Nabeel Pervaiz Nigel Colterjohn Forough Farrokhyar Richard Tozer Alvaro Figueredo Michelle Ghert

1. A systematic meta-analysis of randomized controlled trials for adjuvant chemotherapy for localized resectable soft-tissue sarcoma Nabeel Pervaiz Nigel Colterjohn Forough Farrokhyar Richard Tozer Alvaro Figueredo Michelle Ghert

2. Background • Systemic treatment for localized STS controversial • Doxorubicin-based chemotherapy • Very little Level I evidence to direct clinical practice • Prospective randomized studies have had discrepant results • Studies are limited by sample size

3. Background • Sarcoma Meta-analysis Collaboration (SMAC)---originated at Hamilton Regional Cancer Centre • Landmark publication, Lancet 1997 • 14 RCTs • Results: • Hazard ratio 0.75 (95% CI .64-0.87) for overall recurrence • Hazard radio 0.89 (95% CI 0.76-1.03)* for survival (absolute benefit of 4%) • *not statistically significant

4. Ten years later… • Further published RCTs • Intensification of doxorubicin dosage and addition of ifosfamide to regimens

5. Objective • To update the 1997 meta-analysis with data from subsequent published randomized controlled trials • Increase statistical power and narrow confidence intervals

6. Methods: Study Identification • Databases: Medline, EMBASE, Cochrane • Search criteria: sarcoma, chemotherapy, randomized controlled trial • Over 700 results • Inclusion criteria: soft-tissue, localized, resectable, control arm: no chemotherapy, adult • Exclusion criteria: bone sarcoma, advanced disease, no control arm, pediatric (rhabdomyoscaromca), non-randomized

7. Study Evaluation • Studies evaluated by 2 independent reviewers • Modified Detsky Quality Scale for Randomized trials • Interobserver reliability

8. Outcome measures • Local recurrence • Distant recurrence • Overall recurrence • Overall survival

9. Statistical Methods • Funnel plot for publication bias • Test for heterogeneity between studies • Pooled odds ratio • 95% confidence intervals • Fixed effect method (statistical control for non-analzyed variables)

10. Results • 4 studies met inclusion and exclusion criteria, 385 patients • All 4 studies scored over 75% on Detsky Scale (reliability 94%) • Total 18 studies and 1953 patients • One study: neo-adjuvant vs control (analysis performed with and without data) • Mean follow-up 4.9 years (3.4-7.8 years)

11. Chemotherapy regimens • SMAC: • 13 Doxorubicin based, 1 Doxorubicin and Ifosfamide • Additional trials: • All 4 trials Doxorubicin and Ifosfamide • Dosage intensities varied

12. Funnel Plot

13. Local Recurrence • 17 trials • 1700 patients • 296 events • Overall hazard ratio of 0.73 (95% CI: 0.56- 0.94) in favor of chemotherapy • Absolute risk reduction of 4% (15% vs. 19%) • Number needed to treat: 25

14. Odds ratio for local recurrence Test for heterogeneity Q=15.81, df=16, p=0.4664

15. Distant Recurrence • 17 trials • 1700 patients • 553 events • overall hazard ratio of 0.65 (95% CI: 0.53-0.80) in favor of chemotherapy • Absolute risk reduction 9% (28% vs 37%) • Number need to treat: 12

16. Odds ratio for distant recurrence Test for heterogeneity Q=7.8451, df=16, p=0.9533

17. Overall Recurrence • 18 trials • 1747 patients • 884 events • Overall hazard ratio of 0.67 (95% CI: 0.56-0.82) in favor of chemotherapy • Absolute risk reduction 10% (46% vs 56%) • Number needed to treat: 10

18. Odds ratio for overall recurrence Test for heterogeneity Q=10.2308, df=17, p=0.8937

19. Overall Survival • 18 trials • 1953 patients • 829 deaths • overall hazard ratio of 0.77 (95% CI: 0.64-0.93*) in favor of chemotherapy • Absolute risk reduction of 6% (40% vs 46%) • Number needed to treat: 17 • *note: upper limit of confidence interval in SMAC 1.03

20. Odds ratio for overall survival Test for heterogeneity Q=15.9325, df=17, p=0.5286

21. Discussion • Additional 385 patients narrowed confidence intervals • Overall survival became statistically significant • Definite but minimal benefit of chemotherapy in reducing LR, DR, OR and overall survival (6% risk reduction, 40% vs 46%)

22. Statistical methodologies • SMAC accumulated individual data for each patient • Modern meta-analysis uses fixed effect method to control for non-analyzed variables • Individual data not required • However, time-dependent outcomes not possible without individual data points

23. Chemotherapy regimens • Addition of ifosfamide in later studies • Therefore difference in treatment regimens between the 18 studies • Test for heterogeneity presumably controls for these differences

24. Subgroup analysis • Not performed due to lack of individual data points • HOWEVER, subgroup analysis can be flawed • Small sample size • Differences found due to chance alone

25. EORTC 62931 • Presented at ASCO meeting June 2007 RCT adjuvant chemo (Dox and Ifos) vs. control in resectable STS • 351 patients recruited 1995-2003 • 5 yr RFS 52% in both groups, OS 64% (control) and 69% (chemo) • Conclusion: “The hypotheses that adjuvant CT improves RFS and OS…can both be rejected”

26. EORTC 62931 • Data not available for inclusion in this analysis (authors felt that release of information would be premature)

27. Conclusions • Despite limitations, valuable Level I evidence • 1953 randomized patients with localized resectable STS

28. Conclusions • Absolute risk reductions: • Local recurrence 4% • Distant recurrence 9% • Overall recurrence 10% • Overall survival 6% (40% vs. 46%) • Individual patient care: These real but small benefits must be weighed against the toxicities associated with intensive chemotherapy

29. Brodowicz et al, Sarcoma 2000 Frustaci et al, JCO 2001 Gortzak et al, EJC 2001 Petrioli et al, AJCO 2002

30. Neoadjuvant vs. Adjuvant • One trial, Gortzak et al, EJC 2001: Neo-adjuvant chemotherapy • Analysis performed with and without data from this study • Confidence intervals and statistical outcome not statistically different • Therefore data included to increase statistical power