Key points

Introduction

Early detection has led to stage migration toward smaller and more localized forms of kidney cancer, and many individuals experience outstanding outcomes. However, approximately 10% of individuals present with stage 3 disease and up to 40% of small tumors have adverse pathologic characteristics found at surgery. For these high-risk patients, despite removal of all visible disease, approximately 50% recur within 6 years.

As in many solid tumors, there is interest in providing high-risk patients with an effective adjuvant therapy that could decrease the likelihood of disease recurrence and ultimately translate into improved overall survival (OS). Numerous adjuvant therapy trials for high-risk renal cell carcinoma (RCC) have been undertaken to evaluate a wide range of agents. However, only a single trial thus far, the S-TRAC trial has shown a disease-free survival (DFS) benefit. Given the potential toxicities of sunitinib, the lack of an OS benefit, and the discordance of S-TRAC’s findings with other adjuvant trials, most clinicians have not changed their current practice patterns and the National Comprehensive Cancer Network (NCCN) guidelines still endorse clinical trial as the preferred option. This article reviews the concepts and clinical data pertaining to adjuvant therapy for localized, high-risk RCC.

Patterns of recurrence, risk factors, and risk stratification

Between 20% and 40% of all patients with localized kidney cancer experience a recurrence following surgery, with nearly 50% of the highest-risk patients recurring within 6 years. ^{, ,} Most recurrences occur within the first 3 years of complete surgical resection; however, many occur even after 10 years following surgery. ^, The most common systemic sites of recurrence are the lung (64%), liver (11%), bone (15%), regional lymph nodes (9%), and the renal fossa (9%). Rates of local recurrence are 1% to 6% following partial nephrectomy and 1% to 3% following radical nephrectomy, with or without systemic recurrences. ^,

Risk factors for recurrence include nuclear tumor grade (including Fuhrman), tumor stage, nodal involvement, microvascular invasion, necrosis, margin status, and high-risk features such as sarcomatoid or rhabdoid differentiation. Specific histologic subtypes such as collecting duct, medullary, and clear cell kidney cancer may have the highest risk of dissemination. ^, Various series have attempted to show that histology is an independent predictor of outcome; however, all forms of renal cancer can behave aggressively.

Risk stratification is critical for identifying a population at highest risk for recurrence, and several staging systems exist for the prediction of DFS. Most rely heavily on surgical pathologic data, such as pathologic T stage, tumor size, nuclear (Fuhrman) grade, and presence of necrosis, although a presurgical nomogram exists as well ( Table 1 ). Because these nomograms use slightly different criteria, the calculated risk of recurrence varies between them. In general, the more complex a model is, the more difficult it is to use because several histologic features may not be uniformly reported on from the surgical specimens. Even among adjuvant trial patients with the highest risk, many of these nomograms still perform poorly.

Attempts have been made to move beyond traditional clinical and pathologic criteria and incorporate somatic genetic information to create more accurate prognostic models in the high-risk patient population. This information has included protein expression and gene expression scores. A molecular classification system, although promising, would increase the cost and complexity of identifying patients at highest risk. Before widespread adoption, it will be important to understand whether they add incremental value justifying their use.

Concepts underlying adjuvant therapy

The goal of adjuvant drug therapy is to provide additional therapy following treatment of the primary tumor in order to reduce the risk of disease recurrence and death by eliminating residual micrometastatic disease that is destined to recur. Adjuvant treatment differs from salvage therapy in that treatment is administered based on a perceived risk of disease recurrence, but before any definitive evidence of disease recurrence. Adjuvant therapy has been shown to be a successful therapeutic strategy in various solid tumor types, including cancers of the breast, testis, ureter, ovary, and melanoma. For cancers with a serum biomarker (eg, prostate-specific antigen), detection at this level may be a useful surrogate for residual disease burden; however, such a marker does not exist in RCC. As such, clinicians must rely on prognostic models to help identify patients in whom micrometastatic disease is likely to be present.

Successful development of a therapeutic adjuvant agent must overcome the following challenges:

• 1.
  

  Candidate adjuvant agents must be identified. Inferring that agents successful in metastatic disease will be effective in the adjuvant setting likely depends on the mechanism of action. For example, vascular endothelial growth factor (VEGF)–targeting agents, which inhibit angiogenesis, may not function well as inhibitors of micrometastatic disease, whose biology may be less reliant on angiogenesis and nonlethal pathway inhibition. ^,

  
  
• 2.
  

  Inclusion criteria must allow for robust trial enrollment in a reasonable time frame while ensuring patients have enough risk to benefit from adjuvant therapy.

  
  
• 3.
  

  There must be enough power to detect a small but modest benefit. Inclusion of lower-risk patients with fewer events may limit the power to detect a smaller, but meaningful, benefit.

  
  
• 4.
  

  Side effect profile of any adjuvant agent must be sufficiently acceptable to justify treatment in asymptomatic patients.

  
  
• 5.
  

  Relevant end points must be determined. DFS has been shown to be a useful surrogate of OS in some diseases, and is an US Food and Drug Administration (FDA)–sanctioned end point in colorectal cancer and melanoma. ^, Although used as the primary end point in adjuvant RCC trials, some investigators have called into question whether DFS is an appropriate surrogate for OS. ^, There are various advantages and disadvantages to these end points in the adjuvant setting ( Table 2 ).

  
  
  
  

  Table 2

  
  

  Comparative advantages and disadvantages of disease-free survival and overall survival as adjuvant trial end points

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  	Advantages	Disadvantages
  DFS	• Quicker to obtain • Reliable (when central, blinded review determines recurrence)	• Unblinded investigator determination of recurrence subject to bias • Heterogeneity of imaging modalities (± contrast), detection bias possible • May not correlate with OS
  OS	• Most relevant outcome for patients and physicians • Easy/reliable to collect and interpret	• May be prohibitively long to reach median survival (10–15 y), preventing expedient trial completion • Patients may lose contact after routine surveillance ends, leading to uncaptured events

   
  
  
  
  
• 6.
  

  The median DFS in recent adjuvant clinical trials is more than 6 years, making trials long and expensive. With OS in the setting of metastatic disease now greater than 3 years, showing an OS difference may require a study to be open for longer than 5 years.

Adjuvant trials of classic immunotherapy agents

The poor response of RCC to conventional chemotherapy, radiation, or hormone therapy, along with the discovery of the immune sensitivity of kidney cancer, led to the immunotherapy/cytokine era for advanced and metastatic RCC in the 1980s to 2000s. Cytokine therapy with interferon alfa (IFN-α) and high-dose interleukin-2 (HD IL-2) offered patients with advanced disease at least some hope of a response despite a poor prognosis. Response rates for HD IL-2 in patients with metastatic RCC were 12% to 15%, with a small proportion having complete and durable response (5%–6%). The burden of toxicity with HD IL-2, although high, was offset with the chance of a durable cure because more than 80% of complete responders had no evidence of disease at 10 years without additional treatment. ^, These impressive responses led HD IL-2 to become the first FDA-approved therapy for RCC. HD IL-2 remained an option at some academic centers in the targeted therapy era for highly select patients (younger, healthier, low metastatic burden); however, with impressive responses with new agents, the role of IL-2 has further diminished.

Cytokines have been explored in the adjuvant setting for high-risk individuals. In a randomized study of 247 postnephrectomy patients, IFN-α2b made no difference in the rate of metastases or OS compared with controls. Messing and colleagues randomized 283 patients with completely resected T3 to T4a and/or node-positive disease to IFN-α or observation. There was no benefit with therapy and perhaps a worse median survival in the treatment arm (5.1 years vs 7.4 years, P = .09). Similarly, there was hope for adjuvant HD IL-2 as an adjuvant therapy. The toxicity was high but expected (88% with grade 3/4 toxicity); however, efficacy was poor, with the study being closed at the interim analysis after enrolling 69 patients.

Vaccines were commonly administered in conjunction with cytokines in the 1990s to improve efficacy in the metastatic setting, and were also evaluated in the adjuvant setting. German investigators randomized patients undergoing nephrectomy to 6 monthly intradermal injections of an autologous tumor vaccine versus surveillance. In total, 379 patients were evaluable on the intent-to-treat analysis and a benefit was noted in progression-free survival favoring the vaccine group (hazard ratio [HR], 1.59; P = .0204). However, concerns about loss of patients after randomization and the absence of survival benefit prevented this therapy from becoming established as a new treatment standard. Another phase III randomized trial evaluating a different patient-derived vaccine, vitespen, was studied in 818 patients and showed no recurrence-free survival (RFS) benefit. A subgroup analysis suggested some benefit in patients with intermediate-risk features, leading this agent to be approved in Russia as an adjuvant therapy.

Adjuvant trials of vascular endothelial growth factor–targeted agents

Identification of the genetic basis for RCC in von Hippel-Lindau (VHL) disease led to the discovery that this pathway was also important in sporadic forms of clear cell RCC. ^, VHL acts as a classic tumor suppressor gene. VHL dysregulation leads to hypoxia inducible factor-α/β accumulation and the transcription of products relating to angiogenesis, glucose transport, and cell cycle regulation. ^, A suite of drugs approved for metastatic RCC block the action of the VEGF tyrosine kinases (eg, sorafenib, sunitinib, pazopanib, axitinib, and cabozantinib). Another overlapping pathway resulting in angiogenesis from hypoxic stress involves mammalian target of rapamycin (mTOR), with 2 FDA-approved drugs for RCC (ie, temsirolimus, everolimus).

Based on the positive impact of these therapies in metastatic disease, and the high risk and poor prognosis of recurrent/metastatic RCC, a series of randomized placebo-controlled trials beginning in the mid-2000s sought to evaluate tyrosine kinase inhibitors (TKIs) in the adjuvant setting. However, virtually every trial to date has failed to show an improvement in DFS or OS. A single positive trial, the S-TRAC trial, did show a benefit in DFS, but many investigators believe the potential benefits are insufficient to change the standard of care. These trials are briefly reviewed later, and are summarized in Table 3 . ^,

Table 3

Phase III adjuvant trials using vascular endothelial growth factor/mammalian target of rapamycin pathway targeting agents

Data from Refs. ^,

	ASSURE	PROTECT	ARISER	ATLAS	S-TRAC	EVEREST	SORCE
Studies	Haas et al, 2016	Motzer et al, 2017	Chamie et al, 2017	Gross-Goupil et al, 2018	Ravaud et al, 2016	S0931	Elsen et al, 2019
Enrollment Dates	April 2006 to Sept 2010	Dec 2010 to Sept 2013	June 2004 to April 2013	May 2012 to July 2016	Sept 2007 to April 2011	May 2010 to Sept 2016	July 2007 to April 2013
N	1943	1538	864	724	615	1545	1711
Status	Complete	Complete	Complete	Complete	DFS data mature (await OS data)	Active (not recruiting)	Complete
Eligibility Criteria	pT2-pT4 pTxN+ pT1 G3/4	pT3-pT4 pT2 G3/4 pTxN+	pT3-pT4 pTxN+ pT1b-pT2 G3/G4	pT2-pT4 pTxN+	pT3-pT4 pTxN+	pT2-pT4 pTxN+ pT1b G3/G4	Leibovich score 3–11
Risk Group (Risk System)	Intermediate or high (UISS)	Intermediate or high (SSIGN)	High (TNM 2002)	Intermediate or high (UISS)	High (UISS)	Intermediate high or high (not specified)	Intermediate or high (Leibovich)
Histology	Clear cell (79%) Non–clear cell (21%)	Clear cell only	Clear cell only	Clear cell only	Clear cell only	Clear cell Non–clear cell	Clear cell (84%) Non–clear cell (16%)
Control Arm	Placebo	Placebo	Placebo	Placebo	Placebo	Placebo	Placebo
Intervention arms	Sunitinib 50 or 37.5 mg daily, 4 wk on, 2 wk off Or Sorafenib 400 or 200 mg twice daily	Pazopanib 600 mg or 800 mg daily	Girentuximab 50 mg ×1, 20 mg weekly	Axitinib 5 mg twice daily	Sunitinib 50 mg 4 wk on, 2 wk off	Everolimus 10 mg daily	Sorafenib 400 mg twice daily for 3 y Or Sorafenib twice daily for 1 y, then placebo for 2 y
Treatment Duration (mo)	12	12	6	12–36	12	12	12–36
Minimum Allowed Dose	Sunitinib 25 mg daily Sorafenib 400 mg every other day	Pazopanib 400 mg daily	No dose reductions	Axitinib 1 mg twice daily	Sunitinib 37.5 mg daily	—	Sorafenib 400 mg daily
Key Efficacy Findings	DFS: HR 1.02, 97.5% CI 0.85–1.23 for sunitinib DFS: HR 0.97, 97.5% CI 0.80–1.17 for sorafenib	ITT 600 : HR 0.86, 95% CI 0.70–1.06 ITT 800 : HR 0.69, 95% CI 0.51–0.94 ITT all : HR 0.80, 95% CI 0.68–0.95	DFS: HR 0.97, 95% CI 0.79–1.18 OS: HR 0.99, 95% CI 0.74–1.32	DFS: HR 0.870, 95% CI 0.660–1.147	DFS: HR 0.76, 95% CI 0.59–0.98	Pending	Median DFS not reached for any arm, HR 1.01, 95% CI 0.83–1.23
Trial Conclusion	No benefit for sunitinib or sorafenib	No benefit for pazopanib	No benefit for girentuximab	No benefit for axitinib	DFS benefit for sunitinib, OS data not mature	Pending	No benefit for sorafenib

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