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Radiation dermatitis is a cutaneous lesion induced by ionising radiation. It was at one time considered to be a major risk of conventional radiotherapy, but it has become less common and less severe since the 1970s with the development of high- and medium-energy accelerators. There are several types of radiation dermatitis .
1.1 - ACUTE RADIATION DERMATITIS
The acute lesions induced by ionising radiation predominate in rapidly renewing tissue (the skin, the epidermis). They develop within a few days or weeks from the start of irradiation. They are linked to the total dose but also to the individual doses administered; they are maximised if an identical cumulative dose is received but with lower fractionation (large individual doses). The type of radiation (photons, electrons) and the nominal energy of the beam used are also promoting factors.
Free radicals produced in irradiated keratinocytes cause DNA damage and trigger inflammation, vasodilation, and oedema, and arrest cell growth, causing acute radiation dermatitis and then, with time, fibrosis in the dermis and thinning of the epidermis which characterise chronic radiation dermatitis.
The hair and nails can also be involved , with irradiation of hair follicles being accompanied by temporary loss of the hair shaft after one to two weeks of treatment with biologically equivalent doses of around 20Gy. It can take up to a year for the hair to regrow. At biologically equivalent doses of around 40Gy and higher, approximately 70% of patients may experience reversible dysfunction of the sweat glands. Normalisation appears to take longer the greater the toxicity, sometimes beyond a few weeks, or even six months.
As with all undesirable effects in cancer treatments, the severity of radiation dermatitis is graded using an international classification system, Common Terminology Criteria for Adverse Events, CTCAE (Table I).
Grade I : Erythema developing within a few days to three weeks of exposure to anything from 12 Gy in subjects with a fair phototype. This erythema can appear later, after radiation therapy, when it is delivered over a short period of time (as with brachytherapy).
Erythema is often accompanied by a burning sensation and oedema. It is common and resolves rapidly once treatment is stopped, after a desquamation phase and, often, temporary epilation due to involvement of adnexal structures. This may give way to longer-lasting post-inflammatory pigmentation, especially in patients with a dark phototype.
Grade 2 : Moderate erythema and oedema, exudative plaques confined to the irradiated site.
In areas where these conditions are more marked, it is best to consider briefly interrupting irradiation even if this means discussing an increased total dose to compensate for the loss of efficacy of secondary treatment due to tumour cell repopulation.
Grade 3 : Exudative radiation dermatitis usually follows on from the erythema when irradiation is continued at a dose exceeding 40 Gy. There is confluent skin shedding and ulceration that can expose the dermis a few weeks after irradiation. Re-epithelialisation can take anything from a few weeks to several months depending on the site, although patients may be left with dyschromia or alopecia which is very often permanent. Radiotherapy usually has to be stopped during the healing process.
Grade 4 : Acute radionecrosis is the result of an excessive dose, and is now only seen in exceptional cases except when there are invasive or very extensive superficial tumours (treated with massive radiation doses over a very short time). It develops in a few days manifesting as a very painful inflammatory plaque with necrotic and haemorrhagic phenomena progressing towards deep necrosis, which can expose the muscles, tendons, and bones.
Some factors promote and worsen radiation dermatitis  :
• Concomitant treatment with cytostatic chemotherapy (platinum salts, anthracyclines, and actinomycin) increases acute toxicity .
• The emergence of targeted therapies and especially Epidermal Growth Factor Receptor (EGFR) inhibitors, which trigger a specific type of radiation dermatitis. This will be discussed extensively later.
• Some areas such as skin folds and thin skin (axillary, submammary, and perineal regions) are at greater risk.
• Previous damage to the integrity of surface skin that is then irradiated.
• An advanced age, immunodeficiency (diabetes, HIV), smoking, and a poor nutritional intake are patient-related factors that must be taken into account.
1.2 - RADIOTHERAPY AND ANTI-EGFR AGENTS
Radiotherapy combined with chemotherapy and anti-EGFR agents leads to a greater incidence of radiation dermatitis than radiotherapy alone. (, RR 2,38 ; 95% CI, 1,8-3,2; p < 0,001).
A retrospective study presented in 2009 at ASTRO (American Society for Radiation Oncology) reported acute radiation toxicity to the skin and mucosa classified as grade 3 in 0% of patients treated with radiotherapy alone, in 7% of patients receiving radiotherapy plus chemotherapy, and in 27.6% of patients treated with radiotherapy plus cetuximab .
In the Bonner study, the incidence of grade 3 or 4 radiation dermatitis was 21% in the radiotherapy alone patient group and 35% in the group treated with concomitant cetuximab .
These studies reported an increased frequency of radiation dermatitis and a specific set of symptoms, in particular an inflammatory exudate manifesting as crusts.
These crusts may appear during the early stages but they do not constitute necrosis of the epidermis, so they do not imply the same criterion of severity as they would in patients undergoing radiotherapy alone. The severity of the outbreak is based on how widely it has spread, especially when it is outside the radiation field, whether there is bleeding, and the risk of a secondary infection. The CTCAE classification is not suitable for the symptoms observed in these cases and Bernier recently proposed a new classification specific for radiotherapy plus cetuximab .
Management must take into account the measures normally recommended for treating EGFR inhibitor-induced folliculitis, i.e. topical corticosteroids and topical and systemic antibiotics, together with dressings that aim to debride the crusts such as hydrocolloid or hydrogel dressings. With grade 3 or 4 lesions, treatment adjustment should preferably involve changing the dose of cetuximab so that radiotherapy can be maintained .
1.3 - CHRONIC RADIATION DERMATITIS
Chronic radiation dermatitis results from a delayed and gradual depletion of cells that have a minimal capacity for renewal, i.e. are only able to divide a small number of times. Its pathophysiology is connected to chronic production of transforming growth factor beta (TGF-β) a stimulant for the excessive production of extracellular matrix by fibroblasts which causes fibrosis. Le TGF-β also activates factors involved in neovascularisation through macrophages .
The onset of chronic radiation dermatitis is not linked to the intensity of acute radiation dermatitis and it occurs months (usually more than six) or even years after the irradiation, worsening with time.
The incidence and severity depend on the total dose (higher than 50Gy to the skin), and are increased when radiation is concentrated over a short period, fractionation is minimal, the volume is significant, and in the case of invasive tumours.
In a retrospective study of 1137 subjects who underwent radiation in childhood for treatment of angioma, cutaneous dystrophy was reported in 81% of cases, with a relative risk of 12 in patients who had received more than 30 Gy compared to those who had received less than 10 Gy .
Radiodystrophy manifests as, in variable combinations, cutaneous atrophy, dyschromia, telangiectasia (characteristic poikiloderma), and xerosis cutis. These types of radiodystrophy can become fissured (a common outcome in occupational radiation dermatitis of the fingers) or keratotic, leading to fear of the onset of radiation-induced carcinoma. Sometimes, these trophic changes are dominated by sclerosis that is relatively deep in the skin and soft tissue. This sclerosis surrounds the vasculature and promotes ischaemia and the onset of necrotic ulceration (delayed radionecrosis). Delayed radionecrosis is particularly common around superficial areas of bone or cartilage (sacral region, chest wall, scalp, ears).
Hair and nails
Fibrosis of the hair follicles is associated with permanent loss of the hair shaft. The greater the dose the follicle is exposed to, the greater the frequency of permanent alopecia (for example 50% are affected at 53 Gy to the follicle) but even a single session of 5–7Gy can lead to loss of hair follicles. Chemotherapy and a history of alopecia can worsen permanent alopecia. Nail irradiation can also lead to permanent nail loss. The sebaceous glands are damaged at doses of 12Gy and above, the sweat glands from 40Gy upward, and the hair follicles from 10–20Gy upward .
Cancerization is most likely to develop following chronic radiation dermatitis. It can also be seen after radionecrosis (which promotes ulceration), or even in skin that appears to be healthy in the absence of any other sign of radiation dermatitis. Basal cell carcinoma, cutaneous squamous cell carcinoma, and sarcoma, especially angiosarcoma, are all possible.
1.4 - OTHER RADIATION SKIN INJURIES
Numerous skin disorders have been reported in areas exposed to radiation, and it is always possible for irradiation to play a part in triggering or promoting these reactions. Cases of pemphigoid, pemphigus, erythema multiforme, dermatophytosis, morphea, lichen sclerosus, porphyria cutanea tarda, lupus, comedonal or inflammatory acne (which can sometimes develop up to six months after radiotherapy), and various pruriginous rashes have been reported. Their treatment is not covered in this article.
Radiation recall is a reactivation of acute radiation dermatitis with its onset occurring some time (several months to years) after irradiation. An inflammatory reaction reappears that is confined to a previously irradiated area and triggered by the administration of a treatment (often cytostatic chemotherapy, but also statins, antituberculosis drugs, St John’s wort, tamoxifen, antibiotics etc.). It is not linked to the original radiation dose or to the intensity of radiation dermatitis during radiotherapy. The severity of radiation recall is graded using the international classification system Common Terminology Criteria for Adverse Events, CTCAE (Table I). The standard treatment with corticosteroids does not seem to change the natural course, and rechallenge with the causal drug is often well tolerated .
EPPER syndrome (eosinophilic polymorphic pruritic eruption associated with radiotherapy) manifests histologically as the name suggests as a dermal-epidermal infiltrate rich in eosinophils, sometimes with deposits of IgM or perivascular C3 seen on DIF. Clinically, there is a pruriginous outbreak of papules and/or vesicles, predominantly on the lower limbs and extending beyond the radiation field. It has a predilection for women with an onset during or soon after irradiation (although sometimes later, up to nine months) [11, 12].
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