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The kinetics of ?-H2AX during radiotherapy of head and neck cancer potentially allow for prediction of severe mucositis.

ABSTRACT: Background The aim of the study was to evaluate the changes in ?-H2AX expression in peripheral blood lymphocytes (PBL) according to severity of radiation-induced mucositis. Patients and method Fifty patients with head and neck cancer treated with radiotherapy (RT) or chemoradiation were included in the study. Blood samples were collected before treatment to measure baseline ?-H2AX levels. Second sample was taken 45 minutes after the first RT fraction and then once a week, 45 min after irradiation. In patients treated with chemoradiation the blood sample was taken the day after chemotherapy. Mucositis was evaluated once a week and reported according to CTCAE v4 and RTOG/EORTC scales. PBL were analyzed with flow cytometry and level of H2AX phosphorylation at every time point was evaluated. Results In 35 patients mild to moderate (grade 1-2) mucositis was observed and 15 patients developed severe (grade 3) mucositis. No cases of grade 4 mucositis were observed. The difference in baseline levels of ?-H2AX between groups with mild and severe mucositis was statistically insignificant (p = 0.25). The statistically significant difference in ?-H2AX level was observed in week 7 of treatment (p = 0.01). No significant differences in ?-H2AX level were found neither between group treated with concomitant chemoradiation or RT alone neither between groups with and without common comorbidities. In the analysis of the kinetics of ?-H2AX during treatment, a statistically significant difference (p = 0.0088) between groups with mild and severe mucositis was observed. After fourth week of treatment levels of ?-H2AX decreased significantly in the group with severe mucositis and increased in patients with mild side effects. The observed difference was not caused by the decrease in peripheral lymphocyte count, which was similar in both groups. Conclusions Presented results indicate that severity of radiation-induced mucositis does not correlate directly with ?-H2AX levels measured in vivo in PBL. Prediction of mucositis grade based on ?-H2AX level is not yet possible, either before treatment or early during treatment, but preliminary results, indicating significant differences in ?-H2AX kinetics between groups, encourage further studies.

SUBMITTER: Kazmierska J

PROVIDER: S-EPMC7087415 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The kinetics of γ-H2AX during radiotherapy of head and neck cancer potentially allow for prediction of severe mucositis.

Kazmierska Joanna J Barczak Wojciech W Winiecki Tomasz T Łuczewski Łukasz Ł Marciniak Magdalena M Suchorska Wiktoria W

Radiology and oncology 20200214 1

Background The aim of the study was to evaluate the changes in γ-H2AX expression in peripheral blood lymphocytes (PBL) according to severity of radiation-induced mucositis. Patients and method Fifty patients with head and neck cancer treated with radiotherapy (RT) or chemoradiation were included in the study. Blood samples were collected before treatment to measure baseline γ-H2AX levels. Second sample was taken 45 minutes after the first RT fraction and then once a week, 45 min after irradiatio ...[more]

PMID: 32061167

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Project description:Purpose: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM).Patients and methods: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading.Results: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing.Conclusion: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.

Project description:PurposeCurrent normal tissue complication probability modeling using logistic regression suffers from bias and high uncertainty in the presence of highly correlated radiation therapy (RT) dose data. This hinders robust estimates of dose-response associations and, hence, optimal normal tissue-sparing strategies from being elucidated. Using functional data analysis (FDA) to reduce the dimensionality of the dose data could overcome this limitation.Methods and materialsFDA was applied to modeling of severe acute mucositis and dysphagia resulting from head and neck RT. Functional partial least squares regression (FPLS) and functional principal component analysis were used for dimensionality reduction of the dose-volume histogram data. The reduced dose data were input into functional logistic regression models (functional partial least squares-logistic regression [FPLS-LR] and functional principal component-logistic regression [FPC-LR]) along with clinical data. This approach was compared with penalized logistic regression (PLR) in terms of predictive performance and the significance of treatment covariate-response associations, assessed using bootstrapping.ResultsThe area under the receiver operating characteristic curve for the PLR, FPC-LR, and FPLS-LR models was 0.65, 0.69, and 0.67, respectively, for mucositis (internal validation) and 0.81, 0.83, and 0.83, respectively, for dysphagia (external validation). The calibration slopes/intercepts for the PLR, FPC-LR, and FPLS-LR models were 1.6/-0.67, 0.45/0.47, and 0.40/0.49, respectively, for mucositis (internal validation) and 2.5/-0.96, 0.79/-0.04, and 0.79/0.00, respectively, for dysphagia (external validation). The bootstrapped odds ratios indicated significant associations between RT dose and severe toxicity in the mucositis and dysphagia FDA models. Cisplatin was significantly associated with severe dysphagia in the FDA models. None of the covariates was significantly associated with severe toxicity in the PLR models. Dose levels greater than approximately 1.0 Gy/fraction were most strongly associated with severe acute mucositis and dysphagia in the FDA models.ConclusionsFPLS and functional principal component analysis marginally improved predictive performance compared with PLR and provided robust dose-response associations. FDA is recommended for use in normal tissue complication probability modeling.

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The kinetics of ?-H2AX during radiotherapy of head and neck cancer potentially allow for prediction of severe mucositis.

Publications

The kinetics of γ-H2AX during radiotherapy of head and neck cancer potentially allow for prediction of severe mucositis.

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