Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer.

Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors' knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384.

Patterns of neurological adverse events among a retrospective cohort of patients receiving immune checkpoint inhibitors.

Aim: Neurological adverse events (NAEs) are infrequent immune checkpoint inhibitor (ICI) outcomes poorly characterized in extant research, complicating their clinical management. Methods: This study characterized the frequency, severity, patterning and timing of NAEs using a large retrospective registry, including all patients who received at least one dose of an ICI from 2/1/2011-4/7/2022 within our health network. Results: Among 3137 patients, there were 54 NAEs (1.72% any grade; 0.8% grade 3-4). Most NAEs were peripheral (57.4%) versus central (42.6%). Melanoma and renal cell carcinoma were significantly associated with NAEs. Conclusion: The incidence of NAEs was rare though higher than many prior case estimates; the timing was consistent with other AEs. NAEs frequently occurred in tumor types known to favor brain metastases.

Immune checkpoint inhibitors are new drugs for cancer. They boost your body's defenses to fight cancer cells. These drugs can be used alone or with other cancer treatments. Most people are okay with these medicines, but some might have problems in different parts of the body. This can be tricky to figure out. Rarely, there can be issues in the brain or nerves. These side effects are rare, happening in about 2 in every 100 people who use the drugs. They are more common in certain cancers like melanoma and kidney cancer. As doctors learn more about these side effects, they can better predict, treat, and prevent them.

The Association Between an Electronic Health Record (EHR)-Embedded Frailty Index and Patient-Reported Outcomes Among Patients with Metastatic Non-Small-Cell Lung Cancer on Immunotherapy: A Brief Report.

Background: While frailty is a well-established predictor of overall mortality among patients with metastatic non-small cell lung cancer (mNSCLC), its association with patient-reported outcomes is not well-characterized. The goal of this study was to examine the association between an electronic frailty index (eFI) score and patient-reported outcome measures along with prognostic awareness among patients with mNSCLC receiving immunotherapy. Methods: In a cross-sectional study, patients with mNSCLC who were on immunotherapy completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). We utilized bivariate analyses to compare quality of life, symptoms, supportive services, and prognostic awareness among 3 groups defined by e-frailty status. Results: Sixty patients (mean age 62.5 years, 75% Caucasian, 60% women) participated. Most patients were pre-frail (68%), with 13% being frail and 18% non-frail. Pre-frail and frail patients had significantly lower physical function scores (mean 83.9 fit vs 74.8 pre-frail vs 60.0 frail, P = .04) and higher rates of self-reported pain (75% frail vs 41.5% pre-frail vs 18.2% fit; P = .04) compared to non-frail patients. We found no differences in palliative referral rates. Conclusion: Pre-frail and frail mNSCLC patients identified by the eFI have higher rates of pain and physical functional impairments than non-frail patients. These findings highlight the importance of emphasizing preventive interventions targeting social needs, functional limitations, and pain management, especially among pre-frail patients to reduce further decline.

Use of comprehensive genomic profiling for biomarker discovery for the management of non-small cell lung cancer brain metastases.

Background: Clinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests. Method: In this single institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score. Results: Seventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes. Conclusion: Genetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future. Statement of translation relevance: Using Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.

Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer.

Effective treatments for advanced/recurrent head and neck squamous-cell carcinoma are limited. For cases not curable by conventional local therapies, the immune checkpoint inhibitor pembrolizumab shows modest response rates. Quad-shot, a hypofractionated palliative radiotherapy regimen (14.8 Gy in four twice-daily fractions), can provide symptomatic relief, contributes to local control and may potentiate the effects of immune checkpoint inhibitors. In this study, 15 patients with advanced/recurrent head and neck squamous-cell carcinoma will be treated with pembrolizumab combined with up to three administrations of quad-shot before cycles four, eight and 13. Outcomes include disease response, survival and treatment toxicity. Correlative multiomics analysis of blood and saliva will identify molecular biomarkers of response to immune checkpoint inhibitor and the immune-related impact of quad-shot. Clinical trial registration: This study (WFBCCC 60320) is registered on NCT04454489 (ClinicalTrials.gov).

Advanced and recurrent head and neck cancers are difficult to treat. Most patients receive systemic therapies, such as chemotherapy or immunotherapy, with modest rates of cancer control. We aim to test the effectiveness of an immunotherapy drug called pembrolizumab in combination with a type of low-dose radiation therapy called quad-shot. Patients will receive pembrolizumab every 3 weeks and will be treated with one to three low-dose radiation therapy courses targeted at their cancer in the head and neck approximately every 12 weeks. We plan to measure how well the cancer responds to treatment, how long this response lasts, how long patients survive and treatment side effects.

c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities.

The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.

A Novel Workflow to Create a Checkpoint Inhibitor Pneumonitis Patient Registry.

Background Despite being a groundbreaking cancer therapy, immune checkpoint inhibitors (ICI) can lead to potentially life-threatening toxicity with checkpoint inhibitor pneumonitis (CIP). While treatable, it is easy for clinicians to miss the symptoms of CIP, which can lead to a delay in diagnosis and worsening respiratory function. There is no consensus approach to systematically identifying patients at risk of developing CIP. Thus, we sought to create a workflow that could inform patient selection for ICI therapy based on previously reported risk factors for CIP development. Materials and methods We retrospectively identified 250 patients with lung cancer treated with at least one dose of an ICI over 20 months. Data were collected on comorbidities, cancer type and stage, performance status, ICI cycles, biomarkers, prior curative treatment, diagnostic evaluation, antibiotics, steroids, progression, and survival. A single-blinded radiologist characterized radiographic patterns of suspected CIP cases. Results Among 97 patients who received steroids while admitted to the hospital, 12 (6%) had at least one sign or symptom suggestive of CIP. Chronic obstructive pulmonary disease and non-small cell lung cancer subtypes correlated with suspicion of having CIP. CIP was confirmed in five patients (42%) and ruled out (mimics) in seven (58%). Median times until symptoms were 17 months and one month for confirmed and mimic cases, respectively. The median time to confirm or exclude CIP was 5 ± 4 days. Most suspected cases underwent thoracic imaging, blood cultures, and empiric antibiotics. Radiographic patterns in suspected cases included ground glass opacities, organizing pneumonia, acute interstitial pneumonia/acute respiratory distress syndrome, bronchiolitis, radiation recall pneumonitis, hypersensitivity pneumonitis, and post-radiation fibrotic changes. Conclusions CIP mimics are common in clinical practice; therefore, it is reasonable to empirically treat suspected cases with shorter courses of steroids until diagnostic clarity is achieved. This proof-of-concept study demonstrates that this novel workflow can identify the true incidence of CIP, inform treatment decisions, and lead to the development of implementation studies to improve patient care directly.

Prognostic Mutational Signatures of NSCLC Patients treated with chemotherapy, immunotherapy and chemoimmunotherapy.

Different types of therapy are currently being used to treat non-small cell lung cancer (NSCLC) depending on the stage of tumor and the presence of potentially druggable mutations. However, few biomarkers are available to guide clinicians in selecting the most effective therapy for all patients with various genetic backgrounds. To examine whether patients' mutation profiles are associated with the response to a specific treatment, we collected comprehensive clinical characteristics and sequencing data from 524 patients with stage III and IV NSCLC treated at Atrium Health Wake Forest Baptist. Overall survival based Cox-proportional hazard regression models were applied to identify mutations that were "beneficial" (HR < 1) or "detrimental" (HR > 1) for patients treated with chemotherapy (chemo), immune checkpoint inhibitor (ICI) and chemo+ICI combination therapy (Chemo+ICI) followed by the generation of mutation composite scores (MCS) for each treatment. We also found that MCS is highly treatment specific that MCS derived from one treatment group failed to predict the response in others. Receiver operating characteristics (ROC) analyses showed a superior predictive power of MCS compared to TMB and PD-L1 status for immune therapy-treated patients. Mutation interaction analysis also identified novel co-occurring and mutually exclusive mutations in each treatment group. Our work highlights how patients' sequencing data facilitates the clinical selection of optimized treatment strategies.

Prognostic Awareness, Palliative Care Use, and Barriers to Palliative Care in Patients Undergoing Immunotherapy or Chemo-Immunotherapy for Metastatic Lung Cancer.

Background and Objectives: This study describes patients' prognostic awareness and palliative care use in the setting of immunotherapy for metastatic non-small cell lung cancer (mNSCLC). Design: We surveyed 60 mNSCLC patients receiving immunotherapy at a large academic medical center; conducted follow-up interviews with 12 survey participants; and abstracted palliative care use, advance directive completion, and death within a year of survey completion from the medical record. Results: Forty seven percent of patients surveyed thought they would be cured; 83% were not interested in palliative care. Interviews suggested oncologists emphasized therapeutic options when discussing prognosis and that commonly used descriptions of palliative care may exacerbate misperceptions. Only 7% had received outpatient palliative care and 8% had an advance directive a year after the survey; only 16% of the 19 patients who died had received outpatient palliative care. Conclusions: Interventions are needed to facilitate prognostic discussions and outpatient palliative care during immunotherapy. Clinical Trial Registration Number NCT03741868.

Team-Based Hospice Referrals: A Potential Quality Metric for Lung Cancer in the Immunotherapy Era.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can lead to durable responses in patients with lung cancer but may delay transitions to hospice at the end of life (EOL). We aimed to test the association of continuity of care with EOL outcomes in the ICI era. METHODS: We collected retrospective data on all patients with lung cancer who started ICI treatment at a single comprehensive cancer center in the United States (1/1/14-5/1/18) and subsequently died. We defined a hospice referral as having continuity of care if placed by a provider from the patient's multidisciplinary cancer team (e.g., a medical oncologist, palliative care specialist, intensivist, and hospitalist). RESULTS: In this cohort of 143 patients, 58% had a team-based hospice referral which was associated with a lower risk of death in the hospital. The most common reason patients declined hospice at EOL was an unwillingness to discontinue cancer-directed therapy. As compared to a similar historical cohort of patients treated with chemotherapy alone (2008-2010), there was a similar rate of hospice referral (68% vs 74%) but higher rates of new systemic therapy initiated within 30 days of death (17% vs 6%, p .001) and last dose within 14 days of death (13% vs 5%, p .005). CONCLUSIONS: Future studies should test the continuity of care at EOL as a new quality metric for advanced NSCLC.

A Case Report of Immune Checkpoint Inhibitor-Induced Aortitis Treated with Tocilizumab.

Vasculitic immune checkpoint inhibitor-related adverse events (irAEs) are rare, with limited data to guide their management. Here, we present a case of a 67-year-old female with stage IV cutaneous melanoma who received first-line pembrolizumab. She had completed 21 cycles of pembrolizumab dosed at 200 mg every 21 days over 15 months when she developed fatigue, chills, decreased appetite, night sweats, nausea, diarrhea, dry cough, and chest pain. A routine, staging positron emission tomography (PET) scan revealed aortitis of the transverse aortic arch. An extensive workup was unremarkable for other causes, so her condition was labeled a grade III immune-related vasculitis. Based on this diagnosis, we started high-dose prednisone and discontinued pembrolizumab. After two months of high-dose prednisone, she developed bothersome weight gain and insomnia, leading to a switch from prednisone to tocilizumab as a steroid-sparing agent. The selection of tocilizumab was based on its routine use for giant cell arteritis which can have extracranial symptoms including thoracic aortitis. Her symptoms resolved, and subsequent PET scans showed resolution of the aortitis and no evidence of metastatic melanoma. As the indications for immunotherapy expand, rare complications are becoming more prevalent, and more data will be needed to guide their management. While there is evidence for tocilizumab use as a steroid-sparing treatment for large-vessel vasculitides due to other conditions, this is the first case of its use to treat an aortitis irAE to our knowledge. In this case, it was an effective means of treating the patient while sparing them from prolonged corticosteroids.

Early [18]FDG PET/CT scan predicts tumor response in head and neck squamous cell cancer patients treated with erlotinib adjusted per smoking status.

Translational Relevance: Evaluation of targeted therapies is urgently needed for the majority of patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC) who progress after immunochemotherapy. Erlotinib, a targeted inhibitor of epidermal growth factor receptor pathway, lacks FDA approval in HNSCC due to inadequate tumor response. This study identifies two potential avenues to improve tumor response to erlotinib among patients with HNSCC. For the first time, this study shows that an increased erlotinib dose of 300 mg in smokers is well-tolerated and produces similar plasma drug concentration as the regular dose of 150 mg in non-smokers, with increased study-specific defined tumor response. The study also highlights the opportunity for improved patient selection for erlotinib treatment by demonstrating that early in-treatment [18]FDG PET/CT is a potential predictor of tumor response, with robust statistical correlations between metabolic changes on early in-treatment PET (4-7 days through treatment) and anatomic response measured by end-of-treatment CT. Purpose: Patients with advanced HNSCC failing immunochemotherapy have no standard treatment options. Accelerating the investigation of targeted drug therapies is imperative. Treatment with erlotinib produced low response rates in HNSCC. This study investigates the possibility of improved treatment response through patient smoking status-based erlotinib dose optimization, and through early in-treatment [18]FDG PET evaluation to differentiate responders from non-responders. Experimental design: In this window-of-opportunity study, patients with operable HNSCC received neoadjuvant erlotinib with dose determined by smoking status: 150 mg (E150) for non-smokers and 300 mg (E300) for active smokers. Plasma erlotinib levels were measured using mass spectrometry. Patients underwent PET/CT before treatment, between days 4-7 of treatment, and before surgery (post-treatment). Response was measured by diagnostic CT and was defined as decrease in maximum tumor diameter by ≥ 20% (responders), 10-19% (minimum-responders), and < 10% (non-responders). Results: Nineteen patients completed treatment, ten of whom were smokers. There were eleven responders, five minimum-responders, and three non-responders. Tumor response and plasma erlotinib levels were similar between the E150 and E300 patient groups. The percentage change on early PET/CT and post-treatment PET/CT compared to pre-treatment PET/CT were significantly correlated with the radiologic response on post-treatment CTs: R=0.63, p=0.0041 and R=0.71, p=0.00094, respectively. Conclusion: This pilot study suggests that early in-treatment PET/CT can predict response to erlotinib, and treatment with erlotinib dose adjusted according to smoking status is well-tolerated and may improve treatment response in HNSCC. These findings could help optimize erlotinib treatment in HNSCC and should be further investigated. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00601913, identifier NCT00601913.

Intensity-modulated radiotherapy with planned Gamma Knife radiosurgery boost for head and neck cancer with extensive disease in proximity to critical structures.

BACKGROUND: To describe intensity-modulated radiotherapy (IMRT) with Gamma Knife Radiosurgery (GKRS) boost for locally advanced head and neck cancer (HNC) with disease near dose-limiting structures. METHODS: Patients with HNC treated with IMRT/GKRS as part of a combined modality approach between 2011 and 2021 were reviewed. Local control, overall survival and disease-specific survival were estimated using the Kaplan Meier method. RESULTS: Twenty patients were included. Nineteen patients had T3-4 tumors. Median follow-up was 26.3 months. GKRS site control was 95%. Two patients progressed at the treated primary site, one patient failed at the edge of the GKRS treatment volume, with no perineural or intracranial failure. 2-year OS was 94.7% (95% CI: 85.2%-100%). Concurrent chemotherapy was given in nine patients (45%). One patient (5%) received induction/concurrent chemotherapy. Brain radionecrosis occurred in three patients, one of which was biopsy-proven. CONCLUSIONS: IMRT plus GKRS boost results in excellent disease control near critical structures with minimal toxicity.

Local control outcomes for combination of stereotactic radiosurgery and immunotherapy for non-small cell lung cancer brain metastases.

BACKGROUND: Previous series have demonstrated CNS activity for immune checkpoint inhibitors, yet no prior data exists regarding whether this activity can improve outcomes of stereotactic radiosurgery. METHODS: In this single institution retrospective series, the clinical outcomes of 80 consecutive lung cancer patients treated with concurrent immune checkpoint inhibitors and stereotactic radiosurgery were compared to 235 in the historical control cohort in which patients were treated prior to immune checkpoint inhibition being standard upfront therapy. Overall survival was estimated using the Kaplan Meier method. Cumulative incidence of local progression was estimated using a competing risk model. RESULTS: Median overall survival time was improved in patients receiving upfront immunotherapy compared to the historical control group (40 months vs 8 months, p < 0.001). Factors affected overall survival include concurrent immunotherapy (HR 0.23, p < 0.0001) and KPS (HR 0.97, p = 0.0001). Cumulative incidence of local failure in the historical control group was 10% at 1 year, compared to 1.1% at 1 year in the concurrent immunotherapy group (p = 0.025). Factors affected local control included use of concurrent immunotherapy (HR 0.09, p = 0.012), and lowest margin dose delivered to a metastasis (HR 0.8, p = 0.0018). CONCLUSION: Local control and overall survival were both improved in patients receiving concurrent immune checkpoint inhibitors with radiosurgery compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent use of immunotherapy with SRS.

Just-in-Time Teaching (JiTT) Screencasts: a Randomized Controlled Trial of Asynchronous Learning on an Inpatient Hematology-Oncology Teaching Service.

BACKGROUND: The efficacy of just-in-time teaching (JiTT) screencasts for graduate medical education on an inpatient adult hematology-oncology service (HOS) setting is not known. Our preceding pilot data identified six high-yield topics for this setting. The study objective was to evaluate screencast educational efficacy. METHODS: Internal medicine residents scheduled to start a rotation on the primary HOS of an academic medical center were eligible for this parallel, unblinded, randomized controlled trial with concealed allocation. Participants underwent block randomization to the usual educational curriculum either with or without access to a series of novel screencasts; all participants received an anonymous online end-of-rotation survey and a $20 gift certificate upon completion. The primary outcome was the change in attitude among learners, measured as their self-reported confidence for managing the clinical topics. RESULTS: From 12/9/2019 through 6/15/2020, accrual was completed with 67 of 78 eligible residents (86%) enrolled and randomized. Analysis was by intention-to-treat and participant response rate was 91%. Sixty-four percent of residents in the treatment arm rated their clinical management comfort level as "comfortable" or "very comfortable" versus 21% of residents in the usual education arm (p = 0.001), estimated difference = 43% (95% CI: 21-66%), using a prespecified cumulative cutoff score. Treatment arm participants reported that the screencasts improved medical oncology knowledge base (100%), would improve their care for cancer patients (92%), and had an enjoyable format (96%). CONCLUSION: Residents on a busy inpatient HOS found that a JiTT screencast increased clinical comfort level in the management of HOS-specific patient problems.

Relationship between Tumor Mutational Burden, PD-L1, Patient Characteristics, and Response to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma.

Failure to predict response to immunotherapy (IO) limited its benefit in the treatment of head and neck squamous cell cancer (HNSCC) to 20% of patients or less. Biomarkers including tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) were evaluated as predictors of response to IO, but the results are inconsistent and with a lack of standardization of their methods. In this retrospective study, TMB and PD-L1 were measured by commercially available methodologies and were correlated to demographics, outcome, and response to PD-1 inhibitors. No correlation was found between TMB and PD-L1 levels. High TMB was associated with smoking and laryngeal primaries. PD-L1 was significantly higher in African Americans, patients with earlier stage tumors, nonsmokers, and nonethanol drinkers. Patients with high TMB fared better in univariate and multivariate survival analysis. No correlation was found between PD-L1 expression and prognosis. There was a statistically significant association between PFS and response to IO and TMB. There was no association between response to ICI and PD-L1 in this study, possibly affected by variations in the reporting method. Further studies are needed to characterize the biomarkers for IO in HNSCC, and this study supports further research into the advancement of TMB in prospective studies.

Chemoradiotherapy with high-dose cisplatin compared with weekly cisplatin for locally advanced head and neck squamous cell carcinoma.

INTRODUCTION: Concurrent chemoradiotherapy (CRT) using high-dose cisplatin (HDC) is standard for patients with locally advanced head and neck squamous cell carcinoma (HNSCC); weekly cisplatin (WC) is an alternative. We aim to compare retrospectively the survival and disease control outcomes between these regimens in our institutional experience. METHODS: Patients with stage III-IV HNSCC treated with definitive or postoperative CRT between 2012 and 2018 were identified. Patients were stratified by intent-to-treat CRT. Overall survival (OS) and disease-free survival (DFS) were generated and multivariable Cox models were performed. RESULTS: 193 patients were treated with concurrent HDC (n = 69), WC at 40 mg/m2 (WC40, n = 88) or WC at <40 mg/m2 (WC<40, n = 36). Treatment intent was definitive in 74% and adjuvant in 26%. Baseline differences included age, performance status and HPV status. Cumulative cisplatin dose ≥200 mg/m2 was achieved in 89% (HDC), 86% (WC40) and 25% (WC<40, P < 0.0001). For HDC, WC40 and WC<40, 2-year OS rates were 87%, 77%, 60% and 2-year DFS rates were 75%, 68% and 52%, respectively. Multivariable analysis revealed gender, performance status, primary site, T/N stage and chemotherapy as predictive of OS. Primary site, T/N stage and chemotherapy regimen were associated with DFS. Compared with HDC, no differences in locoregional control (LRC) or distant metastasis were observed between groups. CONCLUSION: Concurrent HDC is associated with increased total cisplatin intensity, OS and DFS compared with weekly cisplatin regimens. LRC was not associated with chemotherapy regimen. HDC remains the standard of care; WC40 is a reasonable alternative that does not appear to sacrifice LRC.

Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC.

PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA (tDNA) and circulating tumor DNA (ctDNA) results were analyzed for mutations in a set of 18 DDR genes as well as in gene subsets defined by technical and clinical significance. Mutations were correlated with demographic and outcome data. The addition of ctDNA to the standard tDNA analysis contributed to identification of a significantly increased incidence of patients with mutations in one or more genes in each of the study subsets of DDR genes in groups of patients older than 60 years, patients with laryngeal primaries, patients with advanced stage at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with DDR gene mutations were found to be significantly less likely to have primary tumors within the in oropharynx or HPV-positive disease. Patients with ctDNA mutations in all subsets of DDR genes analyzed had significantly worse overall survival in univariate and adjusted multivariate analysis. This study underscores the utility of ctDNA analysis, alone, and in combination with tDNA, for defining the prevalence and the role of DDR gene mutations in HNSCC. Furthermore, this study fosters research promoting the utilization of PARP inhibitors in HNSCC precision oncology treatments.

What Oncologists Want: Identifying Challenges and Preferences on Diagnosis Data Entry to Reduce EHR-Induced Burden and Improve Clinical Data Quality.

PURPOSE: Accurate recording of diagnosis (DX) data in electronic health records (EHRs) is important for clinical practice and learning health care. Previous studies show statistically stable patterns of data entry in EHRs that contribute to inaccurate DX, likely because of a lack of data entry support. We conducted qualitative research to characterize the preferences of oncological care providers on cancer DX data entry in EHRs during clinical practice. METHODS: We conducted semistructured interviews and focus groups to uncover common themes on DX data entry preferences and barriers to accurate DX recording. Then, we developed a survey questionnaire sent to a cohort of oncologists to verify the generalizability of our initial findings. We constrained our participants to a single specialty and institution to ensure similar clinical backgrounds and clinical experience with a single EHR system. RESULTS: A total of 12 neuro-oncologists and thoracic oncologists were involved in the interviews and focus groups. The survey developed from these two initial thrusts was distributed to 19 participants yielding a 94.7% survey response rate. Clinicians reported similar user interface experiences, barriers, and dissatisfaction with current DX entry systems including repetitive entry operations, difficulty in finding specific DX options, time-consuming interactions, and the need for workarounds to maintain efficiency. The survey revealed inefficient DX search interfaces and challenging entry processes as core barriers. CONCLUSION: Oncologists seem to be divided between specific DX data entry and time efficiency because of current interfaces and feel hindered by the burdensome and repetitive nature of EHR data entry. Oncologists' top concern for adopting data entry support interventions is ensuring that it provides significant time-saving benefits and increasing workflow efficiency. Future interventions should account for time efficiency, beyond ensuring data entry effectiveness.

Unmet Care Needs and Financial Hardship in Patients With Metastatic Non-Small-Cell Lung Cancer on Immunotherapy or Chemoimmunotherapy in Clinical Practice.

PURPOSE: Immunotherapy or chemoimmunotherapy is now standard treatment for most patients with metastatic non-small-cell lung cancer (mNSCLC), yet patient supportive care needs (SCNs) on immunotherapy are not well defined. This study characterized the SCNs and financial hardship of patients with mNSCLC treated with immunotherapy or chemoimmunotherapy and examined the relationship between patient and caregiver cancer-related employment reductions and patient financial hardship. METHODS: Patients with mNSCLC on immunotherapy or chemoimmunotherapy from a single academic medical center completed the SCNs Survey-34, items indexing material, psychological, and behavioral financial hardship, and the Comprehensive Score for Financial Toxicity. Univariate and bivariate analyses examined care needs, financial hardship, and impact of cancer-related employment reductions on patient financial hardship. RESULTS: Sixty patients (40% male; 75% White, mean age = 62.5 years, 57% on immunotherapy alone) participated. Fifty-five percent reported unmet needs in physical or daily living and psychological domains. Financial hardship was common (33% material, 63% psychological, and 57% behavioral). Fifty-two percent reported hardship in at least two domains. Forty percent reported a caregiver cancer-related employment reduction. Caregiver employment reduction was related to patient financial hardship (68% of those reporting caregiver employment reduction reported at least two domains of hardship v 40% of those without reduction, P = .03) and patient financial distress (mean Comprehensive Score for Financial Toxicity = 19.6 among those with caregiver employment reduction v 26.8 without, P = .01). CONCLUSION: Patients with mNSCLC treated with immunotherapy or chemoimmunotherapy report multiple unmet care needs and financial hardship. Psychological, functional, financial, and caregiver concerns merit assessment and intervention in this population.