Recurrent/Metastatic Nasopharyngeal Carcinoma Treatment from Present to Future: Where Are We and Where Are We Heading?

OPINION STATEMENT: Nasopharyngeal carcinoma (NPC) is distinct in its anatomic location and biology from other epithelial head and neck cancer (HNC). There are 3 WHO subtypes, which considers the presence of Epstein-Barr virus (EBV) and other histopathology features. Despite the survival benefit obtained from modern treatment modalities and techniques specifically in the local and locally advanced setting, a number of patients with this disease will recur and subsequently die of distant metastasis, locoregional relapse, or both. In the recurrent setting, the ideal therapy approach continues to be a topic of discussion and current recommendations are platinum-based combination chemotherapy. Phase III clinical trials which led to the approval of pembrolizumab or nivolumab for head and neck squamous cell carcinoma (HNSCC) specifically excluded NPC. No immune checkpoint inhibitor therapy, to date, has been approved by the FDA to treat NPC although the National Comprehensive Cancer Network (NCCN) recommendations do include use of these agents. Hence, this remains the major challenge for treatment options. Nasopharyngeal carcinoma is challenging as it is really 3 different diseases, and much research is required to determine best options and sequencing of those options. This article is going to address the data to date and discuss ongoing research in EBV + and EBV - inoperable recurrent/metastatic NPC patients.

Medical History, Medication Use, and Risk of Nasopharyngeal Carcinoma.

Because persistent inflammation may render the nasopharyngeal mucosa susceptible to carcinogenesis, chronic ear-nose-throat (ENT) disease and its treatment might influence the risk of nasopharyngeal carcinoma (NPC). Existing evidence is, however, inconclusive and often based on methodologically suboptimal epidemiologic studies. In a population-based case-control study in southern China, we enrolled 2,532 persons with NPC and 2,597 controls, aged 20-74 years, from 2010 to 2014. Odds ratios were estimated for associations between NPC risk and history of ENT and related medications. Any history of chronic ENT disease was associated with a 34% increased risk of NPC. Similarly, use of nasal drops or aspirin was associated with approximately doubled risk of NPC. However, in secondary analyses restricted to chronic ENT diseases and related medication use at least 5 years prior to diagnosis/interview, most results were statistically nonsignificant, except a history of uncured ENT diseases, untreated nasal polyps, and earlier age at first diagnosis of ENT disease and first or most recent aspirin use. Overall, these findings suggest that ENT disease and related medication use are most likely early indications rather than causes of NPC, although the possibility of a modestly increased NPC risk associated with these diseases and related medications cannot be excluded.

[Cancers associated with systemic sclerosis involving anti-RNA polymerase III antibodies]. / Néoplasies associées à une sclérodermie systémique avec anticorps anti-ARN polymérase III.

BACKGROUND: The incidence of cancer is increased in patients with systemic sclerosis (SSc). Further, recent studies have also shown that the presence of anti-RNA polymerase III antibodies is associated with a higher incidence of cancer in this population. PATIENTS AND METHODS: Herein we present the cases of two men aged 56 and 23 years presenting SSc without anti-Scl70 or anti-centromere antibodies but with anti-RNA polymerase III antibodies. Clinical symptoms led us to prescribe more laboratory exams and both patients were diagnosed with cancer of the nasopharyngeal area. DISCUSSION: Anti-RNA polymerase III antibodies are useful for SSc diagnosis in patients without anti-centromere or anti-Scl70 antibodies. Their presence must lead physicians to screen for associated cancer, even in the absence of clinical signs.

Alcohol and tea consumption in relation to the risk of nasopharyngeal carcinoma in Guangdong, China.

To investigate whether alcohol and tea consumption has an etiological association with nasopharyngeal carcinoma (NPC) in a high-incident population, a large scale case-control study was conducted. The study included 2846 individuals in Guangdong Province, China, with 1387 newly diagnosed cases of NPC and 1459 frequency-matched controls. Exposure histories of alcohol and tea consumption were obtained via personal interviews. Information regarding socio-demographic characteristics (age, sex, education, dialect and household type), family history of NPC, Epstein-Barr virus (EBV) infection, dietary habits and other potential confounding factors was also studied. An analysis was performed using unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). The risk of NPC was found to be associated with habitual alcohol consumption and tea consumption. Tea consumption has been associated with a decreased occurrence of NPC (OR = 0.62), while consumption of alcohol was associated with a complex effect. Specifically, moderate consumption of alcohol was associated with decreased risk of NPC, while overuse, especially strong distillate spirits, appeared to be a risk factor.

Epidemiology of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world, with an incidence well under 1 per 100,000 person-years. Exceptions are the Chinese, especially the Cantonese living in the central region of Guangdong Province in Southern China. Other populations with elevated rates include the natives of Southeast Asia, the natives of the Artic region, and the Arabs of North Africa and parts of the Middle East. Intake of preserved foods at an early age has been linked to NPC risk in all population groups with increased NPC rates. Other recognized risk factors for NPC are cigarette smoking, and occupational exposure to formaldehyde and wood dust.

Diet and nasopharyngeal cancer in a low-risk population.

Asian studies have reported that risk of nasopharyngeal cancer (NPC) is increased in individuals who frequently consume salted fish, which contains high levels of N-nitroso compounds. As part of a collaborative, population-based, case-control study in the U.S., where the annual incidence of the disease is low, we investigated whether dietary intake of preformed nitrosamines or nitrosamine precursors, or of antioxidants including vitamin C and carotenoids, was associated with altered risk of NPC overall, or of specific histologic subtypes of disease. Cases (n = 133) identified at 5 population-based cancer registries and controls (n = 212) identified through random digit dialing completed a telephone interview and self-administered food frequency questionnaire. Dietary exposures were expressed as quartiles of intake, and odds ratios (ORs) calculated using the lowest quartile of intake as the reference category. Risk of non-keratinizing and undifferentiated tumors of the nasopharynx was increased in frequent consumers of preserved meats, which contain high levels of added nitrites. ORs in the 2nd, 3rd and highest quartile were 1.99, 4.35 and 4.59, although 95% confidence intervals did not exclude 1.0. Risk of differentiated squamous cell carcinoma, but not other histologic types, was significantly reduced in individuals with vitamin C intake above the lowest quartile (ORs 0.30, 0.33 and 0.30 in the 2nd, 3rd and highest quartiles, respectively). This association was markedly stronger among non-smokers and former smokers than among current smokers. Finally, individuals who reported consuming supplemental vitamins were at an approximately 50% reduced risk of NPC. Our results indicate that future studies should consider the effects of dietary risk factors on the risk of specific histologic subsets of NPC, and not assume that the disease is etiologically homogeneous.

Environmental and dietary risk factors for nasopharyngeal carcinoma: a case-control study in Zangwu County, Guangxi, China.

A case-control study was conducted on 88 incident cases of histologically confirmed undifferentiated nasopharyngeal carcinoma (NPC) in Zangwu County, China, and 176 age- sex- and neighbourhood-matched controls. The design of this study was defined after an anthropological survey on living habits in regions of high NPC incidence and the evidence of carcinogenic substances in some commonly consumed preserved foods. Subjects were interviewed regarding living conditions and diet in the year preceding the diagnosis of NPC and, with the help of their families, during childhood and weaning. After adjustment for a living conditions score to eliminate a confounding effect, an increased risk associated with consumption of salted fish during weaning and childhood was confirmed, especially for salted fish in rice porridge. The consumption of leafy vegetables was associated with a reduced risk for NPC, and consumption of melon seeds between 2 and 10 years of age with an increased risk. After multivariate analysis and adjustment according to the living conditions score, the consumption of salted fish in rice porridge before age 2 (OR = 3.8, P = 0.005), exposure to domestic woodfire (OR = 5.4, P = 0.01) and consumption of herbal tea (OR = 4.2, P = 0.02) were found to be independently related to the risk of NPC. The excess risk associated with the use of domestic wood fire increased if there were no windows in the house and with poor ventilation and cooking outside the house in a shack. As well as confirming the importance of the consumption of salted fish in childhood, this study has been the first to provide unequivocal evidence for two other factors implicated in increasing the risk of NPC in China, the adult consumption of traditional medicines (herbal tea) and exposure to domestic wood fumes.

Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: results from a case-control study.

In a case-control study of NPC conducted in the Philippines, 104 predominantly non-Chinese (< 10% ethnically Chinese) cases of nasopharyngeal carcinoma (NPC) and 205 hospital and community controls were recruited. Risk factor information was obtained through personal interview. The occupational history of each subject was reviewed "blind" by an industrial hygienist to determine estimates of exposure to formaldehyde, solvents, dusts, exhaust and pesticides. After control for confounding, subjects who were first exposed to formaldehyde 25 or more years prior to diagnosis/interview or wo were first exposed before the age of 25 were found, in relation to those never exposed, to be at a 4.0-fold excess risk of disease. Similarly, those first exposed to dust and/or exhaust 35 or more years prior to diagnosis/interview were at a 4.4-fold excess risk of disease and those first exposed before the age of 20 were at a 3.5-fold excess risk of disease. Salted fish consumption was not associated with risk, while consumption of processed meats protected against NPC. Smoking was positively associated with NPC, but only when cases were compared to community controls. Relative to non-smokers, subjects reporting more than 30 years of smoking were at an adjusted 7.2-fold excess risk of disease. Herbal medicine use and burning of anti-mosquito coils were both independently associated with risk of NPC, with ever-users of herbal medicines being at a 2.5-fold excess risk of disease and those reporting daily use of anti-mosquito coils being at a 5.9-fold excess risk of disease relative to never users. Exposure to solvents, pesticides, or use of betel nuts were not associated with NPC risk.

Herbal medicine use, Epstein-Barr virus, and risk of nasopharyngeal carcinoma.

Herbal medicine use is thought to be linked to nasopharyngeal carcinoma (NPC) either through its ability to reactivate the Epstein-Barr virus (EBV) or through a direct promoting effect on EBV-transformed cells. To investigate this, 104 histologically confirmed NPC cases and 205 matched controls were studied in The Philippines. Blood was collected to assess antibody titers against EBV, and an interview was administered which elicited information concerning herbal medicine use and other risk factors for NPC. Subjects strongly positive for anti-EBV antibodies (Epstein-Barr nuclear antigen [EBNA]) (titers greater than or equal to 1:80) were at a 21-fold excess risk of disease (95% confidence interval, 8.4, 51.8). Herbal medicine use was also associated with NPC (relative risk, 2.5; 95% confidence interval, 1.4, 4.5). Associations persisted after adjustment for education, smoking, Chinese ancestry, and consumption of salted fish. Exposure to herbal medicines among subjects testing negative/weakly positive for anti-EBNA antibodies was not associated with an elevation in risk (relative risk, 0.6), strong positivity to anti-EBNA antibodies in the absence of herbal medicine use was associated with a significant 16-fold excess risk of disease, and exposure to herbal medicines among subjects testing strongly positive for anti-EBNA antibodies was associated with a significant 49-fold excess risk of NPC when cases were compared to controls. Similar results were obtained when other serological measures of EBV exposure were used. Anti-EBV antibody titers were elevated in herbal medicine users compared to nonusers among cases but not among control subjects. This suggests that, if herbal medicines interact with EBV in the development of NPC, they do not do so by reactivating EBV infection but rather through a direct proliferative effect on EBV-transformed cells. Although the interaction between EBV and herbal medicines is biologically plausible, larger, more detailed studies need to be conducted to validate this preliminary finding.

Risk factors for nasopharyngeal carcinoma.

In an effort to assess the relative importance of various risk factors of nasopharyngeal carcinoma (NPC), which includes antibodies to Epstein-Barr virus capsid antigen (anti-VCA) and early antigen (anti-EA) as well as other environmental factors, a multivariate logistic regression method was applied to analyze previously collected data from an epidemiologic study on 343 cases with NPC and 1017 neighborhood controls. Anti-VCA and anti-EA titers were found significantly associated with NPC. The relative risk increased with the increase of antibody titers. Individuals who smoked 30 or more cigarettes per day had more than 3.4 times higher risk than those who never smoked, while no increase in the risk was observed for those smoking less than 20 cigarettes per day and ex-smokers. Use of herb drugs, working under poor ventilation and nativity were also found to increase the NPC risk. In cases other than smoking 20 or more cigarettes per day and the frequent use of herb drugs, the synergistic interaction was not observed. In addition, male NPC individuals and Mainland Chinese were found to have relatively lower antibody titers as compared with female individuals or native Taiwanese.

Epstein-Barr virus early antigen induction in Raji cells by Chinese medicinal herbs.

Ether extracts of 495 Chinese medicinal herbs from 106 families were studied for Epstein-Barr virus (EBV) early antigen (EA) induction in the Raji cell system. 15 herbs from 10 families were found to have inducing activity. Water extracts of the same herbs also had inducing activity, but it was not as strong. The significance of these herbs in the activation of EBV in vivo and their relation to the development of nasopharyngeal carcinoma are discussed. No EA-inducing activity was found in 73 samples of 14 different foods tested.

[Dietary behavior, way of life, and nasopharyngeal cancer]. / Comportement alimentaire, modes de vie et cancer du rhinopharynx.

Nasopharyngeal carcinoma is prevalent in Southeast Asia, Maghreb countries and Greenland/Alaska. This cancer, wherever prevalent, is closely associated to the Epstein-Barr virus (EBV), but its geographical repartition also suggests the possibility of a cultural factor. A comparison of food habits and way of life of Cantonese, Maghreb populations and Eskimos shows certain common points: dried fish or meat, fermented and sometimes rotten, as well as salt preserved vegetables. Certain berries of Euphorbiaceae are eaten by children and the plant itself is used in traditional medicine. These Euphorbiacea contain cancer promoting agents, able to reactivate the EBV latency. The hypothesis proposed here is that cancerous effects common to the different regions at high risk for nasopharyngeal carcinoma exists and that they either act separately or reactivate the EBV latency.

Interaction of factors associated with cancer of the nasopharynx.

A retrospective study of nasopharyngeal carcinoma (NPC) revealed that smoking, working under poor ventilation, use of nasal balms or oil for nasal and throat troubles, use of herbal drugs, and anti-EBV antibody titer were found statistically associated. The dural interactions of these factors to the risk of NPC were presented. Except in work conditions with poor ventilation and when herbal drugs are used, all the combinations were synergistic. The synergistic actions were especially remarkable with smoking and other factors. The possible etiological mechanisms of NPC are discussed.

Environmental backgrounds of young Chinese nasopharyngeal carcinoma patients.

Twenty-four Chinese NPC patients under 25 years of age at the time of diagnosis were interviewed. The interviews were carried out in the presence of their families in 22 cases and concentrated on the environmental background of the subject's infancy and early childhood. An analysis of the results eliminated household inhalants, aerial contaminants, medicines, food therapy, spices, fresh foods and soya sauce as likely factors in carcinogenesis. The only remaining foods eaten by all subjects and worthy of consideration were laap cheung, salted fish and tau si. Salted fish was the most commonly eaten and the only one fed to babies. In childhood, the subjects had rarely or never been fed vegetables or fruits. Most had, since childhood, been characteristically sickly, inactive, withdrawn and choosy about their food. It would appear that consumption of salted fish and vitamin C-deficiency in early childhood are important environmental factors and that a certain personality type may be associated with an increased risk.

Etiological factors in nasopharyngeal carcinoma: a hospital-based, retrospective, case-control, questionnaire study.

A total of 379 Singapore Chinese patients with NPC were interviewed by use of a questionnaire covering the following items: occupation, level of education, language medium of education, personal and family history of nasal illnesses, types of medicines used, use of Chinese medicines for the nose and throat, use of soya sauce, Chinese tea, cooling drinks and alcohol, cigarette smoking (number and duration), cooking fuels and use of incense (frequency and duration) and of anti-mosquito coils. The same questionnaire was given to two groups of controls: 595 patients with diseases of the ear, nose and throat other than NPC and 1 044 patients with diseases other than cancer or otorhinolaryngeal disease. NPC patients differed significantly from both groups of controls in that they showed stronger associations with personal history of nasal illnesses, family history of nasal illnesses, use of Chinese medicines for the nose and throat and exposure to smoke from anti-mosquito coils.