The goal of this randomized controlled trial is to compare uncovered, partially covered, and fully covered self-expandable metal stents (SEMS) in the palliative treatment of distal malignant biliary obstruction in a Swedish multicenter study.

The main questions it aims to answer is: Is the stent patency rate different depending of stent type? Is the stent patency time different depending of stent type? Is the patient survival different between the groups? Which complications are seen, and do they differ between the groups? Are there different mechanisms behind the stent failure depending on stent type?

Patients will at ERCP, with a guidewire passed through the stenosis in the bile duct, be allocated to either uncovered, partially covered, and fully covered (SEMS). Totally, 450 patients will be recruited, 150 in each study arm, according to the power analysis.

Patients will be followed in a monthly surveillance by a study nurse up to 12 months after stent insertion. Endpoints are: alive after 12 months with a patent stent, death with a patent stent, stent dysfunction with a subsequent intervention i.e. repeated ERCP or PTC = "objective stent failure", stent dysfunction, jaundice or cholangitis, but not intervention has been undertaken due to a poor condition of the patient, "clinical stent failure", the patient has undergone curative surgery or a bilio-enteric by-pass (a gastro-enteroanastomosis or a duodenal stent is not a reason for exclusion), the patient refuses further follow-up.

Background

Malignancies causing distal malignant biliary obstruction may arise from the pancreas, distal bile duct, the papilla of Vater or the duodenum. Pancreatic cancer is more common with an incidence of 11.9/100,000/year, the other diagnoses account for 2.5/100,000/year, thus a total incidence of some 14.4/100,000/year.

The above-mentioned tumors may cause occlusion of the bile duct with subsequent jaundice. The liver function is impaired, and itching caused by the jaundice is disturbing. Only 15-20% of patients are suitable for curative surgery since symptoms often are vague, and the diagnoses is delayed. Thus, at presentation the tumor may be locally advanced or metastasized. High age and comorbidity may also make surgery impossible. Therefore, therapy is often palliative not least aiming at relieving the jaundice.

The aim of stent treatment is to relieve the jaundice, and symptoms associated with the bile duct occlusion. The ERCP-technique is in general the first choice in the biliary intervention. The stenting may be complicated by dysfunction of the drainage, which may be caused by stent occlusion by debris or tumor overgrowth/ingrowth, and stent migration is not uncommon. A repeated biliary intervention is needed but may be difficult or even impossible due to tumor progression. Thus, it is important that the stent treatment is effective with a rapid relief of jaundice, and that the patency time is long.

Initially, plastic stents were used in the ERCP procedures, but now self-expandable metal stents (SEMS) are more common. There are several randomized controlled trials (RCTs) including one of our own group, and metanalyses showing that SEMS have a longer patency time, and are more cost-effective than the plastic stents in the treatment of distal malignant biliary obstruction. SEMS were initially made of steel but now nitinol alloys are more commonly used and have been found superior having a longer patency time/less rate of stent failure as demonstrated in a recent study. When first developed SEMS were manufactured without a covering (uncovered, UC-SEMS) but in order to prevent tumor ingrowth through the metal mesh SEMS were developed with a plastic covering, covered, C-SEMS. The covering may include the whole length of the SEMS (fully covered, FC-SEMS) or spare the 0.5-1 cm ends of the SEMS (semicovered, SC-SEMS).

There are several RCTs comparing UC-SEMS to SC-SEMS. Results are conflicting with some RCTs demonstrating that SC-SEMS have a longer patency time whereas other have not detected any difference between the two types of SEMS. FC-SEMS have been introduced more recently with different outcomes as compared to UC-SEMS. There are no RCTs comparing FC-SEMS to SC-SEMS and UC-SEMS.

UC-SEMS will often attach firmly to the tissue in the stricture, but tumor ingrowth may impair stent function. The covering may prevent ingrowth but there is increased risk migration. The bare proximal end of the SC-SEMS may decrease this risk but in analogy to UC-SEMS they may attach firmly and preclude stent exchange. Contrarily, FC-SEMS may be exchanged in case of dysfunction. Apart from tumor ingrowth and stent dislocation SEMS dysfunction may be caused by proximal or distal overgrowth or epithelial hyperplasia on the inside of the stent.

In conclusion, FC-SEMS may have advantages as compared to SC-SEMS or UC-SEMS, but these three stent types have not been compared in RCTs.

Aim

The aim of the study is to investigate which type of SEMS is superior with respect to the rate of stent failure and patency time (primary outcome). Also, the mechanisms behind the stent failures are analyzed. The frequency and types of complications are studied, and the patent survival time is recorded. The study is also exploring if there is a difference in difficulty in the placement of the three types of stents.

Methods

The current study is a Swedish, three-armed randomized controlled multicenter trial enrolling 450 patients. These patients with distal, malignant biliary obstruction are not suitable for a radical resection (advanced/metastasized disease, comorbidity, high age) are palliatively treated with SEMS. Patients have been investigated by multi-phase CT. Palliative oncological therapy may also be used. After oral and written consent, the patients are randomized to receive a single 10 mm in diameter UC-SEMS, SC-SEMS, or FC-SEMS inserted at ERCP with a length of six or eight cm, multiple stenting is not allowed. Randomization is performed at ERCP when the guide wire has passed the stenosis in the bile duct. 150 patients are allocated to each arm using a randomization list and sealed envelopes. Blocks of ten envelopes are distributed to the participating centers and refilled on demand. The study has been approved by the Swedish Ethical Review Authority (2017/416).

If the patient condition improves after stenting or the radiology after reevaluation demonstrates that a resection is possible the patient will leave the study and proceed to surgery. The placement of a SEMS in this situation as a temporary biliary drainage, before a resection, is no disadvantage. Contrarily, with the superior function of a SEMS as compared to a plastic stent a more rapid biliary relief without early stent failure is accomplished without making surgery more difficult. Thus, it is acceptable that occasional patients are included in a palliative setting, and after reevaluation may proceed to surgery.

The statistical calculations have been performed by the Uppsala Clinical Research Center, UCR. According to the power calculation a difference in stent failure of 14% may be detected with a power of 80%, alpha =0.05, if 150 patients are included in each study arm. A smaller difference in not judged to be clinically significant. The inclusion time is estimated to be three years, and the follow-up time is 12 months.

There are thirteen participating hospitals, seven university hospitals, and six other major hospitals. The participating centers are:

University hospital in Uppsala, Karolinska university hospital in Huddinge, University hospital in Örebro, University hospital in Lund, University hospital in Malmö, Sahlgrenska University hospital in Gothenburg, University hospital in Umeå, South hospital in Stockholm, Danderyds hospital in Stockholm, Capio S:t Görans hospital in Stockholm, Skaraborgs hospital in Skövde, Central hospital in Västerås, Central hospital in Karlstad.

Inclusion

1. Obstructive jaundice (S-Bilirubin > 50 μmol /L). Initial treatment according to the local routine, laboratory test, abdominal CT, often a thoracic CT, and US. These investigations along with the clinical information support the finding of a distal malignant occlusion, and an ERCP is performed.
2. The ERCP demonstrates a seemingly malignant distal biliary stenosis located more than 2 cm below the hilum of the liver.
3. The patient has been found not suitable for curative surgery having a locally to advanced tumor (not a candidate for down-staging) or metastatic decease. The patient age and comorbidity may also preclude major surgery. If the investigations and evaluation is not complete at the time of the ERCP it is permitted to place a temporary plastic endoprosthesis.
4. Patient information. The study has been approved by the Swedish Ethical Review Authority (2017/416) as a multicenter study including an approval for all of the participating centers. The approval of the patient may be withdrawn during the course of the study and will not affect the further treatment which is carried out according to the routine of the participating clinic.
5. Randomization. If the patient has agreed to participate in the study the randomization is performed at the ERCP procedure when the biliary tract has been cannulated, and the guide wire has passed the stenosis. The patient is allocated to UC SEMS, SC, or FC SEMS by the method of sealed, opaque envelopes.

Endpoint of follow-up -12 months - is when/if:

1. The patient has been followed >12 months with a patent stent.
2. The patient expires with a patent stent <12 months.
3. The patient has been found resectable and undergone curative surgery or a bilio-enteric by-pass (a gastro-enteroanastomosis or a duodenal stent is not a reason for exclusion).
4. Stent dysfunction with a subsequent intervention i.e. repeated ERCP or PTC = "objective stent failure".
5. Stent dysfunction, jaundice or cholangitis, but not intervention has been undertaken due to a poor condition of the patient, "clinical stent failure" is also an endpoint.
6. The patient refuses further follow-up.

Follow-up

There is a follow-up 1 month after the ERCP/randomization including laboratory tests, and if the patient condition permits, also a visit at the out-patient clinic. The following monthly checks are performed by phone with questions regarding symptoms of stent dysfunction.

Significance

If one stent type is superior it should be recommended for further use. If the stents are equal there is an argument for inserting only FC SEMS since they also can be extracted, and replaced when occluded, which may be a better alternative than stent in stent placement (plastic endoprosthesis or SEMS). Parallel to the evolvement of new oncological strategies there will probably be a demand for SEMS extraction or replacement i.e. radio frequency, irreversible electroporation, or photodynamic treatment. Moreover, in a situation when a benign condition cannot be excluded the option of a SEMS removal is important. The storage of SEMS in the endoscopy units will also be simplified, and cheaper if there is only need for one type of SEMS.

Inclusion Criteria:

• Patient age > 20 years.
• The biliary stenosis located > 2 cm below the hilum of the liver, and with a malignant appearance.
• The patient history, and clinical data supporting a malignant bile duct stenosis.
• S-Bilirubin > 50 μmol/L.
• Curative surgery or down-staging not possible due to an advanced decease, or surgery is precluded by high age or co-morbidity. Temporary placement of a plastic endoprosthesis allowed, and after reevaluation within 4 weeks the patient may enter the study.
• The patient has received oral and written information about the study and accepted to participate.
• CT and/or Ultrasound has been performed.

Exclusion Criteria:

• Informed consent has not been obtained or denied.
• The presence of significant intrahepatic stenoses caused by metastatic disease with also intrahepatic obstruction of the bile flow. A malignant stenosis in the hilum of the liver, or a tumor stricture located < 2cm below the hilum of the liver.
• The patient is probably a candidate for curative surgery or down-staging.
• Suspicion of a benign biliary obstruction.
• Anatomical situation making ERCP impossible i.e. prior surgical interventions or a tumor stenosis of the duodenum. If the ERCP is not successful at the first attempt a repeated procedure or a PTC rendezvouz is allowed within one week.
• Prior biliary drainage (> 4 weeks earlier).
• Increased risk of bleeding (INR >1.5)
• The patient has previously been included in the study.

Individual participant data will be available.

Individual participant data that underline the results reported in the article, after deidentification (text, tables, figures, and appendices) will be shared.

Study protocol, statistical analysis plan, consent form, clinical study report, and analytic code will be available.

Data will be available beginning 9 months and ending 72 months after article publication.

Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose may get access to the data.

Individual data used in metaanalyses may be provided.

We may provide deidentified sets of data which was acquired and analyzed in our statistical program.

Nine months after publication up to 72 months

Investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose may get access to the data. Individual data used in metaanalyses may be provided.