ABSTRACT: The increased approval of anticancer agents has led to unprecedented results, with improved quality of life and longer survival times, resulting in millions of individuals living with a diagnosis of cancer. Whereas these novel medical, surgical, and radiation regimens, or combinations thereof, are largely responsible for these remarkable achievements, a new, unexpected constellation of side effects has emerged. Most notably, cutaneous toxicities have gained considerable attention, due to their high frequency and visibility, the relative effectiveness of anti–skin toxicity interventions, and the otherwise decreasing incidence of systemic or hematopoietic adverse events. Optimal care dictates that dermatologic toxicities must be addressed in a timely and effective fashion, in order to minimize associated physical and psychosocial discomfort, and to ensure consistent antineoplastic therapy. Notwithstanding the critical importance of treatment-related toxicities, dermatologic conditions may also precede, coincide, or follow the diagnosis of cancer. This review provides a basis for the understanding of dermatologic events in the oncology setting, in order to promote attentive care to cutaneous health in cancer patients and survivors.
An estimated 1,399,790 cancer diagnoses were made in 2006. Of these, the majority will require interventions with radiation and/or chemotherapy, which, in turn, will contribute to 65% of individuals surviving 5 years after their initial diagnosis. Consequently, the number of cancer survivors has reached considerable numbers—about 9.8 million (or 3.5% of the total population) in the United States.[2,3] This longer survival has underscored the importance of emotional, social, and medical problems as integral components of continued cancer care. Notably, dermatologic issues occur frequently in individuals affected by cancer, leading to significant physical and psychosocial discomfort along with dose modification and/or interruption of important antineoplastic therapy.[4-6]
Despite their high frequency and negative impact on quality of life and clinical outcome in some cases, the majority of these untoward events are underrecognized and undertreated. This may be attributed, at least in part, to the recent approval of novel agents with unexpected toxicities, the aforementioned longer survival times, and lack of timely access to dermatology-oncology clinical programs. The importance of this field is underscored by an increasing number of published reports in recent years (Figure 1), as well as the establishment of interdisciplinary clinical programs dedicated to the management of untoward events to cancer therapies. This review describes common and clinically significant dermatologic problems in those whose lives have been affected by cancer.
Skin and the Cancer Patient
With dramatic increases in survival rates associated with most cancers and greater use of radiation and novel anticancer agents causing acute and chronic adverse reactions involving the skin, attention has increasingly focused on the dermatologic components of the cancer experience. The skin and its appendages are high-turnover tissues with epithelial, connective tissue, vascular, and neural components—all of which may explain the high frequency of pathobiologic events from drugs directed against rapidly dividing malignant cells. Whereas disorders preceding the diagnosis are of importance, as they may be the first indicators of an underlying neoplasm, and therapy-related events may affect survival, late events can have a significant emotional and physical impact.[4,7,8]
Importantly, conditions affecting dermatologic structures (ie, skin, hair, and nails) may present before the diagnosis of cancer, during therapy, or months to years afterwards. The categorization of such events based on chronology (in relation to the initial cancer diagnosis) allows for a better understanding of (1) malignancy-associated dermatoses, which tend to occur prior to or during the initial diagnosis; (2) therapy-related toxicities, which occur during treatment, and; (3) late events, which are usually chronic or persistent sequelae of therapeutic regimens or indicative of recurrence (Figure 2). Knowledge and management of these various manifestations by oncologists would represent a considerable step toward maximizing clinical outcomes and enhancing patients' well-being. This review describes the clinical presentation of common entities and their etiologies in each of these categories, with a greater emphasis on treatment-related events.
Dermatologic findings prior to or during the diagnosis of cancer may reflect a cancer syndrome that is inherited, caused by environmental carcinogens, or paraneoplastic (Table 1). Whereas the first two entities have well established causal genetic and external culprits, paraneoplastic syndromes are poorly understood, as they represent dermatoses that are distant to an underlying cancer yet believed to be causally and biologically related to it. Overall, the identification of malignancy-associated dermatoses is important, as they may represent the first signs of and allow for earlier diagnosis and treatment of solid or hematologic tumors.
Therapy-Related Dermatologic Toxicities
The clinical presentation and severity of skin toxicities will depend on factors such as dosing, schedule, vehicle, and agent utilized as well as functional status of the patient. Moreover, interactions between anticancer agents should also be taken into consideration, as they may affect drug bioavailability. More than 52 distinct skin toxicities have been reported as a result of 41 unique agents or their combination (Figures 3 and 4).
The appearance of erythematous papules or pustules is a common presentation with many agents, most notably those targeting the epidermal growth factor receptor (EGFR). Often inaccurately referred to as acne or acneiform, these toxicities are frequent, occurring in 45% to 100% of patients receiving these drugs (Figure 5A). Interestingly, some studies have shown a relationship between the severity of the rash and tumor response, underscoring the importance of maintaining patients on therapy, as those who could benefit the most are ones who require dose modification.
An inflammatory mechanism underlies this reaction, likely a consequence of altered keratinocyte proliferation, differentiation, migration, and chemokine expression. Early intervention with topical or oral corticosteroids or antibiotics with anti-inflammatory activity (ie, doxycycline(Drug information on doxycycline), minocycline(Drug information on minocycline)) has produced improvement in uncontrolled reports.[5,13-15]
An ill-defined, erythematous, mildly pruritic rash especially affecting the upper body is one of the most common reactions to all anticancer agents (Figure 5B). These effects are not considered to be allergic (type I) in nature, as repeated exposures do not lead to greater toxicity.[16-18] Histologic specimens of affected skin will show a mixed inflammatory infiltrate, which, when associated with eosinophils, is suggestive of this phenomenon. True allergic reactions—with anaphylaxis, angioedema, and urticaria—are not as frequent but have been reported with intravenous monoclonal antibodies and other agents, including docetaxel(Drug information on docetaxel) (Taxotere) or paclitaxel(Drug information on paclitaxel). Whereas the more common maculopapular rash responds to topical and/or oral corticosteroids, management of severe reactions consists of premedication with corticosteroids, antihistamines, and acetaminophen.
The impressive clinical presentation of blistering reactions and the consequent urgency that they dictate are well founded—the blistering disorders erythema multiforme, Stevens-Johnsons syndrome (SJS), and toxic epidermal necrolysis (TEN) are fatal in as much as 30% to 40% of cases.[20,21] Erythema multiforme lesions appear as asymptomatic targetoid erythematous dusky round maculopapules with violaceous to dusky centers. SJS syndrome manifests as vesiculobullous lesions with tissue denudation that involve the skin, as well as the conjunctiva, oral, and genital mucosa, affecting < 10% body surface area. TEN has a similar clinical presentation, but involves more than 30% of body surface area.
Treatment is supportive and includes transfer to a burn unit with antihistamines for pruritus, topical lidocaine(Drug information on lidocaine) for oral bullae and erosions, and broad-spectrum antibiotic coverage for possible infections. Discontinuation of the offending agent is mandatory, and the use of intravenous corticosteroids or immunoglobulins remains controversial.[19-22]
Mucositis is a common side effect that may lead to significant morbidity, dose modifications, and life-threatening infections. Radiation, chemotherapy, and conditioning regimens for hematopoietic stem cell transplants are common culprits. Underlying mechanisms are a complex interaction of multiple factors.[23-26] Agents frequently implicated in mucositis are the antimetabolites and antibiotics, and pemetrexed (Alimta), a novel multitargeted antifolate agent that possesses antitumor activity against solid tumors such as mesotheliomas, non–small-cell lung, pancreatic, colorectal, gastric, bladder, breast, and head and neck cancers.[23-26]
Preventive and management strategies for oral mucositis include cryotherapy, and granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine). Benefit may also be obtained from amifostine (Ethyol), chlorhexidine(Drug information on chlorhexidine) gluconate mouthwashes, benzydamine(Drug information on benzydamine) (Canadian generic name), antibiotic pastilles, and proper oral hygiene. Palifermin (Kepivance) is a recombinant form of human keratinocyte growth factor that stimulates the growth of cells on the surface of the gastrointestinal tract and was shown to decrease the incidence of mucositis and swallowing difficulties. In the case of pemetrexed-associated mucositis, vitamin B12 and folic acid(Drug information on folic acid) supplementation may reduce most severe toxicities.[23-26]
Another disabling toxicity occurring in 6% to 42% of patients treated with certain agents (such as cytarabine(Drug information on cytarabine), fluorouracil(Drug information on fluorouracil) [5-FU], doxorubicin, and methotrexate(Drug information on methotrexate)), is known as palmoplantar erythrodysesthesia, acral erythema or hand-foot syndrome, and is characterized by the development of erythematous, burning, tender lesions on the palms and soles, with occasional blisters or bullae (Figure 6). This cutaneous toxicity is one of the most common toxicities seen with pegylated liposomal doxorubicin(Drug information on doxorubicin) (Doxil), which is doxorubicin encapsulated in polyethylene-coated liposome, and is thought to have a lower risk of cardiac toxicity than the noncoated formulation of doxorubicin.[27,28]
With docetaxel, there is a 70% incidence of cutaneous reactions (such as erythematous to violaceous macules or plaques) in acral locations, usually beginning 2 to 4 days after initiation of therapy, and occasionally causing pruritus or pain. Interference with activities of daily living is frequent, so it is critical to treat these untoward reactions. Histologic examination reveals apoptotic keratinocytes and nonspecific inflammation. Risk factors include higher peak and cumulative doses, age, and female gender.
Therapies include dose modification, pyridoxine(Drug information on pyridoxine), regional cooling, celecoxib(Drug information on celecoxib) (Celebrex), topical urea(Drug information on urea), and oral corticosteroids. Due to the lack of alternative therapeutic options, these findings have been generalized, so that widespread use of treatments against hand-foot syndrome is recommended for any patient with similar symptoms.
Radiation Dermatitis and Recall
Skin overlying an irradiated site is frequently damaged, which is characterized by erythema, edema, desquamation, pruritus, tenderness, necrosis, and in some cases, ulcers.[30,31] "Recall" occurs when skin overlying previously irradiated sites develops an inflammatory reaction with erythema, vesicles, dermatitis, and desquamation after the administration of antineoplastic agents. This phenomenon occurs from 2 days to 15 years after the initial radiation dose, and may also occur in internal organs, such as the lungs or gastrointestinal system. Data suggest that the late administration of an antineoplastic agent has an effect on tissues defective in stem cells and unable to tolerate an additional insult. Interestingly, higher doses of initial radiation seem to predispose to the development of radiation recall, a phenomenon that may also be secondary to ultraviolet radiation.[30-32]
Intertrigo, Skin Desquamation
Intertrigo appears as pruritic erythematous patches over the axillae, groin, and waist, as well as in high friction areas. It is commonly seen with pegylated liposomal doxorubicin therapy.[33-36] Intertrigo lesions are painful and erosive, and reduction in the drug dose is necessary to alleviate these painful skin lesions. Other treatment options include antifungals if the culprit is Candida species, or low-potency topical steroids. It is important to keep the involved area dry and clean.
Nonspecific erythema and skin desquamation are seen with many chemotherapeutic agents, including alkylating agents, antibiotics, and the camptothecins. Camptothecins exert their antineoplastic activity by binding to the topoisomerase I DNA complex and causing cell death during the S phase of the cell cycle. Two derivatives of camptothecin, irinotecan(Drug information on irinotecan) (Camptosar) and topotecan (Hycamtin), are relatively novel agents used in the treatment of advanced colorectal, gastric, lung, ovarian, and head and neck cancers. Skin erythema and desquamation are seen with camptothecin treatment. Emollients, and ointments, and topical steroids if needed, may help relieve symptoms of pruritus that may be associated with this cutaneous toxicity.
Cutaneous Ulcers and Vasculitic Lesions
Painful leg ulcers, commonly of the lateral malleolus are notoriously associated with hydroxyurea.[38,39] The average onset of ulcers is about 6 years after treatment initiation. Hydroxyurea, a hydroxylated derivative of urea that selectively inhibits DNA synthesis, is used to treat myeloproliferative disorders. Approximately 10% to 35% of patients who are treated with hydroxyurea will manifest skin eruptions. Gemcitabine(Drug information on gemcitabine) (Gemzar), cisplatin, and rituximab(Drug information on rituximab) (Rituxan) have been associated with vasculitis-induced ulceration.[22,40]
Early clinical detection, as manifested by livedoid reticulated pattern of the skin, is essential. In addition, when ulcers occur, a skin biopsy could help distinguish the different etiologies, such as neoplastic, therapeutic, vasculitic or infectious. Management includes discontinuation of the offending agent (hydroxyurea, gemcitabine), and prednisone at 1 mg/kg/d. Appropriate ulcer care is critical for patient comfort and care.
The antimetabolites, especially 5-FU, are known to cause reticulate hyperpigmentation. Hyperpigmentation and melanonychia have been reported to occur in 24% of patients treated with 5-FU. When infused intravenously, 5-FU causes a brown hyperpigmentation of the supravenous skin in 2% to 5% of patients. This hyperpigmentation may persist after discontinuing the drug and may increase in intensity after sun exposure. Eruptive pigmented skin lesions including lentigo maligna–like lesions are also known to occur with 5-FU treatment. Dactinomycin(Drug information on dactinomycin) (Cosmegen) has been associated with an erythematous linear pigmentation with follicular prominence and central desquamation.
Hyperpigmentation—global, localized, or the so-called flagellate—is also known to occur in patients treated with bleomycin(Drug information on bleomycin). Flagellate hyperpigmentation refers to linear streaks of hyperpigmentation, and these streaks are known to occur after a cumulative dose ranging between 90 and 285 mg.[40,41] They can manifest as early as 24 hours or as late as 9 weeks after initiation of bleomycin therapy. As many as 8% to 38% of patients on bleomycin develop these streaks. Fortunately, the hyperpigmentation is reversible after discontinuation of bleomycin.[40,41]
Inflammation of Actinic Keratoses
Inflammation of actinic keratoses occurs with cytarabine, capecitabine(Drug information on capecitabine) (Xeloda), gemcitabine, doxorubicin, bleomycin, vincristine, and 5-FU.[42,43] Actinic (solar) keratoses are highly common erythematous macules with fine gritty scale that are thought to be precursors to squamous cell carcinoma of the skin. When they get inflamed, actinic keratoses become bright red, pruritic, and sometimes painful. It is not surprising that inflammation of actinic keratoses occurs with cytarabine and 5-FU, since topical 5-FU is used to treat these lesions. Therefore, this side effect of 5-FU and cytarabine is considered to be beneficial, and treatment should not be discontinued. Topical steroids can be used to alleviate the inflammation.[42,43]
Connective Tissue Abnormalities
A dermatomyositis-like eruption was observed in patients on long-term treatment with hydroxyurea for myeloproliferative conditions. Such eruption manifests as violaceous erythematous papules over the dorsal metacarpal and interphalangeal joints of the hands (Gottron's papules), as well as periungual telangiectasias and erythema, and cuticular dystrophy. Scleroderma-like reactions were reported to occur in patients receiving taxanes. Docetaxel and paclitaxel are considered among the most potent chemotherapeutic agents that can be used to target multiple solid tumors, especially advanced breast cancer. Their mechanism of action involves the disruption of microtubules, hence, mitosis. Scleroderma-like skin changes include skin tightening of the upper and lower extremities, as well as contracture of the knees and all finger joints. In some cases these fibrotic changes are reversible upon discontinuation of the drug.
5-FU induces skin atrophy that could persist even after discontinuation of the drug, because it inhibits fibroblast proliferation. Collagen(Drug information on collagen), hyaluronic acid, or other fillers can be used to manage such atrophy if it occurs in noticeable areas. In one study, 13% of patients on long-term hydroxyurea developed mucocutaneous atrophy, usually on the legs and other sun-exposed sites.