Spotlight commentary: Navigating the cutaneous side effects of chemotherapy

Despite the advent of targeted drugs and immunotherapies, traditional chemotherapy remains a core element of cancer treatment and is likely to remain so for the foreseeable future. Anticancer therapies can be broadly classified into classic cytotoxic chemotherapies, targeted therapies (eg, small-molecule kinase inhibitors and monoclonal antibodies), immune checkpoint inhibitors and hormonal (endocrine) therapies. Each class is associated with a distinct spectrum of cutaneous adverse effects. These skin-related side effects are among the most visible and impactful treatment toxicities, affecting patients' quality of life, body image and psychological well-being. Indeed, dermatological adverse events range from mild transient rashes to severe, chronic conditions and even life-threatening reactions in rare cases (eg, Stevens-Johnson syndrome). Common examples include alopecia, hand-foot syndrome (acral erythema), maculopapular eruptions, acneiform rash, mucositis, nail changes, photosensitivity and pigmentary disorders. In this Spotlight Commentary, we aim to summarize the cutaneous toxicities across different classes of anticancer agents (Table 1), discuss their mechanisms and management, and highlight emerging strategies to mitigate these effects. In line with the British Journal of Clinical Pharmacology (BJCP) Spotlight Commentary format, we also contextualize recent BJCP publications on this topic.1 For instance, a recent BJCP case report described an immune checkpoint inhibitor causing vitiligo, and a 2025 BJCP pharmacovigilance analysis investigated combination therapy-related dermatological adverse reactions.2, 3 Such studies underscore the clinical significance of these toxicities. Understanding and managing cutaneous adverse effects is essential for optimizing patients' care and adherence to therapy. Prophylaxis: gentle skin care, moisturizers, sunscreen and possibly oral doxycycline from start of therapy. Treatment: topical steroids (eg, hydrocortisone) and antibiotics (clindamycin gel); oral doxycycline or minocycline for moderate cases; isotretinoin for refractory severe rash. Dose modify or interrupt cancer therapy only for severe (Grade 3) cases. Reduce friction/heat exposure to hands/ft during treatment. Preventive: emollients to keep skin supple; avoid hot water. Treatment: topical urea or salicylic acid creams to reduce thickening; cold packs for pain; topical corticosteroids for inflammation; dose interruption or reduction for persistent Grade 2 or any Grade 3 symptoms. Prevention: oral cryotherapy (ice chips) during infusions of mucositis-causing drugs; maintain excellent oral hygiene; consider glutamine supplements or palifermin in select cases. Treatment: bland rinses (salt and baking soda), topical anaesthetic gels, systemic analgesics for pain control. Manage superinfections with antifungals or antivirals as needed. Dose reduce or hold chemotherapy if Grade 3-4 mucositis occurs. Nutritional support (soft or liquid diet, feeding tube if needed) for severe cases. Preventive cooling of hands/feet during nail-toxic chemotherapy (to reduce drug delivery to nail beds). Avoid tight footwear or trauma to nails. Hygiene: keep nails short and clean. For paronychia: warm antiseptic soaks, topical antibiotic or steroid creams; dermatology may perform chemical matricectomy if severe ingrown nails. Pain management as needed. Secondary infection may require systemic antibiotics. Dose adjustments rarely required solely for nail toxicity, except in extreme pain or infections. Classic chemotherapeutic agents have a non-selective mechanism of action, targeting rapidly dividing cells. As a result, skin and its appendages (hair, nails, mucous membranes), which undergo constant renewal, are highly susceptible to off-target damage.4 Chemotherapy-induced skin toxicity arises through multiple mechanisms: direct cytotoxic injury to proliferating keratinocytes, hair matrix cells and nail matrix cells; immune suppression leading to impaired skin defences; microvascular damage (as with capecitabine causing hand-foot syndrome); and induction of inflammation. Many DNA-damaging agents (eg, alkylating agents, antimetabolites) interfere with DNA replication and repair in skin cells, while others trigger cytokine release and inflammation. The combined result is a spectrum of dermatologic side effects. In one cancer registry study, serious adverse effects occurred in nearly 45% of chemotherapy patients, reflecting the broad toxicity of these agents (although only a subset of those are cutaneous).5 Alopecia (hair loss) is one of the most common and emotionally distressing chemotherapy side effects. By attacking hair follicle cells with high mitotic activity, many cytotoxics (eg, anthracyclines, taxanes) cause partial or complete hair loss. The incidence of chemotherapy-induced alopecia approaches ~65% or more, depending on the regimen.4 Although not life-threatening, alopecia can profoundly affect a patient's self-esteem and sense of identity. Encouragingly, this hair loss is usually reversible after therapy ends. Scalp cooling devices can reduce follicular drug exposure and have shown some success in mitigating alopecia. Supportive measures such as wigs, head coverings and counselling are important to help patients cope. Palmar-plantar erythrodysesthesia (hand-foot syndrome) is another frequent chemotherapy reaction, classically seen with capecitabine and liposomal doxorubicin. It presents as painful redness, swelling and peeling of the palms and soles. This arises from drug accumulation in sweat glands and subsequent damage to epidermal cells and dermal microvasculature. Hand-foot syndrome is dose-dependent and can range from mild tingling and erythema to severe blistering that impairs function. It is generally reversible over days to weeks with dose interruption or reduction. Preventive strategies include dose adjustments and regional cooling during drug infusion. Topical emollients (particularly urea-based creams) and corticosteroids are used to manage symptoms, and severe cases may require pain control and treatment breaks.6 Mucositis, an inflammation of the mucous membranes, is a common dose-limiting toxicity of many chemotherapeutics (especially antimetabolites like 5-fluorouracil [5-FU] and methotrexate). It typically affects the oral mucosa, causing mouth ulcers, pain, and difficulty eating or speaking. Severe oral mucositis not only diminishes nutritional intake but also creates a portal for infection. Management emphasizes preventive oral hygiene, saline or bicarbonate rinses, cryotherapy (ice chips) during infusions and pain management with topical anaesthetics or systemic analgesics. In high-risk patients, palifermin (a keratinocyte growth factor) has been used to reduce mucositis incidence. Mucositis usually heals within weeks of stopping chemotherapy, but in rare cases can be life-threatening if superinfected. Notably, patients with dihydropyrimidine dehydrogenase (DPD) deficiency are extremely susceptible to catastrophic mucocutaneous toxicity from 5-FU and capecitabine. Regulatory agencies now recommend dihydropyrimidine dehydrogenase (DPYD) genotype screening for all patients before starting fluoropyrimidines to guide dose adjustments and prevent fatal toxicity.7 Classic chemotherapy can also cause a variety of rash and skin eruptions. Generalized maculopapular rashes may occur with drugs like cytarabine or bleomycin, often reflecting a hypersensitivity reaction. These typically manifest as diffuse reddened patches or small bumps, sometimes with itching. Such rashes are usually reversible and managed with antihistamines or corticosteroid creams; severe cases might require systemic steroids or discontinuation of the offending drug. Certain chemotherapies (eg, methotrexate, cytarabine) have been implicated in rare erythema multiforme or even Stevens-Johnson syndrome, underscoring the need for prompt recognition of severe widespread rashes. Photosensitivity is another cutaneous hazard. Agents such as 5-FU, vinblastine and methotrexate can induce phototoxic reactions, wherein ultraviolet (UV) exposure leads to exaggerated sunburn-like changes on exposed skin.8 Patients may develop erythema, blistering or hyperpigmentation in sun-exposed areas. Preventive counselling about sun avoidance and high-SPF sunscreen is essential for any patient on a photosensitizing chemotherapy. With precautions, phototoxicity is largely avoidable; if it occurs, it is usually acute and heals over days, though residual hyperpigmentation can persist longer. Pigmentary changes are also observed with some cytotoxics. Hyperpigmentation (diffuse or localized darkening of the skin) can result from increased melanin or deposition of the drug in the skin. For example, cyclophosphamide and busulfan can cause a slate-grey or brown hyperpigmentation, and 5-FU may produce serpentine hyperpigmented streaks along veins. These changes are mostly benign and cosmetic, but often long-lasting or permanent. In contrast, depigmentation (vitiligo-like patches) is uncommon with classical chemotherapy but can occur in the context of immunotherapy (discussed below). There is no specific treatment to reverse chemotherapy-induced hyperpigmentation aside from cosmetic measures; management focuses on reassurance and sun protection to prevent further darkening. The nails and acral skin appendages are not spared by chemotherapy. Fast-growing nail matrix cells are damaged, leading to Beau's lines (transverse ridges), nail brittleness and sometimes onycholysis (separation of the nail from the bed). Taxanes such as docetaxel and paclitaxel are notorious for causing painful onycholysis and subungual haemorrhages. These nail changes are usually temporary, but nails may take months to regrow normally. Preventive cold therapy (cooling hands/feet during taxane infusion) has been explored to reduce nail toxicity. Management includes keeping nails short, avoiding trauma and using antiseptic soaks or antibiotics if secondary infection occurs. Targeted drugs can also affect nails (see below), often in distinct ways, such as periungual inflammation. Certain patient and treatment factors modulate the risk and severity of chemotherapy skin reactions. Genetic predispositions (eg, DPD deficiency as noted or human leukocyte antigen (HLA) alleles for severe drug rashes) can make individuals unusually vulnerable. Concurrent radiation can precipitate radiation recall dermatitis, where giving chemotherapy after radiotherapy triggers an inflammatory reaction confined to prior irradiated skin. Agents like doxorubicin and paclitaxel are well-known triggers of recall phenomena, which can resemble severe sunburn on the previously irradiated field. Management of recall reactions involves corticosteroids and avoiding further radiation to the area. Overall, virtually all patients receiving cytotoxic chemotherapy will experience some degree of cutaneous or mucosal side effect during treatment. This reality underscores the importance of anticipating and proactively managing these toxicities. Targeted therapies, including monoclonal antibodies and small-molecule kinase inhibitors, have distinct dermatologic side effect profiles that differ from classical chemotherapy. By design, targeted agents inhibit specific molecular pathways often also involved in skin homeostasis, leading to characteristic adverse reactions. Cutaneous side effects occur in up to 90% of patients on targeted therapies, underscoring the need for dermatologic surveillance and tailored management strategies.9 One of the hallmark toxicities of epidermal growth factor receptor (EGFR) inhibitors is the acneiform rash. EGFR is expressed in the skin, where it regulates keratinocyte growth and differentiation. Blocking EGFR (with agents such as cetuximab, panitumumab, erlotinib or gefitinib) induces an acne-like follicular rash in the majority of patients, an incidence of papulopustular eruptions is reported in ~75-90% of patients on EGFR inhibitors. This usually presents within the first few weeks of therapy as erythematous papules and pustules on the face, scalp and upper trunk. While often mild to moderate, EGFR rashes can be severe and lead to secondary bacterial infections or significant discomfort. Paradoxically, the development of a rash has been correlated with better tumour responses to EGFR inhibitors, making its management a delicate balance between tolerability and maintaining dose intensity.10 Management of EGFR-inhibitor rash is proactive and multi-modal. Prophylactic measures – moisturizers, gentle skin care and sunscreen to prevent photosensitive exacerbation – are recommended from the start of therapy. For mild rash, topical corticosteroids and clindamycin or metronidazole gels can reduce inflammation and pustules. Moderate cases often benefit from oral antibiotics such as doxycycline or minocycline for their anti-inflammatory properties. In severe Grade 3 rash (with pain or extensive skin involvement), dose interruptions and systemic corticosteroids may be necessary. Treatment algorithms for EGFR-inhibitor rash have been published to guide clinicians. Importantly, patient education is crucial: patients should be advised that this rash is a common side effect (not a worsening of cancer or an infection) and that early reporting of symptoms allows for prompt management. Several targeted kinase inhibitors (TKIs) beyond EGFR also cause cutaneous reactions. Vascular endothelial growth factor (VEGF) / vascular endothelial growth factor receptor (VEGFR) inhibitors (eg, sorafenib, sunitinib, pazopanib) frequently induce hand-foot skin reaction, a localized variant of hand-foot syndrome characterized by hyperkeratotic painful plaques on pressure areas of palms and soles. These lesions stem from interference with vascular repair in the skin and typically appear a bit later in treatment than classic chemotherapy hand-foot syndrome. Management similarly involves dose modification, keratolytic creams (urea or salicylic acid) and pain control. B-Raf proto-oncogene, serine/threonine kinase (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors (used in melanoma and other cancers with BRAF mutations) can paradoxically induce cutaneous lesions, including new keratoses, squamous cell carcinomas and rashes. For example, vemurafenib often causes a photosensitivity rash and can lead to secondary skin malignancies due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in wild-type BRAF cells. Dermatologic monitoring is therefore imperative for patients on these agents, and concomitant MEK inhibitors (eg, combining dabrafenib with trametinib) can mitigate some of these skin effects. Other targeted drug classes, such as anaplastic lymphoma kinase (ALK) inhibitors and Bruton's tyrosine kinase (BTK) inhibitors, may cause non-specific rashes in a minority of patients. Nail and hair alterations are also seen with targeted therapies. EGFR inhibitors cause a unique paronychia (inflammation of nail folds) and fissuring of the skin at the fingertips in ~10-15% of patients, typically after several months of therapy. This can be painful and predispose to infection (S. aureus is a common culprit). Treatment involves antiseptic soaks, topical antibiotics/steroids and, in refractory cases, chemical matricectomy. Some TKIs (eg, pazopanib) can cause hair depigmentation (patients notice their hair turning grey or white) due to effects on melanocytes. Unlike chemotherapy-induced alopecia, targeted therapy usually does not cause complete hair loss, although hair texture changes (curly hair development) or slowed growth can occur. Immune checkpoint inhibitors (ICIs) such as anti-PD-1 (programmed death (PD))/ PD-L1 (eg, nivolumab, pembrolizumab) and anti-CTLA-4 (eg, ipilimumab) have transformed oncology, but they introduce a distinct category of side effects termed immune-related adverse events (irAEs). Skin is the most commonly affected organ system by irAEs. In clinical trials of ICIs, up to 30-40% of patients develop some form of rash or pruritus. These rashes are typically diffuse maculopapular eruptions or eczema-like dermatitis, often accompanied by itching. They result from immune activation against cutaneous antigens, essentially autoimmune dermatitis triggered by heightened immune surveillance. Fortunately, most ICI-induced rashes are mild (Grade 1-2) and manageable. Treatment involves topical corticosteroids and oral antihistamines for pruritus, without discontinuing the immunotherapy. If a skin irAE progresses to Grade 3 (widespread intense rash or intolerable symptoms), systemic corticosteroids (eg, prednisone 0.5-1 mg/kg) are indicated, and the ICI is usually held until toxicity improves. Severe bullous dermatitis or life-threatening Stevens-Johnson syndrome is rare under immunotherapy, but if it occurs, the ICI must be permanently discontinued and aggressive immunosuppressive therapy initiated. One striking cutaneous irAE is vitiligo, a patchy depigmentation of the skin. Vitiligo is most famously associated with immunotherapy for melanoma, it occurs in roughly 10-25% of melanoma patients on anti-PD-1 therapies, and its appearance has been correlated with favourable tumour responses. The depigmentation is thought to reflect immune destruction of melanocytes alongside melanoma cells. A noteworthy case reported in BJCP described vitiligo developing in a lung cancer patient treated with pembrolizumab. In that case, new white patches appeared on the patient's chest (overlying the area of her lung tumour) after 3 months of therapy, and this coincided with an excellent tumour response.2 The vitiligo-like lesions persisted through treatment, illustrating that while skin depigmentation is largely irreversible, it can be a marker of robust immunotherapy Management of vitiligo is usually – patients are about sun protection skin is to and cosmetic – and immunotherapy is as as the patient can the skin can also other dermatologic such as rash, or of skin (eg, in susceptible These further highlight the of and the skin. are combined with other agents, the dermatologic toxicity can For example, combining a inhibitor with a may skin toxicity. A recent pharmacovigilance analysis in adverse for TKIs and a increased reporting of and dermatologic events with the Notably, patients on combined therapy of cutaneous to those on agents, underscoring the need for heightened skin monitoring in combination This of and (endocrine) therapies, used in and generally have severe cutaneous side effects to targeted or immune therapies. they are not of dermatologic and are a well-known side effect of therapies like or inhibitors, and while these are phenomena, they can cause skin during the skin and are also for can cause a rash in a subset of patients. Overall, hormonal agents are associated with cutaneous reactions in an of patients at some during treatment, most of which are In cancer patients on cutaneous and rashes have been reported but are inhibitors (eg, may cause hair or mild alopecia due to as as nails or skin but these effects are usually and In receiving therapy for skin and partial hair loss as of body or can occur due to Cutaneous adverse effects of chemotherapy and targeted therapies are frequent and often and management. 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