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Background: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC‐specific survival. Methods: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006–2019) were prospectively collected. Multivariable Cox and Fine and Gray competing‐risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC‐specific/noncancer mortality, respectively. Results: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58–0.87; p =.001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long‐term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56–0.93; p =.001). The 5‐year actuarial rates of HNSCC‐specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54–0.95; p =.019) had reduced HNSCC‐specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC‐specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46–0.91; p =.012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC‐specific mortality in patients who received primary radiation. Conclusions: Smoking cessation before the time of diagnosis reduced overall mortality and cancer‐specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long‐term abstinence (>10 pack‐years) had a significant OS and HNSCC‐specific survival benefit. Any level of smoking cessation improves overall survival and cancer‐specific survival in patients who have head and neck squamous cell carcinoma. Among ever‐smokers, longer periods of abstinence are associated with significant mortality benefits. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)‐positive nasopharyngeal cancer (NPC) versus Epstein–Barr virus (EBV)‐positive NPC and HPV‐positive oropharyngeal cancer (OPC). Methods: Clinical characteristics and presenting signs/symptoms were compared between patients who had viral‐related NPC versus viral‐related OPC treated with intensity‐modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005–2018 cohort to maintain 2 years of minimum follow‐up. Multivariable analysis was used to evaluate the cohort effect. Results: Similar to HPV‐positive OPC (n = 1531), HPV‐positive NPC (n = 29) occurred mostly in White patients compared with EBV‐positive NPC (n = 422; 86% vs. 15%; p <.001). Primary tumor volumes were larger in HPV‐positive NPC versus EBV‐positive NPC (median volume, 51 vs. 23 cm3; p =.002), with marginally more Level IB nodal involvement. More patients with HPV‐positive NPC complained of local pain (38% vs. 3%; p =.002). The median follow‐up for the 2005–2018 cohort was 5.3 years. Patients who had HPV‐positive NPC (n = 20) had rates of 3‐year LRC (95% vs. 90%; p =.360), DC (75% vs. 87%; p =.188), and OS (84% vs. 89%; p =.311) similar to the rates in those who had EBV‐positive NPC (n = 374). Patients who had HPV‐positive NPC also had rates of LRC (95% vs. 94%; p =.709) and OS (84% vs. 87%; p =.440) similar to the rates in those who had HPV‐positive OPC (n = 1287). The DC rate was lower in patients who had HPV‐positive disease (75% vs. 90%; p =.046), but the difference became nonsignificant (p =.220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. Conclusions: HPV‐positive NPC and EBV‐positive NPC seem to be mutually exclusive diseases. Patients who have HPV‐positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV‐positive NPC or HPV‐positive OPC. Human papillomavirus (HPV)‐positive nasopharyngeal carcinoma (NPC) and Epstein–Barr virus (EBV)‐positive NPC seemed to be mutually exclusive diseases, and p16/HPV testing was helpful in EBV‐negative NPC to elucidate potential viral etiology. HPV‐positive NPC presented with a greater local symptom burden compared with EBV‐positive NPC and HPV‐positive oropharyngeal carcinoma, but outcomes were similar. [ABSTRACT FROM AUTHOR]

Background: This study examined long‐term health utility and symptom‐toxicity trajectories among patients with head and neck cancer (HNC). Methods: For patients diagnosed with HNC (2014‐2019), Health Utility Index 3 (HUI‐3), Edmonton Symptom Assessment Scale (ESAS), and MD Anderson Symptom Inventory (MDASI) surveys (including both the core and head and neck cancer modules) were prospectively collected at multiple time points (at the baseline, after surgery, during radiotherapy, and 3, 6, 12, and 24 months after treatment). Locally estimated scatterplot smoothing plots were generated to describe HUI‐3, ESAS, and MDASI trajectories over time by clinicodemographic factors, treatment modality, and tumor subsite. Contributions of clinical factors were assessed with univariable and multivariable analyses. Results: In 800 patients, the treatment modality and the tumor subsite produced unique HUI‐3, ESAS, and MDASI trajectories. Patients treated with surgery alone experienced rapid improvements in HUI‐3, ESAS, and MDASI scores postoperatively. Among patients treated with chemoradiotherapy, patients with nasopharyngeal carcinoma had greater declines in HUI‐3 during treatment in comparison with patients with oropharyngeal carcinoma, but they had similar ESAS/MDASI scores. Among patients treated with radiotherapy, patients with laryngeal carcinoma had better HUI‐3/ESAS/MDASI scores than those with oropharyngeal carcinoma during treatment, but they slowly converged after treatment. Female sex, an age > 75 years, a household income < $40,000, a Charlson comorbidity score > 1, an Eastern Cooperative Oncology Group performance status > 0 (at the baseline), and current smoking were independently associated with worse HUI‐3 trajectories. HUI‐3 had mild to moderate correlations (ρ = 0.2‐0.5) with individual symptom‐toxicity trajectories. Conclusions: Long‐term HUI‐3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, and this may be partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom‐toxicity studies of HNC. Lay Summary: This study indicates that the long‐term health utility and symptoms/toxicities of patients with the most common head and neck cancers (ie, squamous cell carcinomas and nasopharyngeal carcinomas) differ over time with a variety of factors, including the tumor anatomic site, treatment volume, clinicodemographic characteristics (eg, age, human papillomavirus status, tumor stage, gender, smoking status, alcohol status, education, and comorbidities), and treatment modalities.Generalizations across all head and neck cancers should be strongly discouraged.Future studies should evaluate health utility, symptoms and toxicities, and patient need assessments separately for each anatomic site and treatment modality. Long‐term Health Utility Index 3 trajectories are associated with tumor subsite, clinicodemographic, and treatment factors, which are themselves partly explained by relationships with symptoms/toxicities. Separate evaluations by subsite and treatment should occur in health utility and symptom‐toxicity studies of head and neck cancer. [ABSTRACT FROM AUTHOR]

Background: LMB‐100 is an antibody‐toxin conjugate with an antimesothelin Fab linked to a 24‐kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of the current first‐in‐human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin. Methods: Cohorts of 1 to 7 patients received intravenous LMB‐100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21‐day cycle. Results: Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose‐limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB‐100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB‐100 plasma concentrations were dose‐dependent during cycle 1. The development of antidrug antibodies decreased LMB‐100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3. Conclusions: The MTD for single‐agent LMB‐100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first‐generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB‐100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB‐100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer. Lay Summary: Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB‐100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A.In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB‐100, as well as the generation of antidrug antibodies.Ongoing phase 2 clinical trials are evaluating the combination of LMB‐100 plus pembrolizumab in patients with treatment‐refractory mesothelioma and non–small cell lung cancer. The mesothelin‐targeting immunotoxin LMB‐100 is well tolerated with manageable adverse effects. Based on the antitumor efficacy observed in preclinical studies, the combination of LMB‐100 plus pembrolizumab currently is being evaluated in the clinic. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT-hypo) during the COVID-19 pandemic.Methods: HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT-hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT-acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005-2017 were included. Locoregional control (LRC) and distant control (DC) after RT-hypo, RT-acc, and CCRT were compared for various subgroups.Results: The study identified 994 human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT-hypo, RT-acc, and CCRT, respectively) and 1045 HPV- HNSCC cases (with 263, 451, and 331 receiving RT-hypo, RT-acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy-alone patients were older. The median follow-up was 4.6 years. RT-hypo, RT-acc, and CCRT produced comparable 3-year LRC and DC for HPV+ T1-2N0-N2a disease (seventh edition of the TNM system [TNM-7]; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1-T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1-2N2c/T3N0-N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT-hypo or RT-acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV- HNSCC, 3-year LRC and DC were similar with RT-hypo, RT-acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT-hypo and RT-acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT-acc (62%) but not RT-hypo (80%) or CCRT (92%; RT-hypo vs CCRT: P = .270; RT-acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT-hypo or RT-acc in stage IV (73%, 65%, and 66%; P = .336).Conclusions: It is proposed that RT-hypo be considered in place of CCRT for HPV+ T1-T3N0-N2c (TNM-7) HNSCCs, HPV- T1-T2N0 HNSCCs, and select stage III HNSCCs during the COVID-19 outbreak. [ABSTRACT FROM AUTHOR]

Background: Patients with cancer who are treated with immune checkpoint modulators (ICMs) have their health-related quality of life (HRQOL) measured using general patient-reported outcome (PRO) tools. To the authors' knowledge, no instrument has been developed to date specifically for patients treated with ICMs. The objective of the current study was to develop a toxicity subscale PRO instrument for patients treated with ICMs to assess HRQOL.Methods: Input was collected from a systematic review as well as patients and physicians experienced with ICM treatment. Descriptive thematic analysis was used to evaluate the qualitative data obtained from patient focus groups and interviews, which informed an initial list of items that described ICM side effects and their impact on HRQOL. These inputs informed item generation and/or reduction to develop a toxicity subscale.Results: Focus groups and individual interviews with 37 ICM-treated patients generated an initial list of 176 items. After a first round of item reduction that produced a shortened list of 76 items, 16 physicians who care for patients who are treated with ICMs were surveyed with a list of 49 patient-reported side effects and 11 physicians participated in follow-up interviews. A second round of item reduction was informed by the physician responses to produce a list of 25 items.Conclusions: To the authors' knowledge, this 25-item list is the first HRQOL-focused toxicity subscale for patients treated with ICMs and was developed in accordance with US Food and Drug Administration guidelines, which prioritize patient input in developing PRO tools. The subscale will be combined with the Functional Assessment of Cancer Therapy-General (FACT-G) to form the FACT-ICM. Prior to recommending the formal use of this PRO instrument, the authors will evaluate its validity and reliability in longitudinal studies involving substantially more patients. [ABSTRACT FROM AUTHOR]

Background: A subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) in comparison with pretreatment kinetics; this is known as hyperprogression. This study assessed the relation between hyperprogressive disease (HPD) and treatment‐related toxicity and clinical factors. Methods: This study reviewed patients with solid tumors who were enrolled in early‐phase immunotherapy trials at Princess Margaret Cancer Centre between August 2012 and September 2016 and had computed tomography scans in the pre‐immunotherapy (reference) and on‐immunotherapy (experimental) periods. HPD was defined as progression according to Response Evaluation Criteria in Solid Tumors 1.1 at the first on‐treatment scan and a ≥2‐fold increase in TGR between the reference and experimental periods. Treatment‐related toxicities requiring systemic therapy, drug delays, or discontinuation were considered clinically significant adverse events (CSAEs). Results: Of 352 patients, 182 were eligible for analysis. The median age was 60 years, and 54% were male. The Eastern Cooperative Oncology Group performance status was 0 (32%) or 1 (68%). The Royal Marsden Hospital (RMH) prognostic score was 0/1 in 59%. Single‐agent immunotherapy was given to 80% of the patients. Most patients (89%) received anti‐programmed death (ligand) 1 antibodies alone or in combination with other therapies. HPD occurred in 12 of 182 patients (7%). A higher proportion of females was seen among HPD patients (P = .01), but no association with age, performance status, tumor type, RMH prognostic score, combination immunotherapy, or CSAEs was found. The 1‐year overall survival rate was 28% for HPD patients and 53% for non‐HPD patients (hazard ratio, 1.7; 95% confidence interval, 0.9‐3.3; P = .11). Conclusions: HPD was observed in 7% of patients with solid tumors treated with immunotherapy. HPD was not associated with CSAEs, age, tumor type, or the type of immunotherapy but was more common in females. Hyperprogressive disease occurs in 7% of patients with mixed solid tumors treated with immunotherapy (predominantly anti–programmed death [ligand] 1 antibodies). Hyperprogressive disease is more common among females, but no association with other clinical factors or treatment‐related toxicity has been found. [ABSTRACT FROM AUTHOR]

Background: Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737).Methods: Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions.Results: Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure.Conclusions: SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND Genomic testing in cancer (GTC) characterizes genes that play an important role in the development and growth of a patient's cancer. This form of DNA testing is currently being studied for its ability to guide cancer therapy. The objective of the current study was to describe patients' knowledge, attitudes, and expectations toward GTC. METHODS A 42-item self-administered GTC questionnaire was developed by a multidisciplinary group and patient pretesting. The questionnaire was distributed to patients with advanced cancer who were referred to the Princess Margaret Cancer Center for a phase 1 clinical trial or GTC testing. RESULTS Results were reported from 98 patients with advanced cancer, representing 66% of the patients surveyed. Seventy-six percent of patients were interested in learning more about GTC, and 64% reported that GTC would significantly improve their cancer care. The median score on a 12-item questionnaire to assess knowledge of cancer genomics was 8 of 12 items correct (67%; interquartile range, 7-9 of 12 items correct [58%-75%]). Scores were associated significantly with patients' education level ( P < .0001). Sixty-six percent of patients would consent to a needle biopsy, and 39% would consent to an invasive surgical biopsy if required for GTC. Only 48% of patients reported having sufficient knowledge to make an informed decision to pursue GTC whereas 34% of patients indicated a need for formal genetic counseling. CONCLUSIONS Patients with advanced cancer are motivated to participate in GTC. Patients require further education to understand the difference between somatic and germline mutations in the context of GTC. Educational programs are needed to support patients interested in pursuing GTC. Cancer 2014;120:3066-3073. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

The article offers information on a study which investigated the prognostic value of chromogranin A (CgA), a protein secreted by many neuroendocrine cells, and the soluble tumor necrotic factor receptors (sTNF-R) in advances nonsmall cell lung cancer (NSCLC). The study analyzed the CgA and sTNF-Rs in the sera of 88 patients with NSCLC before chemotherapy by enzyme-linked immunoadsorbent assay and in tumors by immunohistochemistry,