Comparative impact of grade on mortality across salivary cancers: A novel, unifying staging system.

BACKGROUND: The comparative impact of histologic variants and grade has not been well described. METHODS: Salivary cancer histologies were profiled using hospital and population-based cancer registries. Multivariable models were employed to assess relationships between histology, grade, and survival. RESULTS: On univariate analysis, histologic variants exhibited a wide spectrum of mortality risk (5-year overall survival (OS): 86% (acinic cell carcinoma), 78% (mucoepidermoid carcinoma), 72% (adenoid cystic carcinoma), 64% (carcinoma ex-pleomorphic adenoma), 52% (adenocarcinoma NOS), and 47% (salivary duct carcinoma) (p < 0.001). However, on multivariable analysis these differences largely vanished. Worsening grade corresponded with deteriorating survival (5-year OS: 89% [low-grade], 81% [intermediate-grade], 45% [high-grade]; p < 0.001), which was upheld on multivariable analysis and propensity score matching. Recursive partitioning analysis generated TNM + G schema (c-index 0.75) superior to the existing system (c-index 0.73). CONCLUSION: Grade represents a primary determinant of salivary cancer prognosis. Integrating grade into stage strengthens current staging systems.

Antagonizing CD105 and androgen receptor to target stromal-epithelial interactions for clinical benefit.

Androgen receptor signaling inhibitors (ARSIs) are standard of care for advanced prostate cancer (PCa) patients. Eventual resistance to ARSIs can include the expression of androgen receptor (AR) splice variant, AR-V7, expression as a recognized means of ligand-independent androgen signaling. We demonstrated that interleukin (IL)-6-mediated AR-V7 expression requires bone morphogenic protein (BMP) and CD105 receptor activity in both PCa and associated fibroblasts. Chromatin immunoprecipitation supported CD105-dependent ID1- and E2F-mediated expression of RBM38. Further, RNA immune precipitation demonstrated RBM38 binds the AR-cryptic exon 3 to enable AR-V7 generation. The forced expression of AR-V7 by primary prostatic fibroblasts diminished PCa sensitivity to ARSI. Conversely, downregulation of AR-V7 expression in cancer epithelia and associated fibroblasts was achieved by a CD105-neutralizing antibody, carotuximab. These compelling pre-clinical findings initiated an interventional study in PCa patients developing ARSI resistance. The combination of carotuximab and ARSI (i.e., enzalutamide or abiraterone) provided disease stabilization in four of nine assessable ARSI-refractory patients. Circulating tumor cell evaluation showed AR-V7 downregulation in the responsive subjects on combination treatment and revealed a three-gene panel that was predictive of response. The systemic antagonism of BMP/CD105 signaling can support ARSI re-sensitization in pre-clinical models and subjects that have otherwise developed resistance due to AR-V7 expression.

Predicting Pathologic Lymph Node Positivity in cN0 Pharynx and Larynx Cancers.

BACKGROUND: Elective neck dissection is a standard of care for pharynx and most larynx cancer patients undergoing surgery, based largely on historical series. It is unclear if this is necessary for all patients in the modern era. METHODS: Patients with cN0 oropharynx, larynx, and hypopharynx cancers diagnosed from 2010-2015 undergoing primary surgery were identified in the National Cancer Data Base. RESULTS: Inclusion criteria were met by 4117 cN0 patients. The presence of lymphovascular invasion (LVI) was the strongest independent predictor of pN+ (odds ratio [OR] = 4.19, 95% confidence interval [CI] 3.56-4.93, p < 0.001). Histologic grade strongly predicted pN+ (OR 2.58, 95% CI 1.88-3.59, p < 0.001). A nomogram predicted less than 10% of cN0 patients had pN+ risk <15%. CONCLUSION: LVI and grade are the strongest predictors of pN+ among patients with cN0 pharynx and larynx cancer. Even in the modern era, pN+ rates warrant neck dissection for cN0 patients. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1660-1666, 2023.

Quantitative Nodal Burden and Mortality Across Solid Cancers.

BACKGROUND: Nodal staging systems vary substantially across solid tumors, implying heterogeneity in the behavior of nodal variables in various contexts. We hypothesized, in contradiction to this, that metastatic lymph node (LN) number is a universal and dominant predictor of outcome across solid tumors. METHODS: We performed a retrospective cohort analysis of 1 304 498 patients in the National Cancer Database undergoing surgery between 2004 and 2015 across 16 solid cancer sites. Multivariable Cox regression analyses were constructed using restricted cubic splines to model the association between nodal number and mortality. Recursive partitioning analysis (RPA) was used to derive nodal classification systems for each solid cancer based on metastatic LN count. The reproducibility of these findings was assessed in 1 969 727 patients from the Surveillance, Epidemiology, and End Results registry. Two-sided tests were used for all statistical analyses. RESULTS: Consistently across disease sites, mortality risk increased continuously with increasing number of metastatic LNs (P < .001 for all spline segments). Each RPA-derived nodal classification system produced multiple prognostic groups spanning a wide spectrum of mortality risk (P < .001). Multivariable models using these RPA-derived nodal classifications demonstrated improved concordance with mortality compared with models using American Joint Committee on Cancer staging in sites where nodal classification is not based on metastatic LN count. Each RPA-derived nodal classification system was reproducible in a large validation cohort for all-cause and cause-specific mortality (P < .001). High quantitative nodal burden was the single strongest tumor-intrinsic variable associated with mortality in 12 of 16 disease sites. CONCLUSIONS: Quantitative metastatic LN burden is a fundamental driver of mortality across solid cancers and should serve as a foundation for pathologic nodal staging across solid tumors.

Nodal staging convergence for HPV- and HPV+ oropharyngeal carcinoma.

BACKGROUND: Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct pathologic nodal systems. Given that quantitative lymph node (LN) burden is the dominant prognostic factor in most head and neck cancers, we investigated whether HPV- and HPV+ OPC warrant divergent pathologic nodal classification. METHODS: Multivariable Cox regression models of OPC surgical patients identified via U.S. cancer registry data were constructed to determine associations between survival and nodal characteristics. Nonlinear associations between metastatic LN number and survival were modeled with restricted cubic splines. Recursive partitioning analysis (RPA) was used to derive unbiased nodal schema. RESULTS: Mortality risk escalated continuously with each successive positive LN in both OPC subtypes, with analogous slope. Survival hazard increased by 18.5% (hazard ratio [HR], 1.19 [95% CI, 1.16-1.21]; P < .001) and 19.1% (HR, 1.19 [95% CI, 1.17-1.21]; P < .001), with each added positive LN for HPV- and HPV+ OPC, respectively, up to identical change points of 5 positive LNs. Extranodal extension (ENE) was an independent predictor of HPV- OPC (HR, 1.55 [95% CI, 1.20-1.99]; P < .001) and HPV+ OPC (HR 1.73 [95% CI, 1.36-2.20]; P < .001) mortality. In RPA for both diseases, metastatic LN was the principal nodal covariate driving survival, with ENE as a secondary determinant. Given the similarities across analyses, we propose a concise, unifying HPV-/HPV+ OPC pathologic nodal classification schema: N1, 1-5 LN+/ENE-; N2, 1-5 LN+/ENE+; N3, >5 LN+. CONCLUSION: HPV- and HPV+ OPC exhibit parallel relationships between nodal characteristics and relative mortality. In both diseases, metastatic LN number represents the principal nodal covariate governing survival, with ENE being an influential secondary element. A consolidated OPC pathologic nodal staging system that is based on these covariates may best convey prognosis. LAY SUMMARY: The current nodal staging system for oropharyngeal carcinoma (OPC) has divided human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) OPC into distinct systems that rely upon criteria that establish them as separate entities, a complexity that may undermine the core objective of staging schema to clearly communicate prognosis. Our large-scale analysis revealed that HPV- and HPV+ pathologic nodal staging systems in fact mirror each other. Multiple analyses produced conspicuously similar nodal staging systems, with metastatic lymph node number and extranodal extension delineating the highest risk groups that shape prognosis. We propose unifying HPV- and HPV+ nodal systems to best streamline prognostication and maximize staging accuracy.

Variations in the association of grade with survival across the head and neck cancer landscape.

BACKGROUND: Although pathologic tumor grade is a well-established prognostic risk factor that impacts staging and treatment decisions across multiple cancer types, its role in head and neck squamous cell carcinoma (HNSCC) is less certain. METHODS: HNSCC patients diagnosed from 2010 to 2015 and undergoing primary surgery in the National Cancer Data Base were identified. Propensity score matching and multivariable Cox regression were performed. RESULTS: Among 27 041 HNSCC patients, 13 941 had oral cavity cancers (OCC). Intermediate-grade (hazard ratio [HR] 1.16, 95% CI 1.07-1.26, P < .001) and high-grade (HR 1.38, 95% CI 1.26-1.52, P < .001) tumors had worse survival than low-grade tumors. This magnitude was comparable to other well-established prognostic factors, including margin positivity, extranodal extension, and lymphovascular invasion. By contrast, there was no association between grade and survival in larynx/hypopharynx or HPV(-) oropharynx cancer. CONCLUSIONS: The prognostic impact of pathologic grade is highly variable across head and neck subsites and is the strongest among OCC patients.

Comparison of Survival After Transoral Robotic Surgery vs Nonrobotic Surgery in Patients With Early-Stage Oropharyngeal Squamous Cell Carcinoma.

Importance: Transoral robotic surgery has been widely adopted since approval by the US Food and Drug Administration in December 2009, despite limited comparative data. Objective: To compare the long-term outcomes of transoral robotic surgery with those of nonrobotic surgery for patients with early-stage oropharyngeal cancer. Design, Setting, and Participants: A retrospective cohort comparative effectiveness analysis was performed of patients in the National Cancer Database with clinical T1 and T2 oropharyngeal squamous cell carcinoma diagnosed between January 1, 2010, and December 31, 2015, who underwent definitive robotic and nonrobotic surgery. Multivariable Cox proportional hazards regression analysis and propensity score matching were performed in patients with known human papillomavirus status to adjust for patient- and disease-related covariates. Survival after robotic and nonrobotic surgery was also compared in 3 unrelated cancers: prostate, endometrial, and cervical cancer. Statistical analysis was performed from April 10, 2019, to May 21, 2020. Main Outcomes and Measures: Overall survival. Results: Of 9745 patients (7652 men [78.5%]; mean [SD] age, 58.8 [9.6] years) who met inclusion criteria, 2694 (27.6%) underwent transoral robotic surgery. There was a significant increase in the use of robotic surgery from 18.3% (240 of 1309) to 35.5% (654 of 1841) of all surgical procedures for T1 and T2 oropharyngeal cancers from 2010 to 2015 (P = .003). Robotic surgery was associated with lower rates of positive surgical margins (12.5% [218 of 1746] vs 20.3% [471 of 2325]; P < .001) and lower use of adjuvant chemoradiotherapy (28.6% [500 of 1746] vs 35.7% [831 of 2325]; P < .001). Among 4071 patients with known human papillomavirus status, robotic surgery was associated with improved overall survival compared with nonrobotic surgery in multivariable Cox proportional hazards regression (hazard ratio [HR], 0.74; 95 CI, 0.61-0.90; P = .002). Similar results were seen when analyzing only the subset of facilities offering both robotic and nonrobotic surgery. The 5-year overall survival was 84.8% vs 80.3% among patients undergoing robotic vs nonrobotic surgery in propensity score-matched cohorts (P = .001). By contrast, there was no evidence that robotic surgery was associated with improved survival in other cancers, such as prostate cancer (HR, 0.92; 95% CI, 0.79-1.07; P = .26), endometrial cancer (HR, 0.97; 95% CI, 0.90-1.04; P = .36), and cervical cancer (HR, 1.27; 95% CI, 0.96-1.69; P = .10). Conclusions and Relevance: This study suggests that transoral robotic surgery was associated with improved surgical outcomes and survival compared with nonrobotic surgery in patients with early-stage oropharyngeal cancer. Evaluation in comparative randomized trials is warranted.

The role of concomitant chemoradiotherapy in AJCC 7th edition T1-2N1 oropharyngeal carcinoma in the human papillomavirus era.

BACKGROUND: Radiotherapy (RT) without chemotherapy is considered a standard of care for the management of American Joint Committee on Cancer (AJCC) 7th edition (7E) T1-2N1 oropharyngeal squamous cell carcinoma (OPSCC). Recent data suggests concurrent chemoradiation (CCRT) may benefit these patients but did not include human papillomavirus (HPV) status. Given the radiosensitivity differences between HPV-positive versus HPV-negative OPSCC, the effect of chemotherapy may differ in these patients. METHODS: We analyzed patients in the National Cancer Database diagnosed between 2010 and 2015 with AJCC 7E stage cT1-2N1M0 OPSCC and known HPV status undergoing definitive RT or CCRT. RESULTS: Overall, 1964 patients were included, including 1297 (66%) HPV-positive and 667 (34%) HPV-negative patients. 66% received CCRT and 34% received RT alone. In multivariate analysis, CCRT was associated with improved survival compared with RT alone (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.57-0.87; P = 0.001). In propensity score-matched cohorts, 4-year overall survival was 87.4% vs 78.4% in HPV-positive patients receiving CCRT and RT alone, respectively (P = 0.002), and 65.5% vs 58.9% in HPV-negative patients, respectively (P = 0.2). There was no evidence that HPV-positivity diminished the association between CCRT and longer survival (HR, 0.57; 95% CI, 0.42-0.81) versus what was observed in HPV-negative patients (HR, 0.86; 95% CI, 0.64-1.16) (interaction P = 0.06). CONCLUSIONS: CCRT is associated with improved survival in AJCC 7E T1-2N1 OPSCC. Despite the radiosensitivity of HPV-positive OPSCC, the association of CCRT with improved survival for T1-2N1 HPV-positive OPSCC was at least as strong, if not stronger, than what was observed in HPV-negative patients.

Predictors of hospital readmission among older adults with cancer.

OBJECTIVE: Older adults with cancer are at higher risk for costly and potentially dangerous hospital readmissions. Identifying risk factors for readmission in this population is important for future prevention of readmission. MATERIALS AND METHODS: Hospital discharges among patients ≥ 65 years with solid tumors on non-surgical services from 2006-2011 were reviewed in this matched case-control study. We abstracted patient/cancer characteristics; functional status; fall risk; chemotherapy line; comorbidities; laboratory values; discharge parameters; and miscellaneous information (Do Not Resuscitate Order, pain scores) from medical records. Conditional logistic regression was used for univariate and multivariable analysis. RESULTS: This analysis included 184 case-patients readmitted within 30 days after discharge from the index admission and 184 sex- and age-matched control-patients discharged from index admission within three months of the cases with no readmission. Cases and controls had no differences in terms of primary cancer type, treatment, and index admission reason. Cases were more likely to have abnormal hemoglobin, albumin, sodium, and SGOT on discharge. Compared to those with ≤1 abnormal laboratory test, patients with 2 or more abnormal test results were 3 times more likely to be readmitted within 30 days. CONCLUSION: This study demonstrated that older adults with cancer who had at least 2 abnormal laboratory results (hemoglobin, albumin, sodium, and SGOT) at discharge were 3 times more likely to be readmitted within 30 days compared to those with ≤1 abnormal results. These laboratory values may be predictive of the risk of readmission, and should be monitored before discharge to potentially prevent readmission.

Stage I HPV-positive oropharyngeal cancer: Should all patients receive similar treatments?

BACKGROUND: Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy. METHODS: The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7 days of the initiation of radiotherapy. RESULTS: The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3 months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P = .012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P < .001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P = .05]). Similar results were noted among propensity score-matched cohorts. CONCLUSIONS: Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCC undergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients.

Impact of insurance on survival in patients < 65 with head & neck cancer treated with radiotherapy.

OBJECTIVES: The United States has a heterogenous health insurance landscape for patients <65 years. We sought to characterise the impact of primary payer on overall survival (OS) in insured patients younger than 65 with head and neck squamous cell carcinoma (HNSCC) treated with definitive radiotherapy. DESIGN/STUDY/PARTICIPANTS: The National Cancer Database was queried for patients <65 years old diagnosed from 2004 to 2014 undergoing definitive radiotherapy ± chemotherapy for cancers of the nasopharynx, oropharynx, hypopharynx and larynx. Uninsured patients and oropharyngeal cancers without known HPV status were excluded. MAIN OUTCOME: Overall survival. RESULTS: Overall, 27 292 insured patients were identified, including 17 060 (62.5%) with private insurance. Median follow-up was 52.1 months. In multivariable models, patients receiving Medicaid (HR = 1.66, 95% CI 1.57-1.75, P < .001), Medicare (HR = 1.64, 95% CI 1.55-1.73, P < .001) and other government insurance (HR = 1.44, 95% CI 1.29-1., P < .001) had independently increased mortality in comparison to those with private insurance. In propensity score-matched cohorts, 5-year OS was 65.5% vs 50.6% for privately vs government-insured patients, respectively (P < .001). In multivariable subgroup analysis, private insurance was associated with improved survival in all subgroups. However, the magnitude of this effect was most pronounced in patients with HPV-positive oropharyngeal cancer vs non-HPV-related cancer (interaction P < .001), younger patients (interaction P = .001), and those without comorbidity (interaction P < .001). CONCLUSIONS: Patients <65 with HNSCC undergoing definitive radiation with private health insurance have markedly longer survival relative to patients with government-sponsored insurance. This illustrates that increasing access to care may be necessary, but is not sufficient, to mitigate the significant disparities in the US healthcare system.

Survival outcomes with concomitant chemoradiotherapy in older adults with oropharyngeal carcinoma in an era of increasing human papillomavirus (HPV) prevalence.

BACKGROUND: Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has dramatically increased in incidence and prevalence among patients aged 70 and older. There are virtually no data regarding outcomes in this population, and thus optimal therapy, including the role of chemotherapy for those undergoing radiotherapy (RT), remains unclear. METHODS: The National Cancer Database was queried for older adults (defined as age 70 years and older) with locally advanced OPSCC (cT1-2N1-3, cT3-4N0-3) diagnosed from 2010 to 2014 with known HPV-status undergoing definitive RT alone or chemoradiation (CRT). RESULTS: Overall, 1,965 older adults with locally advanced OPSCC met inclusion criteria, including 1,141 HPV-positive (58%) and 824 HPV-negative (42%) patients. 1,211 patients (62%) received CRT. In multivariable analysis, CRT was associated with improved survival in older patients when compared to RT alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI] 0.64-0.86, P < 0.001). CRT was associated with improved survival in both HPV-positive (HR = 0.80, 95% CI: 0.64-1.00, P = 0.05) and HPV-negative (HR = 0.69, 95% CI: 0.56-0.85, P < 0.001) subgroups. There was no significant interaction between HPV status and the impact of CRT on survival (P interaction = 0.57). CONCLUSIONS: Despite the radiosensitivity of HPV-positive OPSCC and the challenges in delivering CRT to older adults, CRT was associated with improved survival in older patients with HPV-positive OPSCC, similar in magnitude to the benefit in HPV-negative patients. As the incidence of HPV-positive OPSCC in older patients continues to increase, further studies are needed to investigate optimal therapeutic strategies in this population.

A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) has a dismal prognosis with current treatment modalities and one-third of patients die from local progression of disease. Preclinical studies with orthotopic PC demonstrated dramatic synergy between radiotherapy (RT) and the poly(ADP-ribose) polymerase-1/2 inhibitor (PARPi), veliparib. We conducted a phase I trial of gemcitabine, radiotherapy and dose-escalated veliparib in LAPC. METHODS: This was a single institution investigator-initiated open-label, single-arm phase 1 clinical trial (NCT01908478). Weekly gemcitabine with daily IMRT and veliparib dose escalated using a Bayesian adaptive design were administered in treatment naïve LA or borderline resectable PC. The primary end point was identification of the MTD. Secondary endpoints included efficacy, characterization of PAR levels using ELISA, DDR alterations with targeted next generation sequencing and transcriptome analysis, tumor mutation burden (TMB) and microsatellite instability (MSI) status. FINDINGS: Thirty patients were enrolled. The MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15 fractions). Sixteen DLTs were identified in 12 patients. Grade ≥ 3 adverse events included lymphopenia (96%) and anemia (36%). Median OS for all patients was 15 months. Median OS for DDR pathway gene altered and intact cases was 19 months (95% CI: 6.2-27.2) and 14 months (95% CI: 10.0-21.8), respectively. There were no significant associations between levels of PAR, TMB, or MSI with outcomes. The DDR transcripts PARP3 and RBX1 significantly correlated with OS. INTERPRETATION: This is the first report of a PARPi-chemoradiotherapy combination in PC. The regimen was safe, tolerable at the RP2D, and clinically active as an upfront treatment strategy in patients biologically unselected by upfront chemotherapy. Expression of the DDR transcripts, PARP3 and RBX1, were associated with OS suggesting validation in a follow up phase 2 study. FUND: Phase One Foundation; National Institutes of Health [1R01CA188480-01A1, P01 CA098912]. Veliparib was provided by Abbvie.

Human papillomavirus-associated oropharyngeal cancer among patients aged 70 and older: Dramatically increased prevalence and clinical implications.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence among older adults. However, the role of human papillomavirus (HPV) in driving this trend and its prognostic significance in this population have not been established. METHODS: The National Cancer Database was queried for patients with OPSCC diagnosed from 2010 to 2015 undergoing either surgery or radiotherapy (RT) with known HPV status. Older adults were defined as those aged 70 years or older. RESULTS: Among 43,427 OPSCC patients, the proportion of HPV-positive OPSCC increased from 45.1% to 63.3% in older adults (P < 0.001). In 19,358 patients meeting the inclusion criteria for survival analyses, HPV positivity was associated with improved survival for older adults undergoing either definitive RT (hazard ratio [HR] = 0.63, 95% confidence interval [CI] 0.55-0.72, P < 0.001) or surgery (HR = 0.37, 95% CI 0.25-0.53, P < 0.001) in multivariable analysis. In propensity score-matched cohorts, 3-year overall survival was 69.1% versus 55.5% (P < 0.001) in older adults with HPV-positive and HPV-negative OPSCC undergoing definitive RT, respectively, and 88.5% versus 69.1% (P = 0.001) for older adults undergoing surgery. Although HPV positivity was associated with improved survival among all age groups receiving RT, the magnitude of the effect diminished with increasing age (interaction P < 0.001). No interaction between age and the impact of HPV status on survival was seen for surgical patients (interaction P = 0.72). CONCLUSIONS: The epidemiologic landscape of HPV-positive OPSCC is evolving, with a dramatic increase in the proportion of HPV-associated OPSCC among patients 70 years or older. HPV remains a powerful predictor of improved survival in elderly patients, but with less pronounced effect on older adults undergoing definitive RT.

Quantitative survival impact of composite treatment delays in head and neck cancer.

BACKGROUND: Multidisciplinary management of head and neck cancer (HNC) must reconcile increasingly sophisticated subspecialty care with timeliness of care. Prior studies examined the individual effects of delays in diagnosis-to-treatment interval, postoperative interval, and radiation interval but did not consider them collectively. The objective of the current study was to investigate the combined impact of these interwoven intervals on patients with HNC. METHODS: Patients with HNC who underwent curative-intent surgery with radiation were identified in the National Cancer Database between 2004 and 2013. Multivariable models were constructed using restricted cubic splines to determine nonlinear relations with overall survival. RESULTS: Overall, 15,064 patients were evaluated. After adjustment for covariates, only prolonged postoperative interval (P < .001) and radiation interval (P < .001) independently predicted for worse outcomes, whereas the association of diagnosis-to-treatment interval with survival disappeared. By using multivariable restricted cubic spline functions, increasing postoperative interval did not affect mortality until 40 days after surgery, and each day of delay beyond this increased the risk of mortality until 70 days after surgery (hazard ratio, 1.14; 95% confidence interval, 1.01-1.28; P = .029). For radiation interval, mortality escalated continuously with each additional day of delay, plateauing at 55 days (hazard ratio, 1.25; 95% confidence interval, 1.11-1.41; P < .001). Delays beyond these change points were not associated with further survival decrements. CONCLUSIONS: Increasing delays in postoperative and radiation intervals are associated independently with an escalating risk of mortality that plateaus beyond certain thresholds. Delays in initiating therapy, conversely, are eclipsed in importance when appraised in conjunction with the entire treatment course. Such findings may redirect focus to streamlining those intervals that are most sensitive to delays when considering survival burden. Cancer 2018. © 2018 American Cancer Society.

Perspectives in Head and Neck Medical Oncology.

The modern treatment of locoregionally advanced disease often requires a multimodality combination approach. A number of chemotherapeutic agents can be combined with radiation, but the platinum agent cisplatin, a potent radiation sensitizer, is best studied in head and neck cancer. Newer agents such as cetuximab can be used in combination with radiation therapy for those patients who cannot tolerate cisplatin. For chemotherapy-naïve patients with metastatic head and neck cancer who demonstrate a good performance status, platinum doublet regimens are commonly used. Doublet regimens generally improve response rates compared to single-agent chemotherapies, although they have not demonstrated a survival benefit over single agents and they have added toxicity. Immunotherapies, alternative cytotoxic chemotherapies, and targeted therapies are second-line options for patients with disease that has progressed on platinum-based therapy. Immunotherapy, in particular, has gained focus by enhancing the ability of the immune system to recognize and destroy malignant cells. When multimodal approaches are used, as in combined chemotherapy and radiation therapy, toxicities are increased. It is imperative that patients are followed closely in order to maximize treatment benefit while minimizing complications.

Postoperative chemoradiotherapy in patients with head and neck cancer aged 70 or older with positive margins or extranodal extension and the influence of nodal classification.

BACKGROUND: Postoperative concomitant chemoradiotherapy (CRT) improves outcomes for younger adults with head and neck squamous cell carcinoma (HNSCC) and positive margins or extranodal extension (ENE), but its benefit for older adults is not well established. METHODS: Patients from the National Cancer Data Base (NCDB) with HNSCC undergoing curative-intent resection, neck dissection, and postoperative radiation with positive margins or ENE were identified. RESULTS: This analysis included 1199 patients aged ≥ 70 years with median follow-up of 42.6 months. Postoperative concurrent CRT was associated with improved overall survival (OS; hazard ratio [HR] 0.752; 95% confidence interval [CI] 0.638-0.886) compared to radiation alone in multivariable analysis. Three-year OS was 52.4% with CRT versus 43.4% with radiation (P = .012) in propensity-score matched cohorts. The survival impact of CRT varied by N classification (P = .002 for interaction), with benefit seen only in those with N2 to N3 disease. CONCLUSION: Postoperative concurrent CRT may benefit older patients with HNSCC with positive margins or ENE, particularly those with higher nodal burden.

Association of Quantitative Metastatic Lymph Node Burden With Survival in Hypopharyngeal and Laryngeal Cancer.

Importance: Nodal staging for laryngohypopharyngeal cancers is based primarily on size and laterality, with less value placed on absolute number of metastatic lymph nodes (LNs). We are aware of no studies to date that have specifically addressed the prognostic effect of quantitative nodal burden in larynx or hypopharynx malignancies. Objective: To assess the independent impact of quantitative metastatic LN burden on mortality risk. Design, Setting, and Participants: Univariate and multivariable models were constructed to evaluate the association between patients' number of metastatic LNs and their survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Participants were patients with squamous cell carcinoma of the larynx or hypopharynx undergoing upfront surgical resection for curative intent at a US hospital between 2004 and 2013, as identified in the National Cancer Database. A neck dissection of a minimum of 10 LNs was required. Main Outcomes and Measures: Overall survival. Results: Overall, 8351 cases were included (mean [SD] age, 61 [10.1] years; 6499 men [77.8%]; 4710 patients with metastatic LNs and 3641 with no metastatic LNs). Mortality risk escalated continuously without plateau as number of metastatic nodes increased, with the hazard per node (hazard ratio [HR], 1.19; 95% CI, 1.16-1.23; P < .001) most pronounced up to 5 positive LNs. Extranodal extension was also associated with increased mortality (HR, 1.34; 95% CI, 1.13-1.59; P < .001). Increasing number of nodes examined was associated with improved survival, albeit to a lesser degree (per 10 LNs: HR, 0.97; 95% CI, 0.96-0.98; P < .001) and without a detectable change point. Other nodal factors, including nodal size, contralateral LN involvement (TNM stage N2c), and lower LN involvement (levels 4-5), were not associated with mortality in multivariable models when accounting for number of positive LNs. A novel, parsimonious nodal staging system derived by recursive partitioning analysis exhibited greater concordance with survival than the TNM staging system outlined in the American Joint Committee on Cancer's AJCC Staging Manual, 8th edition. Conclusions and Relevance: The number of metastatic nodes is a predominant independent factor associated with mortality in hypopharyngeal and laryngeal cancers. Moreover, standard nodal staging factors like LN size and contralaterality have no independent prognostic value when accounting for positive LN number. Deeper integration of quantitative metastatic nodal disease may simplify staging and better triage the need for adjuvant therapy.

Facility Volume and Survival in Nasopharyngeal Carcinoma.

INTRODUCTION: Definitive treatment of nasopharyngeal carcinoma (NPC) is challenging owing to its rarity, complicated regional anatomy, and the intensity of therapy. In contrast to other head and neck cancers, the effect of facility volume has not been well described for NPC. METHODS AND MATERIALS: The National Cancer Database was queried for patients with stage II-IVB NPC diagnosed from 2004 to 2014 and treated with definitive radiation. Patients with incomplete staging, unknown receipt or timing of treatment, unknown follow-up duration, incomplete socioeconomic information, or treatment outside the reporting facility were excluded. High-volume facilities (HVFs) were defined as the top 5% of facilities according to the annual facility volume. RESULTS: The present analysis included 3941 NPC patients treated at 804 facilities with a median follow-up duration of 59.4 months, including 1025 patients (26.0%) treated at HVFs. Treatment at HVFs was associated with significantly improved overall survival (OS) on multivariable analysis (hazard ratio 0.79, 95% confidence interval 0.69-0.90; P=.001). In propensity score-matched cohorts, 5-year OS was 69.1% versus 63.3% at HVFs versus lower volume facilities (LVFs), respectively (P=.003). Similar results were seen when facility volume was analyzed as a continuous variable. The effect of facility volume on survival varied by academic status (P=.002 for interaction). At academic centers, the propensity score-matched cohorts had 5-year OS of 71.4% compared with 62.4% (P<.001) at HVFs and LVFs, respectively. In contrast, the 5-year OS was 63.5% versus 67.9% (P=.68) in propensity score-matched patients at nonacademic HVFs and LVFs. CONCLUSIONS: Treatment at HVFs was associated with improved OS for patients with NPC, with the effect exclusively seen at academic centers.

Predictors of survival in head and neck mucosal melanoma.

OBJECTIVES: To evaluate hospital-based data of head and neck mucosal melanoma patients in order to identify predictors of survival. MATERIALS AND METHODS: The National Cancer Data Base was used to identify 1368 patients with head and neck mucosal melanoma diagnosed between the years of 2004 and 2012. The Kaplan-Meier method was utilized to estimate overall survival, and multivariate Cox regression analyses were performed to assess the impact of covariates on survival after adjusting for confounding variables. RESULTS: Median follow-up was 55.2months. Median survival of all patients was 29.3months, and the 5-year survival was 27.4%. After adjusting for other prognostic factors in multivariate analysis, paranasal sinus location [hazard ratio (HR)=1.54, 95% Confidence Interval (CI)=1.30-1.82, P<0.001)] and the use of radiotherapy alone for definitive local treatment (HR=2.27, 95% CI=1.72-2.98, P<0.001) were associated with worse survival. Similar results were seen in the subgroup of patients with complete clinical staging information. In terms of patterns of care, the use of combined surgery and radiotherapy as the primary local treatment modality has significant increased from 2004 and 2012 (P=0.03). CONCLUSION: Outcomes in mucosal melanoma of the head and neck remain suboptimal, despite increased use of multimodality local therapy, likely due to the high risk of distant metastases. Mucosal melanomas arising from the paranasal sinuses have particularly poor prognosis. Novel therapeutic paradigms for head and neck mucosal melanoma, incorporating systemic therapies to decrease the risk of distant relapse, should be pursued in clinical trials.