Recent advances in the treatment of cholangiocarcinoma include use of PDT, ortho-topic liver transplantation, and conformal radiotherapy, such as IMRT. The most promising results have been achieved with combinations of these techniques, including achievement of 5-year survival of greater than 75% with use of neoadjuvant chemoradiotherapy prior to orthotopic liver transplantation at the Mayo Clinic.10
has provided improved survival rates compared with rates reported with use of resection alone or resection followed by adjuvant therapy—eg, generally 5-year survival of 20% to 40%.10
The Mayo Clinic experience, including a report of no residual identifiable tumor in 16 of 38 liver specimens from patients receiving neoadjuvant chemoradiotherapy,10
suggests that cholangiocarcinoma is a chemoradiosensitive disease. The Mayo Clinic protocol requires collaboration of surgeons, medical oncologists, radiation oncologists, gastroenterologists, radiologists, and pathologists to achieve this success. The findings in our own cohort confirm that the multidisciplinary, multimodality treatment of unresectable cholangiocarcinoma is a tolerable treatment approach and may lead to significant improvements in patient outcome.
All 10 patients in our cohort tolerated the radiotherapy portions of their treatment, and the majority tolerated the complete course of capecitabine. In part, the tolerability reflects the close attention given this cohort by the gastroenterology team, with three patients undergoing stent revision for cholangitis during their chemoradiotherapy, with minimal breaks in treatment. The potential for this treatment approach to improve patient outcomes is highlighted by the course of patient 2 ( and ).
Patient 2, a 41-year-old white woman, was diagnosed with a Bismuth IV cholangiocarcinoma after presenting with obstructive jaundice. After her diagnosis in June 2005, she was noted to have peri-portal lymphadenopathy. She underwent a hilar lymphadenectomy in August 2005, revealing no evidence of tumor within these enlarged nodes. After a period of healing, she received a course of chemoradiotherapy in October 2005. Between June 2005 and February 2006, she suffered recurrent obstructive jaundice and underwent seven total stent placements/revisions, including one stent revision during her chemoradiotherapy that resulted in a 2-day break from treatment. Additionally, her capecitabine was discontinued for the last week of treatment due to increased transaminases. This elevation was likely from her obstruction, but capecitabine was held as a precaution. In December 2005, 6 weeks after completing her chemoradiotherapy, she received PDT treatment along with a stent revision. On her follow-up scans, she had substantial changes interpreted as postradiation changes or tumor progression. After a 3-month period with no stent revisions and relatively few symptoms, she underwent a cadaveric liver transplantation in May 2006.
As shown in , histologic specimens from her liver showed no evidence of viable tumor after chemoradiotherapy. Her postoperative course was complicated with several hospital admissions for upper gastrointestinal bleeding due to a duodenal ulcer as well as pseudomembranous colitis and portal vein thrombosis. After healing of these, follow-up scans have shown no evidence of disease, and repeat endoscopy has shown healing of her damaged duodenum. She remains with no evidence of disease 2 years after her initial diagnosis. This patient was the only one in this series who met our institution’s very strict transplantation criteria, including no metastatic disease on laparoscopy before and after chemoradiotherapy and excellent clinical condition predicting the ability to tolerate the operation. The clinical course of this patient highlights the interplay among the treatment modalities and the key role of stents and PDT in providing successful short-term symptom management that increases the ability to provide definitive treatment.
The treatment approach in the Mayo Clinic reports included a brachytherapy boost to the biliary tree, an effort to temporize patient course and decrease the likelihood of cholangitis prior to surgery. In our cohort, we used PDT in a similar manner, allowing us to successfully bridge a patient for a period of 3 months after chemoradiotherapy and PDT. During this time, the decision to attempt a transplant was strengthened by the patient’s continued smooth clinical course and lack of disease progression.
One constant concern regarding patients with cholangiocarcinoma is recurrent cholangitis. This can prove rapidly fatal if not addressed. None of the patients in our cohort is known to have died of cholangitis, and those who developed recurrent cholangitis were effectively treated with antibiotics and stent revision with little difficulty. This is in agreement with other reports.14
PDT involves the intravenous administration of a photosensitizing agent followed by its activation using light illumination of a specific wavelength, resulting in ischemic necrosis15
proportional to tissue oxygenation.18
The technique has shown benefit in the treatment of cholangiocarcinoma in both preclinical and clinical studies.
PDT was demonstrated to reduce human cholangiocarcinoma xenograft tumor volume by 60% in a mouse model.20
In uncontrolled human studies in which porfimer sodium-based PDT was combined with stenting, there was improvement in cholestasis and survival, and few complications related to porfimer sodium were observed.21
A prospective, randomized, controlled trial confirmed a significant advantage attributable to PDT in relief of jaundice, quality of life, and survival.25
Other reports have indicated improvements in patient outcomes with multimodality treatment of cholangiocarcinoma using fluoropyrimidines as radiosensitizing chemotherapy.26
The responses noted in surgical specimens have prompted evaluation of dose escalation. One group reported dose-escalation studies for hepatobiliary cancer with either systemic 5-fluorouracil (5-FU) or 5-FU infused via the hepatic vein that included 81 patients with unresectable cholangiocarcinoma.28
These patients received radiation doses between 23 and 88.2 Gy, with no association between dose and survival being found. Another study analyzed outcome by radiotherapy dose and found no statistically significant difference in patient survival or freedom from local progression with dose escalation.29
These studies were limited by small patient numbers, and there is little additional data available on dose escalation. Thus, it seems that dose escalation with chemoradiotherapy may offer control rates and potentially survival rates on par with the Mayo Clinic reports of liver transplant following chemoradiotherapy.
The use of helical tomotherapy IMRT in the treatment of the biliary disease presents some technical challenges, considering the high degree of conformality as well as the sliced-based nature of delivery. The greatest concern is that organ motion could result in both decreased tumor coverage and increased normal tissue dose. Our experience with target delineation with MRI and magnetic resonance cholangiopancreatography including MRI fusion suggests that this process is relatively accurate, in accordance with prior work.30
PTV expansions on the target included accommodation for respiratory excursion, though we were unable to directly measure this and relied on previously established conventions.31
Several reports have concluded that respiratory motion results in differences between the planned dose and the delivered dose when employing IMRT, though these differences appear to be clinically insignificant in magnitude, particularly when averaged over a treatment course.33
This was found to be true in the treatment of liver tumors, as well.35
The potential for these differences was specifically addressed with the helical tomotherapy device using a motion phantom, and despite the sliced-based delivery, this approach was found to result in clinically insignificant errors in dose delivered for treatment regimens greater than three fractions.36
In addition, helical tomotherapy daily image guidance permits accurate patient alignment, decreasing errors in delivery. Therefore, the coverage of the PTV using helical tomotherapy IMRT appears to be acceptable, despite respiratory motion. In addition, all hot spots are within the PTV, indicating that there is very little chance of delivering significantly increased dose to nearby normal organs, given the above considerations.
The experience reported here, particularly of the patient who underwent ortho-topic transplant, confirms that PTV coverage is adequate despite relatively tight margins, since that patient was noted to have a complete pathologic response. Other forms of nontomotherapy-based IMRT may provide the ability to further reduce the PTV for patients with cholangiocarcinoma with respiratory-gating or breath-hold techniques.
In summary, the multimodality team approach to unresectable cholangiocarcinoma may represent optimal care. This treatment strategy is tolerable and provides flexibility to address symptoms as required on a patient-specific basis. It also allows for the reassessment of patients on a regular basis and thus facilitates easier adjustments in patient care as needed. Our findings add some evidence to the growing body of literature indicating that cholangiocarcinoma is a chemoradiosensitive disease.