Radiation Therapy in the Treatment of Cholangiocarcinoma

Intraoperative Radiotherapy

FIGURE 2
Intraoperative Radiation Therapy

FIGURE 3
HAM Applicator

Intraoperative radiotherapy (IORT) is a technique that delivers single high-dose irradiation to a tumor at surgery. Because the tumor and surrounding normal tissues are directly visualized, nontarget tissues can be shielded or excluded from the IORT field. Low-energy photons (eg, Ir-192) or electrons are typically used for IORT, allowing rapid dose falloff with distance, resulting in minimal dose to the surrounding normal critical structures. Small bowel, stomach, duodenum, liver, and other normal structures can be directly shielded or displaced during the procedure, thus sparing these tissues. Additionally, tumor or tumor-bearing tissues outside the biliary system can be treated. IORT doses range from 10 to 20 Gy in a single fraction. This is usually combined with a course of EBRT dose of 45 to 50.4 Gy over 25 to 28 fractions. Figures 2 and 3 demonstrate the use of IORT with an Ir-192 source via a Harrison-Anderson-Mick (HAM) applicator.

Iwasaki et al reported on the use of IORT alone or in conjunction with EBRT in 20 patients with biliary cancers. They described a 2-year survival rate of 17% in patients receiving IORT and subtotal resection vs a rate of 9% after resection alone.[44] Harvard investigators reported similar results for 15 (12 primary, 3 recurrent) patients treated with IORT with or without EBRT. Median survival of 12 patients with primary disease was 14 months, with disease control in the porta hepatis achieved in 5 of 10 evaluable patients.[45] Monson et al described similar results from the Mayo Clinic with IORT for unresectable cholangiocarcinoma in 13 patients who experienced a median survival of 16.5 months.[46]

Todoroki et al from the University of Tsukuba, Japan, reported on 63 patients with locally advanced cholangiocarcinoma. Forty-two patients received adjuvant radiotherapy (12 IORT alone, 22 IORT plus EBRT, 8 EBRT only). Following extended resection, almost all (41/42) patients had microscopic or macroscopic residual disease. Patients receiving adjuvant radiotherapy for microscopic residual disease experienced improved 5-year survival (34%) vs resection alone (14%). Similarly, local control rates were improved in patients receiving adjuvant radiotherapy vs resection alone (80% vs 31%). The best survival rates were seen in patients who underwent IORT and EBRT (5-year survival: 39%).[47] The results of IORT studies are summarized in Table 3.

Radiosensitization With Chemotherapy

The role of chemotherapy alone or in combination with radiation therapy for biliary carcinomas is undefined. The justification of 5-FU-based chemotherapy in combination with radiation therapy is extrapolated from the survival benefit achieved with this combination in other gastrointestinal malignancies, including pancreatic cancer.[50-52] Multiple studies have employed the use of different combinations and schedules of chemotherapy concurrent with radiotherapy. However, patient numbers are too small to derive definitive conclusions. Despite this, results appear to support the use of concurrent chemotherapy.

In an early study, Kopelson et al from Massachusetts General Hospital reported the feasibility and potential benefit of chemotherapy with radiation therapy.[9] Minsky and coworkers from Memorial Sloan-Kettering Cancer Center evaluated an intensive combined-modality treatment for biliary carcinoma in 12 patients, using EBRT, brachytherapy, and concurrent 5-FU/mitomycin chemotherapy with or without resection.[36] Five patients underwent biliary drainage, and the remaining seven had a biopsy or subtotal resection of the tumor. Median survival for all patients was 17 months, and the 4-year survival rate was 36%. Four patients had no evidence of disease at 16, 30, 40, and 64 months, respectively.

Similarly, Alden and colleagues from Thomas Jefferson University Hospital described an intensive approach in 19 patients with extrahepatic biliary cancers using EBRT, brachytherapy, and chemotherapy (5-FU alone or in combination with doxorubicin(Drug information on doxorubicin) or mitomycin(Drug information on mitomycin)). The 2-year survival rate was 30%.[14] Foo et al reported the Mayo Clinic experience in the treatment of extrahepatic bile duct carcinoma, showing a nonstatistical improvement in survival in patients receiving concurrent 5-FU-based chemotherapy vs EBRT alone.[33]

TABLE 4
Concurrent Chemoradiotherapy for Biliary Carcinomas

In contrast, Crane et al from M.D. Anderson Cancer Center reported no significant survival impact with the addition of 5-FU-based chemotherapy. Because of the lack of significant added toxicity from chemotherapy in these studies and the efficacy of combined therapy in other gastrointestinal malignancies, the authors advised the concurrent administration of 5‑FU with radiation therapy for treatment of biliary cancer patients.[31] A summary of selected studies is listed in Table 4.[9,14,35,53]

Novel Radiation Techniques

Newer radiation therapy modalities include hyperfractionated (multiple daily fractions) EBRT, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and four-dimensional (4D) treatment delivery. Reports from the University of Michigan Medical Center described 22 patients with hepatobiliary cancers treated with concurrent intrahepatic arterial fluorodeoxyuridine and twice daily (hyperfractionated) 3D-CRT to either 48 or 66 Gy (depending on the volume of liver irradiated) at 1.5 to 1.65 Gy per fraction. The median survival of all patients was 16 months, with an actuarial 4-year survival of 20%. Overall freedom from hepatic progression at more than 2 years was approximately 50%.[54-56]

In a follow-up report, Ben-Josef et al treated 46 patients with intrahepatic cholangiocarcinomas with high-dose conformal EBRT with hepatic arterial floxuridine. Median survival was 13.3 months, which the authors felt compared favorably to historical controls. Increasing radiation dose was associated with improved prognosis, with patients receiving ≥ 75 Gy experiencing significantly improved survival vs those receiving lower doses.[57] These results appear promising, notably in the setting of biliary carcinomas with a significant intrahepatic ductal component.

Conventional CT-based radiation planning (3D-CRT) allows the physician to define target and nontarget tissues using computer-based 3D images. Optimal beam orientation is determined to facilitate treatment of tumor with shielding of normal tissues. Recent improvements in radiation planning and delivery have been achieved through the use of computer-aided beam orientation and optimization, referred to as IMRT. With this treatment approach, an "inverse-planning" technique is adopted in which the planning physician defines normal and target tissues, normal tissue dose constraints, and dose to the target volume (eg, tumor ± regional nodes). Computer search algorithms are used to select preferred (and sometimes nonconventional) beam orientations as well as allowing for areas of high and low intensity within the same field using dynamic blocks. This permits optimized dose distribution within the defined target as well as decreased normal tissue irradiation with a decrease in treatment-related side effects. Because less radiation is delivered to normal tissue, EBRT dose escalation may be possible.

Further refinement in treatment delivery has been accomplished with 4D treatment planning and delivery. In the abdomen, movement of tumor and normal organs occurs with normal respiratory motion. This contributes to uncertainty during radiation planning and treatment delivery. To compensate for this, an additional margin is often added to each treatment field, resulting in increased treatment of normal tissues and potentially limiting dose escalation. Gating radiation therapy to normal organ and tumor motion may potentially be beneficial by reducing margins, with enhanced conformal treatment and improved tolerance. Four-dimensional treatment planning incorporates organ/tumor motion, using externally or internally placed fiducial markers that track the tumor during respiration and permit precise treatment delivery. These and other techniques are under active investigation.