The intent of this study was to critically evaluate the endoscopic management of biliary obstruction in inoperable pancreatic cancer patients receiving contemporary chemotherapy. This group of patients, the majority receiving optimally dosed gemcitabine combined with other agents, demonstrated a median survival of greater than one year. In most cases biliary obstruction was managed by permanent self expandable metal stents. Stent related cholangitis was closely correlated with longer survival and required complex management involving additional procedures and significant periods of hospitalization.
In prior studies evaluating the endoscopic therapy of malignant biliary obstruction, the median survival ranged from 4.5-15.1 months (). Most of these studies did not report the use of chemotherapy and most included patients with tumors other than adenocarcinoma of the pancreas [10
]. Among studies in which the majority of subjects had pancreas cancer the longest reported median survival was 11 months. The median survival in our study, 12.7 months, exceeds that in the endoscopic literature but is consistent with improved survival recently reported in patients receiving combination chemotherapy [23
Patency of metal stents and survival in patients with malignant biliary obstruction
In patients with inoperable pancreatic cancer the current strategy is to manage biliary obstruction with metal stents. Major studies of the management of malignant biliary obstruction have demonstrated that the median patency of metal stents ranged from 3.6 to 9.1 months (). The median patency of metal stents in all of the studies, weighted by the relative number of patients, was 5.8 months. Most of our patients were initially managed with metal stents. Consistent with the literature, few of them had problems associated with metal stents during the first 12 months of survival.
However, we observed that after 12 months, far beyond the patency range of metal stents, there was an increase in the development of cholangitis. This result remained significant after adjusting for potential confounders. Patients who developed cholangitis required a two fold increase in the number of endoscopic procedures required to maintain a decompressed biliary system and generally more than one week of inpatient management.
Metal stent occlusion typically results from tumor ingrowth blocking the lumen or overgrowth causing external compression of the stent [25
]. Management of expandable stent obstruction is complex; uncovered metal stents generally are not removable and maneuvers to restore patency, such as the placement of a plastic or metal stent, into the obstructed stent are relatively short lived [26
]. In our study, we found that the length of hospitalization for cholangitis with a metal stent tended to be longer than with a plastic stent. Although this difference did not reach the threshold for statistical significance, larger studies with more events may be able to detect a difference. Additionally, we observed a trend that the longest surviving group of patients who developed cholangitis associated with metal stents frequently developed recurrent infections (data not shown).
An alternative management strategy, used in a minority of our patients, is to employ plastic stents which are prophylactically exchanged. The subsequent use of a metal stent is based on the patient’s response to chemotherapy. In the only major study of prophylactic stent exchange in malignant biliary obstruction, Prat et al.
showed that this approach achieved an equivalent period of symptom free (cholangitis free) survival compared to metal stent placement but that it requires more procedures and hospital management [10
]. However, this study enrolled patients between 1993 and 1995 and the median survival was between 4.5 months (metal stent group) and 5.6 months (prophylactic exchange group), compared to the 12.7 months in our group.
Prat et al.
also demonstrated that metal stents were cost effective in patients surviving more than 6 months with the mean overall cost per patients for patients whose stents were exchanged prophylactically was $6,770 compared to $4,643 for metal stents [10
]. Nearly half of the patients in our study who survived greater than twelve months required inpatient management for stent related cholangitis. The patients who developed cholangitis required a median of eight days of hospitalization. At our institution the cost per day of hospitalization for cholangitis is greater than $5,000. The total cost for an ERCP with plastic stent placement at our institution is $3,400 compared to $4,600 for ERCP with metal stent placement. It is plausible that a strategy of prophylactic plastic stent exchange may be more cost effective than metal stent placement if it diminishes the frequency and duration of hospitalization for cholangitis in patients with long survival.
An additional advantage of plastic stents is that blockage, which is typically due to the formation of a bacterial biofilm within the stent, can be easily remedied by the exchange of the occluded stent with another plastic stent or metal stent [28
]. In our center plastic stent exchange procedures are typically performed as same day, outpatient procedures.
In the past, metal stent placement was proposed for patients with biliary obstruction due to colorectal cancer, lymphoma, and breast cancer [29
]. Over the last ten years the survival of patients with these malignancies has improved [30
]. It is our practice to manage biliary obstruction in this group with serially placed plastic stents, which has also been reported in recent literature [31
]. We have observed that many of these patients survive longer than three years and that bile duct narrowing can improve with chemotherapy; making the placement of permanent metal stents less advantageous. As the survival of pancreatic cancer improves, a similar rationale may emerge.
Another important alternative for potentially long surviving patients is operative biliary bypass. In their randomized trial of endoscopic stenting versus
surgical bypass in distal biliary obstruction, Smith et al
. report that both methods are effective palliative procedures but that surgical procedures are associated with higher initial complications, 29%, compared to 11% for endoscopic stenting but fewer long term complications (9% versus
43%) for endoscopic stent placement [8
]. As the survival of patients with pancreas cancer improves the relative risks and benefits of these modalities will need to be prospectively studied. Artifon et al
. report that endoscopic therapy (with metal stents) may result in a better quality of life and be less costly than surgery [9
]. Nevertheless, the mean survival in their population was only 6.0 months compared to 10.4 months in comparable (metastatic) patients in our group. Additionally, they included only patients with tumor metastatic to the liver which represents only a portion of those with unresectable disease. In the current study the 26 patients with locally advanced disease had a mean survival of 15.8 months. While not statistically significant there was a trend towards a higher rate of cholangitis in these patients compared to those with metastatic disease (35% versus
29%), potentially related to their greater survival. In patients with locally advanced disease, particularly those with good functional status, operative biliary decompression should also be considered in the setting of obstruction.
An informed strategy would be to identify predictors of long survival to optimize therapy. In a multivariate analysis Prat et al
. identified that tumor size less than 3 cm was the best predictor of prolonged survival. The presence of liver metastasis was not found to be a predictor though a comparison of metastatic versus
locally advanced disease was not performed and remains an important topic for future work. Predictors of response to chemotherapy would also inform the endoscopic and surgical management of biliary obstruction. Promising work measuring transporter levels for gemcitabine suggests that this may eventually be done at the molecular level [32
Limitations of this study are that it is retrospective and nonrandomized. In more than 90% of cases metal stents were used to achieve biliary decompression. Serial use of plastic stents (less than 10% of patients) tended to be used later in the period of enrollment. The practical implication of this work is that careful consideration is critical prior to the placement of a stent in patients with inoperable pancreatic adenocarcinoma receiving chemotherapy. While self expandable metal stents have a median patency of 4-9 months and provide superb drainage during this time period, this study has shown that in patients with a prolonged median survival of greater than 12 months, they are associated with a significant increase in serious biliary infections. Plastic stent placement with prophylactic exchange and eventual metal stent placement, while not a perfect alternative, is a consideration in this group. Previous strategies may have to be reconsidered as the survival of these patients improves with contemporary chemotherapy. The use of “covered” metal stents is also a possibility. Although tumor ingrowth along uncovered ends, higher migration rates, and increased risk of cholecystitis may be problematic, they may be removable [17
]. Particularly as chemotherapy improves it will be necessary to revisit operative bypass procedures as a solution for potential long survivors.