Comparative effectiveness of primary tumor resection in patients with stage III pancreatic adenocarcinoma

The incidence of pancreatic ductal adenocarcinoma (PDA) continues to increase. In 2017, an estimated 53670 new cases (female: 25700; male: 27970) of pancreatic cancer were diagnosed within the US and 43090 individuals (female: 20790; male: 22300) were expected to die of the tumor [1]. Primary tumor resection (PTR) is the only curative modality, while more than 80% of tumors were unresectable when present [2]. The 5-year survival of patients with PDA after surgery is approximately 20% (the median survival is 15–23 months) [3‐8].

According to American Joint Committee on Cancer (AJCC) classification version 6, patients with stage III PDA (tumors involved celiac axis and/or superior mesenteric artery) can be divided into borderline resectable and unresectable, depending on the extent of the tumor encasement of major vessels [2, 5, 6]. Previously, chemoradiotherapy has been carried out to reduce the risk of a positive surgical margin and distant metastasis [2, 4, 9]. Since the FOLFIRINOX regimen (irinotecan, oxaliplatin, leucovorin, and fluorouracil) was introduced in 2011 by a prospective randomized controlled trial [10], it has been reported to result in objective response rates that were 2–3 fold higher than other regimens in PDA [11]. Several studies have confirmed that a large number of cases even with locally advanced and unresectable PDA can be converted to be resectable by FOLFIRINOX [12‐14].

Previous publications have reported a discrepant overall survival of PDA patients with advanced disease undergoing PTR and vascular reconstruction (the median survival ranged from 12 to 35 months) [15‐18]. Owing to the varying outcomes regarding to the long-term survival of underline resectable PDA receiving PTR, we designed a population-based cohort study to explore the independent role of PTR in patients with stage III PDA (S-III PDA). We utilized an instrumental variable (IV) analysis to determine variation in outcomes across geographical areas that were different in PTR rates. The IV analysis is aimed to control for potential unknown confounding factors in decision making for surgeries [19, 20]. In the present study, PTR rates in various Health Service Areas (HSA) was employed as our instrument. The treatment option (PTR or non-PTR) for marginal patients (those with a borderline or uncertain need for PTR) may be affected by preferences, beliefs, or surgical skills of surgeons in their HSAs. Patients with S-III PDA would be performed PTR in a high-use HSA, while not in a low-use HSA [21, 22]. The coefficient in the IV analysis represents the adjusted treatment effect for the marginal population rather than the average treatment effect [21].

Pancreatic resection is associated with better outcomes for early-stage PDA. [27] However, for patients with underline resectable PDA, though chemotherapy regimen such as FOLFIRINOX increased the tumor resectability, the long-term survival (OS and DSS) in this study was comparable to those receiving non-surgery treatment in IV analyses. This conclusion is inconsistent with previous studies demonstrating that S-III PDA patients had a better survival after PTR compared to those without surgery [15, 18, 28‐30].

Among previous studies related to PTR versus non-surgical management in cases with advanced PDA, there were two randomized controlled trials (RCTs) [28, 29] comparing PTR versus non-surgical treatments in cases with underline resectable PDA. Both RCTs included patients with locally advanced PDA invading the serosa anteriorly or retroperitoneum posteriorly or involving the major vascular structures. One RCT enrolled cases with PDA in different location of the pancreas and another included only cases with tumor in the pancreatic head or neck. Both studies demonstrated that patients receiving PTR and vascular resection and reconstruction had longer survival compared to patients only undergoing non-surgery treatment such as chemoradiotherapy. However, both researches were at high risk of bias and only a small number of patients (47 and 51 patients in two studies, respectively) were included.

In this study, utilizing IV analyses, we concluded that patients with S-III PDA receiving PTR had a similar long-term prognosis compared to those without PTR (only receive non-surgery treatments). We have applied both traditional regression analyses and propensity score methods to explore relations between surgical methods and long-term survival. However, these analytic methods cannot adjust for unknown confounding factors [15, 26]. In contrast, results from IV analyses (2SRI model) were observed to be more close to outcomes from RCTs [26]. Given the lack of high-quality RCTs associated with PTR vs. none for PDA patients, results of IV analyses may represent the best evidence available to guide treatment decision-making. It should be noted that IV analyses estimate the treatment effect on the marginal population rather than the average treatment effect of PTR [19, 21]. The marginal population represents the population that would receive PTR in a high-use HSA but not in a low-use HSA. The IV analysis does not rely on defining the specific clinical parameters of these populations. Instead, it is based on the hypothesis that patients reside randomly around hospitals and some patients are treated differently in different centers.

There are several limitations to this study. First, although we have acquired the data related to the chemotherapy from SEER database, the detailed regimens and the timing of chemotherapy were yet inaccessible. Patients without chemotherapy or with unknown data of chemotherapy accounted for nearly 80% of patients with pancreatic cancer. In addition, we cannot divide S-III PDA into borderline resectable and unresectable groups based on the extension of tumor invasion, thus we cannot assess whether patients with surgical resection was well chosen. The proportion of patients with R0 tumor resection could not be confirmed in this study. Second, patient performance status and presence of comorbidities are risk factors for patient prognosis. However, the SEER database does not provide these data, thus we cannot adjust these factors by multivariable analyses. Third, details on postoperative morbidities were extremely limited, thus we could not evaluate the influence of treatment methods to the short-term prognosis. Fourth, the observations of this study should be interpreted cautiously, due to some patients with unknown covariates in the SEER database were excluded from the analyses. Finally, even though treatment rate (PTR rate) is a useful practical IV, there remains potential for instrument-outcome confounding, such as receipt of other treatments also associated with our instrument and the outcome. In addition, IV analysis only estimates the effect on marginal population, while the marginal population excludes patients who would always or never receive PTR, focusing on PDA patients whose indications for PTR are more uncertain (Fig. 3). [20, 26, 31]

In conclusion, by integrating results from multivariate COX regression, PSM models and IV analysis, our study demonstrated that PTR provided similar overall and tumor-specific survival benefits in cases with stage III PDA compared to patients with palliative treatments. Further high-quality prospective randomized trials are needed to validate this conclusion and further investigations are required to identify late-stage patients suitable for PTR.