1.  Trial to prolong the metal stent patency:  Focused on drug eluting stent
R4 강 승 경 / Pf. 이 상 협

2. Introduction Ideal stent patency= Patient survival or expected period
” No ideal stent yet ”
SEMS(self-expandable metallic stents)
Lower incidence of recurrent biliary obstruction(RBO) than plastic stents
Stainless steel Nitinol: standard metallic components of SEMS
Uncovered, partially or fully covered
But not different to improve the patient’s quality of life till patient death

3. Introduction Biliary SEMS(Self-Expandable Metal Stents) Advantages
Disadvantages
Uncovered SEMS
Easy deployment(lower shortening rate)
Available hilar portion
Thinner introducer
Stent obstruction
Tumor ingrowth
Tumor overgrowth
Partially covered SEMS
Prevention of tumor ingrowth
Possible removal
Complication
Migration/dislocation
Pancreatitis
Cholecystitis
Fully covered SEMS
High possibility of removal
Uncovered
Partially covered
Fully covered

4. Introduction Mechanical force
Radial force(RF): expansive force to dilate the SEMS against the stricture of tumor compression
Keep luminal patency of the obstructed bile duct
Covering membranes influences the RF: inhibits the expansion of SEMS and movement of wires
Axial force(AF): recovery or straightening force when the SEMS is bended
Conformability of SEMS
Related complications: Bile duct kinking(stent impaction), pancreatitis, cholecystitis, stent migration
AF was reduced depending upon the distance -> longer SEMS demonstrated lower AF

5. Introduction Migration of stent Anti-migration systems
Achilles’ heel of covered SEMS
Removability of covered SEMS increased risk of migration
Risk factor of migration: Low RF, chemotherapy
Anti-migration systems
Covered SEMS with flap, flared end
Partially covered metal stent
Outer uncovered regions
Variation in RF

6. Introduction
Photosensitizer-embeded self-expanding metal stent(PDT stent)
Polymeric photosensitizer (pulluan acetate-congugated pheophorbide A; PPA)
Repeatable endoscopic PDT is possible after stent emplacement

7. Introduction Photodynamic activity evaluation
Laser exposure on stent layered tumor cell lines, HCT-116 tumor -xenograft mouse models(subcutaneously implanted of mice )
Endoscopic intervention of PDT stent on normal bile duct of mini pigs
Potential for the combination therapy(stent + PDT) of cholangiocarcinoma

8. Introduction
Drug-eluting stents(DESs); antitumoral agent inhibiting tumor ingrowth
MSCPM-I: metallic stent covered with a paclitaxel-incorporated membrane
Comperative prospective clinical study
No statistical differences in the duration of stent patency or survival time
Patient characteristics: short survival time (expire 50% before stent occlusion)
Stent membrane: biodegradation of the membrane  short-term release of paclitaxel from MSCPM-I
Developed and modified a new generation stent
MSCPM-II: A metallic stent covered with a paclitaxel incorporated membrane using a Pluronic mixture
Patency duration, safety and patient survival time

9. 첫번째 논문(부논문)
바로 앞에서 언급한 pluronic mixture 를 이용한 paclitaxel emission stent 인 MSCPM-II 를 CMS 와 비교한 논문

10. Methods Patients Double-blind prospective randomized study
Required number : Total 150(75 in each group)(2.5% type I error, 80% statistical power, permeable effective range 20%, drop-out rate 10%
Enroll 72 pt. with unresectable distal malignant biliary obstruction
Inclusion criteria
Exclusion criteria
Age : 19-90years
Unresectable pancreatic cancer or bile duct cancer
Not previously treated with metallic stent insertion
Expected survival time > 3month
Not pregnant
Previous surgical biliary drainage
Severe bleeding diathesis
Malignant hilar and/or intrahepatic duct stricture
Unable endoscopic intervention

11. Methods Stents F/U Chemotherapy
Gemcitabine-based chemotherapy
Gemcitabine / Gemcitabine + Erlotinib / Gemcitabine + Capecitabine
5-FU + Oxaliplatin
Stents
MSCPM-II membrane(Niti-S stent, ComVi type with paclitaxel-eluting membrane)
Double layer: inner PTFE outer Paclitaxel-incorporated Pluronic F-127-polyurethane(PTX-Plu-PU)
10mm diameter, 5-8cm in length
F/U
Clinical Sx, Lab(AST/ALT, ALP, GGT, bilirubin): 0, 3rd, 7th every month
CT: before stent insertion , 6month after stent insertion

12. Definition Statistical analysis
Technical success : successful deployment of a SEMS in the intended location
Functional success: 50% decrease in or normalization of the bilirubin level within 14days of stent placement.
Composite endpoint: recurrent biliary obstruction
Tumor ingrowth: direct growth of tumors through the stent mesh
Tumor overgrowth: growth of tumors at the proximal and/or distal ends of the stent
Statistical analysis
Quantitative data: Student t-test
Categorical parameters: Chi-square test, Fisher exact test
Stent patency, patient survival time: Kaplan-Meier lifetime table and Cox proportional hazard ratio with a 95% confidence interval

13. Result

14. Result

15. Result

16. Discussion
No statistical difference in stent patency between MSCPM-II group and CMS group.
Terminated early without enrolling the target number of patient  high dropout rate in the first 6month caused by early stent occlusion by food scraps
d/t ComVi stent characteristics(16% vs conventional CMS 4%)
Time points of stent occlusion by sludge: limited evaluation of the efficacy
Subgroup analysis excluding patients who underwent early stent occlusion by sludge
No statistical differences in stent patency between MSCPM-II and CMS group

17. Discussion

18. Discussion Very low rate of tumor ingrowth
MSCPM: 2.5%(1/40), CMS: 3.1%(1/32)
Previous MSCPM-I study : 22.4%(13/58)
Suppression of membrane biodegradation by PTFE or local antitumoral effects
Difficult to evaluate the changes of the cancer size
Heterogenous of systemic chemoTx, causative disease of malignant biliary obstruction, time of the f/u CT
Bile duct cancer has no measurable mass for comparative evaluation
Disease progression by mets caused more deaths
Limitations
Early termination of study ITT analysis; not enough to prove the efficacy of stent
Type II error: per protocol analysis was not followed, number of enrolled patients was small
Lack of commercialized PTFE-covered biliary stent
Next generation stent is..

19. Endoscopy. 2018 Nov 9. 두번째 논문(주논문)
앞서 언급한 종양 내 항암제의 침투를 강화하도록 돕기 위해 sodium caprate 를 추가하고 inner wire 노출을 피하기 위해 membrane 사이에 wire 를 삽입한 MSCPM-III 와 CMS 비교

20. Methods Patients Prospective, randomized, open-label, parallel design,
multicenter, controlled, comparative study
Hypothesis : MSCPM-III to be superior to CMS in term of stent patency
Inclusion criteria
Exclusion criteria
Age ≥ 19 years
Malignant mid or distal biliary obstruction
Unresectable cancer
Estimated survival ≥ 3 months
Undergone surgical biliary drainage
Severe bleeding disorder
Polypoid lesion or intra-abdominal abscess
Females of child-bearing potential who could not take adequate contraceptive precautions, or were known to be pregnant or currently breastfeeding an infant

21. Methods MSCPM-III modified from the MSCPM-II
Metal mesh between two membranes
Inner membrane: PTFE
Outer membrane: PTFE + polyurethane
Smooth luminal surface
Flaps on both sides to prevent stent migration

22. Methods F/U Statistical analysis
Clinical Sx, Lab: before, immediately after, at 3rd and 7th days  every month
CT: before stent insertion, at 2 and 6 months after insertion
Tumor size assessment : by CT 2month after stent insertion
Pancreatic cancer or mass-forming type bile duct cancer: measured directly
Infiltrating type bile duct cancer: measured wall thickening or extension along the duct
Statistical analysis
Quantitative data: Student t-test
Categorical parameters: Chi-square test, Fisher exact test
Cumulative time to RBO, patient survival duration: Kaplan-Meier method

23. Result

24. Result

25. Result

26. Result

27. Result

28. Result

29. Result

30. Discussion
No difference in time to RBO, survival between the two groups.
m/c cause of stent occlusion : sludge impaction
reflux of duodenal contents and/or bile acid
PTFE is resistant to bile acid
Stent occlusion↓ by tumor ingrowth: importance of stent membrane composition
prevention of sludge formation or food occlusion due to reflux of duodenal contents is important for maintaining stent patency antireflux stent
Pancreatic cancer: most frequent cause of biliary obstruction
Paclitaxel may not penetrate pancreatic cancer sufficiently  Not affect cancer progression or patient survival duration

31. Discussion High rate of stent migration(n=16[29.6%])
No tumor growth in patients with migrated MSCPM-III stents
Reduction or no change in tumor size/infiltration was significantly higher in the MSCPM-III group(P = 0.04)
Local antitumor effect of MSCPM-III shrinks bile duct cancer migration due to the absence of compression by the tumor.
CT, 2months after no difference in the change in tumor size
Nonpancreatic bile duct cancer
Higher proportion of reduction or no change in tumor size / infiltration of the MSCPM-III
 Differences in the types of cancer
Pancratic cancer: compresses the bile duct extrinsically, small contact area
Intraductal bile duct cancer: relatively large area of contact with MSCPM-III facilitating tumor penetration by paclitaxel

32. Discussion First to analyze local antitumoral effects of a DES But,
Tumor size was not analyzed in previous studies  comparable data(-)
Local antitumor effects are difficult to confirm in clinical studies
Analysis was hampered by the reduction in tumor size due to compression caused by stent expansion

33. Discussion Limitations
1st and 2nd aims of the study did not involve identification of local antitumoral effects of MSCPM-III
not sufficient statistical power exact number of patients(-)
Definitiveness of conclusions is limited
Small number of bile duct cancer pt
Heterogeneous disease
Different chemoradiotherapy regimens
Assessment of antitumor efficacy by CT alone may be inaccurate
Larger studies are needed
Other imaging modalities should be used to evaluate tumor size and infiltration.
Objective indicators of local antitumor effects

34. Clinical appraisal- Internal validity
Different stages of disease
Heterogenous disease and stage
no mention of whether there is a distant meta..
Patient survival time?
Anti-tumor effect of MSCPM-III unify the parameters other than the stent.
Unification of cancer type causing malignant biliary obstruction.
Unification of chemotherapy regimens.

35. Clinical appraisal- Applicability
ComVi stent
Theoretically ideal, difference between theory and reality
Radial force(RF): expansive force to dilate the SEMS against the stricture of tumor compression
Axial force(AF): recovery or straightening force when the SEMS is bended
 RF↑ , AF↓

36. Clinical appraisal- Applicability
Larger diameter stent
Occlusion caused by sludge is the most difficult of all occlusions to resolve
Fully covered SEMS of larger diameters are associated with low incidences of sludge formation

37. 경청해주셔서 감사합니다