Open access peer-reviewed chapter

Current Role of Adjuvant Therapy in High Risk for Recurrence Resected Kidney Cancer

Written By

Fadil Hassan, Shahid Lambe, Kiran Sharma and Anil Kapoor

Submitted: December 21st, 2017 Reviewed: May 14th, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.78684

Chapter metrics overview

886 Chapter Downloads

View Full Metrics


Renal cell carcinoma accounts for about 2% of all adult malignancies. More than 300,000 individuals are affected each year. Unfortunately, around 30% of cases are discovered in advanced stages. Surgical resection remains the mainstay of treatment for localized disease and relapses can reach up to 40% in some cases. The effective treatment of metastatic RCC with systemic targeted therapy gives a strong rationale for its use as adjuvant treatment in high-risk patients. This chapter reviews different modalities that have been used as an adjuvant therapy for nonmetastatic renal cancer. Clinical trials using targeted therapy are discussed in detail, as they are becoming options for treatment in high-risk patients. While the current set of completed adjuvant clinical trials have provided conflicting results, there are additional large-scale trials that are still in progress. Future directions include—incorporating a genetic recurrence score to evaluate risk of relapse in patients, developing an adequate and an objective standardized adjuvant trial design, identifying novel biomarkers, and evaluating novel drug targets. Based upon current clinical trial evidence, motivated high-risk patients should have a discussion with the urology oncology team regarding the benefits of adjuvant TKI sunitinib or consider enrollment in current ongoing immuno-oncology (IO) adjuvant clinical trials.


  • renal cell carcinoma
  • adjuvant treatment for RCC
  • treatment of high-risk RCC
  • targeted therapy as adjuvant

1. Introduction

Every year, approximately 338,000 individuals are diagnosed with kidney cancer globally, representing about 2% of all cancers [1]. Renal cell carcinoma (RCC) accounts for approximately 90% of all kidney cancers—affecting an estimated 300,000 people each year [2, 3]. Approximately 30% of kidney cancer patients represent an advanced disease stage at diagnosis, with an average 5-year survival rate of approximately 16% [4, 5].

The management of RCC, regardless of its histological subtype or stage, involves surgical resection of the tumor through either a radical or partial nephrectomy [6]. While surgery is not curative in cases involving metastatic disease, with localized RCC, surgical intervention is considered the optimal standard of care [6, 7].

But despite that, postsurgical recurrence of cancer is a prevalent issue in cases of localized RCC (stage 2 or 3 disease) with a 5-year relapse rate of 30–40% and, as such, surgery is insufficient for long-term disease free survival [8, 9]. Hence, even though the current standard for postoperative care continues to be radiographic surveillance, the need for effective adjuvant therapy for localized high risk for recurrence RCC would be helpful and desired by the surgical community [8, 9, 10].

In view of these findings and the effective treatment of metastatic RCC with Immunotherapy in the 1990s or more recently with targeted therapy, a strong rationale for systemic adjuvant therapy exists in high risk for recurrence patients.

In this chapter, we review different treatment modalities have been used as an adjuvant therapy for nonmetastatic renal cancer postsurgical resection with emphasis on targeted therapy as becoming an option to offer patients.


2. Stratifying risk of recurrence

A critical element in both the testing and effective clinical use of adjuvant therapy involves determining whether there is a high risk of disease recurrence post nephrectomy and accordingly identifying patients that are most likely to benefit from the therapy. As discussed earlier, the determination of recurrence risk is currently nonstandardized in adjuvant therapy testing. Several models and clinical nomograms have been developed to predict the risk of disease recurrence and progression, as well as evaluate additional oncological endpoints [11, 12, 13, 14, 15, 16, 17, 18, 19]. Examples of some validated models include the Cindolo Recurrence Risk Formula, Leibovich scoring system, Karakiewicz scoring system, Kattan nomogram, Mayo Clinic stage, size, grade, and necrosis scoring system (SSIGN), and the University of California Los Angeles Integrated Staging System (UISS) [11, 12, 13, 14, 15, 16, 17, 18, 19] (Tables 1 and 2). These systems usually incorporate information regarding different variables and various prognostic signs and indictors such as tumor size, stage and characteristics, clinical risk factors, and various other pathological features and signs for a relatively robust evaluation [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. Among these models, the UISS, Kattan and SSIGN nomograms have shown relatively better discriminative accuracy in some comparative studies and hence are most commonly utilized [13, 22, 23].

Dimension<10 cm0
>10 cm1
Tumor necrosisAbsent0
Lymph nodespNx/pN00

Table 1.

Leibovich prognosis score.

T stage1234
Furman grade1–23–41–412–41–4
ECOG PS0>1any>1any0>10>1any
Risk groupLowIntermediateHigh

Table 2.

UISS prognosis score.

In terms of a general approximation, recurrence risk can be segregated into three broad categories based on the UISS nomogram: low, intermediate and high risk [18]. These three risk groups are differentiated based on the probability of survival and disease recurrence and patients, in a clinical setting, can be stratified through an independent clinical assessment of UISS components, such as tumor stage, grade, and other pathophysiological characteristics [18, 19]. While the UISS components have not been formally validated as independent recurrence risk prediction models, they are important prognostic indicators for various oncological outcomes and endpoints that are invariably linked with the risk of disease relapse [18, 19]. As such, an evaluation of tumor characteristics—particularly tumor stage—can serve as a rough guide for preliminary differentiation between high, intermediate and low risk categories in the clinical setting [24, 25, 26, 27]. This correlation has been supported by independent studies which have reported higher recurrence free survival (RFS) rates for smaller, T1a-T1b stage tumors and lower RFS rates for larger, T3-T4 stage tumors [24, 25, 26, 27]. Thus, patients with T1a-T2a tumors can be estimated to have lower recurrence risk while those with T3b-T4 tumors can be placed into the high-risk category [24, 25, 26, 27]. Among these varying risk levels, currently only those who present a high risk of disease recurrence can potentially benefit from adjuvant therapy postsurgical resection of the tumor.

The incorporation of biotechnology and an improved understanding of genetic and molecular markers may potentially lead to the next major advancement in improving the predictive accuracy of relapse risk. Recent studies have reported the development of novel gene assays and have further elucidated several new biomarkers [28, 29, 30, 31]. Nonetheless, further investigation, testing and development is required before molecular approaches can be incorporated for clinical application in an efficient and economically viable manner.


3. Immunotherapy IL2,IFα

Two trials that used adjuvant IFN-α [32, 33] and one study that used adjuvant high-dose IL-2 (82) were negative for any benefit. The latter study was designed and powered to show an improvement in predicted 2-year DFS from 40% for the observation group to 70% for the treatment group. Despite full accrual 30% improvement in 2-year DFS could not be achieved which lead to early study closure.

Combination treatment with IFN-α and IL2 also failed to improve DFS in one trial [34].

The combination of cytokines with 5-fluorouracil (5-FU) also failed to improve DFS in the adjuvant setting [35, 36].

In one randomized adjuvant trial, triple combination therapy using IL-2, IFN-α, and5-FU was associated with significant toxicity which leads to 35% of the patients did not complete the study and also resulted in no benefit in DFS or OS [37].


4. Tumor vaccines

Autologous irradiated tumor cells mixed with bacillus Calmette-Guérin (BCG) were tested in two randomized trials and did not result in prolonged DFS [38, 39, 40].

Similarly, autologous, tumor-derived heat-shock protein (glycoprotein 96)-peptide complex (HSPPC-96; vitespen) did not result in a statistically significant improvement of DFS [41].

A trial with an autologous renal tumor cell vaccine only reported improved DFS in the vaccine group [42], but the number of patients lost after the randomization step, the imbalance of this loss, and the absence of tabulation of OS led to criticism of the results [43].

This therapy has not been implemented in routine clinical practice.


5. Hormonal therapy

The occasional response of patients with metastatic RCC to hormonal therapy with medroxyprogestrone acetate (MPA) provided a rationale in trying it in adjuvant sitting.

In a prospective randomized trial of adjuvant MPA after radical nephrectomy, 136 patients received either MPA 500 g (three times a week) for 1 year or observation. With a median follow up of 5 years. There were no significant differences in relapses between the adjuvant group and the observation group (32.7 vs. 33.9%, respectively) [44].


6. Radiotherapy

Radiotherapy has been used for symptoms palliation in metastatic RCC like hematuria and painful bone metastasis. Also, long-term PFS has been reported for in a subset of patients following radiotherapy for solitary bone metastases [31].

One prospective, randomized study in 72 patients comparing administration of radiation of the kidney bed, and ipsilateral and contralateral lymph nodes for stages II and III RCC versus observation reported relapse rates of 48% in both groups. Forty-four percent of patients in the radiotherapy arm had significant complications that contributed to the death of 19% of patients [45, 46, 47].


7. Adjuvant therapy in the era of the new targeted therapy

7.1. Targeted therapy

Systemic therapy for mRCC has particularly changed over the last decade with the introduction of targeted therapy and the evolvement of tyrosine kinase inhibitors (TKI) [7, 49, 50, 51, 52, 53]. This development has directly resulted from an improved understanding of the pathogenesis and molecular biology of RCC [49, 50, 51, 52, 53, 54]. TKIs have provided a novel therapeutic approach for better managing the pathology through the inhibition of targets such as the mammalian target of rapamycin (mTOR) pathway and the vascular endothelial growth factor receptor (VEGFR), which consequently help inhibit processes that are critical for cancer progression [7, 49, 50, 51, 52, 53]. Particularly in cases of metastatic RCC, these inhibitors have been effective in increasing the overall survival and response rates than previously used immunotherapy and chemotherapy agents [7, 49, 50, 51, 52, 53].

Seven drugs are now approved for targeted therapy, and several others are being evaluated in clinical trials [50, 51, 52, 53, 55]. At the molecular level, the mechanism of these drugs involves interrupting the molecular signal transduction of various signaling pathways which then ultimately affects pathogenic factors like tumor vascularity, growth and progression [50, 51, 52, 53, 55]. Sunitinib and Pazopanib are currently the accepted standard of care for the management of metastatic RCC and are the most widely used first line agent due to their robust clinical efficacy and established toxicity profile [50, 51, 52, 53, 55]. The current set of therapeutic agents used in targeted therapy exploit the Von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathway associated with clear cell RCC pathogenesis [56, 57].

7.2. VHL-HIF pathway

Clear Cell RCC (ccRCC) normally entails a biallelic inactivation of the VHL tumor suppressor gene at the 3p25-26 locus. VHL inactivation, which occurs due to factors such as mutation, hyper-methylation, or deletions, results in the formation of defective pVHL protein—ultimately leading to the activation and upregulation of HIF-1α [56, 57]. Activated HIF protein serves as a transcription factor for various pro-tumorigenic target genes such as vascular endothelial growth factor (VEGF), transforming growth factor-α and platelet-derived growth factor (PDGF) that are involved in pathogenic processes like angiogenesis, tumor cell proliferation and cell survival [56, 57]. Apart from this central pathway, the mTOR pathway also intersects with HIF pathway upstream of the VHL gene and hence also plays a critical role in influencing HIF process and function [56, 57]. Thus, inhibiting different targets in this pathway has yielded favorable results in mRCC cases [50, 51, 52, 53, 55, 56, 57]. Given the success of targeted therapy agents in the metastatic setting, recent efforts have been focused into translating this into the adjuvant setting.

7.3. Clinical trials: targeted therapy in adjuvant setting

The contemporary endeavors to transpose targeted therapy in the adjuvant setting have been inspired by the increased clinical knowledge gained through the development and evaluation of interventions for stage IV disease [9, 10, 58, 59]. There are currently seven multicenter, double-blind, placebo-controlled, randomized adjuvant clinical trials, involving targeted therapy agents [9, 10, 58, 59]. Five of these trials involve tyrosine kinase inhibitors, while one involves an mTOR inhibitor and the other a monoclonal chimeric antibody [9, 10, 58, 59, 60, 61, 62, 63]. So far, four of these trials have been completed including the, ARISER, ASSURE, S-TRAC and PROTECT trials while the other ones are still in progress [60, 61, 62, 63].

7.3.1. ARISER trial

This ARISER trial, completed in 2014, evaluated the efficacy of girentuximab [60], a monoclonal antibody to carbonic anhydrase IX (a HIF downstream target gene), in the adjuvant setting for intermediate to high risk for recurrence patients. This multicenter, phase III trial involved 864 patients with resected clear cell tumors, who were randomized to receive either girentuximab or placebo, once a week, for 24 weeks. Girentuximab recipients received a 50 mg dose during the first week followed by a weekly dose of 20 mg for the next 23 weeks. The median disease free survival (DFS) duration for the participants in the intervention arm was 71.4 months (HR: 0.97; 95% CI, 0.79–1.18) while the endpoint was never reached for the placebo group. As such, the study indicated no interventional advantage but it recommended further investigation of adjuvant girentuximab in patients with high levels of CAIX in affected renal tissue.

7.3.2. ASSURE trial

The ASSURE trial, completed in 2016, was a randomized, double-blind, placebo-controlled, phase 3 clinical trial in which 1943 patients from 226 study centers in North America were assigned to one of three intervention arms—sunitinib, sorafenib or placebo in intermediate to high-risk patients [61]. Sunitinib patients received 50 mg for 54 weeks on a 4 of 6 week cycle; sorafenib recipients received 400 mg twice per day throughout each cycle, and placebo recipients were randomly assigned either the sunitinib placebo or the sorafenib placebo. The interventions were evaluated using DFS as the primary endpoint. Trial results indicated that the median DFS duration was approximately 5.8 years for sunitinib [HR: 1.02; 97.5% CI: 0.85–1.23; P = 0.8038], 6.1 years for sorafenib (HR: 0.97; 97.5% CI: 0.80–1.17; P = 0.7184), and 6.6 years for placebo—hence suggesting no survival benefit from the interventions relative to the placebo. Instead, the results further reported detrimental effects due to the increased toxicity of the treatment despite the dose reductions—suggesting no benefit of the particular TKI in the adjuvant setting. Of note, this trial had a higher number of TKI dose reductions (potentially suggesting suboptimal drug dosing) and more intermediate risk for recurrence patients than other trials.

7.3.3. S-TRAC trial

The S-TRAC study, also completed in 2016, was a prospective, randomized, double-blind, phase 3 clinical trial involving 615 patients from 21 countries [62]. Of the 615 patients who underwent randomization, 309 were assigned to the sunitinib arm and 306 to the placebo arm. These patients were all “high risk of recurrence.” Sunitinib recipients received 50 mg for a year on a 4 of 6 week cycle. The interventions were evaluated by comparing DFS, the primary endpoint of the study, between the two trial arms. The study results indicated that the median DFS duration was 6.8 years (95% CI: 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI: 3.8–6.6) in the placebo group (HR: 0.76; 95% CI: 0.59–0.98; P = 0.03). The adverse effects observed in sunitinib recipients were consistent with its known toxicity profile. As such, the results from this trial support the potential for sunitinib as a treatment option in the adjuvant setting with a DFS advantage. However, overall survival endpoints have not yet been reported.

7.3.4. PROTECT trial

The PROTECT study, completed recently in 2017, was a phase 3 randomized clinical trial that evaluated the efficacy of adjuvant pazopanib as compared to placebo in preventing RCC recurrence in intermediate to high-risk patients [63]. The trial enrolled 1538 participants and the majority of the pazopanib recipients received a revised dosage of 600 mg, daily for a year, following a dose reduction from 800 mg which caused severe side effects. The interventions were evaluated by comparing DFS as the primary endpoint measure between the two trial arms. The study did not meet its primary endpoint and indicated no significant benefit of pazopanib-600 mg in prolonging DFS as compared to placebo (HR: 0.86; 95% CI, 0.70–1.06; P = 0.165). However, a subgroup analysis of pazopanib-800 mg recipients indicated a 31% decline in DFS (HR, 0.69; 95% CI, 0.51–0.94; P = 0.02). While the DFS results were conflicting between the 600 mg and 800 mg groups, the study reported similar adverse event profiles between both the groups.

7.3.5. Comparison of current adjuvant trial design

The differing outcomes that have been indicated in the current set of completed trials may be accounted for by the distinct sample groups, dose regimens, risk assessment criteria and trial methods [60, 61, 62, 63]. This collectively represents a fundamental limitation that underscores all current adjuvant clinical trials. First, the patient inclusion criteria characteristically differ, in multiple ways, across all adjuvant trials [60, 61, 62, 63]. For example, in the S-TRAC trial, the selected sample exclusively included patients with late-stage, loco-regional, clear-cell RCC while other trials such as the ASSURE, ARTISER and PROTECT trials used a less restricted criteria and included patients with stage 1 or stage 2 tumors and non-clear-cell histologies [60, 61, 62, 63]. In addition, another major cause of heterogeneity lies in the risk assessment and stratification criteria as the scoring system used in the current set of adjuvant trials are not standardized, and hence this invariably contributes to a varied assessment of recurrence risk [60, 61, 62, 63]. With respect to the conflicting sunitinib trials (S-TRAC vs. ASSURE), additional sources of variation that might have led to inconsistent outcomes include varying dose regimens, specifically with respect to the midtrial dose reductions for sunitinib, as well as differing trial criteria for establishing disease status and assessing primary end point status [61, 62, 64].

7.4. Targeted immunomodulatory therapy

The development of therapy that targets oncogenic signaling pathways has advanced the treatment landscape for patients with advanced renal cell carcinoma. While nonspecific immunotherapy with IL-2 and IFN-α was the former mainstay in the management of metastatic disease, there was a shift away from it with the advent of targeted therapy which yielded relatively better response rates [32, 33, 34, 48, 49, 50, 51, 52, 53, 54, 65, 66, 67, 68]. However, over the last couple of years, cancer immunotherapy has been revisited and, as a result, targeted immunomodulatory therapy, involving novel immunomodulating agents, has been reincorporated in combination therapy regimes for mRCC management—hence allowing for an induced immuonologic effect in addition to the inhibitory effect on tumor biology and microenvironment [69, 70]. This has been inspired in part by disease resistance that is progressively manifesting itself against standard targeted therapy in the landscape of metastatic disease management [69, 70].

Given that multiple mechanisms are employed by tumors to evade and suppress the immune system, research toward better understanding those mechanisms of immunomodulation has been critical in informing the therapeutic landscape [69, 71]. Particularly, an improved understanding of the factors regulating the antitumor immune response has led to the development a novel form of cancer immunotherapy involving checkpoint inhibitors and other immune therapies such as T-cell agonists, adoptive T-cell therapies and novel vaccines which are being evaluated across different trials for metastatic RCC [69, 71].

7.5. Immune checkpoint inhibitors

Immune checkpoints serve a critical protective function of preventing immune response against host cells through a series of complex interactions [71, 72, 73]. However, investigation into the pathogenic mechanisms of RCC revealed that cancer cells can induce similar interactions with host checkpoint receptors and can hence suppress the human immune response [71, 72, 73]. Immune checkpoint inhibitors counter these molecular mechanisms through which tumor cells evade immune recognition [71, 72, 73].

Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are currently the most well understood inhibitory checkpoint receptors [71, 72, 73]. The PD-1/PD-L1 axis involves an inhibitory interaction between a T-cell inhibitory ligand PD-L1, expressed on tumor cell surface, and a PD-1 receptor on the lymphocyte [71, 72, 73]. Hence, mimicking this interaction ultimately allows tumor cells to evade the adaptive immune response through suppression of T-cell function. The CTLA-4 pathway is similarly exploited by tumor cells [71, 72, 73]. During an adaptive immune response, immune activation occurs through an interaction between the T-cell receptor (TCR) and the antigen-presenting cell (APC) along with the co-stimulation of CD28 on the T cell [71, 72, 73]. This activation is negatively regulated by an inhibitory interaction between CTLA-4 and its ligands—CD80 or CD86 [71, 72, 73]. Thus, the targeted inhibition of these checkpoint receptors through targeted antibodies, in both the pathways mentioned above, could allow for T-cell activation and effective immune function [71, 72, 73].

The first checkpoint inhibitor which demonstrated a survival benefit in patients with metastatic RCC was nivolumab—an anti-PD1 monoclonal antibody [74]. The inhibitor, which received FDA approval in 2015 based on the results from a trial evaluating nivolumab versus everolimus, is effective in yielding positive response rates when used for treatment of advanced RCC in patients who have undergone prior anti-angiogenic therapy [74]. Apart from nivolumab, multiple other checkpoint inhibitors are being currently evaluated in different trials against advanced RCC [71, 72, 73].

7.6. Immunomodulatory therapy in the adjuvant setting

Given their recent development, many immune checkpoint inhibitors are still being evaluated for their efficacy and toxicity against metastatic RCC, and hence investigation of these inhibitors in the adjuvant setting has been limited. Currently, there are a few ongoing clinical trials that are evaluating different checkpoint inhibitors in both the adjuvant setting as well as the neo-adjuvant (presurgery) setting (Table 3) [75, 76, 77, 78].

Adjuvant clinical trials in RCC using immune therapies
AuthorsInterventionPatient populationDesignNo. of patientsOutcome
Pizzocarro et al. [32]IFN-α2b vs. placeboRobson stages II and III (T3aN0M0 and T3bN0M0 or T2/3N1-3M0)Multicenter, randomized, controlled trial2475-year OS: 0.665 (control) vs. 0.660 (treatment) (HR 1.040; 95% CI, 0.671–1.613, P ¼ _0.861)
5-year DFS: 0.671 (control) vs. 0.567 (treatment) (HR 1.412; 95% CI, 0.927–2.149, P ¼ _0.107)
Passalacqua et al. [34]IL-2 and IFN-α _v observationpT1, T2, T3 a-b-c; pN0-pN3,M0MMulticenter, randomized, controlled trial3105-year DFS: 0.73 (control) vs. 0.73 (treatment)
10-year DFS: 0.60 (control) vs. 0.73 (treatment) (HR 0.84; 95% CI, 0.54–1.33, P ¼ _0.47)
Clark et al. [48]IL-2 vs. observationT3b-4 or N1-3 (LA) or M1Multicenter, randomized, controlled trial69 total; 44 LA, 25M1 disease2-year DFS: 48% (control in LA patients) vs. 53% (treatment in LA patients) (P ¼ _0.73)
2-year OS: 77% (control in LA patients) vs. 86%
Messing et al. [33]IFN-α-NL vs. observationpT3–4a and/or node-positiveMulticenter, randomized, controlled trial283At 10.4 years median follow-up: Median survival: 7.4 years (control) vs. 5.1 years (treatment) (P ¼ _0.09). DFS: 3.0 years (control) vs. 2.2 years (treatment) (P ¼ _0.33)
Atzpodien et al. [35]IL-2 and IFN-α2a and intravenous 5 vs. fluorouracilpT3b/c pN0 or pT4pN0), pN, complete resection of tumor relapse or solitary metastasis (R0)Multicenter, randomized, controlled trial203At median follow-up of 4.3 years:
2-year OS: 91% (control) vs. 81% (treatment)
5-year OS: 76% (control) vs. 58% (treatment)
8-year OS: 66% (control) vs. 58% (treatment) (P ¼ _0.0278)
2-year DFS: 62% (control) vs. 54% (treatment)
5-year DFS: 49% (control) vs. 42% (treatment)
8-year DFS: 49% (control) vs. 39% (treatment) (P ¼ _0.2398)
Aitchison et al. [36]IL-2 and IFN-α2a and intravenous 5-fluorouracilT3b-c,T4 or any pT and pN1 or pN2 or positive microscopic margins or microscopic vascular invasionMulticenter, randomized, controlled trial3093-year DFS: 50% (control) vs. 60% (treatment) (HR 0.87; 95% CI, 0.63–1.20)
5-year OS: 60% (control) vs. 68% (treatment) (HR 0.91; 95% CI, 0.60–1.38)
Galligioni et al. [39]Autologous irradiated tumor cells and BCG vs. observationStages I, II, and IIIProspective, randomized, controlled trial120At 61 months median follow-up:
5-year OS: 78% (control) vs. 69% (treatment)
5-year DFS: 72% (control) vs. 63% (treatment)
Adler et al. [40]Autologous irradiated tumor cells & BCG & hormone vs. hormoneAll stagesProspective, randomized, controlled trial43Trend for prolongation of DFS for stage I, II, and III (P o.1)
Wood et al. [41]Autologous, tumor-derived heat-shock protein (glycoprotein 96)-peptide complex (HSPPC-96; vitespen) vs. observationcT1b–T4 N0 M0, or cTanyN1-2M0MulticenterMulticenter, randomized, controlled trial819At 1.9 years median follow-up: recurrence: 39.8% (control) vs. 37.7% (treatment) (HR 0.923; 95% CI, 0.729–1.169, P ¼ _0.506) OS not mature
Jocham et al. [42]Autologous renal tumor cells (Reniale)pT2–3b pN0–3Multicenter, randomized, controlled trial558At 5-year follow-up: DFS: 67.8% (control) vs. 77.4% (treatment) (P ¼ _0.0204). At 70-month follow-up: DFS: 59.3% (control) vs. 72% (treatment). HR for tumor progression: 1.58 (95% CI 1.05–2.37) and 1.59 (1.07–2.36) (P ¼ _0.0204)

Table 3.

Adjuvant clinical trials in RCC using immune therapies.

IFN, interferon; IL, interleukin; NL, neutral lymphoblastoid; LA, locally advanced; BCG, bacillus Calmette-Guérin; CI, confidence interval; LA, locally advanced; HR, hazard ratio; M, metastatic; OS, overall survival; DFS, disease-free survival.

The IMmotion, KEYNOTE-564, and CheckMate 914 are phase III trials evaluating the efficacy and safety of adjuvant atezolizumab, pembrolizumab, and nivolumab/ipilimumab (combinational regimen) respectively in prolonging the DFS of RCC patients who are at high risk of disease recurrence post nephrectomy [75, 77, 78]. In addition to the adjuvant trials, an ongoing study in the neo-adjuvant setting includes the PROSPER trial which is evaluating the efficacy of pre-nephrectomy nivolumab [75]. These trials, which have either started already or are expected to begin later this year, are currently in their recruitment or pre-recruitment phases and are anticipated to be completed by 2022–2024 [75, 77, 78]. Apart from these clinical studies, there are several checkpoint inhibitors that are in development as well as others that are currently being evaluated in trials for mRCC and would subsequently be assessed in the adjuvant setting [71, 72, 73] (Tables 46).

Trial name.Trial IDInterventionSample sizeInclusion criteria (histology; stage/grade)Primary endpoint measureCompletion date
ARISERNCT00087022Girentuximab864ccRCC; T1b,N0, NX,MO, T2,N0, NX,MO (grade ≥ 3) (risk: intermediate-High)DFS,OS2014
ASSURENCT00326898Sorafenib or Sunitinib1943Any; pT1bN0M0 (grades 3–4), pT2-4N1-3M0 (risk: intermediate-high)DFS2016
S-TRACNCT00375674Sunitinib615ccRCC; pT2N0M0 (grades 3–4) or pT3-4N0M0 or pTxN1M0 (risk: High)DFS2016
PROTECTNCT01235962Pazopanib1500ccRCC; pT2N0M0 (grades 3–4) or pT3-4N0M0 or pTxN1M0 (risk: intermediate-high)DFS2017

Table 4.

RCC adjuvant clinical trials that have been completed.

Trial name.Trial IDInterventionSample sizeInclusion criteria (histology; stage/grade)Primary endpoint measureEstimated completion date
SORCENCT00492258Sorafenib1420Any; pT1a N0M0 (grade 4), pT1b N0M0 (grades 3–4), pT2-4N0M0, pT1b-4N1M (risk: intermediate-high)DFS2019
ATLASNCT01599754Axitinib592ccRCC; pT2-4N0M0 or pTxN1M0 (risk: high)DFS2019
EVERESTNCT01120249Everolimus1218Any; pT1bN0M0 (grades 3–4) or pT2-4N1-3M0 (risk: intermediate-high)DFS2021

Table 5.

Current set of adjuvant clinical trials that are still in progress.

Trial nameTrial IDInterventionEstimated enrollmentPrimary endpoint measureStart dateCompletion date
PROSPERNCT03055013Nivolumab (pre-Nx)766DFSFebruary 2, 20172022
KEYNOTE-564NCT03142334Pembrolizumab950DFSJune 9, 20172022
CheckMate 914NCT03138512Nivolumab, ipilimumab800DFSJuly 3, 20172023
IMmotion010NCT03024996Atezolizumab664DFSJanuary 3, 20172024

Table 6.

Ongoing adjuvant and neo-adjuvant clinical trials.

7.7. Change of practice

The European Association of Urology Renal Cell Cancer Guidelines Panel, which includes patient representatives and clinicians, considered a number of different scenarios to determine what would be required from S-TRAC to change practice. The decision on practice change was taken in the context of the data from ASSURE. Results showed that only 1 out of 15 (6%) of the panel would change their standard of care when considering the DFS and OS closest to S-TRAC (DFS: HR 0.75, p < 0.05; OS: HR 1.0, p > 0.05). Standard practice would only be significantly influenced by a significant survival benefit. In addition, kidney cancer patients from the International Kidney Cancer Coalition (IKCC) participated in a questionnaire about the implications for STRAC. The results lacked clarity. Twenty-two patient representatives from the IKCC network were asked what degree of PFS advantage would be needed to justify taking sunitinib for 1 year. Approximately one-third of patients favored not taking sunitinib when faced with the S-TRAC results [79].

Recently, on November 2017, the FDA approved the use sunitinib for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma following nephrectomy. The approval was based on (S-TRAC) trail.


8. Conclusions and future directions

Targeted therapy has become the current mainstay in the management of metastatic RCC and its success with advanced stage disease has been the driving force behind the increasing number of targeted therapy trials in the adjuvant setting. The emergence of immune checkpoint inhibitors in the last couple of years has further led to important advances in our understanding and management of mRCC. However, many ongoing trials are yet to be completed in both cases and there is ample potential for further investigation—especially with respect to combinational therapy regimes. This includes the combination of TKIs with immune therapies (e.g., NCT01513187: Pazopanib with Interferon Alfa 2-A), combination of TKIs with chemotherapeutics (e.g., NCT00556049: Sunitinib with Gemcitabine), and the combination of anti-VEGF antibodies and mTOR inhibitors (e.g., NCT01399918: bevacizumab and everolimus). All of these treatments may be of interest for future adjuvant trials in RCC if they are found to be effective in stage IV disease. However, they may have more side effects, making them less suitable in particular for adjuvant treatment. Nonetheless, the current information, which has resulted from all the progress in the field, remains incongruent. While the current set of completed adjuvant clinical trials have provided negative or conflicting results (ARISER, PROTECT, S-TRAC vs. ASSURE), there are additional large-scale trials that are still in progress. The existing trial design has several limitations, the key one being the overall lack of standardization seen across various assessment criteria. Future directions include incorporating a genetic recurrence score to evaluate risk of relapse in patients, developing an adequate and an objectively standardized adjuvant trial design, identifying novel biomarkers and evaluating novel drug targets.

That based on results from current trials, the “high risk for recurrence” RCC patient population (T3-T4, grade 3-4) may benefit from adjuvant sunitinib providing DFS advantage but pending OS results. Patients, in this category, interested in adjuvant therapy would benefit from a discussion with an oncologist regarding the potential benefits and risks of adjuvant treatment post kidney cancer surgery. Overall, the landscape of adjuvant treatment in nonmetastatic high-risk RCC is expected to expand and to further develop in the coming years.


  1. 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, Cancer Incidence and Mortality Worldwide. Lyon, France: International Agency for Research on Cancer; 2010
  2. 2. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2015. Toronto, ON: Canadian Cancer Society; 2015
  3. 3. Renal Cell Carcinoma. Cleveland Clinic. 2013. Available from:
  4. 4. Kidney Cancer Association. About Kidney Cancer. October, 2016. Available from:
  5. 5. National Cancer Institute: SEER Stat Fact Sheets: Kidney and Renal Pelvis. Key Fact Available from: (link is external)
  6. 6. Kidney Cancer—Mayo Clinic [Internet]. Available from:
  7. 7. Abe H, Kamai T. Recent advances in the treatment of metastatic renal cell carcinoma. International Journal of Urology. Oct 2013;20:944-955
  8. 8. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. The Urologic Clinics of North America. 2003;30:843-852
  9. 9. Janowitz T, Welsh SJ, Zaki K, Mulders P, Eisen T. Adjuvant therapy in renal cell carcinoma—Past, present, and future. Seminars in Oncology. 2013;40:482-491
  10. 10. Pal SK, Haas NB. Adjuvant therapy for renal cell carcinoma: Past, present, and future. The Oncologist. 2014;19(8):851-859. DOI: 10.1634/theoncologist.2014-0105
  11. 11. Cindolo L et al. A preoperative clinical prognostic model for non-metastatic renal cell carcinoma. BJU International. 2003;92:901-905
  12. 12. 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
  13. 13. Sorbellini M et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. The Journal of Urology. 2005;173(1):48-51
  14. 14. Kattan M et al. A postoperative predictive nomogram for renal cell carcinoma. The Journal of Urology. 2001;166:63-67
  15. 15. Frank I et al. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: The SSIGN score. The Journal of Urology. 2002;168(6):2395-2400
  16. 16. Zisman A et al. Improved prognostication of renal cell carcinoma using an integrated staging system. Journal of Clinical Oncology. 2001;19(6):1649-1657
  17. 17. Karakiewicz PI et al. Multi-institutional validation of a new renal cancer-specific survival nomogram. Journal of Clinical Oncology. 2007;25(11):1316-1322
  18. 18. Patard JJ, Kim HL, Lam JS, et al. Use of the University of California, Los Angeles integrated staging system to predict survival in renal cell carcinoma: An international multicenter study. Journal of Clinical Oncology. 2004;22(16):3316-3322
  19. 19. Yaycioglu O, Roberts WW, Chan T, Epstein JI, Marshall FF, Kavoussi LR. Prognostic assessment of nonmetastatic renal cell carcinoma: A clinically based model. Urology. 2001;58(2):141-145
  20. 20. Patard JJ, Dorey FJ, Cindolo L, et al. Symptoms as well as tumor size provide prognostic information on patients with localized renal tumors. The Journal of Urology. 2004;172(6 pt 1):2167-2171
  21. 21. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of Clinical Oncology. 1999;17(8):2530-2540
  22. 22. Cindolo L et al. Comparison of predictive accuracy of four prognostic models for nonmetastatic renal cell carcinoma after nephrectomy: A multicenter European study. Cancer. 2005;104(7):1362-1371
  23. 23. Parker WP et al. Application of the stage, size, grade, and necrosis (SSIGN) score for clear cell renal cell carcinoma in contemporary patients. European Urology. 2017 Apr;71(4):665-673
  24. 24. Crispen PL et al. Outcomes following partial nephrectomy by tumor size. The Journal of Urology. 2008;180(5):1912-1917
  25. 25. Lam JS et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. The Journal of Urology. 2005;174(2):466-472. discussion 472; quiz 801
  26. 26. Adamy A et al. Clinical characteristics and outcomes of patients with recurrence 5 years after nephrectomy for localized renal cell carcinoma. The Journal of Urology. 2011;185(2):433-438
  27. 27. Du Y, Grüllich C, Hadaschik B, Hatiboglu G, Hohenfellner M, Pahernik S. Local recurrence after curative surgical treatment of renal cell cancer: A study of 91 patients. Clinical Genitourinary Cancer. 2016;14(4):e379-e385
  28. 28. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43-49
  29. 29. Klatte T, Seligson DB, LaRochelle J, et al. Molecular signatures of localized clear cell renal cell carcinoma to predict disease-free survival after nephrectomy. Cancer Epidemiology, Biomarkers & Prevention. 2009;18:894
  30. 30. Rini B, Goddard A, Knezevic D, et al. A 16-gene assay to predict recurrence after surgeryin localised renal cell carcinoma: Development and validation studies. The Lancet Oncology. 2015;16:676
  31. 31. Speed J, Trinh Q, Choueiri T, Sun M. Recurrence in localized renal cell carcinoma: A systematic review of contemporary data. Current Urology Reports. 2017;18(2)
  32. 32. Giorgio P et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: A multicentric randomized study. Journal of Clinical Oncology. 2001;19(2):425-431
  33. 33. Messing EM et al. Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: An Eastern Cooperative Oncology Group/Intergroup Trial. Journal of Clinical Oncology. 2003;21(7):1214-1222
  34. 34. Passalacqua R, Buzio C, Buti S, et al. Adjuvant low-dose interleukin-2 (IL2) plus interferon-alpha (IFN) in operable renal cell cancer (RCC). A phase III, randomized, multicenter, independent trial of the Italian Oncology Group for Clinical Research (GOIRC). Journal of Clinical Oncology. 2007;25:18S. 2007 ASCO Annual Meeting Proceedings Part I
  35. 35. Atzpodien J et al. Interleukin-2-and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: A prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Journal of Clinical Oncology. 2004;22(7):1188-1194
  36. 36. Aitchison M, Bray C, Van Poppel H, Sylvester R, Graham J, Innes C, McMahon LVP. Preliminary results from a randomized phase III trial of adjuvant interleu- kin-2, interferon alpha and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC). Journal of Clinical Oncology. 2008;26(suppl)
  37. 37. Ahmedin J et al. Global cancer statistics. CA: A Cancer Journal for Clinicians. 2011;61(2):69-90
  38. 38. Poppel V, Hein SJ, Van Gool SW. Vaccine therapy in patients with renal cell carcinoma. European Urology. 2009;55(6):1333-1344
  39. 39. Galligioni E et al. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and Bacillus Calmette-Guèrin: Five-year results of a prospective randomized study. Cancer. 1996;77(12):2560-2566
  40. 40. Adler A 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. Journal of Immunotherapy. 1987;6(6):610
  41. 41. Wood C 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. The Lancet. 2008;372(9633):145-154
  42. 42. Jocham D 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. The Lancet. 2004;363(9409):594-599
  43. 43. Fishman M, Antonia S. Specific antitumour vaccine for renal cancer. The Lancet. 2004;363(9409):583-584
  44. 44. Maxwell PH et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999;399(6733):271-275
  45. 45. Dorothea FS, Kjølseth I, Lund G. Radiotherapy of metastases from renal cancer. European Urology. 1982;8:340-342
  46. 46. Mogens K, Frederiksen PL, Engelholm S. Postoperative radiotherapy in stage II and III renal adenocarcinoma. A randomized trial by the Copenhagen renal cancer study group. International Journal of Radiation Oncology Biology Physics. 1987;13(5):665-672
  47. 47. Mogens K 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. Scandinavian Journal of Urology and Nephrology. 1987;21(4):285-289
  48. 48. Clark JI et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: A cytokine working group randomized trial. Journal of Clinical Oncology. 2003;21(16):3133-3140
  49. 49. Escudier B, Albiges L, Sonpavde G. Optimal management of metastatic renal cell carcinoma: Current status. Drugs. 2013;73(5):427-438
  50. 50. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England Journal of Medicine. 2007;356(2):115-124
  51. 51. Motzer R, Hutson T, Tomczak P, Michaelson M, Bukowski R, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology. 2009;27(22):3584-3590
  52. 52. Powles T, Chowdhury S, Jones R, Mantle M, Nathan P, Bex A, et al. Sunitinib and other targeted therapies for renal cell carcinoma. British Journal of Cancer. 2011;104(5):741-745
  53. 53. Coppin C, Kollmannsberger C, Le L, Porzsolt F, Wilt T. Targeted therapy for advanced renal cell cancer (RCC): A cochrane systematic review of published randomised trials. BJU International. 2011;108(10):1556-1563
  54. 54. Pal SK, Williams S, Josephson DY, et al. Novel therapies for metastatic renal cell carcinoma: Efforts to expand beyond the VEGF/mTOR signaling paradigm. Molecular Cancer Therapeutics. 2012;11:526-537
  55. 55. Ljunberg et al. Guidelines on Renal Cell Carcinoma. European Association of Urology. 2015. Available from:
  56. 56. Ellis L, Hicklin D. VEGF-targeted therapy: Mechanisms of anti-tumour activity. Nature Reviews. Cancer. 2008;8(8):579-591
  57. 57. Baldewijns M, van Vlodrop I, Vermeulen P, Soetekouw P, van Engeland M, de Bruïne A. VHL and HIF signalling in renal cell carcinogenesis. The Journal of Pathology. 2010;221(2):125-138
  58. 58. Pal SK, Bergerot P, Figlin RA. Renal cell carcinoma: An update for the practicing urologist. Asian Journal of Urology. 2015;2(1):19-25
  59. 59. Patel D, Figlin R, Kim H. Adjuvant treatment for renal cell carcinoma: Do we finally have a major breakthrough? Clinical Advances in Hematology & Oncology. 2016;14(11)
  60. 60. Chamie K, Donin NM, Klöpfer P, Bevan P, Fall B, Wilhelm O, Störkel S, Said J, Gambla M, Hawkins RE, Jankilevich G, Kapoor A, Kopyltsov E, Staehler M, Taari K, Wainstein AJA, Pantuck AJ, Belldegrun AS. Phase III ARISER data for the adjuvant treatment of clear cell renal cancer with RENCAREX® including retrospective subgroup analysis. Presented at ASCO; 1-3 June, 2013
  61. 61. 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;387:2008-2016
  62. 62. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. The New England Journal of Medicine. 2016;375:2246-2254. DOI: 10.1056/NEJMoa1611406
  63. 63. RJM M, Naomi HB, et al. Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT). Journal of Clinical Oncology. 2017;35(15_suppl):4507-4507
  64. 64. Porta C, Chiellino S. ASSURE vs. S-TRAC: Conflicting results of adjuvant treatments for kidney cancer in the era of targeted agents and genomics. Annals of Translational Medicine. 2016;4(Suppl 1)
  65. 65. Atzpodien J, Kirchner H, Illiger HJ. IL-2 in combination with IFN- alpha and 5-FU versus tamoxifen in metastatic renal cell carcinoma: Long-term results of a controlled randomized clinical trial. British Journal of Cancer. 2001;85(8):1130-1136
  66. 66. Atzpodien J, Kirchner H, Jonas U. Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: A prospectively randomized trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Journal of Clinical Oncology. 2004;22(7):1188-1194
  67. 67. Atzpodien J, Schmitt E, Gertenbach U. 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). British Journal of Cancer. 2005;92(5):843-846
  68. 68. Aitchison M, Bray C, Van Poppel H, Sylvester R, Graham J, Innes C, McMahon LVP. Preliminary results from a randomized phase III trial of adjuvant interleukin-2, interferon alpha and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC). Journal of Clinical Oncology. 2008;26(suppl):5040. abstr
  69. 69. De Maeseneer D, Delafontaine B, Rottey S. Checkpoint inhibition: New treatment options in urologic cancer. Acta Clinica Belgica. 2017;72(1):24-28
  70. 70. Kuusk T, Albiges L, Escudier B, Grivas N, Haanen J, Powles T, et al. Antiangiogenic therapy combined with immune checkpoint blockade in renal cancer. Angiogenesis. 2017
  71. 71. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489
  72. 72. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer. 2012;12:252-264
  73. 73. Carlo M, Voss M, Motzer R. Checkpoint inhibitors and other novel immunotherapies for advanced renal cell carcinoma. Nature Reviews. Urology. 2016;13(7):420-431
  74. 74. Motzer R, Escudier B, McDermott D, George S, Hammers H, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. The New England Journal of Medicine. 2015 Nov 5;373(19):1803-1813. DOI: 10.1056/NEJMoa1510665. Epub 2015 Sep 25
  75. 75. US National Library of Medicine. 2017.
  76. 76. US National Library of Medicine. 2017.
  77. 77. US National Library of Medicine. 2017.
  78. 78. US National Library of Medicine. 2017.
  79. 79. Bex A, Albiges L, Ljungberg B, Bensalah K, Dabestani S, Giles RH, Hofmann F, Hora M, Kuczyk MA, Lam TB, Marconi L, Merseburger AS, Staehler M, Volpe A, Powles T. Updated European Association of Urology Guidelines regarding adjuvant therapy for renal cell carcinoma. European Urology. May 2017;71(5):719-722. DOI: 10.1016/j.eururo.2016.11.034

Written By

Fadil Hassan, Shahid Lambe, Kiran Sharma and Anil Kapoor

Submitted: December 21st, 2017 Reviewed: May 14th, 2018 Published: November 5th, 2018