Pancreatic ductal adenocarcinoma (PDAC) is recognized as one of the most aggressive malignant digestive system tumors with a 5-year survival rate less than 10% (1). Because of a high recurrence rate after surgery, the prognosis of pancreatic cancer is dismal even after curative pancreatic resection. The recurrence patterns of PDAC are diverse, with lung metastases being one of the most common sites of distant spread (2, 3). The incidence rates of pulmonary metastases ranging from 2.9% to 21.8% have been reported (4–6). Patients with lung metastases from PDAC tend to have a relatively better prognosis compared to those with other types of hematogenous disseminations, such as liver or peritoneal metastases (7). Median overall survival (OS) after the initial treatment can be varied from 51 to 121 months in metachronous lung metastasis (8).

Chemotherapy is seemed to be the only therapeutic strategy for metastatic pancreatic cancer and surgical resection is generally not recommended. Nonetheless, some studies have shown that resection of the pulmonary metastases in patients with colorectal cancer could prolong survival time (9). In addition, some case reports or case series, as well as few retrospective studies have shown that pulmonary resection of isolated lung metastases is associated with long-term survival in some patients (4, 10, 11). However, the effect of surgical resection on extending the survival is still unclear because the selection of patients with relatively indolent diseases might cause survival benefits after pulmonary resection. Furthermore, oncological outcomes and clinical benefits of pulmonary resection for patients with lung metastases have not been clarified. The aim of our meta-analysis is to evaluate the clinical values of surgical management for lung metastases from PDAC by performing a detailed investigation of postoperative oncological outcomes after pulmonary resection.

This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (12).

Although surgical resection is the only treatment that offers long-term survival in selected patients with resectable pancreatic cancer, among patients who undergo pancreatectomy for PDAC, almost 80% patients develop locoregional and/or distant recurrence after primary pancreatectomy (22). The most common metastatic site is liver, followed by lung (2). Historically, palliative chemotherapy seemed to be the only option for PDAC patients with lung metastases. In recent years, pulmonary metastasectomy has been introduced as a novel treatment (23). We aimed to evaluate the benefits of pulmonary metastasectomy in PDAC patients with lung metastases.

In our meta-analysis, nine articles with 467 PDAC patients with synchronous or metachronous lung metastases were enrolled (10, 14–21). Our pooled analysis showed that pulmonary metastasectomy could significantly improve overall survival of PDAC patients with lung metastases compared to those patients who did not undergo resection of metastatic tumor (the pooled HR: 0.637, 95%CI: 0.531–0.764, I² = 61.5%, p value = 0.008). Meta regression analysis was used to explore the heterogeneity. The p value was 0.045, less than 0.05, and the results indicated that the number of patients who underwent pulmonary metastasectomy might be the source of heterogeneity. Moreover, meta-regression analysis was also used based on the recurrence-free interval (RFI), and the p value was 0.627, suggesting that RFI may not be related to the heterogeneity. We believed that the the number of patients who underwent PM could have a significant impact on the survival, especially in the studies with a small number of patients. The smaller the sample size, the greater the heterogeneity of the results. The heterogeneity caused by publication bias could not be ignored either. In our study, Begg's test and Egger's test were used to evaluate the publication bias, and yielded p-values of 0.048 and 0.001, respectively. The results showed that there was a certain extent of publication bias in our study, which could impact the stability of the pooled results. To mitigate the impact of publication bias in future research, grey literature and unpublished studies should also be inculded. What's more, study design, patient population and treatment protocols might also be the potiential sources of heterogeneity. All included studies were retrospective, which inherently introduces variability in data collection methods and quality. Differences in study design, such as variations in patient selection criteria and the definition of lung metastases, may contribute to the observed heterogeneity. The characteristics of the patient populations varied across studies. Factors such as age, gender distribution, and tumor characteristics (e.g., synchronous vs. metachronous metastases) could influence survival outcomes. Variations in treatment protocols, including the type of pulmonary resection (e.g., wedge resection, segmentectomy, or lobectomy) and the use of adjuvant chemotherapy, could impact survival outcomes as well. The timing and duration of chemotherapy, both before and after pulmonary metastasectomy, may also differ across studies, contributing to the observed heterogeneity. To address this heterogeneity, we conducted subgroup analyses based on the number of patients undergoing pulmonary metastasectomy, the timing of lung metastases, and the RFI. These analyses provided insights into the potential sources of heterogeneity and helped identify subgroups where the benefits of pulmonary metastasectomy may be more pronounced.

Previous studies have revealed that the patients with pulmonary metastases often have a better prognosis than those with metastases at other sites, such as the liver. The prognosis of metastatic PDAC may be related to the duration of recurrence. It has been reported that late recurrence more commonly develops in the lung than in the liver or peritoneum (24). The definition of RFI was the interval between initial primary pancreatectomy and lung metastases. PDAC patients with a longer RFI could receive clinical benefits from pulmonary resection and have a better prognosis (10, 19). In Konishi's study (10), patients with an RFI of <28 months, as expected, had early tumor recurrence, resulting in continuous chemotherapy after lung metastases and poor prognosis, while patients with an RFI of ≥28 months did not have tumor recurrence within 12 months after pulmonary resection and had a longer chemotherapy-free interval. Univariate analyses also revealed that RFI from initial pancreatectomy to lung metastases of ≥28 months was associated with better disease-free survival (DFS) after pulmonary resection. Another study reported, in study of 15 cases, that patients who developed lung metastasis more than 17 months after initial pancreatectomy had a better prognosis compared to those who developed lung metastasis at an earlier time (25). Prolonged RFI from the initial pancreatectomy to the development of lung metastasis could be considered as a prognostic factor of PDAC patients with pulmonary metastases.

The number of lung metastases was also associated with the prognosis of patients. Patients with solitary metastases were more likely to undergo surgical resection and showed a longer median overall survival. In Homma's study, the results of multivariate analysis showed that solitary metastasis was identified as significant prognostic factor after lung resection (HR: 5.03; 95% CI: 1.195–21.144, p = 0.022) (16).

Oligometastases, defined as a state of limited number of metastases, were not equal to solitary metastases, and were considered as an intermediate state between solitary and multiple metastases. which may also benefit from surgical resection. Lung oligometastases were defined as having two to five lesions, based on previous reports on the local treatment of pulmonary metastatic lesions (26, 27). A study has reported that. patients with lung oligometastasis were more likely to undergo surgical resection (41% vs. 0%) and had a significantly better prognosis (41.3 vs. 17.6 months) than those with lung polymetastasis. Oligometastasis (HR, 0.43; 95% CI, 0.24–0.76) was identified as an independent factor predicting favourable OS in PDAC patients with distant metastasis confined to the lung (15). Moreover, the number and location of lung metastases would also determine the method of PM. The modalities for resection of lung metastases were wedge resection, segmentectomy and lobectomy. The type of pneumonectomy also had an effect on prognosis. In general, lobectomy was more thorough than wedge resection, but it also has a greater impact on lung function. Studies have shown that there is no significant difference in overall survival between lobectomy and wedge resection, but lobectomy may provide more complete tumor resection in some cases (28).

The role of chemotherapy was not ignored in the management of PDAC with pulmonary metastases equally. It was widely accepted that multidisciplinary treatment (MDT) was necessary for improving the prognosis of patients with advanced-stage pancreatic cancer (29, 30). In Yun's study, the results of multivariate analyses revealed that chemotherapy (HR = 0.434, p = 0.024), and chemotherapy cycles (HR = 0.300, p < 0.001) had significant effects on survival (17). One study also reported that 24 of 32 patients received adjuvant chemotherapy after pulmonary metastasectomy. The addition of postoperative chemotherapy after pulmonary resection significantly improved the time to recurrence to 41.5 months compared to the group without chemotherapy, and the median time from recurrence to death (RTD) was also longer in patients underwent postoperative chemotherapy (59.0 months vs. 7 months, p = 0.02). In the multivariate analysis, postoperative chemotherapy after metastasectomy (HR: 14.089; 95% CI: 1.729–114.77, p = 0.023) was identified as significant prognostic factors after lung resection (16). In summary, resection of lung metastases, especially lobectomy, combined with long RFI and adjuvant chemotherapy, could significantly improve overall survival of PDAC patients with pulmonary metastases.

While our meta-analysis demonstrates potential survival benefits of pulmonary metastasectomy in PDAC patients with lung metastases, it is crucial to consider the broader clinical context, including perioperative risks and postoperative complications. Patients with pancreatic ductal adenocarcinoma (PDAC) often present with significant systemic disease burdens, which may affect their tolerance to surgery. The decision to proceed with pulmonary metastasectomy should be carefully weighed against the potential risks and benefits for each individual patient. Pulmonary metastasectomy is associated with inherent surgical risks, including anesthesia-related complications, bleeding, infection, and respiratory complications. Given the compromised overall health status of many PDAC patients, these risks may be further exacerbated. Postoperative complications, such as prolonged hospital stays, respiratory failure, and delayed recovery, can significantly impact patient outcomes and quality of life. Therefore, a thorough preoperative assessment is essential to identify patients who are likely to benefit from surgery without undue risk. In addition, stereotactic body radiotherapy (SBRT) might be a promising alternative treatments for managing lung metastases in PDAC patients, offering high local control rates with minimal invasiveness. This approach may be particularly suitable for patients with significant comorbidities or those who are not surgical candidates due to poor performance status. Additionally, multidisciplinary collaboration in selecting patients for pulmonary metastasectomy was crucial for optimizing clinical outcomes.

This meta-analysis has several limitations. Firstly, all the included studies were retrospective. Retrospective studies are inherently prone to selection bias and recall bias, which may significantly influence the interpretation of our findings. Selection bias may arise from the non-randomized allocation of patients to surgical or non-surgical groups, potentially leading to an overestimation of the benefits of pulmonary metastasectomy. Additionally, the reliance on historical data may introduce recall bias, where the accuracy of data collection and reporting may vary between studies. These biases could affect the comparability between the surgical and non-surgical groups, and thus, the observed survival benefits attributed to pulmonary metastasectomy may not be entirely attributable to the intervention itself. Moreover, the retrospective design limits our ability to control for confounding variables that may influence survival outcomes, such as differences in patient demographics, tumor characteristics, and the quality of adjuvant therapies received. While we attempted to mitigate these biases through rigorous study selection criteria and quality assessment using the Newcastle-Ottawa Scale, the inherent limitations of retrospective data cannot be fully overcome. Secondly, the results of Begg's test and Egger's revealed that there was some extent publication bias among included studies. Thirdly, the sample size was relatively small, and large, multicenter RCTs are urgently needed. Moreover, The survival benefit observed in our analysis may not be uniform across all molecular subtypes of PDAC. For instance, patients with specific genetic mutations or biomarker expressions may respond differently to pulmonary metastasectomy. Future research should explore the role of molecular profiling in identifying patients who are most likely to benefit from surgical intervention.

In summary, our meta-analysis revealed that PDAC patients with lung metastases who underwent pulmonary metastasectomy achieved longer survival compared with those who did not. Moreover, patients with long RFI and limited number of metastases are more likely to undergo metastasectomy and have a better survival. However, the retrospective nature of the included studies introduces significant limitations, including selection and recall biases, which may affect the validity of our findings. Therefore, caution should be exercised in interpreting these results. Prospective studies or randomized controlled trials are urgently needed to rigorously evaluate the clinical value of pulmonary metastasectomy in this patient population.