Pancreatic Cancer

Epidemiology

  • Fatal Malignancy
  • 5th leading cause of cancer mortality
  • With all new therapies only very modest benefit in survival achieved
  • Worldwide incidence varies considerably
  • USA ; 9 / 100,000 whites and 15.2 / 100,000 blacks
  • Ratio male-female is 1.3:1
  • Most pateints >60yr

Etiology

  • Chronic pancreatitis
  • Hereditary
    • About 10% of pancreatic ca cases → familial
    • Estimated cumulative risk to age 70: 40 %
    • If paternal pattern of inheritance risk increase to 75
    • Screening recommended to start at age 35
  • Non Hereditary
    • Cumulative risk of 2 % / decade
  • Premalignant lesions:
    • Intraductal papillary mucinous tumor (IPMT)
      • Commonly confused with chronic pancreatitis
      • Characterized by dilation of the main pancreatic duct or branch ducts associated with mucin overproduction
      • Incidence of invasive cancer at surgery is 25 to 50 %
      • Considered premalignant⇒surgery is treatment of choice
    • Mucinous Cystic Neoplasm
      • invasive carcinoma in 36% and 29% of resected specimens
      • All MCN must be considered malignant or premalignant
      • Prognosis for patients with completely resected MCN without invasive carcinoma is excellent.
      • In contrast, the prognosis of patients with invasive mucinous cystadenocarcinoma is grim, with long-term survival rates paralleling those of patients with invasive ductal adenocarcinoma.
    • Pancreatic intraepithelial neoplasias (PanINs)
      • Proliferation of small pancreatic ducts
      • Commonly observed in the resection specimens of patients with ductal adenocarcinoma .
      • As PanINs progress, they accumulate the genetic changes similar to those commonly observed in pancreatic adenocarcinomas.
      • Accepted as “precursor” lesions to ductal adenocarcinoma.
  • Diabetes Mellitus
    • Present in 60 to 80 % of patients with pancreatic Ca
    • Risk is unkown→estimated RR 2.1 (cohort study)
  • Genetic
    • 7 % have positive family history→Familial aggregation RR ~ 5
    • Risk increased in some familial syndrome
      • Peutz-Jeghers syndrome
      • Von Hippel-Lindau syndrome
      • FAP (familial adenomatous polyposis) → RR 4.5
      • Familial atypical multiple mole melanoma syndrome
      • Ataxia-telangiectasia
      • BRCA2
  • Environmental
    • Cigarette smoking (strongest association )
    • Obesity
    • Lack of physical activity
    • 2-Naphtylamine, Benzidine, Gasoline derivatives
    • Diet
      • Cooked meat (particularly smoked or processed meats and fish ) ↑ risk
      • Fuits and vegetables ↓ risk
      • Coffee and alcohol —> conflicting data
  • Iatrogenic
    • History of partial gatrectomy or cholecystectomy

Molecular Biology

  • Similarities to that of colorectal adenocarcinoma
  • regression from normal to neoplastic change
  • Multiple combinations of genetic mutations are commonly found
  • Diploid vs Aneuploid
    • Median survival of 30.1m vs 16m

Anatomy

  • Lying transversely and retroperitoneally in posterior abdomen at ~ L1 and L2 level
  • Head of pancreas lies in duodenal flexure on the right
  • Tail extend to the spleen
  • Close contact with spleen, stomach, duodenum, jejunum, kidneys
  • Divided into: ( most cancers come from head and body —> 80%)
    1. Head and Unciate (considered to be part of the head)
    2. body
    3. Tail
  • The pancreas has two functional components: exocrine and endocrine
    • The exocrine pancreas contains acini —> secrete a variety of enzymes; The main pancreatic duct opens at the duodenal papilla and in 70% of patients joins with the terminal common bile duct at the ampulla of Vater. An accessory (minor) pancreatic duct usually opens independently into the duodenum proximal to the papilla
    • The endocrine pancreas is composed of the islets of Langerhans, distributed throughout the pancreas with a maximum density in the tail and containing several different hormone-producing cell types

Lymphatic Drainage

  • A rich lymphatic network surrounds the pancreas
  • Hepatic artery, the celiac axis, and the pyloric and splenic regions

Pathology

  • Adenocarcinoma ( 75-90% of cases )
    • Twice as common in head
  • Cystadenocarcinoma
    • More in women
    • More indolent
    • Remains localized for years
  • Intraductal Ca
  • Solid and cystic papillary neoplasm
  • Acinar cell ca
  • Giant cell tumour

Clinical Presentation

At the time of diagnosis:

  • 20% —> resectable tumor
  • 30% —> locally advanced, unresectable, but nonmetastatic tumor
  • 50% —> metastatic disease

History

  • Classic trial
    • Jaundice →often accompanied by pruritus, acholic stools, and dark urine
    • Weight loss→ may be associated with anorexia, early satiety, diarrhea, or steatorrhea
    • Abdominal pain(85 %) → radiates to the back
  • New-onset Diabetes-Mellitus

Physical Examination

  • Courvoisier sign in 25 %

‫*‬ Enlarged, painless gallbladder + mild jaundice

  • Abdominal mass or ascites in 20 %
  • Palpable gallbladder
  • Trousseau’s syndrome (migratory superficial phlebitis)
  • Ascites
  • Virchow’s node (left supraclavicular LN) —> same as in Gastric Ca
  • Periumbilical mass (Sister Mary Joseph’s node) —> Same as in Gastric Ca
  • Palpable pelvic shelf on rectal examination (Blumer’s shelf) —> Same as in Gastric Ca

Lab work/ investigations

  • Blood work
  • Imaging
    • CT-Contrast Abdomen
    • Endoscopic US
    • ERCP
      • Biopsy
      • Decompress biliary tree

How do we know a tumour is resectable by surgery ( RESECTABLITY )

  • Contrast-enhanced helical CT scan with timed image sequences that permit evaluation of vascular structures and subtle metastatic implants
Crietria of unresectability
  • Extrapancreatic involvement
  • Distant metastases → No role for resection of primary tumour
  • Encasement or occlusion or involvement of major vessels such as
    • Superior mesenteric vein
    • Superior mesenteric artery
    • Inferior vena cava
    • Aorta
    • Celiac axis

Treatment

  • Surgical Resection is the modality of choice
    • Standard pancreaticoduodenectomy called the "Whipple procedure".
  • Absolute contra-indication to surgery:
    • Presence of metastases
  • Relative contra-indication to surgey:
    • Tumor in the tail of pancreas
      • Tumours in tail do not cause obstruction of the intrapancreatic portion of the common bile duct, ⇒ early diagnosis is rare ⇒ vast majority have locally advanced or metastatic disease at the time of presentation

Overview of Treatment

  • Resectable pancreatic cancer
    • Surgery
    • Curative resection is possible in only 15 – 20% of pts
    • Standard pancreatojejunostomy in resectable patient
    • Most common surgery performed is the Whipple procedure

Whipple Procedure:

  • Removal of:
    • Distal half of the stomach (antrectomy)
  • Gallbladder and its cystic duct (cholecystectomy)
  • Common bile duct (choledochectomy)
  • Head of the pancreas
  • Duodenum
  • Proximal jejunum
  • Regional LN.
  • Reconstruction:
    • Attaching the pancreas to the jejunum (pancreaticojejunostomy)
    • Attaching the hepatic duct to the jejunum (hepaticojejunostomy)
    • Attaching the stomach to the jejunum (gastrojejunostomy)

Results:

  • 5 yrs. OS —> 10 to 25 %
  • Most important prognostic factor is nodal status
  • Other prognostic factor for favorable outcome:
    • Tumor size < 3 cm
    • Negative margins
    • Well-differentiated

Role of adjuvant treatment post surgery

  • The rationale of combined modality treatment is that 50 % of patients will develop locoregional failure without evidence of distant metastases

Despite the publication of several randomized trials evaluating postoperative combined chemoradiotherapy or a combination of preoperative plus postoperative treatment in patients with resected pancreatic cancer, its benefit remains unclear.

Options for adjuvant treatment after surgical resection:

  • Radiotherapy alone
  • Chemotherapy alone ( Gemcitabine )
  • ChemoRT
    • Multiple prospective randomized
    • Conflicting data
    • mostly 5FU based
    • GITSG
      • split RT ( x2, 20Gy )
      • 5FU bolus 500mg/m2 in first 3days of RT
      • Poor accrual
        • Only 49
      • Shower better OS
        • 2-yr OS —> 42% vs 15%, 5-yr OS —> 19% vs 5%
        • LR on total —> 30-50%
          • poor RT dose/fractionation(?)
    • EORTC
      • 218 pts with periampullary ca
      • Sx vs Sx+ChemoRT
        • post-op RT (40 Gy in split-course fashion over 6 weeks)+5FU continuous infusion
      • ONLY 114 patients had —> pancreatic adenocarcinoma
        • In this group —> Median survival
          • 17.1 months versus 12.6
      • Total patients:
        • 2-yr OS —> 37% vs 23%, 5-yr OS —> 20% vs 10% (p = .099).
        • No differences in LR
          • ~33%
      • Comments on EORTC Periampullary trial
        • T3 were excluded
        • Pathologic basis for distinguishing between pancreatic and nonpancreatic periampullary lesions was not made clear
        • Adequacy of the retroperitoneal margin was not independently assessed
        • 20% of patients assigned to the chemoradiation trial arm never received that treatment
        • two-sided log-rank test, instead of one-sided test
        • Not sufficient patient numbers
    • ESPAC-1 study
      • Complex design (three separate but concurrent phase III trials)
      • 541 patients with grossly resected pancreas cancer
      • Randomization with a 2 × 2 factorial design:
        1. observation
        2. concomitant chemoradiation alone(20 Gy/10 over 2 wks + 500 mg/m2 5-FU IV bolus during the first 3 days of RT followed by no additional chemotherapy
        3. chemotherapy alone (leucovorin 20 mg/m2 bolus followed by 5-FU 425 mg/m2 administered for 5 consecutive days repeated every 28 days for six cycles)
        4. chemoradiation followed by six cycles of adjuvant 5-FU/leucovorin.
      • Background therapy was allowed before patients
      • Survival advantage for adjuvant chemotherapy
    • Issues
      • More than one randomization scheme
      • “background” therapy in addition to protocol
      • Patients did not have their disease restaged after resection and before adjuvant therapy
      • No quality assurance guidelines for RT
      • Varying patient populations
  • RTOG 97-04
    • Randomized phase III trial
    • Whether gemcitabine before and after 5-FUis better than 5-FU before and after 5-FU–based chemoradiation
    • Gemcitabine group superior
    • Grade 4 neutropenia rate was higher in the gemcitabine arm
      • No difference in febrile neutropenia

Locally advanced pancreatic cancer (unresectable) (30% of cases at presentation)

  • Chemoradiotherapy vs RT alone
  • Chemradiotherapy vs supportive care
  • Chemoradiotherapy vs chemo alone

Complications of Treatment:

  • Radiation
    • Nausea
    • Vomiting
    • Rarely any skin irritation
    • Fatigue
  • Chemotherapy/Gemcitabine
    • Gemcitabine is a nucleoside
    • Attaches to DNA and stops tumour growth
    • IV injection
  • More common side effects( > 30% ) :
    • Flu-like symptoms(muscle pain, fever, headache, chills, fatigue)
    • Fever (within 6–12 hours of first dose)
    • Fatigue
    • Nausea (mild)
    • Vomiting
    • Poor appetite
    • Skin rash
    • Low blood counts.
    • increased risk for infection, anemia and/or bleeding.
    • Nadir ( lowest level in blood cell count ) : 10–14 days→ Recovery: day 21
    • Temporary increases in liver enzymes Blood or protein in the urine
    • Less common side effects (occurring in 10-29%):
    • Diarrhea
    • Weakness
    • Hair loss
    • Mouth sores
    • Difficulty sleeping
    • Shortness of breath (see lung problems)
  • 5FU ( Flourouracile )
    • Antimetabolie
    • Suicide Inactivator
    • Side effects:
      • Myelosuppression
      • Mucositis
      • Dermatitis
      • Diarrhea
      • Cardiac toxicity

5-FU also causes both acute CNS damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths.

When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population having Folic acid may amplify the desired action and the toxicity of 5-FU. The exact mechanism of interaction is unknown.

When 5-FU is given intravenously, it is typically mixed with leucovorin in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40 mg/m2 to 140 mg/m2) had disappointing results and concluded that further studies were needed.[10] There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.