RENAL MASS AND LOCALIZED RENAL CANCER *the following questions are recommended to address the healthcare tests and/or treatments this program should consider:

• What indicators can be used to predict malignancy and/or aggressiveness of disease in patients with a localized renal mass, including demographic information, biopsy data (histology, grade, immunohistochemistry), novel biomarkers, imaging, and blood/urine laboratory findings?
• What is the comparative oncologic efficacy (2, 5 and 10 year survival) associated with radical nephrectomy (open surgical or laparoscopic/robotic), partial nephrectomy/nephron sparing surgery (open surgical or laparoscopic/robotic), percutaneous ablation (cryoablation, radiofrequency, microwave and others), laparoscopic ablation (cryoablation, radiofrequency, microwave and others), radiation therapy, other emerging treatments or active surveillance in the treatment of renal mass or localized renal cancer?
• What is the comparative preservation of renal function associated with radical nephrectomy (open surgical or laparoscopic/robotic), partial nephrectomy/nephron sparing surgery (open surgical or laparoscopic/robotic), percutaneous ablation (cryoablation, radiofrequency, microwave and others), laparoscopic ablation (cryoablation, radiofrequency, microwave and others), radiation therapy, other emerging treatment or active surveillance in the treatment of renal mass or localized renal cancer? What are the implications of renal functional outcomes (survival, morbidities, quality of life) in this patient population?
• What is the comparative type/rate of complications associated with radical nephrectomy (open surgical or laparoscopic/robotic), partial nephrectomy/nephron sparing surgery (open surgical or laparoscopic/robotic), percutaneous ablation (cryoablation, radiofrequency, microwave and others), laparoscopic ablation (cryoablation, radiofrequency, microwave and others), radiation therapy, other emerging treatments or active surveillance in the treatment of renal mass or localized renal cancer?
• What impact do tumor characteristics (size, stage, grade, histologic subtype and other histologic features and composite feature scoring systems [such as R.E.N.A.L/ nephrometry, PADUA classification, and C-Index]) and patient characteristics (age, gender, renal function, comorbidities and others) have on the selection of treatment type or active surveillance?
• What impact do tumor characteristics (size, stage, grade, histologic subtype and other histologic features, and composite feature scoring systems [such as R.E.N.A.L/ nephrometry, PADUA classification, and C-Index]) and patient characteristics (age, gender, renal function, comorbidities and others) have on oncologic outcome, preservation of renal function and type/rate of complications in patients with renal mass or localized renal cancer?
• What clinical tools, models, nomograms, etc. are available for the prediction of risk and how are they best used to communicate risk to patient and provider during clinical decision making for the management of localized renal tumors?
• Is there a role and what are the risks and benefits of administering systemic therapy prior to intended partial or radical nephrectomy?
• What are the possible benefits, complications, and indications for lymph node dissection when performing extirpative surgery for a renal mass?
• What are the possible benefits, complications, and indications for adrenalectomy when performing extirpative surgery for a renal mass?
• What is the role of competing risks of death, related to age and medical-co-morbidities, in managing patients with renal masses (i.e. many will die of other causes before their renal mass causes problems or threatens health, and does this need to be incorporated in decision-making)?
• What is the role of percutaneous renal mass sampling (biopsy or aspiration) in determining management of renal masses?
• What are the pertinent considerations in determining local treatments failure or tumor recurrence in the treated kidney, and what treatments are optimal?

The evidence report should compare and contrast the following diagnostic and management strategies:

Prognostic Markers:

• Tumor characteristics
• Standard histological findings (cell-type, grade, microvascular invasion,

necrosis, etc.)

• Immunohistochemistry
• Imaging findings (size, stage, degree of enhancement, nephrometry

score and other measures of tumor complexity, etc.) Patient Characteristics

• Age, gender
• Obesity (BMI and other measures)
• Renal function
• Medical co-morbidities (quantified with Charlson Index or other

measures) Blood and urine laboratory tests Biomarkers

• Pigment epithelium-derived factor (PEDF)
• Vascular endothelial growth factor (VEGF)
• Carbonic anhydrase IX (CA-IX)
• KI-67
• Proliferating cell nuclear antigen (PCNA)
• Cyclooxygenase-2 (COX-2)
• Thymidine phosphorylase (TP)
• Genetic and epigenetic markers Percutaneous Biopsy:
• Technique (FNA vs. Core, Size of Sample, No. of Samples, etc.)
• Imaging Modality (US or CT/MRI Guided)
• Factors influencing success (Tumor factors (tumor diameter, cystic lesions, necrosis, location, depth), Patient factors (anticoagulation), operator)
• Complication profile Active Surveillance:
• Utility of renal mass sampling (biopsy or aspiration)
• Kinetics of tumor growth
• Surveillance protocol (i.e. modalities and frequency of interval imaging,

including abdomen and chest)

• Triggers for treatment (i.e., surgical procedure) Surgery:
• Radical Nephrectomy
• Open vs. laparoscopic/robotic
• Nodal dissection: none versus any and extent/anatomic boundaries
• Adrenalectomy, pros/cons features which predict need for

removal

• Partial Nephrectomy
• Open vs. laparoscopic/robotic
• Use/type of ischemia (e.g., none, warm, cold)
• Method of hilar clamping (artery only, artery and vein, branch versus main artery)
• Method of hemostasis
• Use of intra-operative ultrasound
• Use of intra-operative frozen section
• Intraoperative imaging of the vasculature
• Use of renal protective agents (i.e. mannitol, albumin, dopamine,

furosemide)

• Percutaneous Ablation
• Modality of localization and tracking (MR/CT/US)
• Cryoablation vs. Radiofrequency vs. Microwave vs. others
• IV sedation / local anesthesia vs. general anesthesia
• US vs. CT guidance
• Associated biopsy techniques
• Laparoscopic Ablation
• Cryoablation vs. Radiofrequency vs. Microwave vs. others
• Associated biopsy techniques Radiation:
• Types of radiation (standard external beam, IMRT, etc.) Systemic therapy
• Afinitor (Everolimus)
• Avastin (Bevacizumab)
• Inlyta (Axitinib)
• Nexavar (Sorafenib Tosylate)
• Proleukin (Aldesleukin)
• Sutent (Sunitinib Malate)
• Torisel (Temsirolimus)
• Votrient (Pazopanib Hydrochloride)

Relevant patients, group(s) or subgroups of people (this may include details such as age range, gender, coexisting diagnoses, and reasons for therapy.) The National Cancer Institute estimates incidence rates of renal cancer for 2013, totaling 65,150 new cases (40,430 in men and 24,720 in women) and 13,680 deaths (8,780 men and 4,900 women). The average age at diagnosis is 64 years, affecting an older population.

This increase in incidence is due largely to an increase in incidence of small renal masses detected incidentally. Mortality rates from kidney cancer have also continued to escalate despite greater rates of detection of smaller renal tumors and increased rates of renal surgery. Statistics show that renal cancer has one of the highest mortality rates of the common urologic cancers. Renal cancer is the third most common urologic malignancy, and contributes to 4% of total adult cancers. Approximately 30% of tumors recur and 20% of adult instances of renal cancer result in death.

Indicators for renal cell cancer therapy include stage (based on the TNM classification system), as well as tumor size and location.

Renal function and comorbidities are now also primary considerations.

Subgroups include men, as incidence is higher in men than women. African American males have the highest incidence rates of renal cancer, followed by Hispanic males. Studies are revealing a disparity in care for African Americans (less treatment and more observation) and women (less nephron-sparing), which emphasize the need for such reviews by the Agency for Healthcare Research and Quality (AHRQ) .

Epidemiological risk factors include: tobacco use, obesity, and hypertension (may differ between populations). Additional factors may include low physical activity, increased alcohol consumption, occupational exposure to trichloroethylene (high parity among women). Genetic factors and their interaction with environmental exposures are also thought to influence risk of developing renal cancer .

The burden of disease with respect to cost is also significant. The total expenditures for kidney cancer were $401 million in 2000, representing a 46% increase from 1994. With the rising incidence of renal cancer, it is reasonable to expect that the total expenditures are now significantly greater.

The important health-related benefits and harms you are interested in. For example, improvements in symptoms or problems with diagnosis. Health-related benefits of interest include the following: treatment-related morbidity, renal functional outcomes and their sequelae, local and systemic recurrence-free survival, cancer-specific survival and overall survival.

Mortality rates, a priority harm of concern, from kidney cancer have not improved despite greater rates of detection of smaller renal tumors and increased rates of renal surgery. Statistics show that renal cancer has one of the highest mortality rates of the common urologic cancers. Renal cancer is the third most common urologic malignancy and contributes to 4% of total adult cancers4.

While a direct cause has not been identified, there are several risk factors that have been shown to increase the likelihood of renal cancer. Individuals who are obese, for example, have an increased risk of developing renal cancer, and new research may give even more insight to already known risk factors. For example, timing of obesity onset may affect risk for renal cancer as well as outcomes .

Hypertension is now also a well-established risk factor for renal cancer.

Studies have also identified tobacco use as a risk factor in the development of renal cancer, when compared to nonsmokers . Additional co-occurring disorders have also been suggested as risk factors for development of renal cancer such as patients who undergo dialysis for kidney failure, as well as patients who suffer from Von Hippel-Lindau disease, hereditary papillary renal cell carcinoma, or other familial syndromes of renal cancer.

Patients in end stage renal disease also appear to be at increased risk for renal cancer, which has important implications for screening and transplantation .

Harms or side effects from testing and/or treatment are also very important to consider. These include:

• Complications following interventions. This data should be evaluated based on timeframe after procedure as morbidity can differ between early post-procedure (up to 90 days) vs. late post-procedure (after 90 days).

Major Urologic Complications

• Ureteral injury
• Urine leak
• Urinary tract infection
• Acute kidney injury/failure
• Renal vascular injury/arterio-venous fistula formation
• Renal hemorrhage
• Renal fracture
• Perinephric abscess
• Loss of renal function
• Complete renal loss

Major nonurological complications

• Unplanned additional surgical procedures
• Injury/damage to other intra-abdominal structures
• Need for blood transfusion
• Respiratory complications
• Cardiovascular complications
• Venous thromboembolism
• Death

-Other perioperative events

-Local and systemic recurrence-free survival, cancer-specific survival and overall survival (Early versus late post-procedure outcomes)

Evidence from the National Cancer Institute shows that in 2013, 65,150 new cases of renal cancer will be diagnosed, resulting in 13,680 deaths.

Renal cancer is described as "one of the most lethal of the urologic cancers" and the third most common urologic malignancy contributes to 4% of total adult cancers. Mortality rates from kidney cancer have not declined despite greater rates of detection of smaller renal tumors and increased rates of renal surgery. Statistics show that renal cancer has one of the highest mortalities of urologic cancers. The increase in incidence of renal masses is due largely to an increased detection of small renal masses (<4cm) due to the recent liberal use of cross sectional imaging .

There has been significant progress in the area of drug development resulting in 7 new FDA approved systemic agents for RCC which have increased the life expectancy in advanced cases.

Advances in surgical technique (laparoscopy/robotics) have developed in parallel but without the requisite perspective of their impact on the biology of the disease or patient related survival outcomes. This new literature may provide new insights into treatment, positively affecting patient outcomes.

The AUA first developed a Guideline for the Management of the Clinical Stage 1 Renal Mass in 2009. As part of AUA's guidelines process, guidelines are reviewed at least every 2 years to ensure that they remain both current and accurate. The AUA performed a review in 2012, in which new literature was assessed and the guidelines were reevaluated.

It was determined that the body of new literature published was significant enough to inform and expand the existing guideline to also include renal cancer beyond clinical stage 1. In addition to the subject matter encompassed by the current Clinical Stage 1 Renal Mass guideline, the AUA suggests widening the scope of this topic to allow for a broader inclusion of different approaches to the management of the renal mass and localized renal cancer, including surgery, various approaches to ablation, active surveillance, and better risk stratification using biopsy and prognostic markers.

The AUA has a rigorous, evidence based, high quality guideline development and dissemination process. The AUA Board of Directors has mandated that the AUA increase its number of guidelines as well as periodically assess existing guidelines on a regular basis; as such, the AUA Guidelines team develops and /or revises a minimum of three new guidelines per year and assesses existing guidelines every one to three years. The AUA publishes guidelines on its website as well as on the NGC and G-I-N websites, and these are accompanied by pocket guides and smartphone APPs for physicians as well as patient education materials. Following a guideline's publication, a summary manuscript is published in the Journal of Urology, which has extensive readership spanning both national and international clinical communities. Additionally, the AUA widely disseminates information about its guidelines through its annual meeting, the AUA Health Policy Brief, AUA News, social media and through its Board of Directors and members. The AUA also provides extensive education for its members and other participants on guideline topics via in person courses, and enduring materials such as toolkits. In addition, AUA is utilizing informaticists to help make guideline statements more actionable and relevant for electronic health records (EHRs). The creation of an AHRQ evidence report on Renal Cancer and Renal Mass will enable the AUA to develop a guideline to enhance physician knowledge and reduce treatment inequalities among both the urologic and primary care medical communities.

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Professional Society.

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American Urological Association (AUA).

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The AUA has previously partnered with AHRQ in the development of evidence reports on the Management of Female Overactive Bladder (OAB), Urinary Retention, Medical Recurrent Nephrolithiasis, Cryptorchidism and Bladder Cancer. The AUA has developed high quality clinical practice guidelines, utilizing the evidence reports developed on all of the topics AUA has submitted to AHRQ. In keeping with its vision to serve as a premier professional association for the advancement of urologic patient care, the AUA continually works to fulfill the need for quality, evidence-based education for medical professionals. The AUA produces and disseminates Clinical Practice Guidelines, fostering the highest principles of urologic care by ensuring that members are current on the latest peer-reviewed evidence and practices in the field.