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Objective: Radiotherapy (RT) against head and neck squamous cell carcinomas (HNSCC) may lead to severe toxicity in 30-40% of patients. The normal tissue complication probability (NTCP) models, based on dosimetric data refined the normal tissue dose/volume tolerance guidelines. In parallel, the radiation-induced nucleoshuttling (RIANS) of the Ataxia-Telangiectasia Mutated protein (pATM) is a predictive approach of individual intrinsic radiosensitivity. Here, we combined NTCP with RADIODTECT©, a blood assay derived from the RIANS model, to predict RT toxicity in HNSCC patients., Methods: RADIODTECT© cutoff values (i.e. 57.8 ng/mL for grade⩾2 toxicity and 46 ng/mL for grade⩾3 toxicity) have been previously assessed. Validation was performed on a prospective cohort of 36 HNSCC patients treated with postoperative RT. Toxicity was graded with the Common Terminology Criteria for Adverse Events (CTCAE) scale and two criteria were considered: grade⩾2 oral mucositis (OM2), grade⩾3 mucositis (OM3) and grade⩾2 dysphagia (DY2), grade⩾3 dysphagia (DY3). pATM quantification was assessed in lymphocytes of HNSCC patients. The discrimination power of the pATM assay was evaluated through the Area Under the Receiver Operator Characteristics Curve (AUC-ROC). Two previously described NTCP models were considered, including the dose to the oral cavity and the mean dose to the parotid glands (OM2 and OM3) and the dose to the oral cavity, to the larynx and the volume of pharyngeal constrictor muscles (DY2 and DY3)., Results: Combining NTCP models with RADIODTECT© blood test improved the AUC-ROC. Considering the prediction of mucositis, AUC-ROC NTCP+RADIODTECT© =0.80 was for OM2, and AUC-ROC NTCP+RADIODTECT© =0.78 for OM3. Considering the prediction of acute dysphagia, AUC-ROC NTCP+RADIODTECT© =0.71 for DY2 and for DY3., Conclusions: Combining NTCP models with a radiosensitivity biomarker might significantly improve the prediction of toxicities for HNSCC patients.

Background and Purpose: Explainable models of long-term risk of biochemical failure (BF) after post-prostatectomy salvage radiotherapy (SRT) are lacking. A previously introduced radiobiology-based formula was adapted to incorporate the impact of pelvic nodes irradiation (PNI)., Materials and Methods: The risk of post-SRT BF may be expressed by a Poisson-based equation including pre-SRT PSA, the radiosensitivity α, the clonogen density C, the prescribed dose (in terms of EQD2, α/β = 1.5 Gy) and a factor (1-BxλxPSA) accounting for clonogens outside the irradiated volume, being λ the recovery due to PNI. Data of 795 pT2-pT3, pN0/pN1/pNx (n = 627/94/74) patients with follow-up ≥ 5 years and pre-RT PSA ≤ 2 ng/mL were randomly split into training (n = 528) and validation (n = 267) cohorts; the training cohort data were fitted by the least square method. Separate fits were performed for different risk groups. Model performances were assessed by calibration plots and tested in the validation group., Results: The median follow-up was 8.5y, median pre-SRT PSA and EQD2 were 0.43 ng/mL and 71.3 Gy respectively; 331/795 pts received PNI. The most clinically significant prognostic grouping was pT3b and/or ISUP4-5 versus pT2/3a and ISUP1-3. Best-fit parameters were α eff  = 0.26/0.23 Gy -1 , C = 10 7 /10 7 , B = 0.40/0.97, λ = 0.87/0.41 for low/high-risk group. Performances were confirmed in the validation group (slope = 0.89,R 2  = 0.85). Results suggested optimal SRT dose at 70-74 Gy. The estimated reduction of post-SRT BF due to PNI at these dose values was > 5 % for PSA > 1/>0.15 ng/mL for low/high-risk patients, being > 10 % for high-risk patients with pre-SRT PSA > 0.25 ng/mL., Conclusion: An explainable one-size-fits-all equation satisfactorily predicts long-term risk of post-SRT BF. The model was independently validated. A calculator tool was made available., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: To assess bowel dose-volume relationships for acute patient-reported intestinal symptoms of patients treated with whole-pelvis intensity-modulated radiotherapy (WPRT) for prostate cancer., Materials and Methods: Complete data of 415 patients enrolled in a multi institute, prospective trial (#NCT02803086) treated with radical (31%), adjuvant (33%) and salvage (36%) intent at a median dose to pelvic nodes/lymph-nodal area of 53 Gy were available. The most severe changes between baseline and radiotherapy mid-point/end toxicity assessed by Inflammatory Bowel Disease Questionnaire (only Bowel Domain) were considered (ΔIBDQ). The 25th percentile values of these score variations were set as endpoints. DVHs of bowel loops for patients with/without toxicity were compared for each endpoint, having excluded patients with baseline scores <5 (rate ranging between 2% and 7% according to the endpoint): the resulting best dosimetric predictors were combined with selected clinical parameters through multivariate logistic regression (MVA) to derive predictive models., Results: ΔIBDQ ranged between 0.2-1.5 points considering separately each IBDQ symptom. Only four symptoms (IBDQ1 = frequency, IBDQ5 = diarrhea, IBDQ17 = gas passage, IBDQ24 = urgency) showed a median worsening ≥ 1; DVH predicted the risk of worse symptoms for IBDQ5, IBDQ24 and overall Bowel Domain. At multivariable analysis DVHs (best cut-off: V46Gy ≥80 cc) and baseline scores (Odd-Ratio:0.35-0.65) were independently associated to the three end-points. The resulting models were reliable (H&L test: 0.453-0.956), well calibrated (calibration plot: slope = 0.922-1.069, R 2  = 0.725-0.875) and moderately discriminative (Area Under the Curve:0.628-0.669). A bootstrap-based validation confirmed their robustness., Conclusion: Constraining the bowel loops (V46 < 80 cc) may reduce the risk of several moderate intestinal symptoms, with a much greater impact for patients with lower IBDQ baseline scores., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: The best therapeutic approach for local relapses of previously irradiated prostate cancer (PC) is still not defined. Re-irradiation (Re-I) could offer a chance of cure for highly selected patients, although high quality evidences are lacking. The aim of our study is to provide a literature review on efficacy and safety of Re-I., Methods: Only studies where Re-I field overlaps with previous radiotherapy were considered. To determine 2 and 4 years overall mortality (OM), 2 and 4 years biochemical failure (BF) and pooled acute and late G ≥ 3 toxicities rate, a meta-analysis over single arm study was performed., Results: Thirty-eight studies with 1194 patients were included. Median follow-up from Re-I was 30 months (10-94 months). Brachytherapy (BRT) was the most used Re-I technique (27 studies), followed by Stereotactic Body Radiotherapy (SBRT) (9) and External Beam Radiation Therapy (EBRT) (2). Re-I prescription doses ranged from 19 Gy in single HDR fraction to 145 Gy (interstitial BRT). The pooled 2 and 4 years OM rates were 2.1% (95%CI:1.1-3.7%, P < 0.001) and 12.5% (95%CI:8.1-19.5%; P < 0.001). The pooled 2 years BF rate was 24% (95% CI: 19.1-30.2%, P < 0.001). The pooled 4 years BF was 35.6% (95% CI: 28.7-44.3%, P < 0.001). The pooled result of G ≥ 3 acute toxicity was 1.4% (95%CI: 0.7-3%, P < 0.001). One hundred and three G ≥ 3 late adverse events were reported, with a pooled result of G ≥ 3 late toxicity of 8.7% (95%CI: 5.8-13%, P < 0.001)., Conclusions: Re-I of local failures from PC showed promising OM and biochemical control rates with a safe toxicity profile., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aims: The limbic circuit (LC) is devoted to linking emotion to behavior and cognition. The injury this system results in post-RT cognitive dysfunction. The aim of this study is to create the first radiation oncologist's practical MR-based contouring guide for the delineation of the LC for the everyday clinical practice and education., Methods: An anonymized diagnostic 3.0 T T1-weighted BRAVO MRI sequence from a healthy patient with typical brain anatomy was used to delineate LC. For each structure key anatomical contours were completed by radiation oncologists, along with a neuro-radiologist to generate the final version of the LC atlas., Results: a step-by-step MR-based atlas of LC was created. Key structures of the LC, such as, cingulate gyrus, fornix, septal region, mammillary bodies, thalamus and the hippocampal-amygdala formation were contoured., Conclusions: This article provides the recommendations for the first contouring atlas of LC in the setting of patients receiving RT and education., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: We evaluated the prognostic role of gross tumor volumes (GTVs) of primary tumor and positive lymph nodes on overall survival (OS) and progression-free survival (PFS) in locally advanced unresectable sinonasal cancer (SNC) treated with definitive intensity-modulated radiotherapy (IMRT) with or without chemotherapy., Methods: Primary tumor GTV (GTV-T), pathologic neck nodes GTV (GTV-N), and positive retropharyngeal nodes GTV (GTV-RPN) of 34 patients with epithelial nonglandular SNC receiving IMRT with or without chemotherapy were retrospectively measured. The GTV variables were analyzed in relation with OS and PFS. Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. We also estimated the crude cumulative incidence of locoregional relapses only. The optimal volume cutoff value was determined using an outcome-oriented method among the observed values., Results: GTV-T was significantly associated with decreased OS ( P =0.003) and PFS ( P =0.003). Moreover, patients with disease total volumes (GTV) smaller than 149.44 cm³ had better OS and PFS than patients with higher volumes ( P <0.0001 for both). Neck nodal metastasis impacted on OS and PFS ( P =0.030 and P =0.033, respectively), but GTV-N did not ( P =0.961; P =0.958). Retropharyngeal nodes metastasis was not associated with prognosis (OS: P =0.400; PFS: P =0.104). When GTV-RPN was added to GTV-N (GTV-TN), a relation with PFS ( P =0.041) and a trend toward significance for OS ( P =0.075) were found., Conclusions: Our results show that tumor volume is a powerful predictor of outcome in SNC. This could be useful to identify patients with worse prognosis deserving different treatment strategies.

Background: To report the long-term outcome of patients undergoing re-irradiation (re-RT) for a recurrent or second primary head and neck cancer (RSPHNCs) in seven Italian tertiary centers, while testing the Multi-Institution Reirradation (MIRI) recursive partitioning analysis (RPA) recently published., Methods: We retrospectively analyzed 159 patients. Prognostic factors for overall survival (OS) selected by a random forest model were included in a multivariable Cox analysis. To externally validate MIRI RPA, we estimated the Kaplan-Meier group-stratified OS curves for the whole population., Results: Five-year OS was 43.5% (median follow-up: 49.9 months). Nasopharyngeal site, no organ dysfunction, and re-RT volume <36 cm 3 were independent factors for better OS. By applying the MIRI RPA to our cohort, a Harrell C-Index of 0.526 was found indicating poor discriminative ability., Conclusion: Our data reinforce the survival benefit of Re-RT for selected patients with RSPHNC. MIRI RPA was not validated in our population., (© 2019 Wiley Periodicals, Inc.)

In the original publication, the 6th author's first name and the last name was inverted and incorrectly published. The correct author name is Letizia Ferella.