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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 3  |  Page : 526-536

Radiation dermatitis: A narrative review of the Indian perspective


1 Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra, India
2 Department of Radiation Oncology, All India Institute of Medical Sciences, Patna, Bihar, India
3 Department of Dermatology and Cosmetology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra, India

Date of Submission21-May-2020
Date of Decision18-Jun-2020
Date of Acceptance29-Jul-2020
Date of Web Publication19-Sep-2020

Correspondence Address:
Isha Jaiswal
Department of Radiation Oncology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_209_20

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  Abstract 


One of the common and visible symptoms of radiation toxicity is radiation-induced dermatitis, which varies in intensity from slight erythema to dry and moist desquamation, ulceration, and sometimes skin necrosis. Radiation depletes the basal cell layer of the skin and initiates a complex sequence of events, leading to dose-dependent acute or late sequelae. These skin reactions may cause irritation and pain, delay treatment, and also reduce the quality of life of the patient undergoing radiotherapy. It is also a subject of major concern for female patients undergoing radiotherapy for the treatment of head-and-neck and breast cancers. Despite the technological advancements achieved in planning and delivery in the field of radiotherapy, most patients still experience radiation dermatitis (RD) as a side effect of the treatment. The severity of RD depends on multiple patient- and treatment-related factors. Although severe RD is rare in the current practice of megavoltage radiotherapy, some occasions necessitate active intervention by a multidisciplinary group to manage both acute and late radiation effects over the epidermis and sometimes the dermis. Management policies vary as per the institutional guidelines and personal preferences and are mostly based on individual experiences and reviews. This is a narrative literature review of the various articles focusing on the diverse spectrum of RD. The primary search for the articles was carried out via Google Scholar, PubMed, and MEDLINE with keywords such as “radiation dermatitis,” “radiation-induced skin toxicity,” and “radiation recall phenomenon,” “radiation erythema,” and “radionecrosis.” Additional articles were found through references from the relevant articles. In this review, we discuss the incidence of RD, its presentation, the key aspects that put Indian patients at an increased risk of RD, and the management strategies for the prevention and treatment of radiation dermatitis.

Keywords: Aloe vera, erythema, radiation dermatitis, radiation recall phenomenon, steroids, superoxide dismutase


How to cite this article:
Talapatra K, Singh P, Jaiswal I, Rais S, Pandey S. Radiation dermatitis: A narrative review of the Indian perspective. Cancer Res Stat Treat 2020;3:526-36

How to cite this URL:
Talapatra K, Singh P, Jaiswal I, Rais S, Pandey S. Radiation dermatitis: A narrative review of the Indian perspective. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Oct 30];3:526-36. Available from: https://www.crstonline.com/text.asp?2020/3/3/526/295543




  Introduction Top


Radiotherapy forms an integral component of the multidisciplinary disease management in modern oncology. Skin reactions, also known as radiation dermatitis (RD), are the most common toxicity seen in patients undergoing radiotherapy and can be a limiting factor in the patients' compliance to therapy.[1] Irradiation of the epidermis results in an intricate pattern of cellular injuries that damage the epithelial as well as the endothelial cells followed by inflammatory cell recruitment. It has acute effects such as erythema and desquamation or late consequences, such as fibrosis, telangiectasia, and skin atrophy.[2],[3] It is a deterministic, dose-dependent effect of radiation, which typically presents within 2–3 weeks of starting radiotherapy.[4] The onset varies depending on various patient- and treatment-related factors.[5],[6] RD may also manifest as radiation recall phenomenon (RRP), which is an acute inflammatory reaction in the irradiated tissues after the administration of various pharmacologic compounds. It is an idiopathic reaction seen in around 6% of the patients, but the pathophysiology is not well established.[7] In this article, we aim to cover the various aspects of RD, with an emphasis on Indian patients.


  Materials and Methods Top


The current article is a narrative review of the various articles focusing on the diverse spectrum of RD published in the English language from 1975 to July 2020. The primary search for the articles was carried out via Google Scholar, PubMed, and the MEDLINE databases with keywords such as “radiation dermatitis,” “radiation-induced skin toxicity,” “radiation recall phenomena,” “radiation erythema,” and “radionecrosis.” Only full-text articles were considered while studies for which only an abstract was available were excluded. Studies reporting on radiation-induced skin cancer and those involving other causes of dermatitis were also excluded. The references cited in the potentially eligible studies were subsequently hand searched to identify additional studies. A search strategy was developed, and a PRISMA flowchart was used in the study selection process [Figure 1].
Figure 1: PRISMA flow diagram

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  Discussion Top


Radiation dermatitis-a historical perspective

Soon after the discovery of X-rays in the early 1900s, the effect of X-rays on the skin had been realized as one of the crucial dose-limiting toxicities for delivering radical doses of radiation. The initial radiobiological discoveries led to the understanding that if radiation could be delivered in a fractionated manner, then the acute and late effects of radiation on the skin and other normal tissues of the body could be minimized.[8],[9] Historically, physicians using radiation for therapeutic purposes used the skin on the forearm to calibrate the level of exposure, labeled as “tissue erythema dose.”[10] Earlier, radiation treatment utilized orthovoltage X-rays, thus delivering the maximum radiation dose to the skin and superficial tissues, leading to significant skin reactions. In comparison, the cobalt-60 and modern linear accelerator, which produce X-ray beams of ≥4 MV, have the advantage of the “skin-sparing” phenomenon and therefore can reduce the incidence and severity of RD.[11] Despite these historic developments in technology and a better understanding of the radiobiological effects of radiation on the skin, RD is still probably the most undesirable, yet unavoidable consequence of radiotherapy.

Types of radiation dermatitis

Acute radiation dermatitis

Acute reactions occur within a few days from the start of radiotherapy. Initially, a transient early erythema is seen. This is believed to be due to the release of histamine-like substances which cause dermal edema and skin erythema from the increased permeability and dilatation of capillaries.[12] The main erythematous reaction appears two weeks after the start of radiation and reflects the varying severity of the loss of epidermal basal cells. It has been shown that fields treated with 2 Gy daily fractionation do not show changes in the basal cell density until a total dose of 20–25 Gy is delivered.[13] Dry desquamation is clinically characterized by scaling and pruritus and usually occurs 3–4 weeks after the start of radiation. Moist desquamation occurs when the basal stem cells are eradicated, resulting in serous discharge and exposure of the underlying dermis. Moist desquamation may occur after four weeks of radiotherapy.[14]

Chronic radiation dermatitis

This may develop from months to years after treatment. It is usually a permanent and progressive change in the irradiated skin, which affects the patients' quality of life.[15] It usually occurs due to the imbalance between the proinflammatory and profibrotic cytokines, resulting in skin atrophy, hyperpigmentation, hypopigmentation, skin induration, ulceration, telangiectasia, alopecia, chronic wounds, ulcers, necrosis, etc., Chronic RD is diagnosed clinically with a detailed history of previous irradiation, local examination, and occasionally, a skin biopsy.

Radiation recall phenomena

It is an acute inflammatory reaction confined to the area previously exposed to radiation that occurs after the use of a chemotherapeutic agent or other medication. Clinically, radiation recall manifests in a similar manner as acute radiation dermatitis (ARD) with erythema, rash, dry desquamation, pruritus, swelling, and ulcerations. It has been reported to occur in up to 6% of the patients undergoing radiotherapy, but these reactions are drug specific and can occur weeks to months after the initial radiotherapy and the subsequent chemotherapy.[8] However, majority of the recall reactions have occurred when the drug was given within two months from radiation.[16] Radiation recall is most frequently associated with traditional chemotherapeutic agents, including anthracyclines, taxanes, and antimetabolites,[17],[18],[19] but reactions have been reported with inhibitors of the epidermal growth factor receptor (EGFR) and BRAF[20] and other non-chemotherapeutic agents.

Radiation-induced fibrosis

Radiation-induced fibrosis of the skin and subcutaneous tissues may develop at any treatment site; however, fibrosis most commonly occurs in cancers of the head-and-neck, breasts, etc., which receive multimodality treatments, such as combined surgery and radiotherapy. When the skin and the subcutaneous tissue develop fibrosis, there can be a limited range of motion, contractures, and pain.[15] These patients may experience pain, skin retraction and induration, restricted arm and neck movement, lymphedema, and skin necrosis and ulcerations.[21] Radiation boost dosing is an added risk factor for the development of fibrosis. Fibrosis in the skin and the subcutaneous tissue is usually diagnosed by clinical examination and is limited to the region treated with radiotherapy. If tumor recurrence is suspected, magnetic resonance imaging may be performed to differentiate between fibrosis and recurrence; however, a biopsy should be obtained for confirmation.[22]

Pathophysiology of radiation dermatitis

RD occurs due to the effect of radiation on the basal epithelial layer of the skin encompassing the microvasculature in the epidermis and the dermis.[23] This leads to the depletion of epithelial cells along with an inflammatory and avascular response with extracapillary cell injury and capillary dilatation.[24] An acute effect such as hyperpigmentation is caused by the migration of melanocytes to the superficial layer, and erythema takes place as a consequence of capillary dilatation in the dermis. Epilation results from damage to the epithelial lining of the hair follicles. Dry desquamation is shedding of the damaged epidermal cells followed by moist desquamation caused by subdermal lymphatic exposure. RD is a dose deterministic effect, and its incidence and severity vary based on the factors such as dose, technique, field size, and combination treatment.[25] Skin doses are higher with electron therapy than with photon therapy. Considering the dose threshold for acute effects, epilation occurs at an approximate dose of 20 Gy, and hyperpigmentation and dry desquamation occur after a dose of 45 Gy. Moist desquamation occurs at a dose of 50–60 Gy, and radiation doses above 60 Gy lead to ulcers and necrosis. Chronic effects such as telangiectasia result from the excessive loss of microvascular endothelium, causing capillary loops to contract and fuse into dilated channels beneath an atrophied epidermis. Radiation fibrosis occurs when the skin and the subcutaneous tissue develop fibrosis, and there can a limitation in the range of motion, contractures, and pain associated with it. The pathophysiology of radiation recall dermatitis, on the other hand, is idiopathic and not well established. Epithelial stem cell inadequacy, hypersensitivity, and radiosensitization by drugs have been suggested as the possible causes of RRPs.

Grading of radiation dermatitis

The quantification of dermatitis has been tried with many scales, and the requirement for a holistic, valid, and reliable tool has been stressed upon from time to time. A variety of systems are used for the grading of RD.[26],[27] [Table 1][26],[27],[28] elaborates on the grading of ARD as per the different scoring systems commonly used in oncology practice.
Table 1: Acute radiation dermatitis scoring systems

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Incidence of radiation dermatitis in India

India is a developing nation. Most of the patients in India are diagnosed with cancer at an older age and advanced stage of the disease.[29] There are various aspects pertaining to the incidence and presentation of radiation toxicity, in which the Indian population is different from the rest of the world.[30] These toxicities may affect the usefulness of therapy, quality of life, therapy compliance, and treatment-related morbidity. The following few paragraphs are focused on the variation in radiation-induced dermatitis in the Indian population and the possible reasons for it.

Patient-related factors

The Indian skin

The skin of Indian patients differs from that of the Western population in terms of sun exposure, melanin production, sebum content, and transepidermal water loss, leading to different moisture levels.[31] Moreover, the weather adds to the effect of moisture in various parts of the country. A study by Saini etal.[30] estimating the pattern of acute radiation-induced skin reactions among patients visiting the dermatology outpatient clinic at a tertiary care center in Western India reported that the incidence of grade 1 skin erythema was only 17%; this is significantly lower than the incidence of 80% reported in the studies from the West. The authors concluded that the differences in the incidence may be due to the wheatish skin color, as a result of which the early skin changes may go unnoticed. Moreover, the difference can also be attributed to the attitude of the patient and the treating physician whereby minimal erythema may not be appreciated and ignored.

Older patients

Various hospital-based cancer registries have stated that one-third of their patients with cancer belong to the geriatric age group.[32] Older adults with cancer are a distinctive set of patients, who bring a unique set of management complexities for radiation oncologists. Data generated from various clinical trials conducted on the younger population cannot be applied directly to the older population, given the numerous age-related physiological and pathological changes, leading to a decline in the functional organ reserve of the skin. This makes them more prone to the toxicities of radiotherapy than is reported in the literature. It is brought on by cell aging, epidermis thickening, collagen loss, and a decrease in capillary networking. The recovery of the skin and the subcutaneous tissue injury might be additionally delayed because of nutritional deficiencies, multiple comorbidities, preexisting skin disorders, and allergic reactions.

Personal habits

Smoking and alcohol consumption are well-known risk factors for cancer. A large proportion of the Indian patients with cancer has a history of smoking or alcohol consumption or both.[33] This is also one of the reasons for the high prevalence of head-and-neck cancers in India. In smokers, several mechanisms such as reduced oxygenation and elevated carboxyhemoglobin interrupt the post-irradiation recovery of the skin. Nicotine reduces the blood flow and makes the skin dry and discolored. It may also aggravate ARD as well as chronic RD, owing to ischemic injury and premature cell loss.[34] Smoking and alcohol consumption also deplete many essential minerals and vitamins, such as vitamin C, which act as antioxidants and reduce and repair the skin damage.

Socioeconomic status

Being a developing nation, most of the patients with cancer in India have limited access to healthcare facilities and have to face a lot of difficulties to undergo treatment. Radiotherapy is a long process and is usually administered over 5–6 weeks. Most patients and their attendants come from distant places with limited resources. Some patients have to struggle to obtain hygienically prepared food and sanitized accommodation. The process of skin healing might be interrupted as a result of poor sanitation and poor nutrition. Adequate nutrition and hydration are key to the successful completion of external beam radiotherapy without treatment breaks and with acceptable toxicities.

Medical comorbidities

Various medical comorbidities impair skin repair and wound healing. In addition, they expose the individual to a greater risk of secondary infections and inflammation. Some of these include diabetes, diabetic neuropathy, hypertension, peripheral vascular diseases, chronic obstructive pulmonary disease, and autoimmune diseases.

Genetic factors

Various genetic factors have been identified that directly or indirectly affect the sensitivity of the tissue to radiotherapy, including both clinical response and toxicity. Radiation kills cancer cells by inducing DNA damage caused by single-strand breaks, double-strand breaks, or DNA crosslinks. Multiple interconnected signaling networks respond to radiation damage that can lead to cell death, cell senescence, genomic instability, mutations, and inflammatory response. Some of the key genes involved in the processes are ATM, MRE11, RAD, AKT, XRCC, CDK2, etc.[35] Various genetic syndromes have been identified that predispose individuals to an increased risk of radiation toxicity; a few of these syndromes are xeroderma pigmentosum, Bloom syndrome, and ataxia telangiectasia.[36]

Skin and connective tissue disorders

Certain skin conditions such as eczema, psoriasis, and acne predispose patients to an increased risk of ARD and chronic RD because of the associated poor hygiene and repeated skin trauma.[37] Several cases have been reported in which there was an association between a higher incidence of late radiation skin toxicity and connective tissue disorders, such as systemic lupus erythematosus, scleroderma, and rheumatoid arthritis.[15] A review of eight observational studies with connective tissue disorders treated with radiotherapy has shown that there was a statistically significant association with late radiation-induced complications in normal tissues (fibrosis, osteonecrosis, and bone fractures).[38]

Treatment-related factors

Type of radiation and energy

Photons and electron beams have different physical properties contributing to different skin doses. Photons tend to have a skin-sparing effect; however, electrons deposit maximum energy close to the surface. Furthermore, as the photon energy increases, the surface dose decreases; contrastingly, for electrons, as the energy increases, the surface dose also increases.[39]

Treatment technique

The treatment technique also affects the proportion of patients manifesting RD. Two-dimensional radiotherapy with larger fields and low-energy radiation has a higher risk of RD than the highly conformal, intensity-modulated radiotherapy.[40] A larger target reduces the dose homogeneity and may lead to the generation of a specific hotspot. Studies have shown the dosimetric correlation between hotspot generation and severe ARD.

Beam-modifying devices

Various beam-modifying devices such as wedges and bolus or field-in-field techniques are used to achieve the desired coverage in external beam radiotherapy. Tissue equivalent bolus is used in head-and-neck and breast cancers to increase the surface dose. Wedges are used for tangential beams in breast radiotherapy to reduce hotspots and improve the coverage. For radiotherapy planning at an irregular surface, compensators are used to get a homogenous dose distribution and reduce Dmax and doses to the skin and other organs at risk.

Types of machine

One of the reasons for the increased risk of RD in the Indian patients is that conventional radiotherapy is still used in some centers because of limited resources. The Atomic Energy Regulatory Board reported in early 2014 that there were 362 radiotherapy centers, equipped with 308 medical linear accelerators, 238 telecobalt units, 4 cyber knife units, 3 tomotherapy units, 8 gamma knife units, and 1 super-gamma unit. Thus, a significant proportion of the Indian population, especially in the remote areas, is still treated with cobalt therapy and do not have access to the modern, skin-sparing, highly conformal radiation techniques.

Location of treatment field

The severity of radiation-induced skin reactions may vary depending on the location of the treatment field. For instance, sites with loose skin or skin folds such as the neck, axilla, and groin have a greater risk of RD.

Volume of irradiated tissue

Most patients in India present in the advanced stages of the disease and have a greater disease burden compared to their Western counterparts.[41] Hence, radiation treatment involves larger fields with a greater volume of tissue irradiated which may result in an increased incidence of skin toxicity. In addition, as the field size increases, the surface dose increases to some extent with low-energy radiation. The impact of volume of tissue on the likelihood of dermatitis can also be appreciated by the fact that RD is more common in carcinomas of the nasopharynx than in those of the hypopharynx and larynx, because of larger fields extending from the base of the skull to the lower neck.

Time dose and fractionation

Archambeau etal.[39] noted a strong correlation between the radiation doses and the grade of dermatitis. Doses of radiation higher than 50–60 Gy may lead to moist desquamation, whereas radiation doses above 60 Gy lead to radionecrosis. Altered fractionation regimens such as hyperfractionation and concomitant boost have a greater risk of ARD. On the other hand, hypofractionated regimens have been associated with lesser acute skin toxicity.[42].

Additional treatment

Most of the patients in India present with cancer in the locally advanced stage. The standard approach for stage III/IV cancers in most of the sites involves multimodality treatment including surgery, chemotherapy, radiotherapy, and immunotherapy where indicated.[43]

Concurrent chemotherapy

Several chemotherapeutic agents may escalate the risk of RD. Doxorubicin, 5-fluorouracil, bleomycin, cisplatin, etc., are some chemotherapeutic agents known to cause skin toxicity.[44] The outcomes of a randomized clinical trial evaluating sequential versus concurrent chemotherapy in head-and-neck and breast cancers showed a substantially greater radiation-induced fibrosis in the concurrent setting.[45]

Concurrent targeted therapy

Targeted therapy is a novel strategy used in various malignancies in the concurrent and adjuvant settings. Studies using targeted therapy with radiation show better tolerance and fewer side effects compared to concurrent chemoradiotherapy.[46] However, these targeted agents are associated with a skin-related complication in the form of rashes commonly seen with EGFR inhibitors such as cetuximab.[47],[48]

Incidence of radiation dermatitis and its impact on various cancer sites

The need for evaluating the impact of RD on the patients' quality of life has been recently recognized. The overall incidence of grade 1–2 acute erythematous reactions is 80%–90%, while moist desquamation is seen in around 10%–15% of the patients undergoing radiation at radical doses.[30] The RD incidence varies greatly through various cancer sites depending upon the target, doses, and technique.

Head-and-neck cancer

Head-and-neck cancer-specific studies have reported grade 3 skin reactions in 20%–25% of the patients.[2] The incidence is higher with an altered fractionation schedule and concurrent chemotherapy or immunotherapy.[15] In the Radiation Therapy Oncology Group 9003, the incidence of grade ≥3 RD was observed to be greater with hypofractionation (11%) and accelerated fractionation with concomitant boost (11%) in contrast to conventional fractionation (7%).[49]

Breast cancer

RD has been extensively addressed in patients with breast cancer, because of the important role it plays in women's appearance and self-confidence.[50],[51],[52],[53] There are various factors contributing to the increased risk of RD in patients with breast cancer. They have been divided into patient-specific and treatment-specific factors. Women with higher body mass index, larger breasts, tight clothing, smoking history, and lack of personal care are at a greater risk for RD.[28] Treatment-related factors include the type of beams, technique, energy, dose fractionation, field size, photon versus electron treatment, etc. Pignol etal.[54] randomized patients with breast cancer into two arms, namely intensity-modulated radiation therapy (IMRT) and tangential with wedges arm, thereby demonstrating that the occurrence of acute reactions in the IMRT group was as low as 17%. Various studies have also shown that the incidence of ARD is less in the hypofractionated schedule than in the conventional regimen;[55] however, some studies have also reported increased grade 1–2 late fibrosis in patients who undergo breast conservation surgery and hypofractionated radiotherapy.[56]

Gynecological cancers

Radiotherapy is an integral constituent of the treatment of gynecological malignancies. The majority of cancers of the cervix, endometrium, vagina, and vulva are treated with radical or adjuvant radiation to a dose 40–60 Gy by external beam radiation followed by brachytherapy. Grade 2 skin reactions are generally observed with 40 Gy external radiation, and grade 3 reactions develop when the skin receives doses beyond 50–60 Gy.[57] Grade 1–2 skin reactions are commonly noticed in gynecologic radiotherapy, with an incidence of 10%–50% reported in randomized clinical trials of endometrial and cervical cancers.[58],[59] The incidence is higher in vaginal and vulvar cancers and ranges from 40% to 100%. Grade 3–4 skin reactions are less common in cervical and endometrial cancers (range, 1%–5%); however, patients with vulvar cancer have a substantially greater risk of grade 3–4 skin reactions (range, 24%–53%).[60],[61] A smaller target and the use of IMRT decrease the risk of vulvar skin toxicity; one series reported no grade 3 groin skin desquamation in patients with vulvar cancer treated with IMRT.[62]

Skin cancers

Radiation therapy is an integral component of the management of skin cancers, both in the definitive and the adjuvant settings. It has several advantages over surgery, such as comparable local control with organ preservation and minimal cosmetic and functional impairment. The common acute and late toxicities seen during radiotherapy for skin tumors include alopecia, desquamation, hyperpigmentation or hypopigmentation, erythema, and pruritus.[63] RD is one of the most common toxicities seen during radiotherapy for skin tumors; however, here, the scenario is different. RD is considered one of the end points of the treatment for skin cancers; this is unlike mucosal cancers where it is considered toxicity. In skin cancers, the non-skin-sparing techniques of radiation are used to maximize the dose to the skin and effectively treat the tumor. Grade 2–3 RD is commonly seen while treating skin cancers; however, higher grades of toxicity should be avoided. There are many reasons for the higher incidence of skin toxicities in such cases.[64] Radiotherapy for skin cancer treatment aims to cover the involved skin with a therapeutic high dose of radiation which results from the use of brachytherapy, bolus, electrons, low-energy photons, oblique fields, etc. This increases the dose to the uninvolved adjacent skin. However, unlike mucosal cancers, RD is an expected and acceptable side effect of radiation. This is because first, in-field RD is a surrogate marker for accurate dose distribution, and second, at times, RD can be confused with tumor necrosis. This has led to the ambiguous reporting of grades of RD in skin cancers. Kim etal.[63] reported no grade 3 skin reactions in 19 head-and-neck skin cancers treated with adjuvant or definitive radiation, and Smith et al. in a retrospective review of 15 patients treated with concurrent chemoradiotherapy reported a 13% incidence of grade 3 skin reactions, which is less than expected because bolus was used in 75% of the patients.[64]

Management

Overall, the preventive methods for ARD include keeping the area clean, dry, and friction-free; wearing loose-fitting clothes with natural fibers; avoiding harsh soaps and cosmetics; preventing heat or direct sunlight; and avoiding smoking.[65],[66] [Table 2] lists some of the preventive measures used for RD. An array of substances has been utilized for RD prevention and treatment.[67],[68] Out of these, several substances have been shown to have a favorable effect. Many topical agents such as sucralfate cream, petroleum jellies, calendula, aqueous cream, and aloe vera have been explored for decreasing the dehydrating consequences of RD.[69] [Table 3] gives an insight into the grade-wise management of RD. A detailed description of different agents used for the management of RD is given below.
Table 2: General skin care precautions in radiation fields during radiotherapy treatment

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Table 3: Grade-wise management of radiation dermatitis

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Gentian violet

Gentian violet is an antiseptic dye that was commonly used in the past for the management of RD. It has few advantages such as low cost, combined antifungal and antibacterial actions, astringent effects, and easy application. The drawbacks include skin irritation, staining of clothes, and masking of the wound. Despite its effective role, its utility has declined over the past few years because of the disturbing reports of its carcinogenic potential in animal model studies.[70] In addition, the tissue irritant effect of gentian violet raises the question of whether it should be used for radiation-induced moist wounds.

Various studies[71],[72] have compared conventionally used 1% gentian violet with hydrogel dressing for the treatment of radiation-induced moist wounds. It was observed that wound healing was better with the latter; however, it comes at an increased cost. Although gentian violet is still a common alternative for RD, its continued use is difficult to justify because of its proven carcinogenic potential.[73],[74]

Aloe vera

Aloe vera is a plant of the genus Aloe. It belongs to the Liliaceae family and is generally grown for medicinal and agricultural use.[75],[76] Aloe vera has 75 likely lively constituents, including amino acids, salicylic acids, saponins, lignin, sugars, minerals, enzymes, and vitamins.[77] It acts as a hydrating agent, thereby attenuating the dryness due to radiation. Moreover, aloe vera acts as an anti-infective agent. It has been used in the treatment of eczema, skin burns, frostbite, and other dermatologic diseases for many years.[78] It has also shown some benefits in radiation-induced dermatitis in various studies. Although aloe vera has been widely utilized by radiation oncologists for RD, its benefit has been questioned many times. Merchant etal.[80] demonstrated that an anionic polar phospholipid cream is much more effective than an aloe vera-based gel intended for the treatment of RD. In addition, Ahmadloo etal.[81] in their study showed that aloe vera had no positive influence on the occurrence or severity of RD. Contrary to this, Haddad etal.[77] demonstrated a beneficial effect of aloe vera lotion on reducing the incidence of radiation-induced dermatitis; the benefit was a lot more in individuals treated with larger therapy fields and increased doses of radiation. Moreover, it has been found that the prophylactic use of an aloe vera-based lotion works well in reducing the darkness of the skin for head-and-neck cancers.[81],[82],[83] Thus, the usage of aloe vera remains a subjective consideration rather than a unanimous decision.

Steroids

Many studies have suggested the benefits of steroid ointments in RD.[84],[85],[86] Meghrajani etal.[87] confirmed that the prophylactic use of topical corticosteroids in patients undergoing radiotherapy lowers the incidence of ARD, particularly wet desquamation, in contrast to various other solutions. Ulff etal.[88] suggested that prophylactic use of steroids is effective for the prevention as well as the treatment of ARD in patients with breast cancer treated with adjuvant radiotherapy. A systematic review and a meta-analysis by Haruna etal.[89] showed that topical corticosteroids could be effective at minimizing the incidence of wet desquamation and also improve the quality of life of the patients with cancer. The favorable effect of topical steroids in preventing severe RD has been associated with their anti-inflammatory action, whereby steroids cause suppression of the inflammatory cytokines, such as interleukin 6 (IL-6), IL-1B, transforming growth factor beta 1, and tumor necrosis factor alpha produced during radiotherapy.

Amniotic membrane

The amniotic membrane comprises extracellular matrix, collagen, biologically energetic cells, and regenerative molecules. The extracellular matrix provides a framework and contains large amounts of special proteins, such as laminins, fibronectin, and proteoglycans, which along with collagen provide structural strength to the membrane. The biologically energetic cells include stem cells, whose function it is to regenerate the latest cellular substances to the coating of the membrane. Fibroblasts help to strengthen the tissue, and the epithelial cells aid in the healing process mediated by the receptors present on the cellular surface. Regenerative molecules essential for healing and growth are also present in the amniotic membrane. These primarily include fibroblast growth factors, platelet-derived growth factors, and metalloproteinase. In a study by Lobo Gajiwala and Sharma,[90] the cryopreserved human amniotic membrane has been successfully used in the management of moist desquamations. It can conform to the area of moist desquamation and provide an effective barrier to trauma and microbial penetration. It also helps in retaining a physiologically moist microenvironment which promotes healing. Amniotic membrane promotes epithelialization and hence decreases the need for multiple dressings.[91] Its use is limited due to the lack of availability, and it is contraindicated in the presence of infection.

Hydrocolloid occlusive dressing

This consists of a hydrocolloid occlusive material such as gelatin or cellulose embedded in a self-adhesive, absorbent, occlusive dressing impermeable to gas, vapor, water, and bacteria, thus creating a favorable environment for wound healing.[73],[92] A noncomparative study was performed on 20 individuals with a hydrocolloid occlusive dressing (Duoderm) that aimed at evaluating its efficacy in wound healing.[93] The dressing was evaluated based on comfort, bacterial growth, wound temperature, safety, and healing time. Information was collected using patient evaluations, temperature probes, bacterial cultures, and photographs. The average healing period was 12 days, and the outcomes of this analysis suggest that hydrocolloid occlusive dressing could be a good alternative for RD wound healing.

Other barrier dressings

Studies have shown that prophylactic safety of high-risk anatomical locations such as the axilla and the inframammary fold of the breast could stop or at the very least reduce the seriousness of radiation-induced moist desquamation, thereby improving the quality of life in addition to reducing treatment breaks in patients with breast cancer.[94] Recently, Schmeel etal.[95] suggested a prophylactic application of a hydrofilm in adjuvant radiotherapy for patients with breast cancer to reduce and even prevent RD. Some recent studies have boasted about the use of soft silicone dressings to protect the sublethally damaged skin from frictional damage for doses of less than 40 Gy.[96] However, more robust studies are required for bringing these into practice.

Hyperbaric oxygen therapies

Hyperbaric oxygen is described as 100% oxygen at a pressure which is twice or three times the atmospheric pressure at sea level. It leads to an arterial oxygen tension of 2000 mmHg and tissue oxygen tension of nearly 400 mmHg. Such doses of oxygen have numerous beneficial biochemical, cellular, and physiologic consequences.[97],[98] Hyperbaric oxygen therapy (HBOT) has been suggested as a remedy for late radiation injuries, such as radiation fibrosis.[99] It is specifically beneficial for osteoradionecrosis and complications of pelvis irradiation such as radiation cystitis and proctitis.[99] In a systematic review by Eskes et al.,[100] HBOT was found to be an effective solution for wounds that are difficult to heal. A Cochrane review based on 11 randomized trials also found HBOT to have improved healing outcomes in late radiation-induced injury to irradiated tissues of the head, neck, and pelvis.[101]

Future research

Researchers are investigating newer agents for the effective treatment of RD. One among them is topical keratin for patients with breast cancer to improve skin hydration and appearance postradiation. This is currently under evaluation in a Phase I trial at the National Cancer Institute (NCT03374995), and the results are awaited. Topical LUT014 is another agent being investigated for treating acneiform rashes in patients with metastatic colorectal cancer treated with EGFR inhibitors (NCT03876106); the results are pending. Hence, future research in the field of oncology, dermatology, and cosmetology will help discover newer agents for the effective management of both ARD and chronic RD.


  Conclusion Top


RD is a commonly encountered adverse event of definitive radiation therapy. The severity of RD is influenced by multiple patient- and treatment-related factors. Although severe RD is rare in the current practice, some occasions necessitate active intervention by a multidisciplinary group to manage both late and acute radiotherapy effects over the skin and the subcutaneous nerves. Management policies vary as per the institutional guidelines and personal preferences and are mostly based on the individual experiences and reviews. Aloe vera, steroid creams, and barrier dressings such as amniotic membranes help alleviate the symptoms of ARD and might be utilized effectively and safely in the Indian patients. The objectives of the treatment are mostly to enhance patient comfort, reduce the risk of additional damage, and improve wound healing. Rigorous, well-designed scientific studies are essential as we move ahead to enhance the prevention and management of RD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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