1

Introduction

Cetuximab, an anti–epidermal growth factor receptor (EGFR) antibody, is approved for the treatment of colorectal cancer and squamous cell carcinoma of the head and neck (SCCHN). The most common adverse reaction to cetuximab is dermatologic toxicity, especially in the form of acneform rash, which occurs in 75% to 90% of recipients . Minocycline is one of the agents known to be able to decrease the severity of rash and prevent interruption of cetuximab therapy . In spite of there being more than 100 kinds of drugs regarded as potential causes of toxic epidermal necrolysis (TEN) , cetuximab plus minocycline has never previously been mentioned as a culprit of TEN.

We describe a Taiwanese man with recurrent SCCHN with cetuximab plus minocycline–induced TEN during chemoradiation in June 2008. Toxic epidermal necrolysis interrupted the course of chemotherapy and the tumor recurred in October 2008.

We review the literature in association with cetuximab, minocycline, and TEN and discuss the impact of TEN on cancer patients, especially when the chemotherapy is indicated.

2

Case report

This 49-year-old man had been a heavy smoker, heavy drinker, and had chewed betel nut for 20 years but had stopped for the past 7 years.

He had locoregional recurrence of buccal squamous cell carcinoma (SCC) and received a composite resection and fibular osteocutaneous flap reconstruction on April 27, 2008. The pathologic report revealed recurrent SCC with a stage of T1N2bM0 with perineural invasion and close surgical margins. Cetuximab plus chemoradiation, weekly cisplatin 40 mg and 3-dimensional conformal radiotherapy to 66 Gy in 33 fractions, were subsequently arranged. He had a normal renal function (creatinine clearance rate, 75.5 mL/min) and his body surface area (BSA) was 1.58 m ² .

One week after the initiation of cetuximab, acneform rash appeared over his face, shoulders, and anterior chest. As the skin toxicity progressed to annoy the patient, minocycline was added thereafter. As the radiation dose accumulated, oral mucositis with ulceration arose from June 10.

On June 15 (5 days after the fifth course of cetuximab plus chemotherapy), a high fever of 39°C and generalized erythematous macules with flaccid blisters developed. The next day, he was admitted to our hospital.

On physical examination, the blistering erythematous lesions, which were almost symmetrically spreading over the trunk, arms and legs, had become confluent and had a positive Nikolsky sign ( Fig. 1 ). There was no jaundice, no palpably enlarged lymphadenopathy, and no pustules. Laboratory tests showed white blood cell count of 2600/mm ³ , eosinophil count of 0.02 × 10 ⁹ /L, hemoglobin 13.4 g/dL, aspartate aminotransferase 42 IU/L, alanine aminotransferase 43 IU/L, blood urea nitrogen 11 mg/dL, creatinine 0.65 mg/dL, and C-reactive protein 0.265 mg/dL. The chest plain film showed clear contours without inflammation. He denied any discomfort except for tender skin lesions and painful oral mucositis with ulceration. There was no evidence of infection, no obvious tumor burden, and no history of autoimmune disease. Following the course, the blistering skin lesions became larger and then ruptured with skin sloughing ( Fig. 2 ), in total over about 36% of the BSA.

Generalized erythematous macules with flaccid blisters at admission. (A) Gross view of the back. (B) Close-up view of the thigh. The white patches in the pictures were from the antibiotic cream.

Exposure of the denuded dermis after blister rupture and skin sloughing. (A) Left buttock. (B) Right arm.

We suspended all medications immediately. Supportive care was given to the patient, including wound care, fluid and electrolyte management, nutrition supply, and prevention of superinfection. The patient kept receiving radiotherapy throughout the course of blistering disease (TEN) because of good performance. The skin lesions slowly progressed throughout June but then spontaneously recovered well in the beginning of July. Toxic epidermal necrolysis was diagnosed based on clinical features.

After evaluating the benefits of tumor control and the risk of TEN reattack, the patient decided to continue chemotherapy with cisplatin because there is no direct evidence that links cisplatin to TEN in the literature. He received 3 cycles of chemotherapy in July and August without any recurrent adverse skin reactions. Therefore, we excluded the suspicion of the medications via re-exposure, including cisplatin, steroids, antihistamines, serotonin 5-HT ₃ antagonist, and mannitol, and concluded that cetuximab plus minocycline was the culprits of TEN in our case.

Unfortunately, the patient had a recurrence of the tumor over the contralateral neck in October 2008.