Patterns of Care and Prognosis of Retroperitoneal Sarcomas

in the Primary and Advanced Settings

A Large Multicentric Retrospective Analysis from the French Sarcoma Group

M. Toulmonde, E Stoeckle, S. Bonvalot, N. Isambert, E Bompas, N. Penel, V. Brouste, J-Y. Blay, S. Piperno-Neumann, C. Chevreau, P. Terrier,

D. Ranchère-Vince, J-M. Coindre, B. Nguyen Bui, A. Italiano

Retroperitoneal Sarcomas (RPS)

• Rare and heterogeneous• Poor prognosis

• Heterogeneous data• Controversies- Type of surgery - Role of radiotherapy

• Diversity of presentations in advanced setting

Objectives

Description of patterns of care Prognostic factors Subgroup analyses according to histological subtypes

I) On a Large homogeneous cohort of patients with completely resected primary RPS

II) In the advanced setting

Patients and Methods

• Prospective database of the French Sarcoma Group• Retrospective review of medical charts• Patients ≥ 18 years with primary RPS• Diagnosis between 01/01/1988 and 31/12/2008 • Referred to one of 12 participating French Comprehensive

Cancer Centers • Systematic histological review by an expert

pathologist member of the GSF-GETO• Statistical analyses according to standard methods (Log-

rank, Cox model)

Results • 586 patients• Median follow-up = 6.5 years [5.9-7.1]

26 patients not operated

19 patientsinitial abdominal sarcomatosis

30 patients initial distant metastasis

586 patients

537 patients M0

511 patients operated

110 patientsR2

12 patientsunknown resection status

389 patients R0/R1

Characteristics at diagnosis

Patients(n=586) %

Median age 57 years (18-89)Sex ratio M/F 0.87Median tumor size 17 cm (4-85)HistologyDDLPSWDLPSLMSUSOther

2441351094256

41.5%23%

18.5%7%

10%Grade 1 2 3NS

15224417911

26%41.5%30.5%

2%Multifocality 95 16%LR involvement 248 42%Vascular involvement 60 10%

DDLPS: Dedifferentiated LiposarcomaWDLPS: Well-Differentiated Liposarcomas LMS: LeiomyosarcomasUS: Unclassified SarcomasOther: Other subtypesLR: Locoregional

Patients(n=511) %

Type of surgerySimple LargeCompartmentalNS

189200120

2

37%39%24%

-Expert surgeon 222 43.5%Complete resection 389 76%Tumor rupture 80 15.5%≥1 resected organ 332 65%Perioperative RT 146 29%Perioperative CT 89 17%

Initial treatment modalitiesPatients(n=586) %

Preoperative biopsy 234 40%

Pretherapeutic multidisciplinary assessment

165 28%

Evolution (389 patients R0/R1)

5-year LR relapse-free Survival = 46% [41-52]

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10 11Time (years)

389 326 258 197 138 94 70 52 41 26 20 13 Number at risk

95% CILR relapse-free Survival

LR relapse-free SurvivalProbability

Evolution (389 patients R0/R1)

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10 11 Time (years)

389 370 339 294 233 169 121 96 80 58 45 38 Number at risk

95% CIOverall Survival

Probability Overall Survival

5-year overall survival = 66% [61-71]

Predictive factors for complete surgery (511 patients operated )

Multivariate analysis

OR [I95%CI] (p)

Histology (WDLPS)DDLPSLMSUSOther

2.40.31.52.8

[1.1-4.9[0.08-0.91][0.46-4.8][0.99-8.1]

(p= 0.02)(p= 0.03)(p= 0.5)

(p= 0.05)

Grade Not significant

Multifocality 3 [1.4-6.3] (p= 0.005)

LR involvement 14.1 [5.8-34.4] (p<0.001)

Type of surgery (simple)CompartmentalLarge

0.020.04

[0.005-0.9][0.02-0.1]

(p<0.001)(p<0.001)

Expert Surgeon 0.3 [0.12-0.6] (p=0.001)

Prognostic factors for LR relapse

Multivariate analysisHR [95%CI] (p)

Male sex 1.5 [1.1-2] (p=0.006)

Histology Not significant

Grade Not significant

LR involvement 1.6 [1.2-2.1] (p=0.004)

Type of surgery Not significant

Expert Surgeon 0.5 [0.4-0.7] (p<0.001)

Tumor rupture 2.9 [1.9-4.5] (p<0.001)

Perioperative RT 0.5 [0.4-0.7] (p<0.001)

0

50

100

0 1 3 5 7 9 11Time (years)

LR relapse-free survivalaccording to surgeon’s expertise

No expert surgeonExpert surgeon

0

50

100

0 1 3 5 7 9 11Time (years)

LR relapse-free survivalaccording to perioperative radiotherapy

No perioperative radiotherapyPerioperative radiotherapy

Prognostic factors for abdominal sarcomatosis

Multivariate analysisHR [95%CI] (p)

Grade (1)23

1.42.1

[0.7-3.0] [1.0-4.6]

(p=0.4)(p= 0.05)

LR involvement 1.8 [1.0-3.1] (p=0.04)

Expert surgeon 0.5 [0.3-0.9] (p=0.02)

Tumor rupture 4.2 [2.2-7.9] (p<0.001) 0

50

100

0 1 3 5 7 9 11

Sarcomatosis-free survivalaccording to tumor rupture

Tumor ruptureNo tumor rupture

Time (years)

Prognostic factors for distant metastasis

Multivariate analysisHR [95%CI] (p)

Tumor size < 18 cm Not significantHistology (WDLPS)DDLPSLMSUSOther

2.611.93.19.6

[1.1-6.2][5.3-26.9][0.8-12.3][3.8-24.1]

(p=0.027)(p<0.001)

(p=0.1)(p<0.001)

Grade Not significantLR involvement 1.6 [1-2.5] (p=0.034)

Vascular involvement Not significant

Perioperative RT Not significant

0

50

100

0 1 3 5 7 9 11

Time (years)

DDLPSWDLPS

LMSUS

Others

Distant metastasis-free survivalaccording to histology

Prognostic factors for overall survival

Multivariate analysisHR [95%CI] (p)

Age ≥ 56 years 1.4 [1-1.9] (p=0.04)

Male sex 1.7 [1.3-2.3] (p<0.001)

Histology Not significantGrade (1)23

2.14.1

[1.4-3.2][2.7-6.2]

(p=0.001)(p<0.001)

LR involvement 1.6 [1.2-2.2] (p=0.002)

Tumor rupture 2 [1.3-3] (p=0.002)

0

50

100

0 1 3 5 7 9 11Time (years)

Overall survivalaccording to tumor rupture

Tumor ruptureNo tumor rupture

Time (years)

0

50

100

0 1 3 5 7 9 11

grade 1

grade 3grade 2

Overall survivalaccording to grade

Sub-group analysis according to histology for LR relapse

Multivariate analysis

HR [95%CI] (p)

WDLPS

Tumor size ≥ 18 cm 2.6 [1.2-6] (p=0.02)

Tumor rupture 4 [1.6-9.7] (p=0.002)

DDLPS

Expert surgeon 0.6 [0.4-0.9] (p=0.01)

Perioperative RT 0.6 [0.4-0.9] (p=0.028)

LMS

Tumor rupture 10.1 [3.3-30.5] (p<0.001)

Sub-group analysis according to histology for OS

Multivariate analysisHR [95%CI] (p)

WDLPSAge ≥ 56 years 3.3 [1.5-7.5] (p=0.004)

Multifocality 3.1 [1.2-8.3] (p=0.02)

LR involvement 2.3 [0.97-5.5] (p=0.05)

DDLPSMale sex 1.8 [1.1-2.8] (p=0.014)

Grade 3 1.8 [1.1-2.8] (p=0.015)

Tumor rupture 2.3 [1.2-4.2] (p=0.008)

LMSLR involvement 2.4 [1.1-5.6] (p=0.035)

Type of surgerySimpleCompartmental

1.82.5

[0.7-4.5][1.2-5.3]

(p=0.2)(p=0.018)

Patterns of care in advanced stage

299 patients palliative CT for

advanced disease

586 patients

50 patients palliative surgery

• First line palliative CT - Monotherapy = 49% - Anthracycline-based = 75%• Median number of line = 2 (1-8)- 33% received ≥ 3 lines

OS from first line of palliative CT

Median Overall Survival

All 15.8 months [13-18]

WDLPS 26.8 months [12-65]

LMS 19.6 months [16-25]

US 14.4 months [6-19]

DDLPS 13.5 months [11-17]

Other 11.8 months [5-16]

0

25

50

75

100

0 1 2 3 4 5 6 7 8 9 10Time (years)

299 168 85 44 28 12 4 2 1 0 0 Number at risk

95% CIOverall survival

Overall Survival

OS from first line of palliative CT

Median Overall Survival

All 15.8 months [13-18]

WDLPS 26.8 months [12-65]

LMS 19.6 months [16-25]

US 14.4 months [6-19]

DDLPS 13.5 months [11-17]

Other 11.8 months [5-16]

DDLPS

WDLPSLMSUS

Other

0

25

50

75

100

0 1 3 5 7 9

Time (years)

Overall survival according to histology

Prognostic Factors for overall survival from first line of palliative CT

Multivariate analysis

HR [95%CI] (p)

Male sex 1.5 [1.1-1.9] (p=0.009)

PS (0)1≥ 2

1.73

[1.2-2.2][1.9-4.8]

(p=0.001)(p<0.001)

Grade (1)23

1.72.3

[1.1-2.7][1.5-3.7]

(p=0.02)(p<0.001)

Histology Not significant

0

50

100

0 1 3 5 7 9Time (years)

Overall survival according to grade

grade 1

grade 3grade 2

0

50

100

0 1 3 5 7 9Time (years)

PS = 0PS =1PS ≥ 2

Overall survival according to PS

Stage of the disease Palliative surgery no difference

Discussion

• Predominance of DDLPS• Poor conformity to practice guidelines • Surgical expertise is a major prognostic factor

• DDLPS

• WDLPS LR involvement and OS• LMS limits of surgery on OS

• Need for histology-specific clinical trials

- Radiotherapy and LR relapse - Grade and OS

Acknowledgements• V. Brouste• J-B. Courrèges• E. Stoeckle• G. Kantor• A. Neuville• J-M. Coindre • B. Nguyen Bui• A. Italiano

• O. Riou• N. Isambert• E Bompas• N. Penel• C. Delcambre-Lair• F. Duee• E. Saada• M. Jean-Denis

• P. Terrier • D. Ranchère-Vince • A. Lecesne• S. Bonvalot • J-Y. Blay• S. Piperno-Neumann• C. Chevreau • J-O. Bay• A. Thyss

Survivals according to histology

LR relapse-free survival

[95%CI]Distant metastasis-free

survival [95% CI]overall survival

[95%CI]

At 5 years At 10 years At 5 years At 10 years At 5 years At 10 years

WDLPS 53% [42-63] 21% [10-35] 96% [90-99] 94% [87-98] 92% [84-96] 63% [47-75]

DDLPS 40% [32-49] 24% [14-36] 86% [79-91] 81% [70-88] 61% [52-68] 31% [21-42]

LMS 55% [42-67] 55% [42-67] 47% [34-59] 28% [14-43] 61% [49-72] 30% [16-44]

US 25% [9-46] - 73% [34-91] - 35% [14-57] -

Other 48% [28-66] 48% [28-66] 63% [43-78] 55% [32-74] 43% [26-59] 31% [14-50]

Sub-group analysis according to histology for overall survival after first line palliative CT

Multivariate analysis

HR [95%CI] (p)

DDLPS

PS (0)1≥ 2

1.62.96

[1-2.5] [1.3-6.8]

(p=0.04)(p=0.01)

Grade (1*and 2)3 1.7 [1.1-2.6] (p=0.03)

LMS

PS Not significantGrade (1)23

35

[1.1-9.2][1.6-15.4]

(p=0.037)(p=0.005)

Stage (LR)SarcomatosisDistant metastasis

0.80.4

[0.3-2][0.2-0.7]

(p=0.59)(p=0.003)

025

5075

100

0 1 2 3 4 5 6 7 8 9 10 11Time (years)

389 326 258 197 138 94 70 52 41 26 20 13 Number at risk

95% CILR-free Survival

LR relapse- free Survival(Probability)

111 50 16 9 4 3 2 1 0 0 0grade_pal = 3125 75 46 21 14 4 1 0 0 0 0grade_pal = 246 30 16 10 7 3 1 1 1 0 0grade_pal = 1

Number at risk

grade_pal = 1 grade_pal = 2grade_pal = 3

0

50

100

0 1 3 5 7 9Time (years)

Overall Survival according to grade

grade 1

grade 3grade 2

28 8 1 0 0 0 0 0 0 0 0ps_pal_recup_2c = 2 ou 397 47 22 10 4 1 0 0 0 0 0ps_pal_recup_2c = 1150 98 59 31 22 9 4 2 1 0 0ps_pal_recup_2c = 0

0

25

50

75

100

Number at risk

0 1 3 5 7 9Time (years)

PS = 0PS =1PS ≥ 2

Overall Survival according to PS

Sub-group analysis according to histology

WDLPSLR Relapse HR [95%CI] (p)

Tumor size ≥ 18 cm 2.6 [1.2-6] (p=0.02)

Expert surgeon Not significant

Tumor rupture 4 [1.6-9.7] (p=0.002)

Perioperative RT Not significant

Overall survivalAge ≥ 56 years 3.3 [1.5-7.5] (p=0.004)

Multifocality 3.1 [1.2-8.3] (p=0.02)

LR involvement 2.3 [0.97-5.5] (p=0.05)

DDLPSLR Relapse HR [95%CI] (p)

Expert surgeon 0.6 [0.4-0.9] (p=0.01)

Perioperative RT 0.6 [0.4-0.9] (p=0.028)

Overall survivalAge ≥ 56 years Not significant

Male sex 1.8 [1.1-2.8] (p=0.014)

Grade 3 1.8 [1.1-2.8] (p=0.015)

Tumor rupture 2.3 [1.2-4.2] (p=0.008)

LMSLR Relapse HR [95%CI] (p)

Tumor rupture 10.1 [3.3-30.5] (p<0.001)

Overall survivalLR involvement 2.4 [1.1-5.6] (p=0.035)Type of surgery (large)SimpleCompartmental

1.82.5

[0.7-4.5][1.2-5.3]

(p=0.2)(p=0.018)