An Evidence-Based Approach to the Management of Nasopharyngeal Cancer: From Basic Science to Clinical Presentation and Treatment

An Evidence-Based Approach to the Management of Nasopharyngeal Cancer: From Basic Science to Clinical Presentation and Treatment provides a comprehensive overview with updated management procedures for nasopharyngeal carcinoma. Written by experts on the subject, it is organized in a simple yet comprehensive manner to aid in the understanding of this complex condition. The book discusses several topics related to NPC, including epidemiology, pathophysiology, risk factors and treatment (surgical and non-surgical). Additionally, it discusses key features of clinical presentation of NPC, recent advances and promising new therapies.

This will be a valuable source for clinicians, graduate students, oncologists and several members of the biomedical field who are interested in understanding nasopharyngeal cancer in a practical and applicable way.

• Discusses current trends in surgery, including the use of endoscopy and robotic and navigation technology in the management of NPC
• Presents a summary with diagrams and workflows at the end of every chapter as a quick reference guide
• Encompasses colorful figures of pathology, clinical cases, endoscopic findings, surgical approaches, resection of tumors, brachytherapy and robotic and navigation technology so readers fully comprehend content

• Language: English
• Publisher: Academic Press
• Release date: May 22, 2020
• ISBN: 9780128144046

Book preview

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Introduction

William Ignace Wei¹ and Raymond K. Tsang²,    ¹Department of Surgery, Hong Kong Sanitorium and Hospital, Happy Valley, Hong Kong SAR, China,    ²Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

Abstract

Nasopharyngeal carcinoma (NPC) is a unique cancer in every aspect. Its incidence varies drastically worldwide, with endemic areas having an incidence more than ten times greater than nonendemic areas. First described in the late 1800s in Western medical literature, NPC was considered incurable at that time. Advances in every area of Western medicine, including diagnostic techniques, radiotherapy, chemotherapy, and surgery have made NPC one of the more curable head and neck cancers with cure rates of over 80% in cases diagnosed during early stages. Endemic NPC is associated with Epstein–Barr virus and is one of the first described virus associated cancers. This virus association is now exploited as a tumor marker and a model for studying virus-induced carcinogenesis. This book is aimed to present the latest knowledge in all the aspects of NPC with reference to the latest evidence presented in the medical literature.

Keywords

Nasopharyngeal carcinoma; Epstein–Barr virus; head and neck cancer; cancer epidemiology; radiation therapy

Nasopharyngeal carcinoma (NPC) is a unique cancer in every aspect, including its epidemiology, pathogenesis, and the evolution of its treatment. It is also a cancer for which modern medicine can be proud of the progress made in combatting it. From the first description of NPC in the late 19th century, to introduction of the first curative therapy via radiation in the first half of the 20th century, to modern diagnosis and treatment in the 21st century, we have come a long way in understanding this cancer and are now able to offer curative treatment for the majority of the patients. Yet this cancer is still not fully understood. The precise cause of differences in distribution by race is still an enigma and we have not elucidated the exact role of the Epstein–Barr virus (EBV) in carcinogenesis. Much more research, both basic and clinical, is still required in order to eradicate this disease. Reviewing the history of how modern medicine learned to understand this cancer is a synopsis of how modern medicine came to understand and treat many cancers in the last one and a half centuries.

Historical aspect

As NPC is relatively rare in Europe, there is no record of the disease until the 19th century. Early reports of suspected cases of NPC might be confused with other cancers like paranasal sinus cancers, which probably involved the nasopharynx and adjacent structures in their late stage. Muir in 1960 summarized the reports of the suspected cases of NPC in the non-English literature (Muir, 1983). Bosworth was the first to write about the disease in English in his textbook Diseases of the Nose and Throat and devoted a chapter to describe the disease (Bosworth, 1892). Bosworth considered the disease incurable and advised for palliative treatment only. The famous endoscopist Chevalier Jackson wrote about the disease in 1901 and also agreed that radical curative surgeries did not offer a cure and only increased the suffering of the patient (Jackson, 1901).

While the disease was relatively rare in the West, Western medical practitioners working in the Far East recognized the common occurrence of the disease and wrote about the presentation of the cancer. While practicing medicine in Guangzhou, Todd wrote about cancers in the posterior nares metastasizing to the cervical glands (Todd, 1921). K.H. Digby, Professor of Surgery in the University of Hong Kong, wrote in detail regarding the different presentations of the disease, including the various cranial neuropathies, for the benefit of the medical students and young doctors (Digby, Thomas, & Tse, 1930). A sample of his drawings can be seen in Fig. 1.1.

Figure 1.1 Selected drawings from Digby’s monograph on presentation of nasopharyneal carcinoma (NPC). (A) Proptosis of right eye with ophthalmopeglia and bilateral massively enlarged neck lymph nodes. (B) Right proptosis with right facial nerve palsy. (C) Right hypoglossal nerve palsy with atropy and fibrillation of right tongue. (D) Enlarged neck lymph nodes and left axillary lymph node. Source: From Digby, K., Thomas, G. H., & Tse, H. S. (1930). Notes on carcinoma of the nasopharynx. The Caduceus, 9, 45–68.

Despite the rarity of NPC in the West, it received attention from the media and medical community when the famous baseball player Babe Ruth suffered from the disease and received an early form of radiotherapy and chemotherapy in 1946 and 1947 (Bikhazi, Kramer, Spiegel, & Singer, 1998). Babe Ruth’s disease was initially controlled with teropterin, a folic acid analog, which resulted in regression of the cancer. The cancer ultimately became nonresponsive to teropterin and Babe Ruth succumbed to the disease. Teropterin later was developed into amethopterin, now known as methotrexate. Babe Ruth’s treatment was one of the earliest uses of chemotherapeutic agents in a solid organ cancer.

Geographical distribution and familial clustering

NPC is a peculiar cancer that has a ten-fold difference in incidence in endemic areas versus nonendemic areas. As mentioned above, Western physicians working in South China in the early 20th century noted the remarkably high incidence of NPC among the local population in South China, especially in Guangdong province. By 1950–60, the disparity in the incidence of the disease worldwide was well recognized. Increased incidence of the disease was noted in the overseas Chinese communities both in South East Asia and the West. Hayes Martin from Memorial Sloan Kettering Hospital in New York City described his case series of 358 cases of NPC and noted a disproportionally high percentage (10%, 37 patients) of Chinese individuals suffering from the disease (Martin & Quan, 1951). The stark difference in the incidence among the local population and the immigrant Chinese population had already led to a speculation on the genetic basis of the disease. Fig. 1.2 shows the difference in incidence of the cancer among different countries in 2012.

Figure 1.2 Worldwide incidence of nasopharyngeal carcinoma, age-adjusted, both sexes, in 2012. Source: Adapted from Ferlay, J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, … Bray, F. (2013). GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon: International Agency for Research on Cancer. <http://gco.iarc.fr/today/home> Accessed 16.04.18.

The disease has the highest incidence in Southern China, whereas in Northern China the incidence is lower and comparable to that of the West. Even within Guangdong province, the area with highest incidence in China, there was a difference in the incidence among population groups speaking different dialects. The population that spoke Cantonese had a higher incidence compared with the population that spoke Hakka. Further, among the Cantonese speaking population, fisherman that lived in boats had a two-fold increased risk compared to the population living on land (Li, Yu, & Henderson, 1985). Here both genetic and environmental factors cause the disparity in the incidence. Compared to the land living counterparts, Cantonese fishermen consumed large amounts of preserved salted fish, which has been shown to increase the risk of developing NPC.

In areas of the West with high incidence of NPC like New York City and San Francisco, invariably there are high concentrations of immigrants from China, mostly from arriving from Guangdong province since the late- 19th century. Other areas in South East Asia like Singapore, Malaysia, Thailand, and Indonesia also have significant numbers of Chinese immigrants and relatively high incidence of the disease.

Apart from the high incidence in Southern Chinese communities, indigenous populations from Malaysia and Indonesia also have moderate incidence of NPC, though not as high as Southern Chinese. Another population with moderate incidence are people of Middle East and North African origin. Inuit people residing in the Artic circle of North America and Greenland also have moderate incidence of the disease (Torre et al., 2015). On the other hand, Northern Chinese, Koreans, and Japanese populations have a low incidence of the disease similar to the incidence in Caucasians (Forman et al., 2014).

Apart from the wide difference in incidence among different population, the phenomenon of familial clustering of NPC has long been observed in both high incidence and low incidence populations (Albeck et al., 1993; Gajwani, Devereaux, & Beg, 1980; Jia et al., 2004). The cause of familial clustering can be inheritance of a susceptibility gene or common exposure to the environmental carcinogen in the family. A complex segregation analysis done in Southern China on more than 1900 Cantonese patients showed that the inheritance was multifactorial and no single gene was responsible for susceptibility to the cancer (Jia et al., 2005).

With the presence of familial clustering, family members of NPC patients have increased risk of developing the disease. The risk was estimated to be increased 4–10 fold in individuals with a first degree relative suffering from the disease (Chang & Adami, 2006). Therefore it is logical to offer screening to family members of NPC patients. A study in Hong Kong showed that compared with symptomatic patients, NPC patients detected by the familial screening program were both younger and suffering from earlier stages of the disease (Ng et al., 2009).

Association with Epstein–Barr virus

NPC is one of the first cancers found to be associated with a viral infection, the EBV. It is the first head and neck cancer found to have a virus as a causative agent. As NPC is a relatively rare disease in the West, the implication of a virus associated cancer was less studied until the discovery of another virus associated cancer four decades later, the human papilloma virus associated with oropharyngeal cancer. Old et al first identified the presence of antibodies against an antigen in Burkitt’s lymphoma cell line in sera from patients suffering from NPC in 1966 (Old et al., 1966). The antigen was later identified as the EBV, a virus belonging to the family of herpes viruses. Later, it was confirmed that patients suffering from NPC had elevated EBV antibodies, especially anti-EBV IgA antibodies (de Schryver et al., 1969; Henle et al., 1970). The anti-EBV IgA antibodies have since been used as a tumor marker for NPC for more than four decades.

By the turn of the 21st century, improvement in molecular biology technologies allowed detection of the DNA of EBV in both NPC cells and the plasma of NPC patients. Lo et al. first developed the use of plasma EBV DNA titers as a screening tool for NPC (Lo et al., 1999) and a recent large-scale population study has shown that plasma EBV DNA titer is a sensitive and specific tool for screening high risk population for NPC. The test is able to detect asymptomatic individuals and diagnose patients in earlier stages of disease (Chan et al., 2017). Moreover, the use of the plasma EBV DNA titer is not just limited to screening. The plasma EBV DNA titer can be used as an assessment of tumor load (Mäkitie et al., 2004), a prognostic marker (Lo et al., 2000), for monitoring therapeutic response (Ngan et al., 2001), and for detection of recurrence (Lo et al., 1999). NPC is the first head and neck cancer to have such a unique and versatile biomarker for clinical use. These applications will be further discussed in subsequent chapters of this book.

Improvement in treatment outcomes in the last five decades

NPC is one of the few head and neck cancers that have shown dramatic reductions in death rates in the last half century. In 1983, the age adjusted mortality from NPC was 9.8 per 100,000 individuals in Hong Kong, but by 2015 the age adjusted mortality rate had reduce to 2.8 per 100,000 (Fig. 1.3). This nearly fourfold reduction of morality, which could not be attributed to the 30% reduction in incidence of the disease in the last three decades. More importantly, the main contributing factor in the dramatic increase in cure rate is the improvement in modern radiotherapy techniques, primarily the introduction of intensity modulated radiotherapy (IMRT), and application of adjuvant treatment modalities like chemotherapy.

Figure 1.3 Age standardized death rate from nasopharyngeal carcinoma in Hong Kong, both sexes, 1983–2015. Source: Data from Hong Kong Cancer Registry, Hospital Authority of Hong Kong.

The nasopharynx is situated in the center of the skull, adjacent to critical structures like the optic nerves and brain stem (Fig. 1.4). The dose limits of these critical structures are less than 60 Gy, while over 66 Gy of radiation would be required to successfully control the tumor. With older two dimensional radiation techniques, many times it would be very difficult, if not impossible, to cover the tumor with adequate radiation dosage without imparting significant toxicities to the adjacent critical structures. With the introduction of new radiation machines like IMRT and tomotherapy machines around the turn of the 21st century, radiation oncologists could deliver adequate radiation dosage to cover the whole tumor while sparing the adjacent critical structures from high levels of radiation. This ability dramatically improved control of tumor spreading into the skull base, parapharyngeal space, and muscles of mastication. This improvement in local control is reflected in the new eighth edition of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) cancer staging manual where invasion of tumor to the prevertebral muscles, medial pterygoid, and lateral pterygoid muscles are now staged as T2 instead of T3 as in the previous eighth edition staging system (Lydiatt et al., 2017).

Figure 1.4 From left to right, axial, coronal, and sagittal CT scan of the head with arrow pointing to a small tumor in the central nasopharynx. Note the nasopharynx is in the center of the skull, far away from the surface of the head in all directions.

By the end of the 20th century, it was recognized that addition of chemotherapy to radiotherapy would improve local control and possibly reduce distant failure in NPC. The landmark trial of Intergroup 0099 reported by Al-Sarraf et al. in 1998 demonstrated the benefit of concurrent chemotherapy in addition to radiotherapy in improving the progression free survival and overall survival in advanced stage NPC (Al-Sarraf et al., 1998). Since then, multiple trials have confirmed the benefit of concurrent chemoradiotherapy and now concurrent chemoradiotherapy is the standard of care in stage II or above NPC.

While surgery has never played a role in the primary treatment of NPC, since the late 1980s salvage surgery has proven to be an effective and less toxic alternative in the management of small, local, recurrent disease that failed radiotherapy. While there are no large randomized control trials to compare the efficacy of salvage surgery versus second radiation in managing locally recurrent NPC, multiple case series with various surgical techniques have shown that surgery is comparable to second radiation in salvaging the local recurrence (Wei, Chan, Ng, & Ho, 2011; Yu et al., 2005). Second radiation also incurs a significant morbidity due to the large dose of radiation the surrounding normal tissue must receive. Therefore in centers where there is surgical expertise, salvage surgery is routinely performed for locally recurrent NPC.

The techniques of salvage surgery have also improved over the last three decades. While open approaches to the nasopharynx were standard in the 1980s and 1990s, by the first decade of the 21st century improvement in endoscopes and endoscopic instruments allowed selected tumors to be resected with a minimally invasive approach. Endoscopic nasopharyngectomy and its derivative, robotic-assisted nasopharyngectomy (Tsang et al., 2015) has been described in the literature, mainly to salvage smaller local recurrences (Fig. 1.5). Early results showed that these minimally invasive approaches have similar local control when compared with open nasopharyngectomy and second radiation (Ho et al., 2012; You et al., 2015).

Figure 1.5 Photo showing deployment of the new da Vinci SP surgical robot for transoral robotic nasopharyngectomy.

Conclusion

Nasopharyngeal carcinoma is truly a unique cancer in every aspect. It is a model for the study of virus-induced cancer. In the last five decades, ongoing research has steadily improved our understanding of the cancer and our ability to cure it. There are still significant gaps in our understanding of the carcinogenesis and behavior of the cancer. This book aims to present our current understanding in the pathophysiology and management of the cancer and highlight the deficits in our knowledge. Closing these gaps of knowledge will allow us to understand and conquer this cancer and other cancers in the future.

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