Early‐onset pancreatic cancer research: Making sense of confounding and bias

Though relatively uncommon, earlyonset pancreatic cancer (EOPC), generally defined as pancreatic cancer diagnosed in patients younger than 50 years, appears to be increasing in incidence over time. In 2017, the global incidence of pancreatic cancer was highest for men aged 65 to 69 years and for women aged 75 to 79 years. Between 1992 and 2005, the incidence of pancreatic cancer in US patients aged 20 to 49 years old increased 1.5% annually in men and 1.6% annually in women. The relative rarity of EOPC means that data from randomized clinical trials or other prospective studies are scant. Also, there are few large, longitudinal, observational data sources with the necessary granularity about patient, tumor, and treatment details to draw firm conclusions about agerelated differences in biology, presentation, treatment patterns, and outcomes for patients with EOPC. The article by Saadat et al entitled “Treatment Patterns and Survival in Patients With EarlyOnset Pancreatic Cancer” explores characteristics of patients with EOPC in the National Cancer Data Base. This retrospective study adds important findings to the literature by evaluating treatment patterns for patients with EOPC diagnosed from 2004 to 2016; overall, treatment intensity for patients with EOPC has increased over time. This change is consistent with evolving guidelines and clinical trial data about systemic therapy for pancreatic cancer in the neoadjuvant/adjuvant setting and in the advanced setting. Despite this progress, a substantial proportion of patients with EOPC (19%) did not have documented receipt of any therapy. This discordance in practice patterns, although better than that seen for patients with averageageonset pancreatic cancer (AOPC), reflects a huge missed opportunity for appropriate care. Efforts to confirm the treatment pattern trends found in this study should consider sources of potential bias common in observational research. For EOPC, a prominent source of confounding (ie, a variable that influences both a dependent variable such as treatment choice and an outcome of interest such as survival) is age. Because age has both biological and socioeconomic implications, its effect on receipt of treatment and survival may be competing. For example, younger patients may be healthier and, therefore, more likely to undergo intensive treatment that is associated with better outcomes. In contrast, younger patients may also be less likely to seek medical care (patient factor) or to be evaluated for this rare disease (clinician factor); therefore, patients with EOPC may be diagnosed at an advanced stage when outcomes are poorer. Although an upward stage shift for patients with EOPC was not observed in this hospitalbased cohort study, this stage trend is suggested in other populationbased US studies. Thus, findings from this hypothesisgenerating observational study indicate that the net and the individual effects of several sources of potential agerelated bias should be further explored. Other types of confounding common in retrospective studies may be less relevant for patients with EOPC. For example, health comorbidities and frailty are typical confounders for which data are not available (ie, unmeasured confounders). Only confounders that are measured with adequate granularity can be controlled analytically, although sophisticated approaches such as propensity score analysis may be required in complex cases. Because younger patients tend to have fewer comorbidities, healthrelated unmeasured confounding may be a less salient source of potential bias for patients with EOPC. In this analysis, the authors used a multinomial regression approach to describe the association of the treatment received (multimodality vs single modality vs no treatment) with outcome. Patients with EOPC had nearly 4fold higher odds for receiving multimodal therapy than patients with AOPC after adjustments for measured confounders (odds ratio, 3.89; 95% confidence interval, 3.664.15; P < .001). Coupled with the improved survival observed in this study, these