ANTI-TUMOUR TREATMENT
Esophagogastric cancer: Targeted agents

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Summary

Because of the poor prognosis for patients with locally advanced and metastatic esophageal, gastroesophageal junction and gastric cancers, increasing attention has focused on the integration of targeted agents into current therapies. The molecular targets of these agents include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or its receptor, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle. In this review article, we briefly discuss pre-clinical data and the rationale for targeting these pathways and summarize the results of clinical trials to-date, including completed and ongoing phase III evaluations.

Introduction

Despite ongoing research in the treatment of esophagogastric cancers (EGC), the prognosis for long-term survival remains poor. Surgery alone for locally advanced disease results in 5-year survival rates of only 20–25%.1, 2 The addition of combined modality strategies – namely pre- or post-operative chemoradiotherapy or peri-operative chemotherapy – results in 5-year survival rates of only 30–35%.2, 3, 4, 5 Pre-operative chemoradiotherapy produces pathologic complete responses (pCR) in no more than 20–30% of patients,4 while pre-operative chemotherapy alone is only rarely associated with pCRs.2, 6

In the metastatic setting, chemotherapy is the mainstay of palliative therapy and results in objective response rates (ORRs) of only 20–40% and median overall survivals (OS) of 8–10 months.7 Recent investigations have focused on the incorporation of a third chemotherapy agent into two-drug regimens, resulting in modest improvements in survival but at the expense of considerable additional toxicity.8, 9 Such toxicities potentially limit the adaptation of these three-drug regimens by a patient population that is often elderly and has associated medical comorbidities.

Therefore, many investigators believe that the potential for making significant progress lies in understanding and exploiting the molecular biology of these tumors. The focus of recent study has shifted toward testing newer agents that target specific molecular abnormalities known to occur in EGCs.

The molecular targets of agents that are currently under active clinical evaluation have mostly included epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) or its receptor (Fig. 1, Fig. 2). Other targets include cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle.

These trials have had variable eligibility requirements and have grouped together combinations of patients with esophageal, gastroesophageal (GE) junction and/or gastric primary tumors. Histologies on these trials are squamous cell carcinomas (SCC), which mostly occur in the proximal third of the esophagus and adenocarcinomas, which arise in the distal two-thirds of the esophagus, GE junction and stomach.

Section snippets

Epidermal growth factor receptor

EGFR or ERBB1 is a member of the ERBB transmembrane growth factor receptor family, which initiates signal transduction by activation of a receptor-associated tyrosine kinase (TK); ERBB also includes ERBB2 (Her2/neu), ERBB3 and ERBB4.10

The known ligands of the EGFR are epidermal growth factor (EGF) and transforming growth factor (TGF)-α. Binding of a ligand to the EGFR causes it to dimerize either with itself or with another member of the ERBB family. Dimerization then leads to activation of the

Vascular endothelial growth factor

Therapies directed against VEGF are the focus of major ongoing research in solid tumor malignancies. Folkman and others have provided compelling evidence linking tumor growth and metastases with angiogenesis.100

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. VEGF produces a number of biologic effects, including endothelial cell mitogenesis and migration and induction of

Mammalian target of rapamycin (mTOR) inhibition

A new target for cancer therapy is the mammalian target of rapamycin (mTOR) serine-threonine kinase, which is a downstream component of the phosphatidylinositol 3-kinase (PI3 K)/Akt kinase pathway. The PI3 K/Akt/mTOR pathway acts as a cellular sensor for nutrients and growth factors and integrates signals from multiple receptor kinases to regulate cellular growth and metabolism. Kinases in the pathway have been found to be activated in several cancers and are thought to be important for many

Cyclooxygenase-2 inhibition

There has been growing pre-clinical evidence to link the expression of cyclooxygenase-2 (COX-2), an inducible enzyme that catalyzes prostaglandin synthesis, and carcinogenesis in Barrett’s esophagus. COX-2 affects several pathways, including those of apoptosis, angiogenesis, inflammation and immune surveillance.144, 145 The use of aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) to inhibit COX-2 has been associated with a lower esophageal cancer rate.146 A meta-analysis of nine

Other targets

Alongside the more established therapies discussed above, other tumor targets have also previously been evaluated. An example is matrix metalloproteinases (MMPs), a family of proteolytic enzymes that breaks down components of the extra cellular matrix. While they play an important role in normal processes of growth and repair, their aberrant expression is thought to contribute to the invasive potential of several solid malignancies.154

Based on phase I results that suggested subjective clinical

Ongoing challenges

Despite the incremental benefits noted in some phase II trials and a recent positive phase III trial, challenges – some unique to EGCs – exist as targeted therapies continue to undergo evaluation. These factors will be mentioned briefly as a full discussion is beyond the scope of this review.

The first of these challenges is that the eligibility criteria for trials in EGCs have not been standardized. Typically, patients are enrolled on the basis of a combination of anatomic location of their

Conclusion

Drug development in cancer therapeutics has been transformed by our increasing understanding of the cellular mechanisms of carcinogenesis and our ability to design rational therapies to specifically target these aberrancies.

A significant milestone was recently reached in EGCs, when the first phase III trial to demonstrate a survival benefit for the addition of a targeted agent (trastuzumab) to chemotherapy was reported. At this time, there are several other ongoing phase III evaluations of

Conflict of interest statement

David Ilson has received research support from Bayer, Pfizer, Sanofi-Aventis, Genentech and Bristol-Myers Squibb.

Geoffrey Ku has no stated conflict of interest.

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