Commentary (Krishnan/Crane): Radiation Therapy in the Treatment of Cholangiocarcinoma

Drs. Czito, Anscher, and Willett provide an informative and comprehensive review of the role of radiation therapy in the treatment of cholangiocarcinoma. The absence of level 1 evidence defining the role of radiation therapy and chemotherapy in the treatment of cholangiocarcinomas makes understanding the experiences of referral centers in the United States, Europe, and Asia particularly important. The authors review historical data and provide insights into treatment techniques, toxicities, and novel treatment options. Within this framework they are able to summarize treatment guidelines and provide a useful compendium for the multidisciplinary team taking care of these patients.

Classification

The most important clinical factor affecting prognosis of cholangiocarcinoma is resectability of the primary tumor, which is highly dependant on location. Surgical resection requires liver resection for all intrahepatic cholangiocarcinomas, resection of the hepatic duct bifurcation with possible liver resection for perihilar tumors, pancreaticoduodenectomy for distal tumors, and radical cholecystectomy often with segmental liver resection for gallbladder cancers.

To permit comparisons with the surgical literature, it is sometimes useful to use the classification system commonly employed by our surgical colleagues. Admittedly, even among surgical series there is considerable inconsistency in nomenclature. One simple system of classification divides these tumors into intrahepatic, perihilar, and distal cholangiocarcinomas, with corresponding resectability rates of 50%, 60%, and 90% respectively.[1]

Postoperative Adjuvant Treatment of Resected Tumors

There is a dearth of clinical data addressing the issue of postoperative adjuvant radiation therapy for gallbladder cancers. Completion radical cholecystectomy is recommended after incidental carcinoma noted at laparoscopic cholecystectomy. The patterns of failure reported by one series suggest a predominantly distant pattern of failure, although local recurrences still do occur.[2] Available systemic treatment agents have poor response rates, but newer regimens with activity are worthy of further study either in conjunction with radiation therapy or by themselves.

Distal cholangiocarcinomas are similar to pancreatic cancers in many ways. They are typically located in proximity to the head of the pancreas, resection requires a pancreatico-duodenectomy, and the proximity of the duodenum or jejunal reconstruction limits the dose of radiation that can be safely given. However, they generally have a better prognosis due to earlier presentation with obstructive jaundice.

As with pancreatic cancers, the postoperative adjuvant treatment of distal cholangiocarcinomas has been the topic of some debate. A relatively small study (25 patients) suggested that radiation therapy may not be needed in resected distal cholangiocarcinomas.[3] Soon thereafter, a relatively large study (80 patients) from Johns Hopkins Hospital demonstrated a lack of benefit from postoperative adjuvant radiation therapy for distal cholangiocarcinomas.[1] The same group later reported an improvement in overall survival for patients with distal cholangiocarcinomas who underwent postoperative adjuvant chemoradiation therapy when chemotherapy was given concurrently and adjuvantly. Similar improvements in outcome have been reported with other postoperative adjuvant chemoradiation therapy studies. High-quality level 1 evidence may never be available, but these data support chemoradiation as a reasonable adjuvant treatment option for distal cholangiocarcinomas.

The data seem more consistent in the case of hilar cholangiocarcinomas. Hilar cholangiocarcinoma has a predominantly locoregional pattern of spread, and patient mortality is most often due to complications related to locoregional tumor recurrence. The mucosal and radial margins are nearly always close and frequently positive. As outlined by the authors of this review, multiple series have demonstrated a survival advantage for postoperative adjuvant radiation therapy of hilar cholangiocarcinomas. Most series demonstrate a survival benefit to the addition of postoperative adjuvant chemoradiation therapy. However, these studies are difficult to interpret due to selection bias. It may be argued that these benefits are due to the selection of healthier or more favorable patients for postoperative treatment. In contrast, patients with poor pathologic features could be selectively referred for postoperative chemoradiation.

For example, the pattern at our institution over the past 20 years has been selective referral of patients with positive lymph nodes or positive margins for chemoradiation. The use of chemoradiation has improved the outcome in these poor-prognosis patients such that their outcome is similar to node-negative/margin-negative patients, suggesting that treatment has made up for these poor prognostic features. The median dose was 50.4 Gy, and intraluminal brachytherapy was not used. No recurrences centered on the ductal remnant, suggesting that intraluminal brachytherapy would not have improved outcome. Due to the higher risk of local tumor-related mortality after surgery alone, perhaps an even stronger case can be made for the benefits of chemoradiation in this group of patients than in the case of distal cholangiocarcinomas.

Definitive Treatment of Unresectable Tumors

As summarized by the authors, multiple small studies have concluded that radiation therapy for unresectable cholangiocarcinomas improves overall survival when compared to no treatment (or stenting alone). These studies have traditionally used 50 Gy of external-beam radiation therapy with or without radiosensitizing chemotherapy. It seems reasonable to assume that a standard 50-Gy dose of radiotherapy (even with radiosensitizing chemotherapy) is unlikely to cure an adenocarcinoma. In addition, multiple small series have failed to demonstrate an improvement in survival with dose escalation using intraluminal brachytherapy. As outlined by one group, this may be attributable to increased toxicity from duodenal stenoses, gastrointestinal bleeding, and cholangitis. These toxicities may be avoidable with three-dimensional (3D) brachytherapy planning techniques currently available.

The possibility of radiation dose escalation is limited by the presence of radiosensitive gastrointestinal mucosa near the tumor. Distal cholangiocarcinomas are less likely to be amenable to intraluminal brachytherapy or external-beam radiation therapy boosts due to the proximity to duodenal mucosa. Similarly, proximity to the hepatic flexure and duodenal mucosa often limits the ability to escalate radiation dose to gallbladder cancers.

However, dose escalation for unresectable hilar and intrahepatic cholangiocarcinomas is technically more feasible. This is especially true with technologic advances in delivery of radiation therapy. Three-dimensional conformal therapy, four-dimensional (4D) planning, 3D brachytherapy planning, intensity-modulated radiation therapy, proton therapy, and respiratory-gated therapy have the theoretical potential to improve therapeutic outcomes. We routinely use intravenous contrast-enhanced 4D computed tomography (CT) scanning to accurately define these tumors and account for their movement with respiration.

Selected series have shown a benefit to dose escalation for primary hepatic tumors (cholangiocarcinoma and hepatocellular carcinoma).[4-6] However, these studies are subject to selection bias and the possibility that smaller tumors receive a higher dose of radiation, thus explaining the observed dose-response effect. Nevertheless, these results are promising and this experience is worth replicating in a multicenter prospective studies.

Toxicity

The authors succinctly summarize the expected and observed toxicities associated with treatment of cholangiocarcinomas using radiation therapy. In our experience, patients seem to tolerate radiation therapy for hilar and intrahepatic cholangiocarcinomas and gallbladder cancers surprisingly well, particularly if the dose to gastroduodenal mucosa can be minimized. We have also not encountered many gastrointestinal complications with brachytherapy, as long as we are able to minimize the gastrointestinal mucosal dose either by generating a CT-based 3D plan or by using the endoscopic retrograde cholangiopancreatography (ERCP) endoscope as a surrogate for duodenal mucosa while planning.

The normal tissue complication probability model for radiation-induced liver disease developed by the University of Michigan has served as a useful tool to help guide the choice of treatment plans.[7] Multidisciplinary collaboration with interventional radiologists and gastroenterologists is important to permit early recognition of and intervention for biliary drainage problems.

Other Approaches

The promising outcomes from the Mayo Clinic using neoadjuvant chemoradiation therapy for hilar cholangiocarcinomas followed by transplantation have led to refinement of the algorithm for listing of patients on the United Network for Organ Sharing. It is worth noting that these results have not led to more widespread use of preoperative radiation therapy for resectable hilar cholangiocarcinomas. This is probably related to the perception that preoperative radiation therapy increases the risk of surgical complications, especially while dissecting around the porta hepatis. In contrast to transplant patients where the unirradiated bile duct, hepatic artery, and portal vein are transected distally, resectable patients require dissection of the irradiated proximal portal triad.

In select scenarios, with close cooperation between the diagnostic radiologist, the radiation oncologist, and the surgeon, a preoperative radiation approach is still worth exploring, especially if there is the possibility of a close or positive margin despite a major hepatectomy.

Conclusions

The authors' comprehensive review of the literature, insightful conclusions, and generalized treatment guidelines provide a valuable resource for the multidisciplinary team taking care of patients with biliary tumors. We endorse the need for prospective evaluation of novel treatment approaches in these tumor sites, but low patient numbers make these prospects challenging. The technologic advances in radiation therapy permitting dose escalation without increasing toxicity and potential novel chemotherapeutic (and biologic) agents would be worthy of such exploration.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Nakeeb A, Pitt HA, Sohn TA, et al: Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224:463-475 (incl discussion), 1996.

2. Jarnagin WR, Ruo L, Little SA, et al: Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: Implications for adjuvant therapeutic strategies. Cancer 98:1689-1700, 2003.

3. Alden ME, Waterman FM, Topham AK, et al: Cholangiocarcinoma: Clinical significance of tumor location along the extrahepatic bile duct. Radiology 197:511-516, 1995.

4. Ben-Josef E, Normolle D, Ensminger WD, et al: Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 23:8739-8747, 2005.

5. Kawashima M, Furuse J, Nishio T, et al: Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 23:1839-1846, 2005.

6. Chiba T, Tokuuye K, Matsuzaki Y, et al: Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res 11:3799-3805, 2005.

7. Lawrence TS, Ten Haken RK, Kessler ML, et al: The use of 3-D dose volume analysis to predict radiation hepatitis. Int J Radiat Oncol Biol Phys 23:781-788, 1992.