Nail and periungual toxicity following capecitabine therapy

We describe a case of moderate hand–foot syndrome and nail toxicity simultaneously occurred in a 69-year-old man with advanced gastric cancer (cT4-N3-M1, G3) previously treated with numerous antineoplastic agents, including PELFw (5-fluorouracil, epidoxorubicin, leucovorin, and cisplatin) and taxoids. Due to a recalcitrant course, the above therapeutic agents were discontinued for 4 weeks and he was given solely capecitabine 1250 mg twice daily for 2 weeks at 3-weekly intervals. After the third course of chemotherapy he developed a moderate hand–foot syndrome, acute paronychia, exudative hyponychial dermatitis, multiple periungual pyogenic granuloma-like lesions, onychomadesis and onycholysis (Figures 1A,B and 2A,B).

Figure 1.

(A,B) Exudative hyponychial dermatitis with transparent nonviscous exudative discharge; hyperkeratosis, onycholysis, onychomadesis and periungual pyogenic granuloma-like lesions

Figure 2.

(A,B) Subungual hyperkeratosis, onycholysis, and Beau's lines; erythema and desquamation involving the hands

Clinical examination revealed subungual hyperkeratosis, onycholysis, onychomadesis, acute paronychia and transparent malodorous, nonviscous, exudative discharge from toenails, especially upon squeezing. Slightly erythematous papular and vascular lesions (granuloma-like) in the proximal nail fold region of four of his toes and Beau's lines were also observed. Hypercurvature on the transverse axis of the nail plates was present, giving a pinched shape to the free edges. No other nail changes such as leukonychia or hyponychium hyperpigmentation were observed. Microbiological examination did not reveal bacterial infections, and repeated potassium hydroxide examinations of the nails did not show fungal hyphae. Treatment was initiated with soaking the nails with 0–5% potassium permanganate solution and application of gentamicin ointment. The hyponychial dermatitis and the above-described nail changes, including periungual pyogenic granuloma-like lesions, gradually resolved after the cessation of capecitabine for 8–12 weeks. The patient lost the nail of the great toes after about 3 weeks.

Naranjo algorithm evaluation obtained a score of 9, which indicates a high probability that the adverse reaction was due to the drug [1].

Several chemotherapeutic agents, including taxoids, cyclophosphamide, doxorubicin/daunorubicin, 5-fluorouracil and vincristine, and combinations have been reported to induce nail and periungual changes: alterations may involve nail matrix (e.g. Beau's lines, onychomadesis, hyperpigmentation), nail bed (e.g. onycholysis, subungual haemorrhage, haematoma), and proximal nail fold (e.g. acute paronychia, periungual pyogenic granuloma) [2]. These adverse events are mostly mild to moderate in severity, but, if not properly managed, can result in significant pain and interfere with activities of daily living.

Capecitabine (Xeloda®; Roche, Basel, Switzerland) is a fluoropyrimidine carbamate with antineoplastic activity. It is an orally administered systemic prodrug of 5′-deoxy-5-fluorouridine which is converted to 5-fluorouracil and preferentially activated at the tumour site. Fluoropyrimidine carbamate is a chemotherapeutic drug currently approved by the US Food Drug Administration for use as first-line therapy in patients with metastatic colorectal cancer or metastatic breast cancer. Capecitabine has also been used, alone or in different combinations, as a treatment of advanced gastric cancer, with interesting results [3, 4]. In clinical trials, the most frequent side-effects include gastrointestinal and haematological complications, hand–foot syndrome, hyperbilirubinaemia and anorexia. Although hand–foot syndrome is observed in up to 50% of patients treated with capecitabine, other mucocutaneous side-effects such as dermatitis, stomatitis, skin/nail discoloration and alopecia have been rarely reported [3, 4]. The incidence of nail changes is probably underestimated and still ill-defined; in particular, although the effects of taxoids [5] and epidermal growth factor receptor inhibitors (anti-EGFR agents) [6] are well described, there are, to our knowledge, only few reports of nail toxicity associated with capecitabine as monotherapy [7–9].

The aetiology of chemotherapy-induced nail changes is unclear; probably, immunosuppression and consequent colonization of the nail bed, change and disruption of the nail plate, subungual oedema with loss of adhesion between nail bed and nail plate and inflammatory and erosive processes may contribute to the development of nail and periungual abnormalities [7–10].

The nail toxicity seen in our patient was unique for the simultaneous occurrence of subungual hyperkeratosis, onycholysis, onychomadesis, paronychia, hyponychial dermatitis and periungual pyogenic granuloma-like lesions. As capecitabine is being increasingly used in the treatment of advanced breast and colorectal cancers as well as other solid cancers, clinicians should be aware of the novel clinical side-effects of this medication that could lead to substantial subjective toxicity, with impairment of quality of life and discontinuation of chemotherapy.