v. Biopsy is an option as part of active observation or prior to ablative therapy vi. Optional Tests: a. CT chest if T2 or T3 b. Bone scan if T2 or T3 or alkaline phosphatase is elevated c. FDG PET/CT imaging is not currently recommended or indicated as part of staging for RCC. B. Therapeutic Options i. Active Surveillance is an appropriate option for the small renal mass (less than 4 cm) in all patients: a. Active surveillance is the preferred option for elderly, frail, and/or highly comorbid patients with a small renal mass that is 4cm or smaller b. Active surveillance is the preferred option for a small renal mass that is 2cm or smaller c. Biopsy is an option if it would alter management. d. Repeat imaging every 6 months. e. Intervention is indicated if there is progression. ii. Surgical Intervention 1, 2 a. Partial nephrectomy should be considered in all cases where surgery is being considered especially small renal masses less than 4cm. This can be done either as an open, laparoscopic, or robotic-assisted laparoscopic procedure, although a minimally invasive partial nephrectomy should be favored when safe, technically feasible and oncologically sound. b. If partial nephrectomy is not feasible, consider minimally-invasive radical nephrectomy. c. If a minimally-invasive surgical procedure cannot be performed due to patient or tumor characteristics, then an open nephrectomy should be done. d. The adrenal gland should not be removed unless involved on imaging. iii. Percutaneous ablation a. Both radiofrequency ablation (RFA) and cryoablation are possible treatments for the small renal mass  . However, this treatment decision should only be made after consultation with a urologist and discussed at multidisciplinary rounds. C. Adjuvant Therapy i. Adjuvant therapy using checkpoint inhibitors has demonstrated some discrepant results with only 1 of 4 trials being positive for the primary endpoint of DFS although OS results are immature. While adjuvant therapy has Health Canada approval, a comprehensive discussion is strongly suggested with each patient before recommending this treatment. a. Adjuvant pembrolizumab can be considered for patients with completely resected clear cell renal cell carcinoma and any of the following features: i. stage pT2 and grade 4 or sarcomatoid features ii. stage pT3-4 N0 iii. Any T-stage with N+ disease iv. M1 NED (i.e. complete metastasectomy within one year of nephrectomy)# Background
In 2022, it is estimated that 8100 Canadians (5400 men and 2700 women) were diagnosed with kidney and renal pelvis cancer, and that 1300 Canadians will died from kidney and renal pelvis cancer .
Renal cell carcinoma (RCC) is the main focus of this guideline. The most common subtype of renal cell carcinoma is clear cell RCC, followed by papillary and chromophobe tumours. Staging of renal cell carcinoma is currently based on the 8th edition (2017) of the American Joint Committee on Cancer's AJCC Cancer Staging Manual (see Appendix).
Guideline Questions 1. What are the appropriate diagnostic tests for renal cell carcinoma? 2. How should renal cell carcinoma be managed (i.e., surgically)? 3. What is the role of systemic therapy and radiotherapy in the management of renal cell carcinoma? 4. Are there other therapies that have shown benefit for patients with renal cell carcinoma? 5. What are the appropriate follow up strategies for renal cell carcinoma?

# Search Strategy
Phase III trials involving 'renal cell carcinoma' that had been published since the last iteration of the guideline were identified and reviewed using the pubmed database. The results of the literature review are available upon request (guru@ahs.ca).

# Target Population
Adult patients (18 years of age) with a diagnosis, or suspected diagnosis of renal cell carcinoma.

# Recommendations
Stage T1-3, N+/-M0, Indications include imaging suspicious for primary renal malignancy localized to the kidney or immediate surrounding structures. ii. Adjuvant therapy using anti-angiogenic therapies is currently not recommended post definitive management of renal cell carcinoma .

# D. Follow-up
Follow up is based on the recommendations of the Canadian Urological Association (CUA) as published on the CUA website (/) and the CUA Journal (CUAJ) in 2018 10 , and is stage dependent: 
(pT1) Hx & PE X X X X X Blood Test X X X X X CXR X X X X X CT or U/S abdomen X X Intermediate Risk (pT2) Hx & PE X X X X X X X X Blood Test X X X X X X X X CXR X X X X X X X X CT or U/S abdomen X X X X High Risk (pT3-4)- Hx & PE X X X X X X X X Blood Test X X X X X X X X CXR X X X X X X X X CT abdomen X X X X X X Very High Risk (pTxN+)- Hx & PE X X X X X X X X X Blood Test X X X X X X X X X CXR X X X X X X X X X CT abdomen X X X X X X X X X
*For High-and Very High-risk patients, consider an extended individualized follow up beyond 60 months.
Stage T4N0M0, cTxN1Mx, TxNxM+ 11 Indications for systemic therapy include locally advanced, unresectable cancer or metastatic disease. The International mRCC Database Consortium (IMDC) risk factors (hypercalcemia, neutrophilia, thrombocytosis, anemia, Karnofsky performance status <80%, and time from diagnosis to treatment <1 year) are used to stratify patients into 3 risk groups. Patients with 0 factors vs. 1-2 factors vs. 3 or more factors are deemed favorable, intermediate, and poor-risk, respectively. 12 An online calculator is available at /.

# Management 13
A. Staging i. CT scan of head, chest, abdomen, pelvis with contrast (or MRI) ii. CBC, creatinine, urea, calcium, albumin, AST, ALT, ALP, bilirubin and TSH.
iii. If an IO is being considered additional targeted bloodwork can be requested at baseline if concerns regarding anticipated auto-immune toxicity from checkpoint inhibitors (eg: a.m. cortisol, lipase, T3, T4, creatine kinase, glucose etc). iv. Other additional imaging modalities can be considered as clinically indicated (bone scan, MRI) v. FDG-PET/CT is not recommended in this setting

# First-line Therapies
Favorable-Risk:
A. Pembrolizumab/Axitinib (Pembro/Axi) 14 i. Indication: a. First-line therapy for advanced RCC based on phase III data.
ii. Dose and Schedule: a. Pembrolizumab at 2mg/kg (capped at 200mg) intravenously once every 3 weeks plus axitinib 5mg orally twice daily. b. Pembrolizumab is given for a maximum of 35 consecutive cycles (~ 2 years). There is no recommended dose adjustment for pembrolizumab. c. Axitinib should be dose adjusted to maximum treatment tolerance by titrating dose higher or lower (maximum 10 mg po twice daily and minimum 1 mg po twice daily). d. Treatment is generally given until disease progression, intolerance or patient decision provided the caveats regarding number of total cycles of pembrolizumab.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pembrolizumab and axitinib and the potential overlapping toxicities. As a general rule, axitinib-induced toxicity would be expected to improve quickly with cessation of therapy, whereas an immune mediated adverse event (irAE) would not improve after stopping axitinib. b. It is important to have early recognition of irAEs that require prompt intervention with immunosuppressing agents (eg: high dose steroids). Colitis (diarrhea), pneumonitis, endocrinopathies (hypophysitis, hypothyroidism, adrenal insufficiency), hepatitis and rash are some examples. Patients should be educated about these toxicities and followed every cycle to look for these adverse events. c. Lenvatinib should be dose adjusted to maximum treatment tolerance by titrating dose higher or lower (maximum 10 mg po twice daily and minimum 1 mg po twice daily). d. Treatment is generally given until disease progression, intolerance or patient decision provided the caveats regarding number of total cycles of pembrolizumab.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pembrolizumab and lenvatinib and the potential overlapping toxicities. As a general rule, lenvatinib-induced toxicity would be expected to improve quickly with cessation of therapy, whereas an immune mediated adverse event (irAE) would not improve after stopping lenvatinib. ii. Dose and Schedule: a. A starting dose at 50 mg/day orally for 4 weeks followed by a 2-week rest period for a 6-week treatment cycle is indicated in the product monograph. However, an individualized schedule optimizing the therapeutic ratio with anywhere from 1-4 weeks on therapy followed by a 1-week break as determined by treatment tolerance is recommended b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of sunitinib and follow patients accordingly with experienced nursing support. Patients should be assessed regularly for treatment tolerance. b. Sunitinib should be dosed to maximum treatment tolerance as there is evidence that higher AUC leads to higher response rates. c. Cardiotoxicity has become an issue and in patients with pre-existing compromised cardiac function. Monitoring of ejection fraction should be considered in high risk or symptomatic patients but routine monitoring in all patients is not indicated. ii. Dose and schedule a. A starting dose 800 mg/day orally taken on a continuous basis is indicated in the product monograph. However, an individualized schedule optimizing the therapeutic ratio with anywhere from 1-4 weeks on therapy followed by a 1-week break as determined by treatment tolerance is recommended. b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity: a. Physicians must be aware of the toxicity profile of pazopanib and follow patients accordingly with experienced nursing support. Patients should be assessed regularly for treatment tolerance. b. Pazopanib should be dosed to maximum treatment tolerance as there is evidence that higher AUC leads to higher response rates. c. Liver enzymes and bilirubin should be frequently measured (at least once every two weeks initially) as they are elevated with this drug more frequently than with other VEGFR-TKIs. d. The COMPARZ and PISCES trial reported safety and quality-of-life profiles may favor pazopanib when compared to sunitinib. ii. Dose and Schedule a. Nivolumab at 3 mg/kg (capped at 240 mg) and Ipilimumab at 1 mg/kg both given intravenously every three weeks for four cycles. This is followed by nivolumab only as maintenance therapy at 3mg/kg (capped at 240mg) every 2 weeks or 6 mg/kg (capped at 480 mg) intravenously every 4 weeks. The maintenance schedule is determined at discretion of the physician and patient. Maintenance treatment can begin anywhere from 4-6 weeks after last dose of ipi/nivo assuming patient is benefiting from treatment. b. Treatment is given until disease progression, intolerance or patient decision.
iii. Toxicity a. It is important to have early recognition of immune mediated adverse events that require prompt intervention with high dose steroids. Colitis (diarrhea), pneumonitis, endocrinopathies (hypophysitis, hypothyroidism, adrenal insufficiency), hepatitis and rash are some examples.
Patients should be educated about these toxicities and followed every cycle to look for these adverse events. 

# Discussion

# Early Stage Disease
For patients with early stage node negative disease, options for first-line therapy include partial nephrectomy, active surveillance or minimally invasive therapy with cryoablation or radiofrequency ablation. Active surveillance is best suited for individuals with small renal masses, who are elderly or medically compromised. In these patients, a biopsy is recommended initially, followed by repeat imaging every six months with intervention upon progression. Cryoablation and radiofrequency ablation can also be considered for patients with T1a disease after consultation with a urologist. Both are excellent treatment options for early stage disease, with long-term disease free survival rates ranging from 92 to 98%. A retrospective study among patients with renal cell carcinoma who underwent percutaneous CT-guided radiofrequency ablation (n=41) or cryoablation (n=70) demonstrated equivalent imaging (e.g. MRI) recurrence rates (11% vs. 7%, respectively; p=.60).  In medically fit patients, including those that are elderly, partial nephrectomy is an excellent option. In an analysis of the SEER database, among patients with T1aN0M0 renal cell carcinoma (n=7,280), cancer-specific mortality for partial-and radical-nephrectomy were 1.8% and 2.5%, respectively (p=.5) for all patients and 1.0% and 3.4% (p=0.7), respectively, for patients aged 70 years and over 1  If surgery is planned, partial nephrectomy should be offered when technically feasible, especially for clinical T1a renal masses. For large renal masses and/or when partial nephrectomy would be technically challenging, radical nephrectomy can be considered. If radical nephrectomy is performed, a laparoscopic approach should be offered when possible.

# Advanced Stage Disease

# Systemic Therapy:
For patients with advanced, unresectable or metastatic disease, systemic therapy is indicated.

# First-line Therapy:
The combination of ipilimumab and nivolumab (ipi/nivo) compared to sunitinib alone was studied in the CHECKMATE 214 study 29  The JAVELIN Renal 101 trial compared the combination of avelumab + axitinib (ave/axi) to sunitinib alone 54 . As per the updated efficacy results based on minimum follow-up period of 13 months 55 , ave/axi significantly improved median PFS compared with sunitinib alone at 13.3 months vs 8.0 months (HR 0.69  p < 0.0001). The overall survival data showed no difference between the two arms however this data is immature. This combination is not Health Canada approved at the time of writing this guideline.
The CheckMate 9ER trial compared the combination of nivolumab + cabozantinib (nivo/cabo) 56 to sunitinib alone. At a median follow-up of 23.5 months 57 , nivo/cabo was superior to sunitinib in terms of PFS (17.0 months vs. 8.3 months, HR 0.52  p 40 mg of prednisone daily or equivalent). Health-related quality of life was superior in combination arm compared to sunitinib. 58 This combination is Health Canada approved but not funded at the time of writing this document.
The CLEAR study compared the combination of lenvatinib + pembrolizumab (len/pembro) or lenvatinib + everolimus (len/eve) to sunitinib alone. 15  ) with a 16.1% CR rate in the len/pembro arm compared to 9.8% and 4.2% in the len/eve and sunitinib arms respectively. Grade 3 or higher AEs occurred in 82.4%, 83.1% and 71.8% of patient in the len/pembro, len/eve, and sunitinib arms respectively. Grade 3 or higher adverse events that occurred in 10% or more of patients in any treatment group included diarrhea, hypertension, an elevated lipase level, and hypertriglyceridemia. The len/pembro combination has been Health Canada approved at the time of writing this guideline although provincial funding has yet to be finalized. The len/eve combination is not Health Canada approved.
Sunitinib and pazopanib may be treatment options first line, but the above mentioned options have demonstrated superiority to sunitinib. Only in patients in whom checkpoint inhibitors are contraindicated or in patients who refuse checkpoint inhibitor therapy should sunitinb or pazopanib be considered in the first line setting.

# After First-line Therapy:
The CheckMate 025 trial demonstrated an overall survival benefit of nivolumab compared to everolimus with fewer grade 3 or 4 adverse events in patients previously treated either 1 or 2 VEGFR-TKIs 35,59 . Median OS was 25.0 months in the nivolumab arm vs. 19.6 months in the everolimus arm (N=821). Median PFS was 4.6 months with nivolumab and 4.4 months with everolimus. Grade 3/4 treatment-related adverse events occurred in 19% of nivolumab patients and 37% of everolimus patients 35 .
Axitinib is a selective second-generation inhibitor of VEGF receptors. It has shown positive results in a phase III trial compared with sorafenib. The 723 patients included in the study had confirmed RCC that progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Median PFS was 6.7 months for axitinib versus 4.7 months in patients receiving sorafenib, with non-significant differences regarding toxicity 44 . Axitinib demonstrated activity in patients previously treated with checkpoint inhibitor in a non-randomized phase 2 trial (n = 40), with a median PFS of 8.8 months. 60 Retrospective analyses have also shown benefits of axitinib in the second and third-line setting, including those who have had previous exposure to checkpoint inhibitor. As of the time of writing this document, axitinib is funded as a treatment after 1 prior VEGFR-TKI but it is not funded as the next immediate option for patients who progressed on first-line checkpoint inhibitor-based regimens. 40,41 Cabozantinib is multi-targeted TKI that uniquely not only target VEGFR but also MET and AXL. Resistance to PD-1/PD-L1 inhibition has been associated with increased expression of VEGFR, MET and AXL. 61 The METEOR trial has reported PFS benefit and an OS benefit for cabozantinib when compared to everolimus in patients that progressed after VEGFR-targeted therapy. 37 Median PFS was 7.4 months with cabozantinib and 3.8 months with everolimus (p<0.001) and the ORR was higher with cabozantinib (21% vs 5% with everolimus; p<0.001). Overall survival was longer with cabozantinib when compared to everolimus (HR 0.66 . 37 Adverse events were managed with dose reduction; dose reduction occurred in 60% of patients who received cabozantinib (vs. 25% in those on everolimus), and discontinuation of treatment due to adverse events occurred in 9% of patients who received cabozantinib vs. 10% in those on everolimus.
In the METEOR trial, a minority of patients had also received immunotherapy in addition to one or two lines of TKI prior to start of cabozantinib. Furthermore, retrospective series from real-world setting have demonstrated the effectiveness of cabozantinib after failure of first-line immunotherapy, as well as those who have been heavily-pretreated, 62,63 with median time-to-treatment failure (TTF) of 8.0 months. In the absence of prospective data, cabozantinib should be a valid treatment option for those who progress on first-line immunotherapy regimen. Currently, it can be accessed through Director's Privilege as a second-line option for patients who progress on first-line pembro/axi. However, it is not funded as a second-line option for those who progress on first-line ipi/nivo.
There is also evidence from retrospective analyses supporting the use of sunitinib or pazopanib postprogression on first-line checkpoint inhibitor, with median PFS reported in the range of 6 to 13 months. 42,64,65 Both treatments are currently funded as a second-line option following ipi/nivo in intermediate or poor risk patients. However, they are not funded as a second-line option following pembro/axi.
A small, randomized, three-arm, phase 2 trial of oral multi-targeted TKI lenvatinib, everolimus, and the combination of both was conducted in patients who progressed after one previous VEGFR TKI. This study demonstrated improved PFS for the combination arm over everolimus alone (median 14.6 months vs. 5.5 months; HR 0.40 [95% CI 0.24 -0.68; p = 0.0005). 59 The combination numerically prolonged PFS compared with lenvatinib alone although this was not statistically significant (median 14.6 months vs. Historically, everolimus monotherapy was considered a reasonable treatment option post progression on a VEGFR-TKI but this is now superseded by the above. There may be rare instances where a VEGFR-TKI is not recommended or tolerated such that everolimus can be considered.
The appropriate sequencing of these agents after first-line therapy is unknown. The current recommended treatment options in Alberta are shown in figure 2. 

# Local Therapy:
Prior to 2018, there is little data to guide clinical practice in relation to cytoreductive nephrectomy (CN) in the era of targeted therapy and decisions are made based on clinical indications. In phase III trials, the majority of patients had undergone a nephrectomy prior to systemic therapy 16,66,67 . Nephrectomy has proven overall survival benefit when used in conjunction with interferon 68,69 . Among patients treated with interferon alfa-2a (n=159), univariate and multivariate statistical analyses showed that prior nephrectomy was a significant prognostic factor for survival 69 . A prospective trial also showed that among patients with metastatic renal-cell cancer who were acceptable candidates for nephrectomy (n=120), the addition of interferon alfa-2b resulted in prolonged median survival (11.1 vs. 8.1 months, interferon alone; p=.05) 68,69 . Patients who appear to benefit most from nephrectomy are those with most of the tumor burden within the kidney, good performance status, and no central nervous system or liver involvement (with rare exceptions) 68,69 . Other considerations include surgical resectability, including possible morbidity to proximal vital structures, encasement of the renal hilum and other complicating factors 46,51 . Laparoscopic nephrectomy is the emerging standard surgical procedure and should be considered whenever technically feasible 70,71 .
The phase III CARMENA 49 trial was published in 2018 and it randomized patients to cytoreductive nephrectomy with sunitinib versus sunitinib alone. It demonstrated that sunitinib alone is non-inferior to the cytoreductive nephrectomy arm. It should be noted that over 40% of patients enrolled had poor-risk disease so the typical CN patient may not have been included in this trial. Thus, there remain patients that should still be considered for CN including patients with limited metastatic disease with large primary tumors and those with symptomatic primary tumors. A retrospective series of 198 patients presented at GU ASCO 2020 72 showed that cytoreductive nephrectomy was associated with improved survival for patients with metastatic renal cell carcinoma treated with immunotherapy. However, there is no prospective data on CN with first line checkpoint inhibitor combinations. Currently, upfront CN should be considered in the following clinical scenario 73  Deferred cytoreductive nephrectomy should be considered in patients with strong responses to systemic therapy. CN should rarely be performed in patients with poor-risk disease or patients with rapidly progressive disease or high disease burden who need systemic therapy.
Lastly, Nephrectomy or renal embolization (when nephrectomy is not possible) can also be offered as palliative procedures at any time when clinically indicated.

# Adjuvant Therapy:
Currently, there is no role for adjuvant therapy using anti-angiogenic therapies in localized, resected renal cell carcinoma. The adjuvant ASSURE trial 74 randomized patients between sunitinib, sorafenib and placebo and did not demonstrate any benefit. The S-TRAC trial 75 randomized higher risk clear cell patients to one year of sunitinib versus placebo. There was a difference in disease free survival however the overall survival data were immature and there was no difference. Additionally, the PROTECT clinical trial of adjuvant pazopanib vs placebo was negative for the primary endpoint. The phase III ATLAS trial evaluating axitinib (Inlyta) as adjuvant therapy for patients at high risk of recurrent RCC after nephrectomy was halted after interim analysis due to futility 76 .
The use of immunotherapy in the adjuvant setting has been tested as per the Keynote 564 study. 77,78 Here, patients with high risk of recurrence after nephrectomy were randomized to pembrolizumab or placebo for 17 cycles (approximately 1 year). After a median of 30 months follow up post randomization, the primary endpoint of disease-free survival (DFS) was met with disease-free survival at 30 months at 752% (95% CI 708-791) in the pembrolizumab group and 655% (609-697) in the placebo group. The HR for DFS was HR 063 (95% CI 050-080] and met statistical. OS data are trending toward significance but still immature. Grade 3 or higher adverse events of any cause occurred in 32% of the patients who received pembrolizumab and in 18% of those who received placebo. No deaths related to pembrolizumab therapy have occurred. Pembrolizumab has recently received Health Canada approval but is awaiting provincial funding.
There have been three other studies looking at treatment with checkpoint inhibitors in the periooperative/adjuvant setting -IMmotion01089 79 , CheckMate 914 80 , and PROSPER 81 . All three were presented at ESMO 2022 and all three did not show any benefit with DFS. It is not clear why these three trials were negative for their primary endpoint of DFS while KEYNOTE564 was positive and further investigation/analysis is pending to explain this discrepancy. Overall survival endpoints have also not been met in any of these above studies, therefore, a comprehensive discussion with each individual patient is suggested prior to recommending adjuvant checkpoint inhibitor therapy.

# Appendix

# Development and Revision History
This guideline was developed by a multidisciplinary working group comprised of members from the Alberta Provincial GU Tumour Team, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. The draft guideline was externally reviewed and endorsed by members of the Alberta Provincial GU Tumour Team who were not involved in the guideline's development, including urologists, radiation oncologists, medical oncologists, nurses, pathologists, and pharmacists. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2005.

# Maintenance
A formal review of the guideline will be conducted in 2024. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. 

# Abbreviations