Outcome of chemotherapy in synovial sarcoma (sys) patients (pts): review of 15

clinical trials from EORTCc involving advanced sys compared to other Soft Tissue

Sarcomas (STS)

Winette T. van der Graaf, Elisa Rizzo , Alessandro Gronchi, Ian Judson, Hans Gelderblom, Sandrine

Marreaud and Saskia Litiere, on behalf of the EORTC Soft Tissue and Bone

Sarcoma Group

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Disclosures

• Research grants from Novartis, Pfizer, GSK

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Background

• Synovial sarcoma (SyS) represents about 8% of all soft tissue sarcomas

• SyS is a relatively more common among teenagers and young adults

• The impression is that it is a more chemosensitive STS• As outcome in metastatic session has not been reported to

have become significantly better during the last decades, we need new synovial sarcoma specific studies.

• Therefore we need solid outcome data as basis for the statistical design of new studies.

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Aim

To evaluate :

• The clinical presentation of SyS pts• The outcome of pts with advanced or metastatic SyS treated

with first line chemotherapy.

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Patients and Methods• Data were used from the EORTC-STBSG database containing information on chemo-naïve advanced and metastatic STS pts who participated in fifteen

chemotherapy trials between 1976 and 2012. • Pts with SyS were compared with other STS patients.

We evaluated overall survival (OS), progression free survival (PFS) and response rate (RR).

The chemotherapy in SyS pts was aggregated in 5 categories:A: anthracyclines alone (121 pts) ,B: ifosfamide alone (42), C: doxorubicin and ifosfamide (112 pts), D: CYVADIC (42 pts) E: Other: Brostallicin, Trabectedin (8pts).

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Selection of Synovial sarcoma patients

From the 15 EORTC pooled sarcoma

trials,313 patients with

SyS sarcoma were identified for

analysis.

3676 patients in the EORTC sarcoma database

192 received prior treatment

313 SyS patients

3171 Other subtypes

3484 received no prior treatment

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Characteristics of SyS pts compared to others STS pts

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a Kruskal -Wallis test; b Chi-square test

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RESULTS

OSPFSRR

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OS Synovial vs. other sub-types

(months)

0 6 12 18 24 30 36 420

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Tumor site254 313 266 184 113 70 38 21 15

2546 3171 2242 1356 844 567 397 278 197Synovial sarcomaOther types

Overall Score test: p=0.009

Tumor siteMedian (95% CI)

(Months)% at 1 Year

(95% CI)Synovial sarcoma

15.0 (13.9, 16.4) 63.7 (57.9, 68.8)

Other types 11.6 (11.1, 12.0)

48.0 (46.2, 49.8)

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PFS Synovial vs. other sub-types

(months)

0 6 12 18 24 30 36 42 480

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Tumor site302 313 165 56 30 15 10 8 5

2979 3171 1169 513 290 191 143 111 92Synovial sarcomaOther types

Overall Score test: p=0.004

Tumor siteMedian (95% CI)

(Months)% at 1 Year

(95% CI)Synovial sarcoma

6.3 (5.8, 6.9) 18.2 (14.2, 22.6)

Other types 3.6 (3.4, 3.9) 16.7 (15.4, 18.0)

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OS univariate analysis

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OS by Performance status

(months)

0 6 12 18 24 30 36 42 48

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Performance status121 157 145 110 68 45 27 15 13114 136 110 70 43 25 11 6 215 16 7 2 0 0 0 0 0

PS 0PS 1PS 2+

Overall Score test: p<0.0001(df=2)

Performance statusMedian (95% CI)

(Months)% at 1 Year

(95% CI)PS 0 17.7 (15.5, 19.7)

75.9 (68.2, 82.0)

PS 1 13.3 (10.8, 15.6)

55.6 (46.6, 63.6)

PS >=2 6.1 (3.1, 8.3)

14.3 (2.4, 36.3)

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OS multivariate analysisFactor Hazard Ratio 95% Lower CL for

Hazard Ratio95% Upper CL for

Hazard Ratio P

Performance status

PS 1 vs. PS 0 1.63 1.24 2.13 <0.001<0.001PS 2+ vs. PS 0 5.80 3.06 11.01

Metastatic site involved Yes vs. No 1.53 1.15 2.04 0.004Primary site involved Yes vs. No 3.13 1.71 5.73 <0.001

Better survival for Synovial patients:• with WHO PS 0 vs. PS 1 & 2• with metastatic site not involved• the role of primary site involved is less clear as it is correlated with

metastatic site involved and it is not statistical significant in the univariate analysis

No significant effect of chemotherapy regimen in first line treatment observed for OS

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PFS univariate analysis

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PFS by Performance status

(months)

0 6 12 18 24 30 36

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Performance status153 157 97 38 18 9 6

129 136 63 17 11 6 4

16 16 3 0 0 0 0

PS 0PS 1PS 2+

Overall Score test: p=0.000 (df=2)

Performance statusMedian (95% CI)

(year)% at 1 Year

(95% CI)PS 0 0.6 (0.5, 0.7)

24.7 (18.2, 31.7)

PS 1 0.5 (0.3, 0.5)

13.7 (8.5, 20.2)

PS >=2 0.3 (0.2, 0.4)

0

18

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PFS multivariate analysis

Factor Hazard Ratio 95% Lower CL for Hazard Ratio

95% Upper CL for Hazard Ratio P

Performance status PS 1 vs. PS 0 1.41 1.10 1.80 0.007

0.004PS 2+ vs. PS 0 2.42 1.33 4.40

Metastatic site involved Yes vs No 3.20 1.87 5.47 <.001

Better PFS for Synovial patients:• with WHO PS 0 vs. PS 1 & 2• with metastatic site not involved

Treatment was borderline not-significant (p=0.051) when adjusting for the different potential prognostic factors for OS

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Response to chemotherapy

RR to chemotherapy overall:28%; no change 46%

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Conclusions

• Prognostic impact of performance status and metastatic site involved on OS an PFSA better outcome for patients with PS 0 compared to PS ≥ 1 and with

metastatic site not involved Variable primary site involved seems to be significant for OS but this

variable is correlated with metastatic site involved

• There was no significant effect of treatment regimen observed neither for PFS nor OS

• 28% responders to chemotherapy among the SyS pts.

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What next?

Given the fact that the prognosis of locally advanced and metastatatic SyS pts is still poor, we should consider cooperative groups for new clinical studies in this not so rare STS

WORK IN PROGRESS!!

Acknowledgements

• Patients who participated in these studies• All investigators of EORTC STBSG • EORTC Headquarters

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Patients and Methods

• Categorical variables were summarized by frequencies and percentages, • continuous variables were summarized by median, range, interquartile

range (IQR). • Comparisons between factors was done using chi-square or Kruskal-

Wallis tests.

• Survival was estimated by Kaplan Meier method• Univariate and multivariate analyses (using backward selection to

reduce the multivariate model) were done using Cox regression for PFS and OS Logistic regression for RR