Importance of Clinical Trials in Breast Cancer in Developing Countries

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					Importance of Clinical Trials in
 Breast Cancer in Developing

              Zeba Aziz
        Professor of Oncology
     Allama Iqbal Medical College
       The Global burden of cancer at the
           Dawn of the 21st Century
Year    Incidence      Mortality (million/year)                Author
                       Total     Industrialized   Developing
                                 Countries        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
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
• Mortality to incidence ratios range from
  45% to 88%.             (Courtesy Dr Hortobagyi)
    Global Differences in Breast Cancer
    Diagnosis and Outcomes: Survival
        • Estimated mortality-to-incidence ratios are
            generally lower in developed regions1

                                                                                ASR 5-year survival
                                                USA (83–88%)2*
                       Europe (60–83%)2*

Developing countries

                Women diagnosed: *1990–1994;            **1982–1992

 1Shibuya, et al. BMC Cancer 2002;2:37; 2Coleman, et al. Ann Oncol 2003;14
 (Suppl 5):V128–V149; 3Sankaranarayanan, et al. IARC Sci Publ 1998;145:135–73
Breast cancer mortality in different countries


    0.25                     0.39                                0.27
      0.32            0.37
                    0.37                     0.42
                                  0.45              0.48

                                             SLIDE CREDIT:Gilberto
Mortality vs. Degree of economic development

 More developed countries         Less developed countries
 0.33 (189 deaths / 579 cases )   0.39 (184 deaths / 471 cases)

                                     SLIDE CREDIT:Gilberto
   Cancer Detection: Early or Too
The situation in developing countries varies
 dramatically. Numerous reasons for late
   1.Low level of public education.
   2.Uninformed physicians.
   3. Inadequate health facilities particularly
      rural areas in developing countries.
   4.Use of traditional medicines.
Treatment of Cancer in Developing
• 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.
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.
 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.
     Current Scenario of Research in
          Developing Countries
•    Industry sponsored research accounts for
     >95% .Open labeled Phase IV studies for
     marketing of new drugs.
1.   No attention paid to the relevance of the
     study with reference to the requirements.
2.   Minimal attention paid to develop
3.   No training of local CRO’s, doctors , nurses etc
     on research methodologies.
4.   Lucrative and easy to conduct.
5.   Patronizing attitude.
  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.
   Number of Biomedical Research Articles Published by
      Investigators in High-Income Countries and in
                  Developing Countries.

                                         High-Income Countries              Developing Countries
Variable                                        (N=54)                            (N=154)

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 353;8,2005
 Developing Countries & Bioethical
• Less than 10% of research and development
  funds are dedicated to addressing problems
  responsible for 90% of world’s burden of
• The number of publications have not increased.
• No publications from 79.9% of developing
        REMEDY: Inclusion of internationally
    representative members on editorial boards,
     partnerships between researchers from high
     income and DC and twinning arrangements.
                                    Borry et al, NEJM 353;8,2005
    Articles published from Developing
    Countries on Breast Cancer (n=141)

•      1979-1989----11
•      1990-2000----70
•      2001-2004----59
    A major problem is finding publications in
     small non-indexed journals of developing
Audit of Research on Breast Cancer in
  Developing Countries (1979-04).
• Total no. of articles:141
• Origin of study: Developing countries:74(52.4%)
                    Developed countries:50(35.4%)
                    IARC & WHO:17(12.2%)
• On Breast Cancer only: 82(58.1%)
• General with breast cancer included:59(42%)
• Asia contributed 68 (48%), Middle East
  11(7.8%),Africa12(8.5%) & South America 9
Audit of Research on Breast Cancer in
Developing Countries (n=141,1979-04).
• Epidemiology:52(36.8%)
• Review:15(10.6%)
• Observational:21(14.8%)
• Education:14(9.9%)
• Screening:7(4.9%)
• Case Control:12(8.5%)
• Treatment: Surgery:3 (2.12%),
              Chemotherapy:5 (3.5%)
• Outcome data:17(12.3%)
       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.
      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 .
    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
         Types of Clinical Trials

•   Observational—Epidemiology, survival.
•   Screening & Early Diagnosis.
•   Interventional Phase I,II, III.
•   Palliative.

• Economic feasibility & Audit of our trials
  are very important .
     Breast Cancer: Age, Tumor Size &

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
                                        Survival of 2294 breast cancer cases by tumour size

                      0.9                                                                                      (30/354)
                      0.8                                                                                      (67/498)
                      0.7                                                                                      (98/461)
Cumulative Survival

                      0.5                                                                                      50+mm




                            1   2   3   4   5   6    7   8   9   10   11 12 13   14 15 16   17 18 19   20 21
                                                    Time since diagnosis (in years)
Early Detection Strategies with and without Screening
       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
 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.
  Breast Cancer & Early Detection
• 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.
 Clinician Response to Breast Cancer in
   Pakistan: A Cross Sectional Survey
           NCI 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.
      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
   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
• 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)
       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
  Breast Cancer , Clinical Trials &

• Epidemiology.
• Locally Advanced Breast Cancer.
• Resource Sparing Radiotherapy in Early
  Breast Cancer.
• Research directed towards and applicable
  to our patients is extremely important to
  develop EBM in developing countries.
• It should be economically viable in our
• Audit of our research is essential.
• Infrastructure needs to be developed.
Projected Change in BREAST CANCER Incidence

                                  +20%   26%

                         1.15               1.38      1.45
                        Million            Million   Million
                              demographic            trend

                                              based on estd.
                                            Change 1990 - 2002

                          Courtesy Dr. Max Parkins
Last but not least research for
us in developing countries, is
 not a luxury but a necessity.

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