Anxiety symptoms predict head and neck cancer survival: Exploring mediation by systemic inflammation and tumor response to treatment.

BACKGROUND: Head and neck cancers (HNC) are associated with high rates of anxiety. Anxiety has been linked to biological pathways implicated in cancer progression, though little is known about its effects on overall survival. We hypothesized that higher pretreatment anxiety levels in patients with HNC would predict poorer 2-year overall survival and expected this relationship to be mediated by both systemic inflammation and tumor response to treatment. METHODS: Patients (N = 394) reported anxiety symptomatology via the GAD-7 at treatment planning. Pre-treatment hematology workup provided an index of systemic inflammation (SII; N = 292). Clinical data review yielded tumor response and overall survival. Logistic and multiple regressions and Cox proportional hazard models tested hypothesized relationships. RESULTS: Higher pretreatment anxiety levels were significantly associated with poorer 2-year survival (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.014-1.066, p = 0.002). The association between anxiety and SII was not significant, though anxiety was associated with poorer tumor response (odds ratio [OR], 1.033; 95% CI, 1.001-1.066, p = 0.043). Tumor response fully mediated the relationship between anxiety symptoms and 2-year survival (HR, 9.290, 95% CI, 6.152-14.031, p < 0.001). CONCLUSIONS: Anxiety was associated with overall survival. Tumor response, but not systemic inflammation, emerged as a potential biological pathway mediating this effect. Screening for anxiety may be beneficial to help prospectively address these concerns and ameliorate potentially detrimental impact on clinically meaningful cancer outcomes.

Depressive Symptoms, Systemic Inflammation, and Survival Among Patients With Head and Neck Cancer.

Importance: Patients with head and neck cancer experience high rates of depression. Depression and systemic inflammation have been found to be associated in numerous cancer types, often independently from disease status. Depression-related inflammation may elevate the risks for poor tumor response to treatment and early mortality, and comprises a mechanism by which depression is associated with survival in head and neck cancer. Objective: To assess mediation pathways incorporating pretreatment depressive symptoms, pretreatment inflammation, and tumor response posttreatment on overall survival among patients with head and neck cancer. Design, Setting, and Participants: This was a prospective observational cohort study of patients with head and neck cancer treated in a single multidisciplinary head and neck cancer clinic from May 10, 2013, to December 30, 2019, and followed up for 2 years. Data analysis was performed from June 29, 2022, to June 23, 2023. Exposures: Patient-reported depressive symptoms using the Patient Health Questionnaire-9 item (PHQ-9) at treatment planning; pretreatment hematology workup for systemic inflammation index (SII) score; and clinical data review for tumor response (complete vs incomplete) and overall survival. Main Outcomes: Two-year overall survival. Results: The total study cohort included 394 patients (mean [SD] age, 62.5 [11.5] years; 277 [70.3%] males) with head and neck cancer. Among 285 patients (72.3%) who scored below the clinical cutoff for depression on the PHQ-9, depressive symptoms were significantly associated with inflammation (partial r, 0.168; 95% CI, 0.007-0.038). In addition, both depression and inflammation were associated with early mortality (PHQ-9: hazard ratio [HR], 1.04; 95% CI, 1.02-1.07; SII: HR, 1.36; 95% CI, 1.08-1.71). The depression-survival association was fully mediated by inflammation (HR, 1.28; 95% CI, 1.00-1.64). Depressive symptoms were also associated with poorer tumor response (odds ratio, 1.05; 95% CI, 1.01-1.08), and the depression-survival association was partially mediated by tumor response (HR, 9.44; 95% CI, 6.23-14.32). Systemic inflammation was not associated with tumor response. Conclusions: In this cohort study, systemic inflammation emerged as a novel candidate mechanism of the association of depression with mortality. Tumor response partially mediated effects of depression on mortality, replicating prior work. Thus, depression stands out as a highly feasible target for renewed clinical attention. Even mild symptoms of depression during the treatment-planning phase may be associated with higher systemic inflammation in addition to poorer tumor response to treatment and survival outcomes; therefore, depression should be clinically addressed.

Radiotherapy Plus Cisplatin With or Without Lapatinib for Non-Human Papillomavirus Head and Neck Carcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC. Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS). Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020. Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo). Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS. Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84). Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Merkel Cell Carcinoma of the Head and Neck: Epidemiology, Pathogenesis, Current State of Treatment and Future Directions.

Merkel cell carcinoma (MCC) is a rare, cutaneous neuroendocrine malignancy with increasing incidence. The skin of the head and neck is a common subsite for MCC with distinctions in management from other anatomic areas. Given the rapid pace of developments regarding MCC pathogenesis (Merkel cell polyoma virus (MCPyV)-positive or virus-negative, cell of origin), diagnosis, staging and treatment, and up to date recommendations are critical for optimizing outcomes. This review aims to summarize currently available literature for MCC of the head and neck. The authors reviewed current literature, including international guidelines regarding MCC pathogenesis, epidemiology, diagnosis, staging, and treatment. Subsequently recommendations were derived including the importance of baseline imaging, MCPyV serology testing, primary site surgery, nodal evaluation, radiotherapy, and the increasing role of immune modulating agents in MCC. MCPyV serology testing is increasingly important with potential distinctions in treatment response and surveillance between virus-positive and virus-negative MCC. Surgical management continues to balance optimizing local control with minimal morbidity. Similarly, radiotherapy continues to have importance in the adjuvant, definitive, and palliative setting for MCC of the head and neck. Immunotherapy has changed the paradigm for advanced MCC, with increasing work focusing on optimizing outcomes for non-responders and high-risk patients, including those with immunosuppression.

Immune Status in Merkel Cell Carcinoma: Relationships With Clinical Factors and Independent Prognostic Value.

BACKGROUND: Immunosuppression (IS) currently is not considered in staging for Merkel cell carcinoma (MCC). An analysis of the National Cancer Database (NCDB) was performed to investigate immune status as an independent predictor of overall survival (OS) for patients with MCC and to describe the relationship between immune status and other prognostic factors. METHODS: The NCDB was queried for patients with a diagnosis of MCC from 2010 to 2016 who had known immune status. Multivariable Cox proportional hazards models were used to define factors associated with OS. Secondary models were constructed to assess the association between IS etiology and OS. Multivariable logistic regression models were used to characterize relationships between immune status and other factors. RESULTS: The 3-year OS was lower for the patients with IS (44.6%) than for the immunocompetent (IC) patients (68.7%; p < 0.0001). Immunosuppression was associated with increased adjusted mortality hazard (hazard ratio [HR], 2.36, 95% confidence interval [CI], 2.03-2.75). The etiology of IS was associated with OS (p = 0.0015), and patients with solid-organ transplantation had the lowest 3-year OS (32.7%). Immunosuppression was associated with increased odds of greater nodal burden (odds ratio [OR], 1.70; 95% CI, 1.37-2.11) and lymphovascular invasion (OR, 1.58; 95% CI, 1.23-2.03). CONCLUSIONS: Immune status was independently prognostic for the OS of patients with localized MCC. The etiology of IS may be associated with differential survival outcomes. Multiple adverse prognostic factors were associated with increased likelihood of IS. Immune status, and potentially the etiology of IS, may be useful prognostic factors to consider for future MCC staging systems.

Surface mould brachytherapy in oral and oropharyngeal cancers.

INTRODUCTION: There are insufficient data on surface mold brachytherapy (SMB) in treating oral cancers. We reviewed our institutional experience to investigate the efficacy and toxicity of this treatment modality. MATERIAL AND METHODS: We retrospectively reviewed all the patients treated between 1989 and 2018 with high-dose-rate iridium-192 SMB for oral and oropharyngeal squamous cell carcinomas at our institution. Surface mold brachytherapy was delivered via an acrylic surface mold with 1-5 inserted catheters spaced 1 cm apart fabricated by our dental oncologist. The Kaplan-Meier product estimator was used to assess local control (LC), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Cox proportional hazards regression analysis was used to assess the relationship of various variables and patient outcomes. RESULTS: Eighteen patients met the inclusion criteria and were evaluated. Indications for treatment were primary tumor (n = 13), local recurrence (2), locoregional recurrence (1), and oligometastatic disease (1). Ten patients received SMB alone and 8 received external beam radiotherapy with an SMB boost. The acute toxicity outcomes were as follows: no toxicity (n = 1), grade 1 (7), grade 2 (9), and grade 3 (1). Late effects were rare, only occurring in 3 patients. The one- and two-year LC were 81% and 68%, LRC 77% and 64%, DMFS 81% and 81%, and OS 77% and 46%. CONCLUSIONS: Surface mold brachytherapy is a viable modality as either primary or boost treatment for superficial oral cancers. In our patients, this treatment method has a low toxicity profile and resulted in reasonable LC.

Tumor infiltrating lymphocyte grade in Merkel cell carcinoma: relationships with clinical factors and independent prognostic value.

INTRODUCTION: Surrogate markers of the host immune response are not currently included in AJCC staging for Merkel cell carcinoma (MCC), and have not been consistently associated with clinical outcomes. We performed an analysis of a large national database to investigate tumor infiltrating lymphocyte (TIL) grade as an independent predictor of overall survival (OS) for patients with MCC and to characterize the relationship between TIL grade and other clinical prognostic factors. MATERIAL AND METHODS: The NCDB was queried for patients with resected, non-metastatic MCC with known TIL grade (absent, non-brisk and brisk). Multivariable Cox regression modeling was performed to define TIL grade as a predictor of OS adjusting for other relevant clinical factors. Multinomial, multivariable logistic regression was performed to characterize the relationship between TIL grade and other clinical prognostic factors. Multiple imputation was performed to account for missing data bias. RESULTS: Both brisk (HR 0.55, CI 0.36-0.83) and non-brisk (HR 0.77, CI 0.60-0.98) were associated with decreased adjusted hazard of death relative to absent TIL grade. Adverse clinical factors such as 1-3 positive lymph nodes, lymphovascular invasion (LVI) and immunosuppression were associated with increased likelihood of non-brisk TIL relative to absent TIL grade (p values <.05). Extracapsular extension (ECS) was associated with decreased likelihood of brisk TIL relative to absent TIL grade (p<.05). DISCUSSION: Histopathologic TIL grade was independently predictive for OS in this large national cohort. Significant differences in the likelihood of non-brisk or brisk TIL relative to absent grade were present with regards to LVI, ECS and immune status. TIL grade may be a useful prognostic factor to consider in addition to more granular characterization of TIL morphology and immunophenotype.

Immune status and the efficacy of radiotherapy on overall survival for patients with localized Merkel cell carcinoma: An analysis of the National Cancer Database.

BACKGROUND: Immunosuppressed (IS) patients with Merkel cell carcinoma (MCC) have worse outcomes compared to immunocompetent (IC) patients, and it is unclear if adjuvant radiotherapy (RT) is beneficial for these patients. We sought to determine the effect of immune status on adjuvant RT efficacy regarding overall survival (OS) for patients with localized MCC. METHODS: This was an observational study of National Cancer Database (NCDB) identifying patients with stage I/II or III MCC with known immune status diagnosed from 2010 to 2014. The median follow-up time was 29 months. OS was described using Kaplan-Meier methods and compared for subgroups by immune status and adjuvant RT using log-rank tests, multivariable Cox regression and interaction effect testing. RESULTS: A total of 2049 IC and 255 IS patients were included. Adjuvant RT was associated with decreased hazard of death for stage I/II MCC (HR 0.65, CI 0.54-0.78) adjusting for factors including immune status. Interaction effect testing did not demonstrate a significant difference in the effect of adjuvant RT on OS between IC and IS status in either stage I/II or III MCC (both P values > 0.05). CONCLUSIONS: In this observational study, adjuvant RT was associated with decreased hazard of death for patients with stage I/II MCC regardless of immune status. Adjuvant RT should be considered for both IS and IC patients with localized MCC.

Optimal adjuvant radiotherapy dose for stage I, II or III Merkel cell carcinoma: an analysis of the National Cancer Database.

BACKGROUND: We performed an analysis of the National Cancer Database to determine optimal doses of conventionally-fractionated adjuvant radiotherapy for patients with stage I/II or III Merkel cell carcinoma. METHODS: The cohort included 2735 patients with resected Merkel cell carcinoma of the head and neck, trunk or extremities receiving radiotherapy. Exclusion criteria included doses of radiotherapy <30 or >80 Gy, or dose per fraction >200 or <180 cGy. Recursive partitioning analysis and spline models were used to select dose thresholds. Multivariable Cox regression was performed to validate thresholds with respect to overall survival. RESULTS: Recursive partitioning analysis models defined a threshold of 57 Gy for stage I/II Merkel cell carcinoma, above which 3-year overall survival rate was decreased (P < 0.0001). The 3-year overall survival rate for patients receiving 50.0-57.0 Gy (81.2%) was greater compared to doses of 30.0-49.9 Gy (75.3%) or >57.0 Gy (70%, P < 0.0001). Doses > 57.0 Gy were associated with an increased hazard of death (1.31, confidence interval 1.07-1.60) with respect to doses of 50.0-57.0 Gy. Doses < 50.0 Gy for stage III Merkel cell carcinoma were associated with worsened 3-year overall survival (P < 0.0001) and increased hazard of death (2.01, confidence interval 1.43-2.82) with respect to doses between 50.0 and 57.0 Gy. CONCLUSIONS: Our results support doses of 50-57 Gy for most patients with stage I/II Merkel cell carcinoma receiving conventionally-fractionated adjuvant radiotherapy. In contrast to a prior National Cancer Database analysis, our results suggest doses ≥ 50 Gy should be strongly considered for patients with stage III Merkel cell carcinoma regardless of anatomic subsite.

Repair of a large primary subtemporal encephalocele in a 3-year-old child: case report.

Primary encephaloceles (PEs) present only rarely in the temporal region; in the rare instance that they project through the floor of the middle fossa they are secondary. In this case report the authors report on the management of a giant PE extending through the floor of the middle fossa.An 8-month-old boy presented to the authors' service with a large PE projecting into his neck through a missing left middle fossa floor; the lesion was causing significant meta-, dys-, and hypoplasia of the structures of the anterolateral neck on that side. Surgical goals for this patient included the following: 1) removal of potentially epileptogenic and dysfunctional tissue; 2) preservation of cranial nerves; 3) prevention of cognitive decline or iatrogenic deficit; 4) prevention of CSF leak; 5) reconstruction of skull base; 6) prevention of airway and swallowing compromise; and 7) cosmesis. After a multidisciplinary evaluation with ENT, plastic surgery, and neurology, an operation was performed using a preauricular infratemporal approach when the patient was 3 years old. Gliotic tissue was resected and amygdala, hippocampus, and middle cerebral artery were preserved.The immediate results of the operation showed good immediate outcome. Seizure freedom and neurodevelopment outcomes remain to be seen at follow-up.

Effects of adjuvant radiation therapy on survival for patients with resected primary tracheal carcinoma: an analysis of the National Cancer Database.

OBJECTIVE(S): To identify predictors for receiving adjuvant radiation therapy (RT) and investigate the impact of adjuvant RT on survival for patients with resected primary tracheal carcinoma (PTC). METHODS: The National Cancer database was queried for patients with PTC diagnosed from 2004 to 2014 undergoing resection. Patients who died within 30 days of resection were excluded to minimize immortal time bias. Kaplan-Meier methods, Cox regression modeling and propensity score weighted (PSW) log-rank tests were considered to assess the relationship between adjuvant RT and overall survival (OS). Logistic regression was performed to identify predictors associated with receiving adjuvant RT. RESULTS: A total of 549 patients were identified with 300 patients (55%) receiving adjuvant RT. Squamous cell carcinoma (SCC) was the most common histology with 234 patients (43%). Adenoid cystic carcinoma (ACC) was second most frequent with 180 patients (33%). Adjuvant RT was not associated with OS by multivariable Cox analysis or PSW log-rank test (P values > 0.05). Patients with positive surgical margins (odds ratio (OR) 1.80, confidence interval (CI) 1.06-3.07) were more likely to receive adjuvant RT than those with negative surgical margins. Patients with ACC (OR 6.53, CI 3.57-11.95) were more likely to receive adjuvant RT compared with SCC. CONCLUSIONS: Adjuvant RT was not significantly associated with OS for patients with resected PTC in this analysis. Surgical margin status and tumor histology were associated with receiving adjuvant RT. Further investigations including prospective registry studies capturing radiation technique and treatment volumes are needed to better define which patients with resected PTC may benefit from adjuvant RT.

Survival Impact of Time to Initiation of Adjuvant Radiation for Merkel Cell Carcinoma: An Analysis of the National Cancer Database.

PURPOSE: This study aimed to determine the impact of time to initiation (TTI) of adjuvant radiation therapy (RT) on overall survival (OS) for patients with stage I or II Merkel cell carcinoma (MCC). METHODS AND MATERIALS: The National Cancer Database was queried for patients with MCC of the head and neck, trunk, or extremities diagnosed between 2006 and 2014. Patients who did not undergo resection or receive adjuvant RT within 180 days of surgery were excluded. TTI was defined as the time from resection to first RT fraction. Linear regression was used to define factors associated with TTI. Recursive partitioning analysis modeling was performed to determine an optimal threshold for TTI. Cox proportional hazards modeling was performed to define covariates associated with OS. RESULTS: A total of 2293 patients were included in this study. The median TTI for the cohort was 62 days (interquartile range, 43-86 days). TTI was not associated with OS for the overall cohort by multivariable Cox modeling (P = .19). Age, treatment facility type, lymph node examination, anatomic subsite, and surgical margin were associated with TTI (P < .05). Age, sex, insurance status, Charlson-Deyo comorbidity score, lymph node examination status, tumor size, and surgical margin were associated with OS (all P < .05). CONCLUSIONS: Increased TTI of adjuvant RT was not associated with OS for patients with early stage MCC in this analysis of the National Cancer Database. The median TTI of 62 days from resection to adjuvant RT initiation for our study cohort contextualizes TTI on a national level and may offer reassurance for patients with prolonged postoperative wound healing or intercurrent illness delaying immediate RT initiation. Despite the lack of a clear detriment to survival with increased TTI up to 180 days from surgery, unnecessary delays in initiating adjuvant therapy should continue to be minimized while ensuring optimal recovery from resection.

Prognostic factors and selection criteria in the retreatment of head and neck cancers.

OBJECTIVES: To determine predictors of treatment selection, outcome, and survival, we examined a cohort of previously irradiated head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: We retrospectively analyzed 100 patients at our institution who were treated for recurrent or second primary (RSP) HNSCC, focusing on subgroups receiving reirradiation (ReRT) alone and those undergoing surgical salvage (SS) with or without post-operative reirradiation therapy (POReRT). Logistic regression modeling was performed to identify factors predictive of retreatment modality. Cox regression modeling was used to determine prognostic factors for progression free survival (PFS) and overall survival (OS). RESULTS: ReRT alone was less likely in current smokers and neck recurrences, with reirradiation more likely in primary site recurrences. POReRT was significantly more likely in patients with positive surgical margins (PSM), neck dissection, or organ dysfunction. POReRT omission negatively impacted PFS when PSM (HR: 8.894, 95% CI: 1.742-45.403) and perineural invasion (PNI) (HR: 3.391, 95% CI: 1.140-10.089) were present. Tracheostomy was associated with worse OS, but ReRT alone and POReRT improved OS. PSM correlated with worse OS, regardless of whether POReRT was given (HR: 14.260, 95% CI: 2.064-98.547). CONCLUSION: This analysis confirms known factors for predicting outcome and shows nonsmoking status and primary site recurrence as predictors for ReRT alone. POReRT for PSM and PNI improves PFS. Tracheostomy patients are more likely to have ReRT due to acute toxicity not limiting treatment and POReRT improves OS compared to surgery alone. The presence of PSM negatively impacts survival which cannot be overcome by POReRT.

Depressive symptoms and actigraphy-measured circadian disruption predict head and neck cancer survival.

OBJECTIVE: Depressive symptoms have demonstrated prognostic significance among head and neck cancer patients. Depression is associated with circadian disruption, which is prognostic in multiple other cancer types. We hypothesized that depressive symptoms would be associated with circadian disruption in head and neck cancer, that each would be related to poorer 2-year overall survival, and that relationships would be mediated by tumor response to treatment. METHODS: Patients (N = 55) reported on cognitive/affective and somatic depressive symptoms (PHQ-9) and wore an actigraph for 6 days to continuously record rest and activity cycles prior to chemoradiation. Records review documented treatment response and 2-year survival. Spearman correlations tested depressive symptoms and circadian disruption relationships. Cox proportional hazard models tested the predictive capability of depressive symptoms and circadian disruption, separately, on survival. RESULTS: Depressive symptoms were significantly associated with circadian disruption, and both were significantly associated with shorter survival (somatic: hazard ratio [HR] = 1.325, 95% confidence interval [CI] = 1.089-1.611, P = .005; rest/activity rhythm: HR = 0.073, 95% CI = 0.009-0.563, P = .012; nighttime restfulness: HR = 0.910, 95% CI = 0.848-0.977, P = .009). Tumor response to treatment appeared to partly mediate the nighttime restfulness-survival relationship. CONCLUSIONS: This study replicates and extends prior work with new evidence linking a subjective measure of depression and an objective measure of circadian disruption-2 known prognostic indicators-to shortened overall survival among head and neck cancer patients. Continued examination should elucidate mechanisms by which depressive symptomatology and circadian disruption translate to head and neck cancer progression and mortality.

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways.

BACKGROUND: Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. METHODS: Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. RESULTS: Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. CONCLUSIONS: Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018;124:1053-60. © 2018 American Cancer Society.

ACS NSQIP risk calculator reliability in head and neck oncology: The effect of prior chemoradiation on NSQIP risk estimates following laryngectomy.

PURPOSE: To determine whether inclusion of chemoradiation history increases estimated risk for complications following total laryngectomy using the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Surgical Risk Calculator. MATERIALS AND METHODS: A retrospective review of 96 patients with laryngeal cancer, approximately half of who had received prior chemoradiation, who underwent laryngectomy between January 2010 and December 2014. NSQIP estimates were calculated and compared to actual event occurrence using receiver operating characteristic (ROC) curves, Brier scores, and risk estimates. RESULTS: Patients who had received prior chemoradiation were at significantly greater risk for complication postoperatively (OR=2.63, 95% CI=1.145-6.043). NSQIP Calculator discriminability and accuracy were generally poor for this sample. While NSQIP estimates significantly predicted risk for any postoperative complication, pneumonia, and discharge to nursing care for primary laryngectomy patients, predictive capability was lost among salvage laryngectomy patients. NSQIP adjustments to both Somewhat Higher and Significantly Higher Risk categories did not improve predictive capability. Of the risk factors considered by NSQIP, preoperative functional status (p=0.041), age at time of surgery (p<0.008), and inclusion of neck dissection (p=0.035) emerged as significant predictors of actual postoperative complications, though again estimates lost significance among salvage laryngectomy patients. CONCLUSIONS: The NSQIP Calculator may be poorly calibrated to estimate postoperative complication risk for patients previously exposed to chemoradiation undergoing salvage laryngectomy. Caution should be used when estimating postoperative risk among patients undergoing salvage procedures, especially those of older age, poorer functional status, and those requiring neck dissection.

Neck dissection for unknown cancer of the head and neck in the era of chemoradiation.

PURPOSE: To report outcomes for patients with cervical lymph node metastases from an unknown primary site of the head and neck treated with either non-operative therapy or neck dissection followed by adjuvant therapy. MATERIALS AND METHODS: All patients with squamous cell carcinoma of an unknown primary site of the head or neck seen between 2003 and 2013 were reviewed. The Kaplan-Meier method was used to estimate overall survival, local recurrence free survival, loco-regional recurrence free survival, and progression free survival. The log-rank test and proportional hazards regression were used to analyze factors influencing outcomes. RESULTS: Of 2258 patients with a new diagnosis of head and neck cancer, no primary site was identified in 66 patients. Twenty-nine patients were treated with definitive non-operative therapy (15 with chemoradiation and 14 with radiation alone). Thirty-seven patients received an upfront neck dissection followed by adjuvant radiation or chemoradiation. Three-year loco-regional recurrence free survival, progression free survival, and overall survival were 55.9%, 55.4%, and 69.4% respectively. Patients treated with preoperative neck dissection had improved local recurrence free survival (96.7% vs 54.1%, p=0.003) and loco-regional recurrence free survival (82.2% vs 46.4%, p=0.068) compared to patients treated with definitive chemoradiation with no difference in overall survival (p=0.641). CONCLUSIONS: Neck dissection improved local and regional control but not overall survival in patients with unknown primary squamous cell carcinoma of the head and neck over non-operative therapy alone.

High-dose versus weekly cisplatin definitive chemoradiotherapy for HPV-related oropharyngeal squamous cell carcinoma of the head and neck.

OBJECTIVES: To compare the outcomes and toxicity of high-dose cisplatin (HDC) versus weekly cisplatin (WC) definitive chemoradiotherapy (CRT) for patients with human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (SCCOPx). METHODS: All patients with p16 positive SCCOPx treated with definitive CRT with cisplatin between 2010 and 2014 at a single institution were retrospectively reviewed. CTCAE v 4.03 toxicity criteria were used. The Kaplan-Meier method was used to estimate event-free survival (EFS) and the overall survival (OS). RESULTS: Of the 55 patients included, 22 were patients treated with HDC at dose of 100mg/m2 on days 1 and 22; and the remaining 33 patients were treated with WC at 40mg/m2. Both cohorts received a median total dose of cisplatin of 200mg/m2. At median follow-up of 31months, there was one local failure and no distant failures in the HDC cohort. In the WC group, there were 6 total failures (2 local, 4 distant). Estimated 2-year EFS was better in HDC cohort as compared to WC (96% vs. 75%; p=0.04). There was no significant difference in 2-year OS (95% vs. 94%; p=0.40). Weight loss, gastric tube dependence at six months, acute renal injury and grade 3 or 4 hematological toxicity were all similar between both groups. CONCLUSIONS: HPV-related SCCOPx treated with definitive CRT with either HDC or WC had similar toxicity profile. HDC had better EFS when compared with WC and this seems to be driven by increased distant failure rates, although the OS was similar.

Fungal contribution in chondroradionecrosis of the larynx.

OBJECTIVE: To assess the prevalence of invasive fungal elements in the specimens of patients who underwent salvage total laryngectomy for chondroradionecrosis (CRN) in the absence of recurrent or persistent malignancy. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary academic medical center. METHODS: One hundred fifty-nine patients were identified who underwent salvage total laryngectomy. Pathology reports were reviewed, and all laryngectomy specimens that did not contain residual malignancy were reevaluated for evidence of invasive fungal elements. RESULTS: Twelve of 159 (7.5%) patients who underwent total laryngectomy after primary radiotherapy or chemoradiotherapy had no evidence of residual malignancy. Each of these specimens contained histopathologic evidence of CRN; invasive fungal elements were identified in 25%. There was no statistical difference in demographic or treatment-related variables between patients who underwent salvage total laryngectomy with evidence of persistent or recurrent malignancy in the laryngectomy specimen versus patients without evidence of tumor on final histopathologic analysis. Patients with evidence of ulceration or necrosis in the laryngectomy specimen had reduced overall survival, irrespective of the presence of persistent malignancy (hazard ratio = 2.923, 95% confidence interval = 1.023-8.352, P = .045). CONCLUSION: Among salvage total laryngectomy patients, no difference was identified between patients who underwent total laryngectomy for recurrent or persistent malignancy after primary radiotherapy and those who received total laryngectomy without evidence of malignancy in their specimens. Invasive fungal elements were detected in several laryngectomy specimens that did not contain residual malignancy. Empiric antifungal therapy may therefore benefit patients diagnosed with CRN who are at risk for progression to nonfunctional larynx. Patients with evidence of ulceration or necrosis in the salvage laryngectomy specimen had worse overall survival. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:E159-E165, 2017.

Organ preservation with neoadjuvant chemoradiation in patients with orbit invasive sinonasal cancer otherwise requiring exenteration.

PURPOSE: We sought to determine if organ preservation (OP) with neoadjuvant chemoradiation (CRT) was feasible in patients with sinonasal cancer determined to require exenteration. MATERIALS AND METHODS: Twenty patients were determined to require exenteration for definitive treatment from 2005 to 2014. Fourteen patients underwent OP and 6 patients received exenteration with adjuvant CRT. Exenteration free survival (EFS), locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) were estimated. RESULTS: Five patients (36%) receiving OP had complete disease response at time of surgery. With a median follow-up of 18.8 months, EFS was 62% at 2 years for patients undergoing OP. At 2 years, there were no significant differences in LRC, PFS or OS (all all p > 0.050) between the groups. Less grade 3 or greater toxicity was seen in patients undergoing OP (p = 0.003). Visual function was preserved in all patients undergoing OP. CONCLUSION: For patients with sinonasal cancer, OP may avoid exenteration, offering similar disease control and improved toxicity.