IMPACT OF CHEMOTHERAPY IN UTERINE SARCOMA (UTS): REVIEW OF 12 CLINICAL

TRIALS FROM EORTC INVOLVING ADVANCED UTS COMPARED TO OTHER SOFT TISSUE

SARCOMA (STS)

I Ray-Coquard, A Natukunda, JY Blay, P Casali, I Judson,

A Krarup Hansen, LH Lindner, AP dei Tos , H Gelderblom,

S Marreaud, S Litière, P Rutkowski, P Hohenberger,

A Gronchi, W van der Graaf.

Background

• Uterine sarcoma : Age 40-60 y 5-10 % of uterine corpus malignancies 7% of all STS , 70% LMS

• Active drugs reported in litt (phase II)*: Doxorubicin, PLD, ifosfamide, gemcitabine,

trabectedin & combo Dox-Ifos, Gem-Tax, Gem-DTIC, Dox-Trabectedin

RR 11 – 54% & median PFS 3 to 6 months

• No data from phase III trials in first line on RR, PFS and OS (except Muss, Cancer 1985, 100 pts)

*Omura 83, Sutton 88, Look 04, Sutton 05, Sutton 09, Hensley 08, Duffaud 10, Garcia del Muro 11, Pautier 13

Objectives

• To give an overview of uterine sarcoma patient characteristics compared to other sarcoma sub-types.

• To evaluate the factors associated with the clinical behavior of patients with advanced or metastatic uterine sarcoma treated by first line chemotherapy

• Using data of 12 EORTC pooled sarcoma trials, from 1977 to 2001.

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 were done

using Cox regression for PFS and OS Logistic regression for RR

Selection of uterine sarcoma patients

3002 patients in the EORTC sarcoma database

175 received prior treatment

2827 received no prior

treatment

225 Uterine Sarcoma patients

2602 Other subtypes

From 1977 to 2001

Results (charact. of Ut. Sarcoma pts compared to all others)

Tumor site

Uterine sarcoma (N=225)

Other types

(N=2602)

Total (N=2827)

P N (%) N (%) N (%)

Performance status

PS 0 103 (45.8) 1051 (40.4) 1154 (40.8) 0.405b

PS 1 98 (43.6) 1186 (45.6) 1284 (45.4)

PS 2+ 21 (9.3) 274 (10.5) 295 (10.4)

Unknown 3 (1.3) 91 (3.5) 94 (3.3)

Age at registration, years

Median 53 51 51 0.0005a

Range 22 - 76 10 - 80 10 - 80

N obs 218 2538 2756

Histopathological grade

Grade I &II 52 (23.1) 856 (32.9) 908 (32.1) <.001b

Grade III 90 (40.0) 781 (30.0) 871 (30.8)

Unknown 83 (36.9) 965 (37.1) 1048 (37.1)

Delay between diagnosis and registration

Median 179.5 189 188 0.924a

Range 0-6071 0-10546 0-10546

Histology

Leiomyosarcoma 159 (70.7) 717 (27.6) 876 (31.0) <.001b

Synovial sarcoma 0 (0.0) 234 (9.0) 234 (8.3)

Other 57 (25.3) 1508 (58.0) 1565 (55.4)

Unknown 9 (4.0) 143 (5.5) 152 (5.4)

Results (charact. of UtS patients compared to others)

Tumor site

Uterine sarcoma (N=225)

Other types

(N=2602)

Total (N=2827)

P N (%) N (%) N (%)

Prior Surgery

No 11 (4.9) 338 (13.0) 349 (12.3) <.001b

Partial 73 (32.4) 675 (25.9) 748 (26.5)

Total 89 (39.6) 734 (28.2) 823 (29.1)

Unknown 52 (23.1) 855 (32.9) 907 (32.1)

Prior radiotherapy

No 155 (68.9) 1881 (72.3) 2036 (72.0) 0.258b

Yes 68 (30.2) 695 (26.7) 763 (27.0)

Unknown 2 (0.9) 26 (1.0) 28 (1.0)

Primary site involved

No 121 (53.8) 973 (37.4) 1094 (38.7) <.001b

Yes 81 (36.0) 1188 (45.7) 1269 (44.9)

Unknown 23 (10.2) 441 (16.9) 464 (16.4)

Treatment

Anthracyclins 96 (42.7) 961 (36.9) 1057 (37.4) 0.029b

DOX+IFO 66 (29.3) 839 (32.2) 905 (32.0)

CYVADIC 23 (10.2) 428 (16.4) 451 (16.0)

IFO ALONE 40 (17.8) 374 (14.4) 414 (14.6)

Overall Survival Uterine vs. other sub types

(months)

0 6 12 18 24 30 36 42 48 54 60

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Tumor site191 225 156 87 59 37 25 18 13 11 10

21632602 1863 1159 719 482 330 225 158 126 103

Uterine sarcoma

Other types

Overall Logrank test: p=0.288

Tumor site Median (95% CI)

(Months) % at 1 Year(s)

(95% CI)

Uterine sarcoma 10.09 (8.97, 11.93) 41.74 (35.12, 48.22)

Other types 11.73 (11.17, 12.12) 48.43 (46.44, 50.39)

Overall Survival - univariate analysis

Covariates Patients(N)

ObservedEvents

(O)Hazard Ratio

(95% CI) P-Value

Performance status

PS 0

103 79 1.00

<0.001 PS 1

98 88 1.67 (1.23, 2.27)

PS 2+ 21 21 3.25 (1.99, 5.30)

Prior Surgery

No

11 10 1.00 0.46

Partial

73 60 0.66 (0.34, 1.30)

Total 89 75 0.66 (0.34, 1.29)

Prior radiotherapyNo

155 127 1.00 0.674

Yes 68 62 1.07 (0.79, 1.45)

Primary site involved

No

121 103 1.00 0.394

Yes 81 7 0.87 (0.64, 1.19)

Histopathological grade

Grade I&II

52 41 1.00 0.002

Grade III

90 81 1.84 (1.25, 2.71)

Treatment

Anthracyclins

96 84 1.00

DOX+IFO

66 58 1.07 (0.77, 1.51) 0.96

CYVADIC

23 20 0.95 (0.58, 1.55)

IFO ALONE

40 29 1.01 (0.66, 1.54)

Age (cts.) 218 185 1.02(1.00, 1.03) 0.037Histology Leiomyo

159 138 1.00

Other

57 45 0.73 (0.51, 1.03) 0.072

Overall Survival multivariate analysis

Factor

Hazard Ratio

95% Lower CL for Hazard

Ratio

95% Upper CL for Hazard

RatioP

Histopathological grade I& II vs. III 0.61 0.41 0.91 0.014

Performance statusPS 1 vs. PS 0 1.87 1.26 2.75 0.002

PS 2+ vs. PS 0 2.41 1.29 4.51

Better outcome for patients with WHO performance status 0 vs. 1 & 2.

Better outcome was observed for uterine patients with histopathological grade I&II compared to grade III

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

Overall Survival by prognostic factors (Grade /PS)

(months)

0 4 8 12 16 20 24 28 32 36 40

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Histopathological grade41 52 47 36 26 20 18 14 14 11 8

84 90 69 50 31 25 16 10 6 4 2

GRADE I&II

GRADE III

%

Overall Logrank test: p=0.002

GradeMedian (95% CI)

(Months)

GRADE I&II 12.53 (9.00, 21.65)

GRADE III 9.23 (7.46, 11.93)

(months)

0 5 10 15 20 25 30 35 40 45

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Performance status79 103 85 60 45 30 24 20 14 8

88 98 73 42 26 17 8 5 5 5

21 21 10 5 2 1 1 0 0 0

PS 0

PS 1

PS 2+

%

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

Performance statusMedian (95% CI)

(Months)0 13.83 (10.38, 17.38)

1 9.07 (6.77, 11.01)

2+ 3.35 (2.04, 7.95)

PFS Uterine vs. other sub types

(months)

0 3 6 9 12 15 18 21 24 27 30

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Tumor site213 225 132 78 47 32 25 20 16 11 11

24402602 1433 965 626 434 318 249 196 162 137

Uterine sarcoma

Other types

Overall Logrank test: p=0.581

Tumor site Median (95% CI)

(Months) % at 1 Year(s)

(95% CI)

Uterine sarcoma 4.1 (3.42, 4.93) 15.10 (10.73, 20.16)

Other types 3.71 (3.48, 4.07) 17.57 (16.11, 19

PFS univariate analysisCovariates Patients

(N)Observed

Events(O)

Hazard Ratio(95% CI) P-Value

Performance statusMissing data n = 3

PS 0

103 93 1.00

0.022 PS 1

98 96 1.31 (0.99, 1.75)

PS 2+

21 21 1.85 (1.15, 2.98)

Prior SurgeryMissing data n= 52

No 11 11 1.00 0.030

Partial

73 69 0.49 (0.26, 0.94)

Total

89 84 0.42 (0.22, 0.80)

Histopathological grade

Grade I&II

52 48 1.00

0.099 Grade III

90 87 1.36 (0.94, 1.95)

Missing 83

Chemotherapy regimen

Anthracyclins

96 89 1.00

0.451DOX+IFO

66 63 1.10 (0.80, 1.52)

CYVADIC

23 23 0.82 (0.51, 1.30)

IFO ALONE

40 38 1.22 (0.83, 1.78)

AgeMissing data n =7

< 40 yrs

23 18 1.00

0.02840-50 yrs

56 54 1.85 (1.07, 3.19)

50-60 yrs

79 77 2.24 (1.32, 3.79)

>=60 yrs

60 57 1.98 (1.16, 3.39)

HistologyMissing data n = 9

Leiomyo sarcoma

159 154 1.00

0.034Other 57 51 0.71 (0.51, 0.98)

Prior RT, CT regimen, histological grade, primary site involved are not prognostic factors

PFS Multivariate analysis

Factor HazardRatio

95% Hazard Ratio

Confidence Limits P

Prior surgery Partial vs. No 0.34 0.15 0.79 0.022Total vs. No 0.31 0.13 0.71

Histopathological grade

I &II vs. III 0.61 0.39 0.95 0.027

Better outcome for patients who had prior partial or total surgery vs. no prior surgery

Better outcome was observed for uterine patients with histopathological grade I&II compared to grade III

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

Response to chemotherapy

52 (23.2%) patients responded to chemotherapy Few response among Ifosfamide alone patientsUnivariate analysis identified high grade (RR 30%) vs low grade

(RR 13%), non leiomyosarcoma (RR 33%) vs leio (RR 20%) and anthracyclins containing CT (RR 27%) vs ifo alone (RR 5%) as predictive factors for RR

Treatment

Total (N=225)

Anthracyclins (N=96)

DOX+IFO (N=66)

CYVADIC (N=23)

IFO ALONE (N=40)

N (%) N (%) N (%) N (%) N (%)

Best overall response

CR 3 (3.1) 2 (3.0) 3 (13.0) 0 (0.0) 8 (3.6)

PR 21 (21.9) 16 (24.2) 5 (21.7) 2 (5.0) 44 (19.6)

NC 41 (42.7) 22 (33.3) 7 (30.4) 15 (37.5) 85 (37.8)

PD 28 (29.2) 19 (28.8) 5 (21.7) 17 (42.5) 69 (30.7)

Inevaluable 3 (3.1) 7 (10.6) 3 (13.0) 6 (15.0) 19 (8.4)

25% 27% 35% 5%

Conclusions

• Poor prognosis for PFS (median 4 months) & OS (10 months)

• Prognostic impact of performance status and grade on OS

• There was no significant effect of chemotherapy regimen observed neither for PFS nor OS. Anthra alone remains a standard of care Do not used Ifosfamide alone for Ut sarcoma pts

• Only 25% responders to chemotherapy among the uterine sarcoma patients.

• Need for new strategies !