Comment
Adverse Events Associated With Vandetanib
Vandetanib is a novel multikinase inhibitor that targets RET tyrosine kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor.1,2 It currently is approved by the US Food and Drug Administration for the treatment of progressive medullary thyroid cancer and is being used in clinical trials for non–small cell lung cancer, glioma, advanced biliary tract cancer, breast cancer, and other advanced solid malignancies. Frequently reported adverse events (AEs) include QT prolongation, diarrhea, and rash.1-3 In a large phase 3 trial, 45% of patients had a rash; of these, 4% were grade 3 and above.3 The most common reasons for dose decrease or cessation were diarrhea and rash (1% and 1.3%, respectively).13 Outside of a trial setting, 75% (45/60) of patients in one French study reported a cutaneous AE, with photosensitivity noted in 22% (13/60). Thus, cutaneous reactions tend to be a common occurrence for patients on this drug, requiring diligent dermatologic examinations.14 In one meta-analysis comprising 9 studies with a total of 2961 patients, the incidence of all-grade rash was 46.1% (95% CI, 40.6%-51.8%), and it was concluded that vandetanib has the highest association of all-grade rash among the anti–vascular endothelial growth factor tyrosine kinase inhibitors. In this meta-analysis, the specific diagnosis of AEs was not further classified.15 In another cohort of vandetanib-treated patients, as many as 37% (28/63) of patients had photosensitivity, with no clarification of the etiology.16
Photoallergic vs Phototoxic Reactions
Photosensitivity reactions are cutaneous reactions that occur from UV light exposure, typically in conjunction with a photosensitizing agent. Photosensitivity reactions can be further classified into phototoxic and photoallergic reactions, which can be distinguished by histopathologic evaluation and history. Although phototoxic reactions will cause keratinocyte necrosis similar to a sunburn, photoallergic reactions will cause epidermal spongiosis similar to allergic contact dermatitis or eczema. Also, phototoxic reactions appear within 1 to 2 days of UV exposure and often are painful, whereas photoallergic reactions can be delayed for 2 to 3 weeks and usually are pruritic. Photosensitivity reactions related to vandetanib have been reported and are summarized in the Table.4-12
Although reported cutaneous reactions to vandetanib thus far in the literature were reported as photoinduced reactions, there have been isolated case reports of other eruptions including cutaneous pigmentation5 and one case of SJS.9 According to a PubMed search of articles indexed for MEDLINE using the terms vandetanib and rash, we found that there are a variety of clinical findings, but most of the reported photosensitivity cases were phototoxic. Fava et al7 and Goldstein et al12 both reported 1 photoallergic reaction each, plus patient 1 in our case series was noted to have a photoallergic reaction. Phototoxic reactions were reported in 4 patients (including our patient 2) who had dyskeratotic keratinocytes and vacuolar degeneration of the basal layer on histopathology.4,8 Fava et al7 described a lichenoid infiltrate with spongiosis consistent with a photoallergic reaction, but Chang et al4 and Bota et al11 described a lichenoid infiltrate with dyskeratotic cells. Also, Giacchero et al16 described a photosensitivity reaction in 28 of 63 patients. Although only 6 patients had biopsies performed, the range of photosensitivity reactions was demonstrated with lichenoid, dyskeratotic, and spongiotic reactions. However, the cases were not further defined as photoallergic or phototoxic.16 Vandetanib also has been associated with cutaneous blue pigmentation after likely phototoxic reactions. Pigment changes occurred after photosensitivity, but the clinical presentation of photosensitivity was not further characterized.5,16
Classic Drug Eruptions
Two patients were described as having classic drug eruptions—EM10 and SJS9—in photodistributed locations. Histologically, these entities are identical to phototoxic reactions, resulting in epidermal necrosis and an interface dermatitis, but the presence of targetoid lesions on the palms prompted the diagnosis of photodistributed EM and SJS in both cases.9,10 Unique to the SJS case was oral involvement.9
Distinguishing between a phototoxic reaction and photodistributed EM or SJS may be inconsequential if both can be prevented with photoprotection. Rechallenging patients with vandetanib while practicing photoprotection would help to clarify the mechanism, though this course is not always practical.
Mechanism of Action
As seen in our case series, cutaneous reactions occurred only on sun-exposed surfaces, and patients presented with sharp cutoff points that spared non–sun-exposed areas. Although clinically organized as a subtype of photosensitivity, the phototoxicity mechanism of action is considered a direct toxic effect on keratinocytes, which explains the histopathologic finding of dyskeratotic cells and the clinical spectrum of sunburn reaction, phototoxic EM, and SJS. UVA1 induces 2 photoproducts of vandetanib via a UVA1-mediated debromination process,17 but these photoproducts are not responsible for epidermal dyskeratosis.18 It was subsequently demonstrated that keratinocyte death was induced by apoptosis through photoinduced DNA cleavage and the formation of an aryl radical, which can induce further DNA damage.18 Caro-Gutierrez et al10 demonstrated a lowered minimal erythema dose in their patient with vandetanib-induced phototoxic EM.
Conversely, photoallergic reactions are considered immune-mediated delayed-type hypersensitivity reactions.4,7,11 Although the mechanism of a photoallergic reaction remains unclear, it is possible that vandetanib or a metabolite (in susceptible patients) induces an immune-mediated delayed-type hypersensitivity reaction with repeated exposure to the compound, which may explain the varied timing of photoallergic onset, including the events featured in the Bota et al11 case that occurred several months after drug initiation.
Conclusion
Considering the high prevalence of cutaneous AEs, especially varied photosensitivity reactions, these cases emphasize the importance of sun protection to help prevent dose reduction or drug cessation among patients taking vandetanib therapy.