Early diagnosis and treatment of breast cancer is the key to reduce mortality. Mammography is considered to be a cost effective technique for the early detection of breast cancer and for many years it has remained to be the recommended modality for both diagnosis and screening (Nsiah-Akoto, Andam, Adisson, & Forson, 2011). Screening mammography involves the evaluation of asymptomatic women with the intention of detecting impalpable breast cancer early in its growth, when recovery is still possible (Kopans, 2007). The first attempt to use X-ray breast imaging as a tool for the early detection of breast cancer was in 1960 by Robert Egan. He used mammography and clinical breast examination to screen 2000 healthy asymptomatic women and identified occult carcinoma in 53 of them (Nass et al., 2001).
The suitable measure for screening mammography benefit is its contribution to the reduction in breast cancer mortality (Marmot et al., 2013). The first screening mammography trial to show a reduction in breast cancer mortality, by using mammography only, was the Swedish two-county trial which demonstrated a reduction of 30% in breast cancer mortality among women aged between 40 and 74 years (Tabár et al., 2011). The most reliable information about screening mammography is provided by the randomised controlled trials. In Table (3- 3) all the randomised trials of mammographic breast cancer screening are summarised. Since a very long time is required for follow up in these trials, most of the randomised controlled
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trials for screening mammography assessment are from the 1980s and earlier. However, many developments in breast cancer treatment and diagnosis (mammography) have occurred since this work (Marmot et al., 2012). Therefore, the effect of screening mammography has continuously been investigated by many researchers throughout the world as time has progressed.
Table (3-3) Summarises the common randomised trials of mammographic breast cancer screening. Screening trial Trial start date Participant age range (year)
Breast cancer mortality reduction New York Health
Insurance Plan (HIP) (Shapiro, 1997)
1963 40-69
25% reduction in breast cancer mortality for women aged 40–49 and 50–59 at time of entry.
Malmö trial
(Andersson et al., 1988) 1976 44-68
Mortality reduction is age dependent; no overall reduction but 20% reduction for women aged 55 year and older.
Swedish Two-County
(Tabár et al., 2011) 1977 40-74
30% reduction in breast cancer mortality resulted from screening mammography. Edinburgh trial
(Alexander et al., 1994) 1978 45-64
20% reduction in breast cancer mortality resulted from screening mammography for women 50 years and older.
Canada trial
(Miller et al., 2014) 1980 40-59
No resulted reduction in breast cancer mortality due to screening mammography. Stockholm trial
(Frisell, Lidbrink, Hellstrom, & Rutqvist, 1997)
1981 40-64
In women 40-49 year there was tendency for mortality reduction, 50-64 year women showed better survival with screening mammography.
Göteborg trial
(Bjurstam et al., 2003)
1982 39-59
20-30% reduction in breast cancer mortality and this reduction may be achieved for younger than 50 year old women by short screening interval. UK Age trial
(Moss et al., 2015) 1990 39-41
Annual screening mammography for women 40-49 year results in mortality reduction.
The recurrent evaluations of the Swedish two-county trial outcome data demonstrated that the relative breast cancer mortality remained constant despite the continuous increase in breast screening invitations. However, the absolute number of lives saved due to screening has increased with time. This is because long screening time is required to reduce the breast cancer mortality. Accordingly, long-term follow up is necessary to prove the benefit effect
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from screening on breast cancer deaths. Overall, a significant and substantial reduction in breast cancer mortality due to screening mammography has been reported by the latest update of Swedish two-county trial (Tabár et al., 2011). These results are consistent with outcome data of other screening trials (Shapiro, 1997; Andersson et al., 1988; Alexander et al., 1994; Frisell, Lidbrink, Hellstrom, & Rutqvist, 1997; Bjurstam et al., 2003; Moss et al., 2015). The Canadian screening trial was the only one which documented that screening mammography does not affect breast cancer mortality (Miller et al., 2014).
In the UK, Marmot et al. (2012) assessed the performance of the UK mammography screening programme by reviewing the results of 11 relevant randomised trials. Marmot and his colleagues concluded that the UK mammography screening programme should continue as it resulted in approximately 20% reduction in breast cancer mortality. In the US, the ACS (2013a) reviewed evidence too, along with the International Agency for Research on Cancer (IARC)(2015) and the US Preventive Services Task Force (Nelson et al., 2016). They illustrated that screening mammography significantly reduces breast cancer mortality for women aged 50-69 years. The Norwegian mammography screening programme invites women aged 50-69 years for biennial screening mammography. The effect of this on breast cancer mortality was studied on four groups of women by Kalager, Zelen, Langmark, and Adami (2010). They reported that only one third of the reduction in breast cancer mortality was due to screening mammography and the other two thirds were attributed to the improvement in breast cancer management and treatment. Consequently, the absolute reduction in breast cancer deaths resulting from the Norwegian mammography screening programme was attributed as 10%.
Gotzsche and Jorgensen (2013) reviewed and critically analysed data from the mammography screening trials and the meta-analysis studies; they documented that breast cancer mortality reduction is mainly due to the improvement in breast cancer awareness and treatment and a minor reduction was brought about by mammography. They also reported that breast cancer mortality reduction is not a reliable measure for screening mammography performance because of overdiagnosis and overtreatment which may result in unnecessary mastectomies and deaths. Accordingly, they recommended the reassessment of screening mammography because of the errors associated with published screening trials and
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overdiagnosis. Similarly, work by Harding et al. (2015), who investigated the breast cancer incidence and mortality in the US counties over 10 years (2000 - 2010), reported that the prominent effect of screening mammography in US population was overdiagnosis and the breast cancer mortality reduction was not significant. Harding et al. (2015) built their conclusions on the fact that there was no reduction in the rate of large breast cancers detection. To this day breast cancer screening remains a controversial area (Gøtzsche & Jørgensen, 2013; Independent UK Panel on Breast Cancer Screening, 2013).
Since the introduction of screening mammography there have been ongoing debates about its harms versus its benefits. Djulbegovic and Lyman (2006) stated that screening mammography could not be recommended unless its benefits outweigh its harms. However, several disadvantages of screening mammography have been identified in literature. Firstly, its false negative rate, which is its inability to detect all breast cancers. Secondly, its false positive rate (wrong diagnosis), which results in time wasted in extra examinations and undesired anxiety. Finally, overdiagnosis, which results in the treatment of low risk breast cancers that may not always cause health problems (Gøtzsche, Hartling, Nielsen, & Brodersen, 2012; Jin, 2014; NHSBSP, 2003). The performance of any screening programme should be assessed by three important parameters. These parameters are sensitivity, specificity, and the positive predictive value. Programme sensitivity is the proportion of truly diagnosed cancer cases to the total number of actual cancer cases in the participants. Programme specificity is defined as the ratio of women truly identified without cancer. Positive predictive value is the ratio of the actual number of cancer cases against the number of abnormal cases detected by the programme. These parameters can be calculated using the following equations (Forrest, 1986; Nass et al., 2001):
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The performance of any screening programme depends on the participant‘s age (Jin, 2014). It has been found that annual screenings from 20-29 years of age may result in more radiation- induced cancer deaths than it prevents (Berrington de Gonzalez & Reeves, 2005). For women aged under 39, screening mammography is not recommended due to the low breast cancer incidence rate within this age group and the lack of evidence of cancer death reduction (Toward Optimized Practice [TOP] Working Group for Breast Cancer Screening, 2013). A reduction in breast cancer mortality of 4 deaths per 10000 screened women is achieved for women aged 40-49 years and 5-8 per 10000 women for the 50-59 years age group. The highest reduction, 12-21 cases per 10000 screened women, occurs in women aged 60-69 years (Nelson et al., 2016). The importance of screening mammography in breast cancer death reduction extends to women aged 70-74 years (IARC, 2015). The net benefit of screening mammography is also related to lifetime risk of radiation-induced cancer, which is an age dependent factor because younger tissues are more radiosensitive. According to NHSBSP (2003), the risk of radiation-induced breast cancer reduces from 16 per million per mGy to 4.2 per million per mGy as women‘s age increase from 40 to 75 years.
Some researchers consider that the reduction in breast cancer mortality of less than 10%, by screening mammography, has no net benefit because of the radiation risk. Consequently they do not recommend screening mammography before the age of 50 years (Berrington de Gonzalez & Reeves, 2005; Djulbegovic & Lyman, 2006). This has added another controversial point of screening mammography. In this context, the recommendations of the Swedish mammography screening programme were changed twice by the National Board of Health and Welfare in Sweden (Olsson et al., 2000). The first change was in 1987 to exclude women aged 40-49 years from screening mammography and the second, in 1998, re-included them in the screening programme (Lind, Svane, Kemetli, & Tornberg, 2010). Malmgren, Parikh, Atwood, and Kaplan (2014) studied the screening outcomes of 1162 women aged 75 years and older. They found that for this age group the obvious mammographic cancer detectability is comparable to that of younger women (younger than 75 years). Beyond the age of 50 years the risk of radiation induced cancer is considered acceptable due to the
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reported benefits of screening mammography (Agt, Fracheboud, Steen, & Koning, 2012; Dellie et al., 2013). This relates directly to the central aim of this thesis; which has been considered in section 1.2 (page 1). Overall screening trials demonstrated a 20% - 30% reduction in breast cancer mortality due to screening mammography. Consequently, the risk of radiation-induced cancer from screening mammography is considered small and acceptable when compared to this mortality reduction.
The risk-benefit argument resulted in the introduction of organised mammography screening programmes in many countries. It must also be noted that the recommendations for screening mammography differ between countries. These differences are related to the age of screening commencement, cessation age of the screens, and the time interval between screens, Table (3-4). The majority of mammography screening programmes (i.e. Belgium, Croatia, Cyprus, Denmark, Finland, Germany, Italy, Latvia, Lithuania, Luxembourg, Norway, Poland, Slovenia, Spain / Catalonia, Switzerland) include women aged 50-69 years. However, other countries (i.e. Australia, Canada, Iceland, India, Japan, Korea, Nigeria, Sweden, United States, and Uruguay) extend screening mammography to those at 40 years and may continue after 70 years. The New Zealand, Portuguese, and Spine (Navarra) mammography screening programmes cover women aged 45-69 years. Because of the early incident breast cancer in China, women aged 40-59 are invited for screening mammography. Biennial screening mammography is recommended by most of the mammography screening programmes except in the United States, United Kingdom, Malta and China. The US recommends annual screening and the others recommend triennial screening (Lerda et al., 2014; ICSN, 2015). The effect of the screening frequency change from annual to biennial was studied by Coldman et al. (2008) in British Columbia. They used the data from the mammography screening programme of British Columbia (SMPBC) between 1988 and 2005. In the first decade of SMPBC (1988 -1997) annual screening was recommended. However, after July 1997 SMPBC had started to invite women for biennial screenings. Coldman et al. (2008) analysed the data of 658151 women to compare breast cancer detectability and mortality during these two periods. They found that this alteration in mammographic screening frequency affected neither the breast cancer detection rate nor the mortality rate.
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Table (3-4) Illustrates the recommendations of mammography screening programmes in different countries across the world for women with an average risk of developing breast cancer (Lerda et al., 2014; ICSN, 2015).
Country(s) Age of screening Time interval between screens Number of screens Australia, Japan, Korea, United State
(AAFP, NCI, and USPSTF) 40-75 2 years 18
Belgium, Croatia, Cyprus, Denmark, Finland, Germany, Italy, Latvia,
Lithuania, Luxembourg, Norway, Poland, Slovenia, Spain (Catalonia), Switzerland
50-69 2 years 10
Canada , France, Israel, Netherlands 50-74 2 years 13
China 40-59 3 years 7 Czech 44-75 2 years 16 Estonia 50-62 2 years 7 Hungary 45-65 2 years 11 Iceland 40-69 2 years 15 India 40-74 1 year (40-49) 2 years (50-74) 23 Ireland 50-64 2 years 8 Malta 50-60 3 years 4
New Zealand, Portugal, Spain (Navarra) 45-69 2 years 13
Nigeria 40-70 2 years 16
Sweden
40-74 18 months (40-49)
2 years (50-74) 19
United Kingdom 47-73 3 years 9
United State (ACOG)
40-75 2 years (40-49)
1 year (50-75) 31
United State (ACS, ACR, and NCCN) 40-75 1 year 36
Uruguay
40-69 2 years (40-49)
1 year (50-69) 25 All the above explained screening categories in Table (3-4) are recommended for average breast cancer risk women. Some mammography screening programmes exclude high risk women, considering them as special cases (e.g. the Australian programme) (Cancer Australia, 2014), while other programmes have a specially designed screening category for them, (e.g. Canada, US and UK programmes), see Table (3-5) (ACS, 2013b; ICSN, 2015; Nelson et al., 2009; NHSBSP, 2013b). Some programmes also use other imaging modalities for screening, for instance ultrasound or magnetic resonance imaging in addition to screening mammography (NHSBSP, 2013).
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Table (3-5) Illustrates the recommendations of mammography screening programmes in different countries across the world for women with a high risk of breast cancer (ACS, 2013b; ICSN, 2015; Nelson et al., 2009; NHSBSP, 2013b).
Country(s) Age of screening Time interval between screens Number of screens Canada 40-74 1 year (40-49) 2 years (50-74) 23
United Kingdom 40-73 1 year 34
United State (ACS) 30-75 1 year 46
United State (NCCN) 25-75 1 year 51
In the UK, the Forrest report (1986) recommended the introduction of single view (MLO) screening mammography for women aged 50-65 years with an interval of 3 years (Forrest, 1986). In 1988, the NHSBSP started to invite women aged 50-64 years for MLO, triennial screening mammography. In 2000, the NHS Cancer Plan proposed additional expansion in NHSBSP by using two views (MLO and CC) in screening mammography and extending the screening age to include women aged 64-70 years (NHSBSP, 2006). The latest age extension in NHSBSP commenced in 2012, to include women aged 47-73. This age extension was predicted to be completely implemented by 2016 (NHSBSP, 2014). These extensions approximately duplicated the number of screens within a woman‘s lifetime and hence the cumulative MGD is duplicated also. The consequent increase in risk of radiation-induced cancer is mainly attributed to earlier screening commencement because breast tissue radio- sensitivity decreases with age (NHSBSP, 2003). According to NHSBSP (2013b) publication #74, high risk women should be invited for annual screening mammography from 40 years old.
In 2009, the US Preventive Services Task Force changed their recommendation of screening mammography to be biennial for women aged 50-74 years (Nelson et al., 2009). However, the American Medical Association, American College of Radiology, American Cancer Society, and National Comprehensive Cancer Network have considered the annual screening mammography starting from 40 years old to be superior (Nelson et al., 2016). For high risk women, such as those with a family history of cancer, the American Cancer Society stated that annual screening mammography should start at 30 years old and continue as long as the women were in good health (ACS, 2013b). Nevertheless, the National Comprehensive
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Cancer Network (NCCN) and the American Academy of Family Physicians (AAFP) recommended that the annual screening mammography for high risk women should commence either at 25 years old or from the earliest age of cancer onset in the client‘s family (5-10 years before the youngest breast cancer case in the family) (Tirona, 2013; Vetto, Luoh, & Naik, 2009). Screening frequency recommendation is critical as it directly relates to the mammographic radiation risk; the radiation risk of annual is twice that of biennial screening. Since breast tissues younger than 40 years are very radio-sensitive, mammographic radiation of early high risk women screening should be considered carefully. Early screening mammography radiation risk causes an additional breast cancer lifetime risk for women younger than 40 years.
3.8 Chapter Summary
Since the first use of X-rays for breast tissue imaging, a great development has been made in both mammographic equipment and techniques. In the early stages the main purpose of these developments was to produce better mammographic images (improve mammographic image quality). After that, the researchers started to consider both mammographic image quality and patient radiation dose. The most revolutionary development was the production of a dedicated mammography machine. This machine‘s use of Mo/Mo target/filter combinations reduced breast radiation dose and improved mammographic image quality. The introduction of other target/filter combinations (Mo/Rh, W/Rh) led to further reductions in radiation dose without affecting the mammographic image quality. Although the use of anti-scatter grids improved image quality, they increased the patient radiation dose. Both image quality and patient dose were improved with developments in breast compression devices. Finally, the development of image recording methods from conventional radiography films to xeroradiography and industrial films, then finally to film-screen decreased the radiation dose several times. After this the introduction of digital detectors resulted in more image quality and a lower radiation dose.
Although FFDM has better breast cancer detectability than film-screen mammography, FFDM still has the same limitations as film-screen. DBT has been developed to overcome the 2D image limitation by producing pseudo 3D images of the breast tissue. Many controversial points about screening mammography have been identified in the literature.
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The most controversial point is the net benefit of screening mammography due to the high reported overdiagnosis rate. Another is the screening programme design (starting / cessation ages and frequency of screening). These controversies lead to major differences in screening mammography recommendations throughout the world. Surprisingly the radiation risk variation due to recommendations differences is not considered. Overall, mammography has been considered as a cost-effective technique for breast cancer screening, and the radiation risk, which generally related to MGD, is minimal and accepted.
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Chapter Four
Mammography Dosimetry
4.1 Chapter Overview
This chapter will demonstrate the dosimetric considerations of mammography, including a general background about the risk of radiation-induced cancer and the minimal radiation dose for this risk occurrence. In this context, the two models, linear no-threshold and threshold, are discussed. Literature from different data sources (e.g. childhood cancers following early life irradiation, cancers following recurrent CT examinations, and cancer incidence in medical radiation workers and in high radiation background areas residence) are reviewed to investigate the reliability of these two models. Mammography dosimetry is then discussed in regard to three areas: MGD, its importance and limitations, with the corresponding calculation methods; the radiation dose for other organs from mammography; and the effective dose and effective risk from screening mammography.
The last three sections of this chapter contain detailed explanations about mammography dosimetric tools, including Monte Carlo simulation software, direct dose measurement instruments and breast tissue equivalent materials, respectively. Monte Carlo simulation software is of great importance in mammographic studies. In addition to its importance in dosimetric studies, to obtain MGD conversion factors, Monte Carlo simulation software is used to develop three-dimensional mammographic imaging modalities (e.g. digital breast tomosynthesis and dedicated breast computed tomography). Monte Carlo simulation softwares are available in different forms and several of them can be used in mammographic studies, especially those designed to simulate electron/photon transport (e.g. PENELOPE and MCNPX (Di Maria et al., 2011). Different dose measurement instruments are utilised in dosimetric studies (e.g. ionisation chambers, semiconductor detectors, thermo-luminescence detectors, and optically stimulated luminescence dosimeters), and each type of these dosimeters are suitable to be used in different circumstances. For instance, thermo- luminescence detectors are more likely to be used for in vivo dose measurement due to their small size and tissue equivalency. Since mammography examination uses ionising radiation (X-ray), dose measurement experiments cannot be directly performed on patients. Therefore,
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breast tissue equivalent materials are used to make breast phantoms necessary for assessing MGD. Different breast tissue equivalent materials and their properties are discussed in the