Presented in part as a multidisciplinary symposium on intrahepatic cholangiocarcinoma at the Annual Americas Hepato-Pancreato-Biliary Association Meeting; February 19-23, 2013; Miami, Florida.
Multidisciplinary approaches to intrahepatic cholangiocarcinoma
Article first published online: 20 AUG 2013
Copyright © 2013 American Cancer Society
Volume 119, Issue 22, pages 3929–3942, 15 November 2013
How to Cite
Maithel, S. K., Gamblin, T. C., Kamel, I., Corona-Villalobos, C. P., Thomas, M. and Pawlik, T. M. (2013), Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer, 119: 3929–3942. doi: 10.1002/cncr.28312
- Issue published online: 4 NOV 2013
- Article first published online: 20 AUG 2013
- Manuscript Accepted: 15 JUL 2013
- Manuscript Revised: 7 JUL 2013
- Manuscript Received: 18 MAY 2013
- intrahepatic cholangiocarcinoma;
After hepatocellular carcinoma, intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy. The etiology of ICC in most patients is not known, but its incidence is on the rise worldwide. There are 3 morphologic subtypes of ICC that can be characterized on cross-sectional imaging, mass forming, periductal infiltrating, and intraductal growth; and the radiographic characteristics of ICC may vary based on the subtype. Complete surgical resection remains the only potentially curative option for patients with ICC. Routine lymphadenectomy at the time of surgical resection should be strongly considered, because lymph node status provides important prognostic information. After surgery, the 5-year survival rate for ICC remains poor at only 25% to 35% in most series. Although numerous clinical trials have been conducted using a variety of chemotherapy regimens to treat ICC, systemic options for ICC remain limited. Doublet gemcitabine and cisplatin therapy is currently considered the standard-of-care first-line therapy for patients with advanced disease. Because ICC is typically confined to the liver and systemic chemotherapy traditionally has had only limited efficacy, there has been increasing interest in locoregional therapy. Although locoregional therapy may include intra-arterial therapies, stereotactic radiotherapy, hepatic artery pump therapy, or ablation, most data are limited. The purpose of this article was to provide a multidisciplinary appraisal of the current therapeutic approaches to ICC. Cancer 2013;119:3929–3942. © 2013 American Cancer Society.
Cholangiocarcinoma is divided into 3 categories based on anatomic location of origin within the biliary system: intrahepatic, hilar, and distal. Each likely represents distinct tumor biology, as reflected by separate staging systems for intrahepatic, hilar, and distal tumors. Although the hilar variant remains the most common type, the incidence of intrahepatic cholangiocarcinoma (ICC) is on the rise.[2-5] After hepatocellular carcinoma (HCC), ICC is the second most common primary hepatic malignancy. It affects approximately 5000 to 8000 individuals per year in the United States and globally accounts for 3% of all gastrointestinal malignancies. Worldwide, there is considerable geographic variation in the incidence of ICC, with a greater incidence in East Asia.[7, 8] Long-term survival is poor because of late presentation of disease and limited therapies; complete resection remains the only opportunity for cure.[5, 9-11] In this review, we focus on the multidisciplinary approach to and treatment of ICC.
Risk Factors, Clinical Presentation, and Evaluation
The cell of origin of ICC is most likely, and most commonly, the bile duct, although there are animal data to suggest that ICCs can arise from hepatocytes rather than biliary epithelial cells. The etiology of ICC in most patients is not known, because 90% of patients who are diagnosed with ICC have no identifiable risk factors. Predisposing conditions include infections that affect the biliary tract, such as hepatitis B/C, Opisthorchis viverini, or Clonorchis sinensis, as well as sclerosing cholangitis, the presence of choledocal cysts, or cirrhosis.[2, 13-17] Given the lack of common predisposing conditions and the rarity of the disease, there is no target population for routine surveillance to facilitate making an early diagnosis. Hence, many patients with ICC are discovered incidentally during an investigation for a nonrelated complaint. When symptomatic, patients may complain of right upper quadrant pain, anorexia, or weight loss. By the time symptoms arise, however, the tumor often has already reached an advanced stage that is not amenable to surgery.
Because metastasis to the liver is more common than primary ICC, a thorough evaluation must be performed to assess for a separate primary malignancy. A complete evaluation includes an esophagogastroduodenoscopy (EGD) to assess for a gastroesophageal primary, a colonoscopy to clear the colon and rectum, chest imaging to assess for lung cancer, and, for women, a mammogram to rule out breast cancer. In addition, 2-[18F] fluoro-2-deoxy-D-glucose–positron emission tomography (FDG-PET) also may be used to help identify a possible occult primary tumor outside the liver. The diagnosis of ICC should be viewed as a diagnosis of exclusion. An elevated serum cancer antigen 19-9 (CA 19-9) level is also suggestive, but not diagnostic, of ICC. On a biopsy specimen, several immunohistochemical diagnostic tests may suggest a primary ICC, such as a negative test for transcription termination factor, RNA polymerase (TTF1) (positive in lung cancer); a negative test for caudal type homeobox 2(CDX2) (positive in colon cancer); and a negative test for deleted in pancreatic carcinoma, locus 4 (DPC4) (positive in pancreas cancer). A cytokeratin (CK) staining profile that is CK7-positive and CK20-negative also suggests biliary etiology.
Imaging Assessment of Intrahepatic Cholangiocarcinoma
There are 3 morphologic subtypes of ICC that can be characterized on cross-sectional imaging: mass forming, periductal infiltrating, and intraductal growth (Fig. 1). Of these 3 the mass forming is most common. Recognition of characteristic radiologic imaging for ICC is critical in the diagnosis and assessment of resectability. The enhancement characteristics may vary based on the ICC subtype. In general, radiographic features of ICC are influenced by the amount of tumor cells and fibrous tissue present. Radiographic workup may include ultrasound, computed tomography (CT) scans, magnetic resonance imaging (MRI), or FDG-PET studies.
On ultrasound, mass-forming ICC often manifests as a homogeneous mass with an irregular, hypoechoic rim. The periductal-infiltrating subtype often appears as a small, mass-like lesion or as diffuse bile duct thickening with or without obliteration of the bile duct lumen. Other findings include mural and periductal soft tissue thickening or focal irregularities of the bile duct (Fig. 2). Despite these general characteristics, ICC is difficult to observe using ultrasound, because often only marked intrahepatic bile duct dilatation with no obstructive mass can be detected.
When evaluating a liver mass with CT, it is important to obtain a multiphase, thin-slice CT. On CT scans, the enhancement characteristics of ICC are influenced by the amount of tumor cells and fibrous tissue. The mass-forming type usually appears as an irregular, low-attenuation mass with minimal peripheral enhancement and focal dilatation of the intrahepatic ducts around the tumor.[21, 22] During the delayed phase, the tumor typically reveals maximum enhancement. The central part of the tumor often is characterized by diffuse, heterogeneous hypoenhancement associated with abundant fibrous stroma. Other findings include capsular retraction, satellite nodules, and occasionally macroscopic vascular encasement of hilar vessels.
Periductal-infiltrating ICC often has a radiologic appearance similar to that of infiltrating hilar cholangiocarcinoma, but it is located within the liver and not at the hilum. It appears as a homogeneous, low-attenuation growth or as enhancing periductal thickening along a dilated or narrowed bile duct, without mass formation. When advanced, the tumor can invade the hepatic parenchyma and hepatic hilum, with the tumor being transformed into a more exophytic hilar carcinoma (Fig. 3). Other possibilities in the differential include periportal lymphangitic metastasis from an extrahepatic tumor.
For the intraductal subtype, the pattern is diffuse, ductal dilatation with multifocal, superficial, spreading, papillary or plaque-like masses. In addition, on precontrast CT images, intraductal ICC often appears as a hypoattenuating or isoattenuating lesion relative to the surrounding parenchyma. Characteristic imaging includes diffuse and marked ductal ectasia with or without a grossly visible papillary mass, an intraductal polypoid mass with localized ductal dilatation, or an intraductal cast-like lesion with mildly dilated duct/focal stricture-like lesion with proximal ductal dilatation.[20, 21, 24]
Magnetic resonance imaging
On MRI, mass-forming ICC typically appears hypointense on T1-weighted images and hyperintense on T2-weighted images with central hypointensity and an irregular margin. On contrast-enhanced MRI, ICC exhibits moderate peripheral enhancement with gradual, centripetal filling within the tumor that is more prominent than on CT. Areas of the tumor with early enhancement and rapid washout indicate active growth, whereas hyperintense areas on delayed phase may be related to the fibrous stroma (Fig. 4). Periductal-infiltrating ICC exhibits marked ductal dilatation that enhances with contrast administration, whereas intraductal ICC can have several different features similar to those observed on CT.
Recent studies with gadolinium ethoxybenzyl diethelenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced MRI demonstrated that the hepatobiliary phase (HBP) may aid in the diagnosis of ICC. Investigators have reported on the use of Gd-EOB-DTPA–enhanced MRI and demonstrated that the HBP exhibited increased lesion conspicuity and better delineation of satellite nodules and hepatic metastasis (Fig. 5).[25, 26]
Fluorodeoxyglucose-positron emission tomography
The use of FDG-PET in staging ICC is poorly defined (Fig. 6). Anderson and colleagues reported on 36 patients with ICC and noted tumor avidity in 85% of tumors with a nodular morphology but in only 18% of tumors with an infiltrating pattern. The real clinical benefit from FDG-PET may be in its ability to identify occult distant metastases that are not detected on CT or MRI studies.[29, 30] Kim and colleagues reported a 36% rate of detecting occult distant metastases. Another study indicated that 78% of tumors were avid by PET, and PET identified occult metastasis in 24% of patients. In a separate study of patients with biliary cancer who underwent PET, occult metastases were not detected by CT or MRI in 20% of patients. Those studies reported altered management in up to 30% of patients when PET was used in the preoperative evaluation.
Complete surgical resection remains the only potentially curative option for patients with ICC. The data on surgical resection of ICC, however, are largely limited to single-institution series with small sample sizes (Table 1). Recently, an international study group was formed to investigate the surgical management of ICC. By combining the experience of high-volume centers around the world, those investigators were able to report on nearly 450 patients who underwent resection of ICC. The median tumor size was 6.5 cm, 75% of patients required a major liver resection, and negative margins were obtained in 81% of patients.
|Author||No. of Patients Undergoing Resection||R0 Resection Rate, %||Median RFS, mo||Median OS, mo||3-Year OS Rate, %||5-Year OS Rate, %|
|de Jong 2011||449||81||NR||27||44||31|
Prognostic information on patients after surgical resection is important for both providers and patients. In the sixth edition of the American Joint Committee on Cancer (AJCC) classification system, ICC was staged the same as HCC. Several authors noted that the sixth edition AJCC system did not accurately stratify ICC patients with regard to prognosis. By using the SEER database to examine nearly 600 patients who underwent resection of ICC, Nathan et al reported that the survival of patients with T1, T2, and T3 ICC tumors was statistically indistinguishable. Given these limitations, 2 different Japanese groups had proposed a separate staging system for ICC.[21, 38] External validation of those Japanese staging systems using data from the West failed to demonstrate an improved stratification of survival. A novel staging system was proposed by Nathan and colleagues based on data from the SEER data set. The most significant revision was the removal of tumor size from the T-classification system. Nathan et al observed that tumor size was not significantly associated with survival when taking into account tumor number and the presence of vascular invasion. This revised T-classification system more accurately discriminated patients who underwent resection compared with the AJCC sixth edition staging system as well as the 2 proposed Japanese systems. These data formed the basis of the T-classification system in the seventh edition of the AJCC Cancer Staging Manual. This revised staging system has been validated externally and independently by the French Surgical Association (AFC)-IHCC 2009 study group.
Undoubtedly, the staging system for ICC will continue to evolve as experience with ICC grows. Currently, multiple tumors are classified as T2b. From a clinical standpoint, it is difficult to distinguish between patients with “multiple” tumors who have multifocal disease versus those with an index lesion and intrahepatic metastasis. In the future, better discrimination of patients with multiple tumors into distinct prognostic groups may better guide therapeutic decision making. Although patients should not be excluded from consideration of resection based solely on tumor size, surgery should be used selectively in patients with multifocal disease. For example, although resection may be reasonable for a patient who had a large index lesion in the presence of a satellite lesion (eg, within 1 cm/same hepatic segment), patients with true multifocal disease or those with intrahepatic metastasis are probably better managed initially with systemic and/or locoregional therapy. Selective resection of these patients after preoperative therapy should then be undertaken on a case-by-case basis, taking into account the underlying tumor biology.
The role of surgical lymphadenectomy has also been poorly defined. The retrieval of lymph nodes for ICC requires a procedure separate from the partial hepatectomy: namely, a portal lymphadenectomy. Because lymph node evaluation at the time of resection offers primarily prognostic information and does not provide any proven therapeutic benefit, there remains a lack of consensus on whether or not it should be routinely performed.[3, 34, 39, 40] Indeed, even among high-volume centers, portal lymphadenectomy was performed in only approximately 50% of patients who underwent resection of ICC. It appears that the incidence of lymph node metastasis ranges from 18% to 30%. Although routine lymphadenectomy is generally warranted at the time of surgery, routine, intraoperatiave frozen-section analysis of lymph nodes probably is not. Frozen-section analysis has variable accuracy, and there are no data to recommend aborting hepatic resection even if microscopic metastatic disease was discovered in the regional lymph nodes at the time of surgery.
Patients with lymph node metastasis, however, do have a particularly poor prognosis. Unlike patients with unsuspected microscopic disease, patients who present with locoregional lymph nodes that are grossly suspicious for metastatic disease on preoperative imaging (eg, CT, PET, etc) should receive neoadjuvant therapy. In turn, only those well selected patients who demonstrate good tumor biology/response should be considered for subsequent surgery. The impact of lymph node status is so strong that other prognostic factors, such as vascular invasion and multiple tumors, have less influence on prognosis among patients with lymph node metastasis. The number of lymph node metastases also influences long-term survival, and patients who have ≥3 lymph node metastases have a worse prognosis compared with those who have only 1 or 2 lymph node metastases. Lymph node status carries important prognostic information and is paramount for the accurate stratification of patients enrolled on clinical trials that incorporate resection of ICC. Routine lymphadenectomy at the time of surgical resection should be strongly considered.
One of the limitations of lymph node evaluation during resection of ICC is that the lymph node yield during portal lymphadenectomy is not robust; often, only 3 lymph nodes are retrieved. In fact, this is the reported median lymph node yield across multiple studies.[3, 32, 41] Some investigators have suggested that at least 6 or 7 lymph nodes are necessary for accurate staging of gallbladder cancer or hilar cholangiocarcinoma, respectively; however, no such number has been established for ICC.[42, 43] Other investigators have suggested surrogate markers for aggressive tumor biology, such as the presence of lymphovascular invasion or perineural invasion, particularly in patients who do not have lymph nodes available for evaluation; however, these factors have yet to be validated in other large series of patients. Given the limited number of lymph nodes retrieved at the time of portal lymphadenectomy, a detailed lymph node evaluation, similar to what is performed for sentinel lymph node evaluation, may offer greater prognostic value.[44, 45]
Overall survival and recurrence
Despite advances in surgical technique, patient selection, and perioperative care, the 5-year survival for ICC remains poor.[3, 5, 11, 32, 33] The 5-year survival rate for patients who undergo resection is reportedly only 25% to 35% in most series (Table 1). Most patients suffer from disease recurrence, and the majority of those occur within the liver itself. Only 20% to 30% of patients seem to develop a recurrence solely outside the liver, although some patients may have both hepatic and extrahepatic disease.[3, 33, 47] These data may have implications for how adjuvant therapies are developed and directed in future trials. The high incidence of recurrence after curative-intent surgery highlights the need for more effective systemic therapy.
Systemic Treatment of Intrahepatic Cholangiocarcinoma
Most patients with ICC present with or eventually develop advanced disease and will need systemic therapy. Numerous clinical trials have been conducted using a variety of chemotherapy regimens to treat ICC. Most trials had significant limitations, including lack of a control arm, small sample size, and inclusion of a spectrum of heterogeneous tumor types (ie, pancreatic, ICC, extrahepatic cholangiocarcinoma [EHCC], ampullary). Combining these tumor types into a single clinical trial is problematic, because they exhibit different behaviors, have different molecular expression patterns, and likely have variable responses to chemotherapy. Even ICC, EHCC, and distal bile duct cancer are distinct entities with different etiologies, risk factors, molecular characteristics, patterns of dissemination, prognoses, and response to treatment.[48, 49] Given their rarity, there have not yet been separate trials in ICC and EHCC or trials stratified by tumor location that are adequately powered to identify true differences in chemotherapy benefit.
The response rate to single-agent 5-fluorouracil-based or gemcitabine-based systemic chemotherapy is only about 10% to30%.[48, 49] In 2010, the ABC-02 phase 3 randomized controlled trial, which studied 410 patients who had locally advanced or metastatic biliary tract cancer, compared doublet therapy with gemcitabine plus cisplatin versus gemcitabine as a single agent. The combination of gemcitabine plus cisplatin demonstrated improved progression-free survival and overall survival (11.7 months vs 8.1 months) compared with gemcitabine alone. In that trial, 241 patients (59%) had bile duct tumors, but the particular site of disease within the bile duct was not specified. Regardless, doublet therapy with gemcitabine and cisplatin is currently considered the standard-of-care, first-line therapy for patients who have advanced cancer of the bile ducts and gallbladder. Recently, there has been growing interest in examining novel, targeted anticancer agents based on an existing understanding of the molecular carcinogenesis of biliary tract cancers (Table 2).
|Regimen||Study Phase||No. of Patients||Response Rate, %||Survival, mo|
|Gemcitabine 1000 mg/m2 and cisplatin vs gemcitabine||III||410||Rate of tumor control (CR + PR+ SD) in the cisplatin/gemcitabine group was significantly increased at 81.4% vs 71.8%; P = .049||11.7 mo vs 8.1 mo (HR, 0.64; 95% CI, 0.52–0.80; P <.001)|
|Capecitabine (Patt 2004)||II||26||19||8.1|
|Erlotinib (Philip 2006)||II||42||8||7.5|
|Gemcitabine and 5FU-leucovorin (Alberts 2005)||II||42||12||9.7|
|Gemcitabine, oxaliplatin, and cetuximab (Gruenberger 2010)||II||30||63||Median PFS, 8.8; median OS, 11.6|
|Bevacizumab and erlotinib (Lubner 2010)||II||49||12||OS, 9.9|
|Gemcitabine, oxaliplatin, panitumumab, and capecitabine (Jensen 2012)||II||42||33||10|
|Sorafenib (El-Khoueri 2012)||II||46||2||4.4|
|Selumetinib MEK1/MEK2 (Bekaii-Sabb 2011)||Phase II||28||12||Median OS, 9.8; PFS, 3.7|
ICC has unique features with regard to tumor biology that can make devising an effective chemotherapy regimen challenging. Specifically, the putative cells of origin in ICC, the cholangiocytes, are multifunctional proproliferative cells. Cholangiocytes produce stimulatory cytokines (including transforming growth factor, interleukin-6, platelet-derived growth factor, and tumor necrosis factor) as part of both autocrine and paracrine modulatory pathways. Cholangiocytes also mediate inflammation in the liver, which is known to play a key role in the initiation and maintenance of carcinogenesis.[59, 60] In addition, cholangiocytes are able to “detoxify” foreign substances as a normal cellular function and, thus are inherently chemotherapy-resistant.
The 2 main areas of clinical need are to first extend the benefit of gemcitabine and cisplatin, potentially by adding 1 or more “targeted” agents to the combination, and second, to develop effective regimens for patients who have failed first-line chemotherapy. Unfortunately, the numerous single-arm clinical trials in advanced biliary tract cancer conducted over the previous 2 decades have done little to advance the field.[61, 62] The foremost task in advancing the field of ICC is to improve our understanding of the functional molecular carcinogenesis of ICC to identify actual oncogenic driver mechanisms or mutations. The development of new anticancer drugs in cholangiocarcinoma must use appropriate preclinical models. Screening of potential new agents and combinations in cholangiocarcinoma cell lines, of which there are very few, is 1 step in assessing new therapeutics. Cell lines, however, have lost many characteristics of the original tumor and, thus, have significant limitations in predicting the behavior of human tumors. In addition, any “ideal” models will need to include investigation into the role of the tumor microenvironment.[67-69] Genetic and genomic profiling using powerful bioinformatics techniques also holds the promise of identifying validated molecular targets in both populations and individuals with ICC. It must be noted, however, that consistent over-expression of a receptor or a protein does not guarantee it is a “driver mechanism” in ICC or that it will be an “actionable” target for drug development.
Llovet and colleagues identified 2 “classes” of cholangiocarcinoma through Genomic Identification of Significant Targets in Cancer (GISTIC) analysis of 149 subject specimens. Tumors could be stratified into 2 distinct categories, a “proliferative” class and an “inflammatory” class, which displayed unique gene signatures, activated oncogenic pathways, and clinical outcomes. Their work represents important progress in developing therapeutic biomarkers in cholangiocarcinoma. Anderson, Thorgeirsson, and colleagues have also carried out extensive genetic profiling of ICC in the Laboratory of Experimental Carcinogenesis at the National Cancer Institute of the National Institutes of Health (Bethesda, Md).[67, 68] This important work performed on 109 patient specimens has also identified several subclasses of cholangiocarcinoma based on clinical outcome, presence or absence of KRAS mutations, growth factor expression, and other markers of malignant transformation.
Locoregional Therapies for Intrahepatic Cholangiocarcinoma
Because ICC is typically confined to the liver and systemic chemotherapy traditionally has only had limited efficacy, there has been increasing interest in locoregional therapy, which may include intra-arterial therapies (IATs) (eg, transarterial chemoembolization [TACE], drug-eluding bead [DEB]-TACE, radioembolization), stereotactic radiotherapy, hepatic artery pump therapy, or ablation.
Two randomized trials in 2002 for HCC established the role of IATs in primary liver cancer and are the basis for considering TACE in patients with ICC.[69, 70] ICC differs from HCC, in that it is not typically a hypervascular tumor; thus, the challenges of drug delivery to the hypovascular areas may influence the effectiveness of this therapy.[71-73] Given the rarity of ICC and the variation in treatment regimens, data on IATs are limited primarily to small, single-institution series. Recently, a 5-center study that included 198 patients was reported in which the safety and efficacy of IATs were examined in patients with ICC. In that study, 65% of patients received conventional TACE, and 23% received Yttrium-90 (90Y). Morbidity was 29%, and most complications were minor. An assessment of response revealed complete or partial responses in 26% of patients and stable disease in 62%. The median overall survival was 13.2 months and did not differ between types of IATs administered. The authors concluded that locoregional therapy was safe and was associated with intrahepatic disease control in up to 70% of patients.
Other studies have examined the use of DEB-TACE, which has been proposed as a means to deliver increased drug concentrations within the tumor with fewer systemic side effects compared with conventional, oil-based TACE.[74-78] Kuhlman et al recently reported on the safety and efficacy of 23 patients with ICC who received irinotecan-based DEB-TACE. The authors reported a progression-free survival of 3.9 months and an overall survival of 11.7 months. Most patients (66%) demonstrated local tumor control, and grade 3 or 4 toxicities were relatively rare. Many patients experienced a “postembolization syndrome” (pain, low-grade fever, and fatigue). That study was 1 of the first to demonstrate the safety and potential efficacy of DEB-TACE in patients with ICC.
Because the liver is radiosensitive, external-beam radiation traditionally has had a limited role for primary liver cancer. In contrast, 90Y is a beta-emitter that can be delivered intra-arterially as either a resin-tagged or a glass-tagged device. 90Y is increasingly used in the management of patients with unresectable HCC; in turn, investigators have begun to consider its role in ICC. Ibrahim et al reported the first case series of 90Y radioembolization in the treatment of 24 patients with unresectable ICC. Clinical toxicities in that series included fatigue (75%), abdominal pain (38%), and vomiting (13%). One patient developed a duodenal ulcer that required operative intervention. The authors noted an overall objective tumor response (any decrease in size) in 19 patients (86%), a complete response in 9%, and a partial response in 77%. At a median follow-up of 17 months, overall survival was 14.9 months. Patients without extrahepatic disease (n = 16) had a survival of 31 months compared with those who had extrahepatic disease (n = 8), whose survival was only 6 months. These early data suggest that 90Y is safe and effective for select ICC patients.
One particular problem in the treatment of patients using IATs is the accurate assessment of treatment response. Current accepted criteria for tumor response include Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST (mRECIST), and European Association for the Study of the Liver (EASL). RECIST considers tumor size reduction, mRECIST considers the longest viable tumor dimension, and EASL considers viable tumor reduction in an area of enhancement for evaluating tumor response. The concept of treatment response based on size, as defined by RECIST, may not be appropriate after IAT. In contrast, the percentage of tumor necrosis by volumetric reduction measurements has been proposed as a better approach to assess treatment response after IAT for ICC. Apparent diffusion coefficient (ADC) can be used to distinguish viable tumor versus nonviable tumor by differences in membrane permeability. Specifically, after IAT, there is increased membrane permeability, causing a rise in ADC values (Fig. 7). Burger and colleagues reported on 17 patients with unresectable cholangiocarcinoma who received 1 or more cycles of IAT. Those authors reported that the percentage of tumor necrosis was a more accurate predictor of tumor response than any reduction in tumor size, and the percentage of tumor necrosis was correlated most strongly with survival (Fig. 8). In a more recent study, Halappa and colleagues reported on 29 patients with unresectable ICC who received 1 to 5 cycles of IAT in whom volumetric changes in ADC and on contrast-enhanced MRIs were assessed. Volumetric changes in ADC were noted as the strongest predictor of survival, rather than EASL or mRECIST. These data suggest that volumetric analysis may be a superior method for assessing tumor response after IAT of ICC.
Hepatic artery infusion therapy
Hepatic artery infusion (HAI) therapy is another type of liver-directed arterial therapy.[82, 83] Direct hepatic arterial administration of chemotherapy allows for increased drug delivery. First-pass extraction minimizes the systemic exposure and toxicity. Vogl et al reported a phase 1 study using HAI gemcitabine in patients with ICC. The maximum tolerated dose of gemcitabine without or with microspheres was established at 1400 mg/m2 and 1800 mg/m2, respectively. HAI therapy typically requires a surgical approach to place the pump apparatus. Because of the limited data in ICC, further reports are needed to define its role in locoregional therapy for ICC.
The energy for ablation is usually generated from either high-frequency alternating radiofrequency current or microwave energy. Ablation may be an efficient therapy in ICC for tumors that measure from <3 to 5 cm in greatest dimension and are not amenable to resection. Kim and colleagues reported on 13 patients with ICC and noted a “success” rate of 88% (eg, complete tumor destruction and no local recurrence) with a median follow-up of 19.5 months. Therapy is considered successful when a tumor is characterized as an unenhanced mass during arterial phase (Fig. 9). Irregular peripheral or nodular enhancement after ablation suggests residual tumor and/or tumor progression. Because most ICC tumors are advanced on presentation, the role of ablation is somewhat limited.
The applicability of stereotactic radiotherapy (SBRT) has expanded to include primary liver cancer. Given the inherent radiosensitivity of the liver, SBRT may be a means to deliver precise therapeutic doses of radiation to the tumor while sparing the normal liver to avoid subsequent liver dysfunction. SBRT also facilitates compensating for the motion of the target during simulation, planning, and treatment by various methods of motion dampening, respiratory gating, breathing coordination, and tumor tracking. This allows for more accurate targeting of the liver lesion.
Blomgren et al reported on 11 patients who underwent SBRT and demonstrated local control after 1 year of follow-up. Since that study, several centers have conducted phase 1 and 2 studies to better define the safety and efficacy of SBRT for liver tumors. Ibarra et al recently pooled the experience from 4 academic medical centers. In their series, 11 of 32 patients who underwent SBRT had unresectable ICC. The median dose delivered was 30 grays. After 3 months, a complete response was reported in 11% of patients, a partial response was reported in 22%, stable disease was reported in 22%, and disease progression was reported in 44%. The median overall survival was 11 months, and no grade 4 toxicities were observed. The authors concluded that SBRT is promising as locoregional therapy for ICC and noted the low incidence of severe side effects coupled with an acceptable duration of freedom from local progression.
ICC is a rare disease with increasing incidence. Complete surgical extirpation remains the mainstay of therapy. Because a minority of patients are candidates for resection at presentation, the focus of investigations has been on locoregional and systemic therapies. Locoregional therapy appears to have a therapeutic role in patients with unresectable disease, particularly for those who have limited or no extrahepatic disease. The current standard of care for systemic therapy remains the doublet regimen of gemcitabine and cisplatin. A better basic understanding of the biology of ICC is necessary for the development of better treatments. In particular, novel targeted regimens are needed and are under investigation in clinical and preclinical settings.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.
- 1Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A, eds. AJCC Cancer Staging Manual. New York: Springer-Verlag; 2010.
- 18The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol. 2000;95:204–207., , , , .Direct Link:
- 36Greene F, Page D, Flemming I, et al. eds. AJCC Cancer Staging Manual. New York: Springer-Verlag; 2002.
- 62Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: a retrospective analysis. Gastrointest Cancer Res. 2011;4:155–160., , , et al.
- 83The role of hepatic arterial infusion of chemotherapy in the management of patients with hepatic metastases from colorectal cancer. In: McCulloch P, Karpeh M, Kerr D, Ajani J, eds. Gastrointestinal Oncology: Evidence and Analysis. New York: Informa; 2007:179–198., .
- 86Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy. J Cancer Res Clin Oncol. 2006;132:745–755., , , et al.