Bile Duct Cancer Treatment Options: How Do You Choose between Surgery and Transplant?
Lewis R. Roberts, MB, ChB, PhD
Associate Professor of Medicine, Director, Hepatobiliary Neoplasia Clinic, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, MN
The critical elements in the care of patients with cholangio-carcinoma (CCA) are early and accurate diagnosis, classification, and staging, which allow selection of the best therapy. Since outcome is dependent on disease stage, it is important to identify individuals at high risk (e.g. primary sclerosing cholangitis [PSC]) and to diagnose CCA early. Given the relative rarity of the disease, screening the general population will not be cost-effective unless it is coupled with screening for more common cancers, such as aerodigestive cancers.1
Classification and staging
CCA has two main subtypes with different therapeutic options. Intrahepatic CCAs arise beyond the secondary radicles of the left and right biliary systems. Extrahepatic CCAs include perihilar CCAs, which extend from the secondary radicles to the cystic duct, and distal bile duct cancers, which extend from the cystic duct to the ampulla of Vater.2
CCA is currently staged according to the tumor-node-metastasis system.3 This system has limitations because the majority of CCA patients are not candidates for surgery. Other prognostic factors are the presence of lobar atrophy and/or vascular encasement, resolution of jaundice with stenting, and performance status.4 Recently, depth of tumor invasion, assessed histologically, has improved survival prediction.5
Diagnosis of CCA
My approach to the diagnosis of CCA proceeds from non-invasive to invasive:
1. The CA19-9 can be useful as a confirmatory test. Levels above 100 U/ml occur in about 50 percent of patients with CCA; levels above 1,000 U/ml suggest extrahepatic metastases, provided the patient does not have cholangitis, which can raise the CA19-9 into the thousands.
2. Chest X-ray or chest CT to exclude metastases.
3. Contrast MRI with magnetic resonance cholangiopancreatography localizes masses and strictures, and shows delayed enhancement of CCA masses in the venous phase. CCAs are typically hypointense on T1-weighted MRI and moderately hyperintense on T2-weighted images. There may be enhancement, thickening and irregularity of the bile duct wall. Metastatic lymphadenopathy may be seen; however, patients with PSC or cirrhosis may have benign hilar lymphadenopathy.
4. ERCP or percutaneous transhepatic cholangiography, brushing for cytology and fluorescence in situ hybridization (FISH), and biopsy if feasible. Because of the desmoplastic stromal reaction surrounding malignant biliary cells, CCAs are difficult to diagnose by cytology. FISH employs hybridization of fluorescent DNA probes complementary to the centromeric regions of chromosomes 3, 7 and 17, and the 9p21 locus of the cyclin dependent kinase inhibitor 2A (p16INK4a) tumor suppressor gene. After diagnostic tissue is obtained, biliary drainage by stent or tube placement can be performed.
5. For patients who are candidates for curative surgery or transplantation, I favor EUS to assess the hilar or regional lymph nodes, with aspiration of suspicious nodes. It is critically important not to sample the primary tumor at EUS (or percutaneously), unless the patient is not a candidate for liver transplantation. The protocol of liver transplantation for hilar CCA excludes patients in whom the bile duct wall has been breached because of the high risk of tumor seeding.
6. Positron emission tomography-CT showed significantly higher accuracy over CT in the diagnosis of regional lymph node metastases and distant metastases.6
Selection of therapy for CCA
Because of the survival advantage after successful surgical resection or liver transplantation, these therapies are preferred if technically feasible.
Typically, because of the shortage of donor organs, patients who qualify for surgical resection are not considered as candidates for liver transplantation, despite having limited disease compatible with the transplant protocols. These patients may elect to pursue transplantation from a living related donor. Because a number of patients enrolled in a liver transplant protocol have intra-abdominal metastases at the staging laparoscopy/laparotomy that precludes transplantation, survival in the liver transplant protocol is approximately equivalent to survival after successful surgical resection.7 Conversely, in a significant number of patients, surgical resection is aborted because of unrecognized intrahepatic, hilar or distant metastatic disease.
The technical feasibility of surgical resection should be determined by an experienced hepatobiliary surgeon (this is discussed in Dr. Fong’s perspective). If surgery is not feasible and the patient is otherwise a candidate, we refer for evaluation for possible liver transplantation.
Liver transplantation is the optimal treatment for the small group of highly-selected patients who are diagnosed at a stage in which it is feasible (described more fully in Dr. Heimbach’s perspective). Our recently published 14-year experience with liver transplantation with neoadjuvant chemoradiation shows that, on an intention-to-treat basis, one-, three- and five-year patient survival were 82 percent, 63 percent and 55 percent, respectively. For patients who received a transplant, one-, three- and five-year survival were 90 percent, 80 percent and 71 percent.8
When surgery may be feasible, but is associated with a high risk of technical failure, we discuss the pros and cons with the patient and allow them substantial input into the decision. This is often difficult because of the recognition that a failed surgical resection usually precludes later transplantation. Patients with PSC and CCA have relatively advanced fibrotic disease. These patients will not tolerate resection and should undergo liver transplantation if they meet criteria.
Medical therapy for CCA includes endoscopic or percutaneous biliary stenting and photodynamic therapy, which promote biliary patency. Although there are no highly effective chemotherapy regimens, gemcitabine is used for palliation. Gemcitabine is attractive because of its low side-effect profile. Occasionally, patients show remarkable responses to therapy, suggesting that there is a role for studies to determine tumor response to chemotherapy regimens.
Gemcitabine may be used in combination with cisplatin, oxaliplatin or capecitabine.9 In a small series, adjuvant gemcitabine significantly improved survival after surgery for hilar CCA.
Radiation therapy for CCA can improve survival, as seen in patients receiving chemo-radiation therapy but falling out of protocol before transplantation. A major concern with radiation is the propensity for repeated episodes of cholangitis, which can be disabling.
Conclusion
Although CCA is a highly fatal malignancy with limited treatment options, recent advances in therapy, including liver transplantation, advances in surgical resection and progress in the development of targeted therapies, hold promise for improvement in therapeutic options for patients with CCA. |
References
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