Treatment of Distal Malignant Biliary Obstruction by Uncovered, Partially Covered, or Fully Covered Metal Stents
- Conditions
- Papillary CarcinomaPancreatic Cancer Non-resectableDuodenal CancerBile Duct Cancer
- Interventions
- Procedure: Randomization to uncovered SEMS treating jaundice due to distal malignant biliary obstruction.Procedure: Randomization to fully covered SEMS treating jaundice due to distal malignant biliary obstruction.Procedure: Randomization to partially covered SEMS treating jaundice due to distal malignant biliary obstruction.
- Registration Number
- NCT06453590
- Lead Sponsor
- Region Stockholm
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 450
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Uncovered SEMS Randomization to uncovered SEMS treating jaundice due to distal malignant biliary obstruction. Allocated to treatment with an uncovered SEMS in the distal bile duct. Fully covered SEMS Randomization to fully covered SEMS treating jaundice due to distal malignant biliary obstruction. Allocated to treatment with a fully covered SEMS in the distal bile duct. Partially covered SEMS Randomization to partially covered SEMS treating jaundice due to distal malignant biliary obstruction. Allocated to treatment with a partially covered SEMS in the distal bile duct.
- Primary Outcome Measures
Name Time Method Stent patency rate During the follow-up time from insertion of the SEMS (inclusion of the study) until reaching an endpoint (up to 12 months with a patent stent or until stent failure occurs) the rate of patent SEMS in the three different groups is calculated Stent patency rate of the three different types of SEMS
Stent patency time The time, days, of patency of the SEMS during follow-up (up to 12 months) until reaching an endpoint is calculated. The time, days, of patency of the SEMS in the three different types of SEMS
- Secondary Outcome Measures
Name Time Method Patient survival time The time, days, of survival after stent insertion (inclusion in the study) until death, or up to 12 months. Survival time of patients in the three groups of different SEMS
Mechanisms of stent failure During the follow-up, from the time of stent insertion until a stent failure is established (up to 12 months), the reason is analyzed at the time of repeated ERCP Different reasons of stent failure is analyzed, ingrowth, overgrowth, migration, food impaction.
Adverse events During follow-up from the time of stent insertion complications are registered until an endpoint is reached (up to 12 months). Complications arising after stent insertion, stent failure, cholangitis, pancreatitis, bleeding, perforation, cholecystitis.
Difficulty of stent insertion This outcome is registered during the ERCP procedure. Problems arising at ERCP deploying the SEMS as easy, moderately difficult, or difficult.
Trial Locations
- Locations (12)
Danderyds hospital
🇸🇪Danderyd, Sweden
Sahlgrenska University hospital
🇸🇪Gothenburg, Sweden
Central Hospital Karlstad
🇸🇪Karlstad, Sweden
University Hospital Lund
🇸🇪Lund, Sweden
University Hospital Malmö
🇸🇪Malmö, Sweden
Skaraborgs Hospital Skövde
🇸🇪Skövde, Sweden
Capio S:t Görans hospital
🇸🇪Stockholm, Sweden
Stockholm South Hospital
🇸🇪Stockholm, Sweden
University Hospital of Umeå
🇸🇪Umeå, Sweden
University hospital Uppsala
🇸🇪Uppsala, Sweden
Central Hospital Västerås
🇸🇪Västerås, Sweden
University Hospital Örebro
🇸🇪Örebro, Sweden