Page 95 - Read Online

Page 2 of 10 Berghen et al. J Cancer Metastasis Treat 2021;7:58 https://dx.doi.org/10.20517/2394-4722.2021.123

Keywords: Particle therapy, proton therapy, carbon ion radiation therapy

INTRODUCTION
Renal cell carcinoma (RCC) accounts for 3% of all cancers worldwide and is the most common solid tumor
[1]
within the kidney representing approximately 90% of all kidney malignancies . There are different RCC
subtypes, of which clear cell carcinoma is the most common histopathology. The majority of the lesions is
diagnosed as small tumors, with a notable proportion of locally advanced disease and up to 20% of patients
presenting with distant metastases at the time of diagnosis . For non-metastatic renal cell carcinoma
[1]
(nmRCC), surgery including partial and radical nephrectomy are considered standard of care, with
radiofrequency ablation and cryoablation as alternative treatment options for selected patients with small
[2]
renal masses . About 20%-40% of non-metastatic patients will eventually develop metastases, for which the
standard management consists of immune checkpoint inhibitors (ICI) and/or targeted therapy . The role
[2,3]
of conventional radiotherapy (RT) in palliation of symptoms of metastatic disease is well established.

Stereotactic body radiotherapy (SBRT), targeting oligometastatic disease as well as treating the primary
tumor, both with the aim to cure, has more recently become part of the therapeutic armamentarium . Due
[3]
to the advancements in treatment planning and delivery techniques, and the increasing availability of
particle therapy using protons or heavy ions such as carbon ions, the interest for SBRT in the field of RCC
has grown substantially. In this review, we summarize the current evidence of (SB)RT as a treatment option
for (m)RCC, with a focus on the advantages of particle therapy.

RADIOTHERAPY IN THE TREATMENT OF RCC
Working mechanism
Unlike healthy kidney cells, which are very sensitive to radiation, RCC has traditionally been considered
radio-resistant. In addition, surrounding organs at risk such as jejunum, duodenum, and colon are also
susceptible to radiation damage. Because of this presumed radio-resistance and the risk of radiation-
induced toxicities, RT was considered marginal when it came to treating primary RCC and/or
[4]
oligometastatic disease. However, preclinical and clinical evidence has shown that RCC is sensitive to
ablative radiation doses (typically > 8 Gy per fraction), resulting in tumor control rates of approximately
90% . SBRT provides the method to deliver these ablative doses. In contrast to conventionally fractionated
[5]
RT, which aims to cause DNA-damage, SBRT also induces endothelial damage and tumor cell killing by
stimulation of the ceramide pathway . After irradiation, hydrolyzation of sphingomyelin takes place in the
[6,7]
cell membrane, and ceramide is generated, which is a proapoptotic messenger. In addition, SBRT has the
ability to activate antitumor host immunity, which can induce the so-called abscopal effect . First reported
[5,8]
in 1953, this phenomenon describes the ability of irradiation to induce tumor regression at non-irradiated,
[9]
distant tumor sites . Although rarely observed historically, the advent of ICI reopened the research interest
in this effect. Certainly the combination of SBRT and ICI is an emerging treatment option for mRCC [10,11] .

Photon SBRT in primary RCC
Several recently published reviews extensively describe the role of SBRT in primary RCC [3,5,10] .
Unfortunately, the number of patients in prospective trials is small, and a comparison with partial or radical
nephrectomy, cryotherapy, or radiofrequency ablation (RFA) is lacking. Globally, SBRT is considered a
valuable alternative to surgery for elderly patients (> 70 years old), patients who are medically inoperable,
and patients with pre-existing comorbidities such as arterial hypertension, diabetes mellitus, chronic kidney
disease, and/or cardiovascular disease . Since cryoablation and RFA both result in less local control (LC) in
[5]
the case of larger tumors, and central/perihilar location could increase the risk of hemorrhage, fistula