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INTRODUCTION

Bile duct cancer (BDC) is an uncommon malignant tumor

that may arise anywhere that biliary epithelium is present rom

the ampulla o Vater to the smallest intrahepatic biliary radi-

cles. BDCs are classifed into three main categories: perihilar

BDCs (also known as Klatskins tumors), distal BDCs, and in-

trahepatic BDCs.1 Perihilar BDCs are urther subclassifed de-

pending on the degree o the proximal tumor extension wi-

thin the intrahepatic biliary radicles according to the classi-

fcation proposed and later modifed by Bismuth.2 Klatskins

tumors are the most common orm o BDCs and account or

approximately 70% o cases o BDCs. Distal and intrahepatic

BDCs account or approximately 25% and 5% o cases, respec-

tively.1

Complete resection with negative margins is the only treat-

ment with the potential or cure, with 5-year survival rates o

20% to 40%.3,4 However, patients with cholangiocarcinoma(CC) usually present at an advanced stage, with more than 50%

Clin Endosc 2013;46:38-44

38 Copyright 2013 Korean Society of Gastrointestinal Endoscopy

being unresectable at the time o diagnosis. Recently, two ran-

domized controlled trials have shown a signifcant survival

beneft in patients with unresectable CC treated with photo-

dynamic therapy (PDT).5,6 One o these studies also showed a

signifcant improvement in quality o lie aer PDT and st-

enting.6

PDT is based on the relatively specifc accumulation o ph-

otosensitizers, such as porphyrins, in dysplastic or malignant

cells. CC cell lines have shown avorable cellular uptake ki-

netics or sodium porfmer and excellent phototoxic cell da-

mage in response to PDT in vitro and in vivo in a human CC

xenogra model in nude mice.7,8 In this paper, we review re-

cent advances o PDT in BDCs.

SPECIFIC FEATURES OF TUMORBIOLOGY OF BDCS ARE SUITABLEFOR PDT

CC is characterized by a usually slow growth rate and a low

propensity or metastasis. e most common orm in BDCs

is a highly desmoplastic cancer with a growth pattern charac-

terized by periductal extension and infltration (Fig. 1).9 is

orm o CC oen obstructs bile ducts and encases blood ves-

sels strangulating these structures mechanically and disrupt-

ing bile and blood ow, respectively. Because these cancers in-

volve both intrahepatic and extrahepatic bile ducts, they will

simply be reerred to as ductal CCs: however, given their pre-

Current Status of Photodynamic erapy for Bile Duct CancerTae Yoon Lee, Young Koog Cheon and Chan Sup Shim

Digestive Disease Center, Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea

e most common orm in bile duct cancers is a highly desmoplastic cancer with a growth pattern characterized by periductal extensionand infltration. e prognosis o bile duct cancers, especially hilar cholangiocarcinoma, is limited by tumor spread along the biliary treeleading to reractory obstructive cholestasis, cholangitis, and liver ailure. Although biliary endoprosthesis improves occlusion rates andreduces the number o therapeutic interventions, median survival time is not ameliorated. Photodynamic therapy (PDT) is a local photo-chemical tumor treatment that consists o a photosensitizing agent in combination with laser irradiation o a distinct wavelength. Tumorablation with PDT combined with biliary stenting reduces cholestasis and signifcantly improves median survival time in selected pa-tients with bile duct cancers.

Key Words:Cholangiocarcinoma; Bile duct neoplasms; Endoprosthesis; Photodynamic therapy; Photosensitizing agents

Open Access

Received: November 7, 2012 Revised: December 14, 2012Accepted: December 14, 2012

Correspondence: Young Koog CheonDigestive Disease Center, Department o Internal Medicine, Konkuk Universi-ty School o Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-729, KoreaTel: +82-2-2030-8195, Fax: +82-2-2030-5029, E-mail: [email protected]

cc is is an Open Access article distributed under the terms o the CreativeCommons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution,and reproduction in any medium, provided the original work is properly cited.

Print ISSN 2234-2400 / On-line ISSN 2234-2443

http://dx.doi.org/10.5946/ce.2013.46.1.38

FOCUSED REVIEW SERIES: Photodynamic Therapy

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Lee TY et al.

39

dilection to occur at the biurcation o the right and le he-

patic duct, others have reerred to these cancers as perihilar

CCs (Klatskins tumor). In contrast, the other principal orm o

this disease grows as a mass lesion within the liver. is orm

o the disease will be reerred to as intrahepatic CCs because

they, in part, mimic hepatocelluar carcinomas. In addition to

dierent growth pattern, current inormation suggests these

two orms o CC may dier in their etiopathogenesis, risk ac-

tors, and perhaps molecular and genetic signatures.10

Although nearly all CCs are well-dierentiated adenocar-

cinoma, their tumor biology is a little dierent rom other gas-

trointestinal adenocarcinoma, especially in hilar bile duct can-

cer (HBDC). In general, hematogenous spread o HBDC is

rare, whereas nodal metastases may be present in up to one-

third o cases.11 Extensive subepithelial tumors spread beyond

the gross tumor margin is common, and longitudinal tumors

may extend 15 to 20 mm proximally and 5 to 10 mm distally,

depending on tumor type.12,13 e papillary variant composes

10% o all CCs and grows primary as an intraluminal so, pol-

ypoid tumor with a limited propensity or transmural growth(Fig. 2). Tumor multicentricity occurs more requently with

the papillary variant and may be reective o a feld change in

the biliary epithelium.11,14,15 e nodular variant occurs most

commonly in the upper and mid bile duct and generally pres-

ents as a fbrotic mass with intraductal projections (Fig. 3). e

sclerosing variant comprises 70% o all tumors at the hilum and

histologically appears as annular thickening o the bile duct

wall with both longitudinal and radial tumor infltrations.

WHAT ARE THE APPROPRIATE INDICA-TIONS OF PDT IN BDCS?

Neoadjuvant PDT or hilar CC showed ecacious tumor

destruction confned to the superfcial 4- to 4.5-mm depth o

the bile duct tumor and high tumor selectivity in the resected

Fig. 1. A sclerosing type of bile duct cancer. A cholangioscopy sh-ows the luminal narrowing with a whitish mucosal discoloration andneovascularization.

Fig. 2. A papillary type of bile duct cancer. A cholangioscopy showsthat slight papillary and mucosal nodularity is seen in the intrahe-patic bile duct. In this type of tumor, the mucosal lesion may be mi-nute and detectable only by careful cholangioscopic examinationof the entire biliary tree.

Fig. 3. A nodular or polypoid type of bile duct cancer. A polypoidmass partially obstructs the lumen of the common hepatic duct.Mucosal irregularity and intense serpiginous neovascularizationare clearly visible on the surface.

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40 Clin Endosc 2013;46:38-44

Current Status of Photodynamic Therapy for Bile Duct Cancer

bile duct specimens.16 is cannot eradicate the primary tumor

when tumor invasion extends to a depth o 7 to 9 mm. ere-

ore the appropriate indications o PDT in BDCs may be as ol-

lows: 1) sclerosing variant without hematogenous metastasis

regardless o nodal metastases; 2) superfcial spreading type

with the papillary variant; and 3) R0 and R1 residual tumoraer resection. e mass-orming intrahepatic CCs, intraduc-

tal mass orm o BDCs and cases o hematogenous metastases

are not indicated or PDT.

RATIONAL OF LOCAL TUMORABLATION IN BDCS

About 80% o BDCs, especially perihilar CCs, are adenocar-

cinomas that exhibit predominantly a longitudinal growth pat-

tern along the biliary tree, most highly desmoplastic tumors

with infltration o adjacent nerve plexus and lymphatics.9

Even with an aggressive surgical approach only 33% to 50%are resectable, and in only 28% are negative histological mar-

gins obtained.17

e majority o patients with tumor stenoses in the distal

and middle part o the bile duct cholestasis can be relieved

quickly by stenting. e role o palliative intervention is lim-

ited in proximal BDCs. Independent o the type o stricture,

technically successul endoprosthesis placement is possible

in 84% to 96% o these patients.18,19 A successul drainage (bi-

lirubin decrease >30% to 50%) is only achieved, however, in

69% to 91% o Bismuth type I and II stenosis and in 15% to

73% o Bismuth type III and IV tumors.18,20

Although metalstent insertion improves occlusion rates and reduces the num-

ber o therapeutic interventions, median survival time is not

ameliorated.21,22 Attempts to aect tumor growth are made

with radiotherapy or chemotherapy. Until now, however, che-

motherapy is unsatisactory in terms o survival times alth-

ough chemotherapy with gemcitabine and platinum achieved

a modest improvement in survival compared to other regi-

mens.23 Whether radiotherapy is able to improve survival is

still on debate. e retrospective comparative study o pallia-

tive radiation therapy showed no signifcantly improved me-

dian survival time (300 days vs. 210 days) between endo-

scopic biliary stenting with or without external-beam radio-

therapy and internal 192Ir brachytherapy.24 Recently, stereotatic

body radiotherapy may be a new promising option but has to

be evaluated urther.25

A treatment modality or local ablation o the primary tu-

mor could improve the outcome o curative as well as pallia-

tive therapies. Palliative brachytherapy with only 192-iridium

(dose o 35 Gy in 1-cm distance) did not prolong median

survival time (4.3 to 5 months),26 but when combined with

external beam radiotherapy (30 Gy), resulted in median sur-

vival times o 10 to 10.5 months.21 Another modality or local

tumor ablation o CC is PDT.

PHOTODYNAMIC EFFECT IN BDCS

e tumor-selective enrichment o porfmer has been con-irmed in human BDC biopsies analyzed with quantitative

uorescence microscopy. e average ratio o specifc uo-

rescence in tumor versus normal tissue was 1.7 and 2.3 at 24

and 48 hours, respectively, aer intravenous administration

o porfmer.26 Porfmer enrichment in CC tissue should be ad-

equate or PDT rom day 1 to 4 aer intravenous administra-

tion.

Wong Kee Song et al.7 showed a reduction o up to 60% o

tumor volume ater PDT with hematoporphyrin and with

chlorine in nude mice inoculated with a human CC cell line.

e PDT eect was evaluated in Bualo emale rats inoculat-

ed with rat hepatoma cells. e mean complete necrosis o asingle session o PDT was 10.2 mm3.27 Neoadjuvant PDT o

CC revealed that the tumoricidal depth o the PDT modality

with porfmer was limited to 4- to 4.5-mm tissue penetration.28

Newer photosensitizers lead to deeper tumor necrosis and a

shorter period o photosensitivity. Meso-tetrahydroxyphenyl ch-

lorine is absorbed in the near-inrared spectrum (652 nm) and

has the above characteristics.29

OUTCOME OF PDT FOR ADVANCEDBDCS

In numerous controlled and uncontrolled studies, the com-

bination o PDT and biliary drainage has shown promising

results in patients with unresectable hilar CC (Table 1).

e frst case report o PDT or CC showed signifcant sur-

vival advantage over 4 years.30 In an early pilot study, Ortner

et al.31 perormed PDT in patients with unresectable CC Bis-

muth type III and IV who ailed endoprostheses placement

and had the poorest prognosis. Two days aer intravenous

application o a hematoporphyrin derivative Photorin II, in-

traluminal photoactivation was perormed cholangioscopi-

cally. Red light at 630 nm was emitted by an argon-dye laser

and laser fbers o 400 m core diameter with exible cylin-

drical diuser tips o 2.5 and 4 lengths were used. With out-

put o 800 mW, the light ux was 310 and 190 mW/cm 2, and

by changing irradiation time the resulting dose was 180 J/cm2.

Bilirubin serum levels declined rom 31872 to 10335 mol/

L (p=0.0039) with no signifcant increase during the 2 month-

ly ollow-ups. Quality o lie indices improved dramatically

(Karnosky index 32.3%8.13% to 68.9%6.1%,p=0.0078;

World Health Organization index 3.20.36 to 1.70.4,p=

0.016; perormance rating scale 13.61.6 to 50.93,p=0.0078)

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Lee TY et al.

41

and remained stable during the ollow-up. irty-day mortality

was 0%, 1-year survival was 77.7%, and median survival time

was 439 days.

In the prospective, open-label, randomized, multicenter

study with a group sequential design comparing PDT in ad-

dition to stenting (group A) with stenting alone (group B) in

patients with nonresectable CC was reported by Ortner et al.6

PDT resulted in prolongation o survival (group A, n=20, me-

dian 493 days; group B, n=19, median 98 days;p

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42 Clin Endosc 2013;46:38-44


stent patency period (median 24466 and 17745 days, re-

spectively,p=0.002) and patient survival (median 356213

and 23073 days, respectively,p=0.006) compared with the

metal stent only group. e ability o PDT to destroy cancer

cells and lessen cholestasis may prolong stent patency.

THE ROLE OF PDT FOR LOCALRECURRENT TUMOR AFTERRESECTION OR AS NEOADJUVANTTREATMENT

We experienced a case whose survival time prolonged re-

markably aer the application o PDT or a postoperative re-

current tumor (Fig. 4). A small (n=8) uncontrolled study sh-

owed marked destruction o the recurrent tumor; 75% o pa-

tients were disease ree aer 2 years.35

Neoadjuvant PDT was evaluated in seven patients with ad-

vanced Bismuth type III and IV carcinoma, which were th-ought to be unresectable.28 Ater PDT, a curative resection

could be perormed in all patients; 83% were recurrence ree

aer 1 year and 5-year survival was 71%. No relevant side e-

ects o PDT occurred except or a minor intraoperative pho-

totoxicity in one patient.

Fig. 4. Photodynamic therapy (PDT) for postoperative recurrent tumor. A 76-year-old man was referred to our hospital with jaundice. He re-ceived Whipples operation due to hilar cholangiocarcinoma 1 year ago. (A) Magnetic resonance imaging shows a contrast enhanced hilarmass with obstructing anastomosis site. (B) Cholangioscopy shows mucosal nodularity and neovascularization in the anastomosis site. Bi-opsy specimens revealed adenocarcinoma. (C) Two days after PDT. Cholangiocopy shows circumferential coagulation necrosis at the PDT-treated lesion. (D) One year after the PDT, recanalized anastomotic site and small papillary changes with no abnormal vessels can be seenon cholangioscopy. Cholangioscopic biopsy specimens revealed chronic nonspecic inammation.

A

C

B

D

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Lee TY et al.

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ASSESSMENT OF RESPONSE TO PDT

Evaluation o the therapeutic eects o PDT or patients

with CC presents a number o challenges. Ortner et al.6 evaluat-

ed the therapeutic eect o PDT in cases o advanced BDC by

comparing the tumor length beore and aer PDT using themother-baby cholangioscopic technique; however, it has been

argued that their assessment was insuciently objective. Al-

though the authors23 reported reduced serum bilirubin levels

aer PDT, plastic biliary endoprostheses were inserted in all

patients ollowing the PDT procedure, making it dicult to as-

sess the direct eect o PDT in reducing serum bilirubin. How-

ever, the PDT group might have mainly benefted rom the

number o ERCP sessions. For this reason, we do not consid-

er the serum bilirubin level to be an objective parameter or

assessing the response to PDT. Ductal CCs characteristically

spread along or within the intrahepatic bile ducts, making it

dicult to defne the response to PDT based on changes inthe tumor mass by computed tomography (CT). Similarly, it

may be dicult to obtain objective results when the evalua-

tion o the response to PDT is based solely on the extent o re-

opening o an occluded segment o the bile duct, as has been

done in some studies.36 Previously, we assessed the thickness

o the tumor mass beore and aer PDT treatment, measuring

the thickest part o the tumor beore the treatment and every

month thereaer.37 e mean thickness o the bile duct mass-

es, as measured by intraductal ultrasound, decreased rom

8.73.7 mm beore PDT to 7.12.0 mm at 1 month (p=0.176),

to 7.12.4 mm at 2 months (p=0.157), and declined signif-cantly to 5.82.0 mm at 3 months (p=0.046) aer PDT.

In murine cancer models, some investigators have ound

that serum interleukin (IL)-6 levels correlate with tumor bur-

den.38,39 Goydos et al.40 reported that serum IL-6 levels were

correlated with the tumor burden as measured by CT in pa-

tients with CC; 2 weeks aer tumor resection in three o 15

patients, IL-6 levels had dropped to undetectable levels in

two patients and by almost tenold in the third. Our results

similarly demonstrated that IL-6 was signiicantly reduced

(38.29.9 pg/mL;p=0.008) 1 month aer PDT compared with

the pretreatment level (282.1121.8 pg/mL); tumor thickness

also decreased ollowing PDT. In contrast, IL-6 levels had not

changed 1 month aer ERBD.39

FACTORS ASSOCIATED WITHINCREASED SURVIVAL AFTER PDT

Recently, actors associated with patients survival aer PDT

were analyzed in two studies.41,42 Prasad et al.41 conducted a re-

trospective study o 25 patients with unresectable CC treated

with PDT in addition to biliary decompression. e presence

o a visible mass on imaging studies, a lower serum albumin

level and longer time between diagnosis and PDT predicted

a poorer survival rate. Similar results were obtained in our re-

trospective analysis o 143 patients with hilar CC.42 We treat-

ed 72 patients with PDT and 71 patients with endoprotheses

alone. We ound that patients treated with PDT lived longerthan those who were not treated with PDT (9.8 months vs.

7.3 months). Furthermore, lower pre-PDT bilirubin level,

multiple PDT treatments and shortened time to treatment a-

ter diagnosis were signifcant predictors o improved survival.

ese two studies indicate the importance o early PDT aer

the diagnosis o unresectable CC.

CONCLUSIONS

Patients with unresectable CC had so ar a very short lie

expectancy. PDT is the frst palliative treatment option that

has shown its ecacy in two randomized prospective studies.PDT improves survival, jaundice, and quality o lie, is well

tolerated and can be repeated without losing its ecacy.43-46

PDT seems to be a promising therapeutic approach or unre-

sectable CC. It combines the aim to treat cholestasis and to re-

duce tumor growth. PDT, thereore, should be considered as

a standard care or the palliation o CC. I the results are con-

frmed one could think o trying new photosensitizers with

greater penetration depth and shorter photosensitivity, or us-

ing better drug targeting or combination therapies to induce

more tumor necrosis. As PDT treatment is not available in all

centers, patients should be reerred to a specialized center withPDT availability. It is still not known whether radiotherapy

and/or chemotherapy urther improve the ate o PDT pa-

tients. It is now necessary to strengthen these data in an ex-

tended randomized multicenter study. PDT or recurrent tu-

mors aer surgery and neoadjuvant PDT is still experimental.

Conicts of Interest

e authors have no fnancial conicts o interest.

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