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Management of Localized and Locally Advanced Disease: Difference between revisions

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==== Indications for intervention (treatment or AS intensity) ====
==== Indications for intervention (treatment or AS intensity) ====
===== AUA =====
* '''<span style="color:#ff0000">2021 AUA (5)[https://www.auanet.org/guidelines/renal-cancer-renal-mass-and-localized-renal-cancer-guideline]:</span>'''
* '''<span style="color:#ff0000">2021 AUA (5)[https://www.auanet.org/guidelines/renal-cancer-renal-mass-and-localized-renal-cancer-guideline]:</span>'''
*# '''<span style="color:#ff0000">Tumour size >3cm</span>'''
*# '''<span style="color:#ff0000">Tumour size >3cm</span>'''
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*# '''<span style="color:#ff0000">Clinical changes in patient/tumour factors</span>''' (e.g. infiltrative on imaging, suspicion of advanced T stage)
*# '''<span style="color:#ff0000">Clinical changes in patient/tumour factors</span>''' (e.g. infiltrative on imaging, suspicion of advanced T stage)
*# '''<span style="color:#ff0000">Additional biopsy results</span>''' (e.g. unfavourable histology)
*# '''<span style="color:#ff0000">Additional biopsy results</span>''' (e.g. unfavourable histology)
===== CUA =====
*'''<span style="color:#ff0000">2022 CUA (4)</span>[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8932428/]'''
*#'''<span style="color:#ff0000">Growth of tumor to >4 cm'''
*#'''<span style="color:#ff0000">Consecutive growth rate >0.5 cm/year'''
*#'''<span style="color:#ff0000">Progression to metastases'''
*#'''<span style="color:#ff0000">Patient’s choice'''


==== <span style="color:#ff0000">Follow-up</span> ====
==== <span style="color:#ff0000">Follow-up</span> ====
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* 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.
* 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
* 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'''
==== <span style="color:#ff00ff">KEYNOTE-564 (NEJM 2021)</span> ====
***'''High-risk for recurrence defined by (4)'''  
* '''Population: 496 patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy'''
***#'''Tumor stage 2 with nuclear grade 4 or sarcomatoid differentiation'''
**'''High-risk for recurrence defined by (4)'''  
***#'''Tumor stage 3 or higher'''
**#'''Tumor stage 2 with nuclear grade 4 or sarcomatoid differentiation'''
***#'''Regional lymph-node metastasis'''
**#'''Tumor stage 3 or higher'''
***#'''Stage M1 with NED'''
**#'''Regional lymph-node metastasis'''
** '''Randomized to pembrolizumab vs. placebo'''
**#'''Stage M1 with NED'''
** '''Primary outcome: disease-free survival'''
* '''Randomized to pembrolizumab vs. placebo'''
** '''Results:'''
* '''Primary outcome: disease-free survival'''
*** '''Disease-free survival significantly improved with pembrolizumab'''
* '''Results:'''
*** Absolute survival benefit at 24 months: 3.1% (96.6% pembrolizumab vs. 93.5% placebo)
** '''Disease-free survival significantly improved by ≈9% at 24 months''' (77.3% pembrolizumab vs. 68.1% 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.]  
** '''Overall survival significantly improved by ≈8% at 48 months''' (64.9% pembrolizumab vs. 56.6% placebo)
*'''S-TRAC'''
* [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.]  
** '''Population: 615 nephrectomy patients with either ccRCC and non-ccRCC, high-risk according to modified UISS (≥T3, regional lymph-node metastasis, or both)'''
* [https://pubmed.ncbi.nlm.nih.gov/38631003/ Choueiri, Toni K., et al. "Overall survival with adjuvant pembrolizumab in renal-cell carcinoma." ''New England Journal of Medicine'' 390.15 (2024): 1359-1371.]
*** '''Higher risk than ASSURE'''
 
** '''Randomized to sunitnib vs. placebo.'''
==== Other Trials ====
 
* 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
*** Sunitnib started within 3 months of nephrectomy
** '''Results:'''
** Results:
*** '''Adjuvant sunitnib significantly improved DFS (improvement comparable to time on therapy) but not OS'''
*** Adjuvant sunitnib significantly improved DFS (improvement comparable to time on therapy) but not OS
*** '''Adjuvant sunitnib FDA approved in 2017, not approved in Canada'''
*** 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'''
** Ravaud, Alain, et al."Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy." ''New england journal of medicine'' 375.23 (2016): 2246-2254.  
** '''Population: 1934 nephrectomy patients with ccRCC, pT1b G3−4 N0 (or pNX where clinically N0) M0 to T (any) G (any) N + (fully resected)'''
* ASSURE
** '''Randomized to sunitinib vs. sorafenib vs. placebo'''
** Population: 1934 nephrectomy patients with ccRCC, pT1b G3−4 N0 (or pNX where clinically N0) M0 to T (any) G (any) N + (fully resected)
** '''Results:'''
** Randomized to sunitinib vs. sorafenib vs. placebo
*** '''No significant difference in DFS or OS between the 3 treatment arms'''
** Results:
*** '''Dose reductions were necessary during study due to a high attrition rate from treatment intolerability'''
*** 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.
** 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'''
 
* PROTECT
** Population: 1500 nephrectomy patients with intermediate and high-risk disease
** Population: 1500 nephrectomy patients with intermediate and high-risk disease
** Randomized to pazopanib vs. placebo
** Randomized to pazopanib vs. placebo
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*** Many required dose reduction due to high attrition rates
*** 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.
** 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'''
 
* SORCE
** A phase III randomized double-blind study comparing sorafenib to placebo in patients with resected intermediate- to high-risk RCC
** A phase III randomized double-blind study comparing sorafenib to placebo in patients with resected intermediate- to high-risk RCC
* '''EVEREST'''
 
* EVEREST
** Randomizing nephrectomy patients to everolimus vs. placebo
** Randomizing nephrectomy patients to everolimus vs. placebo
* '''ATLAS'''
 
* ATLAS
** Population: 724 nephrectomy patients with ≥pT2 and/or N+, any Fuhrman grade RCC
** Population: 724 nephrectomy patients with ≥pT2 and/or N+, any Fuhrman grade RCC
** Randomized to adjuvant to axitnib vs. placebo
** Randomized to adjuvant to axitnib vs. placebo
** Results:
** Results:
*** Trial was stopped due to futility at the prespecified interim analysis, with no significant difference in DFS observed at that time
*** Trial was stopped due to futility at the prespecified interim analysis, with no significant difference in DFS observed at that time
* '''ARIZER'''
 
* ARIZER
** Population: 864 nephrectomy patients with ccRCC, pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater
** 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
** Randomized to girentuximab vs. placebo
* '''PROSPER'''
 
* PROSPER
** Randomizing nephrectomy patients to nivolumab vs. placebo
** Randomizing nephrectomy patients to nivolumab vs. placebo
* '''IMotion'''
 
* IMotion
** Randomizing nephrectomy patients to atezolizumab vs. placebo
** Randomizing nephrectomy patients to atezolizumab vs. placebo
**


== Follow-up after Treatment ==
== Follow-up after Treatment ==
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