Late toxicities management

Late toxicity management

Patients who receive palliative radiation therapy (RT) generally have limited life expectancy. Historically, late toxicity has been uncommon in this population given the typically lower total radiation doses used in palliative RT and the relatively long latency to manifest. However, patients with incurable cancer generally live longer with modern treatments, and palliation is now characterized by more aggressive dose regimens. Practitioners of palliative radiation oncology thus need to consider potential toxicity and how to manage these toxicities.

Palliative radiation may encompass any part of the body, and general toxicity management is included as a part of each chapter in this text. This chapter will focus on two more common late toxicities of RT: skin and spinal cord toxicity. The shared themes between these areas reflect general commonality in the management of late radiation effects.

Part I: Late skin toxicity

The regenerative properties of the epidermis make the skin a highly sensitive organ to radiotherapy (RT). Acute skin reactions are commonly observed during RT courses for a variety of malignancies. There are also chronic manifestations of radiation-induced skin damage which present in the months to years after completion of treatment. The constellation of late skin effects after RT may be referred to as a “late skin reaction” or “chronic radiation dermatitis” in the literature. A late toxicity is traditionally defined as an effect that manifests 90 days or greater after treatment; however, there may be long-term cutaneous changes which appear even sooner. Unlike acute skin toxicities, which occur during or shortly after a course of RT and typically improve as the epidermis regenerates, chronic skin toxicities are much less likely to undergo self-repair and are potentially permanent. Hallmarks of late radiation-induced skin damage include the promotion of inflammation, fibrosis, and disturbance of the microvasculature. These cutaneous effects of treatment can vary widely in their physical manifestation and severity. Available supportive and invasive treatments aim to mitigate symptoms or potentially reverse damage to skin and underlying soft tissue.

Clinical manifestations of late skin toxicity

The chronic skin changes induced by RT may vary significantly in their presentation, onset, and severity. The changes observed may include alterations in skin pigmentation, texture, vascularity, or cellularity. Late cutaneous effects can compromise patient quality of life by causing poor cosmesis, chronic pain, delays in wound healing, or limitations in activities of daily living (ADLs). There are two standardized scales commonly used in the United States to assess the severity of late radiation-induced toxicities: Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group—European Organization for Research and Treatment of Cancer (RTOG—EOTRC) scales. The relevant adverse events included in these scales and their severity grade are summarized in Tables 33.1 and 33.2 . A summary of the described late skin toxicities and their treatment strategies can be found in Table 33.3 .

TABLE 33.1

CTCAE v5.0 Grading Scale for Late Radiation Skin Toxicities

Adverse Event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Atrophy	Covering <10% BSA; associated with telangiectasias or changes in skin color	Covering 10%–30% BSA; associated with striae or adnexal structure loss	Covering >30% BSA; associated with ulceration	–	–
Hyperpigmentation	Hyperpigmentation covering <10% BSA; no psychosocial impact	Hyperpigmentation covering >10% BSA; associated psychosocial impact	–	–	–
Hypopigmentation	Hypopigmentation or depigmentation covering <10% BSA; no psychosocial impact	Hypopigmentation or depigmentation covering >10% BSA; associated psychosocial impact	–	–	–
Induration	Mild induration, able to move skin parallel to plane (sliding) and perpendicular to skin (pinching up)	Moderate induration, able to slide skin, unable to pinch skin; limiting instrumental ADL	Severe induration; unable to slide or pinch skin; limiting joint or orifice movement (e.g., mouth, anus); limiting self-care ADL	Generalized; associated with signs or symptoms of impaired breathing or feeding	Death
Telangiectasia	Telangiectasias covering <10% BSA	Telangiectasias covering >10% BSA; associated with psychosocial impact	–	–	–
Ulceration	Combined area of ulcers <1 cm; nonblanchable erythema of intact skin with associated warmth or edema	Combined area of ulcers 1–2 cm; partial thickness skin loss involving skin or subcutaneous fat	Combined area of ulcers >2 cm; full-thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend down to fascia	Any size ulcer with extensive destruction, tissue necrosis, or damage to muscle, bone, or supporting structures with or without full-thickness skin loss	Death

ADL, Activities of daily living; BSA, body surface area; CTCAE, Common Terminology Criteria for Adverse Events.

TABLE 33.2

RTOG—EORTC Grading Scale for Late Radiation Skin Toxicities

Organ Tissue	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Skin	Slight atrophy; pigmentation change; some hair loss	Patch atrophy; moderate telangiectasia; total hair loss	Marked atrophy; gross telangiectasia	Ulceration	–
Subcutaneous tissue	Slight induration (fibrosis) and loss of subcutaneous fat	Moderate asymptomatic fibrosis; slight field contracture <10% linear reduction	Severe induration and loss of subcutaneous tissue; field contracture >10% linear measurement	Necrosis	–

EORTC, European Organization for Research and Treatment of Cancer; RTOG, Radiation Therapy Oncology Group.

TABLE 33.3

Summary of Treatment of Late Cutaneous Toxicities

Manifestation	Nonpharmacologic Therapies	Pharmacologic Therapies	Comments
Xerosis	Mild, neutral soaps Topical moisturizers
Dyspigmentation	Epilation laser therapy (hyperpigmentation)		May resolve spontaneously with time
Telangiectasia	Pulsed dye laser therapy
Fibrosis	Physical therapy Massage/myofascial release	Pentoxifylline 400 mg PO TID Vitamin E 400 U PO daily Pravastatin 40 mg PO daily × 12 months Experimental agents TGF-β inhibitors Anti-PDGF receptor TKIs (Gleevec) Superoxide dismutase and mimetics
Ulceration and necrosis	Barrier creams Hydrocolloid dressings Low-intensity helium-neon laser HBO Debridement Surgical Autolytic Enzymatic Skin grafting, flap, or skin substitute	Pentoxifylline ± vitamin E as above
Exudative wounds	Absorptive dressings HBO Debridement	Antibiotics Topical, silver-based Oral
Secondary malignancy	Biopsy and surgical removal as indicated
Radiation recall	Symptomatic care Routine skin care	Discontinue the associated medication Topical/oral antihistamines Topical/oral corticosteroids
Morphea	Observation Ultraviolet phototherapy	Topical corticosteroids Topical tacrolimus Intralesional triamcinolone Oral prednisone Methotrexate Cyclosporine
Bullous pemphigoid		High-potency topical corticosteroid Clobetasol 0.05% Oral corticosteroids Immunosuppressive agents Methotrexate Mycophenolate mofetil Rituximab

HBO, Hyperbaric oxygen; PDGF, platelet-derived growth factor; PO, orally; TGF- β, transforming growth factor beta; TID, three times daily; TKI, tyrosine kinase inhibitor.

Skin appearance and texture

The most common late effect of RT on the skin is chronic dyspigmentation, which can present as hyper- or hypopigmented skin within the treatment field. Changes in skin pigmentation are caused by radiation-induced alterations in both melanin production and migration in the epidermis. Skin hyperpigmentation can manifest before the completion of RT and may persist permanently or fade spontaneously over months to years after treatment. Common textural changes that may appear after treatment include chronically dry skin (xerosis), thickened skin (hyperkeratosis), and induration. Chronic xerosis results from radiation-induced damage to sebaceous glands. Epilation occurs as part of the acute cutaneous reaction to RT. Permanent epilation of facial, pubic, or axillary hair is common after definitive courses of RT to these regions. Alopecia of the scalp is typically temporary after cranial irradiation; however, the risk of chronic alopecia is dose-dependent, with the risk rising to 50% at follicle doses of 40 to 45 Gy. The sensitivity of treated skin to sun exposure increases after RT, and precautions should be taken to prevent additional damage that may enhance the late cutaneous effects of RT.

Telangiectasias, often referred to as “spider veins,” are small, dilated blood vessels that may appear on the surface of previously treated skin. They appear as superficial webs of small, linear vessels that blanch upon palpation. The development of telangiectasias is a sign of underlying microvascular damage from RT. The probability of radiation-induced telangiectasia progression is dependent on the total skin dose delivered and the acute skin reaction severity. Telangiectasias can also be characteristic of cutaneous malignancies such as basal cell or Merkel cell carcinoma, and one should be suspicious of malignancy if telangiectasia is associated with papular or nodular appearance of the skin.

Radiation-induced fibrosis, ulceration, and necrosis

Radiation-induced skin fibrosis is the result of growth factors such as transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF), which lead to abnormal collagen and extracellular matrix deposition. The incidence of late skin fibrosis after breast radiotherapy is significantly associated with the use of boost dosing. ^, Fibrotic alterations of the skin may affect the patient by causing a functional limitation or decline in cosmesis. Physical manifestations of fibrosis include skin retraction, induration, pain, atrophy, contracture, and restriction of joint range of motion. Fibrotic changes can appear months to years after RT and are unlikely to improve or resolve spontaneously.

Late fibrosis can decrease the potential of cutaneous tissue to heal, and skin ulceration or necrosis may occur. Disorganized collagen deposition, reduced re-epithelialization, and vascular damage cause atrophy or ulceration of irradiated skin. Fragile skin is susceptible to the development of a wound even after minor traumas. Proper repair of tissue injury requires an organized sequence of early inflammation, formation of granulation tissue, angiogenesis, and tissue remodeling. These processes are often disrupted by the acute and chronic cutaneous damage caused by RT. Wound healing is further impaired by local hypoxia from RT damage to vascular endothelium. Necrosis of the skin results from avascularization and persistent dermal ischemia. Necrotic tissue can cause pain and predisposition to infection, and aggressive management is necessary to prevent the potentially life-threatening consequences of superinfection.

Secondary malignancy

Exposure of the skin and subcutaneous tissue to high doses of radiation may increase the risk of some secondary cutaneous or soft tissue malignancies. Factors that influence the risk of secondary malignancy after treatment include young age at the time of treatment, genetic disorders that increase patient radiosensitivity, RT dose, total treatment volume, and radiation techniques used. The risk of secondary nonmelanoma skin cancers is best documented in childhood survivors of pediatric malignancies, where a sixfold increase in risk has been observed in children receiving RT. Excess nonmelanoma skin cancers have been observed in adult Hodgkin’s lymphoma patients treated with RT compared to those treated with chemotherapy alone. The potential risk of secondary melanoma after RT has not been clearly established; some studies have reported no additional risk while others have demonstrated a slight increase in melanoma incidences in patients who received RT. ^, Any lesions that appear suspicious for a malignancy within a previous radiation field should be biopsied to confirm malignancy.

Radiation-associated angiosarcomas are rare soft tissue sarcomas that may arise within the previous radiation field, with a median latency of approximately 7 to 10 years after RT. ^, Secondary angiosarcomas are most commonly associated with prior breast RT, though occurrences have been reported after RT to other sites, including the neck and pelvis. Angiosarcomas appear as painless violaceous or erythematous nodules with accompanying ecchymoses or macules. Progressive swelling or skin thickening may also occur. The risk of secondary angiosarcoma development increases up to sevenfold after breast RT, though the cumulative incidence of secondary angiosarcoma is exceedingly low. Angiosarcomas are known to be locally aggressive, with a high rate of local recurrence even after a successful surgery. These malignancies also show a higher propensity for distant metastasis compared to other soft tissue sarcomas. Radiation-induced genetic alterations within tumor cells may be responsible for the aggressive nature and overall poor prognosis of RT-associated sarcomas.

Radiation recall, morphea, and rare manifestations

Radiation recall dermatitis (RRD) is an unpredictable phenomenon characterized by the emergence of an inflammatory reaction over previously irradiated skin in response to the administration of a chemotherapeutic agent. Recall is most commonly observed in breast cancer patients who receive sequential RT and cytotoxic chemotherapy. The incidence of RRD in patients receiving RT for breast cancer was reported to be 5.4% in one observational study of 350 patients. The interval from completion of RT to the recall effect can range from one week to multiple years, and it can appear within minutes to days after the first administration of the precipitating drug. RRD is most commonly mild-moderate in nature and can present as skin erythema, edema, desquamation, or maculopapular rash. More severe cases may exhibit ulceration, hemorrhage, or necrosis. The pathogenesis of radiation recall is not fully understood, but a few theories have been postulated. One prevailing hypothesis involves the development of an idiosyncratic hypersensitivity drug reaction, which has been primed by the radiation-induced proinflammatory state within treated skin. Another possible explanation is that chemotherapy pharmacokinetics become altered within previously-irradiated tissue due to vascular damage and permeability. Other hypotheses include impairment of epithelial stem cell function, genetic mutations, and accumulation of cellular damage after sequential therapies. A number of cytotoxic agents have been reported to induce radiation recall. These include, but are not limited to anthracyclines, taxanes, vinca alkaloids, dactinomycin, methotrexate, 5-FU, gemcitabine, and hydroxyurea. While radiation recall has been observed most frequently with cytotoxic chemotherapy use, noncytotoxic systemic agents have also been implicated. There are multiple reports of recall dermatitis with the use of antiestrogen therapies, such as tamoxifen for breast cancer. ^, Modern targeted systemic therapies such as tyrosine kinase inhibitors (TKIs) and Her2/neu-directed agents have also triggered reactions. In rare cases, RRD has been described after the use of simvastatin or antibiotics for tuberculosis. ^,

Radiation-induced morphea (RIM), also referred to as limited scleroderma, is a rare rheumatologic skin complication that can occur months to years after treatment with RT. The pathogenesis of morphea is not known but is thought to involve disruptions in local immunity and vasculature, which promote increased inflammatory infiltration and autoimmunity. While it is characterized by an increase in collagen deposition and skin thickening, morphea is distinct from radiation-induced fibrosis or other late cutaneous effects in that it may present in skin regions outside of the radiation field. The appearance of RIM may include erythematous plaques, sclerotic plaques, or indurated papules and is often associated with pain. RIM can commonly be mistaken for an unrelated dermatologic condition, infection, or secondary malignancy. A skin biopsy is useful in differentiating RIM from other differential considerations. A distinct feature on histological assessment of RIM is the presence of a marked infiltrate of lymphocytes and plasma cells, which is not seen in radiation fibrosis.

Other extremely rare late cutaneous effects of radiotherapy have also been described. Bullous pemphigoid is an autoimmune subepithelial blistering disorder resulting from the loss of basal keratinocyte adhesion to the basement membrane. There have been reported cases of bullous pemphigoid developing in the months to years after a course of RT, most commonly after breast RT. Radiation-associated bullous pemphigoid appears as subepithelial bullae, often preceded by a nonspecific pruritic rash, which is limited to the radiation field initially but progressively may become generalized. Diagnosis is made through biopsy and direct or indirect immunofluorescence showing Immunoglobulin G (IgG) and complement deposition along the epidermal-dermal junction. Drug hypersensitivity reactions have been reported with concurrent use of radiation with anticonvulsants such as phenytoin or phenobarbital. Erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis have occurred with the use of cranial radiation in conjunction with these medications.

Risk factors for late skin toxicity

There are a variety of factors that predispose patients to the development of late cutaneous changes after RT. The presence and severity of late toxicity are likely influenced by both treatment-related factors and patient factors. Predisposing factors related to treatment include total radiation dose, fractionation, technique, and the use of concurrent or sequential systemic therapy. Patient factors such as age, previous ultraviolet (UV) exposure, genetics, and medical comorbidities also play a role. The severity of a patient’s acute radiation dermatitis does not necessarily predict the subsequent development of late skin changes.

The total radiation dose delivered, dose fractionation schedule, and volume of tissue irradiated are all important determinants of chronic damage to tissue after treatment. ^, Higher total doses of radiation are commonly delivered to the skin during the treatment of breast, head and neck, musculoskeletal, skin, anal, and vulvar cancers. The volume of skin exposed to high radiation dose is dependent on treatment factors such as beam energy, field size required for treatment, boost dosing, use of bolus to increase skin dose, and treatment technique. The development of modern techniques such as 3D-conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) has improved the ability to limit skin exposure to high doses. Fractionation of a radiation dose into smaller daily doses allows for repair of normal tissue while tumors reoxygenate and reassort into sensitive phases of the cell cycle. Thus, hyperfractionated treatment schedules may minimize the risk of late tissue effects. Conversely, larger fraction sizes (>2 Gy/fraction) that are used in hypofractionated or stereotactic radiation treatments have traditionally been thought to increase the risk of late toxicities. This is particularly relevant to palliative RT, where hypofractionated regimens and partial or total re-irradiation are common. However, the use of hypofractionated RT to the breast has not been associated with an increase in late subcutaneous toxicities. The use of concurrent systemic therapies, including cytotoxic chemotherapy or targeted agents, may compound normal tissue damage induced by RT. The use of adjuvant chemotherapy after radiation has the potential to induce a radiation recall reaction over previously-treated skin.

Patient-related factors, both modifiable and non-modifiable, also increase the likelihood of chronic skin dermatitis. The risk of radiation-induced skin damage increases with age due to skin atrophy, microvascular changes, and diminished wound repair seen with normal aging. Preexisting skin damage from chronic sun exposure may also impact the degree of skin repair. There are genetic conditions that are associated with excess toxicity from RT, primarily due to genetic alterations in DNA repair pathways. Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder resulting from mutations in both copies of the AT-mutated (ATM) gene, which encodes the ATM protein responsible for promoting cellular repair of DNA double-strand breaks. Patients with AT exhibit extreme radiosensitivity due to the relative inability to repair DNA double-strand breaks induced by RT, and heterozygous carriers of ATM mutation may also variably show increased sensitivity. Similar genetic disorders of DNA repair pathways associated with radiation hypersensitivity include Nijmegen breakage syndrome (NBS), AT-like disorder (ATLD), and severe combined immunodeficiency (SCID). Pre-existing autoimmune collagen vascular disorders such as scleroderma, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and others are thought to potentially enhance cutaneous radiation toxicity through vasculopathy and tissue repair. Greater postradiation complications have been described in patients with scleroderma, though the impact of other collagen vascular disorders on late radiation toxicity has not been consistently demonstrated in retrospective analyses. The incidence of severe late events may be lower than previously expected. Cardiovascular comorbidities such as tobacco use or diabetes mellitus may augment postradiation vascular damage and incomplete healing.

Pathophysiology of late skin toxicity

Chronic radiation-induced skin damage is caused by an imbalance in proinflammatory and profibrotic cytokines. Ionizing radiation interacts with water within tissue, generating reactive oxygen species (ROS) capable of inducing oxidative damage and local pro-inflammatory responses. The release of cytokines such as tumor necrosis factor-α (TNFα), interleukin-1 (IL-1), and interleukin-6 (IL-6) promote an early inflammatory cascade in acute skin reactions. These generally inhibit fibrosis. The cytokines involving acute inflammation are typically short-lived, with most actions peaking at 4 to 8 hours after exposure to RT. However, the cytotoxic effects of RT may cause continued release of pro-inflammatory cytokines as affected cells undergo mitotic death days to weeks after RT. Oxidative stress, hypoxia, and endothelial damage can trigger tissue fibrosis through multiple cytokines and growth factors, namely TGF-β and PDGF. Overexpression of TGF-β1 is recognized as a key event in the production of matrix-producing myofibroblasts in response to ionizing radiation. TGF-β1 receptor binding leads to phosphorylation of Smad proteins that act as transcriptional promotors of target genes responsible for fibroblast proliferation and differentiation. These actions result in the disorganized deposition of excessive collagen and other extracellular matrix components that produce cutaneous fibrosis. Enzymes that degrade collagen, such as metalloproteinases, are inhibited by TGF-β.

PDGF also plays an important role in radiation-induced fibrogenesis. It stimulates the growth and migration of mesenchymal cells such as fibroblasts to a site of tissue injury. PDGF is stored in platelet granules; however, it is produced by other cell types, including macrophages, smooth muscle, and endothelial cells. Overexpression of PDGF occurs in the presence of hypoxia or proinflammatory cytokines, leading to pathogenic fibrosis. These fibrotic responses can be further perpetuated by radiation-induced damage of the vascular endothelium. Endothelial damage triggers microvascular thrombosis and restricted tissue perfusion, which further promote fibrosis, skin atrophy, necrosis, and diminished capacity to heal.

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