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Www3.gehealthcare.com.auPrevention and the of breast cancer
A report commissioned by GE Healthcare, authored by
Bengt Jönsson and Nils Wilking
Br grow cure
nodes Among although
familiar screening malignant
About the authors
Professor Bengt Jönsson
Nils Wilking MD PhD
Bengt Jönsson is Professor Emeritus (Health Economics), department of economics, Stockholm School of Economics, and Director of the Associate Professor Nils Wilking MD PhD has worked in clinical Center for Health Economics. He is currently member of the European oncology for 30 years after graduating from the Karolinska Institute Academy of Cancer Sciences, and of the EU Expert Panel on effective in Stockholm, Sweden. He has worked for many years in the field of ways of investing in health.
surgical oncology, but has since the late 1980s mainly worked within medical oncology with a focus on breast and GI cancer.
He has been a member of the Karolinska University Hospital Board, and the Scientific Advisory Board, National Board of Health and He headed the Breast and GI Cancer Unit at the Karolinska Hospital Welfare, Sweden. He was also Chair of the Expert Group to the during 1992-1998. During this period, he also set up and headed the Committee on Funding and Organization of Health Services and clinical trial unit at the Department of Oncology.
Medical Care in Sweden (HSU 2000), and a member of the National Social Insurance Board from 1992 to 1994, and of SBU (The Swedish In 1998, he joined Eli Lilly as a senior research physician. In 2001, he Council on Technology Assessment in Health Care), Scientific Advisory moved to BMS where he held a European position in their oncology Board 1988-2004.
team. Since 2003, he has worked in a research context linked to the Karolinska Institute. Since 2010, he also serves as Senior Strategic Professor Jönsson is a member of the editorial boards of several Advisor for the Southern Health Care Region in Sweden.
journals, including the Journal of Cancer Policy, European Journal of Health Economics, and International Journal of Technology His main focus has been on research in relation to health service Assessment in Health Care. He has also been a temporary adviser to delivery. This work, in collaboration with Professor Bengt Jönsson the WHO and a consultant to OECD and UNIDO. Professor Jönsson's at the Stockholm School of Economics, has resulted in a number of extensive publications in the field of health economics include over reports with a focus on patient's access to cancer therapy. These 200 papers, reports, and book chapters. Presently he is past president reports include information on more than 55 countries.
and member of the board of the SHEA, the Swedish Health Economics Association and past president of iHEA, the international Health As of 2013 Nils Wilking is the head of the department of oncology at Skånes University Hospital, Lund/ Malmö Sweden.
Prevention and the economic burden of breast cancer Executive Summary Disease Adjusted Life Years (DALYs) Outcome in breast cancer Prevention in high risk groups Secondary prevention, early diagnosis Mammography screening programs Current controversy about screening Breast MRI and other emerging technologies Cost effectiveness of breast cancer screening Conclusions and policy implications Prevention and the economic burden of breast cancer • New evidence on chemoprevention to reduce breast cancer risk
has resulted in revised guidelines, recommending this preventive
• The disease burden of breast cancer is high; every year over 1.4
option for women at high risk.
million women worldwide get breast cancer, and approximately
459,000 women die of the disease. Breast cancer is the second most
• While screening has contributed to improvements in survival,
common cancer form overall and the most common cancer for
there is a debate about benefits, harms and cost-effectiveness of
women, constituting 25% of all female cancer.
alternative approaches to screening. While decreasing incidence in
some populations and improved outcome of treatment may have
• Accurate data on breast cancer incidence at a national level
reduced the benefits of screening, this is not evidence for dismissing
is lacking in several countries due to limited cancer registration.
this option for prevention. In populations with increasing incidence
Available data show that breast cancer incidence rates have
and high mortality/incidence rate, the potential benefits of early
steadily increased in developed countries over the last 50 years.
detection are increasing. There is still a need and opportunities for
In the last decades increased incidence rates are also being seen
appropriately designed screening programs, and for new options
in many developing countries, in particular in parts of Asia. The
for early detection. Targeting specific risk groups and improving
increased incidence of breast cancer is mainly due to increased life
the internal efficiency of the diagnostic process can improve
expectancy but also relates to lifestyle changes, such as women
cost-effectiveness. The present focus in health care systems on
having fewer children as well as hormonal interventions like post-
comparative effectiveness makes it mandatory for new effective
menopausal hormonal therapy.
methods to provide data for assessment of their value in relation to
• The mortality trends are diverging, with declining mortality
in many developed countries, while mortality is increasing in
developing and newly industrialized countries. Survival rates are
also lower in these countries mainly due to the late stage of the
The sustainability of health care systems, and the need to make disease when diagnosed, but also due to limitations in access to
priorities for investments in improved health are at the top of the proper diagnostics and treatment of both early and advanced
health policy agenda (1). Breast cancer is an important and interesting breast cancer.
example of the issues involved. The disease is well defined, and over the last four decades a number of new technologies for prevention, • The economic burden of breast cancer is considerable in terms
early detection and treatment have been introduced, that have of both direct and indirect costs. The direct health care costs
significantly improved the outcome. But the implementation varies attributable to breast cancer vary greatly between countries,
between health care systems, and the search for evidence on best reflecting differences in total health care spending. Hospitalizations
practices is still far from completed. The epidemiology of the disease dominate the direct costs, but costs of pharmaceuticals are also
is also changing, and the most important change is the growing high and increasing. The indirect costs of breast cancer are larger
incidence of breast cancer in developing countries. It is also in the than the direct treatment costs since many breast cancer cases
developing countries that we see the shortest survival due to late occur in women below 65 years.
diagnosis of the disease. There are also variations in survival within developed countries related to socioeconomic status. In the US, despite • While progress in treatment has contributed to improvements
improvements in survival across poverty levels for all known stages in survival, the cost of treatment, particularly for advanced breast
of disease, relative survival remains lower among women residing in cancer, has also increased significantly. The potential benefit of
poor areas compared with affluent areas. This poor outcome probably primary and secondary prevention thus remains high, both in
relates to a more advanced stage of disease at diagnosis. In 2008, health and economic terms, and this applies to both developed and
51.4% of poor women had undergone a screening mammogram in the developing countries.
past 2 years compared with 72.8% of more affluent women (2).
Prevention and the economic burden of breast cancer Investing in health is not only about sustainability of the health care the ageing of populations is a major factor behind the increasing systems, equity in health and access to health care. Breast cancer is an example where investments in health create benefits outside the health care system as breast cancer affects many women of working age. The opportunities to reduce the number of working days lost are an important additional benefit from investment in improving outcomes in breast cancer.
This paper reviews the economic burden of breast cancer, with particular focus on opportunities to reduce the burden through prevention and early detection. The focus on prevention and early detection is important for several reasons. During the last decade focus has been on the costs and survival benefits from the introduction of new drugs for treatment of breast cancer, and to some extent on the refinement of breast surgery, aimed at improving quality of life. During the same period we have seen a growing controversy about the benefits and harms of mammography for early detection in developed countries with decreasing incidence of breast cancer. But at the same time we see increasing incidence in developing and newly industrialized countries, where cases are detected at a late stage. There is thus the need to review the case for development of cost- a Data taken from GLOBOCAN (31).
b ASR = age standardised rate per 100,000 population, using the WHO World Standard Population (32).
c MR:IR= ratio of mortality rate to incidence rate for the region specified in the mortality column. effective methods for prevention and early detection of breast cancer. Table 1 Estimated number of cases and age-standardized rates* for
incidence and mortality of female breast cancer by world region in
2008. Source (3).
Epidemiological data is the basis for determining the burden of a *An age-standardized rate (ASR) is a summary measure of the rate that a population would have if it had a standard age structure. Breast cancer is the most common cancer form in women; with Table 1 shows the incidence and mortality for breast cancer in different an estimated 1.4 million new cases worldwide each year, breast regions of the world in 2008. The total number of cases, or crude cancer constitutes about 25% of all cancer cases in women and is incidence, and mortality, are the best measures for assessing the the second most common cancer form overall (3). Breast cancer can actual health and economic burden of breast cancer in a country or also occur in men, but this is very uncommon. Incidence rates of region. The age-adjusted incidence and mortality is of interest as it breast cancer are significantly higher in developed countries than in shows the influence of risk factors other than age in the development developing countries (72 and 29 per 100,000 respectively, see table 1); of breast cancer. The age span of women affected by breast cancer is the difference in incidence rates between developed and developing broad. Although uncommon, breast cancer may affect women already countries is probably due to a combination of demographic, hereditary, in their 20s and 30s, but close to 90% of all cases are diagnosed from environmental and lifestyle risk factors. Incidence rates are rapidly the age of 40 and onwards .Countries with younger populations have increasing in many newly industrialized countries due to changing lower crude than age-adjusted incidence rates. lifestyles reflecting those patterns in developed countries where we already see high incidence rates. Risk factors that may contribute to The ratio of mortality divided by incidence is an indicator of how breast cancer incidence include: low parity, late first pregnancy, early successful a country is in early detection and treatment of breast start of menstruation as well as exposure to hormonal treatment, oral cancer; the lower the ratio in Table 1 the better. If all cases were cured, contraception, obesity and alcohol consumption. As explained below, Prevention and the economic burden of breast cancer
i.e. women diagnosed with breast cancer would die from something Figures 1a and 1b show incidence and mortality, both crude and age- else, the ratio should be zero, and if all die from breast cancer, the ratio adjusted, for a selection of countries. As can be seen when comparing is 1.0. The ratio of mortality to incidence is 0.24 in more developed figures, in Mexico, Brazil, and Turkey, the crude incidence is lower than regions, and 0.40 in less developed regions. The differences are large the age-adjusted incidence since these countries have relatively young with a ratio of 0.20 in countries such as Sweden for example, and a populations. In these countries the burden of breast cancer is expected ratio of 0.60 in parts of Africa and Melanesia. This difference is mainly to increase rapidly with increasing life expectancy and life style explained by differences in the stage of the tumour at diagnosis, which changes. For example, the total number of reported cases in Mexico reflects the presence of screening programs as well as education and in 1999 was 10,000 compared to 7,000 in Sweden in 2007, although public awareness. Well organized breast cancer care is also a key Mexico has a population 10 times as large as the Swedish population. Figure 2 (below), illustrates the age distribution across the total number North America has an age adjusted incidence and mortality of 83.5 of breast cancer cases in Mexico and Sweden respectively. In Mexico, and 16.7 respectively which gives a mortality incidence ratio of 0.20, the average age at diagnosis of breast cancer is approximately 50 similar to the countries in Western Europe. A closer look at statistics years while the average age at diagnosis in Sweden is 60 years due to from the US, reveals large differences between segments of the the younger population on average in Mexico compared to Sweden [5, population. There are ethnic differences with a higher rate of breast 6]. In both countries, the majority of women are under 65 years when cancer and an inferior outcome in African American women compared they are first affected by breast cancer, which contributes to the large to white. On the other hand the incidence in Asian American women health and economic burden of the disease.
and in Hispanic/ Latina women is lower than that among white and African American women (2).
Figure 2a Breast cancer cases per age group in Mexico and Sweden.
Figure 1a and 1b. Source (4).
Prevention and the economic burden of breast cancer
A barrier to the estimation of global breast cancer incidence is the limited data availability in many countries. Incidence figures in many countries are based on data from small geographic areas that are pooled and extrapolated to represent national data. This is not only the case in most developing countries; the majority of the European countries do not have a 100% national coverage of cancer registration. The Nordic countries are exceptions and Denmark was the first of the countries to establish a national cancer registry in 1942, and other Nordic countries followed with registration on a national level in the 1950s. (10, 11). Figure 3 presents the breast cancer incidence and mortality trends over the last 60 years from the Nordic registries (12).
Figure 2b shows the huge difference in the incidence of breast cancer
at different ages in Sweden and Mexico. Source (4).
China currently has the lowest age-adjusted incidence of the study countries, but one may expect that the fundamental changes in reproductive patterns in China brought about by the implementation in the 1970s of the one-child policy, as well as current lifestyle changes in China caused by rapid economic growth, will potentially lead to dramatically increased rates of breast cancer in Chinese women. Such trends can already be seen in the middle-aged population in urban areas of China, where a 20–30% increase in breast cancer incidence has been documented over the past decade, although part of the increase may also be due to earlier diagnosis and better diagnostic Figure 3 Breast cancer incidence and mortality rates in the Nordic
methods, such as the introduction of mammography (7). countries since the 1950s. Source (4).
A review of breast cancer incidence and mortality in 9 countries in The main picture is one of increasing incidence, and since mid 1990s a the Middle East (8) showed that incidence rates are comparatively declining mortality. Incidence rates seem to have been stable or fallen low, with Lebanon as an exception, which partly can be explained by slightly during the last part of the period. Still, in countries like Sweden underreporting. Incidence rates are increasing, and rates also vary there has been an increased incidence over the last 5 years (see figure within countries between different parts of the population. While 4) (overleaf). This increase is at present difficult to explain, especially progress is made in terms of early detection, many cancers are since the use of post-menopausal hormone therapy has declined diagnosed at a late stage.
significantly over the last decade.
The incidence of breast cancer is low in India, but rising. Due to low awareness of the disease, and absence of screening programs, the majority of breast cancers are diagnosed in a rather late stage (9). Prevention and the economic burden of breast cancer
US and Canada show a similar pattern to the Nordic countries, with reduced incidence and mortality since the early 2000s. For Asian countries, including Japan, incidence is increasing rapidly. (76).
Disability- adjusted life years (DALYs)
Disability-adjusted life years (DALYs) is a measurement for the overall
burden of disease that combines years of potential life lost due to
premature mortality and years of productive life lost due to disability,
with the intention to quantify the gap between current health status
and an ideal health situation (13).
Figure 5 (below), shows the estimated disease burden of breast cancer in DALYs per 100,000 women, separated into years of life lost and years lost due to disability, in the relevant WHO MDG (Millennium Development Goals) Regions.
Figure 5 Number of DALYs lost per 100,000 women, 2004. Distributed
after loss due to mortality and morbidity respectively. Source (13).
The first conclusion is that mortality is the main contributor to the burden of breast cancer measured by DALY. But when more cases are detected, and survival increases, the impact of quality of life during and after treatment is of increasing importance. Although the burden per 100,000 women is highest in developed countries, where incidence rates are high, it is important to recognize Figure 4 Recent development of incidence and mortality of breast
that the disease burden per breast cancer case is higher in developing cancer in Sweden. Number of cases per 100,000 women 1997-2011.
countries due to higher mortality rates in breast cancer and the younger age of women at diagnosis.
Prevention and the economic burden of breast cancer DALYs estimates must be interpreted with some caution. The incidence COST ITEM
TOTAL MILLION SEK
PER CENT OF TOTAL
and mortality data that serve as input to the DALYs estimates are for some countries based on estimates and extrapolation and the Direct cost
calculation method in itself is based on a range of assumptions in order to make this kind of assessment possible. However, the DALY estimates are important both for comparisons between diseases, countries and over time. Table 2 shows an update from 2008 of DALYs lost distributed on more or less developed regions. About two thirds of DALYs lost occur in developing countries, mainly due to reduced survival. Breat cancer (2008)
Estimated disability-adjusted life years (DALYs), years of life lost (YLLs) and years lived with disability (YLDs)
Table 3 Cost of breast cancer distributed by the different cost items.
Source (14). 1 SEK=0.15 USD=0.11 Euro.
This Swedish study estimated that direct health care costs account for less than 10 per cent of the total social costs. Indirect costs for loss of Table 2 Breast cancer (2008) Estimated disability-adjusted life years
production are twice the direct costs. Screening accounts for about (DALYs), years of life lost (YLLs) and years lived with disability (YLDs).
two percent of the total social costs and drugs only about one percent. However, since 2002 the costs for drugs have increased, and in 2011 expenditures on trastuzumab (Herceptin) (for the treatment of HER2 positive breast cancer; approximately 20% of the total breast cancer population) alone was 326 million Swedish Krona (SEK); four times Breast cancer is not only a large health burden but also a significant higher than the total cost of drugs in 2002 (83 million SEK). economic burden to society. The economic burden of breast cancer is not well documented and comprehensive estimations of the cost of Intangible costs are valued at 600,000 SEK per Quality Adjusted Life breast cancer are limited. A Swedish cost-of-illness study estimated Years (QALY) lost, which is less than what is accepted for cancer drugs that while the direct costs (the costs directly linked to treatment, in Sweden (1 million SEK) (77), but a figure representing a more relevant detection, prevention, or care), of breast cancer are significant, the value for intra-marginal changes. It is slightly higher than what has indirect costs of the disease (the cost of lost productivity due to the been accepted in National Institute for Clinical Excellence (NICE) patients' disability and illness and premature mortality), are more decisions about recommending cancer drugs for the NHS in England.
than twice as large as the direct costs (14). This Swedish study also estimated a monetary value of intangible costs due to loss of quality of The estimates above represent the cost of breast cancer from a life and reduced survival, thus providing a link to the measure of health social perspective. It is common that estimates of the costs of breast burden as DALY lost. A comparison of the size of the different cost cancer only take into account part of the social costs. In a study of the components is shown in table 3 below. cost of breast cancer in the Nordic countries, direct treatment costs were estimated at 538 million Euro or just over 20 million Euro per million population, and the public expenditures for sickness and early retirement payments at 216 million Euro (Denmark excluded due to lack of data) (15). The direct cost estimates also excluded part of the costs for ambulatory care, and public expenditures for sickness and Prevention and the economic burden of breast cancer early retirement account for only about one third of the social costs due to lost productivity. Indirect costs due to premature mortality were ignored as well.
Variability in the methodology used and costs included in different studies should be kept in mind when assessing estimates from different countries of the total cost of breast cancer. In France, the total healthcare cost for breast cancer was calculated to be €1,456 million in 2004, of which 55% was for hospital care and 45% was for primary care. Surgery represented approximately 34% of the total hospital care, drug administration and drugs 37%, and radiotherapy 13%. Total indirect costs in France due to potential lost production capacity were estimated to be €1,652 million (16). In Germany the total direct cost of female breast cancer in 2008 was estimated to be €1,956 million. In addition, there is 59,000 years of lost production annually; 17,000 due to disability, 19,000 due to invalidity and 23,000 due to premature mortality (17). In Finland, the cost of breast cancer including direct costs and transfer payments, i.e. healthcare costs, sick day payments and invalidity pension, were estimated to be €65 million in 2004 (16).
Figure 6 gives an overview of the cost estimated from a identified sample of studies. Figure 6b Average indirect costs per breast cancer case (16-19).
Data was recalculated to the average cost per new breast cancer case to make it possible to relate data from different countries; however explicit comparisons between countries must be done with caution since the studies have used different methods. The indirect cost per breast cancer case in Germany presented in the figure was calculated by multiplying the years of lost productivity due to breast cancer in Germany with the average gross salary in Germany.
Most of these cost analyses were based on cost data that are now 5- 7 years old. Since then, some relevant changes have taken place in the treatment of breast cancer, specifically when it comes to the range of drugs available to patients. Drugs were estimated to constitute approximately 10% of direct healthcare costs in breast cancer care in the Swedish study based on data from 2002 (14). The drug share of the total cost of care in cancer has increased in recent years with the introduction of new, targeted biological therapies for the treatment of breast cancer (15). In metastatic breast cancer, according to available data, drug costs constitute a significantly larger share of total healthcare costs in Sweden. They represent 35-40% of total costs (20, 21) and 25% of total costs in the UK (22). The treatment of advanced Figure 6a Average direct costs per breast cancer case (16-19).
Prevention and the economic burden of breast cancer stages of breast cancer is generally more expensive than treatment in There is no direct link between per capita expenditures in healthcare earlier stages (19- 23). (see figure 7 above) and the resources or health care services available to the individual patient. Therefore, one must also take into account Studies of the cost of breast cancer from an incidence perspective how efficiently available resources are utilized in the healthcare system generally only include estimates of the direct health care expenditures. and the different relative costs of, for example, healthcare personnel A review of studies of the cost of treating breast cancer in the US, in different countries. For countries with low health care spending in reveal that the costs are high during the first year after diagnosis an international context, it is important to make a distinction between and in the last phases of the disease (24). Estimates of lifetime per- resources that are available locally at relatively low costs, and those patient costs of breast cancer ranged from $US20,000 to $US100,000. that need to be imported at international prices.
Estimates of life time costs are important as a source of data for modeling the cost-effectiveness of different interventions, from Some of the therapies used in the treatment of breast cancer, such as screening and initial treatment to strategies for management of late radiation and diagnostic equipment, require sophisticated technology stages of the disease. It is thus not surprising that cost estimates vary, for which the cost of establishing and maintaining these medical but a consistent result is that treatment costs for later stages (stage III facilities is high. The WHO recommends that in limited-resource and IV), are higher than for treatment of breast cancer in stage I and II.
countries, medical facilities should initially be concentrated in relatively few places to optimize the use of resources. On the other hand, in Economic evaluations of trastuzumab (Herceptin®) in Sweden, indicate countries with social and economic inequalities, high-tech medical typical life time costs for both adjuvant treatment and treatment of facilities may often be based in areas of the country where wealth is recurrent disease are, 50-60,000 Euros, over an estimated survival concentrated, resulting in a sharp contrast in access to treatments that time of 12 versus 2 years respectively. Cost for adjuvant treatment is the wealthier and poorer populations can achieve, which can be further reduced due to lower costs from fewer recurrences (25-26).
compounded by the remoteness of the more often poorer rural regions(28). Even though data on the economic burden of breast cancer is only available from a selection of countries, the available cost analysis Access to innovative medicines may also be a problem in countries presented above illustrates how the cost per patient differs significantly with low income and health care expenditures, since prices are between countries. This is, to a large extent, a consequence of the total determined by ability to pay in high income countries with well healthcare resources available in a country, and difference in the care established health insurance systems. Patients may thus have to wait provided (e.g. access to high cost cancer drugs).
for access to these medicines until the patent has expired and low price generics become available. However, it should be recognized that there is also a challenge to make optimal use of old medicines, since resources are needed for diagnosis and follow-up to make the treatments effective in clinical practice.
Outcome in breast cancer
The long-term prognosis for breast cancer patients has improved significantly; 10-year survival rates are now 80% in those countries with the best outcomes compared to just over fifty per cent 50 years ago. But we can observe very large differences in survival rates between countries. Such comparisons must be interpreted with caution, since studies often refer to different time periods and patient Figure 7 Per capita expenditure on health for selected countries.
populations. Table 4 below shows latest data from GLOBOCAN 2008(3) Prevention and the economic burden of breast cancer Estimates of 5-year relative survival for female breast cancer in selected countries.a 5-year relative survival (%)
(95% confidence intervalb)
Unites States of America 2005-2007 Republic of Korea a Data taken from Refs. [47,68,70,74-78].
b Confidence intervals are not intended for comparative purposes, but rather to indicate the precision of the estimate.
c Country estimates were only provided to integer precision n.a. = 95% confidence interval not available Table 4 Five year survival rates for female breast cancer in different
countries 2008. Source (3).
Survival rates are higher for developed than developing countries and regions. This is mainly due to the observed differences in survival linked to different stages of the disease at diagnosis. Much of the variation in breast cancer survival between countries is thus likely to be caused be disparities in early detection programs and access to appropriate diagnostics and treatment services. Figure 8 below illustrates the continuous improvement in 5 year survival over time, but also the persistent great difference in long term survival for breast cancer detected at different stages.
The 5-year observed survival rate refers to the percentage of patients who live atleast 5 years after being diagnosed with cancer (Figure 8). Many of these patients live much longer than 5 years after diagnosis. A relative survival rate compares the observed survival with what would be expected for people without the cancer. This helps to correct for the Figure 8 Survival by disease stage in Norway. Source: Kreftregisteret
deaths caused by something besides cancer, and as an alternative way Institutt for populasjonsbasert kreftforskning" (Cancer statistics,
to describe the effect of cancer on survival.
Institute for population based cancer research), Norway, 2009.
Prevention and the economic burden of breast cancer Latest five-year relative survival figures from the US shows 100% in The specific life-style risk factors of breast cancer that are susceptible stage I, 93% in stage II, 72% in stage III and 22% in stage IV. (78).
to primary prevention measures include: breast feeding, obesity after menopause, diet, alcohol, physical activity, oral contraception close to Early detection and treatment are thus the major strategies for menopause, and post-menopausal hormonal treatment (33). The more improved survival after diagnosis. We will later discuss strategies for extensive treatment guidelines from some countries discuss breast prevention and early detection. The importance of early treatment can cancer risk factors, but in the majority of guidelines, risk factors are be illustrated with the introduction of traztuzumab for HER 2 positive only mentioned briefly or not at all (34).
breast cancer. The drug was first introduced for metastatic disease, and in that stage, gave an improved survival corresponding to 0.60–1.00 QALY per treated woman, compared to treatment without trastuzumab, while when used for adjuvant (early) treatment, gave a survival benefit of 0.97–1.22 QALY per treated woman in an estimate for Sweden (29), and 0.56 QALY versus 1.70 QALY in an estimate for the US (30). Since the cost of early treatment is about the same as the cost of treatment of metastatic disease, (50-60 000 USD), but there is improved effectiveness with early treatment, the cost-effectiveness of early treatment is better than later treatment. But it should also be noted that the estimated survival increases are limited to about one year, which reinforces the point that to have a significant effect on the burden of disease, further improvement in survival from primary and secondary prevention is necessary. New drugs show promise for further improvement in outcome of treatment, but they also come at a significant increase in costs (31-32).
The quality of life of patients during and after disease and treatment is an important outcome of breast cancer care and is considered an Prevention in high-risk groups
essential outcome measure in cancer clinical trials. There is still very limited information on quality of life of breast cancer patients from It is estimated that 20–30% of breast cancers are related to genetic clinical trials as well as from clinical practice. Quality of life is more factors that in combination with lifestyle factors can trigger the affected in younger women with breast cancer and in women with development of the disease. Around 4-7% of breast cancer cases are recurrent and metastatic disease (4). directly attributable to certain genetic mutations, most commonly in the BRCA1 and BRCA2 genes, which predispose women to a 60-80% life-time risk of developing breast cancer, often already at a young Primary prevention age. For women with a high genetic predisposition for breast cancer, preventive measures can be taken including; more frequent screening, Primary prevention measures aim to reduce the risk factors for a and at a younger age, or chemoprevention with endocrine therapy. specific disease and/or the individual perceptibility for such risk factors. These drugs however, may have limited impact since BRCA1 carriers Primary prevention of breast cancer is more difficult to achieve than are frequently endocrine unresponsive. The most established strategy for some other cancer forms, for example lung cancer, since most of is preventive surgery including removal of the breasts, although the the breast cancer risk factors are currently not amenable to primary evidence base for this strategy is limited (35).
prevention interventions. However it should be noted that a healthy lifestyle reduces the risk for breast cancer as well as many other Tamoxifen and raloxifen have been available for use as preventive agents in the US for many years (36-39). A recent review, confirms Prevention and the economic burden of breast cancer that the prophylactic use of tamoxifen and raloxifen reduces the Secondary prevention/early diagnosis
incidence of invasive breast cancer. Subgroup analyses and decision models suggest that high-risk women, particularly those who have The aim of secondary prevention is to reduce the severity of disease had a hysterectomy, derive the most benefit with the least harm, the (risk of recurrent and/or metastatic disease) and the risk of dying from researchers report (40).
it. As discussed earlier, outcomes are significantly better if the breast cancer is detected before it has spread outside of the breast. Both drugs have recently been granted market authorization for this indication from EMA in Europe. Women in England with a family However, early-stage breast cancer is not symptomatic in all patients. history of cancer will be able to get the drugs tamoxifen and raloxifen The main objective of early detection or secondary prevention through on the National Health Service as a protection against breast cancer, screening is to detect early stage cancers when they can be treated under new guidelines from the National Institute of Health and Care most effectively. Early detection has been shown to be important Excellence (NICE)(41). It is estimated that about 3% of the female due to the strong association between stage at diagnosis (or tumor population would be indicated for prevention. However, experience size) and survival (44). For most types of breast cancer the likelihood from the US market tells that rather few women use this treatment, of lymph node invasion and worsening tumor grade increases as mainly due to the side effects involved.
tumor size increases (45), leading to poorer long-term survival. Early detection is only valuable if it leads to timely diagnostic follow-up and The American Society of Clinical Oncology (ASCO) has recently issued effective treatment. The principal secondary prevention measure in updated guidelines for chemoprevention (42). In women at increased breast cancer is population-based mammography, combined with risk of breast cancer age ≥ 35 years, tamoxifen (20 mg per day for 5 ultrasound examination in dense breasts in some countries, which has years) should be discussed as an option to reduce the risk of estrogen been shown to improve outcomes as it leads to a larger share of breast receptor (ER)–positive breast cancer. In postmenopausal women, cancers being diagnosed at an early stage in the screened population. raloxifen (60 mg per day for 5 years) and exemestane (25 mg per day Regular self-examination of the breast has also been put forward as for 5 years) should also be discussed as options for breast cancer a measure for early detection of breast cancer. However, there is no risk reduction. Those at increased breast cancer risk are defined as evidence that self-examination has any effect on earlier diagnosis. individuals with a 5-year projected absolute risk of breast cancer ≥ Nevertheless, in many countries with limited coverage of breast cancer 1.66% (based on the National Cancer Institute Breast Cancer Risk screening, the majority of breast cancer is detected when women Assessment Tool or an equivalent measure) or women diagnosed with seek care after having noticed a breast lump, therefore initiatives to lobular carcinoma in situ. Use of other selective ER modulators or other increase the awareness of breast cancer are extremely important so aromatase inhibitors to lower breast cancer risk is not recommended that women are conscious that breast lumps and other changes to the outside of a clinical trial. Health care providers are encouraged to breasts can be a sign of cancer and do not postpone seeking care until discuss the option of chemoprevention among women at increased the symptoms have reached a critical stage. It is also interesting to breast cancer risk. The discussion should include the specific risks and note that a recent retrospective ‘failure analysis' of BC mortality in over benefits associated with each chemo preventive agent.
7000 women found that >70% of deaths from breast cancer occurred However, an ongoing problem is that it is difficult to detect the high- in women who did not receive regular screening mammograms (46). risk woman, who may benefit most from treatment. New research A critical factor in relation to this is access to well organized breast indicates that it may be possible to identify the gene patterns that cancer care, including diagnostic work-up, surgical and non-surgical predict which women are likely to have a positive response to treatment with Selective Estrogen Receptor Modulators (43).
Mammography screening programs
Since the drugs are generic, costs and cost-effectiveness are not an issue, but the resources for identification of risk groups and follow up Although the outcome of breast cancer screening has been debated, may be a matter for consideration. the increased level of evidence available from the countries that implemented screening programs in the 1980s has resulted in breast Prevention and the economic burden of breast cancer cancer screening now being recommended by both the WHO, (in countries where resources are available to ensure effective and reliable screening of at least 70% of the target age group), and the Council of the European Union (EU) (47-49). Screening programs have been implemented for a long time in many countries, while other countries have recently implemented screening programs on the national level or are in the process of doing so. Extensive guidelines for quality assurance of screening programs have been developed for example on the EU level (47). Figure 9 gives an overview of the coverage of screening in a selection of countries. The target population differs between countries but in most, screening is targeted to 50-69 year old women.
In Mexico, mammography is recommended but there is no national population-based screening program and the overall adherence rate to Figure 9 Breast cancer screening coverage in selected countries. (4).
mammography controls is low; a recent survey in Mexico City indicates that many women feel uncomfortable or worried about having Population-based screening is a complex logistical process, from the mammography (50-51). initial invitation of the target population to further referral of patients with a screen result that requires follow-up. The WHO's statement on A recent survey among 1,000 Hong Kong Chinese women aged 18-69 mammography is that it is an expensive test that requires great care years reported that almost 60% of the women had never heard of and expertise both to perform and in the interpretation of results, mammography screening (52). These studies indicate that increased and that therefore population-based screening is not viable in all communication efforts are needed to promote breast examination in countries. Although there is insufficient evidence, good clinical breast groups with low adherence. examinations by specially trained health workers could have an important role when resources are limited (45).
Based on identified data, China, Russia, Mexico, and Denmark have the lowest coverage of breast cancer screening. The situation in the world regarding access to mammography varies. In Russia, where mammography screening is managed at the regional level, coverage and adherence varies greatly between regions (53-55). Prevention and the economic burden of breast cancer One of the goals of Mexican healthcare for the period 2007-2012 is to triple the coverage of mammography screening in women 45-64 years old from the reported coverage of 22% in 2006 (56). In China, the anti-cancer association launched a pilot project called "breast cancer screening for one million women" in 2005, with the objective to offer regular screenings to one million women aged 35-70 years (53). However the project suffered from technical problems and a lack of funding, which meant that the screening could be offered at a reduced price but not free of charge, and by 2006, only 120,000 women had been screened. In 2008, a follow-up project was initiated with the aim to provide screening to women in rural areas and this project has obtained government funding. The ambition is to screen more than half a million women in the next few years. Still this is only a small proportion of the 300 million women that would belong to the target group for mammography screening in China. Some local government schemes have started to offer cancer screening, such as the Beijing government that offers free breast examination for women within a certain age range. One issue with screening in China is that breast cancer is most common in premenopausal women and it is more difficult to detect cancer with mammography in younger women as breast tissue is more dense (57-58). No national or regional breast screening program exists in India. Mammography is available in all major cities in both private and public hospitals for those who are willing to pay for it. Use of mammography for screening is not considered to be cost-effective, partly because of Lately a similar debate has started in the US after the U.S. Preventive the lack of high quality treatment facilities (9). Services Task Force recommendation in 2009 that there was no evidence that women aged 40-49 benefit from routine screening. While Also in countries with a high overall coverage, it has been shown mammography undoubtedly detects early stages of breast cancer, that two groups in particular are underrepresented in breast cancer and reduces mortality in breast cancer (61), there is a renewed debate screening programs; women from lower socio-economic levels and first on the balance between benefits and harms, with consequences generation immigrants. for the way this technology is applied in an optimal manner. The assessment of pros and cons is complicated by the fact that it is Current controversies about screening
difficult to provide evidence about the outcome in clinical practice. It should be noted that this problem is also increasingly evident for new The value of breast cancer screening has been considerably debated, treatments in cancer, where outcome measures used in clinical trials, for example in Denmark (59-60), partly with the argument that such as progression free survival, may not easily be directly translated population-based screening leads to over-diagnosis of cancer in situ into improvements in quality of life and overall survival in clinical that would not have developed into breast cancer, thus incurring unnecessary treatment costs as well as risks and worries for affected women. Recent important evidence comes from a study of the Norwegian breast-cancer screening program that was started in 1996 and expanded geographically during the subsequent 9 years (62). Prevention and the economic burden of breast cancer Women between the ages of 50 and 69 years were offered screening A similar review from the UK estimates that for 10,000 UK women mammography every 2 years. The study compared the incidence- invited to screening from age 50 for 20 years, about 681 cancers will be based rates of death from breast cancer in four groups: two groups found of which 129 will represent over-diagnosis, and 43 deaths from of women who from 1996 through 2005 were living in countries with breast cancer will be prevented. In round terms, therefore, for each screening (screening group) or without screening (non-screening breast cancer death prevented, about three over-diagnosed cases will group); and two historical-comparison groups that from 1986 through be identified and treated. Of the 307,000 women aged 50–52 who are 1995 mirrored the current groups. The rate of death was reduced invited to screening each year, just 1% would have an over-diagnosed by 7.2 deaths per 100,000 person-years in the screening group as cancer during the next 20 years (66). compared with the historical screening group (rate ratio, 0.72; 95% confidence interval [CI],0.63 to 0.81) and by 4.8 deaths per 100,000 These studies conclude that screening for breast cancer has a positive person-years in the non-screening group as compared with the effect on mortality, confirming the results from clinical trials, but that historical non screening group (rate ratio, 0.82; 95% CI, 0.71 to 0.93; the effect is smaller than the effect from improvement of treatment P<0.001 for both comparisons), for a relative reduction in mortality and other factors. It will thus be even more important to optimize the of 10% in the screening group (P = 0.13). Thus, the difference in the screening programs. The development of cost-effective screening reduction in mortality between the current and historical groups methods and strategies is particularly important for developing that could be attributed to screening alone was 2.4 deaths per countries, where the potential health benefits are highest, but the 100,000 person-years, or a third of the total reduction of 7.2 deaths. available resources the lowest (63).
The availability of screening mammography was associated with a reduction in the rate of death from breast cancer, but the screening But also for countries with well-developed screening models, itself accounted for only about a third of the total reduction. improvements in the technology may change the balance of benefits, harms and costs. A particularly important issue is the improvement A recently published paper studied changes in mortality after the in the diagnostic workup to reduce the number of benign biopsies. introduction of screening guidelines for breast and prostate cancers Early detection of tumors through regular screening mammography in the US and UK (67). They used differences in the timing of guideline biennial as per the United States Preventative Services Task Force adoption, which ages are recommended for screening, and which recommendations, (USPSTF), has been shown to reduce breast cancer cancers are detectable by screening to identify the effect of guidelines. but many women turn out to have false positive results. False positive Their quadruple-differencing strategy finds a moderately sized mammograms have large economic consequences due to the cascade mortality benefit from mammography and PSA screening guidelines of tests that follow including diagnostic mammography, ultrasound, among recommended age groups and little change in mortality rates and biopsy. With an estimated 18 million screening mammograms among age groups not recommended to receive screening. The result conducted in the US annually, a false positive rate of 10% amounts to can be compared with an earlier US study, which compared screening almost $1 billion in unnecessary spending (68). Although the number of and adjuvant therapy. The proportion of the total reduction in the rate diagnostic mammograms and ultrasounds prompted by false-positive of death from breast cancer attributed to screening varied in the seven screens each year contributes significantly to the economic burden of models from 28 to 65 percent (median, 46 percent), with adjuvant breast cancer, the most significant cost associated with false-positive treatment contributing the rest (64). mammography screening is the large number of breast biopsies performed, nearly 70% of which result in benign diagnoses (69).
In an attempt to work out the balance between benefits and harm, the EUROSCREEN working group (65) published a "balance sheet" for Simulations performed by a research group at the Fred Hutchinson mammography screening. For every 1000 women screened biennially cancer centre in Washington (70), indicate that the consequences of from age 50–51 until age 68–69 and followed up to age 79, an introducing a new diagnostic in order to reduce the number of positive estimated seven to nine lives are saved, four cases are over-diagnosed, biopsies or as an alternative to diagnostic mammograms and/or 170 women have at least one recall followed by non-invasive ultrasound, are not as clear-cut as may be expected. It comes down to assessment with a negative result and 30 women have at least one a valuation of the different consequences of a false positive and a false recall followed by invasive procedures yielding a negative result.
negative result. But it shows the importance of simulation models as a Prevention and the economic burden of breast cancer tool to help to find cost-effective diagnostic and treatment pathways. These substances include silicone oil and polyacrylamide gel.
Surgical biopsies are still performed at many institutions, but can German investigators reported at the 2013 Breast Cancer Symposium in most instances be replaced by far less expensive percutaneous in San Francisco that an abridged magnetic resonance imaging (MRI) protocol can accurately detect cancers among women whose mammographic screenings were negative. MRI, therefore, may reveal There may be significant opportunities to reduce costs and improve the type of tumor that mammography typically misses, and can do so outcomes also with existing methods for breast cancer screening. A in a time-efficient fashion, thus making MRI feasible for breast cancer Nordic study revealed differences in cost per patient screened between screening (73).
countries; from 34 Euro in Sweden, to 127 in Finland, and with Norway and Denmark in between (15).
Digital breast tomosynthesis (DBT) (74) is a new breast imaging technology that uses tomography and 3-D reconstruction to improve Breast MRI and other emerging technologies
lesion visibility. The U.S. Food and Drug Administration recently approved DBT equipment, and research on its effectiveness continues Magnetic resonance imaging (MRI) has been shown to detect cancers around the world. In 2012, the Automated Breast Ultrasound System not visible on mammograms. The chief strength of breast MRI is its (ABUS) was approved by the FDA as an adjunct to mammography very high negative predictive value. A negative MRI can rule out the for breast cancer screening in asymptomatic women for whom presence of cancer to a high degree of certainty, making it an excellent screening mammography findings are normal or benign (BI-RADS tool for screening in patients at high genetic risk or radiographically Assessment Category 1 or 2), with dense breast parenchyma (BI-RADS dense breasts, and for pre-treatment staging where the extent of Composition/Density 3 or 4), and have not had previous clinical breast disease is difficult to determine on mammography and ultrasound. However, breast MRI has long been regarded to have disadvantages. For example, although it is 27–36% more sensitive, it has been New technological options are welcome, but need to be carefully claimed to be less specific than mammography (72). As a result, MRI evaluated in clinical practice, including an assessment of cost- studies may have more false positives (up to 30%), which may have effectiveness in the screening situation. At present these new undesirable financial and psychological costs. It is also a relatively modalities seems to be very valuable tools in the work-up of women expensive procedure, and one which requires the intravenous injection selected through mammographic screening in order to identify false of gadolinium, which has been implicated in a rare reaction called positive cases, as well as mapping the extent of disease in true positive nephrogenic system fibrosis. Another limitation is access to MRI scanners / available capacity for screening linked to the investment required (cost of the MRI equipment).
Cost-effectiveness of breast cancer screening
Proposed indications for using MRI for screening include: Cost-effectiveness analyses compare the costs and health effects (outcomes) of an intervention to determine the extent to which it • Strong family history of breast cancer can be regarded as providing value for money. This can be used to • Patients with BRCA-1 or BRCA-2 oncogene mutations help inform decision makers who have to determine where and how • Evaluation of women with breast implants to best allocate resources. The cost-effectiveness of breast cancer • History of previous lumpectomy or breast biopsy surgeries screening varies by country and depends on many factors e.g. disease • Axillary metastasis with an unknown primary tumor epidemiology, health care system, costs and compliance rate. The • Very dense or scarred breast tissue majority of studies have been conducted in developed countries and cannot be directly translated to low-resource countries. Many of the In addition, breast MRI may be helpful for screening in women who cost-effectiveness analyses in breast cancer screening have focused have had breast augmentation procedures involving intramammary on comparing different strategies for screening in high-income injections of various foreign substances that may mask the countries, e.g. age range, screening test, frequency of screening appearances of breast cancer on mammography and/or ultrasound. Prevention and the economic burden of breast cancer Assuming that mammography screening reduces mortality in breast discussed, than left to speculation. One advantage of this is that cancer by 20%, 43 deaths are avoided per 10,000 screened using systematic studies usually lead to improvements in the data and figures from the UK screening program (76). The same source gives improved understanding of the drivers of cost-effectiveness, which the estimate of 17 years of life gained per death avoided, which gives can make better decisions and thus better outcomes. The increasing 0.073 LYG per screened woman. The costs of screening programs number of options for early detection of breast cancer makes it also vary between countries, and how the costs are calculated. Ideally, a necessary to use cost-effectiveness to define the detection programs cost-effectiveness calculation should include all costs for screening and that give most value for money. diagnosis and treatment.
Many cost-effectiveness studies of mammography have been Using data from the Nordic study, costs vary from 34 Euro to 127 performed, but since the determinates of both relative effectiveness Euro per woman screened (15). We will use 100 Euro as the base case and costs changes over time, new studies need to be performed. estimate (15). Let us further assume that over a 20-year period, there The development of cost-effective strategies for early detection for are seven screening occasions. This will give a cost per life year gained countries with low and medium income and health care spending of 10,000 Euro. This estimate is consistent with, but in the lower range, levels should be a priority for reducing the burden of breast cancer of earlier studies of cost-effectiveness which have arrived at estimates between 1000 and 30,000 Euro per LYG (75-76). This indicates that screening is a cost-effective method for improving outcomes in breast Conclusions and policy implications
cancer compared to no screening.
• Accurate data on breast cancer incidence and mortality on the
The variation in results between studies is not surprising, taking into national level is lacking in several countries due to limited cancer
account the uncertainties about the clinical outcome of screening. registration. Such data are important for documentation, assessment
There is also limited data to adjust life years gained to quality adjusted and communication of the burden of the disease. There is a need for an life years gained, taking into account both the fact that all life years initiative for collection of such data in a way that makes international gained are not of full quality, and impact of diagnosis and treatment comparisons possible, as well as comparisons over time to assess on quality of life. In addition, it is both conceptually and empirically progress and impact of policy development. difficult to estimate the incremental costs of screening. How much of treatment costs should be included in the cost of screening. Without • Available data show that breast cancer incidence rates have
a screening program, cancer may have been detected later, with a steadily increased in developed countries over the last 50 years.
different stream of costs. Changes in survival also have an impact on In the last decades increased incidence rates are also being seen in costs for treatment of other diseases, and it is debated if changes in many developing countries, in particular in parts of Asia. The increased costs for treatment of other diseases should be included or not. The incidence of breast cancer is mainly due to increased life expectancy inclusion of changes in indirect costs due to reduced morbidity in but also relates to lifestyle changes, such as women having fewer women who are of working age, and the inclusion of costs in added children as well as hormonal interventions like post-menopausal years of life, will also affect the estimates of cost-effectiveness. Finally, hormonal therapy. cost-effectiveness is determined by the design of the screening program, and will differ between patient characteristics, such as age.
• Data on the economic burden of breast cancer in terms of
direct and indirect costs are sparse. Such data are important as
Performing cost-effectiveness studies of screening programs are complements to data on health burden, and for decisions about thus a complicated task and the results will carry a great degree resource allocation for prevention and treatment. They are also of uncertainty. However, decisions about the implementation and necessary for the performance of comparative studies between design of screening programs will be influenced by such estimates. countries and between regions (populations) within countries. There It is therefore better that such studies are performed in a systematic is a need to learn from such comparisons for the development of best way, with data limits recognized and uncertainties around estimates practices for prevention, early detection and treatment. Prevention and the economic burden of breast cancer • The economic burden of breast cancer is considerable in terms of
• New data indicate that options for primary prevention with
both direct and indirect costs. The direct health care costs attributable chemotherapy should be considered in all health care systems.
to breast cancer vary greatly between study countries, reflecting
Programs for this should be developed, and combined with evaluation differences in total health care spending. The indirect costs of breast to find out optimal strategies for different risk groups. cancer are larger than the direct treatment costs since many breast cancer cases occur in women below 65 years, specifically in new • Screening for early detection of breast cancer with the aim of
industrialized countries. improving survival is a key component of a strategy for prevention.
Such programs must be designed to meet the specific situation in
• Improved outcome is related to earlier diagnosis, where there is
different health care systems, taking into account the need to balance a marked correlation between the stage at diagnosis in a country and potential benefits and harms, as well as cost-effectiveness and overall survival rates in breast cancer. Methods for early detection incur affordability. costs and potential harms, as well as benefits, and must be designed according to evidence of the balance between costs and improved • There is great uncertainty around estimates of reductions in
mortality and the magnitude of over-diagnosis from screening, but it
is possible to conclude that breast cancer screening provides important
• The largest survival improvements over the last decades have
benefits and should be continued. Data on cost-effectiveness of been seen in patients diagnosed with stage II or III disease, which
alternative screening strategies are still limited, and both data and is mainly due to early detection and to the introduction of adjuvant methods for evaluation must be improved to provide the basis for treatment. Currently we see a rapid introduction of new effective drugs for treatment of breast cancer that improve survival but also increase the costs of treatment; particularly at the late stages of the disease. • There are significant variations in breast cancer outcomes
in countries with comparable levels of resources dedicated to
healthcare. This indicates an opportunity to improve outcome through
the identification and implementation of best practices in diagnosis
• The lack of detailed, patient linked, data on outcome in relation to
treatment patterns and stage of diagnosis in many countries impedes
and limits analyses of how changes in clinical practice affect outcome.
• Survival is the main focus in the treatment of breast cancer,
but with increasing survival rates more women are living with
the disease, making quality of life during and after treatment
increasingly important. Data on quality of life at different stages of
the disease, and related to different treatment options are still scarce.
There is a need for collecting data on quality of life and quality of care
routinely in clinical practice, for both monitoring and assessment of
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Journal of Modern Medicinal Chemistry, 2014, 2, 1-9 1 Synthesis, Characterization and Microbial Evaluation of Metal Complexes of Molybdenum with Ofloxacin (Levo (S-form) and Dextro (R-form)) Isomers Qadeer K. Panhwar1,2 and Shahabuddin Memon2,* 1Dr. M. A. Kazi Institute of Chemistry, University of Sindh, Jamshoro, Pakistan 2National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080, Pakistan