Editing Management of Localized and Locally Advanced Disease (section)

== Adjuvant Therapy for RCC ==

* '''Adjuvant therapy is defined as post-operative medical therapy after surgical resection with definitive curative intent.'''
* Aim of adjuvant therapy is to decrease the risk of cancer recurrence in patients with features indicative of intermediate- or high-risk for recurrence.
** In patients with kidney cancer, high-risk features for recurrence include (4):
**# High grade (Fuhrman’s Grade 3 or 4)
**# High T-stage (>T2b)
**# Unfavourable histology
**# Nodal involvement

=== Indications ===

==== AUA ====

* '''<span style="color:#ff0000">2021 AUA</span>'''
** '''<span style="color:#ff0000">Standard of care for patients with fully resected renal cancers remains close clinical and radiographic observation.</span>''' Patients with a high risk of recurrence should be counseled regarding systemic adjuvant options and/or considered for enrollment into adjuvant clinical trials

==== CUA ====
*'''2019 CUA'''
**'''Adjuvant therapy is not currently recommended outside of a clinical trial'''

=== Treatments ===
* Despite demonstrable anti-tumor effects in patients with metastatic disease, one RCT with IL-2 and 3 RCTs with interferon alfa did not prove to be beneficial in the adjuvant setting.
* A variety of autologous tumor vaccine–based approaches have been used in the postoperative setting with negative results
*'''<span style="color:#ff00ff">KEYNOTE-564 (NEJM 2021)</span>'''
** '''Population: 496 patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy'''
***'''High-risk for recurrence defined by (4)''' 
***#'''Tumor stage 2 with nuclear grade 4 or sarcomatoid differentiation'''
***#'''Tumor stage 3 or higher'''
***#'''Regional lymph-node metastasis'''
***#'''Stage M1 with NED'''
** '''Randomized to pembrolizumab vs. placebo'''
** '''Primary outcome: disease-free survival'''
** '''Results:'''
*** '''Disease-free survival significantly improved with pembrolizumab'''
*** Absolute survival benefit at 24 months: 3.1% (96.6% pembrolizumab vs. 93.5% placebo)
** [https://pubmed.ncbi.nlm.nih.gov/34407342/ Choueiri, Toni K., et al."Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma." ''The New England Journal of Medicine'' 385.8 (2021): 683-694.] 
*'''S-TRAC'''
** '''Population: 615 nephrectomy patients with either ccRCC and non-ccRCC, high-risk according to modified UISS (≥T3, regional lymph-node metastasis, or both)'''
*** '''Higher risk than ASSURE'''
** '''Randomized to sunitnib vs. placebo.'''
*** Sunitnib started within 3 months of nephrectomy
** '''Results:'''
*** '''Adjuvant sunitnib significantly improved DFS (improvement comparable to time on therapy) but not OS'''
*** '''Adjuvant sunitnib FDA approved in 2017, not approved in Canada'''
** Ravaud, Alain, et al."Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy." ''New england journal of medicine'' 375.23 (2016): 2246-2254. '''ASSURE'''
** '''Population: 1934 nephrectomy patients with ccRCC, pT1b G3−4 N0 (or pNX where clinically N0) M0 to T (any) G (any) N + (fully resected)'''
** '''Randomized to sunitinib vs. sorafenib vs. placebo'''
** '''Results:'''
*** '''No significant difference in DFS or OS between the 3 treatment arms'''
*** '''Dose reductions were necessary during study due to a high attrition rate from treatment intolerability'''
** Haas, Naomi B., et al."Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial." ''The Lancet'' 387.10032 (2016): 2008-2016.
* '''PROTECT'''
** Population: 1500 nephrectomy patients with intermediate and high-risk disease
** Randomized to pazopanib vs. placebo
** Results:
*** No significant difference in DFS or OS
*** Many required dose reduction due to high attrition rates
** Motzer, Robert J., et al."Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma." ''Journal of Clinical Oncology'' 35.35 (2017): 3916.
* '''SORCE'''
** A phase III randomized double-blind study comparing sorafenib to placebo in patients with resected intermediate- to high-risk RCC
* '''EVEREST'''
** Randomizing nephrectomy patients to everolimus vs. placebo
* '''ATLAS'''
** Population: 724 nephrectomy patients with ≥pT2 and/or N+, any Fuhrman grade RCC
** Randomized to adjuvant to axitnib vs. placebo
** Results:
*** Trial was stopped due to futility at the prespecified interim analysis, with no significant difference in DFS observed at that time
* '''ARIZER'''
** Population: 864 nephrectomy patients with ccRCC, pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater
** Randomized to girentuximab vs. placebo
* '''PROSPER'''
** Randomizing nephrectomy patients to nivolumab vs. placebo
* '''IMotion'''
** Randomizing nephrectomy patients to atezolizumab vs. placebo
**