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Effective methods exist to prevent, treat therapy-related dermatologic adverse events
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Skin and mucosal reactions to oral chemotherapeutic agents are common complications of cancer treatment and may severely impair patients’ quality of life.
Further, the past decade has witnessed tremendous growth and development of molecularly targeted agents, which bring a unique set of dermatologic toxicities.
Importantly, the severity of chemotherapy-induced skin reactions often results in dose reductions, delays or discontinuations, potentially limiting therapeutic activity. Clinicians must be familiar with adverse skin reactions associated with oral anticancer agents, as well as the available options for their prevention and treatment.
Papulopustular eruption
The most common skin reaction associated with epidermal growth factor receptor inhibitor therapy is papulopustular eruption, which affects more than 50% of patients. The most commonly affected sites include the scalp, face, back and upper chest.
The eruption itself consists of pruritic, tender, erythematous papules and pustules that typically develop within 8 to 10 days and peak between 4 to 6 weeks of EGFR inhibitor therapy. Rash severity tends to be dose related; thus, dose reductions may help alleviate symptoms but also may compromise efficacy.
Incidence of high-grade dermatologic adverse events among patients treated with small-molecule tyrosine kinase inhibitors range from 2% to 16%, depending on the agent, whereas 20% to 30% of patients treated with monoclonal antibodies experience a grade 3 to grade 4 rash. These findings are consistent with dysregulation of molecular pathways downstream from EGFR signaling, which are known to be important in keratinocyte migration, maturation and survival.
Interestingly, a meta-analysis of 33 studies in patients with non–small cell lung cancer showed that the presence of an EGFR-related rash was associated with a 55% decrease in the risk for disease progression (HR = 0.45; 95% CI, 0.37-0.53). Similar findings have been reported in the settings of metastatic colorectal cancer, pancreatic cancer, and head and neck cancers. However, quality-of-life indices suggest that dermatologic adverse events are the primary reasons for treatment discontinuation, and dosing to toxicity may not be acceptable in clinical practice for obvious reasons.
Prophylactic treatment with systemic tetracycline antibiotics for the first 8 weeks of EGFR inhibitor therapy appears to significantly reduce the severity of the papulopustular eruption, possibly decreasing the need for dose adjustments. Mild to moderate cases may be treated with alcohol-free moisturizers and topical corticosteroids, whereas severe cases should prompt consideration of systemic therapy with oral corticosteroids, low-dose isotretinoin or acitretin.
Menadione, or topical vitamin K3, may restore keratinocyte EGFR signaling in vitro, supporting a phase 2 clinical trial that is underway (NCT01393821). Lastly, although sunscreen was previously recommended for prevention, a study found no decrease in rash incidence or severity with application of daily sunscreen; however, sunscreen still is recommended for overall skin protection.
Newer-generation EGFR TKIs that also inhibit the widely resistant T790M mutation have resulted in impressive response rates and PFS, and they also are very well tolerated compared with older-generation TKIs.
For example, AZD9291 (AstraZeneca) administered to patients with NSCLC who progressed on prior EGFR TKI therapy resulted in a 51% overall response rate and a 61% response rate in those with confirmed T790M mutations. Grade 3 to grade 4 rash occurred in only 1% of all patients, and 0% of patients treated at doses of 80 mg daily or lower.
By selectively targeting EGFR TKI-sensitizing mutations and the T790M resistance mutation, wild-type healthy cells can be spared, resulting in fewer adverse events.
Palmar-plantar erythrodysesthesia
Multi-kinase inhibitors, including sunitinib (Sutent, Pfizer) and sorafenib (Nexavar; Onyx, Bayer) exert their anticancer effects by blocking molecular signaling mechanisms important for cell growth and angiogenesis, which may promote dermatologic adverse reactions.
Furthermore, fluoropyrimidines — particularly capecitabine — cause similar reactions, possibly due to the accumulation of active drug via high levels of thymidine phosphorylase in human epidermal keratinocytes.
Palmar-plantar erythrodysesthesia, or hand–foot skin reaction (HFSR), is one of the most common dermatologic adverse events encountered by patients exposed to sorafenib, sunitinib or capecitabine. HFSR is characterized by painful hyperkeratosis in areas of the body most commonly associated with pressure or friction, including the palms and soles. Reports have indicated potential loss of fingerprints in patients treated with capecitabine who experience severe HFSR.
Multi-kinase inhibition of VEGF receptors disrupts endothelial healing, which may be magnified in areas where vessels experience subclinical injury with daily use. Of note, concomitant administration of bevacizumab (Avastin, Genentech), a VEGF antagonist, increases the incidence of sorafenib-associated HFSR.
HFSR most commonly occurs within the first 6 weeks of treatment and occurs more frequently with sorafenib and capecitabine (all grade, 40% to 60%; grade 3 to grade 4, 10% to 15%) than sunitinib.
Treatment consists of keratolytics, avoidance of friction (eg, use of gloves and comfortable shoes), and topical medium- to high-potency corticosteroids. HFSR resolves spontaneously upon drug discontinuation after 3 to 4 weeks without long-term sequelae.
More recently, a randomized study demonstrated that pyridoxine was not effective for prevention of HFSR in patients with colorectal cancer treated with adjuvant capecitabine compared with no prophylaxis — 60% of patients in each study arm developed HFSR.
Importantly, another randomized study demonstrated that 10% urea cream was superior to mapisal ointment for prevention of HFSR over the first 6 weeks of treatment with capecitabine. Results showed 39.5% of patients assigned mapisal-based ointment and 22.4% of patients assigned urea-based treatment developed HFSR (P = 0.02), suggesting that urea may be the best pharmacological preventative measure for HFSR.
Conclusion
Orally available, molecularly targeted agents have transformed cancer therapy but also have presented challenging side-effect profiles (eg, dermatologic adverse events) that limit drug administration and significantly impair patients’ quality of life.
Other drugs not covered in this column — such as BRAF inhibitors — result in unique, potentially serious skin growths, including squamoproliferative lesions (eg, benign growths, such as verrucous keratoses, skin papillomas, verruca vulgaris, warty dyskeratomas, keratosis pilaris-like eruptions and palmar-plantar hyperkeratosis), as well as precancerous and cancerous skin lesions (eg, actinic keratoses and cutaneous squamous cell carcinomas or keratoacanthomas). Treatment often involves topical agents such as ammonium lactate, salicylic acid or urea at high concentrations. Surgical excision of lesions may be necessary in severe cases.
Future research should focus on how to better predict these severe reactions, such as identification of predisposing genetic variants. For example, a large pharmacogenomic analysis of patients with colorectal cancer who received capecitabine and other fluorouracil-based regimens showed that polymorphisms in dihydropyrimidine dehydrogenase and thymidylate synthase are associated with capecitabine toxicity, including rash.
Therapeutic drug monitoring to target an optimal drug concentration also may be considered in situations in which a clear dose–exposure and exposure–response relationship exists.
Additionally, clinical tools such as the patient-reported HFSR and quality-of-life questionnaire, developed by Anderson and colleagues, may be useful. Mean questionnaire scores stratified by NCI-CTCAE grade showed linear associations of increasing scores by toxicity grade (P < .0001), suggesting that patient-reported outcomes may help with the early identification of signs and symptoms of HFSR.
Clinicians must recognize the presentation and characteristics of common chemotherapy-related dermatologic adverse events and be familiar with effective methods for their prevention and treatment.
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For more information:
Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.
Disclosure: Patel reports no relevant financial disclosures.