Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance

(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients’ treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams.

Preclinical Model of Stereotactic Ablative Lung Irradiation Using Arc Delivery in the Mouse: Is Fractionation Worthwhile?

Lung stereotactic body radiation therapy is characterized by a reduction in target volumes and the use of severely hypofractionated schedules. Preclinical modeling became possible thanks to rodent-dedicated irradiation devices allowing accurate beam collimation and focal lung exposure. Given that a great majority of publications use single dose exposures, the question we asked in this study was as follows: in incremented preclinical models, is it worth using fractionated protocols or should we continue focusing solely on volume limitation? The left lungs of C57BL/6JRj mice were exposed to ionizing radiation using arc therapy and 3 × 3 mm beam collimation. Three-fraction schedules delivered over a period of 1 week were used with 20, 28, 40, and 50 Gy doses per fraction. Lung tissue opacification, global histological damage and the numbers of type II pneumocytes and club cells were assessed 6 months post-exposure, together with the gene expression of several lung cells and inflammation markers. Only the administration of 3 × 40 Gy or 3 × 50 Gy generated focal lung fibrosis after 6 months, with tissue opacification visible by cone beam computed tomography, tissue scarring and consolidation, decreased club cell numbers and a reactive increase in the number of type II pneumocytes. A fractionation schedule using an arc-therapy-delivered three fractions/1 week regimen with 3 × 3 mm beam requires 40 Gy per fraction for lung fibrosis to develop within 6 months, a reasonable time lapse given the mouse lifespan. A comparison with previously published laboratory data suggests that, in this focal lung irradiation configuration, administering a Biological Effective Dose ≥ 1000 Gy should be recommended to obtain lung fibrosis within 6 months. The need for such a high dose per fraction challenges the appropriateness of using preclinical highly focused fractionation schedules in mice.

Volumetric Modulated Arc Therapy Capabilities for Treating Lower-Extremity Skin Affected by Several Merkel Cell Carcinoma Nodules: When Technological Advances Effectively Achieve the Palliative Therapeutic Goal while Minimising the Risk of Potential Toxicities

The peculiar and rare clinical condition below clearly requires a customized care approach in the context of personalized medicine. An 80-year-old female patient who was subjected in 2018 to surgical removal of a cutaneous Merkel cell carcinoma (MCC) nodule located on the posterior surface of the left thigh and to three subsequent palliative radiotherapy treatments developed a fourth relapse in October 2020, with fifteen nodular metastases located in the left thigh and leg. Since the overall macroscopic disease was still exclusively regionally located and microscopic spread was likely extended also to clinically negative skin of the thigh and leg, we performed an irradiation of the whole left lower extremity. For this purpose the total target (65.5 cm) was divided into three sub-volumes. Dose prescription was 30 Gy in 15 daily fractions. A sequential boost of 10 Gy in 5 daily fractions was planned for macroscopic nodules. Plans were calculated by means of volumetric modulated arc therapy (VMAT) with the field overlap technique. Thanks to this, we obtained a homogeneous dose distribution in the field junction region; avoidance structures were delineated in the central part of the thigh and leg with the aim of achieving an optimal superficial dose painting and to reduce bone exposure to radiation. This case study demonstrates that VMAT allows for a good dose coverage for circumferential cutaneous targets while sparing deeper organs at risk. A reproducible image-guided set-up is fundamental for an accurate and safe dose delivery. However, local treatments such as radiotherapy for very advanced MCC of the lower extremities might have limited impact due to the high probability of systemic progression, as illustrated in this case. Radiation is confirmed as being effective in preventing MCC nodule progression toward skin wounding.

Optimized Conformal Total Body Irradiation Among Recipients of TCRαβ/CD19-Depleted Grafts in Pediatric Patients With Hematologic Malignancies: Single-Center Experience

Total body irradiation (TBI) in combination with chemotherapy is widely used as a conditioning regimen in pediatric and adult hematopoietic stem cell transplantation (HSCT). The combination of TBI with chemotherapy has demonstrated superior survival outcomes in patients with acute lymphoblastic and myeloid leukemia when compared with conditioning regimens based only on chemotherapy. The clinical application of intensity-modulated radiation therapy (IMRT)-based methods (volumetric modulated arc therapy (VMAT) and TomoTherapy) seems to be promising and has been actively used worldwide. The optimized conformal total body irradiation (OC-TBI) method described in this study provides selected dose reduction for organs at risk with respect to the most significant toxicity (lungs, kidneys, lenses). This study included 220 pediatric patients who received OC-TBI with subsequent chemotherapy and allogenic HSCT with TCRαβ/CD19 depletion. A group of 151 patients received OC-TBI using TomoTherapy, and 40 patients received OC-TBI using the Elekta Synergy™ linac with an Agility-MLC (Elekta, Crawley, UK) using volumetric modulated arc therapy (VMAT). Twenty-nine patients received OC-TBI with supplemental simultaneous boost to bone marrow—(SIB to BM) up to 15 Gy: 28 patients (pts)—TomoTherapy; one patient—VMAT. The follow-up duration ranged from 0.3 to 6.4 years (median follow-up, 2.8 years). Overall survival (OS) for all the patients was 63% (95% CI: 56–70), and event-free survival (EFS) was 58% (95% CI: 51–65). The cumulative incidence of transplant-related mortality (TRM) was 10.7% (95% CI: 2.2–16) for all patients. The incidence of early TRM (<100 days) was 5.0% (95% CI: 1.5–8.9), and that of late TRM (>100 days) was 5.7 (95% CI: 1.7–10.2). The main causes of death for all the patients were relapse and infection. The concept of OC-TBI using IMRT VMAT and helical treatment delivery on a TomoTherapy treatment unit provides maximum control of the dose distribution in extended targets with simultaneous dose reduction for organs at risk. This method demonstrated a low incidence of severe side effects after radiation therapy and predictable treatment effectiveness. Our initial experience demonstrates that OC-TBI appears to be a promising technique for the treatment of pediatric patients.