Actual practice of Kochi oxydol radiation therapy for unresectable carcinomas by intra‑tumoral administration of hydrogen peroxide as a radiosensitizer

Obata,Shiro; Ishimaru,Yutaka; Miyagi,Shigenori; Nakatake,Mika; Kuroiwa,Akira; Ohta,Yoshiaki; Kan,Tsunehiko; Kanegae,Shinya; Inoue,Yohta; Nishizato,Rhoichi; Miyazaki,Kohki

doi:10.3892/mco.2022.2501

Actual practice of Kochi oxydol radiation therapy for unresectable carcinomas by intra‑tumoral administration of hydrogen peroxide as a radiosensitizer

Authors:
- Shiro Obata
- Yutaka Ishimaru
- Shigenori Miyagi
- Mika Nakatake
- Akira Kuroiwa
- Yoshiaki Ohta
- Tsunehiko Kan
- Shinya Kanegae
- Yohta Inoue
- Rhoichi Nishizato
- Kohki Miyazaki
View Affiliations

Affiliations: Department of Radiology and Radiotherapy, Nagasaki Prefecture Shimabara Hospital, Shimabara, Nagasaki 855‑0861, Japan
Published online on: January 21, 2022 https://doi.org/10.3892/mco.2022.2501
Article Number: 68
Copyright: © Obata et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Kochi oxydol radiation therapy for unresectable carcinomas (KORTUC) is a novel cancer treatment method developed in Japan. KORTUC targets resistance factors in cancer therapy, such as low‑oxygen environments and excessive antioxidant enzymes. This may enhance the effects of conventional treatments. The present study reports the experience of the Nagasaki Prefecture Shimabara Hospital in using KORTUC treatment for a series of 210 patients between January 2010 and June 2019. When this radiosensitizer, a mixture of a dilute hydrogen peroxide solution (0.5 ml, 3%/unit) and sodium hyaluronate (2.5 ml, 0.83%/unit), is administered and applied directly to the cancer lesion, antioxidant enzymes are neutralized and degraded causing reoxygenation as a secondary by‑product, thereby enhancing the cytotoxic effect of radiation. The radiosensitizer was administered twice per week before irradiation. Up to June 2019, KORTUC was administered to 210 patients. The most common disease stage was stage IV in 137 patients (65%), followed by stage III in 25 patients, stage I in 17 patients and stage II in 7 patients (unknown disease stage in 24 patients). Of the 186 patients who could be followed up after the treatment, 28 (15%) patients had a complete response (Response Evaluation Criteria in Solid Tumors version 1.1), 59 (32%) had a partial response, 73 (39%) had stable disease and 26 (14%) had progressive disease. No significant treatment‑related adverse events were observed. The present study highlights the reports of 4 cases (3 cases from among the 28 patients with complete responses): i) A case of advanced, inoperable breast cancer; ii) a refractory patient with recurrence a decade after postoperative irradiation; iii) a patient with advanced, inoperable rectal cancer; and iv) a patient with lymph node metastases. Overall, KORTUC showed good efficacy and tolerable safety for various types of radioresistant tumors, and it has the potential for immediate worldwide use.

View Figures

View References

1	Ogawa Y, Yamashita T, Masunaga S, Kariya S, Tokuhiro S, Aoyama N, Tsuzuki A, Yaogawa S, Kubota K, Nishioka A, et al: A new enzyme-targeting and radio-sensitization treatment; basics and clinical practice of KORTUC Shinoharashinsha Pub. Inc., Tokyo, 2015 (In Japanese).
2	Ogawa Y, Takahashi T, Kobayashi T, Kariya S, Nishioka A, Hamasato S, Moriki T, Seguchi H, Yoshida S and Sonobe H: Immunocytochemical characteristics of human osteosarcoma cell line HS-Os-1: Possible implication in apoptotic resistance against irradiation. Int J Mol Med. 14:397–403. 2004.PubMed/NCBI
3	Kariya S, Sawada K, Kobayashi T, Karashima T, Shuin T, Nishioka A and Ogawa Y: Combination treatment of hydrogen peroxide and X-rays induces apoptosis in human prostate cancer PC-3 cells. Int J Radiat Oncol Biol Phys. 75:449–454. 2009.PubMed/NCBI View Article : Google Scholar
4	Ogawa Y, Takahashi T, Kobayashi T, Toda M, Nishioka A, Kariya S, Seguchi H, Yamamoto H and Yoshida S: Comparison of radiation-induced reactive oxygen species formation in adult articular chondrocytes and that in human peripheral T cells: Possible implication in radiosensitivity. Int J Mol Med. 11:455–459. 2003.PubMed/NCBI
5	Ogawa Y: Paradigm shift in radiation biology/radiation oncology-exploitation of the ‘H₂O₂ Effect’ for radiotherapy using low-LET (Linear Energy Transfer) Radiation such as X-rays and high-energy electrons. Cancers (Basel). 8(28)2016.PubMed/NCBI View Article : Google Scholar
6	Ogawa Y, Kubota K, Aoyama N, Yamanishi T, Kariya S, Hamada N, Nogami M, Nishioka A, Onogawa M and Miyamura M: Non-surgical breast-conserving treatment (KORTUC-BCT) using a new radio-sensitization method (KORTUC II) for patients with stage I or II breast cancer. Cancers (Basel). 7:2277–2289. 2015.PubMed/NCBI View Article : Google Scholar
7	Nimalasena S, Gothard L, Anbalagan S, Allen S, Sinnett V, Mohammed K, Kothari G, Musallam A, Lucy C, Yu S, et al: Intratumoral hydrogen peroxide with radiation therapy in locally advanced breast cancer: Results from a phase 1 clinical trial. Int J Radiat Oncol Biol Phys. 108:1019–1029. 2020.PubMed/NCBI View Article : Google Scholar
8	Tokuhiro S, Ogawa Y, Tsuzuki K, Akima R, Ue H, Kariya S and Nishioka A: Development of a new enzyme-targeting radiosensitizer (KORTUC) containing hydrogen peroxide for intratumoral injection for patients with low linear energy transfer (LET) radioresistant neoplasms. Oncol Lett. 1:1025–1028. 2010.PubMed/NCBI View Article : Google Scholar
9	Christensen ES: Iatrogenic dissemination of tumor cells-dissemination of tumor cells along the needle track after percutaneous, transthoracic lung biopsy. Dan Med Bull. 25:82–87. 1978.PubMed/NCBI
10	Sinner WN and Zajicek J: Implantation metastasis after percutaneous transthoracic needle aspiration biopsy. Acta Radiol Diagn (Stockh). 17:473–480. 1976.PubMed/NCBI View Article : Google Scholar
11	Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 45:228–247. 2009.PubMed/NCBI View Article : Google Scholar
12	National Cancer Institute (NCI): Common Terminology Criteria for Adverse Events (CTCAE) v4.0. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/. Accessed November 25, 2021.
13	Gebski V, Lagleva M, Keech A, Simes J and Langlands AO: Survival effects of postmastectomy adjuvant radiation therapy using biologically equivalent doses: A clinical perspective. J Natl Cancer Inst. 98:26–38. 2006.PubMed/NCBI View Article : Google Scholar
14	ECOG-ACRIN cancer Research Group: ECOG Performance Status. https://ecog-acrin.org/resources/ecog-performance-status. Accessed November 25, 2021.
15	Obata S, Ogihara Y, Ohta Y, Kan T, Kanegae S, Inoue Y, Kuroiwa A, Inoue K, Yamanishi M, Hayashi T, et al: Possibility of a ‘sentinel effect’ in chemoradiotherapy and a new radiosensitizer injection (KORTUC). Jpn J Clin Radiol. 63:317–327. 2018.(In Japanese).
16	U.S. Food and Drug Administration: KYMRIAH (tisagenlecleucel) https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel. Accessed November 25, 2021.
17	Vaupel P: The role of hypoxia-induced factors in tumor progression. Oncologist. 9 (Suppl 5):S10–S17. 2004.PubMed/NCBI View Article : Google Scholar
18	Clevers H: The cancer stem cell: Premises, promises and challenges. Nat Med. 17:313–319. 2011.PubMed/NCBI View Article : Google Scholar
19	Li L and Bhatia R: Stem cell quiescence. Clin Cancer Res. 17:4936–4941. 2011.PubMed/NCBI View Article : Google Scholar
20	Takeishi S, Matsumoto A, Onoyama I, Naka K, Hirao A and Nakayama KI: Ablation of Fbxw7 eliminates leukemia-initiating cells by preventing quiescence. Cancer Cell. 23:347–361. 2013.PubMed/NCBI View Article : Google Scholar
21	Iriuchishima H, Takubo K, Matsuoka S, Onoyama I, Nakayama KI, Nojima Y and Suda T: Ex vivo maintenance of hematopoietic stem cells by quiescence induction through Fbxw7 and alpha; overexpression. Blood. 117:2373–2377. 2011.PubMed/NCBI View Article : Google Scholar
22	Taniyama Y and Griendling KK: Reactive oxygen species in the vasculature: Molecular and cellular mechanisms. Hypertension. 42:1075–1081. 2003.PubMed/NCBI View Article : Google Scholar
23	Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, Squadrito F, Altavilla D and Bitto A: Oxidative stress: Harms and benefits for human health. Oxid Med Cell Longev. 2017(8416763)2017.PubMed/NCBI View Article : Google Scholar
24	Kobayashi M and Harada H: Hypoxic stress and HIF. Seikagaku. 85:187–195. 2013.PubMed/NCBI(In Japanese).
25	Ogawa Y, Ue H, Tsuzuki K, Tadokoro M, Miyatake K, Sasaki T, Yokota N, Hamada N, Kariya S, Hitomi J, et al: New radio-sensitization treatment (KORTUC I) using hydrogen peroxide solution-soaked gauze bolus for unresectable and superficially exposed neoplasms. Oncol Rep. 19:1389–1394. 2008.PubMed/NCBI
26	Miyatake K, Kubota K, Ogawa Y, Hamada N, Murata Y and Nishioka A: Non-surgical care for locally advanced breast cancer: Radiologically assessed therapeutic outcome of a new enzyme-targeting radio-sensitization treatment, Kochi Oxydol-radiation therapy for unresectable Carcinomas, Type II (KORTUC II) with systemic chemotherapy. Oncol Rep. 24:1161–1168. 2010.PubMed/NCBI View Article : Google Scholar
27	Ogawa Y, Kubota K, Ue H, Tadokoro M, Matsui R, Yamanishi T, Hamada N, Kariya S, Nishioka A, Nakajima H, et al: Safety and effectiveness of a new enzyme-targeting radio-sensitization treatment (KORTUC II) for intratumoral injection for low-LET radio-resistant tumors. Int J Oncol. 39:553–560. 2011.PubMed/NCBI View Article : Google Scholar
28	Chapman JD, Dugle DL, Reuvers AP, Meeker BE and Borsa J: Studies on the radio-sensitizing effect of oxygen in Chinese hamster cells. Int J Radiat Biol Relat Stud Phys Chem Med. 26:383–389. 1974.PubMed/NCBI View Article : Google Scholar