Publications by authors named "Barbara Burtness"

189 Publications

Association of epigenetic age acceleration with risk factors, survival, and quality of life in patients with head and neck cancer.

Int J Radiat Oncol Biol Phys 2021 Apr 18. Epub 2021 Apr 18.

Emory University School of Nursing.

Purpose: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy.

Methods And Materials: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy-HNC.

Results: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to <0.001). A non-linear association (quadratic) between body mass index (BMI) and EAA was observed: decreased BMI (when BMI<35,p=0.04) or increased BMI (when BMI≥35,p=0.01), was linked to higher EAA. Increased EAA (per year) was associated with worse OS (hazard ratio (HR)=1.11,95% CI=[1.03,1.18],p=0.004; HR=1.10,95% CI=[1.01,1.19], p=0.02, for EAA at 6-months and 12-months post-treatment, respectively), PFS (HR=1.10, 95% CI=[1.02,1.19], p=0.02; HR=1.14, 95% CI=[1.06,1.23], p<0.001; HR=1.08,95% CI=[1.02,1.14], p=0.01, for EAA before, end, and 6-months post-radiotherapy, respectively), and QOL over time (β=-0.61,p=0.001). An average of 3.25-3.33 years of age acceleration across time, which was responsible for 33% to 44% higher HRs of OS and PFS, was observed in those who died or developed recurrences compared to those who did not (all p<0.001).

Conclusion: Compared to demographic and lifestyle factors, clinical characteristics were more likely to contribute to faster biological aging in patients with HNC. Acceleration in epigenetic age resulted in more aggressive adverse events including OS and PFS. EAA could be considered as a marker for cancer outcomes, and decelerating aging could improve survival and QOL.
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http://dx.doi.org/10.1016/j.ijrobp.2021.04.002DOI Listing
April 2021

STING enhances cell death through regulation of reactive oxygen species and DNA damage.

Nat Commun 2021 Apr 19;12(1):2327. Epub 2021 Apr 19.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.

Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
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http://dx.doi.org/10.1038/s41467-021-22572-8DOI Listing
April 2021

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group.

Radiother Oncol 2021 03 27;156:281-293. Epub 2021 Jan 27.

Cleveland Clinic Foundation, OH, USA; Institut Saint Catherine, France.

Background And Purpose: The Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.

Materials And Methods: Published or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT + CT or adding another timing of CT to LRT + CT (main question), or comparing induction CT + radiotherapy to radiotherapy + concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.

Results: For the main question, 101 trials (18951 patients, median follow-up of 6.5 years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p < 0.0001), the benefit being limited to concomitant CT (HR: 0.83, 95%CI [0.79; 0.86]; 5(10)-year absolute benefit of 6.5% (3.6%)). Efficacy decreased as patients age increased (p_trend = 0.03). OS was not increased by the addition of induction (HR = 0.96 [0.90; 1.01]) or adjuvant CT (1.02 [0.92; 1.13]). Efficacy of induction CT decreased with poorer performance status (p_trend = 0.03). For the secondary question, eight trials (1214 patients) confirmed the superiority of concomitant CT on OS (HR = 0.84 [0.74; 0.95], p = 0.005).

Conclusion: The update of MACH-NC confirms the benefit and superiority of the addition of concomitant CT for non-metastatic head and neck cancer.
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http://dx.doi.org/10.1016/j.radonc.2021.01.013DOI Listing
March 2021

Hypoxia-Guided Therapy for Human Papillomavirus-Associated Oropharynx Cancer.

J Natl Cancer Inst 2021 Jan 12. Epub 2021 Jan 12.

Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1093/jnci/djaa187DOI Listing
January 2021

ECOG-ACRIN 2399: analysis of patient related outcomes after Chemoradiation for locally advanced head and neck Cancer.

Cancers Head Neck 2020 Dec 22;5(1):12. Epub 2020 Dec 22.

Department of Radiation Oncology, Vanderbilt University, B-1003 Preston Research Building, 2220 Pierce Avenue, Nashville, TN, 37232-5671, USA.

Background: We conducted a correlative study for E2399, a function preservation trial for resectable locally advanced oropharynx and larynx cancer, to prospectively assess effects of chemoradiation (CCR) on quality of life (QOL), swallowing and voice. We correlated the results of swallow assessments done via questionnaires and objective assessments by modified barium swallow (MBS).

Methods: The Functional Assessment of Cancer-HN (FACT-HN), the Performance Status Scale - Head and Neck (PSS-HN), swallow assessments (including modified barium swallow studies), and voice assessments: Voice Handicap Index (VHI), the Voice Disability Assessment (VDA), and American Speech-Language Hearing Association's Functional Communication Measure (FCM) were conducted at baseline and periodically post-treatment for 2 years.

Results: Baseline QOL and swallowing function predicted overall survival. Patients experienced a marked decrease in QOL, swallowing, and speech post CCR although the decrease in vocal function was modest. Function and QOL returned towards baseline in the majority of patients by 12 months post treatment. Less than 10% of patients had severe dysphagia and were PEG dependent at 12 months post treatment. There was a high degree of correlation between the FACT-HN and PSS-HN swallow items. Statistically significant correlations were found between subjective and objective measures of swallow function.

Conclusions: Patients experience marked loss in swallowing function post CCR which returned to baseline in the majority of patients. The correlations between the FCM and self-report swallow items on the PSS and FACT-HN appear to be sufficiently strong to justify their use as a surrogate marker for swallowing disability in large therapeutic trials.
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http://dx.doi.org/10.1186/s41199-020-00059-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756946PMC
December 2020

Head and neck squamous cell carcinoma.

Nat Rev Dis Primers 2020 11 26;6(1):92. Epub 2020 Nov 26.

Department of Otolaryngology-Head and Neck Surgery, University of California at San Francisco, San Francisco, CA, USA.

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.
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http://dx.doi.org/10.1038/s41572-020-00224-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944998PMC
November 2020

Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer.

Mod Pathol 2021 03 25;34(3):532-541. Epub 2020 Nov 25.

Late-Stage Immuno-Oncology Research and Development, Merck & Co., Inc., Kenilworth, NJ, USA.

Tumor proportion score (TPS) and combined positive score ([CPS] includes immune cells), 2 methods for scoring programmed death ligand 1 (PD-L1) expression, have been used in clinical trials investigating the immune checkpoint inhibitor pembrolizumab in head and neck squamous cell carcinoma (HNSCC). These trials resulted in regulatory approval for pembrolizumab in the first- and second-line setting outside the United States. We performed a post hoc analysis of the KEYNOTE-040 study (NCT02252042) to determine whether CPS is a practical and suitable alternative scoring method to TPS. In KEYNOTE-040, patients with metastatic HNSCC received pembrolizumab or investigator choice of standard of care (SOC). The relative utility and equivalence of CPS ≥ 50 and TPS ≥ 50% for defining PD-L1 expression status in patients with HNSCC and comparability of scoring methods by tandem receiver operating characteristic (ROC) analysis were analyzed. The cutoff for each method was also evaluated. CPS ≥ 50 appeared equivalent to TPS ≥ 50% for predicting objective response rate (ORR), overall survival, and progression-free survival. ORR for pembrolizumab versus SOC was 26.2 versus 8.5% for TPS ≥ 50%, 28.1 versus 7.7% for CPS ≥ 50, 10.6 versus 11.6% for TPS < 50%, and 10.0 versus 12.0% for CPS < 50. Tandem ROC analysis showed that TPS 50% and CPS 50 maximized delta Youden index and suggested that CPS is more sensitive than TPS at lower cutoffs (i.e., CPS ≥ 1). In conclusion, CPS 50 can be used interchangeably with TPS 50% to determine PD-L1 status in patients with HNSCC. CPS may be more sensitive than TPS at lower cutoffs.
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http://dx.doi.org/10.1038/s41379-020-00710-9DOI Listing
March 2021

Survivin expression and impact on head and neck cancer outcomes.

Oral Oncol 2021 Jan 19;112:105049. Epub 2020 Nov 19.

Fox Chase Cancer Center, United States. Electronic address:

Introduction: Survivin is an inhibitor of apoptosis that is proposed as a target for anti-cancer therapy because of its high expression in cancer cells. It has potential as a prognostic and predictive biomarker of response to radiation and systemic therapies. We report its expression in head and neck squamous cell carcinoma (HNSCC) and its correlation with treatment response and survival.

Methods: We measured survivin protein expression in tumor specimens from 96 patients with HNSCC treated at Fox Chase Cancer Center, of whom 21 were p16+. Quantitative automated immunofluorescence was employed to score nuclear and cytoplasmic survivin in 5 tissue microarrays (TMAs) consisting of 316 H&N tumor cores and 107 control tissue cores. Survivin levels were then correlated to therapy response and survival outcomes.

Results: Using the median score as the cutoff, overall survival (OS) was significantly shorter for the group expressing higher survivin in nuclear (p = 0.013), cytoplasmic (p = 0.018) and total compartments (p = 0.006). No correlation was seen between survivin expression and patient sex or grade of tumor, T or N stage, or p16 status. Survivin expression in metastases did not significantly differ from that in primary tumors. Levels of p53 expression showed a significant positive correlation with higher survivin expression in the cytoplasm (p = 0.0264) and total compartments (p = 0.0264), but not in the nucleus (p = 0.0729).

Conclusions: Survivin expression above the median is associated with shorter overall survival in HNSCC, including for patients treated with chemotherapy or radiation. p16 expression did not correlate with survivin levels.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105049DOI Listing
January 2021

Primary Treatment Selection for Clinically Node-Negative Merkel Cell Carcinoma of the Head and Neck.

Otolaryngol Head Neck Surg 2020 Oct 20:194599820967001. Epub 2020 Oct 20.

Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.

Objective: Merkel cell carcinoma practice guidelines recommend sentinel lymph node biopsy after wide local excision for the initial management of clinically node-negative disease without distant metastases (cN0M0). Despite guideline publication, treatment selection remains variable. We hypothesized that receipt of guideline-recommended care would be more common in patients evaluated at academic centers and institutions with high melanoma case volumes and that such therapy would be associated with improved overall survival.

Study Design: Retrospective cohort analysis.

Setting: The National Cancer Database from 2004 to 2015.

Methods: A total of 3500 patients were included. We utilized Kaplan-Meier analysis and logistic and Cox proportional hazard regressions. Survival analysis was performed on inverse probability-weighted cohorts.

Results: There has been a trend toward evaluation at academic programs at a rate of 1.58% of patients per year (95% CI, 1.06%-2.11%) since 2004. However, the percentage of patients receiving guideline-compliant primary tumor excision and lymph node evaluation has plateaued at approximately 50% since 2012. Guideline-compliant surgical management was more commonly provided to patients evaluated at academic programs than nonacademic programs but only when those institutions had a high melanoma case volume (odds ratio, 2.01; 95% CI, 1.62-2.48). Receipt of guideline-compliant primary tumor excision and lymph node evaluation was associated with improved overall survival (hazard ratio, 0.70; 95% CI, 0.64-0.76).

Conclusion: Facility factors affect rates of receipt of guideline-compliant initial surgical management for patients with node-negative Merkel cell carcinoma. Given the survival benefit of such treatment, patients may benefit from care at hospitals with high melanoma case volumes.
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http://dx.doi.org/10.1177/0194599820967001DOI Listing
October 2020

Prediction of post-radiotherapy locoregional progression in HPV-associated oropharyngeal squamous cell carcinoma using machine-learning analysis of baseline PET/CT radiomics.

Transl Oncol 2021 Jan 16;14(1):100906. Epub 2020 Oct 16.

Section of Neuroradiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 789 Howard Ave, PO Box 208042, New Haven, CT 06519, United States. Electronic address:

Locoregional failure remains a therapeutic challenge in oropharyngeal squamous cell carcinoma (OPSCC). We aimed to devise novel objective imaging biomarkers for prediction of locoregional progression in HPV-associated OPSCC. Following manual lesion delineation, 1037 PET and 1037 CT radiomic features were extracted from each primary tumor and metastatic cervical lymph node on baseline PET/CT scans. Applying random forest machine-learning algorithms, we generated radiomic models for censoring-aware locoregional progression prognostication (evaluated by Harrell's C-index) and risk stratification (evaluated in Kaplan-Meier analysis). A total of 190 patients were included; an optimized model yielded a median (interquartile range) C-index of 0.76 (0.66-0.81; p = 0.01) in prognostication of locoregional progression, using combined PET/CT radiomic features from primary tumors. Radiomics-based risk stratification reliably identified patients at risk for locoregional progression within 2-, 3-, 4-, and 5-year follow-up intervals, with log-rank p-values of p = 0.003, p = 0.001, p = 0.02, p = 0.006 in Kaplan-Meier analysis, respectively. Our results suggest PET/CT radiomic biomarkers can predict post-radiotherapy locoregional progression in HPV-associated OPSCC. Pending validation in large, independent cohorts, such objective biomarkers may improve patient selection for treatment de-intensification trials in this prognostically favorable OPSCC entity, and eventually facilitate personalized therapy.
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http://dx.doi.org/10.1016/j.tranon.2020.100906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568193PMC
January 2021

Reply to "Keynote 48: Is it really for everyone?"

Oral Oncol 2021 Jan 6;112:104983. Epub 2020 Oct 6.

Merck & Co., Inc., Kenilworth, NJ, USA.

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http://dx.doi.org/10.1016/j.oraloncology.2020.104983DOI Listing
January 2021

Predictive classifier for intensive treatment of head and neck cancer.

Cancer 2020 Dec 5;126(24):5263-5273. Epub 2020 Oct 5.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

Background: This study was designed to test the hypothesis that the effectiveness of intensive treatment for locoregionally advanced head and neck cancer (LAHNC) depends on the proportion of patients' overall event risk attributable to cancer.

Methods: This study analyzed 22,339 patients with LAHNC treated in 81 randomized trials testing altered fractionation (AFX; Meta-Analysis of Radiotherapy in Squamous Cell Carcinomas of Head and Neck [MARCH] data set) or chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC] data set). Generalized competing event regression was applied to the control arms in MARCH, and patients were stratified by tertile according to the ω score, which quantified the relative hazard for cancer versus competing events. The classifier was externally validated on the MACH-NC data set. The study tested for interactions between the ω score and treatment effects on overall survival (OS).

Results: Factors associated with a higher ω score were a younger age, a better performance status, an oral cavity site, higher T and N categories, and a p16-negative/unknown status. The effect of AFX on OS was greater in patients with high ω scores (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.85-0.99) and medium ω scores (HR, 0.91; 95% CI, 0.84-0.98) versus low ω scores (HR, 0.97; 95% CI, 0.90-1.05; P for interaction = .086). The effect of chemotherapy on OS was significantly greater in patients with high ω scores (HR, 0.81; 95% CI, 0.75-0.88) and medium ω scores (HR, 0.86; 95% CI, 0.78-0.93) versus low ω scores (HR, 0.96; 95% CI, 0.86-1.08; P for interaction = .011).

Conclusions: LAHNC patients with a higher risk of cancer progression relative to competing mortality, as reflected by a higher ω score, selectively benefit from more intensive treatment.
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http://dx.doi.org/10.1002/cncr.33212DOI Listing
December 2020

Further clinical interpretation and implications of KEYNOTE-048 findings - Authors' reply.

Lancet 2020 08;396(10248):379-380

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; University of Melbourne, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1016/S0140-6736(20)30900-4DOI Listing
August 2020

A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311.

Oral Oncol 2020 11 14;110:104797. Epub 2020 Jul 14.

Yale School of Medicine and Yale Cancer Center, New Haven, CT, United States.

Purpose: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA.

Patients And Methods: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections.

Results: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients.

Conclusions: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771718PMC
November 2020

Potential Added Value of PET/CT Radiomics for Survival Prognostication beyond AJCC 8th Edition Staging in Oropharyngeal Squamous Cell Carcinoma.

Cancers (Basel) 2020 Jul 3;12(7). Epub 2020 Jul 3.

Section of Neuroradiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 789 Howard Ave, New Haven, CT 06519, USA.

Accurate risk-stratification can facilitate precision therapy in oropharyngeal squamous cell carcinoma (OPSCC). We explored the potential added value of baseline positron emission tomography (PET)/computed tomography (CT) radiomic features for prognostication and risk stratification of OPSCC beyond the American Joint Committee on Cancer (AJCC) 8th edition staging scheme. Using institutional and publicly available datasets, we included OPSCC patients with known human papillomavirus (HPV) status, without baseline distant metastasis and treated with curative intent. We extracted 1037 PET and 1037 CT radiomic features quantifying lesion shape, imaging intensity, and texture patterns from primary tumors and metastatic cervical lymph nodes. Utilizing random forest algorithms, we devised novel machine-learning models for OPSCC progression-free survival (PFS) and overall survival (OS) using "radiomics" features, "AJCC" variables, and the "combined" set as input. We designed both single- (PET or CT) and combined-modality (PET/CT) models. Harrell's C-index quantified survival model performance; risk stratification was evaluated in Kaplan-Meier analysis. A total of 311 patients were included. In HPV-associated OPSCC, the best "radiomics" model achieved an average C-index ± standard deviation of 0.62 ± 0.05 ( = 0.02) for PFS prediction, compared to 0.54 ± 0.06 ( = 0.32) utilizing "AJCC" variables. Radiomics-based risk-stratification of HPV-associated OPSCC was significant for PFS and OS. Similar trends were observed in HPV-negative OPSCC. In conclusion, radiomics imaging features extracted from pre-treatment PET/CT may provide complimentary information to the current AJCC staging scheme for survival prognostication and risk-stratification of HPV-associated OPSCC.
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http://dx.doi.org/10.3390/cancers12071778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407414PMC
July 2020

High Dose Cisplatin: Still the One?

Int J Radiat Oncol Biol Phys 2020 07;107(4):615-616

Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.ijrobp.2019.09.026DOI Listing
July 2020

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412.

Future Oncol 2020 Jun 3;16(18):1235-1243. Epub 2020 Jun 3.

Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0184DOI Listing
June 2020

Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040.

J Natl Cancer Inst 2021 Feb;113(2):171-181

Moores Cancer Center at UC San Diego Health, University of California San Diego, La Jolla, CA, USA.

Background: Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen.

Methods: Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires.

Results: The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = -3.00 to 3.78) but worsened for SOC (LSM = -5.86, 95% CI = -9.68 to -2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = -4.57 to 16.99) or pembrolizumab vs cetuximab (-1.44, 95% CI = -11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC.

Conclusions: GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.
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http://dx.doi.org/10.1093/jnci/djaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850527PMC
February 2021

PET/CT radiomics signature of human papilloma virus association in oropharyngeal squamous cell carcinoma.

Eur J Nucl Med Mol Imaging 2020 12 12;47(13):2978-2991. Epub 2020 May 12.

Section of Neuroradiology, Department of Radiology and Biomedical Imaging, Yale School of Medicine, 789 Howard Ave, PO Box 208042, New Haven, CT, 06519, USA.

Purpose: To devise, validate, and externally test PET/CT radiomics signatures for human papillomavirus (HPV) association in primary tumors and metastatic cervical lymph nodes of oropharyngeal squamous cell carcinoma (OPSCC).

Methods: We analyzed 435 primary tumors (326 for training, 109 for validation) and 741 metastatic cervical lymph nodes (518 for training, 223 for validation) using FDG-PET and non-contrast CT from a multi-institutional and multi-national cohort. Utilizing 1037 radiomics features per imaging modality and per lesion, we trained, optimized, and independently validated machine-learning classifiers for prediction of HPV association in primary tumors, lymph nodes, and combined "virtual" volumes of interest (VOI). PET-based models were additionally validated in an external cohort.

Results: Single-modality PET and CT final models yielded similar classification performance without significant difference in independent validation; however, models combining PET and CT features outperformed single-modality PET- or CT-based models, with receiver operating characteristic area under the curve (AUC) of 0.78, and 0.77 for prediction of HPV association using primary tumor lesion features, in cross-validation and independent validation, respectively. In the external PET-only validation dataset, final models achieved an AUC of 0.83 for a virtual VOI combining primary tumor and lymph nodes, and an AUC of 0.73 for a virtual VOI combining all lymph nodes.

Conclusion: We found that PET-based radiomics signatures yielded similar classification performance to CT-based models, with potential added value from combining PET- and CT-based radiomics for prediction of HPV status. While our results are promising, radiomics signatures may not yet substitute tissue sampling for clinical decision-making.
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http://dx.doi.org/10.1007/s00259-020-04839-2DOI Listing
December 2020

Applications of radiomics in precision diagnosis, prognostication and treatment planning of head and neck squamous cell carcinomas.

Cancers Head Neck 2020 4;5. Epub 2020 May 4.

1Department of Radiology and Biomedical Imaging, Division of Neuroradiology, Yale School of Medicine, New Haven, CT USA.

Recent advancements in computational power, machine learning, and artificial intelligence technology have enabled automated evaluation of medical images to generate quantitative diagnostic and prognostic biomarkers. Such objective biomarkers are readily available and have the potential to improve personalized treatment, precision medicine, and patient selection for clinical trials. In this article, we explore the merits of the most recent addition to the "-omics" concept for the broader field of head and neck cancer - "Radiomics". This review discusses radiomics studies focused on (molecular) characterization, classification, prognostication and treatment guidance for head and neck squamous cell carcinomas (HNSCC). We review the underlying hypothesis, general concept and typical workflow of radiomic analysis, and elaborate on current and future challenges to be addressed before routine clinical application.
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http://dx.doi.org/10.1186/s41199-020-00053-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197186PMC
May 2020

Synthetic Lethal Targeting of Mitotic Checkpoints in HPV-Negative Head and Neck Cancer.

Cancers (Basel) 2020 Jan 28;12(2). Epub 2020 Jan 28.

Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Head and neck squamous cell carcinomas (HNSCC) affect more than 800,000 people annually worldwide, causing over 15,000 deaths in the US. Among HNSCC cancers, human papillomavirus (HPV)-negative HNSCC has the worst outcome, motivating efforts to improve therapy for this disease. The most common mutational events in HPV-negative HNSCC are inactivation of the tumor suppressors (>85%) and (>57%), which significantly impairs G1/S checkpoints, causing reliance on other cell cycle checkpoints to repair ongoing replication damage. We evaluated a panel of cell cycle-targeting clinical agents in a group of HNSCC cell lines to identify a subset of drugs with single-agent activity in reducing cell viability. Subsequent analyses demonstrated potent combination activity between the CHK1/2 inhibitor LY2606268 (prexasertib), which eliminates a G2 checkpoint, and the WEE1 inhibitor AZD1775 (adavosertib), which promotes M-phase entry, in induction of DNA damage, mitotic catastrophe, and apoptosis, and reduction of anchorage independent growth and clonogenic capacity. These phenotypes were accompanied by more significantly reduced activation of CHK1 and its paralog CHK2, and enhanced CDK1 activation, eliminating breaks on the mitotic entry of cells with DNA damage. These data suggest the potential value of dual inhibition of CHK1 and WEE1 in tumors with compromised G1/S checkpoints.
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http://dx.doi.org/10.3390/cancers12020306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072436PMC
January 2020

Adjuvant external beam radiotherapy for surgically resected, nonmetastatic anaplastic thyroid cancer.

Head Neck 2020 05 3;42(5):1031-1044. Epub 2020 Feb 3.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut.

Background: EBRT in resected, nonmetastatic anaplastic thyroid cancer (ATC) remains undefined. We evaluated patterns/outcomes with EBRT and chemotherapy in this setting.

Methods: This retrospective analysis included patients identified from the National Cancer Database with nonmetastatic ATC from 2004 to 2014 who underwent non-palliative resection.

Results: Our analysis included 496 patients, including 375 who underwent adjuvant EBRT (among whom 198 received concurrent chemotherapy). The median age was 68 years. On MVA, EBRT was associated with sex (OR 0.5, 95% CI 0.3-0.8, P = .002) and income (OR 2.2, 95% CI 1.4-3.3, P < .001). EBRT was associated with longer OS on UVA (12.3 vs 9.1 months, P = .004) and MVA (HR 0.7 [CI 0.6-0.9], P = .004). Concurrent chemoradiation was associated with longer OS on UVA (14.0 vs 9.1 months, P = .003) and MVA (HR 0.6 [CI 0.5-0.8], P < .001).

Conclusion: Adjuvant EBRT is associated with longer OS in resected, nonmetastatic ATC, with additional improved survival with concurrent chemotherapy.
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http://dx.doi.org/10.1002/hed.26086DOI Listing
May 2020

Randomized, Phase II Study Prospectively Evaluating Treatment of Metastatic Esophageal, Gastric, or Gastroesophageal Cancer by Gene Expression of : SWOG S1201.

J Clin Oncol 2020 02 9;38(5):472-479. Epub 2019 Dec 9.

Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.

Purpose: Platinum-based therapy is the standard of care in patients who have HER2-negative, advanced esophagogastric cancer (AEGC). Retrospective data suggest that intratumoral levels may determine platinum sensitivity. A randomized, phase II study was performed in patients with AEGC to explore whether the efficacy of a platinum-based therapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) versus a non-platinum-containing regimen of irinotecan and docetaxel (IT) differed according to levels.

Patients And Methods: Overall, 202 untreated patients with HER2-negative AEGC and a Zubrod performance status of 0-1 were evaluated prospectively for mRNA expression of level and then randomly assigned to FOLFOX or IT, stratified by the intratumoral statuses of low (< 1.7) or high (≥ 1.7). Objectives were to assess progression-free survival (PFS) and overall survival (OS) in all patients treated with FOLFOX compared with IT, stratified by low and high levels, and to assess for interactive effects between expression and treatment arm.

Results: Eighty-six percent of patients had values < 1.7. Thus, evaluation of the -high subgroup was limited. Grade ≥ 3 anemia, dehydration, diarrhea, and fatigue were greater in patients with IT. Occurrences of grade ≥ 3 neuropathy and decreased neutrophils were greater in patients with FOLFOX. In all patients, FOLFOX had a statistically superior median PFS compared with IT (5.7 2.9 months; hazard ratio, 0.68; = .02). In patients with levels < 1.7 receiving FOLFOX, PFS and response rate were statistically superior to IT, with no significant difference in OS.

Conclusion: The evaluation of in patients with upper GI tumors was thwarted by an overwhelming predominance of low mRNA expression. Nonetheless, distribution of treatment effects on PFS did not vary with expression. For all patients and for those with low expression, FOLFOX was superior in efficacy to IT.
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http://dx.doi.org/10.1200/JCO.19.00925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007287PMC
February 2020

Multi-Institutional Validation of Deep Learning for Pretreatment Identification of Extranodal Extension in Head and Neck Squamous Cell Carcinoma.

J Clin Oncol 2020 04 9;38(12):1304-1311. Epub 2019 Dec 9.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT.

Purpose: Extranodal extension (ENE) is a well-established poor prognosticator and an indication for adjuvant treatment escalation in patients with head and neck squamous cell carcinoma (HNSCC). Identification of ENE on pretreatment imaging represents a diagnostic challenge that limits its clinical utility. We previously developed a deep learning algorithm that identifies ENE on pretreatment computed tomography (CT) imaging in patients with HNSCC. We sought to validate our algorithm performance for patients from a diverse set of institutions and compare its diagnostic ability to that of expert diagnosticians.

Methods: We obtained preoperative, contrast-enhanced CT scans and corresponding pathology results from two external data sets of patients with HNSCC: an external institution and The Cancer Genome Atlas (TCGA) HNSCC imaging data. Lymph nodes were segmented and annotated as ENE-positive or ENE-negative on the basis of pathologic confirmation. Deep learning algorithm performance was evaluated and compared directly to two board-certified neuroradiologists.

Results: A total of 200 lymph nodes were examined in the external validation data sets. For lymph nodes from the external institution, the algorithm achieved an area under the receiver operating characteristic curve (AUC) of 0.84 (83.1% accuracy), outperforming radiologists' AUCs of 0.70 and 0.71 ( = .02 and = .01). Similarly, for lymph nodes from the TCGA, the algorithm achieved an AUC of 0.90 (88.6% accuracy), outperforming radiologist AUCs of 0.60 and 0.82 ( < .0001 and = .16). Radiologist diagnostic accuracy improved when receiving deep learning assistance.

Conclusion: Deep learning successfully identified ENE on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists with specialized head and neck experience. Our findings suggest that deep learning has utility in the identification of ENE in patients with HNSCC and has the potential to be integrated into clinical decision making.
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http://dx.doi.org/10.1200/JCO.19.02031DOI Listing
April 2020

Immunotherapy for head and neck cancer: Recent advances and future directions.

Oral Oncol 2019 12 1;99:104460. Epub 2019 Nov 1.

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA; UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Electronic address:

Three randomized phase III trials have now conclusively proven that exposure to a PD-1 inhibitor prolongs survival in recurrent/metastatic (R/M) HNSCC, and it is clear that such agents should be used in the management of all patients who do not have contraindications to their use. Two of these phase III randomized trials showed that the anti-PD1 antibodies nivolumab and pembrolizumab were superior to investigators' choice chemotherapy in second-line platinum-refractory R/M HNSCC. Recently, a third phase III randomized trial, KEYNOTE-048, showed that pembrolizumab with chemotherapy was superior to the EXTREME regimen (cis- or carboplatin, 5-fluorouracil (5-FU) and cetuximab) in all patients, and pembrolizumab monotherapy was superior in patients whose tumors express PD-L1 in first-line R/M HNSCC. Pembrolizumab is now approved as monotherapy in PD-L1 expressing disease (combined positive score ≥1) or in combination with chemotherapy for all patients with R/M HNSCC. Thus, PD-L1 biomarker testing will be routinely used in R/M HNSCC, and this employs a scoring system that incorporates immune cell staining, referred to as the combined positive score (CPS). Additionally, for the 85% of patients with PD-L1 CPS ≥1, clinical judgment will guide the choice of pembrolizumab monotherapy or pembrolizumab plus chemotherapy, until more detailed clinical data are forthcoming to better inform this decision. In this article we discuss the clinical trials leading to these therapeutic advances and we will review initial results from clinical trials in previously untreated, locally advanced disease, and those using novel combinations of checkpoint inhibitors, co-stimulatory agonists, and therapeutic vaccines.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749717PMC
December 2019

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.

Lancet 2019 11 1;394(10212):1915-1928. Epub 2019 Nov 1.

Peter MacCallum Cancer Centre, Melbourne, VIC, Austrialia; University of Melbourne, Melbourne, VIC, Australia.

Background: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.

Methods: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.

Findings: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group.

Interpretation: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S0140-6736(19)32591-7DOI Listing
November 2019

Impact of contralateral lymph nodal involvement and extranodal extension on survival of surgically managed HPV-positive oropharyngeal cancer staged with the AJCC eighth edition.

Oral Oncol 2019 12 17;99:104447. Epub 2019 Oct 17.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA; Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada. Electronic address:

Objectives: Contralateral lymph node (LN) involvement is a prognostic factor in clinical staging of oropharyngeal squamous cell carcinoma (OPSCC), while pathologic nodal staging in the AJCC 8th edition for human papillomavirus-mediated OPSCC (HPV + OPSCC) focuses exclusively on the number of involved LNs (pLN+). This study assessed if the presence of contralateral pLN+ adds prognostic importance to the number of pLN+.

Materials And Methods: The National Cancer Database was queried for pLN+ HPV + OPSCC treated with surgery with 10 or more LN dissected. Data were evaluated with Cox regression, propensity score matching (PSM), and Kaplan-Meier overall survival (OS) analysis.

Results: Of 3407 patients, 152 (4.5%) patients had contralateral pLN+. Subjects with contralateral pLN+ had higher pT/pN stage, more positive margins, extranodal extension (ENE), and lymphovascular invasion (LVI) (all p < 0.05). On univariate analysis, contralateral pLN+ trended toward worse OS (HR 1.58, 95% CI 0.98-2.55, p = 0.061). In the multivariable model (controlling for age, comorbidities, T-stage, N-stage, LN size, ENE, LVI, margin status and adjuvant therapy), LN laterality had no impact on OS (HR 0.87, 95% CI 0.52-1.45, p = 0.520). Further PSM analysis confirmed that contralateral pLN+ is not associated with OS in this population (HR 0.79, 95% CI 0.41-1.53, p = 0.494).

Conclusion: This study supports the AJCC 8th edition pathologic staging for HPV + OPSCC by observing that LN laterality is not associated with OS. ENE was associated with inferior OS and should be considered for future staging systems. Further study should be directed at the importance of nodal size in this population.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104447DOI Listing
December 2019

Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer.

J Clin Oncol 2019 12 16;37(34):3266-3274. Epub 2019 Oct 16.

Yale University School of Medicine, New Haven, CT.

Purpose: We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

Patients And Methods: Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved.

Results: The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; = .22). At 2, 3, and 4 years, the OS rates were 25.2% 18.1%, 16.4% 10.0%, and 11.8% 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; = .10), with a median OS of 14.2 months on BC 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months 4.3 months with chemotherapy ( = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy ( = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% 0.5%; < .001) and treatment-related deaths (9.3% 3.5%; = .022) with BC versus chemotherapy.

Conclusion: The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.
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http://dx.doi.org/10.1200/JCO.19.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980834PMC
December 2019

Clinical Outcomes of Head and Neck Cancer Patients Who Undergo Resection, But Forgo Adjuvant Therapy.

Anticancer Res 2019 Sep;39(9):4885-4890

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, U.S.A.

Background/aim: This study aimed to evaluate the outcomes of patients with head and neck squamous cell carcinoma (HNSCC) who underwent resection and refused the recommended adjuvant therapy.

Patients And Methods: Locoregional recurrence-free survival (LRRFS) and time to progression (TTP) were assessed in HNSCC patients treated with surgery who declined some or all adjuvant therapy (refusal group (RG)) compared to those who received the recommended adjuvant therapy (TG).

Results: With a median follow-up of 23 months, the 2-year LRRFS was significantly lower in the 17 patients from the RG compared to the 152 patients from the TG: 23.1% vs. 69%, HR=0.30, 95% confidence incidence (CI)=0.15-0.59; p<0.001. The mean TTP was 12 months in the RG and was not reached in the TG (p<0.001).

Conclusion: Patients with HNSCC who declined the recommended adjuvant therapy had a recurrence rate of 50% within a year.
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http://dx.doi.org/10.21873/anticanres.13674DOI Listing
September 2019

Neuregulin Signaling Is a Mechanism of Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma.

Mol Cancer Ther 2019 11 6;18(11):2124-2134. Epub 2019 Aug 6.

Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.

EGFR signaling confers resistance to radiotherapy and is a validated target in head and neck squamous cell carcinoma (HNSCC). The inhibition of EGFR in combination with radiotherapy improves local control and overall survival in these patients; however, therapeutic resistance limits the efficacy of this approach. We therefore sought to identify cellular mechanisms that cause resistance to EGFR inhibition and radiotherapy in HNSCC. Though clonal isolation of carcinoma cells exposed to increasing concentrations of cetuximab, we found that resistant cells upregulate prosurvival ErbB3 and AKT signaling. Using EFM-19 cells and confirmatory analysis of protein levels, we demonstrate that cetuximab resistance is characterized by enhanced neuregulin expression identifying a novel adaptive mechanism of therapeutic resistance. Inhibition of this autocrine loop with CDX-3379 (an ErbB3 specific antibody) was sufficient to block ErbB3/AKT signaling in cetuximab resistant cells. The combination of CDX-3379 and cetuximab reduced proliferation and survival after radiotherapy in several HNSCC cell lines. These findings were confirmed in xenograft tumor growth experiments including an approach using growth factor-supplemented Matrigel. , the delivery of EGFR and ErbB3 antibodies significantly reduced tumor growth in cetuximab-resistant FaDu and CAL27 xenografts. In summary, this work demonstrates that autocrine NRG ligand secretion is a mechanism for therapeutic resistance to cetuximab and radiotherapy. This cross-resistance to both therapeutic modalities identifies NRG as an actionable therapeutic target for improving treatment regimens in HNSCC.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825559PMC
November 2019