Prevention and management of radiotherapy-related toxicities in gynecological malignancies. Position paper on behalf of AIRO (Italian Association of Radiotherapy and Clinical Oncology).

Multi-modal therapies for gynecological cancers management may determine a wide range of side effects which depend on therapy-related factors and patient characteristics and comorbidities. Curative or adjuvant pelvic radiotherapy is linked with acute and late toxicity due to irradiation of organs at risk, as small and large bowel, rectum, bladder, pelvic bone, vagina and bone marrow. Successful toxicity management varies with its severity, Radiation Centre practice and experience and skills of radiation oncologists. This position paper was designed by the Italian Association of Radiation and Clinical Oncology Gynecology Study Group to provide radiation oncologists with evidence-based strategies to prevent and manage acute and late toxicities and follow-up recommendations for gynecological cancer patients submitted radiotherapy. Six workgroups of radiation oncologists with over 5 years of experience in gynecologic cancers were setup to investigate radiotherapy-related toxicities. For each topic, PubMed database was searched for relevant English language papers from January 2005 to December 2022. Titles and abstracts of results were checked to verify suitability for the document. Reference lists of selected studies and review papers were added if pertinent. Data on incidence, etiopathogenesis, prevention, treatment and follow-up of acute and late side effects for each organ at risk are presented and discussed.

Patient-reported persistent symptoms after radiotherapy and association with quality of life for prostate cancer survivors.

PURPOSE: To evaluate the persistence of symptoms after radiotherapy (RT) for localised prostate cancer (PCa) and the association with quality of life (QOL). MATERIALS AND METHODS: Prospective patient-reported outcome (PRO) from a multi-institutional study on PCa treated with radical RT (2010-2014) was analysed. Data was collected at baseline (BL) and follow-ups (FUPs) up to 5 years. Patients with BL and ≥3 late FUPs (≥6 months) were analysed. PRO was scored by means of the IPSS and ICIQ-SF (urinary), LENT-SOMA (gastrointestinal [GI]), and EORTC-C30 (pain, insomnia, fatigue, and QOL) questionnaires. Symptoms were defined 'persistent' if the median score over FUPs was ≥3 (urinary) or ≥2 (GI, pain, insomnia, and fatigue), and worse than BL. Different thresholds were chosen to have enough events for each symptom. QOL was linearly transformed on a continuous scale (0-100). Linear-mixed models were used to identify significant differences between groups with and without persistent symptoms including age, smoking status, previous abdominal surgery, and diabetes as confounders. Mean QOL differences between groups were evaluated longitudinally over FUPs. RESULTS: The analysis included 293 patients. Persistent urinary symptoms ranged from 2% (straining) to 12% (weak stream, and nocturia). Gastrointestinal symptoms ranged from 7% (rectal pain, and incontinence) to 30% (urgency). Proportions of pain, insomnia, and fatigue were 6, 13, and 18%. Significant QOL differences of small-to-medium clinical relevance were found for urinary incontinence, frequency, urgency, and nocturia. Among GI symptoms, rectal pain and incontinence showed small-to-medium differences. Fatigue was associated with the largest differences. CONCLUSIONS: The analysis showed that symptoms after RT for PCa occur with different persistence and their association with QOL varies in magnitude. A number of persistent urinary and GI symptoms showed differences in a comparable range. Urinary incontinence and frequency, rectal pain, and faecal incontinence more often had significant associations. Fatigue was also prevalent and associated with largely deteriorated QOL.

Tomotherapy PET-guided dose escalation: A dosimetric feasibility study for patients with malignant pleural mesothelioma.

AIM: The aim of this study was to investigate whether a safe escalation of the dose to the pleural cavity and PET/CT-positive areas in patients with unresectable malignant pleural mesothelioma (MPM) is possible using helical tomotherapy (HT). MATERIAL AND METHODS: We selected 12 patients with MPM. Three planning strategies were investigated. In the first strategy (standard treatment), treated comprised a prescribed median dose to the planning target volume (PTV) boost (PTV1) of 64.5 Gy (range: 56 Gy/28 fractions to 66 Gy/30 fractions) and 51 Gy (range: 50.4 Gy/28 fractions to 54 Gy/30 fractions) to the pleura PTV (PTV2). Thereafter, for each patient, two dose escalation plans were generated prescribing 62.5 and 70 Gy (2.5 and 2.8 Gy/fraction, respectively) to the PTV1 and 56 Gy (2.24 Gy/fraction) to the PTV2, in 25 fractions. Dose-volume histogram (DVH) constraints and normal tissue complication probability (NTCP) calculations were used to evaluate the differences between the plans. RESULTS: For all plans, the 95 % PTVs received at least 95 % of the prescribed dose. For all patients, it was possible to perform the dose escalation in accordance with the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints for organs at risk (OARs). The average contralateral lung dose was < 8 Gy. NTCP values for OARs did not increase significantly compared with the standard treatment (p > 0.05), except for the ipsilateral lung. For all plans, the lung volume ratio was strongly correlated with the V20, V30, and V40 DVHs of the lung (p < 0.0003) and with the lung mean dose (p < 0.0001). CONCLUSION: The results of this study suggest that by using HT it is possible to safely escalate the dose delivery to at least 62.5 Gy in PET-positive areas while treating the pleural cavity to 56 Gy in 25 fractions without significantly increasing the dose to the surrounding normal organs.

Image-guided radiation therapy (IGRT): practical recommendations of Italian Association of Radiation Oncology (AIRO).

The use of imaging to maximize precision and accuracy throughout the entire process of radiation therapy (RT) delivery has been called "Image-guided RT" (IGRT). RT has long been image guided: in fact, historically, the portal films and later electronic megavoltage images represented an early form of IGRT. A broad range of IGRT modalities is now available and adopted. The target location may be defined for each treatment fraction by several methods by localizing surrogates, including implanted fiducial markers, external surface markers or anatomical features (through planar imaging, fluoroscopy, KV or MV computed tomography, magnetic resonance imaging, ultrasound and X-ray imaging, electromagnetic localization, optical surface imaging, etc.). The aim of the present review is to define practical recommendations for IGRT.

Erratum to: Tomotherapy PET-guided dose escalation--A dosimetric feasibility study for patients with malignant pleural mesothelioma.

Unfortunately, erroneous author affiliations were published in the article "Tomotherapy PET-guided dose escalation ­ A dosimetric feasibility study for patients with malignant pleural mesothelioma". The correct list of author affiliations reads as follows: Angelo Maggio 1, Claudia Cutaia 1, Amalia Di Dia 1, Sara Bresciani 1, Anna Miranti 1, Matteo Poli 1, Elena Delmastro 2, Elisabetta Garibaldi 2, Pietro Gabriele 2 and Michele Stasi 1. 1: Medical Physics Department, Candiolo Cancer Institute ­ FPO, IRCCS, Turin, Italy. 2: Radiotherapy Department, Candiolo Cancer Institute ­ FPO, IRCCS, Turin, Italy. We apologize for any inconveniences caused.

Chondrosarcoma of the nasal septum.

Chondrosarcomas are non-epithelial malignant, slow growing tumors that usually involve pelvis, ribs, and long bones of extremities, scapula and sternum. Median age at diagnosis for head and neck chondrosarcomas is in the fourth decade. The etiopathogenesis of chondrosarcomas remains unknown. Treatment of choice is surgical, with adjuvant therapy having a limited role. In fact, radiation therapy and chemotherapy are reserved for residual or recurrent disease and palliation. As for surgery, several surgical procedures have been described. Recently, endoscopic surgery has allowed for the successful and less invasive treatment of inverting papillomas and even nasopharyngeal angiofibromas, lesions previously requiring extended external approaches. The aim of this paper was to present a case of nasal septal chondrosarcoma that was successfully treated with endoscopic surgery and radiation adjuvant therapy.

Worsening of 2-year patient-reported intestinal functionality after radiotherapy for prostate cancer including pelvic node irradiation.

BACKGROUND AND PURPOSE: To quantify patient-reported 2-year intestinal toxicity (IT) from pelvic nodal irradiation (PNI) for prostate cancer. The association between baseline/acute symptoms and 2-year worsening was investigated. MATERIALS AND METHODS: Patient-reported IT was prospectively assessed through the Inflammatory Bowel Disease Questionnaire (IBDQ), filled in at baseline, radiotherapy mid-point and end, at 3 and 6 months and every 6 months until 5 years. Two-year deterioration of IBDQ scores relative to the Bowel Domain was investigated for 400 patients with no severe baseline symptoms and with questionnaires available at baseline, 2 years, RT mid-point and/or end and at least three follow-ups between 3 and 18 months. The significance of the 2-year differences from baseline was tested. The association between baseline values and ΔAcute (the worst decline between baseline and RT mid-point/end) was investigated. RESULTS: In the IBDQ lower scores indicate worse symptoms. A significant (p < 0.0001) 2-year mean worsening, mostly in the range of -0.2/-0.4 points on a 1-7 scale, emerged excepting one question (IBDQ29, "nausea/feeling sick"). This decline was independent of treatment intent while baseline values were associated with 2-year absolute scores. The ΔAcute largely modulated 2-year worsening: patients with ΔAcute greater than the first quartile (Q1) and ΔAcute less or equal than Q1 showed no/minimal and highly significant (p < 0.0001) deterioration, respectively. Rectal incontinence, urgency, frequency and abdominal pain showed the largest mean changes (-0.5/-1): risk of severe worsening (deemed to be of clinical significance if ≤ 2) was 3-5 fold higher in the ΔAcute ≤ Q1 vs ΔAcute > Q1 group (p < 0.0001). CONCLUSION: A modest but significant deterioration of two-year patient-reported intestinal symptoms from PNI compared to baseline was found. Patients experiencing more severe acute symptoms are at higher risk of symptom persistence at 2 years, with a much larger prevalence of clinically significant symptoms.

Patient and Context Factors in the Adoption of Active Surveillance for Low-Risk Prostate Cancer.

Importance: Although active surveillance for patients with low-risk prostate cancer (LRPC) has been recommended for years, its adoption at the population level is often limited. Objective: To make active surveillance available for patients with LRPC using a research framework and to compare patient characteristics and clinical outcomes between those who receive active surveillance vs radical treatments at diagnosis. Design, Setting, and Participants: This population-based, prospective cohort study was designed by a large multidisciplinary group of specialists and patients' representatives. The study was conducted within all 18 urology centers and 7 radiation oncology centers in the Piemonte and Valle d'Aosta Regional Oncology Network in Northwest Italy (approximate population, 4.5 million). Participants included patients with a new diagnosis of LRPC from June 2015 to December 2021. Data were analyzed from January to May 2023. Exposure: At diagnosis, all patients were informed of the available treatment options by the urologist and received an information leaflet describing the benefits and risks of active surveillance compared with active treatments, either radical prostatectomy (RP) or radiation treatment (RT). Patients choosing active surveillance were actively monitored with regular prostate-specific antigen testing, clinical examinations, and a rebiopsy at 12 months. Main Outcomes and Measures: Outcomes of interest were proportion of patients choosing active surveillance or radical treatments, overall survival, and, for patients in active surveillance, treatment-free survival. Comparisons were analyzed with multivariable logistic or Cox models, considering centers as clusters. Results: A total of 852 male patients (median [IQR] age, 70 [64-74] years) were included, and 706 patients (82.9%) chose active surveillance, with an increasing trend over time; 109 patients (12.8%) chose RP, and 37 patients (4.3%) chose RT. Median (IQR) follow-up was 57 (41-76) months. Worse prostate cancer prognostic factors were negatively associated with choosing active surveillance (eg, stage T2a vs T1c: odds ratio [OR], 0.51; 95% CI, 0.28-0.93), while patients who were older (eg, age ≥75 vs <65 years: OR, 4.27; 95% CI, 1.98-9.22), had higher comorbidity (Charlson Comorbidity Index ≥2 vs 0: OR, 1.98; 95% CI, 1.02-3.85), underwent an independent revision of the first prostate biopsy (OR, 2.35; 95% CI, 1.26-4.38) or underwent a multidisciplinary assessment (OR, 2.65; 95% CI, 1.38-5.11) were more likely to choose active surveillance vs active treatment. After adjustment, center at which a patient was treated continued to be an important factor in the choice of treatment (intraclass correlation coefficient, 18.6%). No differences were detected in overall survival between active treatment and active surveillance. Treatment-free survival in the active surveillance cohort was 59.0% (95% CI, 54.8%-62.9%) at 24 months, 54.5% (95% CI, 50.2%-58.6%) at 36 months, and 47.0% (95% CI, 42.2%-51.7%) at 48 months. Conclusions and Relevance: In this population-based cohort study of patients with LRPC, a research framework at system level as well as favorable prognostic factors, a multidisciplinary approach, and an independent review of the first prostate biopsy at patient-level were positively associated with high uptake of active surveillance, a practice largely underused before this study.

Accurate prediction of long-term risk of biochemical failure after salvage radiotherapy including the impact of pelvic node irradiation.

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/ß = 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 αeff = 0.26/0.23 Gy-1, C = 107/107, 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,R2 = 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.

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer.

Introduction: We hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). Methods: The study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. Results: In REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58. Conclusion: Increasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.

Prostate image-guided radiotherapy by megavolt cone-beam CT.

PURPOSE: To test megavolt cone-beam CT (MV-CBCT) in order to evaluate setup errors in prostate radiotherapy. PATIENTS AND METHODS: The setup of 9 patients was verified weekly by electronic portal imaging (EPI) and MV-CBCT, both per-formed in the same treatment session. EPI were compared with digitally reconstructed radiographies (DRRs). MV-CBCTs were matched to simulation CTs by manual registration based on bone markers (BMR), by manual registration based on soft tissues (STR) - rectum, bladder, and seminal vesicles - and by automatic registration (AR) performed by a mutual information algorithm. Shifts were evaluated along the three main axes: anteroposterior (AP), craniocaudal (CC), and laterolateral (LL). Finally, in 4 additional patients showing intraprostatic calcifications, the calcification mismatch error was used to evaluate the three MV-CBCT matching methods. RESULTS: A total of 50 pairs of orthogonal EPIs and 50 MV-CBCTs were analyzed. Assuming an overall tolerance of 2 mm, no significant differences were observed comparing EPI vs BMR in any axis. A significant difference (p < 0.001) was observed along the AP axis comparing EPI vs AR and EPI vs STR. On the calcification data set (22 measures), the calcification mismatch along the AP direction was significantly lower (p < 0.05) after STR than after BMR or AR. CONCLUSION: Bone markers were not an effective surrogate of the target position and significant differences were observed comparing EPI or BMR vs STR, supporting the assessment of soft tissue position by MVCBs to verify and correct patient setup in prostate radiotherapy.

Hereditary paraganglioma syndrome associated with SDHD gene mutations: a patient with multicentric presentation treated with radiotherapy. Case report.

INTRODUCTION: Extra-adrenal paragangliomas are rare tumors arising from neuroendocrine cells. Sporadic and hereditary forms have been recognized. Among the latter, the PGL1 and PGL4 syndromes are associated with a high risk of multiple localizations. The treatment of choice for paragangliomas is surgical resection, but in some cases surgery can be difficult due to particular or multiple tumor sites or may result in severe neurological deficits. In such cases radiotherapy can be an effective alternative. In this paper we describe the case of a patient affected by hereditary paraganglioma syndrome with multicentric presentation who was treated at our center by external radiotherapy. CASE REPORT: A 55-year-old man presented in April 2008 with multiple paragangliomas: one in the left pontocerebellar angle, two in the middle neck, one mediastinal paraaortic mass, and an abdominal paraaortic lesion. The left pontocerebellar and mediastinal tumors were treated with three-dimensional conformal radiotherapy (3D-CRT) at total doses of 50.40 Gy and 55.80 Gy, respectively. The neck lesions were treated with intensity-modulated radiotherapy (IMRT) at a total dose of 55.80 Gy. The abdominal paraaortic lesion was surgically resected. RESULTS: No severe acute or late toxicity as evaluated with the EORTC-RTOG scale was observed. Fourteen months after the end of radiotherapy a whole body CT scan showed that the tumor lesions were stable in size and in their relations to contiguous structures. The arterial pressure was controlled by medical therapy and urine catecholamine levels were within the normal range. CONCLUSIONS: We believe that in patients affected by unresectable paragangliomas radiotherapy is a safe and effective alternative to surgery. The use of high-dose conformity techniques such as 3D-CRT and IMRT will allow higher local control rates with relatively few side effects thanks to the possibility of dose escalation and reduction of the amount of irradiated healthy tissues.

Predictors of Patient-Reported Incontinence at Adjuvant/Salvage Radiotherapy after Prostatectomy: Impact of Time between Surgery and Radiotherapy.

BACKGROUND: Baseline urinary incontinence (UI) strongly modulates UI recovery after adjuvant/salvage radiotherapy (ART/SRT), inducing clinicians to postpone it "as much as possible", maximizing UI recovery but possibly reducing efficacy. This series aims to analyze the trend of UI recovery and its predictors at radiotherapy start. METHODS: A population of 408 patients treated with ART/SRT enrolled in a cohort study (ClinicalTrials.gov #NCT02803086) aimed at developing predictive models of radiation-induced toxicities. Self-reported UI and personality traits, evaluated by means of the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-SF) and Eysenck Personality Questionnaire - Revised (EPQ-R) questionnaires, were assessed at ART/SRT start. Several endpoints based on baseline ICIQ-SF were investigated: frequency and amount of urine loss (ICIQ3 and ICIQ4, respectively), "objective" UI (ICIQ3 + 4), "subjective" UI (ICIQ5), and "TOTAL" UI (ICIQ3 +4 + 5). The relationship between each endpoint and time from prostatectomy to radiotherapy (TTRT) was investigated. The association between clinical and personality variables and each endpoint was tested by uni- and multivariable logistic regression. RESULTS: TTRT was the strongest predictor for all endpoints (p-values ≤ 0.001); all scores improved between 4 and 8 months after prostatectomy, without any additional long-term recovery. Neuroticism independently predicted subjective UI, TOTAL UI, and daily frequency. CONCLUSIONS: Early UI recovery mostly depends on TTRT with no further improvement after 8 months from prostatectomy. Higher levels of neuroticism may overestimate UI.

Acute patient-reported intestinal toxicity in whole pelvis IMRT for prostate cancer: Bowel dose-volume effect quantification in a multicentric cohort study.

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, R2 = 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.

Irradiation of pacemakers and cardio-defibrillators in patients submitted to radiotherapy: a clinical experience.

AIMS AND BACKGROUND: A prospective analysis was carried out on a group of irradiated patients with pacemakers or implantable cardioverter-defibrillators to identify any relationship between the various types of devices and physical and dosimetric parameters. Cardiac toxicity of the treatment was also investigated. METHODS AND STUDY DESIGN: Forty-five irradiated patients, implanted with pacemakers or implantable cardioverter-defibrillators, were prospectively investigated from 1999 to 2007. An analysis of radiation damage to pacemakers, depending on the geometric and dosimetric characteristics of the radiation beams, was carried out. The electric and magnetic fields of linear accelerators (LINACs) were measured to evaluate any interference. The calculation of dose received by pacemakers was evaluated by dose-volume histograms. RESULTS: No dysfunction was observed in any pacemaker, nor were the substitution times negatively affected. We did not find problems with the devices due to the interaction with the electromagnetic fields. Dose-volume histograms calculated for patients treated in regions close to devices (head & neck, thorax) showed an average maximum dose equal to 2.5 Gy for the head & neck area and equal to 1.8 Gy for the thoracic area. Acute (3 cases) and late (2 cases) cardiac events were observed only in 5 patients who underwent chemoradiation treatment, but no dysfunction was observed in any pacemaker. CONCLUSIONS: Our study confirms the safety of radiotherapy for patients implanted with pacemakers or implantable cardioverter-defibrillators but suggests that chemoradiation represents a probable risk factor for cardiac toxicity. Furthermore, all cardiac events were observed in patients treated in the head and'neck or left thoracic areas. A standardized protocol is advisable in order to improve patient control during the radiotherapy treatment. It is mandatory to calculate the dose received at the pacemaker/heart, even in the case of palliative treatment.

CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth.

Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-γ, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer.

Predictors of 2-Year Incidence of Patient-Reported Urinary Incontinence After Post-prostatectomy Radiotherapy: Evidence of Dose and Fractionation Effects.

Objective: To investigate predictors of patient-reported urinary incontinence (PRUI) in the first 2 years after post-prostatectomy radiotherapy (PORT) with particular emphasis on possible dose-effect relationships. Patients and Methods: Two-hundred-thirteen patients, whose clinical and dosimetric data were prospectively collected within a registered multi-institutional cohort study, underwent PORT with adjuvant (n = 106) or salvage (n = 107) intent with conventional (n = 123, prescribed dose to the prostatic bed: 66.6-79.8Gy in 1.8-2.0Gy/fr) or moderately hypo- (n = 90, 65.8-76.8Gy in 2.1-2.7Gy/fr) fractionation during the period 2011-2017. PRUI was evaluated through the ICIQ-SF questionnaire filled in at baseline and every 6 months thereafter. The analysis focused on three ICIQ-based clinically relevant endpoints: (a) very frequent leakage (FREQUENCY, ICIQ3 score >3), (b) moderate to severe amount of urine loss (AMOUNT, ICIQ4>2) (c) objective severe symptoms (OBJECTIVE, ICIQ3+4>5). Predictors of the incidence within 2 years for the three endpoints were investigated focusing only on patients without endpoint symptoms at baseline. A uni-variable logistic regression analysis was performed in order to determine the best dose metrics describing PRUI risk in terms of 2-Gy equivalent dose (EQD2) calculated with different α/ß values reported in the literature (0.8, 3, 5Gy), and to identify the most significant clinical variables. Variables showing p < 0.20 at uni-variable analysis were entered into a backward stepwise multi-variable logistic regression analysis. Lastly, the goodness of fit and model calibration were evaluated and internally validated. Results: Patients without symptoms at baseline experienced (a), (b), and/or (c) within 2 years in 41/130 (32%), 40/192 (21%), and 41/129 (32%) of the cases, respectively. EQD2 for α/ß = 0.8Gy was the best dose metric associated with PRUI. Multi-variable analysis identified baseline incontinence levels as the strongest predictor for all endpoints (p < 0.006). Both FREQUENCY and OBJECTIVE were significantly influenced also by EQD2(α/ß = 0.8Gy). The goodness of fit was excellent, as was the calibration; internal calibration confirmed apparent performance. Conclusion: Baseline mild urinary incontinence symptoms strongly modulate the 2-year risk of PRUI. In addition, FREQUENCY is characterized by a marked dose-effect relationship also influencing the trend of OBJECTIVE, with results more reliable than AMOUNT as an objective index. A strong impact of fractionation on severe PRUI after post-prostatectomy radiotherapy also emerged.

Expression levels of circulating miRNAs as biomarkers during multimodal treatment of rectal cancer - TiMiSNAR-mirna: a substudy of the TiMiSNAR Trial (NCT03962088).

BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading and lymph node status helped to visualize individual tumor sensitivity to chemoradiotherapy, retrospectively. As the response to neoadjuvant chemoradiotherapy is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed. MicroRNAs are currently under investigation to serve as blood-based biomarkers. To date, no screening approach to identify relevant miRNAs as biomarkers in blood of patients with rectal cancer was undertaken. The aim of the study is to investigate the role of circulating miRNAs as biomarkers in those patients included in the TiMiSNAR Trial (NCT03465982). This is a biomolecular substudy of TiMiSNAR Trial (NCT03962088). METHODS: All included patients in the TiMiSNAR Trial are supposed to undergo blood collection at the time of diagnosis, after neoadjuvant treatment, after 1 month from surgery, and after adjuvant chemotherapy whenever indicated. DISCUSSION: TiMiSNAR-MIRNA will evaluate the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pathological complete response. Moreover, the study will evaluate the role of liquid biopsies in the monitoring of treatment, correlate changes in expression levels of miRNA following complete surgical resection with disease-free survival, and evaluate the relation between changes in miRNA during surveillance and tumor relapse. TRIAL REGISTRATION: Clinicaltrials.gov NCT03962088 . Registered on 23 May 2019.

Radiotherapy after partial laryngectomy: an analysis of 36 cases and a proposal to optimize radiotherapy.

AIMS AND BACKGROUND: Laryngeal cancer treatment options include radical surgery, "organ preservation surgery", radiotherapy and chemotherapy. There is no proven evidence of a significant increase in late toxicity with adjuvant radiotherapy after conservative surgery. The aim of this retrospective study was to evaluate the toxicity, local-regional control and overall survival of adjuvant radiotherapy after conservative surgery. METHODS: A total of 36 patients was treated with radiotherapy after partial laryngectomy at the Radiotherapy Department of the Institute for Cancer Treatment and Research (IRCC) of Candiolo and of the Mauriziano Hospital in Turin, between 1994 and 2007. The postoperative treatment doses ranged from 45 to 70.2 Gy with conventional fractionation. The Kaplan-Meier method was applied for statistical analysis. The RTOG-EORTC scale was used to evaluate late and acute toxicity. RESULTS: Overall 5- and 10-year survival was 93% and 47%, respectively. Local control was 93.5% at 5 and was unchanged at 10 years. Grade 2 acute cutaneous and mucous toxicity was 41% and 62%, and grade 3, 6.9% and 3.5%, respectively. Only one patient required percutaneous endoscopic gastrostomy due to severe dysphagia and one patient required temporary tracheostomy for severe acute laryngeal edema (grade 3). Two patients experienced late toxicity greater than grade 3. The median dose to the residual larynx was 59.5 Gy (range, 45-70.2), and the median dose to the neck was 50.4 Gy (range, 39.6 -55.8). CONCLUSIONS: The results of our study showed a dose-dependent increase in the late toxicity trend at doses over and above 60 Gy, which is higher than the cutoff dose reported in the literature. There was no indication from our data that adjuvant postoperative radiotherapy means additional toxicity. The use of highly conformal techniques can further reduce toxicity of the radiotherapy.

Salvage radiation therapy after radical prostatectomy: survival analysis.

BACKGROUND: To evaluate the outcome of patients treated with salvage radiotherapy after radical prostatectomy and to investigate the effects of independent predictors on survival. METHODS: From January 2000 to December 2015, 234 patients with biochemical/clinical recurrences after radical prostatectomy were submitted to salvage radiotherapy (SRT). One hundred and fifty-seven patients (67%) received three-dimensional (3D) conformal radiotherapy while 77 patients (33%) were treated with intensity-modulated radiotherapy (IMRT) or IMRT/image-guided radiotherapy by tomotherapy. The median RT dose to prostate bed was 70.2 Gy (range: 66-79 Gy). The investigated endpoints were biochemical relapse-free survival (BRFS), clinical relapse-free survival (CRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS). Different covariates were considered to investigate predictors of survival. RESULTS: With a median follow-up of 117 months the BRFS, CRFS, DMFS and PCSS at 10 years were 54%, 84%, 90%, and 94%, respectively. In multivariate analysis (MVA), the pathological Gleason Score (pGS) was the most important factor affecting BRFS, CRFS, DMFS and PCSS (P<0.007, HR>1.55); pathological stage (pT) was predictor of BRFS (P=0.007, HR=1.7) and PCSS (P=0.02, HR=4.2), and the last prostate-specific antigen during follow-up was an important survival predictor of CRFS (P=0.004, HR=1.26) and PCSS (P<0.0001, HR=1.04). The time between surgery and the start of SRT was correlated with BRFS (P<0.0001, HR=0.987) and CRFS (P=0.047, HR=0.989). In univariate analysis (UVA), positive surgical margins at the prostatectomy specimen improved BRFS (P=0.01, HR=0.54), CRFS (P=0.05, HR=0.46) and DMFS (P=0.005, HR=0.13) after SRT. CONCLUSIONS: At long-term follow-up, excellent outcome results of SRT on BRFS, CRFS, DMFS, and PCSS were obtained. Several prognostic factors such as pGS, pT and surgical margin status were found to be predictors of survival.