Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours

Sir, Recent publications have reported various cutaneous side‐effects in patients treated with two epidermal growth factor receptor (EGFR) inhibitors, cetuximab1 (IMC‐C225, Erbitux) and gefitinib2, 3 (ZD1839, Iressa). The most common adverse event is a follicular acneiform eruption, also termed an acne‐like rash or folliculitis.4, 5 Between 1 December 2000 and 1 December 2002, we analysed a series of patients enrolled in phase I, II and III clinical trials of gefitinib (n = 20) or cetuximab (n = 9) in the treatment of solid tumours (Tables 1 and 2). Except for antiemetics and corticosteroids used in association with chemotherapy, no other acne‐inducing drugs6 were used by the patients during the study. Clinical characteristics of patients treated with gefitinib CDDP, cisplatin; CS, corticosteroids; NSCLC, non‐small cell lung cancer; NVB, Navelbine®. Clinical characteristics of patients treated with gefitinib CDDP, cisplatin; CS, corticosteroids; NSCLC, non‐small cell lung cancer; NVB, Navelbine®. Clinical characteristics of patients treated with cetuximab CDDP, cisplatin; CRC, colorectal carcinoma; HNSCC, head and neck squamous cell carcinoma. Clinical characteristics of patients treated with cetuximab CDDP, cisplatin; CRC, colorectal carcinoma; HNSCC, head and neck squamous cell carcinoma. In the group treated with gefitinib, 55% of patients developed an acneiform eruption that was characterized by numerous monomorphic pustular and papular erythematous lesions, mostly with a follicular distribution. In 82% of patients the eruption was located on the face, mainly on the nose, cheeks, nasolabial folds, chin, forehead and in a perioral distribution. Other principal locations included the shoulders and trunk (64% of patients), particularly the V‐shaped areas of the chest and back. The eruption always spared palmar and plantar surfaces and no caudal progression was clearly noted. There was no apparent relation between the severity of the rash and the tumour type or the skin phototype. Symptoms related to the acneiform eruption were generally minimal as compared with the intensity of the cutaneous manifestations, and no associated general symptoms including fever, myalgia or arthralgia were reported. No significant differences were noted between the group treated with corticosteroids and the group treated with gefitinib alone. In one patient, spontaneous and progressive resolution of the eruption occurred despite continuation of the same dose of gefitinib. Total resolution was seen in one patient a few days after reduction of the dose of gefitinib for digestive side‐effects (diarrhoea), and in another patient after treatment discontinuation for tumour progression. Various treatments included daily topical application of antiseptics (hexamidine solution, povidone iodine solution), fusidic acid cream, econazole cream and benzoyl peroxide gel. In two cases, treatment with twice daily topical application of benzoyl peroxide gel led to partial resolution of the eruption despite treatment continuation at the same dose level. In the cetuximab group, all patients were caucasians except one (Asian). Cetuximab was given by intravenous infusion weekly at an initial loading dose of 400 mg m−2, followed by a mean of 18 (range 6–36) consecutive weekly infusions at 250 mg m−2. An acneiform eruption was noted in six patients (67%) and had the same clinical localization as reported above with gefitinib, but appeared to be more severe with a more widespread distribution of the lesions. Three patients presented with clusters of haemorrhagic papules and crusts on the face (Fig. 1). In one patient, spontaneous progressive resolution of the eruption was observed despite treatment continuation. Topical treatment of the eruption included daily application of fusidic acid cream, erythromycin solution and betamethasone dipropionate cream. Systemic antibiotic therapy with fusidic acid was given in two cases, leading to one partial clearing of the eruption despite treatment continuation at the same dose level. In two patients, preventive treatment (initiated at the date of the first infusion and given until treatment discontinuation) with topical 4% erythromycin emulsion and oral fusidic acid was associated with an erythema of the face without papular or pustular lesions. Confluent plaque of haemorrhagic crusts with numerous erythematous papules and pustules located on the nose. Histological analysis was performed in six patients. In five cases, the same histological pattern was noted, characterized by a superficial and florid neutrophilic suppurative folliculitis. A dense monomorphic infiltrate of neutrophils was constantly predominant around the infundibula and was associated with a rupture of the epithelial lining. In one patient, the follicular nature of the inflammation was confirmed, as it was not detected in the absence of follicular structures upon multiple serial sectioning. Special stains for fungi or bacteria and standard bacterial and fungal cultures were negative in all cases. The characteristics and incidence of the cutaneous eruption observed in our series are consistent with recent reports of acneiform dermatoses induced by EGFR inhibitors.4, 5, 7–10 Various treatments for the acneiform eruption induced by EGFR inhibitors have been previously reported without significant clinical benefit.4, 5 In our series, topical benzoyl peroxide seemed to give partial improvement of the eruption in two patients receiving gefitinib. In two patients receiving cetuximab a preventive treatment was started concomitantly with the first injection of cetuximab and continued until treatment discontinuation. A similar facial erythema was noted, but without scaling or follicular pustules, and a preventive role for this treatment seems probable. However, spontaneous clinical improvement was noted in four patients despite treatment continuation. Moreover, the eruption was not dose‐limiting and the patients were able to continue receiving the EGFR inhibitors with the same dose or with infrequent dose interruptions. There was no clear preventive or curative treatment for this eruption.