Review of Adjuvant Therapies in Renal Cell Carcinoma: Evidence to Date

Figures & data

Table 1 UICC TNM Staging of Kidney Tumours

Primary Tumour
T	Features
TX	Primary tumour cannot be assessed
T0	No evidence of primary tumour
T1	Tumour 7cm or less in greatest dimension, limited to the kidney
T1a	Tumour 4cm or less
T1b	Tumour more than 4cm but not more than 7cm
T2	Tumour more than 7cm in greatest dimension, limited to the kidney
T2a	Tumour more than 7cm but not more than 10cm
T2b	Tumour more than 10cm, limited to the kidney
T3	Tumour extends into major veins or perinephric tissues, but not into the ipsilateral adrenal gland and not beyond Gerota fascia
T3a	Tumour extends into the renal vein or its segmental branches, or tumour invades the pelvicalyceal system, or tumour invades perirenal and/or renal sinus fat
T3b	Tumour extends into vena cava below the diaphragm
T3c	Tumour extends into vena cava above the diaphragm or invades the wall of the vena cava
T4	Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)
Regional Lymph Nodes (hilar, abdominal para-aortic and para-caval nodes)
N	Features
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in regional lymph node(s)
Distant Metastasis
M	Features
M0	No distant metastasis
M1	Distant metastasis
Prognostic Stage Groups
Stage	T	N	M
Stage I	T1	N0	M0
Stage II	T2	N0	M0
Stage III	T3	N0	M0
	T1, T2, T3	N1	M0
Stage IV	T4	Any N	M0
	Any T	Any N	M1

Notes: Reproduced with permission from John Wiley and Sons © (2017). TNM Classification of Malignant Tumours, Eighth Edition. Edited by James D. Brierley, Mary K. Gospodarowicz and Christian Wittekind (2017).¹⁷

Table 2 Leibovich Risk Score

Scoring Algorithm to Predict Metastases After Radical Nephrectomy in Patients with ccRCC
Primary Tumour Status (T)		Score
pT1a		0
pT1b		2
pT2		3
pT3a		4
pT3b		4
pT3c		4
pT4		4
Regional Lymph Node Status (N)		Score
pNX		0
pN0		0
pN1		2
pN2		2
Tumour Size (cm)		Score
<10		0
≥10		1
Nuclear Grade		Score
1		0
2		0
3		1
4		3
Histologic Tumour Necrosis		Score
No		0
Yes		1
Risk Groups
Group		Score
Low		0–2
Intermediate		3–5
High		≥6
Estimated Metastasis-Free Survival Rate (%)
Risk Group	Year One	Year Five	Year Ten
Low	99.5	97.1	92.5
Intermediate	90.4	73.8	64.3
High	57.7	31.2	23.6

Notes: Reprinted by permission from John Wiley and Sons © (2003). Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma, Leibovich BC, Blute ML, Cheville JC et al. Cancer. 2003;97(7):1663–1671 .¹⁸

Table 3 UCLA Integrated Staging System (UISS)

UISS
Risk Group	TNM Stage	Grade	ECOG
Low	I	1,2	0
Intermediate	I	1,2	≥1
	I	3,4	0
	I	3,4	≥1
	II	Any	Any
	III	1	0
	III	1	≥1
	III	>1	0
High	III	>1	≥1
	IV	Any	Any
OS (%)
Risk Group	Year One	Year Three	Year Five
Low	97.5	90.5	83.8
Intermediate	95.4	81.6	71.9
High	84.4	55.5	44.0
Disease-Specific Survival (%)
Risk Group	Year One	Year Three	Year Five
Low	100	94.9	91.1
Intermediate	97.2	87.7	80.4
High	89.0	63.7	54.7

Notes: Reprinted with permission © (2002) American Society of Clinical Oncology. . Zisman, A et al: Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol, 2002;20(23):4559–4566.¹⁹

Table 4 Summary of Early Clinical Studies Investigating Adjuvant RCC Therapies

Study	N	Intervention	Primary Endpoint(s)	Outcome
Clark et al 2003^Citation23	69	IL-2 vs observation	DFS	Closed early; interim analysis non-significant (P=0.73)
Messing et al 2003^Citation24	283	IFN-α vs observation	OS	Non-significant (P=0.09)
Pizzocaro et al 2001^Citation25	247	IFN-α2b vs observation	OS, EFS	Non-significant (P=0.86 for OS, 0.11 for EFS)
Passalacqua et al 2014^Citation26	303	IL-2 + IFN-α vs observation	RFS	Non-significant (P=0.44)
Atzpodien et al 2005^Citation27	203	IL-2 + IFN-α2a + 5-FU vs observation	RFS	Non-significant (P=0.24)
Aitchison et al 2014^Citation28	309	IL-2 + IFN-α2a + 5-FU vs observation	DFS	Non-significant (P=0.23)
Kjaer et al 1987^Citation86	65	Radiotherapy vs observation	RFS, OS	Non-significant (P>0.05)
Pizzocaro et al 1987^Citation87	120	Medroxyprogesterone acetate vs observation	RFS	Non-significant (P not presented)
Naito et al 1997^Citation88	66	UFT (tegafur and uracil 1:4) vs observation	NRR, RCC-specific survival rate	Non-significant (P not presented)
Adler et al 1987^Citation29	43	Autologous irradiated tumour cells + hormonal therapy vs hormonal therapy alone	PFS	Non-significant (P<0.1)
Jocham et al 2004^Citation31	379	Autologous irradiated tumour cells vs observation	PFS	Significant, favouring vaccine group (P=0.02)
Galligioni et al 1996^Citation30	120	Autologous irradiated tumour cells vs observation	DFS, OS	Non-significant (P=0.21 for DFS, 0.28 for OS)
Wood et al 2008^Citation32	818	Autologous, tumour-derived heat-shock protein (glycoprotein 96)-peptide complex therapeutic vaccine vs observation	RFS	Non-significant (P=0.51)
Chamie et al 2017^Citation33	864	Girentuximab vs placebo	DFS, OS	Non-significant (P=0.74 for DFS, 0.94 for OS)

Figure 1 Mechanism of action of TKIs used in metastatic RCC. Kinases regulating angiogenesis are frequently overexpressed in RCC, culminating in increased tumour vascular supply. VHL inactivation leads to overexpression of pro-angiogenic factors including VEGF via increased HIFα expression. HIFα is also upregulated via PI3K/mTOR signalling. VEGF binds to VEGFR1/2/3 on endothelial cell surfaces, promoting angiogenesis. Additional cell surface receptors regulating angiogenesis include PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast growth factor receptor), tyrosine-protein kinase MET (hepatocyte growth factor receptor), AXL oncogene (tyrosine-protein kinase receptor UFO) and proto-oncogene tyrosine-protein kinase receptor RET. A range of TKIs have been developed targeting various aspects of these signalling pathways. Adapted by permission from Springer Nature © (2017). Posadas EM, Limvorasak S, Figlin RA. Targeted therapies for renal cell carcinoma. Nat Rev Nephrol. 2017;13(8):496–511.¹³

Abbreviations: PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; GAS6, growth arrest-specific protein 6; GDNF, glial cell line-derived neurotrophic factor.

Table 5 Summary of Newer Generation Studies Testing Adjuvant TKIs

Study	N	Intervention	Primary Endpoint	Outcome
ASSURE^Citation35	1943	Sorafenib or sunitinib vs placebo for one year	DFS	Non-significant; sunitinib HR 1.02, 97.5% CI 0.85–1.23, P=0.8038; sorafenib HR 0.97, 97.5% CI 0.80–1.17, P=0.718
S-TRAC^Citation36	615	Sunitinib vs placebo for one year	DFS	Significant; HR 0.76; 95% CI 5.8-NR; P=0.030
PROTECT^Citation39	1538	Pazopanib (600mg) vs placebo for one year	DFS	Non-significant; HR 0.86; 95% CI 0.70–1.06; P=0.165
ATLAS^Citation40	724	Axitinib vs placebo for three years	DFS	Stopped due to futility; non-significant at interim analysis; HR 0.87, 95% CI 0.66–1.15; P=0.321
SORCE^Citation42	1711	Sorafenib vs placebo for three years	DFS	Non-significant; HR 1.01; 95% CI 0.83–1.23; P=0.950
EVEREST^Citation43,Citation44	1218	Everolimus vs placebo (nine courses of six weeks)	DFS	Results awaited

Figure 2 Mechanism of action of ICIs. In response to recognition of TA presented by cancer cells, T-cell activation depends on coalescence of a range of signals including co-stimulation by CD80/CD86 which bind to CD28 on the T-cell. Cancer cells evade the immune response via competitive binding of CD80/CD86 to CTLA-4 and via binding of PD-L1/PD-L2 to PD-1, inhibiting T-cell activation. Antibodies targeting CTLA-4, PD-1 and PD-L1 prevent activation of immunosuppressive signals, thus enhancing host immune responses against cancer cells. Adapted by permission from Springer Nature © (2020). Xu W, Atkins MB, McDermott DF. Checkpoint inhibitor immunotherapyin kidney cancer. Nat Rev Urol. 2020;17(3):137–150.¹⁶

Table 6 Summary of Newer Generation Studies Testing Adjuvant ICIs

Study	Intervention	N (Estimated/Actual)	Primary Endpoint(s)	Secondary Endpoint(s)
PROSPER^Citation56	Neoadjuvant and adjuvant nivolumab	805	1. RFS	1. OS 2. RFS in ccRCC patients 3. Incidence of toxicity
IMmotion010^Citation57	Adjuvant atezolizumab	778	1. DFS (IRF-assessed)	1. OS 2. Investigator-assessed DFS 3. IRF-assessed DFS in participants with tumour-infiltrating immune cell 1/2/3 4. Investigator-assessed DFS in participants with tumour-infiltrating immune cell 1/2/3 5. Disease-specific survival 6. Distant metastasis-free survival 7. Percentage of participants who are alive and IRF-assessed recurrence free at year three 8. Percentage of participants who are alive and investigator-assessed recurrence free at year three 9. Percentage of participants with AEs 10. Maximum serum atezolizumab concentration 11. Minimum serum atezolizumab concentration 12. Percentage of participants with anti-therapeutic antibodies to atezolizumab
Keynote-564^Citation58	Adjuvant pembrolizumab	950	1. DFS (investigator assessed)	1. OS 2. AEs 3. Study treatment discontinuation due to AEs 4. First local disease recurrence-specific survival as assessed by investigator 5. First local recurrence with visceral lesion or distant metastasis with visceral lesion or secondary systemic malignancy with visceral lesion as assessed by investigator 6. DFS according to participant PD-L1 expression status as assessed by investigator 7. OS according to participant PD-L1 expression status 8. European organisation for the research and treatment of cancer quality of life questionnaire C30 total score 9. Functional assessment of cancer therapy kidney symptom index-disease related symptoms index score
CheckMate 914^Citation59	Adjuvant nivolumab ± ipilimumab	1600	1. DFS	1. OS 2. Incidence of AEs 3. DFS (nivolumab and ipilimumab vs nivolumab and ipilimumab placebo)
RAMPART^Citation60	Adjuvant durvalumab ± tremelimumab	1750	1. DFS (durvalumab + tremelimumab vs observation) 2. DFS (durvalumab vs observation) 3. OS in high-risk patients (durvalumab + tremelimumab vs observation) 4. OS in high-risk patients (durvalumab vs observation)	1. Metastasis-free survival (durvalumab + tremelimumab vs observation) 2. Metastasis-free survival (durvalumab vs observation) 3. RCC-specific survival time (durvalumab + tremelimumab vs observation) 4. RCC-specific survival time (durvalumab vs observation)

Note: Data from Blick et al^14, Xu et al^16, and ClinicalTrials.gov.^{56,57,58,59,60}

Brierley JD, Gospodarowicz MK, Wittekind C. TNM Classification of Malignant Tumours. 8th ed ed. John Wiley &Sons, Inc.; 2017.

 Google Scholar

Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003;97(7):1663–1671. doi:10.1002/cncr.1123412655523

 PubMed Web of Science ®Google Scholar

Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002;20(23):4559–4566. doi:10.1200/JCO.2002.05.11112454113

 PubMed Web of Science ®Google Scholar

Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol. 2003;21(16):3133–3140. doi:10.1200/JCO.2003.02.01412810695

 PubMed Web of Science ®Google Scholar

Messing EM, Manola J, Wilding G, et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol. 2003;21(7):1214–1222. doi:10.1200/JCO.2003.02.00512663707

 PubMed Web of Science ®Google Scholar

Pizzocaro G, Piva L, Colavita M, et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J Clin Oncol. 2001;19(2):425–431. doi:10.1200/JCO.2001.19.2.42511208835

 PubMed Web of Science ®Google Scholar

Passalacqua R, Caminiti C, Buti S, et al. Adjuvant low-dose interleukin-2 (IL-2) plus interferon-alpha (IFN-alpha) in operable renal cell carcinoma (RCC): a Phase III, randomized, multicentre trial of the Italian Oncology Group for Clinical Research (GOIRC). J Immunother. 2014;37(9):440–447. doi:10.1097/CJI.000000000000005525304727

 PubMed Web of Science ®Google Scholar

Atzpodien J, Schmitt E, Gertenbach U, et al. Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer. 2005;92(5):843–846.15756254

 PubMed Web of Science ®Google Scholar

Aitchison M, Bray CA, Van Poppel H, et al. Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. Eur J Cancer. 2014;50(1):70–77.24074763

 PubMed Web of Science ®Google Scholar

Kjaer M, Iversen P, Hvidt V, et al. A randomized trial of postoperative radiotherapy versus observation in stage II and III renal adenocarcinoma. A study by the copenhagen renal cancer Study Group. Scand J Urol Nephrol. 1987;21(4):285–289. doi:10.3109/003655987091807843445125

 PubMed Web of Science ®Google Scholar

Pizzocaro G, Piva L, Di Fronzo G, et al. Adjuvant medroxyprogesterone acetate to radical nephrectomy in renal cancer: 5-year results of a prospective randomized study. J Urol. 1987;138(6):1379–1381. doi:10.1016/S0022-5347(17)43647-02824861

 PubMed Web of Science ®Google Scholar

Naito S, Kumazawa J, Omoto T, et al. Postoperative UFT adjuvant and the risk factors for recurrence in renal cell carcinoma: a long-term follow-up study. Kyushu University Urological Oncology Group. Int J Urol. 1997;4(1):8–12. doi:10.1111/j.1442-2042.1997.tb00130.x9179659

 PubMedGoogle Scholar

Adler A, Gillon G, Lurie H, et al. Active specific immunotherapy of renal cell carcinoma patients: a prospective randomized study of hormono-immuno-versus hormonotherapy. Preliminary report of immunological and clinical aspects. J Biol Response Mod. 1987;6(6):610–624.3330126

 PubMedGoogle Scholar

Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet. 2004;363(9409):594–599. doi:10.1016/S0140-6736(04)15590-614987883

 PubMed Web of Science ®Google Scholar

Galligioni E, Quaia M, Merlo A, et al. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and Bacillus Calmette-Guerin - five-year results of a prospective randomized study. Cancer. 1996;77(12):2560–2566. doi:10.1002/(SICI)1097-0142(19960615)77:12<2560::AID-CNCR20>3.0.CO;2-P8640706

 PubMed Web of Science ®Google Scholar

Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. 2008;372(9633):145–154. doi:10.1016/S0140-6736(08)60697-218602688

 PubMed Web of Science ®Google Scholar

Chamie K, Donin NM, Klopfer P, et al. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ARISER randomized clinical trial. JAMA Oncol. 2017;3(7):913–920. doi:10.1001/jamaoncol.2016.441927787547

 PubMed Web of Science ®Google Scholar

Posadas EM, Limvorasak S, Figlin RA. Targeted therapies for renal cell carcinoma. Nat Rev Nephrol. 2017;13(8):496–511. doi:10.1038/nrneph.2017.8228691713

 PubMed Web of Science ®Google Scholar

Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008–2016. doi:10.1016/S0140-6736(16)00559-626969090

 PubMed Web of Science ®Google Scholar

Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. N Engl J Med. 2016;375(23):2246–2254. doi:10.1056/NEJMoa161140627718781

 PubMed Web of Science ®Google Scholar

Motzer RJ, Haas NB, Donskov F, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma. J Clin Oncol. 2017;35(35):3916–3923. doi:10.1200/JCO.2017.73.532428902533

 PubMed Web of Science ®Google Scholar

Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol. 2018;29(12):2371–2378. doi:10.1093/annonc/mdy45430346481

 PubMed Web of Science ®Google Scholar

Eisen TQG, Frangou E, Smith B, et al. Primary efficacy analysis results from the SORCE trial (RE05): adjuvant sorafenib for renal cell carcinoma at intermediate or high risk of relapse: an international, randomised double-blind phase III trial led by the MRC CTU at UCL. Ann Oncol. 2019;30:891–+. doi:10.1093/annonc/mdz394.050

 PubMed Web of Science ®Google Scholar

Synold TW, Plets M, Tangen CM, et al. Everolimus exposure as a predictor of toxicity in renal cell cancer patients in the adjuvant setting: results of a pharmacokinetic analysis for SWOG S0931 (EVEREST), a Phase III Study (NCT1120249). Kidney Cancer. 2019;3(2):111–118. doi:10.3233/KCA-18004931763512

 PubMedGoogle Scholar

ClinicalTrials.gov. S0931, Everolimus in treating patients with kidney cancer who have undergone surgery. 2010 Available from: https://clinicaltrials.gov/ct2/show/NCT1120249. Accessed 5, 2020.

 Google Scholar

Xu W, Atkins MB, McDermott DF. Checkpoint inhibitor immunotherapy in kidney cancer. Nat Rev Urol. 2020;17(3):137–150. doi:10.1038/s41585-020-0282-332020040

 PubMed Web of Science ®Google Scholar

ClinicalTrials.gov. Nivolumab in treating patients with localized kidney cancer undergoing nephrectomy. 2017 Available from: https://clinicaltrials.gov/ct2/show/NCT3055013. Accessed 4, 2020.

 Google Scholar

ClinicalTrials.gov. A study of atezolizumab as adjuvant therapy in participants with Renal Cell Carcinoma (RCC) at high risk of developing metastasis following nephrectomy (IMmotion010). 2017 Available from: https://clinicaltrials.gov/ct2/show/NCT3024996. . Accessed 4, 2020.

 Google Scholar

ClinicalTrials.gov. Safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy (MK-3475-564/KEYNOTE-564). 2017 Available from: https://clinicaltrials.gov/ct2/show/study/NCT3142334. Accessed 4, 2020.

 Google Scholar

ClinicalTrials.gov. A study comparing nivolumab, nivolumab in combination with ipilimumab and placebo in participants with localized kidney cancer who underwent surgery to remove part of a kidney (CheckMate 914). 2017 Available from: https://clinicaltrials.gov/ct2/show/study/NCT3138512. Accessed 4, 2020.

 Google Scholar

ClinicalTrials.gov. Renal adjuvant multiple arm randomised trial (RAMPART). 2017 Available from: https://clinicaltrials.gov/ct2/show/NCT3288532. Accessed 4, 2020.

 Google Scholar

Blick C, Ritchie AWS, Eisen T, Stewart GD. Improving outcomes in high-risk, nonmetastatic renal cancer: new data and ongoing trials. Nat Rev Urol. 2017;14(12):753–759. doi:10.1038/nrurol.2017.12328762388

 PubMed Web of Science ®Google Scholar