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Pancreatic Cancer
Pratap Sagar Tiwari, MD (Internal medicine)
DM Resident, Hepatology, NAMS
Bir Hospital, Nepal
Content
• Introduction
• Classification
• Risk Factors
• Molecular biology & Embryonic signalling pathways
• Manifestations
• Role of Tumor markers
• Imaging
• Management
Introduction
• Pancreatic cancer is the second MC GI malignancy in the US[1]
• Pancreatic cancer ranks 10th in cancer incidence in the US for men and women.
• A recent study estimating cancer epidemiology in 2014 (within Europe) showed
that PC was the fourth most fatal cancer in men after lung, colorectal, and
prostate cancers . [2]
• Similarly, PC was found to be the fourth most fatal cancer in women after breast,
colorectal and lung cancers .[2]
• Surgical excision is the definitive RX with a 5-yr survival rate (after resection) of
∼20%, but it is only possible in 15%–20% of the pts. Overall, PC carries an
unfavorable prognosis. For all stages combined, the 1- & 5-year survival rates
are 24% & 5%, respectively.[3]
1. American Cancer Society: Cancer Facts and Figures 2008. Atlanta, American Cancer Society, 2008.
2. Malvezzi M, Bertuccio P, Levi F et al. European cancer mortality predictions for the year 2014. Ann Oncol 2014; 25: 1650–1656
3. Ries LAG, Eisner MP, Kosary CL: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md, National Cancer Institute, 2000.
4. .
WHO Classification of Primary Tumors of the Exocrine Pancreas
Data from Hamilton SR, Aaltonen LA. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000.
Pancreatic Tumors
Islet cell tumorsAcinar cells
Ductal epithelium [80-90%]
Endocrine [5%]Exocrine [95%]
• Only 2% of tumours of the exocrine pancreas are benign.
• A number of morphological variants of ductal carcinoma have been characterised, including colloid carcinoma and
medullary carcinoma. Other variants of pancreatic cancer, such as adenosquamous carcinoma and undifferentiated
carcinomas with osteoclast-like giant cells, are important to recognise because they are a/with a poorer prognosis.
• Neuroendocrine tumours of the pancreas are the second most frequent PC.
• Cystic neoplasms represent 10%–15% of cystic lesions of the pancreas.[1] The most commonly encountered cystic
neoplasms include: serous cystadenoma, intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic
neoplasm (either cystadenoma or cystadenocarcinoma).
• Mucinous lesions have potential for malignant progression and/or may harbour a malignancy at the time of DX.
Neuroendocrine tumors
1. Dudeja V, Allen PJ. Premalignant cystic neoplasms of the pancreas. Semin Oncol 2015; 42: 70–85.
Pancreatic tumors
Note: Endocrine tumors of Pancreas
• Endocrine tumors of Pancreas [ETP] are classified as functioning or non
functioning according to the type and level of their hormonal secretion.[1]
Among functioning ETP,
• Insulinomas (50%) and gastrinomas (30%) are the most frequent;
• Tumors secreting vasoactive intestinal peptide (VIPomas), glucagon
(glucagonomas), and somatostatin (somatostatinomas) are much rarer (5–10%);
• Those secreting growth-hormone-releasing factor (GHRH), adrenocorticotropic
hormone (ACTH) or corticotropin-releasing factor (CRF), and parathyroid
hormone related peptide (PTHrp) are anecdotal.
Conversely, at least 15% of ETP are non functioning or secrete non clinically active
peptides such as human pancreatic polypeptide (PPomas).
1. Klöppel G, Heitz P U. Pancreatic endocrine tumors. Pathol Res Pract. (1988);183:155–168.
Note: Endocrine tumors of Pancreas
• Most ETP discovered clinically are functional—that is, they secrete one or more
hormonal products into the blood, which leads to a recognizable clinical syndrome.[1]
• In 1927, Wilder et al described the first hormone-producing pancreatic tumor syndrome
(insulinoma syndrome) in a pt with hypoglycemia and a metastatic islet cell tumor,
extracts of which caused hypoglycemia.[2]
• Zollinger-Ellison syndrome (also termed gastrinoma syndrome), described by Zollinger
and Ellison in 1955.[3]
• The other types comprise a group of three tumor syndromes, termed Verner-Morrison
syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, and
pancreatic cholera (also termed vasoactive intestinal peptide [VIP]–releasing tumor or
VIPoma); these were described by Verner and Morrison in 1958.[4]
• Another is glucagonoma syndrome, described by Mallinson et al in 1974.
• Somatostatinoma syndrome, described by Ganda et al and Larsson et al in 1977.[5, 6]
1. Aluri V, Dillon JS. Biochemical Testing in Neuroendocrine Tumors. Endocrinol Metab Clin North Am. 2017 Sep. 46 (3):669-677.
2. Wilder RM, Allan FN, Power WH. Carcinoma of the islands of the pancreas: Hyperinsulinism and hypoglycemia. JAMA. 1927. 89:348.
3. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955. 142:709.
4. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958. 25:374.
5. Ganda OP, Weir GC, Soeldner JS, et al. "Somatostatinoma": a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med. 1977 Apr 28. 296(17):963-7.
6. Larsson LI, Hirsch MA, Holst JJ, et al. Pancreatic somatostatinoma. Clinical features and physiological implications. Lancet. 1977 Mar 26. 1(8013):666-8.
Characteristics of various ETP
Ductal adenocarcinoma of Pancreas
• Ductal adenocarcinoma accounts for 85% to 90% of pancreatic tumors.[1]
• Autopsy series have shown that 60%-70% of these tumors are localized in
the head of the gland, 5%-10% in the body, and 10%-15% in the tail.
• The average size of carcinomas in the head of the pancreas is 2.5 to 3.5 cm,
compared with 5 to 7 cm for tumors in the body or tail.
1. Ductal adenocarcinoma. In: Hruban RH, Pitman MB, Klimstra DS, ed. AFIP Atlas of Tumor Pathology. Tumors of the Pancreas, Washington, D.C.: American Registry of Pathology; 2007:111-64.
Risk factor: Age
• Age appears to be a significant risk factor for the development of PC with
a median age at DX of 71 years of age, and approximately 88% DX over
the age of 55.[1]
1. HowladerNA, KrapchoM, NeymanN, et al.(eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD; 2011.
Risk factor: Gender
• As per the SEER (Surveillance, Epidemiology, and End Results) database,
the incidence rate of PC in males is 13.9 cases/100 000 people compared
with 10.9 cases in women.[1]
• The death rates are similar in that for males: the death rate is 12.5/100
000 and 9.6/100 000.
1. HowladerNA, KrapchoM, NeymanN, et al.(eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD; 2011.
Risk factor: Race
• The incidence rate of PC in African Americans is 17.6 cases/100 000
people compared with 13.8/100 000 cases in Caucasians.[1]
• The death rate is also higher in the African American population for both
sexes. The reason(s) for these differences remains unknown and an active
area of investigation.
1. HowladerNA, KrapchoM, NeymanN, et al.(eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD; 2011.
Risk factor: Smoking
• The most important environmental factor is cigarette smoking.[1]
• Multiple cohort and case-control studies have found that the RR for
smokers of developing PC is at least 1.5.[2,3,4] 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.[5]
• Furthermore, the risk rises with the amount of cigarette consumption,
and the excess risk level returns to baseline by 15 years after cessation of
the habit.[4]
• Other forms of tobacco, including pipes and smokeless (chewing) and
Environmental smoke exposure [6], have been a/with an ↑ risk as well.[7]
1. Ahlgren JD: Epidemiology and risk factors in pancreatic cancer. Semin Oncol 1996; 23:241-50.
2. Silverman DT, Dunn JA, Hoover RN, et al: Cigarette smoking and pancreas cancer: A case-control study based on direct interviews. J Natl Cancer Inst 1994; 86:1510-16.
3. Fuchs CS, Colditz GA, Stampfer MJ, et al: A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med 1996; 156:2255-60.
4. Ghadirian P, Simard A, Baillargeon J: Tobacco, alcohol, and coffee and cancer of the pancreas. A population-based, case-control study in Quebec, Canada. Cancer 1991; 67:2664-70.
5. Duell EJ, Holly EA, Bracci PM, et al: A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002; 94:297-306.
6. ZhouJ, WelleniusGA, MichaudDS. Environmental tobacco smoke and the risk of pancreatic cancer among non‐smokers: a meta‐analysis. Occup Environ Med2012;69:853.
7. BoffettaP, AagnesB, WeiderpassE, et al.Smokeless tobacco use and risk of cancer of the pancreas and other organs. Int J Cancer2005;114:992.
Risk Factor: Obesity
• The second most modifiable RF of PC is obesity. (ESMO15)
• Tumorigenesis is enhanced by excess adipose tissue, probably through the
mechanism of abnormal glucose metabolism.
• Obesity [body mass index (BMI) > 30 kb/m2] is a/with a 20%–40% higher
rate of death from PC.
Risk factor: Diabetes
• DM is very common in pts with PC.
• DM was a/with a 40% ↑ risk of PC (OR 1.40, 95% CI 1.07, 1.84).
• Risk was highest for those with a duration of diabetes for 2 to 8 years (OR
1.79, 95% CI 1.25-2.55) and no association for those with greater than 9
years of DM (OR 1.02, 95% CI 0.68-1.52).[1]
• In a meta-analysis of 36 studies, the overall relative risk for the
development of PC in a diabetic pt was 1.82 (95% CI 1.66–1.89). [2]
• Meta-analyses have demonstrated associations between both type 1 and
type 2 DM and PC, with odds ratios of ∼2.0 and 1.8, respectively. [3]
1. ElenaJW, SteplowskiE, YuK, et al.Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control2013;24:13.
2. HuxleyR, Ansary‐MoghaddamA, Berrington de GonzalezA, et al.Type‐II diabetes and pancreatic cancer: a meta‐analysis of 36 studies. Br J Cancer2005;92:2076.
3. Yeo TP. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 8–18.
Risk factor: Drugs used in Diabetes
• In the last several years, there has been interest in PC risk conferred by drugs
used to treat diabetes.
• Earlier epidemiological studies suggested a link between DM pts with a HX of
insulin or insulin secretagogs (sulfonylureas and meglitinides) use and an ↑ risk
of PC compared with nonusers. [1,2]
• Metaanalysis of 11 studies (6 cohort, 3 case–control, and 2 RCT) reported 1770
cases of PC in 730 664 pts with DM showed no significant association between
metformin, insulin, or thiazolidinediones use and risk of developing PC.
• Use of sulfonylureas was a/with a 70% ↑ in the odds of PC(n = 8 studies;
adjusted OR 1.70, 95% CI 1.27–2.28, P < 0.001).
• Although sulfonylurea seemed to be a/with ↑ risk of PC, metaanalysis of
existing studies did not support a protective or harmful association between
antidiabetic medication use and risk of PC in pts with DM. [3]
1. BowkerSL, MajumdarSR, VeugelersP, et al.Increased cancer‐related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care2006;29:254.
2. EvansJM, DonnellyLA, Emslie‐SmithAM, et al.Metformin and reduced risk of cancer in diabetic patients. BMJ2005;330:1304.
3. SinghS, SinghPP, SinghAG, et al.Anti‐diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta‐analysis. Am J Gastroenterol2013;108:510; quiz 20.
Risk factor: Drugs used in Diabetes
• Metformin, was compared in a hospital-based case–control study of 973 pts
with PC. A protective effect was seen in users of metformin who had a
significantly lower risk of PC, compared to those that had not taken metformin
(OR 0.38; 95% CI 0.22–0.69; P = 0.001). [1]
• In a small retrospective study of 302 pts, metformin use was a/with improved
outcome of pts with DM and PC[2]. Prospective controlled trials will ultimately
be required to clarify the effects of metformin on PC risk and progression.
• Most recently, there has been controversy surrounding the effects two classes
of drugs, GLP-1 agonists, which enhance insulin secretion, and DPP-4 inhibitors
that elevate GLP-1 levels are in widespread use in the clinic. There are
conflicting reports regarding the association of these agents with the risk of
pancreatitis. [3]
• A recent National Institutes of Health (NIH) consensus conference concluded
that there is insufficient data at present to support a link between GLP-1
agonists or DPP-4 inhibitors and PC. [4]
1. LiD, YeungSC, HassanMM, et al.Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology2009;137:482.
2. SadeghiN, AbbruzzeseJL, YeungSC, et al.Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res2012;18:2905.
3. EngelSS, Williams‐HermanDE, GolmGT, et al.Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract2010;64:984.
4. DoreDD, SeegerJD, Arnold ChanK. Use of a claims‐based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin2009;25:1019.
Risk factor: Chronic pancreatitis
• Chronic pancreatitis accounts for ∼5% of pancreatic cancers.
• The MC cause of CP, in Europe, is excess alcohol consumption. The causal
pathway is not clear, however, alcohol consumption by itself is related to
an ↑ risk of PC.
• There is a strong link between antecedent CP and PC.
• In a metaanalysis of 10 cohort and 12 case–control studies, a statistically
significant ↑ of PC risk for all types of pancreatitis, with summary RRs
(95% CI) of 5.1 (3.5–7.3) for unspecified pancreatitis, 13.3 (6.1–28.9) for
CP, and 69.0 (56.4–84.4) for hereditary pancreatitis. [1,2]
• The single study on tropical pancreatitis provided an even higher RR of
100.0 (95% CI 37.0–218.0). [1]
• Other studies have also demonstrated an ↑ risk of PC in pts with CP. [3]
1. RaimondiS, LowenfelsAB, Morselli‐LabateAM, et al.Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol2010;24:349.
2. LowenfelsAB, MaisonneuveP, CavalliniG, et al.Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med1993;328:1433.
3. TalaminiG, FalconiM, BassiC, et al.Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol1999;94:1253.
Risk factor: Alcohol
• As the MC cause of acute and chronic pancreatitis, alcohol abuse is a
logical candidate for PC risk association. However, the epidemiological
evidence for the role of alcohol use in the etiology of PC is equivocal .[1,2,3]
• The NIH-American Association of Retired Persons (AARP) Diet and Health
Study prospectively examined the relation between alcohol use and the
risk of PC among 470 681 participants who were aged 50–71 years in
1995–1996 .
• The RR of developing PC were 1.45 (95% CI 1.17, 1.80; P = 0.002) for heavy
alcohol use (≥3 drinks/day, ∼40 g of alcohol/day) . These findings suggest a
moderately ↑PC risk with heavy alcohol use.[4]
1. SchneiderA, SingerMV. Alcoholic pancreatitis. Dig Dis2005;23:222.
2. VelemaJP, WalkerAM, GoldEB. Alcohol and pancreatic cancer. Insufficient epidemiologic evidence for a causal relationship. Epidemiol Rev1986;8:28.
3. FriedmanGD, van den EedenSK. Risk factors for pancreatic cancer: an exploratory study. Int J Epidemiol1993;22:30.
4. JiaoL, SilvermanDT, SchairerC, et al.Alcohol use and risk of pancreatic cancer: the NIH‐AARP Diet and Health Study. Am J Epidemiol2009;169:1043.
Risk factor: Dietary influences
• Dietary factors have been studied extensively, and clearly contribute to the
development of PC.
• Independent of their role in causing obesity: butter, saturated fat, red
meat, and processed foods are clearly linked to PC .[1]
• Conversely, a high fruit and folate intake could reduce the risk of PC. [1]
• However, based on data from more than 500 000 persons in 10 countries,
the consumption of fruit and vegetables does not ↓ the risk of PC. [2,3]
1. Larsson SC, Wolk A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. Br J Cancer 2012; 106: 603–607.
2. VrielingA, VerhageBA, van DuijnhovenFJ, et al.Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer2009;124:1926.
3. JansenRJ, RobinsonDP, Stolzenberg‐SolomonRZ, et al.Nutrients from fruit and vegetable consumption reduce the risk of pancreatic cancer. J Gastrointest Cancer2013;44:152.
Hereditary factors
• The first studies to suggest an inherited genetic component to PC risk
were case reports of families in which there were multiple members
afflicted by PC. [1]
• Observational epidemiological studies including case–control and cohort
studies have found that individuals with a family history of PC are at an ↑
risk of developing PC themselves, with odds 1.9- to 13-fold higher when
compared with healthy controls. [2,3]
• The term “familial pancreatic cancer” characterizes families with at least
two first-degree relatives with confirmed exocrine PC. [4]
1. KleinAP, HrubanRH, BruneKA, et al.Familial pancreatic cancer. Cancer J2001;7:266.
2. JacobsEJ, ChanockSJ, FuchsCS, et al.Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer2010;127:1421.
3. GhadirianP, BoyleP, SimardA, et al.Reported family aggregation of pancreatic cancer within a population‐based case‐control study in the Francophone community in Montreal, Canada. Int J Pancreatol1991;10:183.
4. BartschDK, GressTM, LangerP. Familial pancreatic cancer – current knowledge. Nat Rev Gastroenterol Hepatol2012;9:445.
Most common cancer syndromes a/with PC risk
YAMADA 6E
Risk factor: others
• Helicobacter pylori, hepatitis B, and human immunodeficiency virus
infection have also been reported to be related to an ↑ in RR of PC,
although some confounding factors such as cigarette smoking or alcohol
consumption have not always been considered. [1]
• Different chemical substances have been reported to increase the RR of
developing PC, among these are: chlorobenzoil, chlorinated hydrocarbon,
nickel and nickel compounds, chromium compounds, silica dust, and
others.[2]
1. Yeo TP. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 8–18.
2. Ojajarvi IA, Partanen TJ, Ahlbom A et al. Occupational exposures and pancreatic cancer: a meta-analysis. Occup Environ Med 2000; 57: 316–324.
Risk factors: summary
• As a summary, it is possible to say that 5%–10%
of PC are related to a genetic alteration.
• Among the remaining 90%, the major RF are
tobacco, H. pylori infection and factors related
to dietary habits (BMI, red meat intake, low fruit
and vegetables intake, DM, alcohol intake).
• However, about two thirds of the major risk factors a/with PC are potentially modifiable, affording a
unique opportunity for preventing one of the deadliest cancers.
ESMO
Molecular biology
• Multiple combinations of genetic mutations are commonly found in PC and
can be classified as follows:
(i) Mutational activation of oncogenes, predominantly KRAS found in 90-95
% of PC.
(ii) Inactivation of tumour suppressor genes such as TP53 (70%),
p16/CDKN2A (98%), and SMAD4 (55%).
(iii) Inactivation of genome maintenance genes, such as Hmlh1 and MSH2,
which control the repair of DNA damage.
KRAS: Kirsten ras oncogene TP53: Tumor Protein P53 CDKN2A: Cyclin Dependent Kinase Inhibitor 2A
SMAD4: Mothers against decapentaplegic homolog 4 MSH2: MutS protein homolog 2 Hmlh1: Human mutL homolog 1
Most common genetic mutations in PC
YAMADA 6E
Embryonic signaling pathways
• Over the past decade, it is has become increasingly clear that during
carcinogenesis, reactivation of signaling pathways important during
embryogenesis is a common event.
Abundant evidence has accumulated to implicate the Hedgehog, Notch,
and Wnt signaling pathways in pancreatic carcinogenesis. [1,2,3]
• Sonic hedgehog (Shh) is a key regulator of pancreatic development and
epithelial proliferation. Shh is overexpressed in most PC with its
upregulation observed initially in PanIN. [4]
• Numerous Hedgehog pathway inhibitors( eg Vismodegib) have now been developed and are in early
phase trials in PC.
1. JonesS, ZhangX, ParsonsDW, et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science2008;321:1801.
2. BiankinAV, WaddellN, KassahnKS, et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature2012;491:399.
3. MiyamotoY, MaitraA, GhoshB, et al.Notch mediates TGF alpha‐induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell2003;3:565.
4. ThayerSP, di MaglianoMP, HeiserPW, et al.Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature2003;425:851.
Embryonic signaling pathways
• Notch proteins are transmembrane receptors for membrane bound ligands that
are known as key development regulators.
• Typically, Notch functions to maintain cells in an undifferentiated state during
development, a function that has been proposed to be significant during
carcinogenesis as well.
• Notch activation is largely absent in the adult pancreas, with the exception of
activity seen in centroacinar cells.
• Expression of the Notch target gene Hes1, is observed in centroacinar cells and
is increasingly observed during acinar duct metaplasia and the development of
PanIN and PC. [1]
• The role of Notch in PC progression remains under investigation, but drugs targeting γ-secretase, a
regulator of Notch signaling, are currently in early phase clinical trials. [2]
1. MiyamotoY, MaitraA, GhoshB, et al.Notch mediates TGF alpha‐induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell2003;3:565.
2. PlentzR, ParkJS, RhimAD, et al.Inhibition of gamma‐secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology2009;136:1741.
Embryonic signaling pathways
• Wnt proteins play numerous roles in embryonic development.
• In the pancreas, Wnt signaling is critical for the development of the
exocrine pancreas suggesting that, in the pancreas, it may be important
for the expansion of exocrine precursors. [1]
• More recent studies have demonstrated that inhibition of Wnt signaling in
PC cells can inhibit growth and suggests targeting Wnt signaling as a
potential avenue for PC therapy. [2,3]
1. WellsJM, EsniF, BoivinGP, et al.Wnt/beta‐catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol2007;7:4.
2. Pasca di MaglianoM, BiankinAV, HeiserPW, et al.Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE2007;2:e1155.
3. ZhangY, MorrisJPt, YanW, et al.Canonical Wnt signaling Is required for pancreatic carcinogenesis. Cancer Res2013;73:4909.
Manifestations
• Tumors of the head of the pancreas produce symptoms earlier in the
course of disease.
• Tumors in the head of the gland have a propensity for obstruction of the
distal CBD and pancreatic duct.
• Anatomic obstruction of these structures results in jaundice and chronic
obstructive pancreatitis.
• Some tumors can involve the duodenum or the ampulla of Vater.
• Extrapancreatic extension into the retroperitoneal tissues is almost always
present at the time of DX and can result in invasion of the PV or the
superior mesenteric vessels and nerves.
Manifestations
• In contrast, tumors of the distal gland are characterized by their “silent”
presentation, with physical findings appearing only after extensive local
growth or widely metastatic disease has developed.
• Neoplasms of the tail of the pancreas do not cause biliary or pancreatic
duct obstruction.
• Extrapancreatic extension in distal tumors causes invasion of the spleen,
stomach, splenic flexure of the colon, or left adrenal gland.
• In pts with advanced disease, metastases to the lymph nodes, liver, and
peritoneum are common; the lung, pleura, and bone are less commonly
involved.[1]
1. Tumors of the exocrine pancreas. In: Solcia E, Capella C, Kloppel G, ed. Tumors of the Pancreas, Washington, D.C.: Armed Forces Institute of Pathology; 1997:31-144.
Manifestations: major
• Jaundice is often the first sign that brings pts to medical attention, especially
with tumors in the head of the pancreas. Present in >50% of pts, results from
obstruction of the extrahepatic bile duct.
• Pts with concomitant obstruction of the pancreatic duct may also show
pancreatic exocrine insufficiency in the form of steatorrhea and malabsorption.
• Pain can be a major symptom in many pts with PC. Pain is primarily due to
invasion of the celiac or superior mesenteric arterial plexus.[1] The pain is of low
intensity, dull, and vaguely localized to the upper abdomen. In advanced disease,
pain may be localized to the middle and upper back. The pain also may be
postprandial and lead pts to reduce their caloric intake, a situation that
ultimately results in weight loss or cachexia.
1. Fasanella KE, Davis B, Lyons J, et al: Pain in chronic pancreatitis and pancreatic cancer. Gastroenterol Clin North Am 2007; 36:335-64.ix
Manifestations: minor
• Other nonspecific symptoms include nausea, fatigue, anorexia, and
weight loss. These symptoms may or may not be caused by tumor
involvement of the duodenum causing partial obstruction.
• Less common symptoms include those of diabetes and pancreatitis.
• New-onset diabetes mellitus may herald PC and can be observed in 6% to
68% of pts.[1]
• Acute pancreatitis is occasionally the first manifestation of PC.[2]
1. Yalniz M, Pour PM: Diabetes mellitus: A risk factor for pancreatic cancer?. Langenbecks Arch Surg 2005; 390:66-72.
2. Mujica VR, Barkin JS, Go VL: Acute pancreatitis secondary to pancreatic carcinoma. Study group participants. Pancreas 2000; 21:329-32.
Manifestations
• In a multi-institutional series of 185 pts with exocrine PC DX over a 3-yr period (62
% involving the head, 10 % body, 6 % tail, and the remainder not determined), [1]:
Symptoms Signs
Asthenia – 86 percent
Weight loss – 85 percent
Anorexia – 83 percent
Abdominal pain – 79 percent
Epigastric pain – 71 percent
Dark urine – 59 percent
Jaundice – 56 percent
Nausea – 51 percent
Back pain – 49 percent
Diarrhea- 44 percent
Vomiting – 33 percent
Steatorrhea – 25 percent
Thrombophlebitis – 3 percent
Jaundice – 55 percent
Hepatomegaly- 39 percent
Right upper quadrant mass – 15 percent
Cachexia – 13 percent
Courvoisier’s sign (nontender but palpable
distended gallbladder at the right costal margin)
– 13 percent
Epigastric mass – 9 percent
Ascites – 5 percent
1. Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol 2005; 7:189.
Role of tumor markers (A)
• CA 19-9- SN and SP rates for PC range from 70-92, and 68-92%, respectively. [1-5]
• However, SN is closely related to tumor size. CA 19-9 levels are of limited SN for
small cancers. [6-9]
• CA 19-9 is frequently elevated in pts with cancers other than PC and various
benign pancreaticobiliary disorders. [10,11]
• One study found that serum conc> 37 U/mL represented the most accurate cutoff
value for discriminating PC from benign pancreatic disease, but the SN and SP for
PC at this level were only 77 and 87 %, respectively. [10]
• Furthermore, the PPV is low, particularly among asymptomatic individuals. In a
large series of over 70,000 asymptomatic individuals, the PPV of a serum level
>37 U/mL was only 0.9 %. [12] Because of this, expert guidelines recommend
against the use of CA 19-9 as a screening test for PC. [13]
• Even among symptomatic individuals (epigastric pain, weight loss, jaundice), SN,
SP, and PPV of an ↑ CA 19-9 >37 U/mL level are only approxy 80, 85, and 72 %.[14]
Note: References are at the end of the slides
Conditions a/with increased serum levels of CA 19-9
UPTODATE21.6
Role of tumor markers (B)
• Serum levels of CA 19-9 do have some value as prognostic markers and indicator of
disease activity .
• Among pts who appear to have potentially resectable PC, the preoperative CA 19-9 level
can also help to predict the presence of radiographically occult metastatic disease . [1-5]
• As an example, in a report of 491 pts undergoing staging laparoscopy for a
radiographically resectable PC, CA 19-9 >130 units/mL were a significant predictor of
radiographically occult unresectable disease . [2]
• Among pts with tumors in the body/tail , >1/3RD who had a CA 19-9 ≥130 units/mL had
unresectable disease.
• Serial monitoring of CA 19-9 (once every 1-3mnths [7]) is useful to follow pts after
potentially curative SX and for those who are receiving CT for advanced disease. Rising
CA 19-9 levels usually precede the radiographic appearance of recurrent disease, but
confirmation of disease progression should be pursued with imaging
studies and/or biopsy. [7]
• Other markers — Although several marker have emerged from preclinical studies
(macrophage inhibitory cytokine-1, appears particularly promising [6]), none has
replaced CA 19-9 to date.
Note: References are at the end of the slides
Imaging of Pancreatic Cancer
• Although transabdominal US is frequently the first modality used in many
pts with PC(because 50% of them present with jaundice), the method of
choice for DX and staging of PC is CT.[1,2,3]
• The MC appearance of PDAC on CT is that of a low-density mass within
the pancreas. Associated findings include pancreatic gland atrophy,
dilation of the pancreatic and CBD, and contour irregularity of the
pancreatic surface.
• The SN of detecting PC on CT scan varies from 67% to 100% depending on
the size of the primary lesion. [4,5]
1. Coley SC, Strickland NH, Walker JD, et al: Spiral CT and the pre-operative assessment of pancreatic adenocarcinoma. Clin Radiol 1997; 52:24-30.
2. Freeny PC, Traverso LW, Ryan JA: Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography. Am J Surg 1993; 165:600-6.
3. Megibow AJ, Zhou XH, Rotterdam H, et al: Pancreatic adenocarcinoma: CT versus MR imaging in the evaluation of resectability—Report of the Radiology Diagnostic Oncology Group. Radiology 1995; 195:327-32
4. KatzMH, SavidesTJ, MoossaAR, et al.An evidence‐based approach to the diagnosis and staging of pancreatic cancer. Pancreatology2005;5:576.
5. ClarkeDL, ThomsonSR, MadibaTE, et al.Preoperative imaging of pancreatic cancer: a management‐oriented approach. J Am Coll Surg2003;196:119..
DIAGNOSIS: CT
• The pancreatic protocol CT consists of dual-phase scanning using IV
contrast agents.
The first, arterial (pancreatic) phase is obtained 40 secs after
administration of IV contrast agent. At this time maximum enhancement of
the normal pancreas is obtained, allowing identification of nonenhancing
neoplastic lesions.
The second, portal venous phase(Hepatic phase) is obtained 70 secs after
injection of IV contrast agent and allows accurate detection of liver
metastases and assessment of tumor involvement of the portal and
mesenteric veins.
1. Coley SC, Strickland NH, Walker JD, et al: Spiral CT and the pre-operative assessment of pancreatic adenocarcinoma. Clin Radiol 1997; 52:24-30.
2. Freeny PC, Traverso LW, Ryan JA: Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography. Am J Surg 1993; 165:600-6.
3. Megibow AJ, Zhou XH, Rotterdam H, et al: Pancreatic adenocarcinoma: CT versus MR imaging in the evaluation of resectability—Report of the Radiology Diagnostic Oncology Group. Radiology 1995; 195:327-32.
CT SCAN OF PC
A, Arterial phase showing a nonenhancing lesion in the head of the pancreas (arrows).
B, Venous phase showing a noninvolved fat plane around the portal vein (arrows).
SLEISENGER
CT Imaging of pancreatic cancer
• The pancreatic phase allows optimal distinction between normal pancreatic
parenchyma and a pancreatic mass while enabling evaluation of peripancreatic
vessels in order to determine the extent of tumor involvement.
• The goal of the hepatic phase is to differentiate between normal hepatic
parenchyma and hypovascular metastases.
• The diagnostic accuracy of CT for LN metastasis is very poor as it is generally
based on size criteria alone. Enlarged LN may be reactive, particularly following
biliary stenting, while normal-sized nodes may harbor micrometastasis.
Enlarged peripancreatic lymph nodes should therefore not preclude a pt from
surgery as the ability of CT to determine vascular invasion is the single best
predictor of resectability.
• Reports suggest that up to 11% of PC are isoattenuating on the pancreatic and
hepatic phases making it potentially difficult to distinguish tumor from
surrounding normal parenchyma unless other signs such as ductal dilatation or
mass effect are present [95–97].
Endoscopic Retrograde Cholangiopancreatography
• Since its introduction in 1968, ERCP has become a mainstay in the DD of
various tumors of the periampullary region.[1]
• The majority of these tumors originate from the pancreas (85%), and less
commonly from the distal bile duct (6%), ampulla (4%), or duodenum
(4%).
• ERCP allows visualization of the pancreatico-biliary tree to distinguish
benign (stones) from malignant causes of obstruction.
• A “double-duct sign,” representing strictures in biliary and pancreatic
ducts, is classically found in many pts with PC.
1. Sahani DV, Shah ZK, Catalano OA, et al: Radiology of pancreatic adenocarcinoma: Current status of imaging. J Gastroenterol Hepatol 2008; 23:23-33.
Endoscopic Retrograde Cholangiopancreatography
ERCP reveals obstruction of both the CBD
and pancreatic duct (circled area).
YAMADA6E
The two MC causes of the double duct sign are Ca of the head of the pancreas
and ampullary tumours (e.g. carcinoma of the AOV), although occasionally an
impacted gall stone in the distal duct, with associated oedema, can also result in
obstruction of the PD.
• A literature search[1] was performed, which indicated that in
selected pts with a higher likelihood of PC (for example
jaundice or pancreatic mass on radiological imaging) up to
85% of pts do indeed have a PC.
• In an unselected population, regardless of presenting
symptoms, a double-duct sign on ERCP was caused by a PC in
58% of pts.
• In selected pts without jaundice but with a double duct sign,
PC was only seen in 6% of pts.
• SN and SP of the double-duct sign observed by ERCP for PC
varies between 50-76% and 63-80%, respectively.
1. Leendert H. Oterdoom, Stijn J.B. van Weyenberg, Nanne K.H. de Boer. Double-duct Sign: Do Not Forget the Gallstones. J Gastrointestin Liver Dis, December 2013 Vol. 22 No 4: 447-450
Endoscopic Retrograde Cholangiopancreatography
• Tissue sampling can also be obtained during ERCP.
• For tumors of the ampulla or duodenum, biopsy of mucosal lesions is
readily obtained with endoscopic forceps. Tumors of the distal bile duct
may also be sampled via brush biopsy for routine cytology or genetic
analysis.[1,2]
• As discussed earlier, CT allows for identification of pancreatic tumors in the
majority of pts with PC, rendering ERCP unnecessary in most cases. In
practice, however, many pts with PC undergo ERCP, not for the purpose of
DX but rather for stenting of the biliary duct.
1. Glasbrenner B, Ardan M, Boeck W, et al: Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy 1999; 31:712-17.
2. Levy MJ, Baron TH, Clayton AC, et al: Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol 2008; 103:1263-73.
Endoscopic Ultrasonography
• EUS may be the most accurate test for the DX of PC.[1]
• Several studies have shown that EUS has a higher sensitivity and
specificity than CT for detecting pancreatic masses.[2,3]
• EUS also has been found to be more accurate than CT in assessing vascular
invasion and predicting tumor resectability.
• Other advantages of EUS include accurate assessment of peripancreatic
nodal disease, and allowance of tumor biopsy by FNA.[4]
1. Soriano A, Castells A, Ayuso C, et al: Preoperative staging and tumor resectability assessment of pancreatic cancer: Prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J
Gastroenterol 2004; 99:492-501.
2. DeWitt J, Devereaux B, Chriswell M, et al: Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer. Ann Intern Med 2004; 141:753-63.
3. Gress FG, Hawes RH, Savides TJ, et al: Role of EUS in the preoperative staging of pancreatic cancer: A large single-center experience. Gastrointest Endosc 1999; 50:786-91.
4. Gress F, Gottlieb K, Sherman S, et al: Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 2001; 134:459-64.
EUS of PC: Limitations
EUS is highly operator-dependent, and it is estimated that
experience with 100 such examinations is needed to be considered
proficient.[1]
Imaging by EUS can be compromised by the presence of a biliary
stent, which results in imaging artifacts and loss of tissue detail.
Due to technical and anatomic constraints, imaging of the PV and
splenic vein is generally superior to imaging of the superior
mesenteric artery and vein.[2] For this reason EUS may lack
accuracy when assessing vascular invasion at the level of the
superior mesenteric vessels.
Lastly, EUS provides no information regarding metastatic disease,
and a complementary CT or MRI scan is required for complete
staging of disease.
1. Gress FG, Hawes RH, Savides TJ, et al: Role of EUS in the preoperative staging of pancreatic cancer: A large single-center experience. Gastrointest Endosc 1999; 50:786-91.
2. Rosch T, Dittler HJ, Strobel K, et al: Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: A blind reevaluation of videotapes. Gastrointest Endosc 2000; 52:469-77.
This EUS image demonstrates PC invasion of the PV (outlined area)
Magnetic Resonance Imaging
• MRI has been increasingly used in the evaluation of pancreatic tumors, and
several groups have shown results that rival those of helical CT.[1,2]
• In one study, pancreatic tumor detection was reported in 90% of pts for MRI
versus 76% for helical CT.[1]
• Tumors are viewed as low-signal masses against the high-signal background of
normal pancreatic parenchyma.
• Pancreatic masses, ductal dilation, and liver metastasis can be demonstrated in
exquisite detail.
• Additionally, MR angiography and MR venography techniques using gadolinium
contrast enhancement can demonstrate vascular involvement by tumor.
• Unlike CT, MRI does not involve radiation and uses an iodine-free contrast
agent with rare renal toxicity.
1. Ichikawa T, Haradome H, Hachiya J, et al: Pancreatic ductal adenocarcinoma: Preoperative assessment with helical CT versus dynamic MR imaging. Radiology 1997; 202:655-62.
2. Lopez HE, Amthauer H, Hosten N, et al: Prospective evaluation of pancreatic tumors: Accuracy of MR imaging with MR cholangiopancreatography and MR angiography. Radiology 2002; 224:34-41.
MRI/MRCP
• MRCP can also be obtained at the time of MRI.[1]
• In a prospective, controlled study, MRCP was found to be as sensitive as ERCP in
detecting PC.[2] Images obtained are highly comparable with those obtained with
ERCP and readily demonstrate pancreatic ductal obstruction, ectasia, and
calculi.
• MRCP uses heavy T2-weighted images that emphasize fluid-containing structures
such as ducts, cysts, and peripancreatic fluid collections.
• In contrast to ERCP, MRCP is noninvasive and does not require injection of
contrast into the pancreatico-biliary tree, avoiding possible complications such
as allergy, pancreatitis, or infection.
• However, no therapeutic or diagnostic intervention can be performed with
MRCP.
• Limitations of MRI are related to cost & availability.
1. Barish MA, Yucel EK, Ferrucci JT: Magnetic resonance cholangiopancreatography. N Engl J Med 1999; 341:258-64.
2. Adamek HE, Albert J, Breer H, et al: Pancreatic cancer detection with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: A prospective controlled study. Lancet 2000; 356:190-3.
Positron Emission Tomography
• PET is a noninvasive imaging tool that provides metabolic rather than
morphologic information on tumors.[1,2]
• This DX method is based on greater use of glucose by tumor cells than by normal pancreatic
parenchyma. The radioactive glucose analog fluorodeoxyglucose (FDG) F 18 is administered IV,
followed by detection of FDG uptake by the PET scanner.
• The normal pancreas is not usually visualized by FDG-PET. In contrast, PC
appears as a focal area of increased uptake in the pancreatic bed.
• Hepatic metastases appear as “hot spots” within the liver.
1. Inokuma T, Tamaki N, Torizuka T, et al: Value of fluorine-18-fluorodeoxyglucose and thallium-201 in the detection of pancreatic cancer. J Nucl Med 1995; 36:229-35.
2. Zimny M, Bares R, Fass J, et al: Fluorine-18 fluorodeoxyglucose positron emission tomography in the differential diagnosis of pancreatic carcinoma: A report of 106 cases. Eur J Nucl Med 1997; 24:678-82.
Positron Emission Tomography
• Owing to the lack of anatomic detail, PET scanning is not a principal
diagnostic modality for PC.
• However, FDG-PET can be helpful in differentiating benign from malignant
pancreatic masses when morphologic data are equivocal.[1]
• It can also be useful in assessing tumor recurrence after pancreatic
resection, when scar tissue or postoperative changes may be difficult to
differentiate from carcinoma.
• Finally, FDG-PET can be of benefit in assessing tumor response to
neoadjuvant chemoradiation, which may lead to alteration in clinical MX.
1. Rose DM, Delbeke D, Beauchamp RD, et al: 18-Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer. Ann Surg 1999; 229:729-37.
Percutaneous and EUS–Guided Aspiration Cytology
• FNA cytology of the pancreas has been one of the major advances in the MX of
pts with pancreatic tumors.
• CT-guided biopsy has been used for more than 20 yrs and is regarded as a safe,
reliable procedure, with a reported sensitivity of 57% to 96% and virtually no
false-positive results.[1,2]
• Experience with EUS-guided FNA shows similar results.[3]
• Whenever a pt is deemed to have unresectable or metastatic PC, CT- or EUS-
guided FNA biopsy is indicated for histologic confirmation of disease, unless a
palliative surgical procedure is required. Even if the DX of chronic pancreatitis is
reasonably eliminated, proof of malignancy will exclude other rare benign
diseases of the pancreas, such as TB and sarcoidosis. Furthermore, FNA
cytology can usually distinguish between adenocarcinoma and other pancreatic
tumors, such as neuroendocrine neoplasms and lymphomas, which carry a
better prognosis.[4]
1. DelMaschio A, Vanzulli A, Sironi S, et al: Pancreatic cancer versus chronic pancreatitis: Diagnosis with CA 19-9 assessment, US, CT, and CT-guided fine-needle biopsy. Radiology 1991; 178:95-9.
2. Parsons Jr L, Palmer CH: How accurate is fine-needle biopsy in malignant neoplasia of the pancreas?. Arch Surg 1989; 124:681-3.
3. Gress F, Gottlieb K, Sherman S, et al: Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 2001; 134:459-64.
4. Webb TH, Lillemoe KD, Pitt HA, et al: Pancreatic lymphoma. Is surgery mandatory for diagnosis or treatment?. Ann Surg 1989; 209:25-30.
Management
Pancreatic Cancer
Resectable Borderline resectable Unresectable
Metastases
Locally AdvancedSurgery
Adjuvant Chemo
Staging and risk assessment
TNM System / American Joint Committee on Cancer (AJCC)
Staging of Pancreatic Cancer
STAGING
• The system was last revised in 2002, and modifications were made to
better identify unresectable (T4, stages III and IV) from resectable disease
(T1-3, stages I and II).
• Several limitations of the staging system exist.
1. Adequate evaluation of lymph node status cannot be performed
without surgical intervention; this drawback may lead to understaging of
locally advanced disease in pts who are not candidates for laparotomy.
2. The margins of resection, which carry great prognostic significance, are
not taken into consideration when assigning clinical stage.
• Because of these and other shortcomings, the AJCC staging system has
found limited clinical applicability.
Definition of resectability according to NCCN guidelines
Resectability status Arterial Venous
Resectable No arterial-tumour contact [coeliac axis (CA), SMA, or
CHA]
No tumour contact with the SMV, or
PV or <180° contact without vein contour
irregularity
Borderline
Resectable
Pancreatic
head/uncinate
process
• Solid tumour with CHA without extension to coeliac
axis or hepatic artery bifurcation allowing for safe and
complete resection and reconstruction
• Solid tumour contact with the SMA <180°
• Presence of variant arterial anatomy (e.g. accessory
right hepatic artery) and the presence and degree of
tumour contact should be noted if present as it may
affect surgical planning
• Solid tumour contact with the SMV or PV
of >180°, contact of <180° with contour
irregularity of the vein or thrombosis of the
vein but with suitable vessels proximal and
distal to the site of involvement allowing for
safe and complete resection and vein
reconstruction
• Solid tumour contact with IVC
Borderline
Resectable
Pancreatic body/tail
• Solid tumour contact with the CA of <180°
• Solid tumour contact with the CA of >180° without
involvement of the aorta and with intact and uninvolved
gastroduodenal artery (some members prefer these
criteria to be in the unresectable category)
National Comprehensive Cancer Network. NCCN Guidelines Version 2.2015 Pancreatic Adenocarcinoma. http://www.nccn.org.
Definition of resectability according to NCCN guidelines
Resectability status Arterial Venous
Unresectable • Distant metastases
Pancreatic head/uncinate process
• Solid tumour contact with SMA >180°
• Solid tumour contact with the CA >180°
• Solid tumour contact with the first jejunal SMA
branch
Body and tail
• Solid tumour contact with the SMA and CA
• Solid tumour contact with the CA and aorta
Pancreatic head/uncinate process
• Unreconstructible SMV/PV due to tumour
involvement or occlusion (can be due to tumour
or bland thrombus)
• Contact with most proximal draining jejunal
branch into SMV Body and tail
• Unreconstructible SMV/PV due to tumour
involvement or occlusion (can be due to tumour
or bland thrombus)
National Comprehensive Cancer Network. NCCN Guidelines Version 2.2015 Pancreatic Adenocarcinoma. http://www.nccn.org.
Staging workup
• A minimal staging workup for a pt with PC should include a physical exam, and a CT or
MRI of the abdomen and pelvis.[1]
• In selected cases, EUS may complement CT scanning by allowing further assessment of
vascular invasion and tissue sampling.
• However, CT imaging fails to correctly predict resectability in 25% to 50% of pts. In
most cases, lesions missed are beyond the resolution of current radiologic imaging;
they include small implants on the peritoneal surfaces of the liver, abdominal wall,
stomach, intestine, or omentum.
• Additionally, micrometastases only detectable by peritoneal washings are also missed.
• Successful detection of such tumor dissemination depends on access to the peritoneal
cavity and visual inspection, which at present can be achieved only by laparoscopy or
laparotomy.
• It is recommended laparoscopy for all pts with tumors in the body and tail of the
pancreas (in which the frequency of unsuspected metastases approaches 50%) and for
pts with tumors in the head of the pancreas >2 cm, because the yield of laparoscopy in
lesions smaller than 2 cm is <10%.
1. Exocrine pancreas. In: Greene FL, Page DL, Fleming ID, et al ed. AJCC Cancer Staging Manual, New York: Springer-Verlag; 2002:157-62.
Staging workup
• Several large studies have documented the value of staging laparoscopy in
the evaluation of pts with PC.[1-5]
• The staging procedure consists of a simple diagnostic laparoscopy with
biopsy of suspicious nodules and collection of peritoneal washings for
cytologic analysis.
• Peritoneal cytology results are important for staging because pts with
occult metastases detected by this method have been shown to carry a
prognosis similar to that of pts with M1 disease (stage IV).[6,7]
1. Bemelman WA, de Wit LT, van Delden OM, et al: Diagnostic laparoscopy combined with laparoscopic ultrasonography in staging of cancer of the pancreatic head region. Br J Surg 1995; 82:820-4.
2. Fernandez-del Castillo C, Rattner DW, Warshaw AL: Further experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer. Br J Surg 1995; 82:1127-9.
3. Jimenez RE, Warshaw AL, Rattner DW, et al: Impact of laparoscopic staging in the treatment of pancreatic cancer. Arch Surg 2000; 135:409-14.
4. John TG, Wright A, Allan PL, et al: Laparoscopy with laparoscopic ultrasonography in the TNM staging of pancreatic carcinoma. World J Surg 1999; 23:870-81.
5. Minnard EA, Conlon KC, Hoos A, et al: Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg 1998; 228:182-7.
6. Makary MA, Warshaw AL, Centeno BA, et al: Implications of peritoneal cytology for pancreatic cancer management. Arch Surg 1998; 133:361-5.
7. Merchant NB, Conlon KC, Saigo P, et al: Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma. J Am Coll Surg 1999; 188:421-6.
Massachusetts Gen Hospital algorithm for DX and staging of PC
Management
Pancreatic Cancer
Resectable Borderline resectable Unresectable
Metastases
Locally AdvancedSurgery
Adjuvant Chemo
Staging and risk assessment
TREATMENT: Surgical Therapy
• Surgical resection is the only potentially curative RX for PC. Because of
advanced disease at presentation, only about 15% to 20% of pts are
candidates for pancreatectomy.[1]
• The main goal of surgery is to achieve negative (R0) resection margins.
1. Li D, Xie K, Wolff R, et al: Pancreatic cancer. Lancet 2004; 363:1049-57.
TREATMENT: Surgical Therapy
• The MC operation for PC is the Whipple pancreaticoduodenectomy, which
removes primarily the head of the pancreas.[1]
• In the past, total pancreatectomy was advocated as a better operation for PC.[2]
• However, total pancreatectomy has not been shown to improve survival when
compared with the more limited pancreaticoduodenectomy, and results in
exocrine insufficiency and brittle DM, which are difficult to manage.[3,4,5]
• Other extensions to the standard Whipple procedure, such as addition of
retroperitoneal lymphadenectomy, have shown no significant survival benefit
and may result in additional morbidity (longer hospital stays, increased rates of
pancreatic fistula, and higher incidence of delayed gastric emptying).[6,7,8]
1. Jimenez RE, Warshaw AL: Pancreaticoduodenectomy for pancreatic cancer: Results after Kausch-Whipple and pylorus-preserving resection. In: Beger H, Buchler M, Kozarek RA, et al ed. The pancreas: An integrated textbook of basic science, medicine and surgery,
Oxford, UK: Blackwell Publishing; 2008.
2. ReMine WH, Priestley JT, Judd ES, et al: Total pancreatectomy. Ann Surg 1970; 172:595-604.
3. Brooks JR, Brooks DC, Levine JD: Total pancreatectomy for ductal cell carcinoma of the pancreas. An update. Ann Surg 1989; 209:405-10.
4. van Heerden JA, ReMine WH, Weiland LH, et al: Total pancreatectomy for ductal adenocarcinoma of the pancreas. Mayo Clinic experience. Am J Surg 1981; 142:308-11.
5. Andren-Sandberg A, Ihse I: Factors influencing survival after total pancreatectomy in patients with pancreatic cancer. Ann Surg 1983; 198:605-10.
6. Pedrazzoli S, DiCarlo V, Dionigi R, et al: Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: A multicenter, prospective, randomized study.
Lymphadenectomy study group. Ann Surg 1998; 228:508-17.
7. Yeo CJ, Cameron JL, Sohn TA, et al: Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: Comparison of morbidity and mortality and short-term outcome. Ann Surg 1999; 229:613-22.
8. Yeo CJ, Cameron JL, Lillemoe KD, et al: Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: Randomized controlled trial evaluating survival, morbidity, and
mortality. Ann Surg 2002; 236:355-66.
Diagram of the pylorus-preserving pancreaticoduodenectomy
From Jimenez RE, Fernandez-del Castillo C, Rattner DW, et al. Outcome of the pancreaticoduodenectomy with pylorus preservation or with antrectomy in the treatment of chronic
pancreatitis. Ann Surg 2000; 231:293.
TREATMENT: Surgical Therapy
• In the past, PD was a/with high morbidity and mortality rates. Many
contemporary large series now consistently show mortality rates of <3%,
with a concomitant decrease in complications.[1-6]
• Pancreatic fistula, the MC and dreaded complication after the Whipple
procedure, is observed in only 5% to 10% of pts today. These changes have
been attributed to the emergence of ICU, as well as advances in surgical
technique, anesthesia, antibiotics, and interventional radiology.
1. Balcom JH, Rattner DW, Warshaw AL, et al: Ten-year experience with 733 pancreatic resections: Changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136:391-8.
2. Buchler MW, Friess H, Wagner M, et al: Pancreatic fistula after pancreatic head resection. Br J Surg 2000; 87:883-9.
3. Kazanjian KK, Hines OJ, Eibl G, et al: Management of pancreatic fistulas after pancreaticoduodenectomy: Results in 437 consecutive patients. Arch Surg 2005; 140:849-54.
4. Mullen JT, Lee JH, Gomez HF, et al: Pancreaticoduodenectomy after placement of endobiliary metal stents. J Gastrointest Surg 2005; 9:1094-104.
5. Schmidt CM, Powell ES, Yiannoutsos CT, et al: Pancreaticoduodenectomy: A 20-year experience in 516 patients. Arch Surg 2004; 139:718-25.
6. Sohn TA, Yeo CJ, Cameron JL, et al: Resected adenocarcinoma of the pancreas—616 patients: Results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567-79.
TREATMENT: Surgical Therapy
• Ultimately, prognosis for PC remains poor, even after potentially curative SX in
appropriately selected pts.
• Five-year actuarial survival rates range from 10.5% to 25% and median survivals
between 10.5 and 20 months.[1,2,3,4]
Significant predictors of a better outcome
• Tumor size <3 cm
• Absence of lymph node metastases
• Negative resection margins
• Well-differentiated tumors
• Intraoperative blood loss of <750 mL.[1-5]
1. Sohn TA, Yeo CJ, Cameron JL, et al: Resected adenocarcinoma of the pancreas—616 patients: Results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567-79.
2. Geer RJ, Brennan MF: Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993; 165:68-72.
3. Benassai G, Mastrorilli M, Quarto G, et al: Survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Chir Ital 2000; 52:263-70.
4. Millikan KW, Deziel DJ, Silverstein JC, et al: Prognostic factors associated with resectable adenocarcinoma of the head of the pancreas. Am Surg 1999; 65:618-23.
5. Meyer W, Jurowich C, Reichel M, et al: Pathomorphological and histological prognostic factors in curatively resected ductal adenocarcinoma of the pancreas. Surg Today 2000; 30:582-7.
Age and pancreatectomy
• Some authors have proposed a score that accurately predicts the risk of
perioperative mortality in pts undergoing pancreatic resection.
• This surgical outcomes analysis and research (SOAR) pancreatectomy score
is calculated based on preoperative factors
(http://www.umassmed.edu/surgery/toolbox/panc_mortality_custom/) [1]
1. Ragulin-Coyne E, Carroll JE, Smith JK et al. Perioperative mortality after pancreatectomy: a risk score to aid decision-making. Surgery 2012; 152(3 Suppl. 1): S120–S127.
Preoperative biliary drainage ? [ESMO15]
• A recent prospective and randomised trial demonstrated an increased
complication rate a/with routine preoperative biliary drainage. [1]
• However, pts in the trial had a total bilirubin level below 14 mg/dL. Therefore, the
correct approach in pts with higher levels remains undefined.
• If jaundice is present at DX of PC, endoscopic drainage should only be carried out
preoperatively
1. In pts with active cholangitis
2. In those whom resection for cure cannot be scheduled within 2 weeks of DX
3. In those with a bilirubin level below 14 mg/dL
1. van der Gaag NA, Rauws EA, van Eijck CH et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010; 362: 129–137.
Adjuvant Chemoradiation ? / GITSG ; n 43
• From 1980 to 2000, adjuvant chemoradiation was standard of care in the
US and many other countries after potentially curative PC resection. These
recommendations were based on the results of a study conducted by the
Gastrointestinal Tumor Study Group (GITSG) between 1974 and 1982.[1]
• The study randomized 43 pts after surgery to either observation or
chemoradiation. Chemoradiation consisted of 4000 cGy of external beam
radiation with concurrent bolus of 5-fluorouracil (5-FU) as radiosensitizer.
Median survival in the treated group was 20 months, which was
significantly longer than the 11-month survival in the untreated group.
However, the GITSG study was criticized for its small sample size and lack
of statistical power.
1. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985; 120:899-903.
SUMMARY: Adjuvant 5-FU and radiation therapy improved
survival for resected PC.
Adjuvant Chemoradiation ?/ EORTC ; n 114
• In 1999 the results of a study by the European Organization for Research
and Treatment of Cancer (EORTC) questioned the value of adjuvant
chemoradiation in PC.[1]
• Similar to the study design by the GITSG, the EORTC randomized pts after
surgery to observation or chemoradiation (4000 cGy external beam
radiation and concurrent 5-FU by continuous infusion). This time the study
group was relatively large and consisted of 114 pts with PC. The median
survival was 4.5 months longer in the treatment group than in the
observation group (17.1 vs. 12.6 months, respectively), but this difference
was not statistically significant.
1. Klinkenbijl JH, Jeekel J, Sahmoud T, et al: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: Phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999;
230:776-82.
SUMMARY: Adjuvant 5-FU based Chemoradiation did not result
in an improvement in overall survival.
Adjuvant Chemo or Chemoradiation ? / ESPAC-1 trial ; n 289
• Further controversy ensued after the results of a study by the European
Study Group for Pancreatic Cancer (ESPAC-1 trial) were released in
2001.[1,2]
• The study had a complicated design that randomized pts after SX to 4
groups: observation, chemotherapy, chemoradiation, or chemoradiation
plus chemotherapy. The results did not show a difference in median
survival between pts receiving chemoradiotherapy and those who did not
(15.5 vs. 16.1 months).
• Even for pts with positive resection margins who are thought to be prime
candidates for chemoradiation, this RX did not have a survival impact.
1. Neoptolemos JP, Dunn JA, Stocken DD, et al: Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: A randomised controlled trial. Lancet 2001; 358:1576-85.
2. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200-10.
SUMMARY: Systemic chemotherapy(5-FU) improved survival but no
benefit of Adj Chemoradiation.
Adjuvant Chemo ?/ CONKO-001 trial ; n 368
• The results of the CONKO-001 trial comparing gemcitabine (1g/m2 d 1, 8,
15, q 4 weeks) for 6 mnths or to observation. [1]
• The median disease-free survival was 13.4 mnths in the RX group
compared with 6.7 mnths in the observation group; P < .001).
• Pts randomized to adjuvant gemcitabine RX had prolonged overall survival
compared with those randomized to observation alone (P = .01), with 5-
year overall survival of 20.7% vs 10.4% respectively, and 10-year overall
survival of 12.2% vs 7.7% .
OettleH, PostS, NeuhausP, et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative‐intent resection of pancreatic cancer: a randomized controlled trial. JAMA2007;297:267.
SUMMARY: Adjuvant gemcitabine improves survival.
Adjuvant Chemoradiation ?/ ESPAC-3 trial n159
• OBJECTIVE: To determine whether 5-FU or gemcitabine is superior in terms of
overall survival as adjuvant RX following resection of PC.
• DESIGN, SETTING, AND PTS: The European Study Group for Pancreatic Cancer
(ESPAC)-3 trial, an open-label, phase 3, RCT conducted in centers in Europe,
Australia, Japan, and Canada. Included in ESPAC-3 V2 were 1088 pts with
pancreatic ductal adenoca who had undergone resection; pts were randomized
betwn July 2000 and Jan 2007 and underwent at least 2 yrs of follow-up.
• INTERVENTIONS: Pts received either 5-FU plus folinic acid (folinic acid, 20
mg/m(2), IV bolus injection, followed by 5-FU, 425 mg/m(2) IV bolus injection
given 1-5 days q 28 days) (n = 551) or gemcitabine (1000 mg/m(2) IV infusion once
a wk for 3 of every 4 wks) (n = 537) for 6 mnths.
• MAIN OUTCOME MEASURES: Primary outcome measure was overall survival;
secondary measures were toxicity, progression-free survival, and quality of life.
Adjuvant Chemo ?/ ESPAC-3 trial
• RESULTS: Final analysis was carried out on an intention-to-treat basis after a
median of 34.2 mnths' follow-up after 753 deaths (69%).
• Median survival was 23.0 (95% CI, 21.1-25.0) mnths for pts treated with 5-FU plus
folinic acid and 23.6 (95% CI, 21.4-26.4) mnths for those treated with gemcitabine
[95% CI, 0.81-1.08]).
• 77 pts (14%) receiving 5-FU plus folinic acid had 97 treatment-related serious
adverse events, compared with 40 pts (7.5%) receiving gemcitabine, who had 52
events (P < .001).
• There were no significant differences in either progression-free survival or global
quality-of-life scores between the treatment groups.
• CONCLUSION: Compared with the use of 5-FU plus folinic acid, gemcitabine did
not result in improved overall survival in pts with completely resected PC.
SUMMARY: No difference between adjuvant 5-FU and adj gemcitabine
NeoptolemosJP, StockenDD, BassiC, et al.Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA2010;304:1073.
Adjuvant Chemo+Chemoradiation ?/(ACOSOG) 5031 & CapRI-2
• More recently, the role of adjuvant chemoradiation given with an
aggressive combination of 5-FU/cisplatin and α-interferon was evaluated
in a phase II trial by the American College of Surgeons Oncology Group
(ACOSOG) 5031, as well as a small randomized phase II trial, CapRI-2. [1]
• Both of these studies found this regimen to be a/with marked toxicity;
grade 3/4 toxicity was 95 and 85%, respectively.
• Unfortunately, while median survivals were better than expected in the
CapRI-2 study, the 28-mnth median survival of the experimental arm was
essentially identical to that observed in the much less toxic control arm of
5-FU and 5-FU chemoradiation.
1. PicozziVJ, AbramsRA, DeckerPA, et al.Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5‐fluorouracil, and interferon‐alfa‐2b‐based chemoradiation: ACOSOG Trial
Z05031. Ann Oncol2011;22:348.
SUMMARY: Addition of Cisplatin, IFN a and XRT did not improve survival
compared to 5-FU alone.
Superior Chemo ?/ (JASPAC)-01;n378
• The Japanese Adjuvant Study of Pancreatic Cancer (JASPAC)-01 study
compared the oral fluoropyrimidine S-1 to gemcitabine. [1]
• Surprisingly, S-1 was superior to gemcitabine with a HR for survival of
0.56, and a 2-yr survival of 70%, compared to 53% for gemcitabine arm.
• S-1 has increased toxicity in Caucasians as compared to Asians and thus is
not approved in the US or Europe at present.
1. MaedaA, BokuN, FukutomiA, et al.Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S‐1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic
Cancer (JASPAC‐01). Jpn J Clin Oncol2008;38:227.
SUMMARY: S-1 improved survival compared to gemcitabine.
Adjuvant Chemo Vs Combination Chemo?/ The ESPAC-4 trial
• Background The ESPAC-3 trial showed that adj gemcitabine is the standard of care
based on similar survival to and less toxicity than adjuvant 5-FU/folinic acid in pts
with resected PC.
• Aimed to determine the efficacy and safety of gemcitabine and capecitabine
compared with gemcitabine monotherapy for resected PC.
• Methods A phase 3, open-label, multicentre, RCT at 92 hospitals in England,
Scotland, Wales, Germany, France, and Sweden. Eligible pts had undergone
complete macroscopic resection for ductal adenoca of the pancreas (R0 or R1
resection). Randomly assigned pts (1:1) within 12 weeks of surgery to receive 6
cycles of either 1000 mg/m² gemcitabine alone administered once a week for
three of every 4 weeks (one cycle) or with 1660 mg/m² oral capecitabine
administered for 21 days followed by 7 days’ rest (one cycle).
• The primary endpoint was overall survival, measured as the time from
randomisation until death from any cause.
Adjuvant Chemo Vs Combination Chemo?/ The ESPAC-4 trial
• Findings Of 732 pts enrolled, 730 were included in the final analysis. Of
these, 366 were randomly assigned to receive gemcitabine and 364 to
gemcitabine plus capecitabine.
• The median OS for pts in the gemcitabine plus capecitabine group was 28·0
mnths (95% CI 23·5–31·5) compared with 25·5 mnths (22·7–27·9) in the
gemcitabine group (HR0·82 [95% CI 0·68–0·98], p=0·032).
Neoptolemos et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.
The Lancet. Volume 389, No. 10073, p1011–1024, 11 March 2017
Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the
new standard of care following resection for pancreatic ductal adenocarcinoma.
Phase III adjuvant trials in pancreatic cancer.
Recommendations for RX of localised disease
• A multidisciplinary team is necessary.
• Tumour clearance should be given for all seven margins identified by the
surgeon .
• Standard lymphadenectomy should involve the removal of ≥15 lymph
nodes to allow adequate pathologic staging of the disease .
• Adjuvant treatment is done with either gemcitabine or 5-FU folinic acid.
• No chemoradiation should be given to pts after SX except in clinical trials.
ESMO15
Management
Pancreatic Cancer
Resectable Borderline resectable Unresectable
Metastases
Locally AdvancedSurgery
Adjuvant Chemo
Staging and risk assessment
No Adj Chemoradiation
Whipple ‘s PD
Combination of gemcitabine and
capecitabine
Neoadjuvant therapy ?
• Building on the experience in other disease sites, neoadjuvant strategies
have been explored since the 1990s.
• The rationale for neoadjuvant therapy includes the hypothetical benefit of
the early RX of occult micrometastatic disease, the ability to deliver therapy
to a more well-vascularized tumor, and the opportunity to assess
therapeutic activity in vivo.
• Although adjuvant therapy has been a/with a survival benefit for PC pts, in
general the results have been disappointing, showing very modest clinical
benefit and little progress beyond survival achieved in the very first
Gastrointestinal Tumor Study Group (GITSG) trial.
• Unfortunately, no randomized comparisons of the neo- and adjuvant
strategies have been performed to date.
Borderline resectable lesions
• Tumours are considered resectable upon good response to neoadjuvant RX
including induction chemotherapy, preoperative chemoradiation or a
combination of both.
• While the heterogeneity of the trials on neoadjuvant therapy in borderline
resectable PC limits the power of any conclusion, many individual series
demonstrate improved R0 resection rates and promising survival rates.
• The majority of studies used full-dose radiotherapy paired either with
capecitabine, 5-FU or reduced doses of gemcitabine, or even a combination
of gemcitabine plus oxaliplatin.
• It is impossible at this time to recommend any chemoradiation RX other
than the classical combination of capecitabine and radiotherapy.
Borderline resectable lesions
• Recent chemotherapy regimens, such as FOLFIRINOX [folinic acid (leucovorin)/5-
FU/irinotecan/ oxaliplatin], have already shown promising results in small series
of pts with borderline resectable lesions [30%–45% of objective response rate
(ORR)].
• A trial, which was stopped prematurely, reported interesting response rates,
median progression-free survival (PFS) and OS for pts treated with chemotherapy
(gemcitabine) followed by chemoradiation (gemcitabine, 5-FU, cisplatin) versus
chemoradiation alone. [1]
• However, this small trial does not allow any definite conclusions to be drawn.
• Pts with borderline resectable lesions should be included in clinical trials
wherever possible. If this is not feasible, a period of chemotherapy followed by
chemoradiation and then surgery appears to be the best option.
1. Landry J, Catalano PJ, Staley C et al. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic
adenocarcinoma. J Surg Oncol 2010; 101: 587–592.
Recommendations for RX of borderline resectable disease
[ESMO15]
• Pts with borderline resectable lesions should be included in clinical trials
wherever possible.
• In routine practice, if the pt is not included in a trial, a period of
chemotherapy (gemcitabine or FOLFIRINOX) followed by chemoradiation
and then surgery appears to be the best option.
Management
Pancreatic Cancer
Resectable Borderline resectable Unresectable
Metastases
Locally AdvancedSurgery
Adjuvant Chemo
Staging and risk assessment
chemotherapy (gemcitabine or
FOLFIRINOX) followed by
chemoradiation and then surgery
Include in clinical
trial
Locally advanced disease
• When the pt has no metastases and the tumour is not considered as
borderline resectable, the tumour is defined as truly locally advanced .
• Treatment of this group of pts remains highly controversial. Regardless of
the RX strategy, the average OS for these pts remains low (<1 year) in the
oldest studies.
• However, in the recent LAP07 trial [1], which included only pts with locally
advanced disease the overall median survival of the pts RX with
chemotherapy alone was 16 months.
1. Hammel P, Huguet F, Van Laethem J-L et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of
gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin Oncol 2013;31(suppl):abstr LBA4003.
Chemotherapy
Locally advanced disease
• Concerning the comparison with chemotherapy alone, while poor-quality
randomised trials have suggested a benefit in favour of chemoradiation,
two recent trials showed opposite results.
• In a French trial using an obsolete regimen of chemoradiation (50 Gy + 5-FU
/cisplatin), the survival was better in the gemcitabine alone arm (13 versus
8.6 months [1]).
• In another trial, comparing chemoradiation with gemcitabine versus
gemcitabine alone, the OS was significantly improved in the
chemoradiation arm (11.1 versus 9.2 months) yet toxicity also increased by
combining the RX modalities. [2]
1. Chauffert B, Mornex F, Bonnetain F et al. Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced nonmetastatic pancreatic cancer: a FFCD-SFRO
study. J Clin Oncol 2006; 24(suppl):abstr 4008.
2. Loehrer PJ, Sr, Feng Y, Cardenes H et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011; 29: 4105–4112.
Chemotherapy Vs Chemoradiation ?
• While many trials have evaluated the best combined regimen of
chemotherapy and radiotherapy, no clear definition has been made of a
standard of care.
• However, evidence from one randomised trial favoured capecitabine as less
toxic and more active than gemcitabine in this setting (SCALOP trial). [1]
1. Mukherjee S, Hurt CN, Bridgewater J et al. Gemcitabine-based or capecitabinebased chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol 2013; 14: 317–326.
Chemotherapy; Capecitabine vs Gemcitabine ??
• No clear advantage in favour of the chemoradiation was found in a recent large
randomised trial investigating this strategy. This trial was planned to include 722
pts, and was stopped for futility after the inclusion of 449 pts (only 269 assessable
for the main end point, OS). They were treated with 4 months of gemcitabine
±erlotinib (first randomisation) and then randomised to receive either two
supplementary months of gemcitabine or chemoradiation. [1]
• The median OS showed no improvement in the chemoradiation group (15.2
versus 16.4 months) even though local tumour control did seem a little bit better
in this group.
• Several small retrospective and prospective studies have suggested that
FOLFIRINOX may be able to obtain an interesting response rate in this population,
and may have rendered some pts with locally advanced cancers resectable.
However, it is too early to recommend this RX and trials are ongoing.
• Thus, the standard of care for these pts currently remains as 6 months of
gemcitabine
1. Hammel P, Huguet F, Van Laethem J-L et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the
international phase III LAP 07 study. J Clin Oncol 2013;31(suppl):abstr LBA4003.
Chemoradiation ?
Recommendations for RX of locally advanced disease
• The standard of care is 6 months of gemcitabine .
• A minor role of chemoradiation in this subgroup of pts has been observed.
• It is impossible to recommend any chemoradiation RX other than the
classical combination of capecitabine and radiotherapy.
ESMO15
Management
Pancreatic Cancer
Resectable Borderline resectable Unresectable
Metastases
Surgery
Adjuvant Chemo
Staging and risk assessment
capecitabine and
radiotherapy ?
6 months of gemcitabine
Locally Advanced
Treatment of advanced/metastatic disease
Palliative and supportive care
• Before even considering systemic chemotherapy, pts with metastatic PC
may need interventions to provide relief of biliary and/or duodenal
obstruction, malnutrition, and pain.
Palliative Procedures: Jaundice
• Relief of jaundice can also be achieved by biliary stents placed percutaneously
or endoscopically. Because these procedures are usually well tolerated and
perfomed on an outpatient basis, they have become increasingly popular in the
MX of malignant biliary obstruction.
• In experienced hands, endoscopic stent placement has a success rate of more
than 85%, with a 1% to 2% procedure-related mortality.
• Several randomized trials have demonstrated no difference in survival between
pts palliated endoscopically versus surgically for obstructive jaundice.[1,2]
1. Shepherd HA, Royle G, Ross AP, et al: Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: A randomized trial. Br J Surg 1988; 75:1166-8.
2. Smith AC, Dowsett JF, Russell RC, et al: Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet 1994; 344:1655-60.
3. Stark A, Hines OJ. Endoscopic and operative palliation strategies for pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 163–176.
In the event of a biliary obstruction due to a pancreatic tumour, the endoscopic placement of a metallic biliary stent is
strongly recommended. The endoscopic method is safer than percutaneous insertion and is as successful as surgical
hepatojejunostomy. [3]
Duodenal obstruction is preferentially managed by endoscopic placement of an expandable metal stent when possible,
and is favoured over surgery [3]
Palliative Procedures: Stents
• Two types of biliary stents are available: Plastic and self-expandable
metallic stents.
• The plastic stents are preferred for short-term use, and require exchange
Q 3 mnths to prevent complications from stent occlusion or cholangitis.
• The metallic self-expandable stents (Wallstent) have improved long-term
patency rates when compared with plastic stents, and are preferred for
long-term application.[1,2]
• In clinical practice, plastic stents are preferred for pts who are surgical
candidates, whereas metal stents are used for unresectable pts.
1. Kaassis M, Boyer J, Dumas R, et al: Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003; 57:178-82.
2. Soderlund C, Linder S: Covered metal versus plastic stents for malignant common bile duct stenosis: A prospective, randomized, controlled trial. Gastrointest Endosc 2006; 63:986-95.
Palliative Procedures: Pain
• Pain in PC can be extremely distressing and may respond poorly to oral
narcotics.
• Percutaneous or surgical chemical neurolysis with alcohol is an
alternative palliative measure that can help in controlling pain or
decreasing narcotic use. EUS can be used for this purpose as well.
• Randomized trials have shown that neurolysis of the celiac ganglion can
offer relief to many pts.[1,2]
• Lastly, radiation therapy may also be used for pain MX in selected pts.
1. Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 1993; 217:447-55.
2. Polati E, Finco G, Gottin L, et al: Prospective randomized double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer. Br J Surg 1998; 85:199-201.
Chemotherapy for Metastatic Disease
• Chemotherapy in this situation is never curative, and its palliative benefit must
be balanced against its potential toxic side effects.
• Assessment of tumor response to CT is based primarily on serial imaging studies,
serum marker (CA 19-9) trends, and changes in tumor-related symptoms.
• Only two chemotherapy agents have been a/with survivals longer than 5 mnths
in PC: 5-FU and gemcitabine.
• Up until the mid-1990s, 5-FU was the DOC for RX of advanced or metastatic PC.
Monotherapy with 5-FU has a poor objective response rate (0% to 10%) and an
average median survival of about 5 mnths.[1]
• Combination chemotherapy regimens containing 5-FU have increased objective
response rates (15% to 40%) but have failed to show a survival advantage in
randomized trials.[2,3,4,5]
1. Ahlgren JD: Chemotherapy for pancreatic carcinoma. Cancer 1996; 78:654-63.
2. Phase II studies of drug combinations in advanced pancreatic carcinoma: Fluorouracil plus doxorubicin plus mitomycin C and two regimens of streptozotocin plus mitomycin C plus fluorouracil. The Gastrointestinal Tumor Study Group. J Clin Oncol 1986; 4:1794-8.
3. Cullinan S, Moertel CG, Wieand HS, et al: A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 1990; 65:2207-12.
4. Cullinan SA, Moertel CG, Fleming TR, et al: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 1985;
253:2061-7.
5. Oster MW, Gray R, Panasci L, et al: Chemotherapy for advanced pancreatic cancer. A comparison of 5-fluorouracil, adriamycin, and mitomycin (FAM) with 5-fluorouracil, streptozotocin, and mitomycin (FSM). Cancer 1986; 57:29-33.
5FU OR Gemcitabine ?
• Gemcitabine is thought to interfere with DNA synthesis and repair. A well-known
randomized trial by Burris and colleagues compared weekly gemcitabine to
weekly 5-FU infusion in previously untreated pts.[1]
• Pts treated with gemcitabine had a slightly improved median survival compared
with those treated with 5-FU (5.6 vs. 4.4 months, respectively). An impressive
one-year survival advantage was also noted for the gemcitabine arm (18% vs.
2%, respectively).
• Importantly, improvement in disease-related signs and symptoms (pain,
performance status, weight loss) were more likely in the gemcitabine group
(23.8%) than in the 5-FU group (4.8%).
• Gemcitabine has been shown to have clinical benefit even in pts for whom 5-FU
treatment has failed.[2]
1. Burris III HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997; 15:2403-13.
2. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996; 7:347-53.
Gemcitabine
Gemcitabine ; single agent or in combination?
• On the basis of the results of these studies, gemcitabine is currently the
standard of care for pts with metastatic PC.
• However, single-agent gemcitabine RX is a/with poor objective response
rates (5.4%).[1] In an attempt to improve response rates and survival,
multiple gemcitabine-based combination chemotherapy regimens have
been developed.
• In these protocols, gemcitabine has been coupled with either cisplatin,
fluorouracil, irinotecan, oxaliplatin, pemetrexed, or exatecan.[2-7]
Objective response rates have shown improvement with combination
therapy, but this improvement has not translated into a survival benefit.
1. Burris III HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997; 15:2403-13.
2. Abou-Alfa GK, Letourneau R, Harker G, et al: Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 2006; 24:4441-7.
3. Berlin JD, Catalano P, Thomas JP, et al: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002; 20:3270-5.
4. Heinemann V, Quietzsch D, Gieseler F, et al: Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006; 24:3946-52.
5. Louvet C, Labianca R, Hammel P, et al: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23:3509-16.
6. Oettle H, Richards D, Ramanathan RK, et al: A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16:1639-45.
7. Rocha Lima CM, Green MR, Rotche R, et al: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin
Oncol 2004; 22:3776-83.
Gemcitabine ; single agent or in combination?
• Three separate meta-analyses [1] reported a statistically significant survival
advantage of combination therapy compared with gemcitabine alone.
• Capecitabine and cisplatin-based combinations have produced the greatest
benefit. However, due to the low level of evidence, there have been no clear
changes in the daily clinical MX of these pts.
• Even with modern agents such as tyrosine kinase inhibitors or monoclonal
antibodies against various targets, the results of large phase III trials evaluating
the addition of these drugs to gemcitabine have been disappointing. The targeted
therapies tested have included bevacizumab, cetuximab, aflibercept, and anti-
insulin growth factor agents.
• The exception is the combination of gemcitabine and the EGFR TKI erlotinib,
which gained regulatory approval following a 12-day improvement in median
survival compared with gemcitabine alone in a large randomised trial. [2]
• Arguably, however, this duration of survival prolongation is clinically irrelevant
for most pts; therefore, erlotinib has not been widely used in this disease.
1. Ciliberto D, Botta C, Correale P et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013; 49: 593–603.
2. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966.
3. Hammel P, Huguet F, Van Laethem J-L et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the
international phase III LAP 07 study. J Clin Oncol 2013;31(suppl): abstr LBA4003.
Gemcitabine Vs FOLFIRINOX?
• Major improvements in the RX of metastatic disease came with the demonstration of
the efficacy of a 5-FU-based triplet chemotherapy. The FOLFIRINOX regimen has
proven superior to gemcitabine alone, in terms of efficacy. [1]
• This trial included pts who were selected based on their ability to receive this aggressive
chemotherapy [Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1].
• The median OS was 11.1 months in the FOLFIRINOX group compared with 6.8 months
in the gemcitabine group [HR for death, 0.57; 95% CI 0.45–0.73; P < 0.001). More
adverse events were noted in the FOLFIRINOX group; 5.4% of pts in this group had
febrile neutropaenia.
• FOLFIRINOX is an option for the RX of pts with metastatic PC and good performance
status.
1. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817–1825.
FOLFIRINOX
Gemcitabine + paclitaxel Vs Gemcitabine?
• After decades of failed randomised trials that have tried to add a drug to
gemcitabine alone, a recent trial has shown positive results, demonstrating
that the combination of gemcitabine plus nab-paclitaxel is better than
gemcitabine alone in metastatic pts. [1]
• A total of 861 pts were randomly assigned to receive nab-paclitaxel plus
gemcitabine or gemcitabine alone. The median OS was 8.5 months in the
nab-paclitaxel–gemcitabine group compared with 6.7 months in the
gemcitabine group (HR for death, 0.72).
1. Von Hoff DD, Goldstein D, Renschler MF. Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer. N Engl J Med 2014; 370: 479–480.
Gemcitabine + paclitaxel
• There are no data concerning a direct comparison of FOLFIRINOX and
Gem-nab-paclitaxel.
• An indirect comparison of the two regimens may suggest a slightly greater
activity but also higher toxicity of FOLFIRINOX.
• No specific data favours the use of one regimen over the other in a defined
subgroup of pts.
• Thus, either of these two options can be offered to pts with serum
bilirubin levels <1.5× ULN and good PS (ECOG 0-1)
The efficacy of the RX has to be evaluated every 2 months with a comparative CT scan. The treatment has
to be stopped if a RECIST progression is observed and second-line RX has to be discussed.
Management algorithm [ESMO 15]
Gemcitabine
alone
PS 3-4 or
Comorbidites
PS2 and/or
Bilirubin> 1.5 x
ULN
PS 0 or 1
Best Supportive
care
Gemcitabine +
nab-paclitaxel
FOLFIRINOX
Metastatic Pancreatic cancer
Recommendations for oncological RX of advanced/
metastatic disease [ESMO15]
• If the performance status is 3/4, with significant morbidities and a very
short life expectancy: only symptomatic treatment can be considered.
• In very selected pts with ECOG PS 2 due to heavy tumour load,
gemcitabine and nab-paclitaxel can be considered for best chance of
response .
• If the PS of the pt is 2 and/or the bilirubin level is >1.5× ULN: a
monotherapy with gemcitabine should be considered.
• If the PS of the pt is 0 or 1 and the bilirubin level<1.5× ULN two types of
combination chemotherapy—the FOLFIRINOX regimen or the combination
of gemcitabine and nab-paclitaxel—should be considered.
Second-line treatment
• A first randomised trial (168 pts) has shown, in pts with advanced
gemcitabine-refractory PC, that second-line 5-FU, folinic acid and
oxaliplatin, significantly extend the duration of OS when compared with 5-
FU, folinic acid alone.[1]
• These results have not been confirmed by a more recent Canadian trial. [2]
• Very recently, combination of irinotecan, and 5-FU, folinic acid has shown
an improvement of OS (6.1 versus 4.2 months), over 5-FU/LV alone.
1. Oettle H, Riess H, Stieler JM et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014; 32: 2423–2429.
2. Ciliberto D, Botta C, Correale P et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013; 49: 593–603.
Irinotecan, and 5-FU, folinic acid
Targeted Therapeutic Agents in Pancreatic Cancer
• Poor results with conventional chemotherapy have led to ongoing development of novel agents against PC. These
new agents are designed to target specific cellular pathways involved in tumor progression.
• Examples include inhibitors of farnesyltransferase, epidermal growth factor receptor, and matrix
metalloproteinases.[1,2]
• These new biological agents show impressive results in both in vitro and animal studies.[3]
• However, efficacy in human trials has been more difficult to demonstrate.[4,5]
1. Van Cutsem E, van de Velde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22:1430-8.
2. Bramhall SR, Schulz J, Nemunaitis J, et al: A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87:161-7.
3. Jimenez RE, Hartwig W, Antoniu BA, et al: Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: An additive strategy for cancer control. Ann Surg 2000; 231:644-54.
4. Moore MJ, Hamm J, Dancey J, et al: Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada
Clinical Trials Group. J Clin Oncol 2003; 21:3296-302.
5. Bramhall SR, Rosemurgy A, Brown PD, et al: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J Clin Oncol 2001; 19:3447-55.
Biomarker correlatives and future trial design
• Molecular subtypes of PC have been identified with varying responses to
chemotherapy. [1]
• Recent formation of a pancreatic biomarker compendium represents advances in
identifying biomarkers for PC in a global and systematic fashion. [2]
• One such biomarker, human equilibrative transporter 1 (hENT1), thought to
partly mediate cellular entry of cytotoxic chemotherapy, has been suggested as
having a role as a predictive biomarker in PC pts treated with gemcitabine. [3–5]
• In a recent retrospective review of the ESPAC study, high hENT1
immunohistochemistry expression was a/with improved survival with
gemcitabine, with low hENT1 linked to improved survival with 5-FU rather than
gemcitabine. [6]
• Presently, the use of molecular profiling to direct pt care has not been
incorporated into RX guidelines.
1. CollissonEA, SadanandamA, OlsonP, et al.Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med2011;17:500.
2. HarshaHC, KandasamyK, RanganathanP, et al.A compendium of potential biomarkers of pancreatic cancer. PLoS Med2009;6:e1000046.
3. GiovannettiE, Del TaccaM, MeyV, et al.Transcription analysis of human equilibrative nucleoside transporter‐1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res2006;66:3928.
4. FarrellJJ, ElsalehH, GarciaM, et al.Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology2009;136:187.
5. KimR, TanA, LaiKK, et al.Prognostic roles of human equilibrative transporter 1 (hENT‐1) and ribonucleoside reductase subunit M1 (RRM1) in resected pancreatic cancer. Cancer2011;117:3126.
6. NeoptolemosJP. HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5‐FU on the ESPAC trials. J Clin Oncol2013;31:abstract 4006.
Cancer cachexia
• Cancer cachexia is a universal feature of advanced PC. The majority of weight loss is
secondary to the still poorly understood paraneoplastic effects of the tumor on
metabolism and calorie utilization.
• Agents targeting various cytokines such as interleukin-1α (IL-1α), thought to contribute
to cachexia are now being evaluated. [1]
• For PC pts, pancreatic enzyme supplementation should be provided .
• Pancreatic exocrine insufficiency is a result of the loss of pancreatic parenchyma,
pancreatic ductal obstruction, decreased pancreatic stimulation, or acid-medicated
inactivation of pancreatic enzymes. Clinical manifestations are abdominal cramps,
bloating, steatorrhea, and malnutrition with resultant weight loss. Fecal fat
quantification and 13C-triglyceride breath test, are diagnostic.
• Oral administration of exogenous pancreatic enzymes is considered standard therapy
. [2]
• Currently available appetite stimulants such as dronabinol and Megace are generally
relatively ineffective and/or a/with ↑ risk of hyperglycemia and thromboembolic
events.
1. trials.gov C.2013. Available from: http://www.cancer.gov/clinicaltrials/search/view?cdrid=745198&version=HealthProfessional&protocolsearchid=8182450.
2. Dominguez‐MunozJE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol2011;26:12.
END OF SLIDES
References:
1. Sleisenger
2. ESMO 2015 guideline on Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
3. Yamada Textbook of gastroenterology ,6th ed
Pancreatic cancer
Pancreatic cancer
Pancreatic cancer

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Pancreatic cancer

  • 1. Pancreatic Cancer Pratap Sagar Tiwari, MD (Internal medicine) DM Resident, Hepatology, NAMS Bir Hospital, Nepal
  • 2. Content • Introduction • Classification • Risk Factors • Molecular biology & Embryonic signalling pathways • Manifestations • Role of Tumor markers • Imaging • Management
  • 3. Introduction • Pancreatic cancer is the second MC GI malignancy in the US[1] • Pancreatic cancer ranks 10th in cancer incidence in the US for men and women. • A recent study estimating cancer epidemiology in 2014 (within Europe) showed that PC was the fourth most fatal cancer in men after lung, colorectal, and prostate cancers . [2] • Similarly, PC was found to be the fourth most fatal cancer in women after breast, colorectal and lung cancers .[2] • Surgical excision is the definitive RX with a 5-yr survival rate (after resection) of ∼20%, but it is only possible in 15%–20% of the pts. Overall, PC carries an unfavorable prognosis. For all stages combined, the 1- & 5-year survival rates are 24% & 5%, respectively.[3] 1. American Cancer Society: Cancer Facts and Figures 2008. Atlanta, American Cancer Society, 2008. 2. Malvezzi M, Bertuccio P, Levi F et al. European cancer mortality predictions for the year 2014. Ann Oncol 2014; 25: 1650–1656 3. Ries LAG, Eisner MP, Kosary CL: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md, National Cancer Institute, 2000. 4. .
  • 4. WHO Classification of Primary Tumors of the Exocrine Pancreas Data from Hamilton SR, Aaltonen LA. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. Lyon, France: IARC Press; 2000.
  • 5. Pancreatic Tumors Islet cell tumorsAcinar cells Ductal epithelium [80-90%] Endocrine [5%]Exocrine [95%] • Only 2% of tumours of the exocrine pancreas are benign. • A number of morphological variants of ductal carcinoma have been characterised, including colloid carcinoma and medullary carcinoma. Other variants of pancreatic cancer, such as adenosquamous carcinoma and undifferentiated carcinomas with osteoclast-like giant cells, are important to recognise because they are a/with a poorer prognosis. • Neuroendocrine tumours of the pancreas are the second most frequent PC. • Cystic neoplasms represent 10%–15% of cystic lesions of the pancreas.[1] The most commonly encountered cystic neoplasms include: serous cystadenoma, intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (either cystadenoma or cystadenocarcinoma). • Mucinous lesions have potential for malignant progression and/or may harbour a malignancy at the time of DX. Neuroendocrine tumors 1. Dudeja V, Allen PJ. Premalignant cystic neoplasms of the pancreas. Semin Oncol 2015; 42: 70–85. Pancreatic tumors
  • 6. Note: Endocrine tumors of Pancreas • Endocrine tumors of Pancreas [ETP] are classified as functioning or non functioning according to the type and level of their hormonal secretion.[1] Among functioning ETP, • Insulinomas (50%) and gastrinomas (30%) are the most frequent; • Tumors secreting vasoactive intestinal peptide (VIPomas), glucagon (glucagonomas), and somatostatin (somatostatinomas) are much rarer (5–10%); • Those secreting growth-hormone-releasing factor (GHRH), adrenocorticotropic hormone (ACTH) or corticotropin-releasing factor (CRF), and parathyroid hormone related peptide (PTHrp) are anecdotal. Conversely, at least 15% of ETP are non functioning or secrete non clinically active peptides such as human pancreatic polypeptide (PPomas). 1. Klöppel G, Heitz P U. Pancreatic endocrine tumors. Pathol Res Pract. (1988);183:155–168.
  • 7. Note: Endocrine tumors of Pancreas • Most ETP discovered clinically are functional—that is, they secrete one or more hormonal products into the blood, which leads to a recognizable clinical syndrome.[1] • In 1927, Wilder et al described the first hormone-producing pancreatic tumor syndrome (insulinoma syndrome) in a pt with hypoglycemia and a metastatic islet cell tumor, extracts of which caused hypoglycemia.[2] • Zollinger-Ellison syndrome (also termed gastrinoma syndrome), described by Zollinger and Ellison in 1955.[3] • The other types comprise a group of three tumor syndromes, termed Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, and pancreatic cholera (also termed vasoactive intestinal peptide [VIP]–releasing tumor or VIPoma); these were described by Verner and Morrison in 1958.[4] • Another is glucagonoma syndrome, described by Mallinson et al in 1974. • Somatostatinoma syndrome, described by Ganda et al and Larsson et al in 1977.[5, 6] 1. Aluri V, Dillon JS. Biochemical Testing in Neuroendocrine Tumors. Endocrinol Metab Clin North Am. 2017 Sep. 46 (3):669-677. 2. Wilder RM, Allan FN, Power WH. Carcinoma of the islands of the pancreas: Hyperinsulinism and hypoglycemia. JAMA. 1927. 89:348. 3. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955. 142:709. 4. Verner JV, Morrison AB. Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia. Am J Med. 1958. 25:374. 5. Ganda OP, Weir GC, Soeldner JS, et al. "Somatostatinoma": a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med. 1977 Apr 28. 296(17):963-7. 6. Larsson LI, Hirsch MA, Holst JJ, et al. Pancreatic somatostatinoma. Clinical features and physiological implications. Lancet. 1977 Mar 26. 1(8013):666-8.
  • 9. Ductal adenocarcinoma of Pancreas • Ductal adenocarcinoma accounts for 85% to 90% of pancreatic tumors.[1] • Autopsy series have shown that 60%-70% of these tumors are localized in the head of the gland, 5%-10% in the body, and 10%-15% in the tail. • The average size of carcinomas in the head of the pancreas is 2.5 to 3.5 cm, compared with 5 to 7 cm for tumors in the body or tail. 1. Ductal adenocarcinoma. In: Hruban RH, Pitman MB, Klimstra DS, ed. AFIP Atlas of Tumor Pathology. Tumors of the Pancreas, Washington, D.C.: American Registry of Pathology; 2007:111-64.
  • 10. Risk factor: Age • Age appears to be a significant risk factor for the development of PC with a median age at DX of 71 years of age, and approximately 88% DX over the age of 55.[1] 1. HowladerNA, KrapchoM, NeymanN, et al.(eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD; 2011.
  • 11. Risk factor: Gender • As per the SEER (Surveillance, Epidemiology, and End Results) database, the incidence rate of PC in males is 13.9 cases/100 000 people compared with 10.9 cases in women.[1] • The death rates are similar in that for males: the death rate is 12.5/100 000 and 9.6/100 000. 1. HowladerNA, KrapchoM, NeymanN, et al.(eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD; 2011.
  • 12. Risk factor: Race • The incidence rate of PC in African Americans is 17.6 cases/100 000 people compared with 13.8/100 000 cases in Caucasians.[1] • The death rate is also higher in the African American population for both sexes. The reason(s) for these differences remains unknown and an active area of investigation. 1. HowladerNA, KrapchoM, NeymanN, et al.(eds). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD; 2011.
  • 13. Risk factor: Smoking • The most important environmental factor is cigarette smoking.[1] • Multiple cohort and case-control studies have found that the RR for smokers of developing PC is at least 1.5.[2,3,4] 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.[5] • Furthermore, the risk rises with the amount of cigarette consumption, and the excess risk level returns to baseline by 15 years after cessation of the habit.[4] • Other forms of tobacco, including pipes and smokeless (chewing) and Environmental smoke exposure [6], have been a/with an ↑ risk as well.[7] 1. Ahlgren JD: Epidemiology and risk factors in pancreatic cancer. Semin Oncol 1996; 23:241-50. 2. Silverman DT, Dunn JA, Hoover RN, et al: Cigarette smoking and pancreas cancer: A case-control study based on direct interviews. J Natl Cancer Inst 1994; 86:1510-16. 3. Fuchs CS, Colditz GA, Stampfer MJ, et al: A prospective study of cigarette smoking and the risk of pancreatic cancer. Arch Intern Med 1996; 156:2255-60. 4. Ghadirian P, Simard A, Baillargeon J: Tobacco, alcohol, and coffee and cancer of the pancreas. A population-based, case-control study in Quebec, Canada. Cancer 1991; 67:2664-70. 5. Duell EJ, Holly EA, Bracci PM, et al: A population-based, case-control study of polymorphisms in carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst 2002; 94:297-306. 6. ZhouJ, WelleniusGA, MichaudDS. Environmental tobacco smoke and the risk of pancreatic cancer among non‐smokers: a meta‐analysis. Occup Environ Med2012;69:853. 7. BoffettaP, AagnesB, WeiderpassE, et al.Smokeless tobacco use and risk of cancer of the pancreas and other organs. Int J Cancer2005;114:992.
  • 14. Risk Factor: Obesity • The second most modifiable RF of PC is obesity. (ESMO15) • Tumorigenesis is enhanced by excess adipose tissue, probably through the mechanism of abnormal glucose metabolism. • Obesity [body mass index (BMI) > 30 kb/m2] is a/with a 20%–40% higher rate of death from PC.
  • 15. Risk factor: Diabetes • DM is very common in pts with PC. • DM was a/with a 40% ↑ risk of PC (OR 1.40, 95% CI 1.07, 1.84). • Risk was highest for those with a duration of diabetes for 2 to 8 years (OR 1.79, 95% CI 1.25-2.55) and no association for those with greater than 9 years of DM (OR 1.02, 95% CI 0.68-1.52).[1] • In a meta-analysis of 36 studies, the overall relative risk for the development of PC in a diabetic pt was 1.82 (95% CI 1.66–1.89). [2] • Meta-analyses have demonstrated associations between both type 1 and type 2 DM and PC, with odds ratios of ∼2.0 and 1.8, respectively. [3] 1. ElenaJW, SteplowskiE, YuK, et al.Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control2013;24:13. 2. HuxleyR, Ansary‐MoghaddamA, Berrington de GonzalezA, et al.Type‐II diabetes and pancreatic cancer: a meta‐analysis of 36 studies. Br J Cancer2005;92:2076. 3. Yeo TP. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 8–18.
  • 16. Risk factor: Drugs used in Diabetes • In the last several years, there has been interest in PC risk conferred by drugs used to treat diabetes. • Earlier epidemiological studies suggested a link between DM pts with a HX of insulin or insulin secretagogs (sulfonylureas and meglitinides) use and an ↑ risk of PC compared with nonusers. [1,2] • Metaanalysis of 11 studies (6 cohort, 3 case–control, and 2 RCT) reported 1770 cases of PC in 730 664 pts with DM showed no significant association between metformin, insulin, or thiazolidinediones use and risk of developing PC. • Use of sulfonylureas was a/with a 70% ↑ in the odds of PC(n = 8 studies; adjusted OR 1.70, 95% CI 1.27–2.28, P < 0.001). • Although sulfonylurea seemed to be a/with ↑ risk of PC, metaanalysis of existing studies did not support a protective or harmful association between antidiabetic medication use and risk of PC in pts with DM. [3] 1. BowkerSL, MajumdarSR, VeugelersP, et al.Increased cancer‐related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care2006;29:254. 2. EvansJM, DonnellyLA, Emslie‐SmithAM, et al.Metformin and reduced risk of cancer in diabetic patients. BMJ2005;330:1304. 3. SinghS, SinghPP, SinghAG, et al.Anti‐diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta‐analysis. Am J Gastroenterol2013;108:510; quiz 20.
  • 17. Risk factor: Drugs used in Diabetes • Metformin, was compared in a hospital-based case–control study of 973 pts with PC. A protective effect was seen in users of metformin who had a significantly lower risk of PC, compared to those that had not taken metformin (OR 0.38; 95% CI 0.22–0.69; P = 0.001). [1] • In a small retrospective study of 302 pts, metformin use was a/with improved outcome of pts with DM and PC[2]. Prospective controlled trials will ultimately be required to clarify the effects of metformin on PC risk and progression. • Most recently, there has been controversy surrounding the effects two classes of drugs, GLP-1 agonists, which enhance insulin secretion, and DPP-4 inhibitors that elevate GLP-1 levels are in widespread use in the clinic. There are conflicting reports regarding the association of these agents with the risk of pancreatitis. [3] • A recent National Institutes of Health (NIH) consensus conference concluded that there is insufficient data at present to support a link between GLP-1 agonists or DPP-4 inhibitors and PC. [4] 1. LiD, YeungSC, HassanMM, et al.Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology2009;137:482. 2. SadeghiN, AbbruzzeseJL, YeungSC, et al.Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin Cancer Res2012;18:2905. 3. EngelSS, Williams‐HermanDE, GolmGT, et al.Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract2010;64:984. 4. DoreDD, SeegerJD, Arnold ChanK. Use of a claims‐based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin2009;25:1019.
  • 18. Risk factor: Chronic pancreatitis • Chronic pancreatitis accounts for ∼5% of pancreatic cancers. • The MC cause of CP, in Europe, is excess alcohol consumption. The causal pathway is not clear, however, alcohol consumption by itself is related to an ↑ risk of PC. • There is a strong link between antecedent CP and PC. • In a metaanalysis of 10 cohort and 12 case–control studies, a statistically significant ↑ of PC risk for all types of pancreatitis, with summary RRs (95% CI) of 5.1 (3.5–7.3) for unspecified pancreatitis, 13.3 (6.1–28.9) for CP, and 69.0 (56.4–84.4) for hereditary pancreatitis. [1,2] • The single study on tropical pancreatitis provided an even higher RR of 100.0 (95% CI 37.0–218.0). [1] • Other studies have also demonstrated an ↑ risk of PC in pts with CP. [3] 1. RaimondiS, LowenfelsAB, Morselli‐LabateAM, et al.Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol2010;24:349. 2. LowenfelsAB, MaisonneuveP, CavalliniG, et al.Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med1993;328:1433. 3. TalaminiG, FalconiM, BassiC, et al.Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol1999;94:1253.
  • 19. Risk factor: Alcohol • As the MC cause of acute and chronic pancreatitis, alcohol abuse is a logical candidate for PC risk association. However, the epidemiological evidence for the role of alcohol use in the etiology of PC is equivocal .[1,2,3] • The NIH-American Association of Retired Persons (AARP) Diet and Health Study prospectively examined the relation between alcohol use and the risk of PC among 470 681 participants who were aged 50–71 years in 1995–1996 . • The RR of developing PC were 1.45 (95% CI 1.17, 1.80; P = 0.002) for heavy alcohol use (≥3 drinks/day, ∼40 g of alcohol/day) . These findings suggest a moderately ↑PC risk with heavy alcohol use.[4] 1. SchneiderA, SingerMV. Alcoholic pancreatitis. Dig Dis2005;23:222. 2. VelemaJP, WalkerAM, GoldEB. Alcohol and pancreatic cancer. Insufficient epidemiologic evidence for a causal relationship. Epidemiol Rev1986;8:28. 3. FriedmanGD, van den EedenSK. Risk factors for pancreatic cancer: an exploratory study. Int J Epidemiol1993;22:30. 4. JiaoL, SilvermanDT, SchairerC, et al.Alcohol use and risk of pancreatic cancer: the NIH‐AARP Diet and Health Study. Am J Epidemiol2009;169:1043.
  • 20. Risk factor: Dietary influences • Dietary factors have been studied extensively, and clearly contribute to the development of PC. • Independent of their role in causing obesity: butter, saturated fat, red meat, and processed foods are clearly linked to PC .[1] • Conversely, a high fruit and folate intake could reduce the risk of PC. [1] • However, based on data from more than 500 000 persons in 10 countries, the consumption of fruit and vegetables does not ↓ the risk of PC. [2,3] 1. Larsson SC, Wolk A. Red and processed meat consumption and risk of pancreatic cancer: meta-analysis of prospective studies. Br J Cancer 2012; 106: 603–607. 2. VrielingA, VerhageBA, van DuijnhovenFJ, et al.Fruit and vegetable consumption and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer2009;124:1926. 3. JansenRJ, RobinsonDP, Stolzenberg‐SolomonRZ, et al.Nutrients from fruit and vegetable consumption reduce the risk of pancreatic cancer. J Gastrointest Cancer2013;44:152.
  • 21. Hereditary factors • The first studies to suggest an inherited genetic component to PC risk were case reports of families in which there were multiple members afflicted by PC. [1] • Observational epidemiological studies including case–control and cohort studies have found that individuals with a family history of PC are at an ↑ risk of developing PC themselves, with odds 1.9- to 13-fold higher when compared with healthy controls. [2,3] • The term “familial pancreatic cancer” characterizes families with at least two first-degree relatives with confirmed exocrine PC. [4] 1. KleinAP, HrubanRH, BruneKA, et al.Familial pancreatic cancer. Cancer J2001;7:266. 2. JacobsEJ, ChanockSJ, FuchsCS, et al.Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer2010;127:1421. 3. GhadirianP, BoyleP, SimardA, et al.Reported family aggregation of pancreatic cancer within a population‐based case‐control study in the Francophone community in Montreal, Canada. Int J Pancreatol1991;10:183. 4. BartschDK, GressTM, LangerP. Familial pancreatic cancer – current knowledge. Nat Rev Gastroenterol Hepatol2012;9:445.
  • 22. Most common cancer syndromes a/with PC risk YAMADA 6E
  • 23. Risk factor: others • Helicobacter pylori, hepatitis B, and human immunodeficiency virus infection have also been reported to be related to an ↑ in RR of PC, although some confounding factors such as cigarette smoking or alcohol consumption have not always been considered. [1] • Different chemical substances have been reported to increase the RR of developing PC, among these are: chlorobenzoil, chlorinated hydrocarbon, nickel and nickel compounds, chromium compounds, silica dust, and others.[2] 1. Yeo TP. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 8–18. 2. Ojajarvi IA, Partanen TJ, Ahlbom A et al. Occupational exposures and pancreatic cancer: a meta-analysis. Occup Environ Med 2000; 57: 316–324.
  • 24. Risk factors: summary • As a summary, it is possible to say that 5%–10% of PC are related to a genetic alteration. • Among the remaining 90%, the major RF are tobacco, H. pylori infection and factors related to dietary habits (BMI, red meat intake, low fruit and vegetables intake, DM, alcohol intake). • However, about two thirds of the major risk factors a/with PC are potentially modifiable, affording a unique opportunity for preventing one of the deadliest cancers. ESMO
  • 25. Molecular biology • Multiple combinations of genetic mutations are commonly found in PC and can be classified as follows: (i) Mutational activation of oncogenes, predominantly KRAS found in 90-95 % of PC. (ii) Inactivation of tumour suppressor genes such as TP53 (70%), p16/CDKN2A (98%), and SMAD4 (55%). (iii) Inactivation of genome maintenance genes, such as Hmlh1 and MSH2, which control the repair of DNA damage. KRAS: Kirsten ras oncogene TP53: Tumor Protein P53 CDKN2A: Cyclin Dependent Kinase Inhibitor 2A SMAD4: Mothers against decapentaplegic homolog 4 MSH2: MutS protein homolog 2 Hmlh1: Human mutL homolog 1
  • 26. Most common genetic mutations in PC YAMADA 6E
  • 27. Embryonic signaling pathways • Over the past decade, it is has become increasingly clear that during carcinogenesis, reactivation of signaling pathways important during embryogenesis is a common event. Abundant evidence has accumulated to implicate the Hedgehog, Notch, and Wnt signaling pathways in pancreatic carcinogenesis. [1,2,3] • Sonic hedgehog (Shh) is a key regulator of pancreatic development and epithelial proliferation. Shh is overexpressed in most PC with its upregulation observed initially in PanIN. [4] • Numerous Hedgehog pathway inhibitors( eg Vismodegib) have now been developed and are in early phase trials in PC. 1. JonesS, ZhangX, ParsonsDW, et al.Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science2008;321:1801. 2. BiankinAV, WaddellN, KassahnKS, et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature2012;491:399. 3. MiyamotoY, MaitraA, GhoshB, et al.Notch mediates TGF alpha‐induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell2003;3:565. 4. ThayerSP, di MaglianoMP, HeiserPW, et al.Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature2003;425:851.
  • 28. Embryonic signaling pathways • Notch proteins are transmembrane receptors for membrane bound ligands that are known as key development regulators. • Typically, Notch functions to maintain cells in an undifferentiated state during development, a function that has been proposed to be significant during carcinogenesis as well. • Notch activation is largely absent in the adult pancreas, with the exception of activity seen in centroacinar cells. • Expression of the Notch target gene Hes1, is observed in centroacinar cells and is increasingly observed during acinar duct metaplasia and the development of PanIN and PC. [1] • The role of Notch in PC progression remains under investigation, but drugs targeting γ-secretase, a regulator of Notch signaling, are currently in early phase clinical trials. [2] 1. MiyamotoY, MaitraA, GhoshB, et al.Notch mediates TGF alpha‐induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell2003;3:565. 2. PlentzR, ParkJS, RhimAD, et al.Inhibition of gamma‐secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology2009;136:1741.
  • 29. Embryonic signaling pathways • Wnt proteins play numerous roles in embryonic development. • In the pancreas, Wnt signaling is critical for the development of the exocrine pancreas suggesting that, in the pancreas, it may be important for the expansion of exocrine precursors. [1] • More recent studies have demonstrated that inhibition of Wnt signaling in PC cells can inhibit growth and suggests targeting Wnt signaling as a potential avenue for PC therapy. [2,3] 1. WellsJM, EsniF, BoivinGP, et al.Wnt/beta‐catenin signaling is required for development of the exocrine pancreas. BMC Dev Biol2007;7:4. 2. Pasca di MaglianoM, BiankinAV, HeiserPW, et al.Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE2007;2:e1155. 3. ZhangY, MorrisJPt, YanW, et al.Canonical Wnt signaling Is required for pancreatic carcinogenesis. Cancer Res2013;73:4909.
  • 30. Manifestations • Tumors of the head of the pancreas produce symptoms earlier in the course of disease. • Tumors in the head of the gland have a propensity for obstruction of the distal CBD and pancreatic duct. • Anatomic obstruction of these structures results in jaundice and chronic obstructive pancreatitis. • Some tumors can involve the duodenum or the ampulla of Vater. • Extrapancreatic extension into the retroperitoneal tissues is almost always present at the time of DX and can result in invasion of the PV or the superior mesenteric vessels and nerves.
  • 31. Manifestations • In contrast, tumors of the distal gland are characterized by their “silent” presentation, with physical findings appearing only after extensive local growth or widely metastatic disease has developed. • Neoplasms of the tail of the pancreas do not cause biliary or pancreatic duct obstruction. • Extrapancreatic extension in distal tumors causes invasion of the spleen, stomach, splenic flexure of the colon, or left adrenal gland. • In pts with advanced disease, metastases to the lymph nodes, liver, and peritoneum are common; the lung, pleura, and bone are less commonly involved.[1] 1. Tumors of the exocrine pancreas. In: Solcia E, Capella C, Kloppel G, ed. Tumors of the Pancreas, Washington, D.C.: Armed Forces Institute of Pathology; 1997:31-144.
  • 32. Manifestations: major • Jaundice is often the first sign that brings pts to medical attention, especially with tumors in the head of the pancreas. Present in >50% of pts, results from obstruction of the extrahepatic bile duct. • Pts with concomitant obstruction of the pancreatic duct may also show pancreatic exocrine insufficiency in the form of steatorrhea and malabsorption. • Pain can be a major symptom in many pts with PC. Pain is primarily due to invasion of the celiac or superior mesenteric arterial plexus.[1] The pain is of low intensity, dull, and vaguely localized to the upper abdomen. In advanced disease, pain may be localized to the middle and upper back. The pain also may be postprandial and lead pts to reduce their caloric intake, a situation that ultimately results in weight loss or cachexia. 1. Fasanella KE, Davis B, Lyons J, et al: Pain in chronic pancreatitis and pancreatic cancer. Gastroenterol Clin North Am 2007; 36:335-64.ix
  • 33. Manifestations: minor • Other nonspecific symptoms include nausea, fatigue, anorexia, and weight loss. These symptoms may or may not be caused by tumor involvement of the duodenum causing partial obstruction. • Less common symptoms include those of diabetes and pancreatitis. • New-onset diabetes mellitus may herald PC and can be observed in 6% to 68% of pts.[1] • Acute pancreatitis is occasionally the first manifestation of PC.[2] 1. Yalniz M, Pour PM: Diabetes mellitus: A risk factor for pancreatic cancer?. Langenbecks Arch Surg 2005; 390:66-72. 2. Mujica VR, Barkin JS, Go VL: Acute pancreatitis secondary to pancreatic carcinoma. Study group participants. Pancreas 2000; 21:329-32.
  • 34. Manifestations • In a multi-institutional series of 185 pts with exocrine PC DX over a 3-yr period (62 % involving the head, 10 % body, 6 % tail, and the remainder not determined), [1]: Symptoms Signs Asthenia – 86 percent Weight loss – 85 percent Anorexia – 83 percent Abdominal pain – 79 percent Epigastric pain – 71 percent Dark urine – 59 percent Jaundice – 56 percent Nausea – 51 percent Back pain – 49 percent Diarrhea- 44 percent Vomiting – 33 percent Steatorrhea – 25 percent Thrombophlebitis – 3 percent Jaundice – 55 percent Hepatomegaly- 39 percent Right upper quadrant mass – 15 percent Cachexia – 13 percent Courvoisier’s sign (nontender but palpable distended gallbladder at the right costal margin) – 13 percent Epigastric mass – 9 percent Ascites – 5 percent 1. Porta M, Fabregat X, Malats N, et al. Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol 2005; 7:189.
  • 35. Role of tumor markers (A) • CA 19-9- SN and SP rates for PC range from 70-92, and 68-92%, respectively. [1-5] • However, SN is closely related to tumor size. CA 19-9 levels are of limited SN for small cancers. [6-9] • CA 19-9 is frequently elevated in pts with cancers other than PC and various benign pancreaticobiliary disorders. [10,11] • One study found that serum conc> 37 U/mL represented the most accurate cutoff value for discriminating PC from benign pancreatic disease, but the SN and SP for PC at this level were only 77 and 87 %, respectively. [10] • Furthermore, the PPV is low, particularly among asymptomatic individuals. In a large series of over 70,000 asymptomatic individuals, the PPV of a serum level >37 U/mL was only 0.9 %. [12] Because of this, expert guidelines recommend against the use of CA 19-9 as a screening test for PC. [13] • Even among symptomatic individuals (epigastric pain, weight loss, jaundice), SN, SP, and PPV of an ↑ CA 19-9 >37 U/mL level are only approxy 80, 85, and 72 %.[14] Note: References are at the end of the slides
  • 36. Conditions a/with increased serum levels of CA 19-9 UPTODATE21.6
  • 37. Role of tumor markers (B) • Serum levels of CA 19-9 do have some value as prognostic markers and indicator of disease activity . • Among pts who appear to have potentially resectable PC, the preoperative CA 19-9 level can also help to predict the presence of radiographically occult metastatic disease . [1-5] • As an example, in a report of 491 pts undergoing staging laparoscopy for a radiographically resectable PC, CA 19-9 >130 units/mL were a significant predictor of radiographically occult unresectable disease . [2] • Among pts with tumors in the body/tail , >1/3RD who had a CA 19-9 ≥130 units/mL had unresectable disease. • Serial monitoring of CA 19-9 (once every 1-3mnths [7]) is useful to follow pts after potentially curative SX and for those who are receiving CT for advanced disease. Rising CA 19-9 levels usually precede the radiographic appearance of recurrent disease, but confirmation of disease progression should be pursued with imaging studies and/or biopsy. [7] • Other markers — Although several marker have emerged from preclinical studies (macrophage inhibitory cytokine-1, appears particularly promising [6]), none has replaced CA 19-9 to date. Note: References are at the end of the slides
  • 38. Imaging of Pancreatic Cancer • Although transabdominal US is frequently the first modality used in many pts with PC(because 50% of them present with jaundice), the method of choice for DX and staging of PC is CT.[1,2,3] • The MC appearance of PDAC on CT is that of a low-density mass within the pancreas. Associated findings include pancreatic gland atrophy, dilation of the pancreatic and CBD, and contour irregularity of the pancreatic surface. • The SN of detecting PC on CT scan varies from 67% to 100% depending on the size of the primary lesion. [4,5] 1. Coley SC, Strickland NH, Walker JD, et al: Spiral CT and the pre-operative assessment of pancreatic adenocarcinoma. Clin Radiol 1997; 52:24-30. 2. Freeny PC, Traverso LW, Ryan JA: Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography. Am J Surg 1993; 165:600-6. 3. Megibow AJ, Zhou XH, Rotterdam H, et al: Pancreatic adenocarcinoma: CT versus MR imaging in the evaluation of resectability—Report of the Radiology Diagnostic Oncology Group. Radiology 1995; 195:327-32 4. KatzMH, SavidesTJ, MoossaAR, et al.An evidence‐based approach to the diagnosis and staging of pancreatic cancer. Pancreatology2005;5:576. 5. ClarkeDL, ThomsonSR, MadibaTE, et al.Preoperative imaging of pancreatic cancer: a management‐oriented approach. J Am Coll Surg2003;196:119..
  • 39. DIAGNOSIS: CT • The pancreatic protocol CT consists of dual-phase scanning using IV contrast agents. The first, arterial (pancreatic) phase is obtained 40 secs after administration of IV contrast agent. At this time maximum enhancement of the normal pancreas is obtained, allowing identification of nonenhancing neoplastic lesions. The second, portal venous phase(Hepatic phase) is obtained 70 secs after injection of IV contrast agent and allows accurate detection of liver metastases and assessment of tumor involvement of the portal and mesenteric veins. 1. Coley SC, Strickland NH, Walker JD, et al: Spiral CT and the pre-operative assessment of pancreatic adenocarcinoma. Clin Radiol 1997; 52:24-30. 2. Freeny PC, Traverso LW, Ryan JA: Diagnosis and staging of pancreatic adenocarcinoma with dynamic computed tomography. Am J Surg 1993; 165:600-6. 3. Megibow AJ, Zhou XH, Rotterdam H, et al: Pancreatic adenocarcinoma: CT versus MR imaging in the evaluation of resectability—Report of the Radiology Diagnostic Oncology Group. Radiology 1995; 195:327-32.
  • 40. CT SCAN OF PC A, Arterial phase showing a nonenhancing lesion in the head of the pancreas (arrows). B, Venous phase showing a noninvolved fat plane around the portal vein (arrows). SLEISENGER
  • 41. CT Imaging of pancreatic cancer • The pancreatic phase allows optimal distinction between normal pancreatic parenchyma and a pancreatic mass while enabling evaluation of peripancreatic vessels in order to determine the extent of tumor involvement. • The goal of the hepatic phase is to differentiate between normal hepatic parenchyma and hypovascular metastases. • The diagnostic accuracy of CT for LN metastasis is very poor as it is generally based on size criteria alone. Enlarged LN may be reactive, particularly following biliary stenting, while normal-sized nodes may harbor micrometastasis. Enlarged peripancreatic lymph nodes should therefore not preclude a pt from surgery as the ability of CT to determine vascular invasion is the single best predictor of resectability. • Reports suggest that up to 11% of PC are isoattenuating on the pancreatic and hepatic phases making it potentially difficult to distinguish tumor from surrounding normal parenchyma unless other signs such as ductal dilatation or mass effect are present [95–97].
  • 42. Endoscopic Retrograde Cholangiopancreatography • Since its introduction in 1968, ERCP has become a mainstay in the DD of various tumors of the periampullary region.[1] • The majority of these tumors originate from the pancreas (85%), and less commonly from the distal bile duct (6%), ampulla (4%), or duodenum (4%). • ERCP allows visualization of the pancreatico-biliary tree to distinguish benign (stones) from malignant causes of obstruction. • A “double-duct sign,” representing strictures in biliary and pancreatic ducts, is classically found in many pts with PC. 1. Sahani DV, Shah ZK, Catalano OA, et al: Radiology of pancreatic adenocarcinoma: Current status of imaging. J Gastroenterol Hepatol 2008; 23:23-33.
  • 43. Endoscopic Retrograde Cholangiopancreatography ERCP reveals obstruction of both the CBD and pancreatic duct (circled area). YAMADA6E The two MC causes of the double duct sign are Ca of the head of the pancreas and ampullary tumours (e.g. carcinoma of the AOV), although occasionally an impacted gall stone in the distal duct, with associated oedema, can also result in obstruction of the PD. • A literature search[1] was performed, which indicated that in selected pts with a higher likelihood of PC (for example jaundice or pancreatic mass on radiological imaging) up to 85% of pts do indeed have a PC. • In an unselected population, regardless of presenting symptoms, a double-duct sign on ERCP was caused by a PC in 58% of pts. • In selected pts without jaundice but with a double duct sign, PC was only seen in 6% of pts. • SN and SP of the double-duct sign observed by ERCP for PC varies between 50-76% and 63-80%, respectively. 1. Leendert H. Oterdoom, Stijn J.B. van Weyenberg, Nanne K.H. de Boer. Double-duct Sign: Do Not Forget the Gallstones. J Gastrointestin Liver Dis, December 2013 Vol. 22 No 4: 447-450
  • 44. Endoscopic Retrograde Cholangiopancreatography • Tissue sampling can also be obtained during ERCP. • For tumors of the ampulla or duodenum, biopsy of mucosal lesions is readily obtained with endoscopic forceps. Tumors of the distal bile duct may also be sampled via brush biopsy for routine cytology or genetic analysis.[1,2] • As discussed earlier, CT allows for identification of pancreatic tumors in the majority of pts with PC, rendering ERCP unnecessary in most cases. In practice, however, many pts with PC undergo ERCP, not for the purpose of DX but rather for stenting of the biliary duct. 1. Glasbrenner B, Ardan M, Boeck W, et al: Prospective evaluation of brush cytology of biliary strictures during endoscopic retrograde cholangiopancreatography. Endoscopy 1999; 31:712-17. 2. Levy MJ, Baron TH, Clayton AC, et al: Prospective evaluation of advanced molecular markers and imaging techniques in patients with indeterminate bile duct strictures. Am J Gastroenterol 2008; 103:1263-73.
  • 45. Endoscopic Ultrasonography • EUS may be the most accurate test for the DX of PC.[1] • Several studies have shown that EUS has a higher sensitivity and specificity than CT for detecting pancreatic masses.[2,3] • EUS also has been found to be more accurate than CT in assessing vascular invasion and predicting tumor resectability. • Other advantages of EUS include accurate assessment of peripancreatic nodal disease, and allowance of tumor biopsy by FNA.[4] 1. Soriano A, Castells A, Ayuso C, et al: Preoperative staging and tumor resectability assessment of pancreatic cancer: Prospective study comparing endoscopic ultrasonography, helical computed tomography, magnetic resonance imaging, and angiography. Am J Gastroenterol 2004; 99:492-501. 2. DeWitt J, Devereaux B, Chriswell M, et al: Comparison of endoscopic ultrasonography and multidetector computed tomography for detecting and staging pancreatic cancer. Ann Intern Med 2004; 141:753-63. 3. Gress FG, Hawes RH, Savides TJ, et al: Role of EUS in the preoperative staging of pancreatic cancer: A large single-center experience. Gastrointest Endosc 1999; 50:786-91. 4. Gress F, Gottlieb K, Sherman S, et al: Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 2001; 134:459-64.
  • 46. EUS of PC: Limitations EUS is highly operator-dependent, and it is estimated that experience with 100 such examinations is needed to be considered proficient.[1] Imaging by EUS can be compromised by the presence of a biliary stent, which results in imaging artifacts and loss of tissue detail. Due to technical and anatomic constraints, imaging of the PV and splenic vein is generally superior to imaging of the superior mesenteric artery and vein.[2] For this reason EUS may lack accuracy when assessing vascular invasion at the level of the superior mesenteric vessels. Lastly, EUS provides no information regarding metastatic disease, and a complementary CT or MRI scan is required for complete staging of disease. 1. Gress FG, Hawes RH, Savides TJ, et al: Role of EUS in the preoperative staging of pancreatic cancer: A large single-center experience. Gastrointest Endosc 1999; 50:786-91. 2. Rosch T, Dittler HJ, Strobel K, et al: Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: A blind reevaluation of videotapes. Gastrointest Endosc 2000; 52:469-77. This EUS image demonstrates PC invasion of the PV (outlined area)
  • 47. Magnetic Resonance Imaging • MRI has been increasingly used in the evaluation of pancreatic tumors, and several groups have shown results that rival those of helical CT.[1,2] • In one study, pancreatic tumor detection was reported in 90% of pts for MRI versus 76% for helical CT.[1] • Tumors are viewed as low-signal masses against the high-signal background of normal pancreatic parenchyma. • Pancreatic masses, ductal dilation, and liver metastasis can be demonstrated in exquisite detail. • Additionally, MR angiography and MR venography techniques using gadolinium contrast enhancement can demonstrate vascular involvement by tumor. • Unlike CT, MRI does not involve radiation and uses an iodine-free contrast agent with rare renal toxicity. 1. Ichikawa T, Haradome H, Hachiya J, et al: Pancreatic ductal adenocarcinoma: Preoperative assessment with helical CT versus dynamic MR imaging. Radiology 1997; 202:655-62. 2. Lopez HE, Amthauer H, Hosten N, et al: Prospective evaluation of pancreatic tumors: Accuracy of MR imaging with MR cholangiopancreatography and MR angiography. Radiology 2002; 224:34-41.
  • 48. MRI/MRCP • MRCP can also be obtained at the time of MRI.[1] • In a prospective, controlled study, MRCP was found to be as sensitive as ERCP in detecting PC.[2] Images obtained are highly comparable with those obtained with ERCP and readily demonstrate pancreatic ductal obstruction, ectasia, and calculi. • MRCP uses heavy T2-weighted images that emphasize fluid-containing structures such as ducts, cysts, and peripancreatic fluid collections. • In contrast to ERCP, MRCP is noninvasive and does not require injection of contrast into the pancreatico-biliary tree, avoiding possible complications such as allergy, pancreatitis, or infection. • However, no therapeutic or diagnostic intervention can be performed with MRCP. • Limitations of MRI are related to cost & availability. 1. Barish MA, Yucel EK, Ferrucci JT: Magnetic resonance cholangiopancreatography. N Engl J Med 1999; 341:258-64. 2. Adamek HE, Albert J, Breer H, et al: Pancreatic cancer detection with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: A prospective controlled study. Lancet 2000; 356:190-3.
  • 49. Positron Emission Tomography • PET is a noninvasive imaging tool that provides metabolic rather than morphologic information on tumors.[1,2] • This DX method is based on greater use of glucose by tumor cells than by normal pancreatic parenchyma. The radioactive glucose analog fluorodeoxyglucose (FDG) F 18 is administered IV, followed by detection of FDG uptake by the PET scanner. • The normal pancreas is not usually visualized by FDG-PET. In contrast, PC appears as a focal area of increased uptake in the pancreatic bed. • Hepatic metastases appear as “hot spots” within the liver. 1. Inokuma T, Tamaki N, Torizuka T, et al: Value of fluorine-18-fluorodeoxyglucose and thallium-201 in the detection of pancreatic cancer. J Nucl Med 1995; 36:229-35. 2. Zimny M, Bares R, Fass J, et al: Fluorine-18 fluorodeoxyglucose positron emission tomography in the differential diagnosis of pancreatic carcinoma: A report of 106 cases. Eur J Nucl Med 1997; 24:678-82.
  • 50. Positron Emission Tomography • Owing to the lack of anatomic detail, PET scanning is not a principal diagnostic modality for PC. • However, FDG-PET can be helpful in differentiating benign from malignant pancreatic masses when morphologic data are equivocal.[1] • It can also be useful in assessing tumor recurrence after pancreatic resection, when scar tissue or postoperative changes may be difficult to differentiate from carcinoma. • Finally, FDG-PET can be of benefit in assessing tumor response to neoadjuvant chemoradiation, which may lead to alteration in clinical MX. 1. Rose DM, Delbeke D, Beauchamp RD, et al: 18-Fluorodeoxyglucose-positron emission tomography in the management of patients with suspected pancreatic cancer. Ann Surg 1999; 229:729-37.
  • 51. Percutaneous and EUS–Guided Aspiration Cytology • FNA cytology of the pancreas has been one of the major advances in the MX of pts with pancreatic tumors. • CT-guided biopsy has been used for more than 20 yrs and is regarded as a safe, reliable procedure, with a reported sensitivity of 57% to 96% and virtually no false-positive results.[1,2] • Experience with EUS-guided FNA shows similar results.[3] • Whenever a pt is deemed to have unresectable or metastatic PC, CT- or EUS- guided FNA biopsy is indicated for histologic confirmation of disease, unless a palliative surgical procedure is required. Even if the DX of chronic pancreatitis is reasonably eliminated, proof of malignancy will exclude other rare benign diseases of the pancreas, such as TB and sarcoidosis. Furthermore, FNA cytology can usually distinguish between adenocarcinoma and other pancreatic tumors, such as neuroendocrine neoplasms and lymphomas, which carry a better prognosis.[4] 1. DelMaschio A, Vanzulli A, Sironi S, et al: Pancreatic cancer versus chronic pancreatitis: Diagnosis with CA 19-9 assessment, US, CT, and CT-guided fine-needle biopsy. Radiology 1991; 178:95-9. 2. Parsons Jr L, Palmer CH: How accurate is fine-needle biopsy in malignant neoplasia of the pancreas?. Arch Surg 1989; 124:681-3. 3. Gress F, Gottlieb K, Sherman S, et al: Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med 2001; 134:459-64. 4. Webb TH, Lillemoe KD, Pitt HA, et al: Pancreatic lymphoma. Is surgery mandatory for diagnosis or treatment?. Ann Surg 1989; 209:25-30.
  • 52. Management Pancreatic Cancer Resectable Borderline resectable Unresectable Metastases Locally AdvancedSurgery Adjuvant Chemo Staging and risk assessment
  • 53. TNM System / American Joint Committee on Cancer (AJCC) Staging of Pancreatic Cancer
  • 54. STAGING • The system was last revised in 2002, and modifications were made to better identify unresectable (T4, stages III and IV) from resectable disease (T1-3, stages I and II). • Several limitations of the staging system exist. 1. Adequate evaluation of lymph node status cannot be performed without surgical intervention; this drawback may lead to understaging of locally advanced disease in pts who are not candidates for laparotomy. 2. The margins of resection, which carry great prognostic significance, are not taken into consideration when assigning clinical stage. • Because of these and other shortcomings, the AJCC staging system has found limited clinical applicability.
  • 55. Definition of resectability according to NCCN guidelines Resectability status Arterial Venous Resectable No arterial-tumour contact [coeliac axis (CA), SMA, or CHA] No tumour contact with the SMV, or PV or <180° contact without vein contour irregularity Borderline Resectable Pancreatic head/uncinate process • Solid tumour with CHA without extension to coeliac axis or hepatic artery bifurcation allowing for safe and complete resection and reconstruction • Solid tumour contact with the SMA <180° • Presence of variant arterial anatomy (e.g. accessory right hepatic artery) and the presence and degree of tumour contact should be noted if present as it may affect surgical planning • Solid tumour contact with the SMV or PV of >180°, contact of <180° with contour irregularity of the vein or thrombosis of the vein but with suitable vessels proximal and distal to the site of involvement allowing for safe and complete resection and vein reconstruction • Solid tumour contact with IVC Borderline Resectable Pancreatic body/tail • Solid tumour contact with the CA of <180° • Solid tumour contact with the CA of >180° without involvement of the aorta and with intact and uninvolved gastroduodenal artery (some members prefer these criteria to be in the unresectable category) National Comprehensive Cancer Network. NCCN Guidelines Version 2.2015 Pancreatic Adenocarcinoma. http://www.nccn.org.
  • 56. Definition of resectability according to NCCN guidelines Resectability status Arterial Venous Unresectable • Distant metastases Pancreatic head/uncinate process • Solid tumour contact with SMA >180° • Solid tumour contact with the CA >180° • Solid tumour contact with the first jejunal SMA branch Body and tail • Solid tumour contact with the SMA and CA • Solid tumour contact with the CA and aorta Pancreatic head/uncinate process • Unreconstructible SMV/PV due to tumour involvement or occlusion (can be due to tumour or bland thrombus) • Contact with most proximal draining jejunal branch into SMV Body and tail • Unreconstructible SMV/PV due to tumour involvement or occlusion (can be due to tumour or bland thrombus) National Comprehensive Cancer Network. NCCN Guidelines Version 2.2015 Pancreatic Adenocarcinoma. http://www.nccn.org.
  • 57. Staging workup • A minimal staging workup for a pt with PC should include a physical exam, and a CT or MRI of the abdomen and pelvis.[1] • In selected cases, EUS may complement CT scanning by allowing further assessment of vascular invasion and tissue sampling. • However, CT imaging fails to correctly predict resectability in 25% to 50% of pts. In most cases, lesions missed are beyond the resolution of current radiologic imaging; they include small implants on the peritoneal surfaces of the liver, abdominal wall, stomach, intestine, or omentum. • Additionally, micrometastases only detectable by peritoneal washings are also missed. • Successful detection of such tumor dissemination depends on access to the peritoneal cavity and visual inspection, which at present can be achieved only by laparoscopy or laparotomy. • It is recommended laparoscopy for all pts with tumors in the body and tail of the pancreas (in which the frequency of unsuspected metastases approaches 50%) and for pts with tumors in the head of the pancreas >2 cm, because the yield of laparoscopy in lesions smaller than 2 cm is <10%. 1. Exocrine pancreas. In: Greene FL, Page DL, Fleming ID, et al ed. AJCC Cancer Staging Manual, New York: Springer-Verlag; 2002:157-62.
  • 58. Staging workup • Several large studies have documented the value of staging laparoscopy in the evaluation of pts with PC.[1-5] • The staging procedure consists of a simple diagnostic laparoscopy with biopsy of suspicious nodules and collection of peritoneal washings for cytologic analysis. • Peritoneal cytology results are important for staging because pts with occult metastases detected by this method have been shown to carry a prognosis similar to that of pts with M1 disease (stage IV).[6,7] 1. Bemelman WA, de Wit LT, van Delden OM, et al: Diagnostic laparoscopy combined with laparoscopic ultrasonography in staging of cancer of the pancreatic head region. Br J Surg 1995; 82:820-4. 2. Fernandez-del Castillo C, Rattner DW, Warshaw AL: Further experience with laparoscopy and peritoneal cytology in the staging of pancreatic cancer. Br J Surg 1995; 82:1127-9. 3. Jimenez RE, Warshaw AL, Rattner DW, et al: Impact of laparoscopic staging in the treatment of pancreatic cancer. Arch Surg 2000; 135:409-14. 4. John TG, Wright A, Allan PL, et al: Laparoscopy with laparoscopic ultrasonography in the TNM staging of pancreatic carcinoma. World J Surg 1999; 23:870-81. 5. Minnard EA, Conlon KC, Hoos A, et al: Laparoscopic ultrasound enhances standard laparoscopy in the staging of pancreatic cancer. Ann Surg 1998; 228:182-7. 6. Makary MA, Warshaw AL, Centeno BA, et al: Implications of peritoneal cytology for pancreatic cancer management. Arch Surg 1998; 133:361-5. 7. Merchant NB, Conlon KC, Saigo P, et al: Positive peritoneal cytology predicts unresectability of pancreatic adenocarcinoma. J Am Coll Surg 1999; 188:421-6.
  • 59. Massachusetts Gen Hospital algorithm for DX and staging of PC
  • 60. Management Pancreatic Cancer Resectable Borderline resectable Unresectable Metastases Locally AdvancedSurgery Adjuvant Chemo Staging and risk assessment
  • 61. TREATMENT: Surgical Therapy • Surgical resection is the only potentially curative RX for PC. Because of advanced disease at presentation, only about 15% to 20% of pts are candidates for pancreatectomy.[1] • The main goal of surgery is to achieve negative (R0) resection margins. 1. Li D, Xie K, Wolff R, et al: Pancreatic cancer. Lancet 2004; 363:1049-57.
  • 62. TREATMENT: Surgical Therapy • The MC operation for PC is the Whipple pancreaticoduodenectomy, which removes primarily the head of the pancreas.[1] • In the past, total pancreatectomy was advocated as a better operation for PC.[2] • However, total pancreatectomy has not been shown to improve survival when compared with the more limited pancreaticoduodenectomy, and results in exocrine insufficiency and brittle DM, which are difficult to manage.[3,4,5] • Other extensions to the standard Whipple procedure, such as addition of retroperitoneal lymphadenectomy, have shown no significant survival benefit and may result in additional morbidity (longer hospital stays, increased rates of pancreatic fistula, and higher incidence of delayed gastric emptying).[6,7,8] 1. Jimenez RE, Warshaw AL: Pancreaticoduodenectomy for pancreatic cancer: Results after Kausch-Whipple and pylorus-preserving resection. In: Beger H, Buchler M, Kozarek RA, et al ed. The pancreas: An integrated textbook of basic science, medicine and surgery, Oxford, UK: Blackwell Publishing; 2008. 2. ReMine WH, Priestley JT, Judd ES, et al: Total pancreatectomy. Ann Surg 1970; 172:595-604. 3. Brooks JR, Brooks DC, Levine JD: Total pancreatectomy for ductal cell carcinoma of the pancreas. An update. Ann Surg 1989; 209:405-10. 4. van Heerden JA, ReMine WH, Weiland LH, et al: Total pancreatectomy for ductal adenocarcinoma of the pancreas. Mayo Clinic experience. Am J Surg 1981; 142:308-11. 5. Andren-Sandberg A, Ihse I: Factors influencing survival after total pancreatectomy in patients with pancreatic cancer. Ann Surg 1983; 198:605-10. 6. Pedrazzoli S, DiCarlo V, Dionigi R, et al: Standard versus extended lymphadenectomy associated with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the pancreas: A multicenter, prospective, randomized study. Lymphadenectomy study group. Ann Surg 1998; 228:508-17. 7. Yeo CJ, Cameron JL, Sohn TA, et al: Pancreaticoduodenectomy with or without extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma: Comparison of morbidity and mortality and short-term outcome. Ann Surg 1999; 229:613-22. 8. Yeo CJ, Cameron JL, Lillemoe KD, et al: Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: Randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 2002; 236:355-66.
  • 63. Diagram of the pylorus-preserving pancreaticoduodenectomy From Jimenez RE, Fernandez-del Castillo C, Rattner DW, et al. Outcome of the pancreaticoduodenectomy with pylorus preservation or with antrectomy in the treatment of chronic pancreatitis. Ann Surg 2000; 231:293.
  • 64. TREATMENT: Surgical Therapy • In the past, PD was a/with high morbidity and mortality rates. Many contemporary large series now consistently show mortality rates of <3%, with a concomitant decrease in complications.[1-6] • Pancreatic fistula, the MC and dreaded complication after the Whipple procedure, is observed in only 5% to 10% of pts today. These changes have been attributed to the emergence of ICU, as well as advances in surgical technique, anesthesia, antibiotics, and interventional radiology. 1. Balcom JH, Rattner DW, Warshaw AL, et al: Ten-year experience with 733 pancreatic resections: Changing indications, older patients, and decreasing length of hospitalization. Arch Surg 2001; 136:391-8. 2. Buchler MW, Friess H, Wagner M, et al: Pancreatic fistula after pancreatic head resection. Br J Surg 2000; 87:883-9. 3. Kazanjian KK, Hines OJ, Eibl G, et al: Management of pancreatic fistulas after pancreaticoduodenectomy: Results in 437 consecutive patients. Arch Surg 2005; 140:849-54. 4. Mullen JT, Lee JH, Gomez HF, et al: Pancreaticoduodenectomy after placement of endobiliary metal stents. J Gastrointest Surg 2005; 9:1094-104. 5. Schmidt CM, Powell ES, Yiannoutsos CT, et al: Pancreaticoduodenectomy: A 20-year experience in 516 patients. Arch Surg 2004; 139:718-25. 6. Sohn TA, Yeo CJ, Cameron JL, et al: Resected adenocarcinoma of the pancreas—616 patients: Results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567-79.
  • 65. TREATMENT: Surgical Therapy • Ultimately, prognosis for PC remains poor, even after potentially curative SX in appropriately selected pts. • Five-year actuarial survival rates range from 10.5% to 25% and median survivals between 10.5 and 20 months.[1,2,3,4] Significant predictors of a better outcome • Tumor size <3 cm • Absence of lymph node metastases • Negative resection margins • Well-differentiated tumors • Intraoperative blood loss of <750 mL.[1-5] 1. Sohn TA, Yeo CJ, Cameron JL, et al: Resected adenocarcinoma of the pancreas—616 patients: Results, outcomes, and prognostic indicators. J Gastrointest Surg 2000; 4:567-79. 2. Geer RJ, Brennan MF: Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993; 165:68-72. 3. Benassai G, Mastrorilli M, Quarto G, et al: Survival after pancreaticoduodenectomy for ductal adenocarcinoma of the head of the pancreas. Chir Ital 2000; 52:263-70. 4. Millikan KW, Deziel DJ, Silverstein JC, et al: Prognostic factors associated with resectable adenocarcinoma of the head of the pancreas. Am Surg 1999; 65:618-23. 5. Meyer W, Jurowich C, Reichel M, et al: Pathomorphological and histological prognostic factors in curatively resected ductal adenocarcinoma of the pancreas. Surg Today 2000; 30:582-7.
  • 66. Age and pancreatectomy • Some authors have proposed a score that accurately predicts the risk of perioperative mortality in pts undergoing pancreatic resection. • This surgical outcomes analysis and research (SOAR) pancreatectomy score is calculated based on preoperative factors (http://www.umassmed.edu/surgery/toolbox/panc_mortality_custom/) [1] 1. Ragulin-Coyne E, Carroll JE, Smith JK et al. Perioperative mortality after pancreatectomy: a risk score to aid decision-making. Surgery 2012; 152(3 Suppl. 1): S120–S127.
  • 67. Preoperative biliary drainage ? [ESMO15] • A recent prospective and randomised trial demonstrated an increased complication rate a/with routine preoperative biliary drainage. [1] • However, pts in the trial had a total bilirubin level below 14 mg/dL. Therefore, the correct approach in pts with higher levels remains undefined. • If jaundice is present at DX of PC, endoscopic drainage should only be carried out preoperatively 1. In pts with active cholangitis 2. In those whom resection for cure cannot be scheduled within 2 weeks of DX 3. In those with a bilirubin level below 14 mg/dL 1. van der Gaag NA, Rauws EA, van Eijck CH et al. Preoperative biliary drainage for cancer of the head of the pancreas. N Engl J Med 2010; 362: 129–137.
  • 68. Adjuvant Chemoradiation ? / GITSG ; n 43 • From 1980 to 2000, adjuvant chemoradiation was standard of care in the US and many other countries after potentially curative PC resection. These recommendations were based on the results of a study conducted by the Gastrointestinal Tumor Study Group (GITSG) between 1974 and 1982.[1] • The study randomized 43 pts after surgery to either observation or chemoradiation. Chemoradiation consisted of 4000 cGy of external beam radiation with concurrent bolus of 5-fluorouracil (5-FU) as radiosensitizer. Median survival in the treated group was 20 months, which was significantly longer than the 11-month survival in the untreated group. However, the GITSG study was criticized for its small sample size and lack of statistical power. 1. Kalser MH, Ellenberg SS: Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985; 120:899-903. SUMMARY: Adjuvant 5-FU and radiation therapy improved survival for resected PC.
  • 69. Adjuvant Chemoradiation ?/ EORTC ; n 114 • In 1999 the results of a study by the European Organization for Research and Treatment of Cancer (EORTC) questioned the value of adjuvant chemoradiation in PC.[1] • Similar to the study design by the GITSG, the EORTC randomized pts after surgery to observation or chemoradiation (4000 cGy external beam radiation and concurrent 5-FU by continuous infusion). This time the study group was relatively large and consisted of 114 pts with PC. The median survival was 4.5 months longer in the treatment group than in the observation group (17.1 vs. 12.6 months, respectively), but this difference was not statistically significant. 1. Klinkenbijl JH, Jeekel J, Sahmoud T, et al: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: Phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999; 230:776-82. SUMMARY: Adjuvant 5-FU based Chemoradiation did not result in an improvement in overall survival.
  • 70. Adjuvant Chemo or Chemoradiation ? / ESPAC-1 trial ; n 289 • Further controversy ensued after the results of a study by the European Study Group for Pancreatic Cancer (ESPAC-1 trial) were released in 2001.[1,2] • The study had a complicated design that randomized pts after SX to 4 groups: observation, chemotherapy, chemoradiation, or chemoradiation plus chemotherapy. The results did not show a difference in median survival between pts receiving chemoradiotherapy and those who did not (15.5 vs. 16.1 months). • Even for pts with positive resection margins who are thought to be prime candidates for chemoradiation, this RX did not have a survival impact. 1. Neoptolemos JP, Dunn JA, Stocken DD, et al: Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: A randomised controlled trial. Lancet 2001; 358:1576-85. 2. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200-10. SUMMARY: Systemic chemotherapy(5-FU) improved survival but no benefit of Adj Chemoradiation.
  • 71. Adjuvant Chemo ?/ CONKO-001 trial ; n 368 • The results of the CONKO-001 trial comparing gemcitabine (1g/m2 d 1, 8, 15, q 4 weeks) for 6 mnths or to observation. [1] • The median disease-free survival was 13.4 mnths in the RX group compared with 6.7 mnths in the observation group; P < .001). • Pts randomized to adjuvant gemcitabine RX had prolonged overall survival compared with those randomized to observation alone (P = .01), with 5- year overall survival of 20.7% vs 10.4% respectively, and 10-year overall survival of 12.2% vs 7.7% . OettleH, PostS, NeuhausP, et al.Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative‐intent resection of pancreatic cancer: a randomized controlled trial. JAMA2007;297:267. SUMMARY: Adjuvant gemcitabine improves survival.
  • 72. Adjuvant Chemoradiation ?/ ESPAC-3 trial n159 • OBJECTIVE: To determine whether 5-FU or gemcitabine is superior in terms of overall survival as adjuvant RX following resection of PC. • DESIGN, SETTING, AND PTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, RCT conducted in centers in Europe, Australia, Japan, and Canada. Included in ESPAC-3 V2 were 1088 pts with pancreatic ductal adenoca who had undergone resection; pts were randomized betwn July 2000 and Jan 2007 and underwent at least 2 yrs of follow-up. • INTERVENTIONS: Pts received either 5-FU plus folinic acid (folinic acid, 20 mg/m(2), IV bolus injection, followed by 5-FU, 425 mg/m(2) IV bolus injection given 1-5 days q 28 days) (n = 551) or gemcitabine (1000 mg/m(2) IV infusion once a wk for 3 of every 4 wks) (n = 537) for 6 mnths. • MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life.
  • 73. Adjuvant Chemo ?/ ESPAC-3 trial • RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 mnths' follow-up after 753 deaths (69%). • Median survival was 23.0 (95% CI, 21.1-25.0) mnths for pts treated with 5-FU plus folinic acid and 23.6 (95% CI, 21.4-26.4) mnths for those treated with gemcitabine [95% CI, 0.81-1.08]). • 77 pts (14%) receiving 5-FU plus folinic acid had 97 treatment-related serious adverse events, compared with 40 pts (7.5%) receiving gemcitabine, who had 52 events (P < .001). • There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. • CONCLUSION: Compared with the use of 5-FU plus folinic acid, gemcitabine did not result in improved overall survival in pts with completely resected PC. SUMMARY: No difference between adjuvant 5-FU and adj gemcitabine NeoptolemosJP, StockenDD, BassiC, et al.Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA2010;304:1073.
  • 74. Adjuvant Chemo+Chemoradiation ?/(ACOSOG) 5031 & CapRI-2 • More recently, the role of adjuvant chemoradiation given with an aggressive combination of 5-FU/cisplatin and α-interferon was evaluated in a phase II trial by the American College of Surgeons Oncology Group (ACOSOG) 5031, as well as a small randomized phase II trial, CapRI-2. [1] • Both of these studies found this regimen to be a/with marked toxicity; grade 3/4 toxicity was 95 and 85%, respectively. • Unfortunately, while median survivals were better than expected in the CapRI-2 study, the 28-mnth median survival of the experimental arm was essentially identical to that observed in the much less toxic control arm of 5-FU and 5-FU chemoradiation. 1. PicozziVJ, AbramsRA, DeckerPA, et al.Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5‐fluorouracil, and interferon‐alfa‐2b‐based chemoradiation: ACOSOG Trial Z05031. Ann Oncol2011;22:348. SUMMARY: Addition of Cisplatin, IFN a and XRT did not improve survival compared to 5-FU alone.
  • 75. Superior Chemo ?/ (JASPAC)-01;n378 • The Japanese Adjuvant Study of Pancreatic Cancer (JASPAC)-01 study compared the oral fluoropyrimidine S-1 to gemcitabine. [1] • Surprisingly, S-1 was superior to gemcitabine with a HR for survival of 0.56, and a 2-yr survival of 70%, compared to 53% for gemcitabine arm. • S-1 has increased toxicity in Caucasians as compared to Asians and thus is not approved in the US or Europe at present. 1. MaedaA, BokuN, FukutomiA, et al.Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S‐1 in patients with resected pancreatic cancer: Japan Adjuvant Study Group of Pancreatic Cancer (JASPAC‐01). Jpn J Clin Oncol2008;38:227. SUMMARY: S-1 improved survival compared to gemcitabine.
  • 76. Adjuvant Chemo Vs Combination Chemo?/ The ESPAC-4 trial • Background The ESPAC-3 trial showed that adj gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-FU/folinic acid in pts with resected PC. • Aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected PC. • Methods A phase 3, open-label, multicentre, RCT at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible pts had undergone complete macroscopic resection for ductal adenoca of the pancreas (R0 or R1 resection). Randomly assigned pts (1:1) within 12 weeks of surgery to receive 6 cycles of either 1000 mg/m² gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m² oral capecitabine administered for 21 days followed by 7 days’ rest (one cycle). • The primary endpoint was overall survival, measured as the time from randomisation until death from any cause.
  • 77. Adjuvant Chemo Vs Combination Chemo?/ The ESPAC-4 trial • Findings Of 732 pts enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. • The median OS for pts in the gemcitabine plus capecitabine group was 28·0 mnths (95% CI 23·5–31·5) compared with 25·5 mnths (22·7–27·9) in the gemcitabine group (HR0·82 [95% CI 0·68–0·98], p=0·032). Neoptolemos et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. The Lancet. Volume 389, No. 10073, p1011–1024, 11 March 2017 Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.
  • 78. Phase III adjuvant trials in pancreatic cancer.
  • 79. Recommendations for RX of localised disease • A multidisciplinary team is necessary. • Tumour clearance should be given for all seven margins identified by the surgeon . • Standard lymphadenectomy should involve the removal of ≥15 lymph nodes to allow adequate pathologic staging of the disease . • Adjuvant treatment is done with either gemcitabine or 5-FU folinic acid. • No chemoradiation should be given to pts after SX except in clinical trials. ESMO15
  • 80. Management Pancreatic Cancer Resectable Borderline resectable Unresectable Metastases Locally AdvancedSurgery Adjuvant Chemo Staging and risk assessment No Adj Chemoradiation Whipple ‘s PD Combination of gemcitabine and capecitabine
  • 81. Neoadjuvant therapy ? • Building on the experience in other disease sites, neoadjuvant strategies have been explored since the 1990s. • The rationale for neoadjuvant therapy includes the hypothetical benefit of the early RX of occult micrometastatic disease, the ability to deliver therapy to a more well-vascularized tumor, and the opportunity to assess therapeutic activity in vivo. • Although adjuvant therapy has been a/with a survival benefit for PC pts, in general the results have been disappointing, showing very modest clinical benefit and little progress beyond survival achieved in the very first Gastrointestinal Tumor Study Group (GITSG) trial. • Unfortunately, no randomized comparisons of the neo- and adjuvant strategies have been performed to date.
  • 82. Borderline resectable lesions • Tumours are considered resectable upon good response to neoadjuvant RX including induction chemotherapy, preoperative chemoradiation or a combination of both. • While the heterogeneity of the trials on neoadjuvant therapy in borderline resectable PC limits the power of any conclusion, many individual series demonstrate improved R0 resection rates and promising survival rates. • The majority of studies used full-dose radiotherapy paired either with capecitabine, 5-FU or reduced doses of gemcitabine, or even a combination of gemcitabine plus oxaliplatin. • It is impossible at this time to recommend any chemoradiation RX other than the classical combination of capecitabine and radiotherapy.
  • 83. Borderline resectable lesions • Recent chemotherapy regimens, such as FOLFIRINOX [folinic acid (leucovorin)/5- FU/irinotecan/ oxaliplatin], have already shown promising results in small series of pts with borderline resectable lesions [30%–45% of objective response rate (ORR)]. • A trial, which was stopped prematurely, reported interesting response rates, median progression-free survival (PFS) and OS for pts treated with chemotherapy (gemcitabine) followed by chemoradiation (gemcitabine, 5-FU, cisplatin) versus chemoradiation alone. [1] • However, this small trial does not allow any definite conclusions to be drawn. • Pts with borderline resectable lesions should be included in clinical trials wherever possible. If this is not feasible, a period of chemotherapy followed by chemoradiation and then surgery appears to be the best option. 1. Landry J, Catalano PJ, Staley C et al. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol 2010; 101: 587–592.
  • 84. Recommendations for RX of borderline resectable disease [ESMO15] • Pts with borderline resectable lesions should be included in clinical trials wherever possible. • In routine practice, if the pt is not included in a trial, a period of chemotherapy (gemcitabine or FOLFIRINOX) followed by chemoradiation and then surgery appears to be the best option.
  • 85. Management Pancreatic Cancer Resectable Borderline resectable Unresectable Metastases Locally AdvancedSurgery Adjuvant Chemo Staging and risk assessment chemotherapy (gemcitabine or FOLFIRINOX) followed by chemoradiation and then surgery Include in clinical trial
  • 86. Locally advanced disease • When the pt has no metastases and the tumour is not considered as borderline resectable, the tumour is defined as truly locally advanced . • Treatment of this group of pts remains highly controversial. Regardless of the RX strategy, the average OS for these pts remains low (<1 year) in the oldest studies. • However, in the recent LAP07 trial [1], which included only pts with locally advanced disease the overall median survival of the pts RX with chemotherapy alone was 16 months. 1. Hammel P, Huguet F, Van Laethem J-L et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin Oncol 2013;31(suppl):abstr LBA4003. Chemotherapy
  • 87. Locally advanced disease • Concerning the comparison with chemotherapy alone, while poor-quality randomised trials have suggested a benefit in favour of chemoradiation, two recent trials showed opposite results. • In a French trial using an obsolete regimen of chemoradiation (50 Gy + 5-FU /cisplatin), the survival was better in the gemcitabine alone arm (13 versus 8.6 months [1]). • In another trial, comparing chemoradiation with gemcitabine versus gemcitabine alone, the OS was significantly improved in the chemoradiation arm (11.1 versus 9.2 months) yet toxicity also increased by combining the RX modalities. [2] 1. Chauffert B, Mornex F, Bonnetain F et al. Phase III trial comparing initial chemoradiotherapy (intermittent cisplatin and infusional 5-FU) followed by gemcitabine vs. gemcitabine alone in patients with locally advanced nonmetastatic pancreatic cancer: a FFCD-SFRO study. J Clin Oncol 2006; 24(suppl):abstr 4008. 2. Loehrer PJ, Sr, Feng Y, Cardenes H et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011; 29: 4105–4112. Chemotherapy Vs Chemoradiation ?
  • 88. • While many trials have evaluated the best combined regimen of chemotherapy and radiotherapy, no clear definition has been made of a standard of care. • However, evidence from one randomised trial favoured capecitabine as less toxic and more active than gemcitabine in this setting (SCALOP trial). [1] 1. Mukherjee S, Hurt CN, Bridgewater J et al. Gemcitabine-based or capecitabinebased chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol 2013; 14: 317–326. Chemotherapy; Capecitabine vs Gemcitabine ??
  • 89. • No clear advantage in favour of the chemoradiation was found in a recent large randomised trial investigating this strategy. This trial was planned to include 722 pts, and was stopped for futility after the inclusion of 449 pts (only 269 assessable for the main end point, OS). They were treated with 4 months of gemcitabine ±erlotinib (first randomisation) and then randomised to receive either two supplementary months of gemcitabine or chemoradiation. [1] • The median OS showed no improvement in the chemoradiation group (15.2 versus 16.4 months) even though local tumour control did seem a little bit better in this group. • Several small retrospective and prospective studies have suggested that FOLFIRINOX may be able to obtain an interesting response rate in this population, and may have rendered some pts with locally advanced cancers resectable. However, it is too early to recommend this RX and trials are ongoing. • Thus, the standard of care for these pts currently remains as 6 months of gemcitabine 1. Hammel P, Huguet F, Van Laethem J-L et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin Oncol 2013;31(suppl):abstr LBA4003. Chemoradiation ?
  • 90. Recommendations for RX of locally advanced disease • The standard of care is 6 months of gemcitabine . • A minor role of chemoradiation in this subgroup of pts has been observed. • It is impossible to recommend any chemoradiation RX other than the classical combination of capecitabine and radiotherapy. ESMO15
  • 91. Management Pancreatic Cancer Resectable Borderline resectable Unresectable Metastases Surgery Adjuvant Chemo Staging and risk assessment capecitabine and radiotherapy ? 6 months of gemcitabine Locally Advanced
  • 92. Treatment of advanced/metastatic disease Palliative and supportive care • Before even considering systemic chemotherapy, pts with metastatic PC may need interventions to provide relief of biliary and/or duodenal obstruction, malnutrition, and pain.
  • 93. Palliative Procedures: Jaundice • Relief of jaundice can also be achieved by biliary stents placed percutaneously or endoscopically. Because these procedures are usually well tolerated and perfomed on an outpatient basis, they have become increasingly popular in the MX of malignant biliary obstruction. • In experienced hands, endoscopic stent placement has a success rate of more than 85%, with a 1% to 2% procedure-related mortality. • Several randomized trials have demonstrated no difference in survival between pts palliated endoscopically versus surgically for obstructive jaundice.[1,2] 1. Shepherd HA, Royle G, Ross AP, et al: Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: A randomized trial. Br J Surg 1988; 75:1166-8. 2. Smith AC, Dowsett JF, Russell RC, et al: Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet 1994; 344:1655-60. 3. Stark A, Hines OJ. Endoscopic and operative palliation strategies for pancreatic ductal adenocarcinoma. Semin Oncol 2015; 42: 163–176. In the event of a biliary obstruction due to a pancreatic tumour, the endoscopic placement of a metallic biliary stent is strongly recommended. The endoscopic method is safer than percutaneous insertion and is as successful as surgical hepatojejunostomy. [3] Duodenal obstruction is preferentially managed by endoscopic placement of an expandable metal stent when possible, and is favoured over surgery [3]
  • 94. Palliative Procedures: Stents • Two types of biliary stents are available: Plastic and self-expandable metallic stents. • The plastic stents are preferred for short-term use, and require exchange Q 3 mnths to prevent complications from stent occlusion or cholangitis. • The metallic self-expandable stents (Wallstent) have improved long-term patency rates when compared with plastic stents, and are preferred for long-term application.[1,2] • In clinical practice, plastic stents are preferred for pts who are surgical candidates, whereas metal stents are used for unresectable pts. 1. Kaassis M, Boyer J, Dumas R, et al: Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003; 57:178-82. 2. Soderlund C, Linder S: Covered metal versus plastic stents for malignant common bile duct stenosis: A prospective, randomized, controlled trial. Gastrointest Endosc 2006; 63:986-95.
  • 95. Palliative Procedures: Pain • Pain in PC can be extremely distressing and may respond poorly to oral narcotics. • Percutaneous or surgical chemical neurolysis with alcohol is an alternative palliative measure that can help in controlling pain or decreasing narcotic use. EUS can be used for this purpose as well. • Randomized trials have shown that neurolysis of the celiac ganglion can offer relief to many pts.[1,2] • Lastly, radiation therapy may also be used for pain MX in selected pts. 1. Lillemoe KD, Cameron JL, Kaufman HS, et al: Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 1993; 217:447-55. 2. Polati E, Finco G, Gottin L, et al: Prospective randomized double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer. Br J Surg 1998; 85:199-201.
  • 96. Chemotherapy for Metastatic Disease • Chemotherapy in this situation is never curative, and its palliative benefit must be balanced against its potential toxic side effects. • Assessment of tumor response to CT is based primarily on serial imaging studies, serum marker (CA 19-9) trends, and changes in tumor-related symptoms. • Only two chemotherapy agents have been a/with survivals longer than 5 mnths in PC: 5-FU and gemcitabine. • Up until the mid-1990s, 5-FU was the DOC for RX of advanced or metastatic PC. Monotherapy with 5-FU has a poor objective response rate (0% to 10%) and an average median survival of about 5 mnths.[1] • Combination chemotherapy regimens containing 5-FU have increased objective response rates (15% to 40%) but have failed to show a survival advantage in randomized trials.[2,3,4,5] 1. Ahlgren JD: Chemotherapy for pancreatic carcinoma. Cancer 1996; 78:654-63. 2. Phase II studies of drug combinations in advanced pancreatic carcinoma: Fluorouracil plus doxorubicin plus mitomycin C and two regimens of streptozotocin plus mitomycin C plus fluorouracil. The Gastrointestinal Tumor Study Group. J Clin Oncol 1986; 4:1794-8. 3. Cullinan S, Moertel CG, Wieand HS, et al: A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 1990; 65:2207-12. 4. Cullinan SA, Moertel CG, Fleming TR, et al: A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 1985; 253:2061-7. 5. Oster MW, Gray R, Panasci L, et al: Chemotherapy for advanced pancreatic cancer. A comparison of 5-fluorouracil, adriamycin, and mitomycin (FAM) with 5-fluorouracil, streptozotocin, and mitomycin (FSM). Cancer 1986; 57:29-33.
  • 97. 5FU OR Gemcitabine ? • Gemcitabine is thought to interfere with DNA synthesis and repair. A well-known randomized trial by Burris and colleagues compared weekly gemcitabine to weekly 5-FU infusion in previously untreated pts.[1] • Pts treated with gemcitabine had a slightly improved median survival compared with those treated with 5-FU (5.6 vs. 4.4 months, respectively). An impressive one-year survival advantage was also noted for the gemcitabine arm (18% vs. 2%, respectively). • Importantly, improvement in disease-related signs and symptoms (pain, performance status, weight loss) were more likely in the gemcitabine group (23.8%) than in the 5-FU group (4.8%). • Gemcitabine has been shown to have clinical benefit even in pts for whom 5-FU treatment has failed.[2] 1. Burris III HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997; 15:2403-13. 2. Rothenberg ML, Moore MJ, Cripps MC, et al: A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996; 7:347-53. Gemcitabine
  • 98. Gemcitabine ; single agent or in combination? • On the basis of the results of these studies, gemcitabine is currently the standard of care for pts with metastatic PC. • However, single-agent gemcitabine RX is a/with poor objective response rates (5.4%).[1] In an attempt to improve response rates and survival, multiple gemcitabine-based combination chemotherapy regimens have been developed. • In these protocols, gemcitabine has been coupled with either cisplatin, fluorouracil, irinotecan, oxaliplatin, pemetrexed, or exatecan.[2-7] Objective response rates have shown improvement with combination therapy, but this improvement has not translated into a survival benefit. 1. Burris III HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997; 15:2403-13. 2. Abou-Alfa GK, Letourneau R, Harker G, et al: Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J Clin Oncol 2006; 24:4441-7. 3. Berlin JD, Catalano P, Thomas JP, et al: Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol 2002; 20:3270-5. 4. Heinemann V, Quietzsch D, Gieseler F, et al: Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 2006; 24:3946-52. 5. Louvet C, Labianca R, Hammel P, et al: Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005; 23:3509-16. 6. Oettle H, Richards D, Ramanathan RK, et al: A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16:1639-45. 7. Rocha Lima CM, Green MR, Rotche R, et al: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004; 22:3776-83.
  • 99. Gemcitabine ; single agent or in combination? • Three separate meta-analyses [1] reported a statistically significant survival advantage of combination therapy compared with gemcitabine alone. • Capecitabine and cisplatin-based combinations have produced the greatest benefit. However, due to the low level of evidence, there have been no clear changes in the daily clinical MX of these pts. • Even with modern agents such as tyrosine kinase inhibitors or monoclonal antibodies against various targets, the results of large phase III trials evaluating the addition of these drugs to gemcitabine have been disappointing. The targeted therapies tested have included bevacizumab, cetuximab, aflibercept, and anti- insulin growth factor agents. • The exception is the combination of gemcitabine and the EGFR TKI erlotinib, which gained regulatory approval following a 12-day improvement in median survival compared with gemcitabine alone in a large randomised trial. [2] • Arguably, however, this duration of survival prolongation is clinically irrelevant for most pts; therefore, erlotinib has not been widely used in this disease. 1. Ciliberto D, Botta C, Correale P et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013; 49: 593–603. 2. Moore MJ, Goldstein D, Hamm J et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960–1966. 3. Hammel P, Huguet F, Van Laethem J-L et al. Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. J Clin Oncol 2013;31(suppl): abstr LBA4003.
  • 100. Gemcitabine Vs FOLFIRINOX? • Major improvements in the RX of metastatic disease came with the demonstration of the efficacy of a 5-FU-based triplet chemotherapy. The FOLFIRINOX regimen has proven superior to gemcitabine alone, in terms of efficacy. [1] • This trial included pts who were selected based on their ability to receive this aggressive chemotherapy [Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1]. • The median OS was 11.1 months in the FOLFIRINOX group compared with 6.8 months in the gemcitabine group [HR for death, 0.57; 95% CI 0.45–0.73; P < 0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of pts in this group had febrile neutropaenia. • FOLFIRINOX is an option for the RX of pts with metastatic PC and good performance status. 1. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364: 1817–1825. FOLFIRINOX
  • 101. Gemcitabine + paclitaxel Vs Gemcitabine? • After decades of failed randomised trials that have tried to add a drug to gemcitabine alone, a recent trial has shown positive results, demonstrating that the combination of gemcitabine plus nab-paclitaxel is better than gemcitabine alone in metastatic pts. [1] • A total of 861 pts were randomly assigned to receive nab-paclitaxel plus gemcitabine or gemcitabine alone. The median OS was 8.5 months in the nab-paclitaxel–gemcitabine group compared with 6.7 months in the gemcitabine group (HR for death, 0.72). 1. Von Hoff DD, Goldstein D, Renschler MF. Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer. N Engl J Med 2014; 370: 479–480. Gemcitabine + paclitaxel
  • 102. • There are no data concerning a direct comparison of FOLFIRINOX and Gem-nab-paclitaxel. • An indirect comparison of the two regimens may suggest a slightly greater activity but also higher toxicity of FOLFIRINOX. • No specific data favours the use of one regimen over the other in a defined subgroup of pts. • Thus, either of these two options can be offered to pts with serum bilirubin levels <1.5× ULN and good PS (ECOG 0-1) The efficacy of the RX has to be evaluated every 2 months with a comparative CT scan. The treatment has to be stopped if a RECIST progression is observed and second-line RX has to be discussed.
  • 103. Management algorithm [ESMO 15] Gemcitabine alone PS 3-4 or Comorbidites PS2 and/or Bilirubin> 1.5 x ULN PS 0 or 1 Best Supportive care Gemcitabine + nab-paclitaxel FOLFIRINOX Metastatic Pancreatic cancer
  • 104. Recommendations for oncological RX of advanced/ metastatic disease [ESMO15] • If the performance status is 3/4, with significant morbidities and a very short life expectancy: only symptomatic treatment can be considered. • In very selected pts with ECOG PS 2 due to heavy tumour load, gemcitabine and nab-paclitaxel can be considered for best chance of response . • If the PS of the pt is 2 and/or the bilirubin level is >1.5× ULN: a monotherapy with gemcitabine should be considered. • If the PS of the pt is 0 or 1 and the bilirubin level<1.5× ULN two types of combination chemotherapy—the FOLFIRINOX regimen or the combination of gemcitabine and nab-paclitaxel—should be considered.
  • 105. Second-line treatment • A first randomised trial (168 pts) has shown, in pts with advanced gemcitabine-refractory PC, that second-line 5-FU, folinic acid and oxaliplatin, significantly extend the duration of OS when compared with 5- FU, folinic acid alone.[1] • These results have not been confirmed by a more recent Canadian trial. [2] • Very recently, combination of irinotecan, and 5-FU, folinic acid has shown an improvement of OS (6.1 versus 4.2 months), over 5-FU/LV alone. 1. Oettle H, Riess H, Stieler JM et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol 2014; 32: 2423–2429. 2. Ciliberto D, Botta C, Correale P et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2013; 49: 593–603. Irinotecan, and 5-FU, folinic acid
  • 106. Targeted Therapeutic Agents in Pancreatic Cancer • Poor results with conventional chemotherapy have led to ongoing development of novel agents against PC. These new agents are designed to target specific cellular pathways involved in tumor progression. • Examples include inhibitors of farnesyltransferase, epidermal growth factor receptor, and matrix metalloproteinases.[1,2] • These new biological agents show impressive results in both in vitro and animal studies.[3] • However, efficacy in human trials has been more difficult to demonstrate.[4,5] 1. Van Cutsem E, van de Velde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004; 22:1430-8. 2. Bramhall SR, Schulz J, Nemunaitis J, et al: A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87:161-7. 3. Jimenez RE, Hartwig W, Antoniu BA, et al: Effect of matrix metalloproteinase inhibition on pancreatic cancer invasion and metastasis: An additive strategy for cancer control. Ann Surg 2000; 231:644-54. 4. Moore MJ, Hamm J, Dancey J, et al: Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003; 21:3296-302. 5. Bramhall SR, Rosemurgy A, Brown PD, et al: Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J Clin Oncol 2001; 19:3447-55.
  • 107. Biomarker correlatives and future trial design • Molecular subtypes of PC have been identified with varying responses to chemotherapy. [1] • Recent formation of a pancreatic biomarker compendium represents advances in identifying biomarkers for PC in a global and systematic fashion. [2] • One such biomarker, human equilibrative transporter 1 (hENT1), thought to partly mediate cellular entry of cytotoxic chemotherapy, has been suggested as having a role as a predictive biomarker in PC pts treated with gemcitabine. [3–5] • In a recent retrospective review of the ESPAC study, high hENT1 immunohistochemistry expression was a/with improved survival with gemcitabine, with low hENT1 linked to improved survival with 5-FU rather than gemcitabine. [6] • Presently, the use of molecular profiling to direct pt care has not been incorporated into RX guidelines. 1. CollissonEA, SadanandamA, OlsonP, et al.Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med2011;17:500. 2. HarshaHC, KandasamyK, RanganathanP, et al.A compendium of potential biomarkers of pancreatic cancer. PLoS Med2009;6:e1000046. 3. GiovannettiE, Del TaccaM, MeyV, et al.Transcription analysis of human equilibrative nucleoside transporter‐1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res2006;66:3928. 4. FarrellJJ, ElsalehH, GarciaM, et al.Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology2009;136:187. 5. KimR, TanA, LaiKK, et al.Prognostic roles of human equilibrative transporter 1 (hENT‐1) and ribonucleoside reductase subunit M1 (RRM1) in resected pancreatic cancer. Cancer2011;117:3126. 6. NeoptolemosJP. HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5‐FU on the ESPAC trials. J Clin Oncol2013;31:abstract 4006.
  • 108. Cancer cachexia • Cancer cachexia is a universal feature of advanced PC. The majority of weight loss is secondary to the still poorly understood paraneoplastic effects of the tumor on metabolism and calorie utilization. • Agents targeting various cytokines such as interleukin-1α (IL-1α), thought to contribute to cachexia are now being evaluated. [1] • For PC pts, pancreatic enzyme supplementation should be provided . • Pancreatic exocrine insufficiency is a result of the loss of pancreatic parenchyma, pancreatic ductal obstruction, decreased pancreatic stimulation, or acid-medicated inactivation of pancreatic enzymes. Clinical manifestations are abdominal cramps, bloating, steatorrhea, and malnutrition with resultant weight loss. Fecal fat quantification and 13C-triglyceride breath test, are diagnostic. • Oral administration of exogenous pancreatic enzymes is considered standard therapy . [2] • Currently available appetite stimulants such as dronabinol and Megace are generally relatively ineffective and/or a/with ↑ risk of hyperglycemia and thromboembolic events. 1. trials.gov C.2013. Available from: http://www.cancer.gov/clinicaltrials/search/view?cdrid=745198&version=HealthProfessional&protocolsearchid=8182450. 2. Dominguez‐MunozJE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol2011;26:12.
  • 109. END OF SLIDES References: 1. Sleisenger 2. ESMO 2015 guideline on Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up 3. Yamada Textbook of gastroenterology ,6th ed

Editor's Notes

  1. In medicine, a response rate is the percentage of patients whose cancer shrinks or disappears after treatment. The FDA definition of ORR is "the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period.