Familial Nasopharyngeal Carcinoma 6

Concurrent Chemotherapy-Enhanced Radiation: Trials and Conclusions 177for efficacy (Clayman et al. 1998, 1999). A smallrandomizedstudy of recombinant Adenovirusp53(rAd-p53) combined with radiotherapy wasperformed in 42 NPC patients in China and comparedwith a control group of 40 patients treated with radiationtherapy alone (Pan et al. 2009). Patients in thisstudy received an intratumoral injection of rAd-p53 at1 × 10 12 virus particles/mL once a week (on Friday) for8 weeks per tumor via naso-endoscopic guidance orthrough an ultrasound-guided injection for necknodes. Patients on both arms were treated to a tumordose of 70 Gy. Adverse effects of the rAd-p53 administrationwere minimal. Eighty-one percent of patients inthe experimental arm developed a mild and transientfever. At 2 months post radiation therapy, the completeresponse rate of the group receiving rAd-p53 combinedwith radiation was 2.73 times that of the group receivingradiation alone (66.7% vs. 24.4%; p = 0.01). After 6years of follow-up, there was statistically significantdifference in 5-year local-regional failure rate (2.7% vs.28% p = 0.002), but there was no difference in overall ordisease-free survivals or distant metastases rates.NPC is known to overexpress EGFR, COX-2, VEGF,and iNOS (Soo et al. 2005). Newer agents specificallytarget these molecular markers and some of theseagents have already made their way to the clinic.Cetuximab, a monoclonal antibody that targetsthe EGFR receptor, has been shown to improve survivalwhen administered in conjunction with radiotherapyin squamous cell head and neck cancer(Bonner et al. 2006). In NPC, one study has demonstratedthat cetuximab inhibits the growth of NPCcell-lines HK1 and HONE-1 (Sung et al. 2005). TheCUHK group then proceeded to perform a Phase IItrial of cetuximab–cisplatin concurrent with IMRT inpatients with locally advanced NPC in a curative setting(Ma et al. 2008a). Grade 3 mucosal toxicities werecommon but manageable, and the cohort had an 83%complete response rate and a 17% partial responserate when evaluated 3 months post radiotherapy.A small Phase II randomized trial of a humanizedanti-EGFR monoclonal antibody h-R3 administeredconcurrent with radiotherapy vs. radiotherapy alonewas performed in China. While the initial completeresponse rate was significantly higher in the experimentalarm, longer follow-up did not reveal any significantdifferences in 3-year locoregional control,distant metastasis-free survival, and overall survivalrates between the two groups (Wu et al. 2007).The tyrosine kinase inhibitor, Gefitinib, was investigatedin a group of heavily pretreated recurrentNPC patients (Ma et al. 2008b). No objective responsewas seen, and three patients had stable disease for upto 8.5 months. The study was terminated prematurelyat the first stage after 15 patients were accrued.Another trial of sorafinib (Elser et al. 2007), a multitargetedagent, also did not reveal any activity inrecurrent or metastatic NPC patientsIn head and neck squamous cell carcinoma, metaanalysishas shown that positive VEGF staining wasassociated with an almost twofold higher risk of deathat 2 years (Kyzas et al. 2005). In NPC, VEGF has beenshown to play an important role in lymph node metastasisthrough the induction of angiogenesis (Wakisakaet al. 1999). Overexpression of VEGF was seen in 67%of nasopharyngeal cases and the higher expression ofVEGF related to higher rate of recurrence, nodal positivity,and lower survival (Krishna et al. 2006). Arecent pilot study by Druzgal et al (2005). analyzedthe pre- and post-treatment serum levels of angiogenesisfactors as markers for outcome in patients withhead and neck cancer. With a median follow-up of 37months, patients were more likely to remain diseasefreewhen the VEGF level decreased post-treatment vs.those who continued to have increased VEGF levelsafter treatment. In this study, 7% of the patients hadnasopharyngeal carcinoma. The RTOG is currentlyevaluating the current use of bevacizumab withchemoradiotherapy in a Phase II setting.13.8ConclusionThe growing number of trials that have been conductedin a wide variety of locations, including a considerablevariation in patient selection, precise detailsof therapy delivered and selection of endpoints measuredleave little doubt that the addition of chemotherapyconcurrent with radiation therapy has improvedthe outcomes of patients with NPC. Improvements inradiation treatment technology and the adoption ofIMRT has also improved local control and reducedmorbidity. The incorporation of new drugs as well asthe new targeted agents is currently under intenseinvestigation and there is reason to believe that it willfurther improve treatment outcomes. In the horizonare immunotherapeutic strategies, and other treatmentstargeting the Epstein–Barr virus and the NPCepigenome (TAO and Chan 2007). With this proliferationof treatment possibilities, there is potential thatNPC will become a highly curable malignancy in thenear future.