Morbidity in Patients with Nasopharyngeal Carcinoma and Radiation-Induced Skin Lesions: Cause, Risk Factors, and Dermatitis Evolution and Severity.

OBJECTIVE: Radiation-induced skin injuries such as lesions (RSLs) and dermatitis are the most common complication during radiotherapy (RT) for nasopharyngeal carcinoma, but little is known about risk factors unique to oncology. This study sought a greater understanding of these risk factors to stratify patients based on risk and guide clinical decision-making. METHODS: Investigators analyzed the data of 864 consecutive patients referred to the RT center of the Southern Theater General Hospital for a new RSL from 2013 to 2019. These patients were followed up for an average of approximately 16 months until their death or March 30, 2020, whichever came first. Multivariate logistic regression analysis and Cox proportional hazards model were used to identify predictors of grade 3 or 4 dermatitis. RESULTS: The main causes of treatment interruption included dermatitis and oral mucositis. Significant patient-specific risk factors for RSLs included current smoking, current drinking, and lower Karnofsky Performance Scale score and significant procedure-specific risk factors included receiving intensity-modulated radiation therapy (IMRT), hyperfractionated RT, induction chemotherapy, multicycle chemotherapy, and taxol- and cisplatin-based drugs. The three factors that independently predicted risk of RSL were IMRT, lower Karnofsky Performance Scale score, and multicycle chemotherapy. Comparing predictive factors among patients with severe RSL revealed that patients who received IMRT were more likely to develop grade 3 or 4 dermatitis. CONCLUSIONS: Oncology providers should note that IMRT is an aggressive technique with a trend toward increased RSL. Providers should pay special attention to adverse effects to skin in patients with nasopharyngeal carcinoma.

Radiation dermatitis assessment tools used in breast cancer: A systematic review of measurement properties.

PURPOSE: This review aimed to assess the quality and efficacy of tools currently used in breast cancer patients to score radiation dermatitis (RD), a common debilitating side effect of radiotherapy (RT). METHODS: A search was conducted through Ovid Medline, Embase, and Cochrane Central Register of Controlled Trials databases on 14 February 2020. English articles that evaluated an instrument's use in assessing RD among breast cancer patients receiving external beam RT were included. Studies that reported on the reliability, validity, or concordance of items between assessment tools were included in accordance with the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) criteria. RESULTS: Twelve studies were included in this review, with a total of 13 skin toxicity assessment tools discussed. Tools that assessed clinician-reported outcomes (CROs) mostly reported moderate correlation with biophysical parameter (BP) measurements and low correlation with patient-reported outcomes (PROs). Traditionally used CRO scoring tools demonstrated moderate inter-rater reliability between clinicians, likely due to the subjective nature of items on the grading scales. Most commonly used tools were found to be either insufficient or indeterminate in their measurement properties. CONCLUSIONS: Current standardized tools that measure CROs are subject to clinician interpretation and fail to represent the patient experience. Tools designed to assess PROs are promising in their assessments of the impact of RT on patient quality of life; however, most PRO tools are generic to all skin conditions and require further validation for use in breast cancer. Among tools that measure CROs, PROs, and BPs, there is insufficient evidence on their measurement properties to establish a "gold standard" for the assessment of RD in breast cancer patients.

Pet Dogs with Subclinical Acute Radiodermatitis Experience Widespread Somatosensory Sensitization.

Radiation-induced dermatitis (RID) is a common and painful complication of radiotherapy. When severe, radiation-associated pain (RAP) can reduce the efficacy of radiotherapy by limiting the radiation dose given, and/or necessitating breaks in treatment. Current RAP mitigation strategies are of limited efficacy. Our long-term goal is to develop a comparative oncology model, in which novel analgesic interventions for RAP can be evaluated. The aim of this study was to validate quantitative end points indicative of RAP in pet dogs with subclinical and low-grade RID. Extremity soft tissue sarcomas were treated with post-operative irradiation (54 Gy in 18 fractions). Visual toxicity scores, questionnaire-based pain instruments and objective algometry [mechanical quantitative sensory testing (mQST)], were evaluated regularly. Breed-matched control populations were also evaluated to address the effect of potential confounders. Skin biopsies from within the irradiated field were collected at baseline and after 24 Gy irradiation, for analysis of pain-related genes using the nanoString nCounter platform. Relative to control populations, mechanical thresholds decreased in irradiated test subjects as the total radiation dose increased, with the most pronounced effect at the irradiated site. This was accompanied by increased mRNA expression of GFRα3, TNFα, TRPV2 and TRPV4. In a separate set of dogs with moderate-to-severe RID, serum concentrations of artemin (the ligand for GFRα3) were elevated relative to controls (P = 0.015). Progressive reduction in mechanical thresholds, both locally and remotely, indicates widespread somatosensory sensitization during radiation treatment. mQST in pet dogs undergoing radiation treatment represents an innovative tool for preclinical evaluation of novel analgesics.

Cutaneous radiation damage: updating a clinically challenging concern.

Cutaneous radiation damage, commonly referred to as radiation dermatitis, is a finding of considerable concern. The exposure is often from radiation therapy, a double-edged sword, removing malignant cancer cells and improving the lives of countless patients, yet being locally destructive and potentially premalignant. Among its negative consequences and complications, radiation dermatitis, a potentially severe skin reaction that occurs after the receipt of radiation therapy, presents a clinical challenge today. There are two types of cutaneous radiation dermatitis: acute and chronic. Acute radiation dermatitis manifests within 90 days after the induction of radiation therapy while chronic radiation dermatitis develops beyond 90 days of radiation. There are many risk factors associated with radiation dermatitis which can be characterized as intrinsic, extrinsic, or both. Intrinsic risk factors include concurrent chemotherapy and targeted therapy, connective tissue and skin disorders, genetic and personal factors such as age, sex, smoking habits, and nutritional status. Extrinsic factors are mainly related to the type and dose of the radiation received. Treatment options have been enhanced in the last decade, providing patients with better outcomes and improved quality of life. Such treatments include topical ointments and therapies, oral enzymes, wound dressings and surgical treatments. This article aims to review the current medical understanding of radiation dermatitis, its risk factors, pathophysiology, and treatment options.

Psychological stress affects the severity of radiation-induced acute skin reactions in breast cancer patients.

Psychological stress exacerbates many pathological conditions including inflammatory skin conditions. The effect of psychological stress on acute radiation-induced skin reactions has not been documented before. Here, we aimed to explore if psychological stress could aggravate skin reaction severity in breast cancer patients. We conducted a secondary analysis of patient data obtained during a randomised, controlled clinical trial for acute radiation-induced skin reaction severity in 78 breast cancer patients. Patients were assessed three times a week during treatment. Skin reaction severity was measured using the modified Radiation-Induced Skin Reaction Assessment Scale (RISRAS) and Radiation Therapy Oncology Group grades. Stress levels were determined using a 5-point LIKERT scale to rate physical well-being, managing stress levels, house, family, work and other commitments. A total of 20 patients (26%) of the 78-patient cohort were considered stressed. Skin reaction severity in stressed patients was twice that of non-stressed patients (p < 0.001) and stressed patients were five times more likely to develop moist desquamation. Our results show that psychological stress aggravates skin reaction severity during radiation therapy. This research needs to be validated in a more rigorous manner by incorporating a validated scale such as the Distress Thermometer and Impact Thermometer in future skin trials.

Skin Response to Single and Fractionated Irradiation: Dynamic Modeling Approach.

A biologically motivated mathematical model of the dynamics of swine skin epidermis after single acute irradiation () is extended to describe the effects of fractionated irradiation on this vital body system. The extended model, as the initial one, is a system of nonlinear ordinary differential equations whose variables and parameters have clear biological meaning. The performed studies of the model reveal a correlation between the dynamics of the dimensionless concentration of corneal cells of the upper skin layer and the dynamics of the fraction of the area of swine skin epidermis without moist desquamation under fractionated irradiation similar to that after single acute irradiation (). On the basis of these results, the formula, which allows computation of the dynamics of the moist desquamation in irradiated skin proceeding from the respective dynamics of skin epidermal cells, is proposed. It is demonstrated that the modeling predictions of the moist reaction in swine skin under fractionated irradiation in the wide range of total doses agree, on qualitative and quantitative levels, with the respective experimental data. All this bears witness to the validity of employment of the developed model, after appropriate identification, in the investigation and prediction of the effects of fractionated irradiation on skin epidermis in humans.

Development of a guinea pig cutaneous radiation injury model using low penetrating X-rays.

PURPOSE: A guinea pig skin model was developed to determine the dose-dependent response to soft X-ray radiation into the dermis. MATERIALS AND METHODS: X-ray exposure (50 kVp) was defined to a 4.0 × 4.0 cm area on the lateral surface of a guinea pig using lead shielding. Guinea pigs were exposed to a single fraction of X-ray irradiation ranging from 25-79 Gy via an XRAD320ix Biological Irradiator with the collimator removed. Gross skin changes were measured using clinical assessments defined by the Kumar scale. Skin contracture was assessed, as well as histological evaluations. RESULTS: Loss of dermal integrity was shown after a single dose of soft X-ray radiation at or above 32 Gy with the central 2.0 × 2.0 cm of the exposed site being the most affected. Hallmarks of the skin injury included moist desquamation, ulceration and wound contracture, as well as alterations in epithelium, dermis, muscle and adipose. Changes in the skin were time- and radiation dose-dependent. Full-thickness injury occurred without animal mortality or gross changes in the underlying organs. CONCLUSIONS: The guinea pig is an appropriate small animal model for the short-term screening of countermeasures for cutaneous radiation injury (CRI).

RTOG, CTCAE and WHO criteria for acute radiation dermatitis correlate with cutaneous blood flow measurements.

BACKGROUND: Various clinician-assessed scoring criteria have been used to grade acute radiation dermatitis. However, it is not known whether these scoring criteria correlate with changes in objective skin biophysical parameters and patient-reported symptoms following radiotherapy. We seek to correlate three different clinician-assessed scoring criteria with skin biophysical changes and patient-reported symptoms in breast cancer patients undergoing radiotherapy. METHODS: A prospective cohort study was performed in a university hospital medical center. The severity of acute radiation dermatitis in 101 breast cancer patients was graded using the RTOG, CTCAE and WHO clinical scoring criteria. We also measured various skin biophysical parameters (skin blood flow, pigmentation, hydration, and pH) by non-invasive techniques before and after radiotherapy. Patient-reported breast symptoms (pain, itching, local heat, and tightness) were evaluated using a questionnaire. RESULTS: The three different clinician-assessed scoring criteria correlated most strongly with changes in cutaneous blood flow following radiotherapy for breast cancer (correlation coefficient 0.70 for RTOG, 0.68 for CTCAE, and 0.50 for WHO). All three scoring criteria also showed moderate correlation with changes in skin pigmentation (correlation coefficients 0.4-0.5), but showed no significant correlation with skin hydration or pH (correlation coefficients <0.2). The scoring criteria correlated poorly with patient-reported breast symptoms (correlation coefficients <0.3). CONCLUSIONS: The three clinician-assessed scoring criteria (especially the RTOG and CTCAE criteria) show strong correlation with cutaneous blood flow measurements, but correlate less well with other skin biophysical parameters and patient-reported symptoms.

Effectiveness and Acceptability of a Moisturizing Cream and a Barrier Cream During Radiation Therapy for Breast Cancer in the Tropics: A Randomized Controlled Trial.

BACKGROUND: Inconsistent evidence about product effectiveness to prevent moist desquamation during radiation treatment and minimal research about the acceptability to patients of recommended products prompted this study. OBJECTIVE: This randomized controlled trial compared the effectiveness of 2 creams at minimizing the incidence of moist desquamation in a tropical setting and explored which product was most acceptable to patients receiving radiation treatment. METHODS: Participants (n = 255) were stratified according to breast or chest wall radiation treatment and randomly allocated to use a moisturizing or barrier cream. Nurses assessed radiation skin reactions weekly with a standardized grading system, and patients were telephoned 1 month after completing treatment for a final skin assessment. Participants completed an Acceptability Survey at similar times. RESULTS: At treatment completion, 15% of participants had moist desquamation. An additional 26% self-reported this at follow-up. Risk factors for moist desquamation included increased breast cup size and body mass index. The barrier cream significantly reduced the incidence of moist desquamation during treatment in patients receiving radiation to the chest wall (χ = 3.93, P = .047). Participants preferred the barrier cream over the moisturizer (χ = 5.81, P = .02) during treatment. CONCLUSIONS: This study identified a relatively high incidence of moist desquamation in patients receiving radiation therapy for breast cancer. Future patients will have information about product effectiveness in minimizing moist desquamation when choosing skin care products. IMPLICATIONS FOR PRACTICE: Structured discharge planning and patient education need to include information about factors that contribute to the likelihood of developing moist desquamation.

Comparison of acute skin reaction following morning versus late afternoon radiotherapy in patients with breast cancer who have undergone curative surgical resection.

We investigated the relationship between the time of radiotherapy (RT) and treatment outcomes in breast cancer. Patients with pathologic T1-2N0-1 breast cancer who received adjuvant RT in the morning (before 10:00 AM) or late afternoon (after 3:00 PM) were eligible for inclusion in this study. We retrospectively compared the clinicopathologic characteristics, acute skin reaction, and survival outcomes according to the time of RT. The median follow-up duration was 83 months (range, 10-131 months). From the 395 eligible patients, 190 (48.1%) and 205 (51.9%) patients were classified into the morning RT group and the afternoon RT group, respectively. The clinicopathologic characteristics were relatively well balanced between the treatment groups, except for pathologic N-stage (P = 0.0409). Grade 2 or higher acute skin reaction according to the Radiation Therapy Oncology Group criteria was observed in 39 (9.9%) patients, with a higher frequency in the afternoon RT group than the morning RT group (13.7% vs 5.8%, respectively; P = 0.0088). There was no difference in the failure patterns or survival outcomes between the treatment groups. RT in late afternoon was associated with increased Grade 2 or more skin reaction after RT for breast cancer patients, but treatment outcomes did not differ according to the time of RT. Individualized considerations for treatment should be taken into account to reduce the risk of skin reactions.

Acute skin toxicity in Korean breast cancer patients carrying BRCA mutations.

PURPOSE: In contrast to in vitro studies, most clinical trials testing the radiosensitivity of BRCA (Breast cancer susceptibility gene) mutations do not find a correlation between BRCA status and enhanced radiosensitivity. These trials include different ethnicities, and there is a lack of clinical data on BRCA1/2 mutation carriers and radiosensitivity in non-Caucasian patients. The goal of this study was to investigate acute skin toxicity, as a part of radiosensitivity, in breast cancer patients with BRCA1/2 mutations. MATERIAL AND METHODS: BRCA mutation analysis was performed for 213 patients who underwent breast-conserving therapy using radiotherapy. Skin toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) criteria during treatment and during one-month follow-up after radiation therapy. RESULTS: Forty-six patients had BRCA1/2 mutations and 57 patients showed higher than grade 2 (RTOG) skin toxicity. In multivariate analysis, significant associations were found between mean breast volume and acute skin toxicity. BRCA mutation status, however, failed to show a significant correlation. CONCLUSIONS: Our results indicate that carriers of BRCA1/2 mutations among non-Caucasian breast cancer patients showed no enhancement in radiation sensitivity. Multiple genetic markers may be correlated with normal tissue responses after radiotherapy. Further studies are needed to identify genetic predispositions to normal tissue responses after radiotherapy.

Development of a porcine skin injury model and characterization of the dose-dependent response to high-dose radiation.

A porcine skin model was developed to characterize the dose-dependent response to high-dose radiation. The dorsal skin of a mini pig was divided into four paraspinal sections, with 11 small irradiation fields (2 cm × 2 cm) in each section, and a single fraction of 15, 30, 50 or 75 Gy was delivered to each section using a 6 MeV electron beam. A spectrophotometer measured gross skin changes, and a biopsy for each radiation dose was performed in the 1st, 2nd, 4th, 6th and 9th weeks for histology, immunostaining with anti-CD31, and western blotting with IL-6 and TGF-ß1 to determine the degree of skin damage. After a 4-week latency period, erythema and dry desquamation, moist desquamation, and ulceration appeared at 4, 6 and 9 weeks, respectively. Gross skin toxicity was more pronounced, occurred early and continued to progress with irradiation >50 Gy, whereas complete healing was observed 12 weeks after 15 Gy. Spectrophotometry showed erythema indices rapidly increased during the first 4 weeks after irradiation. The number of eosinophils began rising sharply at 4 weeks and normalized after reaching peaks at 7-8 weeks. Microvessel density showed a biphasic pattern with a transient peak at 1 week, a nadir at 4-6 weeks, and maximum recovery at 9 weeks. Increase in the levels of IL-6 and TGF-ß1 was detected soon after irradiation. Most of these parameters indicated complete healing of the skin 12 weeks after 15 Gy. Our porcine skin model provides an effective platform for studying high-dose radiation-induced skin injury, in particular histologic and molecular changes, during the early latency period.

Prophylactic topically applied ice to prevent cutaneous complications of nontarget chemoembolization and radioembolization.

Cutaneous complications can result from nontarget deposition during transcatheter arterial chemoembolization or radioembolization. Liver tumors may receive blood supply from parasitized extrahepatic arteries (EHAs) that also perfuse skin or from hepatic arteries located near the origin of the falciform artery (FA), which perfuses the anterior abdominal wall. To vasoconstrict cutaneous vasculature and prevent nontarget deposition, ice packs were topically applied to at-risk skin in nine chemoembolization treatments performed via 14 parasitized EHAs, seven chemoembolization treatments near the FA origin, and five radioembolization treatments in cases in which the FA could not be prophylactically coil-embolized. No postprocedural cutaneous complications were encountered.

[Experience of contemporary treatment of radiation burns in individuals subjected to ionizing radiation].

The article presents new approach to treatment of radiation disorders presenting as indolent ulcers. The approach is based on autologous multipotent mesenchimal stromal cells applied locally and injected around the injuried zone. The ulcers heal due to the fact that the transplanted cells stimulate local regeneration processes, angiogenesis, ceased inflammation and apoptosis. The method is a new medical technology based on vast preclinical studies and could be put into medical practice.

Hyperspectral imaging for early detection of oxygenation and perfusion changes in irradiated skin.

Studies examining acute oxygenation and perfusion changes in irradiated skin are limited. Hyperspectral imaging (HSI), a method of wide-field, diffuse reflectance spectroscopy, provides noninvasive, quantified measurements of cutaneous oxygenation and perfusion. This study examines whether HSI can assess acute changes in oxygenation and perfusion following irradiation. Skin on both flanks of nude mice (n=20) was exposed to 50 Gy of beta radiation from a strontium-90 source. Hyperspectral images were obtained before irradiation and on selected days for three weeks. Skin reaction assessment was performed concurrently with HSI. Desquamative injury formed in all irradiated areas. Skin reactions were first seen on day 7, with peak formation on day 14, and resolution beginning by day 21. HSI demonstrated increased tissue oxygenation on day 1 before cutaneous changes were observed (p<0.001). Further increases over baseline were seen on day 14, but returned to baseline levels by day 21. For perfusion, similar increases were seen on days 1 and 14. Unlike tissue oxygenation, perfusion was decreased below baseline on day 21 (p<0.002). HSI allows for complete visualization and quantification of tissue oxygenation and perfusion changes in irradiated skin, and may also allow prediction of acute skin reactions based on early changes seen after irradiation.

Management of dermatitis in patients with locally advanced squamous cell carcinoma of the head and neck receiving cetuximab and radiotherapy.

Locally advanced squamous cell carcinoma of the head and neck is generally managed with a combination of surgery, RT, and/or chemotherapy or cetuximab. Appropriate management of radiation dermatitis associated with cetuximab and radiotherapy is necessary to allow adequate drug administration and to improve the quality of life and outcome. We generate a recommendation for radiation dermatitis on the basis of a systematic revision of the literature. Radiation dermatitis is experienced by the majority of patients undergoing radiotherapy for HNSCC, generally being mild to moderate (grades 1-2), showing about 25% severe toxicity (grade ≥ 3). Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed. This paper reviews comprehensive consensus guidelines to help manage the radiation dermatitis in order to make an optimal use of available therapeutic arsenal.

The effects on pain and activity of daily living caused by crusted exudation in patients with head and neck cancer treated with cetuximab and radiotherapy.

PURPOSE: To date, the specific role of "in-field" crusting exudation on pain and on activity of daily living (ADL) in head and neck cancer (HNSCC) patients undergoing treatment with cetuximab and radiochemotherapy has been neglected. The purpose of the study was to evaluate the role of crusting exudation on the severity of pain and ADL METHODS: Thirty-seven of the 45 HNSCC patients enrolled in the alternating radiotherapy, chemotherapy, and cetuximab trial were evaluated in this study. The main radiodermatitis signs (the intensity of erythema, the extension of dry, and moist desquamation and of necrosis)--including crusting exudation severity--pain, ADL, and radiodermatitis scores were registered at least weekly during and after treatment. The correlation between crusting exudation and pain or ADL was evaluated. RESULTS: The "in-field" crusting exudation score seemed to have the strongest correlation with pain (Spearman's rho = 0.897; p < 0.001) and the most intense influence on it (Co-B = 0.715; 95% C.I. = 0.643-0.787). However, it seemed to have a weaker correlation with ADL than the other clinical radiodermatitis signs. CONCLUSIONS: Crusts have the strongest correlation with pain in patients with Cetuximab-related radiation dermatitis. Moreover, the presence of crusts can lead operators to misclassify dermatitis as score 4, causing unnecessary delays or interruptions in treatment.

Erlotinib-induced rash spares previously irradiated skin.

BACKGROUND: Erlotinib is an epidermal growth factor receptor inhibitor prescribed to patients with locally advanced or metastasized non-small cell lung carcinoma after failure of at least one earlier chemotherapy treatment. Approximately 75% of the patients treated with erlotinib develop acneiform skin rashes. CASE REPORT: A patient treated with erlotinib 3 months after finishing concomitant treatment with chemotherapy and radiotherapy for non-small cell lung cancer is presented. Unexpectedly, the part of the skin that had been included in his previously radiotherapy field was completely spared from the erlotinib-induced acneiform skin rash. CONCLUSION: The exact mechanism of erlotinib-induced rash sparing in previously irradiated skin is unclear. The underlying mechanism of this phenomenon needs to be explored further, because the number of patients being treated with a combination of both therapeutic modalities is increasing. The therapeutic effect of erlotinib in the area of the previously irradiated lesion should be assessed.

Management of radiation dermatitis in patients receiving cetuximab and radiotherapy for locally advanced squamous cell carcinoma of the head and neck: proposals for a revised grading system and consensus management guidelines.

BACKGROUND: Radiation dermatitis developing in patients receiving cetuximab concomitantly with radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) is now recognized to have different pathophysiological and clinical characteristics to the radiation dermatitis associated with radiotherapy or concomitant chemotherapy and radiotherapy. Current grading tools were not designed to grade this type of radiation dermatitis; their use may lead to misclassification of reactions and inappropriate management strategies, potentially compromising cancer treatment. PATIENTS AND METHODS: An advisory board of seven leading European specialists (three medical oncologists, three radiation oncologists and a dermatologist) with extensive experience of the use of cetuximab plus radiotherapy produced consensus guidelines for the grading and management of radiation dermatitis in patients receiving cetuximab plus radiotherapy. RESULTS: Modifications to the current, commonly used National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.3 for grading radiation dermatitis were proposed. Updated management guidelines, building on previously published guidelines from 2008, were also proposed. CONCLUSIONS: The proposed revisions to the grading system and updated management guidelines described here represent important developments toward the more appropriate grading and effective management of radiation dermatitis in patients receiving cetuximab plus radiotherapy for LA SCCHN.