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Berghen et al. J Cancer Metastasis Treat 2021;7:58 https://dx.doi.org/10.20517/2394-4722.2021.123 Page 3 of 10

formation, and ureteral strictures, SBRT is an excellent alternative with LC rates of 97% for tumors >
[12]
4 cm . SBRT might be of particular interest in patients under anticoagulation.
In a total of 26 trials, 382 tumors in 372 patients were treated with SBRT, resulting in a random-effect
[5]
estimate for LC of 97.0% (95%CI: 93.9%-99.5%) . LC rates ranged 70%-100% in the eligible studies, with
local failures corresponding to an insufficient biological dose (low-dose arm or in the case of compromise to
mitigate toxicity). The most prominent toxicity was mild nausea, fatigue, or dermatitis. Grade 3-4 events
ranged from 0% to 25%. The wide range should be interpreted with caution, as the number of patients in the
trials was low. Most of the trials report low toxicity, while the 25% toxicity is the result of a phase 1 dose-
escalation trial, where 30 Gy in five fractions resulted in 3 out of 12 patients with Grade 3 fatigue (n = 2) and
[13]
bone pain (n = 1) . The random effect for the mean estimated glomerular filtration rate (eGFR) difference
before and after SBRT was -7.7 mL/min (95%CI: -12.5 to -2.8 mL/min), with the eGFR difference ranging
from -16.7 to +6.0 . This is consistent with the eGFR decrease after partial or radical nephrectomy of 13
[5]
and 24 mL/min, respectively, for a median follow-up of 44 and 57 months . Overlaying SBRT treatment
[14]
plans with functional imaging scans ( Cr-EDTA or -TC-DSMA SPECT-CT), Siva et al. showed that
[15]
51
99m
regional nephropathy and the resulting loss of function occurred clearly in high-dose regions. Fortunately,
the contralateral non-irradiated kidney compensated for this loss except in patients with pre-existing
nephropathy. Interestingly, there was a clear dose-related decrease in eGFR: for every 10 Gy of physical
dose, eGFR decreased by 25%-39% . Of note, late onset (≥ 1 year) of eGFR has been described, implicating
[15]
the need for long-term follow-up and the interest of using functional imaging [5,15] . SBRT for primary RCC
has thus proven to be effective and well-tolerated, and might even lead to more favorable local control rates
when compared to thermal ablative treatments, certainly in case of stage Ib tumors .
[12]

Photon SBRT in metastatic RCC
RCC metastases are usually located in the lymph nodes, lung, liver, bone, and brain . Up to 20% of patients
[3]
have upfront metastatic disease, and about 20%-40% of nmRCC patients will eventually develop
metastases . Oligometastatic disease, the intermediate state between localized and widespread metastatic
[3]
disease, typically involves 1-5 metastases. In this particular situation, metastasis-directed therapy (MDT) has
evolved as a new treatment option in various tumors, with prostate cancer probably being the most studied
[16]
urological tumor . Both metastasectomy and SBRT are excellent options for performing MDT. Studies
reporting on metastasectomy in different organs (lung, bone, brain, liver, etc.) [17-27] have shown excellent LC
and improvement in overall survival (OS) (albeit retrospectively, with an important selection bias), with a
[28]
five-year survival benefit of 45% . SBRT induces LC rates up to 90%-98% while toxicity rates remain very
low [3,8,29-40] . To the best of our knowledge, we are aware of only one (retrospective) trial comparing the two
treatment modalities. In general, this trial shows that the results of SBRT are similar to those of
metastasectomy . Specific to SBRT, there is the theoretical possibility to interfere positively with the
[31]
immune response elicited by ICI and to decrease the rate of the metastatic spread, as has been shown for
other urological malignancies [11,41] .

Whether SBRT will improve outcome in oligometastatic RCC patients in combination with ICI or tyrosine
kinase inhibitors targeting the vascular endothelial growth factor receptor is the subject of several ongoing
trials .
[42]

Particle therapy and RCC
Compared to photons, particle therapy has several advantages, including a favorable dose-depth profile, a
[43]
higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE) , meaning they
have the potential to treat “difficult to treat” tumors, in terms of location (deep seated or critically located),
radio-resistance, or a highly aggressive nature .
[43]