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Skin toxicity during breast irradiation: pathophysiology and management.

Abstract: Radiotherapy is a critical component in the treatment of breast cancer, a disease that is estimated to have affected 203,500 US women in 2002. According to the data from some series, an estimated 90% of patients treated with radiotherapy for breast cancer will develop a degree of radiation-induced dermatitis. This review describes the indications and techniques of radiotherapy for breast cancer. The pathophysiology, clinical presentation, and contributing factors of radiation-related skin injury are discussed. A review of recent clinical research addressing skin toxicity is provided.

Key Words: breast cancer, breast radiotherapy, radiation-induced dermatitis, skin care

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Radiotherapy is a critical component in the treatment of breast cancer, a disease estimated to have affected 203,500 women in 2002. (1) Many women with early stage breast cancer are candidates for breast conservation therapy (BCT), which combines conservative surgery and radiotherapy. (2) In more advanced breast cancer requiring mastectomy, adjuvant radiotherapy has been shown to improve overall survival. (3,4)

Before the development of modern megavoltage x-ray capability, skin toxicity limited the doses that could be safely delivered to the breast. (5) The dose of megavoltage x-rays builds up at a depth below the skin. (6) This characteristic dose distribution spares the skin and allows tumoricidal doses to be delivered to cancers within the breast. Despite these advances, in some series, greater than 90% of patients treated with radiotherapy for breast cancer will develop a degree of radiation-induced dermatitis. (7) With so many patients at risk, it is important for the clinician to become familiar with the presentation and management of radiation-induced skin reactions.

Introduction to Radiotherapy for Breast Cancer

The goal of radiotherapy is to precisely target a tumor volume with megavoltage x-rays while limiting the volume of normal tissue exposed to radiation. The intracellular target for these x-rays is deoxyribonucleic acid, DNA. Damage to DNA can be sufficient to disrupt replication, resulting in cell death. Ionizing radiation also produces DNA damage that can be repaired, known as sublethal damage, and cells remain viable. The therapeutic ratio of radiotherapy is achieved by the greater capacity of normal tissue to repair radiation-induced sublethal DNA damage as compared with rapidly proliferating tumor cells. However, normal tissues that also rapidly proliferate, such as skin, gastrointestinal mucosa, and hematopoietic cells are also relatively radiosensitive. (8)

Breast irradiation following lumpectomy or chest wall irradiation following mastectomy is commonly delivered through medial and lateral tangential x-ray beams for 6 to 7 weeks of daily treatment (Fig. 1). The tangential beam arrangement minimizes the volume of normal lung and cardiac tissue that is irradiated.

The severity of skin reactions during and following breast irradiation is influenced by both treatment-related factors and patient-related factors. Treatment-related factors include the fraction size (the dose delivered with each treatment), the total dose delivered, the volume of tissue treated, the type of radiation, (8) and the addition of chemotherapy. (9) Patient-related factors include breast size, smoking, axillary lymphocele drainage before treatment (suggesting poor lymphatic drainage), age, and infection of surgical wound. (10) A patient's genomic constitution also influences their risk of normal tissue toxicity. Recent data suggests that carrying a single mutated copy of the DNA repair gene, ATM, can predispose patients to late tissue effects following breast radiotherapy. (11) ATM heterozygosity occurs in approximately 1% of the general population (12) and may be more common in breast cancer patients. (13)

[FIGURE 1 OMITTED]

Characteristic distributions of skin injury result from features of breast topology and beam arrangement that increase the skin's dose of radiation. The axilla and inframammary fold, commonly sites of the most severe skin injury, receive higher skin doses because these are sites where redundant skin produces a bolus effect and pulls the higher doses up to the skin surface. Thus, large-breasted women and obese patients are at increased risk of skin toxicity. (10) With the tangential beam arrangement used in breast radiotherapy, there are some regions of the breast, such as the axilla, in which the beam is incident to the skin at nearly a glance angle. At these angles, the skin-sparing effect of megavoltage x-rays is lost, and patients experience greater skin reactions. (14)

Pathophysiology and Sequence of Radiation-induced Skin Changes

The skin is composed of an outer layer, the epidermis, and an underlying connective tissue layer, the dermis. The epidermal layer is 30 to 300 um, and is derived from a basal layer of stem cells. These cells proliferate and migrate to the surface to be sloughed. This migration occurs over a period of approximately fourteen days. The dermal layer is 1 to 3 mm thick and is composed of a papillary level and a deeper, reticular dermis. The dermis is composed of collagen bundles, fibroblasts, and microvessels that sustain the epidermis. (15)

The sequence of gross skin changes occurring with standard schedules and doses of radiotherapy to the breast have been described. (16) These reactions are categorized as early effects or late effects, as determined by the time at which they present.

Early effects are those that occur within 90 days of the initiation of radiation. Those skin reactions occurring during the second to fourth week of therapy include dryness, epilation, pigmentation changes, and erythema. (16) Dryness and epilation result from destruction of the sebaceous glands and hair follicles of the dermal layer. (8) The skin becomes hyperpigmented due to stimulation of epidermal melanocytes. (8) Cytokines mediate inflammatory reactions that cause acute erythema. (17)

During the third to sixth week of therapy, populations of basal-layer stem cells become depleted in the treated area, and dry desquamation can develop. (18) Dry desquamation is clinically characterized by scaling and pruritus. Moist desquamation results if all stem cells are eradicated from the basal layer, and is characterized by serous oozing and exposure of the dermis. Moist desquamation may occur following four to five weeks of therapy. (16)

Late effects are those that present more than 90 days after the completion of radiotherapy, and are associated with injury to the dermis. Following the acute skin changes, the skin appears "normal" for a variable interval of time ranging from months to years. The late effects of atrophy and fibrosis are directly related to dermal fibroblast response to radiotherapy. Atrophy results from the decreased population of dermal fibroblast and the reabsorption of collagen fibers. The remaining atypical fibroblasts are stimulated by growth factors produced in response to injury. The proliferation of these atypical fibroblasts in response to growth factors such as TBF-B results in the deposition of dense fibrous tissue. (19) Radiation-induced fibrosis is characterized by progressive induration, edema formation, and thickening of the dermis. (16)

Pigmentation changes can also occur as a late reaction. These changes are quite variable. Some patients experience gradual hyperpigmentation, while others with more darkly pigmented skin may develop depigmentation due to complete eradication of all melanocytes. (8)

Telangiectasias can develop 6 months to multiple years following the completion of radiotherapy. Telangiectasias are areas in which multiple, prominent, dilated, and thin-walled vessels are visible in the skin. In these areas, microvessels have lost endothelial cells, shortened, and become visible through an atrophied dermal layer. (16)

Dermal necrosis also can occur months to years following radiotherapy. Necrosis is associated with doses higher than those used to treat the breast. (16) This form of skin injury is related to microvascular changes that result in dermal ischemia. (18)

Generally, external beam radiotherapy is a well-tolerated treatment. A clinical trial by Fisher et al, (20) which prospectively assessed skin toxicity over the course of breast irradiation using Radiation Therapy Oncology Group (RTOG) toxicity criteria, found less than 3% of patients developed grade III toxicity.

Preventing and Managing Radiationrelated Skin Toxicity

Skin injury incurred during breast irradiation can produce significant discomfort, limit daily activities, and result in breaks from treatment. Some of the commonly held beliefs regarding preventing skin toxicity have recently been investigated in randomized trials.

Washing the irradiated skin with soap and water was felt to exacerbate radiation dermatitis during the orthovoltage era. Roy et al (21) evaluated the impact of skin washing with soap and water on acute skin toxicity during breast irradiation using modern megavoltage radiotherapy. In this trial, 99 patients undergoing breast irradiation were randomized to skin washing with soap and water or no skin washing. Moist desquamation developed in 33% of those that did not wash the skin as compared with 14% of those that washed the skin. A multivariate analysis of this small trial showed acute skin toxicity correlated with patient's weight, concomitant chemoradiotherapy and regions of higher dose, while there was a trend toward increased toxicity in the nonwashing arm. It is hypothesized that washing may reduce moist desquamation by removing skin microbes which act as inflammatory stimuli at the basal layer of the skin. The authors concluded that washing the skin does not increase skin toxicity.

The efficacy of aloe vera gel, a therapy commonly used to prevent radiation skin toxicity, has been evaluated recently in two randomized trials. Williams et al (22) conducted two trials involving women receiving breast irradiation, and which compared skin toxicity between those receiving aloe vera gel and a control group. The first trial was a double-blinded trail in which 194 women were randomized to receive topical aloe vera gel or a placebo. In the second trial, 108 patients were randomized to aloe vera or no treatment. The scoring of skin toxicity was similar for both arms of the two trials. This suggests that aloe vera has no protective effect for those receiving breast irradiation.

Biafine (Medix Pharmaceuticals, Tampa, FL), a wound-healing product from France, has been touted to reduce radiation-related skin toxicity. (23) The wound-healing properties of Biafine are a result of its capacity to recruit macrophages to epidermal wounds and promote granulation tissue formation. (24) Biafine was compared with best supportive care, which consisted of Aquaphor (Biersdorf, Lindenhurst, NY) and aloe vera, in a randomized trial of women receiving breast irradiation. This trial demonstrated no statistical difference in skin toxicity between those receiving Biafine and those treated with best supportive care. (20)

Topical steroids are commonly used to treat radiation-induced skin inflammation. Corticosteroids have been shown to inhibit the upregulation of the proinflammatory cytokine IL-6 in response to ionizing radiation. (25) The efficacy of the corticosteroid cream mometasone furoate (MMF) as a prophylactic and therapeutic intervention was investigated in a randomized trial. Forty-nine patients receiving breast radiotherapy were randomized in a double-blinded placebo controlled trial to receive MMF and an emollient cream or a placebo emollient cream during their radiotherapy and for three weeks following. This trial demonstrated that prophylactic application of MMF combined with an emollient cream significantly decreased acute radiation dermatitis compared with emollient cream alone. (26)

While there is little empirical evidence to support the use of prophylactic topical therapies, advances in radiotherapy techniques are addressing treatment-related causes of skin injury. The contour of the breast and its varying thickness produces inhomogeneous distribution of the radiation dose. The regions of higher dose are at increased risk of skin injury. The use of three-dimensional (3D) planning systems, which incorporate computerized tomography-based images, allow for more accurate calculation of dose throughout the breast. Aref (27) compared the simple radiotherapy plan utilizing a single contour to a 3D plan using dose-based compensators and lung inhomogeneity corrections. The use of 3D planning, which allowed more accurate dose calculations and dose-based compensators, significantly decreased the volumes of breast that received doses that exceeded 100% of the prescribed dose. Intensity-modulated radiotherapy (IMRT) is a technique that further increases the homogeneity of dose in the breast. IMRT uses the dose calculations obtained from 3D planning and then decreases the transmission of radiation to regions of excessively high doses. In the initial clinical experience with IMRT at William Beaumont Hospital, none of the 32 patients receiving breast irradiation experienced RTOG grade III or greater skin toxicity. (28)

Although not evidence-based, the following practice guidelines to prevent skin injury during and after breast irradiation are recommended by many radiation oncology centers.

* Avoidance of metallic-based topical agents is advised, as these may increase skin dose. Metallic agents include zinc oxide-based creams and deodorants with aluminum bases.

* Avoiding traumatic shear and friction injuries by wearing loose cotton clothing is advised.

* Use of nonadhesive wraps or securing devices allows for wound examination and exposure of the treatment site, without surrounding skin trauma. SNUG wraps (Assurity Medical, Atlanta, GA) are cotton wraps available in various sizes, used to protect wounds without skin adhesives.

Unfortunately, many women will experience some degree of skin injury during breast irradiation. Current therapies used in the treatment of dry and moist desquamation are reviewed below.

Dry Desquamation

Dry desquamation clinically presents as scaling and pruritus of irradiated skin. The goal of therapy for this skin damage is to provide moisture to injured areas, and to decrease patient discomfort. The choice of topical therapy should be hydrophilic, with a neutral pH to avoid excess irritation. There is also evidence, as discussed above, that topical corticosteroids have been shown to decrease the acute dermatitis that may proceed dry desquamation associated with breast irradiation. (26)

Moist Desquamation

Sloughing of the epidermis and exposure of the dermal layer clinically characterize moist desquamation. Management of these partial-thickness wounds has been influenced by the Winter principle of moist wound healing, which suggests that wounds heal more rapidly in a moist environment. (29) Hydrocolloid dressings applied directly to these wounds prevent the evaporation of moisture from the exposed dermis and create a moist environment at the wound site that promotes cell migration.

In a randomized prospective trial, hydrocolloid dressings were compared with gentian violet, a compound with antifungal and antiseptic properties used in some institutions to treat moist desquamation. Unlike the hydrocolloid dressings, gentian violet produces a dry wound bed. Thirty-nine patients who developed a total of 60 wounds during radiotherapy were randomized to treatment with either a hydrocolloid dressing or gentian violet. There were no significant differences in wound healing time. However, patients reported higher satisfaction with the hydrocolloid dressing based on its comfort and aesthetic factors. Gentian violet produced skin discoloration and drying affects that limited mobility. (30) Patient comfort should determine the best clinical practice, and at our institution hydrocolloid dressings are commonly prescribed for moist desquamation.

Conclusion

The skin reactions resulting from breast irradiation can range from mild to severe, and are related to both treatment- and patient-related factors. Guidelines for skin care during radiotherapy are often aimed at preventing further exacerbation of radiation dermatitis that has already developed. There is a paucity of evidence that topical agents are effective in preventing skin reactions. However, advances in radiation planning and delivery, such as IMRT, may dramatically decrease the incidence of severe reactions. Finally, as our understanding of genetic sensitivity to radiotherapy increases, we may be able to predict those at risk for greater skin toxicity and use this information to tailor therapy.
When you do the common things in life in an uncommon way, you will
Command the attention of the world.
--George Washington Carver


Accepted June 14, 2004.

References

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17. Kupper TS. The activated keratinocyte: a model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J Invest Dermatol 1990;94:146S-150S.

18. Hopewell JW. The skin: its structure and response to ionizing radiation. Int J Radiat Biol 1990;57:751-773.

19. Canney PA, Dean S. Transforming growth factor beta: a promotor of late connective tissue injury following radiotherapy? Br J Radiol 1990;63:620-623.

20. Fisher J, Scott C, Stevens R, et al. Randomized phase III study comparing best supportive care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13. Int J Radiat Oncol Biol Phys 2000;48:1307-1310.

21. Roy I, Fortin A, Larochelle M. The impact of skin washing with water and soap during breast irradiation: a randomized study. Radiother Oncol 2001;58:333-339.

22. Williams MS, Burk M. Loprinzi CL, et al. Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345-349.

23. Spitalier J, Amalric M. Value of Biafine in the prevention and treatment of skin reactions following radiotherapy. 1973. Located at: Centre Regional Delutte Centre Le Cancer, Marsille, France, submitted for publication.

24. Coulomb B, Friteau L, Dubertret L. Biafine applied on human epidermal wounds is chemotactic for macrophages and increases the IL-1/IL-6 ratio. Skin Pharmacol 1997;10:281-287.

25. Beetz A, Messer G, Oppel T, et al. Induction of interleukin 6 by ionizing radiation in a human epithelial cell line: control by corticosteroids. Int J Radiat Biol 1997;72:33-43.

26. Bostrom A, Lindman H, Swartling C, et al. Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: results from a double-blind, randomized study. Radiother Oncol 2001;59:257-265.

27. Aref A, Thornton D, Youssef E, et al. Dosimetric improvements following 3D planning of tangential breast irradiation. Int J Radiat Oncol Biol Phys 2000;48:1569-1574.

28. Kestin LL, Sharpe MB, Frazier RC, et al. Intensity modulation to improve dose uniformity with tangential breast radiotherapy: initial clinical experience. Int J Radiat Oncol Biol Phys 2000;48:1559-1568.

29. Winter G. Formation of the scab and the rate of epithelialization of superficial wounds in the skin of the domestic pig. Nature 1962;193:293-294.

30. Mak SS, Molassiotis A, Wan WM, et al. The effects of hydrocolloid dressing and gentian violet on radiation-induced moist desquamation wound healing. Cancer Nurs 2000;23:220-229.

RELATED ARTICLE: Key Points

* Radiotherapy is a modality commonly incorporated in breast cancer therapy.

* Radiation-related skin injury frequently occurs, and is related to both treatment and patient factors.

* While there is a paucity of data to support the prophylactic use of topical agents during therapy, advances in radiation techniques hold promise for preventing severe injury.

Jennifer L. Harper, MD, Lynette E. Franklin, MSN, Joseph M. Jenrette, MD, and Eric G. Aguero, MD

From the Department of Radiation Oncology and the Wound, Ostomy, and Continence Nursing Department, Medical University of South Carolina, Charleston, SC.

Reprint requests to Jennifer L. Harper, MD, Department of Radiation Oncology, Medical University of South Carolina, 169 Ashley Avenue, Charleston, SC. Email: harrper@radonc.musc.edu
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Title Annotation:Review Article
Author:Aguero, Eric G.
Publication:Southern Medical Journal
Date:Oct 1, 2004
Words:3451
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