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From OncoLog, January 2014, Vol. 59, No. 1

Medical Advances Improve Bile Duct Cancer Treatment

By Jill Delsigne  

Cholangiocarcinoma, the most common bile duct cancer, is a clinically silent disease in its early stages; patients usually present with advanced disease, which carries a poor prognosis.

In fact, patients with advanced cholangiocarcinoma have an average overall survival of only 1 year. But advances in diagnostics, radiation therapy, surgical resection, and targeted therapy are improving outcomes for patients with this disease.

Classification and staging

Cholangiocarcinomas are classified on the basis of their anatomical location: intrahepatic, perihilar, or extrahepatic. The importance of tumor location is reflected in the extensive changes to the staging of cholangiocarcinoma made in 2009, when the American Joint Committee on Cancer published the seventh edition of its cancer staging manual. Thomas Aloia, M.D., an associate professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, served on the committee that wrote these revisions. According to Dr. Aloia, “This new classification system recognizes the unique features of each tumor site instead of lumping all three categories together as one disease.” Correctly identifying the site of cholangiocarcinoma and accurately staging the cancer are crucial to determining the best possible treatment.

Image: CT of intrahepatic cholangiocarcinoma
Left: A computed tomography image shows an intrahepatic cholangiocarcinoma before radiation therapy. Right: In an image of the same patient after radiation therapy, the uniform dark gray color indicates dead tumor tissue, which is surrounded by healthy tissue spared by the radiation.

To enable physicians to more accurately diagnose and stage these tumors, Chusilp Charnsangavej, M.D., a professor in the Department of Diagnostic Radiology from 1983 to 2013, developed a computed tomography (CT) protocol for cholangiocarcinoma derived from a multiphasic thin-section pancreatic CT protocol. Dr. Charnsangavej’s innovations include the rapid injection of contrast material (4–5 mL per second for a total of 120–150 mL of contrast agent). The cholangiocarcinoma CT protocol results in much clearer CT images of the bile duct than was previously possible.

Standard treatment options

Therapy decisions for cholangiocarcinoma—most important, whether potentially curative surgery is possible—depend upon the size and location of the tumor, the presence or absence of metastases, and the patient’s general health.

The preferred initial treatment for cholangiocarcinoma has been surgery, when possible. However, only 10% of cholangiocarcinomas are surgically resectable.

Operable intrahepatic cholangiocarcinomas may require partial hepatectomy or hepatic lobectomy. To resect unilateral perihilar cholangiocarcinomas, surgeons may have to remove part of the liver, the involved bile duct, and the gallbladder. Perihilar cholangiocarcinomas with bilateral hepatic duct involvement may warrant a liver transplant. Occasionally, removal of a perihilar or extrahepatic cholangiocarcinoma requires a pancreatoduodenectomy, also called a Whipple procedure.

If a cholangiocarcinoma cannot be completely removed, surgeons may bypass the blocked area and place stents to help keep the bile duct open. “One important cause of death in this disease is biliary sepsis that occurs secondary to obstruction of the bile duct and uncontrolled infection,” said Milind Javle, M.D., an associate professor in the Department of Gastrointestinal Medical Oncology. “Patients with this cancer are at risk of infections like cholangitis that need appropriate attention to biliary stent management and expertise in gastrointestinal endoscopy.”

Other treatments for cholangiocarcinoma include radiation therapy and chemotherapy. Unresectable cholangiocarcinoma may be treated with radiation, chemotherapy, or a combination of the two. For resectable tumors, chemotherapy and/or radiation can be used preoperatively to reduce the size of the tumor before surgery, but they are more often given as postoperative adjuvant therapy.

The most common chemotherapy regimen for cholangiocarcinoma is gemcitabine with cisplatin or oxaliplatin; gemcitabine with capecitabine also is commonly used. For some patients, gemcitabine as a single agent is an appropriate choice of therapy. Regardless of the treatment modality, physicians must be careful not to damage too much healthy liver tissue, as patients need an adequate future liver remnant to survive.

Innovations in surgery

Cholangiocarcinomas with blood vessel involvement were previously considered unresectable, but advances in surgery have made potentially curative surgery possible in patients with such tumors. Surgeons can now perform extended liver resections that include the blood vessels because of advances in surgical techniques for blood vessel reconstruction.

A small group of patients with early-stage cholangiocarcinoma qualifies for liver transplantation. MD Anderson participates in a program in which such patients are selected according to a multimodality treatment protocol to undergo chemotherapy, radiation therapy, and surgical staging of their disease. After cancer treatment is done at MD Anderson, the patients are placed on a waiting list for a transplant, which is done at one of several transplant programs in the region. “Treating the cancer before liver transplantation is an important advance for patients who meet all the criteria,” Dr. Aloia said. He added that the program is currently focused on patients with early-stage cholangiocarcinoma because these patients do extremely well after the transplant.

Advances in radiation therapy

Advances in radiation therapy techniques in the past 5 years have allowed radiation oncologists to control for organ motion during treatment. These advances have greatly improved radiation treatment for intrahepatic cholangiocarcinoma. The radiation oncologists at MD Anderson use special CT protocols for cholangiocarcinoma to guide their treatment planning simulations to accurately target tumors.

Biliary Tract Cancer Conference

Thomas Aloia, M.D., an associate professor in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, will lead the first consensus conference dedicated to biliary tract cancers, which include cholangiocarcinomas and gallbladder cancers, in San Francisco, beginning January 15, 2014. This conference will gather representatives from three major associations (Americas Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology, and the Society for Surgery of the Alimentary Tract) to discuss the multidisciplinary treatment of cholangiocarcinoma and to establish current practice guidelines.

Image-guided radiation therapy and proton therapy allow the delivery of high doses of radiation to cholangiocarcinomas while sparing nearby sensitive structures such as the stomach and intestine and preserving as much of the liver as possible. MD Anderson is one of the few institutions that have a CT scanner in the treatment room for imaging during the radiation procedure, allowing physicians to see organ movement and to identify where the radiation is deposited in real time.

Dr. Javle and Christopher Crane, M.D., a professor in the Department of Radiation Oncology, will be leading a recently approved phase III trial comparing chemotherapy followed by image-guided high-dose radiation therapy to chemotherapy alone in patients with unresectable cholangiocarcinoma. Dr. Crane said that the trial is based on results from a P01 grant–funded phase II study done in collaboration with Massachusetts General Hospital of image-guided proton therapy in a similar cohort of patients. “The majority of primary tumors were successfully controlled with a 3-week course of proton therapy,” Dr. Crane said. “We hope that the phase III trial will confirm these results.” This trial will include intensity-modulated radiation therapy and proton therapy as options and will begin enrolling patients at MD Anderson and other institutions soon. Dr. Crane is hopeful about the new technique. “High-dose radiation for unresectable intrahepatic cholangiocarcinoma appears to have a dramatic survival benefit,” he said, “but this procedure must be done carefully.”

Drs. Crane and Aloia recently developed a new technique that allows radiation therapy for patients with unresectable cholangiocarcinoma near the stomach. Before, these patients could not receive radiation therapy because of the damage that would be done to the stomach. Using the new procedure, surgeons insert a spacer between the stomach and the liver to create enough distance (about an inch) to safely deliver high doses of radiation to the tumor.

Advances in targeted therapy

“Not only is cholangiocarcinoma diverse in terms of anatomical location, but it is also very diverse at the genetic level,” Dr. Javle said. “At MD Anderson, we are establishing a biliary cancer working group of clinical and research faculty and advocates who are committed to eradicating this cancer. The focus of our research is to assess any possible targeted therapy approaches.”

Much of the group’s research involves determining which genetic mutations are clinically relevant in cholangiocarcinoma. The KRAS gene, for example, is mutated in 30% of patients with cholangiocarcinoma, and some targeted therapies are less effective in patients with mutations to this gene. Dr. Javle said that the majority of cholangiocarcinoma patients—those without KRAS mutations—could be candidates for cetuximab, erlotinib, or treatments that are directed against the epidermal growth factor receptor pathway. The results of early studies of such targeted therapies in patients with cholangiocarcinoma are promising.

Dr. Javle said testing for other oncogenes in cholangiocarcinomas can help guide therapy for patients with the disease. His group has found mutations in the ERBB2, BRAF, and FGFR genes as well as in genes responsible for chromatin modification, such as BAP1, ARID1A, and PBRM1. Finding genetic mutations might allow physicians to identify patients with subtypes of cholangiocarcinoma that can be treated with targeted therapies in addition to standard therapy.

Dr. Javle said, “If we can identify what diverse genetic types exist and then tailor therapy individually to those diverse types, we could alter the survival curve of this disease in the near future.”

MD Anderson has reached out to international research groups to continue exploring better treatment options for cholangiocarcinoma. Through the Global Academic Programs initiative, MD Anderson researchers and their international collaborators are investigating tissue banking, chemosensitivity studies, and molecular genetic profiling. Dr. Javle, for example, is collaborating with institutions in Chile and Thailand, and MD Anderson researchers have teamed with other international hospitals to develop collaborative strategies to combat cholangiocarcinoma.

Just as collaboration is essential in cholangiocarcinoma research, teamwork is key to treating patients with the disease. Dr. Javle said, “The treatment for this disease is complicated and in my view is best administered in a tertiary cancer center by an experienced multidisciplinary team. We need the services of experienced gastrointestinal endoscopists; we need experienced surgeons to operate; and innovative radiation techniques must be available for optimal management of this complex cancer.”

FURTHER READING

Aloia TA, Charnsangavej C, Faria S, et al. High-resolution computed tomography accurately predicts resectability in hilar cholangiocarcinoma. Am J Surg. 2007;193:702–706.

Yoon SS, Aloia TA, Haynes AB, et al. Surgical placement of biologic mesh spacers to displace bowel away from unresectable liver tumors followed by delivery of dose-intense radiation therapy. Pract Radiat Oncol. 2013 Aug 29. [Epub ahead of print]

For more information, contact Dr. Thomas Aloia at 713-563-0189, Dr. Christopher Crane at 713-563-2300, or Dr. Milind Javle at 713-792-5434.

Other articles in OncoLog, January 2014 issue:

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