Although oncology treatments have become more targeted, cutaneous toxicities have not disappeared, largely because the biological mechanisms involved differ across therapeutic classes.
Toxic Mechanisms
In conventional chemotherapy, cutaneous manifestations are primarily associated with direct cytotoxicity. The most commonly reported skin toxicity includes alopecia, nail abnormalities such as Beau’s lines and onychomadesis, and palmar-plantar erythrodysesthesia, commonly referred to as hand-foot syndrome.
Sibaud explained that “Toxic erythema related to chemotherapy is less well recognized. Similar to hand-foot syndrome, it represents a nonallergic inflammatory reaction occurring in areas rich in eccrine sweat glands and subject to sweating, friction, or contact. It is a toxic effect linked to local excretion of chemotherapeutic agents.”
This phenomenon has also been observed for taxanes and cytarabine.
“What is often described as an allergy to dressings around implanted venous access devices is actually toxic erythema,” he stated. Occlusive dressing promotes sweating and, therefore, local secretion of chemotherapy. “This should prompt us to limit dressings as much as possible during treatment, because they favor these reactions and may secondarily lead to hyperpigmentation.”
Cutaneous toxicity associated with targeted therapies arises from different mechanisms. In these cases, the therapeutic target is also expressed in skin cells.
An example is the inhibition of the epidermal growth factor receptor (EGFR), also known as HER1. “This receptor is essential for keratinocyte proliferation and differentiation, which explains why its inhibition almost inevitably leads to cutaneous toxicity,” said Sibaud.
Other targeted therapies associated with characteristic skin effects include the following:
- Inhibition of c-KIT, observed with sunitinib, pazopanib, imatinib, and cabozantinib, can cause depigmentation of hair and, in some cases, skin.
- Dual inhibition of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, seen with regorafenib, sorafenib, cabozantinib, and sunitinib, may induce hand-foot syndrome with painful inflammatory hyperkeratosis.
- Bruton tyrosine kinase inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, impair platelet function and increase the risk for cutaneous bleeding.
Immunotherapy-Related Cutaneous Toxicity
Cancer immunotherapy, which has transformed outcomes in metastatic melanoma with approximately 40% survival at 10 years, is also associated with immune-mediated cutaneous toxicity.
Immune checkpoint inhibitors restore immune responses primarily mediated by CD4 and CD8 T lymphocytes. Immune activation can lead to immune-related adverse events that affect multiple organs, including the skin.
The most common manifestation of PD-1 or PD-L1 inhibitors is a nonspecific maculopapular exanthem, which typically appears early after treatment initiation. “These patients require close monitoring, because about half will subsequently develop toxicity involving other organs,” Sibaud emphasized. Increased vigilance is required when atypical cutaneous presentations differ from classic exanthema.
New Therapies, Emerging Risks
More recent therapeutic approaches are also associated with dermatologic toxicity, often through combined and novel mechanisms.
- Antibody-drug conjugates combine monoclonal antibodies with cytotoxic agents that are delivered directly to tumor cells. Therefore, cutaneous toxicity reflects that of chemotherapy. For example, enfortumab vedotin, used in advanced urothelial carcinoma, targets Nectin-4, a protein expressed by certain skin cells, including keratinocytes, and can cause clinically significant skin adverse effects.
- Bispecific humanized monoclonal antibodies, such as talquetamab, which target CD3 (a T-cell surface antigen) and human G-protein coupled receptor family C group 5 member D (GPRC5D; a tumor-associated antigen), are indicated for multiple myeloma and exhibit dermatologic toxicity in approximately 80% of treated patients.
- Chimeric antigen receptor (CAR) T-cell therapies have also been implicated, with approximately 60% of patients developing cutaneous toxicity.
“Given the growing number of patients treated with immunotherapy and the rapid expansion of CAR T-cell therapies, an increase in cutaneous toxicity can be expected in dermatology and oncodermatology clinics,” Sibaud concluded.
Consensus statements, recommendations, and expert reviews developed by the European Academy of Dermatology and Venereology are particularly valuable for navigating this complex landscape and adapting patient management strategies. The most recent include:
- Management of acneiform eruptions associated with EGFR inhibitors
- Prevention and management of immune-mediated cutaneous adverse events
- Erosive pustular dermatosis of the scalp related to EGFR inhibitors
- Recommendations for managing dermatologic adverse events associated with immune checkpoint inhibitors
Chemotherapy-induced skin damage Chemotherapy-induced skin damage