Improving prognostication and treatment of advanced nasopharyngeal carcinoma in the era of intensity-modulated radiation therapy

Abstract

Nasopharyngeal carcinoma (NPC) is endemic in Hong Kong, southern China and some Southeast Asian countries such as Malaysia and Singapore. The prognosis of NPC has been significantly improved over the past decades in part due to widespread application of intensity modulated radiation therapy (IMRT) and broadened therapeutic options as well as more precise risk stratification. Radiation therapy (RT) is the current standard of treatment and the incorporation of concurrent chemotherapy and adjunctive chemotherapy (induction or adjuvant) to RT has contributed to improve survival of patients with locoregionally advanced NPC. Adding induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) which helps improve distant control plays an increasingly important role in the management of locoregionally advanced NPC in the modern era of IMRT. However, the ideal IC regimens and optimal selection of patients for IC are still investigational.

Advances in molecular biotechnology have contributed to decipher NPC oncogenesis and its association with the Epstein-Barr virus (EBV). Plasma EBV deoxyribonucleic acid (DNA) is the archetypal circulating tumour-derived DNA marker for NPC. Studies in the past 20 years have significantly broadened the clinical applications of plasma EBV DNA, including diagnosis and screening, treatment monitoring, surveillance against disease recurrence and prognosis. It is expected that the utility of this biomarker could be further expanded by earlier identification of patients with high-risk of recurrence in particular distant metastasis who will potentially benefit from additional chemotherapy or more intensified treatment. In addition, the complementary role of plasma EBV DNA to the current anatomic TNM (Tumour-Node-Metastasis) classification system has gained considerable attention. Further exploration and more consensus are needed in the best application of this biomarker in NPC staging.

In this thesis, I first focus on the prognostication of half-life clearance of plasma EBV DNA in previously untreated non-metastatic NPC. Our results showed that patients with half-life clearance of > 15 days had worse survival outcomes. We then investigated the optimal regimens of IC for locoregionally advanced NPC. We demonstrated in a pooled analysis of two prospective studies that gemcitabine plus cisplatin (GP) had similar efficacy and potentially fewer treatment-related complications as compared with cisplatin plus fluorouracil (PF) and cisplatin plus capecitabine (PX). In addition, in our network meta-analysis, we showed that docetaxel plus cisplatin (DC), GP and PX were the most efficacious IC regimens among all available IC regimens followed by CCRT. Finally, we attempted to propose a refined M1 classification in de novo metastatic (metastatic at presentation) NPC for future TNM staging classification. Based on the pooled data from two academic institutions, we revealed that subdividing de novo M1 NPC by anatomic factors into M1a (no co-existing liver-bone metastases) vs. M1b (co-existing liver-bone metastases) provides better segregation of overall survival. Furthermore, prognostication was further improved by incorporating plasma EBV DNA within the anatomy-based framework.

In summary, this thesis has provided some new insights on the contemporary management of NPC in the modern era of IMRT. It is highly believed both the current and the next generation of patients with NPC could benefit from our study results.