Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study

Pancreatic cancer (PaC) is one of the deadliest malignancies worldwide; > 340,000 individuals receive this diagnosis annually with similar incidence and mortality rates [1]. PaC incidence is especially high in developed countries, being the fourth leading cause of cancer-related deaths in Western societies [2]. In the EU, PaC incidence has been stable or moderately increasing over the past decades, and it was estimated to have caused 91,500 deaths in 2017 and to cause 111,500 deaths in 2025, potentially becoming the third leading cause of cancer death [3].

The prognosis for PaC is poor, with 5-year survival of only ~ 5% [4]. Due to lack of effective early screening methods, more than half of PaCs are detected at advanced stages and are treated largely palliatively [5, 6]. According to the current guidelines [7‐11], only tumor-node-metastasis (TNM) stages I–II PaCs are usually resectable, although the resectability criteria are differentially and arguably defined [12]. While resection could markedly improve the long-term survival in selected patients, less than one-fifth of diagnosed cases are considered eligible for resection [5, 10]. Patients with resectable PaC who undergo resection have much better survival rates than those who cannot undergo resection [8, 10].

We previously described the low and varying resection rates for PaC in Europe and the USA [13]. When counseling PaC patients who are considering surgery or who have already undergone resection, it is important to provide survival estimates for the resected subgroup. However, at this time, population-based survival estimates are only available for overall patients without differentiation by resection or TNM stage [4], according to which, however, survival might vary greatly. Survival odds in resected PaC data from institutional reports would be accompanied with relatively high patient selection, making the generalizability questionable. Based on multiple national databases, this large investigation aimed to comprehensively and robustly provide 1-month to 5-year overall survival estimates at the population level for overall (resected and unresected) and resected PaC patients diagnosed in the early twenty-first century in Europe and the USA stratified by TNM stage and age. Furthermore, survival trends over time in each country were explored.

This comprehensive, multinational, large-scale, population-based investigation provided overall survival estimates for overall patients and those with resected PaC by TNM stage and age. Furthermore, temporal trends for overall and resected cancer patients with clearly resectable (stages I–II) nd mostly unresectable (stages III–IV) PaCs in four European countries and the USA were shown respectively. In both stages I–II and III–IV tumors, survival rates decreased obviously with increasing age. Limited but encouraging progress in survival over time was detected.

According to EUROCARE-5 [4, 14], overall, the 1-, 3-, and 5-year survival rates of patients with PaC diagnosed during 1999–2007 in Europe were only 26%, 9%, and 7%, respectively. For the European countries investigated in this study, the 1-year survival was 19–34% and 5-year survival was 4–11%. In the USA, 5-year survival was 7–10% [16, 17]. Stage- and treatment-specific survival was not provided by the previous reports [4, 14]. Our study provided more up-to-date estimates by including patients diagnosed during 2003–2014 and further showed survival by TNM stage and age. Survival decreased with advancing stage and age. It is important to provide stratified survival for clinical counseling.

Guidelines [7‐11] state that localized PaCs (stages I–II) are mostly resectable, while T4/stage III and M1/stage IV diseases are largely unresectable. Our results showed that resected patients with stages I–II PaCs had higher survival estimates in all age groups compared to the commonly reported and widely available overall ones. For example, resected patients < 60 years had 3–19%, 1–13%, and 1–9% units higher 1-, 3-, and 5-year survival than overall across countries, respectively. These differences may reflect effects of both resection and selection of fitter patients for resection. Given that most patients would perceive a general PaC prognosis as dismal and thus feel extremely distressed, also generating great burdens to their caregivers, it would be important to show them the objective survival data, especially for the resected patients, potentially rebuilding hope of life.

Survival in patients with stages III–IV PaCs, the majority of the diagnosed cases, was much poorer than that in those with stages I–II tumors, especially in the long term. In locally advanced PaC, the average overall survival remains < 1 year [18], and in metastatic tumors, the median survival is < 6 months [19], with 5-year survival of only ~ 2% [5]. We showed that even for those < 60 years, the overall 3- and 5-year survival was as low as 2–5% and 1–4%, respectively. Most patients with stages III–IV PaCs are deemed unresectable [9, 11]. This may, however, improve in the years to come with the increasing use of FOLFIRINOX [20]. In many of the cases where patients with metastatic PaC underwent resection, the metastasis was unexpectedly detected only during surgery [21]. Although resection rates in advanced tumors were low, notably, in stages III–IV PaCs substantially higher survival was observed for resected compared to total patients in all age groups, and resected patients < 70 years could have a 3-year survival of 5–34%. Even in those ≥ 70 years old, higher survival estimates for the resected subgroup were observed (1-year, 16–42% vs. 5–14%; 3-year, 2–14% vs. 1%–1%). While this difference might again at least partly reflect patient selection, i.e., inclusion of healthier patients or those with more favorable tumor characteristics for resection, our results indicated that not all patients with stages III–IV PaC had such a dismal prognosis as suggested by the overall survival estimates. These strong differences again underline the importance of reporting respective outcomes for stratified resected patients for enhanced counseling of these patients.

The perioperative survival is noteworthy, especially for elderly patients. It is volume-dependent, and is mainly influenced by failure to rescue and surgical expertise [22]. While resection could be safely performed for some proportion of the typically more vulnerable elderly patients [23, 24], at the population level, we found that in stages III–IV PaCs, which are associated with poorer general status, the 1-month survival dropped from 94–99% for patients < 70 years to 81–96% for those ≥ 70 years, which was more dramatic compared to results for the stages I–II disease. Age was negatively associated with survival, necessitating it as a stratification factor when providing survival information. Increasing ages are associated with more frequent comorbidities and complications, decreasing the potential survival benefits of resection. However, some studies suggested that, compared to younger individuals, fit elderly patients might obtain similar survival benefits from resection [23, 24]. The better survival observed for the younger patients might be partly explained by the more aggressive therapeutic strategies applied, which might contribute to survival improvements in the fit elderly as well [4]. These possibilities highlight the importance of geriatric assessment before treatment.

No substantial survival changes (5-year, 5–6%) were reported in PaC in the EUROCARE-5 study [4] over the period 1999–2007. In the USA, 5-year survival improved from 6 to 8% between 1992 and 1996 and 2002–2006 [25] and from 8 to 12% between 2002 and 2004 and 2008–2010 [16]; especially for localized tumors, strong improvement in 5-year survival by 7% units from 1998 to 2003 was observed [17]. We observed modest but nevertheless encouraging improvements in survival in patients both with stages I–II and III–IV tumors from 2003 to 2005 to 2009–2011, which potentially reflects the advancement in surgical skill, technique, and perioperative care. In the USA, 3-year survival increased by 4% units in stages I–II PaCs overall, but only by < 1% units in stages III–IV cancers. For resected cancers, survival increased by 5% units among patients with stages I–II cancer. In Europe, 3-year survival for both overall and resected patients with stages I–II PaC increased in all investigated countries, and a large increment was observed in the Netherlands (overall, 8% units; resected, 11% units), where postoperative mortality is decreasing [26]. Notably, centralization agreements were implemented in the Netherlands since 2005, and promoted more resections [27], which might be associated with the continuous improvement in survival [28]. While further major survival advancement in resected patients could be limited even with surgical technique modification, improved outcomes are likely to come from more effective systemic treatments (e.g., FOLFIRINOX) combined with surgery. The different trends between overall and resected patients further highlight the need to offer survival data in specific subgroups.

This study covered the periods when the sixth and seventh TNM staging systems were in effect, and both are compatible/identical with each other [8]. While potentially improved imaging might result in a shift in stage classification, the proportions of each stage remained relatively stable in investigated countries (data not shown). In the era of the eighth TNM staging, where the definitions of the T4 and M1 categories indicating mostly unresectable cancers remain unchanged [29], our results would still be usable for prognosis counseling.

This study was limited by the small case numbers in some subgroups. Further potentially prognostically important factors (e.g., comorbidity) were not considered because they were unknown/unavailable in the national registries of most countries. Although older ages and more advanced tumor stages herein investigated were the most prominent negative prognostic factors and might contraindicate resection, precise and personalized factors should be considered for evaluation of an individual patient’s prognosis. Some prognostic tools (e.g., the nomogram) might offer more precise prognostic information for a specific patient. Non-surgical treatment was not incorporated considering the low sensitivity in recording in some registries and the varying regimens used. Information from more countries would increase the comprehensiveness of the report. However, treatment or TNM staging data were mostly not readily available in the other national population-based registries. Our study was based on complete-case analysis. Differences in data recording, especially of TNM stage, should be noted, and the stages I–II cancer proportion varied from 25% in Norway and Slovenia to 38% in Belgium. There could be underreporting, especially of advanced-stage disease, with various extents, besides the potential impact of missing staging information. These differences highlight the need for standardization in the registration practice. Potential variation in registration practice, especially for stage, might affect outcomes, and inter-country comparisons were not made considering the possible heterogeneity. Results were only analyzed and interpreted independently in the respective country without pooling or comparison with other countries. Results from a specific national registry might not be generalizable to another country. For counseling of patients not in the studied countries, other aspects including treatment profiles and health care systems should be considered.

In the main analyses, we included PaC cases irrespective of microscopic confirmation, which is in accordance with the real-world situation [15] and which is also consistent with the approach in the EUROCARE studies [4, 14]. While resected cases were mostly microscopically confirmed, the confirmation rates for overall cases varied. The microscopic confirmation rates for PaC have been relatively low [4], and PaC has always been difficult to verify microscopically, especially unresectable PaC. In our complete-case study inclusion of patients with known stage might have an impact on the observed confirmation rates. After limiting the overall cases to the microscopically confirmed ones in sensitivity analyses, the survival estimates mostly became higher in all participating countries except in Belgium, where microscopic confirmation rates were high. Furthermore, the survival increase was the most prominent in patients ≥ 70 years old, who are generally more frail and for whom the selection of treatment is usually more cautious. While including microscopically confirmed cases only could help to further increase the chance of selecting real PaC patients, those not receiving any treatment and usually having poorer patient and/or tumor characteristics might be more likely excluded, potentially partly explaining the higher observed survival estimates in the sensitivity analyses.

We showed that it is important to provide survival estimates separately to resected patients for counseling, as the resected subgroup has substantially higher survival than the overall estimation. We did not show the results for unresected PaC patients and avoided direct comparisons between the resected and the unresected, as they may to a large extent reflect selection effects related to factors including patients’ health status and hospital characteristics. In the resected subgroup, curative and palliative resections were not differentiated from each other, considering the greatly geographically and temporally varying standards for defining clear resection margins in PaC surgery.

Nevertheless, the multinational, population-based, large-scale character of this study with the country-specific respective analysis adds important novel survival data to the literature. In particular, results stratified by TNM stage and age for resected and overall patients will further aid patient counseling in clinical practice, providing more specific survival information for specific patient populations.

Our international population-based study provides comprehensive data on survival expectations of resected PaC patients which are substantially higher than the widely available and known dismal survival prognosis for total patients. The benefits of resection cannot be concluded from this observational study. However, the TNM stage- and age-stratified survival results might be helpful for clinical counseling. Estimated survival for advanced-stage disease should be interpreted with caution due to potential underreporting. Patients with advanced stage and/or old age should undergo careful assessment. Limited but encouraging survival improvement is observed.