Open access peer-reviewed chapter - ONLINE FIRST
Abstract
Radiotherapy (RT) is a cancer treatment that has been widely applied to cancer patients. However, this treatment could induce radiation skin injuries that affect the quality of life of patients. The radiation-induced ulcer is a late-stage complication of radiation burns that could not be self-limited. This chapter summarizes current knowledge relating to RT-induced skin reactions, including epidemiology, pathophysiology, diagnosis, prevention, and management. Additionally, the author also presents the experience of treating RT-induced ulcers by surgical treatments that were shown to give satisfactory results on patients.
Keywords
- flap
- radiotherapy
- radiation treatment
- radiation-induced ulcer
- single-stage reconstructive surgery
1. Introduction
Radiotherapy (RT) is a measure that delivers radiation to cancer cells that consequently killed these cells. Radiation could be delivered in the form of ionizing particles, photons, or electron beams [1]. Recently, hyperthermia (HT) has been deemed to be a potent radiosensitizer that could enhance the efficacy of radiotherapy in cancer patients [2, 3]. RT-induced skin injuries, or radiation burns, were classified into 4 grades according to Radiation Therapy Oncology Group (RTOG) where the ulceration is included in grade 4 [4].
Although RT brings therapeutic potents to cancer patients, its side effects have been reported in many studies including RT-induced ulcers, which are the most severe situations of radiation burns [4, 5]. The presence of HT, which is often in the combination with RT, in some cases also could increase thermal toxicity [6]. These complications significantly impact patients’ quality of life. Thus, a comprehensive understanding of RT-induced ulcers is critical for clinical practices.
This chapter aims to summarize relevant aspects of RT-induced ulcers, including pathophysiology, diagnosis, risks factor of RT-induced skin reactions, epidemiology, prevention, and management of RT-induced skin injuries. The chapter also focuses on the surgical management of RT-induced ulcer, a severe complication of radiation burn.
2. Pathophysiology
When irradiation performed, the radiation will affect the young cells, makes them to divide rapidly. Therefore, when acting on the skin, radiation causes damage to the germ cells of the skin, hair follicles, sebaceous glands, sweat glands. In the other hand, radiation affects vascular endothelial cells, fibroblasts, etc., thereby causing post-radiotherapy skin lesions. Early-stage common lesions after radiotherapy may be edema, congestion, dry desquamation, moist desquamation, acute ulcers or mild pigmentation disorders. In the late stages, the most common lesions are skin atrophy, sclerosis, loss of skin appendages (hair, sebaceous glands, sweat glands), hyperpigmentation or hypopigmentation, dilated capillaries, vascular lesion, ulcers, necrosis or secondary cancer.
2.1 Mechanism of RT-induced skin reactions
RT-induced skin reactions occurred possibly related to tissue damage and inflammation.
Firstly, radiation could cause DNA breaks due to its ability to release electrons from atoms or molecules. Secondly, it could generate reactive oxygen species resulting in the oxidation of proteins and lipids. Consequently, these effects lead to cell death and the impairment of miotic ability [7]. When a great amount of cell death happened and could not recover, cell death, including basal keratinocytes in the basal layer, would distract the self-renewal ability of the epidermis [8]. As a result, the proliferation of new cells could not completely replace damaged cells resulting in a broken epidermis.
Skin reactions in the epidermis could be followed by inflammation. There is a variety of cytokines and chemokines. They include interleukin IL-1α, IL-1β, TNF-α, TGF-β, IL-6, IL-8, CCL-4, CCL2 [9, 10, 11]. The upregulation of these molecules consequently increases the expression of adhesion molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule, and E-selectin [9, 12, 13]. The transendothelial migration of immune cells from the circulation to damaged areas could be deemed as a hallmark of the inflammatory process.
2.2 Mechanism of RT on wound healing
Normally, the wound healing process undergoes some stages: vasoconstriction and hemostasis (immediately after the lesion), inflammatory reaction (0–3 days), granulation regeneration/reproduction (3 days–3 weeks), repair and recovery (3 weeks–3 years). The wound healing is also influenced by local factors (wound moisture, wound ischemia, bacterial infection) and the systemic ones (congenital pathologies related to collagen deficiency or synthesis, pathologies increasing the risk of bacterial infection and nutrition…).
Influence of radiation on wound healing process [14]:
Firstly, within the irradiated skin area, the radiation promotes repeated inflammatory reactions, increases the body’s inflammatory response, disrupts the cell reproductive regenerative process, causes tissular edema.
Secondly, the main components involved in the wound healing process are TGFβ, PDGF and FGF. These components are produced by platelets, but radiation suppresses platelet flow to the wound, delaying wound healing.
Thirdly, radiotherapy directly reduces fibroblasts, the wound elasticity due to decreased collagen production and changed collagen function, thereby delaying the wound healing process.
Fourthly, radiotherapy causes vascular wall edema, vascular stasis and obstruction, thereby blocking platelets, reducing vascular formation, decreasing cytokines and fibroblasts in wounds, and leads to reduced repair capability of the wound.
According to the study by Hopewell, radiation makes the post-radiotherapy wound healing process more complicated and difficult than other common chronic lesions [15].
3. Diagnosis of radiation-induced skin lesions
Radiation-induced skin lesion is a skin reaction and is also a side effect of radiotherapy in cancer treatment or interventional radiography. There are two types of radiation-induced skin lesion, depending on the time of skin reaction: An acute skin reaction develops hours to weeks after the first exposure to the radiation; The next progression is chronic radiation-induced dermatitis, which may develop months, years or even decades after radiotherapy.
3.1 Manifestations of acute radiation-induced skin lesions
Local changes may occur immediately after irradiation, during the entire course of radiotherapy up to 90 days after radiation. The specific clinical symptoms are as follows [16]:
Erythema: This is the earliest symptom of acute skin lesions after radiotherapy, initially manifested of light red, which can then turn into bright red or purple red when the dose accumulation increases. Erythema is the result of an inflammatory reaction, characterized by a red blood cell proliferation and dilated capillaries in the dermis.
Dry skin: Due to the functional reduction of the sebaceous glands, the sweat glands, accompanied by hair brittle and loss.
Edema: Accompanied by erythema is more edema of irradiated skin. This is the post-irradiated inflammatory reaction of the body that will gradually decrease over time.
Hyperpigmentation: Skin pigmentation depends on melanin quantity and distribution [17]. Hyperpigmentation is caused by increased activity of melanocytes, which is often accompanied by erythema. This symptom lasts a few months, then may subside [18].
Dry desquamation: Occurs when the irradiated skin receives a high dose from 3000 cGy, characterized by peeling skin.
Wet desquamation: Occurs when the epidermis is burned, the underlying surface is wet and edematous, at the dose of above 4000 cGy, common in areas with skin folds. Due to the loss or reduction of the protective function of the epidermis, this expression can form acute ulcers.
Folliculitis: This is a symptom of the hair follicle infection, manifested by small erythema.
3.2 Manifestations of chronic radiation-induced skin lesions
In order to diagnose chronic radiation-induced skin lesions, it requires an exploitation of medical history and necessary information on radiotherapy including: radiation field, volume, technique, dose, and segmentation, followed by chemotherapy, surgery or other interventions, pre-and post-radiotherapy skin complications. The clinical evaluation is based on consultation and test. The first examination should provide accurate information about the affected areas due to radiotherapy such as lesion area, depth, morphology and color.
In some special cases, when the clinical manifestations are unknown or suspected, a tissue biopsy is required to diagnose: Secondary cancer, angiosarcoma or to distinguish from scleroderma accompanied by radiotherapy. However, biopsies or invasive interventions can worsen radiation-induced fibrosis and prolong ulcerative conditions [18].
3.3 Clinical diagnosis of chronic radiation-induced skin lesions
Skin atrophy: The most common manifestation of skin atrophy is wrinkles, stronger reactions making skin thin, shiny, scaly. It usually occurs at grade II or III lesions, or may have mild reaction of grade I [19].
Telangiectasia: occurs in which small blood vessels dilate causing red lines or patterns on the skin, often forms spider veins. This is a common symptom in grade II and III lesions. This symptom may disappear after a short time but may reappear and persist for a long time.
Radiation-induced fibrosis (RIF): is a condition that subcutaneous tissue after radiotherapy loses connective tissue stability causing the irradiated area to be sclerosis and firmer.
Dyspigmentation: may appear shortly after irradiation and fade, but may last for months, years or longer. There are two conditions including local hyperpigmentation or hypopigmentation after radiotherapy. According to Ryan et al. and Johansson et al. radiotherapy can cause irreversible damage to pigment cells [19, 20].
Reduction or loss of skin appendages: Radiation can reduce or destroy all hair follicles, sebaceous glands and sweat glands, cause hair loss, reduce sweat secretion, dry the damaged skin.
Radiation-induced ulcers: This is a late lesion that can occur anywhere in the body, often in the areas mostly affected by radiation, ulcers tend to grow and spread if not treated promptly.
3.4 Subclinical diagnostic measures of chronic radiation-induced skin lesion
Sonography: This is a non-invasive diagnostic method, using a probe from 7.5 to 20 MHz that can assess the thickness of the skin layer, as well as the degree of skin sclerosis. A 20 MHz probe can detect epidermis, dermis and subcutaneous fat of about 10 mm deep. A 7.5 MHz probe can investigate further into the radiation-induced aponeurosis, muscle, and fibrosis in subcutaneous tissue as well as deeper ulcers [21].
Thermography: This method uses infrared camera to determine skin surface and body temperature. Skin surface temperature depends on the subcutaneous vascular system, which indirectly evaluates the subcutaneous vascular distribution. Typically, for patients with necrotic lesions, the surface temperature in that area will be lower than that in the inflammatory area.
Capillary microscopy: This is a non-invasive method, used for capillary qualification and quantification in hypodermal layers. Finger and toe capillaries are dilated in patients with acute radiation-induced skin lesions, whereas they are smaller or absent in patients with chronic radiation-induced skin lesions. Furthermore, distal subungual hemorrhage can be seen at both acute and chronic stages after radiotherapy.
Magnetic resonance imaging (MRI): This non-intervention method can assess the signals of the dermis, subcutaneous fat, muscle and bone and tissue morphological changes, then lesions can be identified. For example, a hypersignal on MRI is a result of an increased fluid volume in the tissue, which may be seen in cases of inflammation, edema, or necrosis. If fluid in the tissue decreases, signal on the MRI is decreased, but it is impossible to distinguish whether it is necrosis or inflammation on MRI. MRI images can assess the width and depth of radiation-induced ulcers.
Bone scintigraphy: Helps assess bone lesion beneath ulcer.
Histopathology and immunohistochemistry: Helps to diagnose the degree of lesion, structural changes of irradiated skin.
4. Risk factors of radiation-induced ulcers
There are some risk factors associated with the development of radiation dermatitis.
4.1 Radiotherapy-related factors
Higher total dose and higher irradiated volume are possibly related to a higher risk of skin injury [22, 23, 24]. Several articles revealed that hypofractionated RT contributed to a lower risk of radiation-induced skin injuries [25, 26]. However, a conflict result was shown as a hyperfractionated regime resulting in preferable outcomes [27]. Besides, intensity-modulated radiotherapy (IMRT) could lead to a reduction of skin reactions compared to 2D radiotherapy [28, 29].
Concurrent chemotherapy (i.g. cetuximab) or concurrent targeted therapy might result in a higher risk of skin injuries induced by RT as well [30, 31, 32].
4.2 Patient-related factors
Some regions of the body that are more sensitive to radiation such as the scalp, face, neck, extremities, chest, and abdomen, may be prone to develop skin reactions in patients receiving RT [33]. Patients who are obese (BMI > 30), contract connective tissue diseases, or have skin disorders also have a higher risk of developing radiation burns [34, 35, 36]. In addition, there are some genetic polymorphisms that were supposed to increase incidences of radiation dermatitis. They included polymorphisms in ABCA1 and IL12RB2, stefinA3, and S100A8 genes [37, 38].
5. Epidemiology
Skin reactions developed in 95% of patients who received RT [39]. 85% of patients suffered from a moderate to severe skin injury shown in another report [5]. Skin toxicity was mostly observed in patients with head and neck cancer and breast cancer, which occurred in over 50% of this population [40].
6. Prevention of radiation-induced skin reactions
6.1 Modern radiation therapy
To reduce complications on the skin, some modern techniques have been applied and gave promising results, such as IMRT and volumetric-modulated arc therapy (VMAT) [41, 42]. These techniques will deliver radiation doses conformally targeting tumor cells rather than surrounding normal cells, thus, minimizing skin injuries. A hypofractionated regimen, which reduces the period of time to exposure to radiation, also could prevent patients from suffering from skin injuries [43].
6.2 Topical corticosteroids
Topical corticosteroids possess anti-inflammatory properties that inhibit proinflammatory cytokines initiating the early stage of skin reactions [44, 45]. Mometasone furoate, a highly potent corticosteroid, was daily during RT and shown its benefits to prevent skin toxicity compared to placebo [46]. Other topical corticosteroids, namely methylprednisolone and betamethasone, revealed similar effects delaying the onset of RT-induced skin dermatitis [47, 48].
6.3 Skincare
After RT, the protection of the skin from adverse agents should be also paid attention to. These measures include protecting skin from the sun (i.g. by applying sunscreen or wearing a long-sleeve shirt), and daily cleaning irradiated skin with mild soap and water. It should be avoided to use an electric razor, tape, and adhesive on irradiated skin areas to minimize irritation or friction.
7. Managements of radiation-induced ulcers
7.1 Non-surgical managements
Biafine cream, hydrogel or hydrocolloid dressings, human bone marrow mesenchymal stem cells, hyperbaric oxygen, and laser therapy were reported to benefit wound healing [49, 50, 51, 52, 53].
Biafine promoted wound healing via the attraction of macrophase, an increase in the ratio of IL-1 to IL-6. IL-1 plays an important role in collagen synthesis and collagenase activation and IL-6 stimulates epidermal growth, thus, enhancing skin healing [54]. Human bone marrow mesenchymal stem cells also inhibit the inflammatory process via downregulation of IL-1β levels, activation of CD80+ macrophages, and upregulation of IL-10. Immunoregulation was considered a mechanism for the healing property of human bone marrow mesenchymal stem cells [55].
Hydrocolloid dressings could form a soft gel when they contact with the wound, therefore, the wound surface could keep its moisture, assisting in the liquefaction and separation of debris [56, 57].
7.2 Surgical management
7.2.1 Management of RT-induced ulcers
Complete excision of lesion both in width and depth is important in treating radiation-induced skin lesions. Many authors agreed to thoroughly treat the lesion before performing covering measures. This helps to eliminate damaged tissue, promote wound healing and reduce the risk of recurrence ulcer as well as the abnormal growth of tissue damaged by radiation. According to research by Wei et al. [58], dividing the cut-off depth is a challenge. Theoretically, the most seriously affected area is within 2 cm below the skin surface. Therefore, the depth of the cut-off is at least 2 cm, but it depends on the anatomical region. Above all, the deep removal into healthy tissues is very important. However, according to the author’s experience, no cut-off depth must exceed the muscular layer [58]. In Fujioka’s 2012 research and review [59], it is necessary to remove all infiltrated skin area, damaged bones and cartilage to ensure the cleanest wounds before covering. Removing the chest ulcerative lesion in the absence of recurrent cancer, it requires remove the entire non-important structure such as the large skin area, the bone and the cartilage until covering all lesion areas, then performing the defect covering [60].
However, the removal of all lesion is extremely difficult, because the post-radiotherapy lesion usually progresses lately for months and years, not only in width but depth into the structure under the irradiated area, which makes management more complex and difficult.
7.2.2 Plasty techniques of covering post-resection defects
7.2.2.1 Skin grafting
Most authors in the world said that skin grafting was not effective in covering defects for treating radiation-induced ulcers, because radiation damage is an area of atrophied dry tissue with sclerosis and prolonged anemia, inability to form complete granular tissue. According to the research conducted by Strawberry et al. [61], the rate of skin graft failure in his study was nearly 100%. Vu Quang Vinh in his report 2010, also reached the same conclusion, by reporting one case of radiation-induced ulcer, treated with surgical excision and skin graft on average 9 times, grafted skin still was not alive [62].
Some authors used skin grafting method for lesions of radiation with low dose, or after removing thoroughly the lesion, the lesion base/background was well supplied, or used great omentum flap and fascial flap to cover first, then performed the skin grafts [63].
7.2.2.2 Direct closure
Direct closure of the radiation-induced ulcerative lesion usually has low efficiency with high failure rate. Research by Di Meo et al. showed that direct closure is rarely successful with many complications because of poor vascularization at the lesion area [64]. Research by Luce also suggested that direct closure should not be used in treating radiation-induced skin lesions [65].
7.2.2.3 Plasty technique with random flap
Random flap can be used in different forms: sliding flap, rotation flap, rotation-sliding flap, permutation flap.
Advantages: Softness and elasticity of the flap is compatible with the damaged skin area, the surgery is simple and easy.
Disadvantages: Limited in area, direction and rotation of the flap. Especially in the case of radiation-induced ulcers, the area surrounding lesions are often infiltrated, extensively sclerotic, not suitable for the use of adjacent flap.
According to Fujioka M.’s report 2012, random flap is not recommended in treating radiation-induced skin lesion, because the peri-ulcerative tissue was contaminated, resulting in poorly supplied blood vessels, delaying the recovery process [59]. In Di Meo et al.’ study, they also suggested not choosing random flap because of the high necrotic incidence, so it was preferable to use/select pedicled flaps [64]. According to a study by Strawberry et al. [61], the use of local (random) flaps was also recommended because the peri-ulcerative tissues were often damaged due to radiation, resulting in necrotic flap. However, this kind of flap can still be indicated in case of small area ulcer, early ulcer, low radiation dose, with soft, mobile and well-supplied surroundings.
7.2.2.4 Plasty technique with expander flap
Advantages: avoid large lesion area during surgery, not affect the function of the donor flap. According to a MacMillan et al.’s study, the peri-lesion skin expansion shall provide tissue with well supplied vessels for the ulceration [66].
Disadvantages: Non-applicable to lesion areas without hard base. It requires 2 times surgery, risk of bleeding, exposed dermectasia and infection.
With radiation-induced lesions, using the expander flap can still be applied to the narrow soft the areas surrounding lesion.
7.2.2.5 Plasty technique with seamless pedicled flap
Pedicled flaps are taken from a non-irradiated area, which is a good plasty material, the first choice recommended by many authors. In particular, the skin and muscle flap contribute to treating ulcer easier. Marayuma’s report in 1986 on plasty coverage of thoracic ulcers with rectus abdominis flap on 16 patients gave good results [67].
Advantages: After transferring the flap to the new position, the properties of the flap remain unchanged, thus ensuring the esthetics and functionality, without secondary retraction. A great volume of flap can be obtained more easily in cases of post-radiation ulcers [59].
Disadvantages: The covering ability of the flap is limited because of the length and rotation of the flap. This technique may leave bad scars at flap donor site, difficult direct closure. Sometimes it is not applicable because radiation ulcerative lesions are often accompanied by infiltration and small peri-ulcerative blood vessels.
7.2.2.6 Perforator skin flap
Besides microsurgical and pedicled flaps, perforator flap is also widely used in covering radiation-induced defects. According to Fujioka’s study in 2012 [68], knowledge about perforator anatomy helps select covering flap more diversely, adjacent flaps can cover defects instead of the free flap. The most significant advantage of the perforator flap is not to sacrifice any major blood vessels or muscles and minimize the damage to the flap donor site.
However, because radiation-induced lesion is surrounded by scleroris and vascular lesions, the use of perforator flap is only applicable when perforator branch is found far from the lesion area.
7.2.2.7 Free flap transfer with vascular microsurgery
Micro-surgical flap transfer has been extensively used in plastic surgery of radiation-induced ulcer management with high success rate. This technique allows the surgeon to choose the most suitable tissue for the area and the shape of the lesion. The most difficult in using free flap is to find vascular supply on a sclerotic base. Therefore, when using the microsurgical flap to treat radiation-induced ulcers, it requires dissection of a long enough flap pedicle and discovery of the vascular receiver located far away from the irradiated area [69].
In the plasty of radiation-induced ulcer, microsurgical skin flap is often applied to treat head-face-neck ulcers, which is abundant, constant and well-supplied blood vessels. The radiation-induced ulcerative lesions in this area are often complicated, the ulcer can be communicated with the oral cavity or accompanied by bone exposure and geode. Therefore, the plasty material by microscopic flap can meet the requirement of covering both sides (external and oral cavity) with perforator flap separated from one/the same original vessel or ensure to cover the ulcer by skin flap, and geode formation with microsurgical osteomuscular skin flap.Some consequent reconstructive surgery could be performed to cover defects caused by RT. The uses of full-thickness skin grafts, tissue expanders, random-pattern flaps, perforator flaps or axial-pattern flaps, and free flaps were reported for reconstruction after RT-induced ulcer.
7.2.3 Case illustrations
Deep inferior epigastric perforator (DIEP) free flap and latissimus dorsi muscle flap (LDMF) are commonly used over decades for breast reconstruction. While DIEP is more widely applied because of its advantages, it could be not suitable in some cases because a successful surgery depends on factors consisting of surgeons, equipment, and patients themselves [70, 71, 72]. LDMF would be preferable in the case a short duration of sedation is requested. This flap is also more suitable for Asian patients than Caucasian patients because this population requires smaller breast volume. Illustrations of LDMF for breast reconstruction after RT-ulcers are presented in Figures 1 and 2. These Asian patients were well-healed after the surgery and no recurrence of ulcer happened.
Figure 1.
A 59-year-old female patient with a ulcer at her axilla after RT (left). The wound was debrided and then covered by LDMF (right).
Figure 2.
A 55-year-old patient with a ulcer on her chest along with wide infiltrated and fibrotic areas (left). She underwent debridement followed by a reconstruction with LDMF (right).
If deep lesion can affect the blood vessels, pleura, pericardium, it is necessary to carefully examine the lesions on CT or MRI film to see the lesions level related to organizations, thereby taking measures to treat the bottom of the lesions appropriately and safely. Hereby, we presented one female patient born in 1937, who had a left breast ulcer after 30 years of radiotherapy for breast cancer, and ulcer depth reaching the pericardium. Evaluation on CT showed that the boundary between lesions and pericardium is not clear, there is a risk of pericardial lesion during the management of lesions. We have conducted consultation and coordination with the thoracic surgeons during surgery, to ensure the safety for the patient but also need to eliminate all lesions, minimize the risk of cancer or recurrent ulcer after surgery. The patient was treated with maximum width and depth of lesion, using large back muscle skin flap to cover the defect. Skin flap was good after surgery. The incision healed in the cycle 1. No ulcer recurrence occurred after 3 year (Figure 3).
Figure 3.
Illustration of a RT-induced ulcer case with exposed pericardium. (Above, lef) Before the surgery. (Above, middle) MRI film showed ulcer deep to the pericardium. (Above, right) Lesion removal. (Below, left) After cutting the whole lesion. (Below, middle) 1 week after surgery. (Below, right) 3 years after the surgery.
Free flaps are also common options due to their good vascularization and rapid healing. Figure 4 describes a case of a 44-year-old male patient who had an ulcer on his neck after RT. A free flap was used in this patient after the excision of the ulcer. Three months postoperatively, a favorable result was observed.
Figure 4.
The RT-ulcer appeared on the neck of patient (A). A favorable result was seen after 3 months.
Superior gluteal artery perforator flaps could be useful in the cases of RT-ulcer on the buttock region. The reconstructive surgery gave a favorable result in a 44-year-old male patient after the excision of RT-induced ulcer on his button (Figure 5).
Figure 5.
RT-ulcer on button of a male patient. (Left) Before the surgery. (Right) 3 months after the surgery.
In addition, in the case to avoid intensive surgery and/or to minimize defects on the donor site, a tissue expander or random-pattern flap could be appropriate choices. The expanded flaps have benefits in terms of good blood supply to tissues of RT-induced wounds, minor complications, and satisfactory esthetic results. Necrotic areas and total infiltrated areas should be entirely removed in the cases of first-degree and second-degree ulcers. In the meanwhile, partial excision would be more appropriate for other ulcers because of a dense vessel system or ribs underneath the wound. Generally, if the base of ulcers could not be completely monitored, drainage should be placed for a long time.
8. Conclusions
Radiation burn is a common and severe complication after RT that affected a majority of patients. This chapter provided some general data about the epidemiology, diagnosis, pathophysiology, prevention, and management of RT-induced skin reactions. In addition, the RT-induced ulcer, which is a severe form of radiation burn, could be effectively treated by excision and reconstructive surgery with varied flaps.
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