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Cancer Control Opportunities in Low- and Middle-Income Countries 2 Cancer Causes and Risk Factors and the Elements of Cancer Control A logical way to identify cancer control opportunities is to consider what we know about the causes and risk factors for common cancers, and then to consider how easy or difficult it is to eliminate or modify them in ways that would reduce cancer incidence. Where the causes or risk factors are not well understood, are only weak, or cannot readily be changed, the opportunities lie in how easy or difficult it is to “cure” people who get cancer or to care for those with cancer who cannot be cured. This chapter starts with a review of the causes and known risk factors for the most common cancers in low- and middle-income countries (LMCs), with discussion of the modifiability of these causes and risk factors. The latter part of the chapter is a general review of the approaches to cancer control, beginning with cancer control planning, then prevention and the elements of cancer management (diagnosis and treatment): psychosocial care, radiotherapy, chemotherapy, and surgery. Chapter 7 is devoted entirely to palliative care, the other major pillar of cancer management, so that area is not covered in this chapter. CAUSES OF AND RISK FACTORS FOR CANCER IN LMCS Knowing the causes of cancer provides a basis for understanding the potential for preventing cancer. If a cause is known, it is much easier to know whether it can (e.g., tobacco use) or cannot (e.g., ionizing radiation in the atmosphere) be avoided easily. An accounting of the causes also shows up the gaps in knowledge—for example, few specific causes of colon cancer are known. Table 2-1 lists the major risk factors for the top 10 causes
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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 2-1 Leading Risk Factors for Cancer Deaths in LMCs (or Developing Countries) and Primary Prevention Strategies Cancer Type (number of deaths in LMCs in 2002) Main Risk Factors Theoretical Minimum Exposure Distribution Primary Prevention: Currently Available Strategies PAF % Lung, trachea, and bronchus (770,938) Tobacco use Zero exposure possible Tobacco control as outlined in Framework Convention on Tobacco Control (FCTC) 60 Low fruit and vegetable intake 600 grams/day fruit and vegetable intake for adults Dietary improvements 13 Urban air pollution 7.5 μg/m3 for particles with aerodynamic diameters <2.5 microns 15 μg/m3 for particles with aerodynamic diameters <10 microns Regulation of automobile exhaust and industrial combustion products 7 Indoor smoke from cooking and heating Zero exposure possible Ventilation and improved low-technology heating and cooking 2 Radon in buildings (from the earth) NGE Building regulations to avoid radon seepage into enclosed buildings, mainly in cold climates NGE Various occupational exposures NGE Workplace regulation and controls 9b
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Cancer Control Opportunities in Low- and Middle-Income Countries Cancer Type (number of deaths in LMCs in 2002) Main Risk Factors Theoretical Minimum Exposure Distribution Primary Prevention: Currently Available Strategies PAF % Stomach (695,426) Chronic infection with Helicobacter pylori Zero exposure possible Improved living conditions (nonspecific) Future: Vaccine to prevent infection? Future: Drugs to clear infection? 74a Low fruit and vegetable intake 600 grams/day fruit and vegetable intake for adults Dietary improvements 19 Tobacco use Zero exposure possible Tobacco control as outlined in FCTC 11 Liver (504,407) Chronic hepatitis B (HBV), mainly from infection in infancy and childhood; co-factors, such as fungal toxins (e.g., aflatoxin) Zero exposure possible Hepatitis B vaccination in infancy Reduced fungal contamination of stored grains Future: Cure of chronic HBV? 59a Chronic hepatitis C (HCV) from contaminated blood and unsafe injections, and person to person; co-factors such as fungal toxins (e.g., aflatoxin) Zero exposure possible Blood supply and injection safety and measures Future: Cure of chronic HCV? 33a Alcohol use Zero exposure possible Reduced alcohol use 23 Tobacco use Zero exposure possible Tobacco control as outlined in FCTC 11
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Cancer Control Opportunities in Low- and Middle-Income Countries Cancer Type (number of deaths in LMCs in 2002) Main Risk Factors Theoretical Minimum Exposure Distribution Primary Prevention: Currently Available Strategies PAF % Colon and rectum (356,949) Physical inactivity At least 2.5 hours/ week of moderate-intensity activity or equivalent (4,000 KJ/week) Lifestyle changes 15 Overweight and obesity BMI (weight/height2) of 21 Dietary improvements and exercise 9 Low fruit and vegetable intake 600 grams/day fruit and vegetable intake for adults Dietary improvements 2 Esophagus (379,760) Tobacco use Zero exposure possible Tobacco control as outlined in FCTC 37 Alcohol use Zero exposure possible Reduced alcohol use 24 Low fruit and vegetable intake 600 grams/day fruit and vegetable intake for adults Dietary improvements and exercise 19 Breast (317,195) Physical inactivity At least 2.5 hours/ week of moderate-intensity activity or equivalent (4,000 KJ/week) Exercise 10 Overweight and obesity BMI (weight/height2) of 21 Dietary improvements and exercise 7 Alcohol use Zero exposure possible Reduced alcohol use 4 Mouth and oropharynx (271,074) Tobacco use Zero exposure possible Tobacco control as outlined in FCTC 37 Alcohol use Zero exposure possible Reduced alcohol use 14 Uterine cervix (218,064) Chronic infection with specific strains of human papillomavirus (HPV) Zero exposure possible Screening for precancerous stages Vaccination against HPV in infancy or adolescence 100 Tobacco use Zero exposure possible Tobacco control as outlined in FCTC 2
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Cancer Control Opportunities in Low- and Middle-Income Countries Cancer Type (number of deaths in LMCs in 2002) Main Risk Factors Theoretical Minimum Exposure Distribution Primary Prevention: Currently Available Strategies PAF % Lymphomas and multiple myelomaa Burkitt’s lymphoma (7,800 cases in children in less developed countries): chronic infection with Epstein-Barr virus Very low exposure possible None apparent NGE Leukemia (190,059) Ionizing radiation (natural and medical) Low medical exposure possible; lower radon exposure possible Improved medical practices Improved building practices to exclude radon NGE Tobacco use Zero exposure possible Tobacco control as outlined in FCTC 6 Various occupational exposures Lower exposures possible (varying by exposure) Workplace regulation and controls 2b NOTE: PAFs from the Global Burden of Disease and Risk Factors (Lopez et al., 2006) unless otherwise noted. The Institute of Medicine did not independently recalculate these figures. These PAFs refer to fractions of deaths, and the denominator is all cancer deaths in LMCs (as defined by the World Bank)—about 5 million deaths. The fractions reported from Parkin (Parkin, 2005) refer to cases in developing countries (as defined by the World Health Organization), which total about 6 million. These two types of figures are approximately, but not strictly, comparable. For purposes of this table, however, together they provide a relatively accurate overview of the major risk factors for cancers and cancer deaths. PAF = Population attributable fraction, which is the proportional reduction in disease that would occur if population exposure to the risk factor were reduced to the theoretical minimum risk level. Many cancers are affected by more than one risk factor (e.g., tobacco and alcohol combining to greatly increase the risk of esophageal cancer); elimination of one or another could prevent a particular cancer from occurring. This means that the PAFs are not mutually exclusive, and added together will generally overestimate the cancer reduction possible by eliminating all identified risk factors. NGE = No global estimate available. aData from Parkin (2005). bData from Rosenstock et al. (2006); refers to worldwide PAF, compared with zero exposure, with no breakdown by country economic level. SOURCES: Lopez et al. (2006); Parkin (2005); and Institute of Medicine.
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Cancer Control Opportunities in Low- and Middle-Income Countries of cancer death in LMCs, with their “population attributable fractions” (PAFs). Table 2-2 summarizes the impact of these risk factors for all cancers in LMCs. The PAF represents the proportion of cancer deaths that could be prevented if the risk factor or exposure were reduced to a theoretical minimum. For a number of major risk factors, a zero level of exposure is at least theoretically possible. These include: tobacco use, alcohol use (but see below), indoor smoke from cooking, most carcinogenic infectious agents (if not zero exposure, vastly reduced from current levels). For other factors, zero exposure is not a relevant concept, such as for obesity or for inactivity. The values for those risk factors (from Global Burden of Disease and Risk Factors, Lopez et al., 2006) are based on an achievable level that would minimize the risk of all major diseases associated with that risk factor. Heart disease, stroke, cancer, chronic respiratory diseases, and diabetes—the main chronic diseases—share some common risk factors (Epping-Jordan et al., 2005; WHO, 2005a). Tobacco smoking is overwhelmingly the most significant risk factor for cancer and across the board for chronic diseases. Diet, exercise, and alcohol use also cut across the diseases, and they are significant contributors to cancer, but more significant to other conditions. Of lesser global importance (but in some cases, very important focally), are factors such as occupational exposures to asbestos, coal, and other substances; indoor smoke from cooking and heating; and air pollution, which can cause cancer and a larger burden of chronic respiratory diseases. Beyond these factors, the common cancers in LMCs do not share significant risk factors with other chronic diseases. What stands out is the role of infections in common cancers of LMCs (discussed below). Cancer control will benefit from integrated approaches to chronic disease control, but cancer-specific strategies—which will have little or no impact on other chronic diseases—are also needed. Table 2-1 describes the risk factors associated with current deaths from cancer. Because of the time scale of cancer, the pattern of deaths today reflects the distribution of risk factors some decades ago. For smoking, the peak in smoking-related deaths follows the peak in smoking rates by about 30 years (Figure 2-1). Today’s smoking rates will determine the cancer rates 30 years hence. It is important, therefore, to know about levels and trends in risk factors for cancer control planning (see Chapter 3 for a discussion about monitoring risk factors). Tobacco Tobacco use is the largest single contributor to cancer mortality: It was a cause of nearly one-fifth of all cancer deaths in LMCs in 2002. It is also the leading cause of death from the totality of major noncommunicable diseases. Chapter 5 goes into considerable detail on the effects of tobacco
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Cancer Control Opportunities in Low- and Middle-Income Countries and its control. What should be noted from Figure 2-1 is where the LMCs are on the epidemic curve. The low-income countries are all in either stage 1 or 2 (tobacco use still low but rising, first among males; tobacco-related deaths low and just beginning to rise), and the middle-income countries in stage 2 or 3 (tobacco use rising steeply or having peaked; mortality following). The challenge to tobacco control is to alter the trajectories in those countries by encouraging adults to quit smoking (benefits that appear in a very short timeframe) and discouraging young people from starting (the long-term solution). They do not have to follow the trajectory we now see in retrospect for the high-income countries. If they do, however, the number of deaths from tobacco will continue to increase steeply. In the year 2000, about 4.9 million deaths from all causes were related to tobacco, about half in developed and half in developing countries. In 2020, if current trends continue, 9 million people will die from tobacco-related causes, and 7 million of these will be in developing countries. Infections The three leading types of cancer-causing infections—hepatitis B virus (HBV) and hepatitis C virus, human papillomavirus (HPV), and Helicobacter pylori—follow tobacco in importance as risk factors for cancer incidence in developing countries. It is clear from their much lesser importance in high-income countries (responsible for an estimated 8 percent of all cancers, compared with 26 percent in developing countries) (Parkin, 2005) that the prevalence of these infections can be greatly reduced, although the means to do so differ. HBV is readily preventable by immunization. Preventing the spread of hepatitis C requires blood bank screening and safe injection practices, which is a more difficult set of interventions to implement. HPV-related cancers have been prevented in high-income countries largely through screening and treatment of precancerous lesions, but infection prevention is newly possible by vaccination as well. HBV- and HPV-related cancers represent immediate opportunities for preventing cancer in current generations. H. pylori is one major cause of stomach cancer, a cancer that is poorly responsive to treatment. The prevalence of H. pylori (and stomach cancer) has declined dramatically without targeted measures in much of the world, suggesting the possibility of developing interventions for places where it is not declining, which includes most LMCs. At present, this is a research question focused on treatment of infected individuals with antibiotics that eradicate the bacteria. Work on vaccines is also reported to be progressing (Parkin, 2005). Progress depends on continued support of promising leads. H. pylori research is not pursued further in this report, however. Other types of infection are locally important and account for about
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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 2-2 Summary of Major Risk Factors for All Cancers in LMCs (or Developing Countries) Cancer Type (number of deaths) Main Risk Factors Theoretical Minimum Exposure Distribution All cancers (~5 million cancer deaths) Tobacco use Zero exposure possible All carcinogenic infections HBV and HCV Zero exposure possible HPV Zero exposure possible H. pylori Zero exposure possible Low fruit and vegetable intake 600 grams/day fruit and vegetable intake for adults Alcohol use Zero exposure possible Physical inactivity At least 2.5 hours/week of moderate-intensity activity or equivalent (4,000 KJ/week) Overweight and obesity BMI (weight/height2) of 21 Urban air pollution 7.5 μg/m3 for particles with aerodynamic diameters <2.5 microns 15 μg/m3 for particles with aerodynamic diameters <10 microns Indoor smoke from cooking and heating Zero exposure possible NOTE: PAFs from the Global Burden of Disease and Risk Factors (Lopez et al., 2006) unless otherwise noted. The Institute of Medicine did not independently recalculate these figures. These PAFs refer to fractions of deaths, and the denominator is all cancer deaths in LMCs (as defined by the World Bank)—about 5 million deaths. The fractions reported from Parkin (Parkin, 2005) refer to cases in developing countries (as defined by the World Health Organization), which total about 6 million. These two types of figures are approximately, but not strictly, comparable. For purposes of this table, however, together they provide a relatively accurate overview of the major risk factors for cancers and cancer deaths. PAF = Population attributable fraction, which is the proportional reduction in disease that would occur if population exposure to the risk factor were reduced to the theoretical minimum
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Cancer Control Opportunities in Low- and Middle-Income Countries PAF % Importance of Risk Factor to Other Serious Health Conditions 18 Greater burden of cardiovascular disease Approximately equivalent burden of chronic respiratory disease Smaller but substantial burdens from other conditions 26a 8.2a Significant burden from other serious liver diseases from HBV and HCV 8a Very small burden from other conditions 6.9a 6 Much greater burden of cardiovascular disease 5 Much greater burden of injuries, neuropsychiatric conditions, cardiovascular conditions, and other causes 2 Much greater burden of cardiovascular and other noncommunicable diseases 1 Much greater burden of cardiovascular and other noncommunicable diseases 1 Greater burden of chronic respiratory disease <0.5 Much greater burden of cardiovascular and chronic respiratory conditions risk level. Many cancers are affected by more than one risk factor (e.g., tobacco and alcohol combining to greatly increase the risk of esophageal cancer); elimination of one or another could prevent a particular cancer from occurring. This means that the PAFs are not mutually exclusive, and added together will generally overestimate the cancer reduction possible by eliminating all identified risk factors. NGE = No global estimate available. aData from Parkin (2005). SOURCES: Lopez et al. (2006); Parkin (2005); and Institute of Medicine.
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Cancer Control Opportunities in Low- and Middle-Income Countries FIGURE 2-1 Four stages of the tobacco epidemic. SOURCE: Reprinted, with permission, from Lopez et al. (1994). Copyright 1994 by BMJ Publishing Group Ltd. 4 percent of all cancers (Parkin, 2005). The most significant is Epstein-Barr virus, a risk factor for Burkitt’s lymphoma and cancers of the nasopharynx, to which 2 percent of cancers in LMCs are attributable. Both of these cancers are much more common in developing than developed countries. Next in importance, the human immunodeficiency virus (HIV) is responsible for an estimated 62,500 cases of Kaposi’s sarcoma in developing countries (about 1 percent of all cancers). Somewhat less than 1 percent of cancers are attributable to helminth (worm) infections, including bladder and possibly colorectal cancers (“limited” evidence, according to the International Agency for Research on Cancer, or IARC) (IARC, 1997) caused by schistosomes, and liver cancers caused by liver flukes. Finally, human T-cell lymphotropic virus type 1 (HTLV-1) is the cause of some non-Hodgkin’s lymphomas. It is worth noting that other infectious causes of cancer may be discovered. Current knowledge has been developed largely in the past 30 years. An organism as significant as H. pylori was not recognized until the 1980s, originally as the primary cause of gastritis and stomach ulcers, and it was
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Cancer Control Opportunities in Low- and Middle-Income Countries classified as a human carcinogen by IARC only about a decade ago (IARC, 1997). Diet, Overweight and Obesity, and Physical Inactivity Diet, body weight, and activity levels are interrelated and seem to act in complex ways to either promote or reduce the risk of cancer. Global Burden of Disease and Risk Factors (Lopez et al., 2006) made separate estimates for the three components, based on the best available quantitative evidence and focusing on low fruit and vegetable intake as the best established specific dietary factor. Nine percent of cancer deaths in LMCs are attributable to these three factors, which could be the focus of interventions. As significant as these risk factors are for cancer, they are responsible for considerably greater disability and death from other causes: heart disease, hypertension and stroke, diabetes, and arthritis most important among them. These other conditions are at least five times as important as cancer in terms of disability-adjusted life-years (DALYs) (Lopez et al., 2006). A high intake of fresh fruits and vegetables (generally excluding root vegetables and pulses (peas and beans), which have a higher carbohydrate content than other types of vegetables), has consistently been found in epidemiologic studies to be associated with lower cancer rates. Fruits and vegetables are generally low in calories (supply less than 5 percent of calories in most countries) and high in fiber, vitamins, minerals, and other active molecules. Studies that have looked at vegetables individually or in classes (categorized several different ways, either botanically or culinarily) have not been able to pinpoint more precisely which vegetables or fruits are more or less beneficial, or which components cause which effects. Eventually, this may be possible, but given the state of the science today, it is best to consider fruits and vegetables collectively (World Cancer Research Fund, 1997). The evidence is convincing that an adequate intake of fruits and vegetables (for some cancers, mainly vegetables) lowers the risk of the following cancers: colon and rectum, lung, stomach, esophagus, and mouth and pharynx (IOM, 2003; World Cancer Research Fund, 1997). The risk of a number of other cancers also may be lowered, but the evidence is not as strong. Those with the strongest evidence are cancers of the larynx, pancreas, breast, and bladder. The strength of the totality of the research literature underlies the estimate that 6 percent of cancer deaths are attributable to low fruit and vegetable intake (Lopez et al., 2006). Other estimates of cancers related to “diet and nutrition” are higher. IARC’s 2003 World Cancer Report (Stewart and Kleihues, 2003) states: “Up to 30 percent of human cancers are probably related to diet and nutrition,” using an expansive definition of diet and nutrition. The estimate also refers to the world as a whole, with no separate estimates for countries by
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Cancer Control Opportunities in Low- and Middle-Income Countries Infrastructure Needs and Costs of Radiotherapy Providing a safe and effective radiation oncology service requires an initial capital investment in radiotherapy equipment and specially designed buildings, as well as an ongoing investment in consumable items and maintenance of the equipment; an expert team of doctors, therapists, and physicists; and good access to engineering support. The necessary medical, scientific, and technical expertise is in short supply in many countries and is an even bigger constraint in many LMCs than the shortage of radiotherapy equipment. A shortage of trained staff may limit the number of patients who can be treated, to the point of underutilization of even the existing scarce equipment (Tatsuzaki and Levin, 2001; Radiation Oncology Inquiry, 2002). The introduction or expansion of radiation oncology services in any health care system inevitably has implications for other services. These include surgical and medical oncology, pathology, imaging, general and specialist medical and surgical services, and nursing and psychosocial support services. The costs of radiotherapy include the capital costs of the building and equipment, maintenance costs, and staff salaries. Buildings can be relatively expensive, but are durable, so amortized costs are small. Cobalt machines are considerably cheaper than linacs because they are mechanically and electronically simpler. Capital costs also include equipment for planning treatment, including simulators and computers. Staff costs are for radiation oncologists, physicists, and technologists, each of whom is necessary to assess and treat patients. The cost of establishing a radiotherapy facility in an LMC is about $1 million. If used 12 hours per day, it could deliver half a million doses of radiotherapy over its lifetime, with an amortized cost of about $2 per fraction. Adding the costs of consumables and salaries, each fraction of radiotherapy would cost a few dollars in an LMC. In a study of 11 countries of differing economic status, median costs per treatment dose of radiotherapy were US$11 for linear accelerators and US$4.87 for cobalt machines, with a range from US$1.29 to US$39.59 (Van Der Giessen et al., 2004). One fraction is often enough for producing pain relief for several weeks or months, while 20 to 40 fractions are typically required for curing a cancer such as laryngeal cancer. Radiotherapy is clearly a beneficial technology but is limited in where it can be delivered, in addition to limitations imposed by resources. In general, facilities are limited to urban areas with infrastructure and transportation, and may never be accessible to the largely rural population of much of the developing world.
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Cancer Control Opportunities in Low- and Middle-Income Countries Cancer Management: Chemotherapy Chemotherapy refers broadly to the use of drugs to treat cancer with the intention of producing long-term survival (or “cure”), or at least a substantial increase in the length and possibly quality of life. (Drugs that improve the quality of life of cancer patients during their illness and at the end of life by controlling pain and other symptoms are considered separately in the discussion of palliative care in Chapter 8.) Medical oncologists are the medical professionals trained in the use of chemotherapy. “Cytotoxic” drugs kill cancer cells by several mechanisms. Other drugs—referred to more specifically as hormonal therapy—add, block, or remove hormones to slow or stop the growth of certain cancers (mainly cancers of the breast and prostate). Typically, drugs are used in combinations, not infrequently including three or four drugs, given on a schedule that may be months long. Hormonal therapy with tamoxifen, for breast cancer, may be taken for at least several years. The main classes of cancer chemotherapy drugs are listed in Table 2-6. WHO Model List of Essential Medicines The WHO Model List of Essential Medicines was developed and is periodically revised as a guide for the development of national and local essential medicine lists that “satisfy the priority health care needs of the population” (WHO, 2006a), tailored to each specific situation. The list, organized by category of use, includes a core list and a complementary list. The core list includes the “minimum medicine needs for a basic health care system.” The most efficacious, safe, and cost-effective medicines for “priority conditions”—selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment—are included. Cancer chemotherapeutic agents are on a complementary list (Table 2-7), acknowledging that cancer is a priority condition, but that “specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training” are needed for the appropriate use of the drugs. A full menu of drugs for palliative care, however, is on the core list (see Chapter 7). These are, according to WHO, “intended to be available within the context of functioning health systems at all times in adequate amounts … at a price the individual and the community can afford” (WHO, 2006a). Countries, of course, are free to select the drugs that best meet their needs and budgets, and are available to them. What is actually available may differ considerably from the WHO lists.
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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 2-6 Major Classes of Chemotherapeutic Drugs for Cancer Drug Type Mode of Action and Examples Alkylating agents Kill cells by directly attacking DNA. Used to treat chronic leukemias, Hodgkin’s disease, lymphomas, and certain carcinomas of the lung, breast, prostate, and ovary. Cyclophosphamide is a commonly used alkylating agent. Nitrosoureas Act similarly to alkylating agents and also inhibit changes necessary for DNA repair. Cross the blood–brain barrier and are therefore used to treat brain tumors, lymphomas, multiple myeloma, and malignant melanoma. Carmustine (BCNU) and lomustine (CCNU) are the major nitrosourea drugs. Antimetabolites Block cell growth by interfering with certain activities, usually DNA synthesis, halting normal development and reproduction. Used to treat acute and chronic leukemias, choriocarcinoma, and some tumors of the gastrointestinal tract, breast, and ovary. 6-mercaptopurine and 5-fluorouracil (5-FU) are commonly used. Antitumor antibiotics Diverse group of compounds that generally act by binding with DNA and preventing RNA synthesis. Widely used to treat a variety of cancers. Doxorubicin, adriamycin, mitomycin-C, and bleomycin are the most common drugs in this category. Plant (vinca) alkaloids Act by blocking cell division during mitosis. Commonly used to treat acute lymphocytic leukemia (ALL), Hodgkin’s and non-Hodgkin’s lymphomas, neuroblastomas, Wilms’ tumor, and cancers of the lung, breast, and testes. Vincristine and vinblastine are commonly used agents in this group. Hormonal agents Includes adrenocorticosteroids, estrogens, antiestrogens, progesterones, and androgens that modify the growth of certain hormone-dependent cancers. Tamoxifen, used for estrogen-dependent breast cancer, is an example. The Development of Cancer Chemotherapy Development of chemotherapy began in the 1940s and progressed rapidly through the 1960s. Leukemias and lymphomas were the first major classes of cancer to respond to chemotherapy. Early successes led to extensive screening programs of agents both of biological origin (e.g., plants and sea creatures) and synthesized molecules to find agents with anticancer properties. Early on, it was discovered that cancers easily develop resistance to single agents, leading to the common use of drugs in combination, and a continuing search for more effective combinations. “Responses” to single and multiple agents, leading to a temporary reprieve from the cancer, which may last months or longer, are always more common than long-term free-
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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 2-7 WHO Model List of Essential Medicines: Antineoplastic Drugs Cytotoxic Medicines (complementary lista) Asparaginase Powder for injection Bleomycin Powder for injection Calcium folinate Tablet; injectable liquid Chlorambucil Tablet Chlormethine Powder for injection Cisplatin Powder for injection Cyclophosphamide Tablet; powder for injection Cytarabine Powder for injection Dacarbazine Powder for injection Dactinomycin Powder for injection Daunorubicin Powder for injection Doxorubicin Powder for injection Etoposide Capsule; injectable liquid Fluorouracil Injectable liquid Levamisole Tablet Mercaptopurine Tablet Methotrexate Tablet; powder for injection Procarbazine Capsule Vinblastine Powder for injection Vincristine Powder for injection Hormones and Antihormones (complementary lista) Dexamethasone Injectable liquid Hydrocortisone Powder for injection Prednisolone Tablet Tamoxifen Tablet Medicines Used in Palliative Careb The WHO Expert Committee on the Selection and Use of Essential Medicines recommended that all the drugs mentioned in the second edition of the WHO publication Cancer Pain Relief (WHO, 1996) be considered essential. The drugs are included in the relevant sections of the Model List, according to their therapeutic use, such as analgesics. aThe complementary list includes essential medicines for priority diseases for which specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training are needed. bSee Chapter 7, “Palliative Care.” SOURCE: Reprinted, with permission, from WHO (2005b). Copyright 2005 by WHO. dom (“cure”) from cancer after treatment. A caveat of particular importance in LMCs is that chemotherapy (and other treatments) are more effective in the earlier stages of cancer. Cancers that have spread only locally are often curable; those with distant metastases are much less so (with some exceptions). In this discussion, effective treatment refers mainly to earlier stage cancers. While palliative care and pain control medications can be beneficial
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Cancer Control Opportunities in Low- and Middle-Income Countries to patients with late-stage cancers, even the most effective chemotherapy is unlikely to prolong life significantly. Through the 1980s, effective drugs for testicular cancer and other malignancies of children and young adults were found. Many of these treatments involve only drugs. Drugs are also used as an “adjuvant” to cancer surgery. Adjuvant chemotherapy is given either before or after surgery (or both) to kill both remaining cancer cells at the primary site and cells that are circulating or lodged at distant sites where, left unchecked, they may proliferate into metastatic lesions. Successful adjuvant treatments that produce long-term survival in a large proportion of patients are available for some cancers, including cancers of the breast and colon, among the common cancers. For other common cancers, including cancers of the liver, pancreas, brain, and melanomas, no currently available drugs produce large benefits for a large proportion of patients. For still others, such as stomach cancer, the diagnosis is most often made (outside of screening programs) at a late stage, when treatment is unlikely to be effective. A new era has begun with the advent of “targeted” agents for cancer chemotherapy (Box 2-3). Delivery of Chemotherapy The way chemotherapy is administered has a bearing on the settings in which it can be given. The most common routes of administration are by mouth, intravenously, intramuscularly, and topically. Less commonly, drugs are infused directly into body cavities, such as the abdomen (intraperitoneal), the lung (intrapleural), or the central nervous system (intrathecal). It is not uncommon for more than one route to be used for a chemotherapy regimen that involves several drugs. Depending on the route of administration and other factors (e.g., need for monitoring), treatments can be given in a medical office or clinic, or in a hospital as an inpatient or outpatient. Laboratory tests are usually carried out periodically to monitor the blood and organs for side effects (the specifics depend on the cancer and the treatment). Treatment regimens not uncommonly stretch over 6 months or more, with treatments occurring in cycles (periods of active treatment and rest). In a cycle, treatment may be daily, weekly, or at some other interval. Side Effects The predominant strategy with cytotoxic drugs is to give them at the maximum possible total dosage, but in individual increments and over time. Experience in clinical trials over decades has shown that success rates are best with highest doses. However, dose intensity is limited by side effects that occur because of damage to normal tissues. Certain side effects—such as
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Cancer Control Opportunities in Low- and Middle-Income Countries BOX 2-3 Targeted Cancer Therapies Cytotoxic cancer drugs exploit the rapid growth and division of cancer cells compared with normal cells, preferentially killing cancer cells. But cancer cells may not differ so much from normal cells, so significant damage to normal tissue may occur. Newer “targeted” therapies block cancer cells’ ability to grow, divide, repair, and/or communicate with other cells by interfering with specific molecules associated with cancer cells, but not found on normal cells (or found in very small numbers). The successful targeted therapy homes in on the cancer-specific target. There are, theoretically, many targets in the pathway of a single cancer cell, involved with the development, growth, and spread of cancer. Unlike traditional cancer drugs, targeted therapies are taken over a long period of time, possibly for life. In the United States, the dozen or so approved targeted therapies can cost thousands or tens of thousands of dollars per year. Targeted therapies can be a variety of drug types. Some synthetic small molecule drugs work inside cancer cells to disrupt their function. Monoclonal antibodies target receptors on the cell surface. Antiangiogenesis agents block formation of blood vessels within tumors, causing the cells to die for lack of oxygen. Many of the targeted therapies that have been or are being developed target proteins that are involved in cell signalling, interfering with the molecular signals that instruct cells to grow and divide as cancer cells. These include Herceptin (trastuzumab), a monoclonal antibody; the small molecules Gleevec (imatinib) for some types of myelogenous leukemia (CML) and gastrointestinal stromal tumors; and Iressa (erlotinib), for some cases of lung cancer. Other targeted therapies cause cancer cells to die (undergo apoptosis), including Velcade (bortezomib) to treat multiple myeloma. Avastin (bevacizumab) blocks the formation of blood vessels. About a dozen targeted therapies have been approved in one or another high-income country, most for limited indications. Many more are in clinical trials. The hope is that eventually, an individual’s tumor will be characterized by the particular set of molecular markers present, and treatments will be targeted to interact with them. The specificity of the interactions should mean less damage to normal tissue, hence, fewer side effects. hair loss—can be distressing, but are usually temporary. More serious are effects on proliferating cells in the digestive tract, bone marrow, or elsewhere, which may result in suppression of blood cell formation, debilitating nausea, and other effects (Stewart and Kleihues, 2003). Little information is avail-
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Cancer Control Opportunities in Low- and Middle-Income Countries able on the impacts of chemotherapy on patients in LMCs, who may have different profiles than those in high-income countries in their co-morbidities and nutritional status, at a minimum. Implications for LMCs The facilities and trained personnel for prescribing an appropriate regimen, for administering chemotherapy, for conducting laboratory testing, and for managing side effects are bare necessities where chemotherapy is going to be used. The protracted schedule of chemotherapy regimens means that patients must be able to get to the treatment site and have financial access to treatment. A reliable supply of drugs, which in most LMCs must be imported, is implicit. Based on information assembled for this report, these conditions cannot be met in a large proportion of LMCs. A global view is not available, but in Latin America and the Caribbean, chemotherapy drugs are often not available, out-of-pocket costs for patients are high because few governments cover the costs, and there are few public cancer centers (Eisenchlas, 2006). We know from pediatric cancer treatment experiences in LMCs around the globe that abandonment of treatment—stopping before a long regimen is complete—is among the top problems identified (see Chapter 6). Cancer Management: Psychosocial Services People with cancer may experience psychosocial distress at any point from diagnosis through treatment, during advanced illness, and even during long-term survival. Psychosocial distress is defined as an unpleasant emotional experience that may be psychological, social, or spiritual in nature. These feelings may become severe and disabling, and may result eventually in a diagnosis of major depression. Transition points in treatment (time of diagnosis, awaiting treatment, completion of treatment) often trigger worsening distress (IOM, 2004). Psychosocial support enables patients with cancer to cope and deal with the disease, its impact, and with life after cancer. This form of support can be made available at all stages of the cancer experience—at diagnosis, during treatment, and beyond, including during palliative care. Support may also be needed by family members and others close to the patient. Psychosocial interventions are accepted as an essential component of cancer care, although they are often not well developed. Little information is available about these services in LMCs. At the most basic level, people with cancer need help coping with their illness through personal interaction and empathy from caregivers and other knowledgeable individuals. Social and emotional support focuses on adjusting to the diagnosis, apprehension
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Cancer Control Opportunities in Low- and Middle-Income Countries regarding treatment, and existential concerns (IOM, 2004). In addition to information about the treatment, a wide range of specific interventions have been described, including the following: Psychotherapeutic interventions, including brief crisis counseling, group therapy and counseling, pastoral counseling, family therapy and counseling, grief therapy, and sexual counseling Psychopharmacologic interventions Complementary therapies, such as yoga, massage, exercise, acupuncture, art, music, and dance therapy, and others A variety of providers can deliver psychosocial services. In many places, nurses are on the front lines of cancer care, and this includes psychosocial support. Physicians, including primary care physicians and specialists, also can provide support, if the patient has access to them. Social workers, psychologists, counselors, and religious workers also can give the needed support. Patient support groups organized by cancer survivors are among the most common sources of support. Community-based traditional resource systems can be tapped to offer psychosocial support to patients and family members. Reach to Recovery International (RRI) is an example of psychosocial support from breast cancer survivors, under the auspices of the International Union Against Cancer. RRI affiliates have been established in every region of the world, but are all run locally. The program is built on the premise that one woman who has experienced breast cancer herself and received specialized training gives of her time and experience to support another woman facing the same challenges. The types of services most needed by cancer patients are likely to be similar around the world, but the providers who are available and have sufficient training will vary according to the health care system, as will the resources available, and other social and cultural factors. SUMMARY AND RECOMMENDATION The review of causes and risk factors and of cancer control elements sets the stage for the latter chapters of this report, where the greatest opportunities for cancer control are identified. What comes from this review is that a few causes and risk factors are prominent in cancers common in LMCs: tobacco use; infectious agents, particularly hepatitis viruses, HPV, and H. pylori; and dietary factors, too little exercise, and too much body mass. A lot of factors have smaller, yet not insignificant, effects. The factors vary with how easily they can be modified. Tobacco smoking is addictive and difficult for people to stop once started, yet certain interventions are
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Cancer Control Opportunities in Low- and Middle-Income Countries effective (more in Chapter 5). We have the tools now to prevent nearly all hepatitis B and most cancer-causing HPV infections. Changing behavior related to diet and exercise has proved exceptionally challenging in the high-income countries where work has been done, and there is little to offer in this regard to LMCs at the moment. In 10 years, new knowledge about behavior change and about the causes of cancer could allow greater scope for direct intervention to prevent cancers. Cancer management—the mix of treatment and support interventions for people with cancer—has been developed and continues to evolve in high-income countries. While all the elements of cancer management could be applied in LMCs (not only for the rich minorities in LMCs), they may need modification for best effect (as basic as adjusted doses of chemotherapy for populations with different co-morbidities and nutritional status). However, in all cases, they require careful consideration of the circumstances in which they are being used, which may be vastly different from those in high-income countries. The point is made that cancer management often requires multiple interventions, necessitating a mix of medical expertise and support services, and appropriate facilities. The discussion of how this can best be accomplished continues in Chapter 8, which is about cancer centers in LMCs. Cancer prevention includes an array of activities, some outside the health care system (e.g., increasing tobacco taxes), some in the primary care system (e.g., infant vaccination against HBV), and others under more specialized conditions (e.g., screening for precancerous changes in the cervix). Which prevention activities any country can and will adopt will depend on their specific circumstances. These decisions and others about cancer control at a national level are best approached through a formal process that weighs the opportunities against the costs within the country context. National cancer control planning and the development of national cancer control programs is the obvious means for making such decisions. In this area, we defer the details to WHO, UICC, and other organizations that provide guidelines and recommendations referenced in this chapter. No other specific recommendations come out of this chapter directly, but the discussion here leads to recommendations in the remainder of the report. RECOMMENDATION 2-1. Cancer control plans should be developed, or updated, in each country every 3 to 5 years through a process that involves all major stakeholders, public and private sectors, as described by WHO, UICC, and others. Cancer control plans should be promoted and supported financially and programmatically through both government action and public advocacy.
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Representative terms from entire chapter: