Intratumoural hydrogen peroxide with radiotherapy in locally advanced breast cancer: results from a Phase I clinical trial.
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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.
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Translational Breast Radiobiology
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International journal of radiation oncology, biology, physics, 2020