6
Compelling Opportunities in Global Cancer Control

Where cancer control is currently limited and resources are scarce for all health and social expenditures, decisions about expanding services has to be pragmatic and focus on interventions that are guaranteed to provide substantial benefit. Priority setting among the sectors, within the health sector, and within cancer, all require consideration of economic, political, and ethical perspectives, as well as the qualities of equity and fairness. Different countries with similar circumstances may make very different decisions. This stream of priority setting is not a focus of this report, although the report does attempt, through presentation of evidence, to make a strong case for considering the expansion of cancer control in every country. This chapter discusses interventions that would provide such benefit in most, if not all, countries.

In this report, we have seconded the already-strong efforts in tobacco control, for all the reasons discussed in Chapter 5. Palliative care, the subject of Chapter 7, represents a set of services that will benefit large numbers of people at reasonable cost, and will never become obsolete. In this chapter we identify three additional areas of opportunity with the potential to save lives now and in the future and to build capacity in cancer control where it is currently limited. They are:

  • Increased coverage with hepatitis B virus (HBV) vaccine to prevent most liver cancer globally

  • Cervical cancer prevention through cost-effective screening and treatment, and planning for the expeditious adoption of human papillomavirus



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Cancer Control Opportunities in Low- and Middle-Income Countries 6 Compelling Opportunities in Global Cancer Control Where cancer control is currently limited and resources are scarce for all health and social expenditures, decisions about expanding services has to be pragmatic and focus on interventions that are guaranteed to provide substantial benefit. Priority setting among the sectors, within the health sector, and within cancer, all require consideration of economic, political, and ethical perspectives, as well as the qualities of equity and fairness. Different countries with similar circumstances may make very different decisions. This stream of priority setting is not a focus of this report, although the report does attempt, through presentation of evidence, to make a strong case for considering the expansion of cancer control in every country. This chapter discusses interventions that would provide such benefit in most, if not all, countries. In this report, we have seconded the already-strong efforts in tobacco control, for all the reasons discussed in Chapter 5. Palliative care, the subject of Chapter 7, represents a set of services that will benefit large numbers of people at reasonable cost, and will never become obsolete. In this chapter we identify three additional areas of opportunity with the potential to save lives now and in the future and to build capacity in cancer control where it is currently limited. They are: Increased coverage with hepatitis B virus (HBV) vaccine to prevent most liver cancer globally Cervical cancer prevention through cost-effective screening and treatment, and planning for the expeditious adoption of human papillomavirus

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Cancer Control Opportunities in Low- and Middle-Income Countries (HPV) vaccine to prevent infection with the viral agents that cause cervical cancer Expansion of global capacity to treat the highly curable cancers of children and young adults HBV vaccines have been available for 20 years and are now inexpensive, but still not being used in areas with some of the highest liver cancer rates. The reasons are detailed in the first section of this chapter. This is the most straightforward and obvious cancer control intervention that requires added support from the global community. One vaccine for HPV just entered the market in 2006 and another is soon to follow. A global consortium has given this intervention high visibility, and it, too, deserves continued support toward implementation. In the meantime, advances in understanding the natural history of cervical cancer have led to approaches to screen for and treat precancerous changes in adult women who will not benefit from vaccines. These approaches have proven feasible in some low- and middle-income countries (LMCs), and should be expanded. The final opportunity is to expand the availability of treatment for highly curable cancers of children and young adults. The number of children with cancer is small, but the lives saved can be long and productive. Of all the interventions described, treating children with cancer will give immediate positive results, demonstrating the curability of cancer. REDOUBLED EFFORTS TO INCREASE THE UPTAKE OF HEPATITIS B VACCINATION Liver cancer—hepatocellular carcinoma (HCC)—is the cause of more than 500,000 deaths each year worldwide, making it the third most frequent cause of cancer deaths in LMCs. It is currently the most preventable cancer caused by an infectious agent, chronic infection with HBV. Chronic HBV also causes significant numbers of deaths from liver cirrhosis and liver failure (Lavanchy, 2004), and an estimated 40,000 worldwide die from acute hepatitis infection (Goldstein et al., 2005). The prevalence of HBV varies widely among regions. About 45 percent of the world’s population lives where HBV prevalence is high, with the highest endemicity being in Asia, sub-Saharan Africa, and the Pacific. Other areas where infection rates are high include the southern parts of Eastern and Central Europe, the Amazon basin, the Middle East, and the Indian subcontinent. About 350 million chronic carriers are alive today, of whom 15 to 40 percent will die as a result of HBV, many in middle age. HBV is the 10th leading cause of death worldwide, and HCC is the 5th leading cause of cancer deaths, of which about 80 percent occur in developing countries (Lavanchy, 2004).

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Cancer Control Opportunities in Low- and Middle-Income Countries Infection with HBV and Other Hepatitis Viruses Viral hepatitis—an inflammation of the liver—can be caused by at least six mostly unrelated viruses in humans. Some cause only acute disease (e.g., hepatitis A) and others, like HBV, can cause acute and chronic disease (although an acute phase is not a prerequisite for chronic infection). HBV is the predominant cause of chronic infection and chronic liver disease in the world, but the hepatitis C virus (HCV) is also responsible for one-quarter or more cases. HBV, because of its importance and the existence of an effective vaccine, is the focus of the remainder of this section. HCV vaccine development is ongoing and, if successful, would provide a way to prevent another part of the liver cancer burden. Where HBV is widespread, babies may be infected perinatally by their mothers in the period shortly before and after birth, or during early childhood from contact with other children. Where HBV is less prevalent, more new infections occur among adults, from needle sharing among infected individuals, unprotected sexual contact with an infected person, and blood transfusions of infected blood. HBV is highly infectious and robust, and can survive outside the body. Acute clinical hepatitis may or may not develop at the time of HBV infection. Few babies (about 1 percent of those infected perinatally) develop acute disease, but it becomes more common at older ages (about 30 percent of new infections). Regardless of the development of clinically apparent disease, people who clear their infections become immune for life. However, the earlier the infection occurs, the more likely it is to become chronic. As many as 90 percent of babies infected perinatally, and 30 percent of children infected before age 5, become chronically infected carriers, while the same is true of only about 6 percent of those infected as adults. The Role of Co-Carcinogens in the Development of HCC People with chronic HBV infection are at much higher risk of HCC when they are also exposed to a co-carcinogen that is synergistic with the virus. The most widespread known co-carcinogens are “aflatoxins,” which are chemicals produced by a genus of fungus (Aspergillus) that grows on many types of stored grains and other foods. Groundnuts (peanuts) and corn, dietary staples for millions of people, are particularly susceptible. People with exposures to both HBV and certain common aflatoxins have about a 60-fold increased risk of HCC compared with exposure to neither (Kensler et al., 2003). Other mycotoxins (products of other fungi) contaminate stored foods, mainly in developing countries with hot, humid climates. Up to one-quarter of the world’s food supply may be contaminated with mycotoxins (Turner et al., 2002). Aflatoxin contamination can be reduced by low technology techniques such as drying crops in the sun, discarding

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Cancer Control Opportunities in Low- and Middle-Income Countries moldy kernels before storing, and storing in natural fiber sacks on wooden pallets. Such efforts may be worthwhile, although they are more complex and difficult to achieve than vaccination (Hall and Wild, 2003). The relationship of HBV, aflatoxins, and HCC is probably the best studied example of a virus–chemical interaction acting synergistically to vastly increase the risk of a cancer. The relationships have been established definitively in epidemiologic studies and in animal models. Both HBV and exposure to aflatoxin (through ingesting contaminated food) are detectable in blood samples, a factor that has added to the ability to study their relationship to HCC and other liver diseases (Turner et al., 2002). Preventing Deaths from Hepatocellular Carcinoma (and Other HBV-Related Liver Diseases) If new HBV infections could be prevented, most deaths from HCC and other HBV-related liver diseases would be avoided. Of the 350 million living HBV carriers, some proportion of deaths could also be avoided by modifying exposure to co-carcinogens. There are also treatments for chronic HBV, but they are expensive, toxic, and only partially effective. The intervention with the greatest potential for controlling HBV-related cancer and other deaths is HBV vaccination. For people already infected, reducing exposure to aflatoxin or modifying its effect through diet and reducing excessive alcohol consumption can help. HBV Vaccination An HBV vaccine suitable for widespread public use has been available for more than 20 years. Currently, both a plasma-derived and a recombinant DNA vaccine are available for $0.25–.50 per dose ($0.75–1.50 for the series). The three-dose series of HBV vaccine is 90 to 95 percent efficacious in preventing infection (Centers for Disease Control and Prevention, 2003). The first nationwide vaccination program began in Taiwan in 1984. It was a phased program that first vaccinated babies of carrier mothers, then all newborns, then unvaccinated preschool and elementary children. Since 1991, catch-up vaccinations have been given to unvaccinated children in first grade. Overall HBV prevalence (as measured by hepatitis B surface antigen, or HBsAg, in blood) declined from about 10 percent in 1984 to less than 1 percent in 1999 (Lavanchy, 2004). Similar declines where chronic infection rates were historically high have been documented in the Gambia, China, Indonesia, Senegal, Thailand, and among Alaska natives. Strategies for vaccine use and vaccination schedules may vary by HBV endemicity levels (Table 6-1). The higher the prevalence, the higher the perinatal transmission; this means that giving a first dose within 24 hours

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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 6-1 Preferred Strategies Based on Economic Evaluation, According to the Level of Chronic Hepatitis B Endemicity Level of Endemicity Preferred Strategy Based on Recent Economic Evaluationsa Cost Saving to the Health Care Sectora Cost Saving to Societya High Universal neonatal vaccination NDb Yes Intermediate Universal neonatal, infant, or adolescent vaccinationc No Yes Low Universal adolescent or infant vaccinationc No Yes Very low Selective risk groupd No ND ND = not determined. aGeneralizations, based on baseline calculations of recent evaluations. bDependent on the level of available treatment. cDependent on local economic and epidemiologic situation and efficiency of vaccine delivery system. dMost likely more cost-effective than universal vaccination, provided coverage in risk groups is sufficiently high. SOURCE: Reprinted, with permission, from Beutels (2001). Copyright 2001 by John Wiley & Sons Limited. of birth is most important in high-prevalence areas. Other doses can coincide with regular childhood vaccine schedules. Where transmission is less intense, all three doses can be given along with the other routine childhood vaccines. The United States, a low-endemicity country, adopted universal infant vaccination in 1991, supplemented with targeted vaccinations for older children and adults at highest risk of infection. The recommendations have been revised over time toward ever greater coverage, with the aim of eliminating HBV transmission entirely. Cost-Effectiveness of Hepatitis B Immunization Hepatitis B immunization has been the subject of many economic evaluations, nearly all in industrialized countries. These countries also tend to have relatively low prevalence of HBV, with relatively little perinatal or early childhood transmission, but the availability of hepatitis B vaccines has meant that policy makers have had to make active decisions about what should be recommended. A comprehensive review of studies published worldwide between 1994 and 2000 identified 16 cost-effectiveness analyses, 4 cost-benefit analyses, and 3 combined cost-effectiveness and cost-benefit analyses. Among these were only one study in a middle-income country,

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Cancer Control Opportunities in Low- and Middle-Income Countries Romania, and one in a low-income country, China. Romania is categorized as “intermediate endemicity” and China, “high endemicity.” The Romanian analysis was carried out from two perspectives: the health care payer only, and society as a whole. The main analysis used a relatively high discount rate, 7 percent. In a country like Romania—similar to other middle-income countries and certainly all low-income countries—there is little potential to “save” health care costs because virtually no treatment is offered for either the acute or chronic effects of hepatitis B. Not surprisingly, the Romanian analysis found that the vaccination program was not cost saving to the health care system. It was very sensitive to the discount rate, however. At discount rates lower than 4 percent, universal infant immunization would be cost saving for the health care system, and at rates lower than 6.3 percent, it would be cost saving to society. How Many Deaths Could Be Prevented with HBV Vaccination? Using information on infection rates by age, Goldstein and colleagues (Goldstein et al., 2005) developed a relatively simple model to estimate HBV infection rates and mortality from both acute and chronic disease, and the effect that HBV vaccination would have on these outcomes. The model is electronically accessible and is set up to produce estimates for individual countries (Centers for Disease Control and Prevention, 2003). The model In the model, infection was assumed to occur in one of three age periods: perinatal (at birth); early childhood (after birth through 5 years); and late (>5 years). Deaths from cirrhosis and HCC deaths among chronic HBV carriers were presumed to be HBV related, and were estimated from age-specific, HBV-related cirrhosis and HCC mortality curves, adjusted for background mortality. A complete HBV vaccination series (≥3 doses of hepatitis B vaccine, including the first dose within 24 hours of birth) was estimated to be 95 percent effective in preventing perinatal HBV infection (postexposure immunization) and early childhood and late infection (preexposure immunization), and was assumed to provide lifelong protection. Where the first dose was given more than 24 hours after birth, infants were considered susceptible to perinatal infection, but protected from early childhood and late infection. Values were varied in several sensitivity analyses. The central estimates are discussed here. Calculations using the model Results based on the 2000 birth cohort were calculated. With complete global immunization, including a birth dose, it should be possible to prevent 95 percent of all HBV-related deaths. Without a birth dose, the estimate is 75 percent of HBV-related deaths prevented.

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Cancer Control Opportunities in Low- and Middle-Income Countries With coverage increasing from 50 to 80 to 90 percent, the proportion of deaths prevented increased from 38 to 60 to 68 percent. With 90 percent complete vaccine series coverage, administration of a birth dose to 50 percent and 90 percent of the vaccinated birth cohort increased the proportion of deaths prevented to 77 percent and 84 percent, respectively. This is basically a static model looking at a single birth cohort. As immunization rates rise and prevalence falls, the effect of vaccination will be greater in later cohorts. Results by World Health Organization (WHO) region (Table 6-2) show the greatest potential gains in the Western Pacific, Southeast Asia, and Africa. At the highest coverage, including a birth dose, more than 1 million premature deaths of the 2000 birth cohort could be prevented. Most of these would be deaths from HCC. Global Vaccine Coverage As the price of HBV vaccine declined, universal vaccination became a realistic goal. In 1992, WHO recommended that all countries with a high hepatitis B disease burden introduce HBV vaccine into their routine immunization programs by 1995, and that all countries do so by 1997. These targets were not met, however. The greatest shortfalls were in the poorest countries, most of which have high HBV burdens. Before 2000, only seven TABLE 6-2 Reduction in Future Hepatitis B-Related Deaths: Hepatitis B Disease Burden Model     Proportional Reduction in Deaths with Three Doses of Hepatitis B Vaccine WHO Region Number of Deaths in 2000 Birth Cohort without Vaccination No Birth Dose 50% Birth Dosea 90% Birth Dosea Africa 276,000 70% 78% 84% Americas 28,000 66% 6% 84% Eastern Mediterranean 96,000 74% 80% 84% Europe 56,000 72% 79% 84% Southeast Asia 368,000 71% 78% 84% Western Pacific 581,000 63% 74% 83% Global 1,405,000 68% 77% 84% aProportion of the vaccinated cohort receiving the first dose of vaccine within 24 hours of birth. SOURCE: Reprinted, with permission, from Goldstein et al. (2005). Copyright 2005 by the International Epidemiological Association.

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Cancer Control Opportunities in Low- and Middle-Income Countries BOX 6-1 The Global Alliance for Vaccines and Immunization and the Vaccine Fund The Global Alliance for Vaccines and Immunization (GAVI) was established in 2000 with the goal of increasing immunization rates in the poorest countries and reversing widening global disparities in access to vaccines. Countries with gross national income (GNI) levels below $1,000 are eligible for assistance from GAVI through the associated Vaccine Fund. GAVI partners include governments in industrialized and developing countries, UNICEF, the World Health Organization, the World Bank, nongovernmental organizations, foundations, vaccine manufacturers, and public health and research institutions. The Vaccine Fund has been financed by the Bill & Melinda Gates Foundation and by 10 governments to date—Canada, Denmark, France, Ireland, Luxembourg, the Netherlands, Norway, Sweden, the United Kingdom, and the United States—as well as the European Union and private contributors. Countries eligible on the basis of GNI must submit proposals to GAVI for Vaccine Fund support. Proposals are reviewed by a panel of experts from around the world. Currently, The Vaccine Fund offers the following support to qualifying governments: New and underused vaccines, currently hepatitis B virus (HBV), Hib, and yellow fever; Funding to help governments strengthen their basic immunization services; and Safe injection equipment in the form of auto-disable syringes and safe disposal boxes. As of December 2003, more than 42 million children had been vaccinated with GAVI-supported HBV vaccine. (less than 10%) of the poorest countries were using HBV vaccine in their routine immunization programs. When the Global Alliance for Vaccines and Immunization (GAVI) (Box 6-1) was established in 2000, HBV vaccine was one of the underused vaccines in its portfolio. The GAVI partners set a new milestone, which is for HBV vaccine to be introduced in all countries with adequate delivery systems by 2007. Childhood HBV vaccination has now been adopted by many countries, but there is still a wide gap between rich and poor countries. In 2001, 137 of 191 WHO Member States had universal infant or childhood HBV vaccination programs. An estimated 32 percent of infants were fully vac-

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Cancer Control Opportunities in Low- and Middle-Income Countries cinated, with a range of 65 percent in the Western Pacific, to 58 percent in the Americas, to less than 10 percent in Southeast Asia and Africa. By May 2003, the number of countries with a universal childhood HBV vaccination policy had risen to 151, but that included only about half (24 out of 46) of the African countries (Centers for Disease Control and Prevention, 2003). Eighty-nine WHO Member States have historically high HBV prevalence (HBsAg ≥ 8%), where infant vaccination is of particular importance. Of these, 64 have adopted universal infant vaccination, and of these, 34 have a policy to administer the first dose at birth, which is the best way to prevent perinatal transmission. Fifty of the more than 70 countries eligible for support from the Vaccine Fund, the financing arm of GAVI, had approval for HBV vaccine funding as of December 2004 (although implementation varies). Coverage of at least 50 percent for the basic infant vaccines (three doses of DTP: diphtheria, tetanus, polio) is required before a country can request support for HBV vaccine. For countries with less than 50 percent DTP3 coverage, GAVI offers assistance to improve the immunization infrastructure and boost basic coverage. The Vaccine Fund will cover the purchase of hepatitis B vaccine and safe injection equipment for 5 years, together with a single payment of $100,000 to facilitate the introduction of the new vaccine. GAVI will then work with countries to develop a financial sustainability plan to ensure continued financing for hepatitis B vaccine once Vaccine Fund support ends. Can More Be Done to Increase HBV Vaccine Coverage? The global community can continue to encourage countries to include HBV vaccination with their childhood immunization programs, and particularly in high-prevalence countries, to start with a birth dose. Both a financing mechanism (at least in the short term) and technical assistance are on offer from GAVI and the Vaccine Fund. If some countries have been reluctant to request funds to begin because of the longer term cost, GAVI could extend financing for a longer period (as they are doing with the Hib vaccine in some places). Overall, further gains will depend on improving the vaccination infrastructure and implementation, both of which are likely to be slow processes in the countries that are already lagging. With poor coverage of even the standard childhood vaccines, HBV will not be the main driver for improvement. REDUCING THE TOLL OF CERVICAL CANCER IN LMCS Nearly half a million women around the world develop cervical cancer each year and 270,000 die from it. More than 80 percent of the cases and

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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 6-3 Incidence and Mortality from Cervical Cancer by Income Group of Countries Country Income Group Cases Per Year Deaths Per Year High income 54,000 22,000 Upper middle income 37,000 17,000 Lower middle income 161,000 87,000 Low income 238,000 147,000 World 490,000 273,000 SOURCE: Barton et al. (2005). a slightly higher percentage of the deaths are women in LMCs (Table 6-3) (IARC, 2004). The burden of disease is highest in Africa, Latin America, and South and Southeast Asia. Virtually all cases of cervical cancer are caused by persistent infection with certain oncogenic strains of HPV, a very common sexually transmitted virus. For most women initially infected with HPV, the infection clears with no intervention; these women are no longer at risk for cervical cancer. For those who remain infected, cervical cancer can develop through a long—usually decades-long—process of cellular change. Even before the details of this progression were understood completely, most cervical cancer in high-income countries was being prevented by frequent screening for abnormal (but not yet cancerous) cells on the surface of the cervix, which can be removed using relatively simple, minimally invasive procedures. The more detailed understanding of how cervical cancer develops, and the role of HPV, has led to new screening and treatment approaches, as well as the development of vaccines to protect against HPV infection, one of which just entered the market in 2006. These new approaches, still relatively early in development, are discussed later in this section. Cervical Cancer and HPV The epidemiologic study of cervical cancer dates to the 18th century and Bernardino Ramazzini’s observation that “cancer of the womb” was uncommon among Catholic nuns, but common among married women (American Cancer Society, 2005). A link with sexual activity was long suspected, eventually leading to the discovery that cervical cancer is caused by a sexually transmitted infection. It is now understood that 90 percent of women infected with HPV will clear their infections within a few years. HPV infection will persist in the remaining 10 percent, who make up the population at risk of cervical

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Cancer Control Opportunities in Low- and Middle-Income Countries TABLE 6-4 Distribution of HPV Types in Invasive Cervical Cancer in All Studies HPV Type Estimated Number of Cases Observed Percentage of All Cases Observed Percentage of Cases (cumulative) 16 251,200 53.5 53.5 18 80,900 17.2 70.7 45 31,600 6.7 77.4 31 13,700 2.9 80.3 33 12,100 2.6 82.9 52 11,000 2.3 85.2 58 10,000 2.2 87.4 35 6,600 1.4 88.8 59 6,100 1.3 90.1 56 5,800 1.2 91.3 51 4,600 1.0 92.3 39 3,200 0.7 93.0 68 2,700 0.6 93.6 SOURCE: Adapted from Munoz et al. (2004). cancer (Bosch and Muñoz, 2002). A vast body of evidence supports this understanding and is now fully accepted. To summarize, studies worldwide have consistently found HPV in 95 to 100 percent of cervical cancer cells, and in virtually all cases of cervical intraepithelial neoplasia (CIN) (Bosch et al., 2002). More than 90 percent of cervical cancers have the same 10 to 15 types of HPV (Table 6-4) (Bosch et al., 1995), and metastases contain the same types as in primary sites (Lancaster et al., 1986). Morphological changes in oncogenic HPV studied in cells in the laboratory (in vitro) closely resemble the changes seen during the progression from normal to cancerous tissue in women (Meyers and Laimins, 1994; Steenbergen et al., 1996). In cervical lesions, the HPV viral genome is always active, increasing in viral numbers as the lesion increases in severity (Stoler et al., 1992). In 1995, the International Agency for Research on Cancer (IARC) categorized HPV (types 16 and 18; see below) as “carcinogenic to humans” (“Group 1”), which denotes IARC’s highest level of evidence for a causal association (IARC, 1995). Transmission of HPV HPV is transmitted almost entirely through sexual intercourse. The risk of acquiring HPV increases with the number of sexual partners and with early age at first sexual activity (IARC Working Group, 2005). A history of sexually transmitted infections (STIs) of women and their partners, male circumcision, and the presence of penile HPV have also been shown to be

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Cancer Control Opportunities in Low- and Middle-Income Countries of Central American Pediatric Hematologists-Oncologists. The program would involve collaboration with other international partners already working in the region, including MISPHO and others. The Role of Local Foundations Local nonprofit foundations play two vital roles for IOP partners: they raise funds to support the work of the partners and they run public awareness campaigns about childhood cancers. Governments do not typically provide the resources needed for childhood cancer care, so funds must be supplemented. The IOP, in collaboration with the fundraising arm of St. Jude, sponsors training for members of the local foundations to help ensure their success. The foundations typically develop and support: Care, treatment, and psychosocial support of patients Salaries and training for key personnel Construction and renovation of facilities Efforts to increase government support for childhood cancer treatment Activities to raise public awareness that childhood cancers are curable at early stages The 19 foundations affiliated with IOP partners have raised a total of $12.5 million over the past several years through donations and by soliciting funds from grant-making organizations. These funds have been used to provide housing for patients and families at or near the hospitals, to support salaries of key personnel, and to pay for medications. Paying for medications has proven to be a continuing challenge in most centers. Six foundations reported that some children went without some scheduled treatment because of a lack of funding for medications. Recent Progress St. Jude compiles reports from each IOP partner every year to assess progress. The 2005 report shows progress in a number of major areas for which goals had been set, including the following: Nurse training had been provided to all partner clinical programs over the previous 3 years 18 of 19 programs report a functioning infection control program All partners have immunophenotyping tests (tests that help determine the origin of leukemic cells) routinely available, partially paid for by St. Jude IOP

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Cancer Control Opportunities in Low- and Middle-Income Countries All programs report treatment teams that include four or more subspecialties (pediatric oncologists, oncology nurses, social workers, psychologists, surgeons, dietitians or nutritionists, pharmacists, intensivists) Nearly all report that the hospital has an ethics committee or review board 79 percent of the programs instituted measures to reduce abandonment of treatment (guest houses, food supplements, subsidized transportation, parent support groups, satellite clinics, home visits by social workers) Most sites report active ALL protocols and more than half also have active protocols for a number of other cancers 1,543 patients were treated on protocols from May 2004 to May 2005 Solid tumor diagnosis has been improved in most programs through tumor boards or other special programs The IOP has also encouraged other institutions around the world to collaborate with the IOP-associated programs. New Initiatives Major new initiatives of the IOP include the Central American Retinoblastoma Program to improve survival rates, the Joint ALL Protocol for Beijing and Shanghai, and the Pediatric Oncology Networked Database (POND, a shared electronic database for programs in 10 countries). Improving the Quality of Pediatric Cancer Treatment Through Clinical Trials and Centers of Excellence By the early 1980s, major advances had already raised long-term survival from ALL in the United States and Europe to 70 percent. In LMCs, this was not the case. By way of example, at the Cancer Institute, Madras (now Chennai), India, fewer than 20 percent of the children and adolescents with ALL achieved long-term survival. As a means to improve this situation, a collaboration was established between WIA and the U.S. NCI, and later the NCI-funded INCTR (Shanta, 2000). In the case of the NCI–India collaboration, a more intensive treatment protocol than what had been in use at the time was designed. Although this carried a risk of increased toxicity, in view of the poor results and the extensive disease in most patients, the added risks appeared worth taking. In addition, treatment elements believed to be difficult to administer or particularly costly in India (e.g., high-dose methotrexate) were avoided. An initial trial confirmed that the regimen was feasible and likely to result in much

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Cancer Control Opportunities in Low- and Middle-Income Countries better long-term survival, with high but manageable toxicity. The protocol was taken to two additional major hospitals in India in 1986 and 1992. The process has worked with the use of a locally affordable protocol that has manageable toxicity. During the 1990s, 60 percent of children with ALL treated at the Tata Memorial Hospital (in Mumbai, formerly Bombay) and 41–43 percent of those treated at the All India Institute of Medical Sciences (New Delhi) and the Cancer Institute of Chennai were cured. In addition, deaths from drug toxicity have gradually been reduced as the medical staffs have learned to better manage toxicities. The treatments used do not include unavailable or expensive technologies and could be replicated throughout the country. Results from the three centers differ, and those differences are the basis of further study. The work suggests that not only are there significant differences between Indian populations and patients in the United States and Europe, but among centers in India as well. The India ALL experience demonstrates that although the general principles learned from clinical research in developed countries provide a foundation for treatment strategies, the differences in the populations treated, both genetic and environmental, differences in leukemia cell biology, and differences in the quality of care received can be expected to bring about differences in results when using a standard regimen. It is clear that therapies developed through clinical trials in the relevant populations are essential to quality care. Clinical trials in these settings result in immediate patient benefits. They also contribute to basic scientific knowledge, including gene expression profiling of leukemic cells from patients in these settings, which lead to a better understanding of the genetic and environmental factors relevant both to the pathogenesis of ALL and to the identification of prognostic factors. In the process, three centers of excellence for pediatric cancer have been developed in India that form a strong nucleus for expanding treatment to other centers. Examples of centers of excellence improving the success of pediatric cancer treatment can be found elsewhere. In centers of excellence in Brazil, the 5-year survival rate for childhood ALL is higher than 60 percent, but much lower outside these centers. Another successful model is the national pediatric oncology program in Chile. The Chilean government requires that patients receive their diagnosis and initial treatment in a certified pediatric cancer unit, with follow-up care from more numerous satellite clinics. SUMMARY AND RECOMMENDATIONS Three compelling opportunities to reduce the cancer burden in LMCs have been presented. The first two opportunities, vaccination against HBV to prevent liver cancer and cervical cancer prevention by screening

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Cancer Control Opportunities in Low- and Middle-Income Countries adult women and vaccinating young girls, address two of the three major infection-related cancers. The first, which takes place through existing childhood vaccination programs, is the simplest to implement and is already in place in many countries. The focus there is on many of the poorest countries, where coverage is still poor and liver cancer burdens are high. Cervical cancer prevention, in contrast, is not widely practiced in LMCs. Screening does require a significant infrastructure, not only for the screening itself, but to provide treatment for women who are found with advanced cancers. In some countries, however, the availability of single-visit or two-visit screening (either visual inspection or HPV) may make the opportunity more attractive than it had been. The third opportunity is to establish or improve treatment for the curable cancers of children and young adults. Doing so will build cancer management capacity more generally, and if done properly, will result in a rare class in many LMCs—cancer survivors, whose survival belies an all-too-common belief that cancer is inevitably fatal. Experience has shown that childhood cancer treatment can be financed through a combination of local and foreign sources in countries where it has been seriously attempted. As treatment for children with cancer becomes available, outreach to the public and the medical community can be promoted to develop awareness of childhood cancer and the positive outlook with treatment. RECOMMENDATION 6-1. GAVI and other international partners should continue to assist countries to incorporate HBV vaccination into their childhood immunization programs as quickly as possible, with support from the global cancer community. RECOMMENDATION 6-2. Countries with a high liver cancer burden and significant aflatoxin contamination of foodstuffs should examine the options for aflatoxin exposure reduction. Development partners should help to implement those measures that are feasible and cost-effective. RECOMMENDATION 6-3. Countries should actively plan for the introduction of HPV vaccination as more information becomes available about the vaccines and as they become affordable. The international community should support a global dialogue on HPV vaccine policy and pricing. RECOMMENDATION 6-4. Countries and global partners should follow the evolving information on newer screening approaches and determine the feasibility of adoption, given local resources and infrastructure.

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