Editing Metastatic Kidney Cancer (section)

=== 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.]

==== Guideline Recommendations ====

* '''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'''

===== 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