Photodynamic Surgery for Feline Injection-Site Sarcoma

Abstract

Musculoskeletal sarcomas are rare and aggressive human malignancies affecting bones and soft tissues with severe consequences, in terms of both morbidity and mortality. An innovative technique that combines photodynamic surgery (PDS) and therapy (PDT) with acridine orange has been recently suggested, showing promising results. However, due to the low incidence of sarcoma in humans, this procedure has been attempted only in pilot studies and stronger evidence is needed. Naturally occurring tumors in cats are well-established and advantageous models for human cancers. Feline injection-site sarcoma (FISS) shares with human musculoskeletal sarcomas a mesenchymal origin and an aggressive behavior with a high relapse rate. Furthermore, wide surgical excision is not always possible due to the size and site of development. We assessed the feasibility and the effectiveness of PDS and PDT with acridine orange to prevent FISS recurrence by treating a short case series of cats. For PDS, the surgical field was irrigated with an acridine orange solution and exposed to UV light to enlighten the residual tumor tissue, and the resultant fluorescent areas were trimmed. For PDT, before wound closure, the field was again irrigated with acridine orange solution and exposed to visible light to get the antitumoral cytocidal effect. The procedure was easy to perform and well tolerated, we did not observe any major complications, and all the surgical resection margins were free of disease. Finally, at follow-up, all treated patients did not show evidence of tumor recurrence and had a significantly higher event-free survival rate in respect to a control group treated only by surgery. In conclusion, by this study we demonstrated that, in FISS, PDS and PDT with acridine orange may improve local tumor control, granting a better outcome, and we laid the foundation to validate its effectiveness for the treatment of human musculoskeletal sarcomas.

Sarcoma treatment in the era of molecular medicine

“…An interesting approach, based on photo‐ and radiodynamic therapy following acridine orange administration, has been extensively investigated and successfully applied for the treatment of sarcomas (Matsubara et al , 2013; Kusuzaki et al , 2018; Martano et al , 2019). Photodynamic therapy with hematoporphyrin prevented local recurrence following minimally invasive surgery in preclinical models (Duchi et al , 2016) as well as in clinical settings (Hourigan et al , 1993).…”

“…Acridine orange has the advantage of selectively binding to tumor tissue due to the acidic microenvironment specific to malignant cells (Matsubara et al , 2006) and to specifically exert a strong cytotoxic activity on tumor cells, which is further enhanced by photo‐ and radioactivation (Matsubara et al , 2013; Kusuzaki et al , 2018). Therefore, following marginal or even intralesional gross removal of the tumor, it is possible to selectively target residual sarcoma and spare the surrounding normal tissues, with a satisfactory functional result (Martano et al , 2019). The procedure is safe, without local or systemic complications (Martano et al , 2019).…”

“…Therefore, following marginal or even intralesional gross removal of the tumor, it is possible to selectively target residual sarcoma and spare the surrounding normal tissues, with a satisfactory functional result (Martano et al , 2019). The procedure is safe, without local or systemic complications (Martano et al , 2019). Systemic administration of acridine orange with low‐dose radiation therapy is currently under evaluation in Japan for non‐resectable sarcomas (Kusuzaki et al , 2018).…”

Preclinical In Vivo Modeling of Pediatric Sarcoma—Promises and Limitations

“…Thus, the most translationally relevant modeling approach for metastasis modeling is local tumor resection, typically via limb resection, and holds much promise to further elucidate mechanisms of metastasis for the various pediatric sarcoma entities, as well as possible therapeutic vulnerabilities [ 194 , 195 ]. At the same time, it enables utilization of PDX- and GEM models for improvement of local resection, e.g., via molecular imaging or photodynamic therapy, which, despite promising ongoing efforts, is still a rather unexplored field of pediatric sarcoma research with much unexplored potential to improve clinical outcomes [ 195 , 196 , 197 , 198 , 199 , 200 ].…”

Acid Microenvironment in Bone Sarcomas

“…Furthermore, in the last 20 years, a combined technique of PDT and radioactivation (RDT) of acridine orange has been successfully developed and applied to clinical cases, demonstrating excellent outcomes in terms of inhibition of local recurrence and preservation of limb function after intra-or marginal tumour resection. These studies include humans affected by bone sarcomas, although the same type of approach has been tested in companion animals with spontaneous fibrosarcoma [158][159][160][161][162]. Specifically, following marginal or even intralesional gross removal of the tumour, it was possible to selectively target residual sarcoma and spare the surrounding normal tissues, with a satisfactory functional result.…”