Radiation-Induced Skin Injury: A Challenging Issue in the Outpatient Wound Clinic

Editor’s Note: All images in this article are provided by the author.

Radiation therapy is an important modality in the treatment of numerous cancers. It is estimated that half of all patients diagnosed with cancer receive radiation therapy as part (or all) of their treatment.¹ Unfortunately, in damaging/eradiating the cancer, radiation therapy can cause significant harm to healthy surrounding tissue. This skin injury can cause considerable pain and suffering to patients who are already stressed by the diagnosis. Wound care clinicians who are knowledgeable in the assessment and care of these painful, difficult-to-heal wounds can have a substantial positive impact on their patients’ lives. This article will review the basic effects of radiation on tissue, the clinical presentation of radiation-associated skin changes and damage, and options for treating and healing the wounds that may result.  

ACUTE & CHRONIC EFFECTS
OF RADIATION THERAPY

Radiation therapy can injure any normal tissue in the body that lies within the treatment field of a cancerous tumor. Tissues that have rapid cell turnover, such as the skin, are most sensitive to radiation’s effects.² Damage to the skin from radiation is known as radiodermatitis, radiation dermatitis, radiation-induced dermatitis, or radiation injury.³ The extent of tissue damage is dependent on the total radiation dose, type of beam used, time over which the radiation is delivered (dose per fraction), and size of the tissue irradiated.² Factors that increase the risk for injury include concomitant chemotherapy or targeted therapy (sometimes used to sensitize tissue to radiation); connective tissue disorders; skin disorders such as psoriasis, eczema, or acne; age; female sex; presence of skin folds in radiation field; poor nutrition; cigarette smoking; obesity; ethnicity; and chronic sun damage.⁴ 

Acute radiation injury to the skin, which generally occurs during the first four weeks (and up to three months after the start of treatment), may include erythema, hyper- or hypopigmentation, dry desquamation, hair loss, and wet desquamation. During the acute period, full-thickness damage may occur less commonly, resulting in tissue necrosis and ulcers. Chronic or late effects of radiation on the skin and underlying tissues, which can occur months to several years after treatment, include fibrosis, pigmentary changes, telangiectasia, atrophy, and chronic nonhealing ulcers.⁵ Tissue fibrosis can lead to strictures, reduced range of motion, and decreased tissue tensile strength. 

Radiation has numerous effects on cells, which lead to the acute and chronic changes seen clinically. Acutely, reactive oxygen species (ROS) and other free radicals are generated with initial and subsequent treatments, resulting in immediate damage to cellular structures and DNA. The body’s innate antioxidant defenses are overwhelmed by the high levels of ROS in the tissue and are unable to defend against this assault, resulting in significant oxidative injury. High levels of proinflammatory cytokines are released with irradiation of tissue, leading to acute and chronic inflammation as well as tissue damage. Injury and death of endothelial cells lead to microvascular damage, tissue hypoxia, and further release of ROS. Basal keratinocytes, which are essential to wound repair and reepithelialization, are injured/killed. Over the course of radiation therapy, efforts of surviving basal keratinocytes to heal the skin are repeatedly defeated as, with each treatment, the damage is multiplied. Injury and death of stem and progenitor cells result in both acute and chronic impairment of their ability to replace various functional cells.^2,3,5 Harm to melanocytes leads to pigmentary changes. Thus, damage to the skin and possibly underlying tissue occurs, and delayed/impaired healing results. 

Chronically, fibrosis of irradiated tissue may continue for years due to release of transforming growth factor β1 and connective tissue growth factor from multiple cells in the area.⁶ Ongoing release of these growth factors, even after completion of radiation therapy, stimulates long-term collagen deposition and abnormal remodeling. The microvascular damage seen acutely also becomes chronic and is related to continuing tissue fibrosis, which itself is also worsened by tissue hypoxia from that same microvascular injury. This becomes an enduring cycle of tissue damage.⁶

ASSOCIATED SKIN CHANGES

The majority of patients who receive radiation therapy can be expected to have some level of skin reaction. Modern radiation therapy attempts to minimize the dose to the skin, but secondary damage to normal skin and underlying tissue is almost impossible to avoid when treating tumors of the skin and those that are more superficially located. Areas most at risk for radiation injury are those with cancers of the skin, brain, breast, soft tissue, head and neck, perineum, and anal canal. Early in the course of radiation treatment, erythema may be seen. The skin may then develop dry desquamation, in which the skin is dry, flaking, and peeling, possibly with pruritis. Changes in pigmentation may be present. As radiation therapy continues, moist desquamation may occur, in which the skin blisters, becomes denuded, weeps serous exudate, and becomes very painful, especially in areas of high innervation, such as the anus and perineum.⁷ These skin conditions are usually managed by the radiation therapy department and will rarely be referred to the wound clinic. However, if the wound clinic has certified ostomy nurses on staff, they will commonly see anal and perineal moist desquamation in their colostomy patients undergoing radiation for low-lying rectal or anal cancers. Acute radiation skin changes may be seen in patients living with concurrent wounds, such as those following surgery with postoperative wounds referred to the wound clinic. Table 1 above lists the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) for radiation dermatitis.⁸

Full-thickness ulcers may occur either acutely or as a late effect months to years after treatment. Acute full-thickness radiation-induced ulcers are commonly seen in the radiation of cutaneous basal cell carcinoma and squamous cell carcinoma (SCC) anywhere on the body (Figures 1A-C and Figure 2, at right).  These ulcers may present with pale to necrotic bases with no granulation tissue, or may have poor quality, friable granulation. There may be local edema with moderate to high serous exudate and inflamed, weeping surrounding skin. When skin cancers are treated on the scalp, bone may be exposed if an ulcer occurs. 

Ulcers occurring years later, considered a late effect of radiation, arise from the fibrotic scar in a previously treated area (Figures 3-7, at right and on page 11). Patients may not remember how the wound started. Perhaps they picked at a scab in the radiation scar, or they may have simply scratched the area. Clothing (such as a bra strap) could have also rubbed the fibrotic skin. Sometimes, these wounds start when surgery is required in a previously irradiated area. Regardless, a simple wound in an area previously damaged by radiation frequently becomes a nonhealing ulcer. These chronic ulcers generally present with pale-pink fibrotic bases and/or with necrotic tissue. Healthy granulation tissue is typically absent. Depending on location, there may be bone exposure, which is frequently necrotic. These ulcers do not tend to bleed much with debridement. Surrounding skin may be atrophied, hypo- or hyperpigmented, and fibrotic. Numerous telangiectasia may be present. There may be edema beyond the area of fibrosis due to local damage of veins and lymphatics. Pain is common and ischemic in nature due to small vessel damage in the area. 

TREATMENT

Much of the literature on the treatment of radiation-induced skin injury is based on consensus and/or expert opinions, with few adequate studies to make strong recommendations.^9-11 Chan et al¹¹ conducted a meta-analysis of 47 studies with a total of 5,688 subjects examining oral systemic medications, skin care practices, topical corticosteroids, other topical therapies, and/or dressings, and found there was limited adequate research that provided conclusive results to show that one therapy was better than another. At best, they were able to conclude that it appeared that washing skin was of benefit, and the use of soap versus water alone on affected skin made no difference. They also concluded that use of non-metallic deodorants was of no harm. Table 2 above reviews skin care recommendations for patients undergoing radiation.^9-12 Other therapies for prevention and treatment of radiation dermatitis also lack good evidence, in most cases. In their clinical practice guidelines on the prevention and treatment of radiation dermatitis, Wong et al¹⁰ strongly recommended the use of topical steroids to prevent progression of radiation injury to the skin as well as to treat pruritis, burning, and skin discomfort. The group¹⁰ had a weak recommendation for the prophylactic use of silver sulfadiazine for patients living with breast cancer treated with radiation based on one study showing a reduction in skin injury when used. The authors determined there was insufficient evidence to support or refute the use of topical sucralfate or hyaluronic acid, and concluded there was insufficient evidence to support the use of topical ascorbic acid, light-emitting diode lasers, petrolatum-based ointments, and Theta-cream^® in the care of radiation dermatitis. They strongly recommended against the use of aloe vera gel or trolamine (BIAFINE,^® Johnson & Johnson), based on numerous studies that did not demonstrate efficacy. Feight et al⁹ recommended against the use of gentian violet for any stage of radiation injury based not only on available data, but also on the potential of skin irritation/damage from this topical. 

Regarding the use of dressings for moist desquamation, both Feight et al⁹ and Wong et al¹⁰ noted mixed results in studies of hydrocolloids and hydrogels for this condition. They concluded that effectiveness had not been established for these dressings, and Wong et al¹⁰ could not support a recommendation for or against these products, as well as sucralfate cream, hydrocortisone 1%, honey, or trolamine for moist desquamation. There may be a role for silicone dressings in the prevention of progression and treatment of radiation dermatitis. Herst et al¹³ studied 78 breast cancer patients scheduled to receive radiation therapy. Half of the treatment field received a silicone film (Mepitel Film,^® Mölnlycke Health Care) and the other half had an aqueous cream applied. The skin treated with the silicone film had a 92% reduction in overall severity of skin reaction compared to the cream, and had no moist desquamation compared to 26% of the skin treated with the aqueous cream. A silicone-based foam (Mepilex Lite,^® Mölnlycke) was compared to an aqueous cream for the treatment of radiation-induced erythema in 24 patients currently undergoing radiation therapy.¹⁴ Patients served as their own control, as noted in the prior study. Use of the foam dressing significantly decreased the severity of the erythema compared to the cream (P < .001) and did not increase skin temperature. Use of the silicone-based foam did result in a minimal bolus effect (0.5 mm). Zhong et al¹⁵ randomized 88 patients living with nasopharyngeal carcinoma and moist desquamation to either a silicone-based foam (Mepilex Lite) or regular washing with salted water. Use of the silicone dressing significantly improved median healing time (16 versus 23 days; P=.009) and sleep (P=.005) compared to control. 

Regarding the late effects of radiation, Wong et al¹⁰ made a weak recommendation for the use of long-pulsed dye laser for the treatment of telangiectasia. They also stated there was insufficient evidence to support a recommendation for or against pentoxifylline (PTX) or vitamin E in the treatment of fibrosis. This was most likely due to small study size or lack of comparator. One small double-blind study, in which 24 subjects with fibrosis post-radiation for breast cancer were randomized to receive either PTX 800 mg + vitamin E 1,000 IU daily, PTX + placebo, vitamin E + placebo, or placebo + placebo, showed significant regression of fibrosis over a six-month treatment period in the PTX + vitamin E group versus the placebo + placebo group (60% versus 43%, P=.038).¹⁶ There was no significant difference in the PTX + placebo or the vitamin E + placebo groups compared to placebo + placebo. The second study, which was open-label and a pretest-posttest design, observed 30 patients who received PTX 400 mg three times daily for two months and demonstrated improvements in range of motion, muscle weakness, edema, and pain in the majority of patients.¹⁷ Randomized controlled trials are needed for a stronger recommendation.  

There was no mention of the treatment of full-thickness ulcers in the radiation dermatitis literature researched for this article, either from acute or late effects of radiation, except for the importance of referral to an expert in their care. Wound care clinicians know that, for most wounds, including those associated with radiation, moist wound healing is paramount — as is the treatment of any comorbidities that could affect healing, such as peripheral artery disease, chronic venous insufficiency (CVI), edema, lymphedema, repetitive trauma, infection, smoking, etc. There is an added challenge of dealing with very fragile surrounding skin, local microvascular damage, local edema/lymphedema, and late effects of radiation to wound and surrounding tissue with these types of wounds. Patients may also have significant pain that requires treatment. 

INITIATING HBOT

Interestingly, there was also no mention in any guidelines reviewed by this author concerning the value of hyperbaric oxygen therapy (HBOT) in the treatment of nonhealing ulcers due to late effects of radiation, yet many clinicians consider hyperbarics an integral part of the treatment of these patients. The Undersea & Hyperbaric Medical Society defines HBOT as “an intervention in which an individual breathes near 100% oxygen intermittently while inside a hyperbaric chamber that is pressurized to
> sea level pressure (1 atmosphere absolute [ATA]). For clinical purposes, the pressure must be ≥ 1.4 ATA while breathing near 100% oxygen.”¹⁸ Clinicians specializing in HBOT refer to ulcers secondary to late effects of radiation as soft tissue radionecrosis, and, if bone is affected, osteoradionecrosis.¹⁹ For treatment of these conditions, the chamber is typically pressurized to 2.0-2.4 ATA, breathing 100% oxygen at pressure. HBOT is usually provided five days per week. The total number of treatments (commonly referred to as “dives”) required depends on the type of radiation problem being treated, but varies between 30 and 60. Although there is a lack of prospective randomized controlled trials on the use of HBOT in late radiation skin injury, there are numerous published reports, case studies, case series, and a large cohort study showing improved wound healing and improved symptoms when HBOT is utilized as an adjunctive treatment for this indication.^18-20 Specific effects causing improved wound healing in radiated tissue include stimulation of angiogenesis resulting in an improvement in tissue oxygenation and a reduction in tissue fibrosis.¹⁸ There may also be an effect of stem cell recruitment yet to be confirmed.¹⁸ As HBOT is considered a standard adjunct in the management of the late effects of radiation, Medicare and most other payers do cover this treatment. This author routinely refers patients with chronic radiation injury to an HBOT center for consultation.  

REFERRAL TO PLASTIC SURGERY

Another consultant to consider in the care of patients with late effects of radiation is the plastic surgeon. Resection of a wound and surrounding fibrosis with possible skin grafting or local or free flaps may be the best option when there is significant tissue damage from late effects of radiation.⁶ This may result in wound closure and/or result in improved function, especially with removal and reconstruction of fibrosis in areas where normal range of motion is impaired. 

CONCLUSION

Treatment of patients with skin injury and/or wounds secondary to acute or late effects of radiation poses a special challenge to wound care clinicians. Key to successful treatment involves a holistic approach used in all patients presenting to a wound clinic, which includes addressing any comorbidities or lifestyle issues that negatively impact healing, providing a moist wound environment, and utilizing adjunctive modalities that can potentially reverse or improve the unique tissue changes seen in these patients. n

Susie Seaman is on staff at Sharp Rees-Stealy Wound Clinic, San Diego, CA. She may be reached at susie.seaman@sharp.com.

References

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14. Diggelmann KV, Zytkovicz AE, Tuaine JM, Bennett NC, Kelly LE, Herst PM. Mepilex Lite dressings for the management of radiation-induced erythema: a systematic inpatient controlled clinical trial. Br J Radiol. 2010. 83(995):971-8.

15. Zhong WH, Tang QF, Hu LY, Feng HX. Mepilex Lite dressings for managing acute radiation dermatitis in nasopharyngeal carcinoma patients: a systematic controlled clinical trial. Med Oncol. 2013;30(4):761.

16. Delanian S, Porcher R, Balla-Mekias S, Lefaix JL. Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation-induced fibrosis. J Clin Oncol. 2003;21(13):2545-50. 

17. Okunieff P, Augustine E, Hicks JE, et al. Pentoxifylline in the treatment of radiation-induced fibrosis. J Clin Oncol. 2004;22(11):2207-13. 

18. Indications for Hyperbaric Oxygen Therapy, Definition of Hyperbaric Oxygen Therapy. UHMS. 2017. Accessed online: www.uhms.org/resources/hbo-indications.html 

19. Hampson NB, Holm JR, Wreford-Brown CE, Feldmeier J. Prospective assessment of outcomes with 411 patients treated with hyperbaric oxygen for chronic radiation tissue injury. Cancer. 2012;118(15):3860-8.

20. Borab Z, Mirmanesh MD, Gantz M, Cusano A, Pu LL. Systematic review of hyperbaric oxygen therapy for the treatment of radiation-induced skin necrosis. J Plast Reconstr Aesthet Surg. 2017. 70(4):529-38.