Neck Cancer Clinical Trials Research Articles

Geospatial Mapping of Head and Neck Cancer Research: Assessing Access, Disparities, and Characteristics of Head and Neck Cancer Clinical Trials Across the United States.

To report geographic distribution and characteristics of head and neck cancer (HNC) clinical trials in the United States. We conducted a retrospective analysis of U.S. HNC clinical trials searching ClinicalTrials.gov from January 1, 2017 to December 31, 2021 using the terms "head and neck cancer" or "head and neck neoplasms." A total of 381 clinical trials met inclusion criteria with 2181 trial opportunities, which were correlated with population density. Of the U.S. population, 72% live within a 25-mile radius of trials. California, Pennsylvania, and New York had the greatest number of clinical trial entries. The majority of patients living more than 25 miles from an HNC clinical trial site are located in rural areas. One hundred sixty-five (43.3%) trials were about systemic therapy, of which 138 (83.6%) involved targeted immunotherapy. There were 286 unique principal investigators. One hundred six (37.1%) were females and 180 (62.9%) were males. We demonstrate disparity in the geographic distribution of HNC trials favoring densely populated urban areas, which may limit patient access due to travel burden. Studies are skewed towards immunotherapy drug trials, with fewer radiation and surgery investigations. Level III.

A Review of the Evolution of Quality of Life Measures in Head and Neck Cancer Clinical Trials

A Review of the Evolution of Quality of Life Measures in Head and Neck Cancer Clinical Trials

Racial survival disparities in head and neck cancer clinical trials.

Survival disparities between Black and White head and neck cancer patients are well documented, with access to care and socioeconomic status as major contributors. We set out to assess the role of self-reported race in head and neck cancer by evaluating treatment outcomes of patients enrolled in clinical trials, where access to care and socioeconomic status confounders are minimized. Clinical trial data from the Radiation Therapy Oncology Group studies were obtained. Studies were included if they were therapeutic trials that employed survival as an endpoint. Studies that did not report survival as an endpoint were excluded; 7 Radiation Therapy Oncology Group Studies were included for study. For each Black patient enrolled in a clinical trial, a study arm-matched White patient was used as a control. A total of 468 Black participants were identified and matched with 468 White study arm-specific controls. White participants had better outcomes than Black participants in 60% of matched pairs (P < .001). Black participants were consistently more likely to have worse outcomes. When outcomes were measured by progression-free survival or disease-free survival, the failure rate was statistically significantly higher in Black participants (hazard ratio [HR] = 1.50, P < .001). Failure was largely due to locoregional failure, and Black participants were at higher risk (subdistribution HR =1.51, P = .002). The development of distant metastasis within the paired cohorts was not statistically significantly different. In this study of clinical trial participants using self-reported race, Black participants consistently had worse outcomes in comparison to study arm-specific White controls. Further study is needed to confirm these findings and to explore causes underlying this disparity.

Abstract 1175: Race informs survival disparities in head and neck cancer clinical trials

Abstract Background: Survival disparities between blacks and whites in head and neck cancer are well documented, with access to care and socioeconomic status (SES) as major contributors. However, the impact of race alone on survival is much less clear. Previous attempts to evaluate the role of race have been limited by access to care/SES as major confounders. We set out to directly assess the role of race in head and neck cancer by evaluating treatment outcomes of subjects enrolled in clinical trials. In this population, access to care and socioeconomic confounders are minimized because all patients receive identical treatments. Methods: Clinical trial data from the Radiation Therapy Oncology group (now NRG) studies were obtained by request. Seven RTOG Studies (RTOG 0129, 0234, 9003, 9111, 9501, 9512, 9703) were included for study. Studies were included if they were phase II or III trials that employed survival as an endpoint, e.g. progression free survival (PFS), disease free survival (DFS), overall survival (OS). Studies that were small (&amp;lt;200 patients) or did not use survival as an endpoint (e.g. side effect trial) were excluded. For each black patient enrolled in a clinical trial, a white patient matched in the same arm of that trial was used as a control. The study null-hypothesis was that there would be no race derived impact on survival and thus the chance of survival favoring either whites or blacks in each matched pair would be 50%. Results: Across the seven trials, 468 blacks were identified and matched with 468 white study arm specific controls. Whites had better outcomes than blacks in 60% of matched pairs (p&amp;lt;0.001). Blacks were consistently more likely to have worse outcomes. When outcomes were collapsed by PFS/DFS, the failure rate was significantly higher in blacks (HR=1.46, p&amp;lt;0.001)). Failure was largely due to locoregional failure, and blacks were at higher risk (sHR =1.43, p=0.002). The development of distant metastasis within the paired cohorts was not significantly different (sHR=1.15, p=0.38), suggesting that locoregional failure was the major driver of failure. Conclusions: In this analysis of head and neck cancer patients in clinical trials, blacks consistently had worse outcomes in comparison to study arm specific white controls. This suggests that race alone confers a worse survival independent of socioeconomic and access to care factors. Further study is needed to confirm these findings, and to explore other causes underlying this disparity. Citation Format: Jeffrey C. Liu, Brian Egleston, Elizabeth Blackman, Camille Ragin. Race informs survival disparities in head and neck cancer clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1175.

A Systematic Method to Increase Enrollment in Head and Neck Cancer Clinical Trials

A Systematic Method to Increase Enrollment in Head and Neck Cancer Clinical Trials

Anti-tumor immunity induced by ectopic expression of viral antigens is transient and limited by immune escape

ABSTRACTImmunotherapeutic treatments in head and neck cancer clinical trials include cancer vaccines targeting foreign viral antigens or mutational neoantigens derived from cancer-expressed proteins. Anti-tumor immune responses place cancer cells under selective pressure to lose or downregulate target antigens; therefore, vaccination against virus- or host- “driver” oncogenes are proposed as a strategy to overcome immune escape. Herein, we demonstrate the impact of immunogenic viral antigens on anti-tumor response and immune editing in MOC2-E6E7, a syngeneic murine oral cancer cell line expressing HPV-16 E6 and E7 oncoproteins. Using orthotopic syngeneic models, we observed in vivo tumor growth kinetics of MOC2-E6E7 is delayed in immunocompetent mice compared to parental MOC2 tumors. In contrast, tumor growth remained similar in Rag1-/- mice lacking adaptive immunity. MOC2-E6E7 tumors demonstrated an “inflamed” or immune-activated tumor microenvironment and greater infiltration of CD8+ T cells compared to MOC2. By real-time PCR, we detected downregulation of E6 and E7 genes in MOC2-E6E7 tumors only in immunocompetent mice, suggesting the loss of ectopic viral antigen expression due to immune editing. We then assessed the efficacy of a biomaterials-based mesoporous silica rod (MSR) cancer vaccine targeting HPV-16 E7 in our model. Vaccination induced robust infiltration of antigen-specific CD8+ T cells, which led to tumor growth delay and modestly prolonged survival in MOC2-E6E7 tumors. Increased efficacy was seen in a separate head and neck cancer tumor model, mEER, which obligately expresses E7 antigen. Collectively, our data highlight the need for both immunogenicity and ‘driver’ status of target antigens to be considered in cancer vaccine design.

Immunotherapy highlights of the ASCO annual meeting 2018 for head and neck cancers

Immunotherapeutic strategies are becoming increasingly more important for head and neck cancer and numerous clinical trials were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2018. In this review the most interesting clinical trials and trial results for immunotherapy of head and neck cancer are summarized. All abstracts and presentations on immunotherapy of head and neck cancer at the annual meeting of the ASCO 2018 were screened to select the most interesting trials for amore detailed analysis. For head and neck cancer, practice changing phase III trial results were missing, but several noteworthy new strategies and trial results for immunotherapy were presented. Neoadjuvant immunotherapy trials, results concerning immunotherapy in old age, prognostic implications of immune-mediated adverse events and new immunotherapy combinations are summarized in this article. The role of immunotherapy for the treatment of head and neck cancer is markedly increasing. Many pioneering trials are currently ongoing, in the phase of data analysis or in planning.

The Current Portfolio of Head and Neck Cancer Trials on ClinicalTrials.gov

To describe the current distribution of active head and neck cancer (HNC) clinical trials across the spectrum of definitive, recurrent and metastatic (R/M), and quality of life (QOL)/survivorship care, and to describe funding sources and principal-investigator (PI) leadership of HNC trials. We identified all active, interventional HNC trials on ClinicalTrials.gov as of June 26, 2017, using the search terms “head and neck cancer” and all specific HNC subsites, excluding skin cancers. Logistic regression was used to identify associations between trial characteristics and funding type. We identified 841 active HNC trials on ClinicalTrials.gov, of which 48% are United States (US)-based, 43% international, and 8% both. Fifty percent of trials enrolled curative-intent patients, 44% enrolled R/M patients, and 6% enrolled both. Most trials (76%) included systemic therapy (ST) in the prescribed treatment, 41% included RT, and 12% included surgery; 9% evaluated a QOL/survivorship question. Among trials using ST, 51% were in R/M patients, 46% definitive, and 3% in either. In 2017, immune-oncology (IO) agents were used in 38% of trials including ST, equal in frequency to chemotherapy use, and far surpassing non-IO antibody-based ST (9% ST trials). Most trials enrolled multiple HNC subsites (47%), with specific subsite trials being less common (12% nasopharynx, 10% thyroid, 5% oropharynx, 3% oral cavity, 3% other, 2% larynx/hypopharynx; 18% open to HNC + non-HNC sites, eg esophageal, breast, etc.) Regarding PI leadership, medical oncologists led 34% of trials, radiation oncologists 23%, surgeons 16%, and other specialties 27%. Trials enrolling R/M patients were more likely to have industry funding (54%) relative to trials enrolling definitive patients (18%) (odds ratio [OR]=5.43; P<.001). Trials that included ST (41%) were more likely to have industry funding compared to trials including RT (16%) (OR=3.70; P<.001) or surgery (9%) (OR=7.42; P<.001). Among US trials, a greater proportion of definitive trials are NIH-funded (39%) compared to R/M trials (28%) (OR=1.41; P=.13). There was no association between RT, ST, or surgery use and NIH funding (ST vs. RT, OR=0.83; P=.37; ST vs. surgery, OR 1.05; P=.88). Although most patients with HNC have localized/non-metastatic disease, nearly half of HNC trials are focused on the R/M setting and there are few QOL/survivorship trials especially considering the growing population of HNC survivors. Definitive trials, particularly those not incorporating novel ST agents, are less likely to receive industry funding and are more dependent on NIH funding or other sources of funding. This may have implications for trials that involve de-intensification via minimizing use of ST.

415. The Potency of a Histone Deacetylase Inhibitor and Reolysin in Head and Neck Squamous Cell Carcinoma

Introduction: There is a clear and pressing need for novel therapies with activity against locally advanced head and neck cancers which still carry a dismal prognosis. Oncolytic viruses are powerful, targeted anti-cancer agents. Reovirus is a naturally occurring non-pathogenic virus that was isolated from the human respiratory and gastrointestinal tracts. Moreover, Reovirus type 3 Dearing (Reolysin; Oncolytics Biotech Inc., Calgary, AB, Canada) is currently being tested in phase I-III clinical trials in a variety of tumor types. Histone deacetylase inhibitors (HDACi) comprise a structurally diverse class of compounds that are targeted anticancer agents. The first FDA approved HDACi, vorinostat (suberoylanilide hydroxamic acid-SAHA), is highly effective in the treatment of cutaneous Tcell lymphoma. SAHA is currently being testing in head and neck cancer clinical trials. We previously found a synergistic combination of SAHA and Reolysin in a nude mouse model. Preclinical models of oncolytics are often in immunocompromised mice, negating the significant impact of the immune system. Mounting evidence demonstrates that the immune system is critically important in oncolytic viral response. In this study, we sought to investigate the impact of this combination in an immunocompetent model. Methods: Cell survival experiments were performed with reovirus and SAHA in shPTP-BL-Ras SCC cells. IC50 values were interpolated from a sigmoidal dose-response curve fit of the log-transformed survival data. JAM-1 surface levels were assessed via flow cytometric analysis. Cells were collected after 48 hours and cell death was assessed via Annexin V and PI staining. JAM-1 levels were assessed using anti-JAM-1-PE staining as compared to a control isotype-PE antibody. Whole splenocytes were isolated at the time of death for C57BL/6 mice bearing MTE tumors treated in 4 groups (control, SAHA, reovirus, and combination). Three independent mice were stained per group for the following: B cells (CD19+), NK cells (CD49b+), activated NK cells (CD49b+NKp46+), dendritic cells (CD11c+) and activated DCs (CD11c+MHCII+ or CD11c+CD86+), CD4 T helper (CD3+CD4+), and CD8 cytotoxic cells (CD3+CD8+). Results: Experiments demonstrated significant efficacy of SAHA and Reolysin treatment in vitro and in the immunocompetent mouse model. Combination therapy exhibited a synergistic anti-tumor effect with a significant increased survival of mice compared to any of the agents alone. The Jam1 receptor was upregulated on tumor cells allowing enhanced reovirus uptake. There was marked and significant reduction in circulating B cells in combination treated mice versus all other groups. Activated NK cells were decreased in the combination group. T cells and dendritic cells (CD11c+MHCII+) were reduced in the SAHA groups. SAHA model withdrawal experiments show a significant synergistic response and immune system rebound after SAHA cessation. Conclusion: This data demonstrates that combination of reovirus plus SAHA therapy has significant activity in the treatment of SCCHN, even in an immunocompetent model. Immune inhibition due to SAHA as well as increased Jam1 receptor expression on tumor cells results in a synergistic effect of the combination therapy. Immune system rebound likely plays a significant role in the long-term anti-tumor response. This strong preclinical evidence supports the translation of this combination to phase-I clinical trials.

Characteristics of NIH- and industry-sponsored head and neck cancer clinical trials.

Compare U.S. clinical trials sponsored by the National Institutes of Health (NIH) and industry, especially with regard to trial design, interventions studied, and results reporting rates. U.S. head and neck cancer clinical trials. We used information from ClinicalTrials.gov to compare NIH- and industry-sponsored head and neck cancer clinical trials, specifically analyzing differences in trial design and interventions studied. We examined publication rates and positive results rates using PubMed.gov. About 50% of NIH- and industry-sponsored clinical trials have their results reported in peer-reviewed literature. Industry-sponsored trials had higher rates of positive results than NIH-sponsored trials. NIH- and industry-sponsored clinical trials had similar trial designs, although industry-sponsored trials had significantly lower rates of randomization. Industry trials utilized radiation in 19% of trials and surgery in 2% of trials. NIH trials also had low utilization of both radiation and surgery (27% and 12% of trials, respectively). NIH- and industry-sponsored trials published their results in journals with comparable impact factors. There is significant underreporting of results in U.S. head and neck cancer clinical trials, whether sponsored by NIH or industry. Industry trials have significantly higher rates of positive results, although it is unclear what contributes to this. Both NIH- and industry-sponsored trials underutilize surgery and radiation as treatment modalities, despite the fact that these are standard-of-care therapies for head and neck cancer. We recommend that the NIH and industry report all results from clinical trials and use surgery and radiation as treatment arms in order to arrive at more balanced therapeutic recommendations. N/A. Laryngoscope, 126:E300-E303, 2016.

Analysis of 473 US Head and Neck Cancer Trials (1996-2014): Trends, Gaps, and Opportunities.

To report on types of investigations being conducted in US clinical trials, the types of therapeutic investigations that predominate, and the publication rates. Retrospective analysis. US head and neck cancer clinical trials. We used the information available on ClinicalTrials.gov to identify trends in head and neck squamous cell carcinoma clinical trials to characterize the types of trials and treatments being investigated. The publication rate for these trials was also examined with PubMed.gov. Of the 473 trials analyzed, similar drug regimens have been used repeatedly in head and neck cancer clinical trials. Drug studies are highly represented, composing 62% of all trials. The most common drugs studied were cisplatin, cetuximab, and docetaxel. Among all head and neck cancer clinical trials, 33% included radiation therapy in their treatment, while 10% included a surgical component. Forty-nine percent of trials had their results published in a medical journal, and 70% of the publications reported positive results. Head and neck cancer trials are heavily weighted toward drug trials and demonstrate redundancy. Other therapies are underrepresented, especially surgery. There is a gap between the trials conducted and the rate of reporting, with an emphasis on positive results. Better balance in studying treatment modalities, less redundancy in clinical trials, and reporting all results have potential benefits for head and neck cancer and the public good.

Changing the Perspective: Current Trends in the Assessment of Functional Outcome in Patients with Head and Neck Cancer

Functional outcome and quality of life have become frequent outcome measures in head and neck cancer (HNC) clinical trials. Many thoroughly validated outcome measures are available. Still, there is a low degree of standardization and comparability among measures. It seems difficult to fully translate the new insights into clinical routine. The aims of this paper are 1) to acknowledge the diversity of outcome measures and many of the past milestones that have been reached, but also 2) to capture a growing need to concentrate and reach consensus. The hypothesis is to gain more benefit from changing the perspective toward consensus rather than diversity in functional outcome assessment. The next steps are to adopt a unique "language" to describe functional outcome and implement clear end points that assist clinical decision making. The International Classification of Functioning, Disability, and Health was adopted by the WHO and offers an internationally accepted classification to describe disability in HNC.

Disadvantage of Men Living Alone Participating in Radiation Therapy Oncology Group Head and Neck Trials

This study evaluated whether males without partners were disadvantaged for survival in Radiation Therapy Oncology Group (RTOG) head and neck cancer clinical trials. Patients treated on three RTOG trials were studied. The Cox proportional hazards model was used to determine if sex and the interaction between sex and marital/partner status were independent prognostic variables for overall survival controlling for Karnofsky performance status, tumor stage, nodal stage, primary site, and protocol treatment. A total of 1,901 patients (1,509 men) were entered onto the three RTOG trials, with 1,822 (1,438 men) analyzable patients. Prognostic variables independent of disease-related variables for survival in multivariate analyses restricted to men were age, marital/partner status, and income. The apparent disadvantage of unpartnered men is striking, even after controlling for disease and other demographic variables. Possible explanations could easily be tested in observational studies, leading to evaluation of simple interventions to improve their outcome.

The effect of EGF receptor inhibition on NF kappa b activation in oral cancer cells

Problem: Epidermal Growth Factor Receptor (EGFR) overexpression occurs with over 90% of squamous head and neck tumors clinically and is a promising intervention target currently. Strategies to inhibit these receptors clinically in head and neck cancer patients have met with mixed success. There are multiple mechanisms of action of RTKIs currently under study and the pleiotropic effects of these agents may help explain the current mixed success of these agents clinically. Nf kappa B activation in multiple cancers has been associated with apoptosis resistance and is therefore felt to be a target for intervention in head and neck cancer. In the present study we hypothesized that nf kappa B functional activation in head and neck cancer cells could be downregulated with RTKI therapy. Methods: Ca 9–22 oral cavity cancer cells were treated with PD153035 and AG1478, 2 prototypic EGFR antagonists, and examined for their ability to downregulate nf kappa B functionally, as judged by luciferase reporter gene assays. Cells were also treated with paclitaxel, a known activator of nf kappa B in these cells, following incubation with the above RTKIs, and examined for attenuation of the nf kappa B response. Results: AG1478, but not PD153035 downregulated nf kappa B functional activation by 50% in multiple replicate experiments at low micromolar concentrations. Neither inhibitor affected the functional activation of nf kappa B by paclitaxel. Conclusion: Treatment of squamous carcinoma cells with EGFR TKIs has the potential to lower nf kappa B, an early response gene which is associated with apoptosis resistance. The response of nf kappa B to individual EGFR inhibitors may be variable, as observed in this study. Significance: Early mixed results in head and neck cancer clinical trials with EGFR antagonists may be secondary to pleiotropic effects that different classes of these agents may have on squamous cancer cells. Support: None reported.

Socio-demographic variables influence outcome in Radiation Therapy Oncology Group head and neck trials

6043 Background: The specific aim of this study was to evaluate the influence of socio-demographic factors on local-regional (LR) control and survival of patients treated on RTOG head and neck cancer clinical trials. Methods:Patients treated on RTOG 9003, RTOG 9111 and RTOG 9703 were utilized. The model was stratified by protocol and a step-up procedure using a 0.05 significance level was initially used to build the model. The Cox proportional hazards model was used to determine if any tumor or socio-demographic variables (age, gender, race, Karnofsky Performance Status (KPS), T-stage, N-stage, marital status, number of persons in household, education level, household income prior to cancer diagnosis, and tobacco use) are independent prognostic variables for LR control and/or survival. Results:A total of 1901 patients were entered onto the 3 RTOG trials of which 1822 were analyzable. Fifty-nine percent of the analyzable patients were from 9003, 28% from 9111 and 13% from 9703. In multivariate analyses T and N-Stage, and KPS were significant for both survival and LR control. Variables found to have prognostic value independent of disease related variables were gender, age, marital status and income for survival and marital status and race for LR control. A significant interaction between marital status and gender existed for both endpoints. Male patients currently married or a live-in partner, did significantly better than the other male patients, while no such effect was seen in the female patients. Tobacco use at protocol entry was evaluated in the multivariate model with only RTOG 9003 and 9111, and was significant for both endpoints. Conclusions: The socio-demographic variables race and marital status were found to have independent prognostic value for predicting LR control. Income and marital status were found to have independent prognostic value for predicting survival. These variables may identify patients requiring additional support and early interventions during the course of treatment to improve outcome. No significant financial relationships to disclose.

Socio-demographic variables influence outcome in Radiation Therapy Oncology Group head and neck trials

6043 Background: The specific aim of this study was to evaluate the influence of socio-demographic factors on local-regional (LR) control and survival of patients treated on RTOG head and neck cancer clinical trials. Methods:Patients treated on RTOG 9003, RTOG 9111 and RTOG 9703 were utilized. The model was stratified by protocol and a step-up procedure using a 0.05 significance level was initially used to build the model. The Cox proportional hazards model was used to determine if any tumor or socio-demographic variables (age, gender, race, Karnofsky Performance Status (KPS), T-stage, N-stage, marital status, number of persons in household, education level, household income prior to cancer diagnosis, and tobacco use) are independent prognostic variables for LR control and/or survival. Results:A total of 1901 patients were entered onto the 3 RTOG trials of which 1822 were analyzable. Fifty-nine percent of the analyzable patients were from 9003, 28% from 9111 and 13% from 9703. In multivariate analyses T and N-Stage, and KPS were significant for both survival and LR control. Variables found to have prognostic value independent of disease related variables were gender, age, marital status and income for survival and marital status and race for LR control. A significant interaction between marital status and gender existed for both endpoints. Male patients currently married or a live-in partner, did significantly better than the other male patients, while no such effect was seen in the female patients. Tobacco use at protocol entry was evaluated in the multivariate model with only RTOG 9003 and 9111, and was significant for both endpoints. Conclusions: The socio-demographic variables race and marital status were found to have independent prognostic value for predicting LR control. Income and marital status were found to have independent prognostic value for predicting survival. These variables may identify patients requiring additional support and early interventions during the course of treatment to improve outcome. No significant financial relationships to disclose.

Summary of the proceedings of the United States and Japan Head and Neck Cancer Clinical Trials Summit, 19-20 September 1997, Kyoto, Japan.

Summary of the proceedings of the United States and Japan Head and Neck Cancer Clinical Trials Summit, 19-20 September 1997, Kyoto, Japan.