Radiotherapy With Hepatic Transplant
Because of the poor prognosis of patients with cholangiocarcinoma, investigators have pursued novel treatment approaches to improve outcomes. One method has been to combine chemotherapy and radiation therapy with liver transplantation. A report from the University of Pittsburgh described 61 patients with biopsy-proven cholangiocarcinoma who received a median "preoperative" radiation dose of 49.5 Gy (range: 5.4-85 Gy), including four patients who received intraluminal brachytherapy. Concurrent chemotherapy was also administered in 30 patients. The 5-year survival rate for the entire cohort was 24%. Patients undergoing complete resection had a 54% 5-year survival. Seventeen patients with orthotopic liver transplantation (lymph node-negative) experienced a 5-year survival of 65%. This compared favorably to a 22% 4-year survival in a prior report from this group. The authors concluded that complete surgical resection in combination with combined-modality therapy, with or without transplantation, can be curative in the majority of patients with biliary carcinoma.[58,59]
A report from the Mayo Clinic described 56 patients undergoing "neoadjuvant" EBRT, brachytherapy, and 5-FU-based chemotherapy for early-stage perihilar cholangiocarcinoma. A total of 28 patients underwent transplantation. The 5-year survival rate for all patients was 54%. In patients undergoing transplantation, 5-year survival was 82%. These authors concluded that neoadjuvant chemoradiotherapy with transplantation achieved excellent results for patients with localized and node-negative hilar cholangiocarcinoma. Treatment strategies of chemoradiation with liver transplantation are under active investigation.
Charged particles such as protons and helium ions have also been used in the treatment of gallbladder and biliary cancers. In contrast to photons, the energy deposition patterns from charged particles are highly localized. This is due to a disproportionate absorption of the majority of their energy at the end of their track range—the so-called Bragg peak. The dose unit of charged particles is the Gray equivalent (GyE). Figure 4 demonstrates the energy deposition patterns of 15 MV photons, 9 MeV electrons, 30 MeV neutrons, 160 MeV protons, and Ir-192 seeds. Figure 5 compares dose distributions using IMRT techniques with conventional photon therapy and proton therapy in resected biliary cancer.
Schoenthaler and coworkers at the University of California at San Francisco retrospectively reviewed their experience of 129 patients with extrahepatic biliary ductal carcinoma. At total of 62 patients were treated with surgery alone, and 67 patients received adjuvant radiotherapy (45 with conventional EBRT and 22 with charged particles using helium and/or neon). Patients who underwent gross total resection or received greater than 45 GyE after any surgical procedure were defined as being treated with curative intent. Fifteen patients were defined as being treated with curative intent in the surgery-alone group, 35 in the surgery plus conventional radiotherapy group, and 18 in the surgery plus charged particle group. Five patients in the conventional radiotherapy group also received Ir-192 brachytherapy.
Improved survival was seen in patients undergoing gross total resection vs those undergoing subtotal resection or biopsy only. Patients with microscopic residual disease experienced an improved median survival with the addition of adjuvant irradiation, more so after charged-particle therapy (P = .0005) but also with conventional radiotherapy (P = .01). Patients with gross residual disease had a less marked but still statistically significant improved survival after irradiation (P = .05 for conventional radiotherapy and P = .04 for charged-particle radiotherapy). Median survival with surgery alone, surgery plus conventional radiotherapy, and surgery plus charged-particle therapy was 6.5, 11, and 14 months for the entire group, respectively, and 16, 16, and 23 months for patients treated with curative intent (P = .008).
Based on patterns-of-failure data in resected biliary cancers and the previously discussed data, EBRT concurrent with 5-FU-based chemotherapy should be considered in the pre- or postoperative setting. A similar approach is adopted in patients with locally advanced disease. Patients are restaged following treatment and reevaluated for resection. CT-based treatment planning and multiple-field techniques are used. Customized field shaping is achieved using a computerized blocking system (multileaf collimation) to shield nontarget tissues. High-energy (6-15 MV) photons are used to treat all fields.
Figure 6 represents a digitally reconstructed (computer-generated) radiograph of a patient with a proximal/mid-duct cholangiocarcinoma treated in the preoperative setting. Figures 7 and 8 demonstrate axial images with varying beam orientations used in treatment. Figure 9 demonstrates a dose-volume histogram (DVH) generated through 3D planning. The DVH displays the volume of tumor and surrounding normal tissues and organs receiving a specified radiation dose level.
In the preoperative or postoperative setting, doses ranging from 45 to 54 Gy are delivered at 1.8 Gy/fraction, 5 d/wk, using multiple fields. The final dose is selected individually for each case, depending on factors such as extent of resection, volume of normal tissues irradiated, and so forth. For patients with locally advanced or unresectable disease, "definitive" chemoradiation is utilized. Typically, patients receive EBRT to a dose of 50.4-54 Gy at 1.8 Gy per day, 5 d/wk. As in potentially resectable patients, concurrent 5-FU-based chemotherapy is delivered. Selected patients with a good performance status receive an additional dose by Ir-192 implant (typically 20-30 Gy by LDR techniques, delivered at approximately 10 Gy/d, prescribed 0.5 to 1 cm from the source).
Toxicities and Complications
Potential acute toxicities of EBRT and chemotherapy include nausea, vomiting, anorexia, dehydration, skin irritation, distal esophagitis, gastritis, duodenitis, fatigue, weight loss, asymptomatic elevation in liver function tests (usually alkaline phosphatase), and mild immunosuppression. Most symptoms resolve following treatment completion. Treatment-related late complications include gastrointestinal bleeding (especially duodenal), biliary fibrosis and duct stricture, cholangitis, hepatitis, and small bowel obstruction.
Complications attributable to radiation therapy may be difficult to define precisely, as many patients do not survive long enough to exhibit such effects. Signs and symptoms suggesting treatment-related complications may be nonspecific and potentially related to tumor progression (ie, gastrointestinal bleeding, biliary fibrosis and stricture, cholangitis, and hepatitis). Additionally, many patients have undergone numerous therapeutic interventions that carry similar complications.
When EBRT doses exceed 55 Gy in the treatment of gallbladder and biliary carcinomas, approximately 30% to 50% of patients will develop late effects such as duodenal hemorrhage, ulceration, and obstruction. Care must always be taken to respect the dose tolerance of surrounding normal structures to radiation therapy. When treating with EBRT of 45 to 50 Gy at 1.8 to 2.0 Gy per fraction combined with the brachytherapy boost, gastrointestinal complications including bleeding and ulceration have been reported.[12,15,48] Therefore, LDR brachytherapy doses should be limited to 20 to 30 Gy or less when combined with "curative" EBRT doses of 45 to 50.4 Gy. In addition, it is important to ensure that implant sources not pass beyond the ampulla. This reduces the risk of later bleeding.
When treating biliary carcinomas with IORT, doses in excess of 20 Gy should be avoided to minimize the risk of late treatment effects such as hepatic artery injury. As above, efforts should be made to shield nontarget tissues from the treatment field by mobilization and shielding devices.
Conclusions and Future Directions
Gallbladder and bile duct cancers carry a poor prognosis. Innovative treatment strategies are mandatory to improve upon these poor results. Surgery, when feasible, remains the only curative treatment modality. Most patients undergoing resection are found to have adverse pathologic features (eg, lymphovascular invasion, positive lymph nodes, positive margins), and are often referred for adjuvant irradiation.
It appears that radiotherapy (with or without chemotherapy) decreases the risk of locoregional recurrence and possibly improves survival. Given the rarity of these malignancies, no randomized data exist proving a survival advantage. Patients receiving concurrent chemoradiation appear to have an improved survival compared to radiotherapy alone, possibly due to a radiosensitization effect of chemotherapy.
An aggressive multimodality approach should be considered in appropriate patients who are potentially resectable by combining surgery and EBRT with concurrent chemotherapy. Intraoperative radiotherapy and/or brachytherapy with Ir-192 may be useful for selected patients. For unresectable cancers, combined-modality therapy with EBRT and chemotherapy is advised, followed by restaging and consideration of resection and IORT in select patients. Intraluminal brachytherapy may allow further dose escalation in patients who are not suitable for resection.
Despite these efforts, the majority of patients with biliary cancers will succumb to their disease. The integration of novel therapeutic strategies in this disease is indicated, including combined-modality therapy with transplant as well as potential radiosensitizers such as epidermal growth factor receptor antagonists, receptor tyrosine kinase inhibitors, and vascular endothelial growth factor inhibitors. When combined with traditional chemotherapeutic agents and precision radiation techniques such as IMRT and 4D treatment delivery, these strategies may improve local control and survival in these patients.
Financial Disclosure: Dr. Czito receives research support from Roche Pharmaceuticals.