Impact of prolonged surgical waiting time on cancer-specific mortality in stage I–II pancreatic ductal adenocarcinoma patients who received radical resection

Introduction

Pancreatic cancer is the seventh leading cause of cancer-related death in the world (1). It is expected to become the second leading cause of cancer-related death in the US by 2030 (2). Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers (3), with a 5-year overall survival (OS) of less than 10% (3-5). Surgery remains the potentially curative treatment (6). However, only about 15–20% of patients are considered suitable for surgical resection (7).

Previous studies have reported that the surgical waiting time (SWT) of cancer shows an increasing trend; this includes breast, prostate, lung, colorectal, and pancreatic cancers (8,9). Prolonged SWT is especially concerning for patients with cancer because it may raise the risk of metastasis, deteriorate the patient’s condition, and increase anxiety (10). Some studies have shown that prolonged SWT can adversely affect the prognosis of cancers, including melanoma, renal cancer, and breast cancer (11-13). However, its role in pancreatic cancer is controversial (8,14-22). In most of these studies, the multivariate Cox model was used to analyze the relationship between prolonged SWT and survival of patients with pancreatic cancer. In the medical field, competing events are common. These events have the potential to influence the occurrence of a specific event or hinder its observation. Examples of such events include suicide, accidents, and death caused by other cancers. It is important for researchers to consider these factors when studying death caused by specific cancers (23). However, the Cox model does not take competing events into account and may produce erroneous and biased results (24,25).

The Surveillance, Epidemiology, and End Results (SEER) database, which includes incidence, survival, and mortality data, is a system of population-based cancer registries covering approximately 28% of the US population (26). It was suitable to explore the effect of prolonged SWT on cancer-specific death. To avoid competitive risk bias, we used the multivariate competing risk model to assess the relationship between SWT and PDAC-specific mortality (PSM) in patients with stage I–II who received radical resection; the primary event of interest was PSM, while the competing events were death from non-PDAC and other non-cancer causes. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-518/rc).

Methods

Patient selection

The patients’ data were extracted from the SEER database (Incidence-SEER Research Plus Data, 17 Registries, Nov 2021 Sub). Patients who were pathologically diagnosed with primary PDAC and aged ≥18 years between 2007 and 2017 were selected based on the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) (Codes: 8140/3 and 8500/3). Patients were staged using the 7th edition of the American Joint Committee on Cancer staging system, which is the most current staging system in the SEER database (11). The exclusion criteria were as follows: (I) tumor stage III, IV, or unknown, (II) not undergone radical resection, (III) received systemic therapy or radiotherapy before surgery or unknown treatment order, (IV) period from diagnosis to treatment: ≥4 months or unknown, and (V) survival time less than 1 month. The detailed exclusion process is shown in Figure 1. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval of this publicly available information provided by the SEER program was not required.

Figure 1 Flowchart of exclusion criteria. PDAC, pancreatic ductal adenocarcinoma.

Outcome and variables

The primary outcome is PSM, which is defined as having PDAC as the primary cause of death during the follow-up period. The follow-up endpoint was November 2021. The primary event of interest was PSM, while the competing events were death from non-PDAC and other unknown causes (accounting for 9.9% of all deaths). The exposure factor is SWT, which is defined as the time from diagnosis to receive surgical resection. We divided the SWT into three groups: <1 month, ≥1–<2 months, and ≥2–<4 months. For survival analysis, the confounding variables included sex (male and female), age at diagnosis (<60 years, 60–69 years, and ≥70 years), race (white, black, other, and unknown), marital status (married, unmarried, and unknown), primary tumor site (head, body, tail, overlap, and other), tumor size (≤2 cm, >2 to ≤4 cm, >4 cm, and unknown), adjuvant therapy (received chemotherapy and/or radiotherapy and did not receive either treatment), tumor grade (grade I + II, grade III + IV, and unknown), and tumor stage (stage I and II).

Statistical analysis

The required demographic and clinicopathological information were collected using the SEER*Stat 8.4.0.1 software. The baseline characteristics are expressed as numbers and percentages. In the trends analysis, the association between year of diagnosis and SWT was represented using bar graphs. A logistic regression model was used to assess the independent factors affecting SWT (<1 vs. ≥1 month). Multivariate Fine-Gray competing risk analysis was performed to determine the association between prolonged SWT and PSM. Data analyses were performed using the R software (version 4.1.0). All tests were two-sided, and P values <0.05 indicated statistical significance.

Sensitivity analysis

We conducted a sensitivity analysis to verify the results of the survival analysis. We identified missing data of four variables in the entire cohort: race (unknown in 16/8,309, 0.19%), marital status (unknown in 266/8,309, 3.20%), tumor size (unknown in 109/8,309, 1.31%), and tumor grade (unknown in 273/8,309, 3.29%). Multiple imputations were used to address the missing data by chained equations using MICE of the R package (27). We generated 10 imputed datasets, and multivariate competing risk analyses were then performed on each of the imputed datasets. Finally, the 10 estimates were pooled using Rubin’s rules (28,29).

Results

Patient characteristics

A total of 8,562 patients were included in the trends and predictors analysis, and 8,309 patients were involved in the survival analysis. The baseline characteristics for survival analysis are listed in Table 1. The majority of patients were aged ≥60 years (74.64%), white (80.95%), and married (61.80%); had tumor size of >2 to ≤4 cm (57.09%), tumor grade I + II (61.10%), and tumor stage II (89.40%); underwent pancreaticoduodenectomy (74.45%); and received adjuvant therapy (71.78%). The most frequent primary site was the head of the pancreas (74.58%). The proportion of male patients (50.61%) was similar to that of female patients (49.39%).

Trends

From 2007 to 2017, SWT showed an increasing trend (Figure 2). The proportion of patients with SWT of <1 month decreased from 54.04% to 46.15%; however, the proportion of patients with 1≤ SWT <2 months and 2≤ SWT <4 months had increasing trends (from 34.92% to 39.86% and from 10.14% to 12.69%, respectively). The proportion of patients with SWT of ≥4 months was approximately 1%, and it did not change over the study period (Figure 2A,2B). In terms of tumor stage I, the proportion of patients with SWT of <1 month decreased from 60.22% to 53.60%; however, the proportion of patients with 2≤ SWT <4 months increased from 7.73% to 13.07%. The proportion of patients with 1≤ SWT <2 months was approximately 31%, and it remained stable over the study period (Figure 2C,2D). In terms of tumor stage II, the patterns of change in the proportion of patients with tumor stage II were similar to that of the entire cohort (SWT of <1 month: from 53.19% to 45.38%, 1≤ SWT <2 months: from 35.39% to 40.72%, and 2≤ SWT <4 months: from 10.47% to 12.65%) (Figure 2E,2F). The majority of patients with PDAC underwent radical resection within 2 months after diagnosis.

Figure 2 Number and proportion of patients with surgical waiting time from 2007 to 2017. (A,B) All tumor stages, (C,D) tumor stage I, (E,F) tumor stage II. SWT, surgical waiting time.

Predictors of prolonged SWT

The results of multivariate logistic analysis are presented in Table 2. Patients aged ≥60 years [60–69 years, odds ratio (OR): 1.20, 95% confidence interval (CI): 1.07–1.34; ≥70 years, OR: 1.43, 95% CI: 1.28–1.59] and having pancreatic body cancer (OR: 1.37, 95% CI: 1.15–1.63), tumor size >2 cm (>2 to ≤4 cm, OR: 1.20, 95% CI: 1.06–1.35; >4 cm, OR: 1.25, 95% CI: 1.09–1.45), and tumor stage II (OR: 1.26, 95% CI: 1.09–1.46) were independently associated with a prolonged SWT (≥1 month). Patients who were married (OR: 0.91, 95% CI: 0.82–0.99) and had pancreatic tail cancer (OR: 0.75, 95% CI: 0.65–0.88) were independently associated with a shorter SWT (<1 month).

Survival analysis

In the multivariate analysis, after adjusting for confounding variables, 1≤ SWT <2 months was not associated with PSM [hazard ratio (HR): 0.95, 95% CI: 0.90–1.00], while 2≤ SWT <4 months had a lower risk of PSM than SWT of <1 month (HR: 0.91, 95% CI: 0.84–0.99). For subgroup analysis, prolonged SWT was not independently associated with PSM (1≤ SWT <2 months, HR: 1.20, 95% CI: 0.98–1.48; 2≤ SWT <4 months, HR: 1.07, 95% CI: 0.75–1.52) in patients with tumor stage I. However, prolonged of SWT was independently associated with PSM (1≤ SWT <2 months, HR: 0.93, 95% CI: 0.88–0.99; 2≤ SWT <4 months, HR: 0.90, 95% CI: 0.83–0.98, P for trend <0.01) in patients with tumor stage II (Table 3).

Sensitivity analyses

After multiple imputations, the pooled results confirmed the results of the primary survival analysis, which indicated that 1≤ SWT <2 months was not associated with PSM (HR: 0.95, 95% CI: 0.90–1.00), while 2≤ SWT <4 months had a lower risk of PSM than SWT of <1 months (HR: 0.91, 95% CI: 0.84–0.99).

Discussion

This study is the first to report the effect of prolonged SWT on PSM.We found an increasing rate of prolonged SWT in patients with PDAC. In addition, the indicators independently associated with prolonged SWT were older age, unmarried status, pancreatic body cancer, tumor size >2 cm, and tumor stage II. In the survival analysis, we found that SWT does not significantly impair survival in successfully resected PDAC.

Previous studies have reported that the SWT of cancer has an increasing trend; this includes breast, prostate, lung, colorectal, and pancreatic cancers (8,9). Our results are consistent with these findings. Further, high-volume hospital visits have been reported as a cause of prolonged SWT (30). Patients were referred to high-volume academic hospitals for treatment, resulting in surgical centralization and increased travel burden (31); prolonged SWT is an inevitable result. Other reasons associated with prolonged SWT include older age, having comorbidities, and having medicare insurance (8,20).

In previous studies, the effect of prolonged SWT on the prognosis of patients with pancreatic cancer showed inconsistent results. Several studies with a small sample size showed that prolonged SWT was not associated with OS (14-19). However, two other studies showed that prolonged SWT was associated with improved OS (21,22). Recently, two studies with a large sample size from the National Cancer Database (NCDB) also showed contradictory results. Swords et al. found that prolonged SWT was independently associated with improved OS (8). However, Mirkin et al. found that prolonged SWT between 2 and 12 weeks was not associated with OS (20). To date, no studies have elucidated the effect of prolonged SWT on pancreatic cancer-specific mortality. Compared to NCDB, the SEER database contains cancer-specific mortality data (32), allowing us to exclude competitive risk bias and explore the impact of prolonged SWT on PSM using a competitive risk model. Our results showed that prolonged SWT did not impair PSM in successfully resected PDAC. However, the idea that prolonged SWT provides a survival benefit seems biologically implausible; we need to further explore the underlying mechanisms in future studies, especially considering the presence of unmeasured selection bias. For example, prolonged SWT increases the risk of disease progression, leading to some patients being unable to undergo planned curative resection.

Subgroup analysis showed that prolonged SWT does not affect or worsen PSM in patients with stage I PDAC, while prolonged SWT is associated with survival benefits in the tumor stage II group. Ahola et al. found that a significantly higher proportion of patients with progressive stages of PDAC visit high-volume hospitals than low-volume hospitals (33). In addition, visiting high-volume hospitals has been reported to be a cause of prolonged SWT (30). Meanwhile, some studies have shown that patients admitted to high-volume hospitals had improved OS (33,34). A plausible explanation for subgroup analysis is that compared to patients with tumor stage I, more patients with tumor stage II were referred or admitted to high-volume hospitals, resulting in prolonged SWT and improved survival. Such speculation is beyond the scope of the current study and needs to be verified by further research.

This study has several limitations. First, since this is a retrospective study, selection bias cannot be avoided. Second, due to the inherent limitations of the SEER database, we were unable to include some patients who were originally scheduled for resection but later abandoned due to disease progression. Third, the exact number of days from diagnosis to treatment cannot be obtained from the SEER database; therefore, we could not assess the impact of prolonged SWT on prognosis based on the days of SWT. Fourth, some unmeasured confounding factors could have existed, such as comorbidity and hospital volume. Therefore, we could not assess the effect of these confounding factors on survival.

Conclusions

Taken together, we found that prolonged SWT does not affect or worsen PSM of patients with stage I–II PDAC who underwent successful radical resection. This suggests that allowing time for medical optimization may be safe. Our findings offer useful evidence about the association between prolonged SWT and PSM, which may relieve patients’ and doctors’ psychological stress related to delayed surgery to some extent. However, we need to further explore the underlying mechanism of this phenomenon.

Acknowledgments

The authors acknowledge contributions from SEER program.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-518/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-518/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-518/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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