Page 123 - Read Online

Feuer et al. J Cancer Metastasis Treat 2021;7:68 https://dx.doi.org/10.20517/2394-4722.2021.164 Page 9 of 12

[51]
respectively . However, a criticism of the CARMENA trial was the significant proportion of patients with
poor performance status and poor-risk disease, which was subsequently associated with worse survival
[52]
outcomes in a meta-analysis .

The SURTIME trial randomized 99 patients to immediate cytoreductive nephrectomy with subsequent
sunitinib therapy or sunitinib therapy followed by deferred cytoreductive nephrectomy. Both arms
demonstrated similar progression-free survival while deferred cytoreductive nephrectomy was associated
with improved overall survival (overall survival HR = 0.57, 95%CI: 0.34-0.95, P = 0.03). Median overall
survival was 15.0 and 32.4 months in the immediate and the deferred cytoreductive nephrectomy arms,
respectively . A subsequent systematic review concluded that upfront cytoreductive nephrectomy is not
[53]
associated with survival benefit in patients with the intermediate and poor-risk disease. However, evidence
in patients with good performance status and good or intermediate-risk disease suggest that intervention
may be beneficial , paralleling the findings of observational studies in the metastasectomy literature.
[54]

The introduction of immunotherapy proposed a new set of questions regarding the respective roles of
systemic therapy and cytoreductive nephrectomy in the management of mRCC. A study randomizing 104
patients to receive three combinations of immune checkpoint inhibitors with subsequent cytoreductive
nephrectomy and adjuvant nivolumab was noted to be safe, but survival outcomes were not assessed .
[55]

A retrospective analysis of patients undergoing cytoreductive nephrectomy with neoadjuvant/adjuvant
immunotherapy vs. immunotherapy-alone demonstrated improved overall survival amongst patients who
underwent CN in combination with immunotherapy (HR = 0.23, 95%CI: 0.15-0.37, P < 0.001). In a sub-
analysis exploring differences in the timing of systemic therapy and CN, those undergoing systemic therapy
followed by CN (n = 24) did not reach median overall survival, while median overall survival was 30 months
for patients undergoing upfront CN (n = 197). These findings were not significant, likely due to the small
number of patients receiving neoadjuvant treatment .
[56]
PROSPECTIVE ROLE OF METASTASECTOMY IN THE ERA OF IMMUNOTHERAPY
Review of the available literature suggests that one of the primary goals of metastasectomy should be
complete resection, which is associated with significant survival benefits. However, evidence exploring the
utility of metastasectomy in the era of immunotherapy has been limited to the use of immunotherapeutic
agents in the adjuvant setting [44,45] . A recent animal study evaluating the timing of immunotherapy delivery
strongly supports neoadjuvant, rather than adjuvant, use of these therapies .
[57]

It is well-established that renal cell carcinoma exhibits significant intratumoral heterogeneity [58,59] . Further,
these genomic differences have been associated with differences in therapeutic response to PD-L1
inhibitors . These findings suggest that the use of neoadjuvant, therapy to decrease metastatic burden prior
[60]
to metastasectomy may increase the likelihood of complete resection, thereby conferring a survival benefit
in these patients. However, any associated effect may be modulated by the location, extensiveness, or
genomics of these metastases .
[61]
PROSPER RCC is a phase III RCT, randomizing patients with clinical stage ≥ T2, in a 1:1 fashion, to either
surgery (partial or radical nephrectomy) alone or neoadjuvant PD-L1 blockade with nivolumab, followed by
surgery and adjuvant nivolumab. The planned primary endpoint is 5-year recurrence-free survival. This
trial may have significant implications on the treatment paradigm in the primary management of RCC and,
pending findings, may also impact mRCC treatment strategies .
[62]