Abstract
Dear Editor,
Vandetanib is an oral multikinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2), endothelial growth factor receptor (EGFR), and rearranged during transfection (RET), approved for aggressive, symptomatic RET-positive medullary thyroid cancer with unresectable locally advanced or metastatic disease.1,2
Photosensitivity and other cutaneous adverse events are classified as “very common” (≥1/10), warranting sun avoidance, protective clothing, and/or sunscreen. 1
A meta-analysis by Rosen et al, 3 including 9 prospective trials with 2961 patients treated with vandetanib 300 mg once daily, reported an incidence of rash of any grade of 46.1% (95% CI, 40.6%-51.8%) and 3.5% (95% CI, 2.5%-4.7%) for high-grade events (grade ≥3, Common Terminology Criteria for Adverse Events [CTCAE]). Patients receiving vandetanib had an increased risk of rash compared with controls (relative risk 2.43; 95% CI, 1.37-4.29; P = .002). 3 Severe reactions leading to treatment discontinuation represent a clinically relevant minority requiring close attention in pharmaceutical care.
We report the case of a 62-year-old man with locally advanced medullary thyroid carcinoma, RET-negative, who initiated vandetanib 300 mg once daily off-label due to a lack of therapeutic alternatives. After 15 days of treatment, the patient developed a papular eruption with a photodistributed pattern on the face and dorsal hands, despite prior counseling on photoprotection. Dermatologic evaluation diagnosed a vandetanib-induced phototoxic skin reaction, and drug reaction with eosinophilia and systemic symptoms (DRESS) was excluded. Skin biopsy revealed interface dermatitis with apoptotic keratinocytes and eosinophils. The Naranjo algorithm yielded a score of 7, indicating a probable causal relationship. Vandetanib was permanently discontinued, with progressive resolution following systemic corticosteroid therapy; however, the patient was left without active systemic treatment options.
The intrinsic phototoxic potential of vandetanib may be explained mechanistically. Ultraviolet-visible (UV-Vis) spectroscopy studies have identified a principal absorption band at approximately 339 nm (UV-A range), corresponding to charge transfer between the N-methylpiperidine and quinazoline moieties in its molecular structure. This promotes reactive oxygen species generation and tissue damage. 4 In vitro studies in human keratinocytes have demonstrated that vandetanib exposure combined with UV-A radiation induces mitochondrial damage, lipid peroxidation, DNA fragmentation, and dose-dependent apoptosis. 5 Notably, photosensitivity reactions may persist for up to 4 months after treatment discontinuation, requiring prolonged photoprotection measures. 6
Intensified pharmaceutical care in patients receiving oral antineoplastic agents significantly reduces drug-related problems and severe adverse events (hazard ratio, 0.48; 95% CI, 0.32-0.71). 7 We propose the following recommendations for patients treated with vandetanib: (1) proactive UV-A/UV-B photoprotection from treatment initiation, including broad-spectrum sunscreen (sun protection factor [SPF] ≥30), protective clothing, and avoidance of direct sun exposure; (2) close monitoring during the first 2 to 3 weeks, when the highest incidence of skin toxicity occurs, as observed in this case and reported by Yin et al 8 ; (3) early referral to dermatology for photodistributed lesions to confirm diagnosis and exclude severe reactions such as DRESS or toxic epidermal necrolysis; and (4) systematic pharmacovigilance reporting, particularly in off-label use, to better characterize the drug’s safety profile in underrepresented populations.
In conclusion, this case highlights the importance of pharmacist involvement in the active monitoring of patients receiving oral antineoplastic agents, particularly in off-label settings, where proactive surveillance of cutaneous toxicity may be critical for patient safety and treatment continuity.
