Presentazione a cura del Dottor Gabriele Capurso - "HOT TOPICS IN GASTROENTEROLOGIA - I TUMORI DELL'APPARATO DIGERENTE: cosa è cambiato e cosa bisogna sapere" - Roma 10/11/2018

1. Gabriele Capurso, MD, PhD
Chief Clinical Research
Pancreatobiliary and EUS Unit
Pancreas Center
IRCCS S. Raffaele, Milano
capurso.gabriele@hsr.it
La Prevenzione del tumore del Pancreas
Roma 10 Novembre 2018

2.  On the rise in the EU
 Quest’anno ha superato il tumore del SENO
Tumour-related deaths in EU

3. • #4 cancer-related death cause
• Will be #2 by 2030
Tumour-related deaths in the US

4. Tumour-related 5-year survival in Italy

5. SURGERY
MEDICAL
TREATMENT
EARLY DIAGNOSIS
PREVENTION
A disease in which defense
is the key
< 20%
Not curative

6.  At least a decade
between initiating
mutation and the birth of
the parental, non-
metastatic founder cell
 Five more years for the
acquisition of
metastatic ability and
patients die an average
of two years thereafter
Yachida S, et al. Nature 2010;467:1114-7.
Precancerous Lesions and Pancreatic Cancer:
A question of time

7. Prevenzione – Diagnosi Precoce
Prevenzione primaria = abbattere fattori di rischio
Prevenzione secondaria = screening
Follow-up lesioni precancerose (cistiche)
Chemio (farmaco) prevenzione

8. Prevenzione Primaria = ridurre fattori di rischio
 Prevenzione primaria: ridurre fattori di rischio
(se il fumo di sigaretta «scomparisse» incidenza diminuirebbe del 25% in 15 anni!)
Risk factor Population
Exposed
Relative
Risk
Attributable
Fraction
Tobacco smoking 25-40% 1.5-2.2 PAF 11-32%
Helicobacter pylori infection 25-50% 1.2-1.7 PAF 4-25%
Non-O blood group 50-60% 1.3-1.4 PAF 13-19%
Diabetes mellitus 4-17% 1.4-2.2 PAF 1-16%
Obesity 20-40% 1.2-1.5 PAF 3-16%
Reducing adiponectin level Continuous 1.6* PIF 11%
Increasing red or processed meat Continuous 1.1-1.5* PIF 2-9%
Heavy alcohol intake 5-20% 1.1-1.5 PAF <9%
Family history 5-10% 1.7-1.8 PAF 3-7%
History of chronic pancreatitis 0-1% 2.7-5.1 PAF <3%
Hepatitis B infection 0-5% 1.2-1.4 PAF <1%
History of cholecystectomy 4-8% 1.2 PAF <1%
History of gastrectomy 1-2% 1.5 PAF <1%
Increasing physical activity Continuous 0.75* PIF (5%)
History of allergy 10-20% 0.7-0.8 PPF (3-7%)
Increasing fruit or folate intake Continuous 0.5-1.0* PIF (0-12%)

9. Lifetime Risk of Pancreatic Cancer
and Screening
Situazione Gene Lifetime
Pancreatic Cancer
Risk
What to do?
General Population - 1.5% Primary Prevention
1 Family member with PDAC - 3-5% Primary Prevention
2 Family members with PDAC ??? 8-12% Screening
3 Family members with PDAC ??? 40% Screening
Peutz Jeghers Syndrome STK11 11-36% Screening
Familiar Melanoma Syndrome p16 10-17% Screening
Hereditary Pancreatitis PRSS1 40% Screening

10. 1)Familiar pancreatic cancer with two or more blood
relatives affected by PDAC, of whom at least one 1st
degree relative (FDR).
2) - all patients with Peutz–Jeghers syndrome
- familial atypical multiple mole melanoma syndrome
(FAMMM) and
- BRCA2, and HNPCC mutation carriers only if one
FDR or two family members affected.
Canto M et al. GUT 2012
Who should we screen?

11. What are we looking for?
(target of screening)
1) Small (T1) resectable (R0) adenocarcinoma
2) PanIN3
3) IPMNs with high grade dysplasia

12. Pooled prevalence of
pancreatic
solid lesions
Pooled prevalence of
pancreatic
cystic lesions
5.8%
I2= 77%
20.2%
I2= 88%
breast cancer screening for women over age 40 –12.29% risk
colon cancer screening beginning age 50 – 4.82% risk
Signoretti et al. UEGJ 2018

13. Study name Statistics for each study Event rate and 95% CI
Event Lower Upper
rate limit limit Z-Value p-Value
Kimmey 0,011 0,00 0,15 -3,19 0,00
Canto 2006 0,038 0,01 0,11 -5,47 0,00
Poley 0,068 0,02 0,19 -4,37 0,00
Verna 0,024 0,00 0,15 -3,64 0,00
Ludwig 0,037 0,01 0,09 -6,41 0,00
Canto (CAPS3) 0,014 0,00 0,04 -7,33 0,00
Al-Sukhni 0,004 0,00 0,03 -5,40 0,00
Sud 0,125 0,03 0,39 -2,57 0,01
Harinck 0,007 0,00 0,05 -4,91 0,00
Del Chiaro 0,100 0,04 0,24 -4,17 0,00
Joergensen 0,028 0,01 0,11 -4,94 0,00
Vasen 2016 0,032 0,02 0,05 -12,14 0,00
0,033 0,02 0,05 -13,43 0,00
-0,50 -0,25 0,00 0,25 0,50
Pooled prevalence of lesions
considered a success
I2= 44,8%
1) Small (T1)
resectable (R0)
adenocarcinoma
2) PanIN3
3) IPMNs with high
grade dysplasia
3.3% Signoretti et al. UEGJ 2018

14. Pooled prevalence of lesions
considered a success in subgroups
3%
4%
5%
6.3%
12.2%

15. Pooled prevalence of
lesions in EUS Vs MRI (MRCP)
5%
4%
16.6%
22.4%
2.9%
2.5%

16. So..how do we look for them?
MRCP… better for cystic lesions? EUS… better for solid lesions?

17. Screening in Italy
Paiella, Capurso et al. Am J Gastroenterol in press
After the first-round of screening of the Italian registry
the rate of malignancies was 2.6%.
age > 50 years (OR 3.3, 95%CI 1.4-8)
smoking habit (OR 2.8, 95%CI 1.1-7.5)
having >2 relatives with PC (OR 2.7, 95%CI 1.1-6.4)

18. IPMNs easy to be detected…
PanINs?
PanIN1 PanIN2 PanIN3
Autopsies 77% 28% 4%
Chronic Pancreatitis 83% 14% 2%
Sporadic Pancreatic Cancer - - 35%
Familial Pancreatic Cancer - - 65%
Increase with AGE

19. Are PanINs invisible?

20. Screening for Familiar Pancreatic Cancer: abrupt increased duct wall diameter..FNA = PanIN3 (SURGERY)
Are PanINs invisible?
Courtesy of Mara Petrone
and Paolo Arcidiacono

21. Prevenzione – Diagnosi Precoce
Prevenzione primaria = abbattere fattori di rischio
Prevenzione secondaria = screening
Follow-up lesioni precancerose (cistiche)
Chemio (farmaco) prevenzione

22. Prevalence of Pancreatic Cystic Lesions
in the general population
8.4%
Zerboni et al Pancreatology in press
Vast majority are
low-risk (Branch-Duct) IPMNs

23. IPMN MAIN-DUCT:
Malignancy 40%
IPMN MIXED TYPE
Malignancy 40%
IPMN BRANCH-DUCT
Malignancy 10% in
operated… <1% in
others

24. Surgical Indication for IPMNs
Del Chiaro et al. Evidence Based European Guidelines Gut 2018.
Absolute indications Relative Indications
Positive cytology for malignancy/HGD Grow-rate  5 mm/year
Solid mass Increased levels of Ca 19.9 (> 37 U/ml)
Jaundice (tumor related) MPD dilatation from 5 - 9.9 mm
Enhancing mural nodules ( 5 mm) Cyst diameter  4 cm
MPD dilatation  10 mm New onset of diabetes mellitus
Acute pancreatitis (caused by IPMN)
Enhancing mural nodules (< 5 mm)
Targeting Cancer Targeting Dysplasia

25. Patients with “short life
expectancy, relevant
co-morbidities and/or
with only one relative
indication for surgery
Algorithm
Del Chiaro et al. Evidence Based European Guidelines Gut 2018.

26. Risk of Invasive Pancreatic Neoplasia
in the Follow-up of BD-IPMN without surgical indication
Study name Statistics for each study Rate and 95% CI
Standard Lower Upper Relative
Rate error Variance limit limit Z-Value p-Value weight
Wakabayashi 0,012 0,012 0,000 -0,012 0,036 1,000 0,317 0,90
Sai 0,004 0,006 0,000 -0,007 0,016 0,707 0,480 3,32
Irie 0,005 0,007 0,000 -0,009 0,019 0,707 0,480 2,44
Kobayashi 0,018 0,011 0,000 -0,002 0,039 1,732 0,083 1,19
Pelaez-Lula 0,005 0,005 0,000 -0,005 0,015 1,000 0,317 4,24
Salvia 0,002 0,003 0,000 -0,004 0,008 0,707 0,480 8,73
Sawai 0,012 0,005 0,000 0,002 0,021 2,449 0,014 4,54
Shin 0,007 0,010 0,000 -0,012 0,026 0,707 0,480 1,34
Tanno 0,008 0,004 0,000 0,000 0,017 2,000 0,046 5,53
Bae 0,008 0,004 0,000 -0,001 0,016 1,732 0,083 5,10
Uehara 0,005 0,002 0,000 0,000 0,010 2,000 0,046 10,09
Kang 0,017 0,006 0,000 0,005 0,029 2,828 0,005 3,19
Khanoussi 0,005 0,004 0,000 -0,002 0,013 1,414 0,157 6,32
Ohno 0,028 0,007 0,000 0,013 0,042 3,742 0,000 2,25
Cauley 0,006 0,003 0,000 0,000 0,011 2,000 0,046 8,96
Arlix 0,002 0,003 0,000 -0,003 0,007 0,707 0,480 9,08
Othman 0,034 0,017 0,000 0,001 0,068 2,000 0,046 0,48
Mori 0,004 0,003 0,000 -0,002 0,010 1,414 0,157 8,63
Sahora 0,009 0,002 0,000 0,005 0,013 4,359 0,000 11,39
Kamata 0,020 0,007 0,000 0,005 0,034 2,646 0,008 2,27
0,007 0,001 0,000 0,005 0,010 6,018 0,000
-0,07 -0,04 0,00 0,04 0,07
Development of overall pancreatic malignancy
7/1000 pyrs; 0.7% per year
Crippa, Capurso et al. DLD 2016

27. Del Chiaro M et al. Ann Surg Oncol 2016
Risk of Progression increases
with time

28.  144 patients with FU > 5 years, (median FU 84 months)
 Yearly MRI/MRCP
 Progression in 48%
 Appeareance of WF in 20 pts (14%), HRS in 4 (3%)
 Time to WF 71 months, 77.5 for HRS
 Malignancy 2 patients (1.4%)
Crippa et al. Am J Gastroenterol 2017
Risk of Progression
increases with time
Economical Problem… can we follow-up
7% of the population lifelong?
What else?

29. Is chemoprevention for pancreatic cancer possible?
Archibugi et al. Sci Reports 2017

30. Statins reduce
Pancreatic cancer risk
Archibugi et al. DLD 2018 Risk reduction 30%

31. 31
Characteristic N (%)- (95% CI)
Patients 594
Number of male 228 (38.38)
Mean Age (years) 64.84 (63.95–65.73; 95% CI)
Mean follow-up (months) 44.78 (42.01–47.54; 95% CI)
Smoking 156 (26.94)
1st FH PDAC 27 (4.63)
Diabetes 102 (17.61)
Alcohol (ever) 136 (23.48)
Recent onset diabetes 10 (9.80)
Mean Cyst Diameter (mm) 15.1 (14.42-15.85; 95% CI)
Multifocal Disease 344 (58.10)
Symptomatic 104 (17.56)
Progression (any) 277 (46.86)
Dimensional Progression 243 (41.32)
Mean dimensional increase (mm) 7.77 (6.82–8.72; 95% CI)
Clinically significant progression 46 (7.74)
Chemoprevention on
BD-IPMNs progression
Valente et al. UEGW oral communication October 24 2018

32. Chemoprevention
on IPMNs progression
Any progression:
 STAT HR= 0.72 (0.53-0.97);p=0.03
 ACEI HR=0.69 (0.48-0.98); p=0.04
 Insulin HR= 1.49 (0.99-2-24); p=0.05
Dimensional Progression:
 ACEI HR=0.70 (048-1.01); p=0.06
 STAT HR= 0.67 (0.49-0.93); p=0.01
 Insulin HR 1.65 (1.09-2.51); p=0.01
0
20
40
60
80
100
0 50 100 150 200
Progression free survival
100-Survivalprobability(%) STAT
0=non users
1=users
Valente et al. UEGW oral communication October 24 2018
Statins = Risk reduction 30%

33. Summary & Conclusion
• Pancreatic cancer is fatal but potentially preventable
• Primary prevention should focus on SMOKING and BODY WEIGHT
• Screening in selected individuals (lifelong)
• IPMNs are very common, easily detectable and should be followed-up
(lifelong)
• Possible role for chemoprevention (research issue)

34. capurso.gabriele@hsr.it
https://public.emec-roma.com/cmsweb/Login.asp?IDcommessa=30/2018&Lang=IT