Dermatology

Radiation Dermatitis (radiodermatitis, radiation epidermitis, radiation skin toxicity, acute radiation skin reaction, late radiation skin reaction, post-irradiation morphea)

Radiation Dermatitis (radiodermatitis, radiation epidermitis, radiation skin toxicity, acute radiation skin reaction, late radiation skin reaction, post-irradiation morphea) ICD-9 692.82

History of Radiation Dermatitis

Earliest reports of radiation-induced skin changes date back to 1896, 9 months after Roentgen’s discovery.

Clarence E. Dally, a colleague of Thomas Edison participating in fluorescent lamp construction, developed epilation, skin ulceration of the hands/arms, carcinoma and ultimate death in 1904 due to metastasis.

Radiation has been used extensively in the early 20th century, including fluoroscopy, for diagnostic and therapeutic purposes resulting in acute radiation dermatitis and late risks, including malignancy.

In 1956, reports were published by the Nuclear Regulatory Commission in the United States, and its European counterparts, regarding the hazards of ionizing radiation.

Efforts have evolved to improve both patient and employee safety with regard to ionizing radiation therapy exposure.

Radiation dermatitis is one of the most common toxicities associated with therapeutic radiation and articles have documented that as many as 90% of all patients experience some degree of dermatitis.

Differential Diagnosis (Acute)

Differential diagnosis is far-reaching, but must include the potential presence of recurrent tumor. Despite the healing risk in the radiation setting, if clinical suspicion is high, a biopsy should be performed after consulting with a radiation oncologist.

Additional differential diagnoses would include:

  • Contact dermatitis - usually can be differentiated from radiation dermatitis by skin distribution. Contact dermatitis rarely is limited to only the radiation field, as is seen in radiation dermatitis, unless associated with allergy to skin product(s) being used to treat the skin during therapy, ink used for the tattoo process during radiation therapy, ink pens used for skin markings, or clear dressings used to maintain pen skin markings during the planning/treatment process.

  • Cellulitis/Bacterial superinfection

  • Fungal infection

  • Eczema - usually not confined to treatment portal

  • Lichen planus

  • Pemphigus

  • Erythema multiforme

  • Stevens-Johnson syndrome

  • Toxic epidermal necrolysis

Differential Diagnosis (Late)

Differential diagnosis should include potential presence of recurrent tumor. Despite the healing risk in the radiation setting, if clinical suspicion is high, biopsy should be performed after consulting with a radiation oncologist.

Late skin recurrence/metastasis in previously irradiated chest wall skin (Figure 11).

Additional differential diagnosis would include:

  • Radiation recall - reaction of the skin within the radiated field characterized by the development of cutaneous erythema at least 1 week after complete resolution of acute radiation dermatitis. The pathophysiology associated with this phenomenon is uncertain, however, cytotoxic chemotherapy is most commonly associated.

  • Aseptic cellulitis - has been reported most commonly in the setting of breast conservation therapy. Clinically has the appearance of cellulitis but remains refractory to antibiotic therapy. Postulated to be secondary to the induction of lymphatic circulatory dysfunction by radiotherapy. Treatment may include lymphedema therapy if in association with extremity edema, such as in breast cancer.

  • Post-radiation morphea - rare but reported complication. Generally noted in case reports to be associated with breast radiotherapy, but also reported with radiation exposure of other body areas. Has also been called “localized scleroderma” by some authors and is postulated to be in the same spectrum of disease as lichen sclerosis et atrophicus. Often requires histologic diagnosis to confirm (and exclude other differential such as recurrent malignancy). Differs from the remainder of acute and chronic radiation dermatoses in that it may extend beyond the skin within the radiated field(s). No clear correlation with the radiation dose or severity of acute radiation reaction.

Acute Radiation Dermatitis

Epidemiology

To be defined as radiation dermatitis, the skin reaction must occur within or at the margin of a radiotherapy field. This phenomenon may be produced by both diagnostic (fluoroscopy, CT scan) and therapeutic radiation equipment.

Careful patient history should be obtained if unexplained skin rash with a linear border is encountered. If the reaction is felt to represent acute radiation dermatitis related to a diagnostic radiology procedure, the radiology center and treating physician should both be notified.

This condition is generally noted after a threshold of 10-14 days of therapy with mild diffuse erythema. It can progress to sustained, confluent, blanchable changes postulated to be mediated by cytokines. With ongoing therapy, a cascade of progressive change is noted spanning the spectrum from grade 1 through grade 4 reaction. The most common grading system is the National Cancer Institute CTC version 3 as follows:

Table I. National Cancer Institute CTC version 3 grading system

Table I.

National Cancer Institute CTC version 3 grading system
Acute Radiation Dermatitis
Grade 0 1 2 3 4
Description No Change Faint erythema or dry desquamation Moderate to brisk erythema or patchy moist desquamation, mostly confined to skin folds and creases; moderate edema Confluent moist desquamation, >1.5cm diameter, not confined to skin folds; pitting edema Skin necrosis or ulceration of full-thickness dermis; may include bleeding not induced by minor trauma or abrasion

Grade 1 acute radiation dermatitis of breast 4 weeks into therapy (Figure 1).

Figure 1.

Grade 1 acute radiation dermatitis of breast

Grade 1 acute radiation dermatitis of extremity during radiotherapy for soft tissue sarcoma; localized changes along surgical scar due to radiation technique of adding tissue equivalent material (bolus) for intentional dose build-up in this region (Figure 2).

Figure 2.

Grade 1 acute radiation dermatitis 5 weeks into radiotherapy for soft tissue sarcoma

Grade 1 acute radiation dermatitis of scalp at completion of radiatiotherapy for squamous cell skin cancer of scalp (Figure 3).

Figure 3.

Figure 3. Grade 1 acute radiation dermatitis of scalp

Image of the same patient with complete resolution 3 weeks post therapy (Figure 4).

Figure 4.

Same patient with complete resolution of acute dermatitis 3 weeks post treatment

Grade 2 acute radiation dermatitis of the chest wall (Figure 5).

Figure 5.

Grade 2 acute radiation dermatitis of chest

Grade 3 radiation dermatitis at completion of chemoradiotherapy for vulvar squamous cell carcinoma (Figure 6).

Figure 6.

Grade 3 acute radiation dermatitis of perineum

Predisposing factors: Both treatment and patient parameters have been implicated as contributing to the development of acute radiation dermatitis.

Treatment factors:

  • Exposure to therapeutic radiation, particularly with a minimum total dose of 20-25Gy

  • May be caused by diagnostic radiation equipment, so careful history regarding imaging procedures such as fluoroscopy (or procedures where fluoroscopy was known to be utilized, such as cardiac catheterization) and CT scan with associated body site is imperative

  • Beam energy

  • Higher risk if fractionation more than 2.5Gy per day

  • Radiation field modifiers (such as the use of bolus material on skin)

  • Obtain radiation records (dose per fraction, total dose, field size, field geometry) and evaluate area of radiotherapy exposure on skin as delineated by tattoos for correlation of objective findings and radiation-exposed area

  • Site of field abutment

  • Areas of skin folds

  • When the intended target for treatment is within or close to the skin surface

  • Use of concurrent radiation sensitizers, such as chemotherapy (examples include: cisplatin, 5 Fluorouracil, docetaxel, pacletaxel, doxorubicin, gemcitabine)

Patient Factors:

  • Ataxia telangiectasia: rare form of autosomal recessive disorder resulting in impaired cellular DNA repair capabilities

  • Gorlin syndrome (hereditary basal cell nevus syndrome): multiple basal cell carcinomas develop and have an affected tumor suppressor gene; sequelae of radiation could include the development of diffuse cutaneous tumors

  • Scleroderma places patients at risk for both devastating acute and late toxicity and represents a contraindication to therapeutic radiation

  • Active systemic lupus erythematosus also represents a relative contraindication to therapeutic radiation, increasing the risk for the development of both acute radiation dermatitis and late radiation toxicity

  • Other autoimmune disorders, such as rheumatoid arthritis, polymyositis, and others, have been suggested in the literature to place patients at increased risk for acute radiation reactions, including radiation dermatitis

  • HIV

  • Obesity

  • Poor nutrition

  • Chronic defects in skin integrity

  • As yet incompletely characterized genetic factors (example: polymorphisms of the IL-12RB2 and ABCA1 loci are suggested to increase dermatitis in Japanese breast cancer patients receiving radiotherapy)

Late Radiation Dermatitis:

Epidemiology

Obtain radiation records (dose per fraction, total dose, field size, field geometry) and evaluate area of radiotherapy exposure on skin as delineated by tattoos with potential areas of field abutment.

Predisposing factors:

  • Higher risk if daily fractionation scheme of more than 2.5Gy is utilized

  • Large radiation field volume

  • Treatment field on the trunk, extremities, head and neck

Table II. Objective grading systems for late radiation dermatitis (skin)

Table II.

Objective grading systems for late radiation dermatitis (skin)
Chronic Radiation Dermatitis: Skin
Grade 0 1 2 3 4
Description None Slight atrophy; pigmentation change; some hair loss Patchy atrophy; moderate telangiectasia; total hair loss Marked atrophy; gross telangiectasia Ulceration

Table III. Objective grading systems for late radiation dermatitis (subcutaneous tissue)

Table III.

Objective grading systems for late radiation dermatitis (subcutaneous tissue)
Chronic Radiation Dermatitis: Subcutaneous Tissue
Grade 0 1 2 3 4
Description None Slight induration (fibrosis) and loss of subcutaneous fat Moderate fibrosis but asymptomaticSlight field contracture<10% linear reduction Severe induration and loss of subcutaneous tissueField contracture>10% linear measurement  Necrosis

Grade 1 chronic skin and subcutaneous radiation dermatitis (Figure 7)

Figure 7.

Grade 1 late skin and subcutaneous toxicity

Grade 2 chronic skin and grade 2 chronic subcutaneous dermatitis with superimposed in-field cutaneous squamous cell skin recurrence (Figure 8, Figure 9)

Figure 8.

Grade 2 skin and subcutaneous dermatitis

Figure 9.

Skin recurrence in prior field treated for lung carcinoma

Grade 3 right inframammary fold telangiectasia following altered fractionation radiotherapy (Figure 10)

Figure 10.

Right inframammary fold telangiectasia post altered fraction radiotherapy

Grade 3 late telangiectasia (Figure 11)

Figure 11.

Grade 3 late skin toxicity

Occuring from days to 6 months following radiation exposure

Pathophysiology

This involves a cascade of complex interrelated reactions that begin immediately following first exposure to radiation therapy resulting in the progression of acute radiation dermatitis from erythema to dry desquamation and, potentially, moist desquamation.

Initially free radicals cause DNA damage and subsequent recruitment of inflammatory cells. Stem cells are functionally disrupted, with endothelial cell changes and epidermal cell death, all within a background of inflammation.

Due to the loss of the cutaneous barrier function, patients are at risk for bacterial superinfection. Loss of the basal layer stem cells occurs with reduced mitotic activity, also affecting the hair follicles, sebaceous glands and epidermis.

Basal cells that survive, however, are spread throughout the irradiated area and are able to repopulate the monolayer. For patients who develop acute radiation dermatitis out of proportion to the radiation treatment regimen, consideration should also be given to rheumatological evaluation for potentially undiagnosed autoimmune or connective tissue disorder, particularly in the young patient population.

Erythema: Onset is hours to weeks with recovery time of weeks to 2 months

  • Postulated to be mediated by cytokines as well as free radical production and DNA damage

  • Inflammatory cell recruitment with increased vascularization

  • Increased pigmentation and epilation

  • Cell death

  • Pathologically, dermal/epidermal edema present, with associated vasodilatation, erythrocyte extravasation, thrombi; scattered apoptotic keratinocytes often present

Dry desquamation: Onset is weeks to 2 months with recovery requiring 1 to 2 months post-treatment

  • Results from treatment effect upon basal cells

  • Impaired function of basal cells with reduced production of linoleic acid leading to atypical keratinization

  • Overall reduction in basal cell numbers from loss of mitotic activity

Moist desquamation: Onset is weeks to 2 months with recovery requiring 3 to 6 weeks following therapy

  • Epidermal death potentially associated with loss of linoleic acid and basal cells

  • Loss of barrier function resulting in increased infection risk

  • Pain due to exposure of nerves following epidermal erosion

  • Most problematic in moist skin folds, areas of tangential radiation dose, with the use of concurrent radiation sensitizing chemotherapy and with the use of radiation modifiers on the skin (bolus)

Occuring from ten weeks to years following radiotherapy

Pathophysiology

Fibrosis

  • TGF-ß implicated in the development of late radiation fibrosis

  • Fibroblasts activated to produce extracellular matrix protein

  • Endothelial cell proliferation up-regulated with down-regulation of epithelial growth factor

  • Characterized by slowly progressive process

  • Clinical appearance of edema, epidermal atrophy, progressive induration, contraction

  • Common in an area of prior significant acute radiation reaction

  • Loss of rete peg pattern at dermal interface and papillary dermis contains distorted acellular collagenous bundles

  • Eccentric myointimal proliferation of small arteries and arterioles with possible thrombosis or obstruction

  • Collagen sclerosis with large atypical fibroblasts and telangiectasia help distinguish from post-radiation morphea

Telangiectasia

  • Underlying pathogenesis unknown

  • Postulated to potentially be due to microvascular damage during the acute phase of radiation dermatitis

  • Both vascular sclerosis and radiation fibrosis are related to the development of endothelial cell damage and vascular injury

  • Visible telangiectasia results from the presence of multiple dilated, thin-walled vessels in an atrophic dermis underlying a thinned epidermis

  • Some channels can be in direct contact with the basement membrane

  • Clinical appearance of a pink to red blush of small blood vessels that appear near the skin surface, due to overlying epidermal thinning, in a previously-irradiated field

Ulcer

  • With skin atrophy and decreased dermal fibroblasts, the risk of ulceration is increased

  • Due to continued reduction in stromal support, and probably microvascular damage, cell necrosis results with ulcer development

  • Cytokine mediated delay in re-epithelialization also potentially contributes to ulcer development and persistence

  • Assessment for superinfection required, as increased risk due to avascular nature if tissue and impaired barrier function

  • Increased risk is also associated with medical comorbidity such as vascular disease, hypertension, diabetes, autoimmune/connective tissue disorders

Treatment Options

: Acute Radiation Dermatitis

Prevention

More than 20 trials have been reported in the literature evaluating products for potential prevention of acute radiation dermatitis. Unfortunately, direct comparison is challenging due to varying patient populations, methodology and agents studied. The only preventive measure clearly supported in the literature is cleansing of the skin within the radiation field.

  • Gentle cleansing with water alone or mild soap

  • Non-binding clothing/fabrics that naturally breathe

  • Avoidance of adhesives on the skin within the radiation field

  • Reduce bolus effect of skin folds through patient positioning during treatment.

  • Avoidance of additional skin irritants (examples: talc, aluminum salts found in many deodorants)

  • Avoidance of UV exposure within the radiation field during and after the course of therapy

  • Suggestion in the literature that calendula may have preventive value, with demonstrated reduction in severity of radiation dermatitis

  • Many anecdotal reports of reduction in radiation dermatitis with a variety of additional skin care products, however, no randomized data regarding the reduction in severity of or frequency of radiation dermatitis are available

Topical therapy

Erythema and dry desquamation: Again, the methodology among the trials was varied, with absence of statistical analysis in some trials, a wide range of patient populations included and differing radiation techniques.

Therapy studied in a randomized fashion:

  • Calendula - an extract from a plant in the marigold family, compared to trolamine in a phase III study which demonstrated a significant reduction in the development of RTOG grade 2 or higher radiation dermatitis in breast radiotherapy as well as reported symptomatic relief. Criticism of the study was that nearly 30% of patients found the calendula difficult to apply versus 5% in the trolamine arm and the study was only single-blinded.

  • Corticosteroids - studies report conflicting results regarding the ability of these products to reduce the severity of radiation dermatitis, despite many anecdotal reports by patients of symptomatic relief. Despite a variety of trials in the literature, no proven preventive value and no documented preference with regard to steroid preparation and the degree of symptomatic improvement following the development of radiation dermatitis. Most commonly used topical steroid remains hydrocortisone 1-2.5% strength. No evidence to support or refute whether atrophy, telangiectasia, or infection (documented risks of topical steroid therapy) are increased in the setting of topical steroid use.

  • Hyaluronic acid containing product - studied in a randomized fashion compared to placebo and demonstrated to delay the onset of radiation dermatitis, reduce the severity of symptoms and accelerate tissue repair (studied in breast, head and neck, and pelvic radiotherapy patients).

  • Sucralfate cream - studied with mixed results; in breast cancer radiotherapy, one study suggested reduction severity of radiation dermatitis.

  • Trolamine-containing radioemulsions - studies have not demonstrated clear role for prevention, however, symptomatic improvement reported.

  • Emollients (creams or ointments) - symptomatic relief reported.

Therapy associated with anecdotal or non-randomized evidence:

  • Petrolatum-based emollients

  • Hydrogel dressings

  • Next-generation non-petrolatum based agents (castor oil, balsam of Peru, trypsin)

  • Varied topical agents including: aloe, chamomile, almond ointment, D-panthenol

Topical therapy: moist desquamation

In addition to the products outline above for symptomatic relief, hydrogel dressings are commonly used, if not already in use. For barrier, hydrophilic and lipophilic products are utilized. Topical antibiotic agents such as silver sulfadiazine cream are also used to provide symptomatic relief, promote healing and reduce the risk of superinfection.

Systemic Therapy

In the setting of superinfection, antibiotic coverage is appropriate as the clinical setting dictates (for example: standard coverage of common skin pathogens versus antibiotic coverage appropriate for complicated perineal/perianal wounds). Amifostine has been studied in the setting of rectal cancer and demonstrated a reduction in erythema, however, no randomized studies have been performed to evaluate the use of amifostine for this purpose. The routine use of amifostine for the prevention of radiation dermatitis is not supported.

Treatment Options: Chronic Radiation Dermatitis

Ulceration

Most of the treatment paradigms are gleaned from the wound care literature. Dressings range from transparent films and hydrogel dressings to hydrocolliod or foam dressings.

For persistent eschar formation associated with ulceration, debridement may be required. Risk versus benefit regarding the extent of debridement must be considered due to the potential for delayed healing in the post-radiation setting.

Hyperbaric oxygen has also been used in the management of chronic ulceration. The mechanism of hyperbaric oxygen therapy includes: the formation of neovascularization in irradiated bed, improved neutrophil function, bacteriostasis (including both aerobic and anaerobic), regulation of the gene expression for PDGF-ß receptor and stimulation of prolyl hydroxylase in collagen production.

Fibrosis

To reduce or prevent functional impairment, physical therapy with attention to range of motion and maintenance of tissue integrity is imperative. The most commonly used systemic therapy is pentoxifylline, with or without vitamin E. The most common clinical use of pentoxifylline is in the inhibition of platelet aggregation.

The mechanism of action is felt to include: increase in phagocytic activity of monocytes and PMN leukocytes, decreasing cytokines, modulating intercellular adhesion molecule-1, and antagonizing TNF a and ß.

No effect upon acute radiation dermatitis has been demonstrated with pentoxifylline. In both human and animal studies, however, reduction in the degree of fibrosis was noted even in established disease, in addition to reports of associated reduction in pain. Reduction in fibrotic change was also confirmed histopathologically in studies of pig skin.

Other therapies studied in human and/or animal models include liposomal copper/zinc superoxide dismutase injected intramuscularly and interferon gamma injected subcutaneously. Although studied, these modalities have not gained widespread implementation. Hyperbaric oxygen therapy has not been shown to have an effect on chronic fibrosis. Although corticosteroids may provide symptom reduction for the inflammatory component associated with fibrosis, there is no evidence that corticosteriods are able to treat the established fibrotic process.

Telangiectasia

The only therapeutic modality in common use is vascular laser.

Optimal Therapeutic Approach: Acute Radiation Dermatitis Sequential therapeutic approach for worsening dermatitis:

  • Gently cleanse skin (water alone or water with mild soap)

  • Skin moisturizer (calendula, petrolatum-based, hyaluronic acid-containing, trolamine and/or emollients)

  • Topical corticosteroid if continued pruritis despite above

  • Hydrophilic dressing consideration

  • Topical agents, such as silver sulfadiazine, in the event of moist desquamation

  • Oral antibiotics with suspected superinfection

Optimal Therapeutic Approach: Chronic Radiation Dermatitis

Ulceration

  • Early involvement of full complement of healthcare professionals, including Dermatology, Surgery, Wound Care, Hyperbaric Medicine and Radiation Oncology

  • Debridement of necrotic tissue/eschar

  • Appropriate antibiotic therapy if any sign of superinfection

  • Hyperbaric oxygen therapy once recurrence excluded and if no medical contraindications

Fibrosis

  • Maintenance of functional capacity represents the priority in management, with resultant reduction in quality of life impact. Therefore, with any patient demonstrating radiation induced fibrosis in a location likely to result in functional impairment, referral to physical therapy should be performed. Although there is no randomized literature support, the preference is to refer to a physical therapist who is also certified in lymphedema therapy. Despite the fact that these are two separate diagnoses, this population of physical therapists has increased familiarity with the post-radiation patient population and the management of fibrotic change that often accompanies lymphedema.

  • With significant fibrosis, particularly associated with impairment of function or quality of life, therapy with pentoxifylline and vitamin E should be considered, Dose range for pentoxifylline supported in the literature is up to 400mg, with a dose of 500IU of vitamin E. For patients who demonstrate toxicity to pentoxifylline, studies have shown persistent benefit with continued vitamin E alone. The recommended duration of therapy, pending patient tolerance and continued objective evidence of response, is at least 6 months.

Patient Management

Acute Radiation Dermatitis

  • All patients should be managed in combination with their treating radiation oncologist

  • If clinically required, histologic confirmation of diagnosis may be necessary. Great care should be taken with regard to biopsy in the setting of acute radiation dermatitis and ongoing radiotherapy due to risk (delayed healing, increased risk of superinfection, potential delay in radiotherapy with compromise in cancer outcome) versus benefit (pathologic confirmation, appropriate/altered clinical care based on histopathologic information) ratio.

  • Most patients will require surveillance on an every 1-2 week basis until resolution

Chronic Radiation Dermatitis

  • All patients should be managed in combination with their treating radiation oncologist

  • If clinically required, histologic evaluation may be necessary for diagnostic confirmation

  • Involvement of other healthcare professionals as necessary (surgery, physical Therapy, wound care)

  • Initiation of pentoxifylline and vitamin E in the event of symptomatic radiation fibrosis, particularly with active or potential functional impairment

  • For ulceration, aggressive wound care (debridement, dressings, etc.) as indicated based on degree, with early involvement of hyperbaric medicine physicians once the potential etiology of recurrent disease is excluded from the differential diagnosis

  • Surveillance schedule optimized for the extent of intervention the patient is receiving. For acute intervention (debridement) weekly assessment will be required; for evaluation of effectiveness of oral or hyperbaric therapy, weekly to monthly visits will be required depending on the patient’s clinical status is acceptable.

Unusual Clinical Scenarios to Consider in Patient Management of Acute Radiation Dermatitis

EGFR-inhibitor induced skin change within radiation field: diagnosis and management

Patients receiving EGFR inhibitor concurrent with radiotherapy may present with both acute radiation dermatitis and the classic acne-like rash resulting from this drug class. The most commonly affected patient population is the head and neck cancer patient.

Documented skin changes associated with the use of EGFR inhibitors include: folliculitis (maculopapular pustular rash), hyperpigmentation, dryness, and telangiectasia. The rash can commence within days of drug administration and generally progresses to only Grade 1-2 skin change.

Pathophysiology of the rash includes up-regulation of a negative growth regulator in the epidermis with a possible resultant decline in cell growth and differentiation.

High concentrations of EGFR are expressed in epidermis and hair follicles.

Commonly used treatment modalities for EGFR inhibitor induced skin reaction are oral antihistamines for pruritus, topical anti-inflammatory agents, oral antibiotics with coverage including Staphylococcus aureus, oral tetracyclines for Grade 2 or higher reactions, and/or supplemental topical saline for Grade 3 reactions.

Steroids are generally avoided due to the potential negative impact on cancer therapy efficacy due to the mechanism of action of EGFR inhibitors.

Phase III trials have evaluated the skin toxicity profile of radiation therapy with or without cetuximab. No significant increase in the probability or severity of radiation dermatitis was observed in these trials.

Review of other trials has suggested an increase in skin toxicity (acute radiation dermatitis and/or folliculitis) with other EGFR inhibitors when combined with systemic chemotherapy (particularly multiagent docetaxel and cisplatin).

Unusual Clinical Scenarios to Consider in Patient Management of Late Radiation Dermatitis

Post-radiation morphea: diagnosis and management

Post-radiation morphea may often pose a diagnostic dilemma for clinicians, predominantly due to its involvement outside the previously-radiated skin leading the clinician away from a radiation induced toxicity.

Clinical presentation has been reported to include the development of a maculopapular erythematous abnormality generally within the previously irradiated field, however, non-contiguous sites outside the radiation therapy field have also been reported in association with the primary lesion.

Onset can occur from months to many years following therapy, however, most of the reports suggest most commonly the onset is within 1 year post-treatment.

Early lesions may appear as erythematous plaques with associated edema, however, late lesions are indurated and may become painful.

Confirmation through biopsy demonstrates characteristic histopathological findings and the location of the biopsy should be determined based on the areas of involvement and relative risk associated with post-biopsy complications.

Histologically, dermal lymphoplasmacytic infiltration is found, with possible involvement of the subcutaneous fat. In the early course of these lesions, inflammation is prominent, however, in more established lesions, dermal collagen is found to be thickened and sclerosed.

The literature also suggests that this phenomenon is indistinguishable from idiopathic morphea. The absence of atypical radiation fibroblasts also supports diagnosis of post-radiation morphea (established lesion) rather than chronic radiation dermatitis. Post-radiation morphea has not been reported in the literature to progress systemically.

The most commonly reported treatment is steroid preparations (no preference with regard to specific agent) delivered topically, orally, or by intralesional injection. The disease course is reported as variable, with instances of spontaneous regressions noted. In instances of severe symptomatology, surgical resection has also been performed.

Therefore, there is no ’standard’ management course supported in the literature. However, consideration of topical or oral steroids would be recommended as the primary management modality for persistent symptomatic lesions following pathological confirmation.

What is the Evidence?

Archambeau, J, Penzer, R, Wasserman, T. "Pathophysiology of irradiated skin and breast". Int J Radiation Oncology Biol Phys. vol. 31. 1995. pp. 1171-1185.

(This article provides an excellent overview of some of the history of the change in radiation technology and its impact upon the skin effects. The authors summarize the “anatomic-physiologic/functional skin unit” consisting of the epidermal and dermal shells, with the skin functional unit being the smallest unit of skin that “retains all characteristics of skin” estimated to be 30 micrometers (µm) in diameter by 350µm in length.The authors note that the skin configuration model emphasizes that the dose response of the functional units define the dose response of the skin to radiation.The pathophysiology and radiobiology of skin reactions to radiotherapy are outlined, with particular attention to the changes identified with various fractionation schemes and total doses. These correlate closely with observed experiences in direct patient care, namely the onset of objective acute radiation-associated skin changes only after approximately 2-3 weeks of daily standard fractionated therapy, consistent with the development of change in basal cell density.Based on this and other referenced publications within this article, it is accepted that “skin irradiation with a defined radiation and time-dose schedule produces a reproducible pattern of gross change that is “dose dependent” and reflective of “continuous remodeling of these populations”.)

Bernier, J, Bonner, J, Vermorken, J, Bensadoun, R, Dummer, R, Giralt, J. "Consensus guidelines for the management of radiation dermatitis and coexisting acne-like rash in patients receiving radiotherapy plus EGFR inhibitors for the treatment of squamous cell carcinoma of the head and neck". Annals of Oncology. vol. 19. 2008. pp. 142-149.

(The authors address two prevalent toxicities associated with the current treatment of patients with squamous cell cancer of the head and neck. A common treatment scheme for this patient population includes concurrent radiotherapy and chemotherapy. The class of drugs termed EGFR ingibitors is associated with a characteristic acne-like skin rash which, together with acute radiation dermatitis, can pose a management challenge.The incidence of Grade 0-2 skin toxicity with standard fractionated radiotherapy is 45-95%, with an incidence of Grade 3 or greater toxicity of 6-27%. The increase in toxicity with altered fractionation is also well documented.A phase III randomized study demonstrated no significant increase in the incidence or severity of acute radiation dermatitis with cetuximab. There was a slight increase in the median duration with concurrent cetuximab.The auhors comment that there is currently no evidence that prophylactic treatments, beyond keeping the irradiated area clean and dry, are effective in reducing acute radiation dermatitis. Excellent tables are provided with summaries of possible management options, which are incorporated into the listed options outlined above.)

Bolderston, A, Lloyd, N, Wong, R, Holden, L, Robb-Blenderman, L. "The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline". Support Cancer Care. vol. 14. 2006. pp. 802-17.

(The authors address the topic of acute radiation dermatitis in this review conducted by the Cancer Care Ontario's Supportive Care Guidelines Group (SCGG).As per the article, the report was developed by Cancer Care Ontario's program in Evidence-based Care (PEBC), consisting of four main componenents: systematic review of evidence and interpretation of data, external review by Ontario practitioners, approval by the PGCC before dissemination and regular update of document as new evidence becomes available.The literature reviewed for this publication was published between 1980 and April 2004, with methods described in the publication. The authors cite that the “variety of interventions assessed made it difficult to thoroughly evaluate individual interventions”. A total of 28 trials were included in the review, 25 of which were randomized controlled. Of the randomized controlled, 20 used the patient as the unit of randomization and five used the treatment side.The authors summarize the trials in Tables 1-3, dividing the citations into those directed toward prevention of acute radiation dermatitis and those addressing management options. In addition, Table 3 outlines the tumor type, radiation therapy regimen, adjuvant treatments, and/or co-interventions.Regarding prevention, the authors conclude that gentle skin washing should be unrestricted. Although the authors do summarize the phase III calendula trial, they also summarize some of the criticisms of this trial and, therefore, do not include calendula in the routine prevention of acute radiation dermatitis.With regard to the additional summarized management options, the authors conclude that there is “limited evidence” to support additional topical agents and that “overall, the benefits do not outweigh the risks in the trials evaluating the efficacy of oral and intravenous agents” for prevention of acute radiation dermatitis. With regard to the topic of management of acute reactions, the authors conclude that “as none of the trials demonstrate a positive effect on skin reaction, recommendations on the best management of radiation skin reactions cannot be made”.)

Delanian, S, Balla-Melias, S, Lefaix, J. "Striking regression of chronic radiotherapy damage in a clinical trial of combined pentoxifylline and tocopherol". J Clin Oncol. vol. 17. 1999. pp. 3283-3292.

(As radiation doses have been increased in an attempt to provide higher tumor control rates, the evaluation of normal tissue doses has become more important in limiting the potential for acute and late radiation morbidity. As treatment planning and delivery has evolved, the reduction of normal tissue doses, including skin dose, has been achievable. Unfortunately, high dose exposure is not completely avoidable and, as a result, there remains a risk of chronic radiation damage.The authors outline the pathophysiology of radiation induced fibrosis (RIF) and both the qualitative as well as quantitative changes identified in four patients with 50 “zones” following 400mg pentoxifylline and 500IU alpha-tocopherol (vit E). The therapy was delivered twice daily for at least 6 months, with assessments by two physicians using the SOMA grading scale. Clinical regression was noted in all 41 areas of palpable RIF with a statistically significant mean reduction of the RIF surface by 53% at 6 months. Continuous slow efficacy noted even after 12 months.On the quantitative scale, all fifty assessable patients responded, with 50% reduction in SOMA scores at 6 months. Early poor response was not indicative of the extent and quality of the delayed maximum response. Therapy was well tolerated with six patients requiring alteration: two patients stopped therapy due to other comorbid medical history, two patients with dose reduction of pentoxifylline from 800mg to 400mg daily and continued vit E, and two patients requiring cessation of pentoxifylline with continued vit E.)

Hymes, S, Strom, E, Fife, C. "Radiation Dermatitis: Clinical Presentation, pathophysiology, and treatment 2006". J Am Acad Dermatol. vol. 54. 2006. pp. 28-46.

(The authors provide an extensive overview of the grading systems used for acute and chronic radiation dermatitis. They also review the pathophysiology of radiation-induced changes, including the vascular changes, cytokine pathways, and resultant cellular changes responsible for the objective findings clinically appreciated.The authors provide a summary of risk factors associated with radiation dermatitis and associated pathophysiology. These include: dose fractionation schedules, physical factors, genetic factors, connective tissue disease, infectious disease, and radiosensitizers.The authors review the differential diagnoses when considering radiation dermatitis and outline a variety of management options with associated literature references, where appropriate.In conclusion, the authors note the importance of mulidisciplinary care of this patient population and the impact of advances in radiation therapy delivery on the resultant toxicity. The authors also recognize the role that advancements in immunology are important in the ongoing investigation of therapeutic options for this patient population.)

Maddocks-Jennings, W, Wilkinson, J, Shillington, D. "Novel approaches to radiotherapy-induced skin reactions: A literature review". Complementary Therapies in Clinical Practice. vol. 11. 2005. pp. 224-231.

(The authors provide a summary of topical therapies and supporting literature. Skin toxicity anticipated to impact 87% of patients receiving radiotherapy according to the authors, prompting the interest by researchers and health care providers. The authors review the historical indications, possible pharmacologic mechanisms of action, and literature surrounding the topical uses of: aloe vera, fixed vegetable oils, essential oils, and hydrocortisone.)

Morganroth, P, DeHoratius, D, Curry, H, Elenitsas, R. "Postirradiation morphea: A case report with a review of the literature and summary of the clinicopathologic differential diagnosis". Am J Dermatopathology. vol. 0. 2010. pp. 1-5.

(The differential diagnosis includes recurrent malignancy, acute/chronic radiation dermatitis, radiation recall dermatitis, and cellulitis. The diagnosis is most commonly reported in breast cancer patients, but documented in other cancer patients, including lymphoma, endocervical cancer, gastric cancer, and endometrial cancer.The article summarizes a case report in a 45 year old woman treated for a stage T2N3 carcinoma of the left breast using lumpectomy, chemotherapy and radiation with standard regimens for all. At 6 years post-treatment, the patient developed a blanchable erythematous patch with palpable fullness. Multiple punch biopsies were taken, all of which demonstrated superficial and deep perivascular and interstitial infiltrate composed predominantly of lymphocytes and plasma cells. Thickening and sclerosis of collagen bundles found in deep reticular dermis which these authors treated using 0.5% clobetasol ointment.A reduction in erythema and fullness was noted at 10 week follow-up. Clinical and pathologic images are provided in this publication. Additional references also provided for case reports of post-radiation morphea. This diagnosis is differentiated histopathologically from acute radiation dermatitis in which dermal/epidermal edema is noted with vasodilation and erythrocyte extravasation as well as thrombi. Chronic radiation dermatitis is contrasted by the presence of large, atypical fibroblasts and telangiectasia in addition to the collagen sclerosis also seen in post-radiation morphea.)

Pommier, P, Gomez, F, Sunyach, MP, D'Hombres, A, Carrie, C, Montbarbon, X. "Phase III randomized trial of Calendula ofifcinalis compared with trolamine for the prevention of acute dermatitis during radiation for breast cancer". J Clin Oncol. vol. 22. 2004. pp. 1447-1453.

(This trial was conducted between 1999 and 2001 including 254 patients receiving postoperative radiation therapy in France. The patients were randomized to the application of calendula (126pts) or trolamine (128pts) twice daily or greater at the onset of radiation. They continued application through the entire course of radiation and no other topical agents were allowed.Acute dermal toxicity was rated weekly by the radiation therapist using the RTOG scale at each irradiated volume: breast/chest wall, and, if applicable, submammary fold, axilla, internal mammary nodes, supraclavicular nodes. Pain was assessed using the 10cm visual analog scale (VAS).The patient and treatment characteristics were very similar in both groups except the total radiation dose delivered after lumpectomy (p=0.06), where 15.3% and 6% of patients in the trolamine and calendula groups, respectively, received < 61Gy. The incidence of grade 2-3 toxicity in the calendula group was 41% versus 63% in the trolamine group (p< 0.001).Grade 3 toxicity was seen in 7% (nine patients) in the calendula group and 20% (20 patients) in the trolamine group (p=0.034). Treatment was interrupted in one patient in the calendula group and 12 patients in the trolamine group due to skin toxicity. Multivariate analysis of prognostic factors associated with skin toxicity grade 2 or higher included trolamine ointment (p<0.001), BMI > 25 (p<0.001), lumpectomy and chemotherapy before radiotherapy (p=0.01), and BMI > 25 and chemotherapy before radiotherapy (p=0.013).Calendula was statistically significantly superior to trolamine for the primary end point, prevention of skin toxicity RTOG grade 2 or higher, and for all secondary endpoints, with the exception of ease of application, which was considered more difficult by patients with calendula.)

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

(A total of 99 breast cancer patients receiving radiotherapy (between April and June 1998) were prospectively randomized prior to radiotherapy into two groups: (1) no washing allowed during radiation (2) washing allowed during radiation with water and soap. Acute skin toxicity was rated using the RTOG scale (weekly and at 1 month following completion of radiation) and the VAS scale was used for symptom assessment at the same time intervals.The incidence of moist desquamation was higher in the non-washing group (33% vs. 14%, p=0.03) The maximum toxicity scores reported were also higher in the non washing group when compared to the washing group (p=0.04). On multivariate analysis, after correcting for other treatment variables, skin washing showed a trend toward reduced toxicity that did not reach statistical significance.The authors provide an excellent discussion of other studies, which have suggested the significance of skin washing in the reduction of toxicity. The authors postulate the use of different scales, possible discordance of interobserver grading, and the grouping of a variety of skin toxicities within each RTOG grade level as possible etiologies of these differences. in results.The authors conclude that, at a minimum, gentle skin washing is safe during radiotherapy and should not be discouraged. Based on the available literature, and the possible suggestion that bacterial/fungal overgrowth may play a role in the development of moist desquamation, washing may be beneficial.)

Salvo, N, Barnes, E, van Draanen, J, Stacey, E, Mitera, G, Breen, D. "Prophylaxis and management of acute radiation-induced skin reactions: a systematic review of the literature". Current Oncology. vol. 17. 2010. pp. 94-112.

(This article represents a follow-up study to the above-referenced article by Bolderston et al. A similar template was utilized and a literature review was performed between January 2000 and October 2008. In this review, a total of 39 trials met the inclusion criteria, 33 of which addressed prevention of acute skin reactions and six which evaluated regimens for existing skin reactions.The references are summarized in tabular form (Tables I-III). The authors conclude that “overall, the many trials evaluating a large variety of products and methods for the prevention of acute radiation-induced skin reactions do not support a general consensus on a superior product that should be used in this setting”. With regard to the management of acute reactions, the authors encourage further trials evaluating this subject due to the difficulty in comparing the available literature resulting from the wide variety of studied options.)
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