1. 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

2. 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

3. 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:

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

5. 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.

6. 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:

7. 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:

8. 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

9. 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:

10. 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.

11. 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

12. 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

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

14. 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

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

18. 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

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

20. 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:

21. 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:

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

23. 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)

24. Is CTx associated with stent patency in pancreatic cancers?
Stent migration
Chemotherapy HR: 4.46 (95% CI )
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

25. 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: (95% CI )
in a competing risk analysis

26. 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:

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

28. 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:
Cha BH, Lee SH et al, Asia Pac J Clinical Oncol 2013;9:162-8

29. 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

30. 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?

31. 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.

32. 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.

33. 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

34. Flowchart of enrolled patients

35. 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.

36. Stent patency: BSC vs. Chemotherapy

37. Stent patency: Chemotherapy regimen

38. Overall survival
P<0.001

39. Risk factors for stent patency
Duration
(95% CI), day
Univariate
Multivariate
Odds ratio (95% CI)
p-value
Age
<63
349.2 ( ) 1
≥63
174.6 ( )
( )
0.001
1.448 ( )
0.43
Sex
Male
282.0 ( )
Female
250.0 ( )
1.244 ( )
0.475
Stage
III
260.0 ( ) IV
252.7 ( )
1.295 ( )
0.388
ECOG
0,1
322.6 ( ) 2
162.1 ( )
1.679 ( )
0.095
1.289 ( )
0.339
Treatment
BSC
111.2 ( )
FOLFIRINOX
391.4 ( )
0.175 ( )
<0.001
0.264 ( )
Gemcitabine-based
207.4 ( )
0.478 ( )
0.03
0.528 ( )
0.046
Stent
UCSEMS
280.1 ( )
CSEMS
207.2 ( )
1.435 ( )
0.113
Univariate and Multivariate Analysis consistently showed that Folfirinox chemotherapy was associated with longer stent patency.

40. 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.

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