S y s t e m i c an d Tar g e t e d T h e r a p y f o r B i l i a r y Tr a c t Tu m o r s an d P r im ary L i ver Tu mo r s Melanie Byrne Thomas,

MD

KEYWORDS  Bile duct cancer cholangiocarcinoma  Hepatocellular carcinoma  Systemic therapy  Chemotherapy  Targeted therapies KEY POINTS  There are limited effective chemotherapy options that have shown clinical benefit for patients with metastatic bile duct and hepatocellular carcinoma.  Cancers of the biliary tract and primary tumors of the liver are challenging malignancies to treat in the advanced disease setting. These tumors are known as being chemotherapy resistant, as is well documented in the numerous negative clinical trials that have been conducted using conventional cytotoxic chemotherapy agents.  There is emerging understanding of the unique biology of hepatobiliary cancers that will lead to development of targeted anticancer therapies for hepatobiliary cancers.

INTRODUCTION

Most patients with cancer of the bile ducts and liver eventually develop advanced disease that is not treatable with surgery, radiation therapy, or other liver-directed treatment options. These patients seek systemic therapy hoping for prolonged survival and palliation of tumor-related symptoms such as pain, anorexia, ascites, and fatigue. A large number of clinical trials have been conducted over several decades to evaluate a variety of chemotherapy agents in both tumor types. However, few chemotherapy regimens have produced level-1 evidence of clinical benefit to patients. THE CHALLENGES OF DEVELOPING AN EFFECTIVE SYSTEMIC THERAPY FOR ADVANCED BILIARY TRACT AND LIVER CANCERS

When evaluating systemic therapy for solid tumors, there are several factors that affect the design of clinical trials, selection of study end points, and the agents to be studied. The factors relevant to biliary tract cancer are summarized in this article.

Hollings Cancer Center, College of Medicine, Medical University of South Carolina, 86 Jonathan Lucas Street, Charleston, SC 29425, USA E-mail address: [email protected] Surg Oncol Clin N Am 23 (2014) 369–381 http://dx.doi.org/10.1016/j.soc.2013.11.004 surgonc.theclinics.com 1055-3207/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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Clinical Behavior

As is the case in many solid tumors, but particularly in cholangiocarcinoma, a wide range of tumor behavior is observed. Many of these tumors display indolent clinical behavior, may remain stable for many months, and seem to grow slowly and progress over years rather than months. These indolent intrahepatic cholangiocarcinomas (ICCs) often do not cause tumor-related symptoms until the tumor burden is extensive. Other cholangiocarcinomas have a more aggressive phenotype, progress rapidly, and result in more tumor-related morbidity.1 Imaging Characteristics

Tumors of the bile ducts appear radiographically in 2 general forms: the mass-forming ICCs appear as low-attenuation masses with irregular peripheral enhancement, and may be accompanied by liver capsule retraction, satellite nodules, and peripheral intrahepatic ductal dilatation. The periductal infiltrating cholangiocarcinomas are characterized by growth along dilated or narrowed bile ducts without mass formation.2 Both ICC and extrahepatic cholangiocarcinoma (EHCC) are highly desmoplastic tumors and tend to spread along bile duct walls and periductal tissue, which makes them challenging to image adequately with conventional imaging techniques in order to establish a baseline and assess radiographic tumor response.3–8 Tumor Biology

The putative cell of origin in ICC and EHCC, the cholangiocytes, are multifunctional proproliferative cells. Cholangiocytes produce stimulatory cytokines (including transforming growth factor, interleukin-6, platelet-derived growth factor, tumor necrosis factor) as part of both autocrine and paracrine modulatory pathways. They mediate inflammation in the liver, which is known to play a key role in the initiation and maintenance of carcinogenesis.9,10 The liver-cholangiocyte microenvironment is thought to be procarcinogenic. Cholangiocytes are also able to detoxify foreign substances as a normal cellular function, and thus are inherently chemotherapy resistant.11–13 Patient Comorbid Conditions

Patients with malignancies of the bile ducts or hepatocytes commonly have underlying liver disease that contributes in varying degrees to the initiation and progression of these cancers, as well as to whether the patient is a reasonable candidate for palliative systemic therapy. Comorbid liver-related conditions include fibrosis, cirrhosis, portal hypertension, altered drug metabolism, coagulopathy, hypoalbuminemia, thrombocytopenia, and ascites. Cirrhosis can have a profound impact on tolerance and efficacy of anticancer drug therapy. The liver is central to the metabolism of most foreign and endogenous substances in the body. Hepatic metabolism involves oxidative pathways, primarily via the cytochrome P (CYP) 450 enzyme system, and additional metabolic steps, which include conjugation to a glucuronide, a sulfate, or glutathione. In cirrhosis, the total liver cell mass is reduced and distortion of the microcirculation of the liver and collagen deposition lead to impaired sinusoidal transport and reduced extraction of proteinbound substances. Hepatic cirrhosis not only decreases drug metabolizing enzyme activity but also alters the absorption, plasma protein binding, distribution, and renal excretion of drugs. Intrahepatic vascular shunts that develop as a consequence of cirrhosis allow drugs to be routed around hepatocytes, thus decreasing their firstpass extraction. However, all routes of hepatic metabolism are not equally impaired.

Biliary Tract and Primary Liver Tumors

As hepatic dysfunction progresses in cirrhotic patients, reduced synthesis of albumin occurs and leads to a decrease in the plasma protein binding of drugs. In the setting of hypoalbuminemia, for drugs that are more than 90% protein bound, the increase in the free drug fraction may have substantial clinical consequences. The CYP3A4 subfamily, the most common hepatic enzyme in adult humans, oxidizes more than 50% of currently used drugs. Several studies have shown significant decreases in the CYP3A protein levels in patients with cirrhosis, although contradictory data do exist. Therefore, it is difficult to predict the disposition of a drug in liver disease, and each agent must be studied individually to provide a rationale for adjusting doses. SYSTEMIC THERAPY FOR BILIARY TRACT CANCERS: STATE OF THE CLINICAL SCIENCE

A large number of clinical trials of chemotherapy using single agents, doublets, and multidrug combinations have been published in recent years. Most trials were conducted to ascertain whether chemotherapy can provide clinical benefit to patients with advanced cancer of the biliary tract, in terms of palliation of tumor-related symptoms or increased survival. Most trials have been small, single-arm studies that commonly evaluate tumor response rate at the primary end point. For trials that follow the RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 guidelines, tumor response is defined as complete response (disappearance of all target lesions) or partial response (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters).14 Tumor response is an indication of antitumor activity, but may not correlate with clinical benefit to patients with advanced disease. A few prospective chemotherapy clinical trials have included subgroup analyses to ascertain whether there are differences in clinical outcome based on ICC, EHCC, or gallbladder cancer. However, because of the many challenges in conducting prospective clinical trials in these patients, there have not yet been separate trials in ICC and EHCC, or trials that are stratified by tumor location that are adequately powered to identify differences in chemotherapy benefit. Selected studies are summarized in Table 1. In April 2010, the Advanced Biliary Cancer (ABC)-02 trial was published, and this was the first phase III, randomized controlled trial in subjects with advanced biliary tract cancer. The ABC-02 trial compared doublet therapy consisting of gemcitabine and cisplatin with single-agent gemcitabine in 410 patients with locally advanced or metastatic biliary tract cancer. The combination of gemcitabine plus cisplatin showed improved progression-free survival (PFS) and overall survival (OS) compared with gemcitabine alone. In this trial, 59% (241 patients) had bile duct tumors, but the site of disease within the bile duct was not specified. After a median follow-up of 8.2 months, the combination group had significantly improved OS (11.7 vs 8.1 months).15 This regimen is currently considered the standard-of-care, first-line therapy for patients with advanced cancer of the bile ducts and gallbladder. The results of the ABC-02 trial have prompted many investigators to conduct trials in the second-line setting, as well as of novel targeted anticancer agents based on existing understanding of the molecular carcinogenesis of biliary tract cancers. ADVANCING TREATMENT OF BILIARY TRACT CANCER BY INCORPORATING TARGETED THERAPIES INTO CLINICAL TRIALS

There remains a significant unmet medical need to develop effective and safe systemic therapy regimens for patients with advanced cholangiocarcinoma. The 2 main areas of unmet clinical need are to extend the benefit of gemcitabine and cisplatin, potentially by adding one or more targeted agents to the combination, and to develop

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Table 1 Selected cytotoxic chemotherapy regimens for biliary tract cancer Study Phase

Sample Size

Response Rate (%)

PFS TTP (mo)

Overall Survival (mo)

Gemcitabine plus cisplatin vs gemcitabine15

III

410

81a 71

8.0 5.0

11.7 8.1

Gemcitabine16

II

24

13



7.2

Gemcitabine plus 5-fluorouracil17

II

42

1



9.7

Gemcitabine plus S-118

II

35

34.3

TTP 5.9

11.6

Gemcitabine plus cisplatin19

II

43

28



8.4

Gemcitabine plus capecitabine20

II

45

31



14

GEMOX21

II

53

18.9

PFS 4.8

8.3

GEMOX plus cetuximab22

II

30

63



11.6

CAPEOX23

II

65

37 (GB, ECC) 0 (ICC)



12.8 16.8

Capecitabine24

II

26

19



8.1

FOLFIRI25

II

30 17 ICC 13 GB

10

PFS: 3 5.9

OS: 5.9 9.75

Regimen

Abbreviations: CAPEOX, oxaliplatin plus capecitabine; FOLFIRI, 5-fluorouracil plus leucovorin plus irinotecan; GB, gallbladder; GEMOX, gemcitabine plus oxaliplatin; PFS, progression-free survival; TTP, time to progression. a Tumor control rate 5 stable disease 1 partial response 1 complete response.

effective regimens for patients who have failed first-line chemotherapy. However, the numerous single-arm clinical trials in advanced biliary tract cancer conducted over the previous 2 decades have made little progress.26,27 Some trials of single-agent targeted therapies, and combinations with cytotoxic agents, have been reported, as listed in Table 2. The foremost task in biliary tract cancer research is to improve understanding of the key molecular carcinogenetic mechanisms, with a focus on identifying the oncogenic driver mechanisms or mutations. Table 3 summarizes several of the potential therapeutic targets in biliary tract cancer that have been identified and, in some cases, evaluated in preclinical models. Given the high cost, the time required to complete, and low yield of empirical clinical trials, it is essential that a better understanding of the potential efficacy of new agents and combinations be obtained in the preclinical setting. In order to identify potential relevant molecular targets(s) or combinations of targets in ICC and/or EHCC, some concepts are particularly important:  The results from measuring overexpression of a potential molecular target are highly variable depending on the quality of tumor specimen analyzed.  Consistent overexpression of a receptor or a protein does not guarantee that it is a driver mechanism in the cancer or an actionable target for drug development.  Screening of potential new agents and combinations in cholangiocarcinoma cell lines, of which there are few, is one step in assessing new therapeutics. However, cell lines have lost many characteristics of the original tumor and thus have significant limitations in predicting behavior of human tumors.

Biliary Tract and Primary Liver Tumors

Table 2 Clinical trials of targeted therapies for biliary tract cancer Regimen

Study Phase

Sample Size

Response Rate (%)

PFS TTP (mo)

Overall Survival (mo)

Bevacizumab plus erlotinib28

II

49

18.4

TTP 4.4

9.9

Sorafenib29

II

31



3

9

Sorafenib30

II

46

0

PFS 3

9

Lapatinib31

II

17



PFS 1.8

5.2

Selumetinib32

II

28

12

3.7

9.8

Erlotinib33

II

42

8



7.5

GEMOX plus Panitumumab34

II

46

33

PFS 8.3

10.0

GEMOX vs GEMOX plus erlotinib35

RIII First line

133 135

29 15.7

PFS 4.2 PFS 5.8

9.5 9.5

Sunitinib36

II, 2nd line

56

8.9

1.7

4.8

GEMOX plus bevacizumab37

II, 1st line

35

40

7

12.7

 Development of new anticancer drugs in cholangiocarcinoma must use appropriate preclinical models. The ideal models include the role of the tumor microenvironment.40,43,73  Genetic and genomic profiling using powerful bioinformatics techniques holds the promise of identifying validated molecular targets in both populations and individuals that provide rationales for determining suitable targets for drugs in ICC and EHCC.  Future clinical trials should stratify by tumor location, if targets differ by site, and enrich the trial patient population by the target of interest. Several recent studies that used advanced molecular analytical approaches to ICC have provided insight into molecular classifications of these tumors than can inform the development of rationales for future clinical trials in this malignancy. Llovet and colleagues68 identified 2 classes of cholangiocarcinoma through genomic identification of significant targets in cancer (GISTIC) analysis of specimens from 149 subjects. The categories, including a proliferative class and inflammatory class, had different gene signatures, activated oncogenic pathways, and clinical outcomes. This work represents important progress in developing therapeutic biomarkers in cholangiocarcinoma. SYSTEMIC THERAPY FOR HEPATOCELLULAR CARCINOMA: CURRENT MANAGEMENT

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy in terms of cause and molecular carcinogenesis. HCCs are clinically chemotherapy-resistant tumors, and this observation is supported by low response rates across a wide variety of chemotherapy agents. Cytotoxic chemotherapy agents have shown no clinical benefit to patients with HCC, and can be toxic in individuals with underlying liver dysfunction. Over the course of the previous decades, numerous clinical trials of a wide variety of chemotherapeutic and hormonal agents had shown little or no activity in this complex malignancy.

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Table 3 Novel targeted agents with preclinical rationale for the treatment of biliary tract cancer Pathway/Target

Rationale

Outcome

EGFR plus VEGF inhibition

Both EGFR and VEGF overexpression common in cholangiocarcinoma

Vandetanib, dual VEGF2/EGFR inhibitor significantly decreased in cell lines and xenografts38,39

PDGF

Myofibroblasts are abundant in cholangiocarcinoma microenvironment and display procarcinogenic crosstalk with cancer cells, mediated partly by PDGF-B40–42

Cytotoxic agent navitoclax induced apoptosis in CAF in a cholangiocarcinoma rat model43

EGFR

ERB1 and ERB2 overexpression are prominent in biliary tract.44–48 Activating mutations rate very low49

Several preclinical studies suggest benefit of therapeutic efficacy with EGFR inhibitors50

COX

COX plays important role in biliary cancer cell signaling51–54

COX-2 inhibitor NS-398 showed dose-dependent growth inhibition in rat model of cholangiocarcinoma55

VEGF expression

VEGF expression linked to poor prognostic features and decreased survival29,30,38,56–58

Some suggestion of clinical benefit shown in single-arm clinical trials29,30,37,58,59

MEK ERK

MEK is critical element of Ras/ Raf/MEK/ERK signal transduction pathway60,61

Evidence of gallbladder cancer cell line growth inhibition by MEK inhibitor UO12662,63

c-MET (hepatocyte growth factor)

Several studies show overexpression of c-MET overexpression in preclinical cholangiocarcinoma models64–66

NK4, which acts as an HGF antagonist and angiogenesis inhibitor, when transfected cholangiocarcinoma cell line clones, showed cell growth inhibition by arresting cell cycle progression67

Molecular subclasses including inflammatory and proliferative subclasses

This important work may provide biomarkers of therapeutic efficacy to design biomarker-driven clinical trials68,69



BRAF-activating mutations

Present in 7% of cholangiocarcinoma specimens68–70



Hedgehog signaling

Sonic hedgehog ligand highly expressed by human cholangiocarcinoma tissue specimens and cell lines42,71,72

In vitro inhibition of sonic hedgehog signaling decreased epithelialmesenchymal transition and cholangiocarcinoma cell viability71

Abbreviations: CAF, cancer-associated fibroblasts; COX, cyclooxygenase; EGFR, epidermal growth factor receptor; ERB, eukaryotic ribosome biogenesis protein; ERK, extracellular signal regulated kinase; HGF, hepatocyte growth factor; MEK, mitogen-activated ERK; VEGF, vascular endothelial growth factor.

Biliary Tract and Primary Liver Tumors

Table 4 Randomized prospective trials of cytotoxic chemotherapy in HCC Regimen

Study Phase

Sample Size

RR

PIAF vs Adriamycin74

III

94/94

20.9 vs 10.5

Survival (mo) 8.6 vs 6.83

Nolatrexed vs Adriamycin75

III

444

1.4 vs 4.0

5.5 vs 8 (P 5 .0068)

Until recently there was no published evidence that systemic chemotherapy improves OS in any subset of patients with HCC. The most widely used agent has been Adriamycin as a single agent or in combination. A pivotal phase III trial of Adriamycin versus combination chemotherapy (platinum, interferon, Adriamycin, 5-fluorouracil [PIAF]) showed a statistically significant difference in response rate (RR) favoring PIAF, but no survival difference.74 Table 4 includes the results of the phase II PIAF versus Adriamycin study, as well as one of the few other large randomized trials completed in HCC. Given the disappointing results of the trial by Yeo and colleagues,74 clinicians have become skeptical about the prospects for developing an effective systemic therapy for HCC. Several molecular pathways seem to be commonly aberrant in HCCs, such as growth factor expression, angiogenesis, and cell cycle control. A placebo-controlled international phase III trial of sorafenib was conducted in patients with HCC with Child-Pugh A cirrhosis and showed superior survival in the sorafenib arm compared with placebo (10.7 months vs 7.9 months; P 5 .00058).76 The approval of sorafenib in 2007 for the treatment of patients with HCC in both the United States and the Table 5 Clinical trials of novel targeted therapies for HCC Regimen

Study Phase

Response Sample Size Rate (%)

PFS Overall TTP (mo) Survival (mo)

Sorafenib vs placebo76

III

299 vs 303

Systemic and targeted therapy for biliary tract tumors and primary liver tumors.

Tumors of the biliary tract and hepatocellular carcinoma (HCC) are complex tumors with heterogeneous carcinogenic mechanisms. Patients with hepatobili...
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