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Dermatologic Adverse Events of Cancer Therapy
Key Points
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Dermatologic adverse events (AEs) of cancer therapies can cause patient discomfort and impair their quality of life, increase the cost of medical care, and even result in dose modifications, all of which can negatively impact clinical outcomes.
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The traditional cytotoxic chemotherapies are commonly associated with dermatologic AEs such as alopecia, hypersensitivity reactions, xerosis, skin hyperpigmentation, nail changes, and hand-foot syndrome (HFS).
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Targeted therapies encompass drugs that inhibit selective molecules and pathways critical for carcinogenesis, tumor growth, and survival. The ensuing dermatologic AEs tend to vary depending on the entity targeted (e.g., epidermal growth factor receptor [EGFR], vascular endothelial growth factor/vascular endothelial growth factor receptor, immune checkpoints, mammalian target of rapamycin), although there is overlap.
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Acneiform rash, xerosis, skin hyperpigmentation, alopecia, hair disorders (e.g. dyspigmentation, hypertrichosis, trichomegaly, textural changes), paronychia, and mucosal inflammation are characteristic dermatologic AEs of the EGFR inhibitors. Treatment with inhibitors of angiogenesis often leads to HFS, exanthems, hair disorders (alopecia, dyspigmentation, and textural changes), xerosis, mucositis, and in the case of bevacizumab/aflibercept, impairment of wound healing. The immune checkpoint inhibitors often result in pruritus and maculopapular cutaneous eruptions, although their AE profile, as with other newly developed drugs, is emerging and pending further characterization.
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Timely recognition, prompt management of dermatologic AEs related to cancer treatment, and appropriate counseling are crucial for optimal clinical outcomes, and require a multidisciplinary approach involving oncologists, dermatologists, and nurses.
Introduction
Over the last few decades, treatment of cancer has evolved to include therapies that may be broadly categorized as traditional cytotoxic chemotherapies, hormonal therapies, targeted therapies, and immunotherapies ( Table 18-1 ). From the dermatologic perspective, cytotoxic chemotherapies have long generated much interest because of the potential to cause alopecia, their hallmark adverse event (AE). The introduction of various targeted therapies and immunotherapies in recent years, however, has led to the recognition of a broad spectrum of dermatologic AEs ( Table 18-2 ). Besides the physical and emotional impact, impairments in patients’ quality of life, and financial burden, these AEs may also disrupt cancer treatments. Therefore, their timely recognition and prompt management are crucial for optimal clinical outcomes.
TABLE 18-1
Overview of Drugs Currently Approved in the Treatment of Various Cancers
| Cytotoxic Chemotherapeutic Agents | ||||||
| Alkylating agents | Nitrogen mustards | Aziridines and epoxides | Alkyl sulfonates | Nitrosoureas | Hydrazines and triazine derivatives | |
| Mechlorethamine Cyclophosphamide Ifosfamide Melphalan Chlorambucil |
ThioTEPA Mitomycin-C |
Busulfan | Carmustine Streptozocin |
Procarbazine, Dacarbazine Temozolomide |
Hydroxyurea | |
| Antimetabolite agents | Folate Antagonists Methotrexate Pemetrexed |
Pyrimidine Analogs 5-Fluorouracil Capecitabine Cytarabine Gemcitabine |
Purine Analogs Mercaptopurine Thioguanine Fludarabine Cladribine |
| Topoisomerase-interacting agents | Topoisomerase I inhibitors Irinotecan, Topotecan |
Topoisomerase II inhibitors Anthracyclines Etoposide, Tenoposide Mitoxantrone |
| Antimicrotubule agents | Taxanes Paclitaxel Docetaxel Nab-paclitaxel |
Vinca alkaloids Vinblastine Vincristine Vinorelbine Vindesine Vinflunine |
Estramustine phosphate sodium |
| Epigenetic modulators | Histone deacetylase inhibitors Vorinostat Romidepsin |
Proteasome inhibitors Bortezomib Carfilzomib |
Demethylating agents 5-Azacitidine Decitabine |
| Retinoids | Bexarotene All-trans retinoic acid |
||
| Arsenicals | Arsenic trioxide | ||
| Targeted Anticancer Agents | |||
| EGFR inhibitors | EGFR inhibitors Erlotinib Cetuximab Panitumumab Gefitinib |
EGFR/HER2 inhibitors Afatinib Lapatinib |
EGFR/VEGFR inhibitors Vandetanib |
| Angiogenesis inhibitors | VEGF inhibitors Bevacizumab Aflibercept |
VEGFR inhibitors Sorafenib Sunitinib Pazopanib Axitinib Regorafenib Cabozantinib |
| BRAF inhibitors | Vemurafenib, Dabrafenib | |
| BCR-ABL inhibitors | Imatinib, Nilotinib, Dasatinib, Ponatinib, Bosutinib | |
| mTOR inhibitors | Everolimus, Temsirolimus | |
| MEK inhibitors | Trametinib | |
| SMO inhibitors | Vismodegib | |
| JAK inhibitors | Ruxolitinib | |
| PI3K inhibitors | Idelalisib | |
| BTK inhibitors | Ibrutinib | |
| ALK inhibitors | Crizotinib | |
| Immune checkpoint inhibitors | Ipilimumab, Nivolumab, Pembrolizumab | |
| Other monoclonal antibodies | HER-2 Trastuzumab Ado-trastuzumab emtansine Pertuzumab |
CD20 Rituximab Ofatumumab Obinutuzumab |
CD30 Brentuximab |
CD-52 Alemtuzumab |
| Other Anticancer Agents | ||||||||
| Endocrine agents | SERMs | ERDs | Aromatase inhibitors | LHRH agonists | Androgens | Antiandrogens | Somatostatin analogs | |
| Tamoxifen Toremifene Raloxifene |
Fulvestrant | Exemestane Anastrozole Letrozole |
Leuprolide | Fluoxy-mesterone | Flutamide Bicalutamide |
Megestrol acetate | Octreotide acetate | |
| Miscellaneous | |||
| l -Asparaginase | Bleomycin | Thalidomides Thalidomide Lenalidomide Pomalidomide |
|
EGFR, epidermal growth factor receptor; HER, human epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; BRAF, B-rapidly accelerated fibrosarcoma; BCR-abl, breakpoint cluster region-abelson; mTOR, mechanistic target of rapamycin; MEK, MAPK/ERK (extracellular signal-regulated kinase) Kinase; SMO, smoothened; JAK, janus kinase; Pi3K, phosphoinositide 3-kinase; BTK, Bruton’s tyrosine kinase; ALK, anaplastic lymphoma kinase; CD, cluster of differentiation; SERMs, selective estrogen receptor modulators; ERDs, estrogen receptor downregulators; LHRH, luteinizing hormone-releasing hormone.
TABLE 18-2
Common and Clinically Significant Dermatologic Adverse Events from Targeted Anticancer Agents
| Primary Molecular Target | EGFR | Multikinase | VEGF | VEGFR/PDGFR | BRAF | mTOR/PI3K | CD20 | HER-2 | CTLA-4 | PD-1 |
|---|---|---|---|---|---|---|---|---|---|---|
| Anticancer agents |
Cetuximab, Panitumumab, Erlotinib, Afatinib, Lapatinib | Imatinib (I), Nilotinib (N), Dasatinib (D) | Bevacizumab (B), Aflibercept (A) | Sorafenib (So), Sunitinib (Su), Pazopanib (P), Axitinib (Ax), Regorafenib (R), Cabozantinib (C) | Vemurafenib, Dabrafenib | Everolimus (E), Temsirolimus (T), Idelalisib (I) | Rituximab, Ibritumomab tiuxetan | Trastuzumab (Tr), Trastuzumab emtansine (T-DM1) | Ipilimumab | Nivolumab (Nv), Pembrolizumab (P) |
| Dermatologic adverse event |
||||||||||
| Skin | ||||||||||
| Cutaneous eruptions | +++ | +++ (B) | ++ | ++ | +++ (E, T) ++ (I) | + (Tr) | +++ | +++ | ||
| Maculopapular | ||||||||||
| Papulopustular (“acneiform”) | +++ ∗ | +++ (E, T) | + (Nv) | |||||||
| Keratosis pilaris-like | + | ++ | ||||||||
| Xerosis | ++ | ++ | ++ | ++ | ++ (E, T) | |||||
| Fissures (fingertips, toes) | ++ | |||||||||
| Skin infections (Bacterial, viral, fungal) | + | + | ||||||||
| Pruritus | ++ | ++ | ++ (B) | ++ | + | +++ (E, T) | +++ | +++ | ||
| Hand-foot skin reaction | + | +++ | + | +++ (T-DM1) | ||||||
| Photosensitivity | +++ | + | + | +++ | + (Nv) | |||||
| Pigmentary changes | + | + (A) | ||||||||
| Hyperpigmentation | ||||||||||
| Hypopigmentation | + (I) | + (Su) | ||||||||
| Depigmentation (vitiligo) | ++ (I) | ++ | + | |||||||
| Impaired wound healing | + | +++ | ||||||||
| Skin neoplasms (KA/cuSCC) † | + (So, R) | +++ | ||||||||
| Psoriasis exacerbation or psoriasiform eruptions | ++ (I) | |||||||||
| Lichenoid eruptions | + (I) | |||||||||
| Eruptive nevi | + (So) | |||||||||
| Facial edema | +++ | ++ (Su) | ||||||||
| Appendages | ||||||||||
| Hair | ++ | + | + | ++ (So, Su); + (P) | ++ | ++ (Tr) | + | |||
| Alopecia | ||||||||||
| Hypertrichosis, trichomegaly | +++ | |||||||||
| Curling | ++ | ++ | ++ | |||||||
| Hyperpigmentation | + (P) | |||||||||
| Hypopigmentation | + | + (Su); ++ (P) | + (P) | |||||||
| Nail | ++ | ++ (E, T) | ||||||||
| Paronychia | ||||||||||
| Nail abnormalities | ++ | ++ | ||||||||
| MUCOSAE | ++ | ++ | + | + | +++ (E, T) | |||||
| Mucositis, stomatitis | ||||||||||
| Bleeding, hemorrhages | + (B) | |||||||||
| Cutaneous and mucosal telangiectasia | + | +++ (T-DM1) | ||||||||
| Geographic tongue | + (B) | |||||||||
| Mucocutaneous reactions ‡ | + | |||||||||
∗ Incidence: + <10%, ++ 10% to 30%, +++ >30%.
† KA/cuSCC: keratoacanthoma/cutaneous squamous cell carcinoma.
‡ Mucocutaneous reactions include paraneoplastic pemphigus, lichenoid or vesiculobullous eruptions, Stevens–Johnson syndrome, and toxic epidermal necrolysis.EGFR, epidermal growth factor receptor; BCR-abl, breakpoint cluster region-abelson; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; PDGFR, platelet derived growth factor receptor; CD, cluster of differentiation; BRAF, B-rapidly accelerated fibrosarcoma; mTOR, mechanistic target of rapamycin; HER, human epidermal growth factor receptor; CTLA-4, cytotoxic T-lymphocyte antigen-4; PD-1, programmed cell death.
In this chapter, we provide an overview of the dermatologic AEs associated with major classes of cancer therapies, as well as the management options for common entities. To indicate severity, we have utilized the Common Terminology Criteria for Adverse Events (CTCAE), which is a descriptive tool with unified standards for physicians to communicate AEs using common language. The current version, CTCAE v4.0, was issued by the National Cancer Institute in May 2009, and reflects updates on the new AEs seen with targeted therapies, and grading to guide management ( ).
Cytotoxic Chemotherapeutic Agents
Alkylating Agents
The alkylating agents cause arrest of cell proliferation by forming covalent bonds within DNA bases. The main dermatologic AEs include hyperpigmentation, mucositis, alopecia, hypersensitivity reactions (HSRs), and xerosis associated with pruritus.
Nitrogen Mustards
Mechlorethamine is used intravenously to treat Hodgkin’s disease (MOPP regimen—mechlorethamine (mustargen) [M], vincristine [O], procarbazine [P], and prednisone [P]), and as part of topical formulations to treat cutaneous malignancies (early-stage mycosis fungoides, Langerhans cell histiocytosis, and cutaneous B-cell lymphoma). The dermatologic AEs include infusion-related reactions (phlebitis and chemical cellulitis), pruritus, alopecia, and angioedema. Other less frequent AEs include urticaria, erythema multiforme (EM)-like eruption, and hyperpigmentation (without preceding inflammation). With the topical formulation, irritant or allergic contact dermatitis is the most common acute complication. An increased risk of nonmelanoma skin cancers (NMSCs) with both systemic and topical use of mechlorethamine has also been reported.
Management of the cutaneous eruption includes topical corticosteroids (mild/moderate cases); oral corticosteroids and dose reductions may improve tolerability in a majority of patients with severe reactions. Topical retinoids, hydroquinones, and corticosteroids are effective in treating skin hyperpigmentation.
Cyclophosphamide is widely used in the treatment of various cancers, autoimmune diseases, and also during bone marrow transplantation (preparative stage). The most common dermatologic AE is alopecia (40% to 60%), which develops 3 to 6 weeks after the start of therapy. Other frequent AEs include injection site complications (erythema, swelling, and pain), mucositis, and reversible hyperpigmentation (diffuse or localized to palms and soles, or nails). Facial flushing, toxic erythemas, pruritus, hand-foot syndrome (HFS), and urticarial and anaphylactoid reactions have also been reported.
Ifosfamide , a structural isomer of cyclophosphamide, is indicated in the treatment of various solid tumors, lymphomas, sarcomas, and some pediatric tumors. Since the drug is infused, extravasation reactions can occur, and lead to local cellulitis. Patients may also commonly experience alopecia and hyperpigmentation. Of note, ifosfamide, in combination with other agents such as gemcitabine and etoposide, can result in severe oral mucositis and an extensive sunburn-like erythema with accentuation in the intertriginous and genito-anal areas.
Melphalan is used for the treatment of multiple myeloma (MM), as well as high dose myeloablative treatment prior to stem cell transplantation (SCT). It has been associated with radiation recall, urticarial and anaphylactoid reactions, and nail hyperpigmentation. When used in isolated limb perfusion to treat localized tumors (e.g., melanoma and sarcoma), it may lead to erythema, edema, blistering, temporary loss of nails, and hair growth arrest on the perfused extremity. Localized scleroderma has been reported as a rare complication.
Chlorambucil is used for the treatment of B-cell chronic lymphocytic leukemia (CLL) and lymphomas. Reported dermatologic AEs include HSRs presenting as urticaria and angioedema, erythematous eruptions, and toxic epidermal necrolysis (TEN).
Aziridines and Epoxides
ThioTEPA is used in the treatment of adenocarcinoma of the breast, ovary, and in post-transurethral resection of bladder tumor for papillary bladder cancer, myeloablation prior to SCT, and treatment of cavitary malignant effusions. Allergic reactions and immediate hypersensitivity reactions, alopecia, mucositis, and pruritus are common, while acute-onset, intense erythema of the palmoplantar surfaces, and hyperpigmentation of occluded skin have also been reported. As compared to adults, pediatric patients experience a higher rate of skin erythema progressing to desquamation and hyperpigmentation.
Mitomycin C is an antitumor antibiotic derived from the soil fungus, Streptomyces caespitosus . It is available for systemic use in the treatment of upper gastrointestinal, anal, and breast cancers, and topically for the treatment of ocular surface neoplasias. Intravesical instillation has also been used to treat noninvasive bladder tumors. Extravasation-related tissue injury, mucositis, immediate hypersensitivity reactions, and allergic contact dermatitis have been reported.
Alkyl Sulfonates
Busulfan is a component of many of the myeloablative regimens administered prior to autologous or allogeneic bone marrow transplantation, and is used to treat the chronic phase of chronic myeloid leukemia (CML). It has been associated with immediate hypersensitivity reactions, injection site reactions, toxic erythemas, pruritus, EM, and vasculitis. Hyperpigmentation (“dusky”) is the most characteristic dermatologic AE of busulfan, which presents as diffuse-bronze discoloration, most prominent on the neck, upper portion of the trunk, nipples, abdomen, and palmar creases.
Nitrosoureas
Carmustine (bischlorethylnitrosourea) is used systemically in the treatment of lymphoma, brain tumors, and myeloma, and locally for cutaneous T-cell lymphoma (CTCL) and melanoma. Most of the AEs are related to topical administration, and include erythema, burning, irritant or allergic contact dermatitis, and/or hyperpigmentation. The erythema may be accentuated in the intertriginous areas, and in severe cases, it is followed by telangiectasias, which may be transient or permanent. Secondary skin cancers are rare with topical carmustine.
Streptozocin is used to treat surgically incurable insulinomas and malignant carcinoid tumors. The commonly reported AEs include extravasation reactions leading to local inflammation, allergic dermatitis, and alopecia.
Hydrazines and Triazine Derivatives
Procarbazine is used as part of the MOPP regimen for Hodgkin’s disease, and also for brain tumors and bronchogenic carcinomas. The common dermatologic AEs include alopecia, immediate hypersensitivity reactions, and alcohol-triggered flushing, which is accompanied by headache and diaphoresis.
Dacarbazine is used in the treatment of melanoma, soft tissue sarcomas, neuroblastoma, rhabdomyosarcoma, and medullary thyroid carcinoma. Intravenous infusion may lead to chemical cellulitis and phlebitis. Alopecia and HSRs are common, although pruritic maculo-urticarial erythemas (on sun-exposed areas), and radiation recall dermatitis can occur. Reactions leading to hepatic and hematologic dysfunction can be fatal.
Temozolomide is an oral medication indicated for the treatment of brain tumors and melanoma. Erythematous eruptions, pruritus, immediate hypersensitivity reactions, alopecia, xerosis, erythema multiforme-like eruptions and Stevens–Johnson syndrome (SJS) have been reported.
Hydroxyurea
Hydroxyurea is administered orally in the treatment of myeloproliferative disorders. Dermatologic AEs are common and dose dependent, presenting as xerosis, localized or generalized hyperpigmentation, and painful cutaneous ulcerations (over microtrauma sites). With long-term use, characteristic dermatomyositis-like skin changes (self-limiting Gottron-like papules and streaky erythema, without muscular symptoms), and an increased risk of NMSCs in sun-exposed areas, have been observed. In addition, cutaneous atrophy, cutaneous vasculitis, fixed drug eruption (FDE), and mucositis have also been reported.
Antimetabolite Agents
Antimetabolites are cytostatic agents that block cell division by inhibiting the biosynthesis of nucleotides.
Folate Antagonists
Methotrexate is a common component of regimens that target both solid and hematologic malignancies. It has been associated with a number of dermatologic AEs (especially when used as daily chemotherapy rather than as low dose weekly therapy) including tender palmoplantar erythema and edema with fissures and blisters. These inflamed lesions may also be accompanied by bullous changes. Cutaneous ulcerations within preexisting plaques of psoriasis have been reported commonly with the use of methotrexate, although normal skin may also be affected. Ultraviolet (UV) recall phenomenon is common and presents with erythema on areas of skin that previously developed UV-induced solar erythema. Oral mucositis is a common complication, which significantly impairs the quality of life. Patients may benefit from therapy with systemic corticosteroids, high dose folic acid supplementation, dose modification, and alternative intravenous or intramuscular administration.
Pemetrexed is indicated in the treatment of mesothelioma and non-small cell lung cancer (NSCLC), in combination with cisplatin. Dermatologic AEs include drug eruptions, acute generalized exanthematous pustulosis (AGEP), and SJS/TEN. Radiation recall dermatitis is frequent, and varies from mild blanchable erythema to severe soft tissue necrosis within fields of previous irradiation. Anecdotal reports of topical corticosteroid have suggested benefits; however, there is no effective treatment yet. Edema of the eyelids and limbs, which may be striking and resemble fibrosis, has also been frequently reported.
Pyrimidine Analogs
5-Fluorouracil (5-FU) inhibits thymidylate synthase, and results in the depletion of deoxythymidine triphosphate. It is approved for use in gastroenterologic malignancies. Most patients experience dermatologic reactions, which may lead to discontinuation of therapy in 5% of patients (due to intolerability). Xerosis, alopecia, UV recall reaction, hyperpigmentation, melanonychia and immediate hypersensitivity reactions, and inflammation of actinic keratosis are the most common dermatologic AEs. It can also cause lupus-like lesions with systemic or topical use.
Capecitabine is a prodrug of 5-FU, and is used for the treatment of metastatic breast, pancreatic, and colon cancer. HFS is the most commonly cited dermatologic AE ( Fig. 18-1, A and 18-1, B ), which may represent a surrogate marker of antitumor efficacy. It may also result in dose reductions, although it can be prevented by celecoxib use. Treatment includes high potency topical corticosteroids and salicylic acid. In addition, hyperpigmentation, mucositis/stomatitis, alopecia, onychodystrophy, and cutaneous lupus have also been reported.
Cytarabine is indicated for acute and chronic leukemias and lymphomas. The most common dermatologic AEs include morbilliform eruptions and HFS. In addition, neutrophilic eccrine hidradenitis (NEH, presenting with asymptomatic erythematous plaques), SJS/TEN, mucositis/stomatitis, alopecia, dystrophy, and transient acantholytic dermatosis/Grover’s-like eruptions have all been reported.
Gemcitabine is used in the treatment of breast, ovarian, pancreatic cancers, and NSCLC. Morbilliform erythemas, leg edema ( Fig. 18-2 ), pruritus, alopecia, and photo recall are frequently noted. A specific pseudocellulitis or erysipeloid eruption (confined to edematous skin), radiation recall, HFS, localized skin sclerosis, linear immunoglobulin A (IgA) bullous dermatosis, mucositis, pseudolymphoma, and anal pruritus may occur. In rare instances, patients may experience distal necrosis and SJS/TEN.
Purine Analogs
Mercaptopurine is used in the treatment of acute lymphocytic leukemia (ALL). HFS, alopecia, eruptive nevi, hypersensitivity, and occasional mucositis have been reported. The risk of developing secondary skin cancers (either melanoma or nonmelanoma) may be increased.
Thioguanine is used in the treatment of certain leukemias. The dermatologic AEs include skin eruptions, alopecia, and photosensitivity (UVA) eruptions. There is an increased risk of developing NMSCs, which may be a reflection of skin damage exacerbated by photosensitivity.
Fludarabine is used in the treatment of B-cell CLL, and in some conditioning regimens for acute myeloid leukemia. Mucositis, exacerbation of psoriasis, transfusion-associated graft-versus-host disease (GVHD), and worsening of skin cancers have been reported in low incidences.
Cladribine is indicated for hairy cell leukemia. Erythema, pruritus, morbilliform erythemas (with or without eosinophilia), and injection site reactions have been reported. Rarely, skin necrosis (at the site of infusion) and TEN may develop.
Topoisomerase Inhibitors
These drugs interfere with the action of the topoisomerase enzymes (topoisomerase I and II) and cause DNA strand breaks, leading to checkpoint arrest and apoptosis. They are important components in chemotherapy regimens for the treatment of various cancers.
Topoisomerase I Inhibitors
Irinotecan is a component of first-line therapy (in combination with 5-FU and leucovorin) for metastatic colorectal cancer (mCRC). It is associated with alopecia (∼60%), hyperhidrosis (16%), rash (13%), and HFS (5%).
Topotecan is indicated for the treatment of metastatic ovarian, small cell lung, and cervical cancers in their advanced stages. The most common dermatologic AEs include alopecia (∼49%) and rash (16%), with pruritus and severe dermatitis being rare. Mucositis is common with both irinotecan and topotecan (88% and 32%, respectively).
Topoisomerase II Inhibitors
Anthracyclines , including doxorubicin, liposomal doxorubicin, epirubicin, and idarubicin, are widely used in the treatment of hematologic malignancies (e.g., leukemias, Hodgkin’s disease, MM, and other solid tumors, e.g., thyroid, breast, lung, stomach, ovarian, and bladder cancers, and soft tissue sarcomas). The most common dermatologic AEs include alopecia, morbilliform eruptions, perifollicular erythema and scaling, HFS, nail changes, and photo/radiation recall dermatitis.
Etoposide and teniposide are common components of chemotherapy for hematologic malignancies and many solid tumors. Alopecia, flushing, burning erythema on the face, upper back and chest, and mucositis are common. Rare dermatologic AEs include erythema multiforme-like eruptions SJS/TEN, hyperpigmentation, and radiation recall dermatitis.
Mitoxantrone is indicated for advanced hormone-refractory prostate cancer and acute non-lymphocytic leukemia in adults. The most common dermatologic AEs include alopecia, mucositis, and nail bed changes. Immediate hypersensitivity reactions, including urticaria and angioedema, have been reported.
Antimicrotubule Agents
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