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Page 8 of 12 Feuer et al. J Cancer Metastasis Treat 2021;7:68 https://dx.doi.org/10.20517/2394-4722.2021.164

[36]
prognostic indicator was complete resection .

As previously discussed, the use of pazopanib in the adjuvant setting failed to demonstrate an improvement
in survival and, further, may have worsened outcomes in patients receiving the immunotherapy compared
[44]
to placebo . However, the combined role of metastasectomy and many immunotherapeutic agents remains
unknown. One recent editorial proposed the possibility that metastasectomy may be useful in the setting of
treatment beyond progression due to the intratumor heterogeneity of disease in mRCC .
[46]

Investigators queried the Canadian Kidney Cancer information system database to review the records of 229
patients who underwent complete metastasectomy, matched with 803 patients who did not. Patients who
did not undergo metastasectomy were more likely to receive targeted therapy in this cohort (74% vs. 47%).
The 1- and 5-year overall survival rates were 96% and 63% in the metastasectomy group, as compared to
90% and 51% in the group that did not undergo surgical resection, respectively. The effect of systemic
therapy on these rates was not assessed. Risk of mortality was increased in patients who did not undergo
metastasectomy (HR = 0.41, P < 0.001). Dragomir et al. noted that age > 65 and the presence of brain
[47]
metastases were factors associated with a worse prognosis.

Lyon et al. retrospectively assessed the role of complete metastasectomy in the post-cytokine era,
[48]
including 586 patients who underwent primary treatment for renal cell carcinoma with subsequent
development of metastatic disease between 2006 and 2017. One hundred-fifty-eight patients were treated
with complete metastasectomy, 93% of which did not receive systemic therapy. The authors noted that
cancer-specific survival was improved significantly amongst patients who underwent complete
metastasectomy compared to patients who did not (84% vs. 54%). In a multivariate analysis, the hazard ratio
for death from mRCC was reduced significantly in patients who underwent complete metastasectomy (HR
[48]
= 0.47, P < 0.001), regardless of age, gender, timing, number, and location of metastases .

In a retrospective review of 314 patients with mRCC, 98 patients underwent metastasectomy. Amongst
these 98 patients, 45 patients underwent complete resection, while the remaining 53 were incompletely
resected. The authors reported that metastasectomy status was an independent predictor of overall survival.
The group further analyzed the survival for patients undergoing metastasectomy vs. no resection in the
various systemic therapy eras. The Kaplan-Meier curve demonstrated similar results for metastasectomy in
each era, including the early targeted therapy (2008-2011), late targeted therapy (2012-2016), and
immunotherapy eras (2016-2018). However, the Kaplan-Meier curves for each systemic therapy
demonstrated improving survival in each era, persistently inferior to survival demonstrated in patients
undergoing metastasectomy .
[38]

ROLE OF SURGICAL MANAGEMENT IN THE ERA OF IMMUNOTHERAPY
Given the rapidly evolving landscape of systemic therapy for mRCC, and the sparsity of high-quality studies
specifically addressing the role of systematic therapy in patients undergoing metastasectomy, the role of
surgical management should be considered more broadly.

The role of cytoreductive nephrectomy in early studies demonstrated a survival benefit in men concurrently
treated with interferons [49,50] . In the targeted therapy era, the CARMENA trial randomized 450 intermediate
and poor-risk patients to cytoreductive nephrectomy followed by sunitinib or sunitinib alone. In this study,
the hazard ratio for death amongst patients receiving sunitinib-alone was 0.89 (95%CI: 0.71-1.10),
demonstrating noninferiority compared to patients undergoing nephrectomy followed by sunitinib. Overall
survival was 13.9 and 18.4 months in patients in the nephrectomy-sunitinib and sunitinib cohorts,