Capecitabine-induced stomatitis: a likely pathogenetic mechanism of oral lichenoid mucositis

Capecitabine is an oral prodrug that is converted to its only active metabolite, Fluorouracile (5-FU), which has been used for numerous types of neoplasms, such as breast, esophagus, larynx cancer and, also, for the treatment of metastatic breast cancer as either a single agent or in combination with docetaxel after failure of prior anthracycline-based chemotherapy.1 Recently, FDA approved the combination of Capecitabine and Lapatinib for the treatment of advanced or metastatic breast cancer, overexpressing human epidermal growth factor receptor (HER)-2.2 A 61 year-old female patient with breast cancer, received right mastectomy, homolateral axillary lymphoadenectomy, and radiotherapy, entering in remission. After seven years, due to the metastatic progression of the disease, she received radiotherapy and anthracycline-based chemotherapy, obtaining partial results. Thus, it was administered Lapatinib (1,250 mg PO qd) continuously plus Capecitabine (2,000 mg/m2 PO qd) for a 14 days cycle with 7 days off,3 and, concurrently, Zolendronic acid (4 mg IV monthly) and lansoprazole (15 mg PO qd). During the third cycle she developed a mild palmar-plantar rash that disappeared spontaneously within 24 hours. During the fourth cycle she developed a persistent and painful bullous and lichenoid mucositis localized on the anterior third of the tongue (Fig. 1a), that showed a positive Nikolsky’s sign, as well as erythematous areas on the checks bilaterally (Fig. 1b), accompanied by a severe hand-foot syndrome (HFS). Due to these grade 3 side effects, patient was dechallenge and rechallenge for a fifth cycle at a dosage of Capecitabine adjusted to 50%. 4 Oral lesions disappeared, while HFS presented with a milder clinical aspect. She was not definitively dechallenge, because the discomfort of skin lesions did not interfere with her normal daily activities and quality of life. Oral biopsy revealed hyperparakeratosis, focal hypogranulosis, intraepithelial necrotic keratinocytes, some angiectasic vessels in the lamina propria with focal lymphomonocytic infiltrate (Fig 1c and 1d). Direct immunofluorescence, indirect imunofluorescence, immunoblotting and ELISA tests for Desmoglein 1 and 3, for BP230 and BP180 were negative. These essays allowed us to exclude a paraneoplastic and/or drug-induced autoimmune disease. The Naranjo Adverse Drug Reaction (ADR) Probability Scale showed that Capecitabine was a “probable” cause of HFSS and oral mucositis, given a score of 6 (Table 1).5 No other side effect or hematological abnormalities, except for a mild anemia and neutropenia, was detected. As the dosage of Lapatinib was maintained constant, while the dosage of Capecitabine was reduced, a diagnosis of Capecitabine-induced bullous and lichenoid stomatitis was made