1. The Clinical Trials of HDC/ABMT in Women with Breast Cancer Prof Cindy Farquhar MD MPH University of Auckland, NZ

2. History The first RCTs commenced at the end of 1990 Progress was slow Two US trials took years to randomize 969 women 1990-1998 ASCO 1999: reports 4/5 RCTs no benefit

3. The first published RCT  Bezwoda 1995 - South African trial  3 year survival was 18% vs 4 % in control group  Small study (n=90)  Event rate in the HDC/ABMT group similar to US conventional treatment

4. American Society of Clinical Oncologists 1999 Results of 5 RCTs presented Overall summary:  4/5 concluded “that treatment with HDC/ABMT is no better than conventional chemotherapy”  Jan 2000 - the only trial (South African) to show a benefit was declared fraudulent by the US auditors (Bezwoda 1999)

5. Systematic review of HDC/ABMT in women with breast cancer Aim: To determine the effectiveness and safety of HDC/ABMT in women with metastatic and high risk breast cancer 2 reviews : women with metastatic breast cancer women with high risk breast cancer Methodology: systematic review

6. Systematic review All trials meet the inclusion criteria Assess the quality of the trials Trial results extracted for overall survival, event free survival and treatment related mortality Data was pooled using metanalysis

7. Excluded studies Bezwoda 1995, 1999 – declared fraudulent in 2000 Bergh 2000 – overall dose in conventional group higher than HDC/ABMT group Peters 1996 - – control group crossed over to HDC/ABMT Madan 2000 – control group crossed over to HDC/ABMT

8. Metastatic Breast Cancer: included studies Study nameCountryStudy accrual completed Number of participants Eastern Coop Onc Group US1997199 NCI of CanadaCanada2000219 PEGASE 03France2000180 PEGASE 04France199661 SchmidGermany200192 IBDISInternational2001101

9. HDC/ABMT in women with metastatic BC: treatment related mortality Increased by standard chemotherapy Increased by HDC/ABMT

10. HDC in women with metastatic BC: event free survival 1 year follow up 5 year follow up Increased by standard chemotherapy Increased by HDC/ABMT 3 year follow up

11. HDC in women with metastatic BC: overall survival 3 year follow up 5 year follow up Increased by standard chemotherapy Increased by HDC/ABMT

12. High Risk Breast Cancer: included studies Study NameCountryAccural DateNo. of women ACCOG 1UK6/99605 CALGBUS5/98783 Dutch PilotNetherlands12/9581 Dutch I GroupNetherlands7/99885 GABGGermany11/97302 ECOGUS199893 JCOGJapan199997 ICCGInternational2000281 IBCSGInternational2002344 MDACCUS12/9878 MCGItaly1998398 PEGASE 01France12/98314 WSGGermany2002403

13. HDC in women with high risk BC: treatment related mortality Increased by standard chemotherapy Increased by HDC/ABMT

14. HDC in women with high risk BC: event free survival 3 year follow up 5 year follow up Increased by standard chemotherapy Increased by HDC/ABMT

15. HDC in women with high risk BC: overall survival 3 year follow up 5 year follow up Increased by standard chemotherapy Increased by HDC/ABMT Overall 67% of women survived in HDC group and 71% in the control group

16. Quality of Life Measures ACCOG : 84 women on HDC/ABMT and 82 standard dose. no difference b/w groups at 6 or 12 months CALBG: 106 HDC/ABMT and 104 standard dose. HDC worse at 3 months, but no difference at 12 months Dutch IG trial: HDC/ABMT lower scores at 3 months but no difference at 6 months. Also looked at cognitive functioning in Dutch IG: significantly impaired in HDC/ABMT

17. Conclusions: women with metastatic breast cancer Treatment related mortality was significantly increased At one year of follow up there is a increase in event free survival in women with HCD/ABMT At three and five years of follow up there is no impact on either event free survival or overall survival

18. Conclusions: women with high risk breast cancer Treatment related mortality was significantly increased At three years of follow up there is a reduction in event free survival but no impact on overall survival At five years of follow up there is no impact seen on either event free survival or overall survival

19. Acknowledgements The Commonwealth Fund of New York Robert Wood Johnson Foundation RAND University of Auckland, NZ The Cochrane Breast Cancer Group