Predictors of distant metastasis on exploration in patients with potentially resectable pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most dismal malignancies with an overall 5-year survival rate of < 7% [1, 2]. Despite enormous efforts directed at the treatment of PDAC, radical resection remains the most effective treatment modality, and it increases the 5-year survival rate for PDAC patients to 10–25% [3‐5]. However, due to a lack of presentations at early stages and the aggressive nature of this disease, the majority of PDAC patients present an unresectable disease at the time of diagnosis, and only around 20% of newly diagnosed PDAC patients were suitable candidates for curable surgical resection [6].

Multidetector computed tomography (MDCT) is currently the optimal imaging modality for preoperative diagnosis and staging of PDAC [7, 8]. However, this imaging modality has a poor sensitivity for identifying small liver or peritoneal metastasis [7, 9]. Among the patients subjected to surgical exploration, a significant proportion (40%) of them are found to be unresectable due to occult distant metastasis or infiltration of local structures [10‐12]. The proportion of patients successfully resected during surgical exploration might be as low as 50% [12, 13].

For patients with distant occult metastasis, surgical resection is unnecessary as it does not prolong survival in the overwhelming majority of patients [14, 15]. Besides, unnecessary surgical exploration often delays administration of other treatments, for example systematic chemotherapy, which currently is the preferred treatment for metastatic PDAC patients [16]. Therefore, it is important to differentiate PDAC patients with distant metastasis from those with truly resectable cancers to avoid unnecessary surgery and offer these patients tailored treatments in a timely manners. The objective of this retrospective study was to analyze the predictive factors for distant occult metastasis in patients with resectable PDAC based on preoperative MDCT.

Currently, radical resection provides the only chance for long-term survival for patients with PDAC. As surgical skills and perioperative management developed, mortality after pancreatic surgery has dramatically decreased to less than 5% [17]. However, morbidity after pancreatic surgery is still very high. Non-curative exploratory laparotomy of pancreas can have a morbidity as high as 42.3% and does not increase survival [18]. Moreover, this unnecessary operation can postpone other more suitable therapies such as chemotherapy and can become the last straw to their debilitating state.

Unfortunately, not all patients with PDAC who undergo resection surgery can be resected successfully. Despite thorough pre-operative staging with advanced imaging techniques, incidental occult distant metastasis from PDAC is commonly encountered in during surgery [19]. Previous studies revealed that up to 31% of patients with resectable PDAC staged by MDCT were found to have metastases in sbusequent laparotomy or staging laparoscopy [8, 20‐22]. In patients with locally advanced PDAC, the likelihood of finding unresectable PDAC at operation is much higher [23].

Despite the emerging use of magnetic resonance imaging, endoscopic ultrasound, and positron emission tomography/computed tomography, MDCT remains the most commonly used imaging modality for the diagnosis and staging of PDAC [7, 24, 25]. However, small distant metastases, such as minimal peritoneal deposits and small liver metastases, can remain undetected even with modern computed tomography protocols [26]. Previous studies suggested that patients with PDAC should undergo the operation within 25 or 32 days of diagnostic imaging to reduce the risk of tumor progression to unresectable disease [27, 28]. In the present study, we found that 26% of the patients selected for curative surgery for PDAC had distant metastasis. However, in our study, we found no affects attributable to the time interval between MDCT study and surgery on the accuracy of MDCT in determining the presence or absence of metastatic disease.

Due to the limitation of imaging, other techniques were reported in literature for determining the resectability of PDAC. One such technique is peritoneal lavage cytology (PLC), which is a routinely applied in the diagnosis and staging of several cancers. However, in PDAC, although a positive PLC represents an early recurrence and a worse prognosis, a positive PLC is not regarded as equal to a macrometastasis in patients with PDAC and it does not exclude a curative resection in patients without other distant metastasis [29‐31]. Another technique is staging laparoscopy, which has been used to diagnose occult metastasis to decrease the number of unnecessary laparotomies in PDAC [32‐34]. Patients who were found to harbor distant metastasis by laparoscopy staging received palliative chemotherapy earlier and lived longer than patients who underwent only laparotomy [33]. Moreover, a cost analysis indicated that use of laparoscopy in pancreatic cancer did not significantly increase the overall expense of treatment [34]. A recent review of 1146 patients found that diagnostic laparoscopy prior to laparotomy could decrease the rate of unnecessary laparotomy from 40 to 20% in patients with periampullary cancer [10]. As a minimally invasive modality, staging laparoscopy was suggested to be routinely used to identify radiographically occult metastases and prevent rewardless laparotomies [20, 21, 35, 36]. However, as the proportion of patients found to have metastases at laparoscopy is decreasing, its routine use is challenged, and some studies have investigated the indications for selective use of staging laparoscopy in pancreatic cancer [37]. Identifying patients at an increased risk of distant metastasis seems to be a more reasonable approach, that can increase the diagnostic accuracy of staging laparoscopy and deliver optimal disease management.

By comparing a number of preoperative factors, this study identified that young age, male sex, low ALT level, large tumor size, and high CA 19–9 level were independent predictors of distant metastases in patients with resectable PDAC. Previous studies found that tumors in the pancreas body and tail, tumor size as determined by MDCT, serum CA 19–9 level, CEA, and weight loss were risk factors for unresectability in patients with potentially resectable PDAC [20, 38‐41]. Our study confirmed that tumor in the body and tail, and high CEA were associated with distant metastasis in univariate analysis, but not in multivariate analysis. Weight loss was not associated with distant metastasis. In line with previous studies, CA19–9 and tumor size were independent predictive factors for distant metastasis [37]. Ong et al. found that age < =65 was a predictive factor of resectable disease [42]. On the contrary, our study found that age < =62 was an independent risk factor of distant metastasis. Also, we found that patients with distant metastatic PDAC had significantly lower levels of ALT and AST than patients without distant metastatic PDAC, which might be explained by the following reasons. First, this might be relevant to the population characteristics in our study. For example, all our patients underwent upfront surgery without neoadjuvant chemotherapy, which has liver toxicity and results in elevated levels of ALT and AST. Second, we found that patients with lower ALT levels are more likely to be without jaundice, which, on the one hand is beneficial for liver function, but on the other hand may lead to late diagnosis of PDAC due to lack of symptoms. Third, we found that patients with peritoneal metastases had a slightly lower ALT level than patients with liver metastasis (52.7 ± 139.1 vs 99.2 ± 151.3 U/L, p = 0.212). This implies that liver metastasis could only slightly raise the level of ALT when there are no other contributing factors.

After identifying the risk factors associated with distant metastasis, this study developed a model for predicting occult distant metastasis in patients undergoing non-curative laparotomy for potentially resectable PDAC. When a score of 6 points was taken as the cut-off value, this score system had a sensitivity of 85% and a specificity of 69%. However, it is necessary to point out that the reliability and effectiveness of this score system still needs validation by further studies. Also, because successful resection is the only cure for PDAC, these preoperative predictors alone are not contraindications for pancreatic exploration. The predictive factors identified in this study only indicated that additional preoperative staging modalities, such as selective staging laparoscopy, may be needed before laparotomy is indicated.

This study has several limitations. First, due to the nature of its retrospective design, there was a potential for several biases. For example, small intrahepatic lesions may be missed by palpation. Second, the sample size of the present study is relatively small. Therefore, a well-designed, prospective study with more data will be needed to validate the results of this study. Third, though staging laparoscopy was discussed and suggested in this study, we had limited experience in using it. Lastly, although neoadjuvant therapy has become increasingly common in the practice, our findings may not apply to this group of patients.

In conclusion, we showed that for patients with potentially resectable PDAC based on MDCT, distant metastasis is still frequently encountered during surgery. Younger age, male sex, large tumor size, lower ALT and higher CA19–9 are independent predictive factors for finding distant metastasis during exploration.