A systematic meta-analysis of randomized controlled trials for

adjuvant chemotherapy for localized resectable soft-tissue sarcoma

Nabeel PervaizNigel Colterjohn

Forough FarrokhyarRichard Tozer

Alvaro FigueredoMichelle Ghert

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

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

Ten years later…

• Further published RCTs

• Intensification of doxorubicin dosage and addition of ifosfamide to regimens

Objective

• To update the 1997 meta-analysis with data from subsequent published randomized controlled trials

• Increase statistical power and narrow confidence intervals

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

Study Evaluation

• Studies evaluated by 2 independent reviewers

• Modified Detsky Quality Scale for Randomized trials

• Interobserver reliability

Outcome measures

• Local recurrence

• Distant recurrence

• Overall recurrence

• Overall survival

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)

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)

Chemotherapy regimens

• SMAC: – 13 Doxorubicin based, 1 Doxorubicin and

Ifosfamide

• Additional trials: – All 4 trials Doxorubicin and Ifosfamide

• Dosage intensities varied

Funnel Plot

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Log Odds Ratio

Funnel Plot of Standard Error by Effect Size

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

Citation NTotal Treated Control PValue Effect Lower Upper

Bergonie et al 54 6 / 28 8 / 26 .43 .61 .18 2.10Brodowicz et al 59 2 / 31 6 / 28 .09 .25 .05 1.38DFCI/MGH 46 3 / 21 3 / 25 .82 1.22 .22 6.81EORTC 381 30 / 193 51 / 188 .01 .49 .30 .82Frustaci et al 104 9 / 53 11 / 51 .55 .74 .28 1.98GOG 221 20 / 112 16 / 109 .52 1.26 .62 2.59Gortzak et al 134 11 / 67 13 / 67 .65 .82 .34 1.98IGSC 86 6 / 40 8 / 46 .76 .84 .26 2.66Mayo 45 4 / 22 5 / 23 .77 .80 .18 3.47MDA 35 2 / 18 5 / 17 .18 .30 .05 1.82NCI4 25 2 / 17 4 / 8 .04 .13 .02 1.01NCI5 79 8 / 38 9 / 41 .92 .95 .32 2.78NCI6 41 0 / 21 0 / 20 .98 .95 .02 50.34Petrioli et al 88 6 / 45 9 / 43 .34 .58 .19 1.80Rizzoli et al 38 1 / 16 6 / 22 .10 .18 .02 1.66SAKK 24 0 / 12 0 / 12 1.00 1.00 .02 54.46SSG 240 19 / 121 13 / 119 .28 1.52 .71 3.23

Fixed Combined (17) 1700 129 / 855 167 / 845 .02 .73 .56 .94

0.01 0.1 1 10 100

Chemotherapy Control

Odds ratio for local recurrence

Test for heterogeneity Q=15.81, df=16, p=0.4664

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

Odds ratio for distant recurrence

Citation NTotal Treated Control PValue Effect Lower Upper

Bergonie et al 54 8 / 28 14 / 26 .06 .34 .11 1.06Brodowicz et al 59 6 / 31 10 / 28 .16 .43 .13 1.41DFCI/MGH 46 6 / 21 7 / 25 .97 1.03 .28 3.73EORTC 381 51 / 193 56 / 188 .47 .85 .54 1.32Frustaci et al 104 23 / 53 26 / 51 .44 .74 .34 1.60GOG 221 21 / 112 36 / 109 .02 .47 .25 .87Gortzak et al 134 26 / 67 31 / 67 .38 .74 .37 1.46IGSC 86 4 / 40 13 / 46 .03 .28 .08 .95Mayo 45 6 / 22 6 / 23 .93 1.06 .28 3.98MDA 35 8 / 18 8 / 17 .88 .90 .24 3.41NCI4 25 4 / 17 3 / 8 .47 .51 .08 3.16NCI5 79 12 / 38 16 / 41 .49 .72 .29 1.82NCI6 41 7 / 21 10 / 20 .28 .50 .14 1.77Petrioli et al 88 7 / 45 11 / 43 .24 .54 .19 1.54Rizzoli et al 38 6 / 16 10 / 22 .62 .72 .19 2.68SAKK 24 3 / 12 4 / 12 .65 .67 .11 3.93SSG 240 41 / 121 53 / 119 .09 .64 .38 1.08

Fixed Combined (17) 1700 239 / 855 314 / 845 .00 .65 .53 .80

0.01 0.1 1 10 100

Chemotherapy Control

Test for heterogeneity Q=7.8451, df=16, p=0.9533

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

Odds ratio for overall recurrence

Citation NTotal Treated Control PValue Effect Lower Upper

Bergonie et al 54 11 / 28 19 / 26 .01 .24 .08 .75Brodowicz et al 59 7 / 31 12 / 28 .10 .39 .13 1.20DFCI/MGH 46 7 / 21 8 / 25 .92 1.06 .31 3.66ECOG 47 9 / 24 11 / 23 .47 .65 .20 2.09EORTC 381 92 / 193 105 / 188 .11 .72 .48 1.08Frustaci et al 104 28 / 53 32 / 51 .31 .66 .30 1.46GOG 221 52 / 112 62 / 109 .12 .66 .39 1.12Gortzak et al 134 30 / 67 35 / 67 .39 .74 .38 1.46IGSC 86 14 / 40 25 / 46 .07 .45 .19 1.08Mayo 45 12 / 22 11 / 23 .65 1.31 .41 4.23MDA 35 12 / 18 15 / 17 .13 .27 .05 1.57NCI4 25 9 / 17 5 / 8 .65 .67 .12 3.77NCI5 79 22 / 38 24 / 41 .95 .97 .40 2.38NCI6 41 9 / 21 11 / 20 .44 .61 .18 2.11Petrioli et al 88 13 / 45 20 / 43 .09 .47 .19 1.13Rizzoli et al 38 7 / 16 13 / 22 .35 .54 .15 1.98SAKK 24 4 / 12 4 / 12 1.00 1.00 .18 5.46SSG 240 65 / 121 69 / 119 .51 .84 .51 1.40

Fixed Combined (18) 1747 403 / 879 481 / 868 .00 .67 .56 .82

0.01 0.1 1 10 100

Chemotherapy Control

Test for heterogeneity Q=10.2308, df=17, p=0.8937

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

Citation NTotal Treated Control PValue Effect Lower Upper

Bergonie et al 65 10 / 33 18 / 32 .03 .34 .12 .94Brodowicz et al 59 1 / 31 3 / 28 .25 .28 .03 2.84DFCI/MGH 46 6 / 21 7 / 25 .97 1.03 .28 3.73ECOG 47 9 / 24 10 / 23 .68 .78 .24 2.51EORTC 467 94 / 234 96 / 233 .82 .96 .66 1.39Frustaci et al 104 20 / 53 28 / 51 .08 .50 .23 1.09GOG 225 51 / 113 55 / 112 .55 .85 .50 1.44Gortzak et al 134 22 / 67 28 / 67 .28 .68 .34 1.38IGSC 92 16 / 43 23 / 49 .35 .67 .29 1.54Mayo 57 14 / 28 12 / 29 .51 1.42 .50 4.03MDA 54 15 / 26 20 / 28 .29 .55 .18 1.69NCI4 25 9 / 17 5 / 8 .65 .67 .12 3.77NCI5 79 22 / 38 23 / 41 .87 1.08 .44 2.62NCI6 41 8 / 21 9 / 20 .65 .75 .22 2.61Petrioli et al 88 13 / 45 23 / 43 .02 .35 .15 .85Rizzoli et al 77 12 / 34 25 / 43 .05 .39 .16 .99SAKK 29 5 / 14 3 / 15 .34 2.22 .42 11.83SSG 240 57 / 121 57 / 119 .90 .97 .58 1.61

Fixed Combined (18) 1929 384 / 963 445 / 966 .01 .77 .64 .93

0.01 0.1 1 10 100

Chemotherapy Control

Odds ratio for overall survival

Test for heterogeneity Q=15.9325, df=17, p=0.5286

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%)

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

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

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

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”

EORTC 62931

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

Conclusions

• Despite limitations, valuable Level I evidence

• 1953 randomized patients with localized resectable STS

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

1. Brodowicz et al, Sarcoma 2000

2. Frustaci et al, JCO 2001

3. Gortzak et al, EJC 2001

4. Petrioli et al, AJCO 2002

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