Conventional cytotoxic chemotherapy still plays an important role in cancer treatment. It works primarily through the inhibition of cell division. It is associated with many adverse events (AE), especially in some systems that share with the tumor the property of rapid cell proliferation and therefore a high rate of cell division, such as the hematopoietic and gastrointestinal systems, and the skin.2,4 Examples of common effects are emesis, cytopenias, alopecia, mucositis and nail changes. They are associated with dose, type of drug, time of infusion and are in most cases reversible with the end of chemotherapy cycles.

Belonging to this class of drugs are agents such as antimetabolites (e.g. capecitabine, fludarabine, cladribine, gemcitabine, 5-fluoracil), alkylating agents (e.g. cyclophosphamide, platins), topoisomerase inhibitors (e.g. irinotecan, topotecan, etoposide), anthracyclines (e.g. doxorubicin, daunorubicin), bleomycin, antimicrotubule agents (e.g. taxanes and vinca alkaloids). The related cutaneous adverse events to this class, most frequent causing agents and management (with level of evidence) are summarized in table 1.

In the last decade an enormous development on oncologic treatments have occurred, with the emergence of numerous targeted agents and immune checkpoint related agents. With those new mechanisms of action a totally new scope of adverse reactions has arisen, and professionals may not be familiar with the spectrum of dermatological toxicities.5–8 In one hand, those therapies were crucial for the improvement of survival. On the other hand, they created a new challenge: with the continuous and prolonged use of these drugs, patients and professionals have to deal with the chronic aspects of the toxicities, not anymore related with a specific number of chemotherapy cycles, but lasting for months to years, with an important impact on quality of life.

Targeted therapies inhibit specific molecules involved in tumor development and growth, having a more specific action than conventional chemotherapy, with greater efficacy and less toxicity. Many of those molecules are mutated or overexpressed on tumors, but are also present in normal tissues such as the skin. This justifies the common dermatological side effects related to this class. They might be monoclonal antibodies, large molecules that target extracellular components; or small molecule inhibitors, that can enter cells, block receptor signaling, and interfere with downstream intracellular molecules (they will be referred as Tyrosine Kinase Inhibitors – TKI).9 The main agents on this class are Epidermal Growth Factor Receptor Inhibitors – EGFRi (e.g. cetuximab, panitumumab, gefitinib, erlotinib, lapatinib); antiangiogenic agents, inhibitors of Vascular Endothelial Growth Factor Receptor – VEGFRi (e.g. bevacizumab, sorafenib); inhibitors of the Mitogen-Activated Protein Kinase (MAPK) pathway, such as RAFi (e.g. vemurafenib, dabrafenib), MEKi (e.g. cobimetinib, trametinib); mTOR inhibitors (e.g. everolimus); multikinase inhibitors (e.g. vandetanib, pazopanib, sunitinib); and Hedgehog pathway inhibitors (vismodegib). Related cutaneous adverse events to the agents on this class, their management and levels of evidence are summarized in table 2.

More recently, the comprehension of the regulatory processes involved in the restriction of the immune response to cancer, led to the development of a new promising group of agents, the “immune checkpoint” targeted agents, also known as immunotherapy. They have the goal of releasing the immune system against tumor cells, blocking inhibitory receptors expressed on T-cells such as Programmed Death 1 (PD-1) or Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4). This releasing/activation of the immune system also affects normal cells, explaining the most common adverse events related to this class, also known as Immune-Related Adverse Events (irAE). On this group we find the CTLA-4 inhibitor (ipilimumab), PD-1 and PD-1 ligand inhibitors (nivolumab, pembrolizumab, atezolizumab).7,10–13 Related cutaneous adverse events to the agents on this class, their management and levels of evidence are summarized on table 3.

Hyperpigmentation can occur at different sites and in different patterns (Fig. 1). They can start days to months after initiation and most of the times fade months after discontinuation of therapy. It can occur: (a) On photo distributed areas, preceded or not by photosensitivity signs; (b) As a serpentine supravenous hyperpigmentation after peripheral chemotherapy infusion (e.g. fluorouracil, docetaxel), that might be preceded or not by erythema and inflammation; (c) In a diffuse pattern, sometimes reticulated (doxorubicin, hydroxyurea, methotrexate); (d) Localized in areas of pressure, flexural areas or under occlusive dressings (ifosfamide, thiotepa); (e) As acral pigmentation (along the crease lines or macular, over the palms and soles).4,20

Figure 1.

Different hyperpigmentation patterns: (A) serpentine supravenous hyperpigmentation after peripheral chemotherapy infusion (fluorouracil); (B) nail plate pigmentation (daunorubicin); (C) acral lentiginoses (doxorubicin).

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Flagellate dermatitis and pigmentation is related to bleomycin treatment (20%–30% of patients) and occur as a pruritic erythematous linear streaks, followed by pigmentation (Fig. 2). Busulfan treatment can cause an “Addison-like” pigmentation, with a tan appearance.4

Figure 2.

Flagellate dermatitis associated to bleomycin treatment: (A) pruritic erythematous linear streaks, (B) followed by linear pigmentation.

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Patients should be oriented to adhere to sun-protective measures and bleaching agents might also be used to accelerate clearing.

Targeted therapies can also cause pigmentary changes such as a yellow pigmentation on sunitinib treated patients (VEGFRi). Hypopigmentation (diffuse or localized) is associated with c-kit inhibitors such as imatinib, especially in patients with darker skin, as c-kit also regulates melanocyte function. They are usually reversible with dose reduction or discontinuation.5

More recently, immunotherapy has been linked to vitiligo-like lesions, mainly but not only in melanoma treated patients. Associated hair depigmentation can also be observed. No definitive treatment exists and it usually persists after the completion of immunotherapy. Reports of white hair repigmentation are also available.10–12,21

Nail alterations during cancer treatment are frequent, usually well tolerated and disappear under cessation of treatment. However, in some circumstances they might be symptomatic and interfere with patient's daily activities.22

Conventional chemotherapeutic agents are usually related to alterations such as melanonychia (diffuse, transverse or longitudinal), leukonychia, onycholysis, Beau's lines, onychomadesis and onychorrhexis.

Taxanes are associated with painful subungual hemorrhage, followed by onycholysis and sometimes subungual abscess formation that are quite symptomatic, and might lead to dose reductions or treatment discontinuation (Fig. 3). The use of frozen gloves and socks during infusion might reduce the severity of nail alterations, but they are usually not well tolerated (nail toxicity, one study, 45 patients, side-to-side, 11% vs. 51%, p=0.0001).2,4,20 Drainage of hemorrhage and abscesses might be needed for symptoms relief, as well as culture guided antibiotic treatments.

Figure 3.

PATEO syndrome (PeriArticular Thenar Erythema and Onycholysis): docetaxel treated patient presenting with (A) erythematous lesions with a distinct distribution to the dorsal aspects of the hands and (B) associated nail changes – subungual hemorrhage and onycholysis.

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Both conventional and targeted treatments can cause nail plate alterations such as brittle nails, nail cracking and onychoschizia. Those effects can be handled with preventive measures such as reduction of contact to water, use of cotton gloves beneath plastic or rubber gloves for any wet work, avoidance of any damaging procedure (e.g.: aggressive manicuring), and hydration with thick emollients. Oral biotin and lacquers such as hydroxypropyl chitosan and poly-ureaurethane might be used, although no controlled study is yet available.22

For onycholysis, avoiding traumas (e.g.: keeping nails short) and humidity is important. If signs of pseudomonas colonization (green discoloration), a topical antibiotic might be used (we suggest ophthalmologic solutions such as tobramycin or ciprofloxacin eye drops twice daily).

VEGFRi are associated with asymptomatic splinter subungual hemorrhages (black, red or brown longitudinal lines) in 25–70% of patients, with fingernails being mostly affected.5,7

EGFRi are related to frequent nail toxicities, occurring in around 17.2% of patients on a previous meta-analysis.23 Periungueal fissures, paronychia and pyogenic granuloma-like lesions start to develop two or more months after initiation of therapy, on both finger and toe nails (Fig. 4). They are initially sterile, but secondary infection may occur. Preventive measures include the ones listed above and also the use of comfortable shoes, sometimes with cushioning inserts for the affected nails, adequate nail cutting and the use of antiseptic solutions such as Burrow's solution soaks, white vinegar soaks (1:1), bleach soaks (1/4 cup bleach: approx. 10l water), chlorhexidine or povidone iodine6,24–26 or a solution of sodium hypoclorite 2.5%, sodium chloride 1.0%, deionized water qsp 100mL (5 drops/1l). The use of oral tetracyclines is controversial as they were related to a decrease on the incidence of paronychia in some trials and showed no benefits on others.27 For fissuring, protective coverings such as hydrocolloid, biological glue or even cyanoacrylate glue to relieve pain and promote healing, barrier creams (petroleum jelly, zinc oxide cream) and thick emollients might be used. For granulomas, if secondary infection is suspected, culture is indicated and proper antibiotics should be prescribed. For non infected lesions, destructive measures such as trichloroacetic acid (70–90%) or cryotherapy might be used. Potent topical steroids, occlusive or not, are also indicated.28 Sometimes surgical treatment might be necessary. Recently, the use of topical betaxolol was described for treating a pyogenic granuloma-like lesion induced by EGFRi.29

Figure 4.

EGFR inhibitors related adverse events: (A and B) inflammatory papulopustular rash with associated xerosis (*); (C) trychomegaly and hypertrichosis; (D) periungual fissures and (E) pyogenic granuloma-like lesions. (A, B, D and E on cetuximab treated patients; C on panitumumab treated patient).

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Hand-foot syndrome (HFS), also known as palmoplantar erythrodysestesia, is a DAE related to conventional chemotherapeutic drugs, common with agents such as capecitabine, doxorubicin, cytarabine, 5-FU. It is preceded by prodrome symptoms such as tingling or pain at the extremities, followed by a symmetric, sharply demarcated erythema and edema of the palms and soles (Fig. 5). Vesicles and bullae might also be present. Pain usually limits daily activities and might be a cause of dose reduction or discontinuation. Incidence is higher with prolonged infusions or oral agents.2,4

Figure 5.

Toxic erythema of chemotherapy (TEC): combination of different lesions caused by direct toxicity of chemotherapy agents with (A) lesions on flexural areas (intertriginous eruption associated with chemotherapy) and (B) on palms and soles (Hand-foot syndrome – HFS).

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PATEO syndrome (PeriArticular Thenar Erythema and Onycholysis) is a variant of HFS, specific to the taxanes (docetaxel) (Fig. 3). It is characterized by scaly erythematous lesions with a distinct distribution to the dorsal aspects of the hands (overlying the joints) and thenar eminences. More rarely, it can also affect the dorsum of the feet. Although common, nails are not universally affected. It is usually bilateral, not necessarily symmetric. It may start on the first chemotherapy cycle or develop progressively. Burning sensation and pain are the most reported symptoms.20

Hand-foot skin reaction (HFSR) is another variant of acral toxicity related to targeted therapies, with both monoclonal antibodies and small molecules tyrosine kinase inhibitors especially with those targeting VEGFR (bevacizumab, sorafenib, sunitinib) and BRAF (vemurafenib) (Fig. 6). Despite the similar palmoplantar distribution, dose dependency and associated pain, HFSR develop on friction or trauma-prone areas (pressure areas), such as the heel and lateral aspects of the soles and web spaces. Lesions start 2–4 weeks after beginning of therapy and are characterized by hyperkeratosis, resembling skin calluses, occasionally with superficial blistering and erythematous halos.2,5,6,30,31 Depending on the drug, lesions might improve or not over time.32

Figure 6.

Hand-foot skin reaction (HFSR) associated with antiangiogenic agents (VEGFRi): (A) hyperkeratotic lesions (sorafenib) and (B) bullous lesions (axitinib) on areas of pressure and friction.

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One of the problems of better defining the DAE in many oncology trials is that frequently investigators report the different types of cutaneous eruptions as a skin “rash”. Yet, as we will see, there are different types of cutaneous eruptions, associated with different classes of drugs and with different treatment options.

Acute hypersensitivity reactions: those Type I immunoglobulin E-mediated reactions may occur within minutes to hours of infusion. They manifest as regular hypersensitivity reactions to conventional drugs, as pruritus, flushing, urticaria and even anaphylaxis. The difference relies though on the way we deal with it. With conventional drugs, patients are usually oriented to avoid re-exposure. When dealing with oncologic treatments, the chemotherapeutic agent is fundamental for disease related survival. Therefore, we usually maintain the drug for the next cycles and manage the reaction with a slower infusion, a premedication with corticosteroids and antihistamines before every infusion and a closer monitoring.4,6,7

Exanthema: many treatments may be related to a non-specific maculopapular rash or morbiliform eruption that starts gradually, sometimes weeks after the start of drug, with mild symptoms such as pruritus. Those DAE can be handled with anti-histamines and topical corticosteroids when limited, or with short courses of oral corticosteroids when more disseminated. All class of agents might cause those kind of reactions, such as kinase inhibitors (e.g.: BRAFi – vemurafenib/kit and BCR-ABL inhibitors – imatinib, dasatinib), “checkpoint” inhibitors (ipilimumab, nivolumab), and conventional chemotherapeutic agents (bleomycin, carboplatin, etoposide, etc.).4,6,7 Only in rare occasions severe reactions such as toxic epidermal necrolysis (TEN), Steven-Johnson syndrome (SSJ) or drug rash with eosinophilia and systemic symptoms (DRESS) might occur, but it must be remembered that a maculopapular rash may represent the first manifestation of those life-threatening conditions. Special attention should be given when using a targeted therapy after the use of an immunotherapy (e.g.: melanoma patients treated with immunotherapy and then switched to a BRAFi) as it may be associated with a higher risk of severe skin toxicity (> Grade 3 and SSJ/TEN). Some authors suggest at least a 4 week interval between treatments with those agents.7,48–50

When a patient is on immunotherapy, skin adverse events to conventional drugs (e.g.: antibiotics) might be more intense, so it is always important to exclude other causative agents, before relating the rash to the “checkpoint” inhibitor.

Toxic erythema of chemotherapy (TEC): this term is suggested by some authors to unify different manifestations such as HFS, intertriginous eruption of chemotherapy or other used histopathologic terms such as “eccrine squamous syringometaplasia”, all related to a direct toxicity of the chemotherapeutic agent and not due to an allergic reaction. This type of DAE is characterized by overlapping features of bilateral painful erythema, edema, and even bullous lesions located on hands and feet (see hand-foot syndrome), and sometimes also affecting intertriginous areas such as axilla and groins (less frequently ears, knees and elbows) (Fig. 5). It is important to distinguish, because those manifestations are usually self-limited, often resolving with desquamation and post-inflammatory pigmentation and not demanding aggressive measures. In addition, lesions develop 2–3 weeks after the chemotherapy cycle, usually when patient's defenses are lower (e.g.: neutropenia), being many times misdiagnosed as infections or graft-versus-host disease (GVHD). Treatment relies on topical corticosteroids and emollients, and educating the patient about the nature of the manifestation. It often recrudesces on the subsequent cycles. It might be milder with dose reductions.20,51

Papulopustular rash: also known as “acne-like rash” or “folliculitis”, this is the most common dermatological toxicity of EGFRi treatment (Fig. 4). It usually appears 1–2 weeks after initiation of therapy, starts with erythema, followed by the eruption of papules and pustules (sterile) on the face, scalp, upper chest and back, with a lack of comedones. Sometimes lesions extend to the limbs. Skin is usually dry, itchy and sensible (patients refer sensation of burning, stinging, tenderness). This AE has a high impact on patient's QoL and on social aspects of daily living, being a cause of dose reduction or even treatment discontinuation. The rash tends to improve around the 8th week, but usually persists, as a milder eruption, with periods of improvement and worsening. Other features that are present, especially later on treatment, are the already discussed paronychia, periungual fissures and granulomas, xerosis, pruritus and the yet to be discussed hair alterations such as trichomegaly, hypertrichosis and non-scarring alopecia.6,23–25,52

Treatment

Despite the acne-like appearance, topical agents used to treat acne and acneiform eruptions such as benzoyl peroxide, retinoic acids and salicylic acid containing products are contra-indicated. If the rash occurs, preventive measures should be maintained and to that, topical steroids can be added. If more pronounced and tetracycline was not started for prevention, it can now be initiated.6,23,24 Sometimes dose reductions might be necessary. If excessive crusting or secretion, cultures are indicated to exclude secondary bacterial infection. In those cases, culture guided antimicrobial treatment is indicated. Recently, a single RCT showed benefit with the use of a Chinese herbal topical compound (compared to placebo) for the treatment of the DAE related to targeted therapy, including the papulopustular rash.45 In addition, there are some reports and some personal experience on the use of low dose systemic isotretinoin for refractory cases.55

Acneiform eruption: conventional chemotherapeutic regimens frequently contain high doses of systemic corticosteroids, such as dexamethasone or prednisone. For that reason, steroid related acneiform eruption might occur and should be treated similar to the non-oncologic patients.

Photosensitivity reactions: oncologic treatments have been reported to cause both phototoxic or photoallergic reactions. Many conventional agents such as 5-FU and taxanes (mainly to UVB) have reported inflammatory rashes on photo-exposed areas.4,20 With EGFRi, not only photosensitive eruptions can occur, but also the other DAE can be exacerbated by photo exposure.6 One of the most photosensitizing agent is vemurafenib (BRAFi) with a proved sensitivity for UVA radiation, which is present on fluorescence lamps and passes through windows.5,7,56,57 Vandetanib (TKI) is also associated to a UVA sensitivity. Preventive sun protective measures are fundamental. If reaction occurs, it might be handled with topical steroids or short courses of oral steroids.

Keratosis pilaris-like eruption: this adverse event has been linked to the use of BRAFi and is characterized by diffuse follicular keratotic papules in a generalized distribution, resembling keratosis pilaris. Topical keratolytic agents might be used.7 Vemurafenib could also cause folliculocentric morbilliform rash (Fig. 7).

Figure 7.

BRAF inhibitor related adverse events: multiple keratoachantomas (A) and low grade squamous cell carcinomas (B) after withdrawal of MEK inhibitor and maintenance of BRAF inhibitor; (C) associated keratosis pilaris-like eruption on the lower limbs.

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Some general recommended measures for hair and scalp daily care include the use of a gentle shampoo, avoiding hot water, hair dyes and hair foaming.

Conventional chemotherapy-induced alopecia (CIA): is one of the most distressing events in cancer patients treated with conventional agents. It is caused mainly by an anagen effluvium and is usually (although not always) completely reversible 2–6 months after treatment is discontinued.2,20 It affects more often scalp hair, but eyebrows, eyelashes, and other body areas might also be affected. Hair loss will be influenced not only by the drug, but also by the route of administration, dosing and schedule (e.g.: high dose, intravenous, intermittent regimens are more prone to cause complete alopecia). Examples of agents with a high risk include cyclophosphamide, doxorubicin, irinotecan and taxanes (docetaxel and paclitaxel).

BRAF inhibitors: might be associated to the appearance of eruptive melanocytic nevi (EMN), change of preexisting nevi (both the increase and acquisition of dermatoscopic structures as well as the regression of nevi that have the BRAF mutation) and the appearance of new melanomas.72,73 Therefore, close dermatoscopic follow-up is recommended. The involution of BRAF inhibitor-induced EMN following the concomitant addition of MEK inhibitor has been described.74

Immunotherapy: recently, regression of multiple melanocytic nevi after immunotherapy for melanoma has been described.75,76

Epidermal neoplasms related to BRAF inhibitors: keratoacanthomas, squamous cell carcinomas and verrucal keratosis are a common DAE of BRAFi, they might also occur with some antiangiogenic agents (Fig. 7). This is probably due to the paradoxical stimulation of the MAPK pathway in BRAF wild-type cells. When MEK inhibitors are used in association, this AE is much less frequent. Lesions can be treated with surgical excision (when only a few lesions are present), destructive treatments (cryotherapy, curettage, etc.), topical treatments (keratolytics, 5-FU, imiquimod) or photodynamic therapy.7

Stomatitis related to mTOR inhibitors (rapamycin, everolimus, sirolimus): stomatitis is the most common AE and might be severe leading to dose adjustments. Different from conventional chemotherapy mucositis (broad ulceration with pseudo membrane formations), mTOR related stomatitis manifests as discrete aphthae on non-keratinized epithelium. They can be handled with antiseptic washes, topical steroids and anesthetics.7

Other eruptions related to immunotherapy: a non-specific maculopapular rash, as reported above, represents the most prevalent type of Immune-Related Adverse Events (irAE) to this class of agents. However, peculiar types of reactions have been described and include:

Lichenoid reactions: those eruptions can develop on both skin and/or mucosae (oral and genital). Oral involvement might also include xerostomia and taste change;

Psoriasis and rosacea: this agents might induce exacerbation or new onset of psoriasis;

Auto-immune bullous diseases: the development of auto-immune blistering disorders, especially bullous pemphigoid, have been reported.

Sarcoidosis: also reports of sarcoidosis (new onset or reactivation) are being recently published.

Vitiligo: immunotherapy has been linked to vitiligo-like lesions, mainly but not only in melanoma treated patients.64

A point of discussion is about whether or not the use of corticosteroids may antagonize the efficacy of immunotherapy. Current clinical data is limited and controversial. In some retrospective analyses, it was not associated with inferior responses to the oncologic treatment. A recent systematic review concluded that it “may not necessarily lead to poorer clinical outcomes”.77 On the other hand, retrospective analysis on lung cancer patients using corticosteroids at baseline or for irAE suggested a possible deleterious effect.78,79 Most of the current guidelines and expert panels do not contra-indicate its use.7,10–13 As there are no definitive conclusions, we suggest that corticosteroids should be used with caution and always discussing its use with the rest of the team, especially the oncologists. For steroid-refractory cases, other immunomodulatory agents such as mycophenolate, infliximab, methotrexate and others, and also rituximab for blistering diseases might be necessary and a few reports with their use have been published.