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Page 8 of 12 Mansinho et al. J Cancer Metastasis Treat 2021;7:44 https://dx.doi.org/10.20517/2394-4722.2021.88

everolimus in second or further lines of treatment.

There is an ongoing phase II trial investigating the combined use of pembrolizumab and denosumab in
[72]
clear-cell mRCC that may also shed some light on this treatment option .

Stereotactic ablative radiation therapy
RCC is refractory to conventional radiation therapy but responds to higher doses per fraction. In 2019, the
National Comprehensive Cancer Network guidelines included stereotactic ablative radiotherapy (SBRT) in
the treatment of recurrent and metastatic RCC . Because tumor cell survival and proliferation directly rely
[73]
on blood supply, SBRT has been shown to have a direct effect on tumor vasculature.

The use of SBRT in metastatic bone lesions has also been investigated. Investigators from the Memorial
Sloan Kettering Cancer Center compared the use of single-fraction (18-24 Gy) or hypofractioned (3-5
fractions to 20-30 Gy), by assessing tumor control rates in 105 patients with extracranial mRCC. Local
control rates were best when using high single (24 Gy) compared with low single (< 24 Gy) dose or
[75]
[74]
hypofractionated regimens, with three-year local PFS of 88%, 21%, and 17%, respectively . Jhaveri et al.
investigated pain relief in RCC BM patients treated with SBRT and reported quicker and more durable pain
control in those treated with BED of > 85 Gy compared with < 85 Gy, with 78% and 32% of patients,
respectively, showing symptom control at 10 weeks. A study from the M.D. Anderson Center reported one-
year spine tumor PFS of 82.1% with SBRT, with approximately half of all patients free of symptoms at one
year .
[76]
With additional targeted therapies, the role of systemic therapy in RCC continues to improve, increasing
patients’ survival and QoL. SBRT will play a valuable role in providing not only high local control rates but
also prolonged symptomatic control from months to years.

Surgery
In mRCC, surgical metastasectomy (SM) is mostly performed for patients with pulmonary lesions, which
[77]
represent the most frequent site for RCC metastases . A systematic review of eight studies assessed the role
of local therapy in mRCC and reported a longer OS and cancer-specific survival (CSS) in patients
undergoing complete metastasectomy than in those undergoing either incomplete or no metastasectomy
[40.8 months, interquartile range (IQR): 31.6-48.0 vs. 14.8 months, IQR: 13.3-21.0, respectively]. Patients
with pancreatic, liver, and lung lesions derived the greatest advantage from complete metastasectomy when
compared to incomplete or no metastasectomy .
[77]
Generally, BM are more resistant to systemic therapy and radiotherapy when compared to other metastases
sites, and, additionally, they are highly destructive. The role of metastasectomy in mRCC with BM was
recently reviewed in a retrospective study with 114 patients. Single BM was seen in 68 (59.6%) patients,
whereas 46 (40.4%) had multiple (2-5) BM. BM were located in axial bones (spine, skull, and ribs) in 47
(41.2%) patients, in the appendicular skeleton (extremities, pelvis, clavicle, and scapula) in 20 (17.5%), in
multiple sites in 33 (28.9%), and in unknown exact location in 14 (12.3%) . BM excisional surgery,
[78]
particularly in the spine, is a procedure which is technically very demanding, even for specialized
orthopedic and spine surgeons. Bone metastases from mRCC are destructive and hypervascular [Table 3],
and, in the majority of cases, reconstruction is required after tumor resection to support the operated lesion
against the load. A case series of 36 consecutive patients concluded that, for selected patients, complete
spinal resection of spinal metastases can potentially prolong survival, with a median CSS of 130 months. In
this series, the presence of liver metastases was a potential drawback to this strategy, being associated with