Introduction
Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related deaths worldwide and its annual incidence increased by 2.3 times from 1990 to 2017.[1] In fact, the incidence and mortality of PDAC are nearly equal, and the overall survival of patients with PDAC remains dismal.[2–5] Although surgical resection is the only treatment that can offer prolonged survival and possible cure, only about 20% of patients are diagnosed with resectable disease.
The majority of patients have synchronous metastatic disease at initial presentation. Even after potentially curative resection, around 70% of patients develop recurrence within 2 years.[6–8] The liver is the most common site of distant metastasis from PDAC.[9] Unlike other types of malignancy, such as colorectal cancer and neuroendocrine tumors, there is little evidence supporting surgical resection for metastatic PDAC. Therefore, it is rarely performed in current clinical practice.
However, is metastatic PDAC, especially liver metastases, still a contraindication to surgery in the modern era? Recently, the advent of more effective chemotherapeutic regimens including FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and gemcitabine + nab-paclitaxel, has provided better clinical response and improved survival in patients with metastatic PDAC, with median survival time (MST) of 10.7 to 11.1 months with FOLFIRINOX[2,10] and 8.5 to 13.5 months with gemcitabine + nab-paclitaxel.[11,12] In addition, the effectiveness of FOLFIRINOX for PDAC has been reported in the adjuvant setting as well.[8] Finally, the feasibility of resection of PDAC liver metastases has been reported. This review discusses the potential role of surgical resection for PDAC liver metastases in the modern era.
Survival outcomes and role of surgery for PDAC liver metastases
As opposed to liver metastases from colorectal cancer and neuroendocrine tumors, current national and international guidelines do not recommend resection of PDAC liver metastases,[13,14] as there is little evidence that resection of liver metastases prolongs survival. Most reports regarding resection of PDAC liver metastases are derived from retrospective studies and there are no randomized controlled trials (RCT) so far (Table 1).[15–30]
;)
Table 1: Studies on surgical resection of liver metastases from PDAC
In 2001, Adam et al[15] reported a large-scale survival analysis of patients who underwent hepatic resection for non-colorectal non-endocrine liver metastases. Among 1452 patients, 41 patients had exocrine pancreatic tumors. Of these, the 5-year survival of patients with PDAC, although the number of patients was not described, was 20%. In this study, the authors stratified liver metastases from several tumors into 3 groups based on survival analysis: favorable, intermediate, and poor outcomes. Surprisingly, primary pancreatic tumors including PDAC were classified in the intermediate group, with a 5-year survival rate of 15% to 30%.
Subsequently, several studies investigated long-term outcomes of patients with PDAC liver metastases after resection. One of the largest studies by Hackert et al[24] included 85 patients with synchronous or metachronous PDAC liver metastases. The MST after surgery was 12.3 months and the 5-year survival rate was 8.1%. The authors concluded that resection of PDAC liver metastases can be performed safely and should be considered, as it may be superior to palliative treatment.
Based on this literature review, although MST after resection of PDAC liver metastases is low and ranges between 5.9 and 56 months, some case series reported a potential benefit in selected patients with synchronous and even metachronous disease. In addition, survival after resection of liver metastases may be strongly influenced by variability in inclusion criteria across studies, including perioperative chemotherapy.
Feasibility of liver resection combined with pancreatectomy for PDAC liver metastases
Recent advances in surgical technique and perioperative management have enabled surgeons to perform surgery more safely. Although pancreatic surgery is still challenging, recent studies have reported that pancreatic surgery has become safer and postoperative morbidity and mortality have decreased.[31–39] Accordingly, some studies reported that simultaneous liver resection with pancreatectomy in PDAC patients with synchronous liver metastases could be performed safely, with morbidity and mortality rates of 13% to 62% and 0% to 4.2%, respectively (Table 1). In fact, Hackert et al[24] reported that reoperation and 30-day mortality rates of patients with PDAC liver metastases who underwent pancreas resection with liver resection (n = 62) were comparable to liver resection alone (n = 23) (reoperation rate: 3.2% vs 4.3%, 30-day mortality rate: 1.6% vs 4.3%). These results suggest that simultaneous liver and pancreatic resection for synchronous PDAC liver metastases can be performed with acceptable morbidity and mortality rates in selected patients.
Synchronous and metachronous liver metastases
Three studies compared long-term, post-operative outcomes of patients with synchronous and metachronous PDAC liver metastases. Dunschede et al[18] reported in a retrospective studies of 13 patients that MST was 8 months after synchronous resection versus 31 months after metachronous resection. Zanini et al[21] reported in their retrospective studies of 15 patients that survival after surgery was significantly worse in patients with synchronous metastases than those with metachronous metastases (MST; 8.3 vs 11.4 months, P = 0.038). These 2 studies suggest that metachronous disease could serve as a prognostic factor in patients with PDAC liver metastases after resection. However, the sample size in these studies was too small to draw any conclusions. In comparison, in a larger scale study by Hackert et al[24] including 62 patients with synchronous and 23 patients with metachronous liver metastases, the MST was 10.6 months after synchronous resection and 14.8 months after metachronous resection. Overall, there was no significant difference in patient survival between synchronous and metachronous disease after resection (P = 0.21).
The role of perioperative chemotherapy for liver metastases from PDAC
Palliative chemotherapy is the currently gold standard of treatment for patients with metastatic PDAC.[13,14] However, as already mentioned above, chemotherapeutic regimens such as FOLFIRINOX or gemcitabine + nab-paclitaxel have dramatically improved clinical response and survival in patients with metastatic PDAC.[2,10–12] However, the impact of perioperative chemotherapy on survival after surgery for PDAC liver metastases has not been determined.
In this literature review, preoperative chemotherapy was administered in 9.1% to 100% and postoperative chemotherapy in 35% to 100% of patients (Table 1). Some recent studies included patients who received modern chemotherapy such as FOLFIRINOX or gemcitabine + nab-paclitaxel. Crippa et al[22] reported that among 127 patients with PDAC liver metastases who received primary chemotherapy with various regimens, 56 patients (44%) had a complete (7%) or partial (37%) response, and 11 patients (8.5%) underwent surgical resection with curative intent. The details of the chemotherapy regimens in these 11 patients were as follows; FOLFIRINOX: n = 3, gemcitabine + oxaliplatin: n = 2, cisplatin + capecitabine + gemcitabine + epirubicin: n = 4, cisplatin + capecitabine + gemcitabine + docetaxel: n = 1, cisplatin + epirubicin + fluorouracil + gemcitabine: n = 1. The MST of these resected patients was 39 months, and surprisingly, the MST of patients who underwent surgical resection after chemotherapy with a complete or partial response reached 46 months. The MST of the remaining 116 patients who had chemotherapy only was 11 months.
Another study by Frigerio et al[25] also demonstrated the efficacy of effective preoperative chemotherapy followed by surgical resection. Among 535 patients with metastatic PDAC, 24 patients (4.5%) underwent surgical resection after downstaging with chemotherapy (FOLFIRINOX: n = 16, gemcitabine + nab-paclitaxel: n = 3, gemcitabine lone: n = 5). Downstaging criteria included disappearance of liver metastases and a decrease in carbohydrate antigen (CA) 19-9. R0 resection was achieved in 88% of cases, with 17% achieving complete pathological response, and MST reached 56 months. These remarkably good results is due to the fact that only patients with complete disappearance of liver lesions and a decrease in CA19-9 in response to chemotherapy underwent surgery; if a liver lesion was still evident at laparotomy, fine-needle biopsy was carried out, and if positive, resection was aborted.
For the treatment of PDAC liver metastases, systemic chemotherapy will play a very important role. In particular, preoperative (neoadjuvant) chemotherapy with modern regimens is potentially advantageous for selected patients. In addition, as already mentioned above, a recent RCT already demonstrated the effectiveness of FOLFIRINOX regimen for PDAC in the adjuvant setting.[8] Thus, neoadjuvant/adjuvant chemotherapy and surgery as part of multidisciplinary management could potentially contribute to prolonged survival in patients with metastatic PDAC, especially those with liver metastases.
Prognostic factors for survival in PDAC liver metastases
As with all cancers, appropriate patient selection for surgical treatment is essential. However, there is no clear selection criteria for surgical treatment of patients with PDAC liver metastases. Crippa et al[22] reported that chemotherapy with multiple agents, surgical resection, >5 liver metastases at diagnosis, and CA19-9 reduction <50% of baseline value were independent prognostic factors for survival in 127 patients with PDAC liver metastases, including 11 patients undergoing surgical resection.[22] Previous studies also reported prognostic factors for survival in patients with PDAC liver metastases who underwent resection, including tumor grading (G1/G2 versus G3),[26] resection margin,[26] preoperative chemotherapy,[26] postoperative chemotherapy,[26] timing of metastasis (synchronous versus metachronous),[18,21] and oligometastasis.[30] The concept of “oligometastasis” in cancer was first proposed by Hellman and Weichselbaum[40] as an intermediate state between widespread metastatic disease and localized disease. In other words, distant metastasis to a single or limited number of organs and several metastases consistent with a high potential for a complete resection. Unlike other cancers, surgical resection of oligometastasis from PDAC is still controversial due to its aggressive tumor biology and poor prognosis. However, in reality there are many studies and reviews focusing on oligometastasis in PDAC liver metastases, and they suggest that in a subset of patients with oligometastatic disease, multimodal approach including surgical resection and perioperative chemotherapy may provide prolonged survival.[23,24,30,41–43]
Conclusion
Surgical resection for PDAC liver metastases can be performed safely, even in combination with pancreatectomy. However, only a highly selected population of patients can benefit from surgical resection. At present, appropriate patient selection remains a challenge. Tumor grading of the primary, R0 resection, metachronous disease, oligometastasis, and neoadjuvant chemotherapy appear to be positive prognostic factors for survival. Because responding to chemotherapy may be a minimum requirement in this strategy, more effective chemotherapy with a higher response rate will play a crucial role. From these viewpoints, FOLFIRINOX or gemcitabine + nab-paclitaxel will occupy an important place in both the neoadjuvant and adjuvant setting, and the advent of more effective chemotherapy with biologic agents is desired. Further prospective large-scale studies are warranted to define the indications and confirm the possible benefit of surgical resection for PDAC liver metastases.
Acknowledgments
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Author contributions
All author participated in research design and writing/revising this paper.
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Conflicts of interest
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