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A Systematic Review and Appraisal of International Early
Breast Cancer Guidelines for Systemic Therapy, and a Global
Physician Survey Examining Practice Patterns by Resource
Setting: potential implications for international health policy
By
Dr. Sonal Gandhi
A thesis submitted in conformity with requirements for the degree of
Master of Science (MSc) in Health Technology Assessment and Management
(HTA&M)
Department of Health Policy, Management, and Evaluation
University of Toronto
© Copyright by Sonal Gandhi. 2012.
ii
A Systematic Review and Appraisal of International Early Breast
Cancer Guidelines for Systemic Therapy, and a Global Physician survey
examining Practice Patterns by Resource Setting: Potential implications
for International Health Policy
Dr. Sonal Gandhi
Masters of Science (MSc) in Health Technology Assessment and Management
(HTA&M)
Department of Health Policy, Management, and Evaluation
2012
Abstract
Breast cancer is a growing international health epidemic, and patients in low and middle income
countries (LMCs) have worse outcomes than those in high income countries. High quality,
well-implemented guidelines help improve patient outcomes, but are often not resource-
sensitive, and support therapies that may not be feasible in LMCs. A systematic review to
address the content, quality, and resource-sensitivity of international breast cancer guidelines
was completed. Also, a survey of global physicians evaluated the impact of resource setting on
practice patterns and guideline use. Guideline use did not appear to be directed by quality
(which was variable across guidelines) or resource-sensitivity (found in few guidelines).
However, practice patterns were found to vary by resource setting and by continent, often due to
the cost of certain therapies. In order for guidelines to better impact global breast cancer
outcomes, they need to be of higher quality, more resource-sensitive, and better implemented.
iii
Acknowledgements
Sincere thank you to my Thesis Committee: Dr. Shabbir Alibhai, Dr. Sunil Verma, and
Dr. Christine Simmons. Your guidance, patience, and motivation have been instrumental
to this work.
Thank you to all the global survey respondents, and the International Breast Cancer
Conference (IBCC) 4 (Paris, France, January 2010) meeting organizers.
Thank you to the Ulysses International Program in HTA&M, through the Institute of
HPME at the University of Toronto.
iv
TABLE OF CONTENTS
Chapter 1. Background
1.1 Cancer as a global health priority...........................................................................1-2
1.2 Resource settings and global cancer control..........................................................2-5
1.3 Knowledge as a resource: barriers in low and middle income nations.................5-9
1.4 Clinical practice guidelines: utility, quality, resource sensitivity, and implementation..............................................................................................9-14 1.5 Breast cancer as a global health concern..........................................................14-18
1.6 Focus on early breast cancer.............................................................................18-20
1.7 International breast cancer guidelines................................................................20-23
1.8 Summary............................................................................................................23-24
Chapter 2. Guideline Rationale
2.1 Rationale..................................................................................................................25
2.2 Study objectives.................................................................................................25-26
Chapter 3. Methods
3.1 Overview..................................................................................................................27
3.2 Survey................................................................................................................28–34
3.3 Systematic review...............................................................................................34-36
3.4 Appraisal of guidelines using AGREE 2 instrument...........................................36-37
Chapter 4. Results
4.1 Survey results: physician demographics............................................................38-41
v
Table of Contents (cont’d)
4.2 Survey results: by survey phase.........................................................................42-45
4.3 Survey results: practice patterns........................................................................46-57
4.4 survey results: factors affecting physician decision making...............................57-65
4.5 Results: guideline systematic review..................................................................66-73
4.6 Results: AGREE 2 appraisal of guidelines.........................................................73-76
Chapter 5. Discussion
5.1 Overview.............................................................................................................77-78
5.2 Systematic review of breast cancer guidelines...................................................78-81
5.3 Physician practice patterns in early breast cancer care.....................................81-86
5.4 Physician decision making and barriers to guideline implementation................86-94
5.5 Study limitations.................................................................................................94-99
5.6 Future directions...............................................................................................99-101
5.7 Conclusions....................................................................................................101-102
References........................................................................................................103-110
Appendices........................................................................................................111-177
vi
List of Tables
Table 1. WHO and World Bank Definition of national resource setting...........................4
Table 2. Practice setting by continent and resource setting..........................................39
Table 3. Routine pathologic reporting............................................................................47
Table 4. Routine HER-2 testing.....................................................................................48
Table 5. Adjuvant endocrine therapy given routinely.....................................................49
Table 6. Types of patients treated with adjuvant chemotherapy...................................50
Table 7. Types of chemotherapy given routinely...........................................................51
Table 8. Reasons patients refuse chemotherapy.....................................................53-54
Table 9. Percentage of eligible patients given adjuvant trastuzumab............................55
Table 10. Barriers to trastuzumab use for eligible patients...........................................56
Table 11. Factors influencing therapeutic decisions by demographic..........................58
Table 12. Influence of guidelines on physician decision making...................................59
Table 13. Applicability of international breast cancer guidelines to practice setting..........................................................................60 Table 14. Sources used for latest breast cancer information.......................................61
Table 15. Preferred methods for future guideline updates...........................................65
Table 16. Final guideline list.........................................................................................71
Table17. Final domain and overall guideline AGREE 2 scores....................................74
vii
List of Figures
Figure 1. Study design..................................................................................................27
Figure 2. Physician practice setting..............................................................................39
Figure 3. Physician medical specialty...........................................................................40
Figure 4. Physician years in practice............................................................................40
Figure 5. Country distribution of respondents...............................................................41
Figure 6. Physician demographics by survey phase...............................................43-45
Figure 7. Percentage of patients accepting chemotherapy by continent......................52
Figure 8. Percentage of patients accepting chemotherapy by resource setting.........................................................................................53 Figure 9. Summary of early breast cancer therapies offered by resource setting..........................................................................................57 Figure 10. Top three factors influencing therapeutic decisions....................................58 Figure 11. Use of breast cancer guidelines (all respondents)......................................62 Figure 12. Breast cancer guideline use by continent....................................................63 Figure 13. Breast cancer guideline use by resource setting.........................................63 Figure 14. Guideline dissemination preferences (all respondents)...............................65 Figure 15. MEDLINE search.........................................................................................67 Figure 16. Guideline International Network search.......................................................68
Figure 17. National Guideline Clearinghouse search....................................................69
Figure 18. Google® search............................................................................................70
Figure 19. AGREE 2 domain scores graph...................................................................75
Figure 20. Guideline usage by survey respondents and AGREE 2 domain scores.............................................................................76
viii
List of Appendices
Appendix i. Survey (paper/IBCC meeting version)..............................................112-117
Appendix ii. REB approval (Sunnybrook)...................................................................118
Appendix iii. IBCC survey letter and consent..............................................................119
Appendix iv. Country distribution for online survey..............................................120-121
Appendix v. Email invitation for online survey............................................................122
Appendix vi. Online survey consent....................................................................123-125
Appendix vii. Systematic review early breast cancer guidelines.........................126-128
Appendix viii. Compilation of adjuvant systemic therapy recommendations from breast cancer guidelines.........................129-155 Appendix ix. Summary of AGREE 2 scoring criteria...................................................156 Appendix x. Survey practice and decision making patterns by survey phase..............................................................................157-161 Appendix xi. AGREE 2 raw scores and domain calculations..............................162-174 Appendix xii. Other guidelines and sources of knowledge (survey free-text answers)...............................................................175-176 Appendix xiii. Language preferences for guidelines (survey free-text answers).....................................................................177
1
Chapter 1 Background
1.1 Cancer as a global health priority
Cancer is an international health crisis. The World Health Organization (WHO) recognizes
that cancer is an important cause of global morbidity and mortality, and even rivals infectious
disease in many countries (1). In fact, it is estimated that deaths from chronic, non-
communicable diseases will rise by 17% over the next ten years, and reach 50 million by the
year 2030; in contrast, deaths from infectious ailments will decrease by 3%, and in addition to
maternal, perinatal, and nutritional conditions, these diseases will account for approximately
15.5 million deaths in 2030 (2). Cancer contributes significantly to this burden of chronic
illness; furthermore, a large proportion of new cancers and 70% of cancer deaths occur in low
and middle income countries (LMCs), where 9 million people are projected to die from
malignancies in 2015 (2). Disparities in cancer outcomes are obvious across various national
resource settings, with case fatality rates from cancer (calculated from incidence to mortality
ratios per year) being estimated to be 75% in countries of low income, 72% in countries of low-
middle income, 64% in countries of high-middle income, and 46% in countries of high income
(3). In addition, an estimated 80% of disability-adjusted life-years lost from cancer occur in
LMCs, but unfortunately, these countries in general have less than 5% of the global resources
for cancer care (3); for example, they consume only 5% of cancer cytotoxic agents, with more
than 90% being distributed in higher income nations (4). As 85% of the world’s population
lives in LMCs (5), this means that a significant cancer burden exists in a large proportion of
global citizens, whose longevity and productivity may be greatly decreased by malignancy. In
addition, these individuals may needlessly be suffering from inadequate access to therapies for
cancers that can have excellent outcomes if treated early enough with key, generally evidence-
based modalities. Despite this, cancer control has generally not been made an international
health priority amongst policy makers, the media, and even public health officials (2). In fact,
cancer control is not even specifically part of the Millennium Development Goals (6).
International health efforts in LMCs have focused primarily on providing aid for other health
issues, such
2
infectious diseases like HIV and malaria, which understandably remain top priorities in certain
nations, such as Sub-Saharan Africa (2) (3).
Regardless, the WHO has called for global action towards cancer control (including all realms
of cancer management, from screening to palliation) in no uncertain terms (1). However, it is
only in recent years that the international community has seemed to take more action. In 2007,
the Institute of Medicine (IOM) published a major study entitled ―Cancer Control Opportunities
in Low- and Middle-Income Countries‖ (2) and in 2009 the Global Task Force on Expanded
Access to Cancer Care and Control in Developing Countries was created (3). Other
organizations with mandates to address global cancer control include the International Atomic
Energy Agency (IAEA), government cancer institutions such as the National Cancer Institute
(NCI) of the U.S, National Institutes of Health (NIH), and the International Network for Cancer
Treatment and Research. Cancer societies and advocacy groups also exist, such as the
American Cancer Society (ACS) and the International Union Against Cancer (UICC) (4). These
organizations are instrumental to help fuel more global collaboration towards cancer control;
however, significant progress is still to be made.
One of the greatest challenges in improving global cancer care is addressing the multiple
barriers many LMCs may have towards cancer control. These include poverty, limited
government spending on health care, lack of human health care resources (particularly trained
practitioners in oncology), migration of such experts to higher income nations, and an overall
lack of resources for cancer care (5).
1.2 Resource settings and global cancer control
The WHO recognizes that resources are imperative to consider when developing agendas for
cancer control. As such, three distinct scenarios pertaining to resource level and cancer control
have been outlined by the WHO (1). A country with a low level of resources is defined as a low
income country with limited or absent resources for chronic illness, and ―infrastructure and
human resources for cancer prevention or control are non-existent or very limited in quantity,
quality and accessibility‖ (1). Life expectancy is low, with communicable diseases and
malnutrition representing significant causes for mortality and morbidity. Cancer is not generally
3
appreciated as a large issue, but can be a significant cause of death after the age of 15. Cancer is
often diagnosed in advanced stages; carcinogen exposure is generally low but infectious disease
as a cancer etiology is more common. Health care is often delivered in informal ways, and
alternative medicine is common (1). The corresponding definition of a ―low income‖ nation by
the World Bank criteria, is a country with a gross national income (GNI) of less than $1 005 per
capita, and ―low-middle income‖ nations (with GNI per capita of US$1 006-$3 975) would most
reasonably fall into this category as well(6). It should be noted that low income countries can
―share an economic status but differ in their social, political and cultural barriers to health care.
Some may suffer from political or social instability or excessive bureaucracy, while others may
have large, remote, rural populations, limiting access to centralized health care‖ (7). The WHO
definition of a medium level of resources is a country generally of middle income, where
average life span is greater than 60 years, and cancer is one of the leading causes of morbidity
and mortality. A majority of the population is urban and exposure to exogenous carcinogens
(tobacco, diet etc) is high. In addition, the ―infrastructure and human resources for developing
cancer prevention, early detection, diagnosis, treatment, and palliative care are available but
with limitations in quantity, quality, and accessibility. Weaknesses can be identified in
organization, priority setting, resource allocation, and information systems for adequate
monitoring and evaluation‖ (1). Primary prevention is often neglected in favour of treatment-
related interventions, and cost-effectiveness of therapies is rarely evaluated. The corresponding
World Bank definition would include ―upper-middle income‖ countries (USD$3 976 - $12 275
GNI per capita). High income nations are thus those with USD$12 276 GNI per capita or more
(8). The WHO recognizes these nations as having a high level of resources in terms of health
care. These industrialized countries generally have a life expectancy greater than 70 years, and
cancer is major cause of death. There are many facets of cancer control programmes in place in
these nations; however, elements may not be well integrated and there may be discrepancies
within the population (such as with lower socioeconomic individuals) with regards to access to
services (1). The WHO outlines that ―reorganization of the system could bring benefits in terms
of greater cost effectiveness and improved reach and acceptability of services‖ in these countries
(1). A comparison of these resource setting definitions are found in Table 1.
4
Table 1: WHO and World Bank definitions of national resource settings
WHO National Resource Levels for Cancer Control (1)
World Bank National Income Levels (6)
Low Resource Levels
Limited or absent resources for chronic illness.
Infrastructure and human resources for cancer prevention or control limited
Low life expectancy; communicable diseases and malnutrition significant causes of morbidity/mortality
Cancer is of less concern, but can be major cause of death after the age of 15.
Cancer often diagnosed in advanced stages; carcinogen exposure generally low but infectious disease as a cancer
etiology more common.
Health care often delivered in informal ways, and alternative medicine is common
Low Income Nations:
Low income
Gross National Income (GNI) of less than $1 005 per capita.
Low-middle income
USD$1 006-$3 975 GNI per capita
Middle Resource Levels
Middle income nations; average life span greater than 60 years, and cancer is one of the leading causes of morbidity
and mortality.
Majority of the population is urban; exposure to exogenous carcinogens (tobacco, diet etc) is high.
Infrastructure and human resources for cancer control available but with limitations
Primary prevention often neglected in favour of treatment; cost-effectiveness rarely evaluated.
Middle Income Nations:
Upper-middle income
USD$3 976 - $12 275 GNI per capita
High Resource Levels
Industrialized countries with life expectancy greater than 70 years; cancer is major cause of death.
Many facets of cancer control programmes exist, but elements may not be integrated, and there may be
discrepancies within the population with regards to access to services.
System reorganization could bring greater cost effectiveness and improved reach and acceptability of services.
High Income Nations:
USD$12 276 GNI per capita or more
5
The WHO furthermore stipulates that different strategies are required for each resource
scenario, in order to optimize cancer control in these disparate global realities. Within the
priority setting schema for low, middle, and high income nations, various areas of cancer control
programmes need differing emphasis (for example, primary screening versus palliative care,
versus public education, etc). The WHO ―National Cancer Control Programmes‖ document
outlines these priorities (1). Furthermore, within the WHO mandate and other global cancer
control agendas, it is well stipulated that HICs should aid LMCS in achieving these priorities
(1) (2) (3). In past decades, such international collaboration (with higher income nations
helping lower income nations) has been instrumental in, for example, combating the global
infectious disease burden (especially of HIV) (3). As such, a similar dedicated effort is needed
in sharing resources between HICs and LMCs, to help address the mounting international cancer
burden. These resources include fiscal support, human resources (for medical and public
education, leadership, and infrastructure development), research development, and
scientific knowledge translation (1).
1.3 Knowledge as a resource: barriers in low and middle income nations
One of the challenges of cancer control in LMCs is that primary knowledge generation in the
realm of cancer research can be variable or minimal. It has been suggested that ―research
infrastructure and the capacity to absorb scientific and technical knowledge are also weak in
developing countries, leading to low levels of scientific output and further under-development‖
(8). Indeed, it is obvious that primary scientific data is generally produced in high income
nations; for instance, it has been found that 85% of the world’s top 1% cited publications
between 1993 and 2001, came from researchers in eight nations, all high income (including the
USA, Europe, the UK, and Japan) (9); in contrast, most LMCs that were included in the analysis
produced only 2.5% of such publications. In addition, only 10% of global health research is
done in developing nations, and in the year 2000, only 2% of the 3 000 indexed journals on
MEDLINE were from these nations (8), and this has been cited as both a ―cause and
consequence‖ of the limited visibility of publications from lower income nations (10). Reasons
that have been outlined for the ―low scholarly output‖ in low income nations include:
6
...limited technical competency in scientific writing, which is compounded by English
not being the primary language; lack of health research which would give priority
toward research from low-income geographical settings; high teaching burden which
does not allow time for research and writing; and biases against low-income countries’
authors by journals editors, editorial boards, and publishers from high-income countries
(10).
These barriers can be compounded by a lack of research funding bodies within LMCs, and lack
of international funding support; the perception in these nations may be that research is not a
priority (11), or else a ―luxury‖ (10); finally, a general paucity of local peer-review processes for
primary research publications can be another significant issue (10). Researchers from low
income nations have further relayed concerns that peer reviewers from high income nations may
be ignorant of their local realities, or be inclined towards only ―high technology‖-based
research, which may bias them against accepting research from LMCs (11). Some solutions to
these problems have been suggested, including ―north-south‖ partnerships in publishing
research (10), the ―north‖ representing high income nations, and the ―south‖ representing lower
income countries (8). Furthermore, efforts to improve the flow of information from north to
south, and improve access to scientific knowledge have been multiple Programs such as
HINARI-Access to Research In Health (through the WHO) (12) and the Program for
Enhancement of Research Information (PERI), through the International Network for Access to
Scientific Publications (INASP) (13) venture to provide access to knowledge created in high
income nations and make them more readily available to low income countries (for example by
providing free subscriptions to certain scientific journals), and also support local capacity
building in low income nations for knowledge production, access and dissemination (8). This is
also important, for despite literature from the 1990’s suggesting that low income nations are
immensely dependent on knowledge and information from high income nations (14) (15), more
recently it has been highlighted that knowledge generated in high income nations may not
always be applicable to lower income nations, and that knowledge creation and dissemination
within and between lower income nations (essentially ―south to south‖) is increasingly
essential (8) (16). As an example, is it useful for a physician in a resource-deficient public
hospital in Nigeria to read about the latest high-technology, costly treatments for infertility
published in a Western journal (10)? With regards to cancer therapies, it has been noted that in
high income nations, practitioners are becoming accustomed to the approval of high cost, novel
treatments that sometimes have only marginal benefits (17). Furthermore, in health care settings
7
where these types of treatments may not be covered for the general public (if they are deemed
not cost-effective), pressure from patient advocates on governing bodies to alter these decisions
may be seen. Such situations can be considered quite disparate from the practice reality of a
clinician in an LMC, where older, less costly, but efficacious treatments may still not be readily
available (17). These same clinicians, nonetheless, may be exposed to guidelines, publications,
or academic forums espousing newer, costlier therapies as the ultimate ―standard of care.‖ As
such, one can appreciate why primary research done in lower income nations, with
consideration of local disease patterns and health care settings, is essential in balancing the body
of literature and knowledge on how ―best‖ to treat a condition. Sometimes low cost, older
interventions provide excellent patient benefit (including in cancer treatment) (3), and yet such
data or recommendations may be buried by the growing wealth of more recent data, supporting
new-age, high-cost treatments (which again may not be feasible in all resource settings).
The need for more primary knowledge generation in LMCs recapitulates the fact that these
ventures can be fraught with challenges. Not only can publication of research be difficult as
outlined above, but generation of primary data through clinical studies can present multiple
challenges as well. Several barriers to initiating or sustaining clinical studies in LMCs have
been highlighted that transcend constrained monetary resources. Ethical concerns have been
raised in the realms of informed consent (particularly where populations may be illiterate or
potentially vulnerable to coercion due to political structure or economic factors), trial benefits
(especially when treatments offered on trial are not available off study or as standard of care),
and the sustainability of beneficial treatments after the study is complete (18) (19). Some have
even proposed that ethical standards for trials within LMCs may have to be different than HICs
to account for disparate financial, social, political, and cultural landscapes (19). Finally, trial
protocols developed in HICs which are opened in LMCs may not account for these unique
features, and be less relevant to the local population, or may be biased against patients in LMCs
if study eligibility requires prior treatment with therapies not readily available in LMCs, usually
due to cost (18) (19).
It is thus apparent that while primary knowledge generation in LMCs is essential to be truly
relevant to local populations, the ability to do and publish research in these nations is generally
limited, and knowledge dissemination from HICs may still be essential to help supplement
8
the scientific data and clinical knowledge needs that may exist in LMCs. In addition, if most
of the newest research is indeed being done in high income nations, then physicians in LMCs
should be able to freely access this information (and ideally have the discretion to know if the
information is applicable to their own patients). Proponents of this free information exchange
highlight the need for better access to such knowledge for LMCs, which is particularly feasible
in this age of the world wide web; access to information on websites and through email have
certainly been highlighted as useful strategies to do so in HICs (20). The use of the internet as a
means to improve ―health information for all‖ has been touted as a key resource to help
physicians in LMCs also keep abreast of essential health information, form important
connections with international colleagues, and reduce professional isolation (21). The caveat,
once again, is that this information is ideally contextualized to be relevant to local practice
realities (22); the issue, as outlined above, is that health information generated in one area (such
as in HICs), is not always useable or relevant in other areas (such as certain LMCs). In fact, it is
notable that policy makers and clinicians in low income nations may actually prefer data created
in their local settings over international information in making health care decisions (23). A
survey of physicians, including general practitioners and specialists from selected LMCs
assessed how likely published research from local, regional, or international regions were to
influence changes in clinical practice. This study found that 80% of surveyed physicians would
be willing to change practice in response to local research findings, with 60% also likely to be
influenced by North American data (23). European and regional research was less likely to
influence practice, although response varied from country to country, whereby physicians from
some nations did report being preferentially influenced by European research. Respondents also
reported being more likely to be influenced by local research if the quality were deemed to be
equivalent to other regions in the world, suggesting that surveyed clinicians believe research
conducted in North America and Europe is of better quality than local or regional research (23).
Finally, medical subspecialists (including oncologists) were more likely to be influenced by
international research, compared to general practitioners (23). The authors of this study
concluded that increased local capacity building for good research in LMCs is important, but,
duplication of research from HICs is not always prudent or warranted. In addition, research
from HICs such as those in North America and Europe, can certainly be influential on local
practice in LMCs, and particularly in the absence of evidence from local settings, dissemination
9
of evidence-based recommendations from HICs is still crucial (23). The authors furthermore
highlight that this can be achieved by “creating culturally sensitive evidence-based guidelines
which guide physicians on how to use the results of research findings from settings other than
their own” (23).
1.4 Clinical practice guidelines: utility, quality, resource sensitivity, and implementation
Utility
Clinical practice guidelines (CPGs) can be important tools for knowledge dissemination, and
help influence the uptake of new research findings into clinical practice. One can appreciate
how CPGs can be a vehicle of knowledge transfer between nations (of any resource setting).
There are in fact many benefits of CPGs to clinicians, patients, policy makers and health care
systems at large; these include improving the quality and consistency of clinical practice,
helping to make funding decisions for therapies, improving care processes and efficiency, and
encouraging appropriate resource allocation (24). Evidence-based guidelines and those arising
from systematic reviews of evidence can further highlight the data (or lack thereof) surrounding
certain practices, and draw attention to gaps or inconsistencies in scientific evidence, which
require further research (24). However, poor-quality guidelines can be potentially harmful in all
these same realms, and guidelines based on little or poor quality evidence, or influenced heavily
by certain biases, can be a particular problem in misdirecting users towards practices which
could be unfounded or beneficial to only a few individuals, or in limited settings (24).
The actual definition of a ―guideline‖ is also variable; the IOM and some other groups define a
―high quality‖ guideline as a "systematically developed statements to assist practitioner
decisions about appropriate health care for specific clinical circumstances" (25). However, not
all statements that have the ability to direct practice meet criteria for quality or rigour. Indeed,
the notion of scientific rigour is an important one in this era of evidence-based medicine, which
in theory combines clinical expertise with the best available evidence from systematic research
(26). Many ―statements‖ are apparent in the literature and specific health care settings, and
include clinical practice guidelines (CPGs), practice statements, consensus statements, treatment
algorithms, and a host of other entities that can all, in theory, direct clinical practice. Any of
10
these documents may attempt to ―reduce undesirable variation and optimize health care
delivery.‖ However, a truly high quality CPG should make clinical judgments regarding what
systematically reviewed evidence means, and how it should affect care (27). The Institute of
Medicine further recommends that the CPG development process be distinct from systematic
reviews, and include separate grading systems about the quality of evidence and strength of
recommendations; in addition, it should be clearly defined whether a CPG or specific
recommendations are based on evidence or expert consensus (27). CPGs, in fact, can be
created in a number of ways, including informal consensus, formal consensus, and systematic
evidence assessments. Often a combination of methods is used, and ideally clearly defined steps
and criteria established by various organizations to create high quality CPGs are utilized (27)
(28).
Quality
In general, evidence-based guidelines are considered of higher quality than consensus-based
guidelines. This is because expert consensus can be skewed by personal interpretation of data,
biases, and opinions (28). When evidence is lacking in a particular area, then the reliance on
expert consensus tends to be higher, but the lack of evidence should be clearly outlined in
developing recommendations (28). One study utilized 5 different CPG quality assessment
instruments to evaluate select breast cancer guidelines: evidence-based guidelines scored higher
on quality scores than consensus-based or evidence-consensus based guidelines, although actual
content varied little between the guidelines (29). Consensus-based recommendations were more
commonly found when evidence was poor or lacking for a particular clinical issue (29).
Several instruments in fact have been developed to assess the methodological quality of CPGs.
The Institute of Medicine (IOM) was one of the first groups to develop a tool with dimensions
for appraising guideline quality; few subsequent appraisal tools address all these dimensions.
Of the available appraisal tools, the Cluzeau instrument is the only one that has been extensively
validated (30). Three other tools are based on the Cluzeau instrument, and of these, only the
Appraisal of Guidelines for Research and Evaluation (AGREE) instrument is further validated.
In addition, the AGREE instrument in touted as ―...a validated, easy-to-use, and transparent
instrument, which was internationally developed and widely accepted‖ (30), and which, in fact,
11
is endorsed by the WHO (30) (31). The AGREE Collaboration is ―an international
collaboration of researchers and policy makers who seek to improve the quality and
effectiveness of clinical practice guidelines, by establishing a shared framework for their
development, reporting and assessment‖ (31). A systematic review of guideline appraisal tools
found the AGREE tool to be the most comprehensive yet succinct instrument, that has the
benefit of assigning numerical scores to quality domains(30). These scores are useful to
compare guidelines; in addition, the authors of this review conclude that the AGREE tool may
be the most useful available instrument to utilize as a platform for clinical care pathway
development (29). The AGREE instrument now has a second iteration, the AGREE 2 (32).
Formal guideline appraisal tools such as the AGREE instrument are needed to help drive better
quality CPG development, and allow users to gauge the strengths and weaknesses of existing
guidelines. Systematic reviews of clinical practice guidelines in several medical specialities
have highlighted that most CPGs are of mediocre or modest quality (either overall or in
particular quality domains). For example, a systematic review examining the quality of
endocrinology guidelines in North America found only 29% of the reviewed guidelines scored
above 60% on more than 3 quality domains (33). One group evaluated the scope and quality of
lung cancer guidelines, and found that most of these were of poor quality using the AGREE tool
(34). Finally, another systematic review used the AGREE instrument to evaluate 100 CPGs, 32
of which were oncology guidelines. This study found that in general, most CPGS were of
modest quality; however, oncology CPGs were found to have statistically significant higher
scores in several quality domains (35). This was thought to be explained in part by the
experience of oncology organizations in creating guidelines. Despite this, only 3 of the
oncologic guidelines scored 60% in more than 3 quality domains (35). Another study of
oncology guidelines found significant heterogeneity in realms of guideline development,
structure, user identification, and purpose; the authors do relay that some heterogeneity is
warranted in order to meet divergent guideline needs (36). These examples highlight that
clinical practice guidelines, including those in oncology, can be of low quality, or deficient in
certain key quality domains.
12
Resource Sensitivity
One of the quality domains as assessed by the AGREE 2 instrument is that of Applicability.
This domain assesses if the resource implications of recommendations were considered in the
formulation of the guideline being appraised (32). If CPGs are considered as an important tool
for sharing medical knowledge between HICs and LMCs, then the consideration of resources in
these ventures becomes increasingly salient. Indeed, the development of resource appropriate
guidelines in cancer care has been highlighted by the WHO as one of the strategies to better
improve global cancer control (1). Other task forces for international cancer control have
recognized this as well (2) (3) (4). The IOM 2007 report outlines the need to ―(develop)
resource-level-appropriate guidelines for the clinical and public health management of major
cancers‖ (4). It is also highlighted within the IOM study that in fact guidelines for cancer care
are frequently developed in HICs, and generally focus on effectiveness and safety, with little
attention to the resource implications of recommendations (4). In addition, these guidelines
often focus on the ―newest, high-technology (and expensive) interventions‖ (4). As such, these
guidelines may not be adequate to meet the unique needs of LMCs in cancer control,
particularly if the resource implications of recommendations are not considered.
The concept of resource-appropriate care recommendations is not specific to oncology
guidelines. In fact, it is well-established that resource-sensitive and cost-effective health care
can be more sustainable, better quality health care. A publication by the IOM highlights these
principles clearly within the context of a HIC (the United States), where health innovation and
leadership in clinical care is strong, but health care costs are exceedingly high and deemed not
sustainable (37). In addition, the WHO has a large initiative deemed WHO-CHOICE
(CHOosing Interventions that are Cost-Effective) (38). This includes several education
documents, guidelines, recommendations, and studies on the importance of cost-effectiveness in
medical interventions around the globe. One study highlights the global burden and cost of
chronic illness (including cancer) in LMCs; it also estimates that improvements in patient
survival from chronic illness in LMCs (by 2% per year) can be achieved by using interventions
that are sustainable in these resource settings (39). The WHO has further developed a
framework for cost-effectiveness evaluation and comparison of specific medical interventions
13
(in terms of quality- or disability-adjusted life years, QALYs or DALYS, respectively) (40).
This is meant to allow health care practitioners and policy makers to evaluate the relative trade-
offs between implementing certain interventions, in comparison to others. This is certainly an
important venture in any resource setting, as health care budgets and resources are finite. The
WHO has made recommendations as to what cost-effectiveness ratios (QALYs or DALYS) are
reasonable to accept in certain income settings (as a proportion of total gross domestic product,
GDP); it makes recommendations based on 14 sub-regions of the world, but outlines how this
information may be used at the country level (41). The basic principle that is espoused by these
groups is that of accepting higher impact, lower cost interventions in lieu of higher cost,
lower impact interventions. One can appreciate how vital CPGs can be in disseminating these
principles, and why it is recommended that resource-sensitivity thus be a core component in
guideline formulation. Importantly, recommendations on how to develop ―cost-conscious‖
guidelines do exist (42).
Implementation
Finally, an important concept to consider in evaluating the role of CPGs in cancer care is that of
guideline implementation. The mere publication of guidelines often does not result in change of
clinical practice, even in HICs (15) (43). Cultural, socioeconomic, patient-specific, and
physician-specific factors may greatly mitigate the implementation of recommendations (44),
and this may be a particular challenge in LMCs (7). The actual implementation of guideline-
based care is a complex process which should include vigorous research and strategies to
evaluate guideline effectiveness (45), and to identify barriers to successful guideline
integration into practice (46) (47). One systematic review evaluated physician-identified
barriers to guideline adherence (48). It classified barriers into the impact they have on physician
knowledge, attitudes, and behaviours. Some barriers included a lack of guideline awareness
(highlighting issues in dissemination), lack of agreement with recommendations, inertia to
change, and guideline- and patient-related factors (48). Out of 76 studies, almost half evaluated
the impact of ―environmental‖ barriers, which included resource or cost constraints. At least
10% of respondents from these studies cited such external factors as a barrier to implementing
recommendations. Finally, in both developing and implementing guidelines, the local cultural
context is imperative to consider. One study highlights that even within two HICs (the United
14
States and France), the development and implementation of recommendations on high-risk
breast and ovarian cancer screening were influenced by cultural factors (49).
Thus, in attempting to influence global cancer control by CPGs, an overriding challenge remains
the creation of international high quality guidelines for cancer management, which are reflective
of evidence-based advances in care, but which are also resource-sensitive, and applicable within
disparate cultural and health care settings (50).
1.5 Breast cancer as a global health concern
It has been discussed that cancer globally is becoming a significant international health problem,
particularly in LMCs. Breast cancer accounts for a large proportion of the cancer burden
and cancer mortality in women worldwide; in 2008 it was estimated that there were 1.48
million new breast cancer cases globally (51). Of these cases, it has been estimated that 45%
occur in LMCs (52). Incidence rates across the globe continue to rise, with recent data
suggesting an increase of 2.6 times over 3 decades, from 641 000 cases in 1980, to 1.64 million
cases in 2010 (53). LMCs have tended to have a lower incidence of breast cancer compared to
HICs, (for example age-adjusted incidence of 21 per 100 000 in East Asia, compared to 101 per
100 000 in the United States in 2008) (52); some of this may be related to a lack of formalized
registry data, or a significant number of unreported cases in LMCs (54). Nonetheless, LMCs
with adequate registry data do show a steady increase in breast cancer incidence over several
decades. It is estimated that by the year 2020, 70% of the world’s breast cancers will be in
LMCs (7). In addition, a significant percentage of the world’s population lives in LMCs,
meaning that even with lower incidence rates, the overall burden of disease is large, and
growing (55). Furthermore, a large proportion of breast cancer cases in LMCs occur in younger,
premenopausal women, compared to HICs where breast cancer continues to largely be a disease
of older, postmenopausal women. The social and economic impact of the productivity lost from
these younger patients can be considerable (39). A recent modeling study using extensive
registry and autopsy data showed that two-thirds of breast cancer in 2010 was indeed found in
women over the age of 50, mostly in developed nations. However, in the 15-49 age group,
twice as many breast cancers were recorded in developing (or lower income) nations, with 367
000 cases (53). This study also highlighted that the rate of increase in incident breast cancers
15
over the study period was highest in continents with many LMCs, such as the Middle East,
South Asia, Latin America, and Southeast Asia. The increase in incidence was smallest in
continents with predominately HICs, such as Europe and North America (53). Furthermore,
HICs have shown greater improvement in breast cancer outcomes compared to LMCs (56). For
example, sources cite age-adjusted breast cancer survival ranging from 32% in Sub Saharan
Africa to 81% in the United States (57). It is estimated that more than 55% of global breast
cancer deaths occur in LMCs (52); with mortality rates that continue to be disproportionately
high compared to incidence, as illustrated by increasing mortality to incidence ratios (58). Some
recent data has shown that mortality to incidence ratios in the last few years have actually
decreased in LMCs as well; however, they remain higher in developing nations than in
developed nations, for instance averaging 0.35 in developing nations, compared to 0.20 in
developed nations (53). Another source cites mortality to incidence ratios (or case fatality rates)
of 0.48 in LMCs, compared to 0.24 in HICs (3). Finally, some particularly low income nations
have even higher mortality to incidence ratios; for instance, the age-adjusted mortality to
incidence rate is estimated to be 0.69 in Africa, as compared to 0.19 in North America (52).
Described another way, a woman in Africa diagnosed with breast cancer is three and a half
times more likely to die of her disease than a woman in North America.
Increasing global breast cancer incidence can be attributed to several factors, including an aging
population and greater usage of improved screening modalities. In LMCs, breast cancer
incidence may be further increasing due to greater adoption of westernized lifestyles (including
diet and decreased child-bearing), and improvement in other health care burdens such as
infectious diseases and poor sanitation (52) (59). Furthermore, as maternal outcomes also
improve in LMCs, female malignancies such as breast and cervical cancer represent some of the
greatest causes of mortality in women of reproductive age in these regions (for example 1.7
breast or cervical cancer deaths now occur for every indirect or direct obstetrical death in
LMCs) (53). Outcomes in curable malignancies such as breast cancer have improved due to
heightened awareness, prevention, earlier detection, and better therapies in HICs (3). In
contrast, outcomes in many LMCs are far worse, and vary both between and within nations. For
instance in India, 5-year survival for early-stage breast cancer ranges from 41% to 78% by
region, ―indicating wide variation in health services delivery‖ (60). 5-year breast cancer
survival in Uganda was found to be 46%, and 13% for other all other malignancies (60). One
16
study comparing data from various LMCs in Asia compared to North America and Europe
showed significant variation in breast cancer outcomes, with 5 year overall survival of 62% in
India, 76% in China, 89% in Sweden, and 86% in Canada (61). A lack of resources (or
appropriate resource allocation) in LMCs has been highlighted as a significant contributor to
this problem, as many beneficial breast cancer management strategies, particularly novel
ones developed over the last two decades (such as trastuzumab), are expensive and quite
cost-prohibitive in LMCs (59). However, the differences in breast cancer outcomes between
HICs and LMCs are likely due to a multitude of factors, not all of which are related to a nation’s
resources (59). These include variables such as patient age at presentation, ethnicity, and
tumour biology. Breast cancer is increasing recognized as a heterogeneous disease, where
outcomes are greatly contingent on specific disease characteristics (such as endocrine receptor
and HER-2 receptor status), and the associated responses (or lack thereof) to particular targeted
therapies. Women with breast cancer in LMCs tend to be younger with more aggressive tumour
characteristics as highlighted by one study of breast cancer patients in selected Asian versus
Western countries (61). In Western nations, as highlighted above, breast cancer cases occur
most often in older, postmenopausal women, who tend to have more favourable hormone-
responsive disease with better prognosis; younger, premenopausal women with breast cancer,
representing a large proportion of breast cancer cases in LMCs, may have more hormone
receptor negative, or HER-2 positive breast cancers with more aggressive behaviour and poorer
prognosis (61). The differences in hormone receptor status may in fact be due to inadequate
testing of tumours for endocrine receptors in LMCs; data from Asia suggests that over the last
decade, with improved pathologic techniques for hormone receptor testing some Asian
countries, women in these nations have the same proportion of hormone receptor-positive breast
cancer as Caucasians (54). The resultant underuse of endocrine therapy in these nations in the
past may explain some of the difference in breast cancer outcomes over those time periods.
Nevertheless, there is other evidence still that breast cancer tumour biology and patient
responses to treatment can vary by ethnicity. This includes the identification of certain genetic
polymorphisms in particular cultures which may be associated with tumour behaviour, and
response to or toxicities from medications (54). Another challenge remains the fact that most
large clinical studies in breast cancer mostly enrol Caucasian patients (and certain other select
ethnicities) living in Western countries. Extrapolation of treatment efficacy, toxicity, and
17
pharmacogenomic data from these studies to other ethnic populations may be inaccurate (54).
Although the development and administration of clinical studies in LMCs is thus vital to help
address these issues, as discussed earlier, these initiatives are fraught with many challenges.
Finally, different cultural, social, health care, and political landscapes can also impact breast
cancer outcomes. For example, breast cancer patients in LMCs tend to present with more
advanced tumours and/or decline particular treatments, in part due to differences in public
education, screening practices, and cultural acceptance of cancer diagnoses or therapies (52)
(56) (61). As noted above, epidemiologic breast cancer data from LMCs if often missing or
incomplete, which makes the evaluation of patient outcomes and the factors which may impact
them more difficult (52) (53) (54) (61).
Despite the multiple factors that may contribute to the variations in breast cancer outcomes
across nations, the ability to sustain the costs associated with breast cancer diagnosis and
management prevails as a significant contributor to these disparities. For instance, one study
utilizing WHO data highlighted that although a country’s GDP correlated with breast cancer
incidence (reflecting higher rates of the malignancy in more affluent nations, as discussed
above), the correlation of GDP and breast cancer mortality was less clear (59). However, there
was a trend towards an association of percentage of GDP spent on health care and breast cancer
mortality, whereby countries that spend more on health care have better breast cancer outcomes
(59). In addition, it is evident that countries with variations in health delivery based on
socioeconomic status can have varying breast cancer outcomes. Even HICs like the United
States may have poorer outcomes among citizens from lower income brackets, who potentially
have less access to beneficial but costly breast cancer strategies (59) (61).
As an example of the significant cost that can be associated with some breast cancer therapies,
consider trastuzumab. This treatment is recommended as a cornerstone therapy for HER-2
positive disease by most breast cancer guidelines, including recommendations ―tailored‖ to
particular LMCs (such as in Asia) (62). The cost per QALY of trastuzumab is estimated to
range from $50 000 to $200 000 (US dollars); if one follows the WHO’s recommendations that
a medical intervention should be considered cost-effective by a nation if its cost per QALY is
less than the nation’s per capita GDP, then the cost of this therapy would be excessive for most
18
LMCs (54). More than half of the global breast cancer patients who would be eligible for this
therapy actually reside in these nations (54). Despite this, there are also strategies that exist for
breast cancer treatment which can have a significant impact on patient outcomes, but are
relatively low-cost (and thus sustainable by most nations). One of these strategies is tamoxifen
therapy for hormone receptor positive breast cancer (17) (54). In fact, tamoxifen and some
select cytotoxic chemotherapies are included in the WHO’s Model List of Essential Medicines
(63). This document, updated every two years, outlines medications that should be available
globally as part of any basic health care system, although some treatments (including the anti-
neoplastic agents) are recognized as often requiring some increased or specialized resources
(63).
This complex interplay of biologic, cultural, and economic factors make the ability to evaluate
and address the disparate presentations of breast cancer across the globe a true challenge.
1.6 Focus on early breast cancer
Early breast cancer management, in general, is less resource-intensive than advanced breast
cancer (64); in addition, the potential for curative patient outcomes is possible (65), in
contrast to metastatic disease, where treatments are mainly palliative. Locally advanced
breast cancer (LABC) is a significant issue in LMCs particularly, but optimal LABC treatment
is quite resource-intensive, and overall has poor outcomes, particularly in lower income nations,
(65). Stage-specific breast cancer survival continues to better in stage I and II disease across the
world, in all resource settings. For instance, one study reported 5-year breast cancer survival in
Canada (a HIC) to be 96% for stage I and 86% for stage 2, and in Lucknow, India (a LMC) to
be 90% for stage I and 78% for stage II breast cancer (61). Interestingly, in this study stage III
disease (LABC) was reported to have similar 5-years survivals in both Canada and Lucknow,
India: 59% and 57% respectively. However, it was noted within this study that the particular
institute in India from which data was collected was a high-resource, multidisciplinary cancer
centre with adequate surgical, chemotherapeutic, and radiation facilities to treat LABC (61). In
fact, an extensive registry review of population-based data from nations within Asia, Africa, and
Central America addressed stage-specific survivals for various malignancies. This study found
that for breast cancer, outcomes were notably worse for lower resource nations, especially in
19
LABC (66). For instance, 5-year survival for LABC in India, the Philippines, Costa Rica, Saudi
Arabia, and Thailand combined was estimated to be 47%, compared to 75% in Hong Kong,
Singapore, and Turkey (66). These studies highlight that across the globe, outcomes in locally
advanced breast cancer are poorer compared to earlier stage disease, particularly in settings with
inadequate resources to deal with the intensive, multi-modality treatment requirements of this
breast cancer presentation. Even within certain LMCs (such as India and China), access to
resources to adequately treat breast cancer can be variable, reflected by differences in survival in
different regions of the same country (67). This phenomenon can be seen in HICs as well, for
example within different socioeconomic classes in the United States (61) (67). As such,
guidelines for LABC may be particularly inapplicable to a greater number of physicians
(particularly from LMCs), as treatment is particularly concentrated in certain specialized centres
due to high-resource needs (61) (65). In addition, the ability to treat LABC in some LICs is so
limited, that it is essentially considered a palliative condition with outcomes similar to
metastatic (stage IV) breast cancer (65). For this reason, a preferential focus on early breast
cancer (excluding LABC) may better reflect practice patterns of most global physicians
across various resource settings. This also allows one to compare discrepancies in care at a
stage of the disease that is more likely to have good (curative outcomes), in efforts to
improve these care patterns. Although LABC can represent a significant proportion of breast
cancer in certain LMCs (up to 50%) (66), improving screening practices has been touted as a
vital measure to address advanced breast cancer in LMCs, instead of focusing on therapeutics
(65). As the focus of this particular study is systemic therapy for early breast cancer,
screening practices have been excluded to maintain this scope. Finally, screening practices for
breast cancer have been found to be particularly complicated in LMCs, where social, cultural,
and patient factors tend to weigh heavily on the acceptance of and adherence to screening
recommendations (61) (68). The focus of this study remains clinician practice patterns, and
not patient behaviours. In sum, these factors all support a particular emphasis on early
breast cancer for the purposes of this study, with recognition that LABC remains a particular
challenge across the world, particularly in LMCs, and likely requires specific, dedicated study.
The scope of early breast cancer treatment is broad and includes many modalities of care.
Surgery remains the cornerstone curative treatment for early disease; however, a significant
proportion of patients will still suffer disease relapse, and additional adjuvant therapies aim to
20
decrease this risk. In general, additional local treatment such as adjuvant radiation, impacts
local relapse rates with modest effect on overall survival after 15 year follow-up (69). Adjuvant
systemic therapies, such as endocrine treatments and chemotherapy, can have a significant
impact on decreasing relapse risk and improving overall survival in breast cancer patients
eligible to receive these therapies (70). The HER-2 targeted therapy, trastuzumab, has greatly
improved outcomes in HER-2 positive breast cancer (71). Systemic therapies present with
unique resource implications compared to local therapies, as they require an ongoing supply,
with costs often dictated by the manufacturing or distributing sources. This is in contrast to
surgery, which usually requires an upfront investment into human resource training and
operating facilities, with associated resource needs for maintenance. It is quite apparent that
access to surgical services in LMCs can also be poor compared to HICs (61) (72) (73), and
adequate surgical services often require the collaboration of other health providers and services
(anaesthesiologist, pathologists, etc) (1). Radiation therapy often requires a costly upfront
investment into acquiring the appropriate technology, and is thus often only available in tertiary
health centres; however, the cost of treating individual patients and maintenance of the radiation
machines and technologists can be low (1). In contrast, systemic therapies, particularly newer
generation chemotherapy and targeted treatments such as trastuzumab, may be relatively costly
per patient, be quite variable in their global access, and require more intensive resources
to maintain as patients may require ongoing therapy. Guideline recommendations for these
therapies can also be quite complex, sometimes contingent on specific technologies (for
example, pathologic hormone receptor testing), and potentially beneficial to only certain patient
groups (61). As such, one can appreciate why the development of high quality, resource-
appropriate guidelines is important in optimizing global breast cancer care, particularly with
respect to systemic therapy.
1.7 International breast cancer guidelines
There have been various international guidelines published to establish standards of care in
breast cancer management, such as the St. Gallen consensus (74) ; however, it appears that so far
only the Breast Health Global Initiative (BHGI) has created international guidelines with
recommendations within a formal four-tiered resource setting framework (75). As
mentioned above, this is an important venture, as LMCs often rely on recommendations and
21
primary research conducted in HICs to help direct local practice (4) (59). However, many of the
recommendations arising from higher income nations involve costly strategies which are not
always feasible in LMCs, and therefore resource-appropriate guidelines, such as from the BHGI,
are needed to help local clinicians and policy makers implement beneficial but affordable and
sustainable breast cancer management strategies. Breast cancer guidelines are created in various
different nations, particularly from certain countries within North America and Europe. To
address the origin, scope, and quality of global breast cancer guidelines, an oncology guideline
advisory body in Canada (The Capacity Enhancement Program, CEP), undertook a systematic
review of CPGs published between 2003 and 2008. They reviewed 105 guidelines total (created
by 38 groups), and found that two thirds of the guidelines were produced in the United States or
Canada, and the majority of the rest by international or European agencies (76). Significant
duplication of recommendations was found across many guidelines. Quality was also appraised
using the AGREE 2 instrument, and the overall quality of CPGs was found to be moderate.
Development methods and scope were quite variable, and applicability scores (addressing
resource-sensitivity) were generally low (76). As discussed earlier, guidelines such as these,
created mainly in HICs with resource-insensitive recommendations and modest quality, are
likely suboptimal in helping LMCs to address their breast cancer needs.
Adherence to breast cancer guidelines has been shown to result in improved care and, in turn,
patient outcomes. For instance, a German study named ―BRENDA‖ (Breast Cancer Care under
Evidence Based Guidelines), retrospectively analyzed almost 4 000 early breast cancer patients,
to evaluate their outcomes based on care given either adherent or non-adherent to published
German guidelines (77). This study found that at 5 years, patients who were treated with
interventions that were adherent to the guidelines, had better relapse-free and overall survival,
compared to those receiving care that was non-adherent to guidelines; this was found to be
highly significant (p=0.0001), even after adjusting for potential confounders including disease
characteristics and patient age (77). A more recent report from the same group has further
illustrated that patients with triple negative breast cancer had better relapse-free and overall
survival if they were treated with guideline-adherent breast cancer therapies; these survival
endpoints significantly worsened with the number of guideline violations (78). Finally, they
showed similar findings from a 5 200 patient cohort study examining bilateral versus unilateral
22
breast cancer; once again, guideline adherent care was associated with better patient outcomes
(79). There appears to be a general paucity of such studies specifically in LMCs.
Another important consideration is that physician attitudes towards and adherence to breast
cancer guidelines is also found to be variable (80) (46). Practice has furthermore been found to
vary to different degrees, depending on the realm of breast cancer care. For instance, one study
found that physicians were adherent to guidelines in clarifying indeterminate HER2 status
(85%), initial treatment for early breast cancer (95%) and postsurgical management of locally
advanced breast cancer (82%) (43). However, they performed guideline-discordant measures
with clip placement before neoadjuvant chemotherapy (36%), unnecessary use of PET scanning
for initial assessment (34%), inappropriate assessment of menopausal status (33%),
inappropriate use of tumour markers (22%), and inappropriate use of chest imaging (16%) (43).
The authors of this study thus conclude that:
Oncologists often make guideline-consistent choices, but discordant clinical decisions
may occur in important aspects of care for early breast cancer. Broadening the diffusion
and adoption of guideline recommendations is an important mechanism for addressing
these gaps and may substantially improve the quality of breast cancer care (43).
Another study similarly found discordance in physician staging investigations, with almost 60%
of stage 1 and 2 breast cancer patients being over-investigated; the authors also recommend
improved knowledge translation of guidelines, in order to improve clinician adherence (81).
Indeed, implementation efforts and research appear scarce with breast cancer guidelines. It is
reassuring that a few ventures, such as the BHGI, do include implementation research as part of
their mandates (82); however, this does not seem to be case for most guideline creating bodies
(76).
It is therefore apparent that many breast cancer guidelines exist, with variable scope and quality,
and as expected, are developed primarily in high income nations. In addition, it is evident that
adherence to breast cancer guidelines can improve patient care and patient outcomes, however,
adherence to guidelines is quite variable. Appropriate dissemination of guidelines and
knowledge translation is imperative, and determining the factors that influence physician
decision making and care patterns is important, if guideline-based breast cancer care is to be
truly improved upon.
23
Thus far, the few studies that have been completed to evaluate these concepts have been
undertaken in single institutions or countries, and assessed practice patterns or guideline
adherence according to a single local or national guideline. There do not seem to be any
existing studies on international physician practice patterns in breast cancer care, and
whether these patterns are in accordance with internationally available guidelines.
Furthermore, although a review of international breast cancer guideline scope and quality has
been completed, an in-depth review and compilation of recommendations from those guidelines
most likely to have international impact has not been done. In addition, several advances in the
systemic therapy of breast cancer have been made since 2005 (with the advent of adjuvant
trastuzumab and the classification of molecular breast cancer subtypes), and therefore it is useful
to re-evaluate the more current state of breast cancer guidelines since these developments.
As primary research studies continue to create new knowledge on optimal breast cancer
management strategies, and experts vie to translate these findings into practice
recommendations, the true impact of this research on practicing clinicians (and thus their
patients) is largely unknown in both HICs and LMCs. Furthermore, the actual content and
quality of existing guidelines which espouse this knowledge may be variable, and thus further
complicate the ability to measure the impact of published recommendations on global breast
cancer practice patterns (and thus patient outcomes.) Finally, in addition to the knowledge
dissemination of guidelines, identifying barriers to implementing guideline based care is an
important issue, and one such significant barrier may indeed be the ability for nations to sustain
the cost of certain breast cancer therapies.
1.8 Summary
Cancer is increasingly being recognized as an international health crisis. Cancer control
globally can be better addressed by recognizing that national resource levels can greatly
influence the levels of cancer care that can be provided within a nation, and what is considered a
relevant standard of care in one setting (such as an HIC), may not be feasible (or even relevant)
in another setting. As part of the international agenda to improve cancer control worldwide,
clinical practice guidelines should thus be resource-sensitive, as data suggests that lower income
nations do rely on primary research and guidelines generated in HICs.
24
Breast cancer contributes significantly to the global cancer burden, as it is one of the most
common and deadly malignancies in women. Disparities in breast cancer care and outcomes
clearly exist across resource settings. As many novel and beneficial breast cancer therapies are
quite costly, this malignancy can particularly benefit from resource-appropriate guidelines.
Adherence to breast cancer guidelines have furthermore been shown to improve patient
outcomes. Health care professionals and policy makers may benefit from recommendations that
are tailored to their specific contexts, instead of generalized dictations of standards of care,
which are not always applicable or feasible to local patient populations (4) (13). Several
guidelines on breast cancer care exist, with potential international impact; however, on
preliminary review of the literature, it appears that only one explicitly incorporates resource
setting into its framework.
25
Chapter 2 Study Rationale
2.1 Rationale
It is unclear what the current quality, consistency, and resource-sensitivity of international
breast cancer CPGs are. It is also uncertain if physicians across the world in various
resource settings are using these guidelines, and if clinicians in LMCs are truly relying on
guidelines created in HICs. In addition, literature suggests that resources may be a
significant barrier to implementing guideline-based recommendations. As such, one may
expect to see practice patterns vary by resource setting, and as a corollary, physicians may
identify resources as a barrier to providing certain therapies, particularly in LMCs.
2.2 Objectives
The following are the three main objectives of this study:
1) To perform an up-to-date systematic review of early breast cancer guidelines in systemic
therapy with potential international impact, in order to examine quality (by using the
AGREE 2 instrument), content (consistencies and discrepancies in recommendations), and
resource-sensitivity. A particular focus was whether specific guidelines exist with
recommendations that are stratified by resource setting (HICs versus LMCs).
It was decided to focus solely on guidelines for adjuvant systemic therapy for early breast
cancer, including endocrine, chemotherapeutic, and targeted treatments. This is because
these therapies have some of the greatest potential for improving long term outcomes in breast
cancer, can have a complicated process for selecting eligible patients, and may have significant
barriers to access due to technological and cost constraints. Primary screening was excluded
from this study in order to maintain a manageable scope.
26
2) To investigate, by use of a survey, how physicians are treating early breast cancer
worldwide, and whether their care patterns are reflective of recommendations outlined in
relevant clinical guidelines. A particular focus was on whether there are disparities in care
patterns based on resource settings (HICs versus LMCs).
3) To evaluate the factors which impact physician decision-making in early breast cancer
care, including the utilization of particular breast cancer guidelines. Another goal was to
examine if specific barriers (particularly resource constraints) to implementing guideline-
based recommendations are identified by physicians, and if these patterns vary by resource
setting (HICs versus LMCs).
27
Chapter 3 Methods
3.1 Overview
Figure 1 illustrates the entire study design, which consisted of two main components: a physician
survey and systematic review and appraisal of guidelines.
Figure 1. Study design
Compilation of Survey and Guideline Review
Survey
Email Focus group (Nov. 2009)
Basic literature review (Nov. 2009)
Survey formulation (Dec 2009) -
Physician practice patterns: diagnosis, local, and adjuvant therapies for early breast
cancer
Physicians decision making factors: including use of guidelines
Phase 1 (Jan. 2010) - paper survey administered at oncologic meeting
Phase 2 (Mar. 2010-Sept. 2010) – online
Analysis
Guidelines
1) Systematic Review (Sept. 2010 to Jan. 2011) -
Early breast cancer systemic therapies
Compilation of guideline recommendations
2) AGREE 2 appraisal of guidelines (Feb. 2011 to Mar 2011)
28
3.2 Survey Methods
Survey Design
Background
The use of surveys has been highlighted as an important tool in assessing knowledge
dissemination, behaviours, and practice in implementation research (83). To optimize survey
topic relevance, 10 physicians from surgery, medical oncology, and radiation oncology involved
in breast cancer care at the investigators’ primary practice centre (Sunnybrook Odette Centre,
Toronto, Ontario, Canada), were contacted by email for opinions regarding relevant facets of
early breast cancer care (for instance, if they believed adjuvant chemotherapy was important in
early breast cancer management, and if anthracycline-taxane regimens should be considered
standard of care). These questions were structured in a ―agree/disagree‖ format, and allowed
respondents to include qualitative comments. In addition, 10 physicians were randomly selected
to represent LMCs (using the ASCO membership directory, as below); they were also sent emails
to provide the same input. A total of 8 (out of 20, or 40%) of these invited clinicians responded to
the emails (including 2 from LICs, and 1 from a MIC). They were assured that their opinions
would be considered anonymously, and were only obtained to ensure that the survey content was
in line with relevant breast cancer treatment paradigms. These answers were considered in
developing the content of the survey (after the primary literature search, but prior to question
formulation).
Content
The survey is attached in Appendix i; it was designed to collect information in the following
realms:
1) Physician demographics: including type of physician practice (and proportion dedicated to
breast cancer), years in practice, country (and therefore resource setting and continent), type of
practice centres (academic versus community), and physician involvement in activities such as
guideline creation, teaching, research, or administration.
29
2) Early breast cancer practice patterns and barriers to care: These questions were divided
into several sections, to include diagnosis (imaging/biopsy/pathology), local-regional
management (surgery and radiation), and systemic treatment (endocrine, chemotherapy,
targeted). Specific content of the questions was directed by the results of the focus group (LABC
was excluded for the reasons mentioned above, although a few physicians had highlighted it as an
important topic), breast cancer knowledge of the investigator, and perusal of guidelines as found
by preliminary review of the literature. Respondents were also asked to identify potential barriers
to implementing certain therapies (such as lack of resources, patient concerns, etc). Due to the
fact in many countries there is overlap between medical, surgical, and radiation oncologists, the
questions were thought to be relevant to many of the surveyed physicians. However, for those
practicing in a defined area (example: radiation oncology alone), clinicians were allowed to
answer only questions in their areas of expertise.
3) Decision-making and the use of guidelines: the survey included a section on clinical
decision-making, whereby physicians were asked to indicate what factors influence their
decisions on breast cancer care the most. This section also asked respondents to comment of the
regular use of specific breast cancer guidelines to help direct their clinical practice. These
guidelines were chosen after preliminary review of the literature and personal assessment by the
primary investigator of what may be impactful guidelines. The full systematic review was not
yet completed, and this was thought to be a reasonable approach to allow the formulation and
administration of the survey for phase I (detailed below).
Question Formulation
The survey collected data in a quantitative format to allow for more concrete analyses. Questions
were closed-ended with discrete answer choices; this allowed for easier coding of data and
subsequent analysis. Qualitative (open-ended or free-text) answers were elicited for some
sections of the survey, for example: to indicate additional perceived barriers to a specific
intervention, or to indicate the presence of other guidelines not given as an option in answer
choices. Any relevant free-text answers were planned to be included in the discussion of the
study. A published guide to formulating effective, internationally applicable surveys was utilized
to aid in survey construction (83); this guide was used to help direct such features as survey
30
layout and question framing in order to enhance comprehensibility and response rates. To our
knowledge, there were no standardized questions available in the particular area of this study to
aid in survey formulation; however, other studies of practice patterns in early breast cancer have
use similar quantitative formats (43) (80). Some survey formats examining practice patterns
include the use of clinical vignettes (84); given the broad scope of this survey, and the anticipated
number of questions, this format was not used.
Survey Administration
Pilot testing was not completed due to limited time between agreement by the IBCC meeting
organizers (see below) to administer the survey, and deadline for submission of materials. In
addition, as a second phase of the survey was anticipated (see below), it was planned that if any
significant issues were found with the first phase of the survey, these would be modified for the
second phase.
Research Ethics Board (REB) Approval: REB approval at the investigator’s primary practice and
research institute (Sunnybrook Health Sciences Centre and Research Institute, Toronto, Ontario,
Canada, affiliated with the University of Toronto) was granted for this phase on January 26th,
2010, project ID: 427-2009, final amended protocol April 30th, 2010, project ID: 427-2009.
University of Toronto REB approval was also obtained (protocol reference # 25282). The initial
Sunnybrook REB approval letter is attached in appendix ii.
The survey was administered in two phases:
Phase I (January 2010): The first version of the survey was an English-language, self-
administered, paper questionnaire (appendix i). This survey was distributed at the 4th
International Breast Cancer Conference (IBCC 4), in Paris, France (January 29-31st, 2010),
with the permission and aid of the meeting organizers. This annual educational meeting is
organized by a professional independent global medical education company ―prIME
Oncology©‖, and supported by a major pharmaceutical company (85). It brings together
physicians from across the globe to review the latest updates in breast oncology. The content of
the meeting is in no way controlled by the supporting pharmaceutical company, but the focus of
the meeting is on global physician attendance and evidence-based medical education. In addition,
31
the theme of IBCC 4 was the ―unmet needs of breast cancer in 2010‖ (86). These factors, in
addition to the reasonable size of the meeting (approximately 800 attendees), made it a good
venue for administration of the survey.
The survey, information letter, and implied consent form (Appendix iii) were appended to the
meeting evaluation; and as an incentive, completion of the survey was required for attendees to
receive a USB key of meeting proceedings. The surveys were collected and securely returned to
the investigators by the meeting organizers. The returned surveys were anonymous with no
personal identifying physician information.
Phase II (June 2010 to September 2010): Pilot testing was not completed for the second phase of
the survey either, as the initial phase was deemed to be a reasonable measure of survey
effectiveness based on a review of responses and low level of missing data and/or inappropriate
responses. This phase of the survey was a web-based, self-administered format, which is rapidly
emerging as a useful, accessible, and cost-effective survey technique (87). This survey was
distributed globally via email invitation with a secure link to the online survey (created on a web-
based survey program, Surveymonkey®). There were no significant content changes from the
paper survey to the online survey; formatting of the latter was directed by the online survey
platform.
Phase II Survey Targets: The American Society of Clinical Oncology (ASCO) has more than
30 000 international members, and is the largest body of oncology professionals in the world
(88); therefore, it was deemed to be a prime resource for international survey candidates. The
ASCO membership directory includes scope and country of physician practice, email, and
mailing addresses. Target physicians were thus identified as follows:
1) World bank data (2008) was used to target the top 50 most populous countries in the world
(89). These countries were further stratified by World Bank definitions of income setting: Low
income (14 countries), low-middle income (13 countries), upper-middle income (13
countries), and high income (11 countries). These countries were then re-categorized to better
correspond with the WHO resource setting definitions: low income, including low-middle
income (LICs), middle income (MICs, representing upper-middle income) ), and high income
(HICs). The final distribution of countries was thus 27 LICs, 13 MICs, and 11 HICs. The World
32
Bank has also stratified nations by 7 regions: 1 including all HICs, and 6 LMC regions: East
Asia Pacific, Europe/Central Asia, Latin America/Caribbean, Middle East/North Africa, South
Asia, and Sub-Saharan Africa (31). This method also resulted in representation from all these
regions (appendix iv).
2) The ASCO online membership directory was available to the primary investigator due to
personal membership in the organization. It was used to search for clinicians (medical, surgical,
and radiation oncologists) from each of the highlighted countries, who were identified as treating
breast cancer. The goal was to randomly select 50 physicians per country, and enter only their
email address into a secure database. For countries where there were less than 50 physicians
identified as treating breast cancer, all these clinicians were entered into the database. In
addition, the search was broadened to randomly select physicians identified as practicing general
oncology in that country, in attempts to get 50 total physicians. The United States had a
disproportionately large number of oncologists in the ASCO directory compared to other
countries; to get a better sampling of these clinicians, 100 were selected (1-4 per state.)
3) REB-approved email invitations (Appendix v) were sent to those physicians entered into the
database, with a secure link to the online survey, and a formal REB-approved implied consent
and information form (Appendix vi) was attached to the email. The email invitation allowed
physicians to request a paper version of the survey and accompanying documents, and these were
mailed or faxed to physicians as requested.
4) An email reminder was sent 1 month and 2 months after the initial email. Surveys were only
included in the final analysis if certain key sections were complete (demographics, at least one
treatment section, and the guideline section); this was constructed into the online program
platform. Reponses were collected and tabulated in an anonymous fashion by the program, with
NO correlation of response to email address or any other identifying information. For those
physicians who requested paper surveys, addresses or fax numbers were only collected once for
sending the document, and then destroyed. Returned paper surveys had NO identifying physician
data, and NO reminder was sent to these physicians. This was done to increase confidentiality
for those physicians choosing to respond via paper survey. Participants were responsible for
33
returning completed surveys with their own funds, due to the complexity of providing adequate
and appropriate postage for each country.
Survey Sample Size: Phase I sample size was driven by the number of meeting attendees
(approximately 800). It was estimated that 60-70% of these physicians would complete the
survey in order to obtain the meeting proceedings (480 to 560). The phase II sample size was
estimated to be a maximum of 2 550 (50 physicians x 49 countries + 100 from the USA). The
actual number of physicians as identified through the ASCO directory was 1 292, as several
countries had less than 50 physicians listed. It was anticipated that response rates would be 20-
35% (30), for a total of 258 to 452 responses. Combining both phases, it was thus anticipated
that 738 to 1012 physician surveys would be collected.
On primary analysis, if a target region (LIC, MIC, or HIC) was found to be underrepresented by
poor physician response (<20% of invitees), the goal was to invite a further 20-50 physicians (if
available) from underrepresented countries in that region, and if needed, by selecting a further 2-
5 countries in the target region (if represented in the ASCO directory).
Survey Data Analysis: Data from the paper (IBCC meeting) surveys were manually entered into
the online platform to allow for easier combined data analysis. Questions were identical between
the two surveys; however, to allow for online formatting, multi-part questions became separate
questions (this only affected 6 of the 51 questions on the paper survey). Inputted paper surveys
were flagged so that online and paper versions could also be analysed separately. Error checking
for correct data entry was performed by taking a random sample of 20 surveys for every 100
entered and assessing if at least 90% (18 surveys) were entered with an accuracy of 90% or
greater (46 out of 51 of questions inputted correctly).
Data were summarised by descriptive statistics, using percentages for categorical variables. A
chi-squared test was applied for bivariate analysis, to search for any association between each
response (care patterns), and relevant oncologist demographics (including resource setting,
continent, type of practice setting, years in practice, and percentage of time dedicated to breast
cancer). These associations were considered significant at the 5% critical level (p ≤ 0.05), and
represent interactions between the two variables overall. Statistical resources to perform
34
controlled regression analysis of individual categories within variables (for example: Africa
versus Europe within ―continent‖), were not available.
Combined data analyses were performed on the surveys from phase 1 and phase 2, to maximize
the number of respondents for analysis. Phase 1 and 2 data were also analyzed separately by
simple descriptive statistics, to establish if there were any gross disparities in physician
demographics or responses based on survey phase.
3.3 Methods: Systematic review of guidelines
MEDLINE Search
A systematic review of early breast guidelines focusing on adjuvant systemic therapy was
performed using the MEDLINE database; this included chemotherapy, trastuzumab, and
endocrine therapy (tamoxifen and aromatase inhibitors.) The search was restricted to guidelines
published after 2005, as that is when the most recent major change in systemic therapy was made,
with the establishment of trastuzumab in the adjuvant setting (90). The review included all
relevant publications up until the time the final search was performed, in December 2010. The
language was restricted to English to mitigate the need for translation (of both the survey and
qualitative responses), as the resources to do this were not available. The focus was on
guidelines with an explicit international audience (if found in the relayed mandate of the
guideline) or implicit international impact due to being formulated by a large oncologic society
or agency (most of which are found in HICs as discussed previously). The full search strategy,
including key words and MeSH subject headings are available in the appendix vii. An EMBASE
search was also done, but as described in the appendix, these results were not utilized due to the
inability to apply a practice guideline filter, and a resultant high proportion of non-applicable
results. Furthermore, those citations found to be of relevance showed significant overlap with
those found by the MEDLINE search.
When several versions of the same guideline were found, the most recent update was used, so
long as it addressed the same scope of recommendations. If a more recent version of the
guideline did not explicitly update or endorse recommendations from an earlier version, the
35
earlier version was used as well, and these publications together were considered one guideline
(for example, the St Gallen Consensus 2007 and 2009). If a guideline or guideline creating body
had several documents addressing different therapies, all these documents were consolidated and
addressed as one guideline (for example, the Cancer Care Ontario PEBC). If the same
recommendations were found in individual documents but also addressed in a larger guideline
document, the latter was used (for example, NICE’s guideline on the use of taxanes is addressed
in the larger, NICE guideline on breast cancer, thus the latter was used). As a corollary, the
separate guideline documents were carefully reviewed to ensure that they did not represent
updates to a larger document, in which case they were also included in the review (but still
counted towards the larger guideline).
The preliminary results were reviewed by citation first. Those not addressing breast cancer were
excluded. Documents pertaining to breast cancer but addressing the following subjects were
excluded: metastatic or locally advanced breast cancer, surgery, radiation, diagnosis, screening,
pathology or molecular markers, DCIS or benign breast disease, supportive therapies or toxicities
of therapy, hereditary breast cancer or genetic counselling, breast cancer in pregnancy,
prevention, follow up, and non-standard therapies (such as stem cell transplant). In addition,
documents found not to be clinical practice guidelines, consensus statements, or advice reports
were excluded. Publications commenting on or appraising guidelines were excluded.
Documents with information regarding guideline formulation, mandate, or implementation, were
retained for guideline appraisal purposes, but not considered to be guidelines in themselves.
These narrowed results were then reviewed by abstract and/or full citation to apply the same
exclusion criteria, before rendering the initial list of guidelines to be reviewed.
Gray Literature – Guideline Repositories
The internet was used to search two well-known online guideline repositories: the Guideline
International Network (GIN) and the National Guideline Clearinghouse (Appendix vii). Results
were reviewed using citation, and when necessary, guideline abstract and body to exclude
documents as above. In addition, if any retrieved guidelines of relevance were already found
with the MEDLINE search, these were ―excluded‖ as duplicates (and not counted as new results).
Similarly, if documents were found as part of a larger guideline (such as NICE), these were
36
consolidated with the larger guideline and also counted as a duplicate. Ultimately, only
guidelines created by agencies not found from the MEDLINE search were considered as new,
additional results. Some further guidelines were excluded as the main content was not in English
or the actual full guideline document could not be retrieved.
Gray Literature – Search Engine Google®
A final gray literature search was performed using the Google® search engine. This included a
review of the websites of well-known oncologic societies (particularly those found during the
MEDLINE and guideline repository search), to search for any updates to guidelines or new
documents. Any found guidelines were excluded, consolidated into previously found guidelines,
or included as new documents, as above.
The results from MEDLINE, online guideline repositories, and Google® searches were compiled
to create the final list of relevant guidelines (available in the Results section).
3.4 Methods: Appraisal of guidelines using the AGREE 2 instrument
The final extracted guidelines were appraised using the AGREE 2 Instrument, as found online
(32). A summary of the domains and associated criteria within this instrument are attached in
appendix viii. This instrument utilizes a formal framework to: ―address the issue of variability in
guideline quality. To that end, the AGREE instrument is a tool that assesses the methodological
rigour and transparency in which a guideline is developed‖ (31). The instrument includes 23 key
items organized into six domains which address the following facets of the clinical practice
guideline: 1. Scope and Purpose; 2. Stakeholder Involvement; 3. Rigour of Development; 4.
Clarity of Presentation; 5. Applicability; and 6. Editorial Independence. Each item is
scored from 1 (strongly disagree) to 7 (strongly agree); a further 2 items are included in the
final section denoted ―Overall Guideline Assessment.‖ Two independent reviewers, the primary
investigator (SG) and another researcher familiar with the AGREE instrument and medical
guidelines (HB), used the instrument to independently appraise each guideline. Prior to doing the
formal guideline appraisal, the reviewers appraised an unrelated oncology guideline and
compared scores in order to address any discrepancies in domain item interpretation. It was
37
decided a priori that scores within 2 points of each other (for instance 4 and 6 for item 3 in
domain 1), were congruent. It was decided that if more than 20% of items (or 4 out of 23 items),
within one guideline were given scores more than 2 points apart, then a third appraiser would be
asked to review that particular guideline. This third appraiser (CS) has expertise in both the
AGREE instrument and breast cancer. It is recommended by the AGREE Consortium that at
least two appraisers complete the instrument for any given guideline. The overall domain scores
of the guidelines are then calculated as below; the example use 4 appraisers for a domain with 3
items (32):
The AGREE Consortium outlines that the domain scores are useful for comparing guidelines and
suggesting whether a guideline may be recommended for use; however, no minimum scores
have been outlined to distinguish high and low quality CPGs. It is emphasized that the
appraiser should make these conclusions, which should be guided by the particular contextual
application of the AGREE 2 instrument (32). As such, the domain scores were tabulated using
the above formula for each guideline, recorded and plotted for comparison purposes. Final
guideline scores (which are not considered in an independent domain), and whether each
appraiser thought the guideline should be used, were also recorded (see Results Section)
38
Chapter 4 Results
4.1 Survey Results: Physician Demographics
General
Phase 1 yielded 503 paper surveys from approximately 800 meeting attendees (for a response
rate of 63%). All were complete as per noted criteria. Phase 2 yielded 202 completed surveys
from 1292 invited physicians (for a response rate of 16%), 14 of these were incomplete, and
therefore not analyzed, for a final included count of 188 from phase 2. The survey was a broad
and in-depth assessment of several areas in early breast cancer care (including diagnosis, surgery,
and radiation, in addition to systemic therapy). However, for the purpose of this project, as
mentioned above, only the results for the systemic therapy portion of the survey are presented.
Where the overall association between a survey response and demographic variable was
found to be significant (using chi-squared analysis, with a p ≤ 0.05), the data are highlighted
in yellow in the associated results tables.
Demographics
A total of 691 clinicians from both phases, responded from 70 different countries, 38% were
from LMCs. As noted in the methods section, most geographic regions of the world were
represented, except for the Caribbean islands. Only 193 physicians answered the question on
gender; of these, 73% were male and 27% were female. Physician practice setting is illustrated
in Figure 2; practice setting by continent and resource setting is in Table 2. The majority of
surveyed clinicians from low income nations practice in academic centres (89%), compared to
66% of high income countries (p<0.001); 74% of middle income nations practice in academic
centres. Physician medical speciality and years in practice are illustrated in Figure 4 and 5
respectively. The country distribution of respondents is mapped in Figure 5.
39
Figure 2. Physician Practice Setting (more than one setting allowed)
Table 2.
64.4
30.4
0.6 0.8 3.8
34.4
61.7
3.9
0
10
20
30
40
50
60
70
Perc
en
t
Resp
on
den
ts
Physician Practice Setting
Physician practice setting by continent and resource setting
% Academic
% Community
Chi-Sq
p-value
CONTINENT 16.51 0.006 Africa 89.5 10.5 Asia 80.2 19.8 .
Oceania 82.4 17.6 . Europe 65.9 34.1 .
N. America 73.7 26.3 . S. America 72.0 28.0 .
RESOURCE
SETTING 21.20 <0.001
Low 89.4 10.6 Middle 74.0 26.0 .
High 66.5 33.5 .
40
Figure 3. Physician Medical Specialty (more than one specialty allowed)
Figure 4. Physician Years in Practice
87.3
14.3
15.1
0.31.2 1.5
Medical Oncology
Surgical Oncology
Radiation Oncology
Pathology
Other
Not actively in practice
Percent Respondents
16.1
18.7
35.1
30.1
Percent Respondents
<5 years
5-9 years
10-20 years
>20 years
41
N =
691 N
um
ber
of
co
un
trie
s =
70
LM
Cs =
38%
Fig
ure
5
. C
ou
ntr
y D
istr
ibu
tio
n o
f R
es
po
nd
en
ts
42
4.2 Survey: Results by Survey Phase (IBCC versus Online)
Physician demographics, systemic therapy practice patterns, and guideline usage were compared
between the two phases of the survey to determine if any obvious discrepancies were noted. This
comparison was not a primary focus of the survey, and therefore formal statistical analyses were
not performed. Some differences in physician demographics were noted between the two phases;
for instance, 70% of respondents in phase 1 (IBCC meeting) were from HICs, compared to 34%
of physicians from phase 2 (online). In contrast, phase 2 in fact had more respondents from
MICs (42%), compared to phase 1 (11%). The representation from LICs was somewhat higher in
phase 2 (24%), compared to 18% for phase 1,. With regards to practice patterns, guidelines
usage, and preferences, overall there appear to be few major differences. The overall assessment
from these comparisons is that the combination of the two phases improved the distribution of
physicians across the various resource settings (particularly LMCs), and increased the
number of represented countries, in addition to increasing the sample size. Physician
demographics by survey phase can be found in Figure 6(a-f); practice and guideline usage
patterns can be found in Appendix ix.
43
Figure 6: Physician Demographics by Survey Phase
2
3
5
1
7
1
4
3
1
5
6
4
1
2
1
0
1
2
3
4
5
6
7
8
Online LICs N=46 (24%)
Figure 6b.
Figure 6a.
44
12
9
11
8
13
6 6
12
3
0
2
4
6
8
10
12
14
Online MICsN=80 (42%)Figure 6d.
Figure 6c.
45
6
8
6
3
1
76 6
12
12
4
11
0
2
4
6
8
10
12
Online HICsN= 64 (34%)
Figure 6f.
Figure 6e.
46
4.3 Survey Results: Practice Patterns
As detailed above, practice patterns in systemic therapy were the focus of this analysis, although
the survey evaluated several realms of breast cancer care. Practice patterns were analyzed by all
demographic variables evaluated in the survey; please refer to Appendix i to review the
demographic variables assessed (Survey section 1). Illustrated below are only the results analyzed
by demographic variables that were found to be of statistical significance (with a p value ≤0.05).
Where it was deemed useful (either for purposes of comparison or to address certain hypotheses),
data which was found not to vary with statistical significance are sometimes shown. Responses
by country were further categorized by continent to aid in analysis, and to establish any
trends in specific world regions. Of note, several practice patterns were found to vary (with
significance) by continent; these practices were often found to vary by resource setting as well,
but sometimes these trends were discordant (whereby practices varied by continent but not
resource setting, and vice versa). This may partially be explained by the fact that one continent
may have several resource settings, which may nonetheless share cultural or other local factors
that may influence practice beyond country resources. As these factors could not be readily
evaluated by this study, conclusions on why practice patterns may vary by continent and not
resource setting (and vice versa) cannot be clearly drawn.
Pathology Reporting
Although mainly the systemic therapy portion the survey is presented in this paper, some of the
data on pathology reporting are shown below, as the use of certain systemic therapies (such as
endocrine treatments and trastuzumab) is contingent on these pathologic tests being completed.
No variability was found in pathology reporting of standard tumour features such as stage (which
includes size and lymph node status), grade, or histology. However, the routine reporting of
hormone receptors (estrogen and progesterone receptors) varied both by continent and resource
setting, whereby African respondents reported that routine hormone receptor testing was done
only 78% of the time, versus above 85% for all the other nations (up to 98% in North America).
Low income nations overall reported close to 87% hormone receptor testing, versus greater than
47
90% testing in middle and high income nations. Type of practice setting (academic versus
community) did not appear to impact hormone receptor testing (Table 3).
Table 3: Routine pathology reporting
TUMOUR STAGE TUMOUR GRADE HISTOLOGY HORMONE RECEPTOR
STATUS
% Chi-sq
p-value
% Chi-sq
p-value
% Chi-sq
p-value
% Chi-sq
p-value
PRACTICE SETTING
0.49 0.484 2.66 0.103 0.00 0.973 0.01 0.922
Academic
97.1 96.1 96.9 93.0
Community 98.1 . 98.8 . 96.9 . 93.2 .
CONTINENT 9.50 0.091 18.58 0.002 9.97 0.076 25.48 <0.001 Africa 96.1 94.1 94.1 78.4 Asia 99.2 . 98.3 . 98.3 . 94.2 .
Oceania 97.8 . 100.0 . 100.0 . 87.0 . Europe 96.3 . 96.9 . 96.0 . 95.1 .
N. America 100.0 . 100.0 . 100.0 . 98.0 . S. America 91.5 . 88.1 . 91.5 . 86.4 .
RESOURCE
SETTING 1.01 0.604 3.87 0.145 0.78 0.679 9.05 0.011
Low 97.5 96.7 97.5 86.8
Middle 95.5 . 93.9 . 95.5 . 90.9 . High 97.0 . 97.5 . 96.5 . 94.7 .
The availability of routine HER-2 testing varied by both continent and resource setting: 83% of
LIC clinicians reported HER-2 testing was routinely done, which was lower than both MICs and
HICs (89% and 95% respectively). Once again, HER-2 testing did not vary by practice setting
(academic versus community). Finally, certain continents (such as Africa), with a high
proportion of LICs, did report HER-2 testing to a significantly less degree (75%, compared to
98% in North America). It is thus apparent that even within certain resource setting definitions,
particular nations are likely to have variations in access to certain technologies (Table 4).
48
Table 4. Routine HER-2 testing
Systemic Therapy
Endocrine Treatment of hormone receptor positive breast cancer
Tamoxifen, generally considered to be the gold standard in adjuvant endocrine therapy across the
globe (particularly in premenopausal women), was reported as being prescribed by a high
proportion of physicians in all three resource settings, in all continents (94% of LICs, 98% of
MICs, and 96% of HICs) Therefore, no significant variation in the use of this therapy was found
based on continent (p=0.7) or resource setting (p=0.17), or any other demographic variable. In
contrast, the use of aromatase inhibitors did vary by resource setting (although not by continent),
p=0.042. 87% physicians in LICs reported using aromatase inhibitors in eligible patients, versus
92% of MIC clinicians, and 96% of HIC clinicians.
Finally, the use of ovarian suppression by either surgery (oophorectomy) or chemical ablation
(with LHRH agonists) is supported by older or conflicting data, and practice patterns on the use
% Chisq p-value
PRACTICE SETTING 0.18 0.674
Academic 91.5
Community 92.6 .
CONTINENT 37.69 <0.001
Africa 74.5
Asia 93.3 .
Oceania 82.2 .
Europe 95.4 .
N. America 98.0 .
S. America 84.7 .
RESOURCE SETTING 20.50 <0.001
Low 82.6
Middle 89.3 .
High 95.2 .
49
of these agents may be expected to be variable. The use of oophorectomy varied by continent,
but not by resource setting, which may represent some national or regional patterns or consensus
towards using this technology. In addition, the use of ―chemical‖ ovarian ablation varied by
continent (for instance being used most highly in Europe and Africa, and less commonly in North
America). When assessing this data by resource setting, MICs appeared to use this strategy more
commonly (69%) than LICS (41%) or HICs (67%) (Table 5). 81% of physicians reported ―not
applicable‖ to the question evaluating why endocrine therapy is not given to eligible patients; of
the 19% that did respond to this question, 9% reported that endocrine therapy was not given due
to patient preference, and a total of 7% said it was due to lack of drug approval or cost. Due to
the low numbers, these responses were not analyzed by demographic variables.
Table 5: Adjuvant endocrine therapy given routinely
Oopherectomy Tamoxifen Aromatase Inhibitors
Chemical Ablation
% Chisq p-value
% Chisq p-value
% Chisq p-value
% Chisq p-value
CONTINENT 24.21 <0.001 2.92 0.712 7.09 0.214 25.94 <0.001
Africa 22.4 95.9 85.7 61.2
Asia 15.6 . 95.4 . 94.5 . 48.6 .
Oceania 43.5 . 95.7 . 89.1 . 50.0 .
Europe 17.7 . 95.7 . 92.8 . 72.1 .
N. America 25.5 . 97.9 . 97.9 . 53.2 .
S. America 35.2 . 100.0 . 94.4 . 63.0 .
RESOURCE SETTING
4.25 0.120 3.50 0.174 6.36 0.042 27.44 <0.001
Low 19.8 93.7 87.4 41.4
UMC 28.7 . 98.4 . 92.6 . 68.9 .
High 20.2 . 96.3 . 94.4 . 67.6 .
Chemotherapy
Table 6 outlines the stages of breast cancer offered chemotherapy routinely by survey
respondents. It appears that years in practice affect the proportion of patients with stage I cancer
50
receiving chemotherapy (p=0.45), whereby those physicians who have been in practice for more
than 20 years offer chemotherapy to these group of patient more often (30%) versus those in
practice less than 5 years (16%). The use of chemotherapy for early stage patients also seemed to
vary by continent (p=0.014), but not by resource setting. This trend was also seen for stage 3
breast cancer patients. Finally, type of practice setting seemed to influence the use of
chemotherapy across all disease stages, whereby chemotherapy was offered were often in
academic centres, versus community centres (Table 6).
Table 6: Types of patients treated with adjuvant chemotherapy
Stage I Stage II Stage III All High Risk Pts
% Chisq p-value
% Chisq p-value
% Chisq p-value
% Chisq p-value
YEARS IN PRACTICE
8.04
0.045
4.90
0.179
3.59
0.309
1.34
0.719
< 5 yrs 16.0 60.4 66.0 83.0 5 to 9 23.0 . 68.0 . 66.4 . 79.5 .
10 to 20 26.8 . 67.7 . 67.2 . 80.9 . > 20 yrs 30.3 . 59.1 . 59.1 . 77.8 .
% BREAST CANCER
PRACTICE
1.10 0.778 3.61 0.307 4.17 0.244 13.18 0.004
<25% 26.3 72.4 71.1 76.3 25 to 49% 23.3 . 63.3 . 65.6 . 74.8 . 50 to 75% 27.5 . 65.9 . 67.1 . 87.4 .
> 75% 26.2 . 60.0 . 58.6 . 84.8 .
TYPE OF CENTRE
6.36 0.012 4.35 0.037 3.92 0.048 1.38 0.240
Academic 27.8 66.6 67.3 81.7 Community 17.6 . 57.2 . 58.5 . 77.4 .
CONTINENT 14.27 0.014 10.83 0.055 11.46 0.043 2.47 0.782
Africa 22.0 66.0 74.0 80.0 Asia 37.3 . 69.5 . 67.8 . 78.8 .
Oceania 19.6 . 78.3 . 76.1 . 87.0 . Europe 21.4 . 60.1 . 61.0 . 78.9 .
N. America 32.7 . 73.5 . 75.5 . 83.7 . S. America 28.8 . 57.6 . 55.9 . 83.1 .
RESOURCE
SETTING
3.45
0.178
0.22
0.896
0.59
0.744
2.03
0.362 Low 31.1 64.7 67.2 75.6
Middle 28.2 . 62.6 . 62.6 . 81.7 . High 23.3 . 64.8 . 65.1 . 81.3 .
51
The type of adjuvant chemotherapy routinely given to patients is outlined in Table 7. The use of
older, classical chemotherapy (cyclophosphamide, methotrexate, 5-flurouracil, ―CMF‖) was
found to be uniformly low, with no significant variation found by demographics. However,
although not statistically significant, certain continents still appear to use CMF more than others
(for instance 22% in Africa and 24% in South America, versus 10% in North America). The use
of anthracycline-based chemotherapy varied with statistical significance by type of practice,
continent, and percentage of physician practice dedicated to breast cancer (Table 7). The use of
taxane-based chemotherapy also varied by continent (p=0.005), but by no other demographic,
and was lower than the use of anthracycline-based chemotherapy overall. Finally, the newest
generation in adjuvant chemotherapy, anthracycline and taxane-based regimens, were used most
often, and varied only by resource setting: 88% of HIC physicians reported using these regimens,
compared to 84% of MICs, and 77% of LICs (p=0.017).
Table 7. Types of chemotherapy given routinely
CMF Anthracycline Taxane-based Anthracycline + Taxane
% Chisq p-value
% Chisq p-value
% Chisq p-value
% Chisq p-value
% BREAST PRACTICE
2.08
0.555
12.55
0.006
0.93
0.818
4.47
0.215
<25% 14.5 65.8 51.3 85.5 25 to 49% 17.1 . 69.9 . 53.2 . 82.5 . 50 to 75% 15.6 . 76.6 . 56.3 . 89.8 .
> 75% 11.8 . 58.3 . 51.4 . 84.0 . TYPE OF
PRACTICE
2.55
0.111
5.83
0.016
0.24
0.626
0.11
0.736 Academic 17.4 72.1 52.0 85.0
Community 11.9 . 61.6 . 49.7 . 86.2 . CONTINENT 8.08 0.152 12.86 0.025 16.67 0.005 8.62 0.125
Africa 22.0 66.0 48.0 72.0 Asia 16.9 . 74.6 . 66.9 . 83.9 .
Oceania 15.2 . 80.4 . 56.5 . 84.8 . Europe 12.7 . 68.7 . 47.4 . 87.3 .
N. America 10.4 . 50.0 . 64.6 . 83.3 . S. America 24.1 . 69.0 . 51.7 . 87.9 .
RESOURCE SETTING
10.18
0.006
2.46
0.293
3.11
0.211
8.14
0.017
Low 21.8 74.8 58.8 77.3 Middle 20.0 . 66.2 . 47.7 . 83.8 . High 11.7 . 68.3 . 53.6 . 87.8 .
52
Patient Acceptance of Chemotherapy
Respondents were also asked what percentage of patients who are offered chemotherapy agree to
it. This did not vary significantly by continent, although there was a trend towards this (p=0.056)
(Figure 7). Responses did vary by resource setting (p=0.011), whereby only 63% of LIC
physicians reported that more than 75% of patients agree to chemotherapy, compared to 82% of
MICs and 77% of HIC physicians (Figure 8). Table 8 outlines reported reasons why patients may
refuse chemotherapy, according to responding physicians.
Figure 7. Percentage of patients accepting chemotherapy by continent
0
10
20
30
40
50
60
70
80
90
100
0-49% 50-75% >75%
Perc
en
t R
esp
on
den
ts
Percentage of Patients
Africa
Asia
Oceania
Europe
N America
S America
53
Figure 8. Percentage of patients accepting chemotherapy by resource setting
Table 8. Reasons patients refuse chemotherapy
Side
Effects
Unsure of
Benefit
Time
Daily Life
Impact
% Chisq P value
Chisq P value
% Chisq P value
% Chisq P value
CONTINENT 10.68 0.058 18.93 0.002 12.13 0.033 2.19 0.822
Africa 70.8 43.1 12.5 29.2
Asia 76.9 23.1 2.6 25.6
Oceania 73.9 26.1 0.0 32.6
Europe 75.4 30.4 5.2 26.9
N. America 89.8 42.9 8.2 34.7
S. America 63.0 50.0 1.9 29.6
RESOURCE SETTING
5.87 0.053 7.22 0.027 0.99 0.609 3.75 0.153
Low 72.7 24.8 6.0 22.2
Middle 68.0 41.0 3.3 25.4
High 78.4 32.0 5.0 30.7
0
10
20
30
40
50
60
70
80
90
0-49% 50-75% >75%
Perc
en
t R
esp
on
den
ts
Percentage of Patients
Low
Middle
High
54
Table 8. Reasons patients refuse chemotherapy (cont’d)
Social/ Cultural Beliefs
Wait
Times
Cost
% Chisq P value
% Chisq P value
% Chisq P value
CONTINENT 20.02 0.001 19.49 0.002 116.3 <0.001
Africa 18.8 8.3 50.0
Asia 22.2 0.0 34.2
Oceania 39.1 6.5 26.1
Europe 16.2 1.3 2.9
N. America 22.5 0.0 16.3
S. America 35.2 1.9 9.3
RESOURCE SETTING
7.45 0.024 7.40 0.025 150.7 <0.001
Low 20.5 1.7 52.1
Middle 30.3 4.9 14.8
High 18.8 1.0 5.0
Trastuzumab
The percentage of patients routinely given adjuvant trastuzumab is described in Table 9. This
varied significantly by percentage of physician practice dedicated to breast cancer (p=0.004),
whereby those physicians who spend more than 75% of their practice on breast cancer, prescribe
trastuzumab to more than 75% of eligible patients, compared to 53% by physicians who spend
less than 25% of their time on breast cancer. This trend was also seen by type of oncologist,
whereby medical oncologists prescribe trastuzumab more often to eligible patient than radiation
or surgical oncologists (p <0.001). Trastuzumab varied greatly by continent (p<0.001) and
resource setting (p<0.001). The majority of physicians from Africa and Asia reported giving
trastuzumab to less than 25% or between 25 to 49% of eligible patients only. Approximately half
the physicians from South America reported giving trastuzumab to either less than 75% of
patients, and the other half prescribe it to greater than 75% of patients. However, 85% of North
American and 75% of European clinicians reported using trastuzumab for greater than 75% of
eligible candidates (Table 9). With respect to resource setting, 62% of physicians from LICs
reported giving trastuzumab to less than 25% of their patients; only 11% indicated prescribing it
for greater than 75% of eligible patients. 36% of respondents from MICs reported giving more
55
than 75% of patients the treatment, and the majority indicated using it in less than 49% of
patients. In contrast, 80% of HIC clinicians reported giving trastuzumab to greater than 75% of
eligible patients (Table 9).
Table 9. Percentage of eligible patients given adjuvant trastuzumab
Percent Respondents:
< 25%
25 to 49%
50 to 75%
>75%
Chi-sq
p-value
% BREAST CA PRACTICE
24.46
0.004
<25% 30.4 8.7 7.2 53.6
25 to 49% 24.3 13.8 7.5 54.4 .
50 to 75% 25.9 11.4 8.2 54.4 .
> 75% 14.4 8.6 1.4 75.5 .
TYPE OF SPECIALTY
28.56
<0.001
Med Onc 20.3 11.1 6.4 62.2
Rad Onc 16.7 11.1 16.7 55.6 .
Surg Onc 50.0 14.6 2.1 33.3 .
PRACTICE SETTING
1.26 0.738
Academic 23.1 11.7 7.4 57.7
Community 24.5 11.6 4.8 59.2 .
CONTINENT 128.69 <0.001
Africa 39.0 24.4 17.1 19.5
Asia 50.0 10.2 7.4 32.4 .
Oceania 33.3 15.6 6.7 44.4 .
Europe 11.6 8.3 5.3 74.8 .
N. America 10.9 2.2 2.2 84.8 .
S. America 29.6 16.7 5.6 48.1 .
RESOURCE SETTING
213.37
<0.001
Low 61.9 18.1 8.6 11.4
Middle 33.3 22.2 8.5 35.9 .
High 9.9 4.8 5.1 80.2 .
In exploring the reasons why trastuzumab is not given to eligible patients, Table 10 illustrates
that in academic centres, drug funding was cited to be a barrier based on practice setting, (chosen
by 42% of academic physicians, compared to 26% of community physicians, p=0.004). The
availability of HER-2 testing was also cited to be an issue by 16% of community oncologists
(versus 6% of academics practitioners, p=0.002). However, the lack of HER-2 testing did not
appear to be a significant barrier by continent or resource setting; this was corroborated by the
56
results above, indicating that at least greater than 75% (and in general, greater than 85%) of
responding global physicians reported that HER-2 testing was available to them. Lack of drug
funding and access as barriers to trastuzumab use did vary by continent and resource setting (all p
< 0.001). For instance, 30% of respondents each from Africa and South America cited lack of
drug access as a reason why trastuzumab was not given to patients. In Africa, the lack of drug
funding is cited by 80% of physicians to be a barrier. In contrast, only 13% and 27% of North
American, and 8% and 13% of European physicians considered drug access and funding,
respectively, to be a barrier. 87% of Asian respondents reported drug funding to be an issue,
whereas drug access appeared to be less of a concern (8%). Respondents from the Oceania
nations also reported funding to be a larger concern than access. Lack of facilities to administer
trastuzumab did not seem to a significant barrier to giving the therapy to patients (Table 10).
Table 10. Barriers to trastuzumab use for eligible patients
Her-2 testing not available
Lack of drug access Lack of drug funding Lack of facilities
% Chisq p-value
% Chisq p-value
% Chisq p-value
% Chisq p-value
% BREAST PRACTICE
1.46
0.692
3.98
0.263
11.02
0.012
2.24
0.525
<25% 6.3 16.7 52.1 0.0
25 to 49% 10.2 . 11.8 . 46.5 . 1.6 .
50 to 75% 7.1 . 13.4 . 33.1 . 0.8 .
> 75% 7.3 . 6.1 . 31.7 . 0.0 .
TYPE OF SPECIALTY
5.00
0.082
1.97
0.373
22.21
<0.001
0.47
0.790
Med Onc 7.6 12.4 36.5 1.0
Rad Onc 18.2 . 0.0 . 45.5 . 0.0 .
Surg Onc 17.1 . 8.6 . 77.1 . 0.0 .
PRACTICE SETTING
9.58
0.002
1.70
0.192
8.38
0.004
0.57
0.451
Academic 6.3 13.5 42.0 0.3
Community 16.3 . 8.7 . 26.0 . 1.0 .
CONTINENT 0.57 0.989 26.69 <0.001 176.67 <0.001 12.23 0.032
Africa 8.3 27.8 80.6 5.6
Asia 7.5 . 8.6 . 87.1 . 1.1 .
Oceania 11.4 . 5.7 . 45.7 . 0.0 .
Europe 8.9 . 8.0 . 13.1 . 0.0 .
N. America 9.1 . 13.6 . 27.3 . 0.0 .
S. America 10.0 . 30.0 . 50.0 . 2.5 .
RESOURCE SETTING
0.08
0.962
52.72
<0.001
216.97
<0.001
2.17
0.338
Low 8.2 11.3 93.8 1.0
Middle 9.4 . 32.3 . 62.5 . 2.1 .
High 8.9 . 4.1 . 11.8 . 0.4 .
57
Finally, the graph below summarizes some diagnostic modalities, local treatments, and systemic
therapies for early breast cancer as found from the larger survey (Figure 9); this is to illustrate the
pattern of systemic therapy use, in comparison to other modalities of early breast cancer care
across resource settings.
Figure 9. Summary of early breast cancer therapies offered by resource setting
4.4 Survey Results: Factors influencing physician practice and guideline usage The final section of the survey included questions focused on physician decision making.
Physicians were asked to indicate the top three factors they thought were most influential on
their therapeutic decisions in early breast cancer care. Figure 10 shows the results to this
question from all respondents; there were no statistically significant differences found between
these factors by demographic variable, except in the use of personal training or personal
judgment. These varied by resource setting, whereby more clinicians in LICs relied on these
factors, compared to MIC or HIC physicians (Table 11).
58
Figure 10. Top three factors influencing therapeutic decisions
Table 11. Factors influencing therapeutic decisions by demographic
Personal Training Personal Judgement
% Chisq p-value % Chisq p-value
% BREAST PRACTICE
8.27
0.041
6.41
0.093
<25% 30.3 46.1
25 to 49% 36.4 . 44.9 .
50 to 75% 25.3 . 50.0 .
> 75% 25.7 . 57.4 .
CONTINENT 3.18 0.672 9.11 0.105
Africa 33.3 56.9
Asia 32.5 . 55.8 .
Oceania 34.8 . 56.5 .
Europe 27.5 . 43.4 .
N. America 34.0 . 54.0 .
S. America 35.6 . 49.2 .
RESOURCE SETTING
8.67
0.013
6.48
0.039
Low 41.3 58.7
Middle 31.1 . 43.2 .
High 27.3 . 48.0 .
32.7
51.6
12.2
66.3
15.6
29
21.9
65.5
Personal Training
Personal Judgement
Opinions of Colleagues
Medical Journals
Legal Policy
Regional Guidelines
Government Guidelines/Policy
International Guidelines
0 10 20 30 40 50 60 70
Percent respondents
59
With regards to the influence of published guidelines on decision making, Table 12 highlights
that the use of local, regional, governmental (national), and international guidelines all vary by
continent and resource setting (Table 12). Physicians from LICs and MICs reported more
reliance on international directives than HICs (p<0.001). The use of governmental guidelines or
policies appears to be similar across all resource settings (p=0.63). Finally, the only other
significant association found was between type of oncologic speciality and the use of
international guidelines (p=0.023), whereby radiation oncologists were found to rely less on
international policy than medical or surgical oncologists.
Table 12. Influence of guidelines on physician decision making
Local Guidelines Regional Guidelines Governmental Policy
International Guidelines
% Chisq p-value
% Chisq p-value
% Chisq p-value
% Chisq p-value
TYPE OF SPECIALTY
2.83
0.242
4.57
0.102
0.44
0.804
7.59
0.023
Med Onc 14.8 25.7 21.3 62.8
Rad Onc 26.3 . 42.1 . 21.1 . 31.6 .
Surg Onc 10.5 . 35.1 . 17.5 . 61.4 .
PRACTICE SETTING
0.29
0.591
1.39
0.238
0.34
.558
1.84
0.175
Academic 15.5 26.6 22.0 62.3
Community 17.3 . 31.5 . 19.8 . 56.2 .
CONTINENT 20.31 0.001 16.85 0.005 4.93 0.425 20.63 <0.001
Africa 17.6 17.6 27.5 68.6
Asia 5.8 . 21.7 . 18.3 . 69.2 .
Oceania 10.9 . 23.9 . 23.9 . 63.0 .
Europe 19.3 . 31.2 . 22.9 . 56.6 .
N. America 4.0 . 42.0 . 18.0 . 44.0 .
S. America 22.0 . 15.3 . 13.6 . 78.0 .
RESOURCE SETTING
5.41
0.067
19.18
<0.001
0.93
0.630
16.48
<0.001
Low 9.1 19.8 19.0 62.8
Middle 13.6 . 15.9 . 19.7 . 75.8 . High 17.5 . 33.3 . 22.5 . 56.0 .
60
Clinicians were also asked to indicate how applicable they believe most published international
guidelines on breast cancer care are to their personal practice setting. Table 13 shows that this
varies with statistical significance by continent (p =0.029). As illustrated, only 39% of
respondents from Africa find these publications very applicable, compared to 68% of North
American clinicians (Table 13).
Table 13. Applicability of international breast cancer guidelines to personal practice setting
Percent
Respondents
Very
Applicable
Somewhat Applicable
Not
Applicable
Chi-sq
p-value
YEARS IN PRACTICE
13.95
0.030
< 5 yrs 42.0 57.0 1.0 5 to 9 54.4 42.1 3.5 .
10 to 20 60.2 38.5 1.4 . > 20 yrs 59.4 39.4 1.1 .
CONTINENT 19.97 0.029 Africa 39.1 54.3 6.5
Asia 57.7 42.3 0.0 . Oceania 58.1 39.5 2.3 .
Europe 52.1 45.9 2.0 . N. America 68.1 29.8 2.1 .
S. America 67.9 32.1 0.0 . RESOURCE
SETTING
3.98 0.408
Low 47.2 50.9 1.9 Middle 57.3 40.2 2.6 . High 56.9 41.5 1.6 .
The survey asked respondents to outline the primary sources they utilize to keep updated with
new information on breast cancer therapy (Table 14). The use of medical journals varies both by
continent and resource setting (both p <0.001). For instance, only 47% of physicians from
Africa, 48% from Europe, and 43% from Asia reported using medical journals as a primary
information source, compared to more than 80% of clinicians each from North and South
America. 85% of South American physicians also report using international guidelines, as well as
80% of respondents from Africa, and 84% of those from Asia; this is in contrast to 66% of those
from North America. There appeared to be no significant difference in the attendance at
oncology meetings across any demographic variable.
61
Table 14: Sources used for latest breast cancer information
Medical Journals Internet Local Guidelines Regional/National Guidelines
% Chisq p- value
% Chisq p- value
% Chisq p- value
% Chisq p- value
CONTINENT
44.94
<0.001
5.20
0.392
12.93
0.024
14.05
0.015
Africa 47.1 60.8 13.7 17.6
Asia 42.5 . 57.5 . 5.8 . 16.7 .
Oceania 52.2 . 58.7 . 8.7 . 28.3 .
Europe 48.3 . 54.4 . 15.6 . 30.3 .
North America
80.0 . 52.0 . 4.0 . 38.0 .
South America
83.1 . 42.4 . 8.5 . 23.7 .
RESOURCE SETTING
18.42
<0.001
2.43
0.297
2.84
0.242
13.94
<0.001
Low 42.1 56.2 11.6 17.4
Middle 68.2 . 48.5 . 7.6 . 19.7 .
High 51.3 . 56.0 . 13.0 . 31.8 .
Government Guidelines International guidelines Oncology meetings
% Chisq p-value % Chisq p-value % Chisq p-value
CONTINENT 8.02
0.155
10.70
0.058
6.85
0.232
Africa 13.7 80.4 72.5
Asia 10.0 . 84.2 . 77.5 .
Oceania 15.2 . 69.6 . 76.1 .
Europe 17.4 . 76.8 . 66.4 .
North America
10.0 . 66.0 . 72.0 .
South America
6.8 . 84.7 . 74.6 .
RESOURCE SETTING
3.98
0.136
3.96
0.138
0.68
0.713
Low 10.7 81.0 71.1
Middle 10.6 . 82.6 . 73.5 .
High 16.3 . 75.3 . 69.8 .
62
Figure 11 shows the use of specific guidelines by all respondents. Figures 12 and 13 highlight
the use of specific guidelines by continent and resource setting, respectively. There were
statistically significant differences by continent in the use of the following guidelines: BHGI
(p=0.005), ASCO (p=0.014), NCCN, NICE, CCO, and ESMO (all p<0.001). The use of specific
guidelines was less variable by resource setting, but the BHGI (p=0.014) NCCN (p=0.044),
NICE (<0.001), and ESMO (p=0.022) appeared to vary by resource setting.
Figure 11. Use of specific breast cancer guidelines (all respondents)
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
ASCO BCCA BHGI CCO ECCO ESMO NCCN NICE St Gallen None of Above
Perc
en
t R
esp
on
den
ts
Guideline
Guideline Legend:
ASCO – American Society of Clinical Oncology
BCCA-British Columbia Cancer Agency
BHGI – Breast Health Global Initiative
CCO-Cancer Care Ontario
ECCO-European Cancer Organization
ESMO-European Society of Medical Oncology
NCCN-National Comprehensive Cancer Network
NICE-National Institute of Clinical Excellence
St Gallen-St Gallen Consensus
63
Figure 12. Breast cancer guideline use by continent
Figure 13. Breast cancer guideline use by resource setting
0
10
20
30
40
50
60
70
80
90
100
ASCO BCCABHGI CCO ECCO ESMO NICE NCCN St Gallen
Pe
rce
nt
Re
sp
on
de
nts
Guideline
Africa
Asia
Oceania
Europe
N. America
S. America
0
10
20
30
40
50
60
70
80
90
ASCO BCCA BHGI CCO ECCO ESMO NICE NCCN St Gallen
Perc
et
Resp
on
den
ts
Guideline
LIC
MIC
HIC
64
Clinicians were asked to outline how they most often access CPGs, if they prefer them in their
native language (if not English), and how they would prefer future guideline updates. The
responses from all clinicians are shown in Figure 14. These responses did not vary
significantly by demographic variable, except practice years (p=0.017), whereby more physicians
who have been practicing for 10 to 20 or greater than 20 years currently reported accessing
guidelines through paper copy (46% and 50% respectively). Table 15 shows preferences for
future guideline updates by continent and resource setting. Although the internet was reported as
being used currently by a high proportion of all surveyed clinicians, responses for future CPG
updates did vary by continent (p=0.006) and resource setting (p=0.005). Physicians from certain
continents (such as Asia, 58%) had a higher preference for using the internet than others (for
example, North America, 32%). Notably, LIC clinicians reported a preference for future updates
via the internet (56%), compared to MIC and HIC respondents (40% each). In addition, the
preference for local presentations for future guideline dissemination varied by continent
(p=0.046), with 35% of African clinicians and 32% of North American clinicians having interest
in this mode of dissemination, versus 16 to 20% for the other continents. Finally, the preference
for future breast cancer information to be sent by paper copy varied by resource setting
(p=0.005); 34% of LIC physicians prefer this, compared to 27% of MIC and 20% of LIC
physicians.
65
Figure 14. Guideline preferences (all respondents)
Table 15. Preferred methods for future guideline updates Email Local
presentations Internet Mailed paper
% Chisq p-value
% Chisq p-value
% Chisq p-value
% Chisq p-value
CONTINENT 5.70 0.336 11.31 0.046 16.43 0.006 7.71 0.173 Africa 84.3 35.3 43.1 37.3 Asia 82.5 . 16.7 . 58.3 . 24.2 .
Oceania 71.7 . 26.1 . 39.1 . 30.4 . Europe 75.5 . 20.2 . 39.1 . 22.6 .
N. America 78.0 . 32.0 . 32.0 . 18.0 . S. America 83.1 . 20.3 . 45.8 . 20.3 .
RESOURCE
SETTING
0.31
0.857
0.19
0.910
10.50
0.005
10.75
0.005
Low 79.3 23.1 56.2 33.9
Middle 76.5 . 22.7 . 40.2 . 27.3 .
High 78.3 . 21.5 . 40.0 . 20.0 .
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
Perc
en
t R
esp
on
den
ts
Current Method for AccessingGuidelines
Prefer Guidelines in Native Language?
Preferred Method for Future Guideline Updates
66
4.5 Results: Guideline systematic review
The systematic review of international early breast cancer guidelines was performed using
MEDLINE, online guideline repositories, and a general search engine (Google®). The process is
outlined below (Figures 15 to 18), followed by the resultant final list of guidelines that was
compiled and appraised (Table 16). The complete search strategies, as noted before, are available
in the appendix (vii).
67
Figure 15. MEDLINE Search
Medline Search 1i:
73 Total Publications – Citation Review
Excluded:
Screening/Radiology: 6
Surgery: 1
Radiation: 4
Pathology/Molecular: 7
Not guideline: 4
Not breast cancer: 9
Advanced/metastatic: 6
DCIS: 1
Supportive or toxicity: 7
Pregnancy: 2
Not therapy of interest: 1
Duplicate: 1
Total Excluded: 49
Total Included: 73-49 = 24
24 Guidelines: Abstract and Body Review
Excluded:
Local adaptation of existing guideline: 2
- (NCCN Middle East North Africa, and BHGI HER2 positive Asia)
Implementation documents for larger guideline: 2
- (BHGI)
Older versions/erratums: 6 - (ESMO 2005, 2007, and 2008, International Primary Systemic Treatment 05, NCCN 2005, 2006)
Part of larger guideline or background on guideline: 2
- (St Gallen Use of AIs, BHGI)
Incorrect therapeutic intent: 2 - (ASCO chemoprevention, ASCO follow up)
Total Excluded: 14
New Total Included: 10
1. SEOM
2. ASCO 2006
3. St Gallen 2009
4. NCCN 2009
5. Cordoba
Consensus
6. SIOG 08
7. ESMO 2010
8. NICE 2009
9. BHGI
10. International Panel on Neoadjuvant
Therapy
FINAL GUIDELINE LIST FROM MEDLINE SEARCH:
68
Figure 16. GUIDELINE INTERNATIONAL NETWORK (G.I.N) Search
Total Publications: 139
Citation and Abstract Review
Excluded:
Metastatic: 17
Supportive: 6
Not English: 15
Duplicate: 5 (BHGI, NICE, Neoadj.)
Older than 2005: 2
Part of larger guideline: 1
Wrong intervention: 1
Surgery/local treatment: 8
Radiation: 7
Follow up: 1
Not a guideline: 3
Screening/diagnosis: 38
Pathology/molecular: 9
Prevention: 4
DCIS/benign breast disease: 4
Hereditary/Genetic Counselling: 7
Total Excluded: 128
Total Included: 11
11 Guidelines: 1. NICE: Trastuzumab 2. PEBC: Trastuzumab 3. PEBC: AIs 4. NICE: Paclitaxel 5. Dutch Guidelines 6. New Zealand Guidelines 7. Malaysian Guidelines 8. NCCC (UK) 9. NICE: Docetaxel 10. PEBC: Adjuvant Taxanes 11. PEBC: Adjuvant Bisphosphonates Grouped the following documents into larger guidelines:
NICE: 3 documents , PEBC: 4 documents
New Subtotal: 6
Excluded:
NICE-part of larger guideline (duplicate)
Netherlands – not in English
Malaysia – guideline document not found
NCCC – akin to NICE guidelines (duplicate)
New Total Included: 2
1. Cancer Care Ontario/PEBC
2. New Zealand Guidelines
FINAL GUIDELINE LIST FROM GIN SEARCH:
69
Figure 17. NATIONAL GUIDELINE CLEARLINGHOUSE Search
Total Publications: 57
Citation Review
Excluded:
Metastatic/Advanced: 7
Diagnosis/Screening: 16
Surgery-2
Not breast ca – 2
Pathology/molecular-4
Intervention-1 (bp)
Radiation-3
Supportive-3
Hereditary/Genetic Counselling-2
Prevention-2
DCIS-1
Follow up-3
Duplicates-8
Total Excluded: 54
Included: 3:
3 Guidelines:
Full Guideline Review:
1. New Zealand: Special issues in breast cancer
2. New Zealand: Chemotherapy in early breast cancer
3. New Zealand: Endocrine therapy in early breast cancer
Grouped the following documents as part of larger guideline: New Zealand: 3
New Subtotal: 1
Excluded:
New Zealand: Part of larger guideline (duplicate)
New Total Included: 0
NO NEW GUIDELINES TO ADD.
FINAL GUIDELINE LIST FROM NATIONAL GUIDELINE
CLEARINGHOUSE:
70
Figure 18. GOOGLE® Search
6 publications or web-based documents:
1. WHO breast cancer Eastern Mediterranean
2. AGO
3. SIGN
4. NCCN Asia
5. NCCN Middle East North Africa
6. St Gallen 2007
Subtotal: 6
Excluded:
NCCN – x 2. Adaptation of another guideline (duplicate)
St Gallen – grouped with newer version of guideline
New Total Included: 3
1. AGO 2. SIGN
3. WHO EASTERN MED.
FINAL GUIDELINE LIST FROM GOOGLE SEARCH:
71
Table 16. Final guideline list
1. GERMAN GYNECOLOGICAL ONCOLOGY GROUP (AGO) BREAST COMMISSION [2009-2010, GERMANY] (91) (92).
2. AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) [2006, UNITED STATES] (93).
3. BREAST HEALTH GLOBAL INITIATIVE (BHGI) (2006, 2007, INTERNATIONAL AND UNITED STATES) (50) (75) (94). Asia Summit HER-2 consensus (95), NOT included in guideline compilation table.
4. CANCER CARE ONTARIO (CCO) PROGRAM IN EVIDENCE BASED CARE (PEBC) [2008-2010, CANADA] (96) (97) (98) (99).
5. CORDOBA CONSENSUS [2007, SPAIN] (100).
6. EUROPEAN SOCIETY FOR MEDICAL ONCOLOGY (ESMO) [2010, EUROPE] (101).
7. INTERNATIONAL EXPERT PANEL ON NEOADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER [2006, INTERNATIONAL] (102). (Denoted INST)
8. NATIONAL COMPREHENSIVE CANCER NETWORK (NCCN) [2010, UNITED STATES] (103). *Local Adaptations: Middle East North Africa (104), Asia (62), NOT included in final guideline compilation.
9. NEW ZEALAND GUIDELINES GROUP [2009, NEW ZEALAND] (105).
10. NATIONAL INSTITUTE FOR CLINICAL EXCELLENCE (NICE) [2009, UNITED KINGDOM] (106)
11. SPANISH SOCIETY OF MEDICAL ONCOLOGY (SEOM) [2010, SPAIN] (107).
72
12. SCOTTISH INTERCOLLEGIATE GUIDELINES NETWORK (SIGN) [2005-2007, UNITED KINGDOM] (108).
13. INTERNATIONAL SOCIETY OF GERIATRIC ONCOLOGY (SIOG) [2007, INTERNATIONAL: EUROPE, UNITED STATES] (109).
14. THE ST. GALLEN CONSENSUS [2007 and 2009, INTERNATIONAL] (110) (111).
15. WHO REGIONAL OFFICE FOR THE EASTERN MEDITERRANEAN [2006, EASTERN MEDITERRANEAN] (112).
Some guidelines were found by more than one search process (MEDLINE, guideline repositories,
and/or Google search.) These include the BHGI, NICE, SIOG, St Gallen, and NCCN guidelines.
Others (such as the New Zealand and CCO/PEBC guidelines) were found in the guideline
repositories but not through MEDLINE. Others still (such as the WHO, AGO, and SIGN
guidelines) were found only by online searching, and were not found on the MEDLINE or
guideline repository searches. Once the guidelines were extracted and carefully reviewed for
content, they were compiled into the table found in appendix viii ), which consolidates key
recommendations on adjuvant systemic therapy from each of the guidelines.
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Most guidelines addressed all realms of adjuvant systemic care: endocrine, chemotherapy and
targeted (trastuzumab), except for the guideline on neoadjuvant therapy (Kaufmann et al), which
addressed these treatments in the preoperative, but still early stage breast cancer setting. The
ASCO guideline only pertained to endocrine therapy. A few guidelines also addressed adjuvant
bisphosphonatess. Some guidelines made specific mention of monitoring toxicities of certain
therapies, or ensuring specific pathologic testing to be performed. When this information was
built clearly in the recommendations themselves, it appears in the ―recommendations‖ column.
The ―notes‖ column includes such information if it was found in associated supporting text
within the guideline; this area also includes other relevant information, such as risk stratification
criteria.
Adapted versions of guidelines
The NCCN guideline was found to be adapted into two local contexts: Middle East/North
Africa (MENA), and Asia. In addition, the BHGI recommendations for HER 2 positive disease
were re-evaluated by an expert consensus for use within an Asian context. These three
documents were not included in the final guideline compilation, as these guidelines were
essentially a reiteration of the recommendations in the parent document, with certain qualifying
statements or adjustments to recommendations for the local contexts. Few recommendations
were altered on the basis of resources for systemic therapy; suggestions for different primary
screening modalities (ultrasound versus mammography) due to limited resources was mentioned
in the NCCN Asia document (62). These adapted consensus statements were not appraised by
the AGREE 2 instrument, as the parent document was already evaluated, and it is unclear if the
AGREE 2 instrument can be applied to adapted guidelines. .
4.6 Results: AGREE 2 appraisal of guidelines
The AGREE 2 scores as determined by each appraiser are displayed in appendix x. A third
reviewer (as outlined in the Methods section) was not required for any guideline (no guidelines
had more than 4 items with scores greater than 2 points apart). Nonetheless, these particular
items are highlighted in yellow in the appendix table. Final domain scores as calculated using
the AGREE 2 manual are shown in Table 17, and graphed in Figure 19. This graph shows the
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final scores for every CPG in each of the six domains, expressed as a percentage. Higher
domain scores are mapped towards the outer perimeter (closer to 100%), and lower domain
scores are plotted towards the centre (closer to 0%). The graph allows one to visually gauge the
relative strengths or weakness of each guideline by domain, in comparison to other plotted
guidelines. Table 17 also shows the overall scores (out of 7) given to each guideline overall by
both appraisers; as this is not considered a formal domain, there is no domain score for this. In
addition, whether the guideline is recommended for use by each appraiser (as the final item in
the AGREE tool) is also indicated.
Table 17: Final domain and overall guideline scores
*Overall score for each appraiser is separated by a comma (,). ** Y=Yes, guideline recommended, N=No, guideline not recommended, YWM=Yes, guideline recommended with modifications
NICE NST SEOM SIGN SIOG St Gallen WHO Med
1. Scope & Purpose 97 78 50 86 67 78 83
2. Stakeholder Involvement 94 36 36 86 28 39 64
3. Rigour of Development 94 45 20 77 46 30 33
4. Clarity of Presentation 97 81 47 89 75 61 72
5. Applicability 79 25 25 77 27 35 38
6. Editorial Independence 92 92 67 50 58 21 25
7. Overall Score (/7)* 7,7 6,5 4,3 5,6 3,5 3.4 5,5
Recommend?** Y,Y Y, YWM
N,N Y,Y Y, YWM
N,N YWM YWM
AGO ASCO BHGI CCO Cordoba ESMO NCCN New Zeal
1. Scope & Purpose 72 89 72 78 53 58 72 100
2. Stakeholder Involvement 44 72 61 50 22 47 67 69
3. Rigour of Development 52 84 33 79 29 39 68 81
4. Clarity of Presentation 89 97 72 92 69 72 92 94
5. Applicability 13 65 40 27 17 40 35 40
6. Editorial Independence 63 88 29 92 21 13 42 79
7. Overall Score (/7)* 5,5 6,7 4,4 6, 5 4,3 6,5 3,5 6,6
Recommend?** Y,Y Y,Y YWM, YWM
Y, Y N,N Y,Y YWM YWM
Y,Y
75
Figure 19: AGREE 2 guideline domain scores
76
Figure 20 allows one to compare the relative popularity of the guidelines included in the
physician survey, with the guideline’s quality as evaluated by AGREE 2 domain scores.
Figure 20: Guideline usage by survey respondents and AGREE 2 domain scores
83.1
2.6
4
34.5
66.6
16.1
69.3
0 20 40 60 80 100 120
ASCO
BHGI
CCO
ESMO
NCCN
NICE
St Gallen
Percent Respondents
Gu
idelin
e
Guideline Usage
Editorial Independence
Applicability
Clarity of Presentation
Rigour of Development
Stakeholder Involvement
Scope & Purpose
77
Chapter 5 Discussion
5.1 Overview
Global cancer control should be considered an important international venture. Breast cancer
remains a significant cause for morbidity and mortality in women worldwide, and outcomes in
low and middle income nations (LMCs) continue to be poorer compared to high income
countries (HICs). This may be due to multiple factors, however, resources remain an
important facet of providing optimal breast cancer care, and for establishing cancer control
agendas overall. Knowledge is an important resource that can be shared between nations, and
methods of knowledge dissemination, such clinical practice guidelines (CPGs), can help
improve patient outcomes if recommendations are evidence-based, high quality, and
implemented well. Primary knowledge generation within LMCs is certainly vital as well,
however, research and publication within these nations can be fraught with many challenges.
As such, LMCs often use information which is largely generated in HICs, including guidelines.
However, for these guidelines to be truly impactful in any setting, particularly in those with
constrained resources, recommendations should ideally be stratified by resource
availability. Many novel breast cancer therapies are costly, and may not be feasible (or
relevant) in certain health care settings. Therefore, CPGs that dictate generalized ―standards of
care‖ may be irrelevant or ineffective if disseminated in settings that cannot sustain particular
recommendations. Novel, high-cost treatments are a frequent focus of academic literature,
including CPGs. Nonetheless, there exist lower-cost therapies that can still have significant
patient impact (such as tamoxifen), and the emphasis on these strategies in CPGs should be
balanced with innovations in care (particularly those that may only have marginal incremental
patient benefits). In this manner, clinicians practicing in any practice setting would be able to
make decisions that are more feasible within their local realities. Finally, the clinical decisions
made by physicians are complex; barriers to implementing guideline recommendations include
physician factors, patient factors, local culture, and other external factors (of which resource
constraints may only be a part).
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This comprehensive study of international early breast cancer CPGs for systemic therapy, and
global survey of clinicians treating breast cancer, provides evidence for several of these
concepts.
5.2 Systematic review of breast cancer guidelines
One of the objectives of this study was to perform an up-to-date systematic review of early
breast cancer guidelines with potential international impact, in order to examine quality
(by using the AGREE 2 instrument), content (consistencies and discrepancies in
recommendations), and resource-sensitivity. A particular focus was if specific guidelines
exist with recommendations that are stratified by resource setting.
Guideline Quality
The systematic review of guidelines highlighted the following: most guidelines with likely
international impact were indeed produced in HICs; no such guidelines were found created in
MICs or LICs, with the exception of the WHO Eastern Mediterranean initiative. It is unclear
why there exist no other ―regional offices‖ of the WHO with ventures to create similar
guideline bodies in breast cancer (particularly as the WHO itself does not appear to have a
specific breast cancer treatment guideline). Some guidelines (particularly those with a
stipulated ―international‖ scope, such as the St Gallen Consensus and the BHGI), did include
guideline development panel members from LMCs; however, this is not consistently done
across guidelines (reflected in domain 2 of the AGREE 2 instrument, ―stakeholder
involvement‖). This may highlight the fact that many of these guidelines were not specifically
intended for global application, and as such, it may not have been deemed relevant to include
panel members from disparate global practice settings. It is therefore important that the
intended users of CPGs are made explicit (as evaluated by the ―scope‖ domain in the AGREE 2
instrument). Several CPGs did score low in this domain as well. Stakeholder involvement was
furthermore poor in many guidelines due to the lack of patient or public involvement, and/or in
the involvement of guideline panel members from limited expert groups (such as only medical
oncologists).
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As illustrated in the final domain score chart and graph, most guidelines scored high with
respect to the actual format of their recommendations (domain 4, clarity of presentation).
However, several guidelines scored poorly in rigour (domain 3), and applicability (domain 5).
With respect to rigour, many guidelines did not clearly outline the methods used for data
selection (and many did not seem to use systematic review), nor were formal criteria for grading
evidence used consistently. Interestingly, a few guidelines used other guidelines’ grading
systems (such as the NCCN). Most guidelines had some form of expert consensus either as the
primary basis for the guideline development, or in addition to systematic review of literature;
however, the methods for consensus review were usually poorly described, if described at all.
As reviewed in the Background, purely evidence -based guidelines are generally considered of
higher quality than consensus-based or evidence-based consensus guidelines; the reliance on
expert consensus for recommendations should be highest when there is a paucity of evidence in
the literature. This study highlights that many of the early breast cancer systemic therapy
recommendations were similar across the evaluated CPGs, and as such were likely based on
similar bodies of evidence. However, the explicit grading and disclosure of this evidence in
each CPG is highly variable. Taken together, these findings may illustrate that many CPG
development bodies do not follow recommended protocols for guideline development.
Several guidelines were out of date (last being published before 2009), with only a few
guidelines outlining specific update periods, and then actually following through on these
mandates (such as NCCN and St Gallen). The NCCN guidelines in fact have been updated
again in 2011 and 2012 (94), and the St Gallen Consensus in 2011 (95). These updates were not
considered in this review, as they were not released in the timeframe outlined at the outset of
this study. Most of the guidelines scored relatively poorly within the applicability domain, as
they did not address matters related to implementation or resource needs. The AGREE
Collaboration does not specify absolute cut off values for determining the overall quality of the
guidelines. However, it does allow the appraiser to recommend the guideline for use; 9 out of
the 15 guidelines were recommended by the two appraisers in this study, and some were
recommended for use with ―modifications‖ (to highlight that the CPG would be better utilized
with correction of weak areas). Only a few guidelines scored more than 70% in 4 or more
domains. These include the NICE, SIGN, and New Zealand guidelines. Other studies have
used a threshold of 60% in 4 or more domains (33) (35) to highlight CPGs of higher relative
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quality; once again, these are somewhat arbitrary evaluations as this sort of deduction of overall
guideline quality is not facilitated or validated by the AGREE 2 instrument. Therefore, most of
the early breast cancer CPGs evaluated in this study by the AGREE 2 instrument, were of
modest or mediocre quality. Scores were particularly low in the applicability domain
(which includes the resource implications of recommendations).
Guideline content and resource sensitivity
With respect to the actual content of most of the guidelines, recommendations were quite
uniform across all realms of systemic care (endocrine, chemotherapy, and targeted). These
recommendations may even be considered redundant. Nonetheless, not all guidelines addressed
all realms of systemic therapy. For instance, the ASCO guideline was specific for endocrine
treatment. Variations were noted with the recommendations for LHRH agonists, presumably
because the data on this strategy are older, inconsistent, and with newer data still maturing. This
was also the case for the use of bisphosphonates in the adjuvant setting, addressed only by a few
of the guidelines. The evidence for this strategy is relatively recent, not applicable to all patients,
and trials are ongoing to better address the utility of this strategy (113). Guidelines were
variable in their inclusion of such developing therapies with maturing data. The guidelines were
fairly consistent on their emphasis of determining patient risk when establishing the optimal
adjuvant treatment strategy (for instance, administering chemotherapy for high risk disease).
However, the risk models were varied, and some guidelines referred to others in terms of criteria
for disease risk (for instance, some used the St Gallen criteria). Most of the guidelines
mentioned some type of criteria for utilizing agents specific to certain disease subsets (for
instance hormone receptor positivity for endocrine therapy, and HER-2 positivity for
trastuzumab therapy.) The use of endocrine therapy was almost universally stratified by
menopausal status, and all guidelines recommended the use of AIs for postmenopausal women,
although the optimal strategy was not clear, which was reflective of the data. Specific
chemotherapy regimens were outlined in several guidelines, but doses were less often outlined.
Finally, most guidelines made recommendations for monitoring specific toxicities (such as
cardiac function in trastuzumab treated patients.) Only two guidelines made
recommendations with a clear association to differences in resource availability: the
BHGI, and the WHO Eastern Mediterranean guideline. The NICE guideline does make
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recommendations within the UK resource framework, but does not make recommendations
specific to differing resource scenarios. The BHGI, in fact, was the only guideline that made
recommendations clearly applicable to all resource settings. Although local consensus
statements (as a form of guideline ―adaptation‖) for use within certain regional settings were
found for the NCCN guideline (Asia and Middle East/North Africa), and the BHGI (HER-2
disease in Asia), these versions also made few explicit changes to recommendations based on
differential resource availability. Overall, the CPGs on early breast cancer systemic therapy
evaluated in this study make similar recommendations, but these recommendations in
general are not resource-sensitive.
5.3 Physician practice patterns in early breast cancer care
Another objective of this study was to investigate how clinicians are treating early breast
cancer worldwide, and whether their care patterns are reflective of recommendations
outlined in relevant clinical guidelines. A particular focus was on whether there are
disparities in care patterns based on resource settings (HICs versus LMCs.)
Pathology
The routine use of hormone receptor and HER-2 testing was high across most continents and
resource settings; however, it was lowest in Africa (78%, and 74% respectively), and as
expected, amongst LICs clinicians (87% and 83% respectively). In fact, the rates of HER-2
testing were expected to be slightly lower in general compared to hormone receptor testing, due
to the increased complexity and resources required to perform HER-2 testing. However, as the
rates of HER-2 and hormone testing were found to be quite similar, it can perhaps be
hypothesized that most pathology departments across the globe are either able to perform both
tests or neither. Notably, the BHGI does not recommend routine HER-2 testing in Basic and
Limited resource settings (which would include LICs and some MICs). Nevertheless, it
appears that this is being done in many of these nations.
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Systemic therapy
Endocrine therapy in the form of tamoxifen is widely used across the world, and does not vary
by continent or resource setting. This is in concordance with the BHGI recommendations for
all resource settings (including Basic and Limited). This more than 30-year-old therapy is
considered a cornerstone treatment in adjuvant endocrine therapy for hormone receptor positive
breast cancer, can have an excellent impact on patient outcomes (98), and is relatively low cost;
it has therefore been shown to be a good therapeutic strategy particularly in LICs, for example,
in Ethiopia (99). Aromatase inhibitors, as mentioned above, offer modest relapse-free and
disease-free survival benefits compared to tamoxifen in different strategies, with survival data
still maturing (100). They are considered to represent a new ―standard of care‖ in post
menopausal women by some groups (for example, as outlined in the St Gallen consensus);
however, the cost of AIs compared to tamoxifen is considerably higher (101). As such, this
strategy is recommended for Enhanced and Maximal resource settings (HICs and some
MICs), but not basic or limited resources by the BHGI. This may explain why the use of
AIs did vary by resource setting, with less use in LICs compared to MICs and HICs. However,
the use of AIs was still reported as being quite high in LICs (87%).
Chemotherapy use was not found to vary significantly by resource setting (p=0.178), although
there appeared to be a difference in stage I patients being treated between LICs (31%) and HICs
(23%). A statistically significant effect may have been missed due to the small numbers in this
category. Patients who are offered chemotherapy appeared to vary by continent; this may be
more reflective of local medical culture, versus resources. However, the type of chemotherapy
used did vary by resource setting, particularly with the use of the older ―CMF‖ regimen (higher
in LMCs compared to HICs), and newer, more expensive ―third generation‖ chemotherapy
regimens (including anthracyclines and taxanes, higher in MICs and HICs, compared to LICs.)
Despite these variations, the overall use of older CMF regimens remains low overall, and the
use of third generation chemotherapy combinations remains high (even in LICs, with 77% of
respondents reporting its use.) This is in contrast to recommendations by the BHGI, which
espouse the use of CMF or anthracycline-alone regimens for basic and limited resource settings,
and the use of taxane-based or third generation regimens for enhanced and maximal settings
only. The use of anthracycline single agent regimens was highest in LICs, however this was not
83
found differ with statistical significance, p=0.293. The use of anthracycline- or taxane-alone
regimens did vary by continent, with no specific pattern noted. This again may be reflective of
local medical culture, policies, or access to specific therapeutics (perhaps driven by regional
markets). Trastuzumab utilization varied by percentage of practice dedicated to breast cancer
and oncologic speciality; this is not surprising, and likely reflects the familiarity with new
advances in systemic breast cancer therapy by those physicians with a large breast cancer
practice, or medical oncologists who primarily give systemic therapy. However, this is one of
the only systemic therapies which were found to vary by these demographics, and this may be
due to the fact it is a relatively novel therapy, which may not have diffused to clinicians with
less exposure to breast cancer systemic therapy (or may reflect that the availability of this drug
is restricted to certain experts). In addition, it was quite clear that surveyed physicians from low
income nations, and continents with a significant proportion of LICs (such as Africa), do
not give trastuzumab to a large majority of eligible patients. In this survey, this was shown
to be likely due to lack of drug funding in LICs, and lack of access and funding in MICs.
These two factors seem to be significant barriers in South America as well. This is not
surprising, as trastuzumab is quite a costly therapy, and is generally given for one year total. In
addition, the overall cost effectiveness of this therapy is unclear even in some HICs, given that
long term survival data for this therapy are still accumulating (102). The discrepant fact is that
although prescription practices may be as expected (lower in LICs due to the cost of the
therapy), as noted above, most nations are still doing HER-2 testing. Few physicians
actually highlighted lack of HER-2 testing as a barrier to providing trastuzumab therapy,
although this was statistically more common as an issue in community settings (16%), compared
to academic settings (6%). This may be due to the concentration of specialized services for
pathology in academic centres in some nations, or the availability of greater funding in these
centres, or the presence of research studies that may facilitate these services, or a combination of
these and other factors.
Practice Pattern Summary
Overall, these patterns illustrate that there may be a disconnect between pathologic practices
and related systemic therapy practices in some nations. One may argue that pathologic
parameters are important to establish, regardless of available therapies, due to the prognostic
84
information they provide (for example, patients with untreated HER-2 positive breast cancer can
have a worse prognosis). However, for a given practice setting, it would be important to
establish if the resources used to do HER-2 testing in the absence of the ability to sustain
trastuzumab treatment would be better utilized in other areas of breast cancer care. Another
reason this discrepancy may be present is that some nations may have variable access to
therapeutics across different patient socioeconomic levels. This is the reality in many
nations, particularly LICs (103), but applies also to HICs. As such, trastuzumab may be
affordable to some patients in LICs, and its prescription is contingent on HER-2 testing being
done. Given this, it is understandable that there may be a discrepancy between the widespread
use of HER-2 testing, but unfortunately the inability to give trastuzumab to eligible patients in
all resource settings. In considering these issues, the incremental cost-benefit analysis of doing
or forgoing HER-2 testing in certain settings may be useful to be assessed, and also compared to
the cost effectiveness of administering trastuzumab therapy. These considerations can, in fact,
apply to all resource settings, as cost and access barriers to cancer therapeutics is a reality
across the globe, including higher income nations (114)This was evidenced in this study as
well; physicians from all three resource settings, albeit at different frequencies, cited cost and
drug funding as concerns for specific therapies (such as trastuzumab). The relative impact of
these barriers on treatment administration is likely setting-specific, and would require further
study in particular contexts, in order better understand these factors. For example, access to
trastuzumab was reported as being a barrier to administration by higher proportion of MIC
clinicians (32%), versus LIC (11%) and HIC (4%) physicians; cost appeared to the greatest
barrier in LICs (94% of clinicians, versus 62% of MIC and 12% of HIC respondents). These
patterns may indicate particular differences in health care delivery models, including medication
coverage and reimbursement.
As such, these data confirm that the ability to provide certain therapies for early breast
cancer care, as recommended by various guidelines, is impacted by the resource setting
within which clinicians practice. Resource setting and continent were found repeatedly,
above all other demographic variables, to affect practice patterns with statistical
significance. However, these findings also illustrate that not all practice patterns are impacted
on or constrained by the availability of resources. As discussed earlier, the implementation of
guideline-based recommendations is a complex process with several potential barriers, of which
85
resources (although potentially significant) are only a component. Some practice patterns varied
by continent (whereby those continents with a high proportion of a certain resource settings,
such as Europe and North America with several HICs), still had disparate patterns of care or
decision making. As a corollary, some continents with differing resource settings (such as
Africa with many LMCs, and North America, with many HICs), had similar patterns for a few
practices. This illustrates that practice patterns are indeed impacted by several factors, not
simply resources. Patient preferences are one such important factor that was addressed by this
study. For instance, the refusal of chemotherapy by patients varied across resources setting and
continent, and the reasons for refusing therapy were also variable (for instance more MIC
patients and those in South America refused chemotherapy due to uncertainty regarding
benefits, compared to LIC patients, who more often refused chemotherapy due to costs). These
findings highlight the importance of dedicated CPG implementation efforts to address the
local barriers and facilitators to integrating recommendations into practice. The BHGI, in
fact, has established specific strategies for breast cancer guideline implementation based on
resource setting, and has also stipulated formal implementation agendas in certain LMCs (50);
the mandate for implementation from other guideline bodies is less clear (again as evidenced in
the AGREE 2 scores).
Finally, one may wonder why breast cancer outcomes are found to be variable across resource
settings, if in fact certain key adjuvant therapies (with the exception of trastuzumab) are
reported as being used by a large proportion of surveyed clinicians from all resource settings. In
fact, this study evaluated reported practices based on individual clinician experience; whether
this is truly reflective of the experience of other physicians in these nations is unclear
(particularly in nations with few representative respondents). In addition, the reported usage of
certain therapies by clinicians does not reflect the actual number of patients presenting for (or
having access to) treatment in a given setting, nor does it highlight the relative proportion of
patients presenting within each stage of breast cancer. As discussed earlier, LMCs may
preferentially have patients with more advanced tumours (or certain tumour characteristics) with
associated poorer prognosis. Furthermore, the selection of patients for certain therapies may be
less accurate in LMCs (for instance, due to limitations in endocrine receptor testing and
subsequent under-treatment of some patients deemed to be hormone-receptor negative); this has
been postulated as a reason outcomes have been worse in particular regions of the world (such
86
as Asia) (61). Patient adherence to treatment has also been found to be worse in LMCs,
whereby fewer patients may actually complete prescribed treatment courses (61) (68). Finally,
the use of local treatments (surgery, radiation) was not included in this particular analysis, and
the adequate use of such care modalities can also impact on patient outcomes (70). good
5.4 Physician decision-making and barriers to guideline
implementation
The final objective of this study was to evaluate the factors which impact physician decision-
making in early breast cancer care, including the utilization of particular breast cancer
guidelines. Another goal was to examine if specific barriers (particularly resource
constraints) to implementing guideline-based recommendations are identified by
physicians, and if these patterns vary by resource setting (HICs versus LMCs).
Factors influencing clinical decision-making
More than half of surveyed physicians reported that personal judgement was one of the top three
factors that impacted their clinical decisions; however, the use of personal judgement and
training varied significantly by resources setting, whereby more LIC and MIC physicians
reported reliance on these factors than HIC physicians. It is unclear if this reflects differences in
local medical culture between these nations; for instance, the evidence-based movement in
medical practice, which emphasizes greater integration of scientific evidence into physician
practice, above and beyond individual training, largely began as an initiative in HICs (26).
Nevertheless, as illustrated by this study, LMC physicians do also rely on published evidence to
help direct practice; overall 66% of survey respondents reported using medical journals as one
of the top three resources used to help direct practice. This was found to vary with statistical
significance by resource setting, interestingly with more MIC clinicians using medical journals
(68%) versus LIC (42%) or HIC (51%) physicians, p<0.001. 65% of all respondents reported
the use of international guidelines, however, surveyed physicians from LICs and MICs were
found to rely more on international directives than HICs (please refer to Table 10). This may
reflect the fact that many ―international‖ guidelines are created in HICs, and hence actually
considered regional or local by HIC clinicians. As a corollary, clinicians in some continents,
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such as Africa, actually find international guidelines less applicable, than, for example, North
American physicians. Interestingly, Africa is also the continent which uses the BHGI most
often; perhaps clinicians in this continent are savvy to the need for resource-appropriate
recommendations, rather than the generalized standards of care as dictated by most international
CPGs. Given the large distribution of LICs in Africa, these findings make sense. This may also
explain why dedicated efforts for local adaptations of CPGs to African contexts (such as the
NCCN MENA and WHO Eastern Mediterranean documents) are present. Whether these largely
North African ventures (which include several MICs) are applicable to some lower income
nations in other areas of Africa (or other LICs around the world), is unclear. It is also uncertain
if these guidelines are disseminated even within the African continent. These are important
areas for future study. Guideline adaptation is discussed further within this section.
The use of specific breast cancer guidelines
The three most commonly used guidelines from those elicited in the survey include ASCO,
NCCN, and St Gallen. As noted above, these guidelines were found to be of mediocre quality,
and the ASCO guideline only addresses one realm of early breast cancer systemic therapy. In
contrast, one of the most comprehensive guidelines with highest overall quality, NICE, was used
by relatively few respondents, across most continents and resource settings. This may reflect
that the intended users of this CPG are within the United Kingdom practice setting (as stipulated
clearly in the scope of the guideline). This CPG was nonetheless considered to be of potential
global impact due to the prominence of NICE as a large guideline creating body within Europe,
the pervasiveness of NICE guidelines throughout the systematic review, and reference to this
guideline by other CPGs. The fact that few survey respondents use this guideline can perhaps
even be considered evidence that clear stipulation of the intended users of a CPG does direct its
use. The other guidelines with high quality scores, SIGN and New Zealand, were unfortunately
not included in the survey, as they were not found in the preliminary search for guidelines done
before creating the survey. Nonetheless, it is clear from this study that the visibility or use of
evaluated CPGs did not correlate with guideline quality (as discussed above). As an extension
of this finding, lower quality guidelines were even referenced by other guidelines. These data
may illustrate that CPGs developed by bodies that are historically considered as ―authorities‖ or
have general prominence in a field are more likely to have greater uptake, despite guideline
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quality. One such specific example is the St Gallen consensus, which is touted as a true
international collaboration of breast cancer experts, with a long history of guideline
development in the field of breast cancer (115). This guideline scored quite low in quality, and
was not recommended for use by either of the study appraisers based on AGREE 2 evaluation.
These types of guideline authorities may also have successful dissemination techniques. As an
example, the NCCN guidelines (and associated ―consensus‖ documents) were readily found by
all search strategies in the systematic review. This includes noted prominence during Google®
searches (whereby, for example, if one searches ―breast cancer guidelines‖ using this platform,
the first two ―hits‖ are NCCN guidelines). Given that a high proportion (93%) of all surveyed
clinicians use and prefer the internet for CPG access, this may be one explanation why this
guideline is so frequently used (66% of respondents). In addition, the ASCO guidelines are
found to be 5th
highest ―hit‖ using this search strategy, and these guidelines were reported as
being used by the highest proportion of survey respondents (83%). However, the use of this
particular guideline is also likely impacted by the by the fact that respondents from phase 2 of
the survey were targeted through ASCO membership. In fact, the use of the ASCO guideline
was higher in the phase 2 cohort (92%) compared to 80% of phase 1 physicians. Whether this is
a significant difference is likely not important, given that 80% is still a high usage rate for this
guideline. These trends may again illustrate that respondents may be more likely to use those
guidelines created by large oncologic bodies, such as ASCO, which, in addition to prominence
online, tend to be involved with knowledge dissemination at other levels as well (including
annual academic meetings and travel grants for physicians from LMCs to attend these meetings
and primary research publications (96)). This may also explain the use of the ESMO guideline
(97), which appeared moderately high (35% of respondents). Guidelines tailored to specific
local contexts, such as CCO and BCCA (Ontario, Canada, and British Columbia, Canada,
respectively), do not seem to be commonly used on a large global scale. This is not surprising,
as these organizations may not have any or as much involvement with large-scale academic
meetings and publications, or have specific global dissemination strategies. What is interesting,
nonetheless, is that these guidelines may still be found in online international guideline
repositories (such as the CCO guidelines, which were readily found in the GIN). Given that
many respondents reported accessing guidelines online, it may be that clinicians are searching
specific websites for oncology organizations, or databases such as MEDLINE, and completing
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general Google® searches as above, more often than using these guideline repositories.. Further
study is required to determine what specific resources clinicians are using online for breast
cancer knowledge, in order to better utilize this technology for knowledge dissemination. The
BHGI was found by this review tube only CPG with recommendations truly applicable to
different resource settings across the globe. . However, it was found to be utilized quite
uncommonly by all survey respondents. Nonetheless, more LICs physicians did report using the
guideline, which may be seen as one of the important goals of the initiative, although the use
was still found to be low overall (3%). In addition, as mentioned above, this guideline in fact has
relevance to all resource settings, and yet seems to have limited visibility and uptake so far. It is
unclear what factors account for this, but suboptimal knowledge dissemination of the guideline
is likely a factor. Interestingly, the BHGI is found on the first page of Google® search hits if
one uses ―global breast cancer guidelines‖ as a search strategy. Clearly, simple visibility
through internet search platforms may not be enough to encourage widespread CPG uptake.
Implementation efforts by the BHGI continue in certain LMCs (51), and perhaps such efforts
will continue to improve the impact of this CPG. Some other high-quality guidelines do not
appear to be used widely either. Again, the reasons for this are likely multiple, and include the
intended scope of the guideline being small (such as the UK for NICE guidelines), or
suboptimal dissemination if broad audiences are in fact desired.
As discussed previously, several of the guidelines used most frequently had low or average
scores in many of the key AGREE 2 quality domains. This may reflect the fact that users of
these guidelines may not be aware of (or interested in) the formal quality appraisal of CPGs.
Furthermore, as the AGREE2 instrument does not address the actual quality of the CPG
recommendations, it is likely that certain guidelines are used because their content
(recommendations) are still considered high-quality by users due to the evidence base
supporting them. Indeed, CPGs with both high and low quality scores made similar
recommendations, likely reflecting the use of a similar evidence base. It may be that clinicians
are familiar with how to appraise the quality of evidence more than the quality of guidelines,
and as such, make decisions about using guidelines primarily due to their content (and perhaps
the prominence of the organizations that create them, as above). Further study into this
phenomenon would be useful, particularly involving guidelines in subject areas with little high-
quality evidence to see if findings are different.
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Finally, it should also be noted that only 152 physicians responded to the open-ended/free text
question regarding any other breast cancer guidelines that they may use. Given this small
number, analysis by demographic was not completed. Some of the free-text responses on the use
of additional guidelines were in fact guidelines already included in the survey (such as St
Gallen), indicating a potential misinterpretation of the question. Others answers included local
guidelines in native languages (such as Italian or French), with only a few specific guideline
titles or names of guideline organizations mentioned. Some respondents indicated using
guidelines not included in the survey, but found in the systematic review (such as AGO).
Chinese versions of the NCCN Asia guideline were reported being used; these specific
documents were not found by the systematic review, likely due to the language filter. The use
of ―hospital guidelines‖ was reported by a few physicians; one would not expect to find these
documents readily available in the literature. Finally, several physicians did not indicate the use
of other guidelines, but reported reliance on other educational materials, including textbooks,
online databases/monographs (such as UpToDate®), and attendance at oncology meetings.
Whether there are truly few other breast cancer guidelines being utilized by physicians, or
whether these findings simply show a lack of physician response to this question, is unclear.
Nonetheless, from the limited pool of responses to this question, there appeared to be no highly
used documents revealed that may indicate a CPG with potential global impact, which was not
included in the survey or found by the systematic review. The impact of local guidelines should
not be underestimated, despite the fact few survey respondents explicitly indicated their use.
The relative impact of these guidelines in comparison to ―international‖ CPGs is unclear, and
warrants further study. The results of this question are presented in appendix xii.
Physician preferences for knowledge dissemination methods
As mentioned above, the internet was reported as being used by a large proportion (93%) of
survey respondents to access breast cancer guidelines. In addition, almost 84% of respondents
relayed a preference for email updates of new guidelines. These data illustrate that the
internet and email are important modes of guideline access for most global physicians. In
fact, LIC physicians reported the highest preference for the internet (56%, versus 40% for both
MIC and HIC clinicians). This may reflect that the pervasiveness of the internet use across the
medical world (22), and that LIC physicians may have limitations to the use of other modalities
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for knowledge acquisition (such as attendance at international meetings). However, physicians
from LICs were also more likely to prefer paper copies of guideline updates (34%), compared to
clinicians in MICs or LICs (27% and 20% respectively). This may in fact highlight that access
to consistent internet facilities may be less common in LICs, or else may reflect local medical
culture. Predilection to use the internet by the survey respondents may also explain the higher
usage of CPGs found most easily on the internet (such as the NCCN and ASCO guidelines, as
discussed earlier).
Academic oncology meetings remain an important source of information for clinicians, and
these venues may be important platforms to disseminate guidelines, including those created by
bodies other than the meeting organizers. In fact, one survey respondent commented on his or
her survey that ―Booklets need to be prepared for each yearly conference,‖ perhaps indicating a
preference for attending annual oncology meetings, but also for updated paper versions of new
data (presumably including CPGs) to be made available at these meetings. Many of the
surveyed breast clinicians did report attending oncologic meetings to access breast cancer
information. These findings may be somewhat biased, as the sampled physicians in this study
were present at an oncologic meeting (the IBCC), or else members of an academic oncology
society (ASCO). These clinicians may have a greater propensity be affiliated with academia,
use the internet, or attend academic meetings. However, as shown earlier, the distribution
between academic and community clinicians was overall reasonable in this study, and most
responses did not vary by these affiliations.
The preference for local CME presentations for knowledge dissemination varied more so by
continent than resource setting (being highest in North America and Africa). This may reflect
some cultural preference for CME in these nations, and again warrants further study.
Finally, although almost 40% of respondents indicated a preference for guidelines in their native
language, only 55 respondents answered the open-ended question regarding what specific
language. The most common language preferences were Spanish, French, Italian, and Chinese
(which is likely reflective of the survey respondent demographics). Of note, Spain, France, and
Italy are all HICs; few languages native to certain LMCs (with the exception of Chinese), were
indicated. The results of this question are found in appendix xiii.
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Barriers to guideline implementation and consideration of guideline adaptation
Most of the breast cancer guidelines evaluated by this study fared poorly in outlining specific
dissemination and implementation strategies. Despite this, several guidelines appeared to have
high visibility and usage, either indicating passive dissemination or utilization of dissemination
strategies not clearly present or found in the literature.
The data presented in this study have established practice patterns in global breast cancer care as
reported by surveyed physicians, and have highlighted that resources are indeed a barrier to
providing certain therapies. Other identified barriers include patient factors (as shown by the
data on chemotherapy and trastuzumab acceptance). Additional external factors as evaluated by
the study were not found to be significant barriers to providing systemic therapies (such as wait
times or access to facilities). Physician-related barriers (such as agreement with guideline
recommendations) were not evaluated, but trends in physician knowledge gathering were
established, and may be important to consider for future work on guideline dissemination
strategies. Nonetheless, existing literature suggests that simple dissemination of knowledge is
not sufficient to elicit changes in practice; proactive efforts at the ―point of decision making‖ are
often required (116). One model of guideline implementation is described as a ―knowledge-to-
action cycle‖ (116). This model relies on the principle that:
Existing guidelines can be evaluated and customized to fit local circumstances through
an active, systematic and participatory process. This process must preserve the integrity
of the evidence-based recommendations when differences in organizational, regional or
cultural circumstances may legitimately require important variations in
recommendations (116).
This process emphasizes the importance of involving the end-users of a guideline in the
adaptation process, in order to better appreciate the unique needs of the local practice setting in
which the CPG will be used. The use of formalized and validated tools to measure
implementation is also recommended (116) .
The Adapte Framework, developed by the Adapte Organization, is a formal framework for
guideline adaptation (91). This framework is ―...a systematic approach for the adaptation of
guidelines produced for use in one cultural and organisational context to be used in a different
cultural and organisational context ―(91). Other organizations have also developed systematic
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processes for adapting guidelines, such as Cancerview Canada (92). These frameworks seek to
minimize duplication in guideline development efforts, and also enable organizations that do not
have the expertise or resources to create their own guidelines to adapt CPGs into their own
context; this may be a useful strategy in LMCs. However, whether this is being done on a
consistent basis in LMCs is unclear.
Three local guideline adaptations (with published outputs) were found by this study: NCCN
Middle East and North Africa [MENA], NCCN ASIA, and a HER-2 positive ASIA consortium.
These guidelines did not appear to be adapted using any formal, validated process; it appears
that expert consensus was used to determine what recommendations from the target guidelines
(NCCN or BHGI respectively) were applicable to the local settings; experts from the target
LMCs were included in the consensus process. As an aside, these adapted guidelines were not
formally assessed by the AGREE 2 instrument, as the parent guideline had already been
appraised. However, on reviewing the content of these adapted versions, it is noted that with
regards to systemic therapy, very few changes were made to the recommendations from the
parent guidelines. For instance, the NCCN adapted guidelines for Asia and MENA adjusted
algorithms slightly for endocrine therapy, and adjusted a dose recommendation for taxanes in
the Asian population, but otherwise few changes were made overall, and referral to the parent
document (NCCN 2009 Breast Cancer Guidelines) was made often. The Asian Summit on Her-
2 positive breast cancer (72) is basically a review of the BHGI recommendations for HER-2
positive disease, as updated after the 2007 consensus (34). In addition, the ―adaptation‖ process
included review of other relevant guidelines to help support recommendations, but there were no
specific alterations to the BHGI recommendations. Whether these specific guideline
adaptations are particularly impactful over and beyond the parent guideline is unclear, as the
recommendations are very similar between them. This may reflect that experts involved in the
adaptations of these guidelines believed most recommendations were applicable to the local
context. Implementation studies are required to better ascertain if these efforts were useful.
Finally, adaptation of high quality guidelines may be particularly important as the CPGs
evaluated were generally outdated; it is notable that the updating of guidelines can be
challenging process, given the rapid pace of research and changing primary data. However, if
various guideline creating bodies (usually in HICs) were charged with specific mandates (such
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as one realm of breast cancer care, for instance, endocrine therapy), then perhaps several such
CPGs, covering all realms of care, could be consolidated into a larger body of recommendations
(instead of one large, comprehensive CPG from each organization, which can take more time
and effort to update). These smaller documents may be easier to update (due to smaller scope,
and greater resources from the combined efforts of different CPG bodies), and also be more
easily adapted to local contexts (again due to smaller scope). This sort of venture would require
gross consensus on data interpretation (―best practice‖), and guideline creation techniques. Such
a project would require true international collaboration and may best be overseen by
organizations such as the WHO. As a simpler initiative, formal processes for adapting
guidelines should be disseminated more widely, to make existing CPGs have greater
relevance to specific contexts, and truly help to direct global practice. Tools such as the Adapte
Framework mentioned above, provide step-wise, practical algorithms for adapting guidelines to
specific contexts (117).
5.5 Study Limitations
Survey Limitations
The survey component of this study is subject to certain biases, whereby the measured value of
certain estimators (such as practice patterns), may not actually be reflective of (or be
systematically different from) the expected values or ―true‖ state of the population being
evaluated (international breast cancer clinicians). One such bias that may affect the survey
results arises from the sampling of survey respondents (―selection bias‖). Those clinicians who
attended the IBCC 4 meeting (phase 1) could perhaps be more likely to represent academic
physicians, with the ability (linguistic, financial, and political) to attend continuing medical
education (CME) events, held in English, and with an interest in such ventures. Their tendency
to be acquainted with breast cancer guidelines may be higher, and this may not accurately reflect
the state of other physicians in their respective nations. However, cancer care is often provided
in or connected with academic settings, particularly in LMCs, which is reflective of the
multidisciplinary and highly specialized nature of this discipline. In fact, the 2007 IOM report
on Cancer Control Opportunities in LMCs outlines that ―cancer centres‖ in LMCs more often
have research, training, and leadership roles than those in HICs such as the United States (where
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cancer care is also delivered in community, non-academic, or strictly clinical centres) (4). The
report gives examples of 8 such cancer centres in LMCs (including India, Africa, and Peru),
which provide clinical cancer care for a substantial portion of the nation, and also clearly have
academic roles. The IOM suggests that cancer centres in other LMCs are of similar structure (or
else are or should be working towards such a structure) (4). Other limitations to sampling
include the complete lack of participants from the Caribbean islands, which was the only
geographic area identified with no representation in the survey. In addition, some nations only
had 1 or 2 respondents. As such, the data from these nations is potentially biased by the
opinions of just a few clinicians. Additionally, the survey was only administered in English due
to the lack of translation resources, and as such the responses of those physicians who do not
speak English are unknown. Finally, a good proportion of the survey respondents in this study
identified themselves as practicing in ―community‖ settings, and very few survey responses
were found to vary by practice setting. A potential limitation of this is that the definitions of
―community‖ and ―academic‖ practice setting were not described in the survey; therefore how
physicians identified their practice setting may be variable. However, other demographic
questions in the survey asked respondents specifically about involvement in what can be
considered academic activities (including clinical trials, teaching, and policy making, see
appendix i); none of the practice patterns were found to vary by these parameters.
The surveyed physicians in phase 2 were targeted through ASCO membership; this potentially
introduces a similar bias, whereby these physicians may more likely be academic in nature, or
be aware of certain guidelines (particularly the ASCO guidelines). There were indeed a higher
proportion of physicians in this phase of the survey that reported using the ASCO guidelines,
although 80% of physicians from phase 1 also reported using them. Given that ASCO is the
largest professional body of oncology professionals in the world, a proportion of physicians
sampled in any manner would likely be expected to be ASCO members. As an aside, ASCO
has created a specific mandate to help address cancer control in LMCs. As part of this mandate,
including the creation of an ―International Affairs Committee‖, ASCO seeks to collaborate with
LMCs oncologists, with a particular focus on education, training, and recognition of scholarship
(118). The active global outreach efforts of ASCO in LMCs may also explain the familiarity of
the survey respondents (from both phases of the survey) of ASCO guidelines (in addition to
their membership in the organization. Finally, a high proportion of medical oncologists (versus
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radiation or surgical oncologists) responded to the survey; given that the focus of this study was
on systemic therapy (given primarily by medical oncologists) this may not be a significant issue.
Although on the email invitation to phase 2 participants, it was outlined that if they already
completed this survey as part of the IBCC meeting, not to complete it again, there was potential
for some overlap (the same physicians completing the survey twice, phase 1 and phase 2),
although this was felt to be unlikely, given time pressures on physicians, the instructions given,
and the differing target groups.
Surveys themselves are at risk for response bias. This type of cognitive bias can influence
results if respondents answered questions based on what they thought they should answer, rather
than their true beliefs (also known as social desirability bias). The questions were formulated to
try and minimize this, by giving several options for care patterns, and attempting not to
discriminate towards what responses are deemed most favourable (there were no qualifying
statements, or references to data, care pattern expectations, etc.) Nonetheless, the meeting
survey may have been more susceptible to this type of bias, as respondents had just attended a
meeting discussing standards of breast cancer care, which may have influenced their responses.
A related type of bias that may have influenced physician responses is ―recall bias‖, whereby
clinician recollection of their own practices may be inaccurate, due to the preferential recall of
certain types of patients or treatment experiences.
The response rate of the online survey (phase 2) was quite low (<20%); unfortunately an
incentive could not be offered to the potential participants, which might have increased the
response rate (83). This may result in some unit non-response bias (and the attributes of those
physicians who did not respond to the survey are unclear). Although phase 1 of the survey had a
higher response rate (due to the setting in which it was administered), non response-bias still
applies. Item response bias (introduced by respondents skipping certain questions), was
minimized by discarding those surveys that did not have an adequate completion rate. However,
we did not analyze the responses of partially versus totally completed surveys to determine if
there were any systematic differences between responses. Responses may also have been
affected by the interpretation of questions; this was potentially highlighted by the open-
ended/free text answers as discussed above. In addition, a few of the questions on decision
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making patterns used ―guidelines‖ and ―policy‖ interchangeably (pertaining to government
directives). These are, in fact, quite distinct concepts (although guidelines can be used to help
direct policy), and this may have impacted the accuracy of reporting by some respondents.
In assessing specific associations within demographic variables (for instance, practice patterns
in ―Africa‖ versus ―Europe‖ within ―continent‖), increases the chances for a type I error
(whereby a difference may be found due to chance alone, due to multiple statistical
comparisons). In addition, we examined numerous questions, and the risk of a type I error
increases with the number of questions examined. We did not correct for multiple significance
testing (e.g. with a Bonferroni correction). However, the data were analyzed strictly using
bivariate principles, whereby statistical significance was only attributed to practice patterns
varying by the principle demographic (example: ―continent‖) defined a priori. Therefore,
differences between, for instance, specific continents should best be viewed as hypothesis-
generating, and would require confirmation in an independent data set. Furthermore, the
division of results into multiple sub-variables (again, for instance, ―Africa‖ versus ―Europe‖)
decreased the sample size in each of these sub-categories, increasing the risk of type II error
(missing a statistical difference due to small numbers).
There were a few differences in the demographics of respondents from phase 1and 2 (for
instance, a higher proportion of HIC physicians in phase 1); however, this can in fact be seen as
favourable, given there were more MIC and LIC physicians included in the total sample by
combining the two phases. Whether the type of survey (online versus paper), truly impacted the
results is less clear. Most responses seemed quite similar between the two phases, and any
discrepancies in response trend could perhaps be attributed to the differing demographics of the
respondents (for instance, more MIC and LIC physicians in phase 2). Given that this was not
the primary focus of this paper, it was thought any such relevant trends were better addressed by
combining the responses and evaluating by demographic, as was done. This does not rule out,
however, any significant differences by survey phase (either due to the physicians sampled, or
the nature of the survey format).
This study did not evaluate locally advanced breast cancer, which is a specific concern in
LMCs, as evidenced by the background research for this paper, and as highlighted by the initial
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focus group established to direct survey content. One of the survey respondents did comment
on the need for better guidelines on how to address advanced breast cancer in his/her local
setting. To maintain a manageable scope for this study, this topic was excluded, but may be an
important focus of future study.
Finally, this study could not evaluate the complex impact of various health care delivery
structures and local consumer markets (including the pricing and reimbursement of
pharmaceuticals), on physician practice patterns and decision making. It should be noted that
many physicians reported practicing in a ―public system‖, and there appeared to be no impact on
―public‖ versus ―private‖ practice setting on patterns of care or decision making; the definitions
of these were not described in the survey, and thus the extrapolation of these findings is limited,
given the potential complexity within both public, private, and mixed delivery models.
Guideline systematic review and appraisal limitations
Limitations to the guideline review include the exclusion of non-English publications. Due to
this, relevant documents that may be influencing breast cancer care in certain areas of the world
(particularly LMCs, where English is not a main language), may have been missed. A few of
these guidelines, in fact, were highlighted by the open ended questions of the survey. The more
commonly cited ones included Italian, French, and Chinese guidelines. One of the MEDLINE
searches was run without the language filter, and the GIN search included all languages. A few
additional documents were found, including Dutch, German, and Swiss language documents.
These guidelines may be influencing local practice in these specific settings, noted to be mainly
HICs, not LMCs. As the focus of this survey was on documents with potential international
impact, these guidelines may be of less relevance to a general international audience
(particularly as many global physicians are less likely to speak Dutch, German, Italian, or Swiss,
compared to English). English ranks third in the world of most commonly spoken languages
after Chinese and Spanish), with 112 countries using this language, and about 328 million
speakers (119). Of note, no applicable Chinese or Spanish language guidelines were found by
the systematic review, although a few were mentioned by survey respondents (indicating that
these guidelines are likely only disseminated locally). The relative impact of these local, native-
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language guidelines, compared to ―international‖, English-language guidelines is unknown, and
as above, would be an important area for further study.
This survey also did not evaluate the impact of other tools for knowledge dissemination, such as
clinical platforms found online or available on portable devices (PDAs); examples of these
include UpToDate®, and Eprocrates®. These reviews of clinical practice can direct practice,
although they are not considered formally as guidelines (although they often reference
guidelines within their content). Furthermore, the survey did not evaluate the use of other
decision making tools, such as Adjuvant! Online®. This may have been useful, as although
these tools are not considered guidelines, they can impact therapeutic decision making. In fact,
a few respondents did indicate using the Adjuvant! Online® tool. However, the impact of such
tools on patient care and outcomes is not entirely clear.
Finally, an inherent limitation to most guideline appraisal tools, including the AGREE 2
instrument, is that they do not include formal criteria for grading the actual content of the
evaluated CPGs. Although emphasis is placed on the use of graded evidence and systematic
review, the quality of evidence included in the guidelines in not evaluated. As such, although
the development of a guideline may be considered high quality, the actual recommendations are
only as strong as the evidence used to make them. As a corollary, guidelines scoring low in
quality domains, many still make recommendations based on high-quality evidence; this may
explain why some CPGs which scored low on the AGREE 2 instrument, are still widely used
(due to the strength of the evidence behind the recommendations).
5.6 Future directions
Guidelines
The results of this study may be useful to certain oncologic guideline organizations, as feedback
on the relative visibility, use, and quality of their CPGs. This may improve their future
guideline creation, dissemination, and implementation efforts (particularly for important
international ventures, such as the BHGI). Further evaluation of specific dissemination
techniques for highly-used guidelines as found by this study (for example, ASCO and NCCN),
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may be useful to help inform other guideline groups on successful knowledge translation
methods. Studying how clinicians actually use the internet to access guidelines and other
platforms of knowledge may be particularly useful to help drive success in guideline uptake.
The impact of certain guidelines in particular settings (for example, the BHGI versus NCCN in
specific LICs) may best be evaluated by dedicated local studies in these nations, which could
also be informed by the results of this project (for instance in choosing which guidelines may be
relevant to assess or implement). Such local studies might include site visits to particular
centres to conduct clinician interviews, and assess local practice patterns, including the use of
guidelines by observation.
The gross redundancy in guidelines addressing early breast cancer care is perhaps unwarranted.
On a global scale, it may be more effective to direct efforts towards creating fewer, but
higher-quality guidelines with recommendations that are applicable to broader settings.
The use of available handbooks or standards for guideline creation should be encouraged; in
fact, the Guidelines International Network (G.I.N) has developed a process for guideline
creation informed by a multidisciplinary group of global experts, touted to be rigorous and yet
feasible for groups with even modest resources for such ventures (120). This process in fact
embraces the key tenets of the AGREE 2 instrument in terms of guideline quality; the use of the
AGREE 2 instrument should further be encouraged to help appraise the quality of existing
CPGs, before considering dissemination, uptake, or adaptation of these guidelines.
In this manner, guideline update and implementation efforts may also be facilitated, as guideline
expertise and resources would be better utilized across the entire scope of guideline creation and
implementation. To enhance the applicability of guidelines to specific settings, express
involvement of local experts (and/or training of such individuals) is imperative. This
involvement may also be concentrated in guideline adaptation, for the creation new guidelines
for each practice setting is again, redundant and not always feasible or warranted.
Early breast cancer practice patterns
The variation in specific practice patterns and identified barriers to care delivery (for instance,
limitations to trastuzumab use due to lack of access or drug cost in LMCs), may help better
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inform international health policy makers in breast cancer regarding the global state of
these matters. In addition, this type of data may help efforts to advocate for the lower
pharmaceutical pricing of or increase the global access to certain therapeutics. One can consider
such propositions to be akin to the international movement towards improving access to HIV
medications in LICs in past decades (3). Such movements have already been successful in a
few realms of breast cancer systemic therapy (such as tamoxifen use) (17), but perhaps could be
expanded further to include other treatments (or modalities of care, based on specific needs). As
such, in order to better evaluate other priorities in early breast cancer care by specific resource
settings, the collected data on diagnostic and local treatment patterns from this survey should be
analyzed. Future studies similar to this one on screening practices and LABC management may
help complete the assessment of international breast cancer care patterns, as divulged by
practicing global physicians. Preferential targeting of physicians in regions underrepresented by
this study would be ideal. Methods to target these physicians beyond academic society
membership could be developed. In fact, these future studies might better be coordinated by
organizations such as the BHGI or WHO. Therefore, dissemination of findings from this study
to relevant representatives within these organizations may be useful.
5.7 Conclusions
In order to combat the growing global burden of breast cancer, particularly in LMCs, we require
international alliances that are dedicated to timely data synthesis, active dissemination, and
collaborative implementation of new (and existing) knowledge. As a vital form of knowledge
output, clinical practice guidelines in breast cancer need to be of high quality and resource-
appropriate, and this can benefit physicians and patients in all resource settings. Guideline
developers should follow established standards of guideline creation, with particular
consideration of quality domains, as outlined by tools such as the AGREE 2 consortium.
Furthermore, guidelines should focus on high-quality evidence when available, and any
consensus methods should be clearly described. A greater transparency in guideline
development overall is needed, in addition to specific delineation of who the guideline is
intended to be used by and in what setting. Mandates to regularly update guidelines should be
followed. Breast cancer CPGs are being used by global physicians and certain guidelines have
greater prominence than others (regardless of quality scores); this may reflect the relative high
102
quality of the recommendations themselves. The internet is a key tool for guideline
dissemination and is favoured by clinicians worldwide, particularly in lower income nations.
Practice patterns in systemic therapy for early breast cancer are generally reflective of guideline
recommendations, which are redundant across many CPGs. However, resource constraints
limits the use of some more costly therapies (such as trastuzumab), particularly in LMCs.
Reassuringly, the use of lower-cost but effective therapies (such as tamoxifen and some
chemotherapy) appears to be highly prevalent across the globe. Some treatments and
technologies (such as HER-2 testing), that are considered to be sustainable only in higher
income settings, are being utilized in lower income settings, despite recommendations to the
contrary. This may highlight suboptimal allocation of resources in these areas, and may reflect
low uptake of guidelines recommending the limited use of such modalities. Further study is
required to better establish what physician and patient factors may be influencing these trends,
in addition to the impact of unique practice settings (of which resources and culture likely have
significant roles). The ideal approach to such ventures may be the adaptation of existing, high-
quality CPGs to local settings, with express involvement of local practitioners, and capacity-
building efforts coordinated by international experts. In addition, international guideline
creation efforts might benefit from larger-scale monitoring to optimize CPG content,
applicability (within different settings), and quality (in both content and construct). This could
minimize redundancy in breast cancer recommendations across the globe, and maximize the use
of CPG expertise (with more emphasis on guideline update and implementation efforts). Large
international organizations such as the WHO, and prominent leaders in the oncology world
(such as ASCO) should continue to champion such efforts. This could be an important facet of
improving breast cancer outcomes worldwide, as part of the larger global agenda for cancer
control.
103
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APPENDICES
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Appendix i – Survey (paper/IBCC meeting version)
113
114
115
116
117
118
Appendix ii: REB Approval
119
Appendix iii- IBCC Letter and Consent
Dear Friends,
Breast cancer continues to be a growing global concern. In order to address this, we must strive to improve outcomes in women worldwide, and not just in more developed nations. Guidelines for early breast cancer care are created to recommend standards of best practice, but few actually describe minimum standards of care which are applicable within differing health care resource and cultural settings. To assess if current guidelines have a global impact in directing early breast cancer practice, we have created an international physician survey. This study seeks to identify patterns of practice in early breast cancer worldwide, and assess if these are indeed impacted by guidelines. It hopes to identify barriers and challenges to integrating guideline-based care, as expressed by practicing physicians in different nations.
This survey should take 15-20 minutes to complete. Completion and return of this survey to the meeting organizers will qualify you to receive a CME certificate for attending IBCC 4 January 2010.
DOCUMENTATION OF INFORMED CONSENT
Full Study Title: The Impact of Global Early Breast Cancer Guidelines on Regional Treatment Practice: a survey of international physicians.
Study Investigators: Dr. Sonal Gandhi, Dr. Shabbir Alibhai, and Dr. Sunil Verma (PI).
Sunnybrook Health Sciences Centre (Edmond Odette Cancer Centre) and the University of Toronto. Toronto, Ontario, CANADA.
By Completing and Submitting the survey involved in this study, I give consent to the utilization of my ANONYMOUS answers (data) in study analysis and final report formulation. I understand that my personal identifying contact information will NOT be collected or connected to my answers in any manner. There will be NO disclosure of my ANONYMOUS survey answers to any persons, except to those involved directly with the study for data extraction. My participation or non-participation in this study will NOT impact on my professional practice or reputation in any way.
I understand that I am giving a form of implied consent by completing and returning this survey, and no signature is required by myself or the primary investigators to secure this consent.
Appendix ii – REB APPROVAL
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Appendix iv – Country Distribution for Online Survey
1 China 1,325,640 LMC – east asia pacific 2 India 1,139,965 LMC south asia 3 United States 304,060 High 4 Indonesia 228,249 LMC east asia and pacific 5 Brazil 191,972 UMC latin American and carribean 6 Pakistan 166,037 LMC south asia 7 Bangladesh 160,000 LC South asia 8 Nigeria 151,319 LMC Subharan africa 9 Russian Feder 141,800 UMC Europe and central asia 10 Japan 127,704 HC 11 Mexico 106,350 UMC Latin America and Caribbean 12 Philippines 90,348 LMC east asia pacific 13 Vietnam 86,211 LC east asia pacific 14 Germany 82,140 HC 15 Egypt, Arab Rep. 81,527 LMC middle east and north africa 16 Ethiopia 80,713 LC sub-Saharan africa 17 Turkey 73,914 UMC Europe central asia 18 Iran, Islamic Rep. 71,956 LMC middle east and Africa 19 Thailand 67,386 LMC east asia pacific 20 Congo, Dem. Rep. 64,205 LC SSA 21 France 62,048 a High 22 United Kingdom 61,399 High 23 Italy 59,855 High 24 Myanmar 49,190 LC East asia pacific 25 South Africa 48,687 UMC SSA 26 Korea, Rep. 48,607 High 27 Ukraine 46,258 LMC Europe and central A 28 Spain 45,568 High 29 Colombia 44,534 UMC latin America carrib 30 Tanzania 42,484 b LC SSA 31 Sudan 41,348 LMC SSA 32 Argentina 39,876 UMC Latin 33 Kenya 38,534 LC SSA 34 Poland 38,123 UMC Europe and central A 35 Algeria 34,362 UMC middle east and nAfrica 36 Canada 33,311 High 37 Uganda 31,657 LC SSA 38 Morocco 31,229 LMC Middle east and NAfrica 39 Peru 28,837 UMC Latin carrib 40 Nepal 28,582 LC south asia 41 Venezuela, RB 27,943 UMC latin carib 42 Uzbekistan 27,314 LC Europe and centra asia 43 Malaysia 26,993 UMC east asia pacific 44 Saudi Arabia 24,646 High 45 Korea, Dem. Rep. 23,858 LC east asia pacific 46 Ghana 23,351 LC SSA 47 Yemen, Rep. 23,053 LC middle east n africa
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48 Mozambique 21,781 LC SSA 49 Romania 21,513 UMC Europe and central asia 50 Australia 21,374 High 51 Syrian Arab Republic 21,227 LMC middle east and north Africa
Country Tally By Resource Setting
HIC (High) = 11
MIC (UMC) = 13
LIC (LC + LMC) =27
Continent/Region Tally East Asia Pacific-8, Europe Central/Asia-6, Middle East/north Africa-6 Latin/Carib-6, Sub-Saharan Africa-10, South Asia-4
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Appendix v- Email invitation for online survey
Dear Friends,
Breast cancer continues to be a growing global concern. In order to address this, we must strive to improve outcomes in women worldwide, and not just in more developed nations. Guidelines for early breast cancer care are created to recommend standards of best practice, but few actually describe minimum standards of care which are applicable within differing health care resource and cultural settings. To assess if current guidelines have a global impact in directing early breast cancer practice, we have created an international physician survey. This study seeks to identify patterns of practice in early breast cancer worldwide, and assess if these are indeed impacted by guidelines. It hopes to identify barriers and challenges to integrating guideline-based care, as expressed by practicing physicians in different nations.
Please find below a secure online link to our survey. This should take about 15-20 minutes to complete, and your input will be invaluable to this study. By completing this survey, you consent to the use of your answers in the final data analysis and report. Your responses will be anonymous and will not be connected to personal identifying information in any way. Only your email address has been entered into an online survey platform, and is NOT available for ongoing viewing by the study personnel. Your email address will be destroyed from the study investigators’ secure database on study completion.
*If you have already completed this survey as part of the IBCC 4 meeting in Paris, January 2010, please disregard this email and thank you for your participation.
Please be advised that paper copies of the survey are available, and can be mailed or faxed to you. We will require you to email us your fax or mailing address to send you a paper survey, but this information will be promptly destroyed once the survey is sent. Please let us know via email if you would prefer a survey translated into another language, as we may be able to facilitate this during future versions of the survey, based on demand.
Please email [email protected] with these requests, or any other questions or concerns.
Your time and participation is greatly appreciated; please see attached a formal information consent letter as mandated by our institute. This does not require completion or submission, and is for your reference only.
Please collaborate with your international colleagues in improving breast cancer care across the world!
With sincere thanks,
Dr. Sonal Gandhi, Oncology Fellow
Dr. Sunil Verma, Staff Oncologist.
Dept. of Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Canada
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Appendix vi - Online Survey Consent
INFORMED CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Full Study Title: The Impact of Global Early Breast Cancer Guidelines on Regional Treatment Practice: a survey of international physicians.
Principal Investigators: Sonal Gandhi, MD and Sunil Verma, MD. Sunnybrook Odette Cancer Centre, Toronto, ON, Canada. (416) 480-5243.
Sponsor: This study is being funded by the Department of Medical Oncology, Sunnybrook Health Sciences Centre.
______________________________________________________________________
INFORMED CONSENT
You are being asked to consider participating in a research study. This form explains the purpose of this research study, provides information about the study, the procedures involved, possible risks and benefits, and the rights of participants.
Please read this form carefully and ask any questions you may have. Please ask the study staff or one of the investigator(s) to clarify anything you do not understand or would like to know more about. Make sure all your questions are answered to your satisfaction before deciding whether to participate in this research study.
INTRODUCTION
Outcomes in breast cancer vary across different nations, and in order to improve these outcomes on a global scale, it is important to understand regional barriers to providing minimum or best standards of early breast cancer care, as recommended by published consensus guidelines.
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to examine international patterns of physician practice in treating early breast cancer, and examining if practice is impacted by breast cancer guidelines. It hopes to identify what challenges are present in different nations that need to be addressed in order to facilitate increased integration of guideline based care worldwide.
WHAT WILL HAPPEN DURING THIS STUDY?
You are a physician who has been contacted by email for possible study participation; you have been identified as an oncologist who potentially treats breast cancer. Physicians contacted in this manner are being asked to complete a secure online survey, or email the primary investigators for a paper copy. If you email for a paper copy, your fax number or address will be collected from you with your
124
permission, to send you the survey. This contact information will then be destroyed, your returned survey will have NO personal identifying data, and your responses will be extracted anonymously.
The data from completed surveys will be extracted and entered into a secure database where there is no personal identifying physician information. Preliminary data analysis may be completed by the online survey platform, but again, personal information will not be used.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
It is anticipated that about 2000 physicians worldwide will partake in this study. Final numbers will depend on response rates.
WHAT ARE THE RESPONSIBILITIES OF STUDY PARTICIPANTS?
If you decide to participate in this study you will be asked to do the following:
Complete online or paper survey. If a paper survey is completed, you will be responsible for either faxing or mailing the survey back to the primary investigators.
WHAT ARE THE RISKS OR HARMS OF PARTICIPATING IN THIS STUDY?
No specific material risks are identified. You are participating via an online survey platform, and only your email address has been entered into the program and is NOT available for ongoing viewing by the study personnel. Email addresses will be destroyed from our database of physician emails on completion of the study. NO correlation will be made between your survey responses and email address; responses will be collected by the program in an anonymous fashion. As such you cannot and will not be judged or reprimanded for your survey answers. This survey will be examining trends in guideline knowledge and practice patterns, and NO individual practices will be disclosed to any regulatory body. If you choose NOT to participate in this study, you will also NOT be reprimanded in any fashion. Your participation or non-participation in this study will have NO impact on your professional reputation or medical practice.
WHAT ARE THE BENEFITS OF PARTICIPATING IN THIS STUDY?
The results of this survey will bring to light potential concerns and challenges faced by breast oncologists worldwide, and the final report will outline areas for future implementation research. It will also highlight disparities in global breast cancer care and applicability of published guidelines. This will benefit all physicians treating breast cancer, by improving international efforts to address these challenges and disparities.
CAN PARTICIPATION IN THIS STUDY END EARLY?
Surveys that are incomplete will not be considered in the final data analysis.
WHAT ARE THE COSTS OF PARTICIPATING IN THIS STUDY?
There are no costs to completing the online survey, except for an approximately 20 minute time commitment. Those physicians returning paper surveys may incur fax/mailing costs, but at special request, the primary investigators will attempt to cover these costs.
ARE STUDY PARTICIPANTS PAID TO PARTICIPATE IN THIS STUDY?
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You will not be paid to participate in this study.
DO THE INVESTIGATORS HAVE ANY CONFLICTS OF INTEREST?
There are no conflicts of interest to declare related to this study.
WHAT ARE THE RIGHTS OF PARTICIPANTS IN A RESEARCH STUDY?
All participants in a research study have the following rights:
1. You have the right to have this form and all information concerning this study explained to you and if you wish translated into your preferred language.
2. Participating in this study is your choice (voluntary). You have the right to choose not to participate. However, once your completed survey is submitted, it cannot be withdrawn.
3. You have the right to receive all significant information that could help you make a decision about participating in this study. You also have the right to ask questions about this study and your rights as a research participant, and to have them answered to your satisfaction, before you make any decision. You also have the right to ask questions and to receive answers throughout this study. If you have any questions about this study you may contact the persons in charge of this study (Drs Sonal Gandhi and Sunil Verma, as above, or at [email protected]). If you have questions about your rights as a research participant or any ethical issues related to this study that you wish to discuss with someone not directly involved with the study, you may call Dr. Philip C. Hébert, Chair of the Sunnybrook Research Ethics Board at (416) 480-4276.
The investigator(s), study staff and the other people listed above will keep the information they see or receive about you confidential, to the extent permitted by applicable laws. Even though the risk of identifying you from the study data is very small, it can never be completely eliminated.
When the results of this study are published, your identity will not be disclosed.
The Principal Investigator will keep any personal (contact) information about you in a secure and confidential location for up to 2 years and then destroyed as required by Sunnybrook policy.
DOCUMENTATION OF INFORMED CONSENT
Full Study Title: The Impact of Global Early Breast Cancer Guidelines on Regional Treatment Practice: a survey of international physicians.
By Completing and Submitting the survey involved in this study, I give consent to the utilization of my anonymous answers (data) in study analysis and final report formulation. I understand that my personal identifying contact information will not be collected, unless I request a paper survey. In this case, my mailing address or fax number will be required to send me the survey, but will then be destroyed. If I have been contacted by email, my email address will only be used for providing me a link to the online survey, and for one automated email reminder from the online survey platform. My survey answers will NOT be linked to me personally in any fashion. There will be no disclosure of my survey answers to any persons, except to those involved directly with the study for data extraction.
I understand that I am giving a form of implied consent by completing and returning this survey, and no signature is required by myself or the primary investigators to secure this consent.
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Appendix vii: Systematic Review Early Breast Cancer Guidelines
MEDLINE SEARCH: 1. breast cancer.mp. or exp Breast Neoplasms/ - 133416
2. tamoxifen.mp. or exp Tamoxifen/ -14380
3. aromatase inhibitors.mp. or exp Aromatase Inhibitors/ - 4080
4. exp Antibodies, Monoclonal, Humanized/ or exp Antibodies, Monoclonal/ or herceptin.mp. or exp
Antineoplastic Agents/ or exp Antineoplastic Combined Chemotherapy Protocols/ - 472982
5. trastuzumab.mp. -3972
6. adjuvant.mp. or exp Chemotherapy, Adjuvant/ - 67872
7. chemotherapy.mp. or exp Drug Therapy/ -622775
8. 2 or 3 or 4 or 5 or 6 or 7 -970209
9. 1 and 8 - 45135
10. 9
11. limit 10 to (english language and humans and yr="2005 - 2010" and (consensus development
conference or guideline or practice guideline)) - 73
12. global.mp. - 113512
13. international.mp. or exp International Agencies/ or exp International Cooperation/ - 177344
14. 12 or 13 - 279867
15. 11 and 14 - 20
EMBASE*
1. breast cancer.mp. or exp Breast Neoplasms/
2. tamoxifen.mp. or exp Tamoxifen/
3. aromatase inhibitors.mp. or exp Aromatase Inhibitors/
127
4. exp Antibodies, Monoclonal, Humanized/ or exp Antibodies, Monoclonal/ or herceptin.mp. or exp
Antineoplastic Agents/ or exp Antineoplastic Combined Chemotherapy Protocols/
5. trastuzumab.mp.
6. adjuvant.mp. or exp Chemotherapy, Adjuvant/
7. chemotherapy.mp. or exp Drug Therapy/
8. 2 or 3 or 4 or 5 or 6 or 7
9. 1 and 8
10. 9
11. limit 10 to (english language and humans and yr="2005 - 2010" and (consensus development
conference or guideline or practice guideline))
12. breast cancer.mp. or exp Breast Neoplasms/
13. tamoxifen.mp. or exp Tamoxifen/
14. aromatase inhibitors.mp. or exp Aromatase Inhibitors/
15. exp Antibodies, Monoclonal, Humanized/ or exp Antibodies, Monoclonal/ or herceptin.mp. or exp
Antineoplastic Agents/ or exp Antineoplastic Combined Chemotherapy Protocols/
16. trastuzumab.mp.
17. adjuvant.mp. or exp Chemotherapy, Adjuvant/
18. chemotherapy.mp. or exp Drug Therapy/
19. 13 or 14 or 15 or 16 or 17 or 18
20. 12 and 19
21. 20
22. 21
23. limit 22 to (human and english language and yr="2005 - 2010")
24. limit 23 to "reviews (best balance of sensitivity and specificity)"
128
25. exp international cooperation/ or international.mp.
26. global.mp.
27. 25 or 26
28. 24 and 27 - 428
29. 28
30. limit 29 to "therapy (best balance of sensitivity and specificity)" - 148
GUIDELINE INTERNATIONAL NETWORK (G.I.N)
Search term in International Guideline Database –
“Breast Cancer” – 139
“Adjuvant Breast Cancer” – 16
“Early Breast Cancer” – 14
NATIONAL GUIDELINE CLEARINGHOUSE
Search Process:
Diseases Neoplasms Neoplasms by site Breast – 57 Adjuvant - 26
Notes:
* EMBASE results were not used: no guideline filter could be applied; review of citations revealed mostly review articles and commentaries, irrelevant topics, and any found guidelines were redundant with MEDLINE.
129
Guideline Source
Realm of adjuvant systemic treatment
Guide-line Type
Key recommendations
Notes
GERMAN
GYNECOL-OGICAL
ONCOLOGY GROUP (AGO)
BREAST COMMISSION
2009-2010
[GERMANY]
1. AGO Breast Committee.
Diagnosis and Treatments of Patients with Primary and
Metastatic Breast Cancer.
Guidelines Breast V 20101.1 www.ago-online.de. Accessed
November 2, 2010.
2. Thomssen C and Harbeck N. Update 2010 of
the German AGO Recommendation
s for the Diagnosis and
Treatment of Early and Metastatic
Breast Cancer – Chapter A: Surgery,
Pathology and Prognostic
Factors, Adjuvant and Neoadjuvant
Therapy, Adjuvant
Radiotherapy. Breast Care
1. Endocrine & bisphosphonate 2.Chemotherapy 3. Targeted 4. Neoadjuvant
Evidence-Based
1. Endocrine
Premenopausal High or Intermediate risk: chemotherapy followed by tamoxifen x 5 years +/- GnRHa (if under age 40). Low or Intermediate Risk: Tamoxifen x 5 years +/- GnRHa x 2-5 years.
Postmenopausal: Sequence: Tamoxifen x 2-3 years followed by AI 3-2 years OR AI x 2-3 years followed by tamoxifen x 3-2 years (preferred for node positive patients to be treated with letrozole) OR upfront AI x 5 years OR tamoxifen x 5 years and consider AI for 3-5 years after (extended adjuvant), especially for node positive, long tamoxifen free interval, or patients who become postmenopausal on tamoxifen.
Bisphosphonates Consider clodronate for 2 years or zoledronic acid for 3 years in pre and post menopausal women
Chemotherapy
Anthracyclines and taxanes are essential in adjuvant chemotherapy taxanes are evidence based for node positive disease and should be considered for node negative with high relapse risk. Several anthracycline-taxane regimens are reasonable
DocC (Docetaxel-Cyclophosphamide) can be considered if anthracyclines
Endocrine: endocrine responsiveness is ER and or PR >= 1% AIs not recommended in premenopausal women either with GnRHa, after GnRHa, or after chemotherapy induced amenorrhea GnRHa alone x 2-5 years if tamoxifen contraindicated not recommended; consider anticoagulation if history of DVT while on tamoxifen. fertility preservation counselling recommended to those interested. Chemotherapy: Recommend anthracyclines over CMF, but CMF over no therapy
Appendix viii: Compilation of adjuvant systemic therapy recommendations from international breast cancer guidelines
130
2010;5:259–265. contraindicated, but consider enrolment in clinical trials looking at non anthracycline chemo versus standard anthracycline-taxane regimens
High risk, node positive (> 4 nodes) consider dose dense, dose intensified ddETC if in experienced centre
Targeted
HER-2 testing should be done on all tumours; internal and external quality control measures recommended
Trastuzumab recommended for all node positive, and node negative > or = 1cm. Consider for node negative tumours less > or = 5mm with other risk factors (candidates for chemotherapy.)
Trastuzumab may be given concurrently or sequentially (up to 3 months) after taxane portion of chemotherapy; concurrently is preferred
One year maintenance recommended
Neoadjuvant
NAC is standard of care for large, inoperable tumours or inflammatory breast cancer
pCR can predict for better survival outcomes; young age, negative ER, non lobular, HER-2 positive and gene expression profiling can predict for pCR
any adjuvant anthracycline-taxane combination can be used, but 18 weeks of therapy recommended.
Complete response complete chemotherapy and then proceed to surgery. Partial response
131
mid way consider non cross resistant chemotherapy. Progression immediate surgery or radiation and complete chemotherapy adjuvantly with non-cross resistant regimen
HER-2 positive breast cancer should receive trastuzumab as part of NAC, and complete one year maintenance.
Endocrine sensitive breast cancer should receive adjuvant endocrine therapy
AMERICAN
SOCIETY OF CLINICAL
ONCOLOGY (ASCO)
2006
[UNITED STATES]
Burstein HJ, Prestrud AA,
Seidenfeld J, et al. American Society
of Clinical Oncology Clinical
Practice Guideline: Update
on Adjuvant Endocrine
Therapy for Women With
Hormone Receptor–Positive Breast Cancer. J
Clin Oncol. 2010;28(23): 3784-
3796
1. Endocrine
Evidence -Based - Consensus
1. Endocrine
Postmenopausal: aromatase inhibitor (AI) upfront or after 2-3 years of tamoxifen. 5 year duration total.
Premenopausal or Perimenopausal: tamoxifen x 5 years.
Intolerance to one AI, can consider another 3
rd
generation AI or tamoxifen
Should consider patient preferences and toxicity profiles of AIs and tamoxifen when selecting therapy
BREAST HEALTH
GLOBAL INITIATIVE (BHGI)
2006
[INTERNATIONAL
AND
1. Endocrine 2.Chemotherapy 3. Biologic (Targeted)
Evidence Based - Consensus
1. Endocrine Basic Level Resources
Ovarian ablation
Tamoxifen Limited Resources
Ovarian ablation
Tamoxifen Enhanced Resources
Chemotherapy cytotoxic chemotherapy benefits all patients, particularly node positive or node negative
132
UNITED STATES]
1. Eniu A, Carlson RW, Aziz Z, et al.
Breast health global initiative
Breast Cancer in Limited-Resource
Countries: Treatment
and Allocation of Resources. Breast
J. 2006;12(S1): S38–S53
2. Anderson BO,
Shyyan R, Eniu A, et al. Breast health global
initiative. Breast Cancer in Limited-Resource
Countries: An Overview
of the Breast Health Global Initiative 2005
Guidelines. Breast J. 2006;12(S1):
S3–S15.
3. Anderson BO, Yip CH, Smith RA,
et al. Guideline implementation
for breast healthcare in low-
income and middle-income
countries: overview of the Breast Health
Global Initiative Global Summit 2007.
Cancer 2008 Oct 15;113(8
Suppl):2221-2243.
Aromatase Inhibitors
LHRH agonists Maximal Resources
Aromatase Inhibitors
LHRH agonists 2. Chemotherapy (adjuvant and neoadjuvant) Basic Level Resources
Classic CMF
AC, EC or FAC Limited Resources
Classic CMF
AC, EC or FAC Enhanced Resources
Chemo as above including taxanes
Maximal Resources
Chemo as above including taxanes
Dose dense chemo
Growth factors 3. Biologic (adjuvant and neoadjuvant) Enhanced and Maximal Resources
Trastuzumab for HER-2 positive disease; ** if cost of therapy was lower, could be considered for Limited resource Setting, but also requires resources for HER-2 testing.
with high risk features (age, grade, histology, HR status); HER2 status and LVI have been proposed as prognostic variables. utility of adjuvant taxanes in HR positive patients is controversial. Neoadjuvant therapy: anthracycline based chemo is preferred in neoadjuvant setting; role of sequenced taxane remains to be defined. Responding patients should receive 8 cycles; non responders should have local treatment after 4 cycles. Neoadjuvant endocrine therapy can be considered for chemo non candidates. Data suggests AIs better.
CANCER CARE ONTARIO (CCO)
PROGRAM IN EVIDENCE
BASED CARE (PEBC)
2008-2010
1. Endocrine (Aromatase Inhibitors) 2. Chemotherapy (Taxanes) 3. Targeted
Evidence- Based
1. Endocrine – Aromatase Inhibitors
Postmenopausal: Adjuvant tamoxifen (20mg x 5 years) remains acceptable treatment
Adjuvant anastrazole
Targeted: HER-2 positive is >10% staining by IHC or gene amplification by FISH.
133
[CANADA]
1. Eisen A, Trudeau M,
Shelley W et al. The Role of Aromatase Inhibitors in
Adjuvant Therapy for
Postmenopausal Women with
Hormone Receptor-positive
Breast Cancer: Guideline
Recommendations
Evidence-based Series #1-18:
Section 1 2008. www.Cancercare. on.ca. Accessed
July 10, 2010.
2. CCO. Members of the Breast
Cancer Disease Site Group.
Adjuvant Taxane Therapy for Women with Early-stage,
Invasive Breast Cancer. Evidence-based Series 1-7 Version 2. 2010. www.cancercare .on.ca. Accessed August 1, 2010.
3. CCO. Members of the Breast
Cancer Disease Site Group. The
Role of Trastuzumab in Adjuvant and Neoadjuvant
Therapy in Women with
HER2/neu-overexpressing
(1mg) or letrozole (2.5mg) x 5 years is acceptable alternative to tamoxifen x 5 years
Adjuvant tamoxifen (20mg) x 2-3 years with switch to either exemestane (25mg) or anastrazole (1mg) for total of 5 years is acceptable alternative to 5 years of tamoxifen
Adjuvant letrozole (2.5mg) x 5 years should be considered in women who have completed tamoxifen x 5 years.
2. Chemotherapy – Taxanes The following taxane containing regimens are reasonable options and recommended over their non-taxane containing counterparts:
DAC (docetaxel, doxorubicin, and cyclophosphamide) x 6 cycles every 3 weeks OR
AC (doxorubicin, cyclophosphamide) x 4 cycles, followed by P (paclitaxel) x 4 cycles, every 3 weeks or every 2 weeks with GCSF OR
FEC (5-flurouracil, epirubicin, cyclophosphamide) x 3 cycles followed by D (docetaxel) x 3 every 3 weeks
3. Targeted
Trastuzumab should be offered for one year to all patients with HER2-positive node-positive or node-negative, tumour greater than 1 cm in size, and primary breast cancer and who are receiving or have received (neo)adjuvant chemotherapy. Trastuzumab should be offered after chemotherapy.
4. Bisphosphonates:
Generally given with anthracycline-taxane based regimen, either concurrent with or sequentially after taxane. Evidence for use with other chemotherapy regimens less compelling (vinorelbine, carboplatin, etc)
134
Breast Cancer. Evidence-based
Series 1-24 Version 2. 2010.
Accessed July 10, 2010.
4. M. Clemons, E.
Amir, A.E. Haynes, et al.
Zoledronic Acid as Adjuvant Therapy in
Combination with Adjuvant
Endocrine Therapy for
Premenopausal Women with Early-Stage Hormone
Receptor Positive Breast Cancer.
CED-CCO Special Advice Report
#16. www.cancercare.o
n.ca.. Accessed July 10, 2010.
zoledronic acid
There is insufficient evidence to recommend routine use of zoledronic acid in the adjuvant setting (in combination with endocrine therapy as part one clinical study.)
CORDOBA
CONSENSUS 2007
[SPAIN]
De la Haba-Rodríguez J, Alba E, Barnadas, A et al. Diagnosis and medical treatment of breast cancer.
Cordoba Consensus of
2007. Clin Transl Oncol (2008) 10:552-559
1. Endocrine 2. Chemotherapy (and Targeted) 3. Neoadjuvant
Evidence -Based- Consensus
1. Endocrine Postmenopausal
For hormone sensitive disease, hormone treatment should include an AI (for 5 years or for 2–3 years after tamoxifen20 mg/day to complete the 5 years).
Premenopausal
For hormone-dependent tumours, tamoxifen is the standard treatment; consider adding LHRH analog for 18-24 months if amenorrhea not induced. Not clear if this strategy is useful after anthracycline chemotherapy.
Aromatase inhibitors should not be used initially in women who become amenorrheic after chemotherapy
2. Chemotherapy and Targeted
General: The new classification of breast cancer into molecular subtypes helps better define prognosis and response to treatment; these will be taken into account in future studies. In the meantime, tumour size, degree of differentiation, affected nodes, hormone receptors, HER2 expression, and age will
135
Adjuvant chemotherapy beneficial for DFS and OS. Anthracycline and taxane combinations are superior to anthracyclines alone, which are superior to CMF
Minimum recommended number of cycles is 6; drugs should be at full dose. Some evidence supporting dose dense chemotherapy.
HER-2 over-expressing tumours should receive trastuzumab as well as chemotherapy.
3. Neoadjuvant
Neoadjuvant chemotherapy is standard therapy for locally advanced tumours, and to reduce the size of tumours for conservative surgery, (if no contraindication to chemotherapy.)
The combination of anthracyclines and taxanes, and trastuzumab for HER-2 positive tumours, is the most active (higher response rates)
Minimum number of cycles is 4-6 (unless there is clinical progression.)
Neoadjuvant endocrine treatment with AIs can be considered for elderly patients with hormone positive tumours.
Surgery or radiation should be considered if there is progression on neoadjuvant therapy
continue to define the prognosis and treatment options for each patient. Neoadjuvant: Tumours with lobular Histology, well differentiated, and high hormone receptor expression are very unlikely to respond to neoadjuvant chemotherapy. Endocrine treatment or surgery should be considered first line in these tumours.
EUROPEAN
SOCIETY FOR MEDICAL
ONCOLOGY (ESMO)
2010
[EUROPE]
1. Endocrine 2. Chemotherapy 3. Targeted 4. Neoadjuvant
Evidence -Based -Consensus
1. Endocrine
Premenopausal: tamoxifen x 5 yrs +/- ovarian suppression (oophorectomy or GnRHA x at least 2 years.)
Postmenopausal: AI upfront x 5 years is preferred. If on tamoxifen,
General: risk stratification should be done as outlined by St Gallen Consensus Endocrine:
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Aebi S, Davidson T, Gruber G, et al.
Primary breast cancer: ESMO
Clinical Practice Guidelines for
diagnosis, treatment and
follow-up. Annals of Oncology 21 (Supplement 5):
v9–v14, 2010
sequence to AI after 2-3 years. Low risk patients can get tamoxifen x 5 years. Can consider AI for 2-5 years after completing 5 years of tamoxifen (especially if node positive.)
2. Chemotherapy
For endocrine non responsive or uncertain tumours and/or HER-2 amplified
Anthracycline based chemo recommended for most patients, especially with HER2 positive; for some patients (elderly, cardiac disease) CMF x 6 may be appropriate
Suggested regimens include AC x 4, FECx6, CEF x 6, TC, AC-D, AC-P weekly, dose dense AC-P, DAC, FEC-D, A or E to CMF, AP to CMF.
Optimal duration unknown; at least 4, aim for 6-8 with higher risk
non anthracycline regimens with efficacy similar to or superior to anthracycline combinations being developed (Docetaxel-Cyclophosphamide).
taxanes may be more efficacious in HR negative or HER2 positive disease.
3. Targeted
HER2 positive disease benefit from adjuvant trastuzumab
Three weekly or weekly regimens equal in efficacy
Optimum duration unclear, but currently one year recommended
Trastuzumab may be started concurrently with taxane but not with anthracycline
Even if given after anthracycline can have cardiotoxic effects; must monitor ejection fraction
hormone receptor positive (>= 1%) or unknown should be offered endocrine therapy AIs (even with GnRHA) should not be given to premenopausal tamoxifen not to be given at same time as chemotherapy; unclear if AIs can be safely started with chemo optimal timing of GnRHA unknown Chemotherapy: role for dose dense schedules with GCSF is controversial Bisphosphonates: Bisphosphonates prevent bone loss in patients on AIs. Early data suggests adjuvant zoledronic acid can decrease recurrence in premenopausal on endocrine therapy and postmenopausal on AIs; no data in HR negative or after chemo
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(EF)
Avoid in patients with low EF (less than 50-55%)
To be given with endocrine therapy in absence of chemotherapy is not supported by evidence.
4. Neoadjuvant
Neoadjuvant therapy indicated for locally advanced and inflammatory disease
Choose chemotherapy based on predictive factors as in adjuvant treatment
Trastuzumab should be added chemotherapy in HER2 positive
Primary endocrine therapy can be considered but not supported by clinical trials.
INTERNATIONAL EXPERT PANEL
ON NEOADJUVANT
SYSTEMIC THERAPY FOR
OPERABLE BREAST CANCER
[INTERNATIONAL]
Kaufmann M,
Hortobagyi GN, Goldhirsch A, et al. Recommendations
From an International Expert
Panel on the Use of
Neoadjuvant (Primary) Systemic
Treatment of Operable Breast
Cancer: An Update. J Clin Oncol.
2006;24(12):1940-1949.
1. Neoadjuvant: (Chemotherapy, Endocrine, and Targeted)
Evidence -Based -Consensus
Neoadjuvant
Chemotherapy:
Neoadjuvant systemic therapy (NST) is considered as safe and effective as the same systemic treatment given adjuvantly
NST should be offered to all patients who would be candidates for the same adjuvant therapy. However, NST should be avoided in patients in whom the need and type of adjuvant therapy cannot be defined upfront, to avoid overtreatment.
The decision for adjuvant/neoadjuvant therapy is based on endocrine responsiveness, grade, and size of the tumour, lymph node status, age and menopausal status of the patient
Anthracycline/taxane-based chemotherapy
Neoadjuvant systemic therapy (NST)is considered for three major reasons: to improve surgical options, to determine the response to systemic therapy, and to obtain long-term disease-free survival; the importance of these factors varies by setting. Clinical pathologic markers and gene expression profiling may help predict response to NST. So far
138
regimens have been best studied, with highest response rates. Examples include:
AC followed by docetaxel; docetaxel/doxorubicin/cyclophosphamide; epirubicin/paclitaxel cyclophosphamide/methotrexate/fluorouracil; and a dose-dense sequence of epirubicin and paclitaxel.
Sequential, concurrent, and dose dense regimens have all been studied but none is clearly superior, so there are no recommended standards; paclitaxel in dose dense or weekly schedules seems to be the most promising.
At least 4 cycles of chemotherapy should be given, as long as no disease progression.
Endocrine therapy alone is also efficacious preoperatively. It would be appropriate for frail postmenopausal patients in whom surgery with or without chemotherapy would be of high risk. AIs are superior to tamoxifen but pCR rates are low. Other endocrine strategies are investigational. At least 4 months of endocrine therapy should be given, as long as no disease progression.
Targeted: in Her2/neu-overexpressing tumours,
all immunotherapies are investigational in the neoadjuvant setting, including Trastuzumab.
ER negativity is considered strongest predictor. Switching to non-cross resistant chemotherapy regimens can be considered; it is unclear which group of patients benefits (responders versus non-responders.) Some patients may benefit from longer or shorter courses of neoadjuvant therapy; it is still unclear how to determine who these patients are.
NATIONAL
COMPREHEN-SIVE CANCER
NETWORK
1. Endocrine 2.Chemotherapy 3. Targeted 4. Neoadjuvant
Evidence -Based -Consensus
1. Endocrine
Premenopausal: tamoxifen for 2-3 years +/- ovarian ablation or suppression. If at 2-3
General: Favourable histologies: tubular or colloid
139
2010
[UNITED STATES]
NCCN Guidelines Panel. NCCN
Clinical Practice Guidelines in
Oncology. Breast Cancer V 2.2011. www.nccn.org.
Accessed December 18,
2010.
years, still premenopausal, complete 5 years of tamoxifen. if still premenopausal, no further therapy. If become post menopausal, consider 5 years of AI. If become postmenopausal after 2-3 years of tamoxifen: either complete 5 years of tamoxifen and consider 5 years of AI, or switch to AI to complete 5 years (or longer.)
Postmenopausal: AI for 5 years OR tamoxifen x 2-3 years and AI to complete 5 years or longer OR tamoxifen x 4.5 to 6 years, and 5 years of AI. Patients with contraindications to or intolerance of AIs, tamoxifen x 5 years.
2. Chemotherapy HR positive, HER2 negative:
T1-3 and N0 or N1mi (<2mm mets)
a: if < or =
0.5cm or microinvasive, consider adjuvant endocrine therapy. Tumour > 0.5 cm: consider 21 gene RT PCR assay * not done – endocrine therapy +/- chemotherapy. Low risk (RS <18): endocrine therapy. Intermediate risk (RS 18-30): endocrine therapy +/- chemotherapy. High risk (RS >30): endocrine therapy + chemotherapy.
Node positive (one or more mets > 2mm to one or more lymph nodes)
HR negative, HER 2 negative:
pT1-pT3 and pN0 or pN1mi (<2mm mets): tumour < or = 0.5 cm or microinvasive and p N0
ER/PR positive and N0 or pN1mic, tumour < 1cm: no adjuvant therapy, 1 -2.9 cm: consider endocrine therapy, > or = 3cm: adjuvant endocrine therapy. if node positive: endocrine therapy and consider chemotherapy. if ER/PR negative: retest receptors still negative, treat as per other histologies. Targeted: prognosis in T1a and T1B tumours favourable even if HER2 over-expressed/ amplified. This cohort not studied in randomized trials; must balance toxicities of trastuzumab/ chemotherapy with uncertain benefit.
Neoadjuvant: Completion of all cycles of chemotherapy prior to surgery is preferred. Local-regional treatments (surgical and
140
– no therapy, pN1mi – consider chemotherapy.
Tumour 0.6-1cm: consider adjuvant
chemotherapy.
Tumour > 1cm: chemotherapy
Lymph node positive: adjuvant chemotherapy.
Preferred chemotherapy regimens: TAC, dose dense AC followed by paclitaxel every 2 weeks, AC followed by weekly paclitaxel, TC, AC.
Other chemotherapy regimens: FAC/CAF, FEC/CEF, CMF, AC followed by docetaxel every 3 weeks, EC, A followed by T followed by C every 2 weeks with filgastrim support, FEC followed by docetaxel, FEC followed by weekly paclitaxel.
Targeted HR positive, HER2 positive:
pT1-pT3 and pN0 or pN1mi (<2mm mets): tumour < or = 0.5 cm or microinvasive and p N0 – consider endocrine therapy, pN1mi – endocrine therapy +/- chemotherapy and trastuzumab.
Tumour 0.6-1cm: adjuvant endocrine therapy +/- chemotherapy and trastuzumab.
Tumour > 1cm: endocrine therapy and chemotherapy + trastuzumab
Lymph node positive: endocrine therapy and chemotherapy + trastuzumab
HR negative, HER2 positive:
pT1-pT3 and pN0 or pN1mi (<2mm mets): tumour < or = 0.5 cm or microinvasive and p N0 – no adjuvant therapy,
adjuvant radiation) to be optimized with tumour response; no response consider alternative chemotherapy or radiation complete adjuvant therapy as appropriate after local management: complete chemotherapy if not all delivered pre-operative, followed by endocrine therapy for HR positive disease, complete up to one year of trastuzumab
141
pN1mi – consider chemotherapy + trastuzumab.
Tumour 0.6-1cm: consider chemotherapy and trastuzumab.
Tumour > 1cm: adjuvant chemotherapy + trastuzumab
Lymph node positive: adjuvant chemotherapy + trastuzumab
Preferred trastuzumab containing regimens: AC followed by Paclitaxel, various schedules, with concurrent trastuzumab, TCH (docetaxel, carboplatin, trastuzumab)
Other trastuzumab regimens: Docetaxel + Trastuzumab followed by FEC, AC followed by docetaxel +trastuzumab, any chemotherapy followed by trastuzumab
Neoadjuvant
Stage IIA (T2N0M0), IIB (T2N1 or T3N0), IIIA (T3N1) and fulfils criteria for breast conserving therapy except for tumour size OR locally advanced breast cancer (LABC) IIIA to IIIC appropriate biopsies and staging preoperative chemotherapy: use those regimens recommended in adjuvant setting
assess response after 3-4 cycles and consider alternative chemotherapy if progressing or partial response
HER 2 positive: add trastuzumab to chemotherapy for at least 9 weeks preoperative; preferred regimen is paclitaxel + trastuzumab, followed by CEF + trastuzumab.
Endocrine therapy can be used for HR positive disease in post
142
menopausal women, AIs preferred.
NEW ZEALAND GUIDELINES
GROUP
2009
[NEW ZEALAND]
New Zealand Guidelines Group.
Management of early breast
cancer. Wellington (NZ):
New Zealand Guidelines Group
(NZGG); 2009. P.77-131.
1. Endocrine 2. Chemotherapy (including targeted and neoadjuvant) 3. Bisphosphonates
Evidence -Based
1. Endocrine Premenopausal
Endocrine therapy should be considered with hormone receptor positive breast cancer; there is no benefit in hormone receptor negative breast cancer and should be avoided due to side effects.
Oophorectomy is an acceptable treatment option but is associated with high morbidity and long-term adverse effects
A LHRH agonist in addition to tamoxifen should be considered for a woman at high risk of recurrence (age <40years), who is not postmenopausal (at least 3 months of amenorrhoea) after chemotherapy
LHRH agonist + AI should not be considered outside of a clinical trial
Tamoxifen x 5 years remains the standard of care.
Chemotherapy (including anthracycline and/or a taxane) followed by tamoxifen should be considered; chemotherapy should be given first.
Postmenopausal
AIs should form at least part of endocrine treatment, unless contraindications exist
Treatment should be x 5 years of either an AI alone or sequenced with tamoxifen; patients on tamoxifen should be switched to an AI. The use of tamoxifen alone is only recommended if an
General: Adjuvant therapy can be considered for all women after surgery (ideally to start within 6 weeks and with multidisciplinary team approach.) For low risk of recurrence, option for no chemotherapy or endocrine treatment should be considered (benefits may be outweighed by risks of treatment) When both endocrine and chemotherapy treatment are given, chemotherapy should be given first. Endocrine: In women considering oophorectomy, one month trial of LHRH agonist should be tried to ensure tolerability. The side effects of aromatase inhibitors and tamoxifen should be considered
143
AI is tried and not tolerated or contraindicated.
Late/extended AI treatment (after 5 years of tamoxifen) should only be offered to premenopausal women who have become reliably menopausal during 5 years of tamoxifen, and would have been considered for switch strategy
AIs should be offered with caution to women in their 40’s that have become menopausal after chemotherapy; bone density should be carefully followed.
The use of chemotherapy in addition to endocrine therapy in postmenopausal women with hormone sensitive disease should be considered (considering risks and benefits); benefits are uncertain in women over 70.
2. Chemotherapy
Chemotherapy should be considered for hormone receptor negative breast cancer.
Anthracycline based regimens should be considered as they are more efficacious than cyclophosphamide, methotrexate and fluorouracil (CMF) regimens; absolute benefits should be balanced with side effects on individual basis.
Addition of taxanes should be considered whenever chemotherapy is considered, and benefits versus side effects of taxanes should be discussed.
3. Targeted
Addition of trastuzumab to chemotherapy should be
against the absolute benefit in breast cancer relapse for each patient. For women receiving AIs, baseline assessment of bone density should be completed and ongoing Measurement of estrogen and gonadotrophin levels is recommended before initiating treatment with an AI, where there is a chance that the woman is still premenopausal
Neoadjuvant: Neoadjuvant chemotherapy enables the evaluation of response to systemic treatment; the degree of response gives prognostic information. However, may lose other traditional prognostic information, which would have impacted on other treatment decisions (example radiation).
144
done for HER-2 positive tumours; one year of therapy is considered the standard of care, as overall survival was only improved in trials with this duration of therapy.
Women prescribed trastuzumab should have their cardiac function monitored regularly (every 3 months) by MUGA or ECHO.
4. Neoadjuvant
Preoperative chemotherapy may be considered where a woman with a large breast tumour has a preference for breast conserving surgery
Preoperative chemotherapy is recommended for a woman with inflammatory or inoperable locally advanced breast cancer without evidence of systemic spread
5. Bisphosphonates
Due to the lack of consistent evidence no recommendations were made regarding use of oral bisphosphonate for the reduction of osseous metastases in early breast cancer
NATIONAL
INSTITUTE FOR CLINICAL
EXCELLENCE (NICE)
2009
[UNITED
KINGDOM]
National Collaborating
Centre for Cancer. Early and locally advanced breast
cancer:
1. Endocrine 2. Chemotherapy 3. Targeted 4. Neoadjuvant
Evidence -Based
Endocrine
Premenopausal Do not offer ovarian ablation/ suppression to premenopausal patients being treated with tamoxifen or chemotherapy; offer to patients offered adjuvant chemotherapy but chosen not to have it.
Postmenopausal Women who are not considered to be at low risk should be offered an aromatase inhibitor, either anastrozole
General: Consider using Adjuvant Online®
b to aid
in decision making for adjuvant therapy Endocrine: Conflicting evidence and consensus regarding ovarian suppression recommendatio
145
diagnosis and treatment. TJ
International Ltd, United Kingdom.
2009.
or letrozole, as their initial adjuvant therapy. Offer tamoxifen if an aromatase inhibitor is not tolerated or contraindicated. Offer either exemestane or anastrozole, instead of tamoxifen to postmenopausal women with ER-positive early invasive breast cancer who are not low risk and who have been treated with tamoxifen for 2–3 years. Offer additional treatment with the aromatase inhibitor letrozole for 2–3 years to postmenopausal women with lymph node-positive ER-positive early invasive breast cancer who have been treated with tamoxifen for 5 years.
Chemotherapy
Offer docetaxel to patients with lymph node-positive breast cancer as part of an adjuvant chemotherapy regimen.
Do not offer paclitaxel as an adjuvant treatment for lymph node-positive breast cancer.
Targeted Therapy
Offer trastuzumab, given at 3-week intervals for 1 year or until disease recurrence (whichever is the shorter period), as an adjuvant treatment to women with HER2-positive early invasive breast cancer following surgery, chemotherapy, and radiotherapy when applicable.
Neoadjuvant
Early Breast Cancer: Treat patients with early invasive breast cancer, irrespective of age, with surgery and appropriate systemic therapy, rather than endocrine therapy alone, unless significant
ns Chemotherapy: Adjuvant chemotherapy should be started within 31 days of surgery Targeted: Assess cardiac function before starting treatment with trastuzumab. trastuzumab should not be started in women with significant cardiac dysfunction at baseline (low ejection fraction [EF], arrhythmias, valvular disease, unstable angina, uncontrolled hypertension.) cardiac function should be monitored every 3 months, and trastuzumab held if EF falls by 10% or below 50%. It should only be restarted after discussion of risks/benefits and after EF normalizes. Neoadjuvant: The potential increase in local recurrence after breast conserving
146
comorbidity precludes surgery.
Preoperative systemic therapy can be offered to patients with early invasive breast cancer who are considering breast conserving surgery that is not advisable at presentation. Locally advanced or inflammatory breast cancer
Offer local treatment by mastectomy (or, in exceptional cases, breast conserving surgery) followed by radiotherapy to patients with locally advanced or inflammatory breast cancer who have been treated with chemotherapy.
surgery versus mastectomy after down-staging from neoadjuvant therapy, should be discussed with patients.
SPANISH
SOCIETY OF MEDICAL
ONCOLOGY (SEOM)
2010
[SPAIN]
del Barco Berrón S, Ciruelos Gil E, Tusquets Trías de Bes I, et al. SEOM clinical guidelines for the treatment
of early breast cancer.
Clin Transl Oncol (2010) 12:711-718
1. Endocrine 2. Chemotherapy 3. Targeted 4. Neoadjuvant
Evidence -Based- Consensus
1. Endocrine
Tamoxifen remains the standard adjuvant endocrine treatment for premenopausal women
AIs should be considered for most postmenopausal women with ER-positive breast cancer, either as upfront or after tamoxifen x 2–5 years.
How to select a specific AI and how long to administer AI therapy are unanswered questions; data collection continues
A new molecular assay may help identify patients with node-negative, ER-positive tumours at low risk for recurrence, in whom tamoxifen alone would be adequate treatment.
2. Chemotherapy
Patients with tumours > 1cm or lymph node involvement are candidates for adjuvant chemotherapy; features to consider are grade, peritumoral vascular
General: Algorithm for systemic therapy: HR+ HER2+: chemotherapy + hormone therapy + trastuzumab HR+ HER2–: Hormone therapy or chemotherapy + hormone therapy HR– HER2+: Chemotherapy + trastuzumab HR– HER2–: chemotherapy
Endocrine: Results of ongoing research will likely refine the ability to prescribe endocrine therapy.
147
invasion, HER2, ER and PR, age
Chemotherapy combined with trastuzumab should be considered for HER2+ small tumours (<10 mm);
Table 2 suggests algorithm for chemo; consider regimens: FAC/FEC: fluorouracil, doxorubicin/epirubicin, cyclophosphamide
TAC: docetaxel, doxorubicin, cyclophosphamide,
FEC x four cycles followed by weekly paclitaxel x 8,
Doxorubicin or epirubicin followed by CMF,
AC followed by paclitaxel or docetaxel,
Doxorubicin, paclitaxel, cyclophosphamide each as a single agent x 4 given every two weeks with GCSF, or
Docetaxel plus cyclophosphamide
3. Targeted
Addition of one year of trastuzumab for HER-2 positive breast cancer to anthracycline and/or taxane containing regimens gives substantial benefit
Cardiac monitoring is important.
4. Neoadjuvant
Neoadjuvant systemic treatment is option for operable breast cancers > 2cm
Chemotherapy regimens with anthracyclines and taxanes improve pCR
Should be followed by definitive local surgery and radiation when indicated
Hormone receptor positive breast cancers should receive endocrine therapy; HER-2 positive
148
breast cancers should receive trastuzumab
Preoperative endocrine therapy can be considered for non-chemotherapy candidates and should maintain for 6 months; AIs superior to tamoxifen.
SCOTTISH
INTERCOLLE- GIATE
GUIDELINES GROUP (SIGN)
2005
[UNITED
KINGDOM]
Scottish Intercollegiate
Guidelines group. Management of breast cancer in
women A national clinical guideline. 2005. www.sign.ac.uk.
Accessed August 16, 2010.
1. Endocrine 2. Chemotherapy 3. Targeted 4. Neoadjuvant
Evidence -Based
1. Endocrine Premenopausal
Premenopausal women whose tumours are not shown to have absent estrogen or progesterone receptors should be considered for adjuvant endocrine therapy.
Ovarian suppression has been shown to be as effective as CMF chemotherapy alone and, when given in combination with tamoxifen, to be more effective.
Endocrine therapy alone has never been compared with anthracycline or taxane-based regimens that are now standard; no data to evaluate the benefit of tamoxifen or ovarian suppression to chemotherapy in premenopausal women, although there is no evidence that it is not of additional benefit.
No clear data on the benefit of additional ovarian suppression to women with hormone receptor positive tumours already receiving chemotherapy and tamoxifen.
Postmenopausal
Tamoxifen remains the treatment of choice as initial therapy in the adjuvant setting. If there are relative contraindications to its use (high risk of
Targeted: preliminary results of studies using adjuvant trastuzumab for one year are encouraging; updates on the use of trastuzumab to be available on the SIGN website.
149
thromboembolism or endometrial abnormalities) or intolerance, an AI can be used instead.
There is improved short/medium term survival compared to tamoxifen with: five years of anastrozole, five years of tamoxifen followed by a median of two and a half years of letrozole, or two to three years of tamoxifen followed by two to three years of exemestane or anastrazole. Extended letrozole for 5 years after tamoxifen for 5 years also improves DFS, and OS in lymph node positive cancers.
Postmenopausal patients should be considered for a switch to an aromatase inhibitor after either two to three years or after five years of tamoxifen therapy.
2. Chemotherapy
All women under the age of 70 years, with early breast cancer should be considered for adjuvant chemotherapy.
Women with ER -positive tumours who receive chemotherapy should be considered for additional endocrine therapy, especially if they are under 35 years.
Anthracyclines should be prescribed in preference to non-anthracycline regimens in the adjuvant setting, as they offer additional benefits. Epirubicin may be preferred as it causes less cardiac adverse effects.
Taxanes are active in the adjuvant setting; they have been shown to improve upon some
150
doxorubicin-based regimens, but there is no data yet that taxanes improve survival over optimal anthracycline regimens.
3. Targeted
Trastuzumab should be reserved for those patients whose tumours have HER2 over-expression.
No clear recommendation for or against trastuzumab in the adjuvant setting, as data is still immature, but encouraging.
4. Neoadjuvant
Neoadjuvant chemotherapy should be considered for women with large cancers as it improves the rate of breast conservation and is not detrimental to long term outcome
Endocrine therapy for a few weeks or months has no convincing detrimental or beneficial effects. It may improve surgical outcomes as well.
Letrozole for 4 months has higher response rates than tamoxifen.
INTERNATIONAL
SOCIETY OF GERIATRIC ONCOLOGY
(SIOG)
2007
[INTERNATIONAL: EUROPE AND
UNITED STATES]
Wildiers H, Kunkler I,
Biganzoli L, et al. Management of breast cancer in
elderly
1. Endocrine 2. Chemotherapy 3. Targeted
Evidence -Based Consensus
1. Endocrine
Older patients who are candidates for endocrine treatment should be offered initial treatment with aromatase inhibitors or tamoxifen.
For those initially treated with tamoxifen, consideration should be given to changing to an aromatase inhibitor after 2–3 years of tamoxifen.
2. Chemotherapy
In the absence of cardiac contraindications, four courses of anthracycline-containing regimen are
General: Recommendations specific to women > 65. Consider decision aides such as Adjuvant! Online®
b to
help weigh the risks and benefits of adjuvant treatment together with the patient. Endocrine:
151
individuals: recommendations
of the International
Society of Geriatric
Oncology. Lancet Oncol 2007; 8:
1101–1115.
usually preferred over CMF in elderly patients with breast cancer.
Older patients with node-positive, hormone-negative breast tumours potentially derive the largest survival benefit.
Taxanes could be added to anthracyclines in high-risk fit elderly women.
Docetaxel and cyclophosphamide or CMF can replace anthracyclines in patients at cardiac risk.
3. Targeted
In the absence of cardiac contraindications, adjuvant trastuzumab should be offered to older patients with HER2-positive breast cancer when chemotherapy is indicated (in conjunction with chemotherapy
Age is a risk factor for cardiac dysfunction with trastuzumab, but may be related to comorbid illness rather than age itself.
Cardiac monitoring is essential.
Elderly patients with hormone-sensitive breast tumours benefit from adjuvant hormone treatment. No evidence of age-related differences in the efficacy of tamoxifen and aromatase inhibitors. AIs are slightly more effective than tamoxifen, but elderly patients are more vulnerable to some adverse events, and safety should be an important factor in choosing therapy. Chemotherapy: Treatment with adjuvant chemotherapy should not be an age-based decision, but should consider patient benefit, life expectancy, treatment tolerance, and preference.
THE ST. GALLEN
CONSENSUS
2007 and 2009
[INTERNATIONAL]
1. Endocrine 2. Chemotherapy 3. Targeted
Consensus
1. Endocrine
Include endocrine therapy for almost all patients who have tumours showing endocrine sensitivity
Lower risk features that support endocrine therapy alone: high expression of
General: Patients with small primary tumours (pT1a pN0 and ER negative) might be spared adjuvant
152
1. Harbeck N and Jakesz R. St. Gallen 2007:
Breast Cancer Treatment Consensus
Report. Breast Care 2007;2:130–
134.
2. Goldhirsch A, Ingle JN, Gelber
RD, et al. Thresholds for
therapies: highlights of the
St Gallen International
Expert Consensus on the Primary
Therapy of Early Breast Cancer. Annals Oncol. 2009;20:
1319–1329.
ER and PR (e.g. >50%), grade 1 tumours, low proliferation, negative axillary lymph nodes, no peritumoral vascular invasion, and tumour size < or =2 cm
Tamoxifen + ovarian suppression with LHRH agonist or oophorectomy suggested for premenopausal women (ovarian suppression recommended especially if node positive or HER-2 positive); AI + LHRH agonist only recommended if tamoxifen is contraindicated
Postmenopausal women can still be treated with tamoxifen; AIs recommend upfront (especially for high risk patients), or in switch strategy after 2-3 years of tamoxifen. Extended adjuvant AI (after 5 years of tamoxifen) suggested for lymph node positive patients only.
Chemotherapy
Threshold for use of cytotoxic chemotherapy is the most difficult to define, particularly with ER-positive, HER-2 negative cancer.
Chemotherapy regimens most highly endorsed are anthracycline containing: CAF, CEF, FAC or FEC.
Anthracycline-taxane combinations less well endorsed by panel but options include: AC-T, TAC, FEC-T and TC. Dose dense EC-T or AC-P are also acceptable.
Chemotherapy is the mainstay of adjuvant treatment of patients with triple-negative disease (negative ER, PR, HER-2)
Higher risk features that
systemic therapy; those with ER positivity should be offered endocrine therapy alone (even if other features are suggestive of chemotherapy benefit) The availability and cost drives the usefulness of multigene assays in predicting response to adjuvant therapy. Endocrine: Endocrine sensitive disease is now defined as the presence of any detectable estrogen receptor (ER). The validity of PR in the absence of ER is matter of debate and warrants repeat pathologic review degree of ER positivity may still be important in selecting patients to also receive chemotherapy. Chemotherapy: Some rare histologies (for example medullary, apocrine, and
153
indirectly support chemotherapy: low hormone receptors, grade 3, high proliferation, 4+ lymph nodes involved, peritumoral vascular invasion, tumour size > 5cm.
Scores from mulitigene assays may identify patients with these high risk features who do not gain benefit from chemotherapy in addition to endocrine therapy.
Grade 2 tumours with intermediate scores on multigene assays, tumour size between 2 and 5 cm, and low numbers of involved lymph nodes (one to three) do not provide definitive indications to either give or withhold chemotherapy.
However, with the presence of all these intermediate risk features, chemotherapy is usually recommended.
A validated multigene assay should be taken into account as an adjunct to high-quality pathologic phenotyping if doubt remains regarding the benefit of chemotherapy.
3. Targeted
Anti-HER2 therapy is indicated in patients with HER2-positive disease as defined by the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelines
c.
Patients who meet criteria as used in clinical trials for HER-2 positivity (less restrictive than ASCO/CAP), may also be considered for trastuzumab
Patients receiving anti-HER2 therapy should also
adenoid cystic breast cancers) that are triple negative, but do not have other high risk features (such as positive lymph nodes) can be spared chemotherapy.
154
receive chemotherapy either preceding or concurrent with the anti-HER2 treatment; no specific regimen is endorsed. Cardiac function should be monitored; trastuzumab should be avoided in patients with baseline cardiac dysfunction.
The use of adjuvant anti- HER2 therapy without chemotherapy remains unsupported by evidence (although may be logical.)
WHO Regional Office for the
Eastern Mediterranean
2006
[EASTERN MEDITERRANEAN]
World Health Organization. Guidelines for
Management of Breast Cancer.
EMRO Technical Publications
Series. 2006;31.
1. Endocrine 2. Chemotherapy 3. Neoadjuvant
Evidence- Based- Consensus
1. Endocrine Premenopausal
Node negative, minimum risk: tamoxifen or none
Node negative, average risk: LHRH agonist (or OA), + tamoxifen (+/- chemotherapy) or chemotherapy followed by tamoxifen (+/- OA/LHRH agonist)
Node positive: chemotherapy followed by tamoxifen (+/- OA/LHRH agonist) or OA/LHRH agonist + tamoxifen (+/- chemotherapy)
Postmenopausal
Node negative minimal risk: tamoxifen or none
Node negative average risk: tamoxifen or chemotherapy followed by tamoxifen
Node positive: tamoxifen or chemotherapy followed by tamoxifen
2. Chemotherapy
Chemotherapy recommended for all hormone unresponsive tumours (node negative or positive)
Recommended chemotherapy regimens: 6 CMF or 4 AC or 6 FAC or 6 FEC or 4 AC to P for
General: Despite optimal local treatment, virtually all patients with invasive breast cancer have some risk of systemic relapse. This risk varies with numerous patient and disease related factors: Age, grade, lymph node status, ER/PR, HER-2 and tumour size all considered prognostic. Low risk: ER and PR positive and all the following must be present: pT ≤ 2 cm, grade 1 and age ≥ 35 years Average High Risk: ER or PR positive, plus at least one of the
155
>4 positive lymph nodes or hormone receptor negative
3. Neoadjuvant
Can consider neoadjuvant therapy in women who have a high risk of micrometastatic disease, or for those who need systemic therapy to improve outcome of local treatment.
Neoadjuvant therapy can have high response rate and improve surgical outcomes, but it is less clear if survival is improved; optimal goal is to downstage tumour and hopefully improve clinical outcomes.
following: pT, > 2 cm, grade 2–3, age < 35 years, High risk is nonresponsive to endocrine therapy: ER and PR negative.
156
Appendix ix – Summary of AGREE 2 Instrument Scoring Criteria Domain 1 – Scope and Purpose 1. The overall objective(s) of the guideline is (are) specifically described. 2. The health question(s) covered by the guideline is (are) specifically described. 3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.
Domain 2 – Stakeholder Involvement 4. The guideline development group includes individuals from all relevant professional groups. 5. The views and preferences of the target population (patients, public, etc.) have been sought. 6. The target users of the guideline are clearly defined.
Domain 3- Rigour of Development
7. Systematic methods were used to search for evidence. 8. The criteria for selecting the evidence are clearly described. 9. The strengths and limitations of the body of evidence are clearly described. 10. The methods for formulating the recommendations are clearly described. 11. The health benefits, side effects, and risks have been considered in formulating the recommendations. 12. There is an explicit link between the recommendations and the supporting evidence. 13. The guideline has been externally reviewed by experts prior to its publication. 14. A procedure for updating the guideline is provided. Domain 4 – Clarity of Presentation
15. The recommendations are specific and unambiguous. 16. The different options for management of the condition or health issue are clearly presented. 17. Key recommendations are easily identifiable.
Domain 5 – Applicability 18. The guideline describes facilitators and barriers to its application. 19. The guideline provides advice and/or tools on how the recommendations can be put into practice. 20. The potential resource implications of applying the recommendations have been considered. 21. The guideline presents monitoring and/or auditing criteria.
Domain 6 – Editorial Independence 22. The views of the funding body have not influenced the content of the guideline. 23. Competing interests of guideline development group members have been recorded and addressed.
Overall Score, and Recommended for use?
157
84.0%
86.0%
88.0%
90.0%
92.0%
94.0%
96.0%
98.0%
100.0%
102.0%
Online
IBCC
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%
Online
IBCC
Endocrine Therapy
Routine on Pathology
Appendix x: Survey practice and decision making patterns by Phase
158
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
Stage I Stage II Stage III Any Stage High Risk
Online
IBCC
Types of patientsgiven chemo
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
Online
IBCC
Types of Chemo
159
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
<25% 25%-49% 50-75% >75%
Online
IBCC
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Online
IBCC
Percentage of eligible patients receiving trastuzumab
Reasons Trastuzumab not given
160
0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%
Online
IBCC
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
Not Applicable Somewhat Applicable Very Applicable
Online
IBCC
Applicability of guidelines
Factors influencing decision making
161
0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%90.0%
100.0%
Online
IBCC
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
90.0%
100.0%
Online
IBCC
Sources of information
Breast CPGs used routinely
162
Appendix xi- AGREE 2 appraisal raw scores and domain calculations 1. AGO
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 4 5 15+17=32 32-6/36= 72% SG 6 6 5
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 5 1 5 11+11=22 22-6/36= 44% SG 4 2 5
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 3 1 5 5 6 6 1 6 33+33= 66
66-16/96= 53%
SG 4 2 5 4 7 3 2 6
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 6 6 6 18+ 20=38 38-6/36= 89% SG 7 7 6
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 2 1 1 1 5+9=14 14-8/48= 13% SG 4 2 2 1
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 3 6 9+10=19 19-4/24= 63% SG 4 6
Overall Rate Recommend
HB 5 y
SG 5 y
2. ASCO
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 6 6 18+20=38 38-6/36= 89% SG 7 7 6
163
Domain 2 Item 4 Item 5 Item 6 Total42/6 Score (/36)
HB 5 3 6 14+18=32 32-6/36= 72% SG 5 6 7
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 7 6 5 6 6 7 4 5 46+51= 97
97-16/96= 84%
SG 7 7 6 7 7 6 7 4
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score(/36)
HB 7 6 7 20+21=41 41-6/36= 97% SG 7 7 7
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 6 5 4 2 17+22=39 39-8/48= 65% SG 6 5 6 5
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 6 6 12+13=25 25-4/24= 88% SG 6 7
Overall Rate Recommend
HB 6 y
SG 7 y
3. BHGI
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 4 4 14+18=32 32-6/36= 72% SG 6 6 6
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 4 2 7 13+15=28 28-6/36= 61% SG 6 4 5
164
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 1 1 1 5 6 5 1 1 21+27= 48
48-16/96= 33%
SG 2 3 3 5 4 5 2 3
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 4 5 5 14+18=32 32-6/36= 72% SG 6 6 6
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 2 1 7 1 11+16=27 27-8/48= 40% SG 4 3 7 2
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 5 1 6+5=11 11-4/24= 29% SG 3 2
Overall Rate Recommend
HB 4 ywm
SG 4 ywm
4. CCO
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score
HB 5 7 6 18 + 16 = 34 34-6 / 42-6 = 28/36=78%
SG 5 6 5
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score
HB 4 2 7 13+ 11 = 24 24-6/ 42-6 = 18/36=50%
SG 3 2 6
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score
HB 6 7 7 6 6 6 7 3 48+44= 92
92-16/ 112-16= 76/96=79%
SG 6 6 5 6 6 6 4 5
165
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score
HB 7 7 7 21+ 18 =39 39-6/ 42-6= 33/36=92%
SG 6 6 6
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score
HB 2 2 2 5 11+20=21 21-8/ 56-8 = 13/48=27%
SG 2 2 2 4
Domain 6 Item 22 Item 23 Total 28/4 Score
HB 7 7 14+12 = 26 26-4/ 28-4 =22/24 =92%
SG 6 6
Overall Rate Recommend
HB 6 y
SG 5 Y
5. Cordoba
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 2 6 14+11=25 25-6/36= 53% SG 4 3 4
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 4 1 3 8+6=14 14-6/36= 22% SG 3 1 2
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 1 1 4 3 4 5 2 1 21+23= 44
44-16/96 SG 3 3 3 3 5 4 1 1
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 5 6 6 17+14=31 31-6/36= 69% SG 5 4 5
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 2 3 3 11+5=16 16-8/48=
166
SG 1 1 1 2 17%
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 4 1 5+4=9 9-4/24= 21% SG 3 1
Overall Rate Recommend
HB 4 N
SG 3 N
6. ESMO
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 7 2 4 13+14=27 27-6/36= 58% SG 5 4 5
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 5 1 7 13+10=23 23-6/36= 47% SG 3 1 6
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (96)
HB 3 1 3 5 4 2 6 4 28+25= 53
53-16/96= 39%
SG 4 1 3 3 3 4 2 5
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 6 6 6 18+14=32 32-6/36= 72% SG 4 5 5
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 5 2 1 6 14+13=27 27-8/48= 40% SG 3 4 3 3
Domain 6 Item 22 Item 23 Total 28/4 Score
HB 1 1 2+5=7 7-4/24= 13% SG 2 3
167
Overall Rate Recommend
HB 6 y
SG 5 y
7. NCCN
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 4 6 16+16=32 32-6/36= 72% SG 5 6 5
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score
HB 6 2 5 13+17=30 30-6/36= 67% SG 7 4 6
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score
HB 2 1 3 7 5 6 6 7 37+44= 81
81-16/96= 68%
SG 4 3 6 7 6 6 5 7
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 6 7 7 20+19=39 39-6/36= 92% SG 6 7 6
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 3 1 3 10+15=25 25-8/48= 35% SG 4 4 2 5
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 1 6 7+7=14 14-4/24= 42% SG 3 4
Overall Rate Recommend
HB 5 y
SG 6 y
168
8. New Zealand
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 7 7 7 21 + 21 = 42
42-6 / 42-6 36/36= 100%
SG 7 7 7
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 6 2 7 15 +16=31
31-6/ 42-6 =25/36 =69.4%
SG 6 3 7
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (96)
HB 7 7 6 7 7 7 6 2 49+ 45=94
94-16/ 112-16 78/96=81.2%
SG 6 5 6 6 6 7 7 2
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 7 7 7 21+ 19=40
40-6/42-6 =34/36 = 94.4%
SG 6 6 7
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 2 3 3 6 14+13= 27
27-8/56-8= 19/48= 40%
SG 2 5 2 4
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 7 6 13+10=23 23-4/28-4 19/24= 79%
SG 6 4
Overall Rate Recommend
HB 6 y
SG 6 Y
169
9. NICE
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 7 7 6 20+21=41 41-6/36= 97% SG 7 7 7
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score
HB 6 6 7 19+21=40 40-6/36= 94% SG 7 7 7
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 6 7 6 6 6 7 7 7 52+54= 106
106-16/96=
SG 7 7 6 7 6 7 7 7
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score
HB 7 6 7 20+21=41 41-6/36= 97% SG 7 7 7
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 6 6 7 4 23+23=46 46-8/48= 79% SG 6 5 7 5
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 6 7 13+13=26 26-4/24= 92% SG 6 7
Overall Rate Recommend
HB 7 y
SG 7 y
10. NST
Domain Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 5 7 18+16=34 34-6/36= 78% SG 6 5 5
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score
170
(/36)
HB 5 1 3 9+10=19 19-6/36= 36% SG 5 1 4
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 3 2 5 2 7 7 2 3 31+28= 59
59-16/96= 45%
SG 4 4 3 4 6 5 1 1
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 6 7 5 18+17=35 35-6/36= 81% SG 6 6 5
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 2 1 6 12+8=20 20-8/48= 25% SG 1 2 1 4
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 7 7 14+12=26 26-4/24= 92% SG 5 7
Overall Rate Recommend
HB 6 y
SG 5 y-wm
11. SEOM
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 1 6 13+11=24 24-6/36= 50% SG 5 2 4
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 2 2 7 11+8=19 19-6/36= 36% SG 2 1 5
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 1 1 2 1 4 2 2 1 14+21= 35
35-16/96= 20%
SG 3 2 2 2 5 5 1 1
171
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 3 5 2 10+23=23 23-6/36= 47% SG 5 5 3
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 6 1 2 12+ 8=20 20-8/48= 25% SG 1 3 2 2
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 6 5 11+9=20 20-4/24= 67% SG 5 4
Overall Rate Recommend
HB 4 N
SG 3 N
12. SIGN
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 5 7 5 17+20=37 37-6/36= 86% SG 7 7 6
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 5 7 5 17+20 37-5/36= 86% SG 7 7 6
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (96)
HB 6 3 4 5 6 6 6 5 41+49=90 90-16/96= 77%
SG 7 6 6 6 6 6 7 5
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score(/36)
HB 6 6 7 19+19=38 38-6/36= 89% SG 6 6 7
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 5 6 5 6 22+23=45 45-8/48= 77% SG 5 6 6 6
Domain 6 Item 22 Item 23 Total 28/4 Score(/24)
HB 6 3 9+7=16 16-4/24=
172
SG 5 2 50
Overall Rate Recommend
HB 5 y
SG 6 y
13. SIOG
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 5 2 5 12+18=30 30-6/36= 67% SG 6 6 6
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 2 1 4 7+9=16 16-6/36= 28% SG 5 1 3
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 4 4 3 2 5 6 1 1 26+34= 60
60-16/96= 46%
SG 6 5 5 3 5 5 4 1
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score(/36)
HB 5 6 5 16+17=33 33-6/36= 75% SG 6 6 5
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 3 1 1 8+13=21 21-8/48= 27% SG 4 4 2 3
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 5 6 11+7=18 18-4/24= 58% SG 3 4
Overall Rate Recommend
HB 3 ym
SG 5 ym
173
14. St Gallen
Domain 1 Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 6 5 5 16+18=34 34-6/36= 78% SG 6 6 6
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 4 1 5 10+10=20 20-6/36= 39% SG 4 2 4
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (/96)
HB 3 1 1 3 5 4 1 2 20+25=45 45-16/96= 30%
SG 3 3 2 3 5 4 2 3
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (/36)
HB 3 5 4 12+16=28 28-6/36= 61% SG 5 5 6
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 2 2 1 8+17=25 25-8/48= 35% SG 5 4 4 4
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 4 1 5+4=9 9-4/24= 21% SG 2 2
Overall Rate Recommend
HB 3 n
SG 4 n
174
15. WHO East Med.
WHO med Item 1 Item 2 Item 3 Total 42/6 Score (/36)
HB 7 5 7 19+17=36 36-6/36= 83% SG 6 5 6
Domain 2 Item 4 Item 5 Item 6 Total 42/6 Score (/36)
HB 4 2 7 13+16=29 29-6/36= 64% SG 6 3 7
Domain 3 Item 7
Item 8
Item 9
Item 10
Item 11
Item 12
Item 13
Item 14
Total 112/16
Score (96)
HB 2 1 2 3 3 2 6 1 20+28= 48
48-16/96= 33%
SG 3 3 3 4 5 4 4 2
Domain 4 Item 15 Item 16 Item 17 Total 42/6 Score (36)
HB 5 6 6 17+15=32 32-6/36= 72% SG 5 5 5
Domain 5 Item 18 Item 19 Item 20 Item 21 Total 56/8 Score (/48)
HB 3 2 3 3 11+15=26 26-8/48 =38% SG 4 2 5 4
Domain 6 Item 22 Item 23 Total 28/4 Score (/24)
HB 4 1 5+5=10 10-4/24= 25% SG 4 1
Overall Rate Recommend
HB 5 Y wm
SG 5 Y-wm
175
Appendix xii. Other guidelines and sources of knowledge (survey free-text answers)
Guideline Number of Respondents
Angel Roffo Institute of Oncology. Buenos Aires University Guidelines 1
Adjuvant Online 14
AGO Guidelines 5
AIOM (Italian) 19
ASCO 4
ASTRO 1
BCCA 1
Brazilain Society of Oncology (Portuguese) 1
CCO 1
chemoregimen.com 1
Chinese national guidelines (chinese) 1
Concenso nacional mexican 1
Consenso Nacional Sobre Tratamiento Del Cancer Mamario en Mexico 1
EBCC 3
ECCO 1
English 2
EORTC 1
ESMO 1
Finnish Breast cancer group 3
French Guidelines 3
German National Guideline 1
Guias de cancer de mama de la sociedad mexicana de oncologia 1
Guias de terapeutica oncologica nacional 1
GUIDA 1
Hong Kong Hospital Authority Clinical Practice guidelines 1
Japan Breast Cancer Society 3
LINEE 1
MEDSCAPE 1
National guidelinsd Haute Autorité de la santé (HAS); France; last update breast cancer = 2010
1
NBCG 1
NCCN china 2
NCCN english 6
NCCN-chinese 1
NCI 3
NICE 1
Oncoguides from Catalan Government in Catalan 1
PTOK (Polish Guidelines) 2
Pubmed 1
176
Russian Guidelines 2
Scottish 1
SEOM (Spanish) 1
SMC 1
Society for Surgical Oncologists 1
South Africa Oncology Forum 1
Spanish Medical Oncology Society Guidelines in Spanish 1
St Paul de Vance Report (French) 10
St. Antonio Breast Cancer Conference 12
St. Gallen 4
St. Luke's cancer protocol, (English) 1
TATA memorial hospital guidelines. 1
Third Party Payer's Guidelines (Spanish) 1
Thai Government Guideline 1
UpToDate® 9
WCRI 1
YCO (English) 1
Other sources of knowledge
“E-library
Hospital Guidelines
International Meetings
Latest articles on BC
Meetings, Internet, Journals
More research and uniform criteria for diagnosis, prognosis and prediction
National Guidelines
Only English and Russian
Own national cancer guideline
Phase 3 trials in high impact journals Presentations at International meetings, discussions with experts at meetings/advisory boards etc
Text books eg Perez, De-Vita, Cox, etc
Textbooks, trials, handbooks, articles Clinical trials CME talks”
177
Appendix xiii. Languages preference for guidelines (free-text answers)
