Tissue distribution of epirubicin after severe extravasation in humans

Abstract

Purpose: As critical parameter after extravasation of cytotoxic vesicants, anthracyclines were determined in removed tissue from patients requiring surgical intervention due to tissue necrosis. We monitored their distribution within the affected lesion to establish a possible dose-toxicity relation.

Methods: From six patients scheduled for surgery, removed tissue flaps were systematically analysed by HPLC (epirubicin: 5 subjects; doxorubicin: 1 subject).

Results: After extravasation, tissue concentrations were highly variable with an individual anthracycline distribution pattern ranging from a few nanograms up to 17 µg per 100 mg tissue, which indicated a substantial difference in tissue sensitivity among patients. The resection borders coincided with the extension of the erythema and guided the surgical intervention after demarcation of the lesion, which occurred usually 2 or 3 weeks after extravasation. At that time, drug was hardly detected at the resection borders. Wound drains were negative for the extravasated drugs while showing a time profile of vascular growth factors and inflammatory cytokines, which was highly similar to routine surgery. In all six patients, surgical debridement with immediate wound closure led to healing within approximately 2 weeks, when therapy was resumed in all patients with reasonable time delay.

Conclusion: Surgical intervention after demarcation of the extravasation lesion allows for almost uninterrupted continuation of treatment independent of the amount of extravasated anthracycline. As even minor amounts of the vesicants may trigger tissue necrosis, preventive measures merit the highest priority.

Keywords: Anthracycline; Extravasation; HPLC; Surgery; Tissue concentration.

Fig. 1

Doxorubicin tissue distribution after extensive extravasation (subject 6). A 65-year-old male lymphoma patient suffered a doxorubicin extravasation on the right forearm (upper left picture). Surgery was performed 26 days after the incident (lower left picture). The defect was covered with a split-thickness skin graft (upper right picture). HPLC analysis showed a pyramid-shaped distribution pattern with the highest concentrations in the central area, where the extravasation originally happened (lower right picture)

Fig. 2

Epirubicin extravasation with substantial tissue distribution (subject 4). A 78-year-old female breast cancer patient suffered an epirubicin extravasation on the dorsum of her left hand. After demarcation, surgery was performed 46 days later. The defect was covered with a radial forearm flap. Indocyanine green video angiography immediately after the extravasation event (lower left picture) already predicted the central necrosis (dark area) and the hypervascularized erythema area (white area). HPLC analysis of the resected tissue showed the highest concentration of epirubicin in the most distal part, most likely due to the effects of gravitation affecting the distal extremities (lower right picture)