Gastrointestinal Malignancies

HEPATOCELLULAR CARCINOMA (HCC)

Jean K. Lee

Ghassan Abou-Alfa

Epidemiology

5th most common CA worldwide (626000/y) & 3rd leading cause of worldwide CA mortality (598000/y)

>80% cases of HCC occur in sub-Saharan Africa, eastern & southeastern Asia, & Melanesia

9th leading cause of CA mortality in US Recent ↑ in the incidence of HCC (7/100000) & HCC-related mortality in US

Risk Factors

Viral hepatitis: Caused by HBV & HCV are leading RFs for HCC & accounts for 75% cases worldwide; HCV infxn predominant in Europe, North America, & Japan; HBV in Asia & Africa

Acquired RFs: Excessive EtOH → alcoholic cirrhosis (1/3 of cases of HCC in US), environmental exposure to aflatoxin from Aspergillus fungus, tobacco, autoimmune hepatitis

Metabolic disorders: Metabolic syn, DM, NASH, hereditary hemochromatosis (Mts in HFE gene) & other rare metabolic disorders

Screening and Prevention

Screening w/ultrasonography & AFP testing every 6-12 mos recommended for pts w/hepatitis B and/or C who are at risk for HCC: Additional imaging (at least 3-phase contrast-enhanced CT or MRI in setting of rising serum AFP or identification of liver mass on US

Pathophysiology

Hepatocarcinogenesis begins w/an acute or chronic insult to hepatocytes → induces liver remodeling that results in liver cirrhosis or fibrosis → stepwise accumulation of genetic & molecular aberrations

Up to 20% of HCC cases develop in pts w/o cirrhosis

HBV-induced hepatocarcinogenesis may occur through direct viral DNA insertion

Histopathologic markers of HCC: Granular HepPar-1 staining, positive AFP

Dysplastic nodules evolve into HCC w/loss of IGF-2 receptor oncogene & tumor suppressors p53, PTEN, & p16

Clinical Manifestations

S/s: No pathognomonic s/s for HCC

Exam: Usu. unremarkable, hepatomegaly, & ascites, jaundice & encephalopathy in the setting of adv cirrhosis

Labs: Usu. nonspecific & reflects level of liver dysfunction. ↑ Total bili., low albumin (<30 g/dL), & elevated INR in the setting of adv cirrhosis

Paraneoplastic syn are rare

Diagnostic Workup

Includes imaging, pathologic confirmation of HCC, tumor markers, & LFTs

Imaging: At least 3-phase contrast-enhanced CT scan (arterial, portal venous, & parenchymal phase) or gadolinium-enhanced or contrast-enhanced MRI. U/S primarily used as screening modality. PET/CT not considered adequate

Bx: Core needle bx preferred, or FNA recommended for adv stages. However, bx confirmation may not be required for early stages, as per noninvasive diagnostic guidelines by AASLD

Lab: Hepatitis B & C serologies; tumor markers: Serum AFP; however, not sensitive nor specific

Classification systems for assessment of hepatic dysfunction: Child-Pugh classification

The Child-Pugh Scoring System for Liver Cirrhosis
Parameter	Points
Parameter	1	2	3
Albumin	>3.5 g/dL	2.8-3.5 g/dL	<2.8 g/dL
Total bili.	<2 mg/dL	2-3 mg/dL	>3 mg/dL
INR	<1.7	1.7-2.3	>2.3
Clinical ascites	Absent	Mild	Mod.
Clinical encephalopathy	Absent	Grade 1-2	Grade 3-4

Staging and Prognosis

No unified international classification system. The BCLC system serves as a road map to guide Rx; however, it has its limitations & not been validated in the setting of adv disease

Curative Management

Surgical Resection

<25% of tumors are resectable b/c of underlying liver disease, multifocal nature of disease in the liver, & late detection of disease

Generally for pts w/preserved liver function & low-volume disease, w/o major vessel involvement: AJCC stage I-III A, Child-Pugh class A & no evidence of portal HTN. Highly selected cases of pts w/Child-Pugh class B

5-y OS resected pts range 40-50%, but rates >80% reported. However, tumor recurrence rates high, at 5 y >70%

Ablation: Most common methods are RFA by direct exposure of tumor to alteration in temperature

Liver Transplantation

Potentially curative Rx for pts w/early HCC, w/multinodular disease and/or adv cirrhosis

The Milan Criteria established guidelines for eligibility of liver transplantation: Solitary lesion ≤5 cm or up to 3 lesions each ≤3 cm, no gross vascular invasion, no LN or distant mets

4-y overall & RFS rates at 85% & 92%

MELD score used as measure of liver function & pretransplant mortality to prioritize pts for liver transplantation (MELD = 3.8 [Ln serum bili. (mg/dL)] + 11.2 [Ln INR] + 9.6 [Ln serum Cr (mg/dL)] + 6.4)

Bridging therapies used including RFA, TACE, radioembolization used to control or downstage tumor prior to transplantation

Palliative Management

Locoregional Therapies

Embolization: Bland TAE or TACE used to reduce blood flow to tumor resulting in tumor ischemia & necrosis

Radioembolization, a newer method delivers high-dose radiation to tumor-associated vessels, using yttrium-90 to induce tumor necrosis, indicated in the setting of vascular involvement

Systemic Therapies

Sorafenib, an oral multikinase inhibitor has shown to improve OS (median OS 10.7 mos sorafenib arm vs. 7.9 mos in placebo in 2 phase III trials (SHARP trial, NEJM 2008;359:378; Lancet Oncol 2009;10:25)

Multiple clinical trials are underway in 1st & beyond 1st-line setting. MSKCC carries an extensive portfolio of HCC clinical trials

Best Supportive Care

Best supportive care measures for pts w/unresectable disease who are not candidates for other therapies

CANCER OF THE BILIARY TREE

James J. Harding

Eileen M. O’Reilly

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

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 (NEJM 2010;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

Selected Chemotherapy for Unresectable and Metastatic Disease
Regimen^a	Citation	ORR (%)	Median PFS (mos)	Median OS (mos)
GEM + CIS	NEJM 2010;362:1273	26	8	12
GEM + OX	Ann Oncol 2004;15:1339	22-36	˜4-6	˜8-15
GEM + Cap	JCO 2008;26:3702	25	˜7	˜13
Cap + OX^b	Br J Cancer 2008;98:309	27	˜7	˜13
GEM	Multiple trials	0-30	NR	˜5-12
5-FU or Cap	Multiple trials	10-32	NR	˜5-7
^aGEM, CIS, OX, Cap, 5-FU, NR; all trials w/e GEM + CIS are phase II trials. ^bLower ORR for intrahepatic CC

PANCREATIC CANCER

James J. Harding

Eileen M. O’Reilly

Epidemiology

Incidence: ˜45000 new cases/y & ˜38000 D/y in US; 4th most common cause of CA death in US men & women

Acquired RFs: Age (peak incidence 7th & 8th decade), race, tobacco, EtOH, ↑ BMI, chronic pancreatitis, occupational exposure, DM

Hereditary RFs: ↑ Risk wFHx, ˜5-10% pts have genetic predisposition

Inherited susceptibility to pancreatic CA (NEJM 2008;359:2143)
Familial atypical multiple mole melanoma syn, CDKN2A (p16)
Hereditary breast CA syn, BRAC2 > BRAC1 > PALB2
LS, MSH2, & MLH1
Peutz-Jeghers syn, STK11
Ataxia-telangiectasia, ATM
Hereditary chronic pancreatitis syn, germline Mts in cationic trypsinogen (PRSS1) or secretory trypsin inhibitor (SPINK1)

Clinical Manifestations

Sx dependent on location of lesion, painless jaundice, biliary colic, vague abdominal pain, anorexia, wt loss, back pain (Retroperitoneal (RP) involvement, predictor of unresectable tumor; Surgery 1997;122:53)

New or worsening DM, pancreatitis or malabsorption (steatorrhea)

VTE or migratory thrombophlebitis (Trousseau sign)

Exam: Jaundice, hepatomegaly, ascites, abdominal mass, left supraclavicular LAD (Virchow node), periumbilical LAD (Sister Mary Joseph nodes)

Labs: Hyperglycemia, ↑ AST/ALT, ↑ conjugated bili., ↑ amylase/lipase, anemia, prolonged PT due to malabsorption of fat-soluble vitamins

Diagnostic Evaluations and Staging

Multiphase contrast-enhanced CT scan (arterial, venous, & parenchymal phase) or MRI/MRCP

If (+) pancreatic mass or stricture → EUS or ERCP for bx; if (+) cholangitis → temporary stent by ERCP + ABX; if (+) distant mets → bx

CA19-9 (↑ in biliary obstruction, not appropriate baseline until biliary decompression or surgery), CT-Chest, LFTs, is select cases staging laparotomy

AJCC Staging of Exocrine Pancreas Cancer (Cancer 2007;110:738)
Stage (˜% at DX)	Tumor	Node	Mets	5-y OS (%)^*
IA/B (10%)	Limited to pancreas	None	None	˜12-14
IIA/B (20%)	Limited to pancreas	Regional LN	None	˜5-7
IIA/B (20%)	Beyond pancreas; No involvement of celiac axis (CA)/superior mesenteric artery (SMA)	None or regional LN
III (15%)	Involves CA/SMA (unresectable)	None or regional LN	None	˜3
IV (55%)	Any size	None or regional LN	Distant Mets	<1
^*Includes pts ± pancreatectomy, OS ↑ w/resection

Surgical Treatment

Surgical resection is delivered w/curative intent; R0 resection is ideal.

5-y OS resected pts = 20% (Ann Surg 1997;225:621)

Definitions of resectability (Ann Surg Onc 2009;16:1727)

Resectable = clear fat planes around hepatic artery, celiac axis (CA) or superior mesenteric artery (SMA); no involvement or encasement of PV or SMV
Borderline = abutment/limited involvement of PV, SMV, or hepatic artery. May abut SMA by ≤180°
Unresectable = CA/SMA encasement

High-volume surgical centers = ↓ morbidity & mortality

Type of resection depends on size/location of tumor

Head = pancreatoduodenectomy (Whipple procedure)
Body or tail = distal or subtotal pancreatectomy ± splenectomy
Multifocal = total pancreatectomy

Other surgical considerations: Avoid regional lymphadenectomy (no improved OS); IP drains ↑ rate post-op sepsis, fluid collections & fistula (Ann Surg 2001;234:487); in resectable pt no benefit of preoperative biliary drainage unless other complicating issues (NEJM 2010;362:129)

Radiotherapy and Systemic Treatment

Adjuvant Rx: A standard approach is w/GEM × 6 mos ± 5-FU-based chemoRT (45-54 Gy), key clinical trials in the adjuvant setting:

GITSG: 5-FU + RT vs. obs; chemoRT ↑ OS (Arch Surg 1985:120:899)
CONKO-001: GEM vs. obs; GEM ↑ DFS/OS (JAMA 2007;297:267)
ESPAC-1: Bolus 5-FU + RT vs. 5-FU only vs. 5-FU + RT → 5-FU vs. obs; ↑ DFS/OS for adjuvant 5-FU; ? benefit RT (NEJM 2004;350:1200)
ESPAC-3: GEM vs. 5-FU, no ΔDFS, OS, QoL (JAMA 2010;304:1073)

If chemotherapy only, GEM easier to administer & less tox than 5-FU

Neoadj/Conversion Rx: Limited prospective data, considered for borderline resectable tumors, restage prior to surgery as 15-25% will have POD, ? improvement in surgical margins

Surveillance & Tx of Recurrence: Serial exam, CT-CAP, CA19-9 q3-6mos for 2 y than annually, if local recurrence → ChemoRT (if none prior) or chemo alone; if met see below

Tx for Unresectable & Met Disease

Rx not curative, designed to ↑ survival & ↓ sx

PS dictates Rx

If excellent PS → clinical trial, FOLFIRINOX or GEM-combo
If poor PS → GEM monotherapy or best supportive care
If locally adv disease w/SD or better on chemo → chemoRT

2nd line: Fluoropyrimidine-based if prior GEM-based & vice versa

Selected Chemotherapy for Unresectable and Metastatic Disease
Regimen^*	Citation	ORR (%)	Median PFS (mos)	Median OS (mos)
FOLFIRINOX	NEJM 2011;364:1817	32	6.4	11.1
GTX	CCP 2008;61:167	29	6.3	11.2
GEM + *nab*-P	GI ASCO 2013	23	5.5	8.5
GEMOX	BJC 2006;94:3778	23	4	6
GEM + Cap	JCO 2009;27:5513	19	5	7
GEM	Multiple trials	10-15	2-3	5-7
CapOX	Cancer 2008:113:2046	3	2.5	5.8
^*FOLFIRINOX = 5-FU/LV, irinotecan, & OX; GTX = GEM, docetaxel, & Cap, nab-P = nab-paclitaxel; w/e GTX & CapOX all regimens were compared to GEM in randomized phase II or III studies