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Photodynamic Therapy: Standard of Care for Palliation of Cholangiocarcinoma?

      Palliation of malignant biliary obstruction in patients with unresectable hilar cholangiocarcinoma (CCA) is challenging for surgeons, interventional radiologists, endoscopists, and radiation oncologists alike. Compared with distal bile duct obstruction where palliation is relatively easily achieved operatively and non-operatively, hilar CCA poses particular difficulties. The tumors involve bifurcation and spread progressively and inexorably in a proximal direction such that eventually too many branches of the intrahepatics are involved to permit stent placement to be effective. Indeed it, was Klatskin
      • Klatskin G.
      Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatitis An unusual tumor with distinctive clinical and pathological features.
      who described that these patients die of liver failure and cholangitis from biliary obstruction.
      Photodynamic therapy (PDT) is an ablative treatment for premalignant and malignant lesions. A photosensitizing drug is administered followed by application of a specific wavelength of light leading to intracellular activation of the drug and cellular injury.
      • Petersen B.T.
      • Chuttani R.
      • Croffie J.
      • et al.
      Photodynamic therapy for gastrointestinal disease.
      In addition, thrombosis of vessels and immune response may lead to tumor destruction.
      • Ortner M.A.
      • Dorta G.
      Technology insight: photodynamic therapy for cholangiocarcinoma.
      The wavelength of light necessary to cause activation is 630 nm and is provided by laser fibers that emit light of that wavelength. When used in the esophagus, the fibers are easily placed into the esophageal lumen because the endoscope is in a straightened position.
      The first report of PDT for CCA was published more than 15 years ago.
      • McCaughan Jr, J.S.
      • Mertens B.F.
      • Cho C.
      • et al.
      Photodynamic therapy to treat tumors of the extrahepatic biliary ducts: a case report.
      Since then there have been numerous studies using PDT for CCA — both basic science
      • Wong Kee Song L.M.
      • Wang K.K.
      • Zinsmeister A.R.
      Mono-L-aspartyl chlorin e6 (NPe6) and hematoporphyrin derivative (HpD) in photodynamic therapy administered to a human cholangiocarcinoma model.
      • Kiesslich T.
      • Berlanda J.
      • Plaetzer K.
      • et al.
      Comparative characterization of the efficiency and cellular pharmacokinetics of Foscan- and Foslip-based photodynamic treatment in human biliary tract cancer cell lines.
      • Oertel M.
      • Schastak S.I.
      • Tannapfel A.
      • et al.
      Novel bacteriochlorine for high tissue-penetration: photodynamic properties in human biliary tract cancer cells in vitro and in a mouse tumour model.
      and clinical. It is important to note that the patient selection, primary outcomes, types of fibers and fiber delivery vary between studies. It is also of importance to note that the passage of these fibers through a duodenoscope poses special challenges, particularly in passage around the tight angle in the duodenum toward the bile duct.
      The landmark clinical study using PDT for CCA was published by Ortner et al, nearly 10 years ago.
      • Ortner M.A.
      • Liebetruth J.
      • Schreiber S.
      • et al.
      Photodynamic therapy of nonresectable cholangiocarcinoma.
      Patients with Bismuth type III and IV CCA who did not have a fall in bilirubin levels of at least 50% after bilateral stent placement were treated with PDT. Laser light was delivered cholangioscopically using small caliber fibers. After treatment, a significant fall in bilirubin levels was achieved, and a sustained improvement in indices of quality of life was noted. The same lead investigator then performed a randomized prospective trial of plastic biliary stents alone versus plastic biliary stents and PDT in a similar patient population that failed to have a fall in serum bilirubin levels following bilateral biliary stent placement.
      • Ortner M.E.
      • Caca K.
      • Berr F.
      • et al.
      Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study.
      A significant increase in survival was seen in the PDT group (median survival 493 days vs 98 days). PDT also improved biliary drainage and quality of life over stent placement alone.
      Other groups have published similar results.
      • Berr F.
      • Wiedmann M.
      • Tannapfel A.
      • et al.
      Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival.
      • Wiedmann M.
      • Berr F.
      • Schiefke I.
      • et al.
      Photodynamic therapy in patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study.
      • Zoepf T.
      • Jakobs R.
      • Arnold J.C.
      • et al.
      Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy.
      • Dumoulin F.L.
      • Gerhardt T.
      • Fuchs S.
      • et al.
      Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma.
      • Zoepf T.
      • Jakobs R.
      • Arnold J.C.
      • et al.
      Photodynamic therapy for palliation of nonresectable bile duct cancer—preliminary results with a new diode laser system.
      These studies from outside the US have used thin, flexible, 400-μm diameter fibers. In addition, in some series, patients were re-treated 4–6 weeks later because of advanced Bismuth type IV tumors with residual segmental duct occlusions/stenoses or tumor-positive biopsies at a 1-month follow-up examination.
      • Berr F.
      • Wiedmann M.
      • Tannapfel A.
      • et al.
      Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival.
      There are limited publications using PDT for CCA from centers within the US. Indeed, nearly all reports have come from 1 center.
      • Rumalla A.
      • Baron T.H.
      • Wang K.K.
      • et al.
      Endoscopic application of photodynamic therapy for cholangiocarcinoma.
      • Harewood G.C.
      • Baron T.H.
      • Rumalla A.
      • et al.
      Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma.
      • Prasad G.A.
      • Wang K.K.
      • Baron T.H.
      • et al.
      Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma.
      This group uses standard FDA-approved fibers designed for use in the esophagus without the use of cholangioscopy. Fiber breakage occurs in about one third of patients.
      In this issue of Clinical Gastroenterology and Hepatology, Kahaleh et al,
      • Kahaleh M.
      • Mishra R.
      • Shami V.M.
      • et al.
      Unresectable cholangiocarcinoma: Comparison of Survival in Biliary Stenting alone vs Stenting with Photodynamic Therapy.
      from Virginia publish their results using PDT for unresectable cholangiocarcinoma. Forty-eight patients were treated over a 5-year period. Of these, plastic biliary stents alone were placed in 29 patients; PDT and plastic biliary stents were placed in 19 patients. Laser delivery was achieved using standard rigid 2.5-cm fibers that were preloaded into a 10F delivery system. One or 2 biliary segments were treated per session. Therapy was repeated every 3 months until death or withdrawal from the study. The degree of decline in bilirubin levels was similar in the 2 groups. Kaplan–Meier survival analysis showed a statistically significant prolongation in survival in the PDT group (mean 16.2 ± 2.4 months) compared with the stent only group (mean 7.4 ± 1.6 months).
      The study, while one of the first direct comparative survival studies from the US to show an improved survival using PDT, has a number of flaws. It is a small, retrospective study. Although the majority of patients had Bismuth III and IV lesions, patients with Bismuth I and II lesions were included. Some patients in each group received chemoradiation therapy.
      With so many options available for the palliation of biliary obstruction in patients with inoperable hilar cholangiocarcinoma — chemoradiation, brachytherapy, plastic and metal stents (endoscopically or percutaneously placed) — what can we recommend for these patients? Is there enough data to say that PDT should be given to all patients? Let’s start with the disadvantages of PDT. The treatment is not available at all centers. It requires expertise in both endoscopy and photodynamic therapy. The procedure is time consuming and can be quite prolonged based on number of segments treated; suffice it to say that one should allot at least 90 minutes for the procedure which entails stent removal, treatment, and stent replacement. The fibers available in the US are suboptimal for endoscopic retrograde cholangiopancreatography use. They are stiff and prone to breakage. Because of the stiffness, treatment is generally limited to the main hepatic ducts since the fiber does not bend around corners to reach intrahepatic branches. Finally, let us not forget the photosensitivity that occurs for 4–6 weeks after therapy which may limit quality of life. The advantages of PDT are that it is reasonably well tolerated and seems to be effective. It can be repeated without a ceiling dosage effect.
      • Berr F.
      • Wiedmann M.
      • Tannapfel A.
      • et al.
      Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival.
      PDT is the only treatment to date where there is evidence to support an improvement in survival over plastic stent placement alone for advanced CCA. In fact, one retrospective study suggested that the survival with PDT and stents was similar to those who underwent attempted curative, but incomplete surgical resection.
      • Witzigmann H.
      • Berr F.
      • Ringel U.
      • et al.
      Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to r1/r2 resection.
      Many questions about the role of PDT and CCA remain. In nearly all studies plastic biliary stents have been used. There is little experience with self expandable metal stents and PDT.
      • Dumoulin F.L.
      • Gerhardt T.
      • Fuchs S.
      • et al.
      Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma.
      The downside to metal stent placement is that light may not effectively reach the tumor through the interstices of the stent and/or be scattered during follow-up PDT, leading to inadequate treatment. Some authors, however, routinely combine metal stent placement and PDT, though it requires 10 cm parallel stents placed into the right and left systems following baseline PDT to have access to both sides in the future if bilateral PDT is repeated (Richard Kozarek, personal communication, November 2007). Most studies have used bilateral PDT and stent placement. Is this necessary? What about patients who have parenchymal atrophy on 1 side? Are we exposing those patients to a higher risk of cholangitis as compared to unilateral treatment? Do only patients with Bismuth III and IV lesions benefit? Should type I and II patients be offered PDT? What are the effects of other treatments such as chemoradiation — complementary or antagonistic? Does it make sense to treat patients with large masses when the treatment is relatively superficial? Finally, is cholangioscopic delivery of the laser light superior to fluoroscopic delivery?
      In addition to time constraints and reimbursement, there are several reasons PDT availability in the US is limited. For endoscopists in the US to embrace PDT, smaller and more flexible laser fibers are needed. Furthermore, better delivery methods for the fibers are also needed. For patients to embrace PDT, better photosensitizing agents are needed. Agents with a shorter duration of phototoxicity and more rapid onset (which would allow patients to receive the photosensitizing agent and treatment on the same day, rather than 48 hours apart) would be welcomed. Unfortunately, the number of patients with CCA is relatively small such that the commercial benefit to companies is limited and thus there is not a financial incentive for advancement in this area.
      So, should photodynamic therapy be considered standard of care for palliation of cholangiocarcinoma? The answer is a qualified yes. The data suggest that PDT is an excellent option for patients with unresectable CCA, especially for Bismuth III and IV lesions. However, there are no comparative trials with chemoradiation, and PDT availability is limited. Therefore, these patients could be managed with standard palliative care at their institution or referred to a specialized center with PDT availability. Further comparative trials are needed to determine the optimal regimen for palliation of obstructive jaundice in these patients.

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