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'''INCLUDES 2019 CUA Advanced Kidney Cancer Consensus Statement, 2019 CUA Cytoreductive Nephrectomy Consensus Statement'''
'''INCLUDES 2019 CUA Advanced Kidney Cancer Consensus Statement, 2019 CUA Cytoreductive Nephrectomy Consensus Statement'''


== Prognostic factors in advanced RCC ==
== Prognostic factors in Metasatic RCC ==


* '''2 prognostic models have been developed: Motzer and Heng criteria'''
* '''2 prognostic models have been developed: Motzer and Heng criteria'''
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=== Motzer criteria ===
=== Motzer criteria ===


* '''Developed in''' 463 '''patients with advanced kidney cancer (stage IV) of any histology treated with interferon (IFN)-α as the first-line systematic therapy'''§
* '''Developed in''' 463 '''patients with advanced kidney cancer (stage IV) of any histology treated with interferon (IFN)-α as the first-line systematic therapy[https://pubmed.ncbi.nlm.nih.gov/11773181/ §]'''
* '''Variables significantly associated with decreased overall survival (5):'''
* '''Variables significantly associated with decreased overall survival (5):'''
*# '''Karanofsky performance status (<80)'''
*# '''<span style="color:#ff0000">Karanofsky performance status (<80)'''
*# '''Interval from diagnosis to treatment (<1 year)'''
*# '''<span style="color:#ff0000">Interval from diagnosis to treatment (<1 year)'''
*# '''Hemoglobin (< lower limit of normal)'''
*# '''<span style="color:#ff0000">Hemoglobin (< lower limit of normal)'''
*# '''Corrected Calcium (>10 g/dL)'''
*# '''<span style="color:#ff0000">Corrected Calcium (>10 g/dL)'''
*# '''Lactate dehydrogenase (>1.5x the upper limit of normal)'''
*# '''<span style="color:#ff0000">Lactate dehydrogenase (>1.5x the upper limit of normal)'''
* '''Stratified into 3 risk groups based on the number of risk factors present:'''
* '''<span style="color:#ff0000">Stratified into 3 risk groups based on the number of risk factors present:'''
** '''Favourable-risk: 0 risk factors;''' median survival 30 months
** '''<span style="color:#ff0000">Favourable-risk: 0 risk factors</span>'''; median survival 30 months
** '''Intermediate-risk: 1-2 risk factors;''' median survival 14 months
** '''<span style="color:#ff0000">Intermediate-risk: 1-2 risk factors</span>'''; median survival 14 months
** '''Poor-risk: ≥3 risk factors;''' median survival 5 months
** '''<span style="color:#ff0000">Poor-risk: ≥3 risk factors</span>'''; median survival 5 months
 
'''Heng (IMDC) criteria'''


=== Heng (IMDC) criteria ===
* The use of targeted therapy for advanced kidney cancer has displaced immunotherapy as the first-line systemic treatment due to improved survival and better tolerability
* The use of targeted therapy for advanced kidney cancer has displaced immunotherapy as the first-line systemic treatment due to improved survival and better tolerability
* Heng et al. subsequently '''developed a prognostic model''' '''in''' 645 '''patients with advanced kidney cancer of any histology treated with targeted (anti-vascular endothelial growth factor) therapy as the first-line systematic therapy'''
* Heng et al. subsequently '''developed a prognostic model''' '''in''' 645 '''patients with advanced kidney cancer of any histology treated with targeted (anti-vascular endothelial growth factor) therapy as the first-line systematic therapy'''
* '''6 variables significantly associated with overall survival K-PINCH:'''
* '''<span style="color:#ff0000">6 variables significantly associated with overall survival K-PINCH:</span>'''
** '''4 of the Motzer criteria (without lactate dehydrogenase)'''
** '''<span style="color:#ff0000">4 of the Motzer criteria (without lactate dehydrogenase)</span>'''
** '''Neutrophil count (> upper limit of normal)'''
** '''<span style="color:#ff0000">Neutrophil count (> upper limit of normal)</span>'''
** '''Platelets (> upper limit of normal)'''
** '''<span style="color:#ff0000">Platelets (> upper limit of normal)</span>'''
* '''Stratified into 3 risk groups based on number of risk factors present:'''
* '''<span style="color:#ff0000">Stratified into 3 risk groups based on number of risk factors present:</span>'''
** '''Favourable-risk: 0 risk factors'''; median survival not reached
** '''<span style="color:#ff0000">Favourable-risk: 0 risk factors</span>'''; median survival not reached
** '''Intermediate-risk: 1-2 risk factors'''; median survival 27 months
** '''<span style="color:#ff0000">Intermediate-risk: 1-2 risk factors</span>'''; median survival 27 months
** '''Poor-risk: ≥3 risk factors'''; median survival 9 months
** '''<span style="color:#ff0000">Poor-risk: ≥3 risk factors</span>'''; median survival 9 months
 
== Surgical Management of Metastatic Renal Cell Carcinoma ==
 
=== Cytoreductive Nephrectomy (CN) ===
 
==== Cytokine Therapy (IFN-'''α)''' ====
*Meta-analysis of 2 trials (SWOG 8949 and EORTC 30947) found significantly improved OS by 5.8 months in CN followed by IFN- α group (13.6 months CN IFN α2b vs. 7.8 months IFN α2b, p=0.02) vs. IFN- α alone
 
===== <span style="color:#ff00ff">SWOG 8949 =====
* Randomized 249 patients with metastatic RCC of any histology to IFN-α vs. CN followed by IFN- α
* Results:
** OS was improved, though not significantly, in the CN group (median OS 11 months CN + IFN α2b vs. 8 months IFN α2b, p=0.05)
 
===== <span style="color:#ff00ff">EORTC 30947 =====
* Randomized 85 patients with metastatic RCC of any histology to IFN-α vs. CN followed by IFN-α
* Results:
** OS was significantly improved in the CN group (median OS 17 months CN + IFN-α vs. 7 months IFN-α, p=0.03)
 
==== Targeted Therapy ====
*'''The introduction of effective targeted therapy questioned the role of CN in the modern era'''
 
===== CN followed by Targeted Therapy vs. Targeted Therapy alone =====
 
====== <span style="color:#ff00ff">CARMENA</span> (Clinical Trial to Assess the Importance of Nephrectomy) ======
* '''Population: 452 patients with metastatic ccRCC'''
** 44% had poor-risk disease, 56% had intermediate-risk
*** '''Trial does not apply to patients with favourable-risk'''
* '''<span style="color:#ff0000">Randomized to CN followed by sunitnib vs. sunitnib alone'''
* '''Primary outcome: OS'''
* '''Median follow-up 50.2 months'''
* '''<span style="color:#ff0000">Results'''
** '''<span style="color:#ff0000">OS: sunitinib alone was non-inferior to CN followed by sunitinib</span>''' (HR 0.89; 95% CI 0.71–1.10)
** '''No significant difference PFS or response to treatment'''
* [https://pubmed.ncbi.nlm.nih.gov/29860937/ Méjean, Arnaud, et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379.5 (2018): 417-427.]
 
===== CN before vs. after Targeted Therapy =====
 
* In patients with mRCC who are being considered for CN, the optimal timing relative to the initiation of systemic therapy also remains controversial.
 
* '''Advantages of initiating systemic therapy prior to CN:'''
*# '''May provide symptomatic control and disease stabilization or regression for patients with a large tumour burden'''
*# '''May allow the identification of patients not likely to benefit from CN; specifically, patients who progress rapidly on systemic therapy have a poor prognosis and are unlikely to derive a survival advantage by undergoing CN'''
*# '''Decreases the size of the primary tumour in a proportion of patients'''
*#* The median decrease in size is estimated to be 7-32% and the clinical impact of this is questionable
*#* Tumour may also increase in size or complexity during systemic therapy, reducing the feasibility of resection
* '''Advantages of upfront CN (3):'''
*# '''Palliating symptoms related to the primary tumour'''
*# '''Eliminating a source of secondary metastases'''
*# '''Improving host immune dysfunction'''
 
====== <span style="color:#ff00ff">SURTIME ======
* '''Population: 99 patients with metastatic ccRCC'''
* '''<span style="color:#ff0000">Randomized to upfront CN followed by sunitnib vs. upfront sunitinib followed by CN (deferred CN)'''
** '''Investigated optimal timing of CN relative to initiation of systemic therapy'''
* '''Primary endpoint: disease progression at 28 weeks'''
* '''<span style="color:#ff0000">Results:'''
** '''<span style="color:#ff0000">No difference in disease progression</span>''' (42.0% vs. 42.9%, respectively at 28 weeks of follow-up; p>0.99) '''between upfront vs. deferred CN'''
** '''OS improved in deferred CN group (median OS 32.4 vs. 15 months; p=0.034)'''
*** '''Difficult to interpret this result due to discordance with the disease progression results'''
* [https://pubmed.ncbi.nlm.nih.gov/30543350/ Bex, Axel, 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 5.2 (2019): 164-170.]


== Surgical management of metastatic renal cell carcinoma ==
==== Guideline Recommendations ====


=== Cytoreductive nephrectomy (CN) ===
* '''Trials do not address whether there is a benefit to CN after targeted therapy (sunitnib alone vs. sunitnib followed by CN)'''
* '''Several retrospective observational studies have identified a significant survival advantage in favour of CN for patients treated with targeted therapies'''


* '''The role of CN before systemic therapy (IFN-''' '''α) has been extensively studied in the era of cytokine therapy'''
===== 2019 CUA Cytoreductive Nephrectomy Consensus Statement =====
** '''SWOG 8949'''
* '''Decisions regarding CN should ideally be made in a multidisciplinary setting'''
*** Randomized 249 patients with metastatic RCC of any histology to IFN-α vs. CN followed by IFN- α
* '''In patients with metastatic RCC, offer upfront CN''' followed by metastases-directed therapy, a period of surveillance, or systemic therapy '''in patients with (5):'''
*** Results:
*# '''Good performance status (Eastern Cooperative Oncology Group [ECOG] ≤1 or Karnofsky performance status (KPS) ≥80%)'''
**** OS was improved, though not significantly, in the CN group (median OS 11 months CN + IFN α2b vs. 8 months IFN α2b, p=0.05)
*# '''Resectable primary tumour'''
** '''EORTC 30947'''
*# '''Limited burden of metastatic disease'''
*** Randomized 85 patients with metastatic RCC of any histology to IFN-α vs. CN followed by IFN-α
*# '''Minimal symptoms related to metastases'''
*** Results:
*# '''No active CNS metastases'''
**** OS was significantly improved in the CN group (median OS 17 months CN + IFN-α vs. 7 months IFN-α, p=0.03)
* '''CN should not be done in patients with (2):'''
** Meta-analysis of the 2 trials found '''significant improved OS in CN group by 5.8 months''' (13.6 months CN IFN α2b vs. 7.8 months IFN α2b, p=0.02)
*# '''Rapidly progressing disease'''
* '''The introduction of effective targeted therapy has questioned the role of CN in the modern era'''
*# '''Limited life expectancy'''
** '''CARMENA''' (Clinical Trial to Assess the Importance of Nephrectomy)
* Also consider patient’s age, general health status, and competing health risks when making decisions regarding the role of CN, as these are surrogate markers of OS
*** '''Population: 452 patients with metastatic ccRCC'''
* '''Patients with mRCC but without characteristics listed above (i.e. not optimal candidate but no contraindications) should be offered initial treatment with systemic therapy with consideration of CN given to those with a significant clinical response'''
**** 44% had poor-risk disease, 56% had intermediate-risk
* '''Patients with non-clear-cell mRCC should be offered CN with similar considerations to those with clear-cell mRCC.'''
***** '''Trial does not apply to patients with favourable-risk'''
** The majority of data on CN pertain to patients with clear-cell histology, and thus whether CN provides a survival advantage for appropriately selected patients with non-clear-cell mRCC remains uncertain.
*** '''Randomized to CN followed by sunitnib vs. sunitnib alone'''
*** The 2 CN trials performed in the IFN-era mentioned above did not include information on histological subtypes
*** '''Primary outcome: OS'''
*** '''CARMENA and SURTIME excluded patients with non-clear-cell mRCC.'''
*** '''Median follow-up 50.2 months'''
*** Limited observational data do suggest that CN may provide a survival advantage in patients with non-clear mRCC.
*** '''Results'''
* '''Histologic diagnosis before treatment'''
**** '''OS: sunitinib alone was non-inferior to CN followed by sunitinib''' (HR 0.89; 95% CI 0.71–1.10)
** '''In patients receiving initial systemic therapy, histologic diagnosis SHOULD be obtained''' (biopsy of the primary lesion or a metastatic deposit) '''prior to initiation of therapy to guide systemic treatment'''
**** '''No significant difference PFS or response to treatment'''
*** Systemic therapy will depend on the histologic subtype
*** Méjean, Arnaud, et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379.5 (2018): 417-427.
** '''For patients receiving upfront CN, histologic diagnosis MAY BE PERFORMED IF the results of the biopsy will influence management'''
** '''In patients with mRCC who are being considered for CN, the optimal timing relative to the initiation of systemic therapy also remains controversial.'''
*** As noted above, CN appears to play a role in treating non-clear-cell mRCC, and appropriately selected patients can thus proceed directly to CN without a biopsy. However, if a non-RCC histology is questioned (e.g., imaging characteristics suggestive of urothelial carcinoma, lymphoma, etc.), a biopsy prior to CN should be performed, as the results may significantly alter the patient’s subsequent management.
*** '''Advantages of initiating systemic therapy prior to CN:'''
* In the setting of oligometastatic disease, the link between primary and secondary masses cannot be assumed reliably. Limited data are available with regards to the role of percutaneous biopsy in this setting.
***# '''May provide symptomatic control and disease stabilization or regression for patients with a large tumour burden'''
* CN can be performed through both minimally invasive and open surgical approaches at the discretion of the treating surgeon
***# '''May allow the identification of patients not likely to benefit from CN; specifically, patients who progress rapidly on systemic therapy have a poor prognosis and are unlikely to derive a survival advantage by undergoing CN'''
** Adrenal-sparing is appropriate when there is no evidence of tumour invasion or metastatic spread and when technically feasible.
***# '''Decreases the size of the primary tumour in a proportion of patients'''
* '''Lymphadenectomy'''
***#* The median decrease in size is estimated to be 7-32% and the clinical impact of this is questionable
** '''In patients with mRCC undergoing CN who do not have clinical evidence of nodal disease, retroperitoneal LND is not recommended.'''
***#* Tumour may also increase in size or complexity during systemic therapy, reducing the feasibility of resection
** '''Surgical resection of clinically positive lymph nodes may be considered at the time of CN after weighing the potential for increased surgical morbidity and the uncertain clinical benefit.'''
*** '''Advantages of upfront CN (3):'''
*** '''LND does not appear to provide a survival advantage in mRCC patients.''' Similar findings have been noted in patients with and without clinically positive lymph nodes
***# '''Palliating symptoms related to the primary tumour'''
***# '''Eliminating a source of secondary metastases'''
***# '''Improving host immune dysfunction'''
*** '''SURTIME''' (Immediate Surgery or Surgery After sunitinib Malate in Treating Patients With Metastatic Kidney Cancer) '''TIMING of CN'''
**** '''99 patients with metastatic ccRCC'''
**** '''Randomized to upfront CN followed by sunitnib vs. upfront sunitinib followed by CN (deferred CN)'''
***** '''Investigated optimal timing of CN relative to initiation of systemic therapy'''
**** '''Primary endpoint: disease progression at 28 weeks'''
**** '''Results:'''
***** '''No difference in disease progression''' (42.0% vs. 42.9%, respectively at 28 weeks of follow-up; p>0.99) '''between upfront vs. deferred CN'''
***** '''OS improved in deferred CN group (median OS 32.4 vs. 15 months; p=0.034)'''
****** '''Difficult to interpret this result due to discordance with the disease progression results'''
**** Bex, Axel, 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 5.2 (2019): 164-170.
** '''Several retrospective observational studies have identified a significant survival advantage in favour of CN for patients treated with targeted therapies'''
* '''As per the 2019 CUA Cytoreductive Nephrectomy Consensus Statement:'''
** '''Decisions regarding CN should ideally be made in a multidisciplinary setting'''
** '''In patients with metastatic RCC, offer upfront CN''' followed by metastases-directed therapy, a period of surveillance, or systemic therapy '''in patients with (5):'''
**# '''Good performance status (Eastern Cooperative Oncology Group [ECOG] ≤1 or Karnofsky performance status (KPS) ≥80%)'''
**# '''Resectable primary tumour'''
**# '''Limited burden of metastatic disease'''
**# '''Minimal symptoms related to metastases'''
**# '''No active CNS metastases'''
** '''CN should not be done in patients with (2):'''
**# '''Rapidly progressing disease'''
**# '''Limited life expectancy'''
** Also consider patient’s age, general health status, and competing health risks when making decisions regarding the role of CN, as these are surrogate markers of OS
** '''Patients with mRCC but without characteristics listed above (i.e. not optimal candidate but no contraindications) should be offered initial treatment with systemic therapy with consideration of CN given to those with a significant clinical response'''
** '''Patients with non-clear-cell mRCC should be offered CN with similar considerations to those with clear-cell mRCC.'''
*** The majority of data on CN pertain to patients with clear-cell histology, and thus whether CN provides a survival advantage for appropriately selected patients with non-clear-cell mRCC remains uncertain.
**** The 2 CN trials performed in the IFN-era mentioned above did not include information on histological subtypes
**** '''CARMENA and SURTIME excluded patients with non-clear-cell mRCC.'''
**** Limited observational data do suggest that CN may provide a survival advantage in patients with non-clear mRCC.
** '''Histologic diagnosis before treatment'''
*** '''In patients receiving initial systemic therapy, histologic diagnosis SHOULD be obtained''' (biopsy of the primary lesion or a metastatic deposit) '''prior to initiation of therapy to guide systemic treatment'''
**** Systemic therapy will depend on the histologic subtype
*** '''For patients receiving upfront CN, histologic diagnosis MAY BE PERFORMED IF the results of the biopsy will influence management'''
**** As noted above, CN appears to play a role in treating non-clear-cell mRCC, and appropriately selected patients can thus proceed directly to CN without a biopsy. However, if a non-RCC histology is questioned (e.g., imaging characteristics suggestive of urothelial carcinoma, lymphoma, etc.), a biopsy prior to CN should be performed, as the results may significantly alter the patient’s subsequent management.
** In the setting of oligometastatic disease, the link between primary and secondary masses cannot be assumed reliably. Limited data are available with regards to the role of percutaneous biopsy in this setting.
** CN can be performed through both minimally invasive and open surgical approaches at the discretion of the treating surgeon
*** Adrenal-sparing is appropriate when there is no evidence of tumour invasion or metastatic spread and when technically feasible.
** '''Lymphadenectomy'''
*** '''In patients with mRCC undergoing CN who do not have clinical evidence of nodal disease, retroperitoneal LND is not recommended.'''
*** '''Surgical resection of clinically positive lymph nodes may be considered at the time of CN after weighing the potential for increased surgical morbidity and the uncertain clinical benefit.'''
**** '''LND does not appear to provide a survival advantage in mRCC patients.''' Similar findings have been noted in patients with and without clinically positive lymph nodes


=== Metastatectomy for distant recurrence ===
=== Metastatectomy for distant recurrence ===
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