The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (D_LEM|v and D_MKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: D_MKMVHs lay largely below original constraints; the translated D_LEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal D_MKM|v of the rectum volume, v—1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are D_LEM|5cc ≤ 61 Gy(RBE) and D_LEM|1cc ≤ 66 Gy(RBE).

(1) Background: we proposed an integrated strategy to support clinical allocation of nasopharyngeal patients between proton and photon radiotherapy. (2) Methods: intensity-modulated proton therapy (IMPT) plans were optimized for 50 consecutive nasopharyngeal carcinoma (NPC) patients treated with volumetric modulated arc therapy (VMAT), and differences in dose and normal tissue complication probability (ΔNTCPx-p) for 16 models were calculated. Patient eligibility for IMPT was assessed using a model-based selection (MBS) strategy following the results for 7/16 models describing the most clinically relevant endpoints, applying a model-specific ΔNTCPx-p threshold (15% to 5% depending on the severity of the complication) and a composite threshold (35%). In addition, a comprehensive toxicity score (CTS) was defined as the weighted sum of all 16 ΔNTCPx-p, where weights follow a clinical rationale. (3) Results: Dose deviations were in favor of IMPT (ΔD_mean ≥ 14% for cord, esophagus, brainstem, and glottic larynx). The risk of toxicity significantly decreased for xerostomia (−12.5%), brain necrosis (−2.3%), mucositis (−3.2%), tinnitus (−8.6%), hypothyroidism (−9.3%), and trismus (−5.4%). There were 40% of the patients that resulted as eligible for IMPT, with a greater advantage for T3–T4 staging. Significantly different CTS were observed in patients qualifying for IMPT. (4) Conclusions: The MBS strategy successfully drives the clinical identification of NPC patients, who are most likely to benefit from IMPT. CTS summarizes well the expected global gain.

(1) Background: In this work, we aim to provide selection criteria based on normal tissue complication probability (NTCP) models and additional explanatory dose-volume histogram parameters suitable for identifying locally advanced sinonasal cancer patients with orbital invasion benefitting from proton therapy. (2) Methods: Twenty-two patients were enrolled, and two advanced radiation techniques were compared: intensity modulated proton therapy (IMPT) and photon volumetric modulated arc therapy (VMAT). Plans were optimized with a simultaneous integrated boost modality: 70 and 56 Gy(RBE) in 35 fractions were prescribed to the high risk/low risk CTV. Several endpoints were investigated, classified for their severity and used as discriminating paradigms. In particular, when NTCP models were already available, a first selection criterion based on the delta-NTCP was adopted. Additionally, an overall analysis in terms of DVH parameters was performed. Furthermore, a second selection criterion based on a weighted sum of the $\Delta$NTCP and $\Delta$DVH was adopted. (3) Results: Four patients out of 22 (18.2%) were suitable for IMPT due to $\Delta$NTCP > 3% for at least one severe toxicity, 4 (18.2%) due to $\Delta$NTCP > 20% for at least three concurrent intermediate toxicities and 16 (72.7%) due to the mixed sum of $\Delta$NTCP and $\Delta$DVH criterion. Since, for some cases, both criteria were contemporary fulfilled, globally 17/22 patients (77.3%) would benefit from IMPT. (4) Conclusions: For this rare clinical scenario, the use of a strategy including DVH parameters and NTCPs when comparing VMAT and IMPT is feasible. We showed that patients affected by sinonasal cancer could profit from IMPT compared to VMAT in terms of optical and central nervous system organs at risk sparing.

Rectum and bladder volumes play an important role in the dose distribution reproducibility in prostate cancer adenocarcinoma (PCa) radiotherapy, especially for particle therapy, where density variation can strongly affect the dose distribution. We investigated the reliability and reproducibility of our image-guided radiotherapy (IGRT) and treatment planning protocol for carbon ion radiotherapy (CIRT) within the phase II mixed beam study (AIRC IG 14300) for the treatment of high-risk PCa. In order to calculate the daily dose distribution, a set of synthetic computed tomography (sCT) images was generated from the cone beam computed tomography (CBCT) images acquired in each treatment session. Planning target volume (PTV) together with rectum and bladder volume variation was evaluated with sCT dose-volume histogram (DVH) metric deviations from the planning values. The correlations between the bladder and rectum volumes, and the corresponding DVH metrics, were also assessed. No significant difference in the bladder, rectum, and PTV median volumes between the planning computed tomography (pCT) and the sCT was found. In addition, no significant difference was assessed when comparing the average DVHs and median DVH metrics between pCT and sCT. Dose deviations determined by bladder and rectum filling variations demonstrated that dose distributions were reproducible in terms of both target coverage and organs at risk (OARs) sparing.

Sinonasal cancers (SNCs) are rare and heterogeneous in histology and biological behavior. The prognosis is generally unfavorable, especially in inoperable cases. In recent years, for some histologies, such as undifferentiated sinonasal carcinoma (SNUC), multimodal treatment with a combination of induction chemotherapy, surgery, and chemo/radiotherapy (RT) has improved the prognosis. Nevertheless, still about half of the patients treated incur a recurrence, in most of the cases at the local site. Surgery with and without RT is usually the treatment choice in cases of recurrence after previous RT in combination with systemic therapy or RT in a histology-driven fashion. In the case of inoperable disease or contraindications to surgery, RT is still a valid treatment option. In this context, hadron therapy with protons (PT) or carbon ions (CIRT) is often preferred due to the physical and biological characteristics of charged particles, allowing the administration of high doses to the tumor target while sparing the surrounding healthy tissues and potentially limiting the side effects due to the high cumulative dose. In the absence of a standard of care for the recurrent setting, we aimed to investigate the role of re-RT with PT or CIRT. We retrospectively analysed 15 patients with recurrent, previously irradiated, SNCs treated at our institution between 2013 and 2020. Local control (LC) and overall survival (OS) were estimated by the Kaplan–Meier method. Acute and late toxicities were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events CTCAE version 5.0. A total of 13 patients received CIRT and 2 patients received PT. The median re-RT dose was 54 GyRBE (range 45–64 GyRBE) delivered in 3 or 4 GyRBE/fr (fraction) for the CIRT, and 2 Gy RBE/fr for the PT schedule. LC was 44% at the 1-year follow-up and 35.2% at the 3-year follow-up. OS at 1 and 3 years were 92.9% and 38.2%, respectively. Fourteen patients developed G1–G2 acute toxicity (dermatitis and mucositis), and no patients developed G3–G5. Regarding late toxicity, 10 patients encountered at maximum G1–2 events, and 4 did not experience any toxicity. Only for one patient G3 late toxicity was reported (dysphagia requiring a percutaneous endoscopic gastrostomy).