Matthew Old

Background: Reports from several high-income countries have demonstrated a rising incidence of oral tongue cancer (OTC) among younger adults. However, objective, subsite-specific, global incidence data is lacking. This study aimed to investigate OTC incidence trends in younger and older adults globally as well as sex differences among groups.Methods: Data on OTC incident cases were derived from the IARC Cancer Incidence in Five Continents Detailed Volumes X-XII (2003-17). Only registries reporting in all three volumes with a stable covered population were included. Populations were stratified by age, particularly under 45 (early-onset OTC (EO-OTC)) and 45 or older (average-onset OTC). Age-standardized incidence rates were pooled and derived from 2008-2017 for each country. Average period change was estimated by age- and sex-adjusted quasi-Poisson regressions. Countries were compared as paired observations by Wilcoxon signed rank tests.Findings: A total of 17,374 EO and 142,992 average-onset OTC cases were recorded. Nine of the 10 countries with the highest incidence were designated as high-income countries (HICs). Nine of the 45 countries included showed significant EO increases. Increases in incidence in EO trends exceeded increases in average-onset OTC incidence in 30 of 45 countries. Oral tongue was the leading subsite within the OCC (+11.6% per period). Results by sex demonstrated that trends in females exceeded those in males in 29 of 42 countries (p=0.039) for early-onset and in 36 of 45 in average onset (p < 0.0001).Interpretation: EO-OTC is rising globally, with a disproportionate increase in HICs. The oral tongue contributes the majority of incident cases in the OCC and demonstrates the steepest rise of any subsite. The OTC incident shift is female-predominant, regardless of income status, and raises hypotheses about distinct driving etiopathologies.

Study population representativeness

Trial schema for parts 1–3. *Expansion cohort into patients with neuroendocrine tumors (NET). Based on the lack of efficacy in the combination arm, further monotherapy expansion cohorts were abandoned. † Labeled dose/regimen of avelumab. ‡ Combination therapy safety lead in. No attrition was observed.

Part 1 disease response and SPECT/CT positivity

Injection volume, site size and image guidance criteria

IRRs and CRS related to intravenous VV1 monotherapy (part 2).

DLT definition VV1 combination therapy

Serum IFNß and cytokine levels following VV1 monotherapy and in combination with avelumab. A, Mean serum IFNß following IT administration of VV1 monotherapy dose escalation (part 1). Each DL has 3–6 patients. B, Serum IFNβ following 30–90-minute IV infusions of high-dose VV1 (1 × 1011 TCID50) monotherapy (part 2). Each line represents a unique patient (n = 6). C, Mean [95% confidence interval (CI)] serum IFNβ following IV infusions of VV1 (1.7 × 1010 TCID50) monotherapy (part 2). Each dot represents a unique patient (n = 23). Limit of detection for IFNβ was 1.2 pg/mL. D, Mean (95% CI) serum IFNβ over time following 30-minute IV infusions of VV1 (1.7 × 1010 TCID50) + labeled dose/regimen of avelumab (part 3). Each dot represents a unique patient (n = 16). Limit of detection for IFNβ was 1.2 pg/mL. E, Mean (±SEM) cytokine levels following 30-minute IV infusion of VV1 (1.7 × 1010 TCID50) monotherapy (part 2; n = 7). F, Mean (±SEM) cytokine levels following 30-minute IV infusion of high dose VV1 (1 × 1011 TCID50) monotherapy (part 2; n = 6).