Wound healing deficits in severe generalized recessive dystrophic epidermolysis bullosa along anticancer treatment with cetuximab

Abstract

Generalized severe recessive dystrophic epidermolysis bullosa (gs-RDEB) is caused by mutations in the COL7A1 gene encoding collagen type 7 within anchoring fi brils of the basement membrane zone of skin and mucosae. It is characterized clinically by signifi cant tissue fragility, widespread blister formation, progressive scarring and prominent extracutaneous involvement [ 1, 2 ] . Cutaneous squamous cell carcinoma (cSCC), typically arising early and at multiple sites of chronic wounding and infl ammation, has a highly aggressive, metastatic course and is the leading cause of death in gs-RDEB patients [ 3 ] . Valid data on the effi cacy and safety of systemic anti-tumor treatments in advanced EB-cSCC (as well as non-EB-cSCC) are scarce [ 4, 5 ] . Cetuximab is a recombinant human/mouse chimeric monoclonal antibody that targets the extracellular domain of epidermal growth factor receptor (EGFR) and thereby inhibits proliferative tyrosine kinase downstream signaling [ 6 ] . Cetuximab is currently approved for the treatment of KRAS wild type, EGFR-expressing metastatic colorectal cancer as well as recurrent or metastatic head and neck cancer. It is also used as a second line systemic treatment in advanced cSCC [ 5 ] . Three gs-RDEB patients receiving cetuximab have been reported until now; all had partial responses and progression-free survival for at least three months [ 7, 8 ] . We report on a 33-year-old female RDEB patient who was initially diagnosed with cSCC in a long-standing wound on her right forearm at the age of 29. After surgical excision (which was incomplete due to anatomical constraints and innocuous regular three-monthly clinical follow-up visits for seven months), axillary lymph node metastases as well as in-transit cutaneous metastases on the right upper limb were verifi ed in June 2013. Considering the limited clinical effectiveness and tolerability of classic chemotherapy in our multimorbid EB patient, the high level of EGFR expression in a KRAS wildtype tumor specimen of the primary tumor and axillary metastases prompted us to initiate treatment with cetuximab. A starting bolus of 400 mg/m 2 body surface area (BSA) was followed by weekly administration of 250 mg/m 2 BSA. This regimen resulted in progression-free survival of nine months. However, after six months of treatment the patient started to experience wound healing defi cits with a signifi cant increase in size and depth of long-standing chronic wounds as well as new non-tumorous EB lesions (Figure 1 ). This unfavorable situation was observed in spite of the patient s rather stable tumor disease and general condition. Moreover, a subsequent dose reduction of weekly cetuximab to 125 mg/m 2 BSA improved wound healing, as all skin lesions became more superfi cial. However, in March 2014 we detected an infraclavicular lymph node metastasis, a subcutaneous metastasis on the right upper arm and a local cSCC recurrence on the patient s right forearm. These tumors were treated either by excision (right forearm) or radiotherapy (lymph node and subcutaneous lesions). Incomplete surgical removal due to advanced local invasiveness led to a short-term tumor relapse on the right forearm while the size of all other metastases remained stable. As no distant metastases had developed, therapy with cetuximab was continued at reduced doses of 125 to 187 mg/m 2 BSA and titrated according to the impairment of wound healing. To improve local tumor control in infraclavicular lymph nodes, electrochemotherapy with bleomycin (2 cycles, total dose 40.1 mg) as well as injections of methotrexate (2 cycles of 25 mg each) were also administered. This led to a decrease in local tumor diameter from 2.3 cm to 1.7 cm. During the 90 th infusion of cetuximab, the patient developed a grade 2 allergic reaction with circulatory collapse, tightness in the chest, erythema, fever and chills. Cetuximab therapy was stopped at this point. Despite ongoing attempts of anti-neoplastic therapy (Figure 2 ), including 14 infusions