Self-Expandable Metal Stents in Pancreatic Cancer : Association between stent patency and chemotherapy Sang Hyub Lee, MD. PhD. Seoul National University College of Medicine Seoul National University Hospital Department of Internal Medicine and Liver Research Institute Division of Gastroenterology Pancreatic and Biliary Cancer Center

Background Chemotherapy (CTx) is the mainstay of treatment for unresectable pancreatic cancer Jaundice and subsequent biliary infection caused by tumor Detrimental for the patients with pancreatic cancer Stent insertion for biliary decompression is necessary for the patients with biliary obstruction by pancreatic cancer It is important to keep the stent patent as long as possible

Impact of biliary stent-related adverse events in advanced pancreato-biliary tumours during palliative CTx Mild stent related events group showed longer survival compared to those with severe stent related events Lamarca A et al, World J Gastroenterol 2016;22:6065-75

How to achieve longer stent patency using chemotherapy in pancreatic cancer? Drug eluting stent (Local chemotherapy)? Systemic chemotherapy?

Drug eluting stent (DES) Drug-eluting stents is coated with drug and locally elutes chemotherapeutic agent in order to improve stent patency. This new technology of local stent-based drug delivery system prevent the development of neointimal hyperplasia and restenosis following percutaneous coronary interventions.. Drug-eluting stents were statistically superior to bare-metal stents, So they are mainly used in cardiovascular field Drug-eluting stents is coated with drug and locally elutes in order to improve stent patency. This new technology of local stent-based drug delivery system prevent the development of neointimal hyperplasia and restenosis following percutaneous coronary interventions.. Drug-eluting stents were statistically superior to bare-metal stents, So they are mainly used in cardiovascular field Lee DH. Korean J Gastroenterol. 2007;49:294–9.

A pilot study of 21 humans with malignant biliary obstruction Insertion of Metallic stent covered with a paclitaxel- incorporated membrane (MSCPM) Technically feasible, safe and effective The mean duration of patient survival (350 days) and stent patency (429 days) was longer than those previously reported for metal stent To expand upon animal experiments and evaluate the safety and efficacy of paclitaxel eluting metal stent treatment in human, a pilot study in 21 human patients diagnosed with unresectable malignant biliary obstructions was performed the endoscopic insertion of Metallic stent covered with a paclitaxel- incorporated membrane was technically feasible, safe, and effective in patients with unresectable malignant biliary obstruction. In this study, the mean duration of patient survival (350 days) and stent patency (429 days) was longer than those previously reported for metal stent Suk KT et al. Gastrointest Endosc 2007;66:798-803

MSCPM may exert local antitumor activity because of the steady Periodic measurements of the paclitaxel serum concentration in patients MSCPM may exert local antitumor activity because of the steady release of paclitaxel. Periodic measurements of the paclitaxel serum concentration were performed on an outpatient basis after MSCPM insertion. The highest concentration of paclitaxel in the blood was found between 1 and 10 days after insertion. a low level of paclitaxel continued to be detected over several weeks. MSCPM(metal stent coverd with paclitaxel incorporated membrane) may exert local antitumor activity because of the steady release of paclitaxel. Suk KT et al. Gastrointest Endosc 2007;66:798-803

Prospective comparison of standard covered SEMS to SEMS covered by a paclitaxel-incorporated membrane. Suggestion MSCPM - safe as covered SEMS - not significantly improve stent patency or survival PEMS is safe and Technically feasible in animal study And good result in human pilot study So, comparative study was performed This study is prospective comparison of standard covered SEMS to SEMS covered by a paclitaxel-incorporated membrane Paclitaxel –incorporated membreane metal stent group is 58 patients, CMs is 42 patients Compared to two groups, Mean duration of stent patency was 199 ± 235 days in the paclitaxel-incorporated CMS group and 149 ± 99 days in the CMS group. Mean survival was 270 ± 260 days in the paclitaxel-incorporated CMS group and 182 ± 117days in the covered MS group. there was a trend towards improved patency and survival in the experimental arm, although these differences were not statistically significant. Rates of complications such as cholangitis, pancreatitis, and stent migration were similar between the two groups. The study therefore suggests that paclitaxel-incorporated SEMS are probably as safe as covered SEMS, but do not significantly improve stent patency or survival Jang SI et al. Dig Dis Sci 2012

Prospective, randomized pilot study. 24 patients in the PECMS vs 25 patients in the CCMS complications were similar between the two groups. In another prospective, randomized study, Paclitaxel –incorporated membrane metal stent group is 24 patients, control CMs is 25 patients complications were similar between the two groups. no significant difference was seen in either stent patency or patient survival time when either paclitaxel-eluting covered metal stents or control covered metal stents were inserted in patients with distal malignant biliary obstruction. P = 0.596 P = 0.307 A. Stent patency. B. Patient’s survival. Song TJ et al. Gastrointest Endosc 2011;73:727-733

Why DES is Not effective? Two prospective studies’ results were disappointing DES in malignant biliary obstruction is not effective? Several questions need to check before making a decision. 1. is paclitaxel optimal drug for DES ? gemcitabine or fluorouracil 2. Stent design is problem The Single PU membrane was degraded by the flow of bile The paclitaxel was not released steadily for a long enough time. Two prospective studies’ results were disappointing. DES in malignant biliary obstruction is not effective? But, recent study are enough to conclude that the DES lack additional efficacy compared to covered stents. Several questions need to check before making a decision.

Inner layer – PTFE membrane resistance to bile degradation New-generation metal stent covered with a paclitaxel-incorporated membrane Inner layer – PTFE membrane resistance to bile degradation Outer layer - polyurethane membrane containing the mixture of paclitaxel and Pluronic F-127 (PTX–Plu–PU) : Pluronic micelles facilitate a constant release of paclitaxel from the stent. New-generation metal stent covered with a paclitaxel-incorporated membrane Inner layer are formed by polytetrafluoroethylene (PTFE) membrane for resistance to bile degradation Outer layer are formed by the polyurethane membrane containing the mixture of paclitaxel and Pluronic F-127 (PTX–Plu–PU). The Pluronic micelles facilitate a constant release of paclitaxel from the stent. Jang SI et al. Endoscopy 2012; 44: 825–831

The new paclitaxel-eluting stent with 10% Pluronic F-127 is safe and Histologic changes in the porcine biliary epithelium were acceptable in terms of safety In the porcine serum analysis, released paclitaxel was detected for 28 days with the 10% Pluronic concentration The new paclitaxel-eluting stent with 10% Pluronic F-127 is safe and provides enhanced local drug delivery.. Histologic changes in the porcine biliary epithelium were acceptable in terms of safety In the porcine serum analysis, released paclitaxel was detected for 28 days with the 10% Pluronic concentration This study suggest The new paclitaxel-eluting stent with 10% Pluronic F-127 is safe and provides enhanced local drug delivery.. Jang SI et al. Endoscopy 2012; 44: 825–831

A: MSCPM-II 와 CMS 사이에 Cumulative stent patency 를 보여주는 Kaplan-Meier graph B: MSCPM-II 와 CMS 사이에 Patient survival

40명, 32명 기본 환자 특성은 두 그룹 간 통계학적 차이 없음(나이, 성 비율, 평균 추적관찰 기간, 기저 질환의 상태, 항암 적용) 항암 요법은 pancreatic cancer는 gemcitabine based, common bile duct cancer 는 5-FU based

P=0.94 Jang SI et al. Endoscopy 2018; Epub ahead of print

Drug eluting stent (DES) in pancreatic cancer Drug-eluting stents has been developed in order to improve stent patency. Current available evidence suggests that DES are probably safe, but are no more effective than standard covered MS in malignant bile duct obstruction including pancreatic cancer. Local treatment with DES for malignant biliary obstruction appears to be a challenging treatment modality in case of bile duct cancer. Drug-eluting stents is coated with drug and locally elutes in order to improve stent patency. This new technology of local stent-based drug delivery system prevent the development of neointimal hyperplasia and restenosis following percutaneous coronary interventions.. Drug-eluting stents were statistically superior to bare-metal stents, So they are mainly used in cardiovascular field

Systemic chemotherapy for pancreatic cancer Kamisawa T et al, Lancet 2016;388:73-85

Great leap of CTx in pancreatic cancer: Gemcitabine/Nab-paclitaxel (MPACT) 8.5 vs 6.7 months Conroy T et al, N Eng J Med 2011;364:1817-25

Great leap of CTx in pancreatic cancer: FOLFIRINOX (ACCORD11) 11.1 vs 6.8 months Conroy T et al, N Eng J Med 2011;364:1817-25

Is CTx associated with stent patency in pancreatic cancers? Before Gemcitabine/Nab-paclitaxel (MPACT) and FOLFIRINOX (ACCORD11) in Unresectable Pancreatic Cancer?

Is CTx associated with stent patency in pancreatic cancers? Before previous commented chemotherapy, there were some studies that tried to find the association between chemotherapy and stent patency. This Japanese retrospective study concluded that stent patency was not associated with chemotherapy. There is no difference in stent patency according to chemotherapy. Mean Stent patency: 199 days in Gem vs 167 day in BSC (p=0.283)

Is CTx associated with stent patency in pancreatic cancers? Stent migration Chemotherapy HR: 4.46 (95% CI 1.38-14.45) in a competing risk analysis After several years later, same group tired another retrospective study using competing risk analysis. Chemotherapy was significant risk factors for early stent migration using a competing risk analysis. But, there is no comment in stent patency. CTx 5-FU/ gemcitabine/ gemcitabine+S-1 BSC

Is CTx associated with stent patency in pancreatic cancers? OS in Stage III OS in Stage IV CI in stent patency in Stage IV Our study also could not find the association bwtween chemotherapy and stent patency. The patency of biliary SEMS in unresectable pancreatic cancers might be affected by the stage. After about 400 days, the cumulative curves almost overlapped. This indicates that, with time, stage III changed to stage IV. Exact stent patency can not be achieved due to patient’s death. CI in stent patency in Stage III Stage HR: 2.097 (95% CI 1.38-3.14) in a competing risk analysis

Calculated biliary Stent-Related Events in advanced pancreato-biliary cancers After partially introduction of active chemotherapy, median stent patency was calculated as 12 months Pancreatic cancer:75/96 FOLFIRINOX: 11/75 Gemcitabine Nab-paclitaxel:7/75 Biliary cancer:21/96 Lamarca A et al, World J Gastroenterol 2016;22:6065-75

Is CTx associated with stent patency in Gastroduodenal Obstruction ? Kim SH et al, World J Gastroenterol 2015;21:9134-41 Cha BH, Lee SH et al, Asia Pac J Clinical Oncol 2013;9:162-8

Summary of previous studies : Stent patency and CTx in Pancreatic cancers Gemcitabine affected neither stent-related complications nor stent patency Chemotherapy is a significant risk factor for early migration of CSEMS The patency of biliary SEMS in unresectable pancreatic cancers might be affected by the stage Chemotherapy was statistically associated with an increase in stent patency in malignant gastroduodenal obstruction Chemotherapy does not improve SEMS patency in patients with malignant gastroduodenal obstruction caused by unresectable gastric or pancreatic cancer Nakai Y et al, Pancreas. 2008;37:405-10 Nakai Y et al, J Gastroenterol Hepatol 2014;29:1744-9 Eum Yo, Lee SH, et al, Digestive Endoscopy 2013; 25: 67–75 Kim SH et al, World J Gastroenterol 2015;21:9134-41 Cha BH, Lee SH et al, Asia Pac J Clinical Oncol 2013;9:162-8

Is CTx associated with stent patency in pancreatic cancers? Before Gemcitabine/Nab-paclitaxel (MPACT) and FOLFIRINOX (ACCORD11) in Unresectable Pancreatic Cancer? The effect of the CTx for the biliary stent patency is unknown due to shorter survival of advanced pancreatic cancer patients and Not so many studies

Is CTx associated with stent patency in pancreatic cancers? After Gemcitabine/Nab-paclitaxel (MPACT) and FOLFIRINOX (ACCORD11) Era in unresectable pancreatic cancer? Increased overall survival due to FOLFIRINOX in unresectable pancreatic cancer Better efficacy can lead to better stent patency?

Aim To evaluate the difference of stent patency according to chemotherapy and the factors associated with better stent patency Although such characteristics could be useful findings for identification of PNETs from other pancreatic tumors, there were few studies on the differentiation of tumor grade among PNETs. We aimed to investigate whether CT enhancement pattern is associated with the pathologic tumor grades according to WHO classification and can predict those of pancreatic neuroendocrine tumor.

Patient selection Retrospective study Between January 2015 and May 2017 Included patients: Pathologically confirmed PDAC Stage III/IV PDAC Excluded: Operation within 4wks after stent insertion Follow-up loss within 4wks Plastic stent insertion Chemotherapy with Nab-paclitaxel Previous endoscopic biliary drainage 2011년부터 2015년 사이 병리학적 진단을 통해 NET로 진단받은 143명의 환자 중, 병리학적 확진 전 pancreatobiliary protocol CT를 촬영했던 90명의 환자 기록을 후향적으로 분석하였습니다. We retrospectively analyzed the records of 90 patients who underwent pancreatobiliary protocol CT before pathologic confirmation among 143 patients diagnosed with NET through pathologic diagnosis between 2011 and 2015. Between January 2011 and December 2015, One hundred and forty-three patients were pathologically diagnosed as pancreatic NETs. Ninety patients who underwent multi-phase contrast-enhanced CT by pancreatobiliary protocol in our hospital before pathologic diagnosis were retrospectively reviewed.

Primary outcome Secondary outcome Outcome Overall duration of stent patency Secondary outcome Patency according to chemotherapy regimen Factors for better stent patency Overall survival Adverse events

Flowchart of enrolled patients

Baseline characteristics Total (N=173) BSC (N=36) Chemotherapy (N=137) FOLFIRINOX (N=72) Gem-based (N=65) p-value Age, years (mean±SD) 63.8±10.9 68.8±12.6 60.6±8.6 64.7±11.3 0.002 Sex (Male/Female) 89/84 14/22 33/39 42/23 0.039 Stage (III/IV) 10/26 47/25 32/33 0.083 ECOG (0,1/2) 96/77 9/27 63/9 24/41 <0.001 Stent type 0.248 Uncovered 128 23 (63.9%) 52 (72.2%) 53 (81.5%) Covered 45 13 (36.1%) 20 (27.8%) 12 (18.5%) Complications Pancreatitis 21 (14.8%) 6 (26.1%) 7 (14.6%) 8 (12.9%) 0.254 Bleeding 2 (1.4%) 1 (4.3%) 1 (2.1%) 0.457 Perforation Etc. 1 (1.6%) 0.889 Total bilirubin (day0) 8.9±7.1 7.1±5.4 9.3±6.3 8.4±7.1 0.745 Total bilirubin (1week) 4.2±5.6 4.2±4.4 3.2±5.0 4.3±6.2 0.428 Total bilirubin (1month) 2.7±5.3 1.9±3.1 1.4±1.8 1.7±2.3 0.985 나이, 성별, stage, ECOG 및 total bilirubin은 양군간 큰 차이는 없었고, stent type의 경우 전체 환자의 절반 이상에서 uncovered stent를 삽입.

Stent patency: BSC vs. Chemotherapy

Stent patency: Chemotherapy regimen

Overall survival P<0.001

Risk factors for stent patency Duration (95% CI), day Univariate Multivariate Odds ratio (95% CI) p-value Age <63 349.2 (296.1-402.3) 1 ≥63 174.6 (144.4-204.7) 2.225 (1.404-3.527) 0.001 1.448 (0.882-2.378) 0.43 Sex Male 282.0 (229.0-334.9) Female 250.0 (205.7-294.1) 1.244 (0.683-2.267) 0.475 Stage III 260.0 (201.4-318.6) IV 252.7 (207.7-297.7) 1.295 (0.464-3.612) 0.388 ECOG 0,1 322.6 (270.0-375.1) 2 162.1 (127.9-196.2) 1.679 (0.913-3.085) 0.095 1.289 (0.766-2.170) 0.339 Treatment BSC 111.2 (77.6-144.8) FOLFIRINOX 391.4 (339.5-443.2) 0.175 (0.095-0.321) <0.001 0.264 (0.127-0.549) Gemcitabine-based 207.4 (161.8-252.9) 0.478 (0.288-0.791) 0.03 0.528 (0.315-0.885) 0.046 Stent UCSEMS 280.1 (234.0-326.2) CSEMS 207.2 (138.5-275.9) 1.435 (0.918-2.242) 0.113 Univariate and Multivariate Analysis consistently showed that Folfirinox chemotherapy was associated with longer stent patency.

Summary Compared with patients who received best supportive care only, patients who underwent chemotherapy after stent insertion had better stent patency. Better stent patency can be expected for the patients with Effective chemotherapy including FOLFIRINOX.

Conclusion Effective systemic chemotherapy might prolong the self expandable metal stent patency in pancreatic cancer