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Cholangiocarcinoma: An emerging indication for photodynamic therapy
Photodiagnosis and Photodynamic Therapy (2009) 6, 84—92
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/pdpdt
REVIEW
Cholangiocarcinoma: An emerging indication for photodynamic therapy Ron R. Allison MD a,∗, Emmanuel Zervos b, Claudio H. Sibata a a
PDT Center, Radiation Oncology Department, Brody School of Medicine, Greenville, NC, USA Surgical Oncology Department, Brody School of Medicine, Greenville, NC, USA Available online 7 June 2009
b
KEYWORDS Cholangiocarcinoma; Photodynamic therapy; Radiation therapy; Interlukin-6; PDT
Summary Cholangiocarcinoma (CC) is emerging as an important treatment indication for photodynamic therapy. CCs are generally unresectable locally invasive tumors that occlude the biliary tree leading to fatal cholangitis and liver failure. Biliary decompression via stenting offers symptomatic relief but does not control tumor growth. Founded on an initial case study followed by ever more sophisticated clinical research, including randomized trials, photodynamic therapy has garnered enough momentum to be considered as part of the standard of care for these patients. Further, preliminary clinical data show the potential for benefit of the use of PDT in a neoadjuvant and adjuvant fashion to the minority of patients currently considered resectable or of border line resectability. PDT also impacts interleukin-6 levels and may form the basis for a targeted therapy approach to this disease. We review the clinical rationale, current studies and potential future directions of PDT for patients with CC. © 2009 Elsevier B.V. All rights reserved.
Contents Introduction............................................................................................................... Anatomic consideration ................................................................................................... Staging .................................................................................................................... Epidemiology.............................................................................................................. Natural history ............................................................................................................ Diagnostic procedures ..................................................................................................... Management .............................................................................................................. Surgical therapy........................................................................................................... Palliative treatments ...................................................................................................... Stenting ................................................................................................................... Radiation therapy ......................................................................................................... Chemotherapy............................................................................................................. PDT .......................................................................................................................
∗ Corresponding author at: PDT Center, Radiation Oncology Department, Brody School of Medicine, Cancer Center 166, Greenville, NC 27834-4300, USA. E-mail address: [email protected] (R.R. Allison).
1572-1000/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2009.05.001
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Cholangiocarcinoma
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Adjuvant PDT ............................................................................................................. Morbidity.................................................................................................................. Future directions and conclusions ......................................................................................... References ................................................................................................................
Introduction Cholangiocarcinoma (CC) has emerged as an important treatment indication for photodynamic therapy (PDT). As is not uncommon in medicine this was developed through clinical serendipity [1]. A solitary patient with highly symptomatic unresectable CC was offered palliative PDT as a last resort. A team led by McCaughan et al. had delivered hematoporphyrin (HpD) based PDT on numerous occasions over a several year period. The drug dose chosen, 2.0 mg/kg, light dose of 200 J/cm as well as treatment interval postinfusion of 48—72 h have presciently remained the PDT standard more than three decades later. Further, the treatment approach of repeated PDT sessions illuminating the tumor bed with margin in combination with a bile drainage procedure also appears to be emerging as the current standard of care. Despite having a fatal diagnosis of unresectable CC, the patient in this report was symptomatically palliated in this manner for many years indicating that palliative therapy can not only offer enhanced quality of life but may also impact survival. It also should serve as a reminder for cautious interpretation of current trials survival data as some CC are relatively slowly progressive and the natural history of the disease rather than intervention may ultimately be at play. Nevertheless, this solitary case report appears to have formed the foundation for PDT in CC, once again championing the importance of clinical observation.
Anatomic consideration The location of CC has a direct impact on the utility of PDT intervention. Yet clinically and pathologically, it is often difficult to ascertain where within the biliary tree these lesions originate and where they have spread. Complicating this is that some CCs are multifocal. As anatomic origination also correlates with clinical outcome and the behavior of the malignancy, significant effort is generally made to define this aspect of the disease [2,3]. This allows for interpretation of interventions and outcomes. In its simplest form, CC can be anatomically defined as originating within the liver’s (intrahepatic) biliary tree or outside the liver’s (extrahepatic) biliary tree. Intrahepatic lesions present as a solitary large mass and PDT is rarely used in this setting. Extrahepatic lesions are far more common and come in several varieties. Extrahepatic CCs that are near the hilum of the liver are termed perihilar or Klatskin tumors. By definition Klatskin tumors involve the main extrahepatic bile duct and may extend to the proximal bile duct bifurcation at the level of the liver (Fig. 1). Extrahepatic CC most commonly involves the common bile duct beyond the insertion of the cystic duct of the gall bladder or the distal bile duct extending to the Ampulla of Vater which opens in the duodenum. These extrahepatic tumors appear to be more amenable to PDT as they
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lead to stricture of the bile duct via endoductal growth and only rarely form large biliary compressing masses.
Staging Staging allows for an understanding of how to optimize intervention and also allows for comparisons of outcomes ascertaining which therapy is most appropriate for a given patient. However, given the difficulties with determining the anatomic origination and extension of disease, accurate staging for CC is rather difficult. Further, as some patients are clinically staged while others are surgically staged, interpreting outcome data from different series must be done cautiously. Complicating interpretation is that several staging systems are currently employed. The TNM system relies on surgical staging, which requires histologic specimens obtained at surgery not possible in many patients [4]. The Bismuth classification for hilar lesions appears to be more commonly used [5] (Fig. 1).
Epidemiology While hepatobiliary malignancies are relatively common worldwide, CC remains a rare subtype though its incidence is on the rise [6]. Most patients are elderly at diagnosis with a slight preponderance of males. Risk factors are poorly described but several definite causes have been found. Primary sclerosing cholangitis, usually diagnosed in patients younger than 40 years old, is a risk factor for CC. Liver flukes, stones, cirrhosis, hepatitis C, thorotrast, PVC, dioxin, and particularly biliary malformation (Caroli disease) are linked to CC.
Figure 1 The left side of the figure shows the general descriptions for Klatskin type tumors. Distal tumors are those which involve the intrapancreatic portion of the bile duct and, thereby, require pancreaticoduodenectomy for complete resection. The right side of the figure depicts the Bismuth—Corlette classification which is the standard descriptor today—–all are Klatskin type tumors, i.e. involve the bifurcation.
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Natural history CC is felt to arise from transformation of the cholangiocytes or stem cells that line the biliary tree [7]. Hepatic stem cells may also be the source. The oncogenic process appears to be a result of chronic inflammation within the biliary tree. The biliary environment is rich in cytokines, growth factors, bile acids and other factors that trigger growth and cycling of stem cells. Cells injured by the inflammatory microenvironment are then exposed to these growth factors and may follow a pathway to malignancy. In particular interleukin-6 (IL-6) may have critical activity in this transformation [8]. IL-6 is produced extensively by CC cells and has the ability to promote autocrine/paracrine pathways of uncontrolled growth. CC has over expression of IL-6 receptors, which when activated, leads to growth. It appears then that CC not only produces excess IL-6 but also can put this growth factor to use. While certainly unlikely to be the exclusive cause of transformation and tumor growth, IL-6 appears to be a major factor in CC. Clinically, high IL-6 levels are noted in patients with CC [9]. Further IL-6 levels diminish after PDT and may serve as a means to determine outcome from therapy [10]. Once cancers develop, they clinically express themselves based on anatomic location. Not surprisingly as biliary inflammation may be multifocal many patients develop multifocal tumors. Intrahepatic lesions generally form to masses. These masses become painful and present with right upper quadrant (RUQ) tenderness. Patients often complain of night sweats, malaise and anorexia. Rarely the gall bladder may be palpable (Courvosiers sign). Extrahepatic lesions generally clinically present with painless jaundice though about 10% present with cholangitis. Some of these patients develop virtual complete unilobar biliary obstruction with associated vascular encasement. This results in atrophy of the affected liver lobe. The other liver lobe hypertrophies. This is termed atrophy—hypertrophy complex and on physical exam one can palpate a solitary massive hepatic lobe. Without intervention or when intervention fails, patients often develop fatal cholangitis or liver failure [11]. Lesions have generally progressed locally for many years prior to diagnosis and patients can survive a variable period after the cancer declares itself. Thus the natural history of CC is one of a slowly progressive locally advancing tumor.
R.R. Allison et al. ther enhanced cytologic yield, yet even in expert hands the pathologic confirmation of CC from biopsy remains a challenge. Tumor markers can also assist in diagnosis and follow up of CC. The most common is measuring CA19-9, a carbohydrate antigen secreted by cholangial cells. When at levels >130 U/ml sensitivity and specificity may achieve 79 and 98% for CC [14], but vary significantly in other published reports. It should be cautioned that the CA19-9 can be elevated in bacterial cholangitis. About 10% of the population lacks the blood type Lewis antigen and will not produce this tumor marker. Elevation of other tumor markers such as CEA and CA-125 are nonspecific for CC [15]. Diagnostic studies for tumor location and extent have been defined for CC [16]. Modern CT scanners are invaluable in determining resectability as high resolutions scans with sagittal and coronal reconstruction can establish vascular encasement which is the primary contraindication to surgery. MRI with magnetic resonance cholangio-pancreatography (MRCP) is useful, but not definitive in determining proximal and distal extent of the tumor. Except with obviously resectable middle or distal tumors, no experienced HPB surgeon would rely on MRCP alone to determine resectability in proximal tumors. Similarly endoscopic retrograde cholangiopanchreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) can also reveal lesions and obstructions. The last two have the ability to obtain biopsy tissue at the same sitting. Endoscopic and/or intraductal ultrasound during the ERCP procedure can further assist in evaluating regional lymph nodes and also guide biopsy of suspicious nodes or ducts, an important staging procedure [17]. Ultrasound can also determine the thickness of biliary lesions as well as assist in identifying multifocal biliary tree tumors. Possibly ultrasound differences pre- and post-therapy in terms of treated lesion thickness may also be of value in determining treatment success and the need for additional local therapy [18]. PET/CT is emerging as an important tool to assist in determining local extent of disease and metastasis, important considerations for surgical resection [19]. However, PET/CT is of limited use in patients with cholangitis (many of whom have CC) as the cholangitis can be quite avid for the tracer. PET/CT has so far had limited utility for follow up of patients who have been treated.
Management Diagnostic procedures Histological confirmation for the treatment of CC should be mandatory but is often elusive [3]. CC appears to grow in the sites of cholangitis and differentiating between cholangitis and CC can be a challenge. Some clinical series only had confirmation of disease at autopsy while others include patients with a presumptive diagnosis. CC induces a desmoplastic reaction so that many biopsy samples appear inflammatory in nature requiring multiple biopsies for many patients. To increase yield, Digital Image Analysis of cytologic specimens have been employed nearly doubling diagnostic yield [12]. Fluorescent in situ hybridization (FISH) [13] has fur-
CCs are locally progressive tumors that obstruct biliary and hepatic function. Intervention is aimed at tumor removal if possible, but mainly at biliary drainage. So far permanent tumor elimination can only be achieved by surgical resection though many therapies including radiation, chemotherapy and PDT have been tried. Reestablishing biliary drainage is possible through various methods including surgical approaches, stenting, radiation, chemotherapy and PDT as described in the following sections. It cannot be emphasized strongly enough that with the current state of the art, the only way to achieve cure is based on surgical resection.
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Surgical therapy
ative staging to identify node negative patients and liver transplantation, 5-year survival in excess of 72% have been achieved [24]. Even better results have been reported by the Mayo Clinic with 5-year survival rates in excess of 76%, a number exceeding those obtained even when achieving complete resection in resectable candidates [25].
As this is the only curative approach, each patient must be carefully evaluated by an experienced hepatobiliary surgeon before being termed nonresectable, as this is indeed a terminal option [20]. Evaluation of potentially resectable candidates for surgery should include both ERCP and PTC to determine the lower and upper extent of the lesion. In addition, patients should be evaluated carefully for factors precluding surgical resection including extrahepatic metastatic disease and main trunk portal venous encasement. Unilateral tumor thrombus involving the portal vein is also a relative contraindication to resection unless it can be removed entirely with hepatic resection and does not extend into the venous supply of the remnant liver. Finally, patients must be carefully evaluated for the presence of cholangitis, irreversible jaundice or malnutrition prior to undergoing surgery. Any of these findings should result in postponement of surgery until cholangitis (normal WBC, afebrile, resolution of RUQ pain) is resolved and traditional indices of nutrition (albumin and prealbumin) have returned to normal. In the jaundiced patient in whom hepatic resection is contemplated, jaundice should be minimized prior to hepatectomy in cholangiocarcinoma. In patients whose bilirubin fails to fall below 2 mg/dl despite adequate drainage, adjuvant strategies to improve hepatic reserve such as portal vein embolization or ligation should be considered. Only after patients demonstrate contralateral hypertrophy with improvement or stabilization of the bilirubin should such patients be considered for resectional therapy. The exact cut-off for bilirubin level is unknown and some Asian groups have recommended adjunctive measures of hepatic reserve such as indocyanine green clearance at 15 min as a surrogate to predict liver failure following resection. When applying such methodology to determine resectability, as many as 30% of potentially resectable patients are deemed unresectable. Despite careful selection, perioperative morbidity can reach as high as 44% in patients not undergoing hepatectomy and 63% in those undergoing hepatectomy. Mortality in patients undergoing hepatectomy ranges from 7 to 16% and is significantly lower for patients undergoing extrahepatic resection only [21,22]. So while surgery is the only curative modality it is costly in terms of morbidity and mortality. Overall for those patients able to achieve a complete (RO) resection 5 years survival rates range from 10 to 40%. Outcomes for patients with PSC who develop CC are somewhat worse overall. Outcomes following resection for cholangiocarcinoma depend on the location of the primary tumor and the ability to achieve an R0 resection. Five-year survival following resection of intrahepatic cholangiocarcinoma ranges between 15 and 40% for all comers and 41—67% for those in whom an R0 resection can be achieved. Hilar cholangiocarcinoma 5-year survival ranges from 10 to 40% for all comers and 30—52% in those achieving R0 resection. Five-year survival in patients with distal cholangiocarcinomas range from 23 to 50% for all comers and 27—62% for those undergoing R0 resection [23]. Liver transplantation was initially disregarded due to both a shortage of organs and the poor early 5-year survival (ranging from 0 to 15%). The role of liver transplantation, however, has recently undergone significant evolution. Now, with careful patient selection, neoadjuvant XRT, oper-
Palliative treatments With the realization that most patients are unresectable and virtually all succumb to the effects of local tumor growth and biliary obstruction, numerous palliative interventions aimed at biliary decompression have been employed with various degrees of benefit. Optimal palliative protocols would require multidisciplinary acceptance by GI specialists, surgeons, and oncologists. This in itself is a major difficulty as is the lack of large randomized trials pointing to better approaches than the currently considered standard of care which is stenting alone.
Stenting Various stents including covered plastic devices to selfexpanding metal versions (SEMS) have become the standard palliative option for patients with CC [26]. These devices are generally placed endoscopically and compare favorably with surgical choledochojejunostomy or percutaneous approaches. The latter two are associated with more morbidity, but no greater rate of restoration of biliary drainage. Covered plastic stents come in various sizes and data show those of larger diameter are less prone to occlude [27]. SEMS appear to offer an even greater degree of drainage as compared to covered versions [28]. Randomized trials have shown no benefit of stenting both liver lobes as compared to stenting the obstructed region alone [29]. Some reports show that multiple stents placed may actually lead to occlusion. What is true for all stents is that tumors will eventually occlude them either by growing through the SEMS wire cage or at the entry or exit of the covered versions. As such, routine replacement of stents or at least attempts to achieve repatency is required [30]. Each of these additional procedures increases the risk of introducing infection but failure to maintain patency ultimately affects both quality and quantity of life. While it is true that stenting is the standard approach to unresectable CC, much work is required to optimize both the type of stent and frequency of stent replacement. It would also seem obvious that interventions that assisted in prolongation of stent patency would be a welcome addition to this standard of care.
Radiation therapy RT can be delivered to CC by various means including external beam, brachytherapy and, recently, via radioactive spheres [31]. Intrahepatic CC cannot be routinely treated by brachytherapy catheters as the radioactive source cannot easily traverse the hilum into the upper biliary tree, though brachytherapy sources could be delivered via a CT guided approach transcutaneously. Several retrospective studies have shown either external beam alone or in com-
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bination with brachytherapy (generally for extrahepatic CC) increases biliary flow for palliation and improves quality of life [32]. Life prolongation appeared possible as compared to historic controls. Ultimately though, as the radiation data base for this indication is based on single institution retrospective series, no definitive conclusion as to the efficiency of radiation can easily be made.
Chemotherapy Numerous chemotherapy agents have been tried in multiple phase I/II studies with little positive effects on CC [33]. Currently, the most active agents appear to be 5-FU and Gemcitabine with the latter the preferred agent. Even when all studies are taken together no definitive evidence exists that chemotherapy, when delivered as a single or as multiple agents, has a significant impact on survival or quality of life when employed for palliation in CC [34].
PDT As currently practiced PDT offers local tumor ablation as long as the photosensitizer may accumulate in the region of interest and the appropriate activating energy can be introduced, by light of a specific wavelength and intensity [35]. An underappreciated aspect of PDT is that the clinician can alter the treatment pathway to favor apoptosis or necrosis. The latter likely releases cytokines generating an immune response whereas the apoptosis pathway may be considered a true local therapy. This may have important implications for CC as IL-6 appears to be a critical mediator of tumor initiation and growth. Modification of IL-6 levels by PDT is possible both by tumor destruction and perhaps by systemic effects of PDT and may serve as a surrogate marker of treatment success and disease recurrence or progression [36], something that requires further study and will be touched upon again in the future directions section of this article. As was clinically evident, HpD accumulated in cholangial cells from the first case report [1]. In a well-done subsequent
Table 1
pharmacokinetics study, Pahernik et al. [37], reported a significant differential accumulation of Photofrin® in malignant biliary tissue as compared to normal tissue of the bile duct. The peak difference between tumor and normal tissue was 48 h, the time frame clinically used in the first patient. Similarly several other photosensitizer including Foscan® , LS11, MACE and ALA have also shown accumulation in biliary tissue [37,38]. Appropriate illumination to activate the photosensitizer is the critical second step. This is possible as commercially available fiber optics have been created that allow passage through endoscopes to the level of the biliary tumor bed. Most commonly, the fiber optic follows the biliary tract and the light diffusing region is placed so that it illuminates the entire tumor bed within the bile duct itself. The current generation of light diffusers has radio opaque markers at the proximal and distal end of the light diffuser so that fluoroscopic images can be taken during illumination to insure the entire affected biliary duct is treated. For lesions larger than the diffusers light emitting length, the diffuser is moved proximal or distal to encompass the entire region. This is troublesome as potentially it would allow certain regions of the tumor or biliary tree to be overdosed with light, while other regions may be under dosed. Over dosage with light can allow for excess PDT and creation of additional stricture due to therapy; under dosage allows tumor to regrow. As many of the strictures are not exactly linear it is possible for the light source to be at various distances from the bile duct wall. This too can allow for non-homogenous light dosing, again allowing for over or under dosage of illumination which may be of clinical consequence. A small number of dedicated investigators built upon the first clinical case report’s observation and have published a series of papers evaluating the effects of PDT on CC patients. These have been uniformly positive and ultimately have set the stage for randomized trials which too have shown clinically significant benefit of PDT for patient with unresectable disease.
HpD/Photofrin® studies for CC.
Reference
Patient number
Median survival (months)
30-Day mortality (%)
Photosensitivity (%)
[47] [52] [46] [18] [45] [55] [43] [42] [41] [40] [56] [48] [48] [48] [49] [49]
19 25 68 24 8 23 24 6 23 21 8 20 19 31 16 16
16.2 11.5 12 18 9 11.2 10 10 (est) 11.1 14.6 6 16.3 3.2 14 21 7
0 0 0 0 0 0 0 16 4 0 0 0 5 0 0 14
16 4 12 4 25 13 8 17 13 5 0 15 0
Randomized Control Non-randomized Randomized Control
0 0
Cholangiocarcinoma As will be reviewed in the following section, Photofrin® has been the predominant photosensitizer of choice, generally delivered intravenously at 2 mg/kg with illumination at 48 h post-infusion via 630 nm red light. Virtually all studies deliver light at 180—200 J/cm with one or two increasing this to 240 J/cm. At this drug and light dose combination, based on one case report, tumor destruction of approximately 0.5 cm depth can be expected. Generally, PDT is repeated as clinically indicated every 3—6 months. As summarized in Table 1, this results in a median survival ranging from 6 to 21 months with a uniform improvement of survival over either historic or randomized control arms as well as enhanced quality of life, when measured. The 30day morbidity for Photofrin® based sessions is very low and mild to moderate photosensitivity reactions ranges from 0 to 25%. Ortner et al. [39] published on nine patients with nonresectable Bismuth III/IV who underwent PDT via HpD. Median survival of 14.4 months and a dramatic improvement in Karnofsky and bilirubin levels was achieved. Subsequently 21 patients treated via Photofrin® achieved similarly excellent outcomes [40]. Berr et al. [41], using Photofrin® , treated 23 Bismuth III/IV patients and achieved an 11.1-month median survival. Also improvement in Karnofsky status and diminished biliary levels were reported. A small study on six patients treated with Photofrin® achieved a median survival of greater than 9 months according to Rumalla et al. [42]. Using metal stents and only one Photofrin® based PDT session Dumoulin et al. [43] reported a 10-month median survival, nearly double that of historical controls but did not meet statistical significance. Also important to note is that in this study, as compared to all others, PDT was done on only one occasion. Weidmann et al. [44] published on long term outcome following Photofrin® PDT for nonresectable disease. Median survival was 11.2 months, but eventually all patients progressed either locally or less commonly systemically. Cheon et al. [10] and Shim et al. [18] reported that Photofrin® or HpD PDT and stenting on 27 nonresectable hilar CC patients achieved a median survival of 18 months as compared to a matched control achieving 10 months without PDT. Harewood et al. [45] also showed a survival benefit to Photofrin® PDT on a small study of eight patients with nonresectable disease. In a large study of 184 patients with hilar cholangiocarcinoma, Witzigmann et al. [46] concluded that PDT plus stenting, employed in a subset of 68 patients, was superior to stenting alone with survival nearly doubling to 12 months. Similarly, in a recent article Kahaleh et al. [47] reported that the addition of Photofrin® PDT to stenting alone achieved a 16.2-month vs. 7.4-month survival advantage. Two randomized trials comparing stenting to stenting and PDT for unresectable perihilar CC have been published in the peer review literature and are extremely important. In the study reported by Ortner et al. [48], the trial was prematurely closed after interim analysis due to the great survival advantage of the addition of PDT. A total of 39 patients out of the planned 68 were randomized to either stenting alone or the addition of Photofrin® PDT infused at 2 mg/kg with illumination at 180 J/cm at 48 h post-infusion. A statistically significant survival advantage of 16.3 months vs.
89 3.2 months was achieved with PDT. Further, statistically significant improvement in quality of life was found as was improved physical function, Karnofsky status and bilirubin level. A third group of 31 patients refusing randomization was treated as per protocol with PDT. They too achieved a 14-month median survival with similar improvement in quality of life. A second randomized trial reported by Zoepf et al. [49] showed similar survival advantage with the addition of PDT to stenting. In this study 16 patients underwent stenting and PDT vs. 16 patients who underwent stenting alone. PDT delivered a 21-month median survival vs. 7 months with stenting alone. This study employed the photosensitizer Photosan-3, a drug considered similar if not identical to Photofrin® . It was infused at 2 mg/kg with illumination of 200 J/cm. Neither study was without morbidity, yet these differed. Photosensitivity of self limiting duration and intensity occurred in three patients in Ortner’s et al. trial, but in none from Zoepf et al. Ortner et al. reported cholangitis in 5 patients undergoing PDT as compared to 13 in the control group. In contrast, Zoepf et al. reported a 25% cholangitis rate in the PDT arm though this dropped dramatically once the study switched to a prolonged course of antibiotics. Neither study had any 30-day post-procedure mortality, a critical indicator of safety. The Ortner et al. study has been criticized as only randomizing patients after they failed stenting, likely explaining the short control arm survival while 25% of the patients in Zoept’s et al. trial were treated without histological confirmation of disease. Oral ALA has been tried for CC but at the drug dose (60 mg/kg) and light dose chosen, no clinical benefit was shown [50]. A small phase I/II study of Foscan® for nonresectable biliary strictures from CC or recurrent stent occlusion achieved a median survival of 8 months [51]. This photosensitizer has photosensitivity of cutaneous tissues of about 4 weeks and is activated at 652 nm for somewhat better tissue penetration. All patients underwent successful PDT sessions as well as repeated stent procedures as part of this protocol. Two patients developed significant cholangitis and two others hemobilia within 30 days of PDT resulting in two deaths. Further, two patients had photosensitivity reaction. While Foscan® appears active at the dose of 0.15 mg/kg and illumination 72 h post-infusion at 10—50 J/cm, this drug dose/light dose combination appears to have significant acute morbidity and mortality. A solid body of literature, including two randomized trials, appears to show benefit in terms of median survival for Photofrin® PDT in addition to stenting for unresectable hilar region CC. One should not necessary extend that benefit to patients with intrahepatic or more distal lesions. When analyzing for factors associated with enhanced survival Prasad et al. [52] reported that earlier intervention with PDT improved outcomes. Patients with visible masses on imaging studies did poorly. Other investigators have suggested that the frequency of PDT may be important as is the maintenance of the viability of the stents [4]. Potentially stent viability may be equal if not greater than the benefit from PDT, an important aspect to illuminate, if PDT is to become the standard of care for nonresectable patients [47].
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Adjuvant PDT As resection remains the only curative therapy, several investigators have employed PDT in a neoadjuvant fashion in an attempt to increase resectability. In an early study Berr et al. [53] employed Photofrin® PDT for hilar CC in a single patient. Pathology revealed tumor necrosis from PDT within the bile duct to 4—5 mm depth. The patient had local control for 18 months. Weidmann et al. [44], using Photofrin® , offered neoadjuvant PDT to seven patients with what was described as border line resectable hilar CC. Six patients remained recurrence free at 1 year (85%). Importantly, the biliary anastomosis remained patent after PDT. Nanashima et al. [54] reported on eight patients treated postoperatively with adjuvant PDT therapy. Most patients did not experience failure in the PDT treated region of the biliary tree. The authors felt this offered enhanced control without excessive treatment related stenosis compared to historical controls. Certainly adjuvant and neoadjuvant PDT appear promising but with so few patients treated, definitive recommendation will await clinical trial outcomes.
Morbidity CC is a fatal tumor so some investigators may downplay treatment associated side effects. It is clear that most PDT studies report photosensitivity reactions occurring though generally not life threatening (Table 1). Since many of these same studies use repeated photosensitizer infusions and treatment, it should be emphasized that the last months for many of these patients will exclude normal outdoor daytime activities, a potentially high price to pay for a terminal patient. Additionally, as PDT requires transcutaneous or endoscopic means to introduce the light source, this may cause or trigger infection such as cholangitis which can be fatal. Cholangitis is common in individuals with CC and it is unclear how much added risk, if any, PDT causes. Hemobilia has been reported which may require embolization [41]. With Photofrin® PDT, 30-day mortality rates are very low (Table 1).
Future directions and conclusions Palliation for nonresectable patients appears in large part based on maintaining successful biliary drainage. In Ortner’s et al. [48] and Zoepf’s et al. [49] randomized trials, PDT clearly was able to prolong biliary drainage and this impacted on survival. Despite these excellent results PDT has still not gained worldwide acceptance for its use in CC. It would seem then that the definitive study for PDT would be a multicenter head to head comparison of repeated stenting to stenting and PDT with measurement of survival, morbidity and quality of life. What is also required is a drug and light dosing trial. As it stands 2 mg/kg and roughly 200 J/cm is the standard of care for Photofrin® ; however, higher light doses may prolong biliary patency. Further, lower drug dose may enhance selectivity of treatment, favoring destruction of malignant tissue. What is not clear, but needs to be explored, is the effect of PDT on the normal biliary tree that is illuminated. It is possible that PDT, particularly by
R.R. Allison et al. deeper penetrating photosensitizer/light source, may actually induce some fibrosis or inflammation within the duct and lead to stricture. As each PDT session involves manipulation of the biliary tree, investigators should always attempt to minimize the number of interventions and ideally minimize the risk for cholangitis. Thus studies to review ways to minimize interventions and prolong patency are also needed. As resection remains the only chance for cure the use of adjuvant and/or neoadjuvant PDT should be further explored. Many resection patients actually fail locally at the anastomotic region and others are deemed locally unresectable at the actual surgical exploration. Intra-op PDT may assist in allowing for lesion destruction and improve local control thus potentially curing an additional cohort of individuals. It would also be worthwhile to combine PDT and XRT to see if additive outcomes could be obtained, as both are excellent local therapies. Targeting IL-6 via PDT vaccines or combining PDT with agents that target IL-6 or downstream molecules that are up regulated by IL-6 would be a novel approach to this disease. As IL-6 appears critical in CC growth and progression as well as the finding that IL-6 levels decline after successful PDT, this should be further explored. Given its dismal outcome for most patients novel approaches such as PDT are needed.
References [1] McCaughan Jr JS, Mertens BF, Cho C, et al. Photodynamic therapy to treat tumors of the extrahepatic biliary ducts. A case report. Arch Surg 1991;126(1):111—3. [2] Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology 2008;48(1):308—21. [3] Reddy SB, Patel T. Current approaches to the diagnosis and treatment of cholangiocarcinoma. Curr Gastroenterol Rep 2006;8(1):30—7. [4] Kiesslich T, Wolkersdorfer G, Neureiter D, et al. Photodynamic therapy for non-resectable perihilar cholangiocarcinoma. Photochem Photobiol Sci 2009;8(1):23—30. [5] Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215(1):31—8. [6] Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24(2):115—25. [7] Sell S, Dunsford HA. Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol 1989;134(6):1347—63. [8] Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 2005;41(16):2502—12. [9] Goydos JS, Brumfield AM, Frezza E, et al. Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg 1998;227(3):398—404. [10] Cheon YK, Cho YD, Moon JH, et al. Diagnostic utility of interleukin-6 (IL-6) for primary bile duct cancer and changes in serum IL-6 levels following photodynamic therapy. Am J Gastroenterol 2007;102(10):2164—70. [11] Jarnagin WR, Fong Y, DeMatteo RP, et al. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 2001;234(4):507—17 [discussion 517—9]. [12] Baron TH, Harewood GC, Rumalla A, et al. A prospective comparison of digital image analysis and routine cytology for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol 2004;2(3):214—9.
Cholangiocarcinoma [13] Halling KC, Kipp BR. Fluorescence in situ hybridization in diagnostic cytology. Hum Pathol 2007;38(8):1137—44. [14] Patel AH, Harnois DM, Klee GG, et al. The utility of CA19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 2000;95(1):204—7. [15] Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 2004;24(2):139—54. [16] Slattery JM, Sahani DV. What is the current state-of-theart imaging for detection and staging of cholangiocarcinoma? Oncologist 2006;11(8):913—22. [17] Gleeson FC, Rajan E, Levy MJ, et al. EUS-guided FNA of regional lymph nodes in patients with unresectable hilar cholangiocarcinoma. Gastrointest Endosc 2008;67(3):438—43. [18] Shim CS, Cheon YK, Cha SW, et al. Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy 2005;37(5):425—33. [19] Corvera CU, Blumgart LH, Akhurst T, et al. 18 Ffluorodeoxyglucose positron emission tomography influences management decisions in patients with biliary cancer. J Am Coll Surg 2008;206(1):57—65. [20] Jarnagin WR, Shoup M. Surgical management of cholangiocarcinoma. Semin Liver Dis 2004;24(2):189—99. [21] Zervos EE, Pearson H, Durkin AJ, et al. In-continuity hepatic resection for advanced hilar cholangiocarcinoma. Am J Surg 2004;188(5):584—8. [22] Lang H, Sotiropoulos GC, Sgourakis G, et al. Operations for intrahepatic cholangiocarcinoma: single-institution experience of 158 patients. J Am Coll Surg 2009;208(2):218—28. [23] Aljiffry M, Abdulelah A, Walsh M, et al. Evidence-based approach to cholangiocarcinoma: a systematic review of the current literature. J Am Coll Surg 2009;208(1):134—47. [24] Rea DJ, Rosen CB, Nagorney DM, et al. Transplantation for cholangiocarcinoma: when and for whom? Surg Oncol Clin N Am 2009;18(2):325—37. [25] Heimbach JK, Gores GJ, Haddock MG, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma. Semin Liver Dis 2004;24(2):201—7. [26] Abu-Hamda EM, Baron TH. Endoscopic management of cholangiocarcinoma. Semin Liver Dis 2004;24(2):165—75. [27] Raijman I. Biliary and pancreatic stents. Gastrointest Endosc Clin N Am 2003;13(4):561—92, vii—viii. [28] Kaassis M, Boyer J, Dumas R, et al. Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 2003;57(2):178—82. [29] De Palma GD, Galloro G, Siciliano S, et al. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc 2001;53(6):547—53. [30] Chahal P, Baron TH. Endoscopic palliation of cholangiocarcinoma. Curr Opin Gastroenterol 2006;22(5):551—60. [31] Saito H, Takada T, Miyazaki M, et al. Radiation therapy and photodynamic therapy for biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg 2008;15(1):63—8. [32] Takamura A, Saito H, Kamada T, et al. Intraluminal lowdose-rate 192 Ir brachytherapy combined with external beam radiotherapy and biliary stenting for unresectable extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 2003;57(5):1357—65. [33] Furuse J, Takada T, Miyazaki M, et al. Guidelines for chemotherapy of biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg 2008;15(1):55—62. [34] Takada T, Miyazaki M, Miyakawa S, et al. Purpose, use, and preparation of clinical practice guidelines for the management
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of biliary tract and ampullary carcinomas. J Hepatobiliary Pancreat Surg 2008;15(1):2—6. Allison RR, Downie GH, Cuenca R, et al. Photosensitizers in clinical PDT. Photodiag Photodyn Ther 2004;1(1): 27—42. Mott JL, Gores GJ. Targeting IL-6 in cholangiocarcinoma therapy. Am J Gastroenterol 2007;102(10):2171—2. Pahernik SA, Dellian M, Berr F, et al. Distribution and pharmacokinetics of Photofrin in human bile duct cancer. J Photochem Photobiol B 1998;47(1):58—62. 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. Photochem Photobiol Sci 2007;6(6):619—27. Ortner MA, Liebetruth J, Schreiber S, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology 1998;114(3):536—42. Ortner M. Photodynamic therapy for cholangiocarcinoma. J Hepatobiliary Pancreat Surg 2001;8(2):137—9. Berr F, Wiedmann M, Tannapfel A, et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology 2000;31(2):291—8. Rumalla A, Baron TH, Wang KK, et al. Endoscopic application of photodynamic therapy for cholangiocarcinoma. Gastrointest Endosc 2001;53(4):500—4. Dumoulin FL, Gerhardt T, Fuchs S, et al. Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc 2003;57(7):860—7. Wiedmann M, Caca K, Berr F, et al. Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study. Cancer 2003;97(11): 2783—90. Harewood GC, Baron TH, Rumalla A, et al. Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol 2005;20(3):415—20. 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. Ann Surg 2006;244(2): 230—9. Kahaleh M, Mishra R, Shami VM, et al. Unresectable cholangiocarcinoma: comparison of survival in biliary stenting alone versus stenting with photodynamic therapy. Clin Gastroenterol Hepatol 2008;6(3):290—7. Ortner ME, Caca K, Berr F, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 2003;125(5):1355—63. Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 2005;100(11):2426—30. Zoepf T, Jakobs R, Rosenbaum A, et al. Photodynamic therapy with 5-aminolevulinic acid is not effective in bile duct cancer. Gastrointest Endosc 2001;54(6):763—6. Pereira SP, Ayaru L, Rogowska A, et al. Photodynamic therapy of malignant biliary strictures using meso-tetrahydroxyphenylchlorin. Eur J Gastroenterol Hepatol 2007;19(6): 479—85. Prasad GA, Wang KK, Baron TH, et al. Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007;5(6):743—8. Berr F, Tannapfel A, Lamesch P, et al. Neoadjuvant photodynamic therapy before curative resection of proximal bile duct carcinoma. J Hepatol 2000;32(2):352—7. Nanashima A, Yamaguchi H, Shibasaki S, et al. Adjuvant photodynamic therapy for bile duct carcinoma after
92 surgery: a preliminary study. J Gastroenterol 2004;39(11): 1095—101. [55] 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. Gastrointest Endosc 2004;60(1):68—75.
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journal homepage: www.elsevier.com/locate/pdpdt
REVIEW
Cholangiocarcinoma: An emerging indication for photodynamic therapy Ron R. Allison MD a,∗, Emmanuel Zervos b, Claudio H. Sibata a a
PDT Center, Radiation Oncology Department, Brody School of Medicine, Greenville, NC, USA Surgical Oncology Department, Brody School of Medicine, Greenville, NC, USA Available online 7 June 2009
b
KEYWORDS Cholangiocarcinoma; Photodynamic therapy; Radiation therapy; Interlukin-6; PDT
Summary Cholangiocarcinoma (CC) is emerging as an important treatment indication for photodynamic therapy. CCs are generally unresectable locally invasive tumors that occlude the biliary tree leading to fatal cholangitis and liver failure. Biliary decompression via stenting offers symptomatic relief but does not control tumor growth. Founded on an initial case study followed by ever more sophisticated clinical research, including randomized trials, photodynamic therapy has garnered enough momentum to be considered as part of the standard of care for these patients. Further, preliminary clinical data show the potential for benefit of the use of PDT in a neoadjuvant and adjuvant fashion to the minority of patients currently considered resectable or of border line resectability. PDT also impacts interleukin-6 levels and may form the basis for a targeted therapy approach to this disease. We review the clinical rationale, current studies and potential future directions of PDT for patients with CC. © 2009 Elsevier B.V. All rights reserved.
Contents Introduction............................................................................................................... Anatomic consideration ................................................................................................... Staging .................................................................................................................... Epidemiology.............................................................................................................. Natural history ............................................................................................................ Diagnostic procedures ..................................................................................................... Management .............................................................................................................. Surgical therapy........................................................................................................... Palliative treatments ...................................................................................................... Stenting ................................................................................................................... Radiation therapy ......................................................................................................... Chemotherapy............................................................................................................. PDT .......................................................................................................................
∗ Corresponding author at: PDT Center, Radiation Oncology Department, Brody School of Medicine, Cancer Center 166, Greenville, NC 27834-4300, USA. E-mail address: [email protected] (R.R. Allison).
1572-1000/$ — see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.pdpdt.2009.05.001
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Cholangiocarcinoma
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Adjuvant PDT ............................................................................................................. Morbidity.................................................................................................................. Future directions and conclusions ......................................................................................... References ................................................................................................................
Introduction Cholangiocarcinoma (CC) has emerged as an important treatment indication for photodynamic therapy (PDT). As is not uncommon in medicine this was developed through clinical serendipity [1]. A solitary patient with highly symptomatic unresectable CC was offered palliative PDT as a last resort. A team led by McCaughan et al. had delivered hematoporphyrin (HpD) based PDT on numerous occasions over a several year period. The drug dose chosen, 2.0 mg/kg, light dose of 200 J/cm as well as treatment interval postinfusion of 48—72 h have presciently remained the PDT standard more than three decades later. Further, the treatment approach of repeated PDT sessions illuminating the tumor bed with margin in combination with a bile drainage procedure also appears to be emerging as the current standard of care. Despite having a fatal diagnosis of unresectable CC, the patient in this report was symptomatically palliated in this manner for many years indicating that palliative therapy can not only offer enhanced quality of life but may also impact survival. It also should serve as a reminder for cautious interpretation of current trials survival data as some CC are relatively slowly progressive and the natural history of the disease rather than intervention may ultimately be at play. Nevertheless, this solitary case report appears to have formed the foundation for PDT in CC, once again championing the importance of clinical observation.
Anatomic consideration The location of CC has a direct impact on the utility of PDT intervention. Yet clinically and pathologically, it is often difficult to ascertain where within the biliary tree these lesions originate and where they have spread. Complicating this is that some CCs are multifocal. As anatomic origination also correlates with clinical outcome and the behavior of the malignancy, significant effort is generally made to define this aspect of the disease [2,3]. This allows for interpretation of interventions and outcomes. In its simplest form, CC can be anatomically defined as originating within the liver’s (intrahepatic) biliary tree or outside the liver’s (extrahepatic) biliary tree. Intrahepatic lesions present as a solitary large mass and PDT is rarely used in this setting. Extrahepatic lesions are far more common and come in several varieties. Extrahepatic CCs that are near the hilum of the liver are termed perihilar or Klatskin tumors. By definition Klatskin tumors involve the main extrahepatic bile duct and may extend to the proximal bile duct bifurcation at the level of the liver (Fig. 1). Extrahepatic CC most commonly involves the common bile duct beyond the insertion of the cystic duct of the gall bladder or the distal bile duct extending to the Ampulla of Vater which opens in the duodenum. These extrahepatic tumors appear to be more amenable to PDT as they
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lead to stricture of the bile duct via endoductal growth and only rarely form large biliary compressing masses.
Staging Staging allows for an understanding of how to optimize intervention and also allows for comparisons of outcomes ascertaining which therapy is most appropriate for a given patient. However, given the difficulties with determining the anatomic origination and extension of disease, accurate staging for CC is rather difficult. Further, as some patients are clinically staged while others are surgically staged, interpreting outcome data from different series must be done cautiously. Complicating interpretation is that several staging systems are currently employed. The TNM system relies on surgical staging, which requires histologic specimens obtained at surgery not possible in many patients [4]. The Bismuth classification for hilar lesions appears to be more commonly used [5] (Fig. 1).
Epidemiology While hepatobiliary malignancies are relatively common worldwide, CC remains a rare subtype though its incidence is on the rise [6]. Most patients are elderly at diagnosis with a slight preponderance of males. Risk factors are poorly described but several definite causes have been found. Primary sclerosing cholangitis, usually diagnosed in patients younger than 40 years old, is a risk factor for CC. Liver flukes, stones, cirrhosis, hepatitis C, thorotrast, PVC, dioxin, and particularly biliary malformation (Caroli disease) are linked to CC.
Figure 1 The left side of the figure shows the general descriptions for Klatskin type tumors. Distal tumors are those which involve the intrapancreatic portion of the bile duct and, thereby, require pancreaticoduodenectomy for complete resection. The right side of the figure depicts the Bismuth—Corlette classification which is the standard descriptor today—–all are Klatskin type tumors, i.e. involve the bifurcation.
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Natural history CC is felt to arise from transformation of the cholangiocytes or stem cells that line the biliary tree [7]. Hepatic stem cells may also be the source. The oncogenic process appears to be a result of chronic inflammation within the biliary tree. The biliary environment is rich in cytokines, growth factors, bile acids and other factors that trigger growth and cycling of stem cells. Cells injured by the inflammatory microenvironment are then exposed to these growth factors and may follow a pathway to malignancy. In particular interleukin-6 (IL-6) may have critical activity in this transformation [8]. IL-6 is produced extensively by CC cells and has the ability to promote autocrine/paracrine pathways of uncontrolled growth. CC has over expression of IL-6 receptors, which when activated, leads to growth. It appears then that CC not only produces excess IL-6 but also can put this growth factor to use. While certainly unlikely to be the exclusive cause of transformation and tumor growth, IL-6 appears to be a major factor in CC. Clinically, high IL-6 levels are noted in patients with CC [9]. Further IL-6 levels diminish after PDT and may serve as a means to determine outcome from therapy [10]. Once cancers develop, they clinically express themselves based on anatomic location. Not surprisingly as biliary inflammation may be multifocal many patients develop multifocal tumors. Intrahepatic lesions generally form to masses. These masses become painful and present with right upper quadrant (RUQ) tenderness. Patients often complain of night sweats, malaise and anorexia. Rarely the gall bladder may be palpable (Courvosiers sign). Extrahepatic lesions generally clinically present with painless jaundice though about 10% present with cholangitis. Some of these patients develop virtual complete unilobar biliary obstruction with associated vascular encasement. This results in atrophy of the affected liver lobe. The other liver lobe hypertrophies. This is termed atrophy—hypertrophy complex and on physical exam one can palpate a solitary massive hepatic lobe. Without intervention or when intervention fails, patients often develop fatal cholangitis or liver failure [11]. Lesions have generally progressed locally for many years prior to diagnosis and patients can survive a variable period after the cancer declares itself. Thus the natural history of CC is one of a slowly progressive locally advancing tumor.
R.R. Allison et al. ther enhanced cytologic yield, yet even in expert hands the pathologic confirmation of CC from biopsy remains a challenge. Tumor markers can also assist in diagnosis and follow up of CC. The most common is measuring CA19-9, a carbohydrate antigen secreted by cholangial cells. When at levels >130 U/ml sensitivity and specificity may achieve 79 and 98% for CC [14], but vary significantly in other published reports. It should be cautioned that the CA19-9 can be elevated in bacterial cholangitis. About 10% of the population lacks the blood type Lewis antigen and will not produce this tumor marker. Elevation of other tumor markers such as CEA and CA-125 are nonspecific for CC [15]. Diagnostic studies for tumor location and extent have been defined for CC [16]. Modern CT scanners are invaluable in determining resectability as high resolutions scans with sagittal and coronal reconstruction can establish vascular encasement which is the primary contraindication to surgery. MRI with magnetic resonance cholangio-pancreatography (MRCP) is useful, but not definitive in determining proximal and distal extent of the tumor. Except with obviously resectable middle or distal tumors, no experienced HPB surgeon would rely on MRCP alone to determine resectability in proximal tumors. Similarly endoscopic retrograde cholangiopanchreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) can also reveal lesions and obstructions. The last two have the ability to obtain biopsy tissue at the same sitting. Endoscopic and/or intraductal ultrasound during the ERCP procedure can further assist in evaluating regional lymph nodes and also guide biopsy of suspicious nodes or ducts, an important staging procedure [17]. Ultrasound can also determine the thickness of biliary lesions as well as assist in identifying multifocal biliary tree tumors. Possibly ultrasound differences pre- and post-therapy in terms of treated lesion thickness may also be of value in determining treatment success and the need for additional local therapy [18]. PET/CT is emerging as an important tool to assist in determining local extent of disease and metastasis, important considerations for surgical resection [19]. However, PET/CT is of limited use in patients with cholangitis (many of whom have CC) as the cholangitis can be quite avid for the tracer. PET/CT has so far had limited utility for follow up of patients who have been treated.
Management Diagnostic procedures Histological confirmation for the treatment of CC should be mandatory but is often elusive [3]. CC appears to grow in the sites of cholangitis and differentiating between cholangitis and CC can be a challenge. Some clinical series only had confirmation of disease at autopsy while others include patients with a presumptive diagnosis. CC induces a desmoplastic reaction so that many biopsy samples appear inflammatory in nature requiring multiple biopsies for many patients. To increase yield, Digital Image Analysis of cytologic specimens have been employed nearly doubling diagnostic yield [12]. Fluorescent in situ hybridization (FISH) [13] has fur-
CCs are locally progressive tumors that obstruct biliary and hepatic function. Intervention is aimed at tumor removal if possible, but mainly at biliary drainage. So far permanent tumor elimination can only be achieved by surgical resection though many therapies including radiation, chemotherapy and PDT have been tried. Reestablishing biliary drainage is possible through various methods including surgical approaches, stenting, radiation, chemotherapy and PDT as described in the following sections. It cannot be emphasized strongly enough that with the current state of the art, the only way to achieve cure is based on surgical resection.
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Surgical therapy
ative staging to identify node negative patients and liver transplantation, 5-year survival in excess of 72% have been achieved [24]. Even better results have been reported by the Mayo Clinic with 5-year survival rates in excess of 76%, a number exceeding those obtained even when achieving complete resection in resectable candidates [25].
As this is the only curative approach, each patient must be carefully evaluated by an experienced hepatobiliary surgeon before being termed nonresectable, as this is indeed a terminal option [20]. Evaluation of potentially resectable candidates for surgery should include both ERCP and PTC to determine the lower and upper extent of the lesion. In addition, patients should be evaluated carefully for factors precluding surgical resection including extrahepatic metastatic disease and main trunk portal venous encasement. Unilateral tumor thrombus involving the portal vein is also a relative contraindication to resection unless it can be removed entirely with hepatic resection and does not extend into the venous supply of the remnant liver. Finally, patients must be carefully evaluated for the presence of cholangitis, irreversible jaundice or malnutrition prior to undergoing surgery. Any of these findings should result in postponement of surgery until cholangitis (normal WBC, afebrile, resolution of RUQ pain) is resolved and traditional indices of nutrition (albumin and prealbumin) have returned to normal. In the jaundiced patient in whom hepatic resection is contemplated, jaundice should be minimized prior to hepatectomy in cholangiocarcinoma. In patients whose bilirubin fails to fall below 2 mg/dl despite adequate drainage, adjuvant strategies to improve hepatic reserve such as portal vein embolization or ligation should be considered. Only after patients demonstrate contralateral hypertrophy with improvement or stabilization of the bilirubin should such patients be considered for resectional therapy. The exact cut-off for bilirubin level is unknown and some Asian groups have recommended adjunctive measures of hepatic reserve such as indocyanine green clearance at 15 min as a surrogate to predict liver failure following resection. When applying such methodology to determine resectability, as many as 30% of potentially resectable patients are deemed unresectable. Despite careful selection, perioperative morbidity can reach as high as 44% in patients not undergoing hepatectomy and 63% in those undergoing hepatectomy. Mortality in patients undergoing hepatectomy ranges from 7 to 16% and is significantly lower for patients undergoing extrahepatic resection only [21,22]. So while surgery is the only curative modality it is costly in terms of morbidity and mortality. Overall for those patients able to achieve a complete (RO) resection 5 years survival rates range from 10 to 40%. Outcomes for patients with PSC who develop CC are somewhat worse overall. Outcomes following resection for cholangiocarcinoma depend on the location of the primary tumor and the ability to achieve an R0 resection. Five-year survival following resection of intrahepatic cholangiocarcinoma ranges between 15 and 40% for all comers and 41—67% for those in whom an R0 resection can be achieved. Hilar cholangiocarcinoma 5-year survival ranges from 10 to 40% for all comers and 30—52% in those achieving R0 resection. Five-year survival in patients with distal cholangiocarcinomas range from 23 to 50% for all comers and 27—62% for those undergoing R0 resection [23]. Liver transplantation was initially disregarded due to both a shortage of organs and the poor early 5-year survival (ranging from 0 to 15%). The role of liver transplantation, however, has recently undergone significant evolution. Now, with careful patient selection, neoadjuvant XRT, oper-
Palliative treatments With the realization that most patients are unresectable and virtually all succumb to the effects of local tumor growth and biliary obstruction, numerous palliative interventions aimed at biliary decompression have been employed with various degrees of benefit. Optimal palliative protocols would require multidisciplinary acceptance by GI specialists, surgeons, and oncologists. This in itself is a major difficulty as is the lack of large randomized trials pointing to better approaches than the currently considered standard of care which is stenting alone.
Stenting Various stents including covered plastic devices to selfexpanding metal versions (SEMS) have become the standard palliative option for patients with CC [26]. These devices are generally placed endoscopically and compare favorably with surgical choledochojejunostomy or percutaneous approaches. The latter two are associated with more morbidity, but no greater rate of restoration of biliary drainage. Covered plastic stents come in various sizes and data show those of larger diameter are less prone to occlude [27]. SEMS appear to offer an even greater degree of drainage as compared to covered versions [28]. Randomized trials have shown no benefit of stenting both liver lobes as compared to stenting the obstructed region alone [29]. Some reports show that multiple stents placed may actually lead to occlusion. What is true for all stents is that tumors will eventually occlude them either by growing through the SEMS wire cage or at the entry or exit of the covered versions. As such, routine replacement of stents or at least attempts to achieve repatency is required [30]. Each of these additional procedures increases the risk of introducing infection but failure to maintain patency ultimately affects both quality and quantity of life. While it is true that stenting is the standard approach to unresectable CC, much work is required to optimize both the type of stent and frequency of stent replacement. It would also seem obvious that interventions that assisted in prolongation of stent patency would be a welcome addition to this standard of care.
Radiation therapy RT can be delivered to CC by various means including external beam, brachytherapy and, recently, via radioactive spheres [31]. Intrahepatic CC cannot be routinely treated by brachytherapy catheters as the radioactive source cannot easily traverse the hilum into the upper biliary tree, though brachytherapy sources could be delivered via a CT guided approach transcutaneously. Several retrospective studies have shown either external beam alone or in com-
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bination with brachytherapy (generally for extrahepatic CC) increases biliary flow for palliation and improves quality of life [32]. Life prolongation appeared possible as compared to historic controls. Ultimately though, as the radiation data base for this indication is based on single institution retrospective series, no definitive conclusion as to the efficiency of radiation can easily be made.
Chemotherapy Numerous chemotherapy agents have been tried in multiple phase I/II studies with little positive effects on CC [33]. Currently, the most active agents appear to be 5-FU and Gemcitabine with the latter the preferred agent. Even when all studies are taken together no definitive evidence exists that chemotherapy, when delivered as a single or as multiple agents, has a significant impact on survival or quality of life when employed for palliation in CC [34].
PDT As currently practiced PDT offers local tumor ablation as long as the photosensitizer may accumulate in the region of interest and the appropriate activating energy can be introduced, by light of a specific wavelength and intensity [35]. An underappreciated aspect of PDT is that the clinician can alter the treatment pathway to favor apoptosis or necrosis. The latter likely releases cytokines generating an immune response whereas the apoptosis pathway may be considered a true local therapy. This may have important implications for CC as IL-6 appears to be a critical mediator of tumor initiation and growth. Modification of IL-6 levels by PDT is possible both by tumor destruction and perhaps by systemic effects of PDT and may serve as a surrogate marker of treatment success and disease recurrence or progression [36], something that requires further study and will be touched upon again in the future directions section of this article. As was clinically evident, HpD accumulated in cholangial cells from the first case report [1]. In a well-done subsequent
Table 1
pharmacokinetics study, Pahernik et al. [37], reported a significant differential accumulation of Photofrin® in malignant biliary tissue as compared to normal tissue of the bile duct. The peak difference between tumor and normal tissue was 48 h, the time frame clinically used in the first patient. Similarly several other photosensitizer including Foscan® , LS11, MACE and ALA have also shown accumulation in biliary tissue [37,38]. Appropriate illumination to activate the photosensitizer is the critical second step. This is possible as commercially available fiber optics have been created that allow passage through endoscopes to the level of the biliary tumor bed. Most commonly, the fiber optic follows the biliary tract and the light diffusing region is placed so that it illuminates the entire tumor bed within the bile duct itself. The current generation of light diffusers has radio opaque markers at the proximal and distal end of the light diffuser so that fluoroscopic images can be taken during illumination to insure the entire affected biliary duct is treated. For lesions larger than the diffusers light emitting length, the diffuser is moved proximal or distal to encompass the entire region. This is troublesome as potentially it would allow certain regions of the tumor or biliary tree to be overdosed with light, while other regions may be under dosed. Over dosage with light can allow for excess PDT and creation of additional stricture due to therapy; under dosage allows tumor to regrow. As many of the strictures are not exactly linear it is possible for the light source to be at various distances from the bile duct wall. This too can allow for non-homogenous light dosing, again allowing for over or under dosage of illumination which may be of clinical consequence. A small number of dedicated investigators built upon the first clinical case report’s observation and have published a series of papers evaluating the effects of PDT on CC patients. These have been uniformly positive and ultimately have set the stage for randomized trials which too have shown clinically significant benefit of PDT for patient with unresectable disease.
HpD/Photofrin® studies for CC.
Reference
Patient number
Median survival (months)
30-Day mortality (%)
Photosensitivity (%)
[47] [52] [46] [18] [45] [55] [43] [42] [41] [40] [56] [48] [48] [48] [49] [49]
19 25 68 24 8 23 24 6 23 21 8 20 19 31 16 16
16.2 11.5 12 18 9 11.2 10 10 (est) 11.1 14.6 6 16.3 3.2 14 21 7
0 0 0 0 0 0 0 16 4 0 0 0 5 0 0 14
16 4 12 4 25 13 8 17 13 5 0 15 0
Randomized Control Non-randomized Randomized Control
0 0
Cholangiocarcinoma As will be reviewed in the following section, Photofrin® has been the predominant photosensitizer of choice, generally delivered intravenously at 2 mg/kg with illumination at 48 h post-infusion via 630 nm red light. Virtually all studies deliver light at 180—200 J/cm with one or two increasing this to 240 J/cm. At this drug and light dose combination, based on one case report, tumor destruction of approximately 0.5 cm depth can be expected. Generally, PDT is repeated as clinically indicated every 3—6 months. As summarized in Table 1, this results in a median survival ranging from 6 to 21 months with a uniform improvement of survival over either historic or randomized control arms as well as enhanced quality of life, when measured. The 30day morbidity for Photofrin® based sessions is very low and mild to moderate photosensitivity reactions ranges from 0 to 25%. Ortner et al. [39] published on nine patients with nonresectable Bismuth III/IV who underwent PDT via HpD. Median survival of 14.4 months and a dramatic improvement in Karnofsky and bilirubin levels was achieved. Subsequently 21 patients treated via Photofrin® achieved similarly excellent outcomes [40]. Berr et al. [41], using Photofrin® , treated 23 Bismuth III/IV patients and achieved an 11.1-month median survival. Also improvement in Karnofsky status and diminished biliary levels were reported. A small study on six patients treated with Photofrin® achieved a median survival of greater than 9 months according to Rumalla et al. [42]. Using metal stents and only one Photofrin® based PDT session Dumoulin et al. [43] reported a 10-month median survival, nearly double that of historical controls but did not meet statistical significance. Also important to note is that in this study, as compared to all others, PDT was done on only one occasion. Weidmann et al. [44] published on long term outcome following Photofrin® PDT for nonresectable disease. Median survival was 11.2 months, but eventually all patients progressed either locally or less commonly systemically. Cheon et al. [10] and Shim et al. [18] reported that Photofrin® or HpD PDT and stenting on 27 nonresectable hilar CC patients achieved a median survival of 18 months as compared to a matched control achieving 10 months without PDT. Harewood et al. [45] also showed a survival benefit to Photofrin® PDT on a small study of eight patients with nonresectable disease. In a large study of 184 patients with hilar cholangiocarcinoma, Witzigmann et al. [46] concluded that PDT plus stenting, employed in a subset of 68 patients, was superior to stenting alone with survival nearly doubling to 12 months. Similarly, in a recent article Kahaleh et al. [47] reported that the addition of Photofrin® PDT to stenting alone achieved a 16.2-month vs. 7.4-month survival advantage. Two randomized trials comparing stenting to stenting and PDT for unresectable perihilar CC have been published in the peer review literature and are extremely important. In the study reported by Ortner et al. [48], the trial was prematurely closed after interim analysis due to the great survival advantage of the addition of PDT. A total of 39 patients out of the planned 68 were randomized to either stenting alone or the addition of Photofrin® PDT infused at 2 mg/kg with illumination at 180 J/cm at 48 h post-infusion. A statistically significant survival advantage of 16.3 months vs.
89 3.2 months was achieved with PDT. Further, statistically significant improvement in quality of life was found as was improved physical function, Karnofsky status and bilirubin level. A third group of 31 patients refusing randomization was treated as per protocol with PDT. They too achieved a 14-month median survival with similar improvement in quality of life. A second randomized trial reported by Zoepf et al. [49] showed similar survival advantage with the addition of PDT to stenting. In this study 16 patients underwent stenting and PDT vs. 16 patients who underwent stenting alone. PDT delivered a 21-month median survival vs. 7 months with stenting alone. This study employed the photosensitizer Photosan-3, a drug considered similar if not identical to Photofrin® . It was infused at 2 mg/kg with illumination of 200 J/cm. Neither study was without morbidity, yet these differed. Photosensitivity of self limiting duration and intensity occurred in three patients in Ortner’s et al. trial, but in none from Zoepf et al. Ortner et al. reported cholangitis in 5 patients undergoing PDT as compared to 13 in the control group. In contrast, Zoepf et al. reported a 25% cholangitis rate in the PDT arm though this dropped dramatically once the study switched to a prolonged course of antibiotics. Neither study had any 30-day post-procedure mortality, a critical indicator of safety. The Ortner et al. study has been criticized as only randomizing patients after they failed stenting, likely explaining the short control arm survival while 25% of the patients in Zoept’s et al. trial were treated without histological confirmation of disease. Oral ALA has been tried for CC but at the drug dose (60 mg/kg) and light dose chosen, no clinical benefit was shown [50]. A small phase I/II study of Foscan® for nonresectable biliary strictures from CC or recurrent stent occlusion achieved a median survival of 8 months [51]. This photosensitizer has photosensitivity of cutaneous tissues of about 4 weeks and is activated at 652 nm for somewhat better tissue penetration. All patients underwent successful PDT sessions as well as repeated stent procedures as part of this protocol. Two patients developed significant cholangitis and two others hemobilia within 30 days of PDT resulting in two deaths. Further, two patients had photosensitivity reaction. While Foscan® appears active at the dose of 0.15 mg/kg and illumination 72 h post-infusion at 10—50 J/cm, this drug dose/light dose combination appears to have significant acute morbidity and mortality. A solid body of literature, including two randomized trials, appears to show benefit in terms of median survival for Photofrin® PDT in addition to stenting for unresectable hilar region CC. One should not necessary extend that benefit to patients with intrahepatic or more distal lesions. When analyzing for factors associated with enhanced survival Prasad et al. [52] reported that earlier intervention with PDT improved outcomes. Patients with visible masses on imaging studies did poorly. Other investigators have suggested that the frequency of PDT may be important as is the maintenance of the viability of the stents [4]. Potentially stent viability may be equal if not greater than the benefit from PDT, an important aspect to illuminate, if PDT is to become the standard of care for nonresectable patients [47].
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Adjuvant PDT As resection remains the only curative therapy, several investigators have employed PDT in a neoadjuvant fashion in an attempt to increase resectability. In an early study Berr et al. [53] employed Photofrin® PDT for hilar CC in a single patient. Pathology revealed tumor necrosis from PDT within the bile duct to 4—5 mm depth. The patient had local control for 18 months. Weidmann et al. [44], using Photofrin® , offered neoadjuvant PDT to seven patients with what was described as border line resectable hilar CC. Six patients remained recurrence free at 1 year (85%). Importantly, the biliary anastomosis remained patent after PDT. Nanashima et al. [54] reported on eight patients treated postoperatively with adjuvant PDT therapy. Most patients did not experience failure in the PDT treated region of the biliary tree. The authors felt this offered enhanced control without excessive treatment related stenosis compared to historical controls. Certainly adjuvant and neoadjuvant PDT appear promising but with so few patients treated, definitive recommendation will await clinical trial outcomes.
Morbidity CC is a fatal tumor so some investigators may downplay treatment associated side effects. It is clear that most PDT studies report photosensitivity reactions occurring though generally not life threatening (Table 1). Since many of these same studies use repeated photosensitizer infusions and treatment, it should be emphasized that the last months for many of these patients will exclude normal outdoor daytime activities, a potentially high price to pay for a terminal patient. Additionally, as PDT requires transcutaneous or endoscopic means to introduce the light source, this may cause or trigger infection such as cholangitis which can be fatal. Cholangitis is common in individuals with CC and it is unclear how much added risk, if any, PDT causes. Hemobilia has been reported which may require embolization [41]. With Photofrin® PDT, 30-day mortality rates are very low (Table 1).
Future directions and conclusions Palliation for nonresectable patients appears in large part based on maintaining successful biliary drainage. In Ortner’s et al. [48] and Zoepf’s et al. [49] randomized trials, PDT clearly was able to prolong biliary drainage and this impacted on survival. Despite these excellent results PDT has still not gained worldwide acceptance for its use in CC. It would seem then that the definitive study for PDT would be a multicenter head to head comparison of repeated stenting to stenting and PDT with measurement of survival, morbidity and quality of life. What is also required is a drug and light dosing trial. As it stands 2 mg/kg and roughly 200 J/cm is the standard of care for Photofrin® ; however, higher light doses may prolong biliary patency. Further, lower drug dose may enhance selectivity of treatment, favoring destruction of malignant tissue. What is not clear, but needs to be explored, is the effect of PDT on the normal biliary tree that is illuminated. It is possible that PDT, particularly by
R.R. Allison et al. deeper penetrating photosensitizer/light source, may actually induce some fibrosis or inflammation within the duct and lead to stricture. As each PDT session involves manipulation of the biliary tree, investigators should always attempt to minimize the number of interventions and ideally minimize the risk for cholangitis. Thus studies to review ways to minimize interventions and prolong patency are also needed. As resection remains the only chance for cure the use of adjuvant and/or neoadjuvant PDT should be further explored. Many resection patients actually fail locally at the anastomotic region and others are deemed locally unresectable at the actual surgical exploration. Intra-op PDT may assist in allowing for lesion destruction and improve local control thus potentially curing an additional cohort of individuals. It would also be worthwhile to combine PDT and XRT to see if additive outcomes could be obtained, as both are excellent local therapies. Targeting IL-6 via PDT vaccines or combining PDT with agents that target IL-6 or downstream molecules that are up regulated by IL-6 would be a novel approach to this disease. As IL-6 appears critical in CC growth and progression as well as the finding that IL-6 levels decline after successful PDT, this should be further explored. Given its dismal outcome for most patients novel approaches such as PDT are needed.
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