Importance of Clinical Trials in Breast Cancer in Developing Countries Zeba Aziz Professor of Oncology Allama Iqbal Medical College Lahore The Global burden of cancer at the Dawn of the 21st Century Year Incidence Mortality (million/year) Author Million/year 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 IV. • 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 (45–72%)3** 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 GLOBAL STATISTICS: Breast cancer mortality in different countries 0.38 0.39 0.35 0.25 0.39 0.27 0.32 0.37 0.45 0.37 0.42 0.45 0.48 0.33 0.27 0.32 SLIDE CREDIT:Gilberto Schwartsmann GLOBAL STATISTICS: 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 Schwartsmann 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. 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. 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 infrastructure. 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 Research(1990-2003) • Less than 10% of research and development funds are dedicated to addressing problems responsible for 90% of world’s 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 353;8,2005 Articles published from Developing Countries on Breast Cancer (n=141) 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. 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 (6.3%) 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 setback. 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 & 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 Survival of 2294 breast cancer cases by tumour size 1 1-9mm 0.9 (30/354) 10-14mm 0.8 (67/498) 15-19mm 0.7 (98/461) Cumulative Survival 20-29mm (182/534) 0.6 30-49mm (152/295) 0.5 50+mm (116/152) 0.4 0.3 0.2 0.1 0 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 countries. 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 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. 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 cancer. 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) 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 & INCTR • Epidemiology. • Locally Advanced Breast Cancer. • Resource Sparing Radiotherapy in Early Breast Cancer. 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. Projected Change in BREAST CANCER Incidence 2002-2010(World) +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.