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Keywords:

  • Cholangiocarcinoma;
  • ERCP;
  • liver transplantation;
  • PDT;
  • photodynamic therapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)-directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol-driven neoadjuvant chemoradiation and ERCP-directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP-directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention-to-treat disease-free survival was 75% at mean follow-up of 28.1 months. In summary, ERCP-directed 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.


Abbreviations
5-FU

5-fluorouracil

AdenoCA

adenocarcinoma

CCA

cholangiocarcinoma

CHD

common hepatic duct

CI

confidence interval

ERCP

endoscopic retrograde cholangiopancreatography

FISH

fluorescence in situ hybridization

Fr

French (unit)

Gy

Gray (unit)

HD

hepatic duct

HR

hazard ratio

LT

liver transplantation

MELD

Model for End-Stage Liver Disease

MRI

magnetic resonance imaging

OR

operating room

PDT

photodynamic therapy

PSC

primary sclerosing cholangitis

PTC

percutaneous transhepatic cholangiography

Seg

segments

UNOS

United Network of Organ Sharing

XRT

external beam radiation

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

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 [1]. Five-year survival for patients with perihilar CCA is poor at 10–40% [2].

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% [4]. In this series, 75% of patients underwent brachytherapy as a means of providing local control.

However, this same study [4] 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 [5]. 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 [6]. 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 [7].

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 [8]. 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 [11], which might also limit damage to the surrounding normal biliary tissue [12].

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 [12], 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.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

An institutional protocol including criteria for eligibility, treatment and follow-up was created a priori and subsequently submitted to the United Network of Organ Sharing (UNOS), which was similar to that used at other transplant centers [4] with the exception that ERCP-directed PDT was used instead of brachytherapy for locoregional control. Patients who had undergone PDT followed by protocol LT for unresectable CCA were identified using an institutional LT database, medical records and endoscopic logs. Electronic medical records were retrospectively reviewed to collect patient information. This study was approved by our institutional review board. All patients were consented prior to their procedures, including specialized informed consent for ERCP-directed PDT.

Patient selection for protocol LT

Patients with unresectable CCA were reviewed by a multidisciplinary team of transplant hepatologists, pancreatico-biliary endoscopists, medical oncologists, radiation oncologists and hepatobiliary and transplant surgeons to determine that they were not candidates for surgical resection and if they were suitable for protocol LT. Patients were considered eligible for neoadjuvant therapy followed by LT if they met any of the following criteria that were considered diagnostic for CCA: (1) a mass lesion on cross-sectional imaging, (2) a malignant-appearing biliary stricture with either CA 19-9 > 100 U/mL or fluorescence in situ hybridization (FISH) polysomy, (3) a transluminal biopsy that confirmed CCA, or (4) positive or suspicious cytology obtained by biliary brushings during ERCP (Figure 1). Indeterminate diagnoses of CCA were reviewed on a case-by-case basis. Exclusion criteria included maximal tumor diameter larger than 3 cm on cross-sectioning imaging, intrahepatic CCA, prior biliary resection or prior attempted CCA resection, evidence of intrahepatic or extrahepatic metastases, or prior transperitoneal biopsy.

image

Figure 1. Cholangiogram (from Patient 2) showing a stricture in the bile duct draining segments five and eight with proximal intrahepatic dilation. Here, a cytology brush is obtaining a sample from the stricture, which was found to be dysplastic and suspicious for cholangiocarcinoma.

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Neoadjuvant chemoradiation

Patients underwent XRT with 45 Gy delivered at 1.5 Gy fractions to the hepatic hilum and associated lymph node regions twice daily with 30 total fractions over 3 weeks. Concurrent radiosensitizing capecitabine (825 mg/m2) was given orally, twice per day, on radiation days. Dose adjustments were performed according to standard practices. Approximately 2 weeks after the completion of this initial cycle of chemoradiation, PDT was performed (see below), which included ERCP and stent revision.

Two weeks after PDT, patients began capecitabine 1–1.25 g/m2 orally, twice per day, 14 days on and 7 days off until LT. For patients who required exploratory laparoscopy/laparotomy for tumor staging, chemotherapy was discontinued 2 weeks before surgery. During this pretransplant phase, patients had CBC and chemistry panels checked every 3 weeks.

ERCP-directed PDT

After waiting at least 2 weeks after the completion of the first cycle of chemoradiation, PDT was performed as an outpatient procedure in the endoscopy suite. The photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Bannockburn, IL), 2 mg/kg, was infused intravenously over 5 min followed by 500 mL of 0.9% normal saline infusion.

ERCP with peri- and postprocedural antibiotic coverage was performed 2 days after infusion of the photosensitizer. A therapeutic duodenoscope (TJF-160VF; Olympus America, Center Valley, PA) was used to remove indwelling stents. Using a short-wire system, the duct(s) of interest was (were) accessed with a guidewire. A 10-Fr bougie catheter (Soehendra biliary dilation catheter, SBDC-10; Cook Medical, Bloomington, IL) was passed over the guidewire and left below the level of the strictured bile duct. After removal of the guidewire, the laser fiber (3.0-m long fiber with a 2.5-cm long cylindrical diffuser at its distal end; Pioneer Optics, Windsor Locks, CT) was passed through the 10-Fr bougie and placed across the strictured duct under fluoroscopic guidance. A diode-laser-system activating light source (630 nm, 750 s, 180 J/cm2 light dose delivered per activation, InGaAIP Laser Diode; Diomed, Andover, MA) was used to treat one or two dominant biliary strictures (Figures 2 and 3). Plastic bile duct stents were placed following PDT to decompress PDT-treated and opacified biliary radicals.

image

Figure 2. Activated laser fiber emitting light at a wavelength of 630 nm, which was then used to perform ERCP-directed PDT. This fiber can be passed using a 10-Fr bougie catheter inserted through a therapeutic duodenoscope (as done in this study) or by using a choledochoscopy system. ERCP, endoscopic retrograde cholangiopancreatography; PDT, photodynamic therapy.

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image

Figure 3. Cholangiogram taken during ERCP-directed PDT (from Patient 2). PDT was applied to the bile duct draining segments five and eight by using a 10-Fr bougie to pass the laser fiber through the duodenoscope. The arrows delineate the proximal and distal markings on the laser fiber that correspond to the portion of bile duct being treated by PDT. ERCP, endoscopic retrograde cholangiopancreatography; PDT, photodynamic therapy.

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Patients were instructed before and after the procedure to avoid sunlight for 4–6 weeks due to persistent skin photosensitivity. After 4 weeks, patients could be listed for LT. PDT could be repeated every 3 months (at the discretion of the endoscopist), but ERCP and stent replacement could occur earlier, as clinically indicated.

Liver transplantation

Patients were listed for LT and assigned a Model for End-Stage Liver Disease (MELD) exception score as per UNOS. Exploratory laparotomy was done either a few weeks before or at the time of transplant to assess for any metastatic disease. Presence of metastases or local disease extension precluded LT. Post-LT surveillance consisted of computed tomography scans of the chest and abdomen at 4 months, 1 year, 2 years, and then on an as-needed basis, and CA 19-9 levels were obtained at 4 months and then annually for 3 years.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Patient characteristics

Four patients (two women, mean age of 36 years, range: 29–48 years) met the inclusion criteria for confirmed or suspected CCA and were enrolled in the LT protocol, which included neoadjuvant ERCP-directed PDT for locoregional control (Table 1). ERCP and magnetic resonance imaging (MRI) found diffuse biliary strictures and mass lesions in three patients that were consistent with Bismuth IV CCA [14]. Mean tumor size on initial imaging was 2.6 cm (range: 2.3–2.9 cm). For all patients, mean CA 19-9 levels prior to PDT and LT were 244 U/mL (range: 114–494 U/mL), with a corresponding mean serum total bilirubin of 3.1 mg/dL (range: 1.2–6.4 mg/dL).

Table 1. Clinical characteristics of patients with confirmed or suspected CCA who underwent ERCP-directed PDT for local control as a bridge to LT
Patient no.Age (years)SexLesion locationMethod of tissue acquisitionPre-LT cytopathologyOther diagnostic features
  1. CCA, cholangiocarcinoma; ERCP, endoscopic retrograde cholangiopancreatography; EUS/FNA, endoscopic ultrasound guided fine-needle aspiration; HD, hepatic duct; LT, liver transplantation; MRI, magnetic resonance imaging; PDT, photodynamic therapy; PSC, primary sclerosing cholangitis.

148FRight and left HD (Bismuth IV)ERCP brushingsAdenocarcinomaMass on MRI, CA 19-9: 494 U/mL
229MRight HD (Bismuth IIIA)ERCP brushingsSuspicion of adenocarcinomaPSC, CA 19-9: 114 U/mL
329FRight and left HD (Bismuth IV)EUS/FNAAdenocarcinomaMass on MRI, CA 19-9: 189 U/mL
438MRight and left HD (Bismuth IV)ERCP brushingsAtypical cellsMass on MRI, CA 19-9: 179 U/mL

Tolerability of neoadjuvant therapy

All patients required dose delays. Three patients (75%) required interruption in capecitabine treatment due to cholangitis. All four patients (100%) required XRT dose delays because of nausea, vomiting, abdominal pain and/or cholangitis. All four patients (100%) successfully completed neoadjuvant chemoradiation prior to LT.

Distribution of PDT treatments via ERCP

Two patients had PDT applied to both the left and right intrahepatic systems, while two patients had unilateral PDT applied to the duct draining segments five and eight and the proximal common hepatic duct (Table 2).

Table 2. Distribution of biliary PDT treatments, pre- and post-PDT outcomes and post-LT staging and outcomes
Patient no.Time from diagnosis to PDT (months)Area(s) treated with PDTTherapy requiredEpisodes of cholangitisTime from PDT to LT (months)Post-LT pathologyExplant tumor stageCancer-free follow-up (months)CCA recurrence
Pre-PDTPost-PDTPre-PDTPost-PDT
  • AdenoCA, adenocarcinoma; CCA, cholangiocarcinoma; CHD, common hepatic duct; ERCP, endoscopic retrograde cholangiopancreatography; HD, hepatic duct; LT, liver transplantation; PDT, photodynamic therapy; PTC, percutaneous transhepatic cholangiography; Seg, segments.

  • The ERCPs included above were from the time of diagnosis and onward.

  • The ERCP done at the time of PDT was not counted in either the pre-PDT or post-PDT therapy required categories.

  • 1

    In the case of Patient 4, there were two PTC drains that were in place at the time of PDT, which persisted up until the time of LT; however, no other new PTCs were required.

16.5Right and left HDERCP 4, PTC 0ERCP 2, PTC 0424.1AdenoCAypT2 Nx82.7No
24.7Seg 5/8 and CHDERCP 2, PTC 0ERCP 1, PTC 0004.9Moderate dysplasiaBIN 2/39.3No
32.6Right and left HDERCP 3, PTC 2ERCP 1, PTC 1225.8AdenoCAypT2B N09.7Yes
42.8Seg 5/8 and CHDERCP 2, PTC 2ERCP 0, PTC 01101.1AdenoCAypT2B N010.7No

Efficacy of ERCP-directed PDT for local tumor control prior to LT

All four patients (100%) successfully underwent ERCP-directed PDT. None of these patients had evidence of progressive locoregional disease or distant metastasis following PDT on follow-up axial imaging, at time of exploratory laparotomy (when conducted), or at time of LT. Mean time from PDT to LT was 4 months (range: 1.1–5.8 months) (Table 2).

Side effects of ERCP-directed PDT

All four patients (100%) experienced abdominal pain immediately following PDT, ranging from mild to severe. Two patients (50%) had post-PDT nausea and vomiting (above their baseline symptoms) in addition to abdominal pain that required short-term inpatient management. Mild photosensitivity was reported in two patients (50%) after PDT without any severe burns. None of the patients developed pancreatitis, bleeding or perforation following ERCP-directed PDT.

Post-LT pathology and follow-up

All patients survived LT. Post-LT pathology confirmed dysplasia or adenocarcinoma in all explanted livers. Three of four patients had tumor-free margins. One patient had evidence of tumor involvement of the perivascular fibroadipose tissue but had tumor-free vascular and bile duct margins (ypT2B N0). This patient developed omental metastatic disease found on laparotomy 9.7 months following LT (Table 2).

The remaining three patients remain in oncologic remission at mean follow-up of 28.1 months (range: 9.3–82.7 months). This represents an intention-to-treat, disease-free survival of 75%.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

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 [4]. 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% [4]. 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 [18]. Although PDT cannot provide curative treatment for invasive CCA, as it only induces necrosis to a depth of about 4–6 mm (Figure 4) [8], the mortality benefits of PDT are similar to those reported after partial tumor resection [17].

image

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 [19]. 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% [2]. 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.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References
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