Pocket Oncology (Pocket Notebook Series), 1st Ed.

CANCER OF THE BILIARY TREE

James J. Harding and Eileen M. O’Reilly

Definition

Cholangiocarcinomas (CC), tumors of the bile duct (BD) epithelium, differentiated by anatomic site of origin.

Intrahepatic (10%)

Hilar (40%), confluence of R/L hepatic duct (Klatskin tumor)

Distal (50%), involve CBD/Ampulla of Vater

Extrahepatic CC = hilar + distal CC

Gallbladder carcinoma (GBC) is histologically = CC but ≠ epidemiology, staging system, & surgical tx

Anatomic site of origin → fundus (60%), body (30%), neck (10%)

Epidemiology

Incidence: ∼10000 new cases/y & ∼3200 D/y in US of CC & GBC; GBC is more common

Most cases are sporadic (NEJM 1999;341:1368)

↑ Risk w/adv age, ↑ risk w/chronic inflammation

CC specific RFs → PSC, choledochal cysts, Asian liver flukes (O. viverrini & C. sinensis), chronic calculi of BD, HCV, HBV, & male sex

GBC-specific RFs → chronic cholelithiasis, GB calcification (ie, porcelain GB), & female sex

Pathophysiology

Most common histological subtype = adenoca (90% CC, 80% GBC), less common: Small cell CA, SCC, sarcomas

Underlying molecular biology & pathogenesis of GBC & CC is poorly understood, Mts are found in p53KRASBRAFc-METPIK3CAHER2/neu, & EGFR (JCO 2010;28:3531)

Clinical Manifestations

Sx depend on location of lesion; include painless jaundice, pruritus, abdominal pain, biliary colic (especially in GBC), cholangitis, clay-colored stool, cola-colored urine, fevers, anorexia, & wt loss

Exam: Hepatomegaly, palpable GB due to obstruction of cystic duct (Courvoisier sign), jaundice, ascites

Labs & initial studies: ↑ T-bili, ↑ AST/ALT, ↑ γ-GT, US-ABD (±) stones

Diagnostic Evaluations

MRI/MRCP or CT-A/P (multiphase delayed contrast)

Determines anatomy, location & degree of obstruction

Used to plan for bx, surgery and/or stenting

ERCP or PTC: Commonly employed but not required in all cases

ERCP to stent, relieve obstruction, & to bx (cytology, brushings)

If ERCP is non-diagnostic consider EUS or CT-guided for FNA/core

In cases w/suspicious lesion w/o biliary obstruction & distant disease → surgery w/o bx

CA19-9 & CEA, CT-Chest, questionable role for PET

Staging and Prognosis

Four unique AJCC TMN staging systems for CC (intrahepatic, hilar, distal) & GBC

Key differences for staging systems: Intrahepatic T stage based on # of lesions & similar to HCC staging while hilar, distal & GBC T staging reflects degree of invasion through BD epithelium

AJCC staging may not adequately predict surgical resectability (specifically for hilar, consider Bismuth or Blumgart classification)

OS in met setting is poor:

GBC Stage IV → 5-y OS <1%, median OS ∼6 mos

Intrahepatic CC Stage IV → 3 y OS ∼10%, median OS ∼13 mos

Surgical Treatment

Early surgical consultation is critical for CC & GBC

R0 resection improves OS; surgery is the only curative Rx

Avoid needless biliary stenting in resectable pt, no advantage to preoperative biliary decompression (Ann Surg 2002;236:17)

Staging laparoscopy may be required in select cases

Intrahepatic CC Resection

Requires hepatic lobectomy

Contraindication to surgery: Multifocal tumor, extrahepatic extension, & N1 disease

5-y OS s/p resection ∼15–40%

Extrahepatic CC resection

Hilar→ en bloc resection hepatic lobe + involved extrahepatic BD + periportal LND; if L main hepatic duct → caudate lobectomy

Distal → Pancreaticoduodenectomy + extrahepatic BD to confluence (high surgical morbidity & mortality)

5-y OS s/p resection ∼10–40%

GBC

Often laparoscopic surgery for suspected gallstones, incidental CA

Only a T1a lesion can be treated w/simple cholecystectomy (CCY)

Extended (radical) CCY → en bloc resection of GB, wedge resection of GB bed (Seg IVb & V), regional LND

If jaundiced at presentation, curative surgery unlikely

5-y OS depends on T stage, approaches 100% T1, 0–40% T3/T4

Systemic and Local Regional Treatment

Adjuvant Rx: Limited clinical data due to the rarity of the disease; mostly small phase II clinical trials or retrospective series; participation in clinical trials recommended (JCO 2012;30:1934)

Observation is recommend for T1 GBC (long-term OS ∼100%)

Observation can be considered for R0 & N0 intra/extrahepatic CC

In all other cases, adjuvant Rx is recommended due to the high risk of local regional & met recurrence

For R1/R2 intrahepatic CC resections, consider re-resection or ablation

Typical adjuvant regimens: Fluoropyrimidine chemoRT, fluoropyrimidine- or GEM-based chemotherapy

Surveillance & Tx of Recurrence: Serial exam, CT-CAP, CA19–9, CEA q6mos for 2 y than annually, if local recurrence → chemoRT (if none prior), ablation, re-resection or chemo alone; if met see below

Tx for Unresectable & Met Disease

Systemic chemotherapy

ABC-02: Randomized Phase III of GEM + CIS vs. GEM in 410 pts w/adv GBC, CC, ampullary CA; GEM + CIS superior & a standard of care → median PFS/OS ∼8 mos/12 mos vs. ∼5 mos/8 mos in GEM arm (NEJM2010;362:1273)

Addition of Erlotinib to GEM + platinum doublet ↑ ORR & may ↑ PFS in CC (Lancet Onc 2012;13:181)

Concurrent chemoradiation (w/5-FU or Cap, not GEM) in select pts w/unresectable locally adv disease

Supportive care in poor performance pts