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Metastatic Kidney Cancer: Difference between revisions

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=== Cytoreductive Nephrectomy (CN) ===
=== Cytoreductive Nephrectomy (CN) ===


==== CN before systemic therapy ====
==== Cytokine Therapy (IFN-'''α)''' ====
*'''Extensively studied in the era of 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'''
*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)


===== SWOG 8949 =====
===== SWOG 8949 =====
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** OS was significantly improved in the CN group (median OS 17 months CN + IFN-α vs. 7 months IFN-α, p=0.03)
** OS was significantly improved in the CN group (median OS 17 months CN + IFN-α vs. 7 months IFN-α, p=0.03)


* '''The introduction of effective targeted therapy has questioned the role of CN in the modern era'''
==== Targeted Therapy ====
** '''CARMENA''' (Clinical Trial to Assess the Importance of Nephrectomy)
*'''The introduction of effective targeted therapy questioned the role of CN in the modern era'''
*** '''Population: 452 patients with metastatic ccRCC'''
 
**** 44% had poor-risk disease, 56% had intermediate-risk
===== '''CN followed by Targeted Therapy vs. Targeted Therapy alone''' =====
***** '''Trial does not apply to patients with favourable-risk'''
 
*** '''Randomized to CN followed by sunitnib vs. sunitnib alone'''
====== '''CARMENA''' (Clinical Trial to Assess the Importance of Nephrectomy) ======
*** '''Primary outcome: OS'''
* '''Population: 452 patients with metastatic ccRCC'''
*** '''Median follow-up 50.2 months'''
** 44% had poor-risk disease, 56% had intermediate-risk
*** '''Results'''
*** '''Trial does not apply to patients with favourable-risk'''
**** '''OS: sunitinib alone was non-inferior to CN followed by sunitinib''' (HR 0.89; 95% CI 0.71–1.10)
* '''Randomized to CN followed by sunitnib vs. sunitnib alone'''
**** '''No significant difference PFS or response to treatment'''
* '''Primary outcome: OS'''
*** Méjean, Arnaud, et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379.5 (2018): 417-427.
* '''Median follow-up 50.2 months'''
** '''In patients with mRCC who are being considered for CN, the optimal timing relative to the initiation of systemic therapy also remains controversial.'''
* '''Results'''
*** '''Advantages of initiating systemic therapy prior to CN:'''
** '''OS: sunitinib alone was non-inferior to CN followed by sunitinib''' (HR 0.89; 95% CI 0.71–1.10)
***# '''May provide symptomatic control and disease stabilization or regression for patients with a large tumour burden'''
** '''No significant difference PFS or response to treatment'''
***# '''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'''
* Méjean, Arnaud, et al. "Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma." New England Journal of Medicine 379.5 (2018): 417-427.
***# '''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
===== CN before vs. after Targeted Therapy =====
***#* Tumour may also increase in size or complexity during systemic therapy, reducing the feasibility of resection
 
*** '''Advantages of upfront CN (3):'''
* In patients with mRCC who are being considered for CN, the optimal timing relative to the initiation of systemic therapy also remains controversial.
***# '''Palliating symptoms related to the primary tumour'''
 
***# '''Eliminating a source of secondary metastases'''
* '''Advantages of initiating systemic therapy prior to CN:'''
***# '''Improving host immune dysfunction'''
*# '''May provide symptomatic control and disease stabilization or regression for patients with a large tumour burden'''
*** '''SURTIME''' (Immediate Surgery or Surgery After sunitinib Malate in Treating Patients With Metastatic Kidney Cancer) '''TIMING of CN'''
*# '''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'''
**** '''99 patients with metastatic ccRCC'''
*# '''Decreases the size of the primary tumour in a proportion of patients'''
**** '''Randomized to upfront CN followed by sunitnib vs. upfront sunitinib followed by CN (deferred CN)'''
*#* The median decrease in size is estimated to be 7-32% and the clinical impact of this is questionable
***** '''Investigated optimal timing of CN relative to initiation of systemic therapy'''
*#* Tumour may also increase in size or complexity during systemic therapy, reducing the feasibility of resection
**** '''Primary endpoint: disease progression at 28 weeks'''
* '''Advantages of upfront CN (3):'''
**** '''Results:'''
*# '''Palliating symptoms related to the primary tumour'''
***** '''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'''
*# '''Eliminating a source of secondary metastases'''
***** '''OS improved in deferred CN group (median OS 32.4 vs. 15 months; p=0.034)'''
*# '''Improving host immune dysfunction'''
****** '''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.
====== SURTIME ======
** '''Several retrospective observational studies have identified a significant survival advantage in favour of CN for patients treated with targeted therapies'''
* '''Population: 99 patients with metastatic ccRCC'''
* '''As per the 2019 CUA Cytoreductive Nephrectomy Consensus Statement:'''
* '''Randomized to upfront CN followed by sunitnib vs. upfront sunitinib followed by CN (deferred CN)'''
** '''Decisions regarding CN should ideally be made in a multidisciplinary setting'''
** '''Investigated optimal timing of CN relative to initiation of systemic therapy'''
** '''In patients with metastatic RCC, offer upfront CN''' followed by metastases-directed therapy, a period of surveillance, or systemic therapy '''in patients with (5):'''
* '''Primary endpoint: disease progression at 28 weeks'''
**# '''Good performance status (Eastern Cooperative Oncology Group [ECOG] ≤1 or Karnofsky performance status (KPS) ≥80%)'''
* '''Results:'''
**# '''Resectable primary tumour'''
** '''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'''
**# '''Limited burden of metastatic disease'''
** '''OS improved in deferred CN group (median OS 32.4 vs. 15 months; p=0.034)'''
**# '''Minimal symptoms related to metastases'''
*** '''Difficult to interpret this result due to discordance with the disease progression results'''
**# '''No active CNS metastases'''
* 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.
** '''CN should not be done in patients with (2):'''
 
**# '''Rapidly progressing disease'''
==== Guideline Recommendations ====
**# '''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
* '''Trials do not address whether there is a benefit to CN after targeted therapy (sunitnib alone vs. sunitnib followed by CN)'''
** '''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'''
* '''Several retrospective observational studies have identified a significant survival advantage in favour of CN for patients treated with targeted therapies'''
** '''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.
===== 2019 CUA Cytoreductive Nephrectomy Consensus Statement =====
**** The 2 CN trials performed in the IFN-era mentioned above did not include information on histological subtypes
* '''Decisions regarding CN should ideally be made in a multidisciplinary setting'''
**** '''CARMENA and SURTIME excluded patients with non-clear-cell mRCC.'''
* '''In patients with metastatic RCC, offer upfront CN''' followed by metastases-directed therapy, a period of surveillance, or systemic therapy '''in patients with (5):'''
**** Limited observational data do suggest that CN may provide a survival advantage in patients with non-clear mRCC.
*# '''Good performance status (Eastern Cooperative Oncology Group [ECOG] ≤1 or Karnofsky performance status (KPS) ≥80%)'''
** '''Histologic diagnosis before treatment'''
*# '''Resectable primary tumour'''
*** '''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'''
*# '''Limited burden of metastatic disease'''
**** Systemic therapy will depend on the histologic subtype
*# '''Minimal symptoms related to metastases'''
*** '''For patients receiving upfront CN, histologic diagnosis MAY BE PERFORMED IF the results of the biopsy will influence management'''
*# '''No active CNS metastases'''
**** 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.
* '''CN should not be done in patients with (2):'''
** 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.
*# '''Rapidly progressing disease'''
** CN can be performed through both minimally invasive and open surgical approaches at the discretion of the treating surgeon
*# '''Limited life expectancy'''
*** Adrenal-sparing is appropriate when there is no evidence of tumour invasion or metastatic spread and when technically feasible.
* 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
** '''Lymphadenectomy'''
* '''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'''
*** '''In patients with mRCC undergoing CN who do not have clinical evidence of nodal disease, retroperitoneal LND is not recommended.'''
* '''Patients with non-clear-cell mRCC should be offered CN with similar considerations to those with clear-cell mRCC.'''
*** '''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.'''
** 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.
**** '''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
*** 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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