Treatment optimization of nasopharyngeal carcinoma (NPC) in the era of intensity modulated radiation therapy (IMRT)

Abstract

Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Hong Kong, southern China, Taiwan, Singapore and Malaysia, well known for its strong association with genetic predisposition and Epstein-Barr virus (EBV). Recently intensity modulated radiation therapy (IMRT) has developed itself as key player in this battlefield against this radio-sensitive and radio-responsive malignancy for the past 15 years. Numerous studies have confirmed its superiority over traditional techniques for both untreated or locally recurrent diseases. By the use of multiple beams directing to the tumors at numerous angles, together with its further intensity modulation within each beam by the movement and positions of the leaves in the multileaf collimators driven by contemporary linear accelerators, a high radiation dose to the tumor and dose sparing to adjacent organs-at-risk (OARs) can be achieved. Nevertheless, IMRT still gives rise to significant though manageable acute and chronic side effects including nausea/vomiting, xerostomia, impaired hearing ability, dysphagia, etc. Although the dose tolerance to the concerned organs or structures responsible for xerstomia, impaired hearing and dysphagia has been recognized, there are still others organs/structures which can be further explored so the aim of less radiation-related toxicities can be achieved.

Apart from that, post-treatment tumor response evaluation is a major component to demonstrate the superiority of IMRT as compared to other techniques. Imaging tools including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography with integrated computed tomography (PET-CT) may not be sensitive and specific enough to differentiate between recurrent tumors and post-radiation changes. Biomarkers have been developed rapidly as non-invasive and accurate predictors or prognosticators of this disease. It is hoped that biomarkers can complement imaging tools as reliable instruments in diagnosis, surveillance and prognostication.

In this thesis, I first focused on the effect of CT contrast on radiation dose calculation during IMRT treatment planning with emphasis on the dose to the carotid arteries and thyroid which are readily contrast enhancing. Our results showed that contrast injection resulted in an insignificant and clinically negligible dose reduction to the carotid arteries and the thyroid. We then identified that radiation dose to the vestibules in the inner ears are responsible for the development of radiation-induced acute nausea in patients treated with IMRT alone. Furthermore, we investigated the role of plasma EBV deoxyribonucleic acid (DNA) in predicting local clinical remission immediately after IMRT as well as long-term survival outcomes. We demonstrated that though plasma EBV DNA did not correlate well with local clinical remission after completion of IMRT with or without adjunct chemotherapy, it is significantly and strongly prognostic of all prespecified 3-year survival endpoints. Finally we revealed that hyperfractionated IMRT showed a trend of better local failure-free survival and fewer incidences of treatment-related hemorrhage compared to standard-fractionated IMRT as a second-course radiation therapy for locally recurrent NPC.

In summary, this thesis has provided new insights on treatment optimization of NPC in the era of IMRT and it is believed our study results shall benefit the next generation of patients who suffer from this highly curable malignancy.