Radiosensitizers have been widely studied as a method to enhance the effects of RT. Although a number of radiosensitizers, including misonidazole, were developed in the past,9–12 many of them have not been used in clinical settings due to adverse reactions such as peripheral neuropathy. In this context, KORTUC II, a new enzyme-targeting and radiation sensitizer developed at Kochi University, has gathered attention.1–6 The sensitizer contains H2O2 and hyaluronic acid as its main components, which, along with their decomposition products, are harmless to the human body. This suggests it is a safe sensitizer if proper dosage is used and attention is paid to avoid procedural problems such as incorrect administration into blood vessels.5 The severity of acute-phase adverse events, such as radio-dermatitis, has been reported to be comparable with that following adjuvant radiation for regular breast-conserving therapy13–15. Also, no particular delay in acute-phase injuries has been observed. At our institution, we have used KORTUC II to treat over 250 cases of various solid cancers, including the LABC and LRBC reported in this article, but have observed no marked adverse reactions.
In our study, the 30 patients who underwent KORTUC II treatment experienced median MTS of 97%, the cCR rate was 50%, and the LC rate was 100%, 94.7%, and 75.4% at 1, 2, and 3 years, respectively (median follow-up period 19 months). Generally, excellent LC was obtained after therapy. Patients with LABC and LRBC have the potential for long term survival, and treatment that provides continuous symptom relief and local control is desired. The standard treatment for LABC is multidisciplinary treatment, with chemotherapy followed by local therapy (surgery and RT).16–18 Twenty one of the 30 patients who received KORTUC treatment (70%) experienced tumor re-growth, despite all having received chemo or hormonal therapy. Even in these cases, tumor shrinkage was also observed and QOL was improved.
Regarding the radiation dose, it has been reported that irradiation of 30 Gy or more had a significant effect on symptom relief, and that patients who received 60 Gy or more at the primary site had a higher local control rate for 5 years compared with patients who received less than 60 Gy.19.20 Sheldon et al concluded that high-dose RT without mastectomy is an effective means of local control of LABC.19 In our case, we administered a high dose with a median 60.4 Gy3.5, but at this relatively high dose level there was no statistically significant difference in MTS, duration of LC and TTP depending on the irradiation dose. Although the responses of these 30 patients seems favorable considering their pre-treatment conditions, because individualized multidisciplinary treatment is used for LABC and LRBC, it would be difficult to compare the responses with those of patients who did not receive KORTUC II. Future well controlled cohort or retrospective case-control studies are necessary to address this issue.
Takaoka et al reported the in vivo efficacy of radiotherapy combined with prior intratumoral H2O2 injection. A dose-modifying factor of 1.3–1.5 would be expected when combined with fractionated radiotherapy.21 If 3% H2O2 were injected alone, it would cause severe pain at the injection site. However, diluting the sensitizer fivefold with sodium hyaluronate reduces this pain to a mild level in the experience of our institution. In addition, mixing the moderately viscous sodium hyaluronate with the sensitizer retards its enzymatic breakdown and dispersion, resulting in an elevated oxygen partial pressure inside the tumor for over 24 hours.22.214.171.124 Therefore, twice-weekly intra-tumor local injection may be the best regimen, considering the sensitizing effects, need to limit patient discomfort, and the effort of injection. Another major advantage is that H2O2 and sodium hyaluronate are inexpensive agents.
In addition, sodium hyaluronate itself may have the potential to suppress cancer progression and metastasis.23–26 It has highly metabolized in the lymphatic system, and migrates readily via lymphatic capillaries to regional lymph nodes following injection into breast tumor tissue.27–29 When accompanied by H2O2, these two compounds together can sensitize metastatic foci in lymph nodes. In the cases of KORTUC II treatment for first-episode breast cancer in our institution, we have experienced many cases of regression of axillary and supraclavicular fossa lymph node metastases in patients who received local injections of the sensitizer into the primary tumor, although none was injected into the metastatic nodes. CD44, which is highly expressed on the surface of cancer stem cells, is an adhesion molecule for which hyaluronic acid is a ligand.26.30.31 This sensitizer is believed to target even the breast cancer stem cells.14
Generally, KORTUC II aimd for local tumor control and symptom relief in patients with LABC and LRBC. Patients with unresectable LABC and LRBC often have severely compromised QOL, due to massive exudation and bleeding from the lesion, odor, and disfigurement. NCCN guidelines version 5. 202032 recommends multidisciplinary treatment for LABC with a focus on drug therapy supplemented by surgery and RT. However, in many cases, regular RT fails to achieve satisfactory results for patients with unresectable tumors and many of these patients also do not respond to drug therapy. In this study, we have achieved significant local effects in the treatment of LABC and LRBC with a diameter of 10 cm or larger and open skin lesions. KORTUC II has improved greatly QOL and has been appreciated by the patients who received this therapy,15 suggesting it is a highly satisfactory treatment option.
Although the KORTUC II is effective in LC, it requires precautions, as soft tissue necrosis of the chest wall was observed in two patients after treatment. Their common features were that the tumor had invaded deep into the chest wall and the soft tissue necrosis occurred at the same time as the malignant lesions were expanding. The soft tissue necrosis may have been caused by inhibition of normal tissue recovery together with tumor tissue necrosis. Therefore, if imaging shows the tumor is invading deep into the chest wall and the tumor is growing rapidly, it may be best to forego or limit KORTUC II therapy to reduce the risk of soft tissue necrosis. It should be noted that soft tissue necrosis of the chest wall has also been reported with RT alone.33
Many fundamental issues remain to be clarified related to KORTUC II, particularly quantified levels of patient benefit and how KORTUC II can be combined optimally with radiation, chemotherapy and immunotherapy to treat various cancers. To date only a single phase 1 clinical trial has been completed, and this showed no significant adverse effects in patients with LABC.34 Nimalasena et al reported that injection pain was tolerable, dermatitis was not exacerbated, and the tumor regression rate was 50–100%.34 Biomarker tests demonstrated significant changes in IL-4, MIP-1α, IL-1β, and TRAIL compared with those of the patient group without sensitizer, suggesting apoptosis induced by TNF-related apoptosis-inducing ligands associated with activated T-cell signaling and increased macrophage stimulation.34 Kariya et al. reported that H2O2 enhanced lysosome-dependent X-ray-induced apoptosis in an in vitro experiment.35 A phase 2 study has been underway in five sites in the United Kingdom since June 2020 – the only phase 2 trial to date. In the future, we need more clinical trials to promote widespread use of KORTUC II and to include it within insurance coverage.