Cancer prevention and control: alarming challenges in China

China is geographically the third largest country in the world and the most populated low-to-middle-income country. Cancer incidence and mortality rates for some cancers in the USA and European countries have steadily decreased over the last decades, whereas the incidence and mortality of certain cancers in China have been increasing at an alarming speed. Rapid industrialization and urbanization in China have been accompanied by incredible changes in lifestyle and environment combined with an aging population. Mortality caused by lung, colorectal and breast cancers has been steadily increasing, whereas cancer mortality from gastric, esophageal and cervical tumors has tended to decrease. Similar to what has occurred in the United States, unhealthy lifestyles in China, including heavy smoking and poor diet combined with pollution, have contributed to increased cancer risk. China is facing many challenges in cancer treatment and prevention for the general population. The major areas that need to be addressed in the control of cancer in China include cancers associated with environmental pollution, tobacco use, occupational carcinogens, infection, excessive alcohol consumption, dietary deficiencies and obesity. In this perspective, we review the problems in each area and suggest ideas for future directions in cancer research and strategies and actions to reduce the incidence of cancer in China.


INTRODUCTION
Geographically, China is the third largest country in the world and the most populated lowto-middle-income country, with more than 1.36 billion people [1]. Cancer incidence and mortality rates for some cancers in the USA and European countries have steadily decreased over the last decades, whereas the incidence and mortality of certain cancers in China have been increasing at an alarming speed. Rapid industrialization and urbanization in China have been accompanied by incredible changes in lifestyle and environment. These changes, are critically important for cancer control in China. However, addressing environmental pollution and tobacco use are probably the two most urgent priorities because they have widespread influence on health. Next, the infection-related cancers are important because in China, about one fourth to one third of all cancers are associated with infection. Vaccines are effective treatment and prevention measures and are available and approved for use in other countries but not in China. In this perspective, we review the problems in each area and suggest ideas for future directions in cancer research and strategies and actions to reduce the incidence of cancer in China.

ENVIRONMENTAL POLLUTION
Some experts believe that by pursuing economic growth above all else, China is sacrificing the health of its people, ultimately risking future prosperity. Environmental pollution includes outdoor and indoor air pollution, water pollution, and food contamination. No doubt exists that the rapid economic development and dense population in China have increased air and water pollution at an alarming rate and this brutal deterioration of the environment has severely affected human health, and is one of the major sources of morbidity and mortality [5,[8][9][10][11][12].
Air pollution is recognized as an important etiological factor in cancer and other diseases [13][14][15][16][17][18]. The predominant human-associated causes of air pollution in China include transportation, power generation, industry, biomass burning, and domestic heating and cooking [19]. Particulate matter (PM) is the term for particles found in the air, including dust, dirt, soot, smoke, and liquid droplets (EPA.com). Particles less than 2.5 µm in diameter (PM 2.5 ) are referred to as 'fine' particles and are believed to pose the greatest human health risks. Because of their small size, fine particles are able to lodge deeply into the lungs. Sources of fine particles include all types of combustion activities such as motor vehicle emissions, power plant and industrial activities, and wood and coal burning. PM 2.5 is being used more and more as an indication of pollution and, alarmingly, many areas of the world exceed the air quality guidelines for PM 2.5 [20]. Epidemiologic results indicate that longterm exposure to PM 2.5 increases mortality rates in the general population [21] and contributes to lung cancer incidence [22][23][24].
The Ministry of Environmental Protection recently admitted the existence of toxic 'cancer villages' (Aizheng Cun) in China caused by or at least linked to uncontrolled environmental pollution. The existence of these 'cancer villages' (i.e. cancer clusters) provides significant evidence linking environmental carcinogens and cancer incidence. The term 'cancer village' refers to towns or villages where cancer incidence and mortality are higher than what would be expected in people in a particular area or region and are causally associated with environmental pollution [25].
The Chinese Center for Disease Control and Prevention indicates that coal burning causes most of the soot emission that blocks the sun in Chinese cities like Beijing or Shanghai. In addition, high levels of sulfur dioxide cause acid rain and smog, and nitrogen oxide emission results in production of surface ozone. Coal burning also produces carcinogens and mercury and coal ash. Coal ash is China's number one source of solid industrial waste and contains radioactive material and heavy metals, such as arsenic, lead, mercury, and chromium.
In addition to industrial pollution, biomass fuel and coal are burned for cooking and heating using open indoor fires or traditional stoves in almost all rural and many urban households [10], leading to air pollution levels well in excess of what is acceptable. Notably, Chinese women have a substantially higher lung cancer rate compared to women in other countries, despite the fact that they are mostly nonsmokers [13,[26][27][28]. A recent report indicated that exposure to coal fumes due to poor kitchen ventilation increases the risk of lung cancer and the risk increases with length of exposure [29]. Burning coal indoors in unventilated stoves increases PM [30] and toxic byproducts such as polycyclic aromatic hydrocarbons, and heterocyclic aromatic compounds [31] resulting in an elevated risk of lung cancer [32,33].
Besides air pollution, the quality of water has severely deteriorated in many of China's rivers and lakes [34] due to massive discharges of industrial and domestic waste water, solid waste disposal, and extensive fertilizer and pesticide use. Additionally, contamination of food with harmful chemicals or biological agents is an important health problem in China [35,36]. A common contaminant has been aflatoxin, a toxic byproduct of certain fungi, which has been associated with increased risk for liver cancer [37,38] and nasopharyngeal carcinoma [39,40]. Furthermore, arsenic appears to be present in many types of seafood [41] and arsenic in seafood has been reported to be a health risk for consumers because its consumption is associated with an increased cancer risk [42].

Proposed actions
Environmental protection, in cooperation with continued industrialization and economic growth, must become a priority of government, or China will become a nation of unhealthy and weak people.
Protection of the environment needs to be more dependent on legal means instead of administrative measures to deal with environmental violations. Industries should be required to pay substantial fines for violations in order to discourage noncompliance with laws designed to protect the environment. For example, unauthorized dumping of wastewater should be heavily fined. Any newly established industrial or power plants must be required to be equipped with pollution-control facilities and those facilities must be used. China's development and environmental policies must be implemented in both rural and urban areas because they now mostly favor urban areas [43,44].
China must invest in the cleaning up of the many lakes and reservoirs that are currently too polluted for safe drinking, and provide all Chinese people with access to clean running water. China must work toward a more efficient use of natural resources to reduce the generation of waste products.
China must develop and enforce national standards for food safety, including banning illegal food additives [35] and enforcing the clear labeling of all food products. Regulated inspection of food during all phases of production is needed to ensure safety for consumers. Due to past reports of food contamination or adulteration [35,45,46], regulations providing for the careful and thorough inspection of food to detect and eliminate toxic compounds must be considered imperative. All Chinese food processing plants must be regulated and adhere to food safety standards. Alternative and safe sources of energy and modern ventilated stoves need to be made available to rural households to decrease the use of coal for cooking and heating [47].

Research
Research studies must be conducted to determine and confirm that reduction in pollution has resulted in reductions in chronic illnesses and cancer and decreased mortality, especially children. Extensive scientific research studies must be conducted to obtain accurate data documenting the incidence, geographical distribution, and mortality rates of cancer in order to establish efficient and effective policies for cancer control in China.

TOBACCO USE AND CONTROL IN CHINA
Over 1.3 billion people worldwide use some form of tobacco [48]. China's toxic air pollution levels are likely to be a major contributor to the increased lung cancer rates; however, most lung cancers in China are still attributable to cigarette smoking. China produces (42%) and consumes (~350 million smokers) the most tobacco globally. The China National Tobacco Corporation is the largest producer of tobacco products in the world. In 2013, 45.3% of Chinese men and 2.1% of the Chinese women were reported to be smokers compared to 17.2% of American men and 14.2% of American women (http:// canceratlas.cancer.org/data/#?view=map). At least 70% of Chinese are exposed to secondary smoke indoors. Tobacco is estimated to cause over 1.2 million deaths each year in China or about 3000 deaths each day producing a huge economic burden that has quadrupled over the last 8-10 years [49]. Apparently smoking is a social custom in China and giving cigarettes as a gift or at social interaction has been a sign of respect and friendliness. In 2009, the Chinese Ministry of Health completely banned smoking in all health administrative offices and medical facilities by 2011. Findings from a national study [50] suggested that tobacco smoking is responsible for 32.7% of all cancer deaths in Chinese men and 5% of cancer deaths in Chinese women. Although the prevalence of smoking in China will likely decrease based on the results of two (1996 and 2002) national smoking surveys, some experts believe that the burden of tobacco-related cancer will still continue to increase [50].

Actions
Enforce smoke-free law-no smoking in any public area including schools, the work place, and public transportation vehicles. Increase excise taxes on tobacco production and use.
Eliminate provocative advertising and replace with advertisements and graphic illustrations regarding the harms of smoking, emphasizing the relevance to individuals. Prohibit tobacco companies from sponsoring international events or sponsorships on radio, television, and other media. Provide education focusing on accurate awareness of the harms of smoking and secondhand smoke and ban tobacco promotion through any event sponsorship, outdoor displays, or entertainment media. Place explicit photos and health warnings on packs of cigarettes emphasizing the unattractiveness and disfiguring aspects of tobacco use. Use mass media and social media emphasizing the unattractiveness and disfiguring aspects of tobacco use to reach smokers in all socioeconomic groups.
Provide and encourage the use of inexpensive but effective medications for smoking cessation. Encourage behavioral interventions such as self-help counseling or face-to-face counseling to support quitting. Banning tobacco vending machines is also important as is establishing programs and initiatives to encourage tobacco control and increasing the budget for nationwide tobacco control.

Research
Research studies are needed that will provide data to support and confirm the dangers of smoking and the health benefits of tobacco cessation. Population-based behavior studies are also needed. Studies to examine the harmful effects of passive or secondary smoke exposure should be conducted. Scientific research studies confirming the effectiveness of cancer prevention through tobacco cessation should be performed in China. Studies are needed too to determine whether tobacco control could reduce the diabetes-pre-diabetes epidemic.

OCCUPATIONAL CARCINOGENS
Many Chinese are exposed to carcinogens in a variety of occupations. Cancers of the bladder, nasal cavity and larynx, skin, mesothelioma, and liver cancer are all associated with occupational exposure to carcinogens [51]. Other examples of cancers that have been linked to specific exposures include brain cancer (non-ionizing radiation), leukemia (exposure to 1,3-butadiene), lung cancer (air pollution), and prostate cancer (exposure to pesticides and polyaromatic hydrocarbons) [14]. WHO estimates that 19% of all cancers worldwide are attributable to exposure to environmental carcinogens.
Occupational exposure limits (OELs) are well established in many countries and they serve as benchmarks of industrial cleanliness practices at workplaces worldwide. In 2002, China passed a law, referred to as the Occupational Diseases Prevention and Control Act of the People's Republic of China (ODPCAct) and also developed an official document that contains a comprehensive list of new and amended OELs [52]. Some of the most common occupational carcinogens include formaldehyde, silica, lead, and benzene. Formaldehyde is classified as a human carcinogen with an unknown mechanism of action. One group reported that formaldehyde-exposed workers exhibited decreased counts of natural killer cells, regulatory T cells, and CD8(+) effector memory T cells [53]. Crystalline silica is another compound classified as a human carcinogen, but few studies have provided quantitative data on silica exposure and/or smoking. A recent study confirmed silica as a human carcinogen and suggested that current exposure limits in many countries might be too high to protect workers from lung cancer. Notably, this group reported that smoking cessation could help reduce lung cancer risk for silica-exposed individuals [54]. Asbestos is a type of silicate mineral and long-term inhalation of asbestos fibers can cause lung cancer and mesothelioma. Notably

Actions
Obviously, the laws and OELs must be enforced and industries in violation should be fined heavily to encourage compliance. Some sort of monitoring system to detect levels of formaldehyde, silica, lead, benzene, and other occupational carcinogens needs to be established and managed efficiently. Exposure to all occupational carcinogens must be eliminated.

Research
More extensive studies on the effects and mechanism of action for formaldehyde, silica, lead, benzene, and other occupational carcinogens need to be conducted. More studies are needed that examine the levels of toxic occupational carcinogens in different industries and regions of China.

INFECTION-CAUSED CANCERS
Infections with viruses, bacteria, and/or macroparasites are clearly strong risk factors for developing cancer. The most common infections include HBV and HCV, H. pylori, HPV, and Epstein-Barr virus, which are estimated to be causative factors in gastric, liver, cervical, and nasopharyngeal cancers.

Helicobacter pylori
Helicobacter pylori is a type of bacteria that is an important etiological factor in stomach cancer, and more than 50% of the world's population may be infected. Infection with H. pylori is known to contribute to gastric carcinogenesis [55]. In an initial study, Ma et al. demonstrated that H. pylori infection is acquired during early childhood through transmission from parents to children [56]. Anti-H. pylori drugs or eradication of H. pylori has been shown to reduce gastric cancer [57][58][59][60]. A number of treatments have been tested for H. pylori therapy in randomized controlled trials [61][62][63][64][65]. The regimen most commonly recommended for first line treatment of H. pylori is triple therapy with a proton pump inhibitor, and the antibiotics, amoxicillin, and clarithromycin.

HBV and HCV
Hepatitis B and C are infectious diseases that are caused by HBV or HCV, respectively. These viruses primarily cause inflammation of the liver. Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is the second leading cause of cancer death in China [66]. HCC is strongly associated with HBV or HCV infection [67]. However, vaccination against HBV can lower HBV infection [68,69] and presumably the risk of liver cancer. According to a cluster randomized controlled trial of neonatal HBV vaccination which was conducted between 1983 and 1990 in Qidong County (Jiangsu, China), it is noted that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults [70].

HPV
HPV infection is an important risk factor for cervical cancer, a major cancer in China [71]. HPV testing has been shown to be highly effective for cervical cancer prevention in many countries [72]. However, although vaccines against HPV are commonly used in many countries, they do not appear to be available in China at this time, but are undergoing clinical trials in China for future use. If mass vaccination were to be implemented, based on an estimate of $100/person (cost in US dollars), it is predicted that if 100 million women receive the HPV vaccination in China, the cost will be $10 billion (cost in US dollars).

EBV
In 1964, Michael Anthony Epstein, Yvonne Barr, and Bert Achong published a paper in The Lancet [73], describing a newly discovered virus that was the first virus later to be shown to cause cancer in humans. The virus was named the Epstein-Barr virus (EBV) and most commonly causes Burkitt's lymphoma and other B-cell lymphomas, nasopharyngeal carcinoma, and some gastric cancers. Nasopharyngeal carcinoma (NPC) is the most prevalent tumor in southern China and Southeast Asia. Epidemiological studies suggest that NPC is associated with latent EBV infection, genetic susceptibility, early-age exposure to environmental carcinogens [74], and maybe nitrosamines [75]. Tobacco smoke may activate EBV [76]. Unfortunately, even though EBV is the first human tumor virus identified, no specific treatment or vaccine is yet available to prevent or treat EBV infection although efforts are underway to develop an EBV preventive vaccine [77].

Actions
Large-scale programs must be established to identify people with infectious pathogens (H. pylori, HBV, HCV, HPV, and EBV) and provide treatment/vaccination to eradicate these viruses. Treatment and vaccination rates for patients, especially in the broad rural areas of China, need to be increased. Because H. pylori is so widespread, China should also consider running large national trials focusing on the proven triple therapy to eradicate this infectious bacteria.
China must consider investing considerable resources to fund research and vaccine and drug development for prevention of infectious liver and stomach diseases. Programs need to be established to increase awareness of the harmfulness of liver diseases. Infections associated with cancer development must be controlled perhaps by substantial investment in training new doctors and nurses and enhancing or establishing new collaborations worldwide.
Screening for HPV infection is known to be an effective approach for cervical cancer prevention. China needs to move forward in providing an HPV vaccine. Programs must be established to efficiently and effectively screen and vaccinate every Chinese citizen against HPV infection to prevent cervical cancer and against HBV and HCV to prevent liver disease. This will require extensive collaboration between public and reproductive health professionals, health educators, physicians, and disease control entities.
Chinese scientists and their collaborators must continue to work on developing a vaccine to prevent EBV-induced cancers.

Scientific clinical research is needed to determine if H. pylori vaccination and eradication
can reduce the risk of gastric cancer, especially in rural areas. Research studies are needed to predict individual susceptibility to the various infectious diseases. Basic and applied hepatology research needs to be increased. Because no vaccine is yet available for preventing EBV, early detection by screening for EBV by EBV DNA copy number [78] or detecting elevated antibodies against EBV in the lytic phase as predictive markers for NPC risk [79] should be evaluated in populations at high risk.

ALCOHOL AND CANCER
Excessive consumption of alcohol is a primary influence in many non-communicable diseases including liver disease [80] and is an important risk factor for numerous cancers worldwide [81]. Alcohol consumption in China has increased considerably over the last 30 years [82][83][84]. For example, the average annual consumption rose from 2.5 L of pure alcohol in 1978, to 4.4 L in 2005, to 5.9 L in 2006, and to 6.7 L in 2010. Liver cancer is the primary alcohol-related cancer, comprising over 60% of all alcohol-related cancer deaths [85]. In 2005, alcohol consumption was responsible for 4.4% of all cancer deaths in China, most being men [85]. Li et al. examined a combination of case-control and cohort studies and reported that alcohol consumption was associated with an increased risk of esophageal and gastric cancers but not lung cancer [86]. Evidence suggests that alcohol may have different effects on different ethnic groups and the association between alcohol consumption and cancer in the Chinese has been examined [86][87][88][89][90][91]. Notably, abstaining from alcohol has been shown to decrease cancer risk [92].

Actions
Programs need to be established focusing on education to increase awareness of the harmful effects of alcohol. Programs such as alcoholics anonymous should be established. A need exists for more policies and public health programs aimed at reducing alcohol-related illnesses. Easy accessibility to alcohol should be limited. Alcohol advertisement should be monitored by including the dangers of alcohol consumption and taking away the glamour factor. Health programs focused on limiting alcohol intake are probably important for cancer control in China.

Research
Studies need to be conducted on the effects of the amount of drinking, duration of drinking, and frequency of drinking in the Chinese population in different regions. Studies should also be conducted on the health effect of specific types of alcohol and to focus on the interaction of alcohol consumption with other common risk factors, such as tobacco use and lifestyle [86].

DIETARY DEFICIENCIES
Early nutritionists discovered that many diseases could be eliminated by correcting a nutrient deficiency [93]. In the early 1980s, diet was suggested to be responsible for 10%-70% of cancers of the upper digestive tract, esophagus, stomach, large intestine, and breast [94]. Micronutrient insufficiencies were suspected to have a role in esophageal and gastric cancer as suggested by a nutrition assessment in 1980 that was based on blood vitamin levels and nutrient availability calculated from the records of food production [95]. However, the explicit relationship between diet and cancer is still a mystery, because cancer is a multifaceted disease and diet is extremely complex. In addition, large-scale clinical trials in the US and other countries focusing on the effect of diet in cancer prevention have generally been disappointing because they have not provided conclusive positive results [96][97][98][99][100][101][102][103][104]. One possible explanation for these failures might be that subjects were not deficient in the nutrients being studied. Dietary deficiencies might be associated with increased cancer risk and deficiencies are still common in many areas of China. One of the greatest challenges for research scientists is to diminish the continuing accumulation of distortion and half-truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of food or food supplements is not new, but interest in their use has increased dramatically because of perceived health benefits presumably acquired without unpleasant side effects [105]. This is especially true in cancer prevention and treatment. The use of nutritional supplements for cancer prevention is not generally supported by clinical evidence [96]. However, many patients with cancer use supplements in conjunction with traditional cancer treatment, but do not necessarily inform their physicians of their use [106]. Despite their popularity, only limited data are available regarding the safety, efficacy, and effects of long-term use of most supplements in preventing or treating chronic diseases such as cancer [107]. Epidemiologic studies indicate that many people who use dietary supplements assume that these compounds are safe and might be a more natural alternative to conventional medication [108], but no scientific research results have confirmed this assumption. In contrast, the use of aspirin in colon cancer prevention is supported by evidence obtained from observational epidemiology, randomized clinical trials, and large cohort studies in North America and Europe [109][110][111][112][113][114][115]. Evidence indicates that aspirin use for at least 3 years is needed to reduce cancer risk and 5 years or longer is required to decrease cancer mortality. For some individuals, gastrointestinal bleeding is often a serious problem [114], but many believe that the benefits will outweigh the harmful effects [112]. Based on these findings and the inexpensiveness of aspirin, its use for colorectal cancer prevention warrants careful investigation, especially on the issue of gastrointestinal bleeding in the Chinese population.

Actions and research
The nutritional status of different populations in China needs to be studied, and measures to remedy any deficiencies should be developed. Studies need to be conducted to determine the potential benefits of micronutrient supplements in deficient populations.

OBESITY-LACK OF PHYSICAL ACTIVITY
The idea that nutrition is associated with cancer development is not new. As early as 1908 [116], excessive eating and lack of exercise were recognized as pre-disposing factors for cancer, and as early as 1815, excess food consumption was considered dangerous [117]. The rapid economic development and urbanization over the last two to three decades has pushed the Chinese population into a growing state of obesity and overweightness. At least 46 million Chinese adults are obese and another 300 million adults are overweight [118]. In 2010, about 10% of Chinese children were reported to be overweight and another 5% as obese. Obesity is associated with a higher risk of developing cancers, such as colon, esophageal, breast, renal, gallbladder, thyroid, and endometrial [119]. Physical activity has also been associated with a decreased risk of colon cancer and longer survival [120][121][122]. The development of diabetes or pre-diabetes has also increased dramatically in China [123]. Central or abdominal obesity has increased markedly [124] and is believed to be more serious than overall obesity and is associated with diabetes, metabolic syndrome, and nonalcoholic fatty liver disease [125]. Metabolic syndrome and diabetes [126][127][128] have been increasing significantly and are considered to be important health problems in China and, unfortunately, treatment is inadequate [123]. Research studies have reported that diabetes is a risk factor for endometrial, pancreatic, breast, and colorectal cancers [129][130][131][132]. Negative associations were found between smoking and diabetes [123].

Actions and research
The Chinese government should use a proactive approach to nationally promote a healthy lifestyle. Early detection programs should be established for pre-diabetes and diabetes and especially target those high-risk individuals who are already obese, have gestational diabetes, or a family history of diabetes. Programs should be established that provide more awareness, information, and feedback regarding the dangers of smoking, overeating, excessive drinking, and lack of physical activity.
China should work on establishing health care systems that are able to manage and support each citizen's multiple health needs and emphasize good health as a basic human right for all Chinese citizens and perhaps advocate some kind of universal health coverage that works.