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Adjuvant Chemotherapy

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Adjuvant Chemotherapy

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  1. Cohort analysis of 674 patients with localized high-risk extremity soft tissue sarcoma treated at two cancer centers: chemotherapy-associated outcomesJanice N. Cormier, Xuelin Huang, Peter F. Thall, Xuemei Wang, Robert S. Benjamin, Raphael E. Pollock, Cristina R. Antonescu, Robert G. Maki, Murray F. Brennan, Peter W. T. Pisters

  2. Adjuvant Chemotherapy • First generation randomized trials Suboptimal regimens (agent or dosing) Small sample sizes Heterogeneous populations / low risk metastasis • Sarcoma Meta-Analysis Collaboration (Lancet 1997) 1,568 pts from 14 trials, adriamycin-based Overall survival benefit of 4% (p = 0.12) Extremity tumors 7% benefit (p = 0.029) • Second generation post meta-analysis trials have also failed to demonstrate significant improvement in survival.

  3. Objective Create a large, homogeneous, and complete dataset of consecutively treated patients with stage III extremity STS to evaluate chemotherapy associated outcomes.

  4. Eligibility Criteria Inclusion: • Adults > 16 years old • Stage III primary extremity STS (high grade, deep, > 5 cm) • Upper extremity beyond shoulder • Lower extremity beyond inguinal region • Pathologic confirmation of diagnosis Exclusion: • Locally recurrent disease • Palliative therapy • Follow-up < 30 days

  5. 1/84 - 6/99 • Prospective STS tumor registry • Computerized records • Medical records • Screened for eligibility criteria • Telephone follow-up • Prospective STS database • Variable specific data recoded • Chemotherapy confirmed • Screened for eligibility criteria • Follow-up updated N = 386 N = 288 Cohorts Merged 674 patients Median follow-up = 6.1 years

  6. Systemic Therapy Chemotherapy (N = 336, 50%) Preop (212, 64%) Postop (122, 36%)

  7. Chemotherapy Regimens Administered ** 89% received doxorubicin containing regimen 88% received doxorubicin-containing regimens

  8. Characteristics of 674 patients with AJCC stage III extremity STS Characteristic Chemotherapy (N = 336) % No Chemotherapy (N = 338) % Median age, yrs 51 60 Tumor size (cm) > 5 to < 10 10 to < 15 > 15 10 143 113 80 42 34 24 9.8 169 99 70 50 29 21 Sex, male 189 56 190 56 Anatomic site Lower extremity Proximal extremity 288 247 86 74 281 241 83 71 Microscopic margins R0 R1/unknown 254 82 76 24 249 89 74 26

  9. Characteristics of 674 patients with AJCC stage III extremity STS Characteristic Chemotherapy (N = 336) % No Chemotherapy (N = 338) % Histopathologic subtype MFH Liposarcoma Synovial sarcoma Unclassified sarcoma Leiomyosarcoma Other 129 47 47 29 15 69 38 14 14 9 4 21 121 69 42 24 27 55 36 21 12 7 8 16 Location of treatment ** MSKCC MDACC 146 190 43 57 240 98 71 29 ** relative risk chemoMDACC= 2.2 [95% CI = 1.85, 2.60]

  10. Age Gender - males Upper vs lower extremity tumors Proximal vs distal tumors Tumor size > 10 cm Histology Pathologic margin status XRT Treatment location Covariates Examined

  11. Hazard Curves for Disease-Specific Death 0.14 Chemotherapy 0.12 No Chemotherapy 0.10 0.08 Risk of death per year 0.06 0.04 0.02 0 2 4 6 8 10 12 14 Time (years)

  12. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 No Chemotherapy 0.1 Chemotherapy 0 0 2 4 6 8 10 12 14 16 18 Time (years) Disease-Free Survival HR for recurrence or death associated with chemotherapy: < 1 yr HR = 0.67 (0.48, 0.93, p = 0.02) > 1 yr HR = 1.33 (0.97, 1.81, p = 0.08) Cormier et al., n=680 primary, G3/4, T2b

  13. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 No Chemotherapy 0.1 Chemotherapy 0 2 4 6 8 10 12 14 16 18 Time (years) Disease-Specific Survival HR for death associated with chemotherapy < 1 yr: HR = 0.37 (0.20, 0.69, p = 0.002) > 1 yr: HR = 1.36 (1.02, 1.81, p = 0.04) 0 Cormier et al., n=680 primary, G3/4, T2b

  14. Hazard Ratios and 95% CI for time-to-event outcomes Chemotherapy Group Superior Chemotherapy Group Inferior Distant RFI < 1 year > 1 year 0.46 0.67 0.96 1.09 1.54 2.17 Distant DFS < 1 year > 1 year 0.45 0.64 0.91 1.08 1.46 1.96 0.48 0.67 0.93 Overall DFS < 1 year > 1 year 1.33 0.97 1.81 0.20 0.37 0.69 DSS < 1 year > 1 year 1.02 1.36 1.81 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 Hazard Ratio

  15. Summary In this covariate adjusted analysis of 674 patients with stage III extremity STS, the effects of chemotherapy varied over time: • 1st year, there appear to be improvements (6-8%) in clinical endpoints; • beyond 1 year, the effects appear to be reversed, with the use of chemotherapy associated with lower (2%) DFS and DSS. Cormier et al., JCO, November 15, 2004

  16. Conclusions • Level 1 evidence to support the routine administration of anthracycline-based chemotherapy for patients with localized, high-risk, extremity STS is weak. • Aggregate data suggest that anthracycline-based chemotherapy may delay rather than prevent disease progression.

  17. Local Therapy Surgical Resection (N = 674) Limb-sparing (88%) Amputation (12%) XRT (N = 436, 64%) Brachytherapy (137, 20%) Preop EBRT 50 Gy (127, 19%) Postop EBRT 63 Gy (172, 25%)

  18. Local Recurrence-Free Interval 1.0 0.9 0.8 0.7 0.6 0.5 Probability 0.4 0.3 0.2 No Chemotherapy 0.1 Chemotherapy 0 0 2 4 6 8 10 12 14 16 18 Time (years)

  19. 1.24 Hazard Ratios and 95% CI for time-to-event outcomes Chemotherapy Group Superior Chemotherapy Group Inferior Local RFI < 1 year > 1 year 0.33 0.63 1. 21 0.72 2.10 Local DFS < 1 year > 1 year 0.35 0.54 0.85 0.97 1.27 1.67 Distant RFI < 1 year > 1 year 0.46 0.67 0.96 1.09 1.54 2.17 Distant DFS < 1 year > 1 year 0.45 0.64 0.91 1.08 1.46 1.96 Overall DFS < 1 year > 1 year 0.48 0.67 0.93 1.33 0.97 1.81 DSS < 1 year > 1 year 0.20 0.37 0.69 1.02 1.36 1.81 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 Hazard Ratio

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