Unresectable Cholangiocarcinoma: Comparison of Survival in Biliary Stenting Alone Versus Stenting With Photodynamic Therapy

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2008;6: ENDOSCOPY CORNER Unresectable Cholangiocarcinoma: Comparison of Survival in Biliary Stenting Alone Versus Stenting With Photodynamic Therapy MICHEL KAHALEH,* RAJNISH MISHRA,* VANESSA M. SHAMI,* PATRICK G. NORTHUP,* CARL L. BERG,* PENNY BASHLOR,* PETRA JONES,* KRISTI ELLEN,* GEOFFREY R. WEISS, CHRISTIANA M. BRENIN, BARBARA E. KURTH, TYVIN A. RICH, REID B. ADAMS, and PAUL YEATON* *Digestive Health Center, Cancer Center, Departments of Radiation Oncology and Surgery, University of Virginia Health System, Charlottesville, Virginia See Editorial on page 266. Background & Aims: Photodynamic therapy (PDT) for unresectable cholangiocarcinoma is associated with improvement in cholestasis, quality of life, and potentially survival. We compared survival in patients with unresectable cholangiocarcinoma undergoing endoscopic retrograde cholangiopancreatography (ERCP) with PDT and stent placement with a group undergoing ERCP with stent placement alone. Methods: Forty-eight patients were palliated for unresectable cholangiocarcinoma during a 5-year period. Nineteen were treated with PDT and stents; 29 patients treated with biliary stents alone served as a control group. Multivariate analysis was performed by using Model for End-Stage Liver Disease score, age, treatment by chemotherapy or radiation, and number of ERCP procedures and PDT sessions to detect predictors of survival. Results: Kaplan Meier analysis demonstrated improved survival in the PDT group compared with the stent only group (16.2 vs 7.4 months, P<.004). Mortality in the PDT group at 3, 6, and 12 months was 0%, 16%, and 56%, respectively. The corresponding mortality in the stent group was 28%, 52%, and 82%, respectively. The difference between the 2 groups was significant at 3 months and 6 months but not at 12 months. Only the number of ERCP procedures and number of PDT sessions were significant on multivariate analysis. Adverse events specific to PDT included 3 patients with skin phototoxicity requiring topical therapy only. Conclusions: ERCP with PDT seems to increase survival in patients with unresectable cholangiocarcinoma when compared with ERCP alone. It remains to be proved whether this effect is attributable to PDT or the number of ERCP sessions. A prospective randomized multicenter study is required to confirm these data. Cholangiocarcinoma is the second most common malignancy arising within the liver and is associated with significant morbidity and mortality. 1 The majority of patients are found to be unresectable on presentation 2 4 ; their survival is approximately 3 months without intervention and 4 6 months with biliary decompression Successful palliation of biliary obstruction remains the main goal for reducing morbidity and mortality in these patients with unresectable disease. 6,11 Hepaticojejunostomy is associated with a 30-day postoperative mortality rate between 7% and 24%, and significant quality of life after surgery is only improved in a minority because of time needed to recover. 9,17,18 Endoscopy with placement of biliary stents has become the standard to palliate jaundice in this population, with less morbidity and mortality than that associated with surgery. 13,18 23 Limitations of this approach are related to (1) the ability to decompress affected proximal segments and (2) recurrent stent occlusion, because these stents offer no ability to remodel malignant tissues. 6,7,12,24 26 Photodynamic therapy (PDT) is an evolving therapy that involves the intravenous administration of a photosensitizing agent followed by its activation by using light illumination of a specific wavelength, resulting in ischemic necrosis proportional to tissue oxygenation. 30,31 PDT was demonstrated to reduce xenografted human cholangiocarcinoma tumor volume by 60% in a mouse model. 32 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 A prospective, randomized, controlled trial confirmed a significant advantage attributable to PDT in relief of jaundice, quality of life, and survival. 37 The improvement of survival in the PDT group was such that it was considered unethical to continue the study after the first 39 patients were randomized (20 received PDT). This study was criticized because enrollment was limited to those patients in whom technically successful stenting did not result in successful drainage. 38 We reported our experience with PDT in treatment of unresectable cholangiocarcinoma and compared its efficacy and results with patients palliated with only endoscopic biliary drainage. Abbreviations used in this paper: ERCP, endoscopic retrograde cholangiopancreatography; MELD, Model for End-Stage Liver Disease; PDT, photodynamic therapy by the AGA Institute /08/$34.00 doi: /j.cgh

2 March 2008 PDT IN CHOLANGIOCARCINOMA 291 Table 1. Pretreatment Clinical Characteristics of All the Patients in the Study, Showing Comparison Between the Groups With PDT and Stent Versus Stent Only PDT group (n 19) Stent group (n 29) P value Age (y) (mean) Gender (male, female) 11, 8 13, 16 Mean bilirubin at 8.3 mg/dl 12.8 (6.6) mg/dl.08 presentation Mean bilirubin after 90 days 3.5 mg/dl 6.3 mg/dl.09 Mean MELD on presentation Tumor extension Bismuth IV 9 10 Bismuth III 7 10 Bismuth II 1 8 Bismuth I 2 1 Chemotherapy (n 22) Radiotherapy (n 19) 9 10 Mortality 3 mo 0% 27.60% mo 16% 51.70% mo 56% 82.10%.636 Cholangitis No. of interventions, median 3.0 (1 8) 2.0 (1 13).053 (range) Patient alive at the end of 8 2 study Mean & median survival (mo) 16.2 (8) 7.4 (5).003 Materials and Methods Patients Sixty-four consecutive patients were referred to our institution with cholangiocarcinoma between December 2001 and November Sixteen patients (25%) underwent resection. The remaining 48 patients were palliated with endoscopic biliary stents, and of these, 19 received PDT after its availability at the University of Virginia in December All patients were captured in a dedicated database and followed prospectively. Patient pretreatment characteristics are summarized in Table 1. Therapy with PDT was offered to all patients with unresectable cholangiocarcinoma and those with resectable lesions deemed inoperable. No patients had contraindications to porfimer sodium, such as compromised kidney or hepatic function, leukopenia or thrombocytopenia, or evidence of cancer of another organ. Staging and Tissue Diagnosis All patients had clinical and radiologic features characteristic for cholangiocarcinoma. Bismuth classification was documented for all patients (Type I, tumors below the confluence of the left and right hepatic ducts; Type II, tumors reaching the confluence but not involving the left or right hepatic ducts; Type III, tumors occluding the common hepatic duct and either the right (IIIa) or left (IIIb) hepatic duct; Type IV, tumors that are multicentric or that involve the confluence and both the right and left hepatic ducts). Pathologic diagnosis was established in 69% of cases, which is in accordance with published studies. 39,40 Tissue diagnosis was established by endoscopic retrograde cholangiopancreatography (ERCP) with triple sampling 41 in 20 of 26 (77%) cases, by endoscopic ultrasound with fine-needle aspiration in 11 of 14 (78%) cases, percutaneous liver biopsy in 8 of 8 cases, and by laparotomy/laparoscopy in 4 of 4 cases. Staging was performed with computed tomography and/or magnetic resonance imaging. Resectability was defined according to the criteria of Vauthey and Blumgart. 42 Materials and Techniques Duodenoscopes (TJF-140, TJF-160, and TJF-160VF; Olympus America, Center Valley, PA) were used for all procedures. Biliary cannulation was performed with triple lumen sphincterotomes. After biliary sphincterotomy, a cholangiogram defined the extent of ductal involvement. Selective decompression of all opacified, dilated segments was attempted, with bougie and balloon dilation to assist in the placement of polyethylene stents (7F, 8.5F, and 10F diameter [Figures 1 4]). All procedures were performed by 1 of 2 dedicated pancreaticobiliary endoscopists (M.K. or P.Y.), each performing in excess of 500 ERCPs annually. Photodynamic Therapy Each patient to whom PDT was offered underwent a specific, detailed educational process by a dedicated team member (P.B., P.J., or K.E.), after which informed consent was obtained. Porfimer sodium (Photofrin; Axcan Pharma Inc, Quebec, Canada) was used as a photo sensitizing agent, administered intravenously at a dose of 2 mg/kg body weight 48 hours before illumination. A diode laser system (InGaAIP Laser Diode; Diomed Inc, Andover, MA) with a maximum power output of 2000 mw and a wavelength of nm was used as a light source, delivered through a 3.0-m length fiber having a 2.5-cm-long cylindrical diffuser at its distal end (Pioneer Optics, Windsor Locks, CT). During ERCP, the biliary anatomy was defined, and appropriate locations for therapy were identified, after which guidewire access was obtained and dilation was used as necessary to introduce the diffuser within the malignant stricture. The diffuser was inserted into a 10F sheath of a plastic stent delivery system (MAJ-1419; Olympus America), placed at the level of the stricture to be treated (Figures 5 and 6). The sheet was positioned at the appropriate level, after being advanced over a wire. Photoactivation was performed at 620 nm with a light dose of 180 J/cm2, fluence of W/cm2, and irradiation time of 750 seconds. One or 2 segments were treated at the discretion of the endoscopist. After photoactivation, only plastic stents were inserted to decompress opacified radicals proximal to the treated lesion. PDT was repeated at 3-month intervals (Figure 7) at which time all stents were replaced; stents were exchanged earlier in the case of premature occlusion or migration to maintain optimal decompression. All patients received periprocedure antibiotic prophylaxis. Definition of Events Successful therapy was defined by relief of cholangitis, jaundice, and pruritus with decrease of bilirubin to less than 75% of the pretreatment value within 30 days. 43 Complications

3 292 KAHALEH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 3 related to ERCP were defined following consensus criteria 44 and differentiated from complications related to PDT. Follow-Up Those patients undergoing therapy including PDT underwent ERCP with PDT every 3 months until death or withdrawal from the study. All patients were followed in clinic with laboratory values at least 1 month after intervention and every 3 months thereafter or earlier in case of complications. In patients who received plastic stents without PDT, repeat ERCP was performed if indicated (recurrent cholestasis, cholangitis, and/or pruritus) until patient refusal or death. Statistical Analysis Statistical analysis was performed with SAS, version 9.1 (SAS Institute, Cary, NC). Statistical significance was assumed to be at an alpha of.05, and all statistical tests were two-sided. The Fisher exact test or 2 tests were used to compare proportions, and the Student t test or Wilcoxon signed rank test was used for continuous data. Multivariable logistic regression models were constructed with 6-month and 1-year survival end points. Univariate time-to-event survival models were constructed by using the Kaplan-Meier method and compared between groups with the log-rank test. Multivariate survival was analyzed with a Cox proportional hazards model and the method of maximum likelihood estimates. Variables were included in the multivariate model if they achieved a P value of less than.20 in the univariate comparison (Model for End-Stage Liver Disease [MELD], number of sessions), or if they were clinically expected to be important in the disease process (age, radiation, or chemotherapy). MELD and bilirubin are not independent variables, so both were not included in the final model. It was believed that MELD was a better representation of Figure 1. Cholangiogram showing a Bismuth III lesion (patient A). Figure 2. After placement of 2 stents on each side, selective access of segments VI and VII is achieved with a guidewire (patient A). the subjects severity of disease and was therefore chosen to be in the final model instead of total bilirubin. This study was approved by the University of Virginia Institutional Review Board for Health Sciences Research. Results Forty-eight patients (24 male), mean age, 66.6 years (range, years) were palliated. A total of 19 (40%) patients received ERCP and PDT, whereas 29 (60%) underwent ERCP with stenting alone. The pretreatment clinical characteristics of the study population are summarized in Table 1. Mean and median pretreatment carbohydrate antigen 19-9 (n 41/48) was 3203 and 227 U/mL (range, 3 59,100 U/mL), respectively. Mean and median pretreatment carcinoembryonic antigen (n 36/48) was 42.9 and 3.5 (range, ), respectively. Nineteen patients were found to have Bismuth IV cancers (40%), 17 had Bismuth III (35%), 9 had Bismuth II (19%), and 3 patients had Bismuth I (6%) (Table 1). All patients had clinical and cross-sectional imaging compatible with cholangiocarcinoma. No patients were excluded because of a large mass. The median number of ERCP procedures was 3.0 (range, 1 8) in the PDT group, including a mean number of 1.6 (range, 1 3) PDT sessions. The stent only group underwent a median of 2.0 (range, 1 13) ERCP procedures to maintain biliary decompression. There was no significant difference between age, gender, preprocedure total bilirubin, carcinoembryonic antigen, and carbohydrate antigen 19-9 levels in each group (Table 1). The stent only group had a statistically significant (P.03) higher preprocedure MELD score (18.3 vs 14.6) compared with the PDT group.

4 March 2008 PDT IN CHOLANGIOCARCINOMA 293 Table 2. Multivariate Analysis of Factors Predictive of Increased Survival Variable P value Hazard ratio 95% Confidence interval PDT Age Radiation Chemotherapy MELD ERCP sessions Biliary Decompression In both groups, serum bilirubin was successfully decreased ( 75% of the original value) (Figure 8). After 3 months, a greater than 50% reduction of bilirubin was noted in 26 patients. In both groups the decrease in bilirubin was significant when comparing pretreatment versus post-treatment bilirubin (Figure 8) (P.008 in the PDT group and P.0001 in the stent only group). However, when comparing the degree of decrease between the 2 groups, no significant difference was observed (P.78). Chemotherapy and Radiation A total of 22 (46%) patients received chemotherapy with various combinations of gemcitabine and capecetabine. Eleven (58%) were in the PDT group, and 11 (38%) were in the stent only group (P.17). A total of 19 patients also were treated with concomitant extracorporeal radiation. Of these, 9 (47%) were included in the PDT group and 10 (34%) in the stent only group (P.37). Complications and Adverse Events Complications in the stent only group included 10 patients developing cholangitis after endoprosthetic therapy, with 2 patients dying as a consequence. Post-ERCP pancreatitis was observed in 4 patients and duodenal perforation in one. Other adverse events in the stent group included hepatic abscess (1), Billroth II perforation (1), and non-st elevation myocardial infarction (2). In the PDT group, 7 patients (37%) developed cholangitis treated with antibiotics alone. One patient developed a hepatic abscess with prolonged cholangitis, requiring percutaneous drainage. Other complications included hemobilia (2) and cholecystitis (2). Both patients with cholecystitis were managed nonsurgically. Among the adverse events specific to PDT, 3 patients experienced skin phototoxicity, one World Health Organization grade 3; all were managed with topical therapy. Survival At the time of analysis, 10 patients were living, with 8 being in the PDT group. Cause of death included tumor progression (n 30), cholangitis (n 2), pulmonary embolus (n 1), multiorgan failure (n 4), and myocardial infarction (n 1). Overall mean and median survival was and 7 months (range, months), respectively. Kaplan-Meier survival analysis (Figure 9) showed statistically significant (P.003) prolonged survival in the PDT group (mean, months, compared with the stent only group (mean, months). Overall survival at 3, 6, and 12 months was 83%, 33%, and 27%, respectively. In the PDT group the 3-, 6-, and 12-month mortality rates were 0%, 16%, and 56%, respectively. The corresponding mortality rates in the stent only group were 28%, 52%, and 82%, respectively. This difference was statistically significant at 3 (P.01) and 6 months (P.01) but not at 12 months (P.08). On analysis of maximum likelihood estimates, factors predictive of survival were treatment with PDT and number of ERCP sessions. There was no significance related to age, MELD score, chemotherapy, or radiation (Table 2). The proportional hazards survival model was re-run with an interaction term between exposure to PDT and number of ERCP sessions, and there was a trend toward statistical significance of the interaction term (P.08). In this new model, the influence of PDT exposure was persistently statistically significant (P.004), and the remaining conclusions of the study were unchanged. Discussion Almost 80% of patients with cholangiocarcinoma are diagnosed at an unresectable stage. 3,8,45 Effective palliation is essential, because biliary drainage and prevention of cholestasis are crucial to prevent pruritus, cholangitis, and death. The approach to palliative biliary decompression has evolved from surgery with its attendant morbidity and mortality 16,22 Table 3. Table Comparing Studies Performed by Using ERCP With PDT With Photofrin Sodium for Palliation of Cholangiocarcinoma Study Year N (M/F) Study type Median TB before and after PDT (mg/dl) Mean PDT sessions (range) Median survival (mo) Adverse events: phototoxicity, cholangitis Ortner et al Single arm (1 2) (11%), 0 (0%) Berr et al Single arm (1 5) (13%), 8 (35%) Rumalla et al Single arm (1 2) 6 2 (33%), 2 (33%) Dumoulin et al Single arm (mean) (8%), 5 (21%) Ortner et al Randomized N/A (decreased) 2.4 (1 5) (10%), 5 (25%) Ortner et al Nonrandomized (1 4) (10%), 6 (19%) Harewood et al Single arm (1 5) (25%), 2 (25%) Witzigmann et al Single arm N/A (decreased) 2 (1 6) 12 8 (12%), 38 (56%) Prasad et al Single arm (mean) 1.6 (1 4) (4%), 2 (8%) TB, total bilirubin; N/A, not available.

5 294 KAHALEH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 3 and more recently from percutaneous to endoscopic management; the latter has been shown superior to a percutaneous approach in prevention of cholestasis and improved mortality. 46 Unfortunately, the benefit of ERCP with stent placement is often obviated by proximal tumor obstruction. 6,7,10,12 To address this issue, multiple studies have been conducted to investigate the effect of combining bile duct stent insertion and PDT ,47,48 PDT is thought to destroy cancer and neovascular cells and to induce tumor thrombosis through formation of cytotoxic reaction products, including singlet oxygen radicals. 27,28,30 Understanding that survival in cholangiocarcinoma is related to the efficacy of biliary decompression, PDT offers a logical mechanism to use. The efficacy of stenting is limited by stent patency; unlike benign conditions, no tissue remodeling is affected by stenting tumor. PDT offers the possibility of Figure 4. Fluoroscopic image after drainage of all dilated segments (patient A). remodeling tumoral mass, 49 which might enhance or prolong the decompressive effect. Accepting this hypothesis, PDT could improve cholestasis and survival in the setting of incomplete decompression with stents by opening previously inaccessible segments, an observation noted by ourselves and others. In most prospective trials (Table 3) and in our series, PDT was associated with a significant reduction in bilirubin and increase in survival compared with historical data ,39,40,43,50 This study compared the efficacy of PDT with biliary stenting with a group receiving only biliary plastic stenting. Notable differences with most previous published reports were that multiple sessions of ERCP were offered to both groups, and PDT was not restricted to a single session. Our results seem Figure 3. Selective access of segments V and VIII is then achieved by using a sphincterotome preloaded with a guidewire (patient A). Figure 5. Malignant stricture (Bismuth I) before PDT treatment (patient B).

6 March 2008 PDT IN CHOLANGIOCARCINOMA 295 Figure 6. PDT application at the level of the malignant stricture (patient B). similar to those of Ortner et al, 37 in which a dramatic increase in median survival after PDT (16.4 months) was observed, compared with 3.3 months in the patients receiving stent placement alone. Unlike the study by Ortner et al, patients who underwent successful stenting were not excluded from our study, and bilirubin values in both groups were significantly decreased (Figure 8). Our aggressive approach to biliary decompression, as advocated by Prat et al, 51 appeared to influence survival independently of PDT administration (Table 2). The design of this study does not resolve the possibility that an additive effect would be observed combining PDT and stenting. In a recent study by Zoepf et al, 47 in which a hematoporphyrin derivative (Photosan-3; Scotia Pharmaceuticals, Guildford, Figure 8. Mean change in bilirubin at entry and after 3 months of treatment. When comparing the PDT group with the stent only group, there is no statistical difference in either the pretreatment or post-treatment values (P.09), and there is not any statistical difference in the degree of decrease between the 2 groups (P.78). In both groups, decompression was successful by criteria defined in Materials and Methods. UK) was used as a photosensitizer, patients were randomized to stents only or PDT with stents. Stents were changed in both groups every 3 months. Survival in the PDT group was 21 months, compared with 7 months in the stent only group. Although this suggests an additive effect of PDT, there was no multivariate analysis of the number of ERCP sessions as a surrogate of decompression, and by design, those living longer would have had more ERCP sessions. An alternative explanation of the observed results would be improved efficacy with Photosan-3 compared with Photofrin. A recent retrospective study 40 reported 25 patients with unresectable cholangiocarcinoma treated with PDT; on multivariate analysis, the presence of a visible mass on imaging and increasing time between diagnosis and PDT predicted a poorer Figure 7. Cholangiogram at 3-month follow-up (patient B). Figure 9. Cumulative survival of patients treated with PDT and stent (solid line) versus stent only group (broken line). Kaplan Meier analysis showed estimated mean survival of months (95% confidence interval, 7 27 months) after PDT vs months (95% confidence interval, 3 7 months), respectively, which was statistically significant (P.003).

7 296 KAHALEH ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 6, No. 3 Table 4. Comparison of Costs Between ERCP With Biliary Stent Placement and PDT ERCP with biliary stent Physician charge: $1440 Medicare payment: $ Highest commercial payment: $ PDT Physician charge: $ Medicare payment: $53.46 Highest commercial payment: $91.65 survival rate after PDT. Therefore, early treatment with PDT might preserve hepatic function. We used the MELD score to stratify disease severity in our study population. Thirty-four of 48 patients (71%) presented with a MELD 14. Of these 34 patients, 23 (68%) were in the stent only group; despite this observation, MELD was not an independent predictor of survival by multivariate analysis (Table 2). Two groups have attributed improved survival in this population to the use of chemotherapy and radiation. 52,53 We offered chemoradiation to all patients; 22 patients (11 PDT, 11 stent only) received chemotherapy, of whom 19 also received external beam radiation (9 PDT, 10 stent only). This therapy conferred no additional survival advantage by multivariate analysis, confirming the results of other studies that show only limited response in cholangiocarcinoma. 54,55 Finally, as seen in several other studies (Table 3), direct adverse effects of PDT were minor and largely related to phototoxicity. 34,36,56 The incidence of bacterial cholangitis was similar in both the groups (35%) and is compatible with the published results of 25% 35%. 34,50,57 Cholangitis accounted for only 5% of all deaths in our series, again suggesting the value of aggressive biliary decompression. Costs related to ERCP and PDT are provided in Table 4. In summary, ERCP with PDT appears to improve survival compared with ERCP with biliary stenting alone in unresectable cholangiocarcinoma. Although our results are comparable with other published results, the effect we observed is not independent of the number of ERCP sessions, raising a complex issue related to adequacy of stenting. In addition, the uncontrolled design of this study prevented definitive conclusions from being drawn. To definitely prove that PDT confers an additional benefit compared with ERCP with stenting alone, a prospective, randomized, controlled trial is required with strict criteria defining successful stenting (Figures 3 9 and Table 4). References 1. Ahrendt SA, Nakeeb A, Pitt HA. Cholangiocarcinoma. Clin Liver Dis 2001;5: de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341: Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. 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J Gastroenterol Hepatol 2005;20: Address requests for reprints to: Michel Kahaleh, MD, Digestive Health Center Box , University of Virginia Health System, Char- lottesville,va mk5ke@virginia.edu;fax: Part of this work was presented as an oral presentation during Digestive Diseases Week 2007, American Society for Gastrointestinal Endoscopy Topic Forum #140, Washington, DC, May 21, 2007, with reference: Gastrointest Endosc 2007;65:AB96. The authors acknowledge the strong support by the technical staff of the Digestive Health Center s Clinic and Endoscope Staff.