A narrative review of oncologic emergencies in patients with head and neck cancers: initial management and the role of radiation therapy.

BACKGROUND AND OBJECTIVE: Head and neck cancers (HNCs) encompass a complex group of malignancies with high morbidity, often leading to critical emergencies such as pain crises, airway obstruction and hemorrhage. This review aims to outline an evidence-based approach to the multidisciplinary management of HNC oncologic emergencies with a focus on the role of emergent radiotherapy (RT). METHODS: A literature search was performed using Medline, Embase and the Cochrane Central Register of Controlled Trials databases with a focus on three common oncological emergencies using the following keywords: "head and neck cancer", "radiation OR radiotherapy", "pain", "bleeding OR haemorrhage", and "airway obstruction". All English language articles published up to April 2022 were screened to identify studies pertaining to the management of oncologic emergencies in HNC. KEY CONTENT AND FINDINGS: The management of oncologic emergencies in HNC present a unique set of challenges that require early recognition and aggressive treatment. In this narrative review, we summarize the evidence supporting the role of RT in the management of HNC patients presenting with pain crisis, malignant airway obstruction and acute haemorrhage. We demonstrate that while RT can be used as a primary or adjunct therapy, optimal management depends on the involvement of a multi-disciplinary team that includes head and neck surgeons, interventional radiology and palliative care. CONCLUSIONS: RT plays a critical role in the multidisciplinary management of HNC oncological emergencies. Further prospective and comparative studies are needed to assess optimal management strategies.

Outcomes for oligometastatic head and neck cancer treated with stereotactic body radiotherapy: Results from an international multi-institutional consortium.

BACKGROUND: We report the results of an international multi-institutional cohort of oligometastatic (OMD) head and neck cancer (HNC) patients treated with SBRT. METHODS: Patients with OMD HNC (≤5 metastases) treated with SBRT between 2008 and 2016 at six institutions were included. Treated metastasis control (TMC), progression-free survival (PFS), and overall survival (OS) were analyzed by multivariable analysis (MVA). RESULTS: Forty-two patients with 84 HNC oligometastases were analyzed. The TMC rate at 1 and 2 years were 80% and 66%, with a median time to recurrence of 10.1 months. The median PFS and OS were 4.7 and 23.3 months. MVA identified a PTV point maximum (BED)10 > 100 Gy as a predictor of improved TMC (HR = 0.31, p = 0.034), and a cumulative PTV > 48 cc as having worse PFS (HR = 2.99, p < 0.001). CONCLUSION: Favorable TMC and OS was observed in OMD HNCs treated with SBRT.

Dose-Escalated 2-Fraction Spine Stereotactic Body Radiation Therapy: 28 Gy Versus 24 Gy in 2 Daily Fractions.

PURPOSE: Stereotactic body radiation therapy (SBRT) for spine metastases improves pain response rates compared with conventional external beam radiation therapy; however, the optimal fractionation schedule is unclear. We report local control and toxicity outcomes after dose-escalated 2-fraction spine SBRT. METHODS AND MATERIALS: A prospectively maintained institutional database of over 600 patients and 1400 vertebral segments treated with spine SBRT was reviewed to identify those prescribed 28 or 24 Gy in 2 daily fractions. The primary endpoint was magnetic resonance imaging based local failure (LF), and secondary endpoints included overall survival and vertebral compression fracture (VCF). RESULTS: A total of 947 treated vertebral segments in 482 patients were identified, of which 301 segments in 159 patients received 28 Gy, and 646 segments in 323 patients received 24 Gy in 2 fractions. Median follow-up per patient was 23.5 months, and median overall survival was 49.1 months. In the 28 Gy cohort, the 6-, 12-, and 24-month cumulative incidences of LF were 3.5%, 5.4%, and 11.1%, respectively, versus 6.0%, 12.5%, and 17.6% in the 24 Gy cohort, respectively (P = .008). On multivariable analysis, 24 Gy (hazard ratio [HR], 1.525; 95% confidence interval, 1.039-2.238; P = .031), paraspinal disease extension (HR, 1.422; 95% confidence interval, 1.010-2.002; P = .044), and epidural extension in either radioresistant or radiosensitive histologies (HR, 2.117 and 1.227, respectively; P = .003) were prognostic for higher rates of LF. Risk of VCF was 5.5%, 7.6%, and 10.7% at 6, 12, and 24 months, respectively, and was similar between cohorts (P = .573). Spinal malalignment (P < .001), baseline VCF (P = .003), junctional spine location (P = .030), and greater minimum dose to 90% of planning target volume were prognostic for higher rates of VCF. CONCLUSIONS: Dose escalation to 28 Gy in 2 daily fractions was associated with improved local control without increasing the risk of VCF. The 2-year local control rates are consistent with those predicted by the Hypofractionated Treatment Effects in the Clinic spine tumor control probability model, and these data will inform a proposed dose escalation randomized trial.

Mature Local Control and Reirradiation Rates Comparing Spine Stereotactic Body Radiation Therapy With Conventional Palliative External Beam Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) improves complete pain response for painful spinal metastases compared with conventional external beam radiation therapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT versus cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control 24 phase 2/3 trial. METHODS AND MATERIALS: One hundred thirty-seven of 229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT and 71 patients (169 segments) treated with cEBRT. The primary outcomes were magnetic resonance-based local control and reirradiation rates for each treated spine segment. RESULTS: The median follow-up was 11.3 months (interquartile range, 5.3-27.7 months), and median overall survival in the SBRT and cEBRT cohorts were 21.6 (95% confidence interval [CI], 11.3, upper bound not reached) and 18.9 (95% CI, 12.2-29.1) months (P = .428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of mass (paraspinal and/or epidural disease extension). Risk of local failure after SBRT versus cEBRT at 6, 12, and 24 months were 2.8% (95% CI, 0.8%-7.4%) versus 11.2% (95% CI, 6.9%-16.6%), 6.1% (95% CI, 2.5%-12.1%) versus 28.4% (95% CI, 21.3%-35.9%), and 14.8% (95% CI, 8.2-23.1%) versus 35.6% (95% CI, 27.8%-43.6%), respectively (P < .001). cEBRT (hazard ratio [HR], 3.48; 95% CI, 1.94-6.25; P < .001) and presence of mass (HR, 2.07; 95% CI, 1.29-3.31; P = .002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT versus cEBRT were 2.2% (95% CI, 0.4-7.0%) versus 15.8% (95% CI, 10.4%-22.3%) (P = .002) and 22.9 months versus 9.5 months, respectively. cEBRT (HR, 2.60; 95% CI, 1.27-5.30; P = .009) and radioresistant histology (HR, 2.00; 95% CI, 1.12-3.60; P = .020) independently predicted for reirradiation. Eight of 12 iatrogenic vertebral compression fractures were after SBRT and 4 of 12 after cEBRT; grade 3 adverse fracture effects were isolated to the SBRT cohort (5 of 12). CONCLUSIONS: Risk of local failure and reirradiation is lower with SBRT compared with cEBRT for spinal metastases. Although the iatrogenic vertebral compression fracture rates were within expectations, grade 3 vertebral compression fractures were isolated to the SBRT cohort.

Curative intent Stereotactic Ablative Radiation Therapy (SABR) for treatment of lung oligometastases from head and neck squamous cell carcinoma (HNSCC): a multi-institutional retrospective study.

OBJECTIVES: The aim of this retrospective study was to assess outcomes of SABR for metachronous isolated lung oligometastases from HNSCC. METHODS: For patients who developed isolated, 1 or 2 lungs lesions (<5cm) consistent with metastases from HNSCC, the indication of SABR was validated in a multidisciplinary tumor board. All patients were monitored by CT or PET CT after SABR (Stereotactic Ablative Body Radiation) for HNSCC. RESULTS: Between November 2007 and February 2018, 52 patients were treated with SABR for metachronous lung metastases. The median time from the treatment of the primary HNSCC to the development of lung metastases was 18 months (3-93). The cohort's median age was 65.5 years old (50-83). The vast majority (94.2%) received 60 Gy in three fractions. Forty-one patients (78.5%) presented a solitary lung metastasis, while 11 patients (21.5%) had two lung metastases. With a median follow-up of 45.3 months, crude local and metastatic control rates were 74 and 38%, respectively. 1 year and 2 year Overall Survival (OS) were 85.8 and 65.9%, respectively. The median OS was 46.8 months. About one-fourth of patients were retreated by SABR for distant pulmonary recurrence. The treatment was well tolerated with only one patient who reported ≥ grade 3 toxicity (1.9%). CONCLUSION: In selected metastatic HNSCC patients, early detection and treatment of lung metastases with SABR is effective and safe. Prospective studies are required to validate this potential shift. ADVANCES IN KNOWLEDGE: Patients with oligometastases and controlled primary HNSCC seem to benefit from metastasis directed therapies.

Stereotactic body radiotherapy for head and neck skin cancer.

AIM: To report outcomes of Stereotactic Body Radiotherapy (SBRT) for head and neck skin cancer (HNSC) patients treated at a high-volume center. MATERIALS: A retrospective review of HNSC SBRT patients from 2012 to 2019 was conducted. Kaplan-Meier method was used to estimate local control (LC), locoregional control (LRC) outside of SBRT field, overall survival (OS), progression-free survival (PFS) and late toxicity (LT). Univariate and multivariate analyses were performed. Grade 3-4 acute and late toxicities were reported by the Common Terminology Criteria for Adverse Events v5.0. RESULTS: One hundred and six medically unfit HNSC patients (112 lesions) were included. Median follow-up was 8 months. Median patient age at diagnosis was 86 years (range: 56-102 years). The majority of patients had advanced disease (overall stage III-IV [n = 90, 85%]) with median gross tumor volumes (GTV) of 31 cm3 (range: 17-56 cm3). Treated sites were: primary (n = 51), nodal (n = 47) or primary plus nodal (n = 8). SBRT doses ranged from 32-50 Gy delivered twice weekly in 4-6 fractions to the gross tumor volume (GTV). One and 2-year LC rates were 78% (69-88) and 67% (53-82), respectively. One-year LRC outside of SBRT field, OS, PFS and LT rates were 72% (62-84), 53% (43-65), 52% (40-62), and 7% (2-17), respectively. Thirty-three patients (31%) developed acute grade ≥ 3 treatment-related toxicity, most commonly dermatitis (n = 31). Nine patients (8%) experienced late grade ≥ 3 toxicity, including 7 grade 3 fibrosis, 1 grade 3 bone radionecrosis and 1 grade 4 skin ulceration. No treatment-related deaths (grade 5) were observed. CONCLUSION: SBRT provides durable disease control with acceptable toxicity for medically unfit high-risk HNSC patients unable to undergo standard of care curative treatment approaches.

Evaluation of head and neck soft tissue sarcoma 8th edition pathologic staging system and proposal of a novel stage grouping system.

BACKGROUND: The AJCC 8th edition issued a dedicated staging system for head and neck soft tissue sarcomas (HN-STS) with 2 and 4 cm tumor cut-off points, as well as a T4 classification based on invasion of adjacent structures. Stage groupings were not provided due to a paucity of data. METHODS: We identified HN-STS patients undergoing primary surgery without neoadjuvant therapy patients in the Surveillance, Epidemiology, and End Results (SEER) database. We used multivariable analysis to examine adverse prognosticators. Then, using, recursive partitioning analysis (RPA), we established a stage grouping system that was externally validated in the National Cancer Database (NCDB). RESULTS: Multivariable analysis in the SEER cohort (N = 546) demonstrated worsened survival with tumors invading adjacent structures (P < 0.001) and increasing de-differentiation (P < 0.001). There was no prognostic difference based on size for T1-3 tumors; however, when assessed as a continuous variable, a 5 cm tumor size cut-off point was predictive of outcome. RPA generated a stage grouping system with the following five-year overall survival: RPA Stage I (pT1-3N0-1G1-2M0) 71.2%, RPA Stage II (pT4abN0-1G1-2M0/pT1-3N0-1G3-4M0) 53.4%, and RPA Stage III (pT4abN0-1G3-4M0) 17.5%. This was successfully externally validated in the NCDB cohort (P < 0.001). CONCLUSIONS: We confirm the importance of structural invasion and grade and demonstrate that the currently used size cut-off points are not prognostic. We propose a novel stage grouping system. A 5 cm tumor size cut-off point for tumor stage should be further evaluated.

Prognostic Factors Associated With Surviving Less Than 3 Months vs Greater Than 3 Years Specific to Spine Stereotactic Body Radiotherapy and Late Adverse Events.

BACKGROUND: Patient selection is critical for spine stereotactic body radiotherapy (SBRT) given potential for serious adverse effects and the associated costs. OBJECTIVE: To identify prognostic factors associated with dying within 3 mo, or living greater than 3 yr, following spine SBRT, to better inform patient selection. METHODS: Patients living ≤3 mo after spine SBRT and >3 yr after spine SBRT were identified, and multivariable regression analyses were performed. We report serious late toxicities observed, including vertebral compression fractures (VCF) and plexopathy. RESULTS: A total of 605 patients (1406 spine segments) were treated from 2009 to 2018. A total of 51 patients (8.4%) lived ≤3 mo, and 79 patients (13%) survived >3 yr. Significant differences in baseline features were observed. On multivariable analysis, nonbreast/prostate primaries (odds ratio [ORs]: 28.8-104.2, P = .0004), eastern cooperative oncology group (ECOG) ≥2 (OR: 23.7, 95% CI: 3.2-177, P = .0020), polymetastatic disease (OR: 6.715, 95% CI: 1.89-23.85, P = .0032), painful lesions (OR: 3.833-8.898, P = .0118), and paraspinal disease (OR: 2.874, 95% CI: 1.118-7.393, P = .0288) were prognostic for ≤3 mo survival. The 3- and 5-yr rates of VCF were 10.4% and 14.4%, respectively, and 3- and 5-yr rates of plexopathy were 2.2% and 5.1%, respectively. A single duodenal perforation was observed, and there was no radiation myelopathy events. CONCLUSION: Shorter survival after spine SBRT was seen in patients with less radiosensitive histologies (ie, not breast or prostate), ECOG ≥2, and polymetastatic disease. Pain and paraspinal disease were also associated with poor survival. Fractionated spine SBRT confers a low risk of late serious adverse events.

Local control and patterns of failure for "Radioresistant" spinal metastases following stereotactic body radiotherapy compared to a "Radiosensitive" reference.

PURPOSE: The concept of a radioresistant (RR) phenotype has been challenged with use of stereotactic body radiotherapy (SBRT). We compared outcomes following SBRT to RR spinal metastases to a radiosensitive cohort. METHODS: Renal cell, melanoma, sarcoma, gastro-intestinal, and thyroid spinal metastases were identified as RR and prostate cancer (PCA) as radiosensitive. The primary endpoint was MRI-based local failure (LF). Secondary endpoints included overall survival (OS) and vertebral compression fracture (VCF). RESULTS: From a prospectively maintained database of 1394 spinal segments in 605 patients treated with spine SBRT, 173 patients/395 RR spinal segments were compared to 94 patients/185 PCA segments. Most received 24-28 Gy in 2 fractions (68.9%) and median follow-up was 15.5 months (range, 1.4-84.2 months). 1- and 2-year LF rates were 19.2% and 22.4% for RR metastases, respectively, which were significantly greater (p < 0.001) than PCA (3.2% and 8.4%, respectively). Epidural disease (HR: 2.47, 95% CI 1.65-3.71, p < 0.001) and RR histology (HR: 2.41, 95% CI 1.45-3.99, p < 0.001) predicted for greater LF. Median OS was 17.4 and 61.0 months for RR and PCA cohorts, respectively. Lung/liver metastases, polymetastatic disease and epidural disease predicted for worse OS. 2-year VCF rates were ~ 13% in both cohorts. Coverage of the CTV V90 (clinical target volume receiving 90% of prescription dose) by ≥ 87% (HR: 2.32, 95% CI 1.29-4.18, p = 0.005), no prior spine radiotherapy (HR: 1.96, 95% CI 1.09-3.55, p = 0.025), and a greater Spinal Instability Neoplasia Score (p = 0.013) predicted for VCF. CONCLUSIONS: Higher rates of LF were observed after spine SBRT in RR metastases. Optimization strategies include dose escalation and aggressive management of epidural disease.

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

BACKGROUND: EBRT in resected, nonmetastatic anaplastic thyroid cancer (ATC) remains undefined. We evaluated patterns/outcomes with EBRT and chemotherapy in this setting. METHODS: This retrospective analysis included patients identified from the National Cancer Database with nonmetastatic ATC from 2004 to 2014 who underwent non-palliative resection. RESULTS: Our analysis included 496 patients, including 375 who underwent adjuvant EBRT (among whom 198 received concurrent chemotherapy). The median age was 68 years. On MVA, EBRT was associated with sex (OR 0.5, 95% CI 0.3-0.8, P = .002) and income (OR 2.2, 95% CI 1.4-3.3, P < .001). EBRT was associated with longer OS on UVA (12.3 vs 9.1 months, P = .004) and MVA (HR 0.7 [CI 0.6-0.9], P = .004). Concurrent chemoradiation was associated with longer OS on UVA (14.0 vs 9.1 months, P = .003) and MVA (HR 0.6 [CI 0.5-0.8], P < .001). CONCLUSION: Adjuvant EBRT is associated with longer OS in resected, nonmetastatic ATC, with additional improved survival with concurrent chemotherapy.

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

PURPOSE: Extranodal extension (ENE) is a well-established poor prognosticator and an indication for adjuvant treatment escalation in patients with head and neck squamous cell carcinoma (HNSCC). Identification of ENE on pretreatment imaging represents a diagnostic challenge that limits its clinical utility. We previously developed a deep learning algorithm that identifies ENE on pretreatment computed tomography (CT) imaging in patients with HNSCC. We sought to validate our algorithm performance for patients from a diverse set of institutions and compare its diagnostic ability to that of expert diagnosticians. METHODS: We obtained preoperative, contrast-enhanced CT scans and corresponding pathology results from two external data sets of patients with HNSCC: an external institution and The Cancer Genome Atlas (TCGA) HNSCC imaging data. Lymph nodes were segmented and annotated as ENE-positive or ENE-negative on the basis of pathologic confirmation. Deep learning algorithm performance was evaluated and compared directly to two board-certified neuroradiologists. RESULTS: A total of 200 lymph nodes were examined in the external validation data sets. For lymph nodes from the external institution, the algorithm achieved an area under the receiver operating characteristic curve (AUC) of 0.84 (83.1% accuracy), outperforming radiologists' AUCs of 0.70 and 0.71 (P = .02 and P = .01). Similarly, for lymph nodes from the TCGA, the algorithm achieved an AUC of 0.90 (88.6% accuracy), outperforming radiologist AUCs of 0.60 and 0.82 (P < .0001 and P = .16). Radiologist diagnostic accuracy improved when receiving deep learning assistance. CONCLUSION: Deep learning successfully identified ENE on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists with specialized head and neck experience. Our findings suggest that deep learning has utility in the identification of ENE in patients with HNSCC and has the potential to be integrated into clinical decision making.

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

BACKGROUND/AIM: This study aimed to evaluate the outcomes of patients with head and neck squamous cell carcinoma (HNSCC) who underwent resection and refused the recommended adjuvant therapy. PATIENTS AND METHODS: Locoregional recurrence-free survival (LRRFS) and time to progression (TTP) were assessed in HNSCC patients treated with surgery who declined some or all adjuvant therapy (refusal group (RG)) compared to those who received the recommended adjuvant therapy (TG). RESULTS: With a median follow-up of 23 months, the 2-year LRRFS was significantly lower in the 17 patients from the RG compared to the 152 patients from the TG: 23.1% vs. 69%, HR=0.30, 95% confidence incidence (CI)=0.15-0.59; p<0.001. The mean TTP was 12 months in the RG and was not reached in the TG (p<0.001). CONCLUSION: Patients with HNSCC who declined the recommended adjuvant therapy had a recurrence rate of 50% within a year.

Single-Fraction Stereotactic Radiosurgery Versus Hippocampal-Avoidance Whole Brain Radiation Therapy for Patients With 10 to 30 Brain Metastases: A Dosimetric Analysis.

PURPOSE: To compare normal tissue dosimetry between hippocampal-avoidance whole brain radiation therapy (HA-WBRT) and stereotactic radiosurgery (SRS) in patients with 10 to 30 brain metastases, and to describe a novel SRS strategy we term Spatially Partitioned Adaptive RadiosurgEry (SPARE). METHODS AND MATERIALS: A retrospective review identified SRS treatment plans with >10 brain metastases located >5 mm from the hippocampi. Our Gamma Knife Icon (GKI) SPARE (GKI-Spr) technique treats multiple metastases with single-fraction SRS partitioned over consecutive days while limiting the total treatment time to ≤60 minutes per day. Hippocampal and normal brain dosimetry were compared among GKI-Spr, single-fraction single-day GKI (GKI-Sfr), and 30 Gy in 10 fractions HA-WBRT. Dose metrics were converted to equivalent dose in 2 Gy fractions. RESULTS: Ten cases were analyzed. Compared with HA-WBRT, GKI-Spr significantly reduced the median equivalent dose in 2 Gy fractions hippocampal maximum point dose, mean dose, and dose to 40% of the hippocampi (D40%) by 86%, 93%, and 93%, respectively, and similarly for GKI-Sfr by 81%, 92%, and 91%, respectively. The normal brain median mean dose was reduced by 95% with GKI-Spr and 94% with GKI-Sfr. Compared with GKI-Sfr, GKI-Spr further reduced all normal brain and hippocampal dose metrics (P ≤ .014). CONCLUSIONS: GKI yields superior hippocampal and normal brain dosimetry compared with HA-WBRT, and GKI-Spr results in further dosimetric advantages.

Radiation therapy treatment facility and overall survival in the adjuvant setting for locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Treatment at high-volume surgical facilities (HVSFs) provides a survival benefit for patients with head and neck squamous cell carcinomas (HNSCCs); however, it is unknown what role postoperative radiation therapy (PORT) plays in achieving the improved outcomes. METHODS: From the National Cancer Database, 6844 patients with locally advanced invasive HNSCCs of the oral cavity, oropharynx, larynx, and hypopharynx who underwent definitive surgery with PORT between 2004 and 2013 were identified. HVSFs were those in the top percentile for annual case volume during this period. RESULTS: The median follow-up was 54 months. Compared with a lower volume surgical facility (LVSF), an HVSF improved 5-year overall survival (OS; 57.7% at HVSFs vs 52.5% at LVSFs; P = .0003). Overall, 31.6% of the patients changed their radiation therapy (RT) facility after surgery, with this being more common at HVSFs (39.1% vs 28.9% at LVSFs; P < .001). Among those patients undergoing surgery at an HVSF, remaining at the same facility for RT improved 5-year OS (63.1% vs 49.3% with a facility change; P < .0001). A propensity score-matched cohort of patients treated at HVSFs confirmed the improved 5-year OS when patients remained at the treating HVSF for RT (59.2% vs 50.7% with a facility change; P = .005). In a multivariate analysis, treatment at an HVSF and remaining there for RT resulted in a reduced hazard of death (hazard ratio, 0.81; 95% confidence interval, 0.69-0.94; P = .006). CONCLUSIONS: The survival benefit associated with HVSFs persists only when patients remain at the facility for RT, and this suggests that facility specialization and/or high-volume PORT may assist in driving the OS improvement.

HPV status in unknown primary head and neck cancer: Prognosis and treatment outcomes.

OBJECTIVES: Approximately 3% to 9% of head and neck cancer presents with a metastatic node and no identifiable primary tumor. These cases of head and neck carcinoma of unknown primary (HNCUP) present a therapeutic challenge. Therapy of this disease varies based on factors such as institutional, surgeon, and patient preference. Evidence demonstrating the outcomes associated with these therapies for HNCUP is limited, and among the available series, the tumor human papillomavirus (HPV) status is often ignored. Treatment deintensification has been proposed for a subset of these patients. We aim to evaluate the treatment-related outcomes for HPV-associated and HPV-negative HNCUP. METHODS: A retrospective study of 978 adult HNCUP diagnosed from 2010 to 2013 in the NCDB was conducted. Multivariate Cox survival regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: Patients with HPV-associated disease had superior survival, with a 3-year survival of 94.8% (standard error [SE]: 1.0), compared with 80.3% (SE: 2.9) among those with HPV-negative disease. Among HPV-negative patients with clinical nodal classification (cN)2/cN3 disease, treatment with definitive radiotherapy alone compared to definitive chemoradiotherapy was associated with diminished survival (hazard ratio 5.507, P = 0.005). Among patients with HPV-associated cancer and cN2/cN3 disease, all treatments (surgery alone, surgery with adjuvant radiotherapy, surgery with adjuvant chemoradiotherapy, definitive chemoradiotherapy, definitive radiotherapy) resulted in statistically equivalent survival. CONCLUSION: Tumor HPV status has a significant prognostic value for HNCUP and should be considered in future studies of treatment deintensification in this group. Treatment deintensification to radiotherapy alone in cN2/cN3 cases may result in poorer patient survival for HPV-negative patients, whereas it may be a promising option for further investigation in HPV-positive patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:684-691, 2019.

Patterns of failure in high-metastatic node number human papillomavirus-positive oropharyngeal carcinoma.

BACKGROUND: The 8th edition American Joint Committee on Cancer staging system for resected HPV-positive oropharynx carcinoma (HPV+ OPC) highlights high node number as a critical determinant of survival. We sought to characterize outcomes and patterns of failure in patients with high pathologically involved node number oropharynx cancer. METHODS: We retrospectively identified 116 HPV+ OPC patients sequentially treated with neck dissection and either resection or intraoperative brachytherapy of the primary tumor between 2010 and 2016. External beam radiation was given based on the pathologic findings. Cox proportional hazards regression was used for multivariate analysis. RESULTS: With a median follow-up of 27 months, the 3-year overall survival and progression free survival (PFS) were 89% and 81%, respectively. On multivariate analysis, ≥5 involved lymph nodes was significantly associated with worse PFS (hazard ratio 4.3, 95% confidence interval (CI) 1.5-12.0, P = 0.001). Rates of 3-year locoregional recurrence (LRR) in patients with ≤4 vs ≥5 were 6% and 22% (log-rank P = 0.12). Rates of 3-year distant metastases (DM) were 12% and 53% between ≤4 and ≥5 (log-rank P < 0.001). CONCLUSION: Our findings confirm that patients with 5 or more involved lymph nodes appear to have substantially worsened rates of disease recurrence. While these patients appear to be at high risk of both LRR and DM, the predominant mechanism of failure is distant, and the rate of DM in this group was over 50%. Dedicated clinical trials in this patient population are warranted with a focus on mitigating the high DM rate.

Pretreatment Identification of Head and Neck Cancer Nodal Metastasis and Extranodal Extension Using Deep Learning Neural Networks.

Identification of nodal metastasis and tumor extranodal extension (ENE) is crucial for head and neck cancer management, but currently only can be diagnosed via postoperative pathology. Pretreatment, radiographic identification of ENE, in particular, has proven extremely difficult for clinicians, but would be greatly influential in guiding patient management. Here, we show that a deep learning convolutional neural network can be trained to identify nodal metastasis and ENE with excellent performance that surpasses what human clinicians have historically achieved. We trained a 3-dimensional convolutional neural network using a dataset of 2,875 CT-segmented lymph node samples with correlating pathology labels, cross-validated and fine-tuned on 124 samples, and conducted testing on a blinded test set of 131 samples. On the blinded test set, the model predicted ENE and nodal metastasis each with area under the receiver operating characteristic curve (AUC) of 0.91 (95%CI: 0.85-0.97). The model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.