Jpn J Clin Oncol 2014;44(Supplement 1)i38 – i42 doi:10.1093/jjco/hyt206
How Do Cancer Researchers Perceive the Future of Cancer in Asia?
Cross-boundary Cancer Studies at the University of Tokyo: Measures to Control Cancer in Japan Tadao Kakizoe Japan Cancer Society President Emeritus, National Cancer Center, Tokyo, Japan For correspondence, please contact Hideyuki Akaza, MD, Department of Strategic Investigation on Comprehensive Cancer Network, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. E-mail: [email protected] Lecture date May 30, 2012
Key words: cross-boundary cancer studies – the University of Tokyo – cancer control – cancer control measures – early detection
LECTURER PROFILE Tadao Kakizoe is a urologic surgeon who formerly directed the National Cancer Center (NCC), as the 11th President for 5 years and before that, served as Director of the hospital for 10 years. Dr Kakizoe devoted himself to reduce the cancer incidence and mortality in Japan. Presently, he is the President of Japan Cancer Society in close collaboration with the national cancer control strategy. Dr Kakizoe was born in 1941 in Osaka. He graduated from the University of Tokyo in 1967 and had been a teaching staff of the Department of Urology of University of Tokyo from 1972 to 1974. He became a staff of the Urology Division, NCC Hospital in 1975, and has been working in the NCC until March 2007. Between 1972 and 1985, while working as a urologist daytimes, he also worked at the Biochemistry Division of the NCC Research Institute in the evenings and weekends, conducting research on bladder carcinogenesis and bladder cancer prevention with Dr Takashi Sugimura, presently Emeritus President of NCC. Dr Kakizoe has done a great deal of work on bladder cancer from both clinical and basic viewpoints. Dr Kakizoe was awarded Tamiya Prize of NCC and Scientific Prize of Princess Takamatsu Cancer Research Fund for his contribution. Dr Kakizoe went to the University of Toronto, Ontario Cancer Institute from July 1977 to June 1978 and experienced organic chemistry looking for new mutagens and carcinogens in the urine of bladder cancer patients. He identified dibutylnitrosamine in the urine of diffuse carcinoma in situ patient. Dr Kakizoe serves as the Emeritus Board Members of the JSCO (Japan Society of Clinical Oncology) and the Japanese Cancer Association. He is also the Members of the Japanese
Committee of the International Union against Cancer, the Board of the US – Japan Cancer Research Collaboration Program and other important Japanese Governmental Committees. From April 2002, he serves as the Editor-in-Chief of the Japanese Journal of Clinical Oncology. He was the president elect for 65th Annual Meeting of Japan Cancer Association Dr Kakizoe has contributed .200 articles and books and chapters to the scientific literature.
MEASURES TO CONTROL CANCER IN JAPAN MORTALITY RATE TRENDS Japan has fought against a number of diseases to date. The first was tuberculosis, which was followed by cerebrovascular disease. It was in 1986 that cancer became the leading cause of death. As Japanese society ages at the highest pace in the world, the number of people who succumb to cancer will continue to increase. Cancer is a global health issue. In Japan .300 000 people die from the disease each year and one in two men and one in three women will experience the disease during their lifetimes. According to 2007 statistics of the World Health Organization (WHO), around the world there were a total of 11 million new cases of cancer and 7.9 million deaths, with 25 million people living with cancer. These numbers will only continue to increase. It used to be the case that cancer was said to be a disease of the developed world; however, as infectious diseases are brought largely under control in the countries of Asia and Africa, cancer will become an extremely significant issue. This is why cancer is now a major global health issue.
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ by guest on June 23, 2015
Received December 12, 2013; accepted December 13, 2013
Jpn J Clin Oncol 2014;44(Supplement 1)
WHAT KIND OF DISEASE IS CANCER? The characteristics of cancer can be broadly divided into the following three categories.
i39
not just as a health issue, but also in terms of an economic challenge. CANCER REQUIRES A LONG PERIOD OF TIME TO EMERGE PROGRESS, MAKING IT A CHRONIC DISEASE
AND
A CELLULAR DISEASE ORIGINATING AND ADVANCING DUE TO GENETIC ABNORMALITIES
EMERGENCE OF CANCER RELATED TO LIFESTYLE HABITS LIVING ENVIRONMENT
AND THE
According to a paper issued in 1981 by epidemiologists Richard Doll and Richard Peto on the causes of cancer, tobacco accounts for 30%, food accounts for 35% and infection by viruses and bacteria accounts for 10%. As can be seen, therefore, lifestyle habits and the living environment were proposed as being responsible for 75% of cancers, with the remainder being attributed to other causes such as exposure to ultra-violet radiation, drugs and lack of exercise, etc. Similarly, a study by Harvard University entitled ‘Causes of Human Cancer’ published in 1996 examined vast amounts of data to calculate estimates for the causes of cancer, and the findings were similar to the 1981 paper by Doll and Peto: tobacco accounted for 30% and food for 30%. Other risk factors for cancer in this study were cited as lack of exercise, exposure to ultra-violet radiation, pharmaceutical drugs, occupational hazards and genes. The term ‘cancer family’ is occasionally used to describe people in the same family who are prone to cancer, and it is said that genes are related to the emergence of cancer in 5% of cases. Economic factors also have an impact on cancer and the International Agency for Research on Cancer refers to ‘poverty as a carcinogen’. In forums such as the WHO, Union for International Cancer Control and the United Nations, cancer is often deliberated,
MEASURES TO CONTROL CANCER IN JAPAN AND AROUND WORLD
THE
MEASURES TO CONTROL CANCER AROUND THE WORLD In developed countries cancer control is based on the following four pillars: (i) prevent what can be prevented, (ii) achieve early detection and early treatment for cancers that can be dealt with through medical examination, (iii) make every effort to treat cancer and (iv) provide palliative care if cancer does not respond to treatment. As a primary prevention method, measures to control tobacco are of the utmost importance.
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The human body is composed of 60 trillion cells. The nucleus of each cell DNA contains, if stretched out the inside DNA strand, would extend to 1.8 m, to which are attached 20 – 30 000 genes. Among these genes .100 are already known to be either cancer genes or cancer-suppressing genes. Cancer is caused when normal cells are overrun by cancer genes or when cancer-suppressing genes are destroyed. It is said that another way cancer is caused is through a combination of the above, where normal cells turn rogue. This demonstrates that cancer is a cellular disease that emerges due to genetic abnormalities. Cancer in Japanese people has been seen to have undergone significant changes over the course of the last 40 – 50 years. Formerly, it was the case that gastric and cervical cancers were the most prevalent, but this has since changed and now there are increasing numbers of people contracting and dying from lung, bowel, breast and prostate cancers. Given that during this almost half-century period it is unlikely that the genetic composition of Japanese people has changed, the changing disease structure for cancer is therefore likely related to changes in the living environment.
I would now like to discuss data from animal studies, which demonstrate the long period of time that is required for cancer to emerge and the complex course of disease emergence. A study was conducted whereby the very strong hydrocarbon carcinogen 7, 12-dimethylbenz-alpha-anthracene (DMBA) was dissolved in acetone solution and applied once to the back of a mouse. Even after 40 weeks had passed there was no tumor growth. However, since initial animal tests a substance has been discovered that works to promote carcinogenesis, known as 12-O-tetradecanoyl-phorbol-13-acetate (TPA). In a test in which TPA was applied continuously to the backs of mice approximately twice a week, even after 40 weeks there was no tumor growth. However, in an experiment in which DMBA was applied once, after which TPA was applied twice weekly thereafter, a large tumor grew on the backs of the mice. In other words, if a carcinogen is exposed to a tumor promoter such as TPA, cancer will emerge. The experiment I have described shows how if this two-stage process is continued for a prolonged period, skin cancer develops. In animal tests for bladder and bowel cancers and many of the cancers that humans experience, it has been shown that cancer develops in a two-stage process. However, it is thought that cancer in humans develops in a multi-stage process. Damage to genes builds up in stages, resulting in cancer. It is said that there are 100 types of human cancer (Fig. 1). Cancer is different to conditions such as stroke and heart attack, which require minute-by-minute emergency response. Even if a person is told that they might have cancer, during the 1 month it takes to gather information, that person therefore has considerable time to consider the nature of his/her disease and how to tackle it. Although there are some cancers, like pancreatic cancer, that develop quickly, conversely there are also cancers that are extremely slow growing. The most disturbing thing about cancer as a disease is that there are basically no symptoms as it develops in the body.
i40
Measures to control cancer in Japan
National governments are already facing challenges in covering the costs of vaccinations and medical examinations. This raises the question whether countries in Asia and Africa, where cancer is a growing threat, will actually be able to use molecular-targeted drugs at all. This impresses on us once again the fact that cancer is also an economic issue. PREVENTING CANCER THAT CAN BE PREVENTED: TOBACCO, FOOD AND INFECTIOUS DISEASES
The second important measure is to provide medical examinations that will result in early detection of cancer. In the case of breast cancer tests can be performed using mammography, and for bowel cancer a positive test for fecal occult blood is followed by an endoscopic examination. In Japan there are many cases of gastric cancer. However, if a person is not infected with Helicobacter pylori bacteria, there is almost no possibility of that person developing gastric cancer. It will be necessary to consider measures to control gastric cancer as a two-stage process from now, incorporating prevention and medical examination. Cervical cancer can now be 70% prevented through vaccination. As the remaining 30% cannot be covered with the current vaccine, it is necessary to undertake cytological screening. The third measure is to receive proper treatment if cancer is detected. Although effective molecular-targeted drugs have also been developed to tackle cancer, they are extremely expensive. To extend life by merely 1 or 2 months requires expenses running into millions of yen. This is a problem for both patients, who have to bear a portion of medical expenses themselves, and for the government, which covers the remainder. Even in wealthy countries like the USA, the use of such extremely expensive new drugs is a significant issue. The final measure relates to what to do with the 50% of cancers that cannot be cured through treatment. These cancers require the provision of attentive palliative care. It is essential to ensure that patients are not left in pain.
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Figure 1. Multi-stage carcinogenesis model.
TOBACCO-RELATED ISSUES. In 1965 80% of all Japanese men smoked tobacco. By 2004 that figure had dropped to ,50% and currently stands at around 30%. The smoking rate for women over the same period has dropped from 15 to 13%, to stand at around 9% today. Even so, these percentages for smoking rates are still approximately double those of developed countries in Europe and North America. As an interim target for cancer prevention it is important to achieve a decrease in the smoking rate to around 20%. In Japan, what we put in our mouths and noses is strictly controlled by legislation. The Food Sanitation Act covers foods, additives and eating utensils. Drinking water is covered by the Water Supply Act, air by the Air Pollution Control Act and pharmaceutical products by various pharmaceuticalrelated laws. However, despite the fact that tobacco presents significant health-related issues relating not only to cancer, but also to the adverse effect it can have on heart and lungs, it is considered to be a matter relating to personal preference and accordingly is not restricted under any law. Tobacco is covered by two laws, the ancient Tobacco Monopoly Law of 1904 and the Tobacco Industries Act of 1984. These laws were created from the perspective of ensuring fiscal revenues and industry promotion. Tobacco-related taxes bring in revenue of 2.8 trillion yen each year, which is divided between national and local governments. If the Ministry of Health, Labour and Welfare attempts to advance policies that treat tobacco as a health issue, they are met with opposition from the Ministry of Finance and the Ministry of Agriculture, Forestry and Fisheries, which has resulted in a constant reluctance in Japan to face up to and formulate tobacco-related measures. The price of tobacco has remained particularly low in Japan and one effective measure would be to raise it to 500 yen per pack as an interim measure, with a view to raising it to the level of 1000 yen per pack in the future. There are 2000 chemical substances in tobacco smoke. The reason why tobacco smoke makes people’s eyes smart is because it contains formaldehyde. Although present in tiny quantities, tobacco also contains 60 carcinogenic substances, including nitrosamine and b-naphthylamine. When carcinogens enter the throat directly in the form of smoke, they enter the respiratory tract and there is strong correlation between smoking and cancers of the lung, pharynx and larynx. Furthermore, when these carcinogens are dissolved in saliva and swallowed, it can lead to gastric and bowel cancers. Finally, when they are absorbed into the blood stream, they are eliminated from the body as urine by the kidneys, raising
Jpn J Clin Oncol 2014;44(Supplement 1)
the risk of bladder cancer by approximately four times. Although the link between tobacco smoking and lung cancer is well known, tobacco is in fact related to risk of many other cancers also.
Labour and Welfare made patients with chronic gastritis caused by H. pylori bacteria eligible for insurance-reimbursed treatment, which had previously only been available to persons suffering from gastric ulcers caused by the bacteria. However, I believe that given such issues as cost and drug resistance, it is still premature to seek to eradicate the bacteria in all persons. MEDICAL EXAMINATIONS FOR CANCER FOR WHICH EARLY DETECTION IS POSSIBLE The WHO engaged in promotion efforts for the development of an HPV vaccine, and 2 companies, GlaxoSmithKline plc (GSK) and Merck KgaA, successfully developed a vaccine, which they are now selling. There are 100 types of HPV, of which types 16 and 18 are said to be particularly highly virulent, and since the vaccine has been developed it has been approved for use in 100 countries worldwide, having been approved in October 2009 in Japan. As HPV is most often transmitted through sexual contact, it is said that if the vaccine is provided to 12-year old girls this could reduce the incidence of and death from cervical cancer by 70%. However, a series of three vaccinations costs 50 000 yen, there is also the issue of gaining parental consent for vaccinations for children, and the involvement of a pediatrician is also required. Nonetheless, if HPV vaccination and examinations for cervical cancer can be effectively combined, in theory it should be possible to reduce the incidence of cervical cancer to zero. MEASURES TO CONTROL CANCER IN JAPAN N EEDS OF PATIENTS, FAMILIES AND THE G ENERAL PUBLIC CONCERNING CANCER T REATMENT IN JAPAN. The need for measures to control cancer in Japan has been increasing over approximately the last 10 years. Specifically, there is a need to eliminate the following three disparities: (i) elimination of regional disparities concerning the treatment that can be received depending on where in Japan one is located when cancer develops; (ii) elimination of disparities among medical institutions concerning the treatment that can be received depending on which medical institution one first visited and (iii) elimination of information disparities, due to the fact that one would like to receive reliable information on cancer but are unaware where it can be found. During the 15 years I spent as director and then president of the NCC of Japan, I continually emphasized the necessity of developing legislation for measures to control cancer. I spoke with senior officials from the Ministry of Health, Labour and Welfare and with politicians, but I failed to receive any kind of positive response. However, as patients, their families and the wider public began to raise their voices to require concrete measures and action, this meant that the issue could no longer be ignored by politicians. I believe that it is thanks to public opinion that the Cancer Control Act was formulated. BASIC METHODS TO CONTROL CANCER. The Cancer Control Act is very short, comprising only four chapters, which are:
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TACKLING INFECTIOUS DISEASES. I would like to skip discussion of food and its relation to cancer and move on to introduce the relationship between infectious diseases and cancer. In Japan, the following infectious diseases and their relationship to cancer are of significance: hepatitis C virus (HCV) and liver cancer, infection with H. pylori bacteria and gastric cancer, and infection with human papillomavirus (HPV) and cervical cancer. In contrast to the various cancers with which tobacco is related, infectious diseases generally have a one-on-one relationship to a certain type of cancer in terms of cause and effect. For example, if a person is infected with the dysentery bacteria, within the space of 1 week to 10 days that person will suffer abdominal pains and bloody stools. However, once a diagnosis has been made, if the person receives appropriate antibiotics and rehydration treatment the condition will be cured. However, in the case of the three infectious diseases mentioned above, for example HPV infection, it could take sometimes 10 – 20 years from infection until cervical cancer develops. If it is possible to control the cause, so too can the effect be controlled, and therefore the relationship between cancer and infectious diseases is an important one. Infection with HCV results in 70% of all cases becoming chronic hepatitis. Twenty percent of cases result in liver cirrhosis and 10% of cases lead to liver cancer. In the case of the hepatitis B virus (HBV), if there are 100 carriers, 10 of these people will experience chronic hepatitis, 2 will suffer cirrhosis and 1 will develop liver cancer. The difference in canceration between HCV and HBV is therefore a factor of 10. The vaccine for HBV is effective, but HCV can very easily mutate, meaning that there is currently no vaccine available. For the time being, until new vaccines can be developed, treatment is focused on the use of drugs such as peginterferon (telaprevir) and ribavirin, and also the use of liver echo, etc. to help in early detection of the condition. With regard to the H. pylori bacteria, Professor Masahiro Asaka of Hokkaido University implemented a multiinstitution joint study among 51 hospitals nationwide, which studied 505 patients with early stage gastric cancer. The early stage cancers were resected using an endoscope and the secondary cancers in the remaining portion of the stomach were studied. One group in the study took a variety of drugs, including antibiotics, with the aim of eradicating the H. pylori bacteria. A further group was the control group, which received conventional follow-up treatment once a year, including endoscopic examinations. After 3 years, secondary cancer had developed in nine patients in the eradication group, while it had developed in 24 people in the conventional follow-up (control) group. This shows that eradication of H. pylori bacteria reduced the incidence of secondary gastric cancer by two-thirds. As a result of this study, the Ministry of Health,
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Measures to control cancer in Japan
CANCER CONTROL P ROMOTION COUNCIL. The most important section of the Cancer Control Act is Chapter 4, which covers the Cancer Control Promotion Council. In the past such bodies were composed exclusively of cancer experts and academicsand so it was truly groundbreaking for the Cancer Control Act to clearly stipulate that the Cancer Control Promotion Council should also include representatives of patients, families and the bereaved. The Cancer Control Promotion Council convened on five occasions from April to May 2007 and on 15 June 2007, the basic plan to promote cancer control programs was approved by the Cabinet. From April 2013 this basic plan entered the final 5 years of its implementation period. The basic plan includes a new target, which is stated as being the achievement of a ‘society in which people can live with peace of mind, even if they have cancer’. For example, there are 2500 pediatric cancer patients annually and despite the fact that children require specialist treatment, there are some who do not have access to appropriate treatment regimens, meaning that they have fallen through the net of previous cancer control measures. Furthermore, there is still social discrimination against cancer, whereby some people are made redundant by their companies after contracting the disease. It is such issues and challenges that will be tackled during the final 5 years of the basic plan. BASIC PLAN TO PROMOTE CANCER CONTROL PROGRAMS. All the targets created by the Ministry of Health, Labour and Welfare aim to reduce the number of deaths caused by cancer and improve the quality of life for patients and their families. To this end it will be necessary to: (i) promote radiation therapy/ chemotherapy and training of doctors specialized in this area and (ii) implement palliative care from the early stage of treatment. Unless there is improved cancer registration it will be impossible to evaluate the effects of efforts to control cancer, but the Act on the Protection of Personal Information
creates obstacles for such registration. This may be viewed as a modest point, but it is an extremely important one. Also, in terms of the facilities of medical institutions, there are still disparities in the provision of services and facilities among major general hospitals. This is an issue that relates to a lack of human resources and drastic measures are required. In the field of research also, unless further breakthroughs can be achieved, it is unlikely that new drugs to treat difficult cancers such as pancreatic cancer will be developed.
JAPAN CANCER SOCIETY ESTABLISHMENT The Japan Cancer Society was established on 1 August 1958 as a civic organization to spearhead the private sector fight against cancer. It was originally founded as a program to commemorate the 80th anniversary of the Asahi Shimbun newspaper company, with the support of the Japanese Association of Medical Sciences, Japan Medical Association, Ministry of Health, Labour and Welfare and business circles. I currently serve in a voluntary capacity as the president of the society. Although government cancer measures are deployed robustly, backed by national budget and legislation, they tend to be rigid in nature. The Japan Cancer Society aims to supplement government measures on cancer and give them a more human face. CORE MISSION OF THE JAPAN CANCER SOCIETY The Japan Cancer Society has three important targets that form its core mission. These are: (i) promote cancer screenings; (ii) care for cancer patients and survivors and (iii) campaign for a tobacco-free society. In addition to the core mission the society is also active in the ‘Relay for Life’ and ‘Pink Ribbon’ movements that started in the USA. I myself also provide free consultations once a month. The ‘Cancer Hotline’ is another telephone-based service provided by the society, and with a little more effort it should be possible to provide a year-round, 24-h hotline service. The society is also involved in efforts to compile guidelines for cancer examinations. Currently, it is the case that 80% of all patients die in hospitals, but by 2025 it is cannot be expected that deaths in hospitals will have the same rate. It is for this reason that the society has also launched activities relating to home-based medical care. I believe that as we move into the future, it will be of utmost importance for governmental and private sector efforts to control cancer to come together in a cooperative relationship as we seek to continue the fight against cancer.
Conflict of interest statement None declared
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(i) general provisions; (ii) the basic plan to promote cancer control programs, etc.; (iii) based measures and (iv) the cancer control promotion council. The Act states that measures to control cancer are the responsibility of national and local governments, something which is self-evident. However, Article 6 of the Act also stipulates the ‘responsibilities of the public’. It is extremely significant that in this article the Act notes the following: the relationship between smoking, diet, exercise and lifestyle habits and cancer; the importance of medical examinations for cancer and the obligation to make efforts to prevent cancer. It is proved that unless 50% of the population eligible for medical examinations for cancer receive the examinations the number of people who die from the disease will not decrease. However, currently the central government leaves the implementation of such examinations to local governments, and the actual screening rate is still low at around 20%. This screening rate is the lowest among all developed countries and I therefore believe that examinations should be implemented once again as the responsibility of central government.
How Do Cancer Researchers Perceive the Future of Cancer in Asia?
Cross-boundary Cancer Studies at the University of Tokyo: Measures to Control Cancer in Japan Tadao Kakizoe Japan Cancer Society President Emeritus, National Cancer Center, Tokyo, Japan For correspondence, please contact Hideyuki Akaza, MD, Department of Strategic Investigation on Comprehensive Cancer Network, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. E-mail: [email protected] Lecture date May 30, 2012
Key words: cross-boundary cancer studies – the University of Tokyo – cancer control – cancer control measures – early detection
LECTURER PROFILE Tadao Kakizoe is a urologic surgeon who formerly directed the National Cancer Center (NCC), as the 11th President for 5 years and before that, served as Director of the hospital for 10 years. Dr Kakizoe devoted himself to reduce the cancer incidence and mortality in Japan. Presently, he is the President of Japan Cancer Society in close collaboration with the national cancer control strategy. Dr Kakizoe was born in 1941 in Osaka. He graduated from the University of Tokyo in 1967 and had been a teaching staff of the Department of Urology of University of Tokyo from 1972 to 1974. He became a staff of the Urology Division, NCC Hospital in 1975, and has been working in the NCC until March 2007. Between 1972 and 1985, while working as a urologist daytimes, he also worked at the Biochemistry Division of the NCC Research Institute in the evenings and weekends, conducting research on bladder carcinogenesis and bladder cancer prevention with Dr Takashi Sugimura, presently Emeritus President of NCC. Dr Kakizoe has done a great deal of work on bladder cancer from both clinical and basic viewpoints. Dr Kakizoe was awarded Tamiya Prize of NCC and Scientific Prize of Princess Takamatsu Cancer Research Fund for his contribution. Dr Kakizoe went to the University of Toronto, Ontario Cancer Institute from July 1977 to June 1978 and experienced organic chemistry looking for new mutagens and carcinogens in the urine of bladder cancer patients. He identified dibutylnitrosamine in the urine of diffuse carcinoma in situ patient. Dr Kakizoe serves as the Emeritus Board Members of the JSCO (Japan Society of Clinical Oncology) and the Japanese Cancer Association. He is also the Members of the Japanese
Committee of the International Union against Cancer, the Board of the US – Japan Cancer Research Collaboration Program and other important Japanese Governmental Committees. From April 2002, he serves as the Editor-in-Chief of the Japanese Journal of Clinical Oncology. He was the president elect for 65th Annual Meeting of Japan Cancer Association Dr Kakizoe has contributed .200 articles and books and chapters to the scientific literature.
MEASURES TO CONTROL CANCER IN JAPAN MORTALITY RATE TRENDS Japan has fought against a number of diseases to date. The first was tuberculosis, which was followed by cerebrovascular disease. It was in 1986 that cancer became the leading cause of death. As Japanese society ages at the highest pace in the world, the number of people who succumb to cancer will continue to increase. Cancer is a global health issue. In Japan .300 000 people die from the disease each year and one in two men and one in three women will experience the disease during their lifetimes. According to 2007 statistics of the World Health Organization (WHO), around the world there were a total of 11 million new cases of cancer and 7.9 million deaths, with 25 million people living with cancer. These numbers will only continue to increase. It used to be the case that cancer was said to be a disease of the developed world; however, as infectious diseases are brought largely under control in the countries of Asia and Africa, cancer will become an extremely significant issue. This is why cancer is now a major global health issue.
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ by guest on June 23, 2015
Received December 12, 2013; accepted December 13, 2013
Jpn J Clin Oncol 2014;44(Supplement 1)
WHAT KIND OF DISEASE IS CANCER? The characteristics of cancer can be broadly divided into the following three categories.
i39
not just as a health issue, but also in terms of an economic challenge. CANCER REQUIRES A LONG PERIOD OF TIME TO EMERGE PROGRESS, MAKING IT A CHRONIC DISEASE
AND
A CELLULAR DISEASE ORIGINATING AND ADVANCING DUE TO GENETIC ABNORMALITIES
EMERGENCE OF CANCER RELATED TO LIFESTYLE HABITS LIVING ENVIRONMENT
AND THE
According to a paper issued in 1981 by epidemiologists Richard Doll and Richard Peto on the causes of cancer, tobacco accounts for 30%, food accounts for 35% and infection by viruses and bacteria accounts for 10%. As can be seen, therefore, lifestyle habits and the living environment were proposed as being responsible for 75% of cancers, with the remainder being attributed to other causes such as exposure to ultra-violet radiation, drugs and lack of exercise, etc. Similarly, a study by Harvard University entitled ‘Causes of Human Cancer’ published in 1996 examined vast amounts of data to calculate estimates for the causes of cancer, and the findings were similar to the 1981 paper by Doll and Peto: tobacco accounted for 30% and food for 30%. Other risk factors for cancer in this study were cited as lack of exercise, exposure to ultra-violet radiation, pharmaceutical drugs, occupational hazards and genes. The term ‘cancer family’ is occasionally used to describe people in the same family who are prone to cancer, and it is said that genes are related to the emergence of cancer in 5% of cases. Economic factors also have an impact on cancer and the International Agency for Research on Cancer refers to ‘poverty as a carcinogen’. In forums such as the WHO, Union for International Cancer Control and the United Nations, cancer is often deliberated,
MEASURES TO CONTROL CANCER IN JAPAN AND AROUND WORLD
THE
MEASURES TO CONTROL CANCER AROUND THE WORLD In developed countries cancer control is based on the following four pillars: (i) prevent what can be prevented, (ii) achieve early detection and early treatment for cancers that can be dealt with through medical examination, (iii) make every effort to treat cancer and (iv) provide palliative care if cancer does not respond to treatment. As a primary prevention method, measures to control tobacco are of the utmost importance.
Downloaded from http://jjco.oxfordjournals.org/ by guest on June 23, 2015
The human body is composed of 60 trillion cells. The nucleus of each cell DNA contains, if stretched out the inside DNA strand, would extend to 1.8 m, to which are attached 20 – 30 000 genes. Among these genes .100 are already known to be either cancer genes or cancer-suppressing genes. Cancer is caused when normal cells are overrun by cancer genes or when cancer-suppressing genes are destroyed. It is said that another way cancer is caused is through a combination of the above, where normal cells turn rogue. This demonstrates that cancer is a cellular disease that emerges due to genetic abnormalities. Cancer in Japanese people has been seen to have undergone significant changes over the course of the last 40 – 50 years. Formerly, it was the case that gastric and cervical cancers were the most prevalent, but this has since changed and now there are increasing numbers of people contracting and dying from lung, bowel, breast and prostate cancers. Given that during this almost half-century period it is unlikely that the genetic composition of Japanese people has changed, the changing disease structure for cancer is therefore likely related to changes in the living environment.
I would now like to discuss data from animal studies, which demonstrate the long period of time that is required for cancer to emerge and the complex course of disease emergence. A study was conducted whereby the very strong hydrocarbon carcinogen 7, 12-dimethylbenz-alpha-anthracene (DMBA) was dissolved in acetone solution and applied once to the back of a mouse. Even after 40 weeks had passed there was no tumor growth. However, since initial animal tests a substance has been discovered that works to promote carcinogenesis, known as 12-O-tetradecanoyl-phorbol-13-acetate (TPA). In a test in which TPA was applied continuously to the backs of mice approximately twice a week, even after 40 weeks there was no tumor growth. However, in an experiment in which DMBA was applied once, after which TPA was applied twice weekly thereafter, a large tumor grew on the backs of the mice. In other words, if a carcinogen is exposed to a tumor promoter such as TPA, cancer will emerge. The experiment I have described shows how if this two-stage process is continued for a prolonged period, skin cancer develops. In animal tests for bladder and bowel cancers and many of the cancers that humans experience, it has been shown that cancer develops in a two-stage process. However, it is thought that cancer in humans develops in a multi-stage process. Damage to genes builds up in stages, resulting in cancer. It is said that there are 100 types of human cancer (Fig. 1). Cancer is different to conditions such as stroke and heart attack, which require minute-by-minute emergency response. Even if a person is told that they might have cancer, during the 1 month it takes to gather information, that person therefore has considerable time to consider the nature of his/her disease and how to tackle it. Although there are some cancers, like pancreatic cancer, that develop quickly, conversely there are also cancers that are extremely slow growing. The most disturbing thing about cancer as a disease is that there are basically no symptoms as it develops in the body.
i40
Measures to control cancer in Japan
National governments are already facing challenges in covering the costs of vaccinations and medical examinations. This raises the question whether countries in Asia and Africa, where cancer is a growing threat, will actually be able to use molecular-targeted drugs at all. This impresses on us once again the fact that cancer is also an economic issue. PREVENTING CANCER THAT CAN BE PREVENTED: TOBACCO, FOOD AND INFECTIOUS DISEASES
The second important measure is to provide medical examinations that will result in early detection of cancer. In the case of breast cancer tests can be performed using mammography, and for bowel cancer a positive test for fecal occult blood is followed by an endoscopic examination. In Japan there are many cases of gastric cancer. However, if a person is not infected with Helicobacter pylori bacteria, there is almost no possibility of that person developing gastric cancer. It will be necessary to consider measures to control gastric cancer as a two-stage process from now, incorporating prevention and medical examination. Cervical cancer can now be 70% prevented through vaccination. As the remaining 30% cannot be covered with the current vaccine, it is necessary to undertake cytological screening. The third measure is to receive proper treatment if cancer is detected. Although effective molecular-targeted drugs have also been developed to tackle cancer, they are extremely expensive. To extend life by merely 1 or 2 months requires expenses running into millions of yen. This is a problem for both patients, who have to bear a portion of medical expenses themselves, and for the government, which covers the remainder. Even in wealthy countries like the USA, the use of such extremely expensive new drugs is a significant issue. The final measure relates to what to do with the 50% of cancers that cannot be cured through treatment. These cancers require the provision of attentive palliative care. It is essential to ensure that patients are not left in pain.
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Figure 1. Multi-stage carcinogenesis model.
TOBACCO-RELATED ISSUES. In 1965 80% of all Japanese men smoked tobacco. By 2004 that figure had dropped to ,50% and currently stands at around 30%. The smoking rate for women over the same period has dropped from 15 to 13%, to stand at around 9% today. Even so, these percentages for smoking rates are still approximately double those of developed countries in Europe and North America. As an interim target for cancer prevention it is important to achieve a decrease in the smoking rate to around 20%. In Japan, what we put in our mouths and noses is strictly controlled by legislation. The Food Sanitation Act covers foods, additives and eating utensils. Drinking water is covered by the Water Supply Act, air by the Air Pollution Control Act and pharmaceutical products by various pharmaceuticalrelated laws. However, despite the fact that tobacco presents significant health-related issues relating not only to cancer, but also to the adverse effect it can have on heart and lungs, it is considered to be a matter relating to personal preference and accordingly is not restricted under any law. Tobacco is covered by two laws, the ancient Tobacco Monopoly Law of 1904 and the Tobacco Industries Act of 1984. These laws were created from the perspective of ensuring fiscal revenues and industry promotion. Tobacco-related taxes bring in revenue of 2.8 trillion yen each year, which is divided between national and local governments. If the Ministry of Health, Labour and Welfare attempts to advance policies that treat tobacco as a health issue, they are met with opposition from the Ministry of Finance and the Ministry of Agriculture, Forestry and Fisheries, which has resulted in a constant reluctance in Japan to face up to and formulate tobacco-related measures. The price of tobacco has remained particularly low in Japan and one effective measure would be to raise it to 500 yen per pack as an interim measure, with a view to raising it to the level of 1000 yen per pack in the future. There are 2000 chemical substances in tobacco smoke. The reason why tobacco smoke makes people’s eyes smart is because it contains formaldehyde. Although present in tiny quantities, tobacco also contains 60 carcinogenic substances, including nitrosamine and b-naphthylamine. When carcinogens enter the throat directly in the form of smoke, they enter the respiratory tract and there is strong correlation between smoking and cancers of the lung, pharynx and larynx. Furthermore, when these carcinogens are dissolved in saliva and swallowed, it can lead to gastric and bowel cancers. Finally, when they are absorbed into the blood stream, they are eliminated from the body as urine by the kidneys, raising
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the risk of bladder cancer by approximately four times. Although the link between tobacco smoking and lung cancer is well known, tobacco is in fact related to risk of many other cancers also.
Labour and Welfare made patients with chronic gastritis caused by H. pylori bacteria eligible for insurance-reimbursed treatment, which had previously only been available to persons suffering from gastric ulcers caused by the bacteria. However, I believe that given such issues as cost and drug resistance, it is still premature to seek to eradicate the bacteria in all persons. MEDICAL EXAMINATIONS FOR CANCER FOR WHICH EARLY DETECTION IS POSSIBLE The WHO engaged in promotion efforts for the development of an HPV vaccine, and 2 companies, GlaxoSmithKline plc (GSK) and Merck KgaA, successfully developed a vaccine, which they are now selling. There are 100 types of HPV, of which types 16 and 18 are said to be particularly highly virulent, and since the vaccine has been developed it has been approved for use in 100 countries worldwide, having been approved in October 2009 in Japan. As HPV is most often transmitted through sexual contact, it is said that if the vaccine is provided to 12-year old girls this could reduce the incidence of and death from cervical cancer by 70%. However, a series of three vaccinations costs 50 000 yen, there is also the issue of gaining parental consent for vaccinations for children, and the involvement of a pediatrician is also required. Nonetheless, if HPV vaccination and examinations for cervical cancer can be effectively combined, in theory it should be possible to reduce the incidence of cervical cancer to zero. MEASURES TO CONTROL CANCER IN JAPAN N EEDS OF PATIENTS, FAMILIES AND THE G ENERAL PUBLIC CONCERNING CANCER T REATMENT IN JAPAN. The need for measures to control cancer in Japan has been increasing over approximately the last 10 years. Specifically, there is a need to eliminate the following three disparities: (i) elimination of regional disparities concerning the treatment that can be received depending on where in Japan one is located when cancer develops; (ii) elimination of disparities among medical institutions concerning the treatment that can be received depending on which medical institution one first visited and (iii) elimination of information disparities, due to the fact that one would like to receive reliable information on cancer but are unaware where it can be found. During the 15 years I spent as director and then president of the NCC of Japan, I continually emphasized the necessity of developing legislation for measures to control cancer. I spoke with senior officials from the Ministry of Health, Labour and Welfare and with politicians, but I failed to receive any kind of positive response. However, as patients, their families and the wider public began to raise their voices to require concrete measures and action, this meant that the issue could no longer be ignored by politicians. I believe that it is thanks to public opinion that the Cancer Control Act was formulated. BASIC METHODS TO CONTROL CANCER. The Cancer Control Act is very short, comprising only four chapters, which are:
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TACKLING INFECTIOUS DISEASES. I would like to skip discussion of food and its relation to cancer and move on to introduce the relationship between infectious diseases and cancer. In Japan, the following infectious diseases and their relationship to cancer are of significance: hepatitis C virus (HCV) and liver cancer, infection with H. pylori bacteria and gastric cancer, and infection with human papillomavirus (HPV) and cervical cancer. In contrast to the various cancers with which tobacco is related, infectious diseases generally have a one-on-one relationship to a certain type of cancer in terms of cause and effect. For example, if a person is infected with the dysentery bacteria, within the space of 1 week to 10 days that person will suffer abdominal pains and bloody stools. However, once a diagnosis has been made, if the person receives appropriate antibiotics and rehydration treatment the condition will be cured. However, in the case of the three infectious diseases mentioned above, for example HPV infection, it could take sometimes 10 – 20 years from infection until cervical cancer develops. If it is possible to control the cause, so too can the effect be controlled, and therefore the relationship between cancer and infectious diseases is an important one. Infection with HCV results in 70% of all cases becoming chronic hepatitis. Twenty percent of cases result in liver cirrhosis and 10% of cases lead to liver cancer. In the case of the hepatitis B virus (HBV), if there are 100 carriers, 10 of these people will experience chronic hepatitis, 2 will suffer cirrhosis and 1 will develop liver cancer. The difference in canceration between HCV and HBV is therefore a factor of 10. The vaccine for HBV is effective, but HCV can very easily mutate, meaning that there is currently no vaccine available. For the time being, until new vaccines can be developed, treatment is focused on the use of drugs such as peginterferon (telaprevir) and ribavirin, and also the use of liver echo, etc. to help in early detection of the condition. With regard to the H. pylori bacteria, Professor Masahiro Asaka of Hokkaido University implemented a multiinstitution joint study among 51 hospitals nationwide, which studied 505 patients with early stage gastric cancer. The early stage cancers were resected using an endoscope and the secondary cancers in the remaining portion of the stomach were studied. One group in the study took a variety of drugs, including antibiotics, with the aim of eradicating the H. pylori bacteria. A further group was the control group, which received conventional follow-up treatment once a year, including endoscopic examinations. After 3 years, secondary cancer had developed in nine patients in the eradication group, while it had developed in 24 people in the conventional follow-up (control) group. This shows that eradication of H. pylori bacteria reduced the incidence of secondary gastric cancer by two-thirds. As a result of this study, the Ministry of Health,
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Measures to control cancer in Japan
CANCER CONTROL P ROMOTION COUNCIL. The most important section of the Cancer Control Act is Chapter 4, which covers the Cancer Control Promotion Council. In the past such bodies were composed exclusively of cancer experts and academicsand so it was truly groundbreaking for the Cancer Control Act to clearly stipulate that the Cancer Control Promotion Council should also include representatives of patients, families and the bereaved. The Cancer Control Promotion Council convened on five occasions from April to May 2007 and on 15 June 2007, the basic plan to promote cancer control programs was approved by the Cabinet. From April 2013 this basic plan entered the final 5 years of its implementation period. The basic plan includes a new target, which is stated as being the achievement of a ‘society in which people can live with peace of mind, even if they have cancer’. For example, there are 2500 pediatric cancer patients annually and despite the fact that children require specialist treatment, there are some who do not have access to appropriate treatment regimens, meaning that they have fallen through the net of previous cancer control measures. Furthermore, there is still social discrimination against cancer, whereby some people are made redundant by their companies after contracting the disease. It is such issues and challenges that will be tackled during the final 5 years of the basic plan. BASIC PLAN TO PROMOTE CANCER CONTROL PROGRAMS. All the targets created by the Ministry of Health, Labour and Welfare aim to reduce the number of deaths caused by cancer and improve the quality of life for patients and their families. To this end it will be necessary to: (i) promote radiation therapy/ chemotherapy and training of doctors specialized in this area and (ii) implement palliative care from the early stage of treatment. Unless there is improved cancer registration it will be impossible to evaluate the effects of efforts to control cancer, but the Act on the Protection of Personal Information
creates obstacles for such registration. This may be viewed as a modest point, but it is an extremely important one. Also, in terms of the facilities of medical institutions, there are still disparities in the provision of services and facilities among major general hospitals. This is an issue that relates to a lack of human resources and drastic measures are required. In the field of research also, unless further breakthroughs can be achieved, it is unlikely that new drugs to treat difficult cancers such as pancreatic cancer will be developed.
JAPAN CANCER SOCIETY ESTABLISHMENT The Japan Cancer Society was established on 1 August 1958 as a civic organization to spearhead the private sector fight against cancer. It was originally founded as a program to commemorate the 80th anniversary of the Asahi Shimbun newspaper company, with the support of the Japanese Association of Medical Sciences, Japan Medical Association, Ministry of Health, Labour and Welfare and business circles. I currently serve in a voluntary capacity as the president of the society. Although government cancer measures are deployed robustly, backed by national budget and legislation, they tend to be rigid in nature. The Japan Cancer Society aims to supplement government measures on cancer and give them a more human face. CORE MISSION OF THE JAPAN CANCER SOCIETY The Japan Cancer Society has three important targets that form its core mission. These are: (i) promote cancer screenings; (ii) care for cancer patients and survivors and (iii) campaign for a tobacco-free society. In addition to the core mission the society is also active in the ‘Relay for Life’ and ‘Pink Ribbon’ movements that started in the USA. I myself also provide free consultations once a month. The ‘Cancer Hotline’ is another telephone-based service provided by the society, and with a little more effort it should be possible to provide a year-round, 24-h hotline service. The society is also involved in efforts to compile guidelines for cancer examinations. Currently, it is the case that 80% of all patients die in hospitals, but by 2025 it is cannot be expected that deaths in hospitals will have the same rate. It is for this reason that the society has also launched activities relating to home-based medical care. I believe that as we move into the future, it will be of utmost importance for governmental and private sector efforts to control cancer to come together in a cooperative relationship as we seek to continue the fight against cancer.
Conflict of interest statement None declared
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(i) general provisions; (ii) the basic plan to promote cancer control programs, etc.; (iii) based measures and (iv) the cancer control promotion council. The Act states that measures to control cancer are the responsibility of national and local governments, something which is self-evident. However, Article 6 of the Act also stipulates the ‘responsibilities of the public’. It is extremely significant that in this article the Act notes the following: the relationship between smoking, diet, exercise and lifestyle habits and cancer; the importance of medical examinations for cancer and the obligation to make efforts to prevent cancer. It is proved that unless 50% of the population eligible for medical examinations for cancer receive the examinations the number of people who die from the disease will not decrease. However, currently the central government leaves the implementation of such examinations to local governments, and the actual screening rate is still low at around 20%. This screening rate is the lowest among all developed countries and I therefore believe that examinations should be implemented once again as the responsibility of central government.
