Trabectedin is a synthetic antineoplastic drug originally isolated from the Caribbean sea squirt. It binds to the minor groove of DNA, forming adducts and resulting in bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect DNA repair pathways, resulting in G2-M cell cycle arrest and apoptosis  ―a novel anti-cancer mechanism. Trabectedin has shown high anti-tumor efficacy against various soft tissue sarcomas, with a disease control rate of 66.7%  , and thus it was recently approved by the Japanese government for the treatment of soft tissue malignancies. However, its extravasation occasionally induces serious complication of surrounding tissue necrosis followed by the delayed treatment of underlying diseases.
We experienced a case of trabectedin extravasation that induced severe pectoralis major muscle necrosis. A 45-year-old-man with multiple lung metastases of follicular dendritic cell sarcoma first received almost full dose of trabectedin (2.15 mg) through a central venous access device (CVAD) system in the right precordium. He noticed swelling and slight pain of his right frontal chest 21 h after the administration. Erythema and tenderness from the third day were exacerbated, so we suspected extravasation of trabectedin. We administered a subcutaneous injection of triamcinolone acetonide, which was not effective. Computed tomography revealed extensive turbidity of subcutaneous fatty tissue and swelling of the pectoralis major muscle to the upper margin of the liver (Figure 1(a)). The creatine kinase level was elevated to 759 U/L. We performed surgical debridement twice, and removed the CVAD concomitantly; thereafter, skin defect was reconstructed with a split skin mesh graft (Figure 1(b)). We have received an agreement from this patient after informed consent for paper preparation.
Histopathology revealed extreme degeneration of the striated muscle and fatty tissue (Figure 1(c), Figure 1(d)). Although grafted skin was well engrafted and epithelized, abduction failure of the right arm remained due to intense debridement and skin contracture around the right humerus muscle (Figure 1(e)).
Figure 1. (a) Chest CT revealed extensive turbidity of subcutaneous fatty tissue and swelling of the pectoralis major muscle to the upper margin of liver. The red circle indicates turbid subcutaneous fatty tissue and swollen muscle; (b) The skin defect was reconstructed by a split skin mesh graft after surgical debridement and the removal of the CVAD; (c) (d) Histopathological findings showed extreme degeneration of striated muscle (HE, ×200) and overlying fatty tissue (HE, ×400); (e) The patient suffered from disability of the right arm abducens because of debridement around the right humerus muscle.
Since trabectedin was not effective for lung metastatic lesions, we switched to administration of eribulin mesilate as alternative treatment.
Extravasation from a CVAD has occurred in 0.3% - 4.7% of cases  . Pre-marketing surveillance showed that 0.4% of patients (i.e. 4 of 950 cases) suffered from tissue injury caused by extravasation of trabectedin (unpublished data). Extravasation of trabectedin has been reported in seven cases     since Theman et al. first described it in 2009  . A few reports have also shown intense muscular degeneration similar to the present case    . To our knowledge, this is the one that induced tissue degeneration of pectralis major muscle more severely compared to previous reports.
Because trabectedin is a strong vesicant cytotoxic agent, it is principally administered through a CVAD rather than peripheral vessels and is continued during the nighttime; this can lead to a delay in patients or attending doctors noticing any extravasation. Several reasons for extravascular leakage, such as CVAD and/or infusion needle trouble, have been suggested. Extravasation in the present case may have been due to insufficient insertion of the infusion needle not reaching CVAD. No effective method of treating extravasation of trabectedin has yet been determined, aside from curable debridement of damaged soft tissue. To prevent severe complications observed in the present case, medical staff must be instilled with the appropriate pharmacological knowledge regarding trabectedin and its risk of extravasation, and the infusion must be aborted as soon as patients notice local signs of incompatibility.
We reported a rare case of severe muscular necrosis due to extravascular leakage of trabectedin. Newly developed trabectedin has clinical data which indicates high efficiency against various soft tissue sarcomas, but may cause serious cutaneous complication like the present case. We must share a proper knowledge of this drug with both of patients and medical stuff.
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 Yoshimi, K., Otsuka, M., Goto, H., Katagiri, H. and Hosaka, S. (2017) Differential Diagnosis of Trabectedin Extravasation: A Case Report. The Journal of Dermatology, 44, e200-e201.