Familial Nasopharyngeal Carcinoma 6

Molecular Signaling Pathways in Nasopharyngeal Cancer 35expression of VEGF in the primary tumor (Krishnaet al. 2006; Pan et al. 2008). Overexpression ofVEGF-A is associated with poor prognosis in headand neck cancers. A meta-analysis of 12 studiesand 1002 SCCHN patients (7% of cases were NPC)revealed that positive VEGF-A staining by IHC wasassociated with a doubled death rate at 2 years aftertreatment (Kyzas et al. 2005). However, the metaanalysisdid not demonstrate an association betweenVEGF staining and cervical nodal metastasis inSCCHN, possibly due to the heterogeneity of theincluded patient population and the lack of directassessment of VEGF-C expression, which plays alarger role on lymphangiogesis and possibly nodalspread. In an NPC-specific study, Wakisaka et al.(1999) found that the VEGF intensity by IHC stainingcorrelated with the microvessel count in the tumortissue and regional nodal spread in 29 NPC patients,indicating that VEGF-induced angiogenesis may berelated to nodal metastasis in this disease (Wakisakaet al. 1999). A different study of 73 NPC patients (49with locoregional disease and 24 with metastatic disease)demonstrated a significant increase of MVDand VEGF expression in tumor tissue when comparedwith normal nasopharyngeal mucosa. Similarly,both MVD and VEGF expression were significantlyelevated in metastatic NPC when compare with nonmetastaticdisease (Guang-Wu et al. 2000). In thepreviously mentioned study by Krishna et al. (2006),higher expression of VEGF in EBV positive tumorswas associated with a higher rate of tumor recurrence,regional nodal involvement, and poorer survival.Similar results were reported in the study byPan et al. (2008). The intensity of VEGF expressioncorrelated tumor extent by the TNM staging.Interestingly, in an attempt to validate prior smallinstitutional reports, the RTOG (Radiation TherapyOncology Group) evaluate MVD in 123 NPC patientstreated with definitive radiation therapy and foundno significant association between the two parameters(Foote et al. 2005). Measurements of tumorangiogenesis are dependent on tumor size, the size ofthe sampled specimens, location of measurement(tumor edge “hot spots” vs. average), immunostainingtechnique, the scoring system, and method ofmeasurement. The difference in any of the measurementparameters, treatment techniques, and patientcohort sample size can account for the differentresults noted from this and the above-mentionedstudies. A large prospective study using samples froma homogenously treated group of patients is warrantedto address this important question.The serum VEGF level as an indicator of angiogenesishas also been studied in SCCHN includingNPC. In a study of 65 male patients with NPC, serumVEGF was found to be significantly associated withmetastatic disease when compared with healthyindividuals and patients with nonmetastatic NPC,although no significant differences in the levels ofVEGF were detected among various T classifications,N classifications, and clinical stages of nonmetastaticdisease (Qian et al. 2000). However, the significanceof the serum level of VEGF in predicting the outcomeincluding overall survival, disease- or progressionfreesurvival, and local/regional control rates havenot been thoroughly investigated in clinical studies.3.3.4Targeting VEGF and VEGFR in NasopharyngealCancer TreatmentPotential treatment strategies for targeting tumorangiogenesis include VEGF ligand-targeted therapy,VEGFR-2 receptor inhibitor, endothelial cytotoxicmedication, inhibitors of enzymes that degrade theextracellular matrix, and integrin antagonists. Antiangiogenictherapies have been extensively studied,and their efficacy has been confirmed in the treatmentof several malignancies including colorectalcancer, lung cancer, renal cell carcinoma, and livercancer. However, their use in head and neck cancersis relatively limited, especially when used with definitiveradiotherapy (Mauceri et al. 1998).The feasibility of combining antiangiogenic treatmentand chemoradiation therapy to the head andneck cancers has been reported in a phase I trial,which combined bevacizumab, a recombinant humanizedmonoclonal antibody to VEGFs, dosed at 10 mg/kg IV q2 weeks and fluorouracil- and hydroxyureabased(FXH) chemoradiotherapy. The results demonstratedno major additive toxicities and the feasibilityof such combination (Seiwert et al. 2008).A number of phase II clinical trials are currentlyongoing to test the efficacy of other anti-angiogenictherapies such as small molecule TKIs in the treatmentof SCCHN.With the technological advances in the diagnosisand treatment of NPC, local and regional controlrates exceed 90% after IMRT or combinedchemotherapy and IMRT. Distant metastasis hasbecome the most commonly observed mode of treatmentfailure. As higher level of VEGF is noted in tumortissue and serum of patients with metastatic disease,