To identify predictors for synchronous liver metastasis from resectable pancreatic ductal adenocarcinoma (PDAC) and assess unresectability of synchronous liver metastasis.

Retrospective records of PDAC patients with synchronous liver metastasis who underwent simultaneous resections of primary PDAC and synchronous liver metastasis, or palliative surgical bypass, were collected from 2007 to 2015. A series of pre-operative clinical parameters, including tumor markers and inflammation-based indices, were analyzed by logistic regression to figure out predictive factors and assess unresectability of synchronous liver metastasis. Cox regression was used to identify prognostic factors in liver-metastasized PDAC patients after surgery, with intention to validate their conformance to the indications of simultaneous resections and palliative surgical bypass. Survival of patients from different groups were analyzed by the Kaplan-Meier method. Intra- and post-operative courses were compared, including complications. PDAC patients with no distant metastases who underwent curative resection served as the control group.

CA125 > 38 U/mL (OR = 12.397, 95%CI: 5.468-28.105, P < 0.001) and diabetes mellitus (OR = 3.343, 95%CI: 1.539-7.262, P = 0.002) independently predicted synchronous liver metastasis from resectable PDAC. CA125 > 62 U/mL (OR = 5.181, 95%CI: 1.612-16.665, P = 0.006) and age > 62 years (OR = 3.921, 95%CI: 1.217-12.632, P = 0.022) correlated with unresectability of synchronous liver metastasis, both of which also indicated a worse long-term outcome of liver-metastasized PDAC patients after surgery. After the simultaneous resections, patients with post-operatively elevated serum CA125 levels had shorter survival than those with post-operatively reduced serum CA125 levels (7.7 mo vs 16.3 mo, P = 0.013). The survival of liver-metastasized PDAC patients who underwent the simultaneous resections was similar to that of non-metastasized PDAC patients who underwent curative pancreatectomy alone (7.0 mo vs 16.9 mo, P < 0.001), with no higher rates of either pancreatic fistula (P = 0.072) or other complications (P = 0.230) and no greater impacts on length of hospital stay (P = 0.602) or post-operative diabetic control (P = 0.479).

The criterion set up by CA125 levels could facilitate careful diagnosis of synchronous liver metastases from PDAC, and prudent selection of appropriate patients for the simultaneous resections.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and progressive malignancy with increasing incidence and death rates[1,2]. Despite the steady improvement in survival for most cancers, progress has been limited for PDAC, for which the 5-year relative survival rate for all stages combined is 8%[2]. The rate of resection for primary PDAC is only 10%-20%, and approximately 50% of new PDAC cases are discovered to have distant metastases[3]. Some distant micro-metastases are undetectable at diagnosis through a thorough pre-operative imaging tests including positron emission tomography/computed tomography (PET/CT), and may only be confirmed by exploration during planned curative resection. Even those patients undergoing curative pancreatectomy are still at a 25%-50% risk of developing distant metastases[4-6]. The dismal prognosis of PDAC with distant metastasis has been acknowledged by its 5-year relative survival rate of 1%[7].

PDAC shows a remarkable preference for the liver to metastasize due to its portal venous blood draining and lymphatic spread. Weh et al[8] summarized that the incidence of liver metastasis from PDAC ranged from 25% to 75%. About 12% of unsuspected liver metastases are not discovered until surgery, and liver metastasis reduces the survival of patients with PDAC to 5 mo[9,10]. Currently, chemotherapy remains the mainstay of treatment for liver metastasis from PDAC, with two combination chemotherapy regimens-FOLFIRINOX (bolus plus infusional fluorouracil, leucovorin, irinotecan, and oxaliplatin regimen) and gemcitabine plus nanoparticle albumin-bound paclitaxel-emerging as new standards[11-13].

The doctrine that the presence of liver metastasis from resectable PDAC contradicts a curative resection and indicates a palliative surgical bypass, deprives patients of an incremental benefit from simultaneous curative resections for primary and metastatic PDAC, even at a R1 status. An unconventional surgical option to curatively resect primary PDAC and synchronous liver metastasis may be merely justified by prolonged survival, a longer recurrence-free interval and, at least, no more surgical-related morbidity and mortality. Pancreaticoduodenectomy (PD) combined with additional organ resection has been indicated for locally advanced PDAC with the same safety as PD alone[14]. Even if palliative PD can be performed instead, patients can benefit from significantly longer survival and low morbidity rate[15,16]. Thus, simultaneous curative resections for primary PDAC and synchronous liver metastasis can also be advocated on highly individual basis. However, the threshold comprised of conventional clinical indexes has not been first established to pre-operatively distinguish the occurrence of liver metastasis among patients with resectable PDAC. And, the criterion also needs to be set for selection for patients whom the simultaneous resections favor in a proper sense.

As the predictive accuracy of serum CA125 levels has been reported in a two-center clinical study where we were involved[17,18], here we highlighted the relationships between serum CA125 levels and both synchronous liver metastasis from PDAC and unresectability of liver-metastasized PDAC, and focused on the long-term outcome of liver-metastasized PDAC patients after individualized surgeries indicated by serum CA125 levels.

Although incidental liver metastases from PDAC identified during surgeries are not an unusual finding to surgeons, intra-operative surprises probably make patients lose opportunities to receive a more rational treatment modality which surgeons have weighed the pros and cons of. Accurate detection of liver metastases from PDAC and proper selection of patients who are likely to benefit from simultaneous curative resections for primary PDAC and synchronous liver metastasis are a great challenge for individualized therapy for PDAC. As pancreatectomy is performed with relatively high morbidity and mortality, assessment of unresectability of synchronous liver metastases under the circumstance of resectable primary PDAC, needs an objective standard using a series of pre-operative clinical parameters. In the present study, we identified a pre-operative serum signature of CA125 levels over 38 U/mL as one of the predictors for synchronous liver metastasis from PDAC. Serum CA125 levels over 62 U/mL were found not only to imply unresectability for synchronous liver metastasis, but also to indicate a poor survival for PDAC patients with synchronous liver metastasis. These suggest that PDAC patients with synchronous liver metastasis predicted by serum CA125 levels over 38 U/mL could be appropriate for and, more importantly, benefit from the simultaneous resections if serum CA125 levels range between 38 U/mL and 62 U/mL.

Since CA125 has been extensively used as a biomarker of various types of cancers, its diagnostic and prognostic values are gradually attracting great attention for PDAC. Recently it was reported in a two-center clinical study that elevated serum CA125 levels were more pronounced in patients with the metastasis-associated burden, especially liver metastasis[17]. Elevated serum CA125 levels in patients with gastric adenocarcinoma were also observed with the presence of peritoneal metastases and lymph node metastases[31,32]. On the contrary to the similar elevated serum CA19-9 levels in all stages of PDAC, serum CA125 levels for PDAC with distant metastasis were shown to be higher than that for early or locally advanced PDAC[33]. Our result indicated that patients with PDAC were more likely to have synchronous liver metastasis if serum CA125 level exceeded 38 U/mL instead of serum CA19-9 level higher than 1000 U/mL. Thus, it is inferred that serum CA125 levels are insensitive to primary PDAC.

In addition to differential diagnosis, serum CA125 levels reflected the extent of liver metastases as well. We found that the median serum CA125 levels of unexpected liver metastases was lower than that of detected liver metastases (52 U/mL vs 72 U/mL, P = 0.009). The median serum CA125 levels of liver metastases with fewer than 5 nodules smaller than 3 cm, or more than 3 nodules larger than 3 cm, or intermediate nodules was, respectively, 37 U/mL, 67 U/mL and 486 U/mL[17]. Of note, even though patients received curative resection for primary PDAC and post-operatively displayed a decrease in serum CA19-9 level, an early distant metastasis and poor survival still troubled those who did not experience a decrease in serum CA125 levels[17,18], as we observed. Furthermore, CA125 expression in PDAC was also found to directly correlate with tumor stage, grade and metastasis[34,35], and to increase along with loss of differentiation of PDAC[35], which denotes the tendency for distant metastasis[36,37]. Primary PDAC expressed CA125 under the same intensity as metastatic lesions did, demonstrating the maintenance of PDAC for CA125 expression during the metastatic process[35]. Therefore, we believe that CA125 is an effective pre-operative factor for monitoring synchronous liver metastasis from PDAC.

Given that CA19-9 can be influenced by obstructive jaundice or pancreatitis[38] and cannot be detected due to lack of the Lewis antigen[39], CA125 characterized by secretory stability is considered more suitable for objective judgement. Regarding the unresectability of cancer, CA125 has been widely utilized as the therapeutic strategy[40-44]. Compared with CA19-9, the most common tumor marker evaluated in patients with PDAC, CA125 as a predictor for unresectability of primary PDAC had a superior ROC area of 0.81, with a cutoff level of 19.7U/mL[45]. Moreover, elevated CA125 levels over the selected threshold could distinguish factually unresectable PDAC from equivocally resectable PDAC judged by multidetector CT[45]. In the present study, we analyzed a series of clinical parameters, including tumor markers, and found that serum CA125 levels over 62 U/mL might signify unresectability of synchronous liver metastasis even if primary PDAC could be curatively resected at a R0 status. Considering that serum CA125 levels also implied the extent of liver metastasis[17] and that the location and number of liver metastases determined the feasibility and method of surgery[46], our findings were quite deducible and rational. Taken together with predictability of synchronous liver metastasis by serum CA125 level over 38 U/mL, a narrow range of serum CA125 level from 38 U/mL to 62 U/mL denoted simultaneous resectability of primary PDAC and synchronous liver metastasis.

In spite of uneventful curative resections, prolonged survival does not necessarily belong to all patients. On one hand, it was demonstrated that resected patients with pre-operative serum CA125 levels over 18.4 U/mL survived less than half of the life time as those with lower serum CA125 levels (11.3 mo vs 25.3 mo)[17]. More importantly, unlike CA19-9, no discrepancies of predictability by CA125 were found in PDAC patients with hyperbilirubinemia[47]. It was determined in the two-center clinical study that the combination of CA19-9 over 1000 U/mL and either CA125 or CEA indicated a worse surgical outcome, with a median survival of 7.0 mo vs 18.2 mo for the validation cohort from our hospital[18]. In addition, as a good response to curative surgery, deceasing CA125 levels after pancreatectomy were associated with longer survival time as well (40.8 mo vs 14.6 mo)[17]. Our data also reflected that patients with elevated serum CA125 levels did not display a survival advantage following the simultaneous resections. Associated with the incidence of liver metastasis, co-expression of CA125 and mesothelin could signify unfavorable outcome in PDAC patients (19.0 mo vs 34.8 mo)[48]. In this study, we showed that pretreatment serum CA125 level over 62 U/mL was useful for indicating a worse outcome for PDAC patients with synchronous liver metastasis. These imply that our surgical option for primary PDAC and synchronous liver metastasis determined by serum CA125 levels does have an impact on patient survival and that the simultaneous curative resections do improve clinical outcome. Aggressive therapeutic regimens may be more advantageous in patients with lower serum CA125 levels.

On the other hand, Dünschede et al[49] claimed shorter survival in patients with synchronous liver metastasis undergoing simultaneous resections than in those treated by gemcitabine (8.0 mo vs 11 mo) despite no statistical differences. However, resection for metachronous liver metastases instead of gemcitabine might extend survival in highly selected patients. Meanwhile, Klein et al[50] reported that no similar survival was achieved by pancreatectomy and simultaneous liver resection for PDAC, albeit at a R0 status, compared with pancreatectomy for non-metastasized PDAC (13.0 mo vs 26.5 mo)[50] (Table 8). On the contrary, we showed that the survival of PDAC patients with synchronous liver metastasis who underwent simultaneous curative resections (15.7 mo) was not only longer than that of those who underwent palliative surgical bypass alone (4.4 mo) but also similar to that of patients with non-metastasized PDAC who underwent curative pancreatectomy alone (16.9 mo). Such discrepancy with the previous two studies can be explained by inconspicuous residual lesion after liver resection misjudged by pre-operative or intra-operative assessment. In accordance with our data, De Jong et al[51] demonstrated that overall survival appeared not to be different in the patients who underwent PD and liver-directed therapy compared with those with no evidence of liver metastasis who underwent PD (17.7 mo vs 17.9 mo). Therefore, our result of Cox regression analysis showing that serum CA125 levels less than 62 U/mL were independently associated with a prolonged survival, justified our criterion of serum CA125 level as appropriate for simultaneous resections for primary PDAC and synchronous liver metastasis, and certified its benefit for survival of patients with synchronous liver metastasis from PDAC.

Now that pancreatectomy itself is associated with significant morbidity and mortality, a simultaneous liver resection may carry the extraneous risks influencing overall survival, such as bile leak, hemorrhage, or liver abscess[52,53]. The risk of developing a liver abscess reached nearly 40%-50% for liver-directed therapy radiofrequency ablation of liver tumors in patients with a biliary tract procedure such as an enterobiliary anastomosis or biliary stenting[54]. As for liver resection for metastasized PDAC, it is noteworthy that the construction of a biliary-enteric anastomosis during PD may be one of the induction factors of a liver abscess. The development of post-operative complications has been found to be detrimental to survival and to lead to early recurrence in PDAC patients[55,56]. However, our study found no liver-specific complications caused by liver resection and no more severe pancreatic fistula caused by pancreatectomy, suggesting relative safety of simultaneous resections with similar morbidity compared with standard pancreatectomy alone.

The current study had several limitations. Despite a time span of 8 years, only a relatively small sample size of patients was identified as having primary PDAC and synchronous liver metastasis who underwent either simultaneous resections or palliative surgical bypass. As such, this study had limited statistical power. Meanwhile, there may have been selection bias in whether PDAC patients with synchronous liver metastasis were chosen for surgery. For example, if some PDAC patients with resectable tumor of body or tail of the pancreas and unresectable synchronous liver metastases did not present with biliary or upper digestive obstruction, they usually underwent gemcitabine-based chemotherapy instead of palliative surgical bypass first and were excluded from our study. In addition, the focus of our study was the impact of pre-operative factors on diagnosis of liver metastasis and selection of suitable patients for simultaneous resections, which overlooks the influence of intra-or post-operative factors on overall and recurrence-free survival. Furthermore, the role of serum CA125 levels in clinical prediction for metachronous liver metastasis from PDAC was not investigated and hence cannot provide guidance for all patients with liver metastasis from PDAC.

In conclusion, diagnosis and treatment of liver metastasis from PDAC must be individualized in the era of precision medicine because of its highly malignant biological behavior. Serum CA125 level over 38 U/mL predicts synchronous liver metastasis from PDAC, and serum CA125 level over 62 U/mL is associated with unresectability of metastatic disease burden. The criterion set up by serum CA125 levels facilitates the careful diagnosis of synchronous liver metastases from PDAC pre-operatively and the prudent selection of appropriate patients for simultaneous resections for primary PDAC and synchronous liver metastasis for the sake of prolonged survival and substantially reduced morbidity or mortality. Therefore, simultaneous resections for primary PDAC and synchronous liver metastasis are justified by prolonged survival in patients selected by serum CA125. It is foreseeable that the indication for the simultaneous resections for precisely diagnosed liver-metastasized PDAC will be extended with the development of surgical techniques and thus more PDAC patients will have a clear survival benefit.