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Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer.

ABSTRACT: Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.The frequency and absolute numbers of CD4(+), ATP-hydrolyzing CD4(+)CD39(+) and CD8(+) T cells, and expression levels of CD39, CD25, TGF-?-associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT]. All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n = 15), NED (n = 10), and NC (n = 15), in vitro sensitivity of CD4(+) T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V-binding assays.CRT decreased the frequency of circulating CD4(+) T cells (P < 0.002) but increased that of CD4(+)CD39(+) Treg (P ? 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to AICD or cisplatin but conventional CD4(+) T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax.Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC.

SUBMITTER: Schuler PJ

PROVIDER: S-EPMC3855337 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer.

Schuler Patrick J PJ Harasymczuk Malgorzata M Schilling Bastian B Saze Zenichiro Z Strauss Laura L Lang Stephan S Johnson Jonas T JT Whiteside Theresa L TL

Clinical cancer research : an official journal of the American Association for Cancer Research 20131004 23

<h4>Purpose</h4>Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.<h4>Experimental design</h4>The frequency and absolute numbers of CD4(+), ATP-hydrolyzing CD4(+)CD39(+) and CD8(+) T cells, and expression levels of CD39, CD25, TGF-β-associated LAP and ...[more]

PMID: 24097865

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Project description:Agreement between patient- and practitioner-reported toxic effects during chemoradiotherapy for head and neck cancer is unknown.To compare patient-reported symptom severity and practitioner-reported toxic effects among patients receiving chemoradiotherapy for head and neck cancer.Forty-four patients participating in a phase 2 trial of deintensified chemoradiotherapy for oropharyngeal carcinoma were included in the present study (conducted from February 8, 2012, to March 2, 2015). Most treatment (radiotherapy, 60 Gy, with concurrent weekly administration of cisplatin, 30 mg/m2) was administered at academic medical centers. Included patients had no prior head and neck cancers, were 18 years or older, and had a smoking history of 10 pack-years or less or more than 10 pack-years but 30 pack-years or less and abstinent for the past 5 years. Cancer status was untreated human papillomavirus or p16-positive squamous cell carcinoma of the oropharynx or unknown head and neck primary site; and cancer staging was category T0 to T3, category N0 to N2c, M0, and Eastern Cooperative Oncology Group performance status 0 to 1. Baseline, weekly, and posttreatment toxic effects were assessed by physicians or nurse practitioners using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Patient-reported symptom severity was measured using the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE). Descriptive statistics were used to characterize raw agreement between CTCAE grades and PRO-CTCAE severity ratings.Baseline, weekly, and posttreatment toxic effects assessed using CTCAE, version 4.0, and PRO-CTCAE.Raw agreement indices between patient-reported toxic effects, including symptom frequency, severity, and interference with daily activities (score range, 0 [none] to 4 [very severe]), and practitioner-measured toxic effects, including swallowing, oral pain, and hoarseness (score range, 1 [mild] to 5 [death]).Of the 44 patients included in the analysis (39 men, 5 women; mean [SD] age, 61 [8.4] years), there were 327 analyzable pairs of CTCAE and PRO-CTCAE symptom surveys and no treatment delays due to toxic effects. Patient-reported and practitioner-reported symptom severity agreement was high at baseline when most symptoms were absent but declined throughout treatment as toxic effects increased. Most disagreement was due to lower severity of toxic effects reported by practitioners (eg, from 45% agreement at baseline to 27% at the final week of treatment for pain). This was particularly noted for domains that are not easily evaluated by physical examination, such as anxiety and fatigue (eg, severity of fatigue decreased from 43% at baseline to 12% in the final week of treatment).Practitioner-reported toxic effects are lower than patient self-reports during head and neck chemoradiotherapy. The inclusion of patient-reported symptomatic toxic effects provides information that can potentially enhance clinical management and improve data quality in clinical trials.

Project description:ImportanceLocoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC.ObjectiveTo assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC.Design, setting, and participantsThis multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population.InterventionsPatients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal.Main outcomes and measuresThe primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life.ResultsA total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group).Conclusions and relevanceThis study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended.Trial registrationClinicalTrials.gov identifier: NCT01345669.

Project description:IntroductionMuscle wasting conditions such as sarcopenia may be highly prevalent in advanced head and neck cancer (HNC) patients (16-71%), with these prevalence rates substantially greater in those who have received chemo-radiotherapy (CRT). According to the updated European Working Group on Sarcopenia in Older People consensus statement, sarcopenia is defined as the age-related loss of muscle strength, muscle mass and physical performance. The high prevalence of sarcopenia in HNC patients is concerning as it has been associated with substantially increased risk of CRT toxicity, respiratory complications and early mortality. With the high prevalence of HNC and sarcopenia in India and the strong link between sarcopenia and poor HNC patient outcomes, it is important to screen for the presence of sarcopenia in Indian patients receiving CRT for HNC.MethodsThis longitudinal pilot study aimed to routinely monitor 19 men receiving CRT for their HNC for a variety of sarcopenic-related outcomes over three time points during their 7 weeks of CRT. Participants were required to be male, with a minimum age of 30 years, with a Stage III, IVa or IVb diagnosis of HNC and be currently undergoing a 7 weeks course of CRT in an oncology department. Outcomes included probable sarcopenic diagnosis were estimated by the SARC-F, handgrip strength, skeletal muscle mass was estimated by bioelectrical impedance and physical performance was assessed by the Timed Up and Go. Repeated measures ANOVA and Bonferroni post-hoc tests were used to identify significant differences at the three time points with a p < 0.05.ResultsThe 19 participants in this trial at a mean age of 56.5 ± 10.2 years (range = 39-75 years), with most (n = 13, 68.4%) employed in laboring occupations. At baseline, 31.5% (n = 6) of the participants already had probable sarcopenia based on their total SARC-F score, with this increasing to 89.4% (n = 17) at the end of 7 weeks CRT. In addition, significant decreases in strength, skeletal muscle mass and Timed Up and Go performance were observed, with these declines significantly greater at 7 weeks than 3 weeks after commencing CRT.ConclusionsPatients with HNC undergoing 7 weeks of CRT showed clinically significant increases in the incidence of probable sarcopenia based on their total SARC-F score as well as clinically significant declines in handgrip strength, skeletal muscle mass and Timed Up and Go performance. Due to the relationship between sarcopenia and a host of adverse events related to CRT in HNC patients, these results suggest that oncologists and their allied health teams should routinely monitor these patients during CRT and provide the relevant exercise therapy and nutritional support to those patients in need.

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Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer.

Publications

Effects of adjuvant chemoradiotherapy on the frequency and function of regulatory T cells in patients with head and neck cancer.

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