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- Materials and Methods
Cholangiocarcinoma (CCA) is a malignancy of biliary epithelial cells. Up to 70% of CCA arises in the perihilar region and frequently encases the portal veins and hepatic vasculature, making resection difficult or impossible . Five-year survival for patients with perihilar CCA is poor at 10–40% .
Neoadjuvant chemoradiation combined with liver transplantation (LT) offers select patients with otherwise incurable CCA the opportunity for curative surgical therapy. Protocols have been developed to treat patients with unresectable CCA or CCA in the setting of primary sclerosing cholangitis (PSC), which typically involve radiosensitizing 5-fluorouracil (5-FU), external beam radiation (XRT), endoscopic brachytherapy and maintenance chemotherapy with 5-FU or capecitabine up until LT [1, 3, 4]. A multicentered, retrospective study of 287 patients with unresectable perihilar CCA who were treated with multimodality neoadjuvant therapy followed by LT reported a 5-year intention-to-treat survival rate of 53% and a posttransplant recurrence-free survival rate of 65% . In this series, 75% of patients underwent brachytherapy as a means of providing local control.
However, this same study  showed no mortality benefit from the addition of brachytherapy (recurrence-free survival HR 1.05; 95% CI: 0.60–1.85). A retrospective study of 34 patients with malignant obstructive jaundice who underwent percutaneous transhepatic cholangiography (PTC) and stent placement found no significant difference in mortality between patients who received brachytherapy and those who did not . Another study of 64 patients with locally advanced hilar CCA found no significant difference in survival time or stent patency for patients treated with XRT and brachytherapy versus patients treated with XRT alone . Furthermore, brachytherapy has also been shown to have a significant side-effect profile, including 6% gastro-duodenal ulcer, 22% stent displacement and 30% ribbon misplacement rates .
Photodynamic therapy (PDT) is an ablative therapy that causes local tumor destruction by inducing either apoptosis or necrosis in cells that have accumulated a photosensitizer and are exposed to a targeted, activating light of a specific wavelength and intensity . Additionally, PDT-induced thrombosis of vessels and immune response may contribute to further tumor destruction [9, 10]. The photosensitizer porfimer sodium preferentially accumulates in malignant biliary tissue , which might also limit damage to the surrounding normal biliary tissue .
Endoscopic retrograde cholangiopancreatography (ERCP)-directed PDT and biliary stenting has been shown to be effective at treating biliary strictures caused by CCA and offers a survival advantage over ERCP with biliary stenting alone [10, 13]. While neoadjuvant PDT has been shown in a small series to be capable of providing local control in patients undergoing liver resection , the use of PDT as an alternative therapy to brachytherapy for providing local control to patients with CCA awaiting LT has not been studied. Our aim was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT.
- Top of page
- Materials and Methods
Multimodality neoadjuvant therapy followed by LT offers a potentially curative option to a select group of patients with unresectable CCA. However, the reported protocol dropout rate for patients in a study of 12 US transplant centers was 25% after a median of 4.6 months . The main reasons for dropout included treatment intolerance, tumor progression and evidence of metastatic disease. For patients with confirmed malignancy, posttransplantation 5-year intention-to-treat survival was only 50% . New methods for improving local tumor control might allow more patients to ultimately undergo LT and improve survival.
Palliative PDT has been shown to improve survival in patients with CCA. Median survival for patients with CCA treated with PDT in several studies ranged from 6 to 21 months, which was more than double that of controls who underwent biliary stenting alone [2, 13]. This treatment effect has been observed in larger studies and randomized controlled trials [15-17]. A meta-analysis of six studies that included 170 patients who received PDT and 157 patients who had biliary stenting alone found a statistically significant survival advantage in the PDT arm with a weighted-mean-survival difference of 265 days . Although PDT cannot provide curative treatment for invasive CCA, as it only induces necrosis to a depth of about 4–6 mm (Figure 4) , the mortality benefits of PDT are similar to those reported after partial tumor resection .
Figure 4. Low-power histology from an explanted liver (Patient 4). This photomicrograph shows the resected bile duct 4.5 weeks after PDT. Much of the biliary epithelium is gone and has been replaced by granulation tissue following ERCP-directed PDT. White arrows denote a portion of normal bile duct. Black arrows denote a portion of bile duct with post-PDT effect of inflammation and fibrosis. The asterisk denotes an area of necrosis adjacent to PDT site. No tumor visible on this photomicrograph. Special thanks to Edward B. Stelow, MD, for his assistance in obtaining this histopathology photomicrograph. ERCP, endoscopic retrograde cholangiopancreatography; PDT, photodynamic therapy.
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To the best of our knowledge, no other transplant centers routinely use ERCP-directed PDT as part of their LT protocol for CCA. It is noteworthy that all of our patients treated with ERCP-directed PDT made it to LT, with none forced to drop out due to locoregional spread or development of metastasis. While it would not be appropriate to generalize or overstate the results from a series of four patients, if one takes into consideration the broader data about PDT, it is conceivable that the addition of PDT to an LT protocol for CCA might result in fewer patient dropouts because of improved locoregional control and/or decreased episodes of cholangitis. PDT might also offer a reduction in the number of ERCPs and/or PTCs required for biliary decompression, thereby minimizing potential hospitalizations and chemotherapy interruptions. In this study, two patients had improved stricturing noted on post-PDT ERCP. All four patients required fewer ERCPs or PTCs after PDT. Two patients had fewer episodes of cholangitis following PDT.
PDT has been shown to be a feasible addition to other multimodality treatments for CCA, and repeated PDT sessions have been shown to be safe and well tolerated . In our series, side effects of PDT included nausea, vomiting and abdominal pain, and no life-threatening reactions or drug toxicities occurred. One of the biggest disadvantages to PDT is acquired photosensitivity, which can last up to 6 weeks following treatment. Reported rates of photosensitivity range from 0% to 25% . Only two patients (50%) in our series exhibited mild photosensitivity several weeks following PDT. There is a theoretical risk that patients who get their transplants within a 4- to 6-week window following PDT treatment might sustain burns due to the halogen lamps used in the operating room (OR). One patient in this series (Patient 4) had ongoing mild photosensitivity after 4 weeks. A liver became available for him a few days later (at 4–5 weeks after PDT), and this patient tolerated LT well with no burns sustained on exposure to OR lights.
Use of PDT for treatment of CCA has not been approved by the US Food and Drug Administration, and at present this is an off-label use of this medication. Furthermore, ERCP-directed PDT requires specialized equipment and expertise. The cost of Photofrin is also a potential obstacle, with each 75-mg vial costing about $19 000 (a 75-kg person typically requires two vials). However, because of the evidence supporting use of PDT in CCA, Medicare and most private insurers (in our experience) will cover the cost of this medication for treatment of unresectable CCA. Despite the cost of ERCP-directed PDT (estimated charges of $47 253 at our institution), brachytherapy has a similarly high cost (estimated charges of $42 082) and requires an inpatient admission with special protocols due to the radioactive nature of the treatment.
This study is limited by its small number of patients, retrospective nature and lack of a control group. Additionally, two patients had longer pre-PDT treatment intervals as compared to their post-PDT (pre-LT) treatment intervals, due to clinical factors including organ availability. As such, some of our comparisons are prone to lead- and lag-time bias. Furthermore, the relatively short wait times between PDT and LT might have also contributed to our lower dropout rate.
In summary, ERCP-delivered PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT. As studies have shown that brachytherapy does not offer any additional mortality benefit, PDT is very likely to be no worse, and it has the potential to be a better form of neoadjuvant therapy for locoregional tumor control in these patients. A prospective, multicentered study would help to corroborate these preliminary findings.