Manuel Conson

Background: Preclinical animal studies have demonstrated that radiation treatment (RT) can induce effects beyond the anatomical site of irradiation. Non-targeted effects of RT (NTER) have been sporadically reported in clinical settings. However, with the advent of high-dose stereotactic radiation techniques (SRT) and immunotherapy (IT), renewed attention has been given to NTER. This systematic review aims to summarize current knowledge about NTER across various malignancies, with a focus on cases involving SRT. Methods: A systematic database search was performed, and records were screened following PRISMA guidelines. Only full-text original articles written in English and reporting clinical studies involving NTER after SRT were included. The results are categorized by cancer type, with separate general and critical analyses. Results: Sixty-three studies were reviewed, including 32 case reports/case series, 18 retrospective studies, and 13 prospective studies, predominantly published after 2018. NTER was most frequently observed in melanoma and lung cancer and commonly reported as the abscopal effect (AE), albeit with varying criteria. In most cases, IT with suboptimal response was ongoing at the time of SRT, and the median time to NTER onset was 3 months. Overall, NTER was documented in 297 patients: 34 from single cases and 263 from a pool of 1,212 evaluable patients (22%) across other studies. Prospective trials reported an NTER rate of 36%, rising to 56% in lung cancer. Discussion: In prospective clinical studies, the phenomenon of NTER following SRT has been observed in a significant proportion of patients. Nevertheless, the literature is limited, with small patient cohorts. Interest in NTER has grown, particularly in the context of IT. Standardization of definitions and reporting, along with the conduct of more clinical trials, is essential to better understand how NTER can be induced by SRT.

Stereotactic radiation therapy (SRT) is a proven effective treatment for brain metastases (BM); however, symptomatic radiation necrosis (RN) is a late effect that may impact on patient’s quality of life. The aim of our study was to retrospectively evaluate survival outcomes and characterize the occurrence of RN in a cohort of BM patients treated with ablative SRT at Federico II University Hospital. Clinical and dosimetric factors of 87 patients bearing a total of 220 BMs treated with SRT from 2016 to 2022 were analyzed. Among them, 46 patients with 127 BMs having clinical and MRI follow-up (FUP) ≥ 6 months were selected for RN evaluation. Dosimetric parameters of the uninvolved brain (brain without GTV) were extracted. The crude local control was 91% with neither clinical factors nor prescription dose correlating with local failure (LF). At a median FUP of 9 (1–68) months, the estimated median overall survival (OS), progression-free survival (PFS), and brain progression-free survival (bPFS) were 16, 6, and 9 months, respectively. The estimated OS rates at 1 and 3 years were 59.8% and 18.3%, respectively; bPFS at 1 and 3 years was 29.9% and 13.5%, respectively; PFS at 1 and 3 years was 15.7% and 0%, respectively; and local failure-free survival (LFFS) at 1 and 3 years was 87.2% and 83.8%, respectively. Extracranial disease status was an independent factor related to OS. Fourteen (30%) patients manifested RN. At multivariate analysis, adenocarcinoma histology, left location, and absence of chemotherapy were confirmed as independent risk factors for any-grade RN. Nine (20%) patients developed symptomatic (G2) RN, which improved or stabilized after 1–16 months of steroid therapy. With prompt recognition and, when necessary, medical therapy, RN radiological and clinical amelioration can be obtained.

Technological advances in Hodgkin lymphoma (HL) radiation therapy (RT) by high conformal treatments potentially increase control over organs-at-risk (OARs) dose distribution. However, plan optimization remains a time-consuming task with great operator dependent variability. Purpose of the present study was to devise a fully automated pipeline based on the Pinnacle3 Auto-Planning (AP) algorithm for treating female supradiaphragmatic HL (SHL) patients. CT-scans of 10 female patients with SHL were considered. A “butterfly” (BF) volumetric modulated arc therapy was optimized using SmartArc module integrated in Pinnacle3 v. 9.10 using Collapsed Cone Convolution Superposition algorithm (30 Gy in 20 fractions). Human-driven (Manual-BF) and AP-BF optimization plans were generated. For AP, an optimization objective list of Planning Target Volume (PTV)/OAR clinical goals was first implemented, starting from a subset of 5 patients used for algorithm training. This list was then tested on the remaining 5 patients (validation set). In addition to the BF technique, the AP engine was applied to a 2 coplanar disjointed arc (AP-ARC) technique using the same objective list. For plan evaluation, dose-volume-histograms of PTVs and OARs were extracted; homogeneity and conformity indices (HI and CI), OARs dose-volume metrics and odds for different toxicity endpoints were computed. Non-parametric Friedman and Dunn tests were used to identify significant differences between groups. A single AP objective list for SHL was obtained. Compared to the manual plan, both AP-plans offer comparable CIs while AP-ARC also achieved comparable HIs. All plans fulfilled the clinical dose criteria set for OARs: both AP solutions performed at least as good as Manual-BF plan. In particular, AP-ARC outperformed AP-BF in terms of heart sparing involving a lower risk of coronary events and radiation-induced lung fibrosis. Hands-on planning time decreased by a factor of 10 using AP on average. Despite the high interpatient PTV (size and position) variability, it was possible to set a standard SHL AP optimization list with a high level of generalizability. Using the implemented list, the AP module was able to limit OAR doses, producing clinically acceptable plans with stable quality without additional user input. Overall, the AP engine associated to the arc technique represents the best option for SHL.

Acute toxicity in head and neck (H&N) cancer patients treated with definitive radiotherapy (RT) has a crucial role in compliance to treatments. The aim of this study was to correlate doses to swallowing-associated structures and acute dysphagia.

Oral cavity mucosal melanomas (OCMM) represent only 3% of all malignant melanomas. Surgery is the mainstay of treatments and it is often followed by adjuvant radiotherapy. The role of adjuvant immunotherapy and/or chemotherapy is still debated and to date neither treatment is routinely used. From January 1990 to January 2010, we have collected from our database data of 20 patients with a histologically proven diagnosis of OCMM. Upfront surgery, followed by adjuvant radiotherapy was performed in 16/20 (80%) patients. Immunohistochemical analysis was carried out on all tissue samples and the following markers were assessed: Ki-67, HMG-45, Melan-A, S-100, CD31, CD35, CD20, CD21, and CD3. Although Ki-67, HMG-45, Melan-A, and S-100 were assessed in tumor cells, the analysis of CD31, CD21, CD20, CD3, and CD35 was carried out on the tumor-infiltrating lymphocytes. Patient outcome was analyzed and associated with clinical and Immunohistochemical tumor characteristics. The median overall survival (OS) was 12 months, with a 2-year OS rate of 30%. The median progression-free survival (PFS) was 9 months, with a 2-year PFS rate of 25%. Grade of lymphocyte infiltration (CD20 and CD3 expression) correlated strongly with prognosis. Interestingly, overexpression of CD21 along with downregulation of CD31 was significantly associated with better OS and PFS, whereas the reversal features correlated with a poor prognosis. Our report shows that patients affected by OCMM have a poor prognosis despite the administration of multimodal treatments. Moreover, our analysis suggests that the evaluation of several biomarkers, especially in tumor-infiltrating lymphocytes, may identify categories of patients with distinct immune response against the tumor and possibly different treatment response and prognosis.

Background: The clinical benefits of postoperative radiation therapy (PORT) for patients with thymoma are still controversial. In the absence of defined guidelines, prognostic factors such as stage, status of surgical margins, and histology are often considered to guide the choice of adjuvant treatment (radiotherapy and/or chemotherapy). In this study, we describe our single-institution experience of three-dimensional conformal PORT administered as adjuvant treatment to patients with thymoma. Methods: Twenty-two consecutive thymoma patients (eleven male and eleven female) with a median age of 52 years and treated at our institution by PORT were analyzed. The patients were considered at high risk of recurrence, having at least one of the following features: stage IIB or III, involved resection margins, or thymic carcinoma histology. Three-dimensional conformal PORT with a median total dose on clinical target volume of 50 (range 44–60) Gy was delivered to the tumor bed by 6–20 MV X-ray of the linear accelerator. Follow-up after radiotherapy was done by computed tomography scan every 6 months for 2 years and yearly thereafter. Results: Two of the 22 patients developed local recurrence and four developed distant metastases. Median overall survival was 100 months, and the 3-year and 5-year survival rates were 83% and 74%, respectively. Median disease-free survival was 90 months, and the 5-year recurrence rate was 32%. On univariate analysis, pathologic stage III and presence of positive surgical margins had a significant impact on patient prognosis. Radiation toxicity was mild in most patients and no severe toxicity was registered. Conclusion: Adjuvant radiotherapy achieved good local control and showed an acceptable toxicity profile in patients with high-risk thymoma.

Gastrointestinal (GI) toxicity is a common effect following radiation therapy (RT) for prostate cancer. Purpose of the present work is to compare two Normal Tissue Complication Probability (NTCP) modelling approaches for prediction of late radio-induced GI toxicity after prostate external beam radiotherapy. The study includes 84 prostate cancer patients evaluated for late rectal toxicity after 3D conformal radiotherapy. Median age was 72 years (range 53-85). All patients received a total dose of 76 Gy to the prostate gland with daily fractions of 2 Gy. The acute and late radio-induced GI complications were classified according to the RTOG/EORTC scoring system. Rectum dose-volume histograms were extracted for Lyman-Kutcher-Burman (LKB) NTCP model fitting using Maximum Likelihood Estimation. The bootstrap method was employed to test the fit robustness. The area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive power of the LKB and to compare it with a multivariate logistic NTCP model previously determined. At a median follow-up of 36 months, 42% (35/84) of patients experienced grade 1-2 (G1-2) acute GI events while 25% (21/84) of patients developed G1-2 late GI events. The best-estimate of fitting parameters for LKB NTCP model for mild\moderate GI toxicity resulted to be: D 50 = 87.3 Gy, m = 0.37 and n = 0.10. Bootstrap result showed that the parameter fit was robust. The AUC values for the LKB and for the multivariate logistic models were 0.60 and 0.75, respectively. We derived the parameters of the LKB model for mild\moderate GI toxicity prediction and we compared its performance with that of a data-driven multivariate model. Compared to LKB, the multivariate model confirmed a higher predictive power as showed by the AUC values.

The purpose of this study is to compare different normal tissue complication probability (NTCP) models for predicting heart valve dysfunction (RVD) following thoracic irradiation. All patients from our institutional Hodgkin lymphoma survivors database with analyzable datasets were included (n = 90). All patients were treated with three-dimensional conformal radiotherapy with a median total dose of 32 Gy. The cardiac toxicity profile was available for each patient. Heart and lung dose-volume histograms (DVHs) were extracted and both organs were considered for Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP model fitting using maximum likelihood estimation. Bootstrap refitting was used to test the robustness of the model fit. Model performance was estimated using the area under the receiver operating characteristic curve (AUC). Using only heart-DVHs, parameter estimates were, for the LKB model: D₅₀ = 32.8 Gy, n = 0.16 and m = 0.67; and for the RS model: D₅₀ = 32.4 Gy, s = 0.99 and γ = 0.42. AUC values were 0.67 for LKB and 0.66 for RS, respectively. Similar performance was obtained for models using only lung-DVHs (LKB: D₅₀ = 33.2 Gy, n = 0.01, m = 0.19, AUC = 0.68; RS: D₅₀ = 24.4 Gy, s = 0.99, γ = 2.12, AUC = 0.66). Bootstrap result showed that the parameter fits for lung-LKB were extremely robust. A combined heart-lung LKB model was also tested and showed a minor improvement (AUC = 0.70). However, the best performance was obtained using the previously determined multivariate regression model including maximum heart dose with increasing risk for larger heart and smaller lung volumes (AUC = 0.82). The risk of radiation induced valvular disease cannot be modeled using NTCP models only based on heart dose-volume distribution. A predictive model with an improved performance can be obtained but requires the inclusion of heart and lung volume terms, indicating that heart-lung interactions are apparently important for this endpoint.