Neurological complications of modern radiotherapy for head and neck cancer.

Radiotherapy is one of the mainstay treatment modalities for the management of non-metastatic head and neck cancer (HNC). Notable improvements in treatment outcomes have been observed in the recent decades. Modern radiotherapy techniques, such as intensity-modulated radiotherapy and charged particle therapy, have significantly improved tumor target conformity and enabled better preservation of normal structures. However, because of the intricate anatomy of the head and neck region, multiple critical neurological structures such as the brain, brainstem, spinal cord, cranial nerves, nerve plexuses, autonomic pathways, brain vasculature, and neurosensory organs, are variably irradiated during treatment, particularly when tumor targets are in close proximity. Consequently, a diverse spectrum of late neurological sequelae may manifest in HNC survivors. These neurological complications commonly result in irreversible symptoms, impair patients' quality of life, and contribute to a substantial proportion of non-cancer deaths. Although the relationship between radiation dose and toxicity has not been fully elucidated for all complications, appropriate application of dosimetric constraints during radiotherapy planning may reduce their incidence. Vigilant surveillance during the course of survivorship also enables early detection and intervention. This article endeavors to provide a comprehensive review of the various neurological complications of modern radiotherapy for HNC, summarize the current incidence data, discuss methods to minimize their risks during radiotherapy planning, and highlight potential strategies for managing these debilitating toxicities.

Update on olfactory neuroblastoma.

Olfactory neuroblastomas are uncommon malignancies that arise from olfactory receptor cells located high in the nasal cavity. Accurate diagnosis plays a crucial role in determining clinical results and guiding treatment decisions. Diagnosis can be a major challenge for pathologists, especially when dealing with tumours with poor differentiation. The discovery of several molecular and immunohistochemical markers would help to overcome classification difficulties. Due to the paucity of large-scale studies, standardisation of diagnosis, treatment and prediction of outcome remains a challenge. Surgical resection by endoscopic techniques with the addition of postoperative irradiation is the treatment of choice. In addition, it is advisable to consider elective neck irradiation to minimise the risk of nodal recurrence. Molecular characterisation will help not only to make more accurate diagnoses but also to identify specific molecular targets that can be used to develop personalised treatment options tailored to each patient. The present review aims to summarise the current state of knowledge on histopathological diagnosis, the molecular biology and management of this disease.

Proton Beam Radiation Therapy for Oropharyngeal Squamous Cell Carcinoma.

Purpose: To discuss the role of proton beam therapy (PBT) in the treatment of patients with oropharyngeal squamous cell carcinoma (OPSCC). Materials and Methods: A review of the pertinent literature. Results: Proton beam therapy likely results in reduced acute and late toxicity as compared with intensity-modulated radiation therapy (IMRT). The extent of the reduced toxicity, which may be modest, depends on the endpoint and technical factors such as pencil beam versus passive scattered PBT and adaptive replanning. The disease control rates after PBT are likely similar to those after IMRT. Conclusion: Proton beam therapy is an attractive option to treat patients with OPSCC. Whether it becomes widely available depends on access.

Current management of xerostomia in head and neck cancer patients.

Radiotherapy (RT) continues to play a key role in the management of head and neck cancer (HNC). Xerostomia remains a principal detriment to the quality of life (QoL) for 80 % of surviving patients receiving head and neck radiation. Radiation-induced injury to the salivary glands is dose-dependent, and thus efforts have been focused on decreasing radiation to the salivary glands. Decreased saliva production reduces both short-term and long-term quality of life in head and neck survivors by impacting on taste and contributing to dysphagia. Several radioprotective agents to the salivary gland have been investigated. Although not widely practiced, surgical transfer of the submandibular gland prior to RT is the mainstay of surgical options in preventing xerostomia. This review focuses on the strategies to improve xerostomia following radiation therapy in head and neck cancers.

Specimen-Based Resection Margins and Local Control during Transoral Robotic Surgery for Oropharyngeal HPV-Mediated Squamous Cell Carcinoma.

OBJECTIVES: The aim of the study was to investigate the association of surgical margin conditions, including positive specimen margins revised to negative relative to local recurrence, disease-free survival, and overall survival (OS) within a cohort of HPV-mediated oropharyngeal squamous cell carcinoma (OPSCC) who underwent en bloc resection via transoral robotic surgery (TORS). MATERIALS AND METHODS: Retrospective cohort of patients with untreated HPV-mediated OPSCC cT1 or T2 undergoing TORS resection between October 2014 and March 2020. The methodologic description of our interdisciplinary institutional approach, number of cut-through margins (CTMs) during intraoperative consultation, percentage of final positive margin cases, and disease-free survival and OS stratified by margin status and margin tumor-free distance is identified. RESULTS: 135 patients with primary cT1/T2 HPV-mediated OPSCC met inclusion criteria. Twenty-eight of 135 (20.7%) specimens revealed CTM and were revised during the same operative setting. Three of 135 (2.2%) surgical cases had positive final margin status. Local control rate was 97%. On univariate analysis, margin distance did not impact OS. CTM and final positive margins had lower OS than initially negative margins (p = 0.044). Pathologic N-stage significantly impacted OS (p < 0.001). CONCLUSIONS: High local control rate and low final positive margin status confound the study of specimen margin-based techniques in HPV-mediated OPSCC resected en bloc with TORS. Pathologic N-stage may impact OS more than margin status. Larger numbers are needed to confirm differences.

Outcomes Stratification of Head and Neck Cancer Using Pre- and Post-treatment DNA Methylation From Peripheral Blood.

PURPOSE: Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification. METHODS AND MATERIALS: Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts. RESULTS: Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P < .05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015). CONCLUSIONS: We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.

Long-Term Update of NRG/RTOG 0522: A Randomized Phase 3 Trial of Concurrent Radiation and Cisplatin With or Without Cetuximab in Locoregionally Advanced Head and Neck Cancer.

PURPOSE: The combination of cisplatin and radiation or cetuximab and radiation improves overall survival of patients with locoregionally advanced head and neck carcinoma. NRG Oncology conducted a phase 3 trial to test the hypothesis that adding cetuximab to radiation and cisplatin would improve progression-free survival (PFS). METHODS AND MATERIALS: Eligible patients with American Joint Committee on Cancer sixth edition stage T2 N2a-3 M0 or T3-4 N0-3 M0 were accrued from November 2005 to March 2009 and randomized to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Outcomes were correlated with patient and tumor features. Late reactions were scored using Common Terminology Criteria for Adverse Events (version 3). RESULTS: Of 891 analyzed patients, 452 with a median follow-up of 10.1 years were alive at analysis. The addition of cetuximab did not improve PFS (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.89-1.26; P = .74), with 10-year estimates of 43.6% (95% CI, 38.8- 48.4) for arm A and 40.2% (95% CI, 35.4-45.0) for arm B. Cetuximab did not reduce locoregional failure (HR, 1.21; 95% CI, 0.95-1.53; P = .94) or distant metastasis (HR, 0.79; 95% CI, 0.54-1.14; P = .10) or improve overall survival (HR, 0.97; 95% CI, 0.80-1.16; P = .36). Cetuximab did not appear to improve PFS in either p16-positive oropharynx (HR, 1.30; 95% CI, 0.87-1.93) or p16-negative oropharynx or nonoropharyngeal primary (HR, 0.94; 95% CI, 0.73-1.21). Grade 3 to 4 late toxicity rates were 57.4% in arm A and 61.3% in arm B (P = .26). CONCLUSIONS: With a median follow-up of more than 10 years, this updated report confirms the addition of cetuximab to radiation therapy and cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status.

Oncologic Outcomes After Clinically Node-Negative Salvage Laryngectomy.

Importance: Controversy exists regarding management of the clinically node-negative neck in patients with recurrent larynx or hypopharynx cancers who received total laryngectomy after definitive radiation with or without chemotherapy. Objective: To explore clinical and oncologic outcomes after elective neck dissection vs observation in patients who received clinically node-negative salvage total laryngectomy. Design, Setting, and Participants: This cohort study was performed from January 2009 to June 2021 at a single, high-volume tertiary care center. Follow-up was conducted through June 2021 for all patients. Survival outcomes were based on at least 2 years of follow-up. Patients aged 18 years or older with recurrent, clinically node-negative larynx or hypopharynx tumors after definitive nonsurgical treatment who were treated with a salvage total laryngectomy were included. Data were analyzed from October 2021 through September 2022. Exposures: Elective neck dissection. Main Outcomes and Measures: Presence and location of occult nodal metastasis in electively dissected necks, along with differences in fistula rates and overall and disease-free survival between patients receiving elective neck dissection vs observation. Results: Among 107 patients receiving clinically node-negative salvage total laryngectomy (median [IQR] age, 65.0 [57.8-71.3] years; 91 [85.0%] men), 81 patients underwent elective neck dissection (75.7%) and 26 patients underwent observation (24.3%). Among patients with elective neck dissection, 13 patients had occult nodal positivity (16.0%). Recurrent supraglottic (4 of 20 patients [20.0%]) or advanced T classification (ie, T3-T4; 12 of 61 patients [19.7%]) had an occult nodal positivity rate of 20% or more, and positive nodes were most likely to occur in levels II and III (II: 6 of 67 patients [9.0%]; III: 6 of 65 patients [9.2%]; VI: 3 of 44 patients [6.8%]; IV: 3 of 62 patients [4.8%]; V: 0 of 4 patients; I: 0 of 18 patients). There was a large difference in fistula rate between elective neck dissection (12 patients [14.8%]) and observed (8 patients [30.8%]) groups (difference, 16.0 percentage points; 95% CI, -3.4 to 35.3 percentage points), while the difference in fistula rate was negligible between 50 patients undergoing regional or free flap reconstruction (10 patients [20.0%]) vs 57 patients undergoing primary closure (10 patients [17.5%]) (difference, 2.5 percentage points; 95% CI, -12.4 to 17.3 percentage points). Undergoing elective neck dissection was not associated with a clinically meaningful improvement in overall or disease-free survival compared with observation. Recurrent hypopharynx subsite was associated with an increased risk of death (hazard ratio, 4.28; 95% CI, 1.81 to 10.09) and distant recurrence (hazard ratio, 7.94; 95% CI, 2.07 to 30.48) compared with glottic subsite. Conclusions and Relevance: In this cohort study, patients with recurrent supraglottic or advanced T classification tumors had an increased occult nodal positivity rate, elective neck dissection was not associated with survival, and patients with recurrent hypopharynx subsite were more likely to have a distant recurrence and die of their disease. These findings suggest that underlying disease pathology rather than surgical management may be associated with survival outcomes in this population.

Current Radiotherapy Considerations for Nasopharyngeal Carcinoma.

Radiotherapy is the primary treatment modality for nasopharyngeal carcinoma (NPC). Successful curative treatment requires optimal radiotherapy planning and precise beam delivery that maximizes locoregional control while minimizing treatment-related side effects. In this article, we highlight considerations in target delineation, radiation dose, and the adoption of technological advances with the aim of optimizing the benefits of radiotherapy in NPC patients.

The impact of operability status on outcomes in patients with T4 larynx cancer undergoing larynx preservation.

BACKGROUND: Large analyses of T4 larynx cancer (LC) have raised concerns that larynx preservation (LP) contributes to reduced survival compared with laryngectomy (LGX). The role of operability has not been previously considered as a confounder. METHODS: We queried the National Cancer Database for T4M0 LC diagnosed 2004-2015. Patients were categorized as undergoing LGX, chemoradiotherapy but operable (LP-operable), and chemoradiotherapy inoperable (LP-inoperable). Overall survival (OS) was estimated by Kaplan-Meier. Cox multivariate analysis (MVA) identified variables associated with OS. RESULTS: We identified 1405 LGX, 164 LP-operable and 1969 LP-inoperable patients. Compared with LGX, MVA demonstrated worse OS among LP-inoperable (HR 1.28 95%CI 1.17-1.40, p < 0.01) but not LP-operable patients (HR 1.12 95%CI 0.91-1.39, p = 0.28). CONCLUSIONS: LP-operable patients did not have significantly worse OS than those undergoing LGX.

Retreatment of Recurrent or Second Primary Head and Neck Cancer After Prior Radiation: Executive Summary of the American Radium Society Appropriate Use Criteria.

Retreatment of recurrent or second primary head and neck cancers occurring in a previously irradiated field is complex. Few guidelines exist to support practice. We performed an updated literature search of peer-reviewed journals in a systematic fashion. Search terms, key questions, and associated clinical case variants were formed by panel consensus. The literature search informed the committee during a blinded vote on the appropriateness of treatment options via the modified Delphi method. The final number of citations retained for review was 274. These informed 5 key questions, which focused on patient selection, adjuvant reirradiation, definitive reirradiation, stereotactic body radiation, and reirradiation to treat nonsquamous cancer. Results of the consensus voting are presented along with discussion of the most current evidence. This provides updated evidence-based recommendations and guidelines for the retreatment of recurrent or second primary cancer of the head and neck.

The Selective Role of Open and Endoscopic Approaches for Sinonasal Malignant Tumours.

Endoscopic endonasal surgery has been demonstrated to be effective in the treatment of selected cases of sinonasal cancers. However, in cases of locally advanced neoplasms, as well as recurrences, the most appropriate approach is still debated. The present review aims to summarize the current state of knowledge on the utility of open approaches to resect sinonasal malignant tumours. Published comparative studies and meta-analyses suggest comparable oncological results with lower morbidity for the endoscopic approaches, but selection biases cannot be excluded. After a critical analysis of the available literature, it can be concluded that endoscopic surgery for selected lesions allows for oncologically safe resections with decreased morbidity. However, when endoscopic endonasal surgery is contraindicated and definitive chemoradiotherapy is not appropriate, craniofacial and transfacial approaches remain the best therapeutic option.

Comparison of the Seventh and Eighth Edition of American Joint Committee on Cancer (AJCC) Staging for Selected and Nonselected Oropharyngeal Squamous Cell Carcinomas.

OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.

Onboard cone-beam CT-based replan evaluation for head and neck proton therapy.

PURPOSE: Quality assurance computed tomography (QACT) is the current clinical practice in proton therapy to evaluate the needs for replan. QACT could falsely indicate replan because of setup issues that would be solved on the treatment machine. Deforming the treatment planning CT (TPCT) to the pretreatment CBCT may eliminate this issue. We investigated the performance of replan evaluation based on deformed TPCT (TPCTdir) for proton head and neck (H&N) therapy. METHODS AND MATERIALS: Twenty-eight H&N datasets along with pretreatment CBCT and QACT were used to validate the method. The changes in body volume were analyzed between the no-replan and replan groups. The dose on the TPCTdir, the deformed QACT (QACTdir), and the QACT were calculated by applying the clinical plans to these image sets. Dosimetric parameters' changes, including ΔD95, ΔDmean, and ΔD1 for the clinical target volumes (CTVs) were calculated. Receiver operating characteristic curves for replan evaluation based on ΔD95 on QACT and TPCTdir were calculated, using ΔD95 on QACTdir as the reference. A threshold for replan based on ΔD95 on TPCTdir is proposed. The specificities for the proposed method were calculated. RESULTS: The changes in the body contour were 95.8 ± 83.8 cc versus 305.0 ± 235.0 cc (p < 0.01) for the no-replan and replan groups, respectively. The ΔD95, ΔDmean, and ΔD1 are all comparable for all the evaluations. The differences between TPCTdir and QACTdir evaluations were 0.30% ± 0.86%, 0.00 ± 0.22 Gy, and -0.17 ± 0.61 Gy for CTV ΔD95, ΔDmean, and ΔD1, respectively. The corresponding differences between the QACT and QACTdir were 0.12% ± 1.1%, 0.02 ± 0.32 Gy, and -0.01 ± 0.71 Gy. CTV ΔD95 > 2.6% in TPCTdir was chosen as the threshold to trigger QACT/replan. The corresponding specificity was 94% and 98% for the clinical practice and the proposed method, respectively. CONCLUSIONS: The replan evaluation based on TPCTdir provides better specificity than that based on the QACT.

Learning-based synthetic dual energy CT imaging from single energy CT for stopping power ratio calculation in proton radiation therapy.

OBJECTIVE: Dual energy CT (DECT) has been shown to estimate stopping power ratio (SPR) map with a higher accuracy than conventional single energy CT (SECT) by obtaining the energy dependence of photon interactions. This work presents a learning-based method to synthesize DECT images from SECT image for proton radiotherapy. METHODS: The proposed method uses a residual attention generative adversarial network. Residual blocks with attention gates were used to force the model to focus on the difference between DECT images and SECT images. To evaluate the accuracy of the method, we retrospectively investigated 70 head-and-neck cancer patients whose DECT and SECT scans were acquired simultaneously. The model was trained to generate both a high and low energy DECT image based on a SECT image. The generated synthetic low and high DECT images were evaluated against the true DECT images using leave-one-out cross-validation. To evaluate our method in the context of a practical application, we generated SPR maps from synthetic DECT (sDECT) using a dual-energy based stoichiometric method and compared the SPR maps to those generated from DECT. A dosimetric comparison for dose obtained from DECT was performed against that derived from sDECT. RESULTS: The mean of mean absolute error, peak signal-to-noise ratio and normalized cross-correlation for the synthetic high and low energy CT images was 36.9 HU, 29.3 dB, 0.96 and 35.8 HU, 29.2 dB, and 0.96, respectively. The corresponding SPR maps generated from synthetic DECT showed an average normalized mean square deviation of about 1% with reduced noise level and artifacts than those from original DECT. Dose-volume histogram (DVH) metrics for the clinical target volume agree within 1% between the DECT and sDECT calculated dose. CONCLUSION: Our method synthesized accurate DECT images and showed a potential feasibility for proton SPR map generation. ADVANCES IN KNOWLEDGE: This study investigated a learning-based method to synthesize DECT images from SECT image for proton radiotherapy.

The omission of intentional primary site radiation following transoral robotic surgery in 59 patients: No local-regional failures.

BACKGROUND: We assessed locoregional control with omission of intentional primary site radiation after transoral robotic surgery (TORS) and quantified nontargeted primary site dose. METHODS: Following Institutional Review Board (IRB) approval, patients treated with primary TORS resection for squamous cell carcinomas of the oropharynx were reviewed. Patients with cT1-2 tumors, >2 mm margins, in whom the surgeon resected the primary without revising specimen-driven margins, qualified for omission of primary site radiation. RESULTS: From 2014 to 2019, 112 patients met criteria. Fifty-nine (52%) patients did not receive radiation targeting the primary site; of whom, 22 received no radiation. In this group, there were no local failures; mean age was 58 years and median follow-up was 25 months. Thirty-seven patients received adjuvant radiation targeting the neck, mean bystander dose to the primary site was 28.8 Gy (range, 13.3-50.6 Gy). CONCLUSION: In a 59 patient population, omission of radiation to the primary site after TORS resulted in no locoregional failures.

Automated delineation of head and neck organs at risk using synthetic MRI-aided mask scoring regional convolutional neural network.

PURPOSE: Auto-segmentation algorithms offer a potential solution to eliminate the labor-intensive, time-consuming, and observer-dependent manual delineation of organs-at-risk (OARs) in radiotherapy treatment planning. This study aimed to develop a deep learning-based automated OAR delineation method to tackle the current challenges remaining in achieving reliable expert performance with the state-of-the-art auto-delineation algorithms. METHODS: The accuracy of OAR delineation is expected to be improved by utilizing the complementary contrasts provided by computed tomography (CT) (bony-structure contrast) and magnetic resonance imaging (MRI) (soft-tissue contrast). Given CT images, synthetic MR images were firstly generated by a pre-trained cycle-consistent generative adversarial network. The features of CT and synthetic MRI were then extracted and combined for the final delineation of organs using mask scoring regional convolutional neural network. Both in-house and public datasets containing CT scans from head-and-neck (HN) cancer patients were adopted to quantitatively evaluate the performance of the proposed method against current state-of-the-art algorithms in metrics including Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (HD95), mean surface distance (MSD), and residual mean square distance (RMS). RESULTS: Across all of 18 OARs in our in-house dataset, the proposed method achieved an average DSC, HD95, MSD, and RMS of 0.77 (0.58-0.90), 2.90 mm (1.32-7.63 mm), 0.89 mm (0.42-1.85 mm), and 1.44 mm (0.71-3.15 mm), respectively, outperforming the current state-of-the-art algorithms by 6%, 16%, 25%, and 36%, respectively. On public datasets, for all nine OARs, an average DSC of 0.86 (0.73-0.97) were achieved, 6% better than the competing methods. CONCLUSION: We demonstrated the feasibility of a synthetic MRI-aided deep learning framework for automated delineation of OARs in HN radiotherapy treatment planning. The proposed method could be adopted into routine HN cancer radiotherapy treatment planning to rapidly contour OARs with high accuracy.

Plasma Metabolic Phenotypes of HPV-Associated versus Smoking-Associated Head and Neck Cancer and Patient Survival.

BACKGROUND: Metabolic differences between human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and smoking-associated HNSCC may partially explain differences in prognosis. The former relies on mitochondrial oxidative phosphorylation (OXPHOS) while the latter relies on glycolysis. These differences have not been studied in blood. METHODS: We extracted metabolites using untargeted liquid chromatography high-resolution mass spectrometry from pretreatment plasma in a cohort of 55 HPV-associated and 82 smoking-associated HNSCC subjects. Metabolic pathway enrichment analysis of differentially expressed metabolites produced pathway-based signatures. Significant pathways (P < 0.05) were reduced via principal component analysis and assessed with overall survival via Cox models. We classified each subject as glycolytic or OXPHOS phenotype and assessed it with survival. RESULTS: Of 2,410 analyzed metabolites, 191 were differentially expressed. Relative to smoking-associated HNSCC, bile acid biosynthesis (P < 0.0001) and octadecatrienoic acid beta-oxidation (P = 0.01), were upregulated in HPV-associated HNSCC, while galactose metabolism (P = 0.001) and vitamin B6 metabolism (P = 0.01) were downregulated; the first two suggest an OXPHOS phenotype while the latter two suggest glycolytic. First principal components of bile acid biosynthesis [HR = 0.52 per SD; 95% confidence interval (CI), 0.38-0.72; P < 0.001] and octadecatrienoic acid beta-oxidation (HR = 0.54 per SD; 95% CI, 0.38-0.78; P < 0.001) were significantly associated with overall survival independent of HPV and smoking. The glycolytic versus OXPHOS phenotype was also independently associated with survival (HR = 3.17; 95% CI, 1.07-9.35; P = 0.04). CONCLUSIONS: Plasma metabolites related to glycolysis and mitochondrial OXPHOS may be biomarkers of HNSCC patient prognosis independent of HPV or smoking. Future investigations should determine whether they predict treatment efficacy. IMPACT: Blood metabolomics may be a useful marker to aid HNSCC patient prognosis.

Incidence trends of squamous cell carcinoma of the head and neck (SCCHN) in the aging population--A SEER-based analysis from 2000 to 2016.

BACKGROUND: Tobacco and alcohol use are risk factors for Squamous Cell Carcinoma of the Head and Neck (SCCHN); however, there is growing recognition of HPV as a risk factor for SCCHN. HPV-related SCCHN is thought to affect mostly middle-aged individuals but as the US population ages, it is important to evaluate the change in incidence of HPV- and non-HPV-related SCCHN in individuals who are ≥65 years old. METHODS: This was a retrospective study using data from a population-based cancer registry (SEER) to identify individuals ≥65 years old diagnosed with SCCHN between 2000 and 2016 also stratified by sex, race, and birth cohort. The subgroups of HPV-associated and non-HPV associated sites were analyzed independently. The incidence per year was calculated and joinpoint detection was used to identity significant changes in incidence trends and annual percent change (APC). RESULTS: For HPV-associated sites from 2000 to 2016, there was an average annual rate of 10.8 per 100,000 individuals with an APC of 2.92% (p = <0.05). For HPV- and non-HPV-related SCCHN males had a higher annual rate compared to females, 54.5 versus 18.0 in non-HPV-related and 19.1 versus 4.4 in HPV-related sites. For non-HPV-related sites there was a decrease in APC across all stratified groups. For HPV-related sites there was an increase in APC across all stratified groups, especially males (APC 8.82% 2006-2016 p < 0.05) and White individuals (APC 8.19% 2006-2016 p < 0.05). When stratified by birth cohort, HPV-related SCCHN sites had a higher APC in ages 65-69 (8.38% p < 0.05) and 70-74 (8.54% p < 0.05). CONCLUSION: Among the population ≥65 years old from 2000 to 2016, the incidence rate for HPV-related SCCHN sites has increased across all stratified groups, especially in White individuals, males, and age groups 65-74. The incidence rate for non-HPV-related sites has decreased across all stratified groups during this time.