Unresectable/Locally Advanced Disease
Palliative radiation therapy has frequently been employed in the management of patients with locally advanced and unresectable tumors. Palliative irradiation after biliary bypass prolongs survival in many studies. For example, Mayo Clinic investigators reported the outcome of 103 patients with unresectable cholangiocarcinoma. The 3-year survival rate was 9% for the entire group of patients. Multivariate analysis showed a significant survival benefit for patients receiving radiation therapy. Similarly, Cleveland Clinic investigators observed a survival advantage for patients with locally advanced disease who received EBRT vs those who did not (median survival: 12.2 vs 2.2 months).
Investigators from Rotterdam reported a 14% 2-year survival and 10-month median survival in 42 patients with unresectable extrahepatic biliary tumors who received EBRT with or without an Ir-192 implant boost. Patients undergoing subtotal resection followed by radiation therapy experienced a longer median survival than those receiving radiation alone (15 vs 8 months).
A report from M.D. Anderson Cancer Center described 52 patients with unresectable cholangiocarcinoma treated with radiation doses ranging from 30 to 85 Gy. Twenty-seven (52%) patients ultimately developed radiographic disease progression, and 20 of these experienced local recurrence. The first site of disease progression was local in 72% of cases. Median survival for all patients was 10 months, with 1- and 2-year survival rates of 44% and 13%, respectively. Increasing the radiation dose and the use of concurrent chemotherapy did not influence outcome.
Investigators from Erlangen reported on 25 patients with locally advanced or recurrent biliary malignancies. Patients received a median EBRT dose of 51 Gy. Four patients with Klatskin tumors underwent intraluminal brachytherapy, and 24 patients received concurrent chemotherapy. Median survival in all patients was 16.5 months, compared with 9.3 months in patients undergoing stenting alone. A summary of studies describing outcomes in patients with unresectable disease is shown in Table 2.[28-32]
Intraluminal Transcatheter Brachytherapy
Despite moderate- to high-dose EBRT, most patients with gallbladder and bile duct cancer die of complications secondary to local progression and obstruction of the biliary tree. Doses of 50 to 54 Gy in 1.8- to 2-Gy fractions are insufficient to eradicate all disease. Radiation therapy techniques such as intraluminal brachytherapy have been used alone or in conjunction with EBRT in the treatment of these malignancies.
Intraluminal transcatheter brachytherapy allows the delivery of radioactive sources such as Ir-192 to the tumor through a percutaneous transhepatic biliary drainage tube under fluoroscopic guidance or through catheters placed in the tumor bed during surgery. Advantages of intraluminal brachytherapy include focal delivery of high radiation doses with rapid dose falloff over a short distance from the radioactive source. This approach spares adjacent normal tissues. Typical doses delivered with intraluminal therapy range from 20 to 30 Gy prescribed to 0.5-1 cm from the source within the duct (low-dose rate). This treatment is often combined with a course of EBRT (45-50.4 Gy in 25-28 fractions).
Since the original report by Fletcher and coworkers on the use of intraluminal brachytherapy with Ir-192, many investigators have demonstrated the feasibility of using brachytherapy alone or in combination with EBRT for treating gallbladder and bile duct cancer.[11-13,30,33-39] Although no randomized trials have compared EBRT vs brachytherapy or combinations, studies have suggested enhanced survival for patients undergoing combination treatment with both techniques. Combined EBRT and intraluminal brachytherapy can also provide durable palliation.[14,40,41]
Institutional series have described long-term survival in unresectable patients with the use of EBRT and transcatheter brachytherapy boost. Foo et al reported the Mayo Clinic experience of 24 patients with un-resectable extrahepatic biliary ductal cancer treated to a median EBRT dose of 50.4 Gy in 28 fractions and median brachytherapy boost of 20 Gy at a 1-cm radius. Median survival for all patients was 12.8 months with a 5-year survival rate of 14%. Three patients were still alive at the time of the report at 10 years, 8.2 years, and 6.9 years since diagnosis. The authors recommended that Ir-192 catheter brachytherapy boost be limited to 20-30 Gy when combined with EBRT of 45-50 Gy in 25-28 fractions.
Of 20 patients treated with curative intent at Washington University, patients receiving an Ir-192 implant had an improved survival (15 months) vs patients who received EBRT alone (7 months). Japanese investigators reported the results of 93 patients with unresectable extrahepatic bile duct carcinoma (including 5 patients with metastatic disease) receiving EBRT and Ir-192 boost. EBRT was delivered at 2 Gy per fraction to a total dose of 50 Gy followed by an intraluminal boost to a mean dose of 39 Gy (range: 20-50 Gy). Median survival for all patients was 11.9 months. The 1- and 5-year survival rates were 50% and 4%, respectively. Four patients survived longer than 5 years. The locoregional failure rate was 44%, usually associated with distant metastases. No dose-response relationship to survival was observed.
Combining EBRT with intraluminal brachytherapy has also been shown to extend stent patency. Eschelman et al described a mean metal stent patency of 19.5 months and mean survival of 22.6 months in 11 patients with cholangiocarcinoma treated with EBRT plus brachytherapy. This compared favorably with the results of stenting alone on patients with malignant biliary obstruction (mean stent patency ranged from 5 to 10 months).
Takamura summarized the results in 88 patients undergoing metallic stenting with EBRT/Ir-192 therapy for unresectable disease. Forty-six (49%) patients developed reobstruction at a mean duration of 11.6 months posttherapy. In half of these patients, tumor recurrence resulted in obstruction. Cumulative biliary patency rates at 1 and 3 years were 52% and 29%, respectively. For 20 patients undergoing autopsy, obstruction from debris, sludge, stones, and bleeding was observed in 17. Figure 1 shows the placement of intraluminal Ir-192 seeds via a percutaneous transhepatic biliary drainage tube.
In contrast to low-dose-rate (LDR) brachytherapy, high-dose-rate (HDR) brachytherapy uses a high-activity source, allowing rapid dose delivery (generally over minutes) compared to LDR techniques, which often require several days to deliver treatment. University of Miami investigators described a phase I/II dose-escalation trial utilizing HDR brachytherapy. Eighteen patients with unresectable or incompletely resected extrahepatic biliary duct carcinoma received 45 Gy EBRT with concurrent 5-FU concomitant with HDR brachytherapy using either 1, 2, or 3 weekly fractions of 7 Gy delivered at 1-cm depth. Median survival was 12.2 months and 2-year survival 28%; three patients survived more than 5 years. Improved response was seen with increasing doses in the three groups (median survival: 9 vs 12 vs 20 months). The authors concluded that HDR brachytherapy of 21 Gy in three divided weekly treatments with 45 Gy and 5-FU-based chemotherapy is well tolerated.
Investigators from the University of Heidelberg described 30 patients undergoing palliative resection or with inoperable disease receiving HDR intraluminal brachytherapy using Ir-192. Most patients received weekly fraction sizes of 5 to 10 Gy, to a total dose of 20 to 45 Gy, along with EBRT to doses of 30 to 45 Gy. Median survival was 10 months, with a 3-year survival rate of 8%. Seven patients developed duodenal ulceration; however, in patients receiving 20 Gy in four fractions, only one patient developed this complication. The authors concluded that a treatment schedule of 40 Gy EBRT along with 20 Gy (5 Gy × 4) was appropriate for treatment of cholangiocarcinoma. The role of HDR brachytherapy in biliary cancers remains an ongoing area of investigation.
In sum, retrospective data suggest improved survival may be possible with the addition of intraluminal brachytherapy to EBRT. This combination may be beneficial due to increased delivery of radiation dose to the primary tumor along the bile ducts, where the highest volume of gross disease often exists. Table 3 summarizes the outcomes of selected studies utilizing intraluminal therapy.[33,37,39-42]