Management of skin toxicity

Introduction

Radiation-induced skin reaction (RISR), or radiation dermatitis, is one of the most common side effects of radiation therapy (RT). RISR can vary in severity, impact the quality of life (QoL), and limit the extent of treatment tolerance by patients. Acute skin toxicity, occurring during or soon after treatment, is common and typically temporary. In contrast, late skin toxicity occurs in relatively fewer patients, can take months to years to develop, and is more likely to be permanent.

Although RISR occurs in the majority of patients, there is a lack of consensus on the best management strategies, leading to large variations in practice. ^, Multiple guidelines for skin care management have been published, but there has been inconsistent adoption of any guideline recommendations. Almost 90% of radiation oncology departments report using “in-house” guidelines for managing RISR over national guidelines. ^{, ,} Other surveys from Europe and North America also found wide variations in skin toxicity management, largely based on historical or anecdotal practices rather than evidence-based recommendations. ^{, ,} The inconsistent use of best practices for this common toxicity leads to suboptimal management as well as unnecessary burden and restrictions on patients that are not supported by data. ^, Evidence-based approaches to general prevention and management for acute and late skin toxicity will be discussed here.

Epidemiology

The likelihood of developing RISR as well as the severity of the reaction are impacted by various treatment- and patient-specific factors. Treatment factors include radiation dose, fractionation, modality, and technique. The proximity of the target to the skin surface, treatment volume, and use of concurrent systemic therapies, including chemotherapy and targeted agents, can also play a role. Technological improvements have led to increased use of higher energy photons and intensity-modulated radiation therapy (IMRT)/volumetric-modulated arc therapy (VMAT), which reduce the incidence of severe skin toxicity. Patient-specific factors include patient anatomy, body habitus (e.g., larger breast size for breast cancer treatment), malnutrition, smoking history, chronic sun exposure, older age, and genetic susceptibility.

Multiple studies have looked at the impact of skin type on radiation reaction. Ulff et al. suggested increased reaction in patients with fair skin but a better response to corticosteroids. Others found more severe post-treatment skin reactions in African American patients than Caucasians. ^, This is potentially due to ionizing radiation creating more free radicals in the presence of melanin, which ultimately results in increased deoxyribonucleic acid (DNA) damage.

These are also cancer types where the risk of RISR is higher due to anatomy and the need to prescribe full-dose radiation to the skin surface, such as in the treatment of vulvar and anal cancer. In these cases, more severe side effects are common in areas of skin folds due to the inevitable self-bolus effect as well as mechanical damage to the skin in this region. Minimizing skin folds, particularly during treatment positioning, and using skin-sparing radiation techniques can help to reduce acute and long-term side effects. For example, prone positioning for radiation of patients with large breasts can reduce skin folds, improve distribution, and reduces the risk of RISR, including moist desquamation.

Increased radiation dermatitis has also been noted in patients with various genetic DNA repair deficiencies, such as Fanconi anemia and ataxia-telangiectasia syndrome. There is also a risk of exaggerated response in diabetes and various connective tissue disorders, such as scleroderma and systemic lupus erythematosus. ^, The incidence of postradiation fibrosis is higher in patients with connective tissue disorders. Thus these are relative contraindications to RT. Appropriate patient selection and minimizing of treatment field size and dose are the keys to limiting toxicity for these patients.

Pathogenesis

Acute radiation injury to the skin results from DNA damage to the basal layer with the stem cell population, resulting in disruption of the regeneration of the skin layers. Late radiation injury is largely attributed to changes within the supporting dermis that consists of fibroblasts, vasculature, and lymphatics. ^, The normal process where the epidermal layer is replaced approximately every 4 weeks is delayed, leading to desquamation or peeling of the epidermis. With increasing time from the start of radiation, and thus increasing dose, the ongoing injury results in inflammation, which further exacerbates the impact of radiation injury. There is a release of proinflammatory cytokines and an increase in blood flow, with rapid histamine release causing erythema, edema, and pruritis. Tanning of skin is also common and more prominent in patients with darker skin, largely due to the migration of melanin. Radiation also causes hair loss, sometimes permanent, by inducing hair follicles into a resting phase of the cell cycle. ^, At doses less than 50 Gy, regrowth of hair may occur at 2 months after the end of radiation. Radiation can also cause acute and/or long-term xerosis of the skin by damaging the sweat and sebaceous glands responsible for lubrication. Healing upon completion of radiation usually results from re-epithelialization with growth from the basal membrane. A moist wound healing environment is most supportive of the healing.

Radiation dermatitis—expected time course

Understanding the pathogenesis and expected time course of side effects with radiation is important so that one can monitor for unexpected, excessive, or inadequate skin reactions. Either can be an indication of a problem with treatment delivery or patient factors. Additionally, knowing the course and exacerbating factors of expected and common side effects such as RISR and communicating this knowledge effectively to the patient and caregivers is a key component of providing high-quality management of toxicity. Multiple studies have demonstrated the positive impact of improved physician-patient communication on outcomes in various diseases. ^, Similarly, as patients undergo RT, communicating what to expect in terms of timing of erythema, folliculitis, hyperpigmentation and local alopecia is crucial and can allow for appropriate reassurance as well as improved outcomes for common temporary side effects. It is helpful to educate all of the staff who will regularly have contact with the patients (e.g., nurses, medical assistants, and therapists) regarding common side effects so they can assist and reaffirm patient education. ^,

RISR that arises within 90 days of the RT is considered an acute reaction, while late reactions can occur months to years after treatment ( Fig. 28.1 ). In patients receiving standard fractionated radiation, the first symptom can be primary transient erythema which occurs within 24 hours after the initial treatment and may last for a few days to 10 days. Transient erythema may progress and become more generalized erythema throughout the field, typically between the second to fourth week of radiotherapy. Following erythematous changes, skin dryness, hair loss, and hyperpigmentation are also frequent manifestations. Pruritus with or without dry desquamation, scaling, and flaking of the skin typically occurs within the third to fourth week up to the sixth week of the treatment, once the cumulative radiation dosage reaches 20 Gy. Moist desquamation characterized by tender red skin with serous exudate, crusting, or occasionally bullae typically manifests after 4 weeks or cumulative radiation dosage above 40 Gy and can be associated with significant pain. Closer monitoring and active intervention are required once moist desquamation develops, as skin ulceration increases the risk of superinfection. ^,

Grading

Several grading systems are used to quantify the severity of radiation dermatitis ( Table 28.1 ). The use of uniform grading is important for monitoring side effects, research, and uniformity of practice. The most commonly used criteria are National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) and Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC), which have similar grading of skin toxicity. Both scales grade severity from grade 1 through grade 5, as described in Table 28.1 . Fig. 28.2 shows corresponding images of skin reactions. There is increasing interest in patient-reported outcomes, and the NCI developed a tool to capture symptomatic adverse events that integrates patient feedback, termed patient reported outcome (PRO)-CTCAE. ^, It has been demonstrated that this tool favorably aids in the assessment of symptomatic adverse reactions from RT.