Kidney Cancer Today

The History of Cytoreductive Nephrectomy

Cytoreductive Nephrectomy in the Targeted Therapy Era

Introduction

Cancers of the kidney and renal pelvis (when considered in aggregate despite different histology) represent the 6^th most common newly diagnosed tumors in men and 8^th most common in women in the United States in 2020¹, representing an estimated 73,750 new diagnoses and 14,830 deaths. The vast majority of these cancers will be renal parenchymal tumors with renal cell carcinoma (RCC) comprising the large majority with clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma. Due to its prevalence, the vast majority of advances in systemic therapies for RCC have been made for patients with ccRCC. However, there have been important recent advances in treatment for patients with non-clear cell renal cell carcinomas (nccRCC) as well in recent years.

Despite ongoing stage migration as a result of widespread use of axial abdominal imaging for non-specific abdominal complaints², a large proportion (up to 35%) of patients present with advanced disease, including metastases³. Historically, metastatic RCC has been early uniformly fatal, with 10-year survival rates less than 5%⁴. However, there has been transformational change in this disease space over the past fifteen years and, with newer immunotherapy-based approaches, the potential for long-term cure is something that may be considered. Certainly, a significantly longer natural history is feasible given available therapeutic options.

The Historical and Near Past

The immunologically active nature of RCC has been recognized for many years and, as a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC: interferon-alfa and interleukin-2 were among the only available treatment options prior to 2005. However, despite a response rate between 10 to 15%⁵, even among patients treated at a center of excellence, median overall survival was only 30 months in favorable risk patients, 14 months in intermediate risk patients and 5 months in poor risk patients⁶. Interleukin-2 had similar response rates to interferon-based therapies (~15 to 20%)⁷, but distinctly had evidence of durable complete responses in approximately 7 to 9% of patients⁸. This observation led to the U.S. Food and Drug Administration (FDA) approval of high-dose IL-2 in 1992. However, IL-2 is associated with significant toxicity which has limited its widespread use.

The more recent past includes the “targeted therapy” era which began with the introduction of sorafenib in 2005 followed by sunitinib in 2006 and temsirolimus in 2007, along with a number of other agents in the years that followed.

These treatments were developed based on work into the molecular biology underlying ccRCC through targeting of the vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR). This pathway plays a key role in regulating HIF-α, thus modulating the pathway between abnormalities in VHF and proliferation. 

While no longer used as monotherapy in the first-line setting, bevacizumab, a humanized monoclonal antibody against VEGF-A, was the first inhibitor of the VEGF pathway used in clinical trials. In head-to-head trials against interferon-alfa, the addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival^9,10.

In contrast, tyrosine-kinase inhibitors (TKIs) quickly became standard of care, used as first-line monotherapy. For nearly 15 years, sunitinib was the standard of care, and as such, it has formed the control comparison for testing of newer approaches. As with bevacizumab, TKIs also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-β, raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). As alluded to above, sorafenib was one the first molecularly targeted agents clinically available, in 2006, based on demonstrated biologic activity in ccRCC. However, despite FDA approval, sorafenib was quickly supplanted by sunitinib as a first-line VEGF inhibitor. Sunitinib was first tested among patients who had previously received cytokine therapy and then, in a pivotal phase III trial, demonstrated superiority (both in terms of progression free survival and quality of life) in a head-to-head comparison with interferon-α¹¹. Since the approval of sunitinib and sorafenib, there has been development and subsequent approval of many other tyrosine kinase inhibitors. For the most part, the goal of these agents has been to reduce the toxicity of VEGF inhibitors while retaining oncologic efficacy. Comparative data of pazopanib and sunitinib have demonstrated non-inferior oncologic outcomes with decreased toxicity among patients receiving pazopanib¹². Axitinib was evaluated first as second-line therapy¹³ and then in the first-line setting compared to sorafenib¹⁴. Finally, tivozanib has been compared to sorafenib among patients who had not previously received VEGF or mTOR-targeting therapies. While this study demonstrated tivozanib’s activity, it was not FDA approved and it therefore not used.

Most recently, cabozantinib, a multikinase inhibitor (acting on tyrosine kinases including MET, VEGF receptors), and TAM family of kinases (TYRO3, MER, and AXL), has been approved for the first-line treatment of mRCC based on the phase II CABOSUN trial. In the initial report of this study, cabozantinib demonstrated significantly improved progression free survival (HR 0.66, 95% CI 0.46 to 0.95), compared to sunitinib in the first line treatment of patients with intermediate or poor risk mRCC¹⁵. In an updated analysis utilizing independent PFS review, comparable PFS results were observed (HR 0.48, 95% CI 0.31 to 0.74)¹⁶. However, this trial has yet to demonstrate an overall survival benefit to cabozantinib compared to sunitinib (HR 0.80, 95% CI 0.53 to 1.21). 

Mammalian target of rapamycin (mTOR) inhibitors were developed in parallel to VEGF inhibitors. Unlike TKIs, for the most part, these agents have not been used in first-line therapy, though temsirolimus has been used in patients with poor-risk disease based on a comparison or  temsirolimus, interferon, and the combination in 626 patients with pre-defined poor risk metastatic RCC who had not previously received systemic therapy¹⁷. Patients who received temsirolimus had significantly improved overall survival compared to those receiving interferon-alfa (HR 0.73, 95% CI 0.58 to 0.92). 

In addition to the recent, though now well-established, role of immunotherapy in patients with mRCC, there remains ongoing interest in the development of targeted therapies based on our understanding of mRCC biology. Notably, on the basis of an understanding of ccRCC carcinogenesis, the potent, selective, small molecular HIF-2α inhibitor belzutifan (MK-6482) was granted priority review by the FDA for patients with von Hippel-Lindau (VHL) associated RCC. This approval was provided based on the phase II Study-004 trial among patients with renal tumors not requiring surgical intervention (NCT03401788). In data presented at ASCO-GU 2021, treatment with belzutifan was associated with an overall response rate of 36.1% (95% confidence interval 24.2-49.4%). MK-6482 also demonstrated benefits in non-RCC tumors including pancreatic lesions and central nervous systemic hemangioblastomas. This novel therapy was relatively well tolerated with 13% experiencing grade 3 treatment-related adverse events and none experiencing grade 4 or 5 treatment-related adverse events. While this approval was based on treatment in patients with renal masses not requiring surgical intervention, there are ongoing phase III trials of belzutifan both as monotherapy and in combination regimes as first-line treatment for advanced ccRCC.

The Return of Immunotherapy for Advanced RCC

While the cytokine era faded with the introduction of targeted therapies, the immunologic basis for mRCC treatment re-emerged around 2015 with the use of nivolumab monotherapy for patients who had previously received systemic therapy.

Published now more than 3 years ago, CheckMate 214 was the first study to demonstrate a benefit for immune checkpoint inhibitors in the first-line treatment of mRCC, showing an overall survival (OS) benefit for first-line nivolumab + ipilimumab vs sunitinib¹⁸. This trial randomized 1096 patients to the combination immunotherapy approach of nivolumab + ipilimumab (550 patients) or sunitinib (546 patients). Most patients had intermediate or poor risk disease (n=847). OS was significantly improved in the overall patient population; however, stratified analyses provide more nuanced results with benefits restricted to those with intermediate or poor-risk RCC while, in patients with favorable risk disease, progression-free survival and overall response rate were higher among patients who received sunitinib. 

Since the initial publication, there have been a number of follow-up and subgroup analyses from CheckMate 214. Long-term follow-up among patients with at least four years of follow-up was reported at ESMO 2020 by Dr. Albiges. Among these patients, in the intention-to-treat population, results were very similar to the initial analysis previously published with the combined nivolumab + ipilimumab approach continuing to demonstrate superiority (HR 0.69, 95% CI 0.59 to 0.81). In sub-groups defined according to IMDC criteria, those with intermediate or poor risk had improved survival with nivolumab/ipilimumab (HR 0.65, 95% CI 0.54 to 0.78) while there continued to be no appreciable difference between treatment approaches among those with favorable risk disease (HR 0.93, 95% CI 0.62 to 1.40). Presented at the same meeting, Dr. Regan and colleagues used these long-term follow-up data to assess a novel outcome metric, treatment-free survival with and without toxicity. The rationale for this approach is that conventional measures (OS, rPFS, etc) may not fully capture the effects on immuno-oncology (IO) approaches, particularly patients may have long periods of disease control without subsequent anticancer therapy following discontinuation of IO regimes. Thus, the authors defined treatment free survival (TFS), as the time between protocol therapy cessation and subsequent systemic therapy or death. They stratified this as TFS with or without toxicity by counting the number of days with ≥1 grade ≥3 treatment-related adverse events reported. As of 42-months of follow-up, 56% of patients randomized to nivolumab + ipilimumab and 47% of those randomized to sunitinib were alive with 13% and 7%, respectively, remaining on their original therapy. A further 31% of patients randomized to nivolumab + ipilimumab and 12% of those randomized to sunitinib were surviving free of subsequent, second line therapy. 42-month restricted TFS was higher for patients randomized to nivolumab + ipilimumab (7.8 months) than those randomized to sunitinib (3.3 months). Toxicity-free TFS was 7.1 months and 3.0 months, respectively. In each case, the 95% confidence interval of the difference in median TFS excluded unity demonstrating that these are significant differences. Unlike the differences in PFS and OS which appear to be restricted to patients with intermediate and poor risk disease, Dr. Regan and colleagues showed that the benefits in TFS were dramatic in patients with both IMBC intermediate and poor risk disease (median TFS 6.9 vs 3.1 months) and favourable risk disease (median TFS 11.0 vs 3.7 months).

One of the final important subgroup analyses comes from Dr. Escudier and colleagues who demonstrated that the objective response rate was stable across increasing numbers of IMDC risk factors (from zero to 6) for those who received nivolumab and ipilimumab, while the ORR in patients treated with sunitinib decreased with an increasing number of IMDC risk factors¹⁹.

The BIONIKK trial, an open-label, phase II biomarker-driven randomized trial, was also presented as ESMO 2020. This trial relied upon previous analyses which demonstrated that immune and angiogenic signatures can allow for the differentiation of four groups of patients (ccrcc1-4) with immune and angiogenic high/low features, which could allow better identification of responders to either nivolumab, nivolumab + ipilimumab or TKI. ccrcc1 “immune-low” and ccrcc4 “immune-high” tumors have been associated with the poorest outcomes, whereas ccrcc2 “angio-high” and ccrcc3 “normal-like” tumors have been associated with the best outcomes. In this biomarker driven trial, patients with ccrcc1 and ccrcc4 signatures were randomized to nivolumab versus nivolumab + ipilimumab, whereas those with ccrcc2 and ccrcc3 signatures were randomized to receive nivolumab + ipilimumab versus TKI. As a phase II trial, the primary endpoint for this study was objective response rate (ORR, RECIST1.1) per treatment and group. Secondary endpoints included PFS, OS, and tolerability. 202 patients were randomized of a targeted 187. Among patients with the ccrcc1 signature, objective response rates were higher among those who received combination therapy with nivolumab + ipilimumab (39.4%; 6.1% complete response rate) than those who received nivolumab alone (20.7%; 0% complete response rate) whereas among those with a ccrcc4 signature, objective response rates were 50.3% in those receiving the combination approach (11.8% complete response rate) as compared to 50% in those receiving nivolumab alone (7.1%). Median progression free survival among patients with the ccrcc1 signature was 8.0 months in those receiving nivolumab + ipilimumab and 4.6 months among those receiving nivolumab alone. In the ccrcc4 group, median progression-free survival was 12.2 months in the combination arm and 7.8 months in the nivolumab monotherapy arm. In patients with the ccrcc2 signature, objective response rates were 48.3% in the nivolumab + ipilimumab arm (13.8% complete response rate) and 53.8% in the TKI arm (0% complete response rate) whereas among patients with the ccrcc3 signature, 25% receiving nivolumab + ipilimumab had objective responses (0% complete response rate) and 0% receiving TKI had objective response.  These are the first randomized data based on molecular risk group assessment to guide first-line therapy in metastatic ccRCC. In particular, among patients with the ccrcc4 signature, use of combination therapy may not be required and thus ipilimumab may be spared.

In terms of first line therapy, immunotherapy approaches have predominately focused on combination therapy approaches. However, in the past month, data regarding the use of pembrolizumab monotherapy has emerged²⁰. This phase II single-arm study demonstrated an objective response rate of 36.4% among 110 enrolled patients with a median progression-free survival of 7.1 months (95% CI 5.6 to 11.0 months). Clearly, compared to the data highlighted both above from CheckMate214 and in the sections that follow, these results are inferior to combination therapy.

Combination Approaches: Targeted Therapy and Immunotherapy

Combination therapy has been well established in the treatment of advanced RCC, including the use of interferon-alfa and bevacizumab^9,10. Following the data from CheckMate 214 demonstrating the role for immune checkpoint blockade in advanced RCC, data began to emerge on the combination of targeted therapies with checkpoint inhibitors. 

The first of these studies was IMmotion151, first presented at GU ASCO 2018 and subsequently published, which compared first-line atezolizumab + bevacizumab vs sunitinib among 915 patients with previously untreated metastatic RCC²¹. The combined approach demonstrated a significant benefit in progression-free survival (11.2 months versus 7.7 months; HR 0.74, 95% CI 0.57 to 0.96) among the whole cohort of patients and had lower rates of significant (grade 3-4) adverse events (40% vs 54%). 

Subsequently, further combination approaches have been approved on the basis of published phase III trials, including pembrolizumab + axitinib (KEYNOTE-426) and avelumab + axitinib (JAVELIN Renal 101). Additionally, the recent presentation and publication of CheckMate-9ER and CLEAR have added the combination of nivolumab + cabozantinib and lenvatinib + pembrolizumab, respectively, to the armamentarium of first line mRCC treatment.

In KEYNOTE-426, 861 patients with metastatic clear cell RCC, predominately with intermediate or poor risk disease, who had not previously received systemic therapy were randomized to pembrolizumab + axitinib or sunitinib and followed for the co-primary endpoints of overall survival and progression free survival²². While median OS was not reached, patients who received pembrolizumab + axitinib had improved OS (HR 0.53, 95% CI 0.38 to 0.74) and progression free survival (HR 0.69, 95% CI 0.57 to 0.84), as well as overall response rate. These results were consistent across subgroups of demographic characteristics, IMDC risk categories, and PD-L1 expression level. Grade 3 to 5 adverse events were somewhat more common among patients getting pembrolizumab and axitinib, though rates of discontinuation were lower. 

Similarly, JAVELIN Renal 101 randomized 886 patients to avelumab + axitinib or sunitinib²³. Again, the preponderance of patients had IMDC intermediate or poor risk disease. In this analysis the primary endpoints were PFS and OS in patients with PD-L1 positive tumors. Notably, 560 of the 886 patients had PD-L1 positive tumors. Among the PD-L1 positive subgroup, progression free survival (HR 0.61, 95% CI 0.47 to 0.79) was improved in patients receiving avelumab + axitinib compared to sunitinib while OS did not significantly differ (HR 0.82, 95% CI 0.53 to 1.28). In the overall study population, progression-free survival was similarly improved, as compared to the PD-L1 positive population (HR 0.69, 95% CI 0.56 to 0.84). 

Third, in data initially presented at ESMO 2020 and published in February 2021, the CheckMate-9ER trial (NCT03141177), randomized 651 patients in a 1:1 fashion to nivolumab + cabozantinib or sunitinib, in the first-line treatment of patients with advanced or metastatic renal cell carcinoma, with randomization was stratified by IMDC risk score, tumor PD-L1 expression, and region. The primary outcome was progression-free survival with overall survival, objective response rate, and toxicity comprising important secondary outcomes. Over a median follow-up of 18 months, median progression-free survival was significantly longer among those randomized to nivolumab + cabozantinib (16.6 months) than those randomized to sunitinib (8.3 months), with a relative difference of 49% (HR 0.51, 95% CI 0.41 to 0.64) as was OS (medians not reached; HR 0.60, 98.89% CI 0.40 to 0.89). Notably, these benefits were seen consistently across pre-specified subgroups defined according to IMDC risk categories and PD-L1 expression. Any grade treatment related adverse events were common in both groups: 96.6% among those receiving nivolumab + cabozantinib and 93.1% among those receiving sunitinib. High grade events (grade 3 or greater) were somewhat higher among those receiving nivolumab + cabozantinib (60.6% vs 50.9%). One grade 5 event occurred in the nivolumab + cabozantinib arm while 2 occurred in the sunitinib treated group. Notably, quality of life was maintained for those receiving nivolumab + cabozantinib while there was a decline in quality of life among those receiving sunitinib. 

The fourth kinase inhibitor and immune checkpoint inhibitor combination is lenvatinib and pembrolizumab, based on the CLEAR study presented at ASCO-GU 2021 and simultaneously published²⁴. As with the other three trials, CLEAR enrolled patients with previously untreated advanced RCC. Unlike the other trials, this was a three-arm randomization in a 1:1:1 fashion to lenvatinib 20 mg orally once daily + pembrolizumab 200 mg IV every 3 weeks; or lenvatinib 18 mg + everolimus 5 mg orally once daily; or sunitinib 50 mg orally once daily (4 weeks on/2 weeks off in 6-weekly cycles). The authors assessed the primary endpoint of progression-free survival by Independent Review Committee per RECIST v1.1 with key secondary endpoints including OS, objective response rate (ORR) and safety. The authors randomized 1069 patients, 355 who received lenvatinib and pembrolizumab, 357 who received lenvatinib and everolimus, and 357 who received sunitinib. The baseline characteristics of the study population were in keeping with those observed in other first-line mRCC trials. Notably, intermediate and poor risk disease comprised just over 70% of the cohort. Over a median follow-up of 27 months, PFS was significantly improved among patients receiving lenvatinib and pembrolizumab (median 24 months) vs sunitinib (median 9 months; HR 0.39, 95% CI 0.32–0.49) and among patients receiving lenvatinib and everolimus (median 15 months) vs sunitinib (HR 0.65, 95% CI 0.53–0.80). The benefit of lenvatinib and pembrolizumab versus sunitinib with respect to progression-free survival was consistent across many subgroups, comprising age, sex, geographic region, PD-L1 expression, IMDC risk group, prior nephrectomy, and sarcomatoid features. Further, OS was significantly longer among patients who received lenvatinib and pembrolizumab compared to sunitinib (HR 0.66, 95% CI 0.49–0.88), whereas there was no significant difference in OS for patients receiving lenvatinib and everolimus compared to sunitinib (HR 1.15, 95% CI 0.88–1.50). As with progression-free survival, these findings were consistent across all relevant tested subgroups for the comparison of lenvatinib and pembrolizumab, except patients with favorable risk group. Grade ≥3 treatment-related adverse events occurred in 72% of pts in the lenvatinib and pembrolizumab arm and 73% of pts in the lenvatinib and everolimus arm compared with 59% of pts in the sunitinib arm.

While not yet ready for clinical practice, interesting data from COSMIC-021, a multicenter phase 1b study, evaluating the combination of cabozantinib + atezolizumab in various solid tumors (NCT03170960), including first-line treatment of clear cell RCC, was presented at ESMO 2020. Cabozantinib, a standard-of-care for the treatment of advanced RCC, is potentially particularly well suited to combination therapy with immune checkpoint inhibitors as it promotes an immune-permissive environment which may enhance response to immune checkpoint inhibitors. In combination with immune checkpoint inhibitors, cabozantinib has shown promising activity for other tumor types including urothelial carcinoma, castration-resistant prostate cancer, lung cancer, and hepatocellular carcinoma. The ccRCC subset of the COSMIC-021 trial included 10 patients in the dose escalation stage and 60 in the expansion stage of the study. Patients were enrolled sequentially to receive atezolizumab 1200 mg IV every three weeks with either cabozantinib 40 mg (dose level 40 [DL₄₀], n=34) or cabozantinib 60 mg (DL_60, n=36) PO daily in each stage as first line therapy. The primary endpoint for this trial is the ORR per RECIST v1.1 by investigator, the secondary endpoint was safety, and exploratory endpoints include PFS and correlation of biomarkers with outcomes. For DL₄₀, the ORR was 53% (80% CI 41-65), with one complete response (3%) and 17 partial responses (50%), the disease control rate was 94%, duration of response was not reached (range: 12.4 months to not reached), and the median time to objective response was 1.4 months (range: 1-19). For DL₆₀, the ORR was 58% (80% CI 46-70), with four complete responses (11%) and 17 partial responses (47%), the disease control rate was 92%, the median duration of response was 15.4 months (range: 8.1 to not reached), and median time to objective response was 1.5 months (range: 1-7). For DL₄₀, the median PFS was 19.5 months (95% CI 11.0 to not reached) compared to 15.1 months (95% CI 8.2-22.3) for DL₆₀. This approach is currently being further investigated in the CONTACT-03 trial (NCT04338269), a phase III RCT comparing atezolizumab + cabozantinib to cabozantinib alone in patients who had previously received immune checkpoint therapy. 

Non-Clear Cell Histology

In general, randomized trials in advanced RCC have focused on patients with clear cell histology. As a result, there have been little direct data to guide care and we have had to rely on extrapolation from data derived among patients with clear cell histology. However, retrospective data have supported the activity of cabozantinib monotherapy in patients with advanced non-clear cell disease²⁵. At ESMO 2020, Dr. McGregor and colleagues reported a prospective evaluation of the use of cabozantinib + atezolizumab in a subcohort of patients with non-clear cell histology the COSMIC-031 trial. Notably, in this cohort, patients were allowed up to one previously line of TKI (but not previous checkpoint inhibitor therapy or cabozantinib). At the time of data cut-off, 30 patients had been enrolled and followed for a median of 13.0 months. The cohort included 15 patients with papillary, 7 patients with chromophobe, and 8 patients with other histology. Five patients had received previous systemic therapy while 25 (83%) were treatment naïve. Confirmed objective response rate per RECIST v1.1 was 33% (80% confidence interval 22 to 47%), and there were 10 patients with partial responses (papillary, n=6; chromophobe, n=1; ccRCC, n=1; translocation, n=1; and unclassified, n=1) but there were no complete responses, although partial responses occurred in all IMDC risk groups. The median progression-free survival was 9.5 months (95% CI 5.5 to not reached). Notably, patients with nccRCC will be included in the previously mentioned CONTACT-03 trial.

In addition to this combination approaches, a phase II single arm study of pembrolizumab monotherapy in non-clear cell mRCC was recently published²⁶. This phase II single-arm study enrolled 165 patients, of whom 72% had papillary disease, 13% had chromophobe, and 16% had unclassified RCC histology with 70% having intermediate or poor-risk disease, per IMDC criteria. Over a median follow-up of 32 months from enrollment, the objective response rate was 26.7%, with variation according to histology: 29% in those with papillary disease, 10% In those with chromophobe, and 31% for those with unclassified histology. Overall, the median progression-free survival was 4.2 months.

The SAVIOUR phase III randomized controlled trial assessed savolitinib as compared to sunitinib in patients with MET-driven papillary RCC²⁷. After 60 randomized patients, external data on the PFS with sunitinib in patients with MET-driven disease became available and led to closure of the study. At the time of closure, progression-free survival, overall survival, and objective response rates were all numerically higher in patients receiving savolitinib, though the differences were not statistically significant (eg. for PFS, HR 0.71, 95% CI 0.37 to 1.36).

Additionally, at ASCO-GU 2021, the four-armed SWOG 1500 trial was presented and simultaneously published in the Lancet²⁸. This study recruited patients with pathologically verified papillary RCC with measurable metastatic disease and Zubrod performance status 0-1. Patients were eligible for inclusion if they had received up to 1 prior systemic therapy excluding VEGF-directed agents. Patients were randomized in a 1:1:1:1 fashion to receive either sunitinib, cabozantinib, crizotinib, or savolitinib:

There were 152 patients that were enrolled of whom 5 were ineligible. The included patients had a median age of 66 (range:29-89) and the majority (76%) were male. The vast majority (92%) had not received prior systemic therapy. Median PFS was significantly higher with cabozantinib relative to sunitinib (HR 0.60, 95% CI 0.37-0.97). Objective response rates were also higher with cabozantinib than with sunitinib, crizotinib, and savolitinib, with two complete responses and eight partial responses noted among the 44 patients randomized to cabozantinib. Median OS was 20 months for those receiving cabozantinib and 16.4 months for those receiving sunitinib.

Treatment Selection

As highlighted above, there are a number of treatment approaches which have, in phase III RCTs, demonstrated superiority to sunitinib in first-line treatment of clear cell mRCC including atezolizumab + bevacizumab, nivolumab + ipilimumab, pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib, pembrolizumab + lenvatinib. As highlighted in the BIONNIKK trial, a tumor-derived signature may allow for rationale treatment selection, however, prior to this, IMDC risk categories and PD-L1 testing may provide some guidance. Additionally, authors have considered cost-effectiveness analyses to help guide treatment selection^29,30. However, as may be expected, varying the assumptions of these models may change the preferred treatment options. Numerous ongoing trials will continue to shape this rapidly evolving disease space and individual treatment choice will depend on the patient, physician, and system factors with guidelines likely to continue to recommend multiple options.


Written by: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center

Published Date: March 2021

Background

Risk Stratification

Favorable Risk Patients

Intermediate and Poor Risk

Future Therapies

The rapid spread of Coronavirus Disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, has had dramatic effects throughout the world on healthcare systems with impacts far beyond the patients actually infected with COVID-19.

Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.¹ This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that healthcare systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly. In an effort to conserve hospital resources, on March 13^th the American College of Surgeons recommended that health systems, hospitals, and surgeons should attempt to minimize, postpone, or outright cancel electively scheduled operations.² This was done with the primary goal to immediately decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. On March 17^th, the American College of Surgeon then provided further guidance on the triage of non-emergent surgeries, including an aggregate assessment of the risk incurred from surgical delays of six to eight weeks or more as compared to the risk (both to the patient and the healthcare system) of proceeding with the operation.³ In the UK, all non-urgent elective surgical procedures have been put on hold for three months to use all of those clinical resources to care for patients with COVID-19.

Most bodies, including the American College of Surgeons, have recommended proceeding with most cancer surgeries. Thus, clinicians and patients must carefully weigh the benefit of proceeding with cancer treatment as scheduled, the risks of COVID-19 to the individual patient, to healthcare workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. A severe SARS-CoV-2 phenotype is seen more commonly in men and older, more comorbid patients.⁴ Baseline characteristics among 1,591 patients admitted to the ICU in the Lombardy Region, Italy, showed that the median age was 63 years (IQR 56-70), 82% were male, 68% had ≥1 comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing ICU level care at the time of data cut-off.⁵ Work from China demonstrated that patients with cancer had a higher incidence of COVID-19 infection than expected in the general population and had a more severe manifestation of the disease with a significantly higher proportion requiring invasive ventilation in the ICU or death.⁶ Patients at increased risk of COVID-19 are comparable to the kidney cancer population, namely more likely male, hypertensive, and with more than one comorbidity.⁵


Thus, considering the differences in the natural history of different cancers may meaningfully change this balance of risks and benefits. Kidney cancer has a wide range of phenotypic presentations ranging from very indolent, incidentally diagnosed small renal masses to large, symptomatic tumors with vascular or adjacent organ invasion and de novo metastatic disease. Previous articles in the UroToday Kidney Cancer Today Center of Excellence have discussed the Epidemiology and Etiology of Kidney Cancer and particular nuances of staging and management for Malignant Renal Tumors. The vast majority of patients have localized disease at the time of presentation. According to Siegel et al., 65% of all patients diagnosed with kidney and renal pelvis tumors between 2007 and 2013 had localized disease at the time of presentation while 16% had regional spread, and 16% had evidence of distant, metastatic disease.⁷

While the effect of delays in surgical intervention has been most thoroughly explored in muscle-invasive bladder cancer and prostate cancer in the urologic literature, both data and inference may help guide the management of patients with kidney cancer at this time. A single previous narrative review has assessed this question,⁸ however, conclusions from this study are limited. In the absence of data, the guidance of care relies on expert opinion, including a collaborative review pre-published in European Urology (Wallis et al.). This article will discuss the impact of potential delays among patients with kidney cancer, providing recommendations as to who can safely defer treatment until after the pandemic is over versus those that should be treated without delay.

While there are no randomized data, numerous institutional studies have demonstrated both the safety and feasibility of active surveillance (AS) with delayed intervention in patients with small renal masses (SRMs).^9,10

Among 457 patients treated at Fox Chase Cancer Center, McIntosh et al. found that rates of delayed intervention were 9%, 22%, 29%, 35%, and 42% at one-, two-, three-, four-, and five-years following diagnosis.¹¹ Importantly, delayed intervention was not associated with overall survival (OS) (hazard ratio [HR] 1.34, 95% confidence interval [CI] 0.79-2.29), and of the 99 patients on AS without delayed intervention for more than five years, only one patient metastasized. Interestingly, they found a median initial linear growth rate was 1.9 mm/year (IQR 0-7) which was not associated with OS.

Data from the University of Michigan has also assessed the effect of delayed resection (at least six months from presentation) after initial surveillance for patients with SRMs.¹² In this study, there were 401 patients that underwent early resection and 94 patients (19%) that underwent delayed resection. The median time to resection was 84 days (IQR 59-121) in the early intervention group and 386 days (IQR 272-702) in the delayed intervention group. Importantly, there was no difference in adverse final pathology (grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage ≥ pT3) comparing those that underwent early vs late intervention.

Among 497 patients in the DISSRM registry, 223 (43%) chose AS and 274 (57%) chose primary intervention with 21 (9%) eventually undergoing delayed intervention after a period of AS. There was no difference in cancer-specific survival (CSS) at five-years between the groups (primary intervention: 99%; AS 100%, p=0.3) though patients choosing surveillance had lower five-year OS (75% vs 92%), likely attributable to comorbidity which drove their initial selection of surveillance.

Taken together, there is robust data supporting AS for masses < 4cm, even up to five years after the initial diagnosis, without age restriction.^13,14 Thus, delays in the diagnosis and management of these patients during the COVID-19 pandemic is unlikely to meaningfully affect their outcomes.

Although the data is less robust, several studies have assessed the impact of a surgical delay for larger localized kidney tumors (≥pT1b). An institutional cohort from Memorial Sloan Kettering Cancer Center examined 1,278 patients who underwent radical or partial nephrectomy with renal masses > 4 cm between 1995 and 2013. The authors tested the association between surgical wait time and disease upstaging at the time of surgery, as well as two- and five-year recurrence rates.¹⁵ Among these patients, 267 (21%) had a surgical wait time of more than three months, including 82 patients (6%) with a wait time of more than six months. On multivariable analysis, the surgical wait time was not associated with disease upstaging, recurrence or CSS, but longer wait time was associated with worse OS (HR 1.17, 95% CI 1.08-1.27), potentially reflecting comorbidity which necessitated the initial delays.

Similarly, an institutional cohort from the Fox Chase Cancer Center of patients with cT1b/cT2 renal masses assessed the safety of active surveillance.¹⁶ Twenty-three patients (34%) underwent delayed intervention. Over a median follow-up of 32 months (range 6-119), no patients progressed to metastatic disease or died of kidney cancer. The median linear growth rate was 0.34 cm/year (range 0-1.48) suggesting that delays of months to years are unlikely to affect the resectability of these tumors.

Finally, a retrospective review of 722 patients undergoing partial or radical nephrectomy for relatively large kidney tumors (mean tumor size of 6.4 +/- 4.4cm; 64.7% ≥pT1b and 49.0% ≥pT2) from Stec et al. assessed the effect of delays to surgery on survival.¹⁷ They found that the mean time from initial visit to surgery was 1.2 months (range 0-30 months) and that 64.1% of patients underwent surgery within 30 days of initial visit and 94.3% within three months. The authors found no difference in OS for patients receiving early vs. late surgery, whether using a threshold of one month (p=0.87), two months (p=0.46), three months (p=0.71), or six months (p=0.75). However, T-stage was a significant predictor of recurrence-free survival (RFS), independent of time to surgery.

There are essentially no available data on the effect of delays in treating patients with locally advanced kidney cancer. However, several large institutional studies have described timing of preoperative imaging for assessing renal vein/inferior vena cava (IVC) thrombus, which may guide the urgency of surgical timing. While Woodruff et al. recommended the longest interval between imaging (CT/MRI) and surgery being no longer than 30 days,¹⁸ studies from the Mayo Clinic and Berlin, Germany report a median interval from imaging to resection of 4 and 16 days, respectively.^19,20 As a result, the collaborative review pre-published in European Urology suggested that these patients should be prioritized for intervention given the locally advanced nature of their disease, unknown risk of delayed resection, and potential for significant symptomatic complications including bleeding and IVC occlusion.

In contrast, in patients with known metastatic kidney cancer, cytoreductive nephrectomy during the ongoing pandemic was not recommended in this collaborative review on account of the evidence from the CARMENA trial which failed to demonstrate a survival benefit to the addition of cytoreductive to systemic therapy with sunitinib.²¹ Additionally, the SURTIME trial found that upfront systemic therapy followed by cytoreductive nephrectomy was associated with longer survival than patients who received upfront cytoreduction followed by systemic therapy.²²

The question of when to initiate systemic therapy in patients with metastatic kidney cancer is also pertinent during this pandemic and depends on symptoms, patient comorbidities, and tumor risk stratification. In treatment-naïve patients with favorable and intermediate-risk disease who are asymptomatic or minimally symptomatic with limited disease burden, a number of studies, including two narrative reviews^23,24 and two prospective trials,^25,26 have assessed the safety and feasibility of delaying the initiation of systemic therapy. In the largest prospective study of surveillance in patients with metastatic kidney cancer, Rini et al. enrolled fifty-two asymptomatic patients in a Phase II trial.²⁶ All but one patient had favorable (23%) or intermediate (75%) risk disease according to IMDC criteria with the vast majority (80%) of patients having only one or two organ sites with metastases. The median time on surveillance was 14.9 months and 37 of 43 patients experiencing RECIST-defined disease progression started systemic treatment. The median PFS and OS from the start of surveillance was 9.4 and 44.5 months, respectively. In a smaller study of 15 patients who received CN followed by observation until progression, Wong et al. found a median time to progression of eight weeks and a median OS of 25 months.²⁵ Neither of these studies have compared outcomes with patients who started systemic therapy upfront. However, this has been assessed in two large retrospective studies. Among a European cohort of patients ineligible for active surveillance, Iacovelli and colleagues found that a delay of more than six weeks in the initiation of systemic therapy did not significantly affect the cancer-specific outcomes.²⁷ Further, delayed treatment initiation was not independently associated with worse OS in an analysis based on the National Cancer Database utilizing multivariable logistic regression analyses.²⁸

There is no evidence to guide the choice of systemic therapy during the COVID-19 pandemic and thus, standard guideline recommendations should prevail. However, at least theoretically, the risk of severe adverse reactions associated with immunotherapy using checkpoint inhibitors, as well as the requirement for infusion, may preferentially support the use of VEGF-targeted therapy with the convenience of oral administration.

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: April 2020

Brief Overview of Adrenal Physiology

Adrenal Pathology

Investigation of Adrenal Lesion

Treatment of Adrenal Lesions

Early years: cytokine therapy

A new standard: molecularly targeted agents

What’s old is new: immunotherapy for RCC

The next frontier: combinations of targeted therapy and immunotherapy

Dead-ends

Integration of treatment options for patients with metastatic ccRCC

What about surgery?

Cytokine Therapies for Advanced ccRCC

Inhibitors of the VEGF Pathway for Advanced ccRCC

Inhibitors of mTOR for Advanced ccRCC

Checkpoint Inhibitors for Advanced ccRCC

Other Agents for Advanced ccRCC

Treatment of Advanced non-ccRCC

Integration of treatment options for patients with advanced RCC

The Opioid Crisis in Urology

1. A historic failure to address acute pain in hospitalized patients, leading to the American Pain Society suggesting that pain should be akin to the fifth vital sign.⁶ Subsequently, physicians became more aware of their patients’ pain and were expected to treat their pain leading to an environment where liberal use of narcotics was tolerated.
2. Over the past two decades, reimbursement, specifically through the Center for Medicare and Medicaid Services (CMS), has been linked to Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. In the questionnaire, there were three questions dedicated to how well the patient’s pain was managed. These additional measures emphasizing the importance of pain management likely influenced the number of narcotics prescribed at discharge in order to maintain positive survey scores.
3. Because narcotics must be prescribed via a hand-written prescription and obtaining additional pain medication is inconvenient for both patient and physician, providers may be more likely to overprescribe narcotics at discharge “just in case”.

The American Urological Association’s (AUA) Quality Improvement Summit on Opioid Stewardship in Urology

• Session 1: Physician-led Multicomponent Interventions in Opioid Stewardship. Dr. Richard Barth discussed procedure-specific opioid prescribing guidelines, Dr. Jonah Stulberg discussed opioid reclamation efforts, and Dr. Jim Dupree presented the Michigan MUSIC initiative on opioid stewardship.
• Session 2: Understanding Post-operative Pain. Dr. Brooke Chidgey discussed the pathophysiology of post-operative pain, Dr. Meghan Sperandeo-Fruge highlighted complementary alternative medicine pain management strategies, and Dr. Margaret Rukstalis discussed cognitive behavioral therapy and other non-pharmacologic approaches to pain management. In a sub-session discussing challenging cases in opioid management, Dr. Vernon Pais discussed the impact on prescription opioid use in patients with kidney stones, Dr. Matthew Nielsen highlighted the University of North Carolina Health Care System’s opioid stewardship program, and Dr. Benjamin Davies discussed his initiative of no opioids after a robotic prostatectomy.
• Session 3: High-Risk Patients and Expectations. Dr. Behfar Ehdaie presented on the expectation setting for opioid prescribing, Dr. Margaret Rukstalis discussed a surgeon’s role in the management of opioid misuse disorders, and Dr. Brooke Chidgey discussed the role of pain specialists for managing high-risk patients.
• Session 4: Policy and Outreach. Dr. Jennifer Waljee discussed opioid education and outreach, Dr. Scott Winiecki presented on opioid prescribing and the FDA safe use initiative, and Dr. Gregory Murphy completed the program discussing policy change and legislature to address the opioid crisis.

Non-Opioid Measures for Pain Control

• Pre-operative: Oral neurontin, acetaminophen, +/- celebrex
• Quadratus lumborum block (ropivicaine, decadron, precedex)
• Intraoperative: separate infusions of propofol, ketamine, and precede
• Post-operative: Toradol 15 mg IV PRN while in the hospital
• Tylenol and Motrin for 48 hours

Prospective Initiatives

Conclusions

Background 

Kidney cancer is the 12^th most common cancer in the world, with over 300,000 new cases annually, of which 65,340 new cases will be diagnosed in the United States in 2018.¹ The incidence of renal cell carcinoma (RCC) varies substantially based on the country – rates of RCC are higher in Europe and North America and much lower in Asia and South America.²

Most kidney cancers (>90%) are renal cell carcinomas, and of renal cell carcinomas, the majority of cases (80%) will be the clear cell subtype.³ Of the remaining 20% of cases, the two major histological subtypes are papillary (10-14%) and chromophobe (5%)^3,4, but also include collecting duct, translocation carcinoma, medullary carcinoma, and unclassified RCC. These histological subtypes are distinct from clear cell carcinoma and independently predict for survival.³ For example, after controlling for TNM status, age, gender, and tumor size, patients with early stage clear cell RCC are more than twice as likely to die of RCC than patients with papillary or chromophobe RCC.³ Some of these subtypes also have unique risk factors. For example, renal medullary carcinomas are an aggressive non-clear cell carcinoma that are almost exclusively associated with patients with sickle cell trait.⁵

Non-clear cell RCCs (ncRCC) also have unique mutational landscapes.⁶ For example, MET mutations can be found in 15-30% of papillary RCCs.^6,7 Papillary RCCs also have a higher mutation rate compared with chromophobe RCCs and renal oncocytomas. Durinck et al evaluated 167 primary human tumors including papillary, chromophobe and translocation subtypes and were able to use a five gene set to help molecularly distinguish between chromophobe carcinoma, renal oncocytoma and papillary carcinoma.⁶

Treatment

Given the rarity of non-clear cell RCC (ncRCC), there is a paucity of large randomized phase III trials to help guide the optimal therapy for ncRCC. Some trials for ncRCC have had to stop due to slow accrual. Given this lack of data, patients are encouraged to participate in clinical trials when they are available and appropriate. Below is a summary of the most common systemic therapies in use for ncRCC.

Sunitinib

Single agent sunitinib has been evaluated as part of an expanded access trial as well as several small phase II trials (Table 1). In a single arm phase II clinical trial, 23 patients were given sunitinib 50 mg in cycles of four weeks on followed by 2 weeks off. The trial was stopped early due to slow accrual and the median progression free survival (PFS) was 5.5 months.⁸  In a another phase II trial evaluating both sunitinib and sorafenib, 19 patients with ncRCC were given sunitinib – median PFS was 11.9 months in the papillary arm and 8.9 months in the chromophobe arm.⁹ The largest of these studies was reported by Gore et al, which included 588 ncRCC patients who received sunitinib as part of the expanded access study encompassing 4564 RCC patients who received sunitinib.¹⁰ In their study, 11% of patients had an objective response and median PFS was 7.8 months. Some trials have stratified outcomes by histological subtypes such as chromophobe or papillary, and one trial reported results broken down by type 1 papillary RCC vs type 2 papillary RCC11. Overall, most studies demonstrated that sunitinib led to a median PFS of about 6-7 months for ncRCC.

Everolimus and Temsirolimus

mTOR inhibitors Everolimus and Temsirolimus have been evaluated by a few phase II trials for ncRCC (Table 2). Everolimus was evaluated in a subgroup of REACT (RAD001 Expanded Access Clinical Trial in RCC) and in RAPTOR (RAD001 in Advanced Papillary Tumor Program in Europe).^15,16 In REACT, 1.3% of patients with ncRCC had a partial response and 49.3% had stable disease.¹⁵ In RAPTOR, the median progression free survival (mPFS) was 4.1 months and median OS was 21.4 months. For patients with chromophobe RCC, mTOR directed therapy may be especially effective – case reports show partial responses and stable disease to both Everolimus or Temsirolimus.^17,18 This may be due to the hypothesis that a high number of chromophobe RCC’s have PI3K-mTOR pathway activation as well as frequent TSC1/TSC2 mutations which may sensitize these tumors to mTOR inhibition.¹⁹ 

Sunitinib vs Everolimus

Sunitinib and everolimus have also been examined head to head. The largest trial was ASPEN (Everolimus versus sunitinib for patients with metastatic non-clear-cell renal cell carcinoma), a multicenter open-label, randomized phase II trial which randomized 108 patients to receive either sunitinib or everolimus.²² The primary endpoint of this study was progression free survival. The majority of patients had papillary histology (65%). Median overall survival was 13.2 months in the everolimus group and 31.5 months in the sunitinib group. However, overall survival was not statistically different between the two treatment groups (HR 1.12, 95%CI 0.7-2.1, p=0.6). A second study, ESPN (Everolimus Versus Sunitinib Prospective Evaluation in Metastatic Non–Clear Cell Renal Cell Carcinoma) came to a similar conclusion and found that the median overall survival was 16.2 months with sunitinib and 14.9 months with everolimus (p=0.18).²³

While overall survival between everolimus and sunitinib were not statistically different for the unselected cohorts, ASPEN did find differences in objective responses between the different subtypes, suggesting that each subtype of ncRCC may respond differently to therapies. In ASPEN, 24% (8/33) of papillary RCCs achieved a partial or complete radiographic response on sunitinib compared with 5% of patients on everolimus (2/37). Interestingly, clinical outcomes after receipt of either sunitinib or everolimus also varied based on risk stratification. Patients with good or intermediate risk had improved median progression free survival (mPFS) with first line sunitinib than everolimus. However, patients with poor risk had improved PFS with everolimus over sunitinib. This is concurrent with the ARCC trial, which also demonstrated improved overall survival with an mTOR inhibitor (temsirolimus) in poor risk patients with ncRCC.²⁴

A meta-analysis of five studies (ESPN, ASPEN, RECORD3, ARCC, and SWOG1107) found a nonstatistical trend favoring sunitinib over everolimus for ncRCC but does note that there is considerable patient heterogeneity in these small studies and there was no statistical difference in PFS between these two therapies.²⁵ In the absence of clinical trial options, sunitinib is a reasonable first line choice for treatment naïve patients with ncRCC, especially for those with papillary RCC or MSKCC good risk RCC.

Special Populations

29

Future Direction

A number of active clinical trials are in progress, investigating various MET inhibitors as well as checkpoint inhibitors for ncRCC (Table 3). Preliminary data suggest that PD-1 or PD-L1 blockade may have some activity in this population.^30,31 Given the dearth of data and rarity of ncRCC, it is important to consider these patients for clinical trials, whenever possible.

Published Date: November 29th, 2018

Adjuvant targeted therapy

Tyrosine kinase inhibitors (TKIs) quickly became standard of care for patients with metastatic renal cell carcinoma following their introduction in the early 2000s. They have subsequently been investigated as adjuvant therapy in 4 published randomized trials to our knowledge. In addition, the SORCE trial was presented at ESMO 2019 at the end of September 2019.

Kidney cancer is a broad, encompassing term that borders on colloquial. While most physicians are referring to renal cell carcinoma when they say “kidney cancer”, a number of other benign and malignant lesions may similarly manifest as a renal mass. Considering only the malignant causes, kidney cancers may include renal cell carcinoma, urothelium-based cancers (including urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma), sarcomas, Wilms tumor, primitive neuroectodermal tumors, carcinoid tumors, hematologic cancers (including lymphoma and leukemia), and secondary cancers (i.e. metastases from other solid organ cancers).

Epidemiology

In the United States, cancers of the kidney and renal pelvis comprise the 6th most common newly diagnosed tumors in men and 10th most common in women.¹ In 2018, an estimated 65,340 people will be newly diagnosed with cancers of the kidney and renal pelvis in the United States. In men, this comprises 42,680 estimated new cases in 2018 representing 5% of all newly diagnosed cancers. In women, 22,660 new cases are anticipated in 2018 representing 3% of all newly diagnosed cancers. Additionally, 14,970 people are expected to die of kidney and renal pelvis cancers in 2018 in the United States, with this being the 10^th most common cause of oncologic death among men.

In Europe, results are similar. In 2018, the incidence of kidney cancer is estimated at 136,500 new cases representing 3.5% of all new cancer diagnoses.² This corresponds to an estimated age standardized rate (ASR) of 13.3 cases per 100,000 population. As in the United States, the incidence of kidney and renal pelvis cancers is higher among men (incidence 84,9000, 4.1% of all cancers, ASR 18.6 per 100,000) than women (incidence 51,600, 2.8% of all cancers, ASR 9.0 per 100,000). Correspondingly, 54,700 people were estimated to die of kidney and renal pelvis cancers in Europe in 2018, accounting for 2.8% of all oncologic deaths. The age standardized mortality rate was 4.7 deaths per 100,000 population. Again, death from kidney and renal pelvis cancer was more common among men (mortality 35,100, 3.3% of oncologic deaths, ASR 7.1 per 100,000) than among women (mortality 19,600, 2.3% of oncologic deaths, ASR 2.7 per 100,000). Interestingly, within Europe, there is considerable variation in the incidence and mortality of kidney and renal pelvis cancer between countries.²

While the aforementioned data have already demonstrated that gender is strongly associated with the risk of both diagnosis of and death from kidney and renal pelvis cancers, age also importantly moderates this risk. Among patients in the United States, the probability of developing kidney and renal pelvis cancer rises nearly ten fold from age <50 to age >70 years.¹


Thus, kidney cancer is predominantly a disease of older adults, with the typical presentation being between 50 and 70 years of age. However, over time, rates of diagnosis of kidney cancer have increased fastest among patients aged less than 40 years old.³

In the United States, kidney cancers are more common among African Americans, American Indians, and Alaska Native populations while rates are lower among Asian Americans.⁴ Worldwide, the highest rates are found in European nations while low rates are seen in African and Asian countries.⁴

The vast majority of patients have localized disease at the time of presentation. According to Siegel et al., 65% of all patients diagnosed with kidney and renal pelvis tumors between 2007 and 2013 had localized disease at the time of presentation while 16% had regional spread and 16% had evidence of distant, metastatic disease.¹ This is in large part due to incidental diagnosis due to the increased use of ultrasonography and computed tomography in patients presenting with abdominal distress. In fact, 13 to 27% of abdominal imaging studies demonstrate incidental renal lesions unrelated to the reason for the study⁵ and approximately 80% of these masses are malignant.⁶ Dr. Welch and colleagues demonstrated elegantly that the use of computed tomography is strongly related to the likelihood of undergoing nephrectomy, likely due to detection of renal masses. Thus, with the increasing utilization of abdominal imaging, the incidence of kidney cancer has increased by approximately 3 to 4% per year since the 1970s.

Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common kidney cancer. A number of histological subtypes have been recognized including conventional clear cell RCC (ccRCC), papillary RCC, chromophobe RCC, collecting duct carcinoma, renal medullary carcinoma, unclassified RCC, RCC associated with Xp11.2 translocations/TFE3 gene fusions, post-neuroblastoma RCC, and mucinous tubular and spindle cell carcinoma. Conventional ccRCC comprises approximately 70-80% of all RCCs while papillary RCC comprises 10-15%, chromophobe 3-5%, collecting duct carcinoma <1%, unclassified RCC 1-3%, and the remainder are very uncommon.

Histologically, most of these tumors are believed to arise from the cells of the proximal convoluted tubule given their ultrastructural similarities. Renal medullary carcinoma and collecting duct carcinoma, relatively uncommon and aggressive subtypes of RCC, are believed to arise more distally in the nephron.

Familial RCC Syndromes

While the vast majority of newly diagnosed RCCs are sporadic, hereditary RCCs account for approximately 4% of all RCCs. Due in large part to the work of Dr. Linehan and others, the understanding of the underlying molecular genetics of RCC have progressed significantly since the early 1990s. These insights have led to a better understanding of both familial and sporadic RCCs.

Von Hippel-Lindau disease is the most common cause of hereditary RCC. Due to defects in the VHL tumor suppressor gene (located at 3p25-26), this syndrome is characterized by multiple, bilateral clear cell RCCs, retinal angiomas, central nervous system hemangioblastomas, pheochromocytomas, renal and pancreatic cysts, inner ear tumors, and cystadenomas of the epididymis. RCC develops in approximately 50% of individuals with VHL disease. These tumors are characterized by an early age at the time of diagnosis, bilaterality, and multifocality. Due in large part to improved management of the CNS disorders in VHL disease, RCC is the most common cause of death in patients with VHL.

Hereditary papillary RCC (HPRCC) is, as one would expect from the name, associated with multiple, bilateral papillary RCCs. Due to an underlying constitutive activation of the c-Met proto-oncogene (located at 7q31), these tumors also present at a relatively early age. However, overall, these tumors appear in general to be less aggressive than corresponding sporadic malignancies.

In contrast, tumors arising in hereditary/familial leiomyomatosis and RCC (HLRCC), due to a defect in the fumarate hydratase (1q42-43) tumor suppressor gene, are typically unilateral, solitary, and aggressive. Histologically, these are typically type 2 papillary RCC, which has a more aggressive phenotype, or collecting duct carcinomas. Extra-renal manifestations include leiomyomas of the skin and uterus and uterine leiomyosarcomas which contribute to the name of this sydrome.

Birt-Hogg-Dube, due to defect in the tumor suppressor folliculin (17p11), is associated with multiple chromophobe RCCs, hybrid oncocytic tumors (with characteristics of both chromophobe RCC and oncocytoma), oncocytoma. Less commonly, patients with Birt-Hogg-Dube may develop clear cell RCC or papillary RCC. Non-renal manifestations include facial fibrofolliculomas, lung cysts, and the development of spontaneous pneumothorax.

Tuberous sclerosis, due to defects in TSC1 (located at 9q34) or TSC2 (16p13), may lead to clear cell RCC. More commonly, it is associated with multiple benign renal angiomyolipomas, renal cystic disease, cutaneous angiofibromas, and pulmonary lymphangiomyomatosis.

Succinate dehydrogenase RCC, due to defects in the SDHB (1p36.1-35) or SDHD (11q23) subunits of the succinate dyhydrogenase complex, may lead to a variety of RCC subtypes including chromophobe RCC, clear cell RCC, and type 2 papillary RCC. Extra-renal manifestations including benign and malignant paragangliomas and papillary thyroid carcinoma. In general, these tumors exhibit aggressive behaviour and wide surgical excision is recommended.

Finally, Cowden syndrome, due to defects in PTEN (10q23) may lead to papillary or other RCCs in addition to benign and malignant breast tumors and epithelial thyroid cancers.

Etiologic Risk Factors in Sporadic RCC

While numerous hereditary RCC syndromes exist, they account for only 4% of all RCCs. However, many sporadic RCCs share similar underlying genetic changes including VHL defects in ccRCC and c-Met activation in papillary RCC. A number of modifiable risk factors associated with RCC have been described.⁴

The foremost risk factor for the development of RCC is cigarette smoking. According to both the US Surgeon General and the International Agency for Research on Cancer, observational evidence is sufficient to conclude there is a causal relationship between tobacco smoking and RCC. A comprehensive meta-analysis of western populations demonstrated an overall relative risk for the development of RCC of 1.38 (95% confidence interval 1.27 to 1.50) for ever smokers compared to lifetime never smokers.⁷ Interestingly, this effect was larger for men (RR 1.54, 95% CI 1.42-1.68) than for women (RR 1.22, 95% CI 1.09-1.36). Additionally, there was a strong dose response relationship: compared to never smokers, men who smoked 1-9 cigarettes per day had a 1.6x risk, those who smoked 10-20 per days had a 1.83x risk, and those who smoked more than 21 per day had a 2.03x risk. A similar trend was seen among women. Notably, the risk of RCC declined with increasing durations of abstinence of smoking. Smoking appears to be preferentially associated with the development of clear cell and papillary RCC.⁸ In addition to being associated with increased RCC incidence, smoking is associated with more aggressive forms of RCC, manifest with higher pathological stage and an increased propensity for lymph node involvement and metastasis at presentation.⁹ As a result, smokers have worse cancer-specific and overall survival.⁹

Second, obesity is associated with an increased risk of RCC. While this risk was historically felt to be higher among women, a more recent review demonstrated no such effect modification according to sex.¹⁰ In a meta-analysis of 22 studies, Bergstrom et al. estimated that each unit increase of BMI was associated with a 7% increase in the relative risk of RCC diagnosis.

Third, hypertension has been associated with an increased risk of RCC diagnosis, with a hazard ratio of 1.70 (95%CI 1.30-2.22) in the VITAL study.¹¹ Interestingly, in an American multiethnic cohort, this effect appeared to be larger among women (RR 1.58, 95% CI 1.09-2.28) than in men (RR 1.42, 95% CI 1.07-1.87).¹² Again, as with obesity, there appears to be a dose-effect relationship between severity of hypertension and the risk of RCC diagnosis.¹³

Fourth, acquired cystic kidney disease (ACKD) appears to be associated with a nearly 50x increase risk of RCC diagnosis.¹⁴ ACKD occurs in patients with end-stage renal disease on dialysis. These changes are common among patients who have been on dialysis for at least 3 years.¹⁴ Interestingly, the risk of RCC appears to decrease following renal transplantation.

Finally, a number of other putative risk factors have been described. These lack the voracity of data that the aforementioned four have. Such risk factors include alcohol, analgesics, diabetes, and diet habits.⁴

Published Date: November 20th, 2018

Tumor biology

Pathology

Histologic subgroups

Clinical presentation of RCC

Screening for RCC

Staging of RCC

1. Clinical characteristics:
   1. Performance status
   2. Systemic symptoms
   3. Symptomatic (vs. incidental) presentation
   4. Anemia
   5. Thrombocytosis
   6. Hypercalcemia
   7. Elevated lactate dehydrogenase
   8. Elevated erythrocyte sedimentation rate
   9. Elevated C-reactive protein
   10. Elevated alkaline phosphatase
2. Tumor anatomic characteristics:
   1. Tumor size
   2. Venous extension
   3. Contiguous invasion of adjacent organs (i.e. T4 stage)
   4. Adrenal involvement (i.e. T4 or M1 stage)
   5. Lymph node metastasis (i.e. N1 stage)
   6. Presence and burden of metastatic disease (i.e. M1 stage)
3. Tumor histologic characteristics:
   1. Histologic subtype
   2. Presence of sarcomatoid differentiation
   3. Nuclear grade
   4. Presence of histologic necrosis
   5. Vascular invasion
   6. Invasion of perinephric or sinus fat
   7. Invasion of collecting system
   8. (post-operative) surgical margin status

Treatment of RCC (localized)

As has been highlighted in the accompanying article on the Epidemiology and Etiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6^th most common newly diagnosed tumors in men and 10th most common in women.¹ With the increasing use of abdominal imaging, a growing number of small renal masses are being detected. In fact, 13 to 27% of abdominal imaging studies demonstrate incidental renal lesions unrelated to the reason for the study² and approximately 80% of these masses are malignant.³Thus, a large number of small, incidentally-detected renal masses are now being diagnosed. Due to the increase in diagnosis of small renal masses and the general predilection for diagnosis of renal tumors in older adults (typically diagnosed between age 50 and 70 years), the paradigm for treatment of renal tumors has focused on minimally invasive approaches and nephron sparing in the past few years.

According to the American Urological Association guidelines on the management of stage 1 renal tumors, nephron sparing surgery (partial nephrectomy) is recommended.⁴ However, renal mass ablation is considered an alternative, particularly among the elderly and comorbid.⁴ Renal ablation may be undertaken by percutaneous approaches (nonsurgical) or through laparoscopic or open approaches.

Rationale for Focal Therapy

As with any tumor site, focal ablative therapies offer several potential advantages to traditional surgical approaches. First, focal ablative therapies are less physiologically demanding on the patient than extirpative surgery. As a result, these may often be performed as ambulatory day surgical procedures with a much shorter convalescence and fewer complications when compared to laparoscopic partial nephrectomy.⁵ Second, renal mass ablation is associated with comparable post-operative renal function when compared to partial nephrectomy.^5,6 Third, while laparoscopic partial nephrectomy is a technically challenging operation, requiring advanced laparoscopic skills for tumour resection and renal reconstruction,⁷ focal ablation (either via laparoscopic or percutaneous approach) allows minimally-invasive treatment of renal tumors with relative technical simplicity.⁵ Finally, renal mass ablation may be accomplished by a variety of approaches including open, laparoscopic, and percutaneous approaches.

While long-term data are lacking, intermediate term data (with a median follow-up of approximately 3.5 years) suggest that cancer control is similar between renal tumor ablation (using laparoscopic cryotherapy) and minimally-invasive partial nephrectomy.⁶

Indications for Focal Therapy of Renal Tumors

Treatment choice in the management of small renal masses depends on a complex interplay of patient preference, tumor characteristics, host (patient) factors including age and comorbidity, and the expertise/ability of the treating physician. A number of indications have been well-recognized for the use of renal tumor ablation. Ablation is indicated for patients with small renal tumors who are: poor surgical candidates or at high risk of renal insufficiency. Patients may be at risk of renal insufficiency due to underlying nephron-threatening conditions such as diabetes or hypertension, due to a solitary kidney (either congenital or due to prior nephrectomy), or due to oncologic factors such as bilateral tumors or hereditary syndromes which predispose to recurrent, multifocal tumors.

However, given the good outcomes of renal mass ablation in the treatment of small renal masses among these patients, a number of authors have now advocated the use of renal mass ablation in otherwise healthy patients.⁸

Approaches to Focal Therapy

Non-surgical focal therapy refers to a therapeutic strategy, rather than a specific treatment modality. A number of different focal therapy modalities have been employed in the treatment of small renal masses. Foremost among these are cryoablation and radiofrequency ablation (RFA).

Prior to ablation, the American Urologic Association guidelines recommend biopsy of the renal mass either prior to ablation or at the time of treatment.⁹

Cryotherapy

Cryoablation, also known as cryotherapy, is the therapeutic use of extremely cold temperature. While first employed in the treatment of breast, cervical, and skin cancers, cryoablation has subsequently been used in the treatment of a variety of benign and malignant conditions. Initially, liquified air was used, then solidified carbon dioxide, liquid oxygen, liquid nitrogen, and finally argon gas. Today, the majority of commercially available systems rely on argon gas.

It wasn’t until Onik et al. identified that the cryogenic ice-tissue interface was highly echogenic on ultrasound that an accurate, controlled treatment of intra-abdominal malignancies could be undertaken.¹⁰ Today, cryotherapy of renal tumors is undertaken under real-time imaging.

Ablation during cryoablation occurs during both the freezing and thawing phases of the treatment cycle. During freezing, the rapid decrease in temperature immediately adjacent to the probe causes the formation of intracellular ice crystals which lead to mechanical trauma to plasma membranes and organelles and subsequent cell death through ischemia and apoptosis.¹¹ More distal to the probe, a slower freezing process occurs in which extracellular ice crystals form, causing depletion of extracellular water and inducing an osmotic gradient which causes intracellular dehydration. During the thaw cycle, extracellular ice crystals melt leading to an influx of water back into the cells, resulting in cellular edema. In addition to these cellular effects, the freezing cycle results in injury to the blood vessel endothelium resulting in platelet activation, vascular thrombosis and tissue ischemia. The result of these process is coagulative necrosis, cellular apoptosis, fibrosis and scar formation. Due to evidence that multiple freeze-thaw cycles led to larger areas of necrosis, the current treatment paradox suggests a double freeze-thaw cycle.

For optimal cellular death, the preferred target temperature for cryotherapy is at or below -40o C. As temperatures at the edge of the ice ball are 0o C, most authors suggest that the ice ball extends at least 5 or 10mm beyond the edge of the target lesion. In some cases, this will require the use of multiple probes.

Radiofrequency Ablation

In contrast to cryotherapy which utilizes freeze-thaw cycles to induce cellular damage, radiofrequency ablation (RFA) relies upon radiofrequency energy to heat tissue until cellular death. Using monopolar alternating electrical current at a frequency of 450 to 1200 kHz, RFA induces vibrations of ions within the tissue which leads to molecular friction and heat production. The resulting increased intracellular temperature leads to cellular protein denaturation and cell membrane disintegration. The success of RFA treatment depends on the power delivered, the resulting maximal temperature achieved, and the duration of ablation.

A number of variations in RFA delivery have been described: temperature- or impedance-based guidance, single or multiple tines, “wet” vs “dry” ablation, and mono- or bi-polar electrodes.

Unlike cryoablation which relies upon real-time imaging guidance, RFA may be guided by either temperature-based or impedance-based monitoring. Systems which rely on temperature-based guidance measure temperature at the tip of the electrode. However, they do not measure temperature within the surrounding tissue. Systems which rely on impedance-based guidance measure the resistance to alternating current (the impedance). These systems are calibrated to achieve a predetermined impedance level. There is no data to support the superiority of either of these approaches. For temperature-based systems, the target is 105o C with a minimum of 70o C during the heating cycle. For impedance-based systems, the target is 200 to 500 ohms, which is achieved by progressively increasing the power beginning from 40-80W to 130-200W at a rate of 10W/minute.

A number of studies have demonstrated that multi-tine electrodes are associated with more complete tissue necrosis and improved treatment outcomes.¹²

In addition to the guidance approach and number of tines, RFA technology may be stratified according to “wet” vs. “dry” approach. Through the tissue ablation process, tissue desiccation leads to charring which can increase impedance. This in turn increases the resistance to the current emanating from the electrode and limits the size of the ablation field. A “dry” approach functions within these limitations and cannot treat more than 4cm with a single electrode. In contrast, a “wet” approach continuously infuses saline through the probe tip. This cools the tissue and prevents the tissue charring. As a result, larger ablation zones are possible.

Finally, energy delivery may be either through monopolar or bipolar electrodes. The benefit of bipolar electrodes is both increased temperature generation¹³ and a larger treatment field.¹⁴

The efficacy of RFA is affected not only by the characteristics of the tissue being treated but also by the surrounding tissues. For example, large vessels may dissipate heat and result in relative undertreatment of adjacent tissues.

Monitoring following Focal Therapy

The definition of treatment success following renal mass focal ablation has been controversial. Currently, radiographic assessment utilizing computed tomography or magnetic resonance imaging is considered an accepted measure of treatment effect.¹⁵ Typically, this is performed 4-12 weeks following treatment. However, some rely on post-ablation biopsy to confirm treatment success though this is not well accepted.

The most reliable radiographic marker of successful ablation is the lack of contrast enhancement, corresponding to complete tissue destruction.¹⁶ Persistent enhancement is considered incomplete treatment and re-treatment or an alternative treatment strategy may be warranted. Alternatively, subsequent enhancement on surveillance imaging in an area with prior loss of enhancement suggests local recurrence.¹⁷ Many tumors following cryoablation have a significant reduction in tumor size while this is uncommon following RFA.

The AUA guidelines recommend contrast enhanced CT or MUI at 3 and 6 months following treatment and then each year for the following 5 years.⁹

Oncologic Outcomes

Long-term outcomes are lacking for renal ablation techniques. The summary data from the AUA guidelines panel suggests local recurrence free rates of approximately 90% for patients undergoing cryoablation and 87% for patients undergoing RFA.⁴ Outcomes between cryoablation and RFA appear to be comparable. Compared to partial nephrectomy, the available data suggest higher rates of local recurrence despite shorter follow-up. However, metastasis-free survival and cancer-specific survival appear to be comparable.

Complications

Major complications following renal mass ablation are uncommon. Further, percutaneous, nonsurgical ablation has lower complication rates than other approaches.¹⁸ As with oncologic outcomes, complication rates are comparable between RFA and cryoablation. Major urologic complications occurred in 3.3-8.2% of patients undergoing ablation while non-urologic complications occurred in 3.2-7.2%. These rates are lower than extirpative approaches including open or laparoscopic nephrectomy.

The most common complication is pain or paresthesia at the percutaneous access site.¹⁹ The most concerning complications relate to inadvertent injury to intra-abdominal organs. A variety of tumor characteristics including anterior location, proximity to collecting system and those without easy percutaneous access increase the risk of complications when percutaneous ablation is undertaken. Permanent urologic damage including injury to calyces, the ureteropelvic junction, or the ureter is uncommon.²⁰

Hemorrhage is the most common serious complication of cryoablation. This is less common with RFA. Bleeding is more common when multiple probes are used to treat large tumors.²¹

Published Date: November 20th, 2018