Liver and Bile Duct Cancer
Ghassan K. Abou-Alfa, William Jarnagin, Maeve Lowery, Michael D’Angelica, Karen Brown, Emmy Ludwig, Anne Covey, Nancy Kemeny, Karyn A. Goodman, Jinru Shia and Eileen M. O’Reilly
Summary of Key Points
Liver Cancer
• There is a continued rise of hepatocellular carcinoma (HCC) incidence especially in the Western hemisphere.
• HCC main risk factors are hepatitis B, hepatitis C, alcohol, and nonalcoholic steatohepatitis.
• Screening programs continue to evolve, but depend mainly on ultrasound and α-fetoprotein (AFP) evaluations.
• Staging of HCC depends on evaluating the two aspects of the disease: the cancer itself, and the commonly associated cirrhosis.
• Pathology evaluation may help distinguish variants or combined HCC and cholangiocarcinoma.
• Patterns of spread are hematogenous, and may involve lung and bones.
• Surgery, liver transplantation, and radiofrequency ablation (RFA), are the sole proven curative therapies for HCC.
• Locally advanced disease is generally treated with different forms of local therapies, including but not limited to, transarterial chemoembolization, bland embolization, radioembolization, and radiation therapy.
• Sorafenib is the sole drug approved for the treatment of advanced HCC, based on an improvement in survival compared with placebo.
• Future developments are likely to be dependent on the evaluation of combination therapies and/or the development of new targets.
• Future studies are most likely to entail enriched patient populations based on biology, risk factors, and/or etiology.
Biliary Tumors
• The majority of biliary tumors are adenocarcinomas.
• Despite their similarities, biliary tumors are now better understood as three different diseases: gallbladder cancer, extrahepatic, and intrahepatic biliary tumors, with different clinical and biological characteristics.
• Gallbladder resection may require resection of segments IVA and V of the liver plus a locoregional lymph node dissection for better tumor control and staging.
• Preoperative considerations for extrahepatic biliary tumors include percutaneous transhepatic biliary drainage.
• Surgical therapy for distal extrahepatic cholangiocarcinoma is a pancreaticoduodenectomy, as for all periampullary malignancies.
• No adjuvant therapy has been proven effective for biliary tumors.
• The standard of care for advanced disease consists of gemcitabine plus cisplatin based on the ABC-02 study.
1. Transplantation is effective therapy for HCC in patients:
B With any extent of disease in the liver provided there is no extrahepatic disease
C With limited disease defined by the Milan criteria
D With major vascular involvement
E None of the above—transplantation is not indicated in patients with HCC
2. Patient is a 63-year-old man with hepatitis B stage IV HCC with metastatic disease to the lung and bone. Patient’s Child-Pugh score is A6. What would be the standard-of-care treatment?
3. Why is a hepatic resection a necessary component of the surgical treatment of hilar cholangiocarcinoma?
A This resects occult metastatic disease.
B It makes the biliary reconstruction safer.
C It is associated with a significantly higher margin negativity and survival rate.
4. An otherwise healthy 55-year-old man presents with an incidentally diagnosed T2 gallbladder cancer after a laparoscopic cholecystectomy for symptomatic gallstones. The cystic duct margin was negative and the surgeon did not see any evidence of disseminated cancer at surgery. What is the next step in management?
A Palliative care, since the cancer has been disseminated and there are no treatment options
B Surgical exploration and partial hepatectomy to encompass the liver bed and portal lymphadenectomy if no distant metastatic disease is found
5. Level I evidence supports the use of which of the following combination chemotherapy regimen for treatment of stage IV biliary tract cancer?
1. Answer: C. Transplantation is effective treatment for patients with a limited volume of cancer within the liver, as defined by the Milan criteria. Patients with more extensive disease have an extremely high risk of recurrence and do not benefit from transplantation. Extrahepatic disease and major vascular involvement are both absolute contraindications.
2. Answer: A. Sorafenib is the only therapy that is approved as a standard of care for advanced HCC. In the SHARP trial, a phase III study, that randomized patients with advanced HCC and Child-Pugh A to sorafenib versus placebo, there was an improvement in median overall survival of 10.7 months versus 7.9 months (HR 0.69, P < 0.001) in favor of sorafenib. Although phase II studies of sorafenib plus doxorubicin and erlotinib plus bevacizumab did show an improvement in outcome with overall survival beyond the 1 year, these options could not be recommended pending ongoing clinical trials aimed at verifying those results. A difference in the magnitude of median overall survival between patients treated on sorafenib on the SHARP and another similar study conducted in the Asia-Pacific region suggested a possible correlation with the etiology of HCC, specifically hepatitis B versus hepatitis C. In a subset of hepatitis C and B patients enrolled in the SHARP study, median overall survival was 14 months versus 7.4 months and 9.7 months versus 6.1 months with placebo, respectively. A potential explanation is that the hepatitis C viral core protein can activate Raf-1 kinase in HCC cells, theoretically sensitizing them to sorafenib. This potential difference has also been noted in a subgroup analysis of patients treated with sorafenib as part of the phase III trial comparing first-line sunitinib to sorafenib. The magnitude of overall survival benefit with sorafenib varied widely based on etiology and ethnicity, ranging from 18.3 months for patients from ex-Asia with hepatitis C, to 7.9 months for patients outside of Asia with hepatitis C. Despite these discrepancies, these data are not enough to recommend any difference in usage of sorafenib based on etiology. Nonetheless, it is clear that future studies may very well be etiology and/or ethnicity specific based on the molecular basis of a specific therapy or combination of therapies
3. Answer: C. Bile duct resections without hepatic resection are associated with high positive margins and poor outcome. Hepatic resection that includes the central portion of the liver and the caudate lobe is associated with significantly higher margin negativity rates and better survival. Therefore hepatic resection is a recommended part of the routine resection for hilar cholangiocarcinoma
4. Answer: B. Hepatic resection and regional lymphadenectomy for localized but incidentally discovered gallbladder is the standard of care because this approach is associated with as good an outcome as those patients that present with recognized gallbladder cancer. Furthermore, re-resection is associated with dramatically better outcomes than cholecystectomy, along with a much higher long-term survival rate. This is true when matched for stage. Chemotherapy and/or radiation has never been proven to improve outcomes after cholecystectomy. It should not be assumed that the cancer has spread with no treatment options, as reoperation is associated with curative potential.
5. Answer: C. The ABC-02 trial was a randomized phase III trial comparing gemcitabine and cisplatin with gemcitabine alone in patients with advanced biliary tract cancers. Compared with gemcitabine, combination therapy significantly improved overall survival (11.7 months vs. 8.1 months, P < 0.001), progression-free survival (8.0 months vs. 5.0 months, P < 0.001), and disease control (81.4% vs. 71.8%, P = 0.049). Although other chemotherapy doublets, such as gemcitabine and oxaliplatin, gemcitabine and capecitabine, and oral or IV fluoropyrimidines with cisplatin,have shown comparable activity, these combinations have not yet been prospectively compared to gemcitabine and cisplatin. The addition of erlotinib to gemcitabine and oxaliplatin therapy failed to improve survival over chemotherapy alone in patients with advanced biliary tract malignancy, although subgroup analysis did show a modest progression-free survival benefit to the combination in patients with cholangiocarcinoma.
