Oligometastases in pancreatic cancer (Synchronous resections of hepatic oligometastatic pancreatic cancer: Disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis)

Abstract The aim of the present review was to analyze the current data on surgery of synchronous liver metastases in pancreatic ductal adenocarcinoma (PDAC) in curative intent. A review of the literature was carried out to identify the current international concepts regarding surgery of liver metastases of PDAC and, furthermore, we addressed the current challenges of resection of liver metastases of PDAC. Resection of liver metastases in PDAC may provide survival benefit without compromising safety and quality of life in a highly selected group of patients.


| INTRODUC TI ON
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers among gastrointestinal tumors. Incidence and tumor-dependent deaths increase year by year. 1 Because of the tumor's invasiveness and rapid development of lymph node and distant metastases, 5-year overall survival is poor, yet in patients with resectable PDAC, negative resection margins, and no evidence of lymph node metastases, overall 5-year survival can reach 36 months. 2 Although in other types of cancer, progress in therapy and lifetime prolongation for the patient are being made, striking improvements in the therapy of pancreatic cancer are sparse. 3,4 At time of diagnosis, most patients already harbor distant metastases resulting in only 10%-20% of patients being in a curable stage depending on the classification of actual guidelines. The gold standard for patients in stage IV is systemic chemotherapy with FOLFIRINOX or gemcitabine with palliative intent. 5 In 1995, Hellman and Weichselbaum first proposed the clinically significant condition of oligometastasis, which is a state between local and systemic disease, and advocated the potential of curatively intended local treatment. 6 In contrast to many other cancers, resection of hepatic oligometastasis in patients with PDAC is still a controversial issue. Whereas liver and lung metastases are no contraindication for even sequential resections in patients with metastatic colorectal cancer, most surgeons would not carry out any type of resection of distant metastases in PDAC. 2,7 This is mainly based on the high morbidity and mortality of pancreatic resections, the short survival of stage IV patients, and the lack of any randomized controlled trials (RCT). Furthermore, national and international guidelines do not recommend resection in cases of distant metastases. 8,9 Yet, does the principle that the presence of especially synchronous liver metastasis in resectable PDAC denies a curative resection deprive patients of a possible benefit from a simultaneous resection?

R E V I E W A R T I C L E
Oligometastases in pancreatic cancer (Synchronous resections of hepatic oligometastatic pancreatic cancer: Disputing a principle in a time of safe pancreatic operations in a retrospective multicenter analysis) Resection of primary PDAC and synchronous liver metastasis should ideally result in prolonged survival and a longer recurrencefree interval without major surgical-related morbidity and mortality.
Indeed, there are some retrospective studies that showed better survival after resection of hepatic oligometastasis for PDAC. Moreover, staging of the disease has improved greatly and therefore identifying oligometastatic disease, in particular, isolated liver metastasis is far more accurate. Buc et al 10 reported two patients with no recurrence 26 and 24 months after one or two-stage resection of a single liver metastasis and the pancreatic tumor. With these thoughts in mind, we undertook a review of the current literature related to the role of potential curative surgery for hepatic metastasis in PDAC.

| HEPATI C ME TA S TA S E S IN PDAC
Because of the venous drain of the upper gastrointestinal organs via the portal vein, liver metastases are very common and the liver is the most affected organ for distant metastases in PDAC, followed by peritoneum, and lung. 11,12 In most stage IV patients, at the time of Oligometastases means less than five metastases in one organ. 2 As a result of better preoperative imaging, metastases are detected earlier and at smaller size. The probability of detecting lymph node and distant metastases becomes higher, because of better resolution in computed tomography (CT) scans. However, this determines whether or not the patient is in a curable, resectable stage, depending on actual guidelines. 8,9 Nevertheless, up to 12% of patients present liver metastases or peritoneal metastases in the explorative laparotomy, being occult in the preoperative staging. 13 These metastases might be too small to be seen in CT scans or masked because of distinct cholestasis. Cases of young patients with resectable primary and metastases are particular subjects of current discussions.

| CHEMOTHER APY FOR LIVER ME TA S TA S E S IN PDAC
In 2011, Conroy et al 14 conducted a study and randomly assigned 342 patients with metastatic PDAC and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 to receive FOLFIRINOX or gemcitabine. Six months of chemotherapy were recommended in both groups. The authors reported a median overall survival of 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (P < 0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (P < 0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P < 0.001). The authors concluded that, compared with gemcitabine, FOLFIRINOX is associated with a survival advantage yet had increased toxicity. After that study, FOLFIRINOX became the gold standard for first-line treatment of patients with stage IV PDAC. Therefore, all curatively intended surgical procedures, which are now being debated, should achieve a higher median survival rate of at least 11 months.

| SURG ERY FOR LIVER ME TA S TA S E S IN PDAC
Surgical resection of liver metastases in colorectal cancer and for neuroendocrine tumors has shown 5-year survival rates as high as 40%-71% and 61%-76%, respectively. 5 So why is it still such an emotional debate as to whether hepatic oligometastases be resected even when it is technically achievable?
First, although pancreatic surgery became safer as perioperative morbidity and mortality decreased, it is still a challenging field of surgery. Very recently, Nimptsch and colleagues aimed to determine the unbiased mortality rate for pancreatic surgery in Germany. 15 They analyzed the data of 58 000 patients and found a mortality rate that ranged from 7.3% to 22.9%, depending on the procedure (distal vs total pancreatectomy) and on the number of cases carried out by the clinic. Carried out in high-volume centers, mortality rates lie under 5%. 16 Of course, synchronous hepatic resections increase morbidity and mortality, making it a high-risk procedure, although some reports have shown no significant increase in perioperative morbidity or mortality after pancreatectomy with synchronous hepatic metastasectomy. 17,18 Clearly, these operations should only be done in high-volume centers.
Second, as already mentioned, national and international guidelines do not recommend resection in cases of distant metastases in PDAC, 8,9 neither if these appear during the preoperative staging, nor intraoperatively, even if they are technically resectable and even if a R0 situation can be achieved; this is mainly due to the following viewpoint.
There is no evidence from any RCT that synchronous or metachronous resection of liver metastasis in PDAC prolongs survival.
Most data are derived from retrospective single-center studies, lacking any RCT until now ( Table 1).
The largest study so far by Hackert et al 19 reported 85 patients after pancreatic and synchronous or metachronous liver resection. Patients had a median age of 60 years, 96% had three lesions in the liver and 4% had more than three lesions. 19 Surgical morbidity and 30-day mortality after synchronous resection of M1 tumors were 45.0% and 2.9%, respectively. After metachronous resection for liver metastases, surgical morbidity was 21.7% and 30-day mortality was 4.3%. Seventy-three patients completed adjuvant therapy, including gemcitabine as the most commonly given drug. From the timepoint of liver resection, median survival was 12.3 months and 5-year survival was 8.1%. There was no significant difference between the synchronously and metachronously resected patients. Furthermore, there was no survival difference observed with regard to tumor localization in the pancreas (head/ body/tail), number of liver metastases (one vs two vs three or more metastases), size of liver metastases (0-1 cm vs >1 cm) or preoperative CA 19-9 levels. The authors concluded that resection of liver metastases in PDAC can be done safely and should be considered as it may be superior to palliative chemotherapy. 19 Since this paper was published some years ago, most of the patients received gemcitabine. Nowadays, FOLFIRINOX is the gold standard of chemotherapy in metastatic PDAC, but also after curative resection of PDAC. 14,25 Therefore, one might argue that survival would improve further when FOLFIRINOX instead of gemcitabine is given after resection of hepatic metastases in PDAC. After restaging, only 11 patients (8.5%) underwent surgical resection. Noteworthily, the operation was carried out after a median of 12 months from initial diagnosis. The small group of patients that had neoadjuvant chemotherapy with a complete or partial response plus surgery had an impressive median OS of 46 months. 21  Another trial found an OS of 31 months after metachronous resection versus 8 months after synchronous resection.
The OS of the synchronously resected group was even lower than the OS of the chemotherapy group that had no surgery (11 months). 24 The fact of having synchronous or metachronous liver metas-

| WHAT S HOULD B E THE CRITERIA FOR HEPATI C ME TA S TA S E S RE S EC TI ON? WHI CH PATIENTS S HOULD B E S ELEC TED FOR SURG ERY ?
As mentioned earlier, the proper selection of surgical candidate patients seems to be crucial.

| CON CLUS IONS
Surgery for liver metastases in stage IV PDAC patients can be done safely. Adding hepatic resection to pancreatectomy often does not lead to higher mortalities than pancreatic resection alone. Although in some reports mortality rate is up to 9.1%, most of the high-volume centers describe a much lower mortality, minimizing the risk for the patient.

D I SCLOS U R E
Conflicts of Interest: Authors declare no conflicts of interest for this article.