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

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 radiation therapy (RT). We report the first phase 1 trial testing the safety and tolerability of intratumoral 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 Twelve patients with breast tumors ≥3 cm (surgically or medically inoperable) received intratumoral 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 ± locoregional lymph nodes in a single-center, nonrandomized study. H2O2 was mixed in 1% sodium hyaluronate gel (final H2O2 concentration 0.5%) before administration to slow drug release and minimize local discomfort. The mixture was injected intratumorally under ultrasound guidance twice weekly 1 hour before RT. The primary endpoint was patient-reported maximum intratumoral pain intensity before and 24 hours postinjection. Secondary endpoints included grade ≥3 skin toxicity and tumor 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%. Five of 12 patients reported moderate pain after injection (grade 2 Common Terminology Criteria for Adverse Events v4.02) with median duration 60 minutes (interquartile range, 20-120 minutes). Skin toxicity was comparable to RT alone, with maintained partial/complete tumor response relative to baseline in 11 of 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 tumor response.Conclusions Intratumoral H2O2 with RT is well tolerated with no additional toxicity compared with RT alone. If efficacy is confirmed in a randomized phase 2 trial, the approach has potential as a cost-effective radiation response enhancer in multiple cancer types in which locoregional control after RT alone remains poor

Investigation of the effects of hydrogen peroxide in combination with ionising radiation in cancer

Introduction In the early 2000s, Japanese colleagues reported sensitisation of normal and tumour cell lines to cytotoxic doses of ionising radiation (IR) by low concentrations of hydrogen peroxide (H2O2), research that prompted clinical studies testing intratumoural (IT) injections of 0.5% H2O2 in 1% sodium hyaluronate gel during radiotherapy in patients with inoperable breast cancer. Five-year local control rates were substantially higher than expected from the radiotherapy dose intensities used, with no additional late adverse effects. Methods Using the radioresistant cell lines HCT116 and HN5, the effect of H2O2 + IR was investigated in 2D clonogenic survival and 3D spheroid growth assays. A dual hypoxia marker technique was used to capture the effect of IT H2O2 in murine xenografts. In paralleL, a phase I clinical trial of IT H2O2 + radiotherapy was conducted in 12 patients with breast cancer to evaluate safety and cute toxicity. Results 2D clonogenic assays did not confirm sensitisation of HCT116 or HN5 under normoxic conditions. Growth inhibition was demonstrated in HCT116 spheroids treated with H2O2 + IR, compared with H2O2/IR alone. Xenograft tumours injected with H2O2 + sodium hyaluronate exhibited a reduction in hypoxia staining compared to baseline. A significant difference in pimonidazole versus CCI-103F staining was demonstrated in H2O2-injected tumours (p0=02), with no significant difference in the control groups. The phase I clinical trial confirmed safety with no additional toxicity compared to RT alone. Conclusion 3D spheroid results are in keeping with clinical reports of enhancement of radiation effect by H2O2. Reoxygenation by IT H2O2 may be an important mechanism by which tumour response is enhanced for therapeutic gain, and which has implications for scheduling of H2O2 relative to radiotherapy in the clinical setting. If this method of increasing oxygen delivery to tumours is confirmed to be successful, it has potential to be utilised in several other tumour types

Paraneoplastic endocrine syndromes

The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. However, occasionally neoplasms, with or without endocrine differentiation, acquire the ability to secrete a variety of bioactive substances or induce immune cross-reactivity with the normal tissues that can lead to the development of characteristic clinical syndromes. These syndromes are named endocrine paraneoplastic syndromes when the specific secretory components (hormones, peptides or cytokines) are unrelated to the anticipated tissue or organ of origin. Endocrine paraneoplastic syndromes can complicate the patient’s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. These syndromes can precede, occur concomitantly or present at a later stage of tumour development, and along with the secreted substances constitute the biological ‘fingerprint’ of the tumour. Their detection can facilitate early diagnosis of the underlying neoplasia, monitor response to treatment and/or detect early recurrences following successful initial management. Although when associated with tumours of low malignant potential they usually do not affect long-term outcome, in cases of highly malignant tumours, endocrine paraneoplastic syndromes are usually associated with poorer survival outcomes. Recent medical advances have not only improved our understanding of paraneoplastic syndrome pathogenesis in general but also enhanced their diagnosis and treatment. Yet, given the rarity of endocrine paraneoplastic syndromes, there is a paucity of prospective clinical trials to guide management. The development of well-designed prospective multicentre trials remains a priority in the field in order to fully characterise these syndromes and provide evidence-based diagnostic and therapeutic protocols