Pancreatic cancer

(Pancreatic ductal adenocarcinoma)

Epidemiology

• Increasing incidence - unknown reason
• 3rd most common cause of cancer death in USA
• Men more commonly affected
• Mean age at diagnosis 72yo
• 4000 cases annually in Australia. 10th most common, 4th most deadly.

Risk factors

• Genetic
  • PRSS1 (familial pancreatitis) - 40% lifetime risk
  • SPINK1 (familial pancreatitis) - 50x risk
  • STK11 (Peutz-Jeghers) - 100x lifetime risk
  • CDKN2A (familial atypical mole and melanoma syndrome) - >40x lifetime risk
  • CFTR (CF) - thick secretions lead to chronic pancreatitis and 30x lifetime risk
  • BRCA2 - 10x risk
  • MLH1 (Lynch) - 8x risk
  • APC (FAP) - 4x risk
  • Familial pancreatic cancer - two or more first-degree relatives with PDAC that do not fulfil the criteria for other genetic conditions - 18x increased risk, especially if diagnosed <50yo
• Environmental
  • Smoking - 1-3x RR - linear association
  • Obesity
  • Diabetes - especially, new-onset diabetes in elderly patients with weight loss or abdominal pain - can be caused by PDAC - should be imaged

Pathophysiology

• Refers to primary cancers of the ductal epithelium, as well as cancers arising from MCN and IPMN
• Progression from pancreatic intra-epithelial neoplasia (PanIN) to invasive cancer
  • KRAS2 oncogene is activated in >95% and is thought to be the initiating event in tumourigenesis
  • CDKN2A, p53 and SMAD4 are tumour suppressor genes that may also play critical roles
  • PanIN: progressive abnormality of the ductal epithelium
    • PanIN-1A: columnar, mucin-producing ductal epithelium that maintains basally-located homogenous nuclei without atypia
    • PanIN-1B: Development of papillary architecture
    • PanIN-2: nuclear atypia
    • PanIN-3: Prominent nuclear abnormalities with complete loss of polarity and marked cytologic atypia (carcinoma-in-situ)
  • Low-grade PanIN is present in >50% of 50yo

Presentation

• Obstructive jaundice - defining feature of PDAC in the periampullary region
• Weight loss - seen in >50%
• Abdominal pain - typically epigastric, radiating through to back
• HOP tumours present with jaundice, while tumours in body and tail cause pain and weight loss
• New-onset diabetes in an elderly patient, especially with weight loss and pain, can be an early presenting symptom of pancreatic cancer
• Examination findings unremarkable. 30% have a distended GB. Virchow's node may be palpable, or Sister Mary Joseph nodule. Peritoneal tumour involvement may be palpable on Blumer shelf.

Evaluation

• Bloods
  • LFTs and coags
  • Ca 19-9 - most sensitive (82%)
    • Can get false elevation from biliary obstruction
    • Normalisation after neoadjuvant therapy is an important prognostic marker

Preoperative CA 19-9 levels and tumor resectabilty and survival rates in pancreatic cancer

CA 19-9 (U/mL)	Number of patients	Resectability (%)	R0 resection (%)	Survival after resection		Survival if unresectable
				5-year (%)	Median (months)	Median (months)
<5	99	73.7	48.6	21.9	26.8	10.1
5 to <37	281	79.7	52.7	27.2	28.5	9.1
37 to <100	216	83.3	46.9	19.1	26.9	8.6
100 to <250	247	82.2	42.1	16.8	22.5	5.4
250 to <500	204	72.1	37.0	8.3	20.1	9.2
500 to <1000	184	67.4	44.7	7.0	15.4	8.9
1000 to <2000	126	61.1	32.5	0.0	12.0	6.8
2000 to <4000	92	45.7	31.0	0.0	12.3	6.2
≥4000	94	38.3	27.8	0.0	14.4	7.2
		p<0.0001	p = 0.0009		p<0.0001	p = 0.065

• CEA
• AFP

• CT pancreas protocol (non-con, arterial, PV, with 3mm slices, and 3D reconstruction)
  • Hypoattenuating lesion in PV phase
  • Ability to accurately predict resectability is about 85%. Mistakes are generally due to small liver or peritoneal mets.
  • Look at level of biliary obstruction, relationship to vascular structures, and presence of regional or metastatic disease
• ERCP
  • Good for biopsy, but controversial role of stenting
  • Indications for stenting:
    • Active treatment:
      • Acute cholangitis
      • Debilitating symptoms (e.g. pruritus)
      • Expected delay in surgical intervention >2 weeks (neoadjuvant therapy)
    • Palliative
      • Relieve symptoms of jaundice or pruritus
      • Cholangitis
      • Optimise medical status prior to CRT
• EUS
  • Sensitivity and specificity far higher than brush cytology
  • Diagnostic accuracy 92-95%
  • May have another role in the delineation of suspicious lesions <2cm
• MRCP
  • When detailed assessment of luminal anatomy is necessary
• FDG-PET
  • Can differentiate between benign and malignant pancreatic tumours
  • Not routinely used

Staging

• Tissue to confirm. If biopsies inadequate, repeat them.
  • EUA - best approach - se/sp >90%
  • Percutaneous biopsy - quite good sp/se, and low rates of seeding
• At a minimum, good quality CT C/A/P including pancreatic protocol, before considering any intervention including stenting
• Staging laparoscopy for those at high risk of unidentified metastatic disease (tumours >3cm, CA 19-9 >100U/mL, equivocal CT, or body/tail tumours) to prevent non-therapeutic laparotomies. Also consider it for those with significant constitutional symptoms but no known metastases. Yield is 6% (changing management).
• Then stage and classify into resectable, borderline resectable or unresectable

Exocrine pancreatic cancer TNM staging AJCC UICC 8th edition

Primary tumor (T)
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ. This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.
T1	Tumor ≤2 cm in greatest dimension
T1a	Tumor ≤0.5 cm in greatest dimension
T1b	Tumor >0.5 and <1 cm in greatest dimension
T1c	Tumor 1 to 2 cm in greatest dimension
T2	Tumor >2 and ≤4 cm in greatest dimension
T3	Tumor >4 cm in greatest dimension
T4	Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in one to three regional lymph nodes
N2	Metastasis in four or more regional lymph nodes
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis
M1	Distant metastasis
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
Tis	N0	M0	0
T1	N0	M0	IA
T1	N1	M0	IIB
T1	N2	M0	III
T2	N0	M0	IB
T2	N1	M0	IIB
T2	N2	M0	III
T3	N0	M0	IIA
T3	N1	M0	IIB
T3	N2	M0	III
T4	Any N	M0	III
Any T	Any N	M1	IV

• Resectability (based on international consensus definitions 2017, Isaji et al). Note encasement is >180 degree involvement; abutment is <180 degree involvement.
  • Resectable - localised to pancreas, with no evidence of SMV or PV involvement, and a preserved fat plane surrounding SMA and coeliac artery branches
  • Borderline resectable - one or more of the following:
    • Venous involvement
      • Reconstructable SMV or PV encasement
      • Reconstructable SMV or PV abutment with contour irregularity/narrowing of the vein, or thrombosis of the vein
    • Arterial involvement
      • SMA or CHA abutment
    • Biological - CA19-9 > 500, or regional lymph nodes on biopsy or PET
    • Performance status 2 or more
  • Unresectable - metastasis, including lymph node metastasis outside the field of resection, ascites, or vascular involvement beyond the above.
    • SMA or CHA encasement
    • Contact with coeliac artery or RHA/LHA
    • Occlusion of SMV, PV, or SMV-PV without suitable vessels for reconstruction above and below
• Most present with locally advanced or metastatic disease - about 80%

Treatment

• ECOG 3 or 4: straight to best supportive care
• Resectable (stage I or II): either upfront surgery or neoadjuvant treatment with FOLFIRINOX + CRT then surgery
• Borderline resectable - Neoadjuvant CTX +/- RTX for 2/12, then re-image, and assuming no progression, can be resected, then adjuvant therapy
  • Some centres may do a second stage of neoadjuvant therapy prior to OT
• Locally advanced unresectable - CTX, it may become resectable later, but this is rare. Consider RTx if persistent disease after CTx (although RCT 2016 'LAP07' suggested doesn't help)
  • Irreversible electroporation is an area of study
• Unresectable (stage IV) - CTX

Neoadjuvant therapy

• Rationale
  • PREOPANC trial 2019 - RCT - median survival for borderline resectable tumours was different by a meaningful amount with neoadjuvant CTx, and R0 resections were much higher. Additionally, this was with gemcitabine CRT, not FOLFIRINOX, which is thought to have superseded gemcitabine CRT. 5-year OS was 20% with vs 6% with up-front surgery. Few hundred patients total. Also showed benefit to neoadjuvant CTx for 'resectable' patients.
  • 25% of patients never receive adjuvant CTX, because of refusal, complications, or inability to recover from surgery
  • Maximise therapy to an intact gland with intact blood supply
  • Response to therapy can be assessed more readily - avoid surgery for patients that progress on CTX
  • Physiological stress test to establish who can recover from surgery
  • For borderline resectable cases, improved overall survival and R0 resections
  • Foreseeable that eventually standard of care will be neoadjuvant chemotherapy for all
• Preparation
  • Need tissue
  • Need biliary drainage with SEMS
• Regime
  • FOLFIRINOX is most common - aggressive therapy requiring good performance status
  • Gemcitabine-based chemoradiotherapy is an alternative, but used less often
• Defining response to treatment
  1. Presence or absence of clinical benefit
  2. CT findings to suggest stable or improving disease (cross-sectional diameter)
  3. Serum CA 19-9
• ERCP and short metal stent if necessary (gets blocked less than plastic stents)

Surgery:

• Head of pancreas tumours - pancreaticoduodenectomy
• Body and tail tumours
  • Rarely resectable, because they don't produce much symptoms (5-7% will undergo surgery)
  • Distal pancreatectomy and en bloc splenectomy is operation of choice

Surveillance

• Variable, with no specific guidelines
• Generally CA 19-9 +/- CT every 6 months, with other workup guided by symptoms
• Controversial since recurrent disease is incurable

Palliation

• Chemotherapy
  • FOLFIRINOX
• Pain
  • Coeliac plexus neurolysis - effective, reduces opioid use
  • Can be done if cancer is found unresectable at laparotomy
  • Indication - uncontrolled pain with non-invasive methods
  • Injection of 3mL 0.25% bupivacaine and 10mL ethanol into each coeliac plexus, either via EUS, percutaneously, or at operation
• Biliary obstructive symptoms
  • Endoscopic
    • ERCP + stent is preferred method
    • Metal stents more durable, best for those where it will need to stay patent for >6 months
    • Technically possible in >90% of cases
    • PTC sometimes possible where ERCP is not
  • Surgical
    • Roux-en-Y hepaticojejunostomy - excellent long-term patency
• Gastric outlet obstruction
  • Seen in 20% of patients with locally advanced pancreatic cancer
  • Endoscopic stenting is as effective as gastrojejunostomy, with almost immediate improvement in oral intake, but limited long-term patency
  • Gastrojejunostomy is preferable for patients with longer expected survival
• Hypersplenism
  • Splenectomy may be useful, improving platelet counts, allows resumption of chemotherapy, and likely enhances survival

Prognosis

• <8% survive 5 years
• Those with metastatic disease rarely survive >6 months
• Locally advanced disease with palliative chemotherapy generally survives 10-12 months
• Post-surgical: