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Review
. 2020 Aug 12;12(8):2258.
doi: 10.3390/cancers12082258.

Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents

Cameron M Callaghan  1   2 , M M Hasibuzzaman  1   3 , Samuel N Rodman  1   4 , Jessica E Goetz  4 , Kranti A Mapuskar  1 , Michael S Petronek  1 , Emily J Steinbach  1 , Benjamin J Miller  4 , Casey F Pulliam  3 , Mitchell C Coleman  4 , Varun V Monga  2 , Mohammed M Milhem  2 , Douglas R Spitz  1 , Bryan G Allen  1   2
Affiliations
Review

Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents

Cameron M Callaghan et al. Cancers (Basel). .

Abstract

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins-but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.

Keywords: limb preservation; neoadjuvant radiotherapy; radioprotective agents; radiotherapy complications; soft tissue sarcoma; wound healing.

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Conflict of interest statement

The sponsors had no role in the design, execution, interpretation, or writing of this study. This review covers previous publications by some of its co-authors. No authors wrote, reviewed, or made editorial comments on their past work. Allen, Milhem, and Monga all report working on SARC032, a clinical trial involving pembrolizumab for sarcomas which is partially funded by Merck. Monga additionally reports Honoraria from Forma Therapeutics, a research grant from Amgen, and travel expenses from Deciphera, Glaxo-Smith-Klien. Milhem additionally reports funding in the past 2 years for unrelated research from Merck™. Allen, Callaghan, Mapuskar, and Spitz, and Petronek have received grant funding for research related to Pharmacologic Ascorbate. Allen, Mapsuskar, and Spitz, and Petronek and Hasibuzzaman have received funding and/or participated in research related to SOD mimetics. Allen, Mapuskar, and Spitz, and Petronek have received funding, fees, and/or participated in research with Galera, a producer of a SOD mimetic agent. Miller reports the Orthopaedic Research and Education Foundation grant for unrelated work. All other authors (Coleman, Steinbach, and Rodman) declare no conflict of interest.

Figures

Figure 1
Figure 1
Clinical case of a patient treated with neoadjuvant radiotherapy in extremity soft tissue sarcoma. Wound necrosis (red arrow) was observed in the radiated area.
Figure 2
Figure 2
Chronic inflammation is the key feature in the radiogenic wound. In normal wound healing, there is a balance between the production of pro-inflammatory and anti-inflammatory cytokines, which is shifted towards a prolonged inflammatory phase in the radiogenic wound. Later, in the remodeling phase, there is an imbalance in the synthesis of matrix metalloproteinases (MMPs) and their tissue inhibitor (TIMP) in radiated skin.
Figure 3
Figure 3
Summary of the key steps in wound healing dysregulated by radiation and the prospective therapeutic intervention of the events.
See this image and copyright information in PMC

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