Intratumoral Hydrogen Peroxide With Radiation Therapy in Locally Advanced Breast Cancer: Results From a Phase 1 Clinical Trial.

Published on Nov 15, 2020in International Journal of Radiation Oncology Biology Physics5.859
· DOI :10.1016/J.IJROBP.2020.06.022
Samantha Nimalasena1
Estimated H-index: 1
(ICR: Institute of Cancer Research),
Lone Gothard15
Estimated H-index: 15
(ICR: Institute of Cancer Research)
+ 21 AuthorsNavita Somaiah12
Estimated H-index: 12
(The Royal Marsden NHS Foundation Trust)
Abstract Purpose Hydrogen peroxide (H2O2) plays a vital role in normal cellular processes but at supraphysiological concentrations causes oxidative stress and cytotoxicity, a property that is potentially exploitable for the treatment of cancer in combination with radiotherapy (RT). We report the first Phase I trial testing the safety and tolerability of intratumoural H2O2 + external beam RT as a novel combination in patients with breast cancer, and exploratory plasma marker analyses investigating possible mechanisms of action. Methods and Materials 12 patients with breast tumours ≥3 cm (surgically or medically inoperable) received intratumoural H2O2 with either 36 Gy in 6 twice-weekly fractions (n=6) or 49.5 Gy in 18 daily fractions (n=6) to the whole breast +/- loco-regional lymph nodes in a single-centre, non-randomised study. H2O2 was mixed in 1% sodium hyaluronate gel (final H2O2 concentration 0.5%) before administration to slow drug release and minimise local discomfort. The mixture was injected intratumourally under ultrasound guidance twice-weekly 1h prior to RT. The primary endpoint was patient-reported maximum intratumoural pain intensity before and 24h post-injection. Secondary endpoints included ≥grade 3 skin toxicity and tumour response by ultrasound. Blood samples were collected before, during and at the end of treatment for cell-death and immune marker analysis. Results Compliance with H2O2 and RT was 100%. 5/12 patients reported moderate pain following injection (grade 2 CTCAE v4.02) with median duration 60min (interquartile range 20-120min). Skin toxicity was comparable to RT alone, with maintained partial/complete tumour response relative to baseline in 11/12 patients at last follow-up (median 12 months). Blood marker analysis highlighted significant associations of TRAIL, IL-1β, IL-4 and MIP-1α with tumour response. Conclusions Intratumoural H2O2 with RT is well-tolerated with no additional toxicity compared to RT alone. If efficacy is confirmed in a randomised Phase II trial, the approach has potential as a cost-effective radiation response enhancer in multiple cancer types where locoregional control after RT alone remains poor.
#1Noemi Di Marzo (University of Milano-Bicocca)H-Index: 1
#2Elisa Chisci (University of Milano-Bicocca)H-Index: 6
Last. Roberto Giovannoni (University of Milano-Bicocca)H-Index: 19
view all 3 authors...
Hydrogen peroxide (H2O2) is an important metabolite involved in most of the redox metabolism reactions and processes of the cells. H2O2 is recognized as one of the main molecules in the sensing, modulation and signaling of redox metabolism, and it is acting as a second messenger together with hydrogen sulfide (H2S) and nitric oxide (NO). These second messengers activate in turn a cascade of downstream proteins via specific oxidations leading to a metabolic response of the cell. This metabolic re...
62 CitationsSource
#1Caitlin Yee (Sunnybrook Health Sciences Centre)H-Index: 7
#2Katie Wang (Sunnybrook Health Sciences Centre)H-Index: 3
Last. Edward Chow (Sunnybrook Health Sciences Centre)H-Index: 70
view all 10 authors...
Abstract Radiation dermatitis is a common side effect of radiotherapy. Radiation dermatitis has been investigated for decades, and many approaches have been proposed to limit its incidence and severity. The purpose of the present systematic review was to summarize the approaches and findings of studies testing various methods for management of radiation dermatitis in breast cancer patients. Medline, Cochrane, and Embase were searched for studies pertaining to radiation-induced skin toxicity in b...
20 CitationsSource
#1Yolande Lievens (Ghent University Hospital)H-Index: 23
#2Mary Gospodarowicz (Princess Margaret Cancer Centre)H-Index: 53
Last. Advisory CommitteesH-Index: 1
view all 10 authors...
15 CitationsSource
#1Steffen LöckH-Index: 24
#2Rosalind Perrin (HZDR: Helmholtz-Zentrum Dresden-Rossendorf)H-Index: 5
Last. Michael Baumann (HZDR: Helmholtz-Zentrum Dresden-Rossendorf)H-Index: 20
view all 12 authors...
Abstract Background Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [ 18 F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several...
76 CitationsSource
#1Helmut Sies (HHU: University of Düsseldorf)H-Index: 154
Abstract Hydrogen peroxide emerged as major redox metabolite operative in redox sensing, signaling and redox regulation. Generation, transport and capture of H 2 O 2 in biological settings as well as their biological consequences can now be addressed. The present overview focuses on recent progress on metabolic sources and sinks of H 2 O 2 and on the role of H 2 O 2 in redox signaling under physiological conditions (1–10 nM), denoted as oxidative eustress. Higher concentrations lead to adaptive ...
679 CitationsSource
#1Ophira Ginsburg (U of T: University of Toronto)H-Index: 22
#2Freddie Bray (IARC: International Agency for Research on Cancer)H-Index: 119
Last. Lesong Conteh (Imperial College London)H-Index: 29
view all 21 authors...
Summary Every year, more than 2 million women worldwide are diagnosed with breast or cervical cancer, yet where a woman lives, her socioeconomic status, and agency largely determines whether she will develop one of these cancers and will ultimately survive. In regions with scarce resources, fragile or fragmented health systems, cancer contributes to the cycle of poverty. Proven and cost-effective interventions are available for both these common cancers, yet for so many women access to these is ...
361 CitationsSource
#1May Abdel-Wahab (IAEA: International Atomic Energy Agency)H-Index: 18
#2Elena Fidarova (IAEA: International Atomic Energy Agency)H-Index: 20
Last. A. Polo (IAEA: International Atomic Energy Agency)H-Index: 1
view all 3 authors...
Abstract Over the last 60 years, the International Atomic Energy Agency (IAEA) has been working to introduce, expand and improve radiotherapy services, working with partners such as the World Health Organization (WHO) to improve cancer diagnosis, treatment, care and control through collective action in low- and middle-income countries (LMICs). The Lancet Oncology Commission on radiotherapy published a report that defined five calls for action to expand global access to radiotherapy, drawing on t...
28 CitationsSource
#1Lorenzo GalluzziH-Index: 127
#2Aitziber BuquéH-Index: 23
Last. Guido KroemerH-Index: 254
view all 5 authors...
Initiation of an adaptive immune response depends on the detection of both antigenic epitopes and adjuvant signals. Infectious pathogens and cancer cells often avoid immune detection by limiting the release of danger signals from dying cells. When is cell death immunogenic and what are the pathophysiological implications of this process?
960 CitationsSource
#1N. Aoyama (Kōchi University)H-Index: 5
#2Yasuhiro OgawaH-Index: 25
Last. Mitsuhiko Miyamura (Kōchi University)H-Index: 15
view all 13 authors...
: Linac-based radiotherapy has a negligible effect on the majority of advanced neoplasms. Therefore, a novel radiosensitization treatment Kochi Oxydol Radiation Therapy for Unresectable Carcinomas II (KORTUC II), which utilizes hydrogen peroxide and sodium hyaluronate was developed. The effectiveness of KORTUC II for the treatment of chemotherapy-resistant supraclavicular lymph node metastases and recurrent breast cancers has previously been demonstrated. The present study evaluated the safety a...
6 CitationsSource
#1Jinmei Xiang (HAU: Huazhong Agricultural University)H-Index: 3
#2Chun-yun Wan (HAU: Huazhong Agricultural University)H-Index: 2
Last. Dingzong Guo (HAU: Huazhong Agricultural University)H-Index: 6
view all 4 authors...
Hydrogen peroxide is currently the most widely used apoptosis inducer due to its broad cytotoxic efficacy against nearly all cell types. However, equivalent cytotoxicity is achieved over a wide range of doses, although the reasons for this differential sensitivity are not always clear. In this study, three kinds of cells, the 293T cell line, primary fibroblasts, and terminally differentiated myocardial cells, were treated with a wide range of H2O2 doses. Times to apoptosis initiation and end wer...
49 CitationsSource
Cited By4
#1Tomas BertokH-Index: 20
#2Aniko BertokovaH-Index: 4
Last. Jan TkacH-Index: 42
view all 8 authors...
The review initially provides a short introduction to prostate cancer (PCa) incidence, mortality, and diagnostics. Next, the need for novel biomarkers for PCa diagnostics is briefly discussed. The core of the review provides details about PCa aetiology, alternative biomarkers available for PCa diagnostics besides prostate specific antigen and their biosensing. In particular, low molecular mass biomolecules (ions and metabolites) and high molecular mass biomolecules (proteins, RNA, DNA, glycoprot...
Hydrogen peroxide (H2O2) with a high level in solid tumor microenvironments has been widely investigated as an important target in the design and application of various novel anticancer strategies. Among these strategies, H2O2 can be used as an oxygen supplier to improve the therapeutic effects of hypoxia-limited treatment modes including chemotherapy (CT), radiotherapy (RT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and starvation therapy (ST). Moreover, it can participate in Fento...
#1Rong Hu (Juntendo University)
#2Anneyuko I. Saito (Juntendo University)H-Index: 9
Last. Keisuke Sasai (Juntendo University)H-Index: 21
view all 8 authors...
#2Ken Yoshida (Kansai Medical University)H-Index: 10
view all 16 authors...
In order to improve oncologic outcomes in radiotherapy treatments of patients with unresectable pelvic sidewall recurrences of uterine cervical cancer, we combined high-dose-rate interstitial brachytherapy (HDR-ISBT) with newly tested hypoxic radiosensitizer Kochi oxydol-radiation therapy for unresectable carcinomas (KORTUC II), an enzyme-targeting radiosensitization treatment involving intra-tumoral injection of sodium hyaluronate mixed with hydrogen peroxide. We report on a 63-year-old patient...