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Page 6 of 12 Feuer et al. J Cancer Metastasis Treat 2021;7:68 https://dx.doi.org/10.20517/2394-4722.2021.164

whole-brain radiotherapy, while 18 patients did not. Overall survival at 1 and 5 years was 51% and 8.5%,
[29]
respectively .
Lymph nodes
Lymph nodes are involved in 60%-65% of mRCC cases . These are typically identified as synchronous
[3]
[30]
metastases, as local nodal recurrence is rare . The initial management of lymph node dissection at the time
[31]
of nephrectomy was assessed when Blom et al. randomized 732 patients, 1:1, to undergo lymph node
dissection at the time of nephrectomy or nephrectomy alone. Lymph node dissection did not improve
overall survival (HR = 1.02, 95%CI: 0.80-1.29), local regional progression (HR = 0.77, 95%CI: 0.46-1.28) or
distant progression (HR = 1.05, 95%CI: 0.73-1.50) . However, the major criticism of this study was that
[31]
investigators included many low-risk patients with T1 and T2 tumors less likely to harbor nodal metastasis.

The role of lymph node dissection at the time of radical nephrectomy for patients with suspected nodal
[32]
metastases was studied by Pantuck et al. . There was no increase in median survival for patients without
preoperative evidence of nodal metastases undergoing lymph node dissection vs. those who underwent
radical nephrectomy alone. However, there was a survival benefit noted amongst patients with concern for
nodal metastases who underwent lymphadenectomy as compared to those that did not. The authors
reported a 5-month improvement in median overall survival in this cohort . Subsequent studies noted no
[32]
benefit in patients with preoperatively diagnosed mRCC [33,34] . To date, the role of lymph node dissection in
high-risk patients has not been prospectively studied .
[35]

INFLUENCE OF PRIMARY TUMOR HISTOLOGY
Primary tumor histology has been demonstrated to impact prognosis in patients undergoing
metastasectomy significantly. A recent systematic review demonstrated that primary tumor features,
including findings of Fuhrman high-grade histology and sarcomatoid features, were associated with worse
[36]
[37]
outcomes . Takagi et al. noted similar findings with regard to the presence of sarcomatoid features (HR
= 8.89, P = 0.028), however, found that Fuhrman grade was not independently associated (HR = 0.83, P =
0.757). Another study by Ishihara et al. found that the risk of death amongst patients with non-clear cell
[38]
histology was double that of patients with clear cell histology.
The impact of primary tumor histology on outcomes has not been directly explored as a primary outcome,
and stratification by cell types has been limited given the proportionally low number of patients with non-
clear cell findings. However, given the lack of effective systemic therapies for patients with non-clear cell
histology, the role of surgical management should be further explored.

COMPLICATIONS OF METASTASECTOMY
Despite the potential for successful management of mRCC, metastasectomy carries the risk of surgical
complications. Palumbo et al. reviewed 351 patients who underwent metastasectomy, noting a
[39]
complication rate of 55%, including 22% pulmonary complications, which were not further defined, and a
need for transfusion in 15.7% of patients. A recent retrospective review of 1102 patients who underwent
metastasectomy noted an overall complication rate of 45.7%, with a major complication rate Clavien III-IV
of 27.5%. The investigators reported that older age, Charlson-Deyo score ≥ 2, and resection of hepatic
metastases were associated with an increased risk of major complications (OR = 2.59, P < 0.001), while
resection of pulmonary metastases was associated with a decreased risk (OR = 0.63, P < 0.001) . Despite
[40]
these complications, resection of metastases has a range of value and chance for intermediate-term survival
depending on metastatic disease site.