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The Oncologist, Vol. 10, No. 8, 590-601, September 2005; doi:10.1634/theoncologist.10-8-590
© 2005 AlphaMed Press

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 Targeted Therapies for Esophageal Cancer
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Targeted Therapies for Esophageal Cancer

William P. Tew, David P. Kelsen, David H. Ilson

Memorial Sloan-Kettering Cancer Center, Department of Medicine, Gastrointestinal Oncology, New York, New York, USA

David H. Ilson, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. Phone: 212-639-8306; Fax: 212-717-3320; e-mail: ilsond{at}mskcc.org


   LEARNING OBJECTIVES
Top
 Learning objectives
Abstract
 Introduction
 Standard treatments
 Targeted therapy approaches
 Disclosure of potential...
 References
 
After completing this course, the reader will be able to:

  1. Discuss the epidemiology of esophageal cancer.
  2. Explain the current status of diagosing and treating esophageal cancer.
  3. Describe potential novel targets for new drug development in esophageal cancer.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning objectives
 Abstract
Introduction
 Standard treatments
 Targeted therapy approaches
 Disclosure of potential...
 References
 
Esophageal cancer is a highly aggressive neoplasm. In 2005, 14,520 Americans will be diagnosed with esophageal cancer, and more than 90% will die of their disease. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000—more than lung, breast, or colorectal cancer. Although esophageal squamous cell carcinoma cases have steadily declined, the incidence of gastroesophageal junction adenocarcinoma has increased 4%–10% per year among U.S. men since 1976, more rapidly than for any other cancer type, and parallels rises in population trends in obesity and reflux disease.

With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past three decades. However, the 5-year overall survival rate (14%) remains poor, even in comparison with the dismal survival rates (4%) from the 1970s. The underlying reasons for this disappointingly low survival rate are multifold: (a) ineffective screening tools and guidelines; (b) cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation; (c) high risk for recurrent disease after esophagectomy or definitive chemoradiotherapy; (d) unreliable noninvasive tools to measure complete response to chemoradiotherapy; and (e) limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease. Clearly, additional strategies are needed to detect esophageal cancer earlier and to improve our systemic treatment options. Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. This review focuses on novel targeted treatments in development for esophageal squamous cell carcinoma and distal esophageal and gastroesophageal junction adenocarcinoma.

Key Words. Gastroesophageal junction adenocarcinoma • Carcinoma • Esophageal squamous cancer • Targeted therapy


   INTRODUCTION
Top
 Learning objectives
 Abstract
 Introduction
Standard treatments
 Targeted therapy approaches
 Disclosure of potential...
 References
 
Esophageal cancer is a highly aggressive neoplasm. In 2005, 14,520 Americans will be diagnosed with esophageal cancer, and more than 90% will die of their disease [1]. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000—more than lung, breast, or colorectal cancer [2]. Although esophageal squamous cell carcinoma cases have steadily declined, the incidence of gastroesophageal junction adenocarcinoma has increased 4%–10% per year among U.S. men since 1976, more rapidly than for any other cancer type, and parallels rises in population trends in obesity and reflux disease [3, 4].

With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past three decades. However, the 5-year overall survival rate (14%) remains poor, even in comparison with the dismal survival rates (4%) from the 1970s [5]. The underlying reasons for this disappointingly low survival rate are multifold: (a) ineffective screening tools and guidelines; (b) cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation; (c) high risk for recurrent disease after esophagectomy or definitive chemoradiotherapy [6]; (d) unreliable noninvasive tools to measure complete response to chemoradiotherapy [7, 8]; and (e) limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease. Clearly, additional strategies are needed to detect esophageal cancer earlier and to improve our systemic treatment options. Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. This review focuses on novel targeted treatments in development for esophageal squamous cell carcinoma and distal esophageal and gastroesophageal junction adenocarcinoma.


   STANDARD TREATMENTS
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 Learning objectives
 Abstract
 Introduction
 Standard treatments
Targeted therapy approaches
 Disclosure of potential...
 References
 
Locally Advanced Disease
The optimal treatment of locally advanced esophageal cancer, a potentially curable disease, is controversial. Through several nonrandomized cooperative group trials, concurrent cisplatin (Platinol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com)-based chemoradiation or surgery alone represent acceptable standards of care for patients with resectable tumors. Both modalities offer similar rates of local control (60%–90%), 5-year survival (20%–40%), and treatment-related mortality (2%–9%) [9–15].

Treatment decisions are often individualized with respect to the patient’s stage and underlying comorbidities. For patients with bulky advanced tumors unlikely to be cured surgically, upfront chemoradiation is often preferred. With sufficient tumor downstaging, preoperative chemoradiation can be followed by salvage surgery, especially for those patients with residual disease [16]. Preoperative chemoradiation has yet to show a significant improvement in overall survival compared with surgery alone in a prospective randomized trial, although there is a trend of higher survival rates (40%–60%) in those with pathologic complete responses (pCRs) at surgery [17, 18]. In recent retrospective reviews with longer follow-up, disease-free and overall survival were predicted by post-therapy pathologic stage [19, 20]. Although pathologic stage appears to be the best predictor of cure, pCR can only be attained in less than one third of all patients, even with the most intensive chemoradiotherapy regimens [21].

One current research focus has been the development of more active and tolerable preoperative cisplatin-containing chemoradiation regimens. Standard chemotherapy regimens with paclitaxel (Taxol®; Bristol-Myers Squibb) or irinotecan (Camptosar®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) are being studied, as well as those with newer targeted agents. Hopefully, these phase II trials will contribute to our efforts to improve the pCR rate. However, formal randomized comparisons with standard cisplatin/fluorouracil (5-FU)–based regimens will eventually need to be performed to determine the effect on survival rates.

Metastatic/Unresectable Disease
Metastatic or unresectable esophageal cancer is found at presentation in more than 50% of patients and remains incurable. Chemotherapy is considered palliative, improving quality of life and dysphagia in 60%–80% of patients [22–24]. Typical clinical and radiographic responses last for fewer than 4 months, with a median overall survival time of 8–10 months. Although a survival benefit has yet to be demonstrated with chemotherapy in advanced esophageal cancer, clinical trials in metastatic gastric cancer have consistently shown a survival benefit with chemotherapy compared with best supportive care alone [25].

Chemotherapy can be given as a single agent or in combination, usually in a cisplatin-containing regimen. Active agents include cisplatin, 5-FU, the taxanes, irinotecan, mitomycin C (Mutamycin®; Bristol-Myers Squibb), etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb), and vinorelbine (Navelbine®; Glaxo Smith Kline, Philadelphia, http://www.gsk.com). Response rates for single agents range from 15%–30% [25]. Combination regimens, usually containing cisplatin, tend to produce higher response rates (30%–57%), with occasional patients achieving complete responses (0%–11%) [22–24, 26–29]. However, with the combination regimens, the median survival time remains less than 10 months. Recent randomized trials have indicated that adding a third agent to the combination of 5-FU and cisplatin, either epirubicin (Ellence®; Pfizer Pharmaceuticals) ordocetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com), may modestly improve response rates, time to progression, and survival with greater therapy-related toxicity [30, 31]. Nonetheless, distant failure remains the primary cause of death. With the addition of novel targeted therapies, the goal is to improve the response rate and reduce distant metastasis without significant additive side effects.


   TARGETED THERAPY APPROACHES
Top
 Learning objectives
 Abstract
 Introduction
 Standard treatments
 Targeted therapy approaches
Disclosure of potential...
 References
 
Over the past decade, the field of drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. However, the difficult decision is which target to select and for what population. In choosing a target, one can look at genes mutated at a high frequency, regulators of key cancer phenotypes, or receptors overexpressed in cancer cells.

For esophageal squamous cell carcinoma and gastro-esophageal (GE) adenocarcinoma, potential tumor targets/markers have been described (Table 1Go). These include those related to growth regulation (epidermal growth factor receptors [EGFR, HER-2/Neu] and Ki-67), angiogenesis (vascular endothelial growth factor [VEGF]), inflammation (cyclooxygenase [COX]-2 pathway), cell cycle control (p16, p21, cyclin D1, flavopiridol), apoptosis (p53, bax, and bcl-2), metastatic potential (tissue inhibitor of metalloproteinase, E-cadherin), and sensitivity to chemotherapy (p-glycoprotein, thymidylate synthase, glutathione S-transferase, metallothionine, ecision cross complementing gene-1) [32]. Most have been studied solely as markers to predict clinical outcomes, such as pathologic response after preoperative chemotherapy or chemoradiotherapy [32–37]. For example, EGFR overexpression has repeatedly been shown to predict poor prognosis in both esophageal squamous cell carcinoma and GE adenocarcinoma [38–41]. However, the prognostic values of other markers have been mixed, in particular the mutations in p53 and their ability to predict pathologic response to preoperative chemoradiation [32, 35, 42].


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  		Table 1. Esophageal cancer: potential targets and markers
 
Many targeted therapies for esophageal cancer are in various phase I/II clinical trials; these include monoclonal antibodies (mAbs) and signal transduction/tyrosine kinase inhibitors (TKIs) for EGFR, mAbs to the HER-2/Neu receptor and VEGF ligand, oral COX-2 inhibitors, and other novel drugs.

EGFR
EGFR (ERBB1) is a member of the ERBB receptor tyrosine kinase family that includes ERBB2 (HER-2), ERBB3, and ERBB4 [43]. It consists of an extracellular ligand-binding domain, a transmembrane region that anchors the receptor to the plasma membrane, and a cytoplasmic region containing a tyrosine kinase domain. The known natural ligands of EGFR include EGF and transforming growth factor alpha (TGF-{alpha}), which both activate the receptor by binding to the extracellular domain and inducing the formation of receptor homodimers or heterodimers, which is followed rapidly by activation of the receptors’ intrinsic tyrosine kinase. In this signal network, ERBB2 is the major partner of EGFR because activated heterodimer complexes containing ERBB2 are more stable at the cell surface than complexes containing other EGFR family members [44, 45].

Ligand stimulation of EGFR initiates one of the most important cellular growth–regulatory pathways. As a trans-membrane glycoprotein, the extracellular domain of the EGFR is a ligand-binding site for TGF-{alpha} and EGF ligand. Binding of a stimulatory ligand to the extracellular domain of EGFR results in receptor dimerization, activation of the cytoplasmic tyrosine kinase, and initiation of potentially many intracellular signal transduction cascades, depending on the tyrosine kinase substrate, thereby triggering cellular mechanisms that regulate cell growth [46].

The EGFR is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle. Overexpression of EGFR, as wild type or with mutations, occurs in many types of human tumors, including esophageal (92%), head and neck (90%), colorectal (72%), prostate (65%), bladder (65%), ovarian (60%), cervical (60%), pancreatic (89%), renal cell (50%), and lung (50%) cancers [47–49]. Expression of EGFR correlates with poor prognosis and advanced disease.

The EGFR signal transduction network plays an important role in various tumorigenic processes, including cell-cycle progression, angiogenesis, and metastasis, as well as protection from apoptosis [43, 50].

Currently, we have two distinct methods to target EGFR: mAbs to the EGFR and small-molecule TKIs.

EGFR mAbs
Cetuximab (C225, Erbitux®; ImClone Systems, Inc., New York, http://www.imclone.com) is a mouse–human chimeric antibody of the IgG1 subclass and binds to EGFR (HER-1, cERBB1). Cetuximab blocks EGF and TGF-{alpha} binding to EGFR and effectively blocks phosphorylation and activation of EGFR tyrosine kinase [51]. Cetuximab also stimulates EGFR internalization, effectively removing the receptor from the cell surface for interaction with the ligand [52]. This results in inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and VEGF production.

Over the past years, cetuximab has shown promising results in colorectal and head and neck cancer trials. For metastatic colon cancer patients who previously failed irinotecan, cetuximab plus irinotecan produced a response rate of 23%, and as a single agent, the response rate was 9%–11% [53, 54]. The median time to progression was significantly greater in the irinotecan/cetuximab group than in the cetuximab monotherapy group (4.1 months versus 1.5 months, p < .001). However, there was no significant difference in overall survival (8.6 months versus 6.9 months, p = .45) [53]. These results suggest that the addition of cetuximab helps overcome irinotecan resistance and led to the U.S. Food and Drug Administration (FDA) approval of cetuximab for metastatic colorectal cancer. Patients enrolled in these trials were required to have immunohistochemical (IHC) evidence of positive EGFR expression. Recent studies illustrate that EGFR-negative tumors have the potential to respond to cetuximab and that IHC techniques do not have a predictive value [55]. However, acneiform skin rash consistently correlates with response and survival [53, 56].

In head and neck cancer, several phase II studies have evaluated the combination of cetuximab with platinum-based regimens in pretreated patients with recurrent or metastatic head and neck cancer, with a control rate (complete response [CR] + partial response [PR] + stable disease [SD]) in the range of 29%–66%. In the randomized Eastern Cooperative Oncology Group phase III trial, there was a significant difference in response rate between cisplatin plus cetuximab and cisplatin alone (22.6% versus 9.3%, p = .05). While there was a trend favoring the combination arm in terms of progression-free and overall survival, this underpowered study did not reach statistical significance [57].

In locally advanced head and neck cancers, a phase III international trial with more than 400 patients compared weekly cetuximab plus radiation with radiation alone. Pre-clinical in vitro and in vivo model systems demonstrated radiosensitization with EGFR signaling inhibition. The addition of cetuximab to radiation resulted in a significantly longer median survival time (54 months versus 28 months, p = .02) and significantly greater 3-year survival rate (57% versus 44%). There was no major difference in the incidences of grade 3/4 mucositis (55% versus 52%), although as expected, patients in the cetuximab arm did develop more infusion reactions (3% versus 0%) and skin reactions (34% versus 18%) [58].

Given these encouraging results from the colorectal and head and neck cancer trials, there is active clinical research in esophageal cancer patients with antibody inhibition of the EGFR. Overexpression of EGFR via IHC analysis occurs in 30%–90% of esophageal cancer cases and correlates with poor prognosis [32, 38, 40, 48, 59, 60]. In a retrospective review of 38 patients with resected gastroesophageal adenocarcinoma, Wilkinson et al. demonstrated that poorly differentiated adenocarcinomas of the esophagus demonstrated higher EGFR expression than low-grade tumors based on IHC analysis (57% versus 13%, p = .02). The median overall survival times were 35 months for EGFR-negative patients and 16 months for EGFR-positive patients [59]. Kitagawa and colleagues showed that the cumulative survival rate for patients with EGFR gene amplification in their primary tumors was significantly lower than that for patients without amplification (p < .001). A significant correlation was also observed between extensive lymph node involvement at the time of surgery and EGFR gene amplification (p < .05) [41].

We eagerly await the results of the many cooperative group and single-institution clinical trials exploring the role of cetuximab in esophageal cancer. These include a South-west Oncology Group (SWOG) trial of cetuximab as second-line therapy in patients with metastatic esophageal adenocarcinoma, a Memorial Sloan-Kettering Cancer Center study of cetuximab in irinotecan/cisplatin-refractory patients with metastatic esophageal cancer and a Dana-Farber Cancer Institute preoperative trial with cisplatin, irinotecan, cetuximab, and radiation in locally advanced esophageal cancer. In two phase I studies, EGFR-directed antibodies have shown activity in patients with esophageal cancer. In the phase I study of the humanized EGFR mAb EMD72000, one patient with metastatic, pretreated squamous cell carcinoma had a durable, 6-month PR [61]. In addition, a phase I trial with ABX-EGF, a high-affinity, fully human IgG2 EGFR mAb, reported stable disease for 7 months in one esophageal cancer patient [62]. Preclinical and these early clinical studies suggest potential activity and minimal toxicities with EGFR antibodies for esophageal cancer.

TKIs
TKIs are a class of oral, small molecules that inhibit ATP binding within the TK domain, which completely inhibits EGFR autophosphorylation and signal transduction [63]. Erlotinib (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) and gefinitib (Iressa®; AstraZeneca Pharmaceuticals, Wilmington, DE, http://www.astrazeneca-us.com) have been approved for second-line treatment in metastatic non-small cell lung cancer (NSCLC). In several large, randomized trials for metastatic NSCLC, both single-agent gefitinib and erlotinib showed significant objective response rates (9%–19%), disease control (36%–54%), and symptomatic improvement as second- or third-line treatment (35%–43%) [64–67]. Only erlotinib as a single agent compared with placebo showed a survival advantage (6.7 months versus 4.7 months, p < .001) [66]. No improvement in survival, however, was seen in platinum combination regimens with either erlotinib or gefitinib [68]. In those studies, higher response rates were correlated with skin rash, adenocarcinoma/bronchioalveolar carcinoma histology, female gender, Japanese heritage, nonsmoking, and mutations in ATP-binding site of the TK domain on EGFR (exons 18–21) and Kirstenras (K-Ras) [69–73].

Given these promising results in NSCLC, single-agent TKIs have been studied, with varied outcomes, in several different pretreated cancer types, including head and neck squamous cell carcinoma (response rate [RR], 4%–11%), breast cancer (RR, 2%–9%), and gastric adenocarcinoma (RR, 1%) [74–77]. Four phase II trials with TKIs in esophageal and GE junction cancers have been described in abstract form. The response rates for single-agent TKIs for several cancer types are summarized in Table 2Go.


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  		Table 2. Tyrosine kinase inhibitors: partial response (PR) rates in metastatic cancers
 
Our group reported a phase II trial with erlotinib (150 mg) in metastatic, pretreated esophageal squamous cell carcinoma or adenocarcinoma [78]. In the 22-patient cohort, two (9%) had PRs, 10 (45.5%) had SD, and 10 (45.5%) had disease progression after the 4 weeks. One patient had a durable 9-month PR/SD. Both patients with PRs had squamous-cell histology, EGFR overexpression, and nodal-limited disease. No other clinical characteristic appeared to predict response. Retrospective DNA extraction and sequencing of EGFR (exons 18, 19, 21) from tumor pathology was performed from five patients in this trial, including one responder, and no EGFR mutations were found.

Three additional abstracts describe similar modest response rates (12%) with either erlotonib or gefitinib in esophageal squamous cell carcinoma and GE junction adenocarcinoma [79–81]. In the SWOG trial, patients with gastric and GE junction adenocarcinomas were treated with daily erlotinib. Although no responses were seen in the 25 patients with gastric cancer, responses were seen in 4 of the 44 patients with GE junction adenocarcinoma. Moreover, no mutations in EGFR were found, relative to response [81]. In all studies, the TKIs were well tolerated, with the most common side effects being grade 1–2 (skin rash and diarrhea).

HER-2/Neu
The HER-2/neu gene (cERBB2) is part of a four-member family of growth factor receptors, including the EGFR. The protooncogene HER-2/neu is localized to chromosome 17q and encodes a transmembrane tyrosine kinase growth factor receptor, similar to EGFR. Amplification of the HER-2/Neu antigen has been identified in up to 30% of invasive breast cancers and increases the aggressiveness of the tumor [82, 83]. Trastuzumab (Herceptin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) is a humanized IgG1 antibody that targets the HER-2/Neu antigen and was approved by the FDA for the treatment of Her-2/Neu–positive metastatic breast carcinoma [84]. In patients with meta-static HER-2/Neu–overexpressed breast cancer, trastuzumab is well tolerated, with a modest single response rate (15%), lasting 9 months [85]. In combination with taxanes or anthracyclines, trastuzumab significantly improved the response rate, time to progression, and overall survival [86, 87]. Like cetuximab, trastuzumab appears to act via multiple mechanisms, including downregulation of HER-2 expression, induction of G1 cell-cycle arrest and downstream cell regulatory signals, initiation of antibody dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and promotion of apoptosis [83].

Several studies have shown HER-2/Neu overexpression in gastrointestinal tumors, including esophageal squamous cell carcinoma (mean, 23%; range, 0%–52%), GE adenocarcinoma (mean, 22%; range, 0%–43%), and gastric adenocarcinomas (mean, 19%; range, 6%–43%) [88]. The wide range of expression reflects the differences in receptor testing and reagents, as well as the varied cancer stages of the patients. In esophageal squamous carcinoma, HER-2/Neu overexpression has been correlated with extramural invasion and poor response to neoadjuvant chemotherapy. In GE junction adenocarcinoma, some studies suggest a correlation with increasing depth of invasion, lymph node and distant organ metastasis, and overall poor survival [88].

HER-2/Neu is therefore a potential target in esophageal cancers, particularly as part of a standard combined-modality treatment regimen. Prior studies reported that trastuzumab is synergistic or additive with cisplatin, paclitaxel, and radiation [89, 90]. Therefore, Safran and colleagues conducted a phase I/II trial of weekly trastuzumab, paclitaxel (50 mg/m2), cisplatin (25 mg/m2), and radiation (total 50.4 Gy) in patients with locally advanced GE junction adenocarcinoma [91]. They found that HER-2/Neu was overexpressed in one third of GE junction adenocarcinomas (12/36 patients, 33%), similar to the breast cancer rates. Eighteen HER-2/Neu–negative patients were used in a control arm, receiving the same chemoradiotherapy without trastuzumab. They reported that full-dose trastuzumab (initial bolus 4 mg/kg, then weekly 4 mg/kg) can be incorporated into this concurrent chemoradiotherapy safely without cardiotoxicity or increased esophagitis.

pCR is the most validated end point in determining the efficacy of preoperative chemoradiotherapy. However, this study included patients with advanced locoregional and distant adenopathy. Therefore, these patients were not surgical candidates, and pathologic response rates were undetermined. As a surrogate, endoscopic response was used to assess locoregional activity control. Five of 10 (50%) patients in the trastuzumab arm and 10 of 13 (77%) patients in the control arm had no tumor on postchemoradiation endoscopic biopsy. However, endoscopic CR may not be a reliable surrogate for pCR [91]. Nonetheless, that trial proved the feasibility of trastuzumab with a standard combined-modality regimen. Further phase II trials with trastuzumab in esophageal cancer are under way.

Antiangiogenesis—VEGF
Tumor growth and metastasis are regulated by the recruitment of new blood vessels, angiogenesis, via a diverse group of endogenous proangiogenic and antiangiogenic factors, including VEGF, basic fibroblast growth factor (bFGF), interleukin-8, placenta-like growth factor, TGF, platelet-derived endothelial growth factor, pleiotrophin, hypoxia-inducible factor-1, and others [92, 93].

Of the identified angiogenic factors, VEGF is the most potent and specific and has been identified as a crucial regulator of both normal and pathologic angiogenesis [94]. VEGF produces various biologic effects to induce tumor growth/spread, including endothelial cell mitogenesis and migration, induction of proteinases, increased vascular permeability, and maintenance of survival for newly formed blood vessels. The biologic effects of VEGF are mediated through binding and stimulation of two receptors on the surface of endothelial cells: Flt-1,4 (fms-like tyrosine kinase) and flk-1, kinase domain region (KDR) [93]. VEGF is overexpressed in human cancer cells and is frequently correlated with greater microvessel density, advanced disease stage, and poor overall survival [95].

VEGF is overexpressed in 30%–60% of patients with esophageal cancers, and several studies have demonstrated a correlation among high levels of VEGF expression, advanced stage, and poor overall survival in patients undergoing a potentially curative esophagectomy [96–99]. The prognostic value of VEGF in patients treated with preoperative chemoradiation is less clear. In a cohort of patients with esophageal squamous cell carcinoma and adenocarcinoma, Kulke and others found no significant association between VEGF expression and treatment response or overall survival [100, 101]. This discrepancy may be in part explained by the potential induction of VEGF and increased angiogenic activity that may occur with the delivery of preoperative chemo-radiotherapy. The treatment-induced development of more aggressive and resistant tumor phenotypes might weaken potential associations among pretreatment VEGF levels, treatment response, and overall survival [100]. However, two smaller studies of preoperative chemoradiation in patients with esophageal cancer have suggested an association between high VEGF level and poor prognosis [102, 103].

VEGF expression in Barrett’s dysplasia and esophageal adenocarcinoma appears to correlate with vascularization. Lord and colleagues demonstrated that mRNA expression levels of VEGF and bFGF are significantly upregulated in most adenocarcinom as of the esophagus or GE junction, and thus, likely increase tumor angiogenesis. There was considerable variation at all histopathologic stages, but a grouped analysis showed that there was a highly significant greater level of expression of both VEGF and bFGF in adenocarcinoma tissues compared with normal esophageal mucosa or Barrett’s esophagus [104]. Auvinen and colleagues compared Barrett’s dysplasia with normal esophageal mucosa. They reported that Barrett’s specific glandular epithelium secretes VEGF-A, in addition to a mixture of sialomucin and sulfated mucins. The receptor of VEGF-A (VEGFR-2) is strongly expressed on angiogenic blood vessels feeding the Barrett’s epithelium. These results raised the possibility that the proliferating endothelial cells of new blood vessels might serve as an important additional source for angiogenic, diagnostic markers specific for the progression of Barrett’s epithelium [105].

VEGF blockade may be a potential targeted treatment option for esophageal cancer. There are two classes of angiogenesis inhibitors—direct and indirect. Direct angiogenesis inhibitors target the microvascular endothelial cells that are recruited to the tumor bed and prevent them from responding to various endothelial mitogens and motogens. Examples include: (a) angiostatin, which binds to ATP synthase, angiomotin, and annexin II on endothelial cells to inhibit endothelial-cell proliferation and migration; (b) bevacizumab (Avastin®; Genentech, Inc.), a recombinant humanized mAb against VEGF; (c) arresten, believed to bind integrin-{alpha}1ß1 to inhibit endothelial-cell proliferation, migration, tube formation, and neovascularization; (d) canstatin, believed to bind integrin-{alpha}vß3 to inhibit endothelial-cell proliferation, migration, and tube formation; (e) combretastatin, which induces reorganization of the actin cytoskeleton and early membrane blebbing in human endothelial cells; (f) endostatin, believed to target integrin-{alpha}5ß1 to inhibit endothelial-cell proliferation and migration, and induce apoptosis of proliferating endothelial cells; (g) NM-3, an isocoumarin small-molecule inhibitor of VEGF, shown to selectively inhibit endothelial-cell proliferation, sprouting, and tube formation in vitro; (h) thrombospondin, which blocks endothelial-cell migration and neovascularization in the cornea but might not be specific for endothelial cells; (i) tumstatin, which binds to integrin on endothelial cells, inhibits endothelial-cell proliferation, and neovascularization; (j) vitaxin A, the humanized mAb against integrin; and (k) VEGF-Trap [92].

Indirect angiogenesis inhibitors target proteins—such as EGF tyrosine kinase and its products bFGF, VEGF, and TGF-{alpha}, or their receptors, on endothelium—that are expressed by tumor cells. Among its many effects, tumor-cell signaling through this receptor induces the expression of VEGF, TGF-{alpha}, and bFGF, which promotes angiogenesis. Examples include (a) EGFR tyrosine kinase blockade with cetuximab, erlotinib, gefitinib, ZD6474, CI1033, or PKI1666 (which lower VEGF, bFGF, and TGF-{alpha} levels); (b) VEGFR tyrosine kinase inhibition with PTK787, ZD6474, SU6668, or SU11248; (c) platelet-derived growth factor (PDGF) tyrosine kinase inhibition with PTK787 or SU11248; (d) HER-2/Neu receptor blockade with trastuzumab (lowers VEGF, angiopoietin-1, TGF-ß, plasminogen activator inhibitor-1; upregulates thrombospondin-1); and (e) interferon (IFN)-{alpha} receptor blockade with IFN-{alpha} (inhibits expression of bFGF by cancer cells) [92]. Many of these indirect angiogenesis inhibitors were described earlier in this review.

VEGF mAbs
For the direct angiogenesis inhibitors, bevacizumab has been most well studied. Bevacizumab, a recombinant humanized mAb, binds to all isoforms of human VEGF with high affinity and prevents the binding of VEGF to its receptor [106]. More than 30 clinical trials with bevacizumab in solid tumors and hematologic cancers are ongoing or completed, with various designs including bevacizumab as a monotherapy or in combination with chemotherapy, radiotherapy, other antiangiogenic agents (i.e., interferon, thalidomide [Thalomid®; Celgene Corporation, Warren, NJ, http://www.celgene.com]), targeted agents (i.e., erlotinib, trastuzumab, imatinib [Gleevec®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, http://www.pharma.us.novartis.com], cetuximab), or immunotherapy (i.e., dendritic cells pulsed with tumor antigen) [107]. Thus far, activity has been reported in colon, renal cell, non-small cell lung, ovarian, and breast cancers [107–111]. In particular, bevacizumab combined with an irinotecan-based regimen (IFL) improved overall survival compared with placebo (15.6 months versus 20.3 months) in metastatic colon cancer patients, leading to its FDA approval [109]. Potential toxicities include hypertension, thrombosis, proteinuria, gastrointestinal perforation, poor wound healing, and bleeding.

For esophageal cancer, bevacizumab is in the early stages of clinical development. Most trials have been limited to GE adenocarcinomas, given the life-threatening hemoptysis described in bevacizumab-treated patients with squamous cell carcinoma of the lung [110]. A multi-center phase II study of irinotecan, cisplatin, and bevacizumab in 20 patients with unresectable or metastatic gastric or GE adenocarcinoma has shown encouraging preliminary results [112]. Shah and colleagues reported an 87% control rate (PR/SD). Of the 10 patients with measurable disease who completed at least two cycles, the investigators reported PRs in five (50%), minor PRs in four (40%), and stable disease in one. The combination therapy was well tolerated, although, as detailed in a recent update, six (25%) of 24 patients developed thromboembolic events, one patient had a gastric perforation, and another had a near perforation on imaging [113]. No patients had significant bleeding.

Given that most patients with locally advanced esophageal cancer are treated with concurrent chemoradiation, there may be a possible integrative role for VEGF blockade. Neoadjuvant chemoradiation has a minimal effect on the angiogenic tumor profile (VEGF, von Willebrand factor, CD68, macrophage infiltration), portending a bad prognosis [114]. VEGF blockade reduces tumor interstitial pressure and vascular permeability, thus enhancing radiation and delivery of chemotherapy to tumors [115, 116]. The radiosensitizing effect of VEGF antibody has been demonstrated in several xenograft models, including those of glioma, colon, lung, and esophageal adenocarcinoma [117–120]. VEGF antibody with radiation induced supra-additive tumor growth delay and sustained cell death over a significant period of time in vivo (4–6 months) without schedule dependency [90]. Moreover, radiation potentiation occurred under both hypoxic and normal tumor oxygenation [119]. These preclinical data were explored further in a recent phase I rectal cancer clinical trial with neoadjuvant 5-FU, radiation, and bevacizumab. The addition of bevacizumab to concurrent chemoradiotherapy was feasible and had no significant additive toxicities [121]. A preoperative trial with bevacizumab, cisplatin, irinotecan, and concurrent radiation in locally advanced esophageal adenocarcinoma is set to open at Memorial Sloan-Kettering Cancer Center later this year.

COX-2 Inhibition
Over the last decade, there has been growing preclinical evidence to link the expression of COX-2, an inducible enzyme that catalyzes prostaglandin synthesis, and carcinogenesis in Barrett’s esophagus. COX-2 affects several pathways in carcinogenesis, including those of apoptosis, angiogenesis, inflammation, and immune surveillance [122, 123]. The use of aspirin and other nonsteroidal anti-inflammatory drugs to nonselectively inhibit COX-2 has been associated with a lower esophageal cancer rate [124, 125]. In addition, a recent meta-analysis of nine epidemiologic studies pooling 1,813 cancer cases showed a 43% lower rate of esophageal cancer in patients who use nonsteroidal anti-inflammatory drugs (50% for aspirin), with a trend toward a dose response [126].

The role of selective COX-2 inhibitors (i.e., celecoxib, Celebrex®; Pfizer Pharmaceuticals) in the prevention or treatment of esophageal cancer remains unsubstantiated and possibly risky, given the greater risk for thrombosis with these drugs at higher doses, as seen in the colon cancer prevention trials. Prior to when this toxicity risk was established, the National Cancer Institute had sponsored two large prevention trials with selective COX-2 inhibitors in Barrett’s esophagus—the first to determine if COX-2 inhibitors could reverse dysplastic changes and the second to determine if COX-2 inhibitors could prevent dysplasia recurrence after thermal ablation. At the present, these trials are on hold until the toxicity profile is clarified.

In addition to their potential as chemoprevention, several phase II trials have recently been reported, in abstract form, with combinations of COX-2 inhibitors and concurrent chemoradiotherapy for locally advanced esophageal cancer. In a single-arm trial with 31 patients, celecoxib was combined with cisplatin, 5-FU, and radiotherapy, followed by surgery and maintenance celecoxib [127]. Of the 22 patients (71%) who underwent surgery, six had pCRs (19% of those enrolled and 27% of those who underwent surgery). The 2-year survival rate for the entire study population was 31% ± 12%, with a median survival time of 17 months. The toxicity profile was not reported, and baseline COX-2 expression in esophageal cancer tissues did not predict survival. In comparison with historical controls, there does not appear to be much added benefit from a COX-2 inhibitor. A second phase II trial has been reported with celecoxib combined with cisplatin, irinotecan, and radio-therapy followed by surgery and maintenance celecoxib [128]. On preliminary analysis, 25 patients (of 36 total) had completed chemoradiation and surgery, and 11 had pCRs (31% of those enrolled and 44% of those who went to surgery). The toxicity profile did not reveal any further thrombosis risk. This high response rate is encouraging; however, we await further follow-up.

Conclusions
Drug development has been transformed with the identification of and ability to direct treatment at specific molecular targets. In esophageal cancer, novel targeted treatments are in early development, although encouraging results have been reported with antibodies directed at the EGFR and VEGF ligand, as well as with the oral TKIs. Within the coming years, new research trials will expand our treatment options greatly, given the wealth of potential targets and the plethora of new agents in clinical development. Future trials will include cancer prevention in Barrett’s esophagus and the addition of targeted agents to chemotherapy in metastatic esophageal cancer and to combined chemoradiotherapy in locally advanced disease. Moreover, as we have learned from the lung cancer trials, future research directions must focus on tailoring therapy to specific patient populations, such as those with genetic mutations on receptors, for optimal therapeutic effect.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning objectives
 Abstract
 Introduction
 Standard treatments
 Targeted therapy approaches
 Disclosure of potential...
References
 
Dr. Ilson has acted as a consultant for and has received support from Pfizer, Roche, and Sanofi-Aventis.


   REFERENCES
Top
 Learning objectives
 Abstract
 Introduction
 Standard treatments
 Targeted therapy approaches
 Disclosure of potential...
 References
 

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