Skin Toxicity in Palliative Radiation Therapy

Chapter 10

Skin Toxicity in Palliative Radiation Therapy L. Hertan Brigham and Women’s Hospital; Dana-Farber Cancer Institute, Boston, MA, United States

Chapter Outline Introduction Acute Skin Toxicities From Radiation Pathology and Timeline Grading of Toxicity Prevention Treatment Chronic Skin Toxicities From Radiation

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Pathology Grading Prevention Treatment Radiation Recall Dermatitis Conclusion References

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INTRODUCTION G

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Radiation-induced skin toxicity is a commonly reported toxicity of definitive radiation therapy, with almost half of patients reporting grade 2 or higher skin reactions [1]. Multiple factors, both radiation- and patientspecific, contribute to the likelihood of developing skin toxicity. Radiation-specific factors include total dose, dose per fraction, beam energy, size of field, anatomic location of the radiation, and concomitant systemic treatments. Patient-related factors, particularly age and comorbidities, also influence the likelihood of developing toxicity. Skin is composed of an outer epidermis above a layer of dermis (Fig. 10.1). The epidermis has two layers, an outer protective layer and an underlying basal layer. The dermis is composed of collagen and elastic fibers that helps to give sturdiness to skin. The blood supply for the epidermis is supplied by the underlying dermis [2]. Hair follicles, sebaceous glands, and sweat glands are contained within the dermis and hypodermis. Sebaceous glands are associated with hair follicles and secrete sebum, which acts to lubricate and waterproof the skin and hair [2].

Handbook of Supportive and Palliative Radiation Oncology. Copyright © 2017 Elsevier Inc. All rights reserved.

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Hair shaft

Epidermis Sebaceous gland Collagen fibers

Dermis

Hair follicle Subcutaneous layer

Artery Vein

Sweat gland

Adipose tissue

FIGURE 10.1 Skin anatomy.

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Epidermal cells, hair follicles, and sebaceous glands all contain rapidly dividing cells that are exquisitely sensitive to radiation. Radiation can cause both acute and late toxicity to the skin. Acute toxicity, often occurring around 2 weeks after the start of radiation, can manifest as dryness, itchiness, pain, hair loss, and desquamation. Late toxicity, occurring months to years after the completion of radiation, can present as fibrosis, telangiectasias, changes in skin pigmentation, and wound healing issues. With most palliative doses of radiation (ranging from 8 Gy 3 1 to 3 Gy 3 10) the rates of acute and late skin toxicity are low. RTOG 9714 randomized patients with uncomplicated bony metastases to either singlefraction (SF, 8 Gy 3 1) or multifraction (MF, 3 Gy 3 10) radiation. There was a very low rate of acute skin toxicity in both arms (4% in SF vs 12% in MF), with the majority being grade 1. The late toxicity was even less common (2% SF vs 1% MF), with again the majority being grade 1 [3]. In studies done on re-irradiation, the acute skin toxicity was slightly higher, although still very low (16% in SF vs 22% in MF) at 7 days after radiation [4].

ACUTE SKIN TOXICITIES FROM RADIATION G

Acute reactions to the skin from radiation include erythema, hyperpigmentation, dryness, pain, itchiness, hair loss, and desquamation. The severity of acute reactions can vary greatly between patients due to multiple factors including total radiation dose, dose per fraction, beam energy

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used, size of radiation field treated, concomitant systemic therapy, and anatomic location of the radiation. Additionally there are patient-related factors including age, connective tissue disorders, and comorbidities that are not fully understood but also play a role in determining the severity of the reaction.

Pathology and Timeline G

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The initial reaction to radiation is often erythema, although not always visible to the human eye, that can occur within a few hours and is caused by capillary dilatation and increased capillary permeability [5]. Ten to fourteen days after the start of radiation, sustained erythema, likely mediated by cytokines, becomes apparent (Fig. 10.2) [6]. With continued radiation, generally with doses of radiation above 40 Gy, one can see moist desquamation characterized by vascular dilatation, epidermal necrosis, fibrinous exudates, and pain (Fig. 10.3). Histologically, fibrin thrombi obstruct arterioles, extravasation of erythrocytes and leukocytes, as well as edema can be seen [5,6]. The peak skin reaction occurs between 1 and 2 weeks after the completion of radiation therapy with regeneration occurring between weeks 3 and 5 [6]. The majority of patients will have completely recovered from their acute toxicities by 3 months after treatment, although often much sooner. Hair follicles, sebaceous glands, and sweat glands are also affected by radiation and can lead to dry skin and hair loss. Although hair loss often doesn’t occur for a few weeks, generally the damage was done early in

FIGURE 10.2 Acute grade 2 dermatitis (erythema and dry desquamation).

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the radiation course [5]. New hair can take up to 1 year to regrow and in some situations the hair loss can be permanent.

Grading of Toxicity The two most widely used scales for grading acute adverse events due to cancer therapy are the National Cancer Institute’s Common Toxicity Criteria for Adverse Events (CTCAE) version 4 [7] and the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) grading system [8]. Both of these tools have specific criteria for acute radiation toxicity to the skin (Tables 10.1 and 10.2) and allow for consistent grading between practitioners.

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FIGURE 10.3 Acute grade 3 dermatitis (erythema, hyperpigmentation, and moist desquamation).

TABLE 10.1 CTCAE v. 4 Dermatitis Radiation Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation Grade

Description

1

Faint erythema or dry desquamation

2

Moderate to brisk erythema; patchy moist desquamation, mostly confined to skinfolds and creases; moderate edema

3

Moist desquamation in areas other than skinfolds and creases; bleeding induced by minor trauma or abrasion

4

Life-threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site; skin graft indicated

5

Death

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TABLE 10.2 RTOG/EORTC Skin (Acute) Grade

Description

0

No change over baseline

1

Follicular, faint, or dull erythema/epilation/dry desquamation

2

Tender or bright erythema, patchy moist desquamation/moderate edema

3

Confluent, moist desquamation other than skinfolds, pitting edema

4

Ulceration, hemorrhage, necrosis

Prevention G

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There is wide practice variation between institutions and even practitioners regarding the use of agents for prevention of radiation dermatitis. Most fall into one of two schools of thought regarding prophylaxis. Some believe in having patients use moisturizer up front, thinking that it can help prevent dry skin and delay the onset of acute toxicity. Others believe there is no benefit to initiation of moisturizer before the development of symptoms and cite concerns over confusion that could occur if the patient has a reaction to the lotion. Although there are many publications regarding the use of different products to prevent the development of radiation dermatitis, mostly within the breast and head and neck literature, the data can be contradictory and confusing. However on some topics, such as the use of routine washing and the use of antiperspirant, the literature is clear. Hygiene: Three trials evaluated and found no detriment to the use of routine washing with soap or shampoo and water during radiation therapy [9 11]. All three recommended continued normal hygiene practices during the course of radiation. Antiperspirant: Some practitioners believe the use of antiperspirant during radiotherapy could lead to a bolus effect on the skin, thereby worsening radiation toxicity. At least four randomized controlled trials have shown no difference in toxicity with the use of antiperspirant, even in preparations containing aluminum, compared to gentle washing alone [12 15]. Topical Steroids: Multiple randomized controlled trials have been done examining the role of topical steroids to prevent or ameliorate acute radiation dermatitis. Although the trials are heterogeneous, the outcomes have consistently shown a benefit to use of topical steroids [16 20]. Topical Trolamine: Trolamine, an oil-in-water emulsion with nonsteroidal antiinflammatory properties, has been relatively widely studied. The results

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of the published data is mixed with some trials showing a benefit to the use [21,22] and others showing no benefit [23 26]. Topical Aloe vera: As Aloe vera is a commonly used treatment for a variety of skin conditions, from dry skin to sunburns, it is a natural extension to believe it may be helpful to prevent radiation dermatitis. Results from one trial suggested a benefit to the use of Aloe vera gel in delaying the onset [27], however, multiple trials as well as a systemic literature review did not find evidence to suggest a benefit [28 30]. Topical Hyaluronic Acid: Similarly the results from studies evaluating hyaluronic acid also show mixed results with some studies showing a benefit [31] and others failing to do so [32]. Topical Sucralfate: Three different trials evaluating the use of topical sucralfate have shown three different outcomes: a benefit [33], no difference [34], and possibly a detriment [35]. Topical Petroleum Ointments: Aquaphor, a petroleum-based ointment, is a very commonly recommended topical treatment during radiation therapy. The published data on Aquaphor for prevention is mostly as a control arm and thus is difficult to determine effectiveness. However, there is some data that suggests there is no benefit to petroleum-based treatment compared to control [16,26]. Additionally, the study by Gosselin et al., also looked at RadiaCare gel and again did not find a benefit over control [26]. Topical Calendula: One randomized control trial has evaluated the use of calendula (vs trolamine) and found an improvement in rate of acute dermatitis and patient satisfaction with calendula [23]. Oral Agents: Minimal data has been published on the use of oral agents for prevention of radiation dermatitis. Two randomized, although not blinded, control trials comparing oral proteolytic enzymes (a combination of papain, trypsin, and chymotrypsin) to no treatment showed improvement in acute radiation side effects, including dermatitis [36,37]. Preclinical data and a single small double blind randomized control trial have suggested that oral zinc supplementation may decrease acute radiation dermatitis [38,39]. Studies on other oral agents, such as oral sucralfate and oral pentoxifylline, have not shown benefit to the development or severity of acute radiation dermatitis [40,41]. The Multinational Association for Supportive Care in Cancer (MASCC) published guidelines in 2013 after a thorough review of the literature. x A strong recommendation was made for washing of the skin and hair with water, either with or without a mild soap or shampoo, as well as allowing patients to use antiperspirants. Additionally, a strong recommendation for use of topical steroids to prevent radiation dermatitis was made [42]. x The MASCC recommended against the prophylactic use of Aloe vera or trolamine. For multiple other agents, sucralfate, hyaluronic acid, silver

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dressing, silver sulfadiazine cream, and others they did not make a recommendation for or against use due to insufficient evidence [42]. Other Skin Care Tips: Other tips on skin care given to patients undergoing radiation therapy include staying out of the sun, wearing loose clothing, avoiding extreme heat or cold (i.e., heating pads or ice packs) directly onto the skin being treated, and avoiding products with alcohol or scents. Additionally, for those patients who are getting treated to the face or neck, it is advisable to use an electric razor rather than a manual one. For patients getting treated to the head, gentle brushing of hair and avoiding use of styling tools (i.e., curling irons, straightening irons) is recommended.

Treatment G

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Despite a thorough literature review there is a paucity of well designed, blinded, randomized trials evaluating treatment options. The intervention with the most data is on the use of dressings, however, the outcomes of these studies are mixed, with some showing longer healing times with use of moist dressings [43,44], while others showed faster healing times [45]. Additionally, there are a few publications on the use of topical steroids, none of which showed a benefit compared to their control group [46,47]. Sucralfate has also been studied and has found to have no benefit when mixed with sorbolene cream versus sorbolene cream alone [48]. In lieu of randomized evidence, many institutions and practitioners have developed treatment recommendations for patients. x Once a patient develops erythema, hypopigmentation, or dry desquamation, a common recommendation is for use of an emollient-based cream, such as Aquaphor, RadiaCare, or Biafine. x If the patient has pain or burning, a mixture of Aquaphor mixed with lidocaine jelly (1:1 formulation) can be prescribed. x Oral pain medication can also be used for severe skin reactions, although this is rarely, if ever, seen when treating a patient to palliative doses. x If a patient notes itchiness, a topical steroid cream can be recommended. Steroid creams can be layered underneath or alternated with an emollient-based cream. x If moist desquamation occurs, Domeboro soaks, Silvadene, or Xenaderm can be used. An example treatment regimen is offered in Fig. 10.4. Specific recommendations for patients undergoing treatment to the lower pelvis (i.e., gynecologic cancers): x A recently published review [49] on complications of pelvic radiation gives some suggestions regarding treatment of skin toxicity in this unique population.

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At start of radiation: -

Provide tips for prevention regarding hygiene, clothing, etc. To consider asking patient to start using an unscented gentle white lotion at least daily. To consider asking patient to use a topical steroid cream based on above data.

When dry desquamation develops: -

Recommend treatment with Aquaphor, 2–4 times daily

If itch develops: -

Add a topical steroid cream (i.e.,hydrocortisone) to patient’s skin care regimen. Can alternate with Aquaphor or layer Aquaphor over the top.

If burning/pain develops: -

Recommend Aquaphor with lidocaine: Aquaphor mixed 1:1 with lidocaine jelly

If moist desquamation develops: -

Continue Aquaphor (+– lidocaine) To consider Domeboro soaks

FIGURE 10.4 Example regimen for skin care during radiation therapy.

x Recommendations are made for prophylactic moisturizing, encouraging loose cotton clothing, and the use of a sitz bath with addition of sodium bicarbonate, Epsom salt, or Domeboro soaks. x Early identification and treatment for Candida is also recommended. x For patients who develop desquamation, nonadherent, silver clear nylon or hydrogel dressings can be applied [49]. x Additional recommendations may include the use of a peri bottle to assist with cleansing and instructions to pat rather than wipe after urination.

CHRONIC SKIN TOXICITIES FROM RADIATION G

Late toxicity from radiation can begin to appear anywhere from months to years after radiation therapy is completed. The late toxicity from radiation includes telangiectasias, fibrosis, hypo- or hyperpigmentation (Fig. 10.5), dryness, ulcers, and difficulty with wound healing. The likelihood and severity of developing a late radiation reaction is not completely understood but likely depends on multiple factors including total dose, dose per fraction, and patient-related factors.

Pathology G

Radiation-induced fibrosis is characterized by thickening and reduced compliance of the skin. Histologically, excessive collagen deposition,

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FIGURE 10.5 Late grade 1 dermatitis (hyperpigmentation).

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atrophy, and excess mesenchymal cells are present [50]. Severity of acute injury does not seem to play a role in development of fibrosis, although total dose, dose per fraction, and other patient-related factors, such as age, have been shown to have an association [51,52]. Telangiectasias (Fig. 10.6) are small dilated blood vessels close to the skin’s surface. After radiation they appear as a result of damage to the microvascular endothelial cells and basement membrane [5]. Research into factors that influence the likelihood of developing telangiectasias have found an association with total dose of radiation, presence of severe acute injury (i.e., moist desquamation), as well as patient-related factors, such as age, long-term smoking, and certain comorbidities (allergies and hypertension) [52,53]. Chronic dryness can be due to permanent damage to sebaceous and sweat glands.

Grading G

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Similar to acute toxicity, commonly used grading tools include the RTOG/EORTC tool [8] as well as the Late Effect on Normal Tissue (LENT)/Symptom Objective Measures, Management, Assessment (SOMA) [54]. The RTOG/EORTC grading tool has specific criteria for late skin toxicity (Table 10.3). The LENT/SOMA tool has a general grading system

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FIGURE 10.6 Late grade 2 dermatitis (telangiectasia).

TABLE 10.3 RTOG/EORTC Skin (Late) Grade

Description

0

None

1

Slight atrophy, pigmentation change, some hair loss

2

Patch atrophy, moderate telangiectasia, total hair loss

3

Marked atrophy, gross telangiectasia

4

Ulceration

5

Death

(Table 10.4) as well as a more complex grading system for late skin toxicity with multiple factors separately assessed within categories of subjective, objective, management, and analytic. Examples of criteria within each category include scaliness/roughness, objective fibrosis/scar (Table 10.5), management fibrosis/scar, and color photographs.

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TABLE 10.4 LENT/SOMA (General Grading System) General Grade

Description

0

None

1

The most minor symptoms that require no treatment

2

Moderate symptoms, requiring only conservative treatment

3

Severe symptoms, which have a significant negative impact on daily activities, and which require more aggressive treatment

4

Irreversible functional damage, necessitating major therapeutic intervention

TABLE 10.5 LENT/SOMA (Symptom Specific—Fibrosis/Scar) Objective—Fibrosis/Scar Grade

Description

0

None

1

Present/asymptomatic

2

Symptomatic

3

Secondary dysfunction

4

Total dysfunction

Prevention G

Little data has been published on the prevention of late toxicity from radiation. Early data suggests lower fibrosis scores at 18 months in patients who started pentoxifylline and vitamin E after the completion of radiation and continued for 6 months [55].

Treatment G

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Similarly, minimal data is available regarding treatment of late toxicity from radiation. Pulse dye laser has been shown to improve the appearance of telangiectasias from radiation [56]. The MASCC skin toxicity study group gave a weak recommendation for the use of the pulsed dye laser to improve cosmetic appearance [42].

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The use of vitamin E and pentoxifylline in the treatment of radiation fibrosis has mixed results. A few studies have shown an improvement in fibrosis following use of pentoxifylline and vitamin E [57 59], however, other studies have not shown a benefit [60]. One study compared pentoxifylline combined with vitamin E, pentoxifylline alone, vitamin E alone, or placebo and found a benefit only in the combination of the two drugs [59]. The MASCC Skin Toxicity Study Group notes insufficient evidence to make a recommendation either for or against the use of pentoxifylline for treatment of radiation-induced fibrosis [42].

RADIATION RECALL DERMATITIS G

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Radiation recall dermatitis is a poorly understood and uncommon phenomenon where a skin reaction similar to an acute radiation dermatitis develops in a previously irradiated area. The onset of this reaction is most often associated with administration of a medication, either intravenously or orally. The severity of the reaction can range from mild to severe and does not appear to correlate with the severity of either the acute radiation reaction or late radiation changes. A large number of systemic agents (Fig. 10.7) have been linked to radiation recall reactions [61 67]. The time from radiation therapy to

Actinomycin D

Edatrexate

Pemetrexed

Adriamycin

Etoposide

Simvastatin

Azithromycin

Erlotinib

Sorafenib

Bleomycin

Everolimus

Sunitinib

Capecitabine

5-Flurouracil

Sunlight

Cetuximab

Gemcitabine

Tamoxifen

Cisplatin

Hydroxyurea

Temsirolimus

Cyclophosphamide

Interferon alpha

Trimetrexate

Cytarabine

Levofloxacin

Vemurafenib

Dacarbazine

Melphalan

Vinblastine

Daunorubicin

Methotrexate

Vinorelbine

Docetaxel

Oxaliplatin

Doxorubicin

Paclitaxel

FIGURE 10.7 List of agents thought to be associated with radiation recall reactions.

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development of a radiation recall reaction varies widely from 7 days to 2 years, although some reports are up to 25 years postradiation. x In general, the shorter the time interval between the end of radiation therapy and the developing of a radiation recall dermatitis, the more severe the reaction [66,67]. x It has been suggested that anything shorter than 7 days should be attributable to an acute radiation reaction rather than a radiation recall reaction [67]. The time from drug exposure to the onset of dermatitis as well as the duration of the dermatitis varies greatly. Onset can occur immediately up to months after exposure [66,67]. The length of time the dermatitis persists also varies greatly from hours to weeks [66,67]. Although there are suggestions that treatment with oral or topical steroids, antihistamines, or nonsteroidal antiinflammatory drugs shortens the reaction, there is no conclusive data on this topic. Additionally, whether a patient can be safely rechallenged with the offending agent is also controversial, with conflicting reports in the literature [67].

CONCLUSION Radiation-induced skin reactions are common in definitive radiation but can also occur in palliative courses. Acute radiation toxicity, generally occurring during or shortly after treatment can range from mild (erythema, hyperpigmentation) to severe (moist desquamation). A wide variety of products exist to help prevent and treat acute radiation dermatitis, although further research is needed on efficacy of many of these products. Similarly, products to help prevent and treat late radiation toxicity, occurring months to years after radiation, also need further research.

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