First Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma

As previous UroToday Center of Excellence articles have highlighted, clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC). Likely due to its much higher prevalence, the vast majority of systemic therapies for RCC have been investigated among patients with ccRCC.

Second perhaps only to advanced prostate cancer, the metastatic clear cell renal cell carcinoma disease space has undergone rapid and transformational change over the past fifteen years. This rapidly shifting treatment landscape was highlighted recently at the American Society of Clinical Oncology 2019 Annual Meeting:

figure-1-treatment-landscape-metastatic-RCC2x.jpg

Early years: cytokine therapy

It has been recognized for many decades that renal cell carcinoma is an immunologically active tumor. As a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC. Prior to 2005, treatment for metastatic RCC (mRCC) was limited to cytokine therapies (interferon-alfa and interleukin-2).

Interferon-α was one of the first cytokines assessed for the treatment of metastatic ccRCC. Based on early data suggesting a response rate between 10 to 15%5 and comparative data demonstrating a survival benefit compared to other available systemic therapies available at the time6, interferon-alfa retained utilization despite significant toxicity. Further, it was among patients with metastatic RCC receiving interferon-alfa that the Motzer prognostic criteria were derived6. In their seminal paper in the Journal of Clinical Oncology, Motzer and colleagues demonstrated that low Karnofsky performance status, high lactate dehydrogenase, low serum hemoglobin, high corrected serum calcium, and short time from initial RCC diagnosis to start of interferon-alfa therapy (<1 year) could be used to risk-stratify patients with renal cell carcinoma. However, 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 five months in poor-risk patients6.

Other immunologic therapies were explored including interleukin-2. While response rates were similar to interferon-based therapies (~15 to 20%)7, interleukin-2 was distinct in that durable complete responses were observed 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.
Combinations of interferon and interleukin therapies were explored subsequently those these data demonstrated no improvement in overall survival9, with significantly increased toxicity compared to monotherapy with either agent.

A new standard: molecularly targeted agents

Based on work into the molecular biology underlying ccRCC, researchers were led to “rational targeted therapeutics” including targeting of the vascular endothelial growth factor (VEGF) pathway and mammalian target of rapamycin (mTOR). Mammalian target of rapamycin (mTOR) plays a key role in regulating HIF-α, thus modulating the pathway between abnormalities in VHF and proliferation.

Bevacizumab, a humanized monoclonal antibody against VEGF-A, was the first inhibitor of the VEGF pathway used in clinical trials. As is standard in an oncology pathway, it was first tested in patients who had progressed on the current standard of care (cytokine therapy) and subsequently tested in untreated patients. In head-to-head trials against interferon-alfa, the addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival10,11. Today, bevacizumab is uncommonly used as monotherapy in untreated patients but is considered as second-line therapy in patients who have failed prior therapy with tyrosine kinase inhibitors.

Tyrosine-kinase inhibitors also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-β, raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). In 2006, sorafenib was shown to have biologic activity in ccRCC. Subsequent studies demonstrated improvements in progression-free survival compared with placebo in patients who have previously failed cytokine therapy and improvements in tumor regression compared to interferon in previously untreated patients. As highlighted in the Figure above, sorafenib was one the first molecularly targeted agents clinically available. However, despite FDA approval, sorafenib was quickly supplanted by sunitinib as a first-line VEGF inhibitor.

In keeping with the aforementioned oncology pipeline, sunitinib was first evaluated among patients who had previously received cytokine treatment. Subsequently, it was compared to interferon-α in a pivotal Phase III randomized trial12. Among 750 patients with previously untreated, metastatic RCC randomized, median progression-free survival was significantly longer among those who received sunitinib (11 months) than those who received interferon-alfa (5 months; hazard ratio 0.42, 95% confidence interval 0.32 to 0.54). Similar benefits were seen in the overall response rate with subsequent follow-up demonstrating a strong trend towards improved overall survival. In the pivotal trial, patients who received sunitinib had a significantly better quality of life than those who received interferon-alfa12, despite class-based toxicity profile including gastrointestinal events, dermatologic complications including hand-foot desquamation, hypertension, and general malaise. On account of these data, sunitinib is widely used as a first-line treatment of RCC.

Since the approval of sunitinib and sorafenib, there has been the development and subsequent approval of a number of 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 pazopanib13. Axitinib was evaluated first as second-line therapy14 and then in the first-line setting compared to sorafenib15. Among 192 patients with previously untreated ccRCC randomized to axitinib and 96 patients randomized to sorafenib, median progression-free survival was not significantly different (10.1 months and 6.5 months, respectively; hazard ratio 0.77, 95% confidence interval 0.56 to 1.05)15. 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 is therefore not used.

Most recently, a multikinase inhibitor, cabozantinib has been approved for the first-line treatment of mRCC. In the Phase II CABOSUN trial, cabozantinib was compared to sunitinib in the first-line treatment of patients with intermediate or poor-risk mRCC16. Assessing the primary outcome of progression-free survival, the 79 patients randomized to cabozantinib had significantly longer progression-free survival (8.2 months) compared to the 78 randomized to sunitinib (5.6 months; hazard ratio 0.66, 95% confidence interval 0.46 to 0.95). A recent update on this trial utilizing independent progression-free survival (PFS) review demonstrated comparable results (hazard ratio 0.48, 95% confidence interval 0.31 to 0.74)17. Even with an increased follow-up (median 34.5 months), no significant difference in overall survival was demonstrated (26.6 months in patients receiving cabozantinib and 21.2 months in those receiving sunitinib; hazard ratio 0.80, 95% confidence interval 0.53 to 1.21). While this appears to demonstrate a significant benefit to cabozantinib, median survival in the sunitinib arm was lower than may be expected18 which would serve to exaggerate the apparent benefit of cabozantinib.

In parallel to the development, clinical appraisal and utilization of VEGF inhibitors have come the development of mTOR inhibitors. Temsirolimus was the first mTOR inhibitor to reach clinical utility in patients with metastatic RCC. In the Global ARCC Trial, temsirolimus, interferon, and the combination were compared among 626 patients with pre-defined poor-risk metastatic RCC who had not previously received systemic therapy19. Notable compared to many trials in this disease space that have utilized progression-free survival as the primary outcome, overall survival was the primary outcome, with the study powered based on comparisons of the temsirolimus group and the combination group to the interferon-alfa group. Patients who received temsirolimus had significantly improved overall survival compared to those receiving interferon-alfa (hazard ratio 0.73, 95% confidence interval 0.58 to 0.92). Notably, the combination arm did not offer a benefit compared to interferon alone. Unlike temsirolimus which must be administered intravenously, everolimus is an oral agent.

What’s old is new: immunotherapy for RCC

The immunologic basis for the treatment of advanced RCC has been well established, including the aforementioned cytokine therapies. Thus, it should not be surprising that the use of checkpoint inhibitors has demonstrated benefit in patients with metastatic RCC.

First presented at ESMO in the fall of 2017 and subsequently published in the spring of 2018, CheckMate 214 demonstrated an overall survival (OS) benefit for first-line nivolumab plus ipilimumab vs sunitinib20. This trial randomized 1096 patients to the combination immunotherapy approach of nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients). The majority of patients had intermediate or poor-risk disease (n=847). Overall survival was significantly improved in the overall patient population; however, stratified analyses provide more nuanced results. Among the subgroup of patients with intermediate or poor-risk RCC, treatment with nivolumab plus ipilimumab resulted in significantly improved overall response rate, comparable progression-free survival, and significantly improved overall survival. In contrast, among patients with favorable-risk disease, progression-free survival and overall response rate were higher among patients who received sunitinib. Recently, Escudier and colleagues have assessed the efficacy of nivolumab and ipilimumab according to the number of IMDC risk factors21. In keeping with the previously reported differences in the comparative benefit of nivo/ipi versus sunitinib on the basis of risk category (intermediate/poor versus favorable), the authors demonstrated stable overall response rate (ORR) across increasing numbers of IMDC risk factors (from zero to six) for those who received nivolumab and ipilimumab, while the ORR in patients treated with sunitinib decreased with an increasing number of IMDC risk factors.

The next frontier: combinations of targeted therapy and immunotherapy

Shortly after the data from CheckMate214 emerged, the results of IMmotion151 were presented at GU ASCO in the spring of 2018 and subsequently published. This Phase III trial compared first-line atezolizumab + bevacizumab versus sunitinib among 915 patients with previously untreated metastatic RCC22. This regime was active with a significant benefit in progression-free survival (11.2 months versus 7.7 months; hazard ratio 0.74, 95% confidence interval 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%). 

Since the publication of CheckMate214 and IMmotion151, two trials have reported on combinations of checkpoint inhibitors and tyrosine kinase inhibitors: KEYNOTE-426 and JAVELIN Renal 101.

In KEYNOTE-426, 861 patients with metastatic clear cell RCC who had not previously received systemic therapy were randomized to pembrolizumab plus axitinib or sunitinib and followed for the co-primary endpoints of overall survival and progression-free survival23. Similar to CheckMate214, the majority of patients had intermediate or poor-risk disease. While median survival was not reached, patients who received pembrolizumab and axitinib had improved overall survival (hazard ratio 0.53, 95% confidence interval 0.38 to 0.74) and progression-free survival (hazard ratio 0.69, 95% confidence interval 0.57 to 0.84), as well as overall response rate. These results were consistent across subgroups of demographic characteristics, IMDC risk categories, and programmed death-ligand 1 (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 and axitinib or sunitinib24. Again, the preponderance of patients had IMDC intermediate or poor-risk disease. This analysis of the primary endpoints was progression-free survival and overall survival 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 (hazard ratio 0.61, 95% confidence interval 0.47 to 0.79) was improved in patients receiving avelumab and axitinib compared to sunitinib while overall survival did not significantly differ (hazard ratio 0.82, 95% confidence interval 0.53 to 1.28). In the overall study population, progression-free survival was similarly improved, as compared to the PD-L1 positive population (hazard ratio 0.69, 95% confidence interval 0.56 to 0.84).

Dead-ends

Numerous chemotherapeutic agents have been explored in ccRCC. These include 5-FU, gemcitabine, vinblastine, bleomycin, and platinum. Meta-analyses of these data demonstrate poor response25 and thus cytotoxic chemotherapy is not indicated in the treatment of advanced RCC. Similarly, hormonal therapies including medroxyprogesterone have been explored but have no role in the modern management of advanced RCC.

Integration of treatment options for patients with metastatic ccRCC

Due to the rapid proliferation of treatment options in first-line treatment of metastatic clear cell renal cell carcinoma, there is a paucity of direct comparative data. The majority of new agents have been compared to sunitinib which was the standard of care at the time that trials were designed. Due to the lack of comparative data, it may be difficult to ascertain which treatment to offer patients who present in clinic. There are a number of ways to approach this issue. First, one may take a quantitative approach, utilizing the available comparative data in a network meta-analysis; second, one may rely upon eminence, as in expert-informed guidelines; finally, one may rely on individual clinical experience.

Assessing this quantitatively, we have recently performed a network meta-analysis of first-line agents in metastatic RCC26. Assessing agents which are commonly utilized in 2019, we examined 12 relevant trials. Depending on the outcome of interest (progression-free survival, overall survival, or adverse events), the preferred treatment varied. However, pembrolizumab and axitinib appeared to have a high likelihood of being preferred for oncologic outcomes.
Second, considering a panel of expert opinion, the European Association of Urology recently updated its guidelines on the treatment of renal cell carcinoma. Their recommendations are highlighted in the following figure, taken from the EAU guideline:

figure-2-EAU-guidelines-RCC-treatment2x.jpg
Notably, the most recent version of these guidelines alludes to the recently published data but have not yet integrated the role of atezolizumab plus bevacizumab, pembrolizumab plus axitinib, or avelumab plus axitinib in guideline recommendations.

Finally, we may rely on the guidance of individual clinical experience.


What about surgery?
The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma has dramatically changed with the publication of the CARMENA and SURTIME studies. The available evidence suggests that systemic therapy should be prioritized ahead of cytoreductive nephrectomy. However, there remains a role of cytoreductive nephrectomy in select patients.
Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References: 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
2. Welch HG, Skinner JS, Schroeck FR, Zhou W, Black WC. Regional Variation of Computed Tomographic Imaging in the United States and the Risk of Nephrectomy. JAMA internal medicine. 2018;178(2):221-227.
3. 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;17:2530-2540.
4. Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2002;13(9):1460-1468.
5. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(1):289-296.
6. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005(1):CD001425.
7. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am. 1997;3 Suppl 1:S73-78.
8. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
9. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. The New England journal of medicine. 1998;338(18):1272-1278.
10. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(33):5422-5428.
11. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111.
12. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England journal of medicine. 2007;356(2):115-124.
13. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. The New England journal of medicine. 2013;369(8):722-731.
14. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
15. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. The lancet oncology. 2013;14(13):1287-1294.
16. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(6):591-597.
17. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. European journal of cancer. 2018;94:115-125.
18. Buti S, Bersanelli M. Is Cabozantinib Really Better Than Sunitinib As First-Line Treatment of Metastatic Renal Cell Carcinoma? Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(16):1858-1859.
19. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England journal of medicine. 2007;356(22):2271-2281.
20. Escudier B, Tannir NM, McDermott D, et al. LBA5 - CheckMate 214: Efficacy and safety of nivolumab 1 ipilimumab (N1I) v sunitinib (S) for treatment-naive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Annals of Oncology. 2017;28(Supplement 5):621-622.
21. Escudier B, Motzer RJ, Tannir NM, et al. Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214. European urology. 2019.
22. Motzer R, Powles T, Atkins M, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology. 2018;36(Suppl 6S).
23. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2019;380(12):1116-1127.
24. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2019;380(12):1103-1115.
25. Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol. 1995;22(1):42-60.
26. Hahn AW, Klaassen Z, Agarwal N, et al. First-line Treatment of Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. Eur Urol Oncol. 2019;2(6):708-715.

Approach to Adrenal Masses

The small size and, in benign states, almost inconspicuous appearance of the adrenals belies both their physiologic and pathophysiologic complexity. As a result of this complexity, management of adrenal disorders often requires the involvement of endocrinologists, cardiologists, nephrologists, and anesthesiologists in addition to urologists. In this article, we will focus on non-functional and functional adrenal disorders. Though there are pathophysiologic states characterized by decreased adrenal function, these are typically beyond the purview of the urologist.

Brief Overview of Adrenal Physiology

The adrenal is histologically divided into a three zoned cortex and the inner medulla. The adrenal cortex is involved in the multistep process of steroidogenesis. Each region of the cortex (glomerulosa, fasciculata, and reticularis) produces different steroidal end-products (mineralocorticoids, glucocorticoids, and androgens, respectively) as a result of differing ratios and types of enzymes that catalyze steroidogenesis. The adrenal medulla produces catecholamines (norepinephrine, epinephrine, and dopamine) under the control of the sympathetic branch of the autonomic nervous system.

Adrenal Pathology

The differential diagnosis of an adrenal mass is broad, including a number of benign and malignant conditions as summarized in Table 1. In patients with bilateral adrenal masses, the differential diagnosis is somewhat shorter but includes metastases, congenital adrenal hyperplasia, adenomas, lymphoma, infectious causes, hemorrhage, pheochromocytoma, and amyloidosis, and ACTH-dependent Cushing's disease.
table-1-approach-to-adrenal-masses@2x.jpg

In urologic practice, many adrenal masses represent adrenal incidentalomas, masses >1 cm found on imaging performed for other reasons. While incidentally detected, a relatively large proportion (up to 20%) of these lesions may warrant surgical resection.1 Additionally, more than 10% of these lesions will prove to be biologically active. Therefore, metabolic testing (as detailed below) is recommended for all adrenal incidentalomas.2

Primary adrenal malignancies are uncommon. Adrenocortical carcinoma (ACC) has an incidence of less than 2 per million population.3 While there are associated hereditary syndromes, the majority of ACCs are sporadic. ACC may be biochemically functional or non-functional. Among functional lesions, hypercortisolism is the most common.

From an oncologic perspective, metastases are a much more common cause of adrenal lesions than primary adrenal pathology. Primary cancers with a particular predilection for adrenal metastases including melanoma, lung cancer, renal cell carcinoma, breast cancer, and medullary thyroid cancer.4 However, a wide variety of other cancer may also spread to the adrenal. In patients with known extra-adrenal malignancy, a new adrenal mass is likely to represent metastasis in approximately 50% of cases4. Thus, standard functional assessment is advocated.4

While we will not dwell on it further, a brief mention of congenital adrenal hyperplasia is warranted. This is an autosomal recessive congenital condition characterized by low cortisol production as a result of enzymatic defects in the steroidogenesis pathway. Deficiency in 21-hydroxylase is the cause of nearly 95% of cases. Due to a lack of feedback, there is overproduction of ACTH and resulting overproduction of adrenal androgens. This condition is most often diagnosed and managed in childhood, thus, it will be uncommon as a presentation for adults with newly diagnosed adrenal lesions.

Investigation of Adrenal Lesion

With a newly identified adrenal lesion, there are two primary questions which will guide further management. First, could this mass be malignant? Second, is this mass functional? That is, are there any physical signs and symptoms or biochemical evidence of excess hormonal activity that could be attributed to excess secretion of an adrenally derived hormone. 

Imaging is warranted (and likely the reason for assessment) for patients with adrenal lesions. Ultrasound is relatively poor at visualizing and characterizing adrenal lesions. Therefore, axial imaging using CT or MRI is advised. Unenhanced CT scan is the first line test of choice. In more than 70% of cases, it is possible to identify adrenal adenomas on the basis of this test alone. Low attenuation (<10 HU) is the characteristic finding on this study. Enhanced CT with adrenal washout protocols may be used where unenhanced CT is unclear. Adenomas exhibit characteristic rapid enhancement washout after administration of CT contrast. MRI is an alternative to CT scan. Again, there are characteristic findings of adrenal adenomas including a loss of signal intensity of out-of-phase sequences.5

Imaging findings help to guide the answer to the question of whether a given adrenal lesion may be malignant. There is a relationship between the size of an adrenal lesion and the likelihood of malignancy. Thus, all lesions larger than 6 cm should be considered malignant until proven otherwise. Due to diagnostic uncertainty, may would advocate resection for lesions 4 cm or larger.1 Additionally, as the incidence of benign lesions increases with age, additional concern should be taken for younger patients with even small adrenal lesions. On axial imaging, ACC exhibit increase attenuation on non-contrast CT, irregular borders and enhancement, and calcification and necrosis. 

Functional assessment of adrenal lesions begins with history and physical examination. Cushing's syndrome, caused by excess production of glucocorticoids, may present with central obesity, proximal muscle weakness, thinning of the skin, a so-called buffalo hump, or moon facies. Primary hyperaldosteronism, also known as Conn’s disease, may present with hypertension and hypokalemia. In many patients, hypertension is quite severe with mean blood pressures in the range of 180/1106. Pheochromocytomas, which secrete catecholamines, may present with hypertension, arrhythmia, anxiety, headache, pallor, diaphoresis, and tremor. The classic triad comprised headache, episodic sudden perspiration and tachycardia.7 Adrenocortical carcinoma may produce functional syndromes as described above or may also cause mass-related effects including abdominal fullness, back pain, nausea, and vomiting.

Biochemical assays are employed to confirm functional lesions. For Cushing's syndrome, the diagnosis may be confirmed with a 24-hour urinary free cortisol test or a low-dose dexamethasone suppression test. Following diagnosis, a number of subsequent tests may be performed to ascertain the underlying etiology. While these are typically coordinated by an endocrinologist, they will be briefly summarized here. Determination of serum ACTH (adrenocorticotropic hormone) can distinguish ACTH-dependent Cushing’s from ACTH-independent causes. Among patients with elevated ACTH, determination of the anatomic source, whether pituitary or ectopic, can drive further management. However, modern imaging remains relatively insensitive and non-specific for the detection of both pituitary and ectopic sources of ACTH.8,9 Therefore, direct measurement of venous levels of ACTH in the inferior petrosal sinus following CRH stimulation has been accepted to distinguish pituitary and ectopic sources of ACTH.8 High-dose dexamethasone suppression testing is no longer routinely used.8

Due to the underlying pathophysiology, patients must stop mineralocorticoid receptor antagonist antihypertensives prior to investigation for primary hyperaldosteronism. Further, hypokalemia should be corrected. For these patients, it is critical to determine whether this is a primary process or driven by perturbations in renin levels. Thus, determination of the ratio of serum aldosterone to plasma renin activity (PRA) is critical. This is known as the aldosterone to renin ratio (ARR). For patients with a positive ARR screening test, confirmatory testing typically seeks to identify suppression of aldosterone production following sodium loading. Options include fludrocortisone suppression testing, oral sodium loading, and intravenous saline infusion. Other, less commonly utilized, tests include captopril suppression testing, the furosemide-upright test, and the ACTH stimulation test. However, a number of etiologies may contribute to primary hyperaldosteronism including bilateral or unilateral hyperplasia, adenomas, and tumors. Therefore, following confirmation, subtype investigations may be undertaken among patients who are surgical candidates. This is typically performed with cross-sectional imaging. For patients without identified unilateral nodules, adrenal venous sampling may allow lateralization of the lesion. In the case of a non-diagnostic sampling, other optics including nuclear scintigraphy and postural stimulation testing.

Pheochromocytomas are potentially the most worrisome of functional adrenal lesions given the potential for significant cardiovascular instability if they are not recognized prior to intervention. Evaluation of these masses should include both biochemical and radiographic studies. Biochemical studies assess catecholamines and their metabolites including plasma free metanephrines, catecholamines, urinary fractionated metanephrines, total metanephrines, and vanillylmandelic acid. Each of these tests have varying sensitivity and specificity. Today, most advocate testing of plasma free metanephrine levels10 as this is more sensitive than serum levels of catecholamines. For patients with equivocal findings, use of the clonidine suppression test has been suggested by some.11 Chromogranin A is an alternative confirmatory test though the sensitivity is somewhat poor for this function.

As with all adrenal lesions, imaging of pheochromocytoma begins with computed tomography (CT). Unlike adrenal adenomas, pheochromocytoma typically has an increased attenuation (mean 35 HU).12 Magnetic resonance imaging (MRI) is an alternative. Classically, these lesions have a bright signal, termed the "light bulb" sign. Functional imaging may be undertaken using 18F-FDG PET scanning or metaiodobenzylguanidine (MIBG) scintigraphy.

As hereditary lesions account for nearly 1/3 cases of pheochromocytoma, familial testing has been suggested among patients who have a family history, present at age <50 years, have multiple lesions, malignant pheochromocytoma, or bilateral pheochromocytoma.13

Investigations to assess the functionality of adrenal lesions are summarized in Table 2.
table-2-approach-to-adrenal-masses@2x.jpg
Investigation of suspected ACC should assess excesses of glucocorticoids, sex steroids, catecholamines, and mineralocorticoids. The Weiss pathologic criteria are used to distinguish benign and malignant adrenal lesions (Table 3).14 The presence of three or more of these criteria is highly associated with malignancy. 
table-3-approach-to-adrenal-masses.jpg

Treatment of Adrenal Lesions

For patients with small non-functional adrenal lesions with benign imaging findings, surveillance may be appropriate. However, surgery is the mainstay for patients with adrenal lesions. There are particular nuances on the basis of the underlying histology and functional status. In general, laparoscopic adrenalectomy is considered the gold standard as, in experienced hands, oncologic outcomes are equivalent with improved convalescence.

For patients with adrenocortical carcinoma, surgical resection is the standard of care. In these cases, wide margins are critical. Thus, for larger tumors with possible adjacent organ involvement, some authors advocate that these cases should be performed open in order to ensure negative margins given the potential need for adjacent organ resection. Unfortunately, recurrence is common following even aggressive resection. Radiotherapy can be used in an adjuvant setting for patients with positive margins and for treatment of bone or central nervous system metastases. Systemic therapy may be undertaken with mitotane, a synthetic derivative of DDT.

For patients with Cushing's disease, the management varies widely based on underlying etiology. The overall goals included correction of the cortisol excess, restoration of the underlying hormonal axis, and management of the sequelae. Approaches to this, depending on underlying etiology, include weaning of exogenous steroids, transsphenoidal resection of pituitary lesions, unilateral or bilateral adrenalectomy, resection of ectopic sources of ACTH, and medical therapy with blockers of steroidogenesis.

Treatment of primary aldosteronism seeks to control blood pressure and prevent sequelae of hormonal excess. This may be accomplished medically or surgically depending on the underlying cause and patient suitability for operation. Medical treatment may be undertaken with aldosterone receptor antagonists such as spironolactone or eplerenone.

Pheochromocytoma is primarily a surgical disease. However, extensive medical consultation and optimization is required to prevent significant intraoperative cardiovascular complications. Further, these patients are at risk of cardiomyopathy and, therefore, consultation with a cardiologist or anesthesiologist prior to surgery is advisable. Catecholamine blockade is required prior to surgery on pheochromocytoma. Classically, this has been achieved with the non-competitive alpha-blocker phenoxybenzamine. However, selective reversible alpha-blockers including doxazosin or terazosin are alternatives. Following alpha-blockade, beta-blockade may be undertaken due to the risk of reflex tachycardia or arrhythmia.13 An alternative to alpha- and beta-blockade which has been proposed utilized calcium channel blockade.15 Finally, catecholamine synthesis blockade through the use of alpha-methyltyrosine (metyrosine) may be added. In the perioperative period, repletion of the intravascular volume is critical. This may be achieved through liberal consumption of salt and liquid or intravenous resuscitation. Careful postoperative monitoring is key as these patients are at risk for hypotension and hypoglycemia. Additionally, as these lesions have a predilection for recurrence, ongoing monitoring is required.
Written by: Christopher J.D. Wallis, MD, PhD
References:
  1. Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass. The New England journal of medicine 2007;356:601-10.
  2. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med 2003;138:424-9.
  3. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. The Journal of clinical endocrinology and metabolism 2013;98:4551-64.
  4. Lenert JT, Barnett CC, Jr., Kudelka AP, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001;130:1060-7.
  5. Namimoto T, Yamashita Y, Mitsuzaki K, et al. Adrenal masses: quantification of fat content with double-echo chemical shift in-phase and opposed-phase FLASH MR images for differentiation of adrenal adenomas. Radiology 2001;218:642-6.
  6. Young WF, Jr., Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin North Am 1988;17:367-95.
  7. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003;24:539-53.
  8. Porterfield JR, Thompson GB, Young WF, Jr., et al. Surgery for Cushing's syndrome: an historical review and recent ten-year experience. World J Surg 2008;32:659-77.
  9. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet 2006;367:1605-17.
  10. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA : the Journal of the American Medical Association 2002;287:1427-34.
  11. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. The Journal of clinical endocrinology and metabolism 2003;88:2656-66.
  12. Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 2005;185:684-8.
  13. Pacak K. Preoperative management of the pheochromocytoma patient. The Journal of Clinical Endocrinology and metabolism 2007;92:4069-79.
  14. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-9.
  15. Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC. Successful outcomes in pheochromocytoma surgery in the modern era. The Journal of Urology 1999;161:764-7.

The Opioid Crisis in Urology

The United States (U.S.) is currently in an opioid epidemic. Although the U.S. makes up only 4% of the global population, Americans consume 80% of worldwide opioids. Data from the U.S. National Institute on Drug Abuse indicates that 21-29% of patients prescribed opioids for chronic pain misuse them, and 8-12% of patients subsequently develop an opioid use disorder.1 Furthermore, an estimated 4-6% of patients who misuse an opioid prescription transition to heroin; 80% of people who use heroin first previously misused prescription opioids.1 Data from the CDC notes that 55% of patients that abuse opioids obtain them free from a friend or relative, while 17.3% of abusers obtained a prescription from a medical doctor. However, overprescribing of opioids is not a straightforward issue, as clinicians are faced with addressing acute postoperative pain, acute painful disease processes (ie. kidney stones), and chronic pain. This article will review the literature highlighting the opioid crisis in urology, assess non-opioid measures for pain control, and highlight prospective studies in an effort to stem the opioid crisis in urology.

The Opioid Crisis in Urology

A study in 2011 from the University of Utah provided surveys to consecutive patients undergoing surgery during a 3-month time frame to assess perception of pain control, type and quantity of medication prescribed, quantity of leftover medication, refills needed, disposal instructions, and surplus medication disposition.2 Surveys were performed 2 to 4 weeks postoperatively, and with the exception of the investigators, prescribing physicians had no prior knowledge of the study. Among the 586 patients undergoing surgery, 47% participated in the study. Hydrocodone was prescribed most commonly (63%), followed by oxycodone (35%); 86% of the patients were satisfied with pain control. Of the dispensed narcotics, only 58% were consumed, while 12% of patients requested refills. A total of 67% of patients had surplus medication from the initial prescription and an alarming 92% received no disposal instructions for surplus medication. Among patients with leftover medication, 91% kept the medication at home while 6% threw it in the trash, 2% flushed it down the toilet, and less than 1% returned it to a pharmacy. Indeed, the retained surplus of medication provides a readily available source of opioid excess.

In a prospective observational study of 155 opioid naïve patients who underwent a major prostate or kidney operation, investigators conducted a telephone survey 3-4 weeks postoperatively to assess the number of 5 mg oxycodone-equivalents prescribed, opioid use, and disposal.3 Most patients were male (86%), most were married (74%), the median was age 64 (IQR 59-70) years of age, and the majority were Caucasian (84%). Most patients reported social alcohol use (56%), but most denied current tobacco use (77%) or current and/or previous drug use (76%). Opioid prescribing exceeded use from 1.9- to 6.8-fold for all procedural categories. Overall, a total of 4,065 oxycodone-equivalents were prescribed during the study and 60% of pills prescribed went unused, resulting in 2,622 excess pills in the community.

Unfortunately, opioid overprescribing is not limited to the adult population, as it has also been demonstrated in pediatric urology patients. At the University of North Carolina, 117 pediatric urology patients’ parents were contacted with 39% completing a two-week post-operative telephone survey. The three most common pediatric urology procedures were inguinal hernia repair (n = 39), circumcision (n = 27), and cystoscopy (n = 16). Across all procedures, there was an average excess of 9.8 doses prescribed, corresponding to an over-prescription rate of 64%. Among the patients prescribed opioids, 41 (62%) had leftover opioid medication two weeks postoperatively. Thirty-two of 41 (78%) patients did not dispose of their leftover medication. Furthermore, only 13 patients received perioperative counseling on appropriate storage and disposal of opiates. A recent randomized control trial among 202 pediatric patients undergoing otolaryngologic or urologic procedures found that compared with providing only standard postoperative discharge instructions on opioid use, storage, and disposal, also providing a drug disposal bag significantly increased the rate of proper disposal of excess opioids by approximately 20%.4 These results suggest that a greater availability of disposal products may complement ongoing prescribing reduction efforts aimed at decreasing opioid misuse.

There are several reasons for the opioid crisis in urology, namely a culture of overprescribing.5 This may be due to:
  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 rates of opioid dependence and overdose after urological surgery are as follows:

table 1 opiods in urology2x

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

The AUA Quality Improvement Summit took place at AUA headquarters in December 2018 and was divided into four sessions:
  • 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.

The full resources and slides for the AUA Quality Improvement Summit are available at: https://www.auanet.org/education/educational-calendar/quality-improvement-summit

Non-Opioid Measures for Pain Control

Data from Sweden suggests that opioid dependence may be specific to the U.S. Among 25,703 men in the National Prostate Cancer Register of Sweden who underwent radical prostatectomy, 16,368 men (64%) filled an opioid prescription during the 13 months before or after surgery.8 The use of strong opioids increased with time and the use of weak opioids decreased. There were 1.9% of men that had opioid prescriptions during the baseline period, followed by a spike to 59% around the time surgery, which sharply decreased by two months postoperatively. However, thereafter the proportion of men with opioid prescriptions remained slightly higher at 2.2% compared to the baseline before radical prostatectomy. Of chronic late users, 57% were previous users and 43% were new chronic users. Higher cancer risk category, greater comorbidity, unmarried status and low educational level were associated with the risk of new chronic opioid use. Although more than half of male Swedish patients filled an opioid prescription after radical prostatectomy, less than 1% of men became chronic opioid users.

Professor Benjamin Davies from the University of Pittsburgh has been a thought leader and advocate for minimizing opioid prescriptions among patients undergoing urologic procedures, namely advocating for the “No Opioid Robotic Radical Prostatectomy”.9,10 This protocol is as follows:
  • 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
Amid the opioid crisis, there has been an increased focus on increasing the use of regional anesthesia as part of opioid-sparing multimodal analgesia. Tranversus abdominis plane (TAP) block has been shown to improve early and late pain, and reduce opioid consumption after minimally surgery.11 These benefits have indirectly reduced the incidence of postoperative delirium, pneumonia, urinary retention, and falls. Furthermore, compared to epidural analgesia, a TAP block provides similar pain control, has a lower incidence of hypotension, and is associated with a shorter length of stay. A TAP block provides a safe intervention and should be integrated into enhanced recovery protocols for patients undergoing urologic procedures.

Prospective Initiatives

In an effort to evaluate the effect of opioid reduction after radical prostatectomy on post-discharge opioid prescribing, use, and disposal, the ORIOLES trial was designed as a prospective, non-randomized, pre-post interventional trial.12 An evidence-based intervention included a discharge sheet, nursing education, and standardized prescribing guideline; the primary outcome was total oral morphine equivalents used after surgery. Secondary outcomes included opioid prescribing, opioid disposal, need for additional opioid medication, and presence of incisional/post-surgical abdominal pain beyond 30-days. There were 214 men in the pre-intervention arm and 229 men in the post-intervention arm with 100% follow-up. The intervention reduced post-discharge opioid prescribing from 224.3 mg to 120.3 mg (p=0.01), reduced opioid use from 52.1mg to 38.3mg (p<0.01), and increased opioid disposal by 13.5% (p<0.01). Greater post-discharge opioid use was associated with greater prescribing of opioids at discharge, higher body mass index, and use of opioid medication prior to surgery.

From this prospective initiative, the authors demonstrate that a simple, three-component opioid reduction intervention was able to reduce opioid prescribing, reduce opioid use, and increase opioid disposal at 30-days after radical prostatectomy. Importantly, this prescribing guideline met the needs of 84% of patients, while only 2.2% of patients required additional opioid medication for pain. Furthermore, an impressive one-third of patients used no opioid pain medication after discharge.

Investigators from the Mount Sinai School of Medicine have also recently assessed the effect of implementing a nonopioid protocol for patients undergoing robotic-assisted radical cystectomy with extracorporeal urinary diversion.13 Among 52 patients undergoing surgery, patients received a multimodal pain management protocol, including a combination of nonopioid pain medications and regional anesthesia. These patients were compared to 41 patients undergoing robotic cystectomy prior to the implementation of the nonopioid protocol. In this study, the authors found that patients on the nonopioid protocol received a much lower dose of postoperative morphine milligram equivalents (2.5 vs. 44, p < 0.001), with no difference in pain scores. In the non-opioid protocol patients, the median time to regular diet was significantly shorter (4 days vs. 5 days, p = 0.002), and the length of stay was two days shorter compared to the control group (5 days vs. 7days, p < 0.001).

Conclusions

The urologic community has by no means been spared by the current opioid epidemic across the U.S. Several studies in both the adult and pediatric settings have demonstrated overprescribing measures with little to no counseling or options for appropriate disposal of opioids. Several measures are now in place to solve this problem5, including (i) greater utilization and implementation of Prescription Drug Monitoring Programs (PDMPs) to provide alerts to providers to patients who may be filling opiate prescriptions with multiple providers; (ii) CMS has removed the three questions from the HCAHPS survey related to pain control, effective January 2018; (iii) increased utilization of Enhanced Recovery After Surgery (ERAS) pathways as a measure for decreasing intra- and post-operative use of opioids; (iv) each of the 50 states have passed legislation to make readily available naloxone, which rapidly reverses the effects of opioids in the overdose setting; (v) the creation of procedure-specific guidelines for discharge opioid recommendations. For example, a Johns Hopkins expert panel assessing 20 common surgical procedures suggest that the ideal range of oxycodone 5-mg tablets prescribed to opioid naïve patients at discharge is 0-1014; (vi) the DEA sponsored “National Rx Takeback” initiative, providing collection sites (primarily pharmacies) for returning opioids. Certainly, the current opioid epidemic is multifactorial. However, judicious prescribing of opioids amongst the urology community is one actionable item that will make a difference for the betterment of our patients.
Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References: References:
1. National Institute on Drug Abuse. Opioid Crisis. 2017. Available at: www.drugabuse.gov/drugs-abuse/opioids/opioid-crisis
2. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011;185(2):551-555.
3. Theisen KM, Myrga JM, Hale N, et al. Excessive Opioid Prescribing After Major Urologic Procedures. Urology. 2019;123:101-107.
4. Lawrence AE, Carsel AJ, Leonhart KL, et al. Effect of Drug Disposal Bag Provision on Proper Disposal of Unused Opioids by Families of Pediatric Surgical Patients: A Randomized Clinical Trial. JAMA Pediatr. 2019:e191695.
5. Theisen K, Jacobs B, Macleod L, Davies B. The United States opioid epidemic: a review of the surgeon's contribution to it and health policy initiatives. BJU Int. 2018;122(5):754-759.
6. Quality improvement guidelines for the treatment of acute pain and cancer pain. American Pain Society Quality of Care Committee. JAMA. 1995;274(23):1874-1880.
7. Shah AS, Blackwell RH, Kuo PC, Gupta GN. Rates and Risk Factors for Opioid Dependence and Overdose after Urological Surgery. J Urol. 2017;198(5):1130-1136.
8. Loeb S, Cazzaniga W, Robinson D, Garmo H, Stattin P. Opioid Use After Radical Prostatectomy: Nationwide, Population Based Study in Sweden. J Urol. 2019:101097JU0000000000000451.
9. Theisen KM, Davies BJ. A Radical Proposition: Opioid-sparing Prostatectomy. Eur Urol Focus. 2019.
10. Pekala KR, Jacobs BL, Davies BJ. The Shrinking Grey Zone of Postoperative Narcotics in the Midst of the Opioid Crisis: The No-opioid Urologist. Eur Urol Focus. 2019.
11. Shahait M, Lee DI. Application of TAP Block in Laparoscopic Urological Surgery: Current Status and Future Directions. Curr Urol Rep. 2019;20(5):20.
12. Patel HD, Faisal FA, Patel ND, et al. Effect of a Prospective Opioid Reduction Intervention on Opioid Prescribing and Use after Radical Prostatectomy: Results of the ORIOLES Initiative. BJU Int. 2019.
13. Audenet F, Attalla K, Giordano M, et al. Prospective implementation of a nonopioid protocol for patients undergoing robot-assisted radical cystectomy with extracorporeal urinary diversion. Urol Oncol. 2019;37(5):300 e317-300 e323.
14. Overton HN, Hanna MN, Bruhn WE, et al. Opioid-Prescribing Guidelines for Common Surgical Procedures: An Expert Panel Consensus. J Am Coll Surg. 2018;227(4):411-418.

Systemic Therapy for Advanced Renal Cell Carcinoma

As highlighted in prior articles on the Etiology and Epidemiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6th most common newly diagnosed tumors in men and 10th most common in women1 and account for an estimated 65,340 people new diagnoses and 14,970 cancer-related deaths in 2018 in the United States. Despite a previously mentioned stage migration due to an increase in incidental detection, a large proportion (up to 35%) of patients present with advanced disease, including metastases.2 Historically, metastatic RCC has been early uniformly fatal, with 10-year survival rates less than 5%.3

As emphasized in the article on Malignant Renal Tumors, clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma (RCC). Likely due to its much higher prevalence, the vast majority of systemic therapies for RCC have been investigated among patients with ccRCC. Historically, treatment for metastatic RCC (mRCC) had been limited to cytokine therapies (interleukin-2 and interferon-alfa). However, the development of tyrosine kinase inhibitors (TKIs), which target vascular endothelial growth factors (VEGF), and mammalian target of rapamycin (mTOR) inhibitors have replaced cytokine-based therapies as the standard of care. More recently, immunotherapy-based approaches using checkpoint inhibitors have demonstrated significant benefits and have joined the repertoire of available agents for patients with metastatic RCC.

Cytokine Therapies for Advanced ccRCC

The host immune system has long been implicated with RCC tumor biology. As a result, modulators of the immune system were among the first therapeutic targets for advanced ccRCC.

Interferon-α was one of the first cytokines assessed for the treatment of metastatic ccRCC. Interferons have a range of biologic functions, including immunomodulation. Early data demonstrated response rates in the range of 10 to 15% for patients treated with interferon-α.4 Compared with other available systemic therapies available at the time, interferon therapy conferred a survival benefit.5

An alternative form of immunologic modulation was examined using interleukin-2. While response rates were similar to interferon-based therapies (~15 to 20%)6, interleukin-2 was distinct in that durable complete responses were observed in approximately 7 to 9% of patients.7 On the basis of these data, high-dose IL-2 was approved by the U.S. Food and Drug Administration (FDA) in 1992. However, IL-2 is associated with considerable toxicity which has limited its widespread utilization. Most worrisome is vascular leak syndrome which leads to intravascular depletion, hypovolemia, respiratory compromise and multi-organ failure. Alternatives to the high-dose intravenous bolus administration were explored but lead to worse oncologic outcomes. Thus, high-dose IL-2 is the only recommended approach for patients undergoing cytokine therapy.

Subsequently, combinations of interferon and interleukin therapies were explored. These demonstrated some improvement in response rate but no difference in overall survival.8 Combination therapy resulted in significantly increased toxicity compared to monotherapy with either agent.

With the introduction of VEGF and mTOR targeting agents, interferon is no longer utilized as first-line therapy. However, IL-2 remains an available, though not widely utilized, option on the basis of its ability to induce durable complete responses which these new agents lack. 

Inhibitors of the VEGF Pathway for Advanced ccRCC

Based on work into the molecular biology underlying ccRCC led to “rational targeted therapeutics” including targeting of the VEGF pathway.

The first inhibitor of the VEGF pathway used in clinical trials was bevacizumab, a humanized monoclonal antibody against VEGF-A. While this approach was first explored in patients who had progressed on cytokine-based therapies, it was soon evaluated head-to-head against interferon in previously untreated patients.9,10 The addition of bevacizumab to interferon resulted in significant improvements in response rate and progression-free survival. Today, bevacizumab is uncommonly used as monotherapy in untreated patients but is considered as second-line therapy in patients who have failed prior therapy with tyrosine kinase inhibitors.

Tyrosine-kinase inhibitors also target the VEGF pathway, through inhibition of a combination of VEGFR-2, PDGFR-β, raf-1 c-Kit, and Flt3 (sunitinib and sorafenib). In 2006, sorafenib was shown to have biologic activity in ccRCC. Subsequent studies demonstrated improvements in progression-free survival compared with placebo in patients who have previously failed cytokine therapy and improvements in tumor regression compared to interferon in previously untreated patients. Despite FDA approval, sorafenib is rarely used as first-line therapy today. More widely used is sunitinib. As with agents discussed, sunitinib was first evaluated among patients who had previously received cytokine treatment. Subsequently, it was compared to interferon-α in a large phase III randomized trial.11 While the initial analysis demonstrated significant improvement in progression-free survival and overall response rate, subsequent follow-up has demonstrated a strong trend towards improved overall survival. On account of these data, sunitinib is widely used as first-line treatment of RCC. 

Tyrosine-kinase inhibitors exhibit a class-based toxicity profile including gastrointestinal events, dermatologic complications including hand-foot desquamation, hypertension, and general malaise. However, quality of life appears to be better with these agents than with interferon.11 

Subsequently, a number of more targeted tyrosine kinase inhibitors have been developed with the goal to decrease the toxicity of this treatment strategy. Such agents include pazopanib, axitinib, and tivozanib. Comparative data of pazopanib and sunitinib have demonstrated non-inferior oncologic outcomes with decreased toxicity among patients receiving pazopanib.12 Axitinib was evaluated as second-line therapy compared to sorafenib among patients who had previously received sunitinib, bevacizumab, temsirolimus, or cytokine therapy. Axitinib was associated with improved progression-free survival; on the basis of these data, this agent was approved for second-line therapy of metastatic RCC.13 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 is therefore not used.

Most recently, a multikinase inhibitor, cabozantinib, has been approved for the first-line treatment of mRCC. In the phase II CABOSUN trial, cabozantinib demonstrated improved progression-free survival compared to sunitinib.14 However, these results have proven controversial, with a number of concerns raised including a potential exaggerated effect due to the poor efficacy of sunitinib compared to what would be expected based on previous reports.15

Despite the efficacy of VEGF targeted therapies, resistance to VEGF-inhibition almost inevitably results. Therefore, research into the development of these resistance mechanisms and ways to target these pathways has been undertaken. Agents including nintedanib and dovitinib have been explored though these are not yet in routine practice.

Inhibitors of mTOR for Advanced ccRCC

Mammalian target of rapamycin (mTOR) plays a key role in regulating HIF-α, thus modulating the pathway between abnormalities in VHF and proliferation. Two analogous of sirolimus have demonstrated efficacy in treating advanced RCC, temsirolimus and everolimus.

A three-arm trial comparing temsirolimus, interferon, and the combination was undertaken among patients with pre-defined poor risk disease who had not previously received systemic therapy for RCC.16 This demonstrated improvements in progression-free survival and overall survival for patients receiving temsirolimus. Notably, the combination arm did not offer a benefit compared to interferon alone. Unlike temsirolimus which must be administered intravenously, everolimus is an oral agent. Among patients progressing on sunitinib and/or sorafenib, everolimus demonstrated significantly improved progression-free survival compared to placebo.17

Checkpoint Inhibitors for Advanced ccRCC

The immunologic basis for treatment of advanced RCC has been well established, including the aforementioned cytokine therapies. Recently, immune checkpoint inhibitors have been examined in the treatment of advanced RCC. Two particular regimes warrant focus – nivolumab and ipilimumab and atezolizumab.

First presented at ESMO in the fall of 2017 and subsequently published in the spring of 2018, CheckMate 214 demonstrated an overall survival (OS) benefit for first-line nivolumab plus ipilimumab vs. sunitinib.18 More details regarding this study may be found in the UroToday coverage of ESMO 2017. In short, among the subgroup of patients with intermediate or poor-risk RCC, treatment with nivolumab plus ipilimumab resulted in significantly improved overall response rate, comparable progression-free survival, and significantly improved overall survival.

Similarly, first presented at GU ASCO in the spring of 2018 and subsequently published, IMmotion151 reported a progression-free survival (PFS) benefit for first-line atezolizumab + bevacizumab vs. sunitinib.19 This regime was active with a significant benefit in progression-free survival among the whole cohort of patients, as well as a subset of PD-L1+ patients. More details regarding this study may be found in the UroToday coverage of GU ASCO 2018.

These trials are notable in that they demonstrated improved outcomes in first-line treatment, compared to the current standard of care, sunitinib.

Other Agents for Advanced ccRCC

Numerous chemotherapeutic agents have been explored in ccRCC. These include 5-FU, gemcitabine, vinblastine, bleomysin, and platinums. Meta-analyses of these data demonstrate poor response20 and thus cytotoxic chemotherapy is not indicated in the treatment of advanced RCC. Similarly, hormonal therapies including medroxyprogesterone have been explored but have no role in modern management of advanced RCC.

Treatment of Advanced non-ccRCC

There is a relative dearth of data for treatment of advanced non-clear cell RCC. Therefore, patients with these tumors may receive agents on the basis of their activity in ccRCC. However, VEGF-receptor inhibitors have been shown to have relatively low activity in patients with papillary RCC.21 Responses were somewhat better in patients with chromophobe RCC. Temsirolimus and everolimus appear to have some activity in patients with non-clear cell histology. Similarly, nivolumab monotherapy appears to have biologic activity in patients with non-ccRCC.22

Integration of treatment options for patients with advanced RCC

With so many active agents available for the treatment of advanced RCC, it may be difficult to ascertain which treatment to offer patients who present in clinic. There are a number of ways to approach this issue – first, one may take a quantitative approach, utilizing the available comparative data in a network meta-analysis; second, one may rely upon eminence, as in expert-informed guidelines; finally, one may rely on individual clinical experience. In this setting, all three options are available.

First, assessing this in a quantitative fashion, we performed a network meta-analysis of agents for the treatment of advanced RCC.23 While there are limitations to this approach including the reliance on the assumption of transitivity between studies, interesting conclusions may be drawn. First, assessing progression-free survival, we found that it was highly likely (91% chance) that cabozantinib provided the greatest benefit. However, when assessing overall survival, nivolumab plus ipilimumab had the highest likelihood of being the preferred treatment choice. Finally, when assessing adverse events, it was highly likely that nivolumab plus ipilimumab had the most favorable toxicity profile.

Second, considering a panel of expert opinion, the European Association of Urology updated their guidelines on the treatment of renal cell carcinoma recently. Their recommendations are highlighted in the following figure, taken from the EAU guidelines:
diagram-systemic-therapy@2x.jpg

Finally, we may rely on the guidance of individual clinical experience. Anil Kapoor, MD who has extensive experience in the treatment of both localized and advanced RCC, offered his treatment approach recently to UroToday.


 
Written by: Christopher J.D. Wallis, MD, PhD
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
  2. 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;17:2530-2540.
  3. Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2002;13(9):1460-1468.
  4. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(1):289-296.
  5.  Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005(1):CD001425.
  6. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am. 1997;3 Suppl 1:S73-78.
  7. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
  8. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. The New England journal of medicine. 1998;338(18):1272-1278.
  9. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2008;26(33):5422-5428.
  10. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111.
  11. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England journal of medicine. 2007;356(2):115-124.
  12. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. The New England journal of medicine. 2013;369(8):722-731
  13. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
  14. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2017;35(6):591-597
  15. Buti S, Bersanelli M. Is Cabozantinib Really Better Than Sunitinib As First-Line Treatment of Metastatic Renal Cell Carcinoma? Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2017;35(16):1858-1859.
  16.  Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England journal of medicine. 2007;356(22):2271-2281.
  17. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-456.
  18.  Escudier B, Tannir NM, McDermott D, et al. LBA5 - CheckMate 214: Efficacy and safety of nivolumab 1 ipilimumab (N1I) v sunitinib (S) for treatment-naive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Annals of Oncology. 2017;28(Supplement 5):621-622.
  19.  Motzer R, Powles T, Atkins M, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology. 2018;36(Suppl 6S).
  20.  Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol. 1995;22(1):42-60.
  21. Choueiri TK, Plantade A, Elson P, et al. Efficacy of sunitinib and sorafenib in metastatic papillary and chromophobe renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(1):127-131
  22. Koshkin VS, Barata PC, Zhang T, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother Cancer. 2018;6(1):9.
  23. Wallis CJD, Klaassen Z, Bhindi B, et al. First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. European urology. 2018;74(3):309-321.

Adjuvant Systemic Therapy for High Risk Kidney Cancer

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.

Written by: Zachary Klaassen, MD, MSc
References: 1. Patel HD, Gupta M, Joice GA, et al. Clinical Stage Migration and Survival for Renal Cell Carcinoma in the United States. Eur Urol Oncol 2019; 2(4):343-348
2. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016; 387(10032):2008-16.
3. Motzer RJ, Haas NB, Donskov F, et al. Randomized Phase III Trial of Adjuvant Pazopanib Versus Placebo After Nephrectomy in Patients With Localized or Locally Advanced Renal Cell Carcinoma. J Clin Oncol 2017; 35(35):3916-3923.
4. Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med 2016; 375(23):2246-2254.
5. Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. Ann Oncol 2018; 29(12):2371-2378.
6. Haas NB, Manola J, Dutcher JP, et al. Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial. JAMA Oncol 2017; 3(9):1249-1252
7. Sun M, Marconi L, Eisen T, et al. Adjuvant Vascular Endothelial Growth Factor-targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis. Eur Urol 2018; 74(5):611-620.
8. Spek A, Szabados B, Casuscelli J, et al. Adjuvant therapy in renal cell carcinoma: the perspective of urologists. Int J Clin Oncol 2019; 24(6):694-697.
9. Martinez Chanza N, Tripathi A, Harshman LC. Adjuvant Therapy Options in Renal Cell Carcinoma: Where Do We Stand? Curr Treat Options Oncol 2019; 20(5):44.
10. Gleeson JP, Motzer RJ, Lee CH. The current role for adjuvant and neoadjuvant therapy in renal cell cancer. Curr Opin Urol 2019.
11. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update. Eur Urol 2019; 75(5):799-810.
12. Wood C, Srivastava P, Bukowski R, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet 2008; 372(9633):145-54.
13. Aitchison M, Bray CA, Van Poppel H, et al. Final results from an EORTC (GU Group)/NCRI 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 2011; 29(15 (SUPPL)):4505.
14. Tsimafeyeu ID, L., Kharkevich G, Petenko N, et al. Granulocyte-Macrophage Colony-Stimulating Factor, Interferon Alpha and Interleukin-2 as Adjuvant Treatment for High-Risk Renal Cell Carcinoma. J Cancer Sci Ther 2010; 2:157-159.
15. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018; 378(14):1277-1290.
16. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380(12):1103-1115.
17. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380(12):1116-1127.

Treatment of Metastatic Non-Clear Cell RCC

Background 

Kidney cancer is the 12th 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

diagram-1-treatment-non-clear-cell-RCC@2x.jpg

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.
table-1-treatment-non-clear-cell-RCC@2x.jpg

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.
table-2-treatment-non-clear-cell-RCC@2x.jpg

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

It is well recognized that ncRCC is a heterogenous mix of patients which respond differently to therapies. Thus, there have been a few biomarker or histology driven trials looking at specific subsets of ncRCC. For example, for patients with hereditary leiomyomatosis and papillary RCC, a phase II study of 41 patients found that patients treated bevacizumab plus erlotinib had a median PFS of 24.2 months, compared to 7.4 months for patients with sporadic papillary RCC.26 Patients with papillary RCC frequently have MET mutations and a variety of MET inhibitors including crizotinib, savolitinib, and cabozantinib are being evaluated in clinical trials.27-29 For example, in a study of 41 patients with type 1 papillary RCC, of the 4 patients with MET+ tumors, 2 had achieved a partial response and one had stable disease with crizotinib.28 In a study with Savolitinib, another selective MET inhibitor, patients with MET “driven” tumors had a median PFS of 6.2 months, compared with 1.7 months for MET independent tumors.29

table-3-treatment-non-clear-cell-RCC@2x.jpg

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.

Written by: Jason Zhu, MD
References:

1. Motzer R, Jonasch E, Agarwal N. Kidney Cancer: NCCN Evidence Blocks, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. 2017.

2. Chow W-H, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nature Reviews Urology 2010;7:245.

3. Leibovich BC, Lohse CM, Crispen PL, et al. Histological Subtype is an Independent Predictor of Outcome for Patients With Renal Cell Carcinoma. The Journal of Urology 2010;183:1309-16.

4. Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma. Cancer 2000;89:604-14.

5. Shetty A, Matrana MR. Renal Medullary Carcinoma: A Case Report and Brief Review of the Literature. The Ochsner Journal 2014;14:270-5.

6. Durinck S, Stawiski EW, Pavía-Jiménez A, et al. Spectrum of diverse genomic alterations define non–clear cell renal carcinoma subtypes. Nature genetics 2015;47:13.

7. Carlo MI, Khan N, Chen Y, et al. The genomic landscape of metastatic non-clear cell renal cell carcinoma. American Society of Clinical Oncology; 2017.

8. Molina AM, Feldman DR, Ginsberg MS, et al. Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma. Investigational New Drugs 2012;30:335-40.

9. Choueiri TK, Plantade A, Elson P, et al. Efficacy of Sunitinib and Sorafenib in Metastatic Papillary and Chromophobe Renal Cell Carcinoma. Journal of Clinical Oncology 2008;26:127-31.

10. Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. The Lancet Oncology 2009;10:757-63.

11. Ravaud A, Oudard S, De Fromont M, et al. First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)†. Annals of Oncology 2015;26:1123-8.

12. Tannir NM, Plimack E, Ng C, et al. A phase 2 trial of sunitinib in patients with advanced non–clear cell renal cell carcinoma. European urology 2012;62:1013-9.

13. Lee JL, Ahn JH, Lim HY, et al. Multicenter phase II study of sunitinib in patients with non-clear cell renal cell carcinoma. Annals of Oncology 2012;23:2108-14.

14. Shi H-Z, Tian J, Li C-L. Safety and efficacy of sunitinib for advanced non-clear cell renal cell carcinoma. Asia-Pacific Journal of Clinical Oncology 2015;11:328-33.

15. Blank CU, Bono P, Larkin JMG, et al. Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. Journal of Clinical Oncology 2012;30:402-.

16. Escudier B, Molinie V, Bracarda S, et al. Open-label phase 2 trial of first-line everolimus monotherapy in patients with papillary metastatic renal cell carcinoma: RAPTOR final analysis. European Journal of Cancer 2016;69:226-35.

17. Larkin JMG, Fisher RA, Pickering LM, et al. Chromophobe Renal Cell Carcinoma With Prolonged Response to Sequential Sunitinib and Everolimus. Journal of Clinical Oncology 2011;29:e241-e2.

18. Shuch B, Vourganti S, Friend JC, Zehngebot LM, Linehan WM, Srinivasan R. Targeting the mTOR pathway in chromophobe kidney cancer. Journal of Cancer 2012;3:152.

19. Maroto P, Anguera G, Roldan-Romero JM, et al. Biallelic TSC2 Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus. Journal of the National Comprehensive Cancer Network 2018;16:352-8.

20. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. The cancer journal from Scientific American 1997;3:S73-8.

21. Koh Y, Lim HY, Ahn JH, et al. Phase II trial of everolimus for the treatment of nonclear-cell renal cell carcinoma. Annals of Oncology 2013;24:1026-31.

22. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. The Lancet Oncology 2016;17:378-88.

23. Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non–clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. European urology 2016;69:866-74.

24. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:2271-81.

25. Fernández-Pello S, Hofmann F, Tahbaz R, et al. A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma. European urology 2017;71:426-36.

26. Srinivasan R, Su D, Stamatakis L, et al. 5 Mechanism based targeted therapy for hereditary leiomyomatosis and renal cell cancer (HLRCC) and sporadic papillary renal cell carcinoma: interim results from a phase 2 study of bevacizumab and erlotinib. European Journal of Cancer 2014;50:8.

27. Martinez Chanza N, Bossé D, Bilen MA, et al. Cabozantinib (Cabo) in advanced non-clear cell renal cell carcinoma (nccRCC): A retrospective multicenter analysis. American Society of Clinical Oncology; 2018.

28. Schoffski P, Wozniak A, Escudier B, et al. Effect of crizotinib on disease control in patient with advanced papillary renal cell carcinoma type 1 with MET mutations or amplification: Final results of EORTC 90101 CREATE. American Society of Clinical Oncology; 2018.

29. Choueiri TK, Plimack ER, Arkenau H-T, et al. A single-arm biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer (PRCC). American Society of Clinical Oncology; 2017.

30. Moreira RB, McKay RR, Xie W, et al. Clinical activity of PD1/PDL1 inhibitors in metastatic non-clear cell renal cell carcinoma (nccRCC). American Society of Clinical Oncology; 2017.

31. Chahoud J, Campbell MT, Gao J, et al. Nivolumab (nivo) for patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC): A single-institution experience. American Society of Clinical Oncology; 2018.

Malignant Renal Tumors

Renal cancers are common, accounting for an estimated 65,340 new diagnoses and 14,970 attributable deaths in 2018 in the United States.1 In the article, "Epidemiology and Etiology of Kidney Cancer" both topics are discussed at great length. Despite a large number of histologic tumors which may occur in the kidney, renal cell carcinoma (RCC) is the most prevalent histology.

Tumor biology

Research into the molecular genetics of hereditary RCC has yielded many insights which contribute to the treatment of sporadic RCCs. An understanding of the function of the von Hippel Lindau protein led to the identification of the importance of vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways. Identification of the importance of VEGF aided in both explaining the significant neovascularity associated with ccRCC and providing a therapeutic target for systemic therapy.

Other molecular insights have significant clinical implications as well. First, RCC expresses multi-drug resistance proteins, energy-dependent efflux pumps. These pumps prevent the intracellular accumulation of chemotherapeutics and contribute to the chemotherapy-resistance of RCC. Second, based on observations of tumor-infiltrating immune cells and neoantigens, RCC is highly immunogenic. Thus, immunotherapies beginning with interleukins and interferon and now immune checkpoint inhibitors are efficacious in RCC.

Unfortunately, none of these insights have to lead to validated diagnostic, prognostic, or predictive biomarkers to date.

Pathology

Renal cell carcinoma tends to form relatively spherical tumors with a surrounding pseudo capsule of compressed adjacent parenchyma and fibrosis. With rare exceptions (collecting duct carcinoma and sarcomatoid variants), RCC tends to be relatively well circumscribed without gross infiltrative features. This allows for local treatment, radiographically-guided approaches such as partial nephrectomy and tumor ablation (see linked article on non-surgical focal therapy of renal tumors). Grading of RCC is undertaken using Fuhrman’s system. While this approach was developed for ccRCC,2 more recent evidence suggests that it is prognostic in papillary RCC as well.3 Fuhrman’s grading system relies on the size and shape of the nucleus and the presence or absence of nucleoli.

table-1-malignant-renal-tumors@2x.jpg


A relatively unique pathological characteristic of RCC is its propensity for the involvement of the venous system. This occurs in nearly 10% of all RCCs, at least in historical series, which is much higher than other tumor types.4

Histologic subgroups

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.

Clear cell RCC is formerly described as “conventional” RCC. These tumors, as mentioned prior, are highly vascular and thus tend to respond well to vascular-targeted agents when systemic therapy is indicated. In general, ccRCC is more aggressive than papillary RCC or chromophobe RCC, even after accounting for stage and grade.5

Papillary RCC, formerly known as “chromophilic” RCC, may be subdivided into type 1 and type 2. Type 1 papillary RCC histologically is characterized by basophilic cells with low-grade nuclei. In contrast, type 2 papillary RCC has eosinophilic cells with high-grade nuclei. Correspondingly, type 1 papillary RCC is less aggressive and portends a more favourable prognosis than type 2 papillary RCC. Papillary RCC exhibits a predilection for multifocality.

Chromophobe RCC is histologically characterized by a perinuclear halo. While chromophobe RCC typically have a good prognosis, those with sarcomatoid features are associated with a poor outcome.6

Collecting duct carcinoma and renal medullary carcinoma are relatively rare variants of RCC which exhibit aggressive behaviour and have poor to dismal prognosis. Renal medullary carcinoma is notably found in patients with sickle cell trait.

Finally, rather than its prior classification as a distinct subtype, sarcomatoid differentiation is now noted as a feature accompanying an underlying histologic characterization.

Clinical presentation of RCC

Historically, RCC was diagnosed on the basis of a classic triad of flank pain, gross hematuria, and a palpable flank mass. However, nowadays most RCCs are diagnosed incidentally during abdominal imaging for a variety of nonspecific abdominal complaints.7 Symptoms may arise due to local tumor growth, hemorrhage, paraneoplastic syndromes, or metastatic disease.

While paraneoplastic syndromes are relatively uncommon in other tumors, these occur in 10-20% of patients with RCC. A wide variety of clinical manifestations due to endocrinologically-active compounds may occur including hypertension, electrolyte dysregulation, and cytokine-driven effects such as weight loss, fever, and anemia.

Screening for RCC

Due in large part to the relatively low incidence of RCC, widespread screening is not advocated.

However, certain populations at a much higher risk of RCC warrant screening. This including patients with end-stage renal disease and acquired renal cystic disease, those with tuberous sclerosis, and those with familial RCC syndromes. Patients with end-stage renal disease are generally recommended to undergo RCC screening upon reaching their third year on dialysis assuming that they do not have other major comorbidities which would be life-limiting.

Staging of RCC

Robson’s staging system was widely used until the 1990s. However, there are numerous limitations including the amalgamation of tumors with lymph node metastases and those with venous involvement as stage III and the omission of tumor size. Thus, the TNM (tumor, node, metastasis) system is now widely used.


table-2-malignant-renal-tumors@2x.jpg


Notably, the involvement of the ipsilateral adrenal gland may be classified at T4 if contiguous or M1 if metastatic. Historically, lymph node involvement had been sub-stratified. However, this did not show the prognostic value. Thus, a single present/absent classification is now used.

As may be implied from the characteristics used in the staging schema, clinical staging involves a thorough history, physical examination, radiographic investigation and laboratory investigations (including liver function tests). Contrast-enhanced abdominal computed tomography and chest radiograph are considered standard imaging approaches.8 MRI may be indicated in patients with locally advanced disease, those with unclear venous involvement, and those for whom CT is contraindicated.8 For patients with suspected inferior vena cava involvement, MRI or multiplanar CT are reasonable imaging approaches.8 Doppler ultrasonography is an alternative. Venacavography is rarely utilized today. In patients with suspected metastatic disease, bone scintigraphy is indicated among those with elevated serum alkaline phosphate, bony pain, or poor performance status.9 Similarly, CT chest is indicated in patients with pulmonary symptoms or an abnormal chest radiograph.

A number of prognostic factors have been described for patients with RCC:10
  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
Pathologic stage is the single most important prognostic factor in RCC.10 Interestingly, tumor size has additional independent prognostic value, beyond that which is conveyed in the tumor stage.11 Among patients with IVC thrombus, direct invasion into the caval wall appears to portend a worse prognosis.12

To date, no biomarkers have been adopted in clinical practice for prognostic or predictive purposes. However, a number of nomograms relying on clinical data have been proposed for risk prediction. They may be useful in predicting tumor histology, recurrence rates, and survival.

Treatment of RCC (localized)

There are a number of accepted treatment options for patients diagnosed with localized RCC. These include radical nephrectomy (whether open, laparoscopic or robotic), partial nephrectomy (whether open, laparoscopic, or robotic), surgical or non-surgical ablation, and active surveillance. The most appropriate treatment strategy will depend on the patient (host) and tumor characteristics.

The ability to distinguish between benign and malignant renal masses is relatively limited on the basis of clinical characteristics. The renal mass biopsy may, therefore, be indicated where the results of this test would modify treatment choices.

Radical nephrectomy was historically the treatment of choice for localized RCC. Partial nephrectomy was initially indicated for patients with imperative indications. However, today, partial nephrectomy is the standard of care for small renal masses. Radical nephrectomy remains indicated for patients with larger tumors and those where partial nephrectomy is not feasible (for example, a tumor in a very central location).13 The primary concern regarding radical nephrectomy is the loss of nephron mass and the corresponding risk of surgically induced chronic kidney disease (CKD). Such CKD may predispose to cardiovascular events and premature mortality. However, the only randomized controlled trial to compare radical and partial nephrectomy (EORTC 30904) demonstrated improved overall survival among patients undergoing radical nephrectomy and decreased rates of cardiovascular events.14 These results have proven controversial and have not dissuaded enthusiasm for partial nephrectomy.

A more fulsome discussion regarding nonsurgical renal mass ablation may be found entitled “Focal therapy for renal tumors.”

Finally, active surveillance has gained acceptance. This approach was first employed among asymptomatic elderly patients who were poor surgical candidates with small, incidentally detected RCCs.15 Subsequent follow-up has demonstrated that small renal masses grow quite slowly (0.1-0.3cm/year). AUA guidelines recommend serial abdominal imaging to both ascertain the growth and monitor for progression.16 Biopsy may be considered in order to inform surveillance strategies. For patients found to have biopsy-proven RCC, a chest radiograph may be added to the annual surveillance testing.

The American Urological Association offers a helpful algorithm to guide treatment decision making in patients with small renal masses
Written by: Christopher J.D. Wallis, MD, PhD
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
  2. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-63.
  3. Sukov WR, Lohse CM, Leibovich BC, Thompson RH, Cheville JC. Clinical and pathological features associated with prognosis in patients with papillary renal cell carcinoma. The Journal of urology 2012;187:54-9.
  4. Skinner DG, Pfister RF, Colvin R. Extension of renal cell carcinoma into the vena cava: the rationale for aggressive surgical management. The Journal of urology 1972;107:711-6.
  5. Deng FM, Melamed J. Histologic variants of renal cell carcinoma: does tumor type influence outcome? The Urologic clinics of North America 2012;39:119-32.
  6. Klatte T, Han KR, Said JW, et al. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urologic oncology 2008;26:604-9.
  7. Almassi N, Gill BC, Rini B, Fareed K. Management of the small renal mass. Transl Androl Urol 2017;6:923-30.
  8. Ng CS, Wood CG, Silverman PM, Tannir NM, Tamboli P, Sandler CM. Renal cell carcinoma: diagnosis, staging, and surveillance. AJR Am J Roentgenol 2008;191:1220-32.
  9. Shvarts O, Lam JS, Kim HL, Han KR, Figlin R, Belldegrun A. Eastern Cooperative Oncology Group performance status predicts bone metastasis in patients presenting with renal cell carcinoma: implication for preoperative bone scans. The Journal of urology 2004;172:867-70.
  10. Lane BR, Kattan MW. Prognostic models and algorithms in renal cell carcinoma. The Urologic clinics of North America 2008;35:613-25; vii.
  11. Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. The Journal of urology 2001;166:63-7.
  12. Zini L, Destrieux-Garnier L, Leroy X, et al. Renal vein ostium wall invasion of renal cell carcinoma with an inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. The Journal of urology 2008;179:450-4; discussion 4.
  13. Nguyen CT, Campbell SC, Novick AC. Choice of operation for clinically localized renal tumor. The Urologic clinics of North America 2008;35:645-55; vii.
  14. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. European urology 2011;59:543-52.
  15. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. The Journal of urology 2008;180:505-8; discussion 8-9.
  16. Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. The Journal of urology 2013;190:407-16.

Epidemiology and Etiology of Kidney Cancer

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 10th 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

table 1 epidemiology kidney cancer2x
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

Written by: Christopher J.D. Wallis, MD, PhD
References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.

2. Ferlay J, Colombet M, Soerjomataram I, et al. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. European journal of cancer 2018.

3. Nepple KG, Yang L, Grubb RL, 3rd, Strope SA. Population based analysis of the increasing incidence of kidney cancer in the United States: evaluation of age specific trends from 1975 to 2006. The Journal of urology 2012;187:32-8.

4. Kabaria R, Klaassen Z, Terris MK. Renal cell carcinoma: links and risks. Int J Nephrol Renovasc Dis 2016;9:45-52.

5. Gill IS, Aron M, Gervais DA, Jewett MA. Clinical practice. Small renal mass. The New England journal of medicine 2010;362:624-34.

6. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. The Journal of urology 2003;170:2217-20.

7. Hunt JD, van der Hel OL, McMillan GP, Boffetta P, Brennan P. Renal cell carcinoma in relation to cigarette smoking: meta-analysis of 24 studies. International journal of cancer Journal international du cancer 2005;114:101-8.

8. Patel NH, Attwood KM, Hanzly M, et al. Comparative Analysis of Smoking as a Risk Factor among Renal Cell Carcinoma Histological Subtypes. The Journal of urology 2015;194:640-6.

9. Kroeger N, Klatte T, Birkhauser FD, et al. Smoking negatively impacts renal cell carcinoma overall and cancer-specific survival. Cancer 2012;118:1795-802.

10. Bergstrom A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer--a quantitative review. British journal of cancer 2001;85:984-90.

11. Macleod LC, Hotaling JM, Wright JL, et al. Risk factors for renal cell carcinoma in the VITAL study. The Journal of urology 2013;190:1657-61.

12. Setiawan VW, Stram DO, Nomura AM, Kolonel LN, Henderson BE. Risk factors for renal cell cancer: the multiethnic cohort. American journal of epidemiology 2007;166:932-40

13. Vatten LJ, Trichopoulos D, Holmen J, Nilsen TI. Blood pressure and renal cancer risk: the HUNT Study in Norway. British journal of cancer 2007;97:112-4.

14. Brennan JF, Stilmant MM, Babayan RK, Siroky MB. Acquired renal cystic disease: implications for the urologist. Br J Urol 1991;67:342-8.

The Current Status of Cytoreductive Nephrectomy

Kidney cancer is the 6th most common malignancy among men and 10th most among women.1 Renal cell carcinoma (RCC) accounts for the vast majority of these tumors. Further details regarding the epidemiology of kidney cancer have been discussed in, "Epidemiology and Etiology of Kidney Cancer." While 20-30% of patients undergoing nephrectomy will develop metastases during follow-up,2 a significant proportion (historically up to 25-30%) of patients with renal cell carcinoma present with metastases at the time of diagnosis.3 More recent estimates suggest that, with stage migration due to an increasing incidental diagnosis of kidney cancer, approximately 15% of patients newly diagnosed with kidney cancer have metastases at the time of diagnosis.1 Historically, patients treated with cytokine-based systemic therapy had a median overall survival of 10 months.3 Therefore, options to improve outcomes for these patients were sought.

The History of Cytoreductive Nephrectomy

The notion of cytoreductive nephrectomy (CN), removal of the kidney and primary tumor in the face of metastatic disease, was based on a series of observations. First, patients treated with the primary tumor in-situ who underwent treatment with interferon fared particularly poorly.2,4 Second, case reports demonstrated that a small number of patients treated with CN experienced regression of their metastatic disease.5,6

As a result, two randomized controlled trials were undertaken to assess the value of CN in the era of cytokine-based therapy. In these two methodologically similar randomized controlled trials, Flanigan et al. and Mickish et al. randomized patients to CN plus interferon vs interferon alone.7 Reported in 2001, among 241 American patients, Flanigan et al. demonstrated a 3-month survival benefit8 whereas, among 83 European participants, Mickish et al. demonstrated a 10-month survival benefit.9 Subsequent pooled analyses showed a strongly statistically significant benefit with overall survival of 13.6 months among patients receiving CN plus interferon and 7.8 months among those receiving interferon alone (difference = 5.8 months, p=0.002).7 On the basis of these data, CN became part of the treatment paradigm for metastatic RCC.

It bears mention that despite the proven survival benefits, the mechanism of CN is unclear. Notably, the response to systemic therapy did not differ in the two pivotal RCTs.7 thus, CN does not potentiate the response to (cytokine-based) systemic therapy. Postulated mechanisms include removal of the “immunologic sink”,4,10 decreased production of cytokines and growth factors by the primary tumor,11-13 delayed metastatic progression,14 and survival benefit from nephrectomy induced azotemia.15

However, shortly after the publication of the randomized data demonstrating the survival benefit to adding cytoreductive nephrectomy to cytokine-based systemic therapy, the introduction of targeted therapies revolutionized the systemic therapy of metastatic RCC. From the aforementioned 10-month median overall survival in the cytokine-era,3 median overall survival for patients receiving a sequential regime of targeted therapies may exceed 40 months.16 Much more detail regarding systemic therapy in advanced RCC is available in the article, "Systemic Therapy for Advanced Renal Cell Carcinoma."

Cytoreductive Nephrectomy in the Targeted Therapy Era

A number of retrospective studies have examined the role of cytoreductive nephrectomy in the context of targeted therapy. Summarized by Bhindi et al. in a recent systematic review,17 these 10 retrospective studies consistently demonstrated a significant survival benefit to cytoreduction. However, the potential for selection bias is significant among these studies, particularly among studies in which it was not possible to quantify the burden of metastatic disease.

The CARMENA trial (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques or, alternatively, Clinical Trial to Assess the Importance of Nephrectomy) provides the only available randomized data on the role of cytoreductive nephrectomy in the targeted therapy era.18 This study has been extensively reported on by UroToday authors including “ASCO 2018: Sunitinib Alone Shows Non-inferiority Versus Standard of Care in mRCC - The CARMENA Study," “ASCO 2018: CARMENA: Cytoreductive Nephrectomy Followed by Sunitinib vs. Sunitinib Alone in Metastatic Renal Cell Carcinoma - Results of a Phase III Noninferiority Trial," and “Nephrectomy in the Era of Targeted Therapy: Takeaways from the CARMENA Trial."

To briefly summarize, CARMENA randomized 450 patients with intermediate or poor-risk confirmed clear cell renal cell carcinoma in a 1:1 fashion to nephrectomy followed by sunitinib or sunitinib alone.18 To be eligible for enrollment in CARMENA, patients had to be naïve to systemic therapy, eligible for treatment with sunitinib and deemed amenable for cytoreductive nephrectomy by their treating surgeon. Using the Memorial Sloan Kettering Cancer Center (MSKCC) risk stratification, these patients had intermediate- or poor-risk disease. Additionally, patients had to have an ECOG performance score of 0 or 1 and no evidence of brain metastasis or have undergone prior local therapy for brain metastasis without evidence of progression for at least 6 weeks. After a median follow-up of 51 months, the median overall survival for patients receiving systemic therapy alone was 18.4 months and was 13.9 months for those patients undergoing cytoreductive nephrectomy followed by sunitinib. The resulting Cox models demonstrated non-inferiority with a hazard ratio of 0.89 (95% CH 0.71 to 1.10) based on an intention to treat analysis. In a per-protocol analysis, the resultant analysis showed comparable results (HR 0.98, 95% CI 0.77 to 1.25). However, in this case, the upper limit of the 95% confidence interval crossed the investigator's pre-specified non-inferiority threshold of 1.20.

A number of nuances regarding CARMENA bear consideration. First, the investigators required eight years at 79 sites to accrue 450 of an initially planned 576 patients. Thus, each institution enrolled fewer than a single patient each year – suggesting either that many potentially eligible patients may not have been enrolled due to either their clinician’s lack of equipoise (and thus unwillingness to leave treatment allocation to chance) or the patients’ own unwillingness to be randomized. The resulting cohort, while having a good performance status (ECOG 0 or 1) and deemed fit for cytoreductive nephrectomy, the enrolled patients had a significantly higher burden of disease that may be expected from population-based American cohorts.19 Second, there was significant cross-over within the study, with a large proportion of patients assigned to sunitinib alone eventually undergoing palliative nephrectomy for symptomatic control. Potentially more concerning, given the proven survival benefit of targeted therapy, are the patients who were not able to receive sunitinib following cytoreductive nephrectomy.

To further address the question of the timing of cytoreductive nephrectomy, the SURTIME trial (Immediate Surgery or Surgery after Sunitinib Malate In Treating Patients with Kidney Cancer (NCT01099423) randomized 99 patients to immediate CN followed by sunitinib, beginning 4 weeks after surgery and continuing for four courses, or three 6-week courses of sunitinib (in the absence of disease progression or unacceptable toxicity) followed by CN followed by 2 courses of adjuvant sunitinib. While significantly underpowered due to poor accrual, the trial reported a 28-week progression-free rate of 42% in the immediate CN arm and 43% in the deferred CN arm (p=0.6).20 Interestingly, intention-to-treat analysis of the secondary outcome of overall survival demonstrated significantly longer survival among patients in the delayed CN arm (median 32.4 months) compared to the immediate CN arm (median 15.1 months) (HR 0.57, 95% CI 0.34 to 0.95).

Since these trials were designed and accrued, a number of additional systemic therapy agents have been approved for first-line therapy in metastatic RCC. Many of these agents have demonstrated superiority to sunitinib.21 While improved overall survival increases the time for patients to develop local symptoms which may warrant surgery, improved systemic therapy is likely to reduce the value of local treatments. Notably, the efficacy of nivolumab and ipilimumab did not differ on the basis of whether the patient had previously undergoing nephrectomy.22

Taken together, CARMENA and SURTIME suggest that systemic therapy should be prioritized over cytoreductive nephrectomy for patients with metastatic RCC. However, the EAU guidelines, while emphasizing the CN is no longer the standard of care, highlight that CN may be considered for select patients including those with an intermediate-risk disease who have a long-term sustained benefit from systemic therapy and those with a good-risk disease who do not require systemic therapy.23
Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
  2. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. European Urology. 2011;60(4):615-621.
  3. 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 : official journal of the American Society of Clinical Oncology. 1999;17(8):2530-2540.
  4. Robertson CN, Linehan WM, Pass HI, et al. Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells. The Journal of urology. 1990;144(3):614-617; discussion 617-618.
  5. Marcus SG, Choyke PL, Reiter R, et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. The Journal of urology. 1993;150(2 Pt 1):463-466.
  6. Snow RM, Schellhammer PF. Spontaneous regression of metastatic renal cell carcinoma. Urology. 1982;20(2):177-181.
  7. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. The Journal of urology. 2004;171(3):1071-1076.
  8. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. The New England journal of medicine. 2001;345(23):1655-1659.
  9. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970.
  10. Spencer WF, Linehan WM, Walther MM, et al. Immunotherapy with interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer with in situ primary cancers: a pilot study. The Journal of urology. 1992;147(1):24-30.
  11. Lahn M, Fisch P, Kohler G, et al. Pro-inflammatory and T cell inhibitory cytokines are secreted at high levels in tumor cell cultures of human renal cell carcinoma. European urology. 1999;35(1):70-80.
  12. Kawata N, Yagasaki H, Yuge H, et al. Histopathologic analysis of angiogenic factors in localized renal cell carcinoma: the influence of neoadjuvant treatment. Int J Urol. 2001;8(6):275-281.
  13. Slaton JW, Inoue K, Perrotte P, et al. Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. Am J Pathol. 2001;158(2):735-743.
  14. Lara PN, Jr., Tangen CM, Conlon SJ, Flanigan RC, Crawford ED, Southwest Oncology Group Trial S. Predictors of survival of advanced renal cell carcinoma: long-term results from Southwest Oncology Group Trial S8949. The Journal of urology. 2009;181(2):512-516; discussion 516-517.
  15. Gatenby RA, Gawlinski ET, Tangen CM, Flanigan RC, Crawford ED. The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. Cancer research. 2002;62(18):5218-5222.
  16. Escudier B, Goupil MG, Massard C, Fizazi K. Sequential therapy in renal cell carcinoma. Cancer. 2009;115(10 Suppl):2321-2326.
  17. Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. European Urology. 2019;75(1):111-128.
  18. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. The New England journal of medicine. 2018.
  19. Arora S, Sood A, Dalela D, et al. Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases. European urology. 2019;75(2):352-353.
  20. Bex A, Mulders P, Jewett M, et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2018.
  21. Wallis CJD, Klaassen Z, Bhindi B, et al. First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. European urology. 2018;74(3):309-321.
  22. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2018;378(14):1277-1290.
  23. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma. European Urology. 2018;74(6):805-809.

Nonsurgical Focal Therapy for Renal Tumors

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 6th 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

Written by: Christopher J.D. Wallis, MD, PhD
References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.

2. Gill IS, Aron M, Gervais DA, Jewett MA. Clinical practice. Small renal mass. The New England journal of medicine 2010;362:624-34.

3. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. The Journal of urology 2003;170:2217-20.

4. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. The Journal of urology 2009;182:1271-9.

5. Desai MM, Aron M, Gill IS. Laparoscopic partial nephrectomy versus laparoscopic cryoablation for the small renal tumor. Urology 2005;66:23-8.

6. Fossati N, Larcher A, Gadda GM, et al. Minimally Invasive Partial Nephrectomy Versus Laparoscopic Cryoablation for Patients Newly Diagnosed with a Single Small Renal Mass. Eur Urol Focus 2015;1:66-72.

7. Aboumarzouk OM, Stein RJ, Eyraud R, et al. Robotic Versus Laparoscopic Partial Nephrectomy: A Systematic Review and Meta-Analysis. European Urology 2012;62:1023-33.

8. Stern JM, Gupta A, Raman JD, et al. Radiofrequency ablation of small renal cortical tumours in healthy adults: renal function preservation and intermediate oncological outcome. BJU international 2009;104:786-9.

9. Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. The Journal of urology 2013;190:407-16.

10. Onik G, Gilbert J, Hoddick W, et al. Sonographic monitoring of hepatic cryosurgery in an experimental animal model. AJR Am J Roentgenol 1985;144:1043-7.

11. Baust JG, Gage AA. The molecular basis of cryosurgery. BJU international 2005;95:1187-91.

12. Rehman J, Landman J, Lee D, et al. Needle-based ablation of renal parenchyma using microwave, cryoablation, impedance- and temperature-based monopolar and bipolar radiofrequency, and liquid and gel chemoablation: laboratory studies and review of the literature. J Endourol 2004;18:83-104.

13. Nakada SY, Jerde TJ, Warner TF, et al. Bipolar radiofrequency ablation of the kidney: comparison with monopolar radiofrequency ablation. J Endourol 2003;17:927-33.

14. McGahan JP, Gu WZ, Brock JM, Tesluk H, Jones CD. Hepatic ablation using bipolar radiofrequency electrocautery. Acad Radiol 1996;3:418-22.

15. Matin SF, Ahrar K, Cadeddu JA, et al. Residual and recurrent disease following renal energy ablative therapy: a multi-institutional study. The Journal of urology 2006;176:1973-7.

16. Matsumoto ED, Watumull L, Johnson DB, et al. The radiographic evolution of radio frequency ablated renal tumors. The Journal of urology 2004;172:45-8.

17. Matin SF. Determining failure after renal ablative therapy for renal cell carcinoma: false-negative and false-positive imaging findings. Urology 2010;75:1254-7.

18. Johnson DB, Solomon SB, Su LM, et al. Defining the complications of cryoablation and radio frequency ablation of small renal tumors: a multi-institutional review. The Journal of urology 2004;172:874-7.

19. Farrell MA, Charboneau WJ, DiMarco DS, et al. Imaging-guided radiofrequency ablation of solid renal tumors. AJR Am J Roentgenol 2003;180:1509-13.

20. Johnson DB, Saboorian MH, Duchene DA, Ogan K, Cadeddu JA. Nephrectomy after radiofrequency ablation-induced ureteropelvic junction obstruction: potential complication and long-term assessment of ablation adequacy. Urology 2003;62:351-2.

21. Lehman DS, Hruby GW, Phillips CK, McKiernan JM, Benson MC, Landman J. First Prize (tie): Laparoscopic renal cryoablation: efficacy and complications for larger renal masses. J Endourol 2008;22:1123-7.

First Line Therapy of Metastatic Clear Cell RCC

Background

Kidney cancer represents 5% of all new cancer diagnoses in the United States, with approximately 64,000 new cases and 14,970 deaths in 2018.1,2 The most common type of kidney cancer is renal cell carcinoma (RCC) and the most common histologic subtype of RCC is clear cell RCC, accounting for over 80% of cases.3 RCC is more common in men than women and typically occurs in the sixth to eighth decade of life.1 Localized kidney cancer can often be cured with definitive surgery, with 5-year survival reaching over 90%.However, for patients with advanced disease, 5-year survival remains poor at 11.7% and much progress is needed to develop novel therapies for advanced RCC.4

Risk Stratification

The current treatment paradigm for metastatic clear cell RCC requires stratification of patients into favorable, intermediate, or poor risk disease. Several validated models for risk stratification exist, including the International Metastatic Renal Cell Carcinoma Database Consortium model (IMDC)5 and Memorial Sloan Kettering Cancer Center model (MSKCC).6 Both criteria include time from diagnosis to systemic treatment of less than one year, performance status, as well as hemoglobin and calcium (Table 1). The main differences between these models are that the MSKCC model includes LDH and the IMDC includes neutrophil and platelet count as unique risk factors. Patients with no risk factors fall into the favorable risk group, patients with one to two risk factors are in the intermediate risk group, and those with three or more risk factors are in the high-risk group for both prognostic models. Contemporary clinical trials have found that drug effectiveness may vary depending on risk stratification which has led the FDA to approve some therapies for only certain risk groups.7 Thus, risk stratification is important for the clinician, not only for discussing prognosis with patients, but also for treatment selection. 
table-1-first-line-therapy-clear-cell-RCC@2x.jpg

Favorable Risk Patients

For patients with no adverse risk factors, sunitinib and pazopanib are the preferred first line treatment options, recommended by both the National Comprehensive Cancer Network (NCCN) as well as the European Association of Urology (EAU).8,9 Sunitinib is an oral multikinase inhibitor which targets vascular endothelial growth factor receptors (VEGFR) and platelet derived growth factor receptors (PDGFR). A phase III trial comparing sunitinib to interferon-α showed that sunitinib significantly improved median progression free survival (11 months vs 5 months) and had a higher overall response rate as well when compared with interferon alfa (31% vs 6%).10 Sunitinib also demonstrated longer overall survival in a follow up study, 26.4 months vs 21.8 months.11 Severe adverse events (grade 3-4 toxicities) were minimal, and the most common adverse events were diarrhea, fatigue, and nausea. Hypertension was one notable side effect of sunitinib, which was not seen with interferon alfa. Based on the data above, sunitinib was granted FDA approval in 2007 and has been the benchmark for many future clinical trials in the mRCC space. 

Pazopanib is another oral multikinase inhibitor, which targets VEGFR-1,2,3, PDGFR- and , and c-KIT.12 Pazopanib was established as a safe and efficacious therapy for mRCC based on a large randomized, placebo controlled trial in patients who were treatment naive or cytokine pretreated.12 In this trial of 435 patients, pazopanib increased progression-free survival (9.2 months vs 4.2 months) compared with placebo, both in the treatment naïve cohort as well as the cytokine pretreated cohort. The objective response rate to pazopanib was 30% and pazopanib was well tolerated. Unique toxicities of pazopanib included notable grade 3 hepatotoxicity  30% of patients had elevated ALT and 21% had elevated AST. These results granted pazopanib FDA approval in October 2009. A subsequent phase III study (COMPARZ) with 1,110 patients compared sunitinib to pazopanib, and pazopanib was found to be noninferior to sunitinib with respect to progression-free survival and overall survival.13 Median overall survival was 28.4 months in the pazopanib arm compared with 29.3 months in the sunitinib arm. In terms of safety, similar percentages of patients in both sunitinib and pazopanib experienced dose interruptions of one week or greater, 44% and 49% respectively. Patients in the pazopanib arm more frequently discontinued therapy based on abnormal liver function tests. Patients taking sunitinib had a higher risk of abnormal hematologic labs including leukopenia, thrombocytopenia, neutropenia, and anemia. 

Additional FDA approved therapies for first line management of favorable risk patients include high dose interleukin 2 (HD IL-2)14-17, interferon plus bevacizumab18, and sorafenib.19 These therapies are less commonly used given their tolerability and toxicity profiles. HD IL-2 deserves special mention here given its ability to induce complete responses in a small subset of patients. A recent abstract describing overall survival from the PROCLAIM database show that of favorable risk patients, median overall survival is 63.3 months and 2 year overall survival is 77.6%.14 Of course, patients who are given HD IL-2 are a very carefully selected robust cohort, and cross-trial comparisons are challenging to make. 

Intermediate and Poor Risk

Per the IMDC and MSKCC prognostic models, patients with one or two risk factors are classified as intermediate risk, and poor risk if they have three or more risk factors. Currently, the two major newcomers in this space are cabozantinib and the combination of ipilimumab and nivolumab.  Cabozantinib is a multikinase inhibitor of VEGFR, MET, and AXL.20 In the phase II CABOSUN study, 157 intermediate or poor risk patients were randomized to cabozantinib or sunitinib. In this population, cabozantinib increased median progression free survival (8.2 months vs 5.6 months) and improved overall response rate (33% vs to 12%) compared with sunitinib. Both sunitinib and cabozantinib had about a 67% grade 3/4 adverse event rate and had a similar toxicity profile, including fatigue, hypertension, and diarrhea. Sunitinib had a lower incidence of hand foot syndrome and weight loss compared with cabozantinib, but higher rates of neutropenia and thrombocytopenia. Given this data, Cabozantinib obtained FDA approval for the front-line treatment of mRCC in December 2017. 

The newest therapy to obtain FDA approval is the combination checkpoint inhibitor duo Ipilimumab and Nivolumab (Ipi/Nivo); it was approved in April of 2018, based on the results of CheckMate214.7 CheckMate 214 was a randomized, open-label trial comparing sunitinib with Ipi/Nivo. 1096 patients were enrolled, of which 847 were intermediate or poor risk. This study had a coprimary endpoint of overall survival, objective response rate, and progression free survival among patients who were intermediate or poor risk. The overall response rate was 42% with ipi/nivo vs 27% with sunitinib, with a complete response rate of 9% vs 1%. Median overall survival has not been reached with ipi/nivo vs 26 months for sunitinib. Progression free survival was 11.6 months for ipi/nivo compared with 8.4 months for sunitinib. 46% of patients receiving ipi/nivo experienced grade 3/4 toxicities compared with 63% of patients receiving sunitinib. The most common grade 3/4 adverse events with ipi/nivo was fatigue, diarrhea, and elevated lipase compared with hypertension, hand-foot syndrome, and increased lipase with sunitinib. 35% of patients required high dose corticosteroids for immune related toxicities with ipi/nivo.  With this data, the European Association of Urology has recommended that ipi/nivo be the new standard of care for patients with intermediate and poor risk disease, and the NCCN has also listed ipi/nivo as a category 1, preferred treatment option for patients with intermediate and poor risk disease.8,9
table-2-first-line-therapy-clear-cell-RCC@2x.png

Future Therapies

Front-line treatment options for mRCC are rapidly evolving.24 Data shown at ASCO and GU ASCO has demonstrated that antiangiogenic agents in combination with checkpoint inhibitors may prolong progression-free survival when compared with kinase inhibitors.25 Several phase III trials exploring this hypothesis are now underway (Table 3). IMmotion 151 is a randomized phase III trial comparing the combination of atezolizumab + bevacizumab vs sunitinib. Progression-free survival was 11.2 months in the intention to treat analysis for patients atezolizumab and bevacizumab, compared with 8.4 months in the sunitinib arm. JAVELIN Renal 100 is investigating avelumab in combination with axitinib and phase I results show a promising overall response rate of 54.5% out of 55 patients.26 KEYNOTE-426 is investigating pembrolizumab in combination with axitinib, compared with sunitinib alone.27 These trials are important and exciting for our patients with mRCC and their future results may alter the standard of care for frontline mRCC.
table-3-first-line-therapy-clear-cell-RCC@2x.png
Written by: Jason Zhu, MD
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians 2018;68:7-30.2018. at https://www.cancer.org/cancer/kidney-cancer/about/key-statistics.html.)
  2. Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ. Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma. Cancer 2000;89:604-14.
  3. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 2.2017, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 2017;15:804-34.
  4. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. The lancet oncology 2013;14:141-8.
  5. 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;17:2530-.
  6. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2018;378:1277-90.
  7. Motzer R, Jonasch E, Agarwal N. Kidney Cancer: NCCN Evidence Blocks, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. 2017.
  8. Powles T, Albiges L, Staehler M, et al. Updated European Association of Urology Guidelines: Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer. European Urology 2018;73:311-5.
  9. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:115-24.
  10. Motzer RJ, Hutson TE, Tomczak P, 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;27:3584-90.
  11. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in Locally Advanced or Metastatic Renal Cell Carcinoma: Results of a Randomized Phase III Trial. Journal of Clinical Oncology 2010;28:1061-8.
  12. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma. New England Journal of Medicine 2013;369:722-31.
  13. Fishman MN, Clark JI, Alva AS, et al. Overall survival (OS) by clinical risk category for high dose interleukin-2 (HD IL-2) treated metastatic renal cell cancer (RCC): Data from PROCLAIM. Journal of Clinical Oncology 2018;36:4578-.
  14. Amin A, White RL. Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a Still-Viable Option? Journal of Kidney Cancer and VHL 2014;1:74-83.
  15. Alva A, Daniels GA, Wong MKK, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunology, Immunotherapy 2016;65:1533-44.
  16. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. Journal of clinical oncology 1995;13:688-96.
  17. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. The Lancet 2007;370:2103-11.
  18. Escudier B, Szczylik C, Hutson TE, et al. Randomized Phase II Trial of First-Line Treatment With Sorafenib Versus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology 2009;27:1280-9.
  19. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. The New England journal of medicine 2015;373:1814-23.
  20. Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144-50.
  21. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. New England Journal of Medicine 2007;356:2271-81.
  22. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of Clinical Oncology 2017;35:591-7.
  23. Zarrabi K, Wu S. Current and emerging therapeutic targets for metastatic renal cell carcinoma. Current oncology reports 2018;20:41.
  24. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC). Journal of Clinical Oncology 2018;36:578-.
  25. Choueiri TK, Larkin JMG, Oya M, et al. First-line avelumab + axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial. Journal of Clinical Oncology 2017;35:4504-.
  26. Rini BI, Powles T, Chen M, Puhlmann M, Atkins MB. Phase 3 KEYNOTE-426 trial: Pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2017;35:TPS4597-TPS.