Air pollution is associated with increased incidence-rate of head and neck cancers: A nationally representative ecological study.

INTRODUCTION: Early studies show conflicting findings regarding particulate matter ≤ 2.5 µm in diameter (PM2.5) exposure and development of head and neck cancers (HNC). We analyzed the relationship between PM2.5 exposure and various types of HNC in a nationally representative ecological sample. METHODS: We determined HNC incidence in 608 US counties from 2011 to 2019 using the Surveillance, Epidemiology and End Results (SEER) Program from the National Cancer Institute. We also collected information on sociodemographic factors from SEER and data on smoking and alcohol intake from CDC data frames (county level). PM2.5 exposure levels were estimated using satellite and meteorological data via previously validated general additive models. Flexible semi-nonparametric regression models were used to test the relationship between PM2.5 exposure levels and HNC incidence, adjusting for demographics, socioeconomic factors, and comorbidity. RESULTS: Increased PM2.5 exposure levels were associated with higher incidence-rates of oral cavity and pharyngeal cancers controlling for confounders in our primary analyses (IRR = 1.04, 95 % CI 1.01, 1.07, p = 0.02 per 1 µg/m3 increase in PM2.5). This relationship was maintained after adjusting for multiple testing (Holm s method, p = 0.04) and in ordinary least squares (OLS) regression (ß = 0.17, 95 % CI 0.01, 0.57, p = 0.01). Increased exposure was also associated with other HNC: esophagus (IRR = 1.06, 95 % CI 1.01, 1.11, p = 0.02), lip (IRR = 1.16, 95 % CI 1.03, 1.31, p = 0.01), tonsil (IRR = 1.10, 95 % CI 1.03, 1.16, p < 0.01). However, these relationships were not maintained in secondary analyses. CONCLUSIONS: This nationally representative ecological study shows that increased levels of air pollution are associated with increased incidence of overall oral cavity and pharyngeal cancers in the US.

A Novel Immobilization Method for the Treatment of Head and Neck Cancer Using 3D Printing.

Proper immobilization is critical for the delivery of high-quality radiation therapy. In cases when traditional immobilization is not feasible, 3-dimensional (3D) printing may provide a better-tolerated custom immobilization that is comparably effective. We present the successful treatment of a patient with inoperable oropharyngeal squamous cell carcinoma who was unable to tolerate traditional immobilization. To avoid covering the face, we created a 3D-printed cradle for the back of his head and neck. This design enabled the patient to tolerate traditional simulation scans with and without intravenous contrast and was subsequently able to undergo volumetric modulated arc therapy treatment. He successfully underwent treatment without evidence of disease more than 2 years after completion. The effect of 3D printing within the context of radiation oncology, as well as in other specialties, will undoubtedly continue to increase the variety of treatment options available to patients.

Current State and Future Directions of EGFR-Directed Therapy in Head and Neck Cancer.

OPINION STATEMENT: Epidermal growth factor receptor (EGFR) is commonly overexpressed in many head and neck squamous cell carcinomas (HNSCC). With the success of EGFR inhibition in other cancer types, there was optimism for efficacy in HNSCC. Unfortunately, the clinical outcomes of EGFR-directed therapy have not provided overwhelming benefit. In the curative-intent setting, cisplatin has proven superior over cetuximab, an EGFR monoclonal antibody, in multiple large trials, and cisplatin should continue to be the treatment of choice when administered with definitive or adjuvant radiation. For cisplatin-ineligible patients, we prefer carboplatin-based treatment over cetuximab. We reserve cetuximab for a small group of patients who are eligible for radiation and systemic treatment but have contraindications to any platinum therapy. The role of EGFR inhibitors in the recurrent/metastatic setting is more robust. Although supplanted by immunotherapy as front-line treatment, cetuximab remains a meaningful second-line option for patients who have progressed on immune checkpoint inhibitors. Overall, EGFR-directed therapies have been of modest value in the treatment of both locally advanced and metastatic HNSCC. The future of EGFR-directed therapies will likely develop from exploring combination therapies, especially with immunotherapy. Early evidence suggests synergistic effects allowing for a more robust immune response, which holds promise for novel regimens in the treatment of HNSCC.

Impact of Routine Surveillance Imaging on Recurrence in Sinonasal Malignancies.

BACKGROUND/AIM: There is significant variation in post-treatment surveillance imaging for sinonasal malignancies. This study examined the utility of surveillance imaging in detecting recurrence in patients treated for sinonasal malignancies. PATIENTS AND METHODS: We performed a retrospective review on an IRB-approved dataset of patients with sinonasal malignancies treated at a single institution between 2005 to 2021. Patients were categorized into groups based on the frequency of annual imaging and total number of imaging studies. We compared time-to-recurrence between the groups using log-rank test. A two-sided p-value of <0.05 was considered as the threshold for significance. RESULTS: A total of 93 patients were eligible for this study with a median follow up of 42.3 months and 25.8% (n=24) of patients had documented recurrence. Sensitivity and specificity for recurrence based on computed tomography (CT) scans within one year of treatment completion were 50.0% and 19.5%; positron emission tomography/CT was 90.0% and 19.5%; and magnetic resonance imaging was 60.0% and 61.0%, respectively. Regardless of the type of imaging, symptomatic presentation after treatment had a specificity of 91.0% with a positive likelihood ratio of recurrence of 2.95 (95%CI=1.06-8.22). The frequency of scans was not associated with the risk of recurrence (HR=0.55; 95%CI=0.23-1.29, p=0.17). Similarly, no association was noted between the total number of scans and risk of recurrence (HR=0.64; 95%CI=0.27-1.51, p=0.31). CONCLUSION: The total number of frequency of scans within the first year after treatment had no association with time to recurrence of sinonasal malignancies. Symptomatic presentation was strongly associated with recurrence and should be investigated with appropriate imaging.

Presence of CrkI-containing microvesicles in squamous cell carcinomas could have ramifications on tumor biology and cancer therapeutics.

Recently, we described a phenomenon whereby apoptotic cells generate and release CrkI-containing microvesicles, which stimulate proliferation in surrounding cells upon contact to compensate for their own demise. We termed these microvesicles "ACPSVs" for Apoptotic Compensatory Proliferation Signaling microvesicles. As immune cells and a majority of current cancer therapeutics destroy tumor cells primarily by apoptosis, we conducted a small pilot study to assess the possibility that ACPSVs may also be generated in squamous cell carcinomas. We first evaluated a primary and a metastatic squamous cell carcinoma cancer cell lines for their ability to produce ACPSVs under normal and apoptotic conditions. We next conducted a pilot study to assess the occurrence of ACPSVs in solid tumors extracted from 20 cancer patients with squamous cell carcinomas. Both cancer cell lines produced copious amounts of ACPSVs under apoptotic conditions. Interestingly, the metastatic squamous cell carcinoma cancer cell line also produced high levels of ACPSVs under healthy condition, suggesting that the ability to generate ACPSVs may be hijacked by these cells. Importantly, ACPSVs were also abundant in the solid tumors of all squamous cell carcinoma cancer patients. Detection of ACPSVs in cancer has potentially important ramifications in tumor biology and cancer therapeutics which warrants further investigation.

A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study.

INTRODUCTION: Previous studies have evaluated stereotactic body radiotherapy (SBRT) in oligometastatic patients with NSCLC, including multimodality treatment with anti-programmed cell death protein-1 monotherapy. Questions remain regarding the timing of SBRT and immunotherapy, safety with dual checkpoint blockade, and the utility in widely metastatic patients. This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to evaluate safety and obtain preliminary activity data. METHODS: Treatment-naive patients with metastatic NSCLC were randomized to concurrent (SBRT with immunotherapy) or sequential (SBRT followed by immunotherapy) treatment. A maximum of four treatment fields received SBRT. Nivolumab and ipilimumab were continued until clinical progression, development of toxicity, or after 2 years. Dose-limiting toxicity was defined as greater than or equal to grade 3 toxicity to the relevant organ system attributed to SBRT and immunotherapy occuring within 3 months. RESULTS: A total of 37 patients were assessable. No dose-limiting toxicity occurred in the concurrent cohort (n = 18). The sequential cohort required a dose reduction in the central lung group owing to two grade 4 pneumonitis events (2 of 19). Overall best response was as follows: 5.4% (2 of 37) complete response, 40.5% (15 of 37) partial response, 16.2% (6 of 37) stable disease, and 37.8% (14 of 37) progressive disease. Median progression-free survival was 5.8 months (95% confidence interval: 3.6-11.4 mo), with median follow-up of 17.0 months. Median overall survival was not reached. CONCLUSIONS: Concurrent nivolumab, ipilimumab, and SBRT were not more toxic than sequential therapy, and multisite SBRT was well tolerated in widely metastatic patients. Multimodality therapy resulted in durable metastasis control and encouraging early overall survival.

A phase I trial adding poly(ADP-ribose) polymerase inhibitor veliparib to induction carboplatin-paclitaxel in patients with head and neck squamous cell carcinoma: Alliance A091101.

OBJECTIVES: We report the results of this phase I study to evaluate the maximum tolerated dose (MTD) and safety of veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin and paclitaxel induction chemotherapy (IC) for locoregionally advanced head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: In a 3 + 3 cohort design, patients with stage IVA-B human papillomavirus-negative HNSCC received 2 cycles of carboplatin (AUC 6, day 1), paclitaxel (100 mg/m2, days 1, 8, 15) and veliparib (days 1-7) every 21 days followed by standard curative-intent chemoradiotherapy. Primary endpoint: MTD and recommended phase II dose (RP2D) as determined by the first IC cycle. RESULTS: Twenty patients enrolled. Two withdrew before treatment; 18 patients were analyzed. Median age was 63 years. Primary disease sites included hypopharynx (n = 5), larynx (n = 5), oral cavity (n = 4), oropharynx (n = 3), and nasal cavity (n = 1). Through all of IC, the most common grade 3 + adverse events (AEs) were neutropenia (33%), thrombocytopenia (33%), anemia (11%), and white blood cell decrease (11%). One patient experienced a hematologic DLT at 350 mg BID. The RP2D for veliparib combined with carboplatin/paclitaxel is 350 mg BID. With 40.9 month median follow-up across dose levels for all patients, the 24-month overall and progression free survival was 77.8% (95% CI 60.8-99.6%) and 66.7% (95% CI 48.1-92.4%), respectively. Medians have not been reached. CONCLUSION: Addition of veliparib to carboplatin and paclitaxel IC was well tolerated in patients with advanced HNSCC. Hematologic toxicities were the most common AEs.

Management of Early Head and Neck Cancer in Elderly Patients.

Head and neck squamous cell carcinoma (HNSCC) frequently affects elderly patients. Given the frailty and comorbid conditions of this population as well as the potential toxicities associated with treatment, there is a risk of undertreatment in older patients. However, there is growing evidence that benefit with standard treatment is similar in the elderly and in younger patients. Few prospective trials specifically target the elderly, which forces clinicians to rely on subgroup analyses and retrospective data. Therefore, adequate pretreatment assessments are vital to anticipate factors that may contribute to morbidity during therapy. In addition, supportive care during treatment is essential. For patients of all ages who present with early or localized disease, curative treatment should be offered whenever possible. With more precise surgical and radiologic techniques, the ability to provide curative treatment while minimizing long-term toxicity has greatly improved. Not only our techniques but also our understanding of the disease have improved. Human papillomavirus (HPV)-related HNSCC has changed the treatment paradigm of advanced-stage disease because of the inherently better prognosis compared with tobacco- and alcohol-related HNSCC. How this will affect early-stage disease remains to be seen, but de-escalated therapy may prove a suitable strategy in eligible elderly patients. With improved therapies and understanding of the disease, additional prospective trials must be carried out in the elderly population.

Predicting Acute Renal Injury in Cancer Patients Receiving Cisplatin Using Urinary Neutrophil Gelatinase-Associated Lipocalin and Cystatin C.

Acute kidney injury (AKI) limits cisplatin use. We tested whether urine cystatin C (uCyC) and neutrophil gelatinase-associated lipocalin (uNGAL) can preidentify patients at risk for AKI. Patients initiating cisplatin-based chemotherapy were prospectively enrolled. uNGAL/uCyC were measured pre/post-cisplatin administration and compared with serum creatinine (sCr). AKI was defined as sCr increase ≥50% or ≥0.3 mg/dL above baseline. In all, 102 patients were enrolled; 95 provided evaluable data. Twenty-five patients developed AKI. Median baseline and pre-cisplatin uNGAL levels were significantly higher in AKI patients. Although immediate changes in uNGAL/uCyC 2 h after cisplatin were not detectable, post-cisplatin peak values over the course of therapy were markedly and significantly elevated in AKI patients. In multivariate modeling with age, baseline glomerular filtration rate, and histology, maximum uCyC was a significant independent AKI predictor. These findings suggest pre-cisplatin uNGAL and peak uCyC levels can identify patients with increased AKI risk, potentially allowing for tailored modification of cisplatin-based treatment regimens.