Kidney Cancer Today COE Articles

Articles

  • Local Tumor Bed Recurrence Following Partial Nephrectomy in Patients with Small Renal Masses - Beyond the Abstract

    Renal cell carcinoma (RCC) affects 64,000 people a year in the United States1. For select patients, partial nephrectomy has become the gold standard as a nephron-sparing alternative to radical nephrectomy2.  As the future of RCC is nonsurgical management options, Wood et al. wanted to further define what characteristics put patients at a higher risk for local tumor bed recurrence. 
    Published July 2, 2018
  • A Multicentered, Propensity Matched Analysis Comparing Laparoscopic and Open Surgery for pT3a Renal Cell Carcinoma: Expert Commentary

    Laparoscopic renal surgery (LRS) has long been recognized for its improvements over open renal surgery for patient quality of life. However, LRS efficiency in terms of oncology and recurrences has yet to be compared. This team attempted to do just that by contrasting ORS and LRS on patients with Pathologic T3a (pT3a).
    Published September 15, 2017
  • 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.
    Published December 6, 2019
  • After Immunotherapy Fails, What's Next?

    (UroToday.com) In conjunction with the Scientific Congress held as part of the American Society of Clinical Oncology’s (ASCO) Annual Meeting in May 2020, an Educational Symposium was convened on August 8 to 10th. In a session entitled “Too Many Choices: How to Select the Best Treatment for Your Patient With Kidney Cancer”, Toni Choueiri, MD, from Dana-Farber Cancer Institute and Harvard Medical School presented a plenary talk discussing the subsequent lines of therapy for patients with metastatic renal cell carcinoma (RCC) who have previously received immunotherapy.
    Published August 11, 2020
  • 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.

    Published Date: January 28th, 2019
    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.

    Published January 29, 2019
  • ASCO 2020: COSMIC-313 Phase III Study of Cabozantinib in Combination with Nivolumab and Ipilimumab in Patients with Previously Untreated Advanced Renal Cell Carcinoma of Intermediate or Poor-Risk

    (UroToday.com) Tyrosine kinase inhibitors and immune checkpoint inhibitors have become standard of care for patients with advanced renal cell carcinoma (RCC). Cabozantinib inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors.

    Published May 30, 2020
  • ASCO 2020: OMNIVORE: Optimized Management of Nivolumab and Ipilimumab in Advanced Renal Cell Carcinoma

    (UroToday.com) Checkmate-214 established combination nivolumab/ipilimumab as an effective first-line therapy for patients with metastatic RCC1. Treatment with nivolumab/ipilimumab begins with an induction phase with 4 cycles of ipi/nivo given every 3 weeks, followed by a maintenance phase with nivolumab given every 2 weeks. This regimen was able to achieve a confirmed objective response rate (ORR) of 42% with a complete response (CR) rate of 9%. However, this was not without toxicity.
    Published May 30, 2020
  • ASCO GU 2019: Beyond First-Line Systemic Therapy for Metastatic Renal Cell Cancer

    San Francisco, CA (UroToday.com) Dr. Heng's presentation focused on second- and third-line therapies for metastatic renal cell carcinoma. In order, to decide which 2nd line therapy patients should receive, there are several determinants. These factors include what prior therapy they received, the overall survival benefit, the cost and reimbursement of the treatment, the associated toxicity and the role of biomarkers in the treatment. The possible choices include: Axitinib, Cabozantinib, Lenvatinib, nivolumab, pazopanib, sunitinib, and tivozanib.
    Published February 18, 2019
  • ASCO GU 2020: A Phase I/II Study of Sitravatinib Combined with Nivolumab in Patients with Advanced Clear Cell Renal Cancer that Progressed on Prior Anti-Angiogenic Therapy

    San Francisco, CA (UroToday.com) The incorporation of combination immunotherapy and immunotherapy/anti-angiogenic therapy combinations has changed the first-line treatment landscape of advanced clear cell renal cell carcinoma (accRCC). In patient who have been previously treated with a VEGF tyrosine kinase inhibitor (TKI), the checkpoint inhibitor nivolumab represents a standard 2nd-line strategy. In the Oral Abstract Session for Renal Cell Carcinoma, Pavlos Msaouel, MD, PhD, of MD Anderson Cancer Center detailed the results of a phase I-II study of sitravatinib combined with nivolumab in patients who have previously progressed on TKI therapy for accRCC.

    Sitravatinib is an orally-available small molecule, multi-targeted TKI. Inhibition of targets such as TAM family, Split family and c-MET is thought to enhance anti-tumor activity through depletion of immunosuppressive cell populations (for example, MDSCs and regulatory T cells) and increasing T cell priming. In a RCC expansion cohort from a phase IB trial of single-agent sitravatinib, a promising 25% conformed objective response rate was observed with 94% achieving clinical benefit and durable responses noted.

    The hypothesis of this study was that sitravatinib could augment nivolumab responses in accRCC. To this end, the study’s primary endpoint was both safety and efficacy (absence of progression within 6 weeks). The patient population included a similar eligibility criteria to CheckMate 025, histologically-confirmed clear cell TCC with disease progression after 1-2 prior lines of TKI therapy and measurable disease. Dose-finding was performed using the sequentially adaptive phase I-II late-onset EffTox strategy. Of note, numerous correlative studies were built into the study design.

    ASCOGU_BaselinePatientCharacteristics.png

    Dr. Msaouel detailed the study cohort of 40 patients, who were predominantly male and intermediate-risk for IMDC criteria. Of note, most patients had 1 prior line of cancer therapy (mostly sunitinib or pazopanib).

    Nivolumab plus sitravatinib showed promising efficacy, with 15/38 (39%) achieving a confirmed objective response and 35/38 (92%) achieving clinical benefit (stable disease or partial response or completed response). Put into historical context, this is promising anti-tumor activity compared to the rate of response of single agents in this setting, such as nivolumab (35%), cabozantinib (17-21%). Furthermore, at a median follow-up of 17.7 months, median overall survival had not been reached with 79% of patients alive. Median duration of treatment (10.3m) compared favorably to historical report of nivolumab alone (4.6 months).

    ASCOGU_MostFrequent_TreatmentAEs.png

    Lastly, Dr. Msaouel noted the safety profile of the combination. Most frequent adverse events included diarrhea, fatigue, liver function test derangement, lipase elevation and proteinuria. The most common high-grade toxicities included lipase/amylase elevation, proteinuria and fatigue. In total 4/40 (10%) patients discontinue treatment due to adverse events. Approximately half the cohort required dose-reduction of sitravatinib due to toxicity, and this occurred mostly in the first 12 weeks. A dose of 120mg is now being explored in other tumor types in combination with nivolumab.

    In summary, this phase I/II study of sitravatinib, a multi-targeted oral TKI, in combination with nivolumab in pre-treated accRCC, showed higher objective response rate and longer PFS than historically reported single-agent nivolumab in this setting. Further studies, including patient-reported outcomes and biological correlatives are underway. This combination represents a promising strategy, however, given that PD-1 inhibition (in combination) is standard 1st-line treatment for this patient population, the role of the combination of sitravatinib plus nivolumab after progression on prior PD-1 inhibitor therapy remains less clear and more data is required.

    Presented by: Pavlos Msaouel, MD, PhD, Medical Oncologist, MD Anderson Cancer Center, Houston, TX

    Written by: Anis Hamid, MBBS, Medical Oncology Research Fellow at Dana-Farber Cancer Institute and Medical Oncologist, PhD candidate, University of Melbourne, Australia (Twitter: @anis_a_hamid) at the 2020 ASCO Genitourinary Cancers Symposium (#GU20), February 13th to 15th, 2020, San Francisco, CA.

    Published February 17, 2020
  • ASCO GU 2020: Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy

    San Francisco, CA (UroToday.com) The role for cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) was established in the cytokine era. In the current era, with more effective therapies (VEGF tyrosine kinase inhibitors [TKI] and immune checkpoint inhibitors [ICI]), the role of CN in metastatic RCC must be reconsidered. A number of studies re-evaluated CN in the VEGF TKI era, all finding it to be associated with improved overall survival. Notably, all of these studies were retrospective and therefore limited by the inherent selection bias of which patients were referred for CN.

    Published February 17, 2020
  • ASCO GU 2020: Overall Survival and Independent Review of Response in CheckMate 214 with 42-month Follow-up: First-line Nivolumab + Ipilimumab versus Sunitinib in Patients with Advanced Renal Cell Carcinoma

    San Francisco, CA (UroToday.com) Data from CheckMate-214 at 17.5 months of minimum follow-up led to approval of combination nivolumab/ipilimumab for first-line treatment of IMDC intermediate/poor risk advanced renal cell carcinoma. This trial showed a statistically significant overall survival benefit relative to sunitinib (HR 0.63, P < 0.001, ~400 patients in each arm). In this talk, Dr. Nizar Tannir reported the extended follow-up data from Checkmate-214 with a minimum follow-up of 42 months.
    Published February 15, 2020
  • Association Between Preoperative Hydration Status and Acute Kidney Injury in Patients Managed Surgically for Kidney Tumours – Beyond the Abstract

    The surgical management of localised kidney cancer by radical or partial nephrectomy is highly efficacious however there are a number of possible adverse effects of renal surgery which need to be considered. Renal impairment is one of these potential sequelae.
    Published September 5, 2018
  • AUA 2022: AUA Guidelines Update: Renal Mass

    (UroToday.com) The 2022 Annual Meeting of the American Urological Association was host to an AUA guidelines update session focused on renal masses, presented by Dr. Steven Campbell, MD, PhD.

    Dr. Campbell began his presentation by stating that the primary focus of these guidelines is clinically localized renal masses suspicious for cancer in adults, including solid enhancing renal tumor and Bosniak 3 and 4 complex cystic renal masses. The literature is updated through January 2021 in this version of the guidelines and updated risk-based surveillance protocols for patients after intervention are merged into this document, whereas previously this was a separate guideline.

    Published May 15, 2022
  • AUA 2022: Management of Incidentally Discovered 3cm Solid Renal Mass Cancer: Panel Discussion

    (UroToday.com) Friday morning at the 2022 AUA kicked off with a panel discussion consisting of thought leaders in the management of incidentally found 3cm solid renal masses. Dr. Costas Lallas, MD moderated the session which began with four-minute presentations from each panelist.

    Published May 14, 2022
  • AUA 2023: Surgical Complications after Robotic Partial Nephrectomy

    (UroToday.com) Alexander Kutikov lead a talk on the surgical complications associated with Robotic Partial Nephrectomy. He starts by highlighting a collaborative review he and I worked on for European Urology that walks through decision making for the management of localized solid renal masses – where a key decision point is the choice to treat the tumor, and at which point, we have to choose between radical nephrectomy, partial nephrectomy, and ablative options. Specifically today, he focuses on the choice to do a partial nephrectomy (PN).

    Published April 30, 2023
  • Cellular and Molecular Features of Clear-Cell Renal Cell Carcinoma Tumors - Expert Commentary

    Clear-cell renal cell carcinoma (ccRCC) represents 75% of renal carcinomas, yet its molecular, cellular, and immune features remain poorly understood. To characterize ccRCC tumors and elucidate factors that contribute to poor response to immune checkpoint inhibitor treatment, Davidson et al. established a high-resolution ccRCC cell atlas using single-cell RNA sequencing.
    Published August 8, 2023
  • Does Reduced Renal Function Predispose to Cancer-specific Mortality from Renal Cell Carcinoma? - Beyond the Abstract

    The arguments in favor of partial nephrectomy (PN) over radical nephrectomy (RN) for patients with localized renal cell carcinoma (RCC) have been diverse and compelling,1 leading many to advocate for PN whenever feasible, even for potentially aggressive tumors.2 However, some patients with tumors with increased oncologic potential and/or high complexity may not be well-served by PN,
    Published June 17, 2021
  • EAU 2019: Minimally-Invasive Partial Nephrectomy: An Operation with Limits

    Barcelona, Spain (UroToday.com) In this session, Professor Kuczyk heeded caution regarding minimally invasive partial nephrectomy for complex surgical cases. Clinically T1b or T2 disease, endophytic or central tumors have greater risk profiles and should likely be performed at higher volume centers by high volume surgeons. Dr. Kuczyk stated that hospitals are putting pressure on surgeons to attract more business by utilizing newer technology or techniques, but that is not without risk.  
    Published March 17, 2019
  • EAU 2019: MUSIC-KIDNEY Collaborative Assesses Patterns of Renal Mass Biopsy

    Barcelona, Spain (UroToday.com) Renal tumor biopsy (RTB) for renal cell carcinoma (RCC), especially for small renal masses, is recommended by international guidelines if the RTB pathology will change treatment management – either favoring surveillance or ablative therapy. Yet, its usage remains relatively low and uptake is sporadic. Its accuracy is reported to be quite high in more recent series but can be very institutional dependent. 
    Published March 22, 2019
  • EAU 2019: Neoadjuvant Therapy in Localized Renal Cell Carcinoma - Who is Going to Benefit?

    Barcelona, Spain (UroToday.com) In this session, Dr. Mir reviewed the role of neoadjuvant therapy in renal cell carcinoma. She reviewed the definition of neoadjuvant therapy, its rationale, how to assess response, the newest data and its future. Neoadjuvant therapy is defined as intervention given prior to primary treatment with the goal of downstaging primary tumors to possibly improve surgical intervention. 
    Published March 17, 2019
  • EAU 2019: Post-Nephrectomy Adjuvant Therapy for Localized Renal Cell Carcinoma: CheckMate 914 Study of Nivolumab + Ipilimumab in Patients at High Risk of Relapse

    Barcelona, Spain (UroToday.com) The current standard for advanced localized renal cell carcinoma (RCC) is nephrectomy. Unfortunately, for better or worse, the series of adjuvant therapy trials in patients with advanced localized RCC with targeted therapies (sutent, sorafenib, axitinib, pazopanib) have been either negative – or slightly positive and associated with significant adverse events.
    Published March 19, 2019
  • EAU 2019: Pre-ablative or Peri-ablative Biopsies: A Comparison of Different Diagnostic Strategies in Small Renal Masses Treated with Ablation

    Barcelona, Spain (UroToday.com) Renal tumor biopsy (RTB) for RCC, especially for small renal masses, is recommended by international guidelines if the RTB pathology will change treatment management – either favoring surveillance or ablative therapy. Yet, its usage remains relatively low and uptake is sporadic. Its accuracy is reported to be quite high in more recent series but can be very institutional dependent. More important, with regards to focal ablative therapy, RTB can either be done at a separate setting from the actual treatment or at the time of treatment itself.
    Published March 22, 2019
  • EAU 2019: The Challenging Landscape in Advanced Renal Cell Cancer Management

    Barcelona, Spain (UroToday.com) Dr. Marc-Oliver Grimm provided an overview of the many changes in the landscape for advanced renal cell carcinoma at the urogenital cancer treatment at a glance session. He started by highlight that the guidelines for advanced kidney cancer have been revamped recently and provided the following two figures based on the: 
    Published March 18, 2019
  • EAU 2020: Immunotherapy Combinations for Intermediate-Poor Risk mRCC: IO + TKI

    (UroToday.com) The virtual EAU 2020 meeting featured a thematic session discussing immunotherapy combinations for intermediate-poor risk metastatic renal cell carcinoma (mRCC). Axel Merseburger, MD, PhD, discussed the utility of combining Immuno-Oncology (IO) treatment with TKIs. Dr. Merseburger notes that according to older versions of the EAU guidelines, the first-line treatment for IMDC intermediate-poor risk patients is ipilimumab plus nivolumab. Additional options (without a strong recommendation) are cabozantinib, sunitinib or pazopanib. In an update of these guidelines (with new data reported recently), the current recommendations for intermediate-poor risk patients is pembrolizumab plus axitinib or ipilimumab plus nivolumab.1 Currently, Dr. Merseburger notes that we have new first-line combination treatments with phase 3 data, including nivolumab plus ipilimumab, axitinib plus pembrolizumab, and axitinib plus avelumab.
    Published July 18, 2020
  • EIKCS 2022: Biomarker Discovery Through Single-cell RNA Sequencing

    (UroToday.com) In the tenth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on biomarker discovery in renal cell carcinoma (RCC), Dr. David Braun discussed the potential of single-cell RNA sequencing to facilitate biomarker discovery. In doing so, he emphasized how single-cell RNA sequencing can improve our understanding of the underlying biology of RCC, with important implications for both biomarker discovery and therapeutics.

    Published April 23, 2022
  • EIKCS 2022: Biomarker Discovery Through TCR Sequencing

    (UroToday.com) In the tenth session of the 2022 International Kidney Cancer Symposium (IKCS): Europe meeting focusing on biomarker discovery in renal cell carcinoma (RCC), Dr. Samra Turajlic presented on the value of T cell receptor (TCR)-related metrics for understanding and predicting the response of immune checkpoint inhibition in clear cell renal cell carcinoma.

    Published April 23, 2022
  • Eosinophilic Solid and Cystic Renal Cell Carcinoma: An Emerging Renal Entity with Distinct Features - Beyond the Abstract

    Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a recently described, emerging renal entity, which demonstrates distinct clinical, pathological and molecular features.1-3 Our recent publication with the collaborators from Brazil highlights the imaging features of two previously undocumented ESC RCC.4  We found two distinct imaging patterns that varied depending on the histopathologic features (solid or cystic predominance). Recognition of the imaging characteristics and pathologic correlation of this novel neoplasm will contribute to its increasing recognition in practice. The true incidence is currently difficult to establish because many of these cases in the past have probably been either misdiagnosed or labeled as “unclassified renal cell carcinoma”. Owing to its very recent description, this entity is currently not included in the 2016 WHO Classification of the tumors of the genitourinary tract.   

    What have we learned so far about ESC RCC? We are currently aware of approximately 60 sporadic ESC RCCs (including our personal files and published cases), collected through a broad international collaboration. About 10% of them occur in patients with documented Tuberous Sclerosis Complex (TSC), but the great majority are sporadic and not associated with TSC.1-3 The patients are typically females exhibiting broad age range; only rare cases have been documented in males. ESC RCC shows a characteristic morphology, with often tan, solid and cystic gross appearance, with cells exhibiting eosinophilic, voluminous cytoplasm demonstrating coarse granular stippling (Fig. 1A-C). These neoplasms are typically solitary, although occasional multifocality was observed. The tumors are frequently relatively small and low stage, although rare cases may show larger size. On Immunohistochemistry, there is frequent CK20 positivity, while CK7 is usually negative or only focally positive (Fig. 1D). ESC RCC demonstrates molecular karyotype profile of a recurring set of genomic alterations, which is different from the currently recognized renal neoplasms.2Frequent copy number gains were found at 16p13-16q23, 7p21 -7q36, 13q14 and 19p12 and frequent copy number losses were documented at Xp11.21 and 22q11.2 Loss of heterozygosity alterations were identified at 16p11.2-11.1, Xq11-13, Xq13-21, 11p11, 9q21-22 and 9q33.2 

    Although great majority of ESC RCC exhibit indolent behavior, two cases have been recently documented with metastatic disease (approximately 3%), which confirms the need for clinical surveillance on an RCC protocol in these patients.5,6 Additional studies are needed to fully characterize this entity, because up to date, there is a limited number of well-documented cases with sufficient follow up. With the growing recognition of this emerging renal entity, we expect that further evidence will be collected to fully validate and establish ESC RCC it as a novel renal neoplasm. 

    Imaging Features of a Novel Neoplasm img1a
    Figure 1: A) Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) shows solid and cystic appearance at low power. B) The septae between the cysts vary in thickness and are composed of eosinophilic (pink) cells, with voluminous cytoplasm; the lining cells often show hobnail arrangement. C) The neoplastic cells typically show coarse cytoplasmic granularity (stippling), consisting of basophilic to purple cytoplasmic granules, which are readily recognizable at higher magnification in all cases. D) Typical immunophenotypic profile found in great majority of ESC RCC includes cytokeratin 20 positivity (shown) and cytokeratin 7 negativity (not shown).

    Written by: Kiril Trpkov, MD, FRCPC Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, Calgary, Alberta, Canada

    References:

    1. Trpkov K, Hes O, Bonert M, et al. Eosinophilic Solid and Cystic Renal Cell Carcinoma: Clinicopathologic Study of 16 Unique, Sporadic Neoplasms Occurring in Women. Am J Surg Pathol 2016;40:60-71.

    2. Trpkov K, Abou-Ouf H, Hes O, et al. Eosinophilic Solid and Cystic Renal Cell Carcinoma (ESC RCC): Further Morphologic and Molecular Characterization of ESC RCC as a Distinct Entity. Am J Surg Pathol 2017;41:1299-308.

    3. Guo J, Tretiakova MS, Troxell ML, et al. Tuberous sclerosis-associated renal cell carcinoma: a clinicopathologic study of 57 separate carcinomas in 18 patients. Am J Surg Pathol 2014;38:1457-67.

    4. Fenelon SS, Santos JMMM, Faraj SF et al. Eosinophilic Solid and Cystic Renal Cell Carcinoma: Imaging Features of a Novel Neoplasm. Urology 2018, Jan 29. pii: S0090-4295(18)30065-7. doi: 10.1016/j.urology. 2018.01.020. [Epub ahead of print]

    5.  Li Y, Reuter VE, Matoso A, et al. Re-evaluation of 33 'Unclassified' Eosinophilic Renal Cell Carcinomas in Young patients. Histopathology  2017, Sep 12. doi: 10.1111/his.13395. [Epub ahead of print] 

    6. McKenney JK, Przybycin C, Trpkov K, Magi-Galluzzi C. Eosinophilic Solid and Cystic (ESC) Renal Cell Carcinomas Have Metastatic Potential. Histopathology 2017 Dec 19. doi: 10.1111/his.13457. [Epub ahead of print]


    Read the Abstract
    Published February 23, 2018
  • 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

    Published Date: November 20th, 2018

    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.

    Published November 20, 2018
  • ESMO 2018: Challenging Established Frontline Therapies in Renal Cancer

    Munich, Germany (UroToday.com) Dr. Laurence Albiges gave a talk on the challenges faced by established frontline therapies in renal cancer. In the ESMO meeting in 2017, the Checkmate 214 trial was presented, which compared sunitinib to Nivolumab + ipilimumab in the treatment of metastatic renal cell carcinoma (mRCC) patients. This trial demonstrated a benefit in favor of the nivolumab + ipilimumab combination in poor and intermediate risk mRCC patients, with median overall survival (OS) that was not reached compared to 26 months in the sunitinib group, p<0.0001. The complete response rate (CR) was 9% vs. 1% in favor of the combination treatment.
    Published October 23, 2018
  • ESMO 2019: A First-in-Human Phase 1/2 Trial of the Oral HIF-2a Inhibitor PT2977 in Patients with Advanced RCC

    Barcelona, Spain (UroToday.com) Hypoxia-inducible factor (HIF)-2α is a transcription factor that is a key oncogenic driver in renal cell carcinoma (RCC) attributed, in 80-90% of patients, to the underlying protein product of von Hippel-Lindau tumor suppressor gene deficiency.1 VHL gene inactivation leads to accumulation of HIF-2α, which heterodimerizes with HIF-1β and activates the transcription of genes associated with tumor progression, such as VEGFA, CCND1, CXCR4, and TGFA2.1 PT2977 is a potent and selective small molecule HIF-2α inhibitor that prevents HIF-2α from heterodimerizing with HIF-1β, blocking the expression of HIF-2α target genes in tumour cells, and inducing regressions in mouse xenograft RCC models. The objective of the current study was to evaluate the efficacy and safety of PT2977 (MK-6482) for the treatment of advanced clear cell RCC, presented at ESMO 2019 by Dr. Eric Jonasch and colleagues.

    In this study, patients with advanced solid tumours were treated with PT2977 in a dose-escalation design to determine the recommended phase II dose. Patients with advanced clear cell RCC who had received at least one prior therapy were enrolled in an expansion cohort at the recommended phase II dose of 120 mg orally once daily.

    ESMO2019_PT2977.png

    There were 55 patients treated with PT2977 120 mg (three in dose escalation; 52 in expansion). The median number of prior therapies was 3 (range 1-9), 73% of patients were intermediate risk and 18% were poor risk by IMDC criteria. As of May 15, 2019, the most common all-grade, all-cause adverse events > 25% were anemia (75%), fatigue (67%), dyspnea (47%), nausea (33%), peripheral edema (29%), and cough (31%). Anemia (26%) and hypoxia (15%) were the most common Grade 3 adverse events and on-target effects of HIF2α inhibition. Discontinuation due to a treatment-related adverse event (AE) was reported in two patients (4%). There were 13 patients (24%) who experienced a confirmed partial response and 31 patients (56%) had stable disease, with a clinical benefit rate of 80%. The median duration of response was not reached and 81.4% of patients experienced response >= 6 months; 16 (29%) of patients continued treatment beyond 12 months. The median progression-free survival (PFS) was 11 months (95% CI 6-17), and the 12-month PFS rate was 49%.

    ESMO2019_median_PFS.png

    Dr. Jonasch’s concluding remarks from this phase I/II trial are as follows:

    • PT2977 is well tolerated and has a favorable safety profile – anemia and hypoxia are on-target toxicities
    • After a median follow-up of 13 months, the clinical activity of PT2977 shows promise for the treatment of heavily pretreated RCC – confirmed response rate of 24%, with 81.4% of patients with response >=6 months
    • A PT2977 monotherapy Phase 3 trial in previously treated advanced RCC patients is planned
    Clinical trial identification

    NCT02974738.

    Presented by: Eric Jonasch, MD, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain

    References:
    1. Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear cell renal cell carcinoma. Nat Genet 2013 Aug;45(8):860-867.

    Published September 30, 2019
  • ESMO 2019: Adjuvant Sorafenib for Renal Cell Carcinoma at Intermediate or High Risk of Relapse, Results from the SORCE Trial

    Barcelona, Spain (UroToday.com) Four large, randomized Phase 3 clinical trials (S-TRAC, ASSURE, PROTECT, and ATLAS) evaluated adjuvant VEGF tyrosine kinase inhibitors in patients with resected renal cell carcinoma (RCC). Only S-TRAC met the primary endpoint of improvement in disease-free survival (DFS). None of these studies demonstrated improvement in overall survival (OS). Dr. Tim Eisen presents the primary efficacy results from the SORCE trial, an international, randomized, double-blind Phase 3 trial that evaluated adjuvant sorafenib for RCC at intermediate or high risk of relapse.

    Published September 28, 2019
  • ESMO 2019: ENTRATA: Randomized, Double-Blind, Phase 2 Study of Telaglenastat + Everolimus vs. Placebo + Everolimus in Patients with Advanced/Metastatic Renal Cell Carcinoma

    Barcelona, Spain (UroToday.com) Altered glucose and glutamine metabolism is a hallmark of renal cell carcinoma (RCC). Abnormal glucose metabolism, known as the Warburg effect, deprives the citric acid cycle (TCA cycle) of critical metabolites. Cancer cells compensate for the Warburg effect by increasing glutamine metabolism to sustain the TCA cycle for growth and proliferation. Glutaminase is a key enzyme in glutamine metabolism and drives proliferation of RCC cells when overexpressed. Telaglenastat is a novel, first-in-clinic, selective glutaminase inhibitor that blocks critical glutamine-dependent pathways and synergizes preclinically with signal transduction inhibitors (eg, everolimus). In a previous phase Ib study in metastatic (mRCC), telaglenastat + everolimus was well tolerated and had encouraging clinical activity – 92% disease control rate and 5.8-month median progression free survival (PFS). During the non-prostate cancer session at the 2019 European Society for Medical Oncology annual meeting (ESMO), Dr. Lee and colleagues presented results of ENTRATA, a randomized phase II study of telaglenastat + everolimus vs. placebo + everolimus in heavily pre-treated mRCC patients.

    Published September 28, 2019
  • ESMO 2019: Patients with Advanced Renal Cell Carcinoma with Sarcomatoid Histology: A Subgroup Analysis on Efficacy and Biomarkers from the Phase 3 JAVELIN Renal 101 Trial of First-Line Avelumab plus Axitinib versus Sunitinib

    Barcelona, Spain (UroToday.com) Sarcomatoid differentiation can occur in all subtypes of renal cell carcinoma (RCC) and is associated with an aggressive phenotype. Sarcomatoid RCC (sRCC) is characterized by immunologic infiltration and has with higher PD-1/PD-L1 on tumor cells and tumor-infiltrating immune cells. JAVELIN Renal 101 demonstrated a significant improvement in progression-free survival (PFS) with avelumab plus axitinib (A + Ax) versus sunitinib (median PFS 13.8 vs 8.4 months, HR 0.69, p < 0.001) in patients with previously untreated clear cell mRCC.1 This abstract reports the efficacy and biomarker results from a post-hoc analysis of patients enrolled in JAVELIN Renal 101 who had sarcomatoid features in their tumor histology.

    The study design is shown below. Eligible patients had treatment-naïve unresectable metastatic RCC (mRCC) with measurable disease. All Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic RCC Database Consortium (IMDC) risk groups were eligible. Patients were randomized 1:1 to A + Ax versus sunitinib and stratified by ECOG performance status and geographic region. Co-primary endpoints were progression-free survival (PFS) and overall survival (OS) in the PD-L1 positive cohort. PFS and OS in the overall cohort was a key secondary endpoint.


    JAVELIN elligibility requirements
























    Of 886 patients with mRCC enrolled in JAVELIN Renal 101, 108 (12.2%) had sarcomatoid components and/or features in their pathology report, 47 in the A + Ax arm and 61 in the sunitinib arm. Baseline characteristics in this subgroup were well-balanced between treatment arms and consistent with the overall trial population. The only notable difference between the two treatment groups in the sRCC population is that the PD-L1 positive status was significantly lower in patients who received A + Ax (72.3%) versus sunitinib (85.2%).

    Patients with sRCC had an improved PFS of 7.0 months in the A + Ax arm compared to 4.0 months in the sunitinib arm (stratified HR 0.57, 0.325-1.003).

    The 12-month OS rate was 83.0% with the combination and 67.0% with sunitinib. The confirmed objective response rate was higher in the A + Ax arm (46.8%) than the sunitinib arm (21.3%). Further, patients in the combination arm had 2.4 months longer median duration of response than those in the sunitinib arm.

    JAVELIN biomarker analyses




















    The investigators reported results of multiple biomarker analyses, which revealed that sRCC tumors had an immunosuppressive tumor microenvironment and higher CD274 and CD8A gene expression. Further, they discovered that approximately 50% of sRCC patients in this cohort had m3 tumors based on the subtype-specific mRNA signatures from molecular analysis of clear cell RCC tumors by the TCGA;2 m3 is the molecular subset of RCC tumors associated with the poorest survival. Similar to results from the overall population, patients with sRCC who had m3 tumors that were also CD8- or CD8A-positive had longer median PFS with A + Ax (6.2 and 8.3 months) than sunitinib (2.9 and 2.8 months). These characteristics may help explain the poorer prognosis of sRCC patients when treated with VEGF inhibitor alone, but comparable response to the overall cohort when treated with A + Ax.

    In conclusion, this study found that patients with sRCC who received A + Ax had PFS and ORR benefit over sunitinib, consistent with the results in the overall trial population. This analysis provides insight into the biology of an aggressive subtype of RCC and suggests a potential new treatment option.

    Presented by: Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology, Director of the Kidney Cancer Center, the Dana-Farber Cancer Institute, Jerome and Nancy Kohlberg Chair, Professor of Medicine, Harvard Medical School, Boston, Massachusetts

    Written by: Jacob Berchuck, MD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, Twitter: @jberchuck at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct, 2019 in Barcelona, Spain 

    References:

    1. Motzer, Robert J., Konstantin Penkov, John Haanen, Brian Rini, Laurence Albiges, Matthew T. Campbell, Balaji Venugopal et al. "Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma." New England Journal of Medicine 380, no. 12 (2019): 1103-1115.
    2. Cancer Genome Atlas Research Network. "Comprehensive molecular characterization of clear cell renal cell carcinoma." Nature 499, no. 7456 (2013): 43.
    Published October 1, 2019
  • ESMO 2019: Tailored Immunotherapy Approach with Nivolumab for Advanced Renal Cell Carcinoma (TITAN-RCC)

    Barcelona, Spain (UroToday.com) In pretreated metastatic renal cell carcinoma (RCC), single agent checkpoint blockade immunotherapy with the PD-1 antibody nivolumab is associated with a response rate of 25% and improvement in overall survival relative to everolimus.1 In the frontline setting, combination immunotherapy consisting of the CTLA-4 antibody ipilimumab (1 mg/kg) with nivolumab (3 mg/kg) is associated with a response rate of 42% and improved survival relative to sunitinib for patients with intermediate or poor risk disease.2 However, combination checkpoint blockade is associated with a relatively high degree of toxicity, with 46% of patients experiencing a grade ≥3 adverse event compared to just 19% with nivolumab monotherapy. In an effort to spare toxicity, investigators carried out TRITON-RCC, a phase II trial of nivolumab in international metastatic RCC database (IMDC) intermediate-high risk mRCC with per-protocol ipilimumab “boosts” for patients who fail to achieve an up-front response to nivolumab.

    Published September 28, 2019
  • ESMO 2022: Adjuvant Nivolumab Plus Ipilimumab vs Placebo for Localized Renal Cell Carcinoma at High Risk of Relapse After Nephrectomy: Results From the Randomized, Phase 3 CheckMate 914 Trial

    (UroToday.com) On Sunday, September 11, 2022, in Presidential Symposium II at the European Society for Medical Oncology (ESMO) Annual Congress, Dr. Motzer presented highly awaited results from the CheckMate 914 trial, examining the role of adjuvant nivolumab and ipilimumab in patients treated with nephrectomy for localized renal cell carcinoma (RCC) at a high risk of relapse.

    Published September 11, 2022
  • ESMO 2022: Do the Results of the Perioperative Renal Cancer Trials Make Any Sense?

    (UroToday.com)  The 2022 European Society of Medical Oncology (ESMO) annual meeting featured a kidney cancer session, including a discussant presentation by Dr. Tom Powles discussing two key abstracts including “IMmotion010: efficacy and safety from the Phase III study of atezolizumab vs placebo as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection” presented by Dr. Axel Bex, and “Phase III RandOmized Study Comparing PErioperative Nivolumab versus Observation in Patients with RCC Undergoing Nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial” presented by Dr. Mohamad Allaf. Dr. Powles notes that the story to date for immune checkpoint inhibition in clear cell renal cancer has been relatively straight forward:

    Published September 10, 2022
  • Exposure to Multiple Lines of Treatment and Survival of Patients With Metastatic Renal Cell Carcinoma: A Real-world Analysis - Beyond the Abstract

    In the past decade, the introduction of new therapeutic agents has improved the survival of patients with metastatic RCC (mRCC). The 5-year survival for RCC has improved from 52% in 1975 to 74% in 2014. 
    Published April 3, 2018
  • 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 time,6 interferon-alfa retained utilization despite significant toxicity. Further, it was among patients with metastatic RCC receiving interferon-alfa that the Motzer prognostic criteria were derived.6 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 patients.6

    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 patients.8 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 survival,9 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 survival.10,11 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 trial.12 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 pazopanib.13 Axitinib was evaluated first as second-line therapy14 and then in the first-line setting compared to sorafenib.15 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 mRCC.16 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 therapy.19 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 sunitinib.20 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 factors.21 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 RCC.22 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 survival.23 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 sunitinib.24 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 RCC.26 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.

    Published Date: March 17th, 2020

    Written by: 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. 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.
    Published March 17, 2020
  • Germline Variants in Renal Cell Carcinoma Patients - Expert Commentary

    Renal cell carcinoma (RCC) accounts for approximately 2% of all cancers. The predisposing risk factors for RCC are still not well-defined. Understanding germline genetic predisposition for RCC in different ethnic groups is an area of unmet need.
    Published June 17, 2021
  • How I Manage First-Line Therapy for Advanced Kidney Cancer

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 1
    Published Date: March 2018

    Urologists are primed to acquire the knowledge to use targeted agents and immuno-oncologic (IO) therapies for the treatment of advanced and metastatic renal cell carcinoma (RCC). Toxicities are manageable given appropriate patient/caregiver education, on-call, and nursing support, and multi-disciplinary care with consulting specialists. 
    Published August 14, 2018
  • Impact of Positive Surgical Margins on Overall Survival After Partial Nephrectomy, a Matched Comparison Based on the National Cancer Database - Beyond the Abstract

    En-bloc resection with negative surgical margins (NSM) has been a key fundamental in the surgical treatment of almost all localized tumors. Positive surgical margins (PSM) is often considered equivalent to failure for oncologic clearance, and results in additional adjuvant treatments, more frequent clinical visits and more anxiety among patients. Interestingly, many studies on partial nephrectomy (PN) seem to suggest that cancer-specific and overall survivals (OS) are not affected by PSM. Concurrently, owing to the increasing use of high-definition imaging modalities, most renal cancers (RCC) are diagnosed as small renal masses (SRMs). Over time, the ‘gold standard’ treatment of SRMs shifted from radical nephrectomy to PN, which results in better OS. Various adjuncts, such as pre-operative 3-dimensional CT reconstruction, renal arterial mapping, intra-operative frozen sections, on-table ultrasound and florescence imaging, have been used to reduce PSM in PN. Having the largest matched samples in the published literature and working from a well-known national database, we showed that PSM do impact on OS after PN.
    Published January 18, 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

    Published Date: April 16th, 2019
    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.
    Published April 16, 2019
  • Nephrectomy in the Era of Targeted Therapy: Takeaways from the CARMENA Trial

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 3

    Published Date: September 2018

    A 62-year-old man presents with a one-week history of hematuria. Ultrasound and computed tomography identify a 7-cm exophytic anterior left renal tumor, adenopathy, and two
    small lung nodules. No bone or central nervous system lesions are detected. His Eastern Cooperative Oncology Group (ECOG) performance-status (PS) and Memorial Sloan-Kettering Cancer Center (MSKCC) scores are 1. The patient asks whether to undergo cytoreductive nephrectomy. What do you tell him? 

    Published December 4, 2018
  • 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

    Published Date: November 20th, 2018

    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.

    Published November 20, 2018
  • Outcomes of Patients with Renal Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies: Comparison between the Cytokine and Targeted Therapy Eras: Expert Commentary

    Though nephrectomy is the gold standard treatment for renal cell carcinoma, 20%-40% of patients have a recurrence and 20-30% of patients present with metastatic disease1. Sarcomatoid dedifferentiation is found in approximately 5% of all RCC and can be an associated feature with any RCC histological subtype. But they are historically associated with a poor prognosis and a median overall survival of 4 to 9 months2-4. The objective of this study was to then analyze the outcome of patients with metastatic sRCC in different therapeutic eras and explore factors associated with patient survival.
    Published November 15, 2017
  • Perceptions of DNA Sequencing Among Patients with Cancer from Diverse Ancestries - Expert Commentary

    Genomic profiling is increasingly used in the clinic for treatment selection. Bergerot et al. tested whether patient characteristics and perceptions affect their choice to opt in for DNA sequencing.
    Published November 21, 2023
  • Percutaneous Renal Biopsy in the Ambulatory Surgery Center: A Primer

    Published in Everyday Urology - Oncology Insights: Volume 5, Issue 1
    Published Date: March 2020

    The earliest renal biopsies were obtained by open surgical techniques performed by urologists or transplant surgeons, or by pathologists at the time of autopsy. In 1951, physicians in Copenhagen published the first clinical report of percutaneous renal biopsy.1 They placed patients in a seated position and used intravenous pyelogram (IVP) as the imaging guide. Not surprisingly, both the yield and quality of biopsy tissue samples were low by contemporary standards, with only about half to two-thirds of specimens permitting histologic examination.
    Published April 16, 2020
  • Predictors of Long-Term Survival after Renal Cancer Surgery - Beyond the Abstract

    Renal cancer surgeries (radical nephrectomy or partial nephrectomy) are standard of care procedures for patients diagnosed with renal cell carcinoma. In order to preserve renal function, partial nephrectomy has been shown to be better in terms of functional outcomes without compromising oncologic outcomes. Long-term outcomes after partial and radical nephrectomy remain unanswered. 
    Published July 2, 2018
  • Screening Programs for Renal Cell Carcinoma: A Systematic Review by the EAU Young Academic Urologists Renal Cancer Working Group - Beyond the Abstract

    The incidence of renal cell carcinoma (RCC) is increasing, with over 430.000 new cases diagnosed per year and over 175.000 new deaths per year in 2020 worldwide.1 Although most RCCs are diagnosed at an early stage in asymptomatic patients2 and up to 25% present with metastasis showing a 1-year and 5-year survival of 39% and 12%.3
    Published August 1, 2022
  • Sequencing and Combining Targeted and Immunotherapy

    (UroToday.com) The 2020 American Society of Clinical Oncologists (ASCO) virtual education program featured a session on the evolution of renal cell carcinoma (RCC) treatment, including a presentation by Dr. Jaleh Fallah from the Cleveland Clinic discussing sequencing and combining targeted and immunotherapy. Over the last couple of years, trials have utilized combination therapy to continue improving outcomes among patients with metastatic RCC. 
    Published August 9, 2020

Page 1 of 2