GenSurg.nz

Pancreatic Cancer

Section: Hepatobiliary Sub-section: Pancreas Curriculum: Curriculum, page 90

Definition

  • At presentation – only 15% have resectable disease.
  • 4th most common cause of cancer death.
  • Adenocarcinoma accounts for 95% of pancreatic malignancies.
  • Can also get NETS, mesenchymal tumours are rare.

Differential diagnosis

  • Lymphoma
  • Autoimmune pancreatitis
  • Focal chronic pancreatitis.
  • Pseudo papillary neoplasm.
  • Metastatic disease – RCCs or melanoma.

Risk factors

Pathology

  • Ductal adenocarcinoa 80%
  • IPMN with an associated invasive carcinoma – 2 to 3 percent
  • MCN with an associated invasive carcinoma – 1 percent
  • Solid pseudopapillary neoplasm – <1 percent
  • Acinar cell carcinoma – <1 percent
  • Pancreatoblastoma – <1 percent
  • Serous cystadenocarcinoma – <1 percent

Precursor lesions

  • Stepwise progression
    • From pancreatic ductal intraepithelial neoplasia to pancreatic cancer
    • Mutation are similar to the ones in the conventional colorectal cancer pathway i.e. KRAS, TP53, SMAD4.

  •  intraepithelial neoplasia (PanIN) - progress from 1→3 then IC
  • adenoma–carcinoma sequence

Notable genes

  • KRAS
    • 90%
    • oncogene – mutated lead to it being activated
  • TP53, p16/CDKN2A and SMAD4
    • Loss of tumour suppressor genes

Histology

  • vary from well-differentiated duct-forming carcinomas (that may mimic non-neoplastic glands) to poorly differentiated carcinomas, with epithelial differentiation demonstrable only on immunolabelling.

Clinical

History

  • Early satiety
  • Obstructive jaundice (± pain)
  • Unexplained weight loss
  • Endoscopy-negative epigastric/back pain
  • Late-onset diabetes
  • Signs of malabsorption without defined cause

Examination

  • Courvoisier’s sign (palpable gallbladder with painless jaundice)
  • Virchow’s node (left supraclavicular node associated with upper gastrointestinal malignancy)
  • Thrombophlebitis migrans (non-specific paraneoplastic)
  • Sister Mary Joseph nodule (umbilical metastatic lesion via the falciform ligament)
  • Hepatomegaly may reflect hepatic metastases
  • Blumer’s shelf (rectally palpable rectovesicle or rectovaginal mass)

Investigations

CA 19-9

  • Used as a prognostic marker and to helps assess response to treatment.
  • Only 65% of patients with resectable disease have an elevation
  • Can be elevated in chronic pancreatitis
  • Is indicative of occult metastatic disease
  • Can be elevated in patients with biliary obstruction thus needs to be rechecked once obstruction is relieved.
  • 10% of patients don’t secrete CA19-9.
  • A preoperative serum CA 19-9 level ≥500 IU/ml indicates a worse prognosis after surgery

CT findings

  • Double duct signs is suggestive.
  • Usually present as a hypodense poorly defined mass.
  • Pancreatic atrophy, loss of glandular contour are other signs.
  • Often don’t enhance well on arterial imaging and then will become isodense on delayed imaging.
  • You should assess SMA, coeliac axis, SMV, PV, SMV/PV confluence, regional lymph nodes, any evidence of distant disease.

MRI

  • MRI does not give much more information than a pancreatic protocol CT
  • Better for relationship to biliary and pancreatic ducts and vascular structures.
  • Is better at detecting liver metastasis < 1cm.

EUS

  • Is not mandatory in patients who have resectable disease but is probably preferred.
  • Is mandatory in patients who will receive neoadjuvant treatment (as it allows you to obtain tissues diagnosis)
  • If very good for picking up small lesions (<2cm)
  • Can have false negative (i.e. can miss the tumour)

Staging laparoscopy

  • Is done routinely for lower oesophageal and stomach cancers.
  • Not routine but often will be done for high risk tumours i.e. ascites, high CA-19-9, large tumours (>3cm), small indeterminate liver or peritoneal lesions on CT.
  • Up to 30% of patients with pancreatic cancer undergo a non-therapeutic laparotomy thus there is still a role for diagnostic laparoscopy and IOUS.
  • Looking for
    • Peritoneal nodules
    •  Hepatico-duodenal ligament is inspected for nodal disease.
    • Lesser sac is opened by incising the gastrocolic omentum to inspect for tumour, and biopsies of the primary may be undertaken.
  • The role of peritoneal cytology taken during laparoscopic staging not well defined,
    • It may improve staging accuracy.

Preoperative biliary decompression

  • Area of debate
  • Has been shown to be associated with post-operative complications

  • 250, cholangitis, secondary features or undergoing neoadjuvent treatment then yes

Stage

TMN

TNM is often not used

  • T1 - tumour < 2cm
  • T2 - tumour 2-4cm
  • T3 - tumour >4cm
  • T4 - tumour involving coeliac axis or SMA
  • N1 - metastasis in 1-3 regional nodes.
  • N2- metastasis in 4+ nodes.

Staging continued

  • Often divided into resectable, borderline resectable, locally advanced unresectable, and metastatic.

Resectability

Assessing resectability (Use ABC)

  • A – anatomy of the tumour, which vessels involved etc.
  • B – biology of the tumour i.e. levels of CA 19-9, evidence of lymphadenopathy, evidence of metastatic disease
  • C – condition of the patient – performance status and co-morbidities.

Three groups

  1. Resectable
  2. Borderline resectable
  3. Locally advanced unresectable tumours

The National Comprehensive Cancer Network Guidelines Version 2.2022 Pancreatic Adenocarcinoma summarises resectabilty criteria:

Resectable

  • No arterial tumor contact
  • No contact or <180 contact with no contour irregularity for SMV and PV

Borderline resectable

  • Can have distortion, narrowing, and even occlusion of SMV or PV as long as there is suitable vessel proximally and distally to allow reconstruction.
  • Contact of <180 degrees) of SMA or coeliac trunk
  • If adjacent organs are involved are they resectable.

Locally advanced unresectable tumours.

  • Encasement of arteries (>180 degrees)
  • Occlusion of vein with no option of reconstruction.

Currently patients with resectable disease generally proceed directly to surgery followed by adjuvant chemotherapy. Even patients with T1 disease, have a high rate of developing metastatic disease thus there is an argument that a significant amount of patients with resectable pancreatic cancer already have metastatic disease at time of diagnosis. Currently, there are no good RCT’s comparing neoadjuvant chemotherapy versus adjuvant chemotherapy.

Resectable

Neo-adjuvant treatment

  • Resectable
    • Guidelines are conflicting
      • Currently not the standard of care
    • Reasonable option although limited evidence
      • Possible benefits
        • Improved selection of patiets
        • Higher R0
        • Early treatment of micrometastases
        • Great chance to have peri-operative chemotherapy
    • Dutch PREOPANC-1 trial
      • The 2020 initial results showed BR benefit specifically; resectable subgroup was negative
      • The 2022 long-term results showed statistically significant ITT benefit (p=0.025) and a consistent effect across both subgroups
    • Prep-02/JSAP-05 (Japan, Lancet Gastroenterol Hepatol)
      • Potentially resectable pancreatic cancer to two preoperative courses of gemcitabine versus upfront surgery
        • Significantly longer median OS (36.7 versus 26.6 months).
        • Significant OS benefit for NAT in resectable PDAC — but used gemcitabine + S-1 (not mFOLFIRINOX); S-1 not widely available outside Japan/Asia.
    • NorPACT-1 trial (Lancet Gastroenterol Hepatol 2024)
      • Neoadju mFOLFIRINOX (4 cycles neo + 8 adj) vs surgery then 12 cycles of mFOLFIRINOX adjuvant.
        • No difference in overall survival : neoadjuvant FOLFIRINOX was not superior — median OS 25.1 months (NAT) vs 38.5 months (upfront surgery), HR 1.52, p=0.09>
    • PANACHE01
      • Arm 1: mFOLFIRINOX × 4 cycles → surgery → adjuvant; Arm 2: FOLFOX × 4 cycles → surgery → adjuvant; Control: upfront surgery → adjuvant
      • FOLFOX arm was discontinued after interim analysis — failed to meet H0 threshold for 1-year OS (71.4% vs prespecified threshold). Only mFOLFIRINOX met the primary feasibility/efficacy threshold
      • mFOLFIRINOX confirmed feasible and safe in the neoadjuvant resectable setting
      • 1-year EFS numerically favoured mFOLFIRINOX (51.4%) over upfront surgery (38.7%). 1-year OS was similar between mFOLFIRINOX (84.1%) and upfront surgery (80.8%) — not significantly different
      • Trial was not powered for survival comparison 
  • Most common regime is modified FOLFIRINOX – fluorouracil, irinotecan, leucovorin and oxaliplatin
  • This is the same protocol as given adjuvantly

NCCN, ESMO, and ASCO all support NAT selectively in resectable PDAC for high-risk biological features:

High-risk featureRationale
CA19-9 >500 U/mLMarker of systemic burden; predicts early recurrence
Suspicious but non-diagnostic regional lymph nodesOccult nodal disease
Large primary tumour (>4 cm)Higher systemic micrometastatic burden
Equivocal/indeterminate imaging findingsPossible occult vascular involvement
Extreme pain / excessive weight lossPoor post-operative recovery predicted
ECOG PS requiring optimisationTime needed to improve fitness

On going studies: PREOPANC-3 and ALLIANCE A021806** — the two ongoing phase III RCTs that will finally answer whether perioperative mFOLFIRINOX is superior to adjuvant-only mFOLFIRINOX in resectable PDAC

Borderline resectable

Induction chemotherapy

  • NAT is the standard of care for BR-PDAC — endorsed by NCCN, ESMO, and REDISCOVER International Consensus 2024
    • Improves R0 resection rate
    • Improves survival
  • Evidence
    • PREOPANC-1 (Lancet Oncol 2022)
      • Neoadjuvant gem-CRT vs upfront surgery — statistically significant OS benefit in BR-PDAC subgroup (median OS 17.6 vs 13.2 months; HR 0.62, 95% CI 0.40–0.95)
    • ESPAC-5 — BR-PDAC Arms (Lancet Gastroenterol Hepatol 2023)
      • 1-year OS: NAT arms 77% vs immediate surgery 40% (p<0.001)
      • All three NAT regimens (gem/cap, FOLFIRINOX, gem-CRT) outperformed immediate surgery
      • Confirms NAT regardless of regimen is superior to upfront surgery in BR-PDAC
  • Following induction therapy, medically fit patients without disease progression and with a decrease in CA 19-9 should undergo surgical exploration, unless contraindicated

Neo-adjuvant chemoradiotherapy

  • Often given in combination with “induction” chemotherpay
  • There are some studies looking at giving neoadjuvant radiotherapy for downstaging.
    • The PREOPANC trial gave chemoradiotherapy.
    • Higher R0 rate in borderline resectable and progression free-survival
  • Most common regime is modified FOLFIRINOX – fluorouracil, irinotecan, leucovorin and oxaliplatin

Locally advanced

Induction chemotherapy

  • Locally advanced
    • A small amount of patients will locally advanced tumours will have downstaging allowing respectability

Adjuvant chemotherapy

  • CONKO-1 trial in 2013 showed a survival advantage for patients with resectable pancreatic cancer when given gemcitabine chemotherapy.
  • ESPAC-3 trial showed Gemcitabine was equivlent to 5FU
  • ESPAC-4 trial showed Gemcitabine and Capecitabine better then Gemcitabine mono-therapy
  • PRODIGE-24 trial showed significant superiority for modified FOLFIRINOX versus Gemcitabine mono-therapy
    • The overall survival rate at 3 years was 63.4% in the modified FOLFIRINOX group and 48.6% in the gemcitabine group.
    • Of note, grade 3/4 toxicities occurred in 75.9% of patients receiving modified FOLFIRINOX compared to 52.9% of those who received gemcitabine
  • Fit patient
  • Les fit patients
  • Borderline

Adjuvant Radiotherapy

  • May be some role in patients without R0 resecetion or LN postive

  • Not recommend with FOLFIRINOX but can be added to Gemcitabine chemotherapy

  • Palliative

    • Can be used in the palliative setting and has been shown to prolong survival.

Advance disease

Systemic treatment - same as adjuvant

  • Fit patient
  • Les fit patients
  • Borderline or bilirubin >1.5x normal
  • The efficacy of treatment should be typically evaluated every 8-12 weeks and should be based on clinical status, CA 19-9 trajectory and imaging
  • Patient should undergo BRCA genetic testing - better response to platinum based chemotherapy

Complications after surgery

  • Pancreatic leak/pancreatic fistula. 
    • If patient is unwell, associated with a poor outcome.
    • Risk factors include having a soft pancreas, narrow duct, or significant intra-operative blood loss.
  • Bleeding and pseudoaneurysm
    • Often associated with a pancreatic leaks
  • Bile leak
  • Delayed gastric emptying
    • There is controversy on whether you should preserve or remove the pylorus – a Cochrane review showed no difference.
      • Thought to decrease postoperative dumping, marginal ulceration, and bile reflux gastritis
  • Diabetes
  • Exocrine dysfunction.
  • Dumping syndrome.

Risk of mortality after a pancreatic resection is 1-2%.

Palliative treatments

Biliary treatments

  • ERCP and stenting.
  • PTC and stenting.
  • Axios
  • Typically a self-expanding metal stent is used.
  • Surgical option
    • Cholecysto-jejunostomy
    • Choledocho-jejunostomy

Gastric outlet obstruction

  • Endoscopic treatment with a duodenal stent or AXIOS
    • If this is done it can make accessing the ampulla difficult so need to think about this before.
  • Laparoscopic gastrojejunostomy

Operations

  • R0 if margin >1mm
  • Lymphadenectomy is recommended and should involve the removal of ≥16 lymph Pancreatic resections

Controversies in Pancreaticoduodenectomy

Vascular Reconstruction

  • Reasonable to do SMV/PV reconstruction — UpToDate considers this a standard approach if reconstructable and R0/R1 resection is achievable
  • Higher morbidity and mortality with arterial reconstruction — not recommended
  • Divestment in adventitial/sub-adventitial plane may maximise chance of clear margin — severe diarrhoea is a common side effect

Pylorus Preserving vs Classical Whipple

  • Preserving the pylorus may reduce dumping syndrome and bile reflux, but the pylorus may be involved with tumour or have poor blood supply
  • Preserving the pylorus may worsen problems with delayed gastric emptying (DGE)
  • No trials showing superiority of one approach (Sabiston)

Other Attempts to Reduce DGE

  • Separate Roux limb for GJ
  • Braun enterostomy

Pancreaticojejunostomy vs Pancreaticogastrostomy

  • Gastrostomy may reduce leak/fistula rate — not confirmed in trials

Somatostatin Analogues to Reduce Fistula

  • Perioperative octreotide or pasireotide (longer-acting) thought to reduce rates of fistula
  • Trials report mixed results
  • Generally discouraged/abandoned

Extent of Lymphadenectomy

  • Popular in Japan to resect aortocaval nodes
  • Japanese data suggest improved survival, but other trials report no benefit and increased morbidity
  • Extended lymphadenectomy involves clearing hilar and retroperitoneal nodes from coeliac axis to IMA and between both renal hilae

Laparoscopic Whipple

  • LEOPARD-II trial suggests much higher morbidity and mortality
  • Other trials more positive
  • Performed in multiple centres worldwide but robotic is becoming more popular

Antecolic vs Retrocolic Duodenojejunostomy

  • Antecolic may improve gastric emptying

Drain vs No Drain

  • Little evidence to suggest much benefit from omitting a drain
  • Drain considered standard of care

Separate Roux Limb for PJ

  • No proven benefit (Heidelberg study)

Graph View

Backlinks