1. Management of pancreatic adenocarcinoma
Moderator: Dr A. Saraya
Presenter: Ujjwal

2. EPIDEMIOLOGY
13th most common cancer and 8th most common cause of cancer related deaths
Pancreatic cancer is the second most common gastrointestinal malignancy in the United States
For all stages combined, the one- and five-year relative survival rates are 24% and 5%
American cancer society, facts and figures, 2004

3. EPIDEMIOLOGY
80% to 90% of tumors are diagnosed at an unresectable stage
In India, incidence increasing over last 2 decades in both males and females
Cancer mortality and morbidity in Mumbai, Indian cancer society,1997

4. India has the lowest incidence of pancreatic cancer
/100,000 males and /100,000 females
Dhir V et al, Indian J gastroenterol 1999
No significant decrease in mortality over last 2 decades even in developed countries
GLOBOCON 2008 Cancer Incidence and Mortality

5. RISK FACTORS ENVIRONMENTAL
Cigratte smoking (most important) (OR 1.74, 95% CI 1.61–1.87),
Consumption of red processed meat (OR 1.55, 95% CI 1.16–2.07)
Occupational exposure to benzidine and beta-napthylamine
The risk may be particularly elevated in smokers who have homozygous deletions of the gene for glutathione S-transferase T1 (GSTT1), which is a carcinogen metabolizing enzyme.16

6. BMI of more than 35 (OR 1.55, 95% CI 1.16–2.07)
consumption of more than 6 alcoholic beverages per day (OR 1.46, 95% CI 1.16– 1.83)
Klein AP. Identifying people at high risk of developin pancreaticcancer. Nat Rev Cancer 2013

7. presence of non–type O blood antigens (OR 1. 42, 95% CI 1. 21–1
presence of non–type O blood antigens (OR 1.42, 95% CI 1.21–1.66), which display aberrant expression on pancreatic ductal cells, and affect signal transduction and cellular adhesion
Wolpin BM. Genotype derived ABO blood groups alleles and the risk of pancreatic cancer. Cancer Res 2010

8. Chronic pancreatitis (risk: 2% per decade,independent of the type of pancreatitis)
RR: 7.2
Bracci PM et al, cancer 2009

9. family history of pancreatic cancer (OR 2.41, 95% CI 1.04– 4.74)
GENETIC FACTORS
family history of pancreatic cancer (OR 2.41, 95% CI 1.04– 4.74)
hereditary pancreatic cancer syndrome
Hereditary pancreatitis (RR: 50-80)
Peutz-jeghers syndrome (RR: 132)
HNPCC (RR: unknown)
FAMMM (RR: 20-30)
Familial atypical mole melanoma: Two or more blood relatives with melanoma and an underlying CDKN2A/p16 mutation.
Assocation with pancreatic cancer: OR 47.8, 95% CI 28.4–74.7. Prevalence: >1/1000.

10. CLINICAL PRESENTATION
The pancreas is located in the retroperitoneum, where initial growth of the cancer is silent; therefore, symptoms are usually a sign of advanced disease.
Depends on the stage of disease and the location of the primary tumour

11. CLINICAL PRESENTATION
Right–upper quadrant or epigastric pain (79%)
Jaundice (56%)
Nausea or vomiting secondary to obstruction of the gastric outlet (51%)
Diarrhea (43%) and steatorrhea due to pancreatic insufficiency (25%)
New or worsening back pain (49%) could signal cancer in the pancreatic body or tail.

12. systemic manifestations may include:
New onset or worsening of previously stable diabetes, although not usually due to the cancer, should alert the physician to the possibility of pancreatic cancer
systemic manifestations may include:
rapid weight loss (85%) and anorexia (83%)
thromboembolic disease (3%)
...Porta Mand stage. Clin Transl Oncol 2005
At diagnosis, one third of tumours of the pancreas head were in stage I and another third in stage IV. None of the tumours of the body and tail were in stage I, and over 80% were in stage IV (p < 0.001) . At presentation, the most frequent symptoms were asthenia (86%), anorexia (85%), weight-loss (85%), abdominal pain (79%), and choluria (59%). Cholestatic symptoms were more common in tumours affecting only the pancreatic head (p < 0.001) . There was a clear trend toward more localized tumours with increasing numbers of cholestatic signs (p < 0.001) . Asthenia, anorexia and weight-loss were unrelated to stage. An increased symptom-to-diagnosis interval was associated with more advanced stage (p = 0.048

13. PANCREATIC CANCER ACCORDING TO SITE
pancreatic head, neck or uncinate process (70%)
body or tail (20%)
Multifocal disease (10%)
Artinyan A et al. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB 2008

14. SURGERY/EXTENT ACCORDING TO SITE
HEAD
N=18666
BODY/TAIL
N=5192
P-VALUE
CANCER DIRECTED
SURGERY
5637
29%
960
16%
< 0.001
EXTENT OF DISEASE
METASTATIC
6252
35%
3841
67%

15. SURVIVAL ACCORDING TO SITE

16. DIAGNOSIS AND STAGING
Triphasic contrast-enhanced abdominal CT (sensitivity 89%–97%, specificity 95%)
Most validated imaging study for both diagnosis and staging
Useful in assessing resectibility
70-85 % of those who have resectable disease on CT undergo curative resection

17. Sensitivity poor for peritoneal metastasis and tumor < 2 cm in size
MRI is considered equivalent to CT (sensitivity 81%–99%, specificity 70%–93%), its more limited availability has restricted its use to patients with contraindications to CT (e.g., pregnancy, nephropathy) or where resectability is unclear after CT.
Optimal study: NCCT plus arterial, portal venous and pancreatic protocol phase with 3 mm cuts

18. Optimal study: Non-contrast plus arterial, portal venous and pancreatic protocol phase with 3 mm cuts

19. ROLE OF EUS
Diagnosis:
For tumors < 2 cm in size which are not well visualised on CT
Inflammotory head mass in the setting of chronic pancreatitis
To discriminate between benign and malignant strictures

20. ROLE OF EUS STAGING: Complimentary to CT and MRI
Mainly in patients whose scans show doubtful vascular or lymph node involvement

21. ROLE OF PET-CT Has a role in staging of disease
Adjunct to multiphasic CT/MRI
Has increased sensitivity for detection of distant metastasis
Can prevent unnecessary pancreatic resection in upto 25 % of patients by detecting unsuspected metastasis
Saif MW et al, J. gastrointestin liver disease, 2008

22. ROLE OF LAPROSCOPY Role in staging:
High sensitivity for peritoneal and liver capsular metastasis
Not a substitute for poor quality imaging

23. ROLE OF LAPROSCOPY Considered when high risk of metastatic disease:
Tumor size > 2cm
Border line resectable disease
Tumor of body/tail
Markedly elevated CA 19-9

24. ROLE OF BIOPSY No role in resectable disease
Required in unresectable disease and metastatic disease to confirm diagnosis before starting chemotherapy
EUS FNA is preferable to CT guided FNA
Less bleeding and infection and metastatic seeding

25. BIOMARKERS Various biomarkers:
CA 19-9 (best validated and most useful)
CA 125
CEA
Pancreatic oncofetal antigen

26. CA 19-9:
Sialylated lewis A blood group antigen
Good diagnostic marker (sensitvity: 80%, specificity: 82-90%)
Correlates with staging and resectibility

27. Prognostic marker:
Low post-operative levels and serial decrease in levels after surgery correlate with survival post curative resection
Berger AC et al J. Clin oncology 2008
Pre-treatment levels are an independent prognostic factor for survival in advanced pancreatic cancers
Hess V et al, lancet oncology 2008

28. Predictor of response:
Change in CA 19-9 levels after chemotherapy in patients with advanced disease predicts response to treatment

29. FALSE – ve: lewis antigen negative patients
Biliary obstruction
Cholangitis
Biliary malignanciaes
Pre-operative levels should be measured after biliary drainage and normalisation of blirubin levels

30. SUMMARY

32. STAGING stage Tumor grade Node status Distant metastasis 5yr survival,%
Median Survival,mo
Characteristics IA T1 No Mo 14 24
Tumor <2cm in pancreas only IB T2 12 21
Tumor >2cm in pancreas only
IIA T3 7 15
Tumor extends beyond the pancreas, but with no involvement of the celiac or SMA
IIB
T1-3 N1 5 13
Regional lymph node metastasis
III T4
N0-1 3 11
Tumor involves the celiac or SMA IV
T1-4 M1 1

33. CLASSIFICATION PANCREATIC ADENOCARCINOMA BOREDERLINE RESECTABLE
PPANCREATIC
BOREDERLINE
RESECTABLE
RESECTABLE
ADVANCED
METASTASIS
ENCASEMENT OF ARTERIES
EXTENSIVE INVOLVEMENT OF VEINS
NO METASTASIS
NO VASCULAR INVOLVEMANT
PARTIAL ABUTMENT OF PORTAL OR SMV

34. Stage of disease
SMA
Celiac axis
Common Hepatic Artery
SMV-PV
Resectable(all four required)
No extension; normal fat plane between the tumor and the artery
Patent (may include tumor abutment or encasement)
Boderline resectable (one required)
Abutment
Abutment or short segment encasement if reconstruction possible
Short segment occlusion if reconstruction possible
Unresectable (one required)
Encasement
Extensive encasement with no technical option for reconstruction
Occluded with no technical option for reconstruction

35. RESECTABLE DISEASE Only 15% -20 % of newly diagnosed cases
SURGERY is the only curative treatment
Procedure depends on the location of the tumour:
Pancreaticoduodenectomy (Whipple procedure): lesions of the head, neck and uncinate process
Distal pancreatectomy: lesions of the body or tail
Total pancreatectomy: multifocal disease

36. Overall 5-year survival after pancreatic resection is 14
Overall 5-year survival after pancreatic resection is 14.6%, but higher in well-differentiated disease (30%–40%) and disease that has not metastasized to the lymph nodes (25%–30%)
Cleary SP, et al J Am Coll Surg 2004
Negative margin status, tumor size and lymph node status are the strongest predictors of survival

37. ADJUVANT CHEMOTHERAPY
Recommended for all patients who undergo curative resection
Either gemcitabine or 5 - fluorouracil (5-FU) prolongs median survival by 3 months (95% CI 0.3–5.7)
Boeck S et al Oncology 2007 metaanalysis

38. We performed a retrospective review 472 consecutive patients who underwent complete
resection with negative margins (R0) for invasive carcinoma (T1-3N0-1M0) of the pancreas
between 1975 and 2005 at the Mayo Clinic in Rochester, MN.

39. For the 466 surviving patients, median follow-up was 32
For the 466 surviving patients, median follow-up was 32.4 months; median OS was 21.6 months. Median OS after adjuvant CT-RT was 25.2 versus 19.2
months after no adjuvant therapy (P .001). Two-year OS was 50% versus 39%, and 5-year OS was 28% versus 17%.

40. Adverse prognostic factors identified by univariate and multivariate analysis included positive lymph nodes (risk ratio [RR] 1.3; P .001), high histologic grade (RR 1.2; P .001), and no adjuvant therapy (RR 1.3; P .001).

41. Gemcitabine has been recommended as the first-line adjuvant agent owing to its lower toxicity profile

42. ROLE OF ADJUAVENT RADIATION
The benefit of adjuvant radiation therapy is
unclear based on the results of the ESPAC-1
trial.28 Median survival with chemoradiation
(13.9 mo, 95% CI 12.2–17.3) was similar to that
seen with observation alone (16.9 mo, 95% CI
12.3–24.8), but was longer when chemoradiation
was followed by chemotherapy (19.9 mo, 95%
CI 14.2–22.5) and longest with adjuvant
chemotherapy alone (21.6 mo, 95% CI 13.5–
27.3).

45. ROLE OF ADJUAVENT RADIATION
No clear benefit of radiation therapy in addition to adjuvant chemotherapy

46. ROLE OF NEOADJUAVENT THERAPY
Benefit of neoadjuvant therapy at the cost of delaying surgery is controversial
No phase III trials comparing outcomes between neoadjuvant and adjuvant therapy
most centres refrain from using neoadjuvant therapy outside of research protocols

47. A meta -analysis mainly consisting of heterogenous phase I and II studies found a median overall survival of 23.3 (range 12–54) months, with perioperative mortality of 5.3% (95% CI 4.1%– 6.8%).

48. A total of 111 studies (n = 4,394) including 56 phase I-II trials were analyzed. A median of 31 (interquartile range [IQR] 19-46) patients per study were included.

49. ROLE OF PRE-OPERATIVE DRAINAGE
Goal
To alleviate symptoms of pruritis
To provide drainage in patients with cholangitis
Decrease surgical morbidity by improving liver function

50. Studies have failed to show decreased mortality in patients who underwent pre-operative drainage

51. RCT in 2010

53. Recommended:
Cholangitis
Significant pruritis and > 1 week delay of surgery
If patient has to receive neoadjuvant therapy
Plastic stents are preferred over metal stents

54. BORDERLINE RESECTABLE DISEASE
Surgery is attempted only if complete resection is possible
Role of neoadjuvant therapy is debatable
No phase 3 RCTs
A 6-year prospective study involving 110 patients with resection of the hepatic portal vein, SMV or both for suspected tumour infiltration showed median overall survival of 14.5 (range 7.3–24) months, with perioperative mortality of 3.7%.
Müller SA, Hartel M, Mehrab A, et al. Vascular resection in pancreatic cancer surgery: survival determinants. J Gastrointest Surg 2009;13:
These results suggest that major venous resection and reconstruction is safe in experienced hands and results in oncologic results equivalent to those of complete resection.

55. A role and optimal regimen for neoadjuvant therapy in borderline resectable disease is unclear, based on inconclusive findings regarding median survival in a retrospective study of neoadjuvant treatment versus immediate surgery (35 mo v. 27 mo; p = 0.7).
Barugola G et al. Outcomes after resection of borderline resectable pancreatic cancer after neoadjuvant therapy. Am J Surg 2012

56. ADVANCED DISEASE
Median overall survival of 2–3 months without treatment
Chemotherapy is advised as it improves survival
Distant organ involvement, typically that of the liver, peritoneum or lung, occurs in 50% of cases.

57. 51 trials involving 9,970 patients met the inclusion criteria, and 33 of these trials involving 6,026 patients were included in the meta-analyses

58. N=432 mortality reduction = 36 %
51 trials involving 9,970 patients met the inclusion criteria, and 33 of these trials involving 6,026 patients were included in the meta-analyses.
N=432 mortality reduction = 36 %

59. Journal of clinical oncology, 1997
Gemcitabine better than 5 FU
Journal of clinical oncology, 1997

61. ROLE OF COMBINATION CHEMOTHERAPY
No overall improved survival as compared to monotherapy
Survival benefit in a subset of patient who have good performance status
Individual clinical trials of combination gemcitabine with various cytotoxic agents53–56 have failed to show a survival benefit over gem citabine alone (Appendix 1), but significantly improved overall survival was seen when these studies were pooled (HR 0.91, 95% CI 0.85–0.97).37 Furthermore,
patients with a good performance status (Karnofsky performance score > 90%) survived longer with combination gem citabine (HR 0.76, 95% CI 0.67–0.87), whereas patients with a poor performance status did not (HR 1.08, 95% CI 0.90– 1.29).

63. improve
Meta analysis for combination chemotherapy in advanced pancreatic cancer – overall survival with regard to combination partner (platinum analog, fluoropyrimidine or other) for gemcitabine.

64. Meta-analysis for combination chemotherapy in advanced pancreatic cancer-overall survival with regard to performance status

65. Reserved for patients with good performance status
Individual clinical trials of combination gemcitabine with various cytotoxic agents have failed to show a survival benefit over gemcitabine alone but significantly improved overall survival was seen when these studies were pooled (HR 0.91, 95% CI 0.85–0.97)
Reserved for patients with good performance status
Combination therapy also showed higher grade 3/4 toxicity: neutropenia (risk difference [RD] 5%, 95% CI 1%–10%), thrombocytopenia
(RD 5%, 95% CI 2%–8%) and nausea or vomiting (RD 3%, 95% CI 0%–5%).57 Combination chemotherapy is reserved for patients with a good
performance status.

66. GEMCITABINE + ERLOTINIB
Targeted therapy in pancreatic cancer has centred on the epidermal growth factor pathway
Erlotinib: tyrosine kinase inhibitor of EGFR

67. Kaplan-Meier curves for (A) overall survival;
(B) progression-free survival; and
(C) overall survival in the 100-mg cohort.

68. This phase III study of the epidermal growth factor receptor inhibitor erlotinib with gemcitabine versus gemcitabine alone showed marginally increased overall survival (6.24 v mo,vs p = 0.04)58 and 1-year survival (23% [95% CI 18%–28%] v. 17% [95% CI 12%–21%], p = 0.02).
combination gem - citabine/ erlotinib is considered for patients with good performance status in the metastatic setting.

69. GEMCITABINE + ERLOTINIB
Recommended as an option for patients with locally advanced and metastatic disease
Benefit more in patients who develop skin rash

70. FOLFIRINOX
FOLFIRINOX (5-FU, leuco - vorin, irinotecan and oxaliplatin)
Increase in median overall survival over gemcitabine alone in metastatic pancreatic cancer (11.1 mo v. 6.8 mo; HR 0.57, 95% CI 0.45– 0.73, p < 0.001).

71. FOLFIRINOX

72. Folfirinox: 11.1 months gemcitabine: 6.6 months

73. Folfirinox: 6.4 months gemcitabine: 3.3 months

74. FOLFIRINOX

76. THANK YOU