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Background: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC)., Methods: The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, and progression-free survival duration., Results: A total of 17 patients were included in the final analysis. Fifteen (88%) received more than two lines of prior systemic therapy and 10 (59%) had prior exposure to anti-PD-1/programmed death-ligand 1 (PD-L1) therapy. The median age was 67.5 years. Ten patients had grade ≥3 adverse events related to selinexor treatment. Responses to treatment occurred in patients who did and did not undergo previous anti-PD-1/PD-L1 therapy and in patients with activating driver mutations. The median overall survival and progression-free survival were 11.4 months (95% CI, 3.4-19.8 months) and 3.0 months (95% CI, 1.7-5.7 months), respectively. The overall response rate was 18% and the 6-month disease control rate was 24%., Conclusions: Selinexor in combination with pembrolizumab demonstrated promising antitumor activity in patients with mNSCLC, including those who had previously received anti-PD-1/PD-L1 therapy. The therapy-related toxic effects were consistent with the prior safety data for both drugs, and no overlapping toxic effects were observed., Trial Registration: ClinicalTrials.gov identifier: NCT02419495., Plain Language Summary: New strategies to prevent or reverse resistance to immune checkpoint inhibitors are under investigation. Selective inhibitors of nuclear export proteins, such as selinexor, can induce restoration of tumor-suppressing pathways and induce potent immunomodulatory activities. This article contains the clinical safety and early efficacy data on the combination of pembrolizumab and selinexor in treatment of metastatic non-small cell lung cancer., (© 2023 American Cancer Society.)

Background: This study investigated the association of hearing loss and tinnitus with overall health-related quality of life (HRQoL) among long-term oropharyngeal cancer (OPC) survivors., Methods: This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their "difficulty with hearing loss and/or ringing in the ears" from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1-4 for mild, and 5-10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory Head & Neck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference., Results: Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild (OR, 5.83; 95% CI; 1.48-22.88; p = 0.012) and moderate (OR, 30.01; 95% CI; 7.96-113.10; p < 0.001) hearing loss and tinnitus were associated with higher odds of reporting moderate to severe symptom interference scores in comparison to no hearing loss and tinnitus. This association of hearing dysfunction was consistent with all domains of HRQoL., Conclusions: Our findings provide preliminary evidence to support the need for continued audiological evaluations and surveillance to detect hearing dysfunction, to allow for early management and to alleviate the long-term impact on QoL., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: As a result of the approval of several immune checkpoint inhibitors (ICIs) for the treatment of non-small cell lung cancer (NSCLC), many older adults are being treated with ICIs. Older adults are underrepresented in most pharmaceutical clinical trials. Therapy outcomes in this population with ICIs is particularly important since, age related factors may have an influence on the immune system., Methods: We utilized the MD Anderson Cancer Center Gemini Team's Lung Cancer Database to retrospectively study patients ≥70 years of age with advanced NSCLC treated with anti-PD-(L)1 monotherapy to look at the clinical outcomes., Results: 179 patients met the inclusion criteria for this retrospective analysis. There were 106 men and 73 women. The median age of the cohort was 74.9 years, and overall survival was 20.6 months. 27.6% of all patients had an objective response to therapy. In 33 patients who had radiological progression, treatment continued beyond progression due to clinical benefit. In this group, 6 patients had subsequent improvement in radiologic assessment. Age groups were not significantly associated with differences in clinical outcomes., Conclusions: This study suggests that anti-PD-(L)1 monotherapy is effective and well tolerated among older adults with advanced NSCLC. While pseudoprogression is rare, treatment beyond progression may provide clinical benefit in a subset of patients and warrants further investigation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1, P = 4.3 × 10 -7 ; 5p13.2-p13.1, rs16903936, MA = G, EGFLAM, P = 5.1 × 10 -6 ; 4q21.1, rs10518156, MA = G, SHROOM3, P = 7.1 × 10 -6 ; 19q13.42, rs11882068, MA = G, NLRP9, P = 1.7 × 10 -5 ; 12q24.33, rs4760542, MA = G, GLT1D1, P = 1.8 × 10 -5 ; and 3q27.3, rs11714564, MA = G, RTP1, P = 2.9 × 10 -5 . Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826, a ncRNA class RNA gene, P = 1.5 × 10 -5 ). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia., (© 2022. The Author(s).)

Background: The study objective is to identify risk factors associated with fatigue among long-term OPC survivors., Methods: This cross-sectional study included disease-free OPC survivors treated curatively between 2000 and 2013 who were surveyed from September 2015 to July 2016. The outcome variable was patient-reported fatigue. Multivariable logistic regression was used to identify factors associated with moderate to severe fatigue., Results: Among 863 OPC survivors, 17.4% reported moderate to severe fatigue. Self-reported thyroid problems (OR: 2.01; p = 0.003), current cigarette smoking at time of survey (OR: 3.85; p = 0.001), late lower cranial neuropathy (OR: 3.44; p = 0.002), and female sex (OR: 1.91; p = 0.010) were concurrent risk factors of reporting moderate to severe fatigue. Ipsilateral intensity-modulated radiotherapy (OR: 0.18; p = 0.014) was associated with lower risk of reporting moderate to severe fatigue., Conclusions: Our study identified thyroid problems, smoking, and late lower cranial neuropathy as associated with moderate to severe fatigue. These findings should be further validated in prospective studies to address fatigue among OPC survivors., (© 2022 Wiley Periodicals LLC.)

Purpose: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study., Patients and Methods: Patients with advanced HER2 exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response., Results: Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis., Conclusion: Poziotinib showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy., Competing Interests: Yasir Y. ElaminConsulting or Advisory Role: Lilly, AstraZeneca, Turning Point TherapeuticsResearch Funding: Spectrum Pharmaceuticals, AstraZeneca, Takeda, Xcovery, Lilly, Elevation Oncology, Turning Point TherapeuticsTravel, Accommodations, Expenses: Lilly Jacqulyne P. RobichauxResearch Funding: Spectrum Pharmaceuticals, TakedaPatents, Royalties, Other Intellectual Property: Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations, Patent application Mehmet AltanConsulting or Advisory Role: GlaxoSmithKline, Shattuck LabsResearch Funding: Lilly, Bristol Myers Squibb, Novartis, GlaxoSmithKline, Jounce Therapeutics, Adaptimmune, Genentech, Nektar, Shattuck Labs Don L. GibbonsStock and Other Ownership Interests: Exact Sciences, NektarConsulting or Advisory Role: Sanofi, GlaxoSmithKline, Janssen Research & Development, Ribon Therapeutics, Mitobridge, Lilly, Menarini, Napa TherapeuticsResearch Funding: Janssen Research & Development, Takeda, AstraZeneca, Mitobridge, Ribon Therapeutics, Boehringer Ingelheim, Mirati Therapeutics, NGM BiopharmaceuticalsTravel, Accommodations, Expenses: AstraZeneca/MedImmune, BerGenBio, Takeda Vincent K. LamConsulting or Advisory Role: Takeda, Seattle Genetics, Bristol Myers SquibbResearch Funding: Guardant Health, Takeda, GlaxoSmithKline, Bristol Myers Squibb Anisha B. PatelConsulting or Advisory Role: OnQuality Pharmaceuticals, Novartis, Deciphera, NanOlogyResearch Funding: Lutris, Pfizer, OnQuality PharmaceuticalsTravel, Accommodations, Expenses: Novartis, OnQuality Pharmaceuticals Marcelo V. NegraoConsulting or Advisory Role: Mirati TherapeuticsResearch Funding: Mirati Therapeutics, AstraZeneca, Pfizer, Novartis, ZIOPHARM Oncology, Checkmate Pharmaceuticals Xiuning LeConsulting or Advisory Role: AstraZeneca, Lilly, EMD Serono, Spectrum Pharmaceuticals, Daiichi Sankyo/LillyResearch Funding: Lilly, Boehringer Ingelheim Jianjun ZhangHonoraria: Roche, Sino-USA Biomedical Platform, Geneplus, Origimed, Innovent Biologics, CancerNet, Zhejiang Cancer Hospital, Geneplus, Innovent Biologics, Zhejiang Cancer HospitalConsulting or Advisory Role: AstraZeneca, Geneplus, Capital Medical University, Johnson & Johnson/JanssenResearch Funding: MerckTravel, Accommodations, Expenses: Innovent Biologics, Zhejiang Cancer Hospital George Blumenschein JrEmployment: Janssen (I), Johnson & Johnson (I)Stock and Other Ownership Interests: Virogin BiotechConsulting or Advisory Role: Bristol Myers Squibb, Bayer, Celgene, Clovis Oncology, AbbVie, ARIAD, Genentech, Novartis, Xcovery, Adicet, Amgen, AstraZeneca, Roche, MedImmune, Maverick Therapeutics, Johnson & Johnson (I), Virogin Biotech, Gilead Sciences, Daiichi Sankyo Inc, Novartis, Tyme, Janssen Oncology, Lilly, InstilResearch Funding: Merck, Celgene, Genentech, Xcovery, Novartis, Bristol Myers Squibb, GlaxoSmithKline, Adaptimmune, Macrogenics, Kite Pharma, Immatics, Torque, Incyte, MedImmune, Exelixis, Immunocore, Roche, AstraZeneca, Bayer, Tmunity Therapeutics, Inc, Regeneron, BeiGene, Repertoire Immune Medicines, Daiichi Sankyo Inc, Verastem Anne S. TsaoConsulting or Advisory Role: Novartis, Boehringer Ingelheim, Genentech/Roche, Lilly, Bristol Myers Squibb, Epizyme, AstraZeneca/MedImmune, ARIAD, EMD Serono, Takeda, HERONResearch Funding: Merck, Genentech/Roche, Seattle Genetics, Millennium, Bristol Myers Squibb, Boehringer Ingelheim, Polaris, EMD Serono, Seattle Genetics, TakedaPatents, Royalties, Other Intellectual Property: UptoDate John V. HeymachStock and Other Ownership Interests: Cardinal Spine, Bio-TreeConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Lilly, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Catalyst Biotech, Foundation medicine, Novartis, Mirati Therapeutics, BrightPath Biotheraputics, Janssen, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, Leads BiolabsResearch Funding: AstraZeneca, Spectrum Pharmaceuticals, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutationsNo other potential conflicts of interest were reported.

Background: This study was conducted to identify clinicodemographic risk factors for xerostomia among long-term oropharyngeal cancer (OPC) survivors., Methods: This cross-sectional study included 906 disease-free, adult OPC survivors with a median survival duration at the time of survey of 6 years (range, 1-16 years); self-reported xerostomia scores were available for 877 participants. Study participants had completed curative treatment between January 2000 and December 2013 and responded to a survey administered from September 2015 to July 2016. The primary outcome variable was cancer patient-reported xerostomia measured with the MD Anderson Symptom Inventory Head and Neck Cancer Module. Clinicodemographic risk factors for moderate to severe xerostomia were identified via multivariable logistic regression., Results: Moderate to severe xerostomia was reported by 343 of the respondents (39.1%). Female sex (odds ratio [OR], 1.82; 95% CI, 1.22-2.71; P = .003; Bayesian false-discovery probability [BFDP] = 0.568), high school or lower education (OR, 1.73; 95% CI, 1.19-2.52; P = .004; BFDP = 0.636), and current cigarette smoking at the time of survey (OR, 2.56; 95% CI, 1.19-5.47; P = .016; BFDP = 0.800) were risk factors for moderate to severe xerostomia, and bilateral intensity-modulated radiotherapy (IMRT) combined with proton therapy and ipsilateral IMRT were protective., Conclusions: In this large xerostomia study, modern radiotherapy was a protective factor, and continued cigarette smoking at the time of survey, female sex, and high school or lower education were identified as other contributing risk factors associated with moderate to severe xerostomia. Importantly, these findings need to be confirmed in prospective studies. These results can inform future research and targeted patient-centered interventions to monitor and manage radiation therapy-associated xerostomia and preserve quality of life among patients with OPC., (© 2021 American Cancer Society.)

Introduction: The efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR -mutant or ALK -rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence., Methods: We reviewed the database of the MD Anderson Cancer Center and identified metastatic LUSC with classic EGFR or ALK alterations., Results: There were eight patients with EGFR -mutant LUSC (median age = 58 y) and six patients with EML4-ALK LUSC (median age = 50 y) who received tyrosine kinase inhibitors (TKIs) that were identified. Of the 14 patients, 11 (79%) were females and 12 (86%) were never smokers, similar to the demographics of EGFR or ALK LUAD. With TKI treatment, seven of eight cases of EGFR LUSC and four of six cases of ALK LUSC achieved partial response or stable disease, but the progression-free survival was 4.9 months and 2.9 months for EGFR -mutant and ALK -rearranged LUSC, respectively. In addition, we compared comutation profile of EGFR -mutant LUAD (The Cancer Genome Atlas, n = 46) versus LUSC (n = 19) and found that the comutation patterns are more consistent with squamous disease with a higher incidence of PIK3CA ( p  = 0.02) and KRAS or BRAF ( p  = 0.04) alterations., Conclusions: EGFR or ALK alterations occur in patients with LUSC, especially never-smoker females. TKI treatments render clinical benefit in disease control, but the duration was considerably truncated compared with those historically observed in LUAD., (© 2020 The Author(s).)

Background: Induction chemotherapy (IC) has been associated with a decreased risk of distant metastasis in locally advanced head and neck squamous cell carcinoma. However, its role in the treatment of oropharyngeal squamous cell carcinoma (OPSCC) is not well established., Methods: The outcomes of patients with OPSCC treated with IC followed by concurrent chemoradiation (CRT) were compared with the outcomes of those treated with CRT alone. The primary outcome was overall survival (OS), and the secondary end points were the times to locoregional and distant recurrence., Results: In an existing database, 585 patients met the inclusion criteria: 137 received IC plus CRT, and 448 received CRT. Most patients were positive for human papillomavirus (HPV; 90.9%). Patients receiving IC were more likely to present with a higher T stage, a higher N stage, and low neck disease. The 3-year OS rate was significantly lower in patients receiving IC (75.7%) versus CRT alone (92.9%). In a multicovariate analysis, receipt of IC (adjusted hazard ratio [aHR], 3.4; P < .001), HPV tumor status (aHR, 0.36; P = .002), and receipt of concurrent cetuximab (aHR, 2.7; P = .002) were independently associated with OS. The risk of distant metastasis was also significantly higher in IC patients (aHR, 2.8; P = .001), whereas an HPV-positive tumor status (aHR, 0.44; P = .032) and completion of therapy (aHR, 0.51; P = .034) were associated with a lower risk of distant metastasis. In HPV-positive patients, IC remained associated with distant metastatic progression (aHR, 2.6; P = .004) but not OS., Conclusions: In contrast to prior studies, IC was independently associated with worse OS and a higher risk of distant metastasis in patients with OPSCC. Future studies are needed to validate these findings., (© 2021 American Cancer Society.)

Purpose: In locoregionally advanced, resectable cutaneous squamous cell carcinoma of the head and neck (CSCC-HN), surgery followed by radiotherapy is standard but can be cosmetically and functionally devastating, and many patients will have recurrence., Patients and Methods: Newly diagnosed or recurrent stage III-IVA CSCC-HN patients amenable to curative-intent surgery received two cycles of neoadjuvant PD-1 inhibition. The primary endpoint was ORR per RECIST 1.1. Secondary endpoints included pathologic response [pathologic complete response (pCR) or major pathologic response (MPR; ≤10% viable tumor)], safety, DSS, DFS, and OS. Exploratory endpoints included immune biomarkers of response., Results: Of 20 patients enrolled, 7 had recurrent disease. While only 6 patients [30%; 95% confidence interval (CI), 11.9-54.3] had partial responses by RECIST, 14 patients (70%; 95% CI, 45.7-88.1) had a pCR ( n = 11) or MPR ( n = 3). No SAEs ocurred during or after the neoadjuvant treatment. At a median follow-up of 22.6 months (95% CI, 21.7-26.1), one patient progressed and died, one died without disease, and two developed recurrence. The 12-month DSS, DFS, and OS rates were 95% (95% CI, 85.9-100), 89.5% (95% CI, 76.7-100), and 95% (95% CI, 85.9-100), respectively. Gene expression studies revealed an inflamed tumor microenvironment in patients with pCR or MPR, and CyTOF analyses demonstrated a memory CD8 + T-cell cluster enriched in patients with pCR., Conclusions: Neoadjuvant immunotherapy in locoregionally advanced, resectable CSCC-HN is safe and induces a high pathologic response rate. Pathologic responses were associated with an inflamed tumor microenvironment., (©2021 American Association for Cancer Research.)

Importance: Voice and speech production are critical physiological functions that affect quality of life and may deteriorate substantially after oropharyngeal cancer (OPC) treatment. There is limited knowledge about risk factors associated with voice and speech outcomes among survivors of OPC., Objective: To identify the risk factors of voice and speech symptoms among long-term survivors of OPC., Design, Setting, and Participants: This retrospective cohort study with cross-sectional survivorship survey administration includes cancer-free survivors of OPC who were treated curatively between January 2000 and December 2013 at MD Anderson Cancer Center (Houston, Texas) who participated in a survey from September 2015 to July 2016. Of 906 survivors of OPC with a median survival duration at time of survey of 6 years (range, 1-16 years), patient-rated voice and speech outcomes for 881 were available and analyzed. The data were analyzed from June 30, 2020, to February 28, 2021., Main Outcomes and Measures: The primary outcome variable was patient-reported voice and speech scores that were measured using the MD Anderson Symptom Inventory-Head and Neck Cancer Module. Voice and speech scores of 0 to 4 were categorized as none to mild symptoms, and scores of 5 to 10 were categorized as moderate to severe symptoms. Risk factors for moderate to severe voice and speech symptoms were identified by multivariable logistic regression., Results: Among 881 survivors of OPC (median [range] age, 56 [32-84] years; 140 women [15.5%]; 837 White [92.4%], 17 Black [1.9%], and 35 Hispanic individuals [3.8%]), 113 (12.8%) reported moderate to severe voice and speech scores. Increasing survival time (odds ratio [OR], 1.17; 95% CI, 1.06-1.30) and increasing total radiation dose (OR, 1.16; 95% CI, 1.00-1.34), Black race (OR, 3.90; 95% CI, 1.02-14.89), Hispanic ethnicity (OR, 3.74; 95% CI, 1.50-9.35), current cigarette smoking at the time of survey (OR, 3.98; 95% CI, 1.56-10.18), treatment with induction and concurrent chemotherapy (OR, 1.94; 95% CI, 1.06-3.57), and late (OR, 7.11; 95% CI, 3.08-16.41) and baseline lower cranial neuropathy (OR, 8.70; 95% CI, 3.01-25.13) were risk factors associated with moderate to severe voice and speech symptoms. Intensity-modulated radiotherapy split-field regimen (OR, 0.31; 95% CI, 0.12-0.80; P = .01) was associated with lower likelihood of moderate to severe voice and speech symptoms., Conclusions and Relevance: This large OPC survivorship cohort study identified many treatment-related factors, including increasing total radiotherapy dose, multimodality induction and concurrent chemotherapy regimens, and continued smoking, as well as clinical and demographic factors, as risk factors that were associated with moderate to severe voice and speech symptoms. The key findings in this study were the protective associations of split-field radiation and that longer-term survivors, and those who continued to smoke, had worse voice and speech symptoms. These findings may inform research and effective targeted clinical voice and speech preservation interventions and smoking cessation interventions to maximize voice and speech function and address quality of life among patients with OPC.

Background: The outcomes of patients treated with cytotoxic or targeted systemic therapy is not well defined for cutaneous squamous cell carcinoma of the head and neck (cSCCHN)., Methods: Patients with cSCCHN treated with cytotoxic or targeted systemic therapy were included. Patients were divided into two groups based on the presence of distant metastasis (M1 vs. M0) at presentation. A proportional hazards model was used to assess for independent predictors of overall survival., Results: Of 129 patients with cSCCHN, 20 (16%) were M1 and 109 (84%) were M0. Independent predictors of improved survival were M0 status, treatment of locally advanced disease with radiotherapy, and lower Eastern Cooperative Oncology Group (ECOG) score., Conclusions: Survival was worse in M1 patients treated with cytotoxic or targeted systemic therapy and poor baseline performance status but improved in those receiving radiotherapy. These data can serve as historical controls for future systemic therapy trials, including immunotherapy., (© 2021 Wiley Periodicals LLC.)

Objective: The purpose of this study was to estimate prevalence/severity of self-reported trismus, determine association with quality of life (QOL), and examine clinical risk factors in a large population of patients treated for oropharyngeal cancer., Materials and Methods: A cross-sectional survivorship survey was conducted among patients who completed definitive treatment for oropharyngeal carcinoma, disease-free ≥ 1-year post-treatment (median survival, 7 years among 892 survivors). Associations between trismus and QOL were also analyzed using MDASI-HN, EQ-5D, and MDADI. Dietary and feeding tube status were also correlated to trismus status., Results: Trismus was self-reported in 31%. Severity of trismus positively correlated (r = 0.29) with higher mean interference scores reflecting a moderate association with quality of life (p < 0.0001). There was a negative correlation for MDADI composite scores (r = - 0.33) indicating increased perceived dysphagia related to trismus severity (p < 0.0001). EQ-5D VAS scores were also negatively correlated with trismus severity (r = - 0.26, p < 0.0001). Larger T-stage (p ≤ 0.001), larger nodal stage (p = 0.03), tumor sub-site (p = 0.05), and concurrent chemoradiation (p = 0.01) associated with increased prevalence of trismus. Diet negatively correlated (r = - 0.27) with trismus severity (p = < 0.0001), and survivors with severe trismus were also more likely to be feeding tube-dependent., Conclusion: Severity of trismus appears to negatively impact quality of life and associate with various adverse functional outcomes in long-term oropharyngeal cancer survivorship. Trismus remains associated with advanced disease stages, tumor sub-site (tonsil), and addition of chemotherapy. Further investigation is merited for the dose-effect relationship to the muscles of mastication.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.

Purpose: HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) carries a favorable prognosis for patients, yet nearly 30% of patients will experience disease relapse. We sought to detail patterns of failure, associated salvage therapy, and outcomes for patients with recurrent HPV-positive OPSCC., Methods and Materials: This is a single institution retrospective study of patients with recurrent HPV-positive OPSCC irradiated from 2002 to 2014. The primary study outcome was overall survival (OS, calculated using the Kaplan-Meier method). Secondary aims included patterns of first failure with descriptive details of salvage therapy. Solitary recurrences were defined as initial presentation of recurrence in a single site (primary, neck or oligometastatic), and multi-site was defined as local and regional and/or multiple sites of distant recurrence. Survival outcomes were compared using the log-rank test., Results: The cohort consisted of 132 patients. The median follow-up was 59 months for surviving patients. Estimated 2-year and 5-year OS rates were 47% and 32%, respectively. Comparative 2-year and 5-year OS rates were 65% and 46% versus 19% and 9% for the solitary group and multi-site group, respectively (p < .001)., Conclusions: Patients with recurrent HPV-positive OPSCC experience 5-year survival of approximately 32%. However, patients with a "solitary" recurrence including disease at the primary site, neck or oligometastatic site have more favorable long-term outcomes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: Evaluate the use of induction chemotherapy (IC) in oropharyngeal cancer (OPC) and its impact on subjective functional outcomes using a validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) survey tool., Methods: A single institution retrospective review of OPC patients who received IC, including reasons given for using IC, regimens employed, responses, and patient-reported outcomes (PRO). The latter included pain, distress, dysphagia, xerostomia, and feeding tube placement and dependency. PRO's were assessed using the validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) conducted at baseline, during treatment, and at six-month follow up., Results: One hundred and twenty-five patients were evaluable. They were more likely to have large primary and/or bulky or low neck nodal disease as a reason for IC. A taxane-containing regimen was most common. Primary tumor response was seen in 83.2% and the nodal response in 81.6%. Pain and xerostomia improved with IC, dysphagia was not adversely affected with IC. These symptoms all increased with consolidation chemoradiotherapy (CRT) but returned to baseline by 6 months post treatment. Feeding tube placement did not increase with IC but did with CRT, most patients were no longer feeding tube dependent at 6 months., Conclusion: This retrospective review of subjective functional outcomes, especially swallowing and feeding tube dependency, using the MDASI survey tool in 125 oropharyngeal cancer patients with large primary tumors and/or bulky adenopathy treated predominantly with platinum-taxane based induction chemotherapy showed that such outcomes were not adversely impacted. While not standard, such approach may be beneficial in such patients., Level of Evidence: 2., Competing Interests: There are no financial disclosures or conflicts of interest., (© 2020 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Introduction: Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC., Methods: PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed., Results: PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival., Conclusions: PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non-small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint., Patients and Methods: Eligible patients had stage IB (≥4 cm)-IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m 2 ), docetaxel (75 mg/m 2 ) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%., Results: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%-32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%-54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%-93%) and 91% (95% CI, 79%-100%), respectively. Most frequent treatment-related grade 3-4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3 + and cytotoxic CD3 + CD8 + T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm 2 , P = 0.048; 142.3 vs. 35.6 cells/mm 2 , P = 0.018)., Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies. See related commentary by Blakely and McCoach, p. 3499 ., (©2020 American Association for Cancer Research.)

Background : Immune checkpoint inhibitors (ICIs) have dramatically expanded the therapeutic landscape of non-small-cell lung cancer (NSCLC). In a previous study, gender, smoking history, and PD-L1 status were found to influence the efficacy of single-agent ICI in NSCLC. This meta-analysis evaluated the clinical and molecular factors that could predict a benefit from adding ICIs to first-line chemotherapy in metastatic NSCLC. Patients and Methods : The pooled hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) among the selected subgroups were analyzed using the random effects model. The correlation between PD-L1 expression and outcome was analyzed by meta-regression. Results : Seven phase III randomized controlled trials comparing chemo-immunotherapy (CIT) with chemotherapy in untreated stage 4 NSCLC were included. CIT evenly improved PFS irrespective of age, gender, histology, smoking history, and performance status. Among patients with baseline hepatic metastasis treated with Atezolizumab-containing CIT, PFS improvement was only detected with the addition of Bevacizumab. Whereas patients with EGFR/ALK-driven cancer exhibited greater PFS with the addition of ICI to a Bevacizumab (BEV)-based regimen, the derived benefit was no longer statistically significant among those treated with non-BEV-based regimens. Although the superior PFS conferred by CIT was noticeable across all PD-L1 expression subgroups, this benefit correlated with PD-L1 level and was more pronounced in the "PD-L1 high" cohort. Except for patients harboring EGFR/ALK aberrations or squamous histology, CIT consistently improved OS across the other selected subgroups. Conclusions : The survival advantage associated with first-line CIT in metastatic NSCLC was observed in different patient populations, including those for which single-agent ICI has marginal therapeutic benefit. Our findings support the role of chemotherapy with or without VEGF blockade as enhancers of ICI activity in NSCLC., (© 2019 Taylor & Francis Group, LLC.)

Advance Care Planning and End of Life discussions are critical in all cancers but are often overlooked or delayed. Head and Neck Cancer patients have the added stigma of visible morbidity and negative quality of life issues. We present a case example and discussion of these issues in the Head and Neck cancer clinic.

Purpose: Patients with p16/human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma have a favorable outcome after treatment. In this group of patients who could have a long life expectancy, the optimal surveillance strategy and modality is not well established. We aim to determine the ability of a negative postradiation positron emission tomography (PET)/computed tomography scan to predict the risk of subsequent relapse in these patients., Materials and Methods: A retrospective analysis of patients with p16/HPV-associated oropharyngeal squamous cell carcinoma who completed definitive (chemo)radiation therapy and had a posttreatment PET/computed tomography scan from 2006 to 2013 was performed. Patient, tumor, and treatment characteristics and clinical outcomes were recorded. Tumors were considered HPV/p16 positive if either HPV (by in situ hybridization) or p16 (by immunohistochemistry) was positive. Disease-free survival and overall survival rates were estimated using the Kaplan-Meier method., Results: In our study, 327 patients were evaluated. The median age was 57 years. The most common primary sites were base of tongue (50%) and tonsil (48%). Of the patients evaluated, 291 (89%) had a negative posttreatment PET scan. For these 291 patients who had a complete metabolic response after treatment, the 5-year disease-free survival and overall survival rates were 91% and 89%, respectively. The median time to development of recurrence was 16 months. Of the 291 patients, 24 patients (8%) had disease recurrence; 13 recurrences were locoregional, and 13 were distant. Eleven (4%) patients with recurrence had further surgery or radiation, and 8 patients (3%) were without disease as of the last follow-up., Conclusions: Patients who achieve a complete metabolic response on posttreatment PET imaging have an excellent prognosis, and the risk of developing a recurrence in the future is very low. Therefore, a more cost effective surveillance program should be considered for this subgroup of patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: A previous study showed that use of positron emission tomography (PET)/computed tomography (CT) for surveillance after treatment of non-small-cell lung cancer (NSCLC) does not yield a detection or survival benefit over the use of chest CT. However, PET/CT remains a common method of follow-up imaging. Here we estimated and compared the costs of PET/CT versus CT for surveillance of patients with stage III NSCLC and identified patient and provider demographic characteristics associated with preference for use of PET/CT., Patients and Methods: We reviewed 178 patients with stage III NSCLC who had received ≥ 1 PET/CT scan within 6 months of completing radiotherapy (n = 89) or had received CT after radiotherapy (n = 89) from 2000 to 2011. Costs were measured according to Medicare payments converted from institutional billing records. Total and imaging costs were analyzed at 6, 12, 18, and 24 months after the end of treatment. Patient and provider demographic characteristics were also evaluated for potential associations with PET/CT use., Results: Total costs in the PET/CT group were higher during the first 18 months after treatment (P = .002 at 6 months, P = .019 at 12 months, and P = .018 at 18 months) but was marginally significant (P = .05) at 24 months. In univariate analysis of demographic variables, patients who lived in a state different from the treatment center might have been more likely to receive PET/CT (odds ratio [OR], 1.76; P = .051). In multivariate analysis, patients treated in 2007 to 2010 (OR, 29.9; P < .001) or 2003 to 2006 (OR, 11.6; P = .002) were more likely to receive PET/CT than patients treated in 1999 to 2002. In addition, radiation oncologists with > 10 years of experience were more likely to use PET/CT than those with less experience, although this result might be confounded by the small number of providers., Conclusion: Use of PET/CT was associated with higher costs for 18 months after treatment, but the difference was at the borderline of statistical significance at 24 months., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Treatment of Nasopharyngeal Carcinoma (NPC) has been based on the Intergroup 0999 trial with chemoradiation (CRT) and consolidation chemotherapy (CT). While effective, toxicities are significant. As a result, many oncologists use induction chemotherapy (IC) followed by CRT, citing better tolerance with anecdotally no worse outcome. We reviewed 95 NPC patients treated between 2005 and 2015 at MDACC with IC followed by CRT. Median age was 49 years. Fifty-seven were T3/T4 and 62 were N2-3. The most common IC regimen was a platinum-taxane doublet (N = 72). 83 patients completed IC. Grade 3-4 toxicities with IC occurred in 10 patients. There were 15 primary site complete responses (CR), 68 partial responses (PR),6 stable disease (SD), and 2 progressed. There were 10 nodal CR, 73 PR, 4 SD, and 3 progressed. 92 patients received RT, 74 with CRT. At completion of treatment, there were 81 CR and 8 PR patients. Post radiation toxicities included mucositis and skin rash (37), oto- toxicity (25), PEG placement (12), and osteonecrosis (2). Three-year progression free survival (PFS) and distant metastasis free survival (DMFS) were 77.3% and 78%. CRT for advanced NPC is standard, but IC remains controversial. Early trials failed to show a benefit but used older chemotherapy and pre-intensity modulated radiation therapy (IMRT) methods. Modern trials with platinum-taxane regimens and IMRT have shown reasonable PFS and OS results with acceptable toxicity. This retrospective review of IC followed by CRT showed acceptable toxicity and good response and survival outcomes. This approach has, for many oncologists, become a standard., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Communication is the cornerstone of good multidisciplinary medical care, and the impact of conversations about diagnosis, treatment, and prognosis is indisputable. Healthcare providers must be able to have difficult conversations that accurately describe diagnostic procedures, treatment goals, and the benefits and/or risks involved., Methods: This paper reviews the literature about the importance of communication in delivering bad news, the status of communication training, communication strategies, and psychosocial interventions., Results: Although many published guidelines address difficult communication, communication training is lacking. Consequently, many clinicians may have difficulties with, or in the worst-case scenario, avoid delivering bad news and discussing end-of-life treatment. Clinicians also struggle with how to have the last conversation with a patient and how to support patient autonomy when they disagree with a patient's choices., Conclusion: There is a clinical imperative to educate physicians and other healthcare workers on how to effectively deliver information about a patient's health status, diagnostic avenues to be explored, and decisions to be made at critical health junctions. Knowing how to implement the most rudimentary techniques of motivational interviewing, solution-focused brief therapy, and cognitive behavioral therapy can help physicians facilitate conversations of the most difficult type to generate positive change in patients and families and to help them make decisions that minimize end-of-life distress.

Mesothelioma is an insidious disease with long latency after asbestos exposure. New cases are continually diagnosed, although levels are declining with recognition of the asbestos risk and efforts to remove asbestos from the workplace. Treatment for early stage disease with surgery and radiation is potentially curative, but many patients either are too ill to undergo aggressive surgery or present with advanced disease. Chemotherapy with cisplatin and pemetrexed is considered standard, although relapse is common. Second-line therapy is disappointing. New targeted therapies may pose promise and are being addressed in various clinical trial settings. Palliative care remains an important component of the management of this devastating illness.

Patients with non-small-cell lung cancer with positive lymph nodes (stage IIIA and IIIB) have an increased risk for brain metastases. Those with nonsquamous histology are at higher risk. Despite this fact, the use of prophylactic cranial irradiation (PCI) has not shown an improvement in survival in these patients and is still considered to be investigational. The Radiation Therapy Oncology Group attempted to prospectively address this in a randomized trial that recently closed because of poor accrual. We present 2 cases and review the literature and provide an argument for the consideration of PCI in select patients.

Tumor lysis syndrome (TLS) consists of acute hyperuricemic nephropathy, hyperphosphatemia, hypocalcemia, hyperkalemia, and increased serum creatinine. It can be part of the disease presentation, especially in aggressive hematologic malignancies, or a part of the chemotherapy response. There are relatively few reports of TLS in solid tumors. Herein, we present 3 cases-1 small-cell lung cancer case and 2 breast cancer cases-that developed signs consistent with TLS upon initiation of treatment. Identified risk factors include disease bulk, aggressive growth, hepatic involvement, and pretreatment laboratory abnormalities such as elevated lactate dehydrogenase, uric acid, and creatinine. All 3 patients responded to hydration and allopurinol. One patient received rasburicase. Although the reported number of TLS cases associated with solid tumors is small, it may be that it is underdiagnosed or unsuspected in most situations. The purpose of this report is to alert clinicians to the possibility of TLS, even in solid tumors, so they can preemptively manage it.

We conducted a phase II single-institution trial in a homogenous patient population with advanced non-small-cell lung cancer to determine whether changing the carboplatin schedule in the carboplatin/gemcitabine doublet would enhance tolerability and/or results. Thirty patients with stage IIIB (with malignant effusion) or stage IV disease received gemcitabine 1100 mg/m2, days 1 and 8 plus carboplatin at an area under the curve of 5 on day 8. Cycles were repeated every 28 days, up to 6 cycles. A response rate of 10% was demonstrated (none complete), but an additional 45% of patients had stable disease. The median time to progression was 5.8 months and the median survival was 8.3 months. A 1-year survival rate of 27% and a 2-year survival rate of 16% were seen. The main nonhematologic toxicity was non-neutropenic infection. Thrombocytopenia occurred in 8 patients (27%; 7 grade 3, 1 grade 4). Carboplatin/gemcitabine with a day 8 administration of carboplatin is well tolerated with a similar survival to established platinum-based doublets.

We report a case of cytokeratin-positive, CD45-negative primary polymorphic centroblastic lymphoma of the adrenal gland. Additional immunostaining, which demonstrated positivity for CD20 and kappa light chain, as well as detection of the monoclonal rearrangement of the immunoglobulin heavy chain gene, helped to establish the diagnosis of lymphoma and to rule out an initially favored diagnosis of poorly differentiated carcinoma.

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).