Telehealth as an Effective Care Delivery Method During the COVID-19 Pandemic for the Rhode Island Behavioral Health Population.

In response to the COVID-19 pandemic, Rhode Island implemented a telehealth waiver allowing telehealth parity. This study investigated (1) if telehealth allowed for patients who seek mental health services to maintain visit frequency and (2) if subpopulations were less likely to utilize telehealth. We used descriptive statistics to analyze the change in total number of visits, in-person visits from pre-waiver to post-waiver, and a multivariate linear regression to identify relationships between demographics and telehealth utilization. Participants were able to maintain the frequency of visits during the COVID-19 pandemic. Race/ethnicity, age, gender, employment status, and housing status were all statistically significant predictors of telehealth utilization. Telehealth aids in the continuing of care when in-person visits are not a viable option. Access to telehealth is crucial during public health emergencies and aids in maintaining visit frequency. Further research should be done to evaluate subgroups who are less likely to utilize telehealth.

Association between comorbid chronic pain or prior hospitalization for mental illness and substance use treatment among a cohort at high risk of opioid overdose.

INTRODUCTION: Chronic pain and serious mental illness increase risk of opioid use, and opioid use can exacerbate both conditions. Substance use disorder (SUD) treatment can be lifesaving, but chronic pain and serious mental illness may make recovery challenging. We evaluated the association between current chronic pain and prior hospitalization for mental illness and 90-day SUD treatment engagement, among emergency department (ED) patients at high risk of opioid overdose. METHODS: We conducted a cohort analysis of 648 ED patients enrolled in a randomized controlled trial in Rhode Island. We linked baseline study data on chronic pain and prior hospitalization for mental illness to statewide administrative data on state-licensed treatment programs (including methadone) and buprenorphine treatment via prescription. We defined treatment engagement as initiation of a state-licensed treatment program, transfer between state-licensed programs/providers, or a buprenorphine prescription (re-)fill. We used modified Poisson models to estimate the association between each baseline comorbidity and treatment engagement within 90 days following the ED visit, adjusted for a priori potential confounders. In an exploratory analysis, models were stratified by baseline treatment status. RESULTS: The mean age of participants was 37 years; 439 (68 %) were male, and 446 (69 %) had been recently unhoused. Overall, 278 participants (43 %) engaged in treatment within 90 days of the ED visit. Participants with prior hospitalization for mental illness were more likely to engage in treatment than those without (adjusted risk ratio [ARR] = 1.24, 95 % confidence interval [CI] = 1.01-1.53), although this association was only among those already accessing treatment at baseline (ARR = 1.58, 95 % CI = 1.10-2.27). Chronic pain was not associated with 90-day treatment engagement overall (ARR = 1.12, 95 % CI = 0.91-1.38) or within baseline treatment subgroups. CONCLUSIONS: Among ED patients at high risk of opioid overdose and accessing treatment at baseline, those with prior hospitalization for mental illness (but not chronic pain) were more likely to engage in treatment following the ED visit, which may reflect disproportionate initiation of additional treatment programs, transfer between programs/providers, or ongoing buprenorphine treatment. Touchpoints within the medical system should be leveraged to ensure that everyone, including those with serious mental illness, can access high-quality SUD treatment at the desired intensity level.

The impact of polysubstance use patterns on engagement of substance use disorder treatment among emergency department patients at high risk of opioid overdose.

Background: Substance use patterns are diverse, and multiple substances are often involved in fatal and nonfatal overdoses. Additionally, polysubstance use is associated with greater difficulty accessing and remaining in substance use disorder (SUD) treatment. The aim of this study was to identify substance use patterns and determine their association with SUD treatment engagement among emergency department (ED) patients at risk of opioid overdose. Methods: This was a sub-analysis of a randomized controlled trial comparing two behavioral interventions for individuals at two EDs in Rhode Island from 2018 to 2021. Past six-month substance use frequency for eight substances plus injection drug use was self-reported at trial enrollment, and SUD treatment engagement within 90 days after enrollment was obtained using administrative data linkages. Latent class analysis identified substance use patterns and multivariable log-binomial models estimated the association with SUD treatment engagement. Results: Among 607 participants, there were four substance use patterns: 1) low reported use (n = 295), 2) frequent injection and heroin use (n = 131), 3) high frequency broad polysubstance use (n = 62), and 4) low frequency broad polysubstance use (n = 119). Compared to participants with the low reported use pattern, those with the frequent injection and heroin pattern had a greater likelihood of SUD treatment engagement (adjusted risk ratio = 1.28; 95% confidence interval = 1.02-1.61). Conclusions: Distinct and meaningful polysubstance use patterns showed differential SUD treatment engagement after ED discharge. Nuanced relationships between substance use patterns and treatment highlight the necessity for tailored harm reduction, treatment, and recovery services.

Evaluation of a Statewide Policy to Improve Post-Overdose Care in Emergency Departments and Subsequent Treatment Engagement.

OBJECTIVE: To evaluate the impact of a statewide treatment standards policy for post-overdose emergency department (ED) care on services provided and subsequent treatment engagement. METHODS: This pre-/post-study used electronic health record data and surveillance data from Rhode Island. Outcomes were compared for patients attending EDs for opioid overdose before (03/1/2015-02/28/2017) and after (04/01/2017-03/31/2021) policy release. RESULTS: Overall, 2,134 patients attended 2,891 ED visits for opioid overdose. Compared to pre-policy, visits post-policy more often included initiation of buprenorphine in or from the ED (<1% vs. 3%, p<0.01), provision of a take-home naloxone kit or prescription (41% vs. 58%, p<0.01), and referral to treatment (0% vs. 34%, p<0.01). Provision of behavioral counseling in the ED and initiation of treatment within 30 days of the visit were similar during the two periods. CONCLUSIONS: Statewide post-overdose treatment standards may improve provision of some ED services. Additional strategies are needed to improve subsequent treatment engagement.

An evaluation of the association between specific post-overdose care services in emergency departments and subsequent treatment engagement.

Objective: The objective of this study was to estimate the association between receipt of specific post-overdose care services in the emergency department (ED) and subsequent engagement in treatment for opioid use disorder (OUD) after discharge. Methods: This was a retrospective cohort study of Rhode Island residents treated at 1 of 4 EDs for opioid overdose who were not engaged in OUD treatment and were discharged home (May 2016-April 2021). Electronic health record data were used to identify ED services received, and state administrative data were used to define subsequent engagement in OUD treatment within 30 days. Multivariable conditional logistic regression was used to estimate the association between ED services received and subsequent treatment engagement. Results: Overall, 1008 people not engaged in OUD treatment were treated at study EDs for opioid overdose and discharged home, of whom 146 (14%) subsequently engaged in OUD treatment within 30 days. Most patients were aged 25 to 44 years (59%) and non-Hispanic White (69%). Receipt of behavioral counseling in the ED (adjusted odds ratio [aOR] = 1.79, 95% confidence interval [CI] = 1.18-2.71) and initiation of buprenorphine treatment in/from the ED (aOR = 5.86, 95% CI = 2.70-12.71) were associated with treatment engagement. Receipt of a take-home naloxone kit or naloxone prescription and referral to treatment at discharge were not associated with treatment engagement. Overall, 49% of patients received behavioral counseling in the ED, and 3% initiated buprenorphine in/from the ED. Conclusion: Strategies for increasing provision of behavioral counseling and initiation of buprenorphine in the ED may be useful for improving subsequent engagement in OUD treatment after discharge.

Effect of a Peer-Led Behavioral Intervention for Emergency Department Patients at High Risk of Fatal Opioid Overdose: A Randomized Clinical Trial.

Importance: Fatal and nonfatal opioid overdoses are at record levels, and emergency department (ED) visits may be an opportune time to intervene. Peer-led models of care are increasingly common; however, little is known about their effectiveness. Objective: To evaluate the effect of a peer-led behavioral intervention compared with the standard behavioral intervention delivered in the ED on engagement in substance use disorder (SUD) treatment within 30 days after the ED encounter. Design, Setting, and Participants: This randomized clinical trial recruited 648 patients from 2 EDs from November 15, 2018, to May 31, 2021. Patients were eligible to participate if they were in the ED for an opioid overdose, receiving treatment related to an opioid use disorder, or identified as having had a recent opioid overdose. Interventions: Participants were randomly assigned to receive a behavioral intervention from a certified peer recovery specialist (n = 323) or a standard intervention delivered by a hospital-employed licensed clinical social worker (n = 325). A certified peer recovery specialist was someone with at least 2 years of recovery who completed a 45-hour training program and had 500 hours of supervised work experience. After the ED intervention, the certified peer recovery specialists offered continued contact with participants for up to 90 days. Main Outcomes and Measures: The primary outcome was receipt of SUD treatment within 30 days of enrollment, assessed with deterministic linkage of statewide administrative databases. Treatment engagement was defined as admission to a formal, publicly licensed SUD treatment program or receipt of office-based medication for opioid use disorder within 30 days of the initial ED visit. Results: Among the 648 participants, the mean (SD) age was 36.9 (10.8) years, and most were male (442 [68.2%]) and White (444 [68.5%]). Receipt of SUD treatment occurred for 103 of 323 participants (32%) in the intervention group vs 98 of 325 participants (30%) in the usual care group within 30 days of the ED visit. Among all participants, the most accessed treatments were outpatient medication for opioid use disorder (buprenorphine, 119 [18.4%]; methadone, 44 [6.8%]) and residential treatment (44 [6.8%]). Conclusions and Relevance: Overall, this study found that a substantial proportion of participants in both groups engaged in SUD treatment within 30 days of the ED visit. An ED-based behavioral intervention is likely effective in promoting treatment engagement, but who delivers the intervention may be less influential on short-term outcomes. Further study is required to determine the effects on longer-term engagement in SUD care and other health outcomes (eg, recurrent overdose). Trial Registration: ClinicalTrials.gov Identifier: NCT03684681.

Multimodality Management of EBV-Associated Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare cancer of the nasopharyngeal mucosa with a specific geographic predisposition. NPC is often associated with Epstein-Barr Virus (EBV) infection and as a result contains many characteristic biomarkers. Treatment of locally-contained NPC is generally achieved through use of radiotherapy (RT), as part of a multimodality treatment regimen. Induction chemotherapy followed by concurrent RT and platinum-based chemotherapy regimen has emerged as the definitive treatment of choice for locoregionally-advanced NPC. Recently, immunotherapy is finding a role in the treatment of recurrent or metastatic NPC. Immune checkpoint blockade therapies targeted against the programmed death-1 (PD-1) receptor have demonstrated efficacy in early phase clinical trials, with ongoing phase III trials in effect. Biomarkers for treatment efficacy remain an ongoing area of investigation, with important prognostic implications on the horizon.

History of Methadone and Buprenorphine Opioid Agonist Therapy Among People Who Died of an Accidental Opioid-Involved Overdose: Rhode Island, January 1, 2018-June 30, 2020.

To guide intervention efforts, we identified the proportion of individuals previously engaged in opioid agonist therapy among people who died of an accidental opioid-involved overdose. Most individuals (60.9%) had never received any prior buprenorphine or methadone treatment. Individuals who died of an overdose in 2020 had a similar demographic profile and treatment history compared with prior years. To prevent additional accidental opioid-involved overdose deaths, efforts should be directed toward linking individuals to care.

nab-Paclitaxel and cisplatin followed by cisplatin and radiation (Arm 1) and nab-paclitaxel followed by cetuximab and radiation (Arm 2) for locally advanced head and neck squamous-cell carcinoma: a multicenter, non-randomized phase 2 trial.

In locally advanced head and neck squamous-cell carcinoma (LA-HNSCC), clinical complete response (cCR) at the primary site, assessed by clinical examination, after induction chemotherapy predicts for a low relapse risk after subsequent chemoradiotherapy. Prior studies showed a cCR rate of 77% with induction nanoparticle albumin-bound (nab)-paclitaxel given with cisplatin and 5-fluorouracil (APF). The primary aims of this non-randomized phase 2 trial were to determine the cCR rate after induction nab-paclitaxel and cisplatin (Arm 1) and after nab-paclitaxel monotherapy (Arm 2). Eligibility required LA-HNSCC, T2-T4 stage classification, and suitable (Arm 1) or unsuitable (Arm 2) candidates for cisplatin. Arm 1 patients received nab-paclitaxel and cisplatin, then cisplatin with radiation. Arm 2 patients received nab-paclitaxel, then cetuximab with radiation. The primary endpoint was cCR after two cycles of induction chemotherapy. Each arm enrolled forty patients. cCR at the primary site occurred in 28 patients (70%) after nab-paclitaxel and cisplatin and in 8 patients (20%) after nab-paclitaxel monotherapy. The overall clinical response rate was 98% after nab-paclitaxel and cisplatin and 90% after nab-paclitaxel monotherapy. In subset analyses, cCR rates by T stage classifications (T2, T3, T4) were 54, 86, and 69% after nab-paclitaxel and cisplatin, and 14, 11, and 26% after nab-paclitaxel. cCR rates by human papillomavirus status (p16 positive oropharynx vs other) were 72 and 64% after nab-paclitaxel and cisplatin and 35 and 9% after nab-paclitaxel. The cCR rate after nab-paclitaxel and cisplatin was similar to APF; however, the cCR rate after nab-paclitaxel monotherapy was lower. The trial was registered at ClinicalTrials.gov NCT02573493 on October 9, 2015.

Factors Associated with Substance Use Disorder Treatment Completion, Rhode Island, USA, 2018.

INTRODUCTION: The successful retention of individuals with substance use disorders in treatment remains a challenge but is an important indicator of positive post-treatment outcomes. The aim of this study is to advance understanding of pre-admission factors associated with substance use treatment completion in Rhode Island. METHODS: Data for this longitudinal analysis are from the RI Behavioral Health On-Line Database (RI-BHOLD). The primary outcome of interest was substance use treatment completion defined as any planned discharge from treatment, including transfers to other facilities. Associations were assessed using generalized estimating equations (GEE) to account for the potential of repeated measures for the same individuals. RESULTS: Among the 7,351 clients discharged from a substance use treatment program in RI in 2018, the treatment completion rate was 58.1%. There was a positive relationship between the frequency of attendance of voluntary self-help groups and odds of treatment completion. Treatment completion rates were lower among those who reported use of opioids (AOR: 0.59; 95% CI: 0.52-0.66) and other drugs (AOR: 0.52; 95% CI: 0.44-0.62), compared to alcohol and for those with co-occurring mental health conditions (AOR: 0.85; 95% CI: 0.76-0.94). CONCLUSIONS: This study highlights the importance of social connectedness in substance use disorder treatment completion. Future research is needed to identify the characteristics of persons who are most likely to benefit from self-help groups and the optimal combination of treatment participation and attendance of self-help groups across a spectrum of disorder severity and community resources.

The Novel Use of a Commercially Available Video-Conference Platform to Facilitate Multidisciplinary Target Volume Review and Delineation for Skull-Base Radiation Therapy During the Coronavirus Disease 2019 Pandemic.

Multidisciplinary involvement in radiation therapy (RT) treatment planning is currently underused. A radiation oncologist sought input for generating target contours from a neuro-radiologist (NR) and otolaryngologist (OL) for 3 patients requiring skull-base RT during the coronavirus disease 2019 pandemic. A Health Insurance Portability and Accountability Act compliant virtual meeting between the radiation oncologist, NR, and OL was arranged. Involvement of the OL and NR led to significant changes in the clinical target volume for all patients. Our experience highlights the feasibility of using commercially available video-conference platforms for multidisciplinary target volume delineation for complex RT cases. Further applications include interdisciplinary contour review for RT cases requiring special expertise and joint attending/resident physician contour review for resident education. The video-conference platform technology has demonstrated benefit during the coronavirus disease 2019 pandemic, and we believe it will remain an integral component of our field moving forward.

Low-risk human papilloma virus positive oropharyngeal cancer with one positive lymph node: Equivalent outcomes in patients treated with surgery and radiation therapy versus surgery alone.

BACKGROUND: For human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), management recommendations for patients with a single metastatic lymph node <6 cm in diameter remain nebulous, leading to treatment heterogeneity in this common subgroup of patients. METHODS: We utilized the National Cancer Database to perform survival and multivariable analyses of patients with HPV+ OPSCC with one positive lymph node <6 cm and negative surgical margins. RESULTS: We found that 5-year survival is comparable between patients who receive surgery and adjuvant radiation versus surgery alone. In multivariable analyses, we found no significant difference in the hazard ratio of overall survival after adjusting for various potential confounders. CONCLUSIONS: These data suggest that patients with margin-negative HPV+ OPSCC with a single positive lymph node <6 cm have comparable survival with or without adjuvant radiation. Future studies exploring outcomes for this specific group in randomized-controlled trials will be critical for further evaluating these initial observations.

Regional lymph node irradiation in locally advanced Merkel cell carcinoma reduces regional and distant relapse and improves disease-specific survival.

BACKGROUND: One-third of patients with Merkel cell carcinoma (MCC) present with locally advanced disease involving the regional lymph nodes, but indications for regional lymph node radiation therapy (rLN-RT) are not well established. MATERIALS AND METHODS: 72 patients with locally advanced MCC were retrospectively reviewed. Regional lymph nodes were addressed with observation, lymph node dissection (LND) alone, definitive nodal radiotherapy (DnRT), or LND plus adjuvant nodal radiotherapy (AnRT). Cox regression was used to compare treatment modalities in terms of regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS) and disease-specific survival (DSS). RESULTS: rLN-RT, including both DnRT and AnRT, improved RRFS (Hazard ratio (HR): 0.07, 95% confidence interval (CI): 0.01-0.40, p = 0.003), DRFS (HR: 0.28, CI: 0.11-0.76, p = 0.01), DFS (HR: 0.23, CI: 0.09-0.58, p = 0.002), and DSS (HR: 0.23, CI: 0.06-0.90, p = 0.03). AnRT improved DFS and DSS in high-risk subgroups (e.g., extranodal extension (ENE), ≥ 2 positive lymph nodes, or bulkier lymph nodes). The benefit of AnRT increased with higher disease burden. After controlling for these adverse factors, AnRT significantly improved RRFS (HR: 0.04, CI: 0.01-0.37, p = 0.004), DRFS (HR: 0.14, CI: 0.04-0.50, p = 0.003), DFS (HR: 0.09, CI: 0.02-0.33, p < 0.001), and DSS (HR: 0.21, CI: 0.05-0.89, p = 0.03). CONCLUSION: rLN-RT, including both DnRT and AnRT, reduces relapse and death from MCC in patients with node-positive disease. AnRT is particularly beneficial for patients with ENE, multiple involved lymph nodes, or larger nodal foci of disease. These results argue for more liberal use of nodal RT for MCC patients who present with node-positive disease.

Reduced Wide Local Excision Margins are Associated with Increased Risk of Relapse and Death from Merkel Cell Carcinoma.

INTRODUCTION: Current recommendations regarding the size of wide local excision (WLE) margins for Merkel cell carcinoma (MCC) are not well established. METHODS: WLE and pathologic margins were respectively reviewed from 79 patients with stage I or II MCC, who underwent WLE at Washington University in St Louis from 2005 to 2019. Outcomes included local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distant recurrence-free survival (DRFS), disease-free survival (DFS), and disease-specific survival (DSS). RESULTS: Thirty-two percent of patients received adjuvant radiotherapy (aRT). At 1 year, DFS was 51.3%, 71.4%, and 87.8% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). At 3 years, the DSS was 57.7%, 82.6%, and 100% for patients with WLE margins < 1 cm, 1-1.9 cm, and ≥ 2 cm, respectively (p = 0.02). Multivariable Cox analysis demonstrated that every 1-cm increase in WLE margins was associated with improved RRFS [hazard ratio (HR) = 0.28, 95% confidence interval (CI): 0.11-0.75], DRFS (HR 0.30, CI 0.08-0.99), DFS (HR 0.42, CI 0.21-0.86), and DSS (HR 0.16, CI 0.04-0.61). WLE and pathologic margin size were moderately-to-strongly correlated (r = 0.66). Close or positive pathologic margins (< 3 mm) were associated with reduced DRFS (HR 6.83, CI 1.80-25.9), DFS (HR 2.98, CI 1.31-6.75), and DSS (HR 3.52, CI 1.14-10.9). CONCLUSION: Reduced WLE and pathologic margins were associated with higher risk of relapse and death from MCC. Larger WLE margins are important in populations with lower rates of adjuvant radiation.

Outcomes of Patients With Single-Node Metastasis of Human Papillomavirus-Related Oropharyngeal Cancer Treated With Transoral Surgery.

Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known. Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery. Design, Setting, and Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020. Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73). Main Outcomes and Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival. Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival. Conclusions and Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment.

Radiation and Checkpoint Inhibitor Immunotherapy Lead to Long Term Disease Control in a Metastatic RCC patient With Brain Metastases.

Renal cell carcinoma (RCC) comprises 4.2% of all new cancer cases in the United States and 30% of cases are metastatic (mRCC) at diagnosis. Brain metastatic RCC historically has poor prognosis, but the development of immune checkpoint inhibitors has revolutionized their care and may be successfully combined with SBRT to improve prognosis. Here, we present a case of a patient with mRCC who had brain metastases treated with concurrent immune checkpoint inhibitors and SBRT. He continues to survive with good functional status years following his initial diagnosis. We discuss the relevant history regarding treatment approach in patients with brain metastatic RCC, ongoing trials focusing on the combination of immunotherapy and radiation, and the potential and promise of the abscopal effect.

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial.

PURPOSE: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC. PATIENTS AND METHODS: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10%-49%), and pTR-2 (≥50%). Coprimary endpoints were pTR-2 among all patients and 1-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 and T-cell infiltration with pTR were assessed. Tumor clonal dynamics were evaluated (ClinicalTrials.gov NCT02296684). RESULTS: Thirty-six patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). One-year relapse rate among 18 patients with high-risk pathology was 16.7% (95% confidence interval, 3.6%-41.4%). pTR ≥10% correlated with baseline tumor PD-L1, immune infiltrate, and IFNγ activity. Matched samples showed upregulation of inhibitory checkpoints in patients with pTR-0 and confirmed clonal loss in some patients. CONCLUSIONS: Among patients with locally advanced, HPV-unrelated HNSCC, pembrolizumab was safe, and any pathologic response was observed in 44% of patients with 0% pathologic complete responses. The 1-year relapse rate in patients with high-risk pathology was lower than historical.

Duration of radiation therapy is associated with worse survival in head and neck cancer.

INTRODUCTION: Delays in radiation are multifactorial, frequent, and associated with poor outcomes. This study investigates the effect of both primary and adjuvant radiation therapy duration and their interaction with other measures of treatment delay on survival in head and neck squamous cell carcinoma (HNSCC). METHODS: We built a retrospective cohort using the National Cancer Database, consisting of primary oral cavity, hypopharynx, larynx and oropharynx squamous cell carcinoma without distant metastasis and with at least six weeks of radiation. The primary exposure was the duration of radiation therapy (DRT), and the primary outcome was death. We estimated the association between DRT and 5-year overall survival (OS) using Kaplan-Meier curves and hazard ratios (HRs) with Cox proportional hazard regression. RESULTS: In both primary (definitive) and adjuvant (post-surgical) radiation settings, increased DRT results in decreased survival. In the primary radiation cohort, 5-year OS was 59.7% [59.1%-60.3%] among those with 47-53 days DRT, which decreased significantly with each subsequent week to completion (81+ days: 38.4% [36.2%-40.7%]). In the surgical cohort, survival decreased 16.5% when DRT extended beyond 75 days (40-46 days: 68.2% [67.3%-69.1%] vs. 75+ days: 53.3% [50.1%-56.7%]). Multivariate analyses showed increased hazard of death with increased DRT (primary radiation: 81+ days HR: 1.69 [1.58-1.81]); surgical: 75+ days HR: 1.61 [1.37-1.88]), with effects intensifying when restricting to those receiving full-dose radiation. CONCLUSION: A prolonged DRT was associated with worse OS in head and neck cancer. Radiation treatment delays of even a week lead to a significant survival disadvantage. DRT had a stronger association with survival than time to initiation of postoperative adjuvant radiotherapy.