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Page 4 of 10 Berghen et al. J Cancer Metastasis Treat 2021;7:58 https://dx.doi.org/10.20517/2394-4722.2021.123

A brief overview of the physics rationale
Most particle therapy worldwide is performed with protons (PBT) or carbon ions (CIRT). Both modalities
have the potential to deliver a very high radiation dose to the tumor with maximum sparing of the
surrounding healthy tissues . Through the radiation beam entrance path, there is only a low-dose
[44]
deposition, followed by a rapid incline in energy deposition with most of the energy deposited at the end of
[45]
the ionization track (i.e., the location of the tumor) and limited or no exit dose . This peak of dose
deposition at a specific depth is known as the Bragg peak . To adequately cover the target (i.e., tumor
[43]
lesion), the Bragg peak is spread out to an optimal range, called “spread-out Bragg peak”. The characteristic
dose deposition at depth for photon, PBT, and CIRT is depicted in Figure 1. An example of a photon
treatment plan compared to a proton treatment plan for primary RCC is presented in Figure 2.

Secondly, compared to photons, particle therapy has a higher LET, a quantification of the amount of energy
transferred from the ion to the tissue. While photon therapy results in “simple DNA damage”, the “complex
DNA damage” caused by the particle therapy is a clustering of multiple DNA lesions in close proximity,
making DNA repair more difficult . A higher LET thus correlates with a higher relative RBE and
[43]
[43]
consequently produces more cell killing at equivalent doses . Compared to the RBE of 1 for photon
therapy, the RBEs for PBT and CIRT are considered 1.1 and 2.5-3, respectively.

Particle therapy in primary RCC
The initial results of particle therapy in primary RCC are encouraging . The clinical and dosimetric
[3]
comparative trials that have reported on the use of PBT or CIRT for RCC are listed in Table 1. We briefly
describe the trials hereunder.

[4]
In one case report, Frick et al. , reported on the use of proton SBRT in a 47-year-old women diagnosed
with bilateral Grade 1-2 clear cell RCCs. The patient was inoperable due to multiple comorbidities including
stage 2 chronic kidney disease (CKD). A total dose of 30 Gy in five fractions was administered to both
lesions. She experienced acute but transient Grade 1 urinary urgency and urinary incontinence, as well as
Grade 1 fatigue, which recovered to pre-treatment three months after treatment. Marginal deterioration in
renal function was observed (from 34 to 29 mL/min/1.73 m ). The one-year follow-up showed stable tumor
2
findings on the MRI. The authors concluded that proton therapy is feasible and a promising therapeutic
[4]
approach that can be considered for medically inoperable patients .

In a multi-institutional retrospective study, Fukumitsu et al. investigated the efficacy of PBT as a
[46]
treatment for RCC in 22 patients. The majority of these patients had T1a tumors (77%). The total irradiation
dose was 60.0-79.6 Gy (RBE) delivered in 10-36 fractions and the biological equivalent doses ranged from 94
to 110 Gy (median 105 Gy). At a median follow-up of 37 months, the three-year local control, disease-
specific survival, and overall survival rates were 100%, 100%, and 95%. One patient developed Grade 2 acute
dermatitis, and two patients developed Grade 2 renal dysfunction at 9 and 28 months, respectively. The
2
mean estimated glomerular filtration rate was reduced by 7.1 ± 11.2 mL/min/1.73 m , which is comparable
to the above-mentioned renal function decline after photon therapy.

We identified two dosimetric analyses of PBT in kidney cancer [47,48] . Baydoun et al. evaluated the
[47]
dosimetric characteristics of Cyberknife®, Volumetric Modulated Arc Therapy (VMAT), and PBT in the
stereotactic treatment of RCC. The prescribed dose was 48 Gy to be delivered in four fractions. Compared
to Cyberknife®, both VMAT and PBT provided equivalent or superior coverage of the target volume while
reducing treatment time per fraction and consequently also intra-fraction motion. Dose to the remaining
target kidney, contralateral kidney, liver, spinal cord, and intestine was limited.