Late Radiation-induced Toxicity Research Articles

Predictors of radiation-induced late rectal toxicity in prostate cancer treatment: a volumetric and dosimetric analysis.

Prostate cancer (PCa) is a prevalent malignancy in European men, often treated with radiotherapy (RT) for localized disease. While modern RT achieves high success rates, concerns about late gastrointestinal (GI) toxicities persist. This retrospective study aims to identify predictors for late GI toxicities following definitive conventionally fractionated external beam RT (EBRT) for PCa, specifically exploring the dose to the rectal wall. A cohort of 96 intermediate- to high-risk PCa patients underwent EBRT between 2008 and 2016. Rectum and rectum wall contours were delineated, and 3D dose matrices were extracted. Volumetric and dosimetric indices were computed, and statistical analyses were performed to identify predictors using the Mann-Whitney U-rank test, logistic regression, and recursive feature elimination. In our cohort, 15 out of 96 patients experienced grade II late proctitis. Our analysis reveals distinct optimal predictors for rectum and rectum wall (RW) structures varying with α/β values (3.0 and 2.3 Gy) across prescribed doses of 68 to 76 Gy. Despite variability, RW predictors demonstrate greater consistency, notably V68Gy[%] to V74Gy[%] for α/β 3.0 Gy, and V68Gy[%] to V70Gy[%] for α/β 2.3 Gy. The model with α/β 2.3 Gy, featuring RW volume receiving 70 Gy (V70Gy[%]), stands out with a BIC value of 62.92, indicating its superior predictive effectiveness. Finally, focusing solely on the rectum structure, the V74Gy[%] emerges the best predictor for α/β 3.0 Gy, with a BIC value of 66.73. This investigation highlights the critical role of V70Gy[%] in the rectum wall as a robust predictor for grade II late gastrointestinal (GI) toxicity following external beam radiation therapy (EBRT) for prostate cancer (PCa). Furthermore, our findings suggest that focusing on the rectum wall specifically, rather than the entire rectum, may offer improved accuracy in assessing proctitis development. A V70Gy (in EQD2 with α/β 2.3 Gy) of ≤5% and if possible ≤1% for the rectal wall should be achieved to minimize the risk of late grade II proctitis.

Quality of life and clinical outcomes in rectal cancer patients treated on a 1.5T MR-Linac within the MOMENTUM study

Background and purposeThis study assessed quality of life (QoL) and clinical outcomes in rectal cancer patients treated with magnetic resonance (MR) guided short-course radiation therapy (SCRT) on a 1.5 Tesla (T) MR-Linac during the first 12 months after treatment. Materials and methodsRectal cancer patients treated with 25 Gy SCRT in five fractions with curative intent in the Netherlands (2019–2022) were identified in MOMENTUM (NCT04075305). Toxicity (CTCAE v5) and QoL (EORTC QLQ-C30 and -CR29) was primarily analyzed in patients without metastatic disease (M0) and no other therapies after SCRT. Patients who underwent tumor resection were censored from surgery. A generalized linear mixed-model was used to investigate clinically meaningful (≥10) and significant (P < 0.05) QoL changes. Clinical and pathological complete response (cCR and pCR) rates were calculated in patients in whom response was documented. ResultsA total of 172 patients were included, of whom 112 patients were primarily analyzed. Acute and late radiation-induced high-grade toxicity were reported in one patient, respectively. CCR was observed in 8/64 patients (13 %), 14/37 patients (38 %) and 13/16 patients (91 %) at three, six and twelve months; pCR was observed in 3/69 (4 %) patients. After 12 months, diarrhea (mean difference [MD] −17.4 [95 % confidence interval [CI] −31.2 to −3.7]), blood and mucus in stool (MD −31.1 [95 % CI −46.4 to −15.8]), and anxiety (MD –22.4 [95 % CI −34.0 to −10.9]) were improved. ConclusionHigh-field MR-guided SCRT for the treatment of patients with rectal cancer is associated with improved disease-related symptom management and functioning one year after treatment.

Do Barrier Films Impact Long-Term Skin Toxicity following Whole-Breast Irradiation? Objective Follow-Up of Two Randomised Trials.

Purpose: Hydrofilm, a polyurethane-based barrier film, can be used to prevent acute radiation dermatitis (RD) in adjuvant whole-breast irradiation (WBI) for breast cancer. This cost-effective prophylactic measure is currently being recommended to a growing number of patients, yet long-term safety data and its impact on late radiation-induced skin toxicity such as pigmentation changes and fibrosis have not been investigated. Methods: We objectively evaluated patients who were previously enrolled in either of two intrapatient-randomised (lateral versus medial breast halve) controlled trials on the use of Hydrofilm for RD prevention (DRKS00029665; registered on 19 July 2022). Results: Sixty-two patients (47.7% of the initial combined sample size) provided consent for this post-hoc examination, with a median follow-up time (range) of 58 (37-73) months. Following WBI, there was a significant increase in yellow skin tones of the entire breast when compared to baseline measurements before WBI (p < 0.001) and a significant increase of cutis, subcutis, and oedema thickness (p < 0.001, p < 0.001, and p = 0.004, respectively). At follow-up, there were no significant differences in either pigmentation changes or skin fibrosis between the Hydrofilm and standard of care breast halves. Conclusion: These data suggest that Hydrofilm can be safely used in the context of acute RD prevention, without affecting late side effects, supporting its widespread use.

Oncological Outcomes, Long-Term Toxicities, Quality of Life and Sexual Health after Pencil-Beam Scanning Proton Therapy in Patients with Low-Grade Glioma.

To assess oncological outcomes, toxicities, quality of life (QoL) and sexual health (SH) of low-grade glioma (LGG) patients treated with pencil-beam scanning proton therapy (PBS-PT). We retrospectively analyzed 89 patients with LGG (Neurofibromatosis type 1; n = 4 (4.5%) patients) treated with PBS-PT (median dose 54 Gy (RBE)) from 1999 to 2022 at our institution. QoL was prospectively assessed during PBS-PT and yearly during follow-up from 2015 to 2023, while a cross-sectional exploration of SH was conducted in 2023. Most LGGs (n = 58; 65.2%) were CNS WHO grade 2 and approximately half (n = 43; 48.3%) were located in the vicinity of the visual apparatus/thalamus. After a median follow-up of 50.2 months, 24 (27%) patients presented with treatment failures and most of these (n = 17/24; 70.8%) were salvaged. The 4-year overall survival was 89.1%. Only 2 (2.2%) and 1 (1.1%) patients presented with CTCAE grade 4 and 3 late radiation-induced toxicity, respectively. No grade 5 late adverse event was observed. The global health as a domain of QoL remained stable and comparable to the reference values during PBS-PT and for six years thereafter. Sexual satisfaction was comparable to the normative population. LGG patients treated with PBS-PT achieved excellent long-term survival and tumor control, with exceptionally low rates of high-grade late toxicity, and favorable QoL and SH.

Évaluation de facteurs prédictifs de réponse pathologique à la radiothérapie néoadjuvante des sarcomes des tissus mous

PurposeConserving surgery combined with radiotherapy in presence of local recurrence risk factors is standard treatment of soft tissue sarcomas, a group of rare and heterogeneous tumours. Radiotherapy is performed before or after surgery. In neoadjuvant setting, late radiation-induced toxicity is reduced and pathological response to radiotherapy could be achieved. A complete pathological response to radiotherapy has recently been shown to predict better survival. Our study aims at identifying predictive factors of pathological response to neoadjuvant radiotherapy (clinical, radiological or histological) of soft tissue sarcomas. Patients and methodsClinical, imaging (MRI: perilesional oedema, necrosis, tumour heterogeneity, vasculonervous relationships) and pathological (pathological subtype, tumour grade, anticipated/obtained resection quality) data were retrospectively collected. Tumour response (imaging and pathological), patient outcome, acute and late radiation-induced toxicity, predictive factors of pathological response to neoadjuvant radiotherapy were studied. The 2-test or exact-Fisher test (qualitative variables) and by Student's t-test or Kruskal-Wallis test (quantitative variables) were used for statistical analysis. ResultsFrom April 2017 to April 2021, neoadjuvant radiotherapy (50Gy in 25 fractions) followed by surgical excision was performed to 36 consecutive patients with liposarcomas (n=17/36), or undifferentiated sarcomas (n=8/36). MRI response was complete in 1 patient, partial in 9 patients (n=9/36, 25%), stable in 21 patients (n=21/36, 58%) or in progression in 5 patients (n=5/36, 14%). Pathological response was observed in 22 patients (61%). No grade 3-4 acute radiation-induced toxicity was observed. Regarding late toxicity, 28% of patients had grade 1–2 oedema (n=10/36), 39% had a grade 1 fibrosis (n=14/36), and 30% grade 1 pain (n=11/36). No predictive factors of response to radiotherapy was statistically significant. ConclusionsNeoadjuvant radiotherapy is well-tolerated. No clinical, radiological or pathological predictive factors was identified for radiotherapy tumour response.

Time-Dependent ROC Curve Analysis for Assessing the Capability of Radiation-Induced CD8 T-Lymphocyte Apoptosis to Predict Late Toxicities after Adjuvant Radiotherapy of Breast Cancer Patients.

Late fibrosis can occur in breast cancer patients treated with curative-intent radiotherapy. Predicting this toxicity is of clinical interest in order to adapt the irradiation dose delivered. Radiation-induced CD8 T-lymphocyte apoptosis (RILA) had been proven to be associated with less grade ≥2 late radiation-induced toxicities in patients with miscellaneous cancers. Tobacco smoking status and adjuvant hormonotherapy were also identified as potential factors related to late-breast-fibrosis-free survival. This article evaluates the predictive performance of the RILA using a ROC curve analysis that takes into account the dynamic nature of fibrosis occurrence. This time-dependent ROC curve approach is also applied to evaluate the ability of the RILA combined with the other previously identified factors. Our analysis includes a Monte Carlo cross-validation procedure and the calculation of an expected cost of misclassification, which provides more importance to patients who have no risk of late fibrosis in order to be able to treat them with the maximal irradiation dose. Performance evaluation was assessed at 12, 24, 36 and 50 months. At 36 months, our results were comparable to those obtained in a previous study, thus underlying the predictive power of the RILA. Based on specificity and cost, RILA alone seemed to be the most performant, while its association with the other factors had better negative predictive value results.

Reducing Target Volumes of Intensity Modulated Radiation Therapy After Induction Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: Long-Term Results of a Prospective, Multicenter, Randomized Trial

The objective of this study was to estimate the long-term survival, late toxicity profile, and quality of life of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with combined induction chemotherapy (IC) and concurrent chemoradiotherapy from a clinical trial focused on reducing the target volume of intensity modulated radiation therapy (IMRT). This prospective, randomized clinical trial was conducted across 6 Chinese hospitals and included 212 patients with stage III-IVB NPC who were randomly allocated to a pre-IC or post-IC group. Eligible patients were treated with 2 cycles of IC+CCRT. All patients underwent radical IMRT. Gross tumor volumes of the nasopharynx were delineated according to pre-IC and post-IC tumor extent in the pre-IC and post-IC groups, respectively. After a median follow-up of 98.4 months, 32 of 97 (32.9%) and 33 of 115 (28.7%) patients experienced treatment failure or died in the pre-IC and post-IC groups, respectively. None of the patients developed grade 4 late toxicity. Late radiation-induced toxicity predominantly manifested as grade 1 to 2 subcutaneous fibrosis, hearing loss, tinnitus, and xerostomia, whereas grade 3 late toxicity included xerostomia and hearing loss. The 5-year estimated overall, progression-free, locoregional recurrence-free, and distant metastasis-free survival rates in the pre-IC and post-IC groups were 78.2% versus 83.3%, 72.0% versus 78.1%, 90.2% versus 93.5%, and 78.1% versus 82.1%, respectively. The pre-IC group had a significantly higher incidence of xerostomia and hearing damage than the post-IC group. In terms of quality of life, compared with the pre-IC group, the post-IC group showed significant improvement in cognitive function (P=.045) and symptoms including dry mouth (P=.004), sticky saliva (P=.047), and feeling ill (P=.041). After long-term follow-up, we confirmed that reducing the target volumes of IMRT after IC in locoregionally advanced NPC showed no inferiority in terms of the risk of locoregional relapse and potentially improved quality of life and alleviated late toxicity.

Objective, Clinician- and Patient-Reported Evaluation of Late Toxicity Following Adjuvant Radiation for Early Breast Cancer: Long-Term Follow-Up Results of a Randomised Series.

Background and Purpose: This study aimed to differentially assess the frequency and severity of late radiation-induced toxicity following adjuvant whole-breast irradiation for early breast cancer with conventional fractionation (CF) and moderate hypofractionation (mHF). Materials and Methods: Patients recruited in a previous randomised controlled trial comparing acute toxicity between CF and mHF without disease recurrence were included in a post hoc analysis. Spectrophotometric and ultrasonographic examinations were performed for an objective evaluation and subsequent comparison of long-term skin toxicity. Furthermore, patient- and clinician-reported outcomes were recorded. Results: Sixty-four patients with a median age of 58 (37-81) years were included. The median follow-up was 57 (37-73) months. A total of 55% underwent CF and 45% mHF. A total of 52% received a sequential boost to the tumour bed. A significant decrease in mean L* (p = 0.011) and an increase in a* (p = 0.040) and b* values (p < 0.001) were observed, indicating hyperpigmentation. In comparison with the non-irradiated breast, there was a significant increase in both cutis (+14%; p < 0.001) and subcutis (+17%; p = 0.011) thickness, significantly more pronounced in CF patients (p = 0.049). In CF patients only, a sequential boost significantly increased the local cutis thickness and oedema compared to non-boost regions in the same breast (p = 0.001 and p < 0.001, respectively). Conclusions: mHF objectively resulted in reduced long-term skin toxicity compared to CF. A sequential boost increased the local fibrosis rate in CF, but not in mHF. This might explain the subjectively reported better cosmetic outcomes in patients receiving mHF and reinforces the rationale for favouring mHF as the standard of care.

Prospective Pilot study of Quality of Life in patients with severe late-radiation-toxicity treated by Low hyperbaric-oxigen-therapy

Background/purposeThe aim of this study is to assess for the first time the immediate and long term impact on quality-of-life of HBO treatments(HBOT) at 1.45 ATA (Absolute Atmospheric Pressure) Medical Hyperbaric chamber. MethodsPatients over 18 years-old, suffering of grade 3 Common Terminology Criteria for Adverse Events (CTCAE) 4.0 radiation induced late toxicity and progressing to standard support therapy were included in this prospective study. HBOT was given daily, sixty minutes per session by a Medical Hyperbaric Chamber Biobarica System at 1.45 ATA at 100% O2. Forty sessions were prescribed for all patients given in 8 weeks. Patients reported outcomes (PROs) was assessed by the QLQ-C30 questionnaire, before starting, in the last week of the treatment, as well as during follow up. ResultsBetween February-2018/June-2021, 48 patients fulfilled the inclusion criteria. A total of 37 patients (77%) completed the treatment prescribed HBOT sessions. Patients with anal fibrosis (9/37) and brain necrosis (7/37) were the most frequently treated. The most common symptoms were pain (65%) and bleeding (54%). In addition, thirty out of the 37 patients who completed the pre- and post-treatment Patients Reported Outcomes (PROs) assessment also completed the follow up European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire C30 (EORTC-QLQ-C30), and were evaluated in the present study. Mean follow up was 22,10 (6–39) months.The Median score of the EORTC-QLQ-C30, at the end of HBOT and during follow-up, was improved in all assessed domains, except in the cognitive aspect (p = 0.106). ConclusionsHBOT at 1.45 ATA is a feasible and well tolerated treatment, improving long term quality of life in terms of physical function, daily activities and general health subjective state of patients suffering severe late radiation-induced toxicity.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial

Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Is it time to modify the Japanese Uterine Cervical Cancer Guidelines to recommend a higher dose for radio-resistant tumors?

Compared with the European or the United States' uterine cervical cancer management guidelines, which aim to deliver >85Gy EQD2 (the equivalent effective dose in 2Gy per fraction) to the high-risk clinical target volume (CTVHR) D90 (minimal dose of 90% of the CTVHR), the dose goal of the corresponding Japanese guidelines does not recommend delivering such a high dose to the CTVHR D90. Subsequently, while the rate of late radiation-induced toxicities is reported to be much lower in the Japanese schedule, the local control rate is relatively inferior to that of clinical results reported by the IntErnational study on MRI-guided BRAchytherapy in CErvical cancer study (EMBRACE-I) in which the dose goal for CTVHR D90 was >85Gy and showed >90% local control regardless of tumor stage. In daily clinical practice, patients with residual disease supposedly due to insufficient total dose delivery are occasionally referred to our hospital for the possibility of re-irradiation, which is not usually recommended because the risk of late severe radiation-induced toxicity is high. In this report, the authors hope to raise a discussion in our community about modifying our treatment guidelines to recommend a higher dose at least for patients with poor response.

Everything You Always Wanted to Know about Sarcopenia but Were Afraid to Ask: A Quick Guide for Radiation Oncologists (Impact of Sarcopenia in Radiotherapy: The AFRAID Project).

Sarcopenia (SP) is a syndrome characterized by age-associated loss of skeletal muscle mass and function. SP worsens both acute and late radiation-induced toxicity, prognosis, and quality of life. Myosteatosis is a pathological infiltration of muscle tissue by adipose tissue which often precedes SP and has a proven correlation with prognosis in cancer patients. Sarcopenic obesity is considered a "hidden form" of SP (due to large fat mass) and is independently related to higher mortality and worse complications after surgery and systemic treatments with worse prognostic impact compared to SP alone. The evaluation of SP is commonly based on CT images at the level of the middle of the third lumbar vertebra. On this scan, all muscle structures are contoured and then the outlined surface area is calculated. Several studies reported a negative impact of SP on overall survival in patients undergoing RT for tumors of the head and neck, esophagus, rectum, pancreas, cervix, and lung. Furthermore, several appetite-reducing side effects of RT, along with more complex radiation-induced mechanisms, can lead to SP through, but not limited to, reduced nutrition. In particular, in pediatric patients, total body irradiation was associated with the onset of SP and other changes in body composition leading to an increased risk of cardiometabolic morbidity in surviving adults. Finally, some preliminary studies showed the possibility of effectively treating SP and preventing the worsening of SP during RT. Future studies should be able to provide information on how to prevent and manage SP before, during, or after RT, in both adult and pediatric patients.

KS01.5.A Impact of reduced treatment volumes on pattern of tumor recurrence and radiation dose to normal brain parenchyma in glioblastoma

Abstract Background to analyze GBM recurrence pattern after standard chemoradiotherapy according to different target volume delineations. We hypothesized that reduced target volume margins may result in similar pattern of failure. Material and Methods 207 patients with GBM who recurred after standard chemoradiation were evaluated. According to the Advisory Committee for Radiation Oncology Practice (ACROP) committee of the European Organisation for Research and Treatment of Cancer (EORTC) target volume delineation guideline, the clinical target volume (CTV) used for treatment planning consisted of residual tumor and resection cavity plus 2-cm margin. MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. The recurrent lesions were defined as in-field, marginal, or distant if &amp;gt;80%, 20-80%, or &amp;lt;20% of the intersecting volume was included in the 95% isodose line. For each patient a theoretical plan consisting of a reduced CTV using 1-cm margin was created and patterns of failure evaluated. Results The median overall survival and progression-free survival were 15.3 months and 7.8 months, respectively, from the date of surgery. Recurrences were in-field in 180 patients, marginal in 5 patients, and distant in 22 patients. Analysis of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred in-field and distant in 75.6% and 18.6% of methylated patients and in 91.8% and 6% of unmethylated patients, respectively (p=0.0046). Patterns of failure were similar between the different treatment plans. Reduced target volumes were associated with significantly lower doses of 20-50 Gy to normal brain and hippocampi (p=0.0001). Conclusion Most of patients treated with standard chemioradiotherapy have in-field recurrences; however, an increased risk of distant recurrences occurs in methylated tumors. The use of target delineation using 1-cm CTV margin is associated with smaller volumes of normal brain and hippocampi irradiated to high doses, without significant changes in the pattern of failure. The impact of different target delineation in terms of efficacy and risk of late radiation-induced toxicity should be assessed prospectively.

Hypofractionated versus conventional intensity-modulated radiation irradiation (HARVEST-adjuvant): study protocol for a randomised non-inferior multicentre phase III trial

IntroductionShort course regimen has become the major trend in the field of adjuvant radiotherapy for patients with breast cancer. Hypofractionated radiotherapy (HF-RT) regimen of 40–42.5 Gy in 15–16 fractions has...

Cardiotoxicity model-based patient selection for Hodgkin lymphoma proton therapy

Introduction Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability. Material and methods This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection. Results Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy, p < 0.01), to the left ventricle (0.67 Gy vs 0.03, p < 0.01) and to the valves (1.29 Gy vs. 0.06, p < 0.01). For a HL patient without cardiovascular risk factor other than anthracycline-based chemotherapy, the relative risks of late cardiovascular complications were significantly lower after IMPT compared with VMAT for ischemic heart disease (1.07 vs 1.17, p < 0.01), for congestive heart failure (2.84 vs. 3.00, p < 0.01), and for valvular disease (1.01 vs. 1.06, p < 0.01). The median cRRR of cardiovascular adverse events with IMPT was 4.8%, ranging between 0.1% and 30.5%, depending on the extent of radiation fields and on the considered cardiovascular risk factors. The estimated proportion of HL patients currently treatable with IMPT in European countries with proton therapy facilities ranged between 8.0% and 100% depending on the country, corresponding to cRRR thresholds ranging from 24.0% to 0.0%. Conclusion While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

Improving Patients' Life Quality after Radiotherapy Treatment by Predicting Late Toxicities.

Simple SummaryOver 50% of patients with cancer will receive radiotherapy treatment. Five to ten percent of patients who received radiotherapy will develop side effects. Identifying these patients before treatment start would allow for treatment modification to minimize these effects and improve the life quality of these patients. Our team developed a test, which allows predicting these secondary effects before starting the treatment. This will help in proposing personalized treatments to improve the outcome. This review presents how this test is performed, its results, as well as its modification in order to be used in hospitals.Personalized treatment and precision medicine have become the new standard of care in oncology and radiotherapy. Because treatment outcomes have considerably improved over the last few years, permanent side-effects are becoming an increasingly significant issue for cancer survivors. Five to ten percent of patients will develop severe late toxicity after radiotherapy. Identifying these patients before treatment start would allow for treatment adaptation to minimize definitive side effects that could impair their long-term quality of life. Over the last decades, several tests and biomarkers have been developed to identify these patients. However, out of these, only the Radiation-Induced Lymphocyte Apoptosis (RILA) assay has been prospectively validated in multi-center cohorts. This test, based on a simple blood draught, has been shown to be correlated with late radiation-induced toxicity in breast, prostate, cervical and head and neck cancer. It could therefore greatly improve decision making in precision radiation oncology. This literature review summarizes the development and bases of this assay, as well as its clinical results and compares its results to the other available assays.

Impact of sarcopenia on acute radiation-induced toxicity in head and neck cancer patients

Background and purposeSarcopenia is related to late radiation-induced toxicities and worse survival in head and neck cancer (HNC) patients. This study tested the hypothesis that sarcopenia improves the performance of current normal tissue complication probability (NTCP) models of radiation-induced acute toxicity in HNC patients. Material/methodsThis was a retrospective analysis in a prospective cohort of HNC patients treated from January 2007 to December 2018 with (chemo)radiotherapy. Planning CT scans were used for evaluating skeletal muscle mass. Characteristics of sarcopenic and non-sarcopenic patients were compared. The impact of sarcopenia was analysed by adding sarcopenia to the linear predictors of current NTCP models predicting physician- and patient-rated acute toxicities. ResultsThe cut-off values of sarcopenia in the study population (n = 977) were established at skeletal muscle index < 42.0 cm2/m2 (men) and < 31.2 cm2/m2 (women), corresponding to the lowest sex-specific quartile. Compared to non-sarcopenic patients, sarcopenic patients were more frequently smokers (61% vs. 48%, p < 0.001), had more often advanced stage of disease (stage III-IV, p = 0.004), higher age (67 vs. 63 years, p < 0.001) and experienced more pretreatment complaints, such as dysphagia (grade ≥ 2, p < 0.001). Sarcopenia remained statistically significant, next to the linear predictor, only for physician-rated grade ≥ 3 dysphagia (week 3–6 during RT, p < 0.01). However, sarcopenia did not improve the performance of these NTCP models (p > 0.99). ConclusionSarcopenia in HNC patients was an independent prognostic factor for radiation-induced physician-rated acute grade ≥ 3 dysphagia, which might be explained by its impact on swallowing muscles. However, addition of sarcopenia did not improve the NTCP model performance.

Radiotherapy in the Management of Non-Metastatic Inflammatory Breast Cancers: A Retrospective Observational Study.

Simple SummaryInflammatory breast cancer (IBC) is a rare and aggressive clinicopathological presentation of breast cancer. The treatment of non-metastatic IBC usually consists of neoadjuvant systemic therapy, total mastectomy with axillary lymph node dissection, and adjuvant radiotherapy. This single-center retrospective study aims to assess the clinical outcomes of curative-intent multidisciplinary treatment of non-metastatic IBC. We identified 113 patients with a 5-year overall survival of 78.0% and a 5-year locoregional recurrence-free survival of 85.2%, highlighting a high locoregional control with standard fractionation 3D electron or photon therapy in our cohort, despite a pejorative overall survival.(1) Background: Inflammatory breast cancers (IBC) are characterized by a poor prognosis. This retrospective study aims to describe the clinical outcomes of non-metastatic IBC patients treated with a multidisciplinary approach with neo-adjuvant chemotherapy, surgery, and radiotherapy. (2) Methods: This single-center retrospective study included all women patients diagnosed with non-metastatic IBC between January 2010 and January 2018 at the Institut Curie (Paris, France) and treated with neoadjuvant chemotherapy, surgery, and radiotherapy. Overall survival (OS), disease-free survival (DFS), and locoregional free survival (LRRFS) were calculated from the time of diagnosis. Prognostic factors for patient survival were analyzed based on univariate and multivariate regressions. (3) Results: We identified 113 patients with a median age of 51 years. 79.7% had node-positive tumors; triple-negative breast cancers (TNBC) represented 34.6% of the cases. A large majority of patients (91.2%) received adjuvant post-mastectomy while ten patients (8.8%) received preoperative radiotherapy. Non-pathological complete response (non-pCR) was observed in 67.3% of patients. Radiotherapy delivered a median dose of 50 Gy to the breast or the chest wall in 25 fractions. With a median follow-up of 54 months, 5-year OS, DFS and LRRFS were 78% (CI: 70.1–86.8%), 68.1% (59.6–77.7%), and 85.2% (78.4–92.7%), respectively. In multivariate analysis, non-pCR was an adverse prognosis factor for OS, DFS, and LRRFS; pre-operative radiotherapy was an adverse prognosis factor for OS and DFS. Radiation-related adverse events were limited to acute skin toxicity (22% of Grade 2 and 2% of grade 3 dermatitis); no late radiation-induced toxicity was reported. (4) Conclusions: High locoregional control could be achieved with multidisciplinary management of non-metastatic IBC, suggesting the anti-tumor efficacy of radiotherapy in this rare but pejorative clinicopathological presentation. While comparing favorably with historical cohorts, OS and DFS could be potentially improved in the future with the use of new systemic treatments, such as PARP-inhibitors or immunotherapy.

Quantitative assessments of late radiation-induced skin and soft tissue toxicity and correlation with RTOG scales and biological equivalent dose in breast cancer

PurposeRadiation-induced toxicity (RIT) is usually assessed by inspection and palpation. Due to their subjective and unquantitative nature, objective methods are required. This study aimed to determine whether a quantitative tool is able to assess RIT and establish an underlying BED-response relationship in breast cancer.MethodsPatients following seven different breast radiation protocols were recruited to this study for RIT assessment with qualitative and quantitative examination. The biologically equivalent dose (BED) was used to directly compare different radiation regimens. RIT was subjectively evaluated by physicians using the Radiation Therapy Oncology Group (RTOG) late toxicity scores. Simultaneously an objective multiprobe device was also used to quantitatively assess late RIT in terms of erythema, hyperpigmentation, elasticity and skin hydration.ResultsIn 194 patients, in terms of the objective measurements, treated breasts showed higher erythema and hyperpigmentation and lower elasticity and hydration than untreated breasts (p < 0.001, p < 0.001, p < 0.001, p = 0.019, respectively). As the BED increased, Δerythema and Δpigmentation gradually increased as well (p = 0.006 and p = 0.002, respectively). Regarding the clinical assessment, the increase in BED resulted in a higher RTOG toxicity grade (p < 0.001). Quantitative assessments were consistent with RTOG scores. As the RTOG toxicity grade increased, the erythema and pigmentation values increased, and the elasticity index decreased (p < 0.001, p = 0.016, p = 0.005, respectively).ConclusionsThe multiprobe device can be a sensitive and simple tool for research purpose and quantitatively assessing RIT in patients undergoing radiotherapy for breast cancer. Physician-assessed toxicity scores and objective measurements revealed that the BED was positively associated with the severity of RIT.

Association of Baseline Health-Related Quality of Life Metrics With Outcome in Localized Prostate Cancer

While health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localized prostate cancer (LPCa). In this exploratory analysis, we report the association of baseline HR-QoL metrics with overall survival (OS) and risk of late radiation-induced toxicity in men with LPCa treated with combination of radiotherapy (RT) and androgen deprivation therapy (ADT).This is a secondary analysis of a phase III randomized controlled study conducted in two tertiary cancer centers. LPCa patients with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. HR-QoL scores were estimated using European Organization for Research and Treatment of Cancer QoL questionnaire. A multi-state Markov model was used to determine the association of baseline HR-QoL metrics with OS and a multilevel multivariable Cox regression to determine the association with incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P-value < 0.025 was considered as statistically significant. Conditional approach was used to calculate 15-year adjusted OS for patients with and without financial difficulty and patients with and without dyspnea at baseline.Overall, 393 patients with baseline HR-QoL data were included in this analysis - 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio [HR]: 1.020, 95% confidence intervals [CI]:1.010-1.030, P = 0.02), and dyspnea (HR: 1.020, 95% CI:1.003-1.030, P = 0.01) were associated with inferior OS. Adjusted OS for patients with and without financial difficulty at baseline was 15.5% and 45.7%, respectively (P < 0.01). Adjusted OS for patients with and without baseline dyspnea was 21.2% and 46.6%, respectively. Baseline dyspnea was associated with higher incidence of grade ≥3 toxicity (HR: 1.020, 95% CI: 1.010-1.030, P = 0.023).In a cohort of LPCa patients treated with RT and short-term ADT, a 10-point increase in baseline financial difficulty or a 10-point increase in baseline dyspnea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnea, we noted an 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity. These findings underscore the importance of integrating these baseline patient-reported metrics in selecting patients, making informed treatment-decisions, and optimizing overall outcome in men with localized prostate cancer.