Trial to prolong the metal stent patency Focused

Trial to prolong the metal stent patency: Focused on drug eluting stent 2019. 03. 28. R 4 강 승 경 / Pf. 이 상 협

Introduction l Ideal stent patency= Patient survival or expected period ” No ideal stent yet ” l 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

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

Introduction l 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

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

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

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

Introduction l Drug-eluting stents(DESs); antitumoral agent inhibiting tumor ingrowth – MSCPM-I: metallic stent covered with a paclitaxelincorporated 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

Methods l 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 1) 2) 3) 4) 5) Age : 19 -90 years Unresectable pancreatic cancer or bile duct cancer Not previously treated with metallic stent insertion Expected survival time > 3 month Not pregnant Exclusion criteria 1) 2) 3) 4) Previous surgical biliary drainage Severe bleeding diathesis Malignant hilar and/or intrahepatic duct stricture Unable endoscopic intervention

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

l Definition – Technical success : successful deployment of a SEMS in the intended location – Functional success: 50% decrease in or normalization of the bilirubin level within 14 days 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 l 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

Result

Result

Result

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

Discussion

Discussion l 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 l Difficult to evaluate the changes of the cancer size – Heterogenous of systemic chemo. Tx, 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 l 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 l Next generation stent is. .

Endoscopy. 2018 Nov 9.

Methods l 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 1) Age ≥ 19 years 2) Malignant mid or distal biliary obstruction 3) Unresectable cancer 4) Estimated survival ≥ 3 months 1) Undergone surgical biliary drainage 2) Severe bleeding disorder 3) Polypoid lesion or intra-abdominal abscess 4) Females of child-bearing potential who could not take adequate contraceptive precautions, or were known to be pregnant or currently breastfeeding an infant

Methods l 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

Methods l F/U – Clinical Sx, Lab: before, immediately after, at 3 rd and 7 th days every month – CT: before stent insertion, at 2 and 6 months after insertion – Tumor size assessment : by CT 2 month 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 l 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

Result

Result

Result

Result

Result

Result

Result

Discussion l No difference in time to RBO, survival between the two groups. l m/c cause of stent occlusion : sludge impaction – reflux of duodenal contents and/or bile acid l 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 l Pancreatic cancer: most frequent cause of biliary obstruction – Paclitaxel may not penetrate pancreatic cancer sufficiently Not affect cancer progression or patient survival duration

Discussion l 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, 2 months 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

Discussion l First to analyze local antitumoral effects of a DES l 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

Discussion l Limitations – 1 st and 2 nd 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

Clinical appraisal- Internal validity l Different stages of disease – Heterogenous disease and stage • no mention of whethere is a distant meta. . – Patient survival time? l 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.

Clinical appraisal- Applicability l Com. Vi 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↓

Clinical appraisal- Applicability l 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