Hepatobiliary Cancer

Abstract

This chapter will discuss the diagnosis, workup, and management of hepatocellular carcinoma, gallbladder cancer, and intrahepatic and extrahepatic cholangiocarcinoma.

General Pearls

• ∼39,000 cases and 27,000 deaths for liver and intrahepatic bile duct cancers in 2016 in the USA .

• ~11,000 cases and 3700 deaths for gallbladder and other biliary cancers in 2016 in the USA.

• Frequency : hepatocellular carcinoma (most common) > gallbladder cancer > extrahepatic cholangiocarcinoma > intrahepatic cholangiocarcinoma (least common).

Liver (Hepatocellular)

Pearls

• 100–250× more common in patients with chronic hepatitis B.

• Cirrhosis, chronic liver disease, hepatitis C, hereditary hemochromatosis, and aflatoxin B exposure are also risk factors.

• ~3–4× more common in men.

• Prevention: Hepatitis B vaccine, treatment of hepatitis B and C (reduces but does not eliminate risk).

• Milano/Mazzaferro criteria for liver transplantation: solitary tumor ≤5 cm or up to 3 tumors all ≤3 cm.

• UCSF criteria for liver transplanation: solitary tumor < or = 6.5 cm, or < or = 3 nodules with the largest lesion < or = 4.5 cm and total tumor diameter < or = 8 cm

Workup

• Screening tools frequently used in high-risk patients every 6–12 months: serum alpha-fetoprotein, liver ultrasound.

• H&P: jaundice, diarrhea, bone pain or dyspnea (metastases), hepatosplenomegaly, ascites.

• Labs: CBC, LFTs (including bilirubin, transaminases, alk phos), chemistries, coagulation panel, albumin, serum AFP (10–15% false negative), hepatitis B/C panels.

• 3-phase liver protocol CT and/or MRI with IV contrast, including late arterial and portal venous phase.

• Chest CT; bone scan if clinically indicated.

• Assess liver reserve (Child-Pugh score , portal HTN).

• Consider indocyanine green clearance test to assess liver function, if resection is being considered.

• FNA can be performed but is not always needed, if radiographic characteristics are diagnostic.

Staging : Hepatocellular

Editors’ note: All TNM stage and stage groups referred to elsewhere in this chapter reflect the 2010 AJCC staging nomenclature unless otherwise noted, as the new system below was published after this chapter was written.

Table 21.1 (AJCC 7TH ED., 2010)

Table 21.2 (AJCC 8TH ED., 2017)

Definition of Regional Lymph Node (N)

N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis

Definition of Distant Metastasis (M)

M category	M criteria
M0	No distant metastasis
M1	Distant metastasis

AJCC Prognostic Stage Groups

When T is...	And N is...	And M is...	Then the stage group is...
T1a	N0	M0	IA
T1b	N0	M0	IB
T2	N0	M0	II
T3	N0	M0	IIIA
T4	N0	M0	IIIB
Any T	N1	M0	IVA
Any T	Any N	M1	IVB

1. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Treatment recommendations

Table 21.3 TREATMENT RECOMMENDATIONS

Surgery

• Child-Pugh score is used to assess prognosis of chronic liver disease.

  • Score 1–3 each for total bilirubin, albumin, prothrombin time or INR, ascites, hepatic encephalopathy categories.

  • Class A = 5–6 points, good operative risk, 2-yr OS 85%.

  • Class B = 7–9 points, moderate operative risk, 2-yr OS 57%.

  • Class C = 10–15 points, poor operative risk, 2-yr OS 35%.

• Partial hepatectomy is a treatment of choice if tumor can be resected with negative margins and patient has enough functional reserve. Generally, Child-Pugh Class A without portal hypertension; solitary mass without major vascular invasion; adequate future liver remnant.

  • Five-year overall survival ∼35–40%.

• Total hepatectomy with liver transplant is an option for patients with advanced cirrhosis and either a single tumor <5 cm or up to 3 lesions up to 3 cm each, without vascular invasion.

  • Five-year overall survival as high as ∼70% in selected patients.

• MELD score is used to assess severity of liver disease and prioritize allocation of liver transplants. Calculated based on bilirubin, creatinine, and INR to predict survival.

Ablative Procedures

• Consider ablative therapy for pts who are not surgical candidates as it may cure tumors <3 cm and may prolong survival for tumors 3–5 cm. Lesions >5 cm should be considered for arterially directed or systemic therapy.

• Radiofrequency ablation (RFA) is typically used for tumors <4 cm. Usually performed percutaneously by US or CT guidance.

• Technically challenging areas for ablation include subdiaphragmatic location, subcapsular lesions, and proximity of major biliary or vascular structures that could cause biliary injury or heat-sink effect.

• 5-yr local progression after ablation is about 5–15%, but intrahepatic recurrence is 60–75%.

Arterially Directed and Systemic Therapy

• Arterially directed therapy is potentially indicated if arterial blood supply to tumor may be isolated without excessive nontarget treatment.

  • Relatively contraindicated if bilirubin > 3 or if main portal vein thrombosis and Child-Pugh class C.

  • Transarterial chemoembolization (TACE ) involves intra-arterial injection of chemotherapy, often with lipiodol and/or chemotherapeutics.

  • Chemoembolization and intrahepatic artery chemotherapy have response rates of 40–50% but may not improve survival.

  • Transarterial radioembolization (TARE) Y-90 microspheres have increased risk of radiation-induced liver disease in pts with bilirubin > 2. Randomized trials of TARE are ongoing.

• Sorafenib may have survival benefit over supportive care for advanced HCC, although response rates are low (SHARP trial, Llovet NEJM 2008).

• Antiviral therapy for patients with chronic hepatitis.

Radiation Therapy

• Definitive EBRT (3D, IMRT, or preferably SBRT)

  • Option for unresectable tumors or as an alternative to ablation/embolization techniques or when they have failed or are contraindicated. There must be sufficient uninvolved liver and liver radiation tolerance must be respected. There should be no or minimal extrahepatic disease. Most data includes Child-Pugh class A disease, with more limited data for Child-Pugh class B or poorer liver function.

  • Use highly conformal radiotherapy techniques for each lesion, typically with SBRT or protons with modern immobilization, respiratory motion management, and image guidance.

  • Higher doses may improve local control and survival.

  • Concurrent FUDR hepatic arterial chemotherapy may be considered with fractionated conformal radiotherapy.

  • SBRT may be an alternative or adjunct to RFA and TACE as a bridge for pts waiting for a liver transplant because delay to transplant contributes to about 20% of potentially curable pts being delisted before surgery.

• Palliative EBRT

  • Consider for lung, brain, node, and bone metastases with about 70–80% response rate. There is little published data on the role of low-dose palliative whole liver RT for patients with multiple small lesions and liver-related symptoms who are not candidates for other therapies.

Studies

• Huo (JAMA Oncol 2015 ): Meta-analysis of unresectable HCC treated with TACE alone vs. TACE + RT (including SBRT). 25 trials with 2577 patients showed better complete response (OR 2.73), 1-year OS (OR 1.36) with addition of RT, with survival benefit more pronounced with longer follow-up. Increased incidence of ulcers, transaminitis, elevated TBili with TACE + RT.

Conventionally Fractionated EBRT

• Dawson (JCO 2000 ): University of Michigan method for treating with high-dose 3DCRT, delivered 1.5 Gy BID. 68% response rate. Survival improved with tumor doses of 70 Gy or higher.

• Dawson (IJROBP 2002 ): Liver tolerance histograms. No radiation-induced liver disease (RILD) with mean liver dose <31 Gy. Whole organ TD₅₀ for mets 45.8 Gy, for primary hepatobiliary 39.8 Gy.

• French RTF-1 trial (Mornex, IJROBP 2006 ): Prospective phase II trial including 25 patients with small HCC (1 nodule ≤5 cm or 2 nodules ≤3 cm) received 66 Gy in 2 Gy/fraction 3DCRT. CR achieved in 80% and PR in 12%. Stable disease in 8%. Grade 4 toxicities occurred only in Child-Pugh B patients.

• Seong (IJROBP 2007 ): Retrospective analysis of 305 patients undergoing radiotherapy for HCC. Median survival was 11 months. 1-, 2-, and 5-year OS were 45%, 24%, and 6%, respectively.

• Zeng (Cancer J 2004 ): Retrospective analysis of 203 patients with unresectable hepatocellular carcinoma received transcatheter arterial chemoembolization (TACE ) or combination therapy with external beam radiotherapy. 1-/2-/3-yr OS for RT and non-RT groups was 72%/60%/42% vs. 26%/24%/11%, respectively.

SBRT

• See excellent review by McPartlin and Dawson (The Cancer Journal 2016).

• TRIAL 1/2 (Bujold, JCO 2013 ): Phase I (50 patients) and phase II (52 patients) trials of SBRT for Child-Pugh A HCC not suitable for resection, RFA, or TACE . Received 24–54 Gy in 6 fractions, based on RILD model and proximity to GI. 1-year local control 87%, median OS 17 months. Grade ≥ 3 toxicity in 30%. Tumor vascular thrombosis correlated with worse OS.

• Lasley (Practic Radiat Oncol 2015). Phase I/II trial of 38 Child-Pugh A and 26 Child-Pugh B HCC pts treated with SBRT (48 Gy in 3 fx or 40 Gy in 5 fx). 3-yr LC/OS: Child-Pugh A 91%/61%, Child-Pugh B 82%/26%.

• Wahl (JCO 2016 ): Prospective single-institution database of inoperable, nonmetastatic HCC treated with RFA (249 lesions, 161 patients) or SBRT (83 lesions, 63 patients). Larger tumor correlated with worse freedom from local progression for RFA but not SBRT. Lesions ≥2 cm had increased freedom from local progression with SBRT; no difference for smaller lesions. Similar acute grade 3+ complications and 1- and 2-yr overall survival.

• Sanuki (Acta Oncol 2014). 185 pts with single HCC ≤5 cm treated with SBRT. 40 Gy/5 fx for Child-Pugh A, 35 Gy/5 fxfor Child-Pugh B. 3-yr LC 89–91%, OS 66–72%. Acute grade ≥ 3 toxicity 13%.

Radiation Techniques

Simulation and Field Design

• Supine with arms out of field.

• Use Vac-Lok or SBRT body fixation.

  • 3D treatment planning. IV contrast with planning CT to visualize tumor. Consider MRI fusion.

• Recommend 4D-CT imaging and/or respiratory gating motion management.

• CTV is typically the gross tumor.

• PTV = CTV + 0.5–1 cm margin (Often 5mm axially, and 8mm joint).

Dose Prescriptions

Mean Liver Dose (Liver-GTV)
50 Gy/5	13 Gy
45 Gy/5	15 Gy
40 Gy/5	15 Gy
35 Gy/5	15.5 Gy
30 Gy/5	16 Gy
27.5 Gy/5	17 Gy

Dose Limitations

• QUANTEC (Pan, IJROBP 2010) estimates <5% risk of radiation-induced liver disease (RILD):

  • Palliative whole liver: <28 Gy at 2 Gy/fx or <21 Gy at 3 Gy/fx.

  • Partial liver: mean dose (minus GTV) <28 Gy in 2 Gy fx.

  • SBRT: mean dose (minus GTV) <13 Gy/3fx, <18 Gy/6 fx, <6 Gy Child-Pugh B at 4–6 Gy/fx; >700 ml normal liver should receive <15 Gy in 3–5 fx.

  • Other SBRT dose constraints are evolving. Recommend following established constraints in published prospective or large retrospective studies.

Complications

• Fatigue, nausea/vomiting, gastritis/esophagitis, further decline in liver function, uncommonly GI bleeding or ulceration.

• RILD typically occurs 4–8 weeks after treatment but can be as early as 2 weeks or as late as 7 months later.

• Classical RILD (pts without underlying liver disease) may present with fatigue, abdominal pain, hepatomegaly, ascites, and elevated alkaline phosphatase out of proportion to liver enzymes.

• Nonclassical RILD (pts with underlying liver disease) present with elevated transaminase or jaundice.

• There is no specific RILD treatment. Supportive care with paracentesis for ascites and correction of coagulopathy, and consider steroids to reduce hepatic congestion.

Follow-Up

• Office visit, MRI or multiphase CT, and labs (LFTs, AFP) every 3–4 months for 2 years, then every 6 months. Chest CT as clinically indicated.

Gallbladder

Pearls

• <5000 cases per year in the USA.

• Most are asymptomatic and found incidentally during cholecystectomy.

• Chronic gallbladder inflammation is a risk factor, often from gallstones or chronic infection.

• Other risk factors: anomalous pancreaticobiliary duct junction, gallbladder polyps, primary sclerosing cholangitis, porcelain gallbladder.

• Resectable disease in ∼30% of patients.

• Frequently advanced stage at presentation; generally poor prognosis.

• Jaundice is associated with more advanced disease and worse prognosis.

Workup

• Labs: CBC, LFTs, chemistries, coagulation panel.

• Consider baseline serum CEA, CA 19–9.

• Ultrasound (RUQ or endoscopic) and/or abdominal CT scan and/or MRI.

• If suspicious mass is present, a biopsy is not necessary and can lead to peritoneal spread.

• Consider staging laparoscopy, especially for ≥T3, poorly differentiated, or positive margin on cholecystectomy.

• CT chest.

Staging : Gallbladder

Editors’ note: All TNM stage and stage groups referred to elsewhere in this chapter reflect the 2010 AJCC staging nomenclature unless otherwise noted as the new system below was published after this chapter was written.

Table 21.4 (AJCC 7TH ED., 2010)

Table 21.5 (AJCC 8TH ED., 2017)

Definition of Regional Lymph Node (N)

N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastases to one to three regional lymph nodes
N2	Metastases to four or more regional lymph nodes

Definition of Distant Metastasis (M)

M category	M criteria
M0	No distant metastasis
M1	Distant metastasis

AJCC Prognostic Stage Groups

When Tis...	And Nis...	And M is...	Then the stage group is...
Tis	N0	M0	0
T1	N0	M0	I
T2a	N0	M0	IIA
T2b	N0	M0	IIB
T3	N0	M0	IIIA
T1–3	N1	M0	IIIB
T4	N0–1	M0	IVA
Any T	N2	M0	IVB
Any T	Any N	M1	IVB

1. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Treatment recommendations

Table 21.6 TREATMENT RECOMMENDATIONS

Surgery

• Radical cholecystectomy with partial hepatectomy for node-negative patients with invasion of perimuscular connective tissue.

• Before definitive resection, consider staging laparoscopy for poorly differentiated, T3, or positive margin to rule out disseminated disease.

Adjuvant Therapy

• Combination gemcitabine/cisplatin improved survival compared to single-agent chemo for locally advanced/metastatic disease.

• Role of chemoRT uncertain but generally recommended for T2 N1, T3/4, +margins, or residual disease after surgery.

Studies

• Cubertafond (Hepatogastroenterol 1999): Review of surgical data for 724 patients with gallbladder cancer, treated with simple cholecystectomy. Five-year survival for node negative: Tis 93%, T1 18%, T2 10%. No 3-year survivors with T3/4 disease.

• SEER (Wang, JCO 2008): 4180 patients with resected gallbladder cancer, 18% received adjuvant RT. Adjuvant RT improved MS for ≥T2 N+ disease from 8 to 15 months. Some patients with ≥T2 N0 disease may benefit, but to a smaller degree. Nomogram derived in paper.

• SEER (Pollom, Cancer Medicine 2016): 2343 patients with unresectable biliary tract cancer (444 with gallbladder cancer). Longer median survival with RT (10 vs. 9.3 months, P = 0.02). Among patients who received chemo, RT was associated with improved survival (HR 0.82). For patients not receiving chemo, no RT benefit was seen. RT has declined since 1998.

• NCDB (Mantripragada, JNCI 2016): National Cancer Data Base analysis of 4775 patients with T2–3 or node-positive, nonmetastatic gallbladder cancer s/p resection with grossly negative margins. 29% received adjuvant chemo, 13.5% received adjuvant concurrent chemoRT. ChemoRT associated with a 6.7% improvement in 2-year OS for T3 or node-positive disease, but no difference by 5 years. No OS difference in overall cohort.

• Kim (Ann Surg Onc 2016): Retrospective multi-institutional analysis of 291 patients with gallbladder cancer undergoing R0 or R1 resection. 46% with T2 disease, 39% with T3, 38% with positive nodes. 21% with adjuvant chemo, 15% with adjuvant chemoRT. Improved OS with adjuvant chemo (HR 0.38) or chemoRT (HR 0.26). Only those with high-risk features (T3/T4, positive nodes, R1 resection) showed a benefit.

• Engineer (Ann Surg Onc 2016): Prospective study of 28 patients with stage III disease, treated with neoadjuvant chemoRT with 57 Gy in 25 fractions to gross disease and 45 Gy in 25 fractions to nodes with concurrent gemcitabine. 89% completed chemoRT, 71% with partial/complete response. 18 patients underwent surgery, and 14 patients had R0 resections. Median OS 20 months. 5-year OS 24% for entire group and 47% for those with R0 resection.

• SWOG S0809 (Ben-Josef, JCO 2015): Phase II with 79 patients with resected gallbladder carcinoma or extrahepatic cholangiocarcinoma, stages pT2-4 or node positive. Received gemcitabine/capecitabine x 4 cycles, then chemoRT with 45 Gy to regional nodes and 54–59.4 Gy to tumor bed with concurrent capecitabine. 52% with grade 3 and 11% with grade 4 adverse effects. Overall 2-year survival 65%; median OS 35 months.

• ABC-02 (Valle, NEJM 2010): Phase III RCT of 410 patients with locally advanced or metastatic cholangiocarcinoma, gallbladder, or ampullary cancer. Randomized to cisplatin and gemcitabine vs. gemcitabine alone. Combination chemo with better median OS for (11.7 vs. 8.1 mo), median PFS (8 vs. 5 months). More neutropenia with combination chemo but similar neutropenia-associated infection rate.

Radiation Techniques

Simulation and Field Design

• Supine with arms up out of field.

• Use Vac-Lok or alpha cradle to stabilize torso.

• CT scan for treatment planning. Consider IV and/or oral contrast.

• Cover tumor bed and regional lymph nodes including porta hepatis, pericholedochal, celiac, and pancreaticoduodenal.

• Consider 4D-CT and/or respiratory gating.

Dose Prescription

• 45 Gy/25 fx followed by boost to reduced fields, 50.4–54 Gy to tumor bed/+margins, up to 54–55.8 Gy to gross disease (respecting normal tissue tolerance).

Dose Limitations

• Small bowel <45–50.4 Gy/25–28 fx.

• Spinal cord <45 Gy/25 fx.

• Liver (see previous section).

• Kidney ≤1/3 receiving ≥20 Gy.

Complications

• Fatigue, nausea, vomiting, loose bowel movements, gastritis.

• Small risk of RILD.

• Uncommon: bowel ulceration or necrosis, small bowel obstruction, rarely fistula formation.

Follow-Up

• Consider exam and imaging every 6 months for 2 years if clinically indicated, then annually up to 5 years, with CEA and CA 19-9 as clinically indicated.

Bile Duct

Pearls

• Divided into intrahepatic (IHCC, ~20%) and extrahepatic (EHCC) cholangiocarcinoma.

• Intrahepatic includes small or large ducts proximal to the bifurcation of the common hepatic duct.

• Extrahepatic includes perihilar (Klatskin) tumors and distal segments.

• Risk factors: primary sclerosing cholangitis (~10% lifetime risk), congenital biliary tree abnormalities, hepatolithiasis, chronic tapeworm infection, Thorotrast. Possible association with cholecystitis.

• Cholecystectomy decreases risk of cholangiocarcinoma.

• Can present concurrently with hepatocellular carcinoma.

• ∼55% of patients are lymph node positive at diagnosis.

Workup

• H&P: For extrahepatic – jaundice, hepatomegaly, pruritis, dark urine, clay-colored stool, pain, weight loss, fever. Intrahepatic may have RUQ pain, weight loss, may be asymptomatic.

• Labs: CBC, LFTs, chemistries, coagulation panel, CA 19–9, CEA, AFP (rule out HCC), hepatitis B/C.

• Right upper quadrant US and/or abdominal multiphasic CT and possibly MRI/MRCP.

• EUS/ERCP with biopsy.

• EGD and colonoscopy.

• Chest CT.

• Consider staging laparoscopy before or in conjunction with resection to rule out disseminated disease.

• Biopsy not necessary for suspicious mass on imaging.

• If potential transplant candidate, refer to transplant center prior to biopsy.

Table 21.7 STAGING (AJCC 7TH ED., 2010): INTRAHEPATIC BILE DUCT

Table 21.8 STAGING (AJCC 7TH ED., 2010): PERIHILAR BILE DUCT

Table 21.9 STAGING (AJCC 7TH ED., 2010): DISTAL BILE DUCT

Table 21.10 STAGING (AJCC 7TH ED., 2010): AMPULLA OF VATER

Staging (AJCC 8TH ED., 2017)

Table 21.11 INTRAHEPATIC BILE DUCT

Definition of Regional Lymph Node (N)

N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis present

Definition of Distant Metastasis (M)

M category	M criteria
M0	No distant metastasis
M1	Distant metastasis present

AJCC Prognostic Stage Groups

When T is…	And N is…	And M is…	Then the stage group is…
Tis	N0	M0	0
T1a	N0	M0	IA
T1b	N0	M0	IB
T2	N0	M0	II
T3	N0	M0	IIIA
T4	N0	M0	IIIB
Any T	N1	M0	IIIB
Any T	Any N	M1	IV

Table 21.12 PERIHILAR BILE DUCT

Definition of Regional Lymph Node (N)

N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreaticoduodenal, and portal vein lymph nodes
N2	Four or more positive lymph nodes from the sites described for N1

Definition of Distant Metastasis (M)

M category	M criteria
M0	No distant metastasis
M1	Distant metastasis

AJCC Prognostic Stage Groups

When T is…	And N is…	And M is…	Then the stage group is…
Tis	N0	M0	0
T1	N0	M0	I
T2a–b	N0	M0	II
T3	N0	M0	IIIA
T4	N0	M0	IIIB
Any T	N1	M0	IIIC
Any T	N2	M0	IVA
Any T	Any N	M1	IVB

Table 21.13 DISTAL BILE DUCT

Definition of Regional Lymph Node (N)

N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis to one to three regional lymph nodes
N2	Metastasis to four or more regional lymph nodes

Definition of Distant Metastasis (M)

M category	M criteria
M0	No distant metastasis
M1	Distant metastasis

AJCC Prognostic Stage Groups

When T is…	And N is…	And M is…	Then the stage group is…
Tis	N0	M0	0
T1a	N0	M0	IA
T1a	N1	M0	IIIA
T1b	N0	M0	IB
T1b	N1	M0	IIIA
T2	N0	M0	IB
T2	N1	M0	IIIA
T3a	N0	M0	IIA
T3a	N1	M0	IIIA
T3b	N0	M0	IIB
T3b	N1	M0	IIIA
T4	Any N	M0	IIIB
Any T	N2	M0	IIIB
Any T	Any N	M1	IV

Table 21.14 AMPULLA OF VATER

Definition of Regional Lymph Node (N)

N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Metastasis in one to three regional lymph nodes
N2	Metastasis in four or more regional lymph nodes

Definition of Distant Metastasis (M)

M category	M criteria
M0	No distant metastasis
M1	Distant metastasis

AJCC 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

1. Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

Treatment recommendations

Table 21.15 TREATMENT RECOMMENDATIONS

Surgery

• Complete surgical resection is the most effective treatment.

• Surgical procedure depends on tumor location and extent of disease.

  • Partial hepatectomy or lobectomy for intrahepatic tumors.

  • Roux-en-y hepaticojejunostomy for hilar tumors.

  • Pancreaticoduodenectomy for distal lesions.

  • Liver transplant.

• Include portal lymphadenectomy.

• Contraindications to resection: lymph nodes beyond porta hepatis, distant metastases. Highly selected cases of multifocal disease can be considered for resection.

• Palliative options – biliary enteric bypass, percutaneous transhepatic biliary drainage, stents.

Adjuvant Therapy

• Limited data; no standard adjuvant regimen.

• Risk factors for local recurrence: lymphovascular invasion, perineural invasion, positive node(s), primary ≥5 cm.

Studies

• Todoroki (IJROBP 2000): 63 patients. Treatment: surgical resection. RT given to 28/47 with microscopic disease and 13/14 with gross residual disease. 5-year OS with RT 32 months vs. surgery alone 13.5 months. RT group OS: IORT + EBRT 39%, IORT alone 17%, EBRT alone 0%. LRC with RT 79% vs. with surgery alone 31.2%. IORT dose recommendations - 20 Gy, 8 MeV electrons, 6 cm cone.

• Schoenthaler (Ann Surg 1994): UCSF experience. 129 patients, retrospective, extrahepatic ducts only. Treatment: 62 patients surgery alone, 45 patients surgery + conventional RT (46 Gy median), 22 patients surgery + charged particles (60 GyE median). MS: 6.5 months with surgery, 11 months with surgery + EBRT, 14 months with surgery + particles, 7 months with gross residual disease, 19 months with microscopic residual disease, and 39 months with negative margins.

• Alden (IJROBP 1994): Unresectable disease. Higher RT doses improve survival. MS: 44 Gy = 4.5 months, 45–54 Gy = 18 months, >54 Gy = 24 months. Recommended dose is 45 Gy EBRT with a 25 Gy intraluminal brachytherapy boost.

• Crane (IJROBP 2002): 52 patients, locally advanced, unresectable treated with RT + chemo (73% of patients, PVI 5FU). Median time to local progression: 9 months after 30 Gy, 11 months after 36–50.4 Gy, 15 months after 54–85 Gy (p = ns). MS 10 months. Grade 3 toxicity similar in all groups.

• Borghero (Ann Surg Oncol 2008): Retrospective analysis of 65 patients with extrahepatic bile duct adenocarcinoma treated with curative-intent resection (S). For those with high-risk of local regional recurrence (42 patients), adjuvant chemoradiation (S-CRT) was implemented. Five-year OS and LRR for S- vs. S-CRT groups were 36% vs. 42% and 38% vs. 37%, respectively.

• Nelson (IJROBP 2009): Retrospective analysis of 45 patients undergoing resection followed by concurrent chemoradiation. Thirty-three patients underwent adjuvant radiotherapy and 12 neoadjuvant radiotherapy. Five-year OS, DFS, and LRC were 33%, 37%, and 78%, respectively. Median survival was 34 months. Patients treated neoadjuvantly showed a trend toward longer 5-year OS (53% vs. 23%) but was not statistically significant.

• Tse (JCO 2008): Phase I trial with 41 patients (31 with HCC and 10 with intrahepatic cholangiocarcinoma ), unresectable Child-Pugh class A treated with 6-fraction SBRT. Median dose 36 Gy. 12% with grade 3 liver enzymes, no grade 4/5 toxicity. Median survival of IHC was 15 months.

• Ben-David (IJROBP 2006): Retrospective single-institution experience of 81 patients with extrahepatic cholangiocarcinoma or gallbladder cancer, all treated with surgery (35% R0/R1) and adjuvant 3D RT to mean dose 58.4 Gy. 54% with concurrent chemo. Median OS 14.7 months, median PFS 11 months. R0 resection was only predictive factor; R1 and R2 outcomes similar. 69% of failures were locoregional.

• Wang (JCO 2013): Nomogram for intrahepatic cholangiocarcinoma treated with partial hepatectomy. Independent factors for survival: CEA, CA 19-9, tumor diameter and number, vascular invasion, lymph node involvement, direct invasion, local extrahepatic metastasis.

• Al-Adra (Eur J Surg Oncol 2015): Systematic review of 12 retrospective studies involving 298 patients treated with Y-90 microspheres for unresectable intrahepatic cholangiocarcinoma. Most had undergone prior treatment. Median overall survival 15.5 months. Stable disease in 54%, partial response in 28%.

• Tao (JCO 2015): Single-institution retrospective analysis of 79 patients with inoperable intrahepatic cholangiocarcinoma, treated with RT +/− chemo. Median OS 30 months, no significant treatment-related toxicities. RT dose correlated with 3-year OS: 73% for BED >80.5 Gy vs. 38% with lower doses.

• Horgan (JCO 2012): Analysis of 20 studies including 6712 patients with gallbladder and bile duct tumors who underwent surgery with curative intent. Nonsignificant improvement in overall survival with any adjuvant therapy compared to surgery (pooled odds ratio 0.74, P = 0.06). Chemo or chemoRT with more benefit than RT alone (OR 0.39, 0.61, and 0.98, respectively). Greatest benefit of adjuvant therapy in node-positive disease (OR 0.49).

• SWOG S0809 (Ben-Josef JCO 2015): Phase II with 79 patients with resected gallbladder carcinoma or extrahepatic cholangiocarcinoma, stages pT2-4 or node positive. Received gemcitabine/capecitabine x 4 cycles, then chemoRT with 45 Gy to regional nodes and 54–59.4 Gy to tumor bed with concurrent capecitabine. 52% with grade 3 and 11% with grade 4 adverse effects. Overall 2-year survival 65%; median OS 35 months.

• ACTICCA-1: Ongoing phase III trial of adjuvant gemcitabine and cisplatin vs. observation for resected colangiocarcinoma or muscle-invasive gallbladder carcinoma.

Radiation Techniques

Simulation and Field Design

• Supine with arms up out of field.

• Use Vac-Lok or alpha cradle to stabilize torso.

• CT scan for treatment planning. Consider IV and/or oral contrast.

• Cover tumor bed, porta hepatis, celiac axis + 1–2 cm margin.

• Consider extending field up to 3–5 cm into liver to cover additional intrahepatic bile duct length for margin as indicated, respecting liver tolerance.

• Add additional margins as needed to account for organ motion secondary to breathing, or perform 4D CT to define ITV. Consider respiratory gating.

Dose Prescription

• 45 Gy/25 fx to large field described above.

• Additional boost dose should be given. Options include EBRT with conedown to tumor bed up to 54–60 Gy total; ¹⁹²Ir intraluminal brachytherapy (20–25 Gy); IORT at time of surgery.

Dose Limitations

• See liver section.

Complications

• Fatigue, nausea, vomiting, loose bowel movements, gastritis.

• RILD uncommon as much of the liver can be excluded from the field.

• Cholangitis after brachytherapy.

• Small bowel damage (ulcer, bleeding, obstruction).

Follow-Up

• No data to support aggressive surveillance imaging.

• Consider imaging every 6 months for 2 years if clinically indicated, then annually up to 5 years.