Radiotherapy-induced Toxicity Research Articles

Revisiting the role of radiotherapy in the treatment of neuroblastoma 4S: 30 years of institutional experience and systematic review

Background and purposeNeuroblastoma 4S is a rare subtype of metastatic neuroblastoma found in children younger than 12 months, characterized by liver, skin, or bone marrow metastases. While the prognosis for patients is generally favorable, rapid progression of liver metastases can lead to life-threatening organ insufficiency. In such cases, immediate treatment with chemotherapy or radiotherapy is necessary. Given the recent decline in radiotherapy utilization, this study aims to reassess its role, evaluating its effectiveness and toxicity. Materials and methodsWe conducted a systematic review and an institutional retrospective analysis to assess the use of radiotherapy for hepatomegaly in patients with neuroblastoma 4S. The study included data from 164 patients from the literature and 16 patients from our institutional cohort. We extracted and analyzed data on short- and long-term outcomes, as well as reports of radiotherapy-induced toxicity. ResultsOur institutional data showed that 81 % of patients responded to low-dose radiotherapy administered at a median dose of 450 cGy in three fractions, resulting in liver shrinkage and symptom resolution. Based on the systematic review, 1-year survival rate was 80 %, while 5-year survival rate was 75 %. No serious toxicity was observed with the current low-dose radiotherapy; however, one case of induced secondary malignancy was reported. ConclusionRadiation therapy is an effective treatment modality for hepatomegaly in patients with neuroblastoma 4S, with a success rate of about 80 %. Despite being administered to infants, a low dose of 450–600 cGy does not result in toxicity related to the kidneys, liver, or posture defects.

Human Intestinal Organoids and Microphysiological Systems for Modeling Radiotoxicity and Assessing Radioprotective Agents.

Radiotherapy is a commonly employed treatment for colorectal cancer, yet its radiotoxicity-related impact on healthy tissues raises significant health concerns. This highlights the need to use radioprotective agents to mitigate these side effects. This review presents the current landscape of human translational radiobiology, outlining the limitations of existing models and proposing engineering solutions. We delve into radiotherapy principles, encompassing mechanisms of radiation-induced cell death and its influence on normal and cancerous colorectal cells. Furthermore, we explore the engineering aspects of microphysiological systems to represent radiotherapy-induced gastrointestinal toxicity and how to include the gut microbiota to study its role in treatment failure and success. This review ultimately highlights the main challenges and future pathways in translational research for pelvic radiotherapy-induced toxicity. This is achieved by developing a humanized in vitro model that mimics radiotherapy treatment conditions. An in vitro model should provide in-depth analyses of host-gut microbiota interactions and a deeper understanding of the underlying biological mechanisms of radioprotective food supplements. Additionally, it would be of great value if these models could produce high-throughput data using patient-derived samples to address the lack of human representability to complete clinical trials and improve patients' quality of life.

Patterns of Failure in Pediatric Craniopharyngioma with Surgery Alone

<h3>Purpose/Objective(s)</h3> Though pathologically benign, craniopharyngiomas are frequently recurrent even with complete surgical resection. Thus, postoperative adjuvant radiation therapy (RT) is often employed for durable local control, with conventional irradiation to the surgical bed of both cystic and solid components of the initial tumor. However, this carries risk of high morbidity in the form of late effects, including learning disabilities, neuroendocrine dysfunction, and secondary malignancy. There exists a potential opportunity to reduce radiotherapy-induced toxicity if radiotherapy can be constrained to the initial solid tumor bed and a minimal cystic component within the sellar region. Motivated by this, we sought to characterize the pattern of recurrence in craniopharyngiomas managed surgically without adjuvant therapy. <h3>Materials/Methods</h3> Medical records of 81 patients with craniopharyngioma diagnosed between 1979 and 2021 were reviewed. We identified a subset of patients treated with surgical resection alone who subsequently experienced local recurrence on surveillance MRI. Patients with unavailable pre-operative or recurrent imaging were excluded. Contours of both cystic and solid components of the initial tumor were created utilizing pre-operative MRI, and the recurrent tumor MRI was fused with these contours using deformable image registration. <h3>Results</h3> Fourteen patients who had received surgical resection without adjuvant RT were identified, with a median age of 10.1 years old. An endoscopic surgical approach was used in 8 (57.1%) patients, while open microsurgical approach was used in 6 (42.9%) patients; 3 (21.4%) resections were gross total resections, while 11 (78.6%) were considered near-total or subtotal resections. Median interval from date of initial surgery to first radiographic evidence of recurrence was 1.55 years. Local recurrence occurred purely in the initial cystic component of the tumor extent in 2 (14.3%) patients, was predominantly cystic and extending inferiorly to the initial solid component in 2 (14.3%) patients, and arising from the solid tumor resection bed in 10 (71.4%) patients. <h3>Conclusion</h3> A significant proportion of craniopharyngiomas recur within the cystic component of the initial tumor without adjuvant therapy, supporting continued incorporation of both solid and cystic components of the pre-surgical tumor extent in radiation therapy treatment plans.

Abstract 2600: AsiDNA® treatment protects healthy cells from anticancer treatment toxicity

Abstract Purpose: Conventional cytotoxic therapies are still the standard of care for the treatment of many cancers. However, the associated severe side effects, especially damage to normal proliferating cells like stem and progenitor cells, often lead to drug dose reduction, which limits treatment success. Indeed, chemotherapy-induced myelosuppression is manifested by neutropenia, lymphopenia, anemia, and thrombocytopenia. Although growth factors ameliorate this myelosuppression, their efficacy is still suboptimal and lineage specific. Pre-clinical and clinical studies have shown that AsiDNA, a double-stranded (DS) DNA molecule that mimics DS DNA breaks to interfere with DNA repair by over-activating a false DNA damage signaling through DNA-PK and PARP enzymes (decoy agonist), is extremely well tolerated in standalone in mammals. These observations led us to assess the potential of AsiDNA to protect healthy cells from toxicities of several anti-cancer treatments. Experimental design: In vivo, we analyzed the safety profile of AsiDNA during a recent clinical trial (DRIIV-1b/NCT03579628) in combination with platinum-based chemotherapy. In vitro, we used isolated blood cells from healthy donors, and epithelial and fibroblast cells as models to study if AsiDNA could protect healthy cells to chemo- and radiotherapy-induced toxicity. We monitored cell survival, DNA damage (comet assays) and repair (53BP1 and Rad51 foci), DNA-PK (HSP90 and H2AX phosphorylation) and PARP (PARylation) activation, cell cycle modulation and p53 dependency to identify mechanisms underlying the effects of AsiDNA on healthy cells. Results: In vivo, long-term treatment of several patients with carboplatine+/-paclitaxel + AsiDNA showed no increase of chemotherapies toxicities allowing longer periods of disease control and suggesting a protective effect of AsiDNA. In the in vitro models, we showed that AsiDNA enters non dividing and dividing healthy cells as revealed by intracellular PARylation but induces its nuclear target engagement (H2AX and HSP90 phosphorylation) only in dividing cells. Association of AsiDNA to antitumor treatments increased survival of healthy proliferative cells. Interestingly, AsiDNA displayed two distinct mechanisms of protection depending on the origin of the cells: p53-dependent G1/S cell cycle arrest in fibroblasts and epithelial cells, and DNA repair “doping” in hematological cells revealed by higher recruitment of Rad51 and 53BP1 at damage sites in those cells. Enzymatic inhibition and gene editing revealed that hyperactivation of DNA-PK/p53 pathway by AsiDNA might be required for healthy cells preservation. Conclusion: These findings suggest that the combination of AsiDNA with anticancer treatments should provide a means to attenuate therapy-induced toxicity, while showing the well-documented synergy in tumor cells, thus providing an opportunity to increase the therapeutic window. Citation Format: Wael Jdey, Anouk Sesink, Agathe Cohendet, Juliette Rieu, Chloe Doizelet, Vincent Hayes, Pierre-Marie Girard, Marie Dutreix, Judith Greciet. AsiDNA® treatment protects healthy cells from anticancer treatment toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2600.

Radiotherapy-induced toxicity in prostate cancer patients with hip prostheses

IntroductionAcute and late toxicity was analysed for prostate cancer patients with bilateral hip prostheses, who received fixed field intensity modulated radiotherapy (IMRT). The aims were (1) to establish whether toxicity rates differed from those of a control group with normal hips, (2) to develop a volumetric modulated arc therapy (VMAT) approach for patients with prostheses and (3) to compare doses to bladder and rectum for the control group, prostheses group and VMAT replans for the prostheses group.MethodsGenitourinary (GU) and gastrointestinal (GI) toxicity was scored using Common Terminology Criteria for Adverse Events version 5.0. The incidence of grade 2 or worse (G2+) toxicity was compared using Fisher’s exact test. Dose volume histograms (DVHs) and mean doses to organs at risk (OARs) were compared using signed rank tests.ResultsThere were 17 patients in the prostheses group and 50 in the control group. Acute and late GU toxicity was similar. G2+ late GI toxicity incidence was 31% for the prostheses group and 14% for the control group (p = 0.14). Significant differences (p < 0.05) were seen between the OAR DVHs of the prostheses group who had IMRT and the control group for a range of intermediate doses. The rectum mean dose was significantly different (p < 0.001), but no difference was seen for the bladder mean dose (p = 0.08).ConclusionsNo significant differences were seen in GU and GI toxicity incidence between patients with bilateral hip prostheses and a control group. The DVHs for bladder and rectum were significantly higher for patients with prostheses planned with IMRT. Replanning using a VMAT technique significantly reduced doses to the OARs, whilst maintaining good planning target volume coverage.

A genome-wide association study of radiotherapy induced toxicity in head and neck cancer patients identifies a susceptibility locus associated with mucositis

PurposeA two-stage genome-wide association study was carried out in head and neck cancer (HNC) patients aiming to identify genetic variants associated with either specific radiotherapy-induced (RT) toxicity endpoints or a general proneness to develop toxicity after RT.Materials and methodsThe analysis included 1780 HNC patients treated with primary RT for laryngeal or oro/hypopharyngeal cancers. In a non-hypothesis-driven explorative discovery study, associations were tested in 1183 patients treated within The Danish Head and Neck Cancer Group. Significant associations were later tested in an independent Dutch cohort of 597 HNC patients and if replicated, summary data obtained from discovery and replication studies were meta-analysed. Further validation of significantly replicated findings was pursued in an Asian cohort of 235 HNC patients with nasopharynx as the primary tumour site.ResultsWe found and replicated a significant association between a locus on chromosome 5 and mucositis with a pooled OR for rs1131769*C in meta-analysis = 1.95 (95% CI 1.48–2.41; ppooled = 4.34 × 10−16).ConclusionThis first exploratory GWAS in European cohorts of HNC patients identified and replicated a risk locus for mucositis. A larger Meta-GWAS to identify further risk variants for RT-induced toxicity in HNC patients is warranted.

Toward Personalized Medicine in Radiotherapy of Hepatocellular Carcinoma: Emerging Radiomic Biomarker Candidates of Response and Toxicity.

Radiology and radiotherapy are currently undergoing radical transformation with use of biomarkers and digital technologies such as artificial intelligence. These current and upcoming changes in radiology speak of an overarching new vision for personalized medicine. This is particularly evident in the case of radiotherapy of cancers, and of liver cancer in particular. The development of modern radiotherapy with stereotactic body radiotherapy allows targeted treatments to be delivered to the tumor site, limiting the dose to surrounding healthy organs, thus becoming a new therapeutic alternative for hepatocellular carcinoma and other liver tumors. However, not all patients have the same response to radiotherapy or display the same side-effect profile. Biomarkers of response and toxicity in liver radiotherapy would facilitate the vision and practice of personalized medicine. This expert review examines the available molecular, radiomic, and radiogenomic biomarker candidates for acute liver toxicity with potential use for prediction of radiotherapy-induced liver toxicity. To this end, I highlight for oncologists and life scientists that radiomics allows diagnostic images to be analyzed using computer algorithms to extract information imperceptible to the human eye and of relevance to forecasting clinical outcomes. This article underscores particularly (1) the microRNA-based biomarker candidates as among the most promising predictors of radiation-induced liver toxicity and (2) the texture features in radiomic analyses for response prediction. Radiotherapy of hepatocellular carcinoma is edging toward personalized medicine with emerging radiomic biomarker candidates. Future large-scale biomarker studies are called for to enable personalized medicine in liver cancers.

PD-0774 Impact of sarcopenia on acute radiotherapy-induced toxicity in head and neck cancer patients

Purpose or Objective: Sarcopenia, i.e. generalised and progressive loss of skeletal muscle mass and muscle function, is related to more late radiation-induced toxicities and worse survival in head and neck squamous cell carcinoma (HNSCC) patients. The objective of this study was to test the hypothesis that sarcopenia improves the performance of NTCP models to predict acute toxicity in HNSCC patients treated with definitive radiotherapy (RT). Materials and Methods: This was a retrospective analysis in a prospective cohort of HNSCC patients treated from January 2007 to December 2018 with RT with or without systemic therapy. Physician- and patient-rated toxicities, including dysphagia, xerostomia, sticky saliva, aspiration, oral mucositis, weight loss and fatigue, were collected prospectively during (week 1-7) and after treatment (week 12, month 6-24. Planning CT-scans were used for evaluating patients’ skeletal muscle mass at the third cervical vertebra for estimation of the skeletal muscle index (SMI). Chi-square and t-tests were used to compare the characteristics and baseline toxicities of sarcopenic and non-sarcopenic patients. The linear predictors for each endpoint from three to seven weeks during treatment were calculated based on the NTCP models developed at our department. The impact of sarcopenia was analysed using multivariable logistic regression analyses. If sarcopenia remained significant next to the linear predictor, likelihood-ratio tests were performed to test whether the model including sarcopenia performed significantly better. Results: A total of 977 HNSCC patients constituted the study population. The cut-off values of sarcopenia were established at SMI 0.99). Considering these results, late dysphagia was analysed as well and results for grade≥2 and grade≥3 dysphagia were similar (6-24 months after RT). In addition, sarcopenic HNSCC patients experienced more physician-rated dysphagia during and after treatment than non-sarcopenic HNSCC patients (Figure 1). Conclusion: This study showed that sarcopenia in HNSCC patients undergoing RT was an independent prognostic factor for the development of physician-rated acute dysphagia grade≥3 and late dysphagia grade≥2 and grade≥3, which might be explained by its impact on the swallowing muscles. However, sarcopenia did not improve the performance of NTCP-models RT-induced other evaluated acute toxicities.

Abstract 684: Effects of preventive interventions on radiotherapy-induced skin toxicity in women with breast cancer: A systematic review and meta-analysis of randomized controlled trials

Abstract Radiation therapy (RT)-induced skin toxicity occurs in 95% of patients undergoing RT for breast cancer. Severe cases can interrupt the original treatment regimen and affect many individuals' overall treatment efficacy and quality of life. Many interventions have been tested for the prevention of RT-induced skin toxicity; however, there are no standard recommendations yet determined. This meta-analysis aimed to evaluate the effect of different preventive interventions for RT-induced skin toxicity among breast cancer patients. We searched PubMed, Web of Science, CINAHL, and PsycINFO databases for randomized controlled trials (RCTs) meeting the inclusion criteria and published until December 2019 following the PRISMA reporting guidelines and the PICO statements. The intervention's effect on the incidence of grade ≥2 acute skin toxicity, moist desquamation, and severity score was estimated using the random-effects meta-analyses. Among 6885 publications identified, 38 studies were included in analyses. A total of 3,380 women age 42-88 years diagnosed with stage 0-III who were undergoing RT for breast cancer from all over the world were included. Identified preventive interventions included non-steroid topical agents, topical steroid agents, oral supplements, laser therapy, and films. The meta-analyses showed that interventions significantly reduced the mean severity score by 0.64 (standardized mean difference=-0.64, 95% CI=-0.85, -0.43; I2=57.6%), the incidence of grade ≥2 skin toxicity by 18% (Risk ratio [RR]=0.82, 95% CI=0.74, 0.90; I2=68.4%), and moist desquamation by 55% (RR=0.45, 95% CI=0.27-0.77, I2=48.2%). Subgroup analyses showed that oral supplements were most promising in preventing grade ≥2 skin toxicity (RR=0.32, 95% CI=0.07-1.34, I2=83.1%), suggesting further replications are needed before definitive conclusions are made. This analysis provided evidence of the effectiveness of interventions on the prevention of RT-induced skin toxicity. The effect was greater in reducing the incidence of more severe cases of moist desquamation. More replicative studies are needed to establish the standard preventive care of RT-induced skin toxicity for women with breast cancer, which can help patients comply with RT regimens and improve patients' quality of life. Citation Format: Claudia R. Figueroa, Rose N. Gelin, Sereen J. Khourshid, Eunkyung Lee. Effects of preventive interventions on radiotherapy-induced skin toxicity in women with breast cancer: A systematic review and meta-analysis of randomized controlled trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 684.

Volumetric-Modulated Arc Radiotherapy with Daily Image-Guidance Carries Better Toxicity Profile for Higher Risk Prostate Cancer.

Purpose:To compare radiotherapy-induced toxicity for localized prostate-cancer (PCa) treated with versus without daily image-guidance. Patients and Methods:We identified consecutive intermediate and high-risk localized PCa patients treated with definitive radiotherapy using intensity-modulated radiotherapy (IMRT) with variable duration of androgen-deprivation therapy (ADT) within 2015-2016 (Arm-A) and 2005-2007 (Arm-B). Arm-A cases received daily online imaging guidance (IGRT) using cone-beam computed tomography (CBCT) unlike Arm-B candidates with no daily IGRT. After reporting demographic, clinico-pathological features and treatment details, we compared acute (within 3 months post-therapy) and late RT-induced toxicities between study groups graded by RTOG/CTCAE criteria. Uni/multivariate analyses (UVA/MVA) were performed to identify independent predictors for RT-related side-effects. Results:We were able to identify 257 cases who met our inclusion criteria. Overall, median age was 73 years (48-85), 67% had intermediate-risk and 47% received ADT. Arm-A included 72 patients who received IMRT delivered using volumetric-modulated arc therapy (VMAT), whereas, Arm-B was formed of 185 cases who utilized step-and-shoot static IMRT. Clinico-pathological features and treatment details were non-different across study arms except that Arm-A had more Grade Group 3, higher median total dose (79.2 vs. 74 Gy) and more pelvic lymph-nodes RT (P<0.05). Although acute toxicity was similar across groups, Arm-B encountered higher late toxicity score, more intense late genitourinary side-effects (P=0.008), with non-different late lower-gastrointestinal toxicities. On MVA, lack of daily CBCT, African-American race and higher comorbidities were independently predictive for late toxicities. Conclusion:IMRT with daily CBCT permitted safe delivery of dose-escalated IMRT with improved toxicity profile for higher-risk prostate cancer.

Functional lung volume mapping with perfusion Single-Photon Emission Computed Tomography scan for radiotherapy planning in patients with locally advanced nonsmall cell lung cancer

Radical chemotherapy-radiotherapy represents the standard treatment for locally-advanced nonsmall cell lung cancer (NSCLC). Conventional radiotherapy achieves limited local tumor control, but dose escalation to the primary tumor is prevented by radiotherapy-induced toxicity. The aim of this study was to evaluate feasibility of tailored intensity-modulated radiotherapy (IMRT) planning based on lung single-photon emission computed tomography (SPECT) perfusion data and to compare functional and conventional dose-volume parameters. A total of 21 patients were prospectively enrolled. Patients underwent IMRT treatment with 2 Gy/fraction (median total dose of 60 Gy). Lung perfusion SPECT images were acquired before radiotherapy and 3 and 6 months after radiotherapy completion. SPECT and planning computed tomography images were co-registered using MIM-MAESTRO software with 3D-PET Edge algorithm. Lung volumes were defined anatomically as total lung and functionally as total not functional lung and total functional lung. Dose-volume histograms were calculated using QUANTEC constraints [mean lung dose (MLD)<20 Gy, V20<20%]. For each patient, conventional and functional radiotherapy plans were generated and compared. A total of 19 of 21 patients with NSCLC were included (mean age 66 years, 11 stage IIIA, 8 stage IIIB), 12/19 patients completed the 6-months follow-up. A significant reduction of mean V20 was observed in functional radiotherapy planning compared to conventional plan (405.9 cc, P < 0.001). Mean MLD was also lower in the SPECT-based plans, but the difference was not statistically relevant (0.8 Gy, P = 0.299). G2 radiation pneumonitis was observed in two patients. Functional radiotherapy planning allowed to decrease functional lung irradiation compared to conventional planning. The possibility to limit radiotherapy-induced toxicity could allow us to perform an effective dose-escalation to target volume.

Fractionated radiation suppresses Kruppel-like factor 2 pathway to a greater extent than by single exposure to the same total dose

Kruppel-like factor 2 (KLF2) is a positive transcriptional regulator of several endothelial protective molecules, including thrombomodulin (TM), a surface receptor, and endothelial nitric oxide synthase (eNOS), an enzyme that generates nitric oxide (NO). Loss of TM and eNOS causes endothelial dysfunction, which results in suppressed generation of activated protein C (APC) by TM-thrombin complex and in upregulation of intercellular adhesion molecule 1 (ICAM-1). Mechanistic studies revealed that activation of extracellular signal-regulated kinase 5 (ERK5) via upregulation of myocyte enhancer factor 2 (MEF2) induces KLF2 expression. Radiation causes endothelial dysfunction, but no study has investigated radiation’s effects on the KLF2 pathway. Because fractionated radiation is routinely used during cancer radiotherapy, we decided to delineate the effects of radiation dose fractionation on the KLF2 signaling cascade at early time points (up to 24 h). We exposed human primary endothelial cells to radiation as a series of fractionated or as a single exposure, with the same total dose delivered to each group. We measured the expression and activity of critical members of the KLF2 pathway at subsequent time points, and determined whether pharmacological upregulation of KLF2 can reverse the radiation effects. Compared to single exposure, fractionated radiation profoundly suppressed KLF2, TM, and eNOS levels, subdued APC generation, declined KLF2 binding ability to TM and eNOS promoters, enhanced ICAM-1 expression, and decreased expression of upstream regulators of KLF2 (ERK5 and MEF2). Pharmacological inhibitors of the mevalonate pathway prevented fractionated-radiation–induced suppression of KLF2, TM, and eNOS expression. Finally, fractionated irradiation to thoracic region more profoundly suppressed KLF2 and enhanced ICAM-1 expression than single exposure in the lung at 24 h. These data clearly indicate that radiation dose fractionation plays a critical role in modulating levels of KLF2, its upstream regulators, and its downstream target molecules in endothelial cells. Our findings will provide important insights for selecting fractionated regimens during radiotherapy and for developing strategies to alleviate radiotherapy-induced toxicity to healthy tissues.

Effect of Gold Nanoparticle on 5-Fluorouracil-Induced Experimental Oral Mucositis in Hamsters.

Background: Oral mucositis (OM) is a severe inflammation of the oral mucosal cells associated with chemotherapy and/or radiotherapy-induced toxicity, resulting in epithelial ulcers and higher risk of death from sepsis. The aim of the present study was to evaluate the nanoparticle (AuNp) effect on OM induced in hamsters. Materials and methods: 5-fluorouracil (5FU) was used on the first and second day of the experimental model in Golden sirian hamsters, and on the fourth day, mechanical trauma was applied to induce OM. The animals were divided into groups, i.e., polyvinylpyrrolidone (PVP), mechanical trauma (MT), 5FU, and groups treated with gold nanoparticles (AuNps) (62.5, 125, and 250 μg/kg). On the 10th day, animals were euthanized for macroscopic, histopathological, immunohistochemical, western blot, quantitative polymerase chain reaction (qRT-PCR), and AuNp quantification. Results: AuNp (250 μg/kg) reduced TNF-α, IL-1β, COX-2, NF-κB, TGF-β, and SMAD 2/3; increased glutathione levels; decreased the expression of Kelch ECH-associated protein 1 (KEAP1); and induced heme oxygenase 1 (HMOX-1) and NAD (P) H quinone oxidoreductase 1 (NQO1) genes. Conclusions: AuNp (250 μg/kg) prevented 5-FU-induced OM in hamsters and improved the parameters of inflammation and oxidative stress.

Does vitamin D prevent radiotherapy-induced toxicity?

Abstract Vitamin D is known as the bone hormone, it is also know that it has effects on cancer because of its anti-inflammatory and immunomodulatory characteristics and its effects on cytokine levels. It is seen that vitamin D use together with radiotherapy can have a positive effect on cancer treatment. It should be investigated whether toxicities due to radiation is prevented by vitamin D metabolites’ increasing the induction of immunomodulator cells and the capacities of immune response cells. Use of 1,25[OH]2 Vitamin D3 analogs as an adjuvant immunomodulator for patients receiving radiotherapy should be evaluated. There is a need for studies to be done in this regard.

Association of Transforming Growth Factor β Polymorphism C−509T With Radiation-Induced Fibrosis Among Patients With Early-Stage Breast Cancer

Whether genetic factors can identify patients at risk for radiation-induced fibrosis remains unconfirmed. To assess the association between the C-509T variant allele in the promoter region of TGFB1 and breast fibrosis 3 years after radiotherapy. This is an a priori-specified, prospective, cohort study nested in an open-label, randomized clinical trial, which was conducted in community-based and academic cancer centers to compare hypofractionated whole-breast irradiation (WBI) (42.56 Gy in 16 fractions) with conventionally fractionated WBI (50 Gy in 25 fractions) after breast-conserving surgery. In total, 287 women 40 years or older with pathologically confirmed stage 0 to IIA breast cancer treated with breast-conserving surgery were enrolled from February 2011 to February 2014. Patients were observed for a minimum of 3 years. Outcomes were compared using the 1-sided Fisher exact test and multivariable logistic regression. A C-to-T single-nucleotide polymorphism at position -509 relative to the first major transcription start site (C-509T) of the TGFB1 gene. The primary outcome was grade 2 or higher breast fibrosis as assessed using the Late Effects Normal Tissue/Subjective, Objective, Medical Management, Analytic scale (range, 0 to 3) three years after radiotherapy. Among 287 women enrolled in the trial, TGFB1 genotype and 3-year radiotherapy-induced toxicity data were available for 174 patients, of whom 89 patients (51%) with a mean (SD) age of 60 (8) years had at least 1 copy of C-509T. Grade 2 or higher breast fibrosis was present in 12 of 87 patients with C-509T (13.8%) compared with 3 of 80 patients without the allele variant (3.8%) (absolute difference, 10.0%; 95% CI, 1.7%-18.4%; P = .02). The results of multivariable analyses indicated that only C-509T (odds ratio, 4.47; 95% CI, 1.25-15.99; P = .02) and postoperative cosmetic outcome (odds ratio, 7.09; 95% CI, 2.41-20.90; P < .001) were significantly associated with breast fibrosis risk. To date, this study seems to be the first prospective validation of a genomic marker for radiation fibrosis. The C-509T allele in TGFB1 is a key determinant of breast fibrosis risk. Assessing TGFB1 genotype may facilitate a more personalized approach to locoregional treatment decisions in breast cancer. ClinicalTrials.gov identifier: NCT01266642.

Therapeutic and prophylactic effects of strontium on radiotherapy-induced skin toxicity in rats

Therapeutic and prophylactic effects of strontium on radiotherapy-induced skin toxicity in rats

Abstract 1615: C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer

Abstract Background: Post-surgery adjuvant radiotherapy (RT) for breast cancer significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASRs) that impact quality of life. Methods: In a large prospective study of 1,000 breast cancer patients undergoing RT, we evaluated an inflammatory biomarker, C-reactive protein (CRP) in predicting RT-induced EASRs. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA CRP assay. RT-induced EASRs were assessed using the Oncology Nursing Society Skin Toxicity Criteria. Association between EASRs and CRP were assessed using logistic regression models after adjusting for potential confounders. Results: The study population includes 405 non-Hispanic White, 280 African Americans, 218 Hispanic Whites, 52 Asians, and 45 others. RT-induced grade 3+ and 4+ skin toxicity at the end of RT were observed in 42% and 15% patients, respectively. CRP levels differ significantly by race/ethnicity at baseline and at the end of RT. RT-induced grade 4+ skin toxicity was significantly associated with: obesity and pre-RT CRP &amp;gt; 2mg/L (OR=3.27; 95%CI=1.88, 5.68), obesity and post-RT CRP &amp;gt; 2mg/L (OR=4.42; 95%CI=2.38, 8.23), or obesity and change of CRP &amp;gt; 1mg/L (OR=3.58; 95%CI=2.00, 6.39). Conclusion: The current data validate our previous findings that the inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity. Impact: Our current findings support the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced EASRs and improve quality of life in breast cancer patients undergoing RT. Citation Format: Jennifer J. Hu, Doug Case, Mark O. Lively, Eunkyung Lee, Cristiane Takita, James J. Urbanic, Glenn J. Lesser, Edward G. Shaw. C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2017-1615

Abstract 3920: Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations

Abstract Radiotherapy-induced skin toxicity is one of the critical quality of life issues in breast cancer patients receiving adjuvant radiation therapy (RT). Finding a biomarker which can predict the development of acute RT-induced toxicity prior to RT is critical to improve precision medicine in radiation oncology. This study evaluated the association of single nucleotide polymorphisms (SNPs) in DNA-repair genes in 268 breast cancer undergoing adjuvant RT. We analyzed 3,747 polymorphisms in 119 DNA repair-related genes; 15 genes in base excision repair (BER), 11 in mismatch repair (MMR), 26 in nucleotide excision repair (NER), 15 in homologous recombination, 5 in non-homologous end-joining (NHEJ), 15 in DNA polymerases, and 47 in other DNA repair-related pathways. Skin toxicity was assessed at post-RT using the modified NCI's Common Toxicity Criteria for Adverse Events (CTCAE) and multiple logistic regression analyses were conducted to assess the associations between SNPs and grade ≥ 4 skin toxicity n = 115). After controlling for covariates, 221 SNPs were significant at p &amp;lt;0.05 and 34 at p &amp;lt; 0.01. Significant associations (p&amp;lt;0.01) were found in 7 SNPs in PAPD5 gene, 1 in POLD1, POLE, and POLI in DNA polymerase; 5 in RAD51L1 and 1 in RAD54L in HR; 4 in MMS19 in NER; 2 in MSH4 and 1 in PMS1 in MMR; 2 in RPA3 in BER; 2 in RAD18, and 1 in UBE2V2 in Rad6 pathway; 2 in CHEK2 in DNA damage response pathway; 1 in MGMT in direct reversal of DNA damage; and 1 in BLM in diseases associated with sensitivity to DNA damaging agents pathways. Among these, most significant association was found in BLM variant (s16944918) which showed that carrying at least one minor T allele was associated with increased risk of RT-induced skin toxicity (odds ratio [OR] = 3.36; 95% confidence interval (CI) = 1.62-6.97, p = 0.001). For RPA3 (rs11978293), carriers with at least one minor G allele were more likely to develop RT-induced skin toxicity (OR = 2.17, 95% CI = 1.34-3.52, p = 0.002). The current study suggests that genetic variations in multiple DNA-repair genes/pathways may contribute to inter-individual variation in RT-induced normal tissue toxicity in breast cancer patients and suggests the possibility of potential predictive values of genetic polymorphisms in RT sensitivity. Further validation studies with larger sample size are warranted. Citation Format: Sung Yong Eum, Eunkyung Lee, Jean L. Wright, Christiane Takita, Eden R, Martin, Susan Slifer, Jennifer J. Hu. Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3920.

Protection against Radiotherapy-Induced Toxicity.

Radiation therapy is a highly utilized therapy in the treatment of malignancies with up to 60% of cancer patients receiving radiation therapy as a part of their treatment regimen. Radiation therapy does, however, cause a wide range of adverse effects that can be severe and cause permanent damage to the patient. In an attempt to minimize these effects, a small number of compounds have been identified and are in use clinically for the prevention and treatment of radiation associated toxicities. Furthermore, there are a number of emerging therapies being developed for use as agents that protect against radiation-induced toxicities. The aim of this review was to evaluate and summarise the evidence that exists for both the known radioprotectant agents and the agents that show promise as future radioprotectant agents.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

AimBoth dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT.Patients and methodsPatients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels.ResultsIn all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis.ConclusionThere was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.