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
  • 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
    Written by: Christopher J.D. Wallis, MD, PhD
    References:
    1. Young WF, Jr. Clinical practice. The incidentally discovered adrenal mass. The New England journal of medicine 2007;356:601-10.
    2. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass ("incidentaloma"). Ann Intern Med 2003;138:424-9.
    3. Fassnacht M, Kroiss M, Allolio B. Update in adrenocortical carcinoma. The Journal of clinical endocrinology and metabolism 2013;98:4551-64.
    4. Lenert JT, Barnett CC, Jr., Kudelka AP, et al. Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy. Surgery 2001;130:1060-7.
    5. Namimoto T, Yamashita Y, Mitsuzaki K, et al. Adrenal masses: quantification of fat content with double-echo chemical shift in-phase and opposed-phase FLASH MR images for differentiation of adrenal adenomas. Radiology 2001;218:642-6.
    6. Young WF, Jr., Klee GG. Primary aldosteronism. Diagnostic evaluation. Endocrinol Metab Clin North Am 1988;17:367-95.
    7. Bravo EL, Tagle R. Pheochromocytoma: state-of-the-art and future prospects. Endocr Rev 2003;24:539-53.
    8. Porterfield JR, Thompson GB, Young WF, Jr., et al. Surgery for Cushing's syndrome: an historical review and recent ten-year experience. World J Surg 2008;32:659-77.
    9. Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing's syndrome. Lancet 2006;367:1605-17.
    10. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA : the Journal of the American Medical Association 2002;287:1427-34.
    11. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. The Journal of clinical endocrinology and metabolism 2003;88:2656-66.
    12. Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. AJR Am J Roentgenol 2005;185:684-8.
    13. Pacak K. Preoperative management of the pheochromocytoma patient. The Journal of Clinical Endocrinology and metabolism 2007;92:4069-79.
    14. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol 1984;8:163-9.
    15. Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC. Successful outcomes in pheochromocytoma surgery in the modern era. The Journal of Urology 1999;161:764-7.

    Published January 29, 2019
  • 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
  • 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
  • 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    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
  • 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 and Christopher J.D. Wallis, MD, PhD
    References: 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
    2. Welch HG, Skinner JS, Schroeck FR, Zhou W, Black WC. Regional Variation of Computed Tomographic Imaging in the United States and the Risk of Nephrectomy. JAMA internal medicine. 2018;178(2):221-227.
    3. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of Clinical Oncology. 1999;17:2530-2540.
    4. Negrier S, Escudier B, Gomez F, et al. Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2002;13(9):1460-1468.
    5. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(1):289-296.
    6. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005(1):CD001425.
    7. Dutcher JP, Atkins M, Fisher R, et al. Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997. Cancer J Sci Am. 1997;3 Suppl 1:S73-78.
    8. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228(3):307-319.
    9. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. The New England journal of medicine. 1998;338(18):1272-1278.
    10. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(33):5422-5428.
    11. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103-2111.
    12. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. The New England journal of medicine. 2007;356(2):115-124.
    13. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. The New England journal of medicine. 2013;369(8):722-731.
    14. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.
    15. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. The lancet oncology. 2013;14(13):1287-1294.
    16. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(6):591-597.
    17. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update. European journal of cancer. 2018;94:115-125.
    18. Buti S, Bersanelli M. Is Cabozantinib Really Better Than Sunitinib As First-Line Treatment of Metastatic Renal Cell Carcinoma? Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(16):1858-1859.
    19. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. The New England journal of medicine. 2007;356(22):2271-2281.
    20. Escudier B, Tannir NM, McDermott D, et al. LBA5 - CheckMate 214: Efficacy and safety of nivolumab 1 ipilimumab (N1I) v sunitinib (S) for treatment-naive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Annals of Oncology. 2017;28(Supplement 5):621-622.
    21. Escudier B, Motzer RJ, Tannir NM, et al. Efficacy of Nivolumab plus Ipilimumab According to Number of IMDC Risk Factors in CheckMate 214. European urology. 2019.
    22. Motzer R, Powles T, Atkins M, et al. IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma. Journal of Clinical Oncology. 2018;36(Suppl 6S).
    23. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2019;380(12):1116-1127.
    24. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2019;380(12):1103-1115.
    25. Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol. 1995;22(1):42-60.
    26. Hahn AW, Klaassen Z, Agarwal N, et al. First-line Treatment of Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. Eur Urol Oncol. 2019;2(6):708-715.
    Published March 17, 2020
  • 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
    Written by: Christopher J.D. Wallis, MD, PhD
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.
    2. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-63.
    3. Sukov WR, Lohse CM, Leibovich BC, Thompson RH, Cheville JC. Clinical and pathological features associated with prognosis in patients with papillary renal cell carcinoma. The Journal of urology 2012;187:54-9.
    4. Skinner DG, Pfister RF, Colvin R. Extension of renal cell carcinoma into the vena cava: the rationale for aggressive surgical management. The Journal of urology 1972;107:711-6.
    5. Deng FM, Melamed J. Histologic variants of renal cell carcinoma: does tumor type influence outcome? The Urologic clinics of North America 2012;39:119-32.
    6. Klatte T, Han KR, Said JW, et al. Pathobiology and prognosis of chromophobe renal cell carcinoma. Urologic oncology 2008;26:604-9.
    7. Almassi N, Gill BC, Rini B, Fareed K. Management of the small renal mass. Transl Androl Urol 2017;6:923-30.
    8. Ng CS, Wood CG, Silverman PM, Tannir NM, Tamboli P, Sandler CM. Renal cell carcinoma: diagnosis, staging, and surveillance. AJR Am J Roentgenol 2008;191:1220-32.
    9. Shvarts O, Lam JS, Kim HL, Han KR, Figlin R, Belldegrun A. Eastern Cooperative Oncology Group performance status predicts bone metastasis in patients presenting with renal cell carcinoma: implication for preoperative bone scans. The Journal of urology 2004;172:867-70.
    10. Lane BR, Kattan MW. Prognostic models and algorithms in renal cell carcinoma. The Urologic clinics of North America 2008;35:613-25; vii.
    11. Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. The Journal of urology 2001;166:63-7.
    12. Zini L, Destrieux-Garnier L, Leroy X, et al. Renal vein ostium wall invasion of renal cell carcinoma with an inferior vena cava tumor thrombus: prediction by renal and vena caval vein diameters and prognostic significance. The Journal of urology 2008;179:450-4; discussion 4.
    13. Nguyen CT, Campbell SC, Novick AC. Choice of operation for clinically localized renal tumor. The Urologic clinics of North America 2008;35:645-55; vii.
    14. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma. European urology 2011;59:543-52.
    15. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. The Journal of urology 2008;180:505-8; discussion 8-9.
    16. Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. The Journal of urology 2013;190:407-16.
    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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    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
  • 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
  • SIU 2019: Adjuvant Therapy for High-risk Renal Cell Carcinoma: Current Status

    Athens, Greece (UroToday.com) Dr. Ricardo Rendon presented on the adjuvant treatment of high-risk renal cell carcinoma (RCC). The cancer-specific survival (CSS) for localized RCC following surgical resection is 84% at 5 years, and 76% at 10 years. However, for patients with high-risk features, the CSS is around 30-40%.

    Published October 18, 2019
  • SIU 2019: PET Imaging in Renal Cell Carcinoma and Urothelial Cancers

    Athens, Greece (UroToday.com) Dr. Eoin MacCraith continued the PET imaging session with a nice overview of the use of PET-FDG in renal cell carcinoma (RCC) and urothelial cancers. PET is beneficial in diagnostics, staging, prognostics, and assessing therapeutic response, but it is currently not recommended for routine use.

    Published October 21, 2019
  • SUO 2018: Cytoreductive Nephrectomy Is No Longer Standard of Care in Patients with Metastatic Renal Cell Carcinoma

    Phoenix, Arizona (UroToday.com) Dr. Tannir gave a discussion on why cytoreductive nephrectomy should not be the standard of care in metastatic renal cell carcinoma (RCC). Dr. Tannir believes that cytoreductive nephrectomy is for intermediate risk patients only. In the cytokine era cytoreductive nephrectomy was shown to prolong overall survival by 6-7 months (1,2). The benefit of cytoreductive nephrectomy is inversely associated with the efficacy of systemic therapies.
    Published December 2, 2018
  • SUO 2019: Better Outcomes at Higher Volume Centers: Evaluating Your Institution’s Data

    Washington, DC (UroToday.com) The second session on renal cell carcinoma at the SUO focused on the management of advanced disease. Dr. Brugarolas was invited to present data regarding the value of a critical assessment of one’s own institution’s outcomes to drive patient outcomes. He is a professor at UT Southwestern (UTSW) Medical Center in both the Department of Hematology/Oncology and Developmental Biology, where he leads the Kidney Cancer Program and as such is uniquely posed to discuss quality outcomes in the multidisciplinary setting.

    Published December 6, 2019
  • SUO 2019: Stratified Surveillance Algorithms after the Treatment of Localized Renal Cell Carcinoma

    Washington, DC (UroToday.com) At the kidney cancer session at the 20th Annual Meeting of the Society for Urologic Oncology, Dr. Suzanne Merrill discussed stratified surveillance algorithms after the treatment of localized renal cell carcinoma (RCC). Dr. Merrill poses the question ‘why should we care about surveillance practices?’ First, cancer follow-up makes up a large part of our practices, from upwards of 35-40% of clinic volume being urologic cancer follow-up patients. Second, we need to drive to be better stewards of medical resources (ordering necessary tests), and our time (see the patients who really need us). Finally, there is increasing oversight by insurance companies who are scrutinizing over imaging intensity and scope of testing.
    Published December 5, 2019
  • The Current Status of Cytoreductive Nephrectomy

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

    The History of Cytoreductive Nephrectomy

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

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

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

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

    Cytoreductive Nephrectomy in the Targeted Therapy Era

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

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

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

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

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

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

    Taken together, CARMENA and SURTIME suggest that systemic therapy should be prioritized over cytoreductive nephrectomy for patients with metastatic RCC. However, the EAU guidelines, while emphasizing the CN is no longer the standard of care, highlight that CN may be considered for select patients including those with an intermediate-risk disease who have a long-term sustained benefit from systemic therapy and those with a good-risk disease who do not require systemic therapy.23

    Published Date: April 16th, 2019

    Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians. 2018;68(1):7-30.
    2. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. European Urology. 2011;60(4):615-621.
    3. Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1999;17(8):2530-2540.
    4. Robertson CN, Linehan WM, Pass HI, et al. Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells. The Journal of urology. 1990;144(3):614-617; discussion 617-618.
    5. Marcus SG, Choyke PL, Reiter R, et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. The Journal of urology. 1993;150(2 Pt 1):463-466.
    6. Snow RM, Schellhammer PF. Spontaneous regression of metastatic renal cell carcinoma. Urology. 1982;20(2):177-181.
    7. Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. The Journal of urology. 2004;171(3):1071-1076.
    8. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. The New England journal of medicine. 2001;345(23):1655-1659.
    9. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970.
    10. Spencer WF, Linehan WM, Walther MM, et al. Immunotherapy with interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer with in situ primary cancers: a pilot study. The Journal of urology. 1992;147(1):24-30.
    11. Lahn M, Fisch P, Kohler G, et al. Pro-inflammatory and T cell inhibitory cytokines are secreted at high levels in tumor cell cultures of human renal cell carcinoma. European urology. 1999;35(1):70-80.
    12. Kawata N, Yagasaki H, Yuge H, et al. Histopathologic analysis of angiogenic factors in localized renal cell carcinoma: the influence of neoadjuvant treatment. Int J Urol. 2001;8(6):275-281.
    13. Slaton JW, Inoue K, Perrotte P, et al. Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. Am J Pathol. 2001;158(2):735-743.
    14. Lara PN, Jr., Tangen CM, Conlon SJ, Flanigan RC, Crawford ED, Southwest Oncology Group Trial S. Predictors of survival of advanced renal cell carcinoma: long-term results from Southwest Oncology Group Trial S8949. The Journal of urology. 2009;181(2):512-516; discussion 516-517.
    15. Gatenby RA, Gawlinski ET, Tangen CM, Flanigan RC, Crawford ED. The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. Cancer research. 2002;62(18):5218-5222.
    16. Escudier B, Goupil MG, Massard C, Fizazi K. Sequential therapy in renal cell carcinoma. Cancer. 2009;115(10 Suppl):2321-2326.
    17. Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. European Urology. 2019;75(1):111-128.
    18. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. The New England journal of medicine. 2018.
    19. Arora S, Sood A, Dalela D, et al. Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases. European urology. 2019;75(2):352-353.
    20. Bex A, Mulders P, Jewett M, et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2018.
    21. Wallis CJD, Klaassen Z, Bhindi B, et al. First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. European urology. 2018;74(3):309-321.
    22. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2018;378(14):1277-1290.
    23. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma. European Urology. 2018;74(6):805-809.
    Published April 16, 2019
  • The Current Status of Stereotactic Body Radiation Therapy in Kidney Cancer

    Renal cancers are common, accounting for an estimated 65,340 new diagnoses and 14,970 attributable death in 2018 in the United States.1 The “Epidemiology and Etiology of Kidney Cancer” is discussed at length in the linked article in the UroToday Center of Excellence series. Despite a large number of histologic tumor types that may occur in the kidney, renal cell carcinoma (RCC) is the most prevalent histology and this article will focus on patients with RCC.

    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 patient (host) and tumor characteristics. These details are discussed more fully in the “Malignant Renal Tumors” article in the UroToday Center of Excellence series.

    Kidney cancer has been historically thought of as a “radio-resistant” tumor. This is based on in vitro studies2 as well as the fact that early trial of adjuvant and neoadjuvant radiotherapy in patients with RCC undergoing surgical resection failed to show benefit.3,4  As a result, traditionally fractionated radiotherapy has been historically limited to palliative intent for patients with RCC. However, hypofractionated, high-dose radiotherapy has proven successful in the local control of RCC metastasis to the brain and other bony and visceral sites (refs 6-15). Coinciding with these clinical data was the emergence of data demonstrating the efficacy of high dose per fraction radiotherapy in the treatment of RCC in a mouse model.5 This led to increasing interest in the use of stereotactic body radiotherapy (SBRT) in the treatment of localized RCC. SBRT is routinely used for the treatment of malignancies of other tissue types including lung, liver, spine, and prostate.6 Compared to other radiation techniques, SBRT utilizes a smaller number of higher dose fractions. This is believed to assist with overcoming the previously believed radioresistance of RCC. Further, compared to other ablative approaches, one of the advantages of SBRT is the ability to treat larger lesions.6

    Given uncertainties about both the efficacy and toxicity of such an approach, initial investigation has focused on patients in whom extirpative surgery, the gold standard approach, is not feasible or safe.

    There are currently both retrospective and prospective reports characterising outcomes for patients treated with SBRT for localized RCC. These studies include a variety of treatment approaches including single fraction treatment (often 26 Gy in 1 fraction) and multiple fraction regimes (including regimes ranging from 2 to 10 fractions and total doses ranging from 5 to 85 Gy). As may be expected from some different treatment approaches, there are differences in both efficacy and toxicity between studies.

    Prospective cohort studies

    A recent systematic review identified eight published prospective studies of SBRT in the treatment of patients with localized RCC.7 Apart from one study published in 2006, the remainder have been published in the last five years. The strength of conclusions that can be drawn from these data are limited by small sample sizes (4 to 40 patients with localized RCC per study) and limited follow-up (13 to 52 months, with most 2 years or less).7 In addition, as previously mentioned, there were significant differences in total dose delivered and radiotherapy prescription between studies.

    In each case, the authors report on patients who were either deemed medically inoperable, at very high risk for surgery due to the risk of dialysis or who refused surgery. Some studies had specific, disease-related criteria (e.g. a single lesion, maximal tumor dimension less than 4 or 5 cm) whereas this was not specified in other manuscripts. Outcomes were variably reported with local control most often reported. Additionally, adverse events were variously, and non-systematically reported.

    Local control rates varied, in large part in correlation to the duration of observation: from 87% local control rate at a median 37 months follow up to 100% at two years in one trial8. Notably, even in the publication from Siva and colleagues who reported 100% local control, 10% of patients experienced distant progression, an outcome that is more likely to contribute to morbidity and mortality than local recurrence.8 Longer-term outcomes remain to be assessed.

    Likely due in part to differing radiotherapy prescriptions, toxicity rates varied significantly. Both Siva and colleagues and Svendman and colleagues reported grade 1-2 toxicity in more than 50% of patients, most notably characterized by chest wall pain, nausea, and fatigue.8,9 In addition to considerations regarding comorbidity, SBRT and other non-surgical approaches to renal masses are often considered in patients with poor renal function for whom nephron preservation is a top priority. Thus, post-procedural renal function is an important outcome and, again, results vary between reports. Kaplan and colleagues reported worsening of renal function in 2 of 12 patients undergoing SBRT for medically inoperable tumors less than 5cm.10 McBride et al., in a similar population of patients, found that 2 of 15 patients (13%) had late grade 3 renal dysfunction with a mean decrease in glomerular filtration rate of 18 mg/dL among the whole study population.11 Similarly, Ponsky and colleagues demonstrated an 11% rate of grade 3 renal dysfunction among 19 patients deemed poor surgical candidates who received SBRT.12 Finally, and perhaps more optimistically, Siva and colleagues found in their cohort of 21 patients that the average decrease in glomerular filtration rate was only 8.7 mL/min at one year following treatment.8. Taken together, evidence suggests that increased fractionation (as in 20 to 30 Gy in 10 fractions) was strongly correlated with renal atrophy.13

    Taken together, these data suggest that, for patients who receive three radiation fractions, a minimum per fraction dose of 11 Gy should be administered as this was the minimum dose that, in prospective cohorts, no patient experienced local failure.7 

    Retrospective cohort studies


    In addition to the aforementioned prospective cohort studies, there are a number of retrospective cohort studies examining the use of SBRT in primary RCC. These, for the most part, have the same limitations are the prospective studies including limited sample size, short follow-up and heterogeneity of radiotherapy prescription. While most of these reports demonstrated local control rates comparable to the prospective literature (93 – 100%), one study demonstrated significantly lower local control (65%) among patients who had a history of radical nephrectomy for RCC in the contra-lateral kidney14. Those patients received 60 to 85 Gy in 5 to 7 fractions using stereotactic gamma-ray irradiation.

    Patient selection

    Surgery remains the mainstay of curative-intent treatment for patients with localized RCC. Ablative approaches, including SBRT, may, therefore, be considered among patients for whom surgery is contraindicated or who refuse surgery. Recent guidelines have recommended emphasizing that SBRT remains an experimental option in RCC due to the relatively limited worldwide experience and lack of long-term data.15

    Treatment recommendations

    The International Radiosurgery Oncology Consortium for Kidney performed a 65 item survey among eight institutions who performed SBRT for primary RCC.16 A number of important conclusions came out of this work and the resulting consensus statement. First, all included centers treat patients with solitary kidneys or pre-existing hypertension. Five of the eight institutions have size cut off criteria ranging from 5 to 8 cm in maximal tumor dimension. The total planning target volume expansion varied between institutions, ranging from 3 to 10 mm. While all centers used pretreatment image verification, seven of the eight utilized intrafractional monitoring of some sort. Radiation prescriptions varied from 1 to 12 fractions with a total dose of 25 to 80 Gy. However, the consensus statement recommends a total dose of 36 to 45 Gy for patients receiving 3 fraction regimes and 40 to 50 Gy for patients receiving 5 fraction regimes. Obviously, the size of the primary tumour and its proximity to critical and adjacent structures will influence the total dose and fractionation regime.

    Ongoing surveillance follow-up for local tumor response and recurrence varied with some institutions relying on computed tomography (CT) alone while others used magnetic resonance imaging (MRI) or PET-CT. Typically, follow-up was performed every three to six months in the first two years and every three to twelve months in the subsequent three years.

    One of the challenges in the post-treatment monitoring of these patients is the interpretation of radiographic studies and identification of imaging studies. Among 41 tumours treated with SBRT, the largest available study of imaging characteristics following treatment found that the linear growth rate regressed by an average of 0.37 cm per year after treatment but that there were no significant changed in enhancement when comparing imaging before and following treatment.17

    Conclusions


    Stereotactic body radiotherapy is an emerging treatment approach for patients with primary renal cell carcinoma. Compared to other ablative approaches (such as radiofrequency ablation or cryotherapy), it offers the opportunity to treat larger tumors and potentially those in closer proximity to critical structures. To date, surgical extirpation via partial or radical nephrectomy remains the gold standard and SBRT has primarily been investigated among patients who are either deemed medically inoperable or who refuse surgery. There are a number of ongoing studies assessing the role of SBRT that will increase the prospective global experience with this approach, however, none will provide comparative data with other treatment approaches. One particular area of interest in the potential for synergistic effects between SBRT and systemic therapy, particularly immunotherapy (ClinicalTrials.gov identifiers: NCT01896271, NCT02781506, NCT02306954, and NCT02334709).
    Written by: Christopher J.D. Wallis, MD PhD and Zachary Klaassen, MD MSc
    References: References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1):7-30.
    2. Deschavanne PJ, Fertil B. A review of human cell radiosensitivity in vitro. Int J Radiat Oncol Biol Phys 1996; 34(1):251-66.
    3. Finney R. The value of radiotherapy in the treatment of hypernephroma--a clinical trial. Br J Urol 1973; 45(3):258-69.
    4. Juusela H, Malmio K, Alfthan O, et al. Preoperative irradiation in the treatment of renal adenocarcinoma. Scand J Urol Nephrol 1977; 11(3):277-81.
    5. Walsh L, Stanfield JL, Cho LC, et al. Efficacy of ablative high-dose-per-fraction radiation for implanted human renal cell cancer in a nude mouse model. Eur Urol 2006; 50(4):795-800; discussion 800.
    6. Francolini G, Detti B, Ingrosso G, et al. Stereotactic body radiation therapy (SBRT) on renal cell carcinoma, an overview of technical aspects, biological rationale and current literature. Crit Rev Oncol Hematol 2018; 131:24-29.
    7. Miccio J, Johung K. When Surgery Is Not an Option in Renal Cell Carcinoma: The Evolving Role of Stereotactic Body Radiation Therapy. Oncology (Williston Park) 2019; 33(5):167-73, 177.
    8. Siva S, Pham D, Kron T, et al. Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial. BJU Int 2017; 120(5):623-630.
    9. Svedman C, Sandstrom P, Pisa P, et al. A prospective Phase II trial of using extracranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma. Acta Oncol 2006; 45(7):870-5.
    10. Kaplan ID, Redrosa I, C. M, et al. Results of a phase I dose escalation study of stereotactic radiosurgery for primary renal tumors. Int J Radiat Oncol Biol Phys 2010; 78:S191.
    11. McBride SM, Wagner AA, Kaplan ID. A phase 1 dose-escalation study of robotic radiosurgery in inoperable primary renal cell carcinoma. Int J Radiat Oncol Biol Phys 2013; 87:S84.
    12. Ponsky L, Lo SS, Zhang Y, et al. Phase I dose-escalation study of stereotactic body radiotherapy (SBRT) for poor surgical candidates with localized renal cell carcinoma. Radiother Oncol 2015; 117(1):183-7.
    13. Yamamoto T, Kadoya N, Takeda K, et al. Renal atrophy after stereotactic body radiotherapy for renal cell carcinoma. Radiat Oncol 2016; 11:72.
    14. Wang YJ, Han TT, Xue JX, et al. Stereotactic gamma-ray body radiation therapy for asynchronous bilateral renal cell carcinoma. Radiol Med 2014; 119(11):878-83.
    15. Muller AC, van Oorschot B, Micke O, et al. [German S3 guideline for renal cell carcinoma : Presentation and discussion of essential aspects for the radiation oncologist]. Strahlenther Onkol 2018; 194(1):1-8.
    16. Siva S, Ellis RJ, Ponsky L, et al. Consensus statement from the International Radiosurgery Oncology Consortium for Kidney for primary renal cell carcinoma. Future Oncol 2016; 12(5):637-45.
    17. Sun MR, Brook A, Powell MF, et al. Effect of Stereotactic Body Radiotherapy on the Growth Kinetics and Enhancement Pattern of Primary Renal Tumors. AJR Am J Roentgenol 2016; 206(3):544-53.
    Published November 20, 2019
  • The Opioid Crisis in Urology

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

    The Opioid Crisis in Urology

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

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

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

    There are several reasons for the opioid crisis in urology, namely a culture of overprescribing.5 This may be due to:
    1. A historic failure to address acute pain in hospitalized patients, leading to the American Pain Society suggesting that pain should be akin to the fifth vital sign.6 Subsequently, physicians became more aware of their patients’ pain and were expected to treat their pain leading to an environment where liberal use of narcotics was tolerated.
    2. Over the past two decades, reimbursement, specifically through the Center for Medicare and Medicaid Services (CMS), has been linked to Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. In the questionnaire, there were three questions dedicated to how well the patient’s pain was managed. These additional measures emphasizing the importance of pain management likely influenced the number of narcotics prescribed at discharge in order to maintain positive survey scores.
    3. Because narcotics must be prescribed via a hand-written prescription and obtaining additional pain medication is inconvenient for both patient and physician, providers may be more likely to overprescribe narcotics at discharge “just in case”.
    The rates of opioid dependence and overdose after urological surgery are as follows:

    table 1 opiods in urology2x

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

    The AUA Quality Improvement Summit took place at AUA headquarters in December 2018 and was divided into four sessions:
    • Session 1: Physician-led Multicomponent Interventions in Opioid Stewardship. Dr. Richard Barth discussed procedure-specific opioid prescribing guidelines, Dr. Jonah Stulberg discussed opioid reclamation efforts, and Dr. Jim Dupree presented the Michigan MUSIC initiative on opioid stewardship.
    • Session 2: Understanding Post-operative Pain. Dr. Brooke Chidgey discussed the pathophysiology of post-operative pain, Dr. Meghan Sperandeo-Fruge highlighted complementary alternative medicine pain management strategies, and Dr. Margaret Rukstalis discussed cognitive behavioral therapy and other non-pharmacologic approaches to pain management. In a sub-session discussing challenging cases in opioid management, Dr. Vernon Pais discussed the impact on prescription opioid use in patients with kidney stones, Dr. Matthew Nielsen highlighted the University of North Carolina Health Care System’s opioid stewardship program, and Dr. Benjamin Davies discussed his initiative of no opioids after a robotic prostatectomy.
    • Session 3: High-Risk Patients and Expectations. Dr. Behfar Ehdaie presented on the expectation setting for opioid prescribing, Dr. Margaret Rukstalis discussed a surgeon’s role in the management of opioid misuse disorders, and Dr. Brooke Chidgey discussed the role of pain specialists for managing high-risk patients.
    • Session 4: Policy and Outreach. Dr. Jennifer Waljee discussed opioid education and outreach, Dr. Scott Winiecki presented on opioid prescribing and the FDA safe use initiative, and Dr. Gregory Murphy completed the program discussing policy change and legislature to address the opioid crisis.

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

    Non-Opioid Measures for Pain Control

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

    Professor Benjamin Davies from the University of Pittsburgh has been a thought leader and advocate for minimizing opioid prescriptions among patients undergoing urologic procedures, namely advocating for the “No Opioid Robotic Radical Prostatectomy”.9,10 This protocol is as follows:
    • Pre-operative: Oral neurontin, acetaminophen, +/- celebrex
    • Quadratus lumborum block (ropivicaine, decadron, precedex)
    • Intraoperative: separate infusions of propofol, ketamine, and precede
    • Post-operative: Toradol 15 mg IV PRN while in the hospital
    • Tylenol and Motrin for 48 hours
    Amid the opioid crisis, there has been an increased focus on increasing the use of regional anesthesia as part of opioid-sparing multimodal analgesia. Tranversus abdominis plane (TAP) block has been shown to improve early and late pain, and reduce opioid consumption after minimally surgery.11 These benefits have indirectly reduced the incidence of postoperative delirium, pneumonia, urinary retention, and falls. Furthermore, compared to epidural analgesia, a TAP block provides similar pain control, has a lower incidence of hypotension, and is associated with a shorter length of stay. A TAP block provides a safe intervention and should be integrated into enhanced recovery protocols for patients undergoing urologic procedures.

    Prospective Initiatives

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

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

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

    Conclusions

    The urologic community has by no means been spared by the current opioid epidemic across the U.S. Several studies in both the adult and pediatric settings have demonstrated overprescribing measures with little to no counseling or options for appropriate disposal of opioids. Several measures are now in place to solve this problem5, including (i) greater utilization and implementation of Prescription Drug Monitoring Programs (PDMPs) to provide alerts to providers to patients who may be filling opiate prescriptions with multiple providers; (ii) CMS has removed the three questions from the HCAHPS survey related to pain control, effective January 2018; (iii) increased utilization of Enhanced Recovery After Surgery (ERAS) pathways as a measure for decreasing intra- and post-operative use of opioids; (iv) each of the 50 states have passed legislation to make readily available naloxone, which rapidly reverses the effects of opioids in the overdose setting; (v) the creation of procedure-specific guidelines for discharge opioid recommendations. For example, a Johns Hopkins expert panel assessing 20 common surgical procedures suggest that the ideal range of oxycodone 5-mg tablets prescribed to opioid naïve patients at discharge is 0-1014; (vi) the DEA sponsored “National Rx Takeback” initiative, providing collection sites (primarily pharmacies) for returning opioids. Certainly, the current opioid epidemic is multifactorial. However, judicious prescribing of opioids amongst the urology community is one actionable item that will make a difference for the betterment of our patients.

    Published Date: December 12th, 2019 
    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    References: References:
    1. National Institute on Drug Abuse. Opioid Crisis. 2017. Available at: www.drugabuse.gov/drugs-abuse/opioids/opioid-crisis
    2. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: a look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011;185(2):551-555.
    3. Theisen KM, Myrga JM, Hale N, et al. Excessive Opioid Prescribing After Major Urologic Procedures. Urology. 2019;123:101-107.
    4. Lawrence AE, Carsel AJ, Leonhart KL, et al. Effect of Drug Disposal Bag Provision on Proper Disposal of Unused Opioids by Families of Pediatric Surgical Patients: A Randomized Clinical Trial. JAMA Pediatr. 2019:e191695.
    5. Theisen K, Jacobs B, Macleod L, Davies B. The United States opioid epidemic: a review of the surgeon's contribution to it and health policy initiatives. BJU Int. 2018;122(5):754-759.
    6. Quality improvement guidelines for the treatment of acute pain and cancer pain. American Pain Society Quality of Care Committee. JAMA. 1995;274(23):1874-1880.
    7. Shah AS, Blackwell RH, Kuo PC, Gupta GN. Rates and Risk Factors for Opioid Dependence and Overdose after Urological Surgery. J Urol. 2017;198(5):1130-1136.
    8. Loeb S, Cazzaniga W, Robinson D, Garmo H, Stattin P. Opioid Use After Radical Prostatectomy: Nationwide, Population Based Study in Sweden. J Urol. 2019:101097JU0000000000000451.
    9. Theisen KM, Davies BJ. A Radical Proposition: Opioid-sparing Prostatectomy. Eur Urol Focus. 2019.
    10. Pekala KR, Jacobs BL, Davies BJ. The Shrinking Grey Zone of Postoperative Narcotics in the Midst of the Opioid Crisis: The No-opioid Urologist. Eur Urol Focus. 2019.
    11. Shahait M, Lee DI. Application of TAP Block in Laparoscopic Urological Surgery: Current Status and Future Directions. Curr Urol Rep. 2019;20(5):20.
    12. Patel HD, Faisal FA, Patel ND, et al. Effect of a Prospective Opioid Reduction Intervention on Opioid Prescribing and Use after Radical Prostatectomy: Results of the ORIOLES Initiative. BJU Int. 2019.
    13. Audenet F, Attalla K, Giordano M, et al. Prospective implementation of a nonopioid protocol for patients undergoing robot-assisted radical cystectomy with extracorporeal urinary diversion. Urol Oncol. 2019;37(5):300 e317-300 e323.
    14. Overton HN, Hanna MN, Bruhn WE, et al. Opioid-Prescribing Guidelines for Common Surgical Procedures: An Expert Panel Consensus. J Am Coll Surg. 2018;227(4):411-418.
    Published December 19, 2019
  • The Risks of Delaying Kidney Cancer Treatment During COVID-19

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

    The question of when to initiate systemic therapy in patients with metastatic kidney cancer is also pertinent during this pandemic and depends on symptoms, patient comorbidities, and tumor risk stratification. In treatment-naïve patients with favorable and intermediate-risk disease who are asymptomatic or minimally symptomatic with limited disease burden, a number of studies, including two narrative reviews23,24 and two prospective trials,25,26 have assessed the safety and feasibility of delaying the initiation of systemic therapy. In the largest prospective study of surveillance in patients with metastatic kidney cancer, Rini et al. enrolled fifty-two asymptomatic patients in a Phase II trial.26 All but one patient had favorable (23%) or intermediate (75%) risk disease according to IMDC criteria with the vast majority (80%) of patients having only one or two organ sites with metastases. The median time on surveillance was 14.9 months and 37 of 43 patients experiencing RECIST-defined disease progression started systemic treatment. The median PFS and OS from the start of surveillance was 9.4 and 44.5 months, respectively. In a smaller study of 15 patients who received CN followed by observation until progression, Wong et al. found a median time to progression of eight weeks and a median OS of 25 months.25 Neither of these studies have compared outcomes with patients who started systemic therapy upfront. However, this has been assessed in two large retrospective studies. Among a European cohort of patients ineligible for active surveillance, Iacovelli and colleagues found that a delay of more than six weeks in the initiation of systemic therapy did not significantly affect the cancer-specific outcomes.27 Further, delayed treatment initiation was not independently associated with worse OS in an analysis based on the National Cancer Database utilizing multivariable logistic regression analyses.28

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

    Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia; Christopher J.D. Wallis, MD, PhD, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    References: 1. Guan, Wei-jie, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu et al. "Clinical characteristics of coronavirus disease 2019 in China." New England Journal of Medicine (2020).
    2. March 13, Online, and 2020. “COVID-19: Recommendations for Management of Elective Surgical Procedures.” American College of Surgeons. Accessed April 20, 2020. https://www.facs.org/covid-19/clinical-guidance/elective-surgery.
    3. March 17, Online, and 2020. “COVID-19: Guidance for Triage of Non-Emergent Surgical Procedures.” American College of Surgeons. Accessed April 20, 2020. https://www.facs.org/covid-19/clinical-guidance/triage.
    4.COVID, CDC, and Response Team. "Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020." MMWR Morb Mortal Wkly Rep 69, no. 12 (2020): 343-346.
    5. Grasselli, Giacomo, Alberto Zangrillo, Alberto Zanella, Massimo Antonelli, Luca Cabrini, Antonio Castelli, Danilo Cereda et al. "Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy." JAMA (2020).
    6. Liang, Wenhua, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li et al. "Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China." The Lancet Oncology 21, no. 3 (2020): 335-337.
    7. Siegel, Rebecca L., and Kimberly D. Miller. "Jemal A (2018) cancer statistics." Ca Cancer J Clin 68, no. 1 (2018): 7-30.
    8. Bourgade, Vincent, Sarah J. Drouin, David R. Yates, Jerôme Parra, Marc-Olivier Bitker, Olivier Cussenot, and Morgan Rouprêt. "Impact of the length of time between diagnosis and surgical removal of urologic neoplasms on survival." World journal of urology 32, no. 2 (2014): 475-479.
    9. Mir, Maria Carmen, Umberto Capitanio, Riccardo Bertolo, Idir Ouzaid, Maciej Salagierski, Maximilian Kriegmair, Alessandro Volpe, Michael AS Jewett, Alexander Kutikov, and Phillip M. Pierorazio. "Role of active surveillance for localized small renal masses." European urology oncology 1, no. 3 (2018): 177-187.
    10. Sanchez, Alejandro, Adam S. Feldman, and A. Ari Hakimi. "Current management of small renal masses, including patient selection, renal tumor biopsy, active surveillance, and thermal ablation." Journal of Clinical Oncology 36, no. 36 (2018): 3591.
    11. McIntosh, Andrew G., Benjamin T. Ristau, Karen Ruth, Rachel Jennings, Eric Ross, Marc C. Smaldone, David YT Chen et al. "Active surveillance for localized renal masses: tumor growth, delayed intervention rates, and> 5-yr clinical outcomes." European urology 74, no. 2 (2018): 157-164.
    12. Hawken, Scott R., Naveen K. Krishnan, Sapan N. Ambani, Jeffrey S. Montgomery, Elaine M. Caoili, James H. Ellis, Lakshmi P. Kunju et al. "Effect of delayed resection after initial surveillance and tumor growth rate on final surgical pathology in patients with small renal masses (SRMs)." In Urologic Oncology: Seminars and Original Investigations, vol. 34, no. 11, pp. 486-e9. Elsevier, 2016.
    13. Kutikov, Alexander. "Surveillance of Small Renal Masses in Young Patients: A Viable Option in the Appropriate Candidate." European urology focus 2, no. 6 (2016): 567-568.
    14. Pierorazio, Phillip M., Michael H. Johnson, Mark W. Ball, Michael A. Gorin, Bruce J. Trock, Peter Chang, Andrew A. Wagner, James M. McKiernan, and Mohamad E. Allaf. "Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry." European urology 68, no. 3 (2015): 408-415.
    15. Mano, Roy, Emily A. Vertosick, Abraham Ari Hakimi, Itay A. Sternberg, Daniel D. Sjoberg, Melanie Bernstein, Guido Dalbagni, Jonathan A. Coleman, and Paul Russo. "The effect of delaying nephrectomy on oncologic outcomes in patients with renal tumors greater than 4 cm." In Urologic Oncology: Seminars and Original Investigations, vol. 34, no. 5, pp. 239-e1. Elsevier, 2016.
    16. Mehrazin, Reza, Marc C. Smaldone, Alexander Kutikov, Tianyu Li, Jeffrey J. Tomaszewski, Daniel J. Canter, Rosalia Viterbo, Richard E. Greenberg, David YT Chen, and Robert G. Uzzo. "Growth kinetics and short-term outcomes of cT1b and cT2 renal masses under active surveillance." The Journal of urology 192, no. 3 (2014): 659-664.
    17. Stec, Andrew A., Benjamin J. Coons, Sam S. Chang, Michael S. Cookson, S. Duke Herrell, Joseph A. Smith Jr, and Peter E. Clark. "Waiting time from initial urological consultation to nephrectomy for renal cell carcinoma—does it affect survival?." The Journal of urology 179, no. 6 (2008): 2152-2157.
    18. Woodruff, Daniel Y., Peter Van Veldhuizen, Gregory Muehlebach, Phillip Johnson, Timothy Williamson, and Jeffrey M. Holzbeierlein. "The perioperative management of an inferior vena caval tumor thrombus in patients with renal cell carcinoma." In Urologic Oncology: Seminars and Original Investigations, vol. 31, no. 5, pp. 517-521. Elsevier, 2013.
    19. Psutka, Sarah P., Stephen A. Boorjian, Robert H. Thompson, Grant D. Schmit, John J. Schmitz, Thomas C. Bower, Suzanne B. Stewart, Christine M. Lohse, John C. Cheville, and Bradley C. Leibovich. "Clinical and radiographic predictors of the need for inferior vena cava resection during nephrectomy for patients with renal cell carcinoma and caval tumour thrombus." BJU international 116, no. 3 (2015): 388-396.
    20. Adams, Lisa C., Bernhard Ralla, Yi-Na Y. Bender, Keno Bressem, Bernd Hamm, Jonas Busch, Florian Fuller, and Marcus R. Makowski. "Renal cell carcinoma with venous extension: prediction of inferior vena cava wall invasion by MRI." Cancer Imaging 18, no. 1 (2018): 17.
    19. Méjean, Arnaud, Alain Ravaud, Simon Thezenas, Sandra Colas, Jean-Baptiste Beauval, Karim Bensalah, Lionnel Geoffrois et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379, no. 5 (2018): 417-427.
    21. Bex, Axel, Peter Mulders, Michael Jewett, John Wagstaff, Johannes V. Van Thienen, Christian U. Blank, Roland Van Velthoven et al. "Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial." JAMA oncology 5, no. 2 (2019): 164-170.
    23. Pickering, Lisa M., Mohammed O. Mahgoub, and Deborah Mukherji. "Is observation a valid strategy in metastatic renal cell carcinoma?." Current opinion in urology 25, no. 5 (2015): 390-394.
    24. Nizam, Amanda, Jonah A. Schindelheim, and Moshe C. Ornstein. "The role of active surveillance and cytoreductive nephrectomy in metastatic renal cell carcinoma." Cancer Treatment and Research Communications (2020): 100169.
    25. Wong, Alvin S., Kian-Tai Chong, Chin-Tiong Heng, David T. Consigliere, Kesavan Esuvaranathan, Khai-Lee Toh, Benjamin Chuah, Robert Lim, and James Tan. "Debulking nephrectomy followed by a “watch and wait” approach in metastatic renal cell carcinoma." In Urologic Oncology: Seminars and Original Investigations, vol. 27, no. 2, pp. 149-154. Elsevier, 2009.
    26. Rini, Brian I., Tanya B. Dorff, Paul Elson, Cristina Suarez Rodriguez, Dale Shepard, Laura Wood, Jordi Humbert et al. "Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial." The Lancet Oncology 17, no. 9 (2016): 1317-1324.
    27. Iacovelli, Roberto, Luca Galli, Ugo De Giorgi, Camillo Porta, Franco Nolè, Paolo Zucali, Roberto Sabbatini et al. "The effect of a treatment delay on outcome in metastatic renal cell carcinoma." In Urologic Oncology: Seminars and Original Investigations, vol. 37, no. 8, pp. 529-e1. Elsevier, 2019.
    28. Woldu, Solomon L., Justin T. Matulay, Timothy N. Clinton, Nirmish Singla, Yuval Freifeld, Oner Sanli, Laura-Maria Krabbe et al. "Incidence and outcomes of delayed targeted therapy after cytoreductive nephrectomy for metastatic renal-cell carcinoma: a nationwide cancer registry study." Clinical genitourinary cancer 16, no. 6 (2018): e1221-e1235.
    Published April 21, 2020
  • The Role of Radiolabeled PSMA PET/CT for the Evaluation of Renal Cancer - Beyond the Abstract

    Prostate specific membrane antigen (PSMA) is highly expressed in the cell surface of the tumor microvasculature of several solid tumors, including renal cell carcinoma (RCC). Radiolabeled PSMA-based positron emission tomography (PET)/computed tomography (CT) has extensively used for the detection of recurrent prostate cancer, but it would be useful also in other solid cancer, like RCC. In the present mini-review, we aim to understand the current role of PSMA PET/CT in patients affected by RCC.
    Published October 16, 2018
  • When Partial Nephrectomy Is Unsuccessful: Understanding the Reasons for Conversion From Robotic Partial to Radical Nephrectomy at a Tertiary Referral Center - Expert Commentary

    Partial nephrectomies are the standard of care with treatment of T1a or T1b tumors due to their better functional outcomes and decrease cardiovascular morbidity. However, with the increasing trend of using robotic partial nephrectomy (RPN) to treat more and more complex tumors, there is a greater risk of conversion to radical nephrectomy (RN). As there is little literature about analyzing the conversion rate and risks, these authors investigated the incidence of RPN to RN conversion and analyzed the preoperative factors that could possibly lead to a RN without having to convert. 
    Published September 20, 2017