Editing 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'''
{| class="wikitable"
|'''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'''
{| class="wikitable"
|'''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
*# Presence or absence of clinical benefit
*# CT findings to suggest stable or improving disease (cross-sectional diameter)
*# 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:
**

[[Category:Pancreas]]