^Citation15	Haas	2016	1943	Sunitinib Sorafenib	DFS	No statistically significant difference
S-TRAC^Citation17	Ravaud	2016	615	Sunitinib	DFS	DFS favors sunitinib (sunitinib: 6.8 years, 95% CI 5.8-not reached; placebo: 5.6 years, 95% CI 3.8–6.6; HR 0.76, 95% CI 0.59–0.98; p = 0.03)
PROTECT^Citation19	Motzer	2017	1538	Pazopanib	DFS (in pazopanib reduced dose)	No statistically significant difference
ARISER^Citation20	Chamie	2017	864	Girentuximab	DFS OS	No statistically significant differences
ATLAS^Citation21	Gross-Goupil	2018	724	Axitinib	DFS	No statistically significant difference
SORCE^Citation22	Eisen	2020	1711	Sorafenib (1 year) Sorafenib (3 years)	DFS (3y sorafenib vs placebo)	No statistically significant difference
KEYNOTE-564^Citation24	Choueiri	2021	994	Pembrolizumab	DFS	DFS favors pembrolizumab (at 24 months, pembrolizumab: 77.3%; placebo: 68.1%, HR 0.54; 95% CI 0.30–0.96)
EVEREST^Citation23	Ryan	2022	1545	Everolimus	DFS	DFS favors everolimus (HR 0.85; 95% CI, 0.72–1.00; p = 0.0246)
IMmotion010^Citation26	Pal	2022	778	Atezolizumab	DFS	No statistically significant difference
CheckMate 914^Citation27	Motzer	2022	816	Nivolumab plus ipilimumab	DFS	No statistically significant difference
PROSPER/ECOG-ACRIN EA8143^Citation28	Allaf	2022	819	Perioperative nivolumab*	DFS	No statistically significant difference

Note: *Patients in the control group of the PROSPER/ECOG-ACRIN EA8143 trial underwent observation only and did not receive a placebo.

Abbreviations: DFS, disease-free survival; OS, overall survival; CI, confidence interval; HR, hazard ratio.

Table 2 Summary of Adverse Events in Major Randomized Controlled Trials Evaluating Adjuvant Therapy for High-Risk Renal Cell Carcinoma

Trial	Study Drug	Adverse Events ≥ Grade 3 in at Least 10% of Patients	# Dropouts Due to Adverse Event	Trial Design Amended Due to Early Toxicity?
ASSURE^Citation15	Sunitinib	Fatigue (18%) Hypertension (17%) Hand-foot syndrome (15%)	124/625 (20%)	Yes
	Sorafenib	Hand-foot syndrome (33%) Hypertension (16%) Rash/desquamation (15%)	128/628 (20%)	Yes
S-TRAC^Citation17	Sunitinib	Hand-foot syndrome (16%)	86/306 (28%)	No
PROTECT^Citation19	Pazopanib	Hypertension (25%) Elevated ALT (16%)	800mg dose: 77/198 (39%) 600mg dose: 201/568 (35%)	Yes
ARISER^Citation20	Girentuximab	51/431 (12%) had any ≥ Grade 3 AE; individual ≥ Grade 3 AEs not reported	7/431 (2%)	No
ATLAS^Citation21	Axitinib	61% had ≥ Grade 3 AE; individual ≥ Grade 3 AEs not reported	19%^a	No
SORCE^Citation22	Sorafenib 1 year	Hand-foot syndrome (24%) Hypertension (26%)	30% ^a	Yes
	Sorafenib 3 years	Hand-foot syndrome (24%) Hypertension (24%)	34% ^a
KEYNOTE-564^Citation24	Pembrolizumab	None	101/488 (21%)	No
EVEREST^Citation23	Everolimus	Mucositis (14%) Hypertriglyceridemia (11%)	37%*	No
IMmotion010^Citation26	Atezolizumab	None	12%	No
CheckMate 914^Citation27	Nivolumab plus ipilimumab	28.5% had ≥ Grade 3 AE; individual ≥ Grade 3 AEs not reported	29%	No
PROSPER/ECOG-ACRIN EA8143^Citation28	Perioperative nivolumab	None	Not reported	No

Note: ^aNumber of patients included in safety analysis not listed.

Abbreviation: AE, adverse event.

Table 3 SABR/SBRT for High-Risk/Morbidity RCC

First Author	N	Inclusion Criteria/Primary Outcome	Experimental Design	Primary Outcome	Result
Correa^Citation52	81	Biopsy confirmed primary RCC of a single lesion within a solitary kidney	Retrospective	PFS, OS, and renal function	Progression-free, cancer specific and overall survival in the solitary cohort were 98.0%, 77.5%, 98.2% and 81.5%, respectively. No significant difference in renal function or oncologic outcomes between groups
Swaminath^Citation142	28	Patient-reported QoL after SBRT for primary kidney cancer.	Prospective	Repeated measures QOL 1 week, 1,3,6 month post-treatment	No significant reduction in any QoL metric
Margulis^Citation143	6	Patients with RCC with IVC tumor thrombus	Prospective single-arm Phase 1 and 2 trial	Absence of grade 4 to 5 AEs within 90 days of RN-IVCT.	No grade 4 to 5 AEs. After a median follow-up of 24 months, all patients are alive.
Tetar^Citation144	36	Patients treated with MRgRT on the MRIdian-system for primary RCC between 2016 and 2020	Retrospective	OS and LC	LC and OS rates at 1 year were 95.2% and 91.2%. No grade ≥3 toxicity was reported.
Siva^Citation145	95	Patients with larger (T1b, >4 cm) RCC not suitable for surgery. Patients with T1a tumors, M1 disease, and/or upper tract urothelial carcinoma were excluded.	Retrospective	Cancer specific survival (CSS), OS, and PFS	CSS, OS, and PFS were 96.1%, 83.7%, and 81.0% at 2 years and 91.4%, 69.2%, 64.9% at 4 years.
Senger^Citation146	10	Histology-confirmed clear cell RCC grade 1 or 2 with evidence of renal dysfunction	Retrospective	LC, and renal function	Persistent LC by robotic SABR in 9/10 patients (92.3% of lesions). Renal function stable with a mean eGFR of 51.3 ± 19.7 mL/min at baseline and 51.6 ± 25.8 mL/min at follow-up.
Grelier^Citation147	23	Patients underwent SBRT for primary RCC	Retrospective	RFS, CSS, and OS	Local RFS, event-free survival, CSS, and OS were 96 (22/23), 74 (18/23), 96 (22/23) and 83% (19/23), respectively.
Grubb^Citation148	11	Patients were required to have localized RCC and be poor surgical candidates due to medical comorbidities.	Prospective analysis, single arm	AE, LC	Three-year local control was 90%. Late grade 2+ and grade 3+ possibly treatment-related events occurred in 18.1% and 9.1%, respectively.
Siva^Citation51	223	Pooled multiinstitutional dataset receiving SABR in single or multifraction	Retrospective	LC, CSS, PFS at 2 and 4 years	The rates of LC, CSS, and PFS were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years.
Siva^Citation53	37	Patients unsuitable for surgery/nephrectomy	Prospective, single arm	AEs, LC, OS	No grade 4–5 toxicities were recorded and six patients (18%) reported no toxicity. Local PFS, distant PFS, and OS at 2 years were 100%, 89% and 92%, respectively.
Siva^Citation59	30	Patients with up to 2 lines of prior systemic therapy with 1–5 oligometastases from ccRCC	Prospective, single arm, phase 1/2	AEs, PFS, OS	There were no grade 4 or 5 AEs. Estimated 1- and 2-yr OS was 90% and 74%. PFS was 60% (1y) and 45% (2y).

Abbreviations: RCC, renal cell carcinoma; QoL, quality of life; SBRT, stereotactic body radiation therapy; SABR, stereotactic ablative radiotherapy; PFS, progression free survival; OS, overall survival; LC, local control; RFS, recurrence free survival; CSS, cancer specific survival; eGFR, estimated glomerular filtration rate.

Table 4 Adjuvant Radiation Therapy for High-Risk RCC

Study	Year	N	5-Year OS (%)		Regional Recurrence		Adjuvant Radiation Toxicity
			Nephrectomy Alone	Adjuvant Radiation	Nephrectomy Alone	Adjuvant Radiation
Finney^Citation65	1973	100	51	45	--	RT did not influence the incidence of local recurrence or distant metastases.	Evidence of liver damage in right-sided lesions irradiated as shown from biochemical liver function tests and isotope scans.
Kjaer^Citation149	1978	65	62	38	--	Recurrence in 43% during the follow-up without difference between the two groups.	Significant complications from stomach, duodenum or liver, median 5 mo., range 1–44 mo. after RT.
Stein^Citation150	1992	119	40	50	Recurrence in T2 N0M0 disease was 2/28; T3 N0M0 was 11/30^a; and T4 N0M0 was 1/2.	Recurrence in T2 N0M0 disease was 0/17; in T3 N0M0 was 4/37 ^a; and T4 N0M0 was 1/5.	Significant complication in three (5%) patients undergoing RT.
Kao^Citation151	1994	24	62	75	The 5-year actuarial local failure rate 30%^a; DFS 62%^a.	No patients who received RT after nephrectomy had loco-regional recurrenc^a; 5 year DFS 75%^a.	No chronic complications resulted from RT.
Makarewicz^Citation152	1998	186	38	30	Local failure in T3N0 15.8%; T3N(+) 33.3%; T4N0 33.3%; T4N(+) 33.3%.	Local failure in T3N0 8.8%, T3N(+) was 33.3%, T4N0 was 33.3%, T4N(+) was 25.0%. The median time to local recurrence (27.0 vs 21.0 months) or distant metastases (16.0 vs 12.5 months) was improved with adjuvant RT compared to without^a.	--
Ulutin^Citation66	2006	40	20	70	5-year DFS 16%^a.	5-year DFS 66%^a.	--

Note: ^aDenotes statistically significant difference.

Abbreviations: DFS, disease-free survival; RT, radiation therapy.

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