Radiation-induced skin injury in the head and neck region: pathogenesis, clinics, prevention, treatment considerations and proposal for management algorithm.

Worldwide increase of head and neck cancers ranks these malignancies among top causes of cancer in human population. Radiation induced skin injury (RISI) is one of the major side effects of radiotherapy (RT). Skin of the neck is exposed to radiation due to necessity of therapeutic or prophylactic (elective) irradiation of neck lymph nodes and target organs, including the larynx and hypopharynx. The location of the neck exposes these regions of the skin to various additional exposomes such as ultraviolet radiation (UVR), pollution and cigarette smoke. There are many controversies or inconsistencies regarding RISI, from molecular aspects and therapy to terminology. There is lack of high-quality and large-sample studies in both forms of RISI: acute (aRISI) and chronic (cRISI). Finally, no gold standards in the management of aRISI and cRISI have been established yet. In this article, the authors discuss the pathogenesis, clinical picture, prevention and clinical interventions and present a proposed treatment algorithm.

Analysis of the association between salivary proteins and oral mucositis in patients with head and neck cancer undergoing IMRT: a longitudinal study.

INTRODUCTION: This longitudinal study assessed the association between salivary protein composition and the clinical onset/severity of oral mucositis (OM) in patients with head and neck tumours treated with intensity-modulated-radiotherapy (IMRT). METHODS: Saliva samples/clinical data were obtained from 40 head and neck cancer patients treated at Guy's Hospital before -IMRT(T0) and after-IMRT (T1 = 6 m, T2 = 12 m) (ethics approval/consent). Salivary flow rate, total protein concentration, and secretion rate were determined from saliva samples and compared with pre-treatment values. OM was assessed, total/specific salivary proteins, including mucin 5B and 7, IgA, cystatin-S, albumin, and α-amylase, were quantified. RESULTS: 95% patients experienced OM during IMRT, with 33 subjects reaching grade 2&3. At T1, there was a significant reduction in salivary flow rate, total protein secretion rate, α-amylase and cystatin-S compared to baseline. Remarkably IMRT did not significantly alter mucin 5B and 7, or the IgA secretion rate at any time point. At T1, all the analyzed proteins were associated with the OM outcomes. In addition, there was a significant inverse correlation between IgA concentration at T0 and the severity of OM during IMRT. CONCLUSION: This study revealed significant associations between several salivary proteins and OM in patients with head and neck cancer undergoing IMRT. Further longitudinal studies are needed to confirm these results. CLINICAL SIGNIFICANCE: The study contributes to the understanding of certain salivary proteins association with OM. This could be the first step towards identifying potential salivary markers that could offer perspectives for personalized medicine approaches to improve their quality of life (QoL). RESEARCH QUESTION: What is the association between salivary proteins and the occurrence and severity of OM in head and neck cancer patients? AIM: To assess the association between salivary protein composition with the clinical onset/severity of oral mucositis (OM) in head and neck cancer patients treated with intensity modulated radiotherapy. NULL HYPOTHESIS: There is no association between salivary proteins and onset/severity of OM in HNC patients.

The benefit of intravenous immune globulin in the treatment of delayed radiation myelopathy.

Delayed radiation myelopathy (DRM) is a rare yet severe complication of radiotherapy. This condition has a progressive pattern that is often irreversible. Several therapeutic strategies have been introduced to alleviate disease complications, including corticosteroids, hyperbaric oxygen, anticoagulants, and antivascular endothelial growth factor (VEGF) agents. However, despite their beneficial effect, they have not been the definitive treatments for DRM. Here we present the case of a 55-year-old woman with a history of multiple myeloma who developed neurological complications 11 months after radiation therapy. As her radiologic findings demonstrated transverse myelitis, based on the DRM diagnostic criteria, the diagnosis of delayed radiation myelitis was reached. Therefore, methylprednisolone pulse therapy was initiated, resulting in the complete resolution of her neurological symptoms. However, on her follow-up examination, although she did not have new neurological complications, magnetic resonance imaging (MRI) demonstrated a residual enhancement in the thoracic spinal cord area. Hence, due to the possibility of myelitis progression and spinal cord atrophy, intravenous immune globulin (IVIG) was administered, resulting in the resolution of lesion enhancement. Considering this outcome and the immunomodulatory properties of IVIG, it could be regarded as a potential therapeutic option in the case of DRM activity.

Genome-wide association study of treatment-related toxicity two years following radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.

An evaluation of concordance between head and neck advanced practice radiation therapist and radiation oncologists in toxicity assessment for nasopharyngeal carcinoma patients.

BACKGROUND: Weekly toxicity assessments for patients undergoing head and neck (HN) radiotherapy are essential to ensure that acute side effects are appropriately managed in order for patients to complete their treatment in a safe and timely manner. The incorporation of Advanced Practice Radiation Therapist (APRT) led treatment reviews has been reported for various subsites, but there is currently a lack of published literature regarding this role for patients with HN cancer. The purpose of this study is to assess the concordance of toxicity assessments performed during weekly radiotherapy treatment reviews for patients undergoing HN radiotherapy between the HN APRT and Radiation Oncologist (RO). METHODS: Twenty-three patients with nasopharyngeal cancer (NPC) under the care of 3 ROs were recruited from June to December 2018; weekly assessments were independently performed by HN APRT and ROs. The HN toxicity assessment was graded according to the Common Terminology Criteria for Advanced Events v4.0. Both assessors were blinded to each other's assessments. The percentage agreement of concordance and agreement level were interpreted by Cohen's Kappa statistic (κ), with the ROs' assessments deemed as the 'gold standard'. RESULTS: The overall concordance for all graded toxicity assessments between HN APRT and ROs was 78.4%. Xerostomia, dysgeusia, pharyngeal pain and dermatitis assessment were evaluated as 'Good' with agreement ranging from κ = 0.608-0.640 between the HN APRT and ROs while dysphagia scored an 'Almost Perfect' agreement of κ = 0.834. 'Moderate' agreement between the HN APRT and ROs was observed for oral pain and mucositis assessment. A scoring discrepancy of 1 and 2 grades was observed in 21.2% and 0.4% for these two toxicities. CONCLUSION:  There was high concordance in scoring of acute toxicity between the HN APRT and ROs. The results support the continuing involvement of HN APRT in weekly assessments for NPC patients.

BMP Antagonists Secreted by Mesenchymal Stromal Cells Improve Colonic Organoid Formation: Application for the Treatment of Radiation-induced Injury.

Radiation therapy is crucial in the therapeutic arsenal to cure cancers; however, non-neoplastic tissues around an abdominopelvic tumor can be damaged by ionizing radiation. In particular, the radio-induced death of highly proliferative stem/progenitor cells of the colonic mucosa could induce severe ulcers. The importance of sequelae for patients with gastrointestinal complications after radiotherapy and the absence of satisfactory management has opened the field to the testing of innovative treatments. The aim of this study was to use adult epithelial cells from the colon, to reduce colonic injuries in an animal model reproducing radiation damage observed in patients. We demonstrated that transplanted in vitro-amplified epithelial cells from colonic organoids (ECO) of C57/Bl6 mice expressing green fluorescent protein implant, proliferate, and differentiate in irradiated mucosa and reduce ulcer size. To improve the therapeutic benefit of ECO-based treatment with clinical translatability, we performed co-injection of ECO with mesenchymal stromal cells (MSCs), cells involved in niche function and widely used in clinical trials. We observed in vivo an improvement of the therapeutic benefit and in vitro analysis highlighted that co-culture of MSCs with ECO increases the number, proliferation, and size of colonic organoids. We also demonstrated, using gene expression analysis and siRNA inhibition, the involvement of bone morphogenetic protein antagonists in MSC-induced organoid formation. This study provides evidence of the potential of ECO to limit late radiation effects on the colon and opens perspectives on combined strategies to improve their amplification abilities and therapeutic effects.

Molecular Profiling for Predictors of Radiosensitivity in Patients with Breast or Head-and-Neck Cancer.

Nearly half of all cancers are treated with radiotherapy alone or in combination with other treatments, where damage to normal tissues is a limiting factor for the treatment. Radiotherapy-induced adverse health effects, mostly of importance for cancer patients with long-term survival, may appear during or long time after finishing radiotherapy and depend on the patient's radiosensitivity. Currently, there is no assay available that can reliably predict the individual's response to radiotherapy. We profiled two study sets from breast (n = 29) and head-and-neck cancer patients (n = 74) that included radiosensitive patients and matched radioresistant controls.. We studied 55 single nucleotide polymorphisms (SNPs) in 33 genes by DNA genotyping and 130 circulating proteins by affinity-based plasma proteomics. In both study sets, we discovered several plasma proteins with the predictive power to find radiosensitive patients (adjusted p < 0.05) and validated the two most predictive proteins (THPO and STIM1) by sandwich immunoassays. By integrating genotypic and proteomic data into an analysis model, it was found that the proteins CHIT1, PDGFB, PNKD, RP2, SERPINC1, SLC4A, STIM1, and THPO, as well as the VEGFA gene variant rs69947, predicted radiosensitivity of our breast cancer (AUC = 0.76) and head-and-neck cancer (AUC = 0.89) patients. In conclusion, circulating proteins and a SNP variant of VEGFA suggest that processes such as vascular growth capacity, immune response, DNA repair and oxidative stress/hypoxia may be involved in an individual's risk of experiencing radiation-induced toxicity.

Dose-response relationship and normal-tissue complication probability of conductive hearing loss in patients undergoing head-and-neck or cranial radiotherapy: A prospective study including 70 ears.

PURPOSE: Head-and-neck (H&N) and cranial radiotherapy may cause hearing loss. Little has been published on the dose-response relationship and normal-tissue complication probability (NTCP) of the conductive subtype of hearing loss. The aims were to observe the incidence of hearing loss in patients undergoing non-intensity-modulated H&N or cranial radiotherapy, obtain the relationship between dose and conductive hearing loss (CHL) and test the current Lyman-Kutcher-Burman (LKB) NTCP model parameters. METHODS: The dose-response in the peripheral auditory system (PAS) of 35 patients (70 ears) was prospectively studied using mean dose and the current LKB model parameters. A wide dose range was obtained by conducting the study at a clinic without advanced treatment techniques. The patients underwent routine external-beam treatments following 3D treatment planning. Hearing status was evaluated by pure-tone audiometry one day before the start and one day and 30 days after the end of radiotherapy. RESULTS: Nineteen ears (27%) experienced hearing loss. Sixteen (23%) had CHL and three (4%) the sensorineural subtype. On average, mean doses of the PAS structures and V95%, V40Gy and V30Gy volumes of the middle-ear planning-organ-at-risk volume (PRV) were significantly greater in ears that suffered CHL. The modelled 50% NTCP of CHL occurred at approximately 30-40 Gy mean dose to middle ear planning organ-at-risk volume. CONCLUSIONS: Incidence of conductive hearing loss in non-intensity-modulated radiotherapy of H&N and brain can be significant. CHL exhibits a dose-effect. This suggests that the PAS should be considered in treatment plan optimization. The LKB NTCP model was reasonably accurate but modifications are indicated.

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer.

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.

[Feasibility study of blood oxygen level-dependent magnetic resonance imaging in evaluating the response of metastatic lymph nodes of rabbit VX2 tumor to radiotherapy].

Objective: To investigate the feasibility of blood oxygen level-dependent magnetic resonance imaging (MRI) in evaluating the response of metastatic lymph nodes of rabbit VX2 tumor to radiotherapy. Methods: Twenty-eight healthy New Zealand white rabbits which were provided by the Laboratory Animal Center of Soochow University, male or female, 2 to 3 months, weighing 2 to 3 kg, were used to establish the animal model of VX2 tumor popliteal fossa metastatic lymph node, and then were divided into either the radiotherapy group (n=16) or the control group (n=12). The radiotherapy group received a 20 Gy radiotherapy per rabbit, the control group received sham radiotherapy. All rabbits underwent MRI scan on four time points, including before (0 day), 3rd, 7th and 14th days after radiotherapy. The two parameters of size and R(2*) value (s(-1)) of lymph node were measured. At each time point,two rabbits in each group were sacrificed randomly to resect lymph nodes for pathological examination, and two parameters of microvessel density (MVD, strip/HP) and apoptosis index (AI, %) were analyzed. The parameters among the four time points in each group or between the two groups were compared. The correlation of lymph node size and R(2*) value with MVD or AI was analyzed, respectively. Results: A significant size difference was neither between the two groups or among the each time points in each group (P>0.05). The R(2*) of lymph node in the radiotherapy group was (29.6±1.7),(36.8±2.6),(44.8±5.8) and (57.7±6.2) s(-1) at the time points of 0, 3, 7 and 14 days, respectively, showing a gradual increase trend; MVD was (52.3±2.5),(41.0±3.6),(34.0±3.6) and (22.7±2.5) strip/HP respectively, showing a decreasing trend; AI was 12.8%±0.5%,14.9%±0.6%,20.6%±0.5% and 27.5%±0.7% respectively, showing a gradual increase trend (all P<0.05). In the control group, both R(2*) value and AI among the four time points did not change statistically (all P>0.05), but MVD showed a gradual increase trend,(50.0±3.0),(53.0±1.7),(60.3±2.5) and (70.0±2.0) strip/HP, respectively, P<0.05. There were significant differences in R(2*) and MVD at 3, 7 and 14 days, in AI at 7 and 14 days between the two groups (all P<0.05). There was a linear correlation of R(2*) value, but not of size, with MVD and AI (r=-0.87 and 0.94, respectively). Conclusion: Blood oxygen level-dependent MRI can indirectly reflect the hypoxic status of metastatic lymph nodes after radiotherapy, and has potential value in evaluating the response of metastatic lymph nodes to radiotherapy.

Adipose-Derived Mesenchymal Stromal Cells Improve the Healing of Colonic Anastomoses Following High Dose of Irradiation Through Anti-Inflammatory and Angiogenic Processes.

Cancer patients treated with radiotherapy (RT) could develop severe late side effects that affect their quality of life. Long-term bowel complications after RT are mainly characterized by a transmural fibrosis that could lead to intestinal obstruction. Today, surgical resection is the only effective treatment. However, preoperative RT increases the risk of anastomotic leakage. In this study, we attempted to use mesenchymal stromal cells from adipose tissue (Ad-MSCs) to improve colonic anastomosis after high-dose irradiation. MSCs were isolated from the subcutaneous fat of rats, amplified in vitro, and characterized by flow cytometry. An animal model of late radiation side effects was induced by local irradiation of the colon. Colonic anastomosis was performed 4 wk after irradiation. It was analyzed another 4 wk later (i.e., 8 wk after irradiation). The Ad-MSC-treated group received injections several times before and after the surgical procedure. The therapeutic benefit of the Ad-MSC treatment was determined by colonoscopy and histology. The inflammatory process was investigated using Fluorine-182-Fluoro-2-Deoxy-d-Glucose Positron Emission Tomography and Computed Tomography (18F-FDG-PET/CT) imaging and macrophage infiltrate analyses. Vascular density was assessed using immunohistochemistry. Results show that Ad-MSC treatment reduces ulcer size, increases mucosal vascular density, and limits hemorrhage. We also determined that 1 Ad-MSC injection limits the inflammatory process, as evaluated through 18F-FDG-PET-CT (at 4 wk), with a greater proportion of type 2 macrophages after iterative cell injections (8 wk). In conclusion, Ad-MSC injections promote anastomotic healing in an irradiated colon through enhanced vessel formation and reduced inflammation. This study also determined parameters that could be improved in further investigations.

Chronic radiation-induced dermatitis: challenges and solutions.

Chronic radiation dermatitis is a late side effect of skin irradiation, which may deteriorate patients' quality of life. There is a lack of precise data about its incidence; however, several risk factors may predispose to the development of this condition. It includes radiotherapy dose, fractionation, technique, concurrent systemic therapy, comorbidities, and personal and genetic factors. Chronic radiation dermatitis is mostly caused by the imbalance of proinflammatory and profibrotic cytokines. Clinical manifestation includes changes in skin appearance, wounds, ulcerations, necrosis, fibrosis, and secondary cancers. The most severe complication of irradiation is extensive radiation-induced fibrosis (RIF). RIF can manifest in many ways, such as skin induration and retraction, lymphedema or restriction of joint motion. Diagnosis of chronic radiation dermatitis is usually made by clinical examination. In case of unclear clinical manifestation, a biopsy and histopathological examination are recommended to exclude secondary malignancy. The most effective prophylaxis of chronic radiation dermatitis is the use of proper radiation therapy techniques to avoid unnecessary irradiation of healthy skin. Treatment of chronic radiation dermatitis is demanding. The majority of the interventions are based only on clinical practice. Telangiectasia may be treated with pulse dye laser therapy. Chronic postirradiation wounds need special dressings. In case of necrosis or severe ulceration, surgical intervention may be considered. Management of RIF should be complex. Available methods are rehabilitative care, pharmacotherapy, hyperbaric oxygen therapy, and laser therapy. Future challenges include the assessment of late skin toxicity in modern irradiation techniques. Special attention should be paid on genomics and radiomics that allow scientists and clinicians to select patients who are at risk of the development of chronic radiation dermatitis. Novel treatment methods and clinical trials are strongly needed to provide more efficacious therapies.

Bowel Radiation Injury: Complexity of the Pathophysiology and Promises of Cell and Tissue Engineering.

Ionizing radiation is effective to treat malignant pelvic cancers, but the toxicity to surrounding healthy tissue remains a substantial limitation. Early and late side effects not only limit the escalation of the radiation dose to the tumor but may also be life-threatening in some patients. Numerous preclinical studies determined specific mechanisms induced after irradiation in different compartments of the intestine. This review outlines the complexity of the pathogenesis, highlighting the roles of the epithelial barrier in the vascular network, and the inflammatory microenvironment, which together lead to chronic fibrosis. Despite the large number of pharmacological molecules available, the studies presented in this review provide encouraging proof of concept regarding the use of mesenchymal stromal cell (MSC) therapy to treat radiation-induced intestinal damage. The therapeutic efficacy of MSCs has been demonstrated in animal models and in patients, but an enormous number of cells and multiple injections are needed due to their poor engraftment capacity. Moreover, it has been observed that although MSCs have pleiotropic effects, some intestinal compartments are less restored after a high dose of irradiation. Future research should seek to optimize the efficacy of the injected cells, particularly with regard to extending their life span in the irradiated tissue. Moreover, improving the host microenvironment, combining MSCs with other specific regenerative cells, or introducing new tissue engineering strategies could be tested as methods to treat the severe side effects of pelvic radiotherapy.