Importance of Clinical Trials in Breast Cancer in Developing Countries

1
Importance of Clinical Trials in Breast Cancer in
Developing Countries

• Zeba Aziz
• Professor of Oncology
• Allama Iqbal Medical College
• Lahore

2
The Global burden of cancer at the Dawn of the
21st Century
Year Incidence Million/year Mortality (million/year) Mortality (million/year) Author
Total Industrialized Countries Developing Countries

1975 5.9 - - - Boycle 1997
1980 6.4 4.3 2.1 2.1 Tomatis 1990
1985 7.6 5.1 2.2 2.9 Pisani 1993
1990 8.4 6.0 2.4 2.9 Murray 1997
1996 10.0 6.4 2.6 3.8 WHO 1997
2020 15-18 10.0 2.5 7.5 WHO 1997
3
Global Breast Cancer Burden

• Incidence 1.1 million new cases diagnosed in
  2002, about 50 in the developing world.
• Three out of 4 breast cancer deaths occur in the
  developing world.
• In some parts, over 75 of new breast cancers are
  diagnosed in stages III and IV.
• Mortality to incidence ratios range from 45 to
  88. (Courtesy Dr Hortobagyi)

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Global Differences in Breast Cancer Diagnosis and
Outcomes Survival

• Estimated mortality-to-incidence ratios are
  generally lower in developed regions1

USA (8388)2
Europe (6083)2
ASR 5-year survival
Developing countries (4572)3
Women diagnosed 19901994 19821992
1Shibuya, et al. BMC Cancer 2002237 2Coleman,
et al. Ann Oncol 200314(Suppl 5)V128V149
3Sankaranarayanan, et al. IARC Sci Publ
199814513573
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GLOBAL STATISTICSBreast cancer mortality in
different countries
SLIDE CREDITGilberto Schwartsmann
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GLOBAL STATISTICSMortality vs. Degree of
economic development
SLIDE CREDITGilberto Schwartsmann
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Cancer Detection Early or Too Late?

• The situation in developing countries varies
  dramatically. Numerous reasons for late
  presentation
• 1.Low level of public education.
• 2.Uninformed physicians.
• 3. Inadequate health facilities
  particularly rural areas in developing
  countries.
• 4.Use of traditional medicines.

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Treatment of Cancer in Developing Countries

• Available data show that the level of cancer
  treatment is not only lower but markedly lower
  than that in the industrialized world.
• Lack of surgical oncology.
• Lack of uniformity of radiation facilities.
• Patient SES.
• Alternative medicines.
• Improvement of treatment facilities by health
  transfer technology.
• Establishment of priorities.
• Guidelines or recommendations.
• Local protocols.
• Local and regional collaborations.

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Decline in Breast Cancer Mortality in Developed
Countries

• Breast cancer mortality has declined in
  developed countries due to
• -Earlier detection of palpable and non
  palpable cancers.
• -Early extirpation of palpable tumors
• -Reduction of burden of micro-metastasis
  .
• -Leads to earlier use of adjuvant
  therapy.
• -Improvements in cancer treatment.

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Epidemiology of Research in Low and Middle Income
Countries (LAMI)

• Over 85 of the worlds population lives in the
  153 countries (World Bank Criteria).
• Research is needed to meet the enormous and unmet
  health needs of LAMI countries.
• Scientific journals play an important role in
  production and dissemination of research.
• The gap between these and high income countries
  is widening in terms of publications.
• At present only a fraction of research published
  in widely accessible oncology journals is from or
  about these countries.

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Current Scenario of Research in Developing
Countries

• Industry sponsored research accounts for gt95
  .Open labeled Phase IV studies for marketing of
  new drugs.
• No attention paid to the relevance of the
  study with reference to the requirements.
• Minimal attention paid to develop infrastructure.
• No training of local CROs, doctors , nurses etc
  on research methodologies.
• Lucrative and easy to conduct.
• Patronizing attitude.

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Current Scenario of Research in Developing
Countries (contd.)

• Academic research activities are mainly limited
  to observational studies
• On epidemiology.
• Few studies have survival or outcome analysis.
• Less than 1 are interventional trials.
• Characterized by poor quality due to lack of
  training in research methodology, guidance, lack
  of funds, ignorance of recent publications.

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Number of Biomedical Research Articles
Published by Investigators in High-Income
Countries and in Developing Countries.
High-Income Countries Developing Countries Variable (N54) (N154) Research articles published no./total 3873/4029 (96.1) 156/4029 (3.9) no. () Countries represented in publications- 28/54 (51.9) 31/154 (20.1) no./total no. () Top 5 countries contributing articles- United States- 2390/3873 (61.7) China -24/156 (15.4) no./total no. () United Kingdom -544/3873 (14.0) Turkey 18/156 (11.5) Canda-160/3873 (4.1) South Africa 17/156 (10.9) Australia -154/3873 (4.0) Hungary 11/156 (7.0) The Netherlands 109/3873 (2.8) Philippines 10/156 (6.4) Borry et al, NEJM 3538,2005
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Developing Countries Bioethical
Research(1990-2003)

• Less than 10 of research and development funds
  are dedicated to addressing problems responsible
  for 90 of worlds burden of disease.
• The number of publications have not increased.
• No publications from 79.9 of developing
  countries.
• REMEDY Inclusion of internationally
  representative members on editorial boards,
  partnerships between researchers from high income
  and DC and twinning arrangements.
• 
  Borry et al, NEJM 3538,2005

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Articles published from Developing Countries on
Breast Cancer (n141) 1979-04.

• 1979-1989----11
• 1990-2000----70
• 2001-2004----59
• A major problem is finding publications in small
  non-indexed journals of developing countries.

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Audit of Research on Breast Cancer in Developing
Countries (1979-04).

• Total no. of articles141
• Origin of study Developing countries74(52.4)
• Developed
  countries50(35.4)
• IARC WHO17(12.2)
• On Breast Cancer only 82(58.1)
• General with breast cancer included59(42)
• Asia contributed 68 (48), Middle East
  11(7.8),Africa12(8.5) South America 9 (6.3)
  

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Audit of Research on Breast Cancer in Developing
Countries (n141,1979-04).

• Epidemiology52(36.8)
• Review15(10.6)
• Observational21(14.8)
• Education14(9.9)
• Screening7(4.9)
• Case Control12(8.5)
• Treatment Surgery3 (2.12),
  Chemotherapy5 (3.5)
• Outcome data17(12.3)

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Problems of Researchers in Developing Countries

• Lack of initiative.
• Poor institutional structure.
• Lack of funding.
• No training in proposal/grant writing.
• Lack of mentors and support.
• Hopeless career structure.
• Very little research culture.
• English as a second language.

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Problems of Researchers in Developing Countries

• Publication barriers include
• 1. Lack of guidance in preparing manuscripts.
• 2. Fear of criticism.
• 3. Use of English as second language.
• 3. Ignorance of how journals operate and
  where to publish.
• 4. Perceived bias against research from
  developing countries as reviewers do not
  understand the difficulties of carrying out
  research and also question the validity of data .
  

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Requirements for a Researcher in Developing
Country

• Imagination/Vision.
• Perseverance.
• Integrity/honesty.
• Belief in oneself.
• Ability to face rejections.
• Devotion.
• Constant self improvement.
• Update of knowledge/new evidence.
• Critical self appraisal of achievements and
  setback.

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Types of Clinical Trials

• ObservationalEpidemiology, survival.
• Screening Early Diagnosis.
• Interventional Phase I,II, III.
• Palliative.
• Economic feasibility Audit of our trials are
  very important .

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Breast Cancer Age, Tumor Size Stage

• Number Age Tumor size (cm) Early
  disease() Late disease() Author
• 774 49 5.4
  40 60
  Hisham(2004)
• 423 45
  28 46
  Rana(1998)
• 3320 45
  23.7 60.2
  Shanta(12000)
• 286 45 4.2
  56.1 43.9
  Aziz(2001)
• 152 48 4.6
  49.3 50.7
  Al-Moundhri(2004)

Large tumors, advanced disease younger age at
presentation are common to all developing
countries
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Early Detection Strategies with and without
Screening
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Problems of Screening in Developing Countries

• Screening requires sophisticated technology, high
  level of expertise which should be available for
  at least 80 of target population.
• Screening by mammography reduces mortality by
  25.
• Etiology of breast cancer is limited.
• Some factors e.g. parity, age at first full term
  pregnancy are not modifiable for purposes of
  cancer prevention.
• At present these conditions cannot be met in our
  countries.

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Breast Cancer in the Third World-Risk Factors
Prevention

• Poverty Very important overall cancer risk
  factor due to a complex play of environmental and
  host factors. Unfortunately we are far from
  controlling poverty.
• Public education Early detection and prevention
  only possible by changing life styles of educated
  people.
• Life Styles Dietary changes and alteration in
  patterns of reproduction are contributing to
  increasing risk .
• Others Intermarriages, unknown factors.

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Breast Cancer Early Detection Programs

• Early Detection Identification of breast cancer
  at a point at a point in its natural history
  where it can be treated with techniques which
  have the least physical impact and maximum chance
  of producing cure.
• Best method to reduce breast cancer mortality is
  early detection combined with proper treatment.
• Early detection has limited value if proper
  treatment for breast cancer is not available.
• In DC countries with low incidence of breast
  cancer, limited resources maybe better invested
  in early detection strategies than in screening
  as the latter requires considerable resources.
  

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Clinician Response to Breast Cancer in Pakistan
A Cross Sectional SurveyNCI US, MD Anderson
AIMC

• Objectives This study concentrated primarily on
  learning about the epidemiology of breast cancer,
  educating physicians as a part of an effort to
  increase patient survival rates, and
  understanding the process by which physicians
  refer patients for epidemiologic investigations.
• Methods A preliminary survey was administered
  to 183 participants in which segments are divided
  into knowledge, attitude and practice sections
  with sub-divided topics including diagnosis,
  treatment, and symptoms.

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Clinician Response to Breast Cancer in Pakistan
A Cross Sectional Survey

• Results Over 90 of participants view clinical
  and self breast examination as important cancer
  risk prevention practice. Yet, only 25 of the
  cluster reported performing regular CBE with a
  gender ratio of 1.3 to 1 male to female
  respondents..
• Almost 40 of physicians lacked knowledge
  about inflammatory and locally advanced breast
  cancer and reported a lack of information about
  LABC despite the high prevalence in the country.
• Conclusions. This study highlights the need for
  increased awareness about breast cancer by
  primary care practitioner in Pakistan, and the
  need for early detection through regular
  screening. Primary care physicians need to be
  more aware of the epidemiology, diagnosis, and
  management of breast cancer.

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General Issues for Consideration in Designing
International Trials

• Is the disease similar in different countries?
• Is the trial relevant to the country are the
  risk factors the
• same?
• Is the treatment relevant and are the outcomes
  approximately the same?
• Do the culture and infrastructure exist to carry
  out this trial?
• Are investigators in LAMI willing/trained to
  conduct trials according to international
  standards.
• Determining the difference between wants and
  needs is crucial to providing effective health
  care solutions in a developing country.

Dr. Salim Yusuf ,(McMaster University, Canada)
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Advantages for Research Researcher in
Developing Countries

• For a defined population.
• In area of interest.
• Need.
• Development of infrastructure.
• Collaboration, training and mentoring.
• Discipline.
• Highlight of deficiencies.
• Most important mental development and ability to
  think

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Breast Cancer , Clinical Trials INCTR

• Epidemiology.
• Locally Advanced Breast Cancer.
• Resource Sparing Radiotherapy in Early Breast
  Cancer.

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Conclusions

• Research directed towards and applicable to our
  patients is extremely important to develop EBM in
  developing countries.
• It should be economically viable in our
  countries.
• Audit of our research is essential.
• Infrastructure needs to be developed.

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Projected Change in BREAST
CANCER Incidence
2002-2010(World)
20 26
1.15 Million
1.45 Million
1.38 Million
demographic trend
based on estd. Change 1990 - 2002
Courtesy Dr. Max Parkins
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Last but not least research for us in developing
countries, is not a luxury but a necessity.