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Clinicopathologic Characteristics and Predictors of Outcomes in Patients with Primary Retroperitoneal Dedifferentiated Liposarcoma Undergoing Surgery Emily.

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Presentation on theme: "Clinicopathologic Characteristics and Predictors of Outcomes in Patients with Primary Retroperitoneal Dedifferentiated Liposarcoma Undergoing Surgery Emily."— Presentation transcript:

1 Clinicopathologic Characteristics and Predictors of Outcomes in Patients with Primary Retroperitoneal Dedifferentiated Liposarcoma Undergoing Surgery Emily Z Keung, 1 Yang Feng, 2 Jason L Hornick, 3 Judith Manola, 2 Monica M Bertagnolli, 1 Elizabeth H Baldini, 4 Chandrajit P Raut 1 Departments of 1 Surgery, 2 Biostatistics, 3 Pathology, and 4 Radiation Oncology Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard Medical School Boston, Massachusetts, USA

2 Disclosures  The authors have no disclosures to report Retroperitoneal Dedifferentiated Liposarcoma

3  Liposarcoma (LPS) is the most common histology among retroperitoneal sarcomas  Dedifferentiated liposarcoma (DDLPS) is 1 of 4 LPS subtypes Dedifferentiated Liposarcoma of the Retroperitoneum Retroperitoneal Dedifferentiated Liposarcoma Dei Tos AP, 2000, Ann Diagn Pathol Ghadimi MP, et al, 2011, Ann Surg Oncol Murphey, et al, 2005, Radiographics Weaver J, et al, 2008, Modern Pathology  DDLPS of the retroperitoneum (RP DDLPS)  Aggressive tumors with 15-20% metastatic rate  Associated with poor patient prognosis  90% diagnosed at first presentation (primary DDLPS)  10% diagnosed in recurrent WDLPS (secondary DDLPS)

4 RP DDLPS: Current Knowledge Deficit Retroperitoneal Dedifferentiated Liposarcoma  To date, studies examining RPS generally include multiple histologies and those examining DDLPS include multiple disease locations  Several studies have compared WDLPS and DDLPS  DDLPS are associated with  Higher local recurrence  Higher distant recurrence  Decreased survival  No study has examined RP DDLPS alone Lahat G, et al, 2008, Ann Surg Onc Singer S, et al, 2003, Ann Surg

5 Study Objective and Methods Retroperitoneal Dedifferentiated Liposarcoma  Objective: To identify factors predictive of outcomes within a cohort exclusively of primary RP DDLPS

6 Study Objective and Methods Retroperitoneal Dedifferentiated Liposarcoma  Objective: To identify factors predictive of outcomes within a cohort exclusively of primary RP DDLPS  A retrospective review of all patients with primary RP DDLPS treated at our institution between 1998 and 2008 was performed (n=119)

7 Study Objective and Methods Retroperitoneal Dedifferentiated Liposarcoma  Objective: To identify factors predictive of outcomes within a cohort exclusively of primary RP DDLPS  A retrospective review of all patients with primary RP DDLPS treated at our institution between 1998 and 2008 was performed (n=119)  Endpoints of interest:  Progression-free survival (PFS)  Local recurrence-free survival (LRFS)  Distant recurrence-free survival (DRFS)  Overall survival (OS)  Survival was calculated from date of diagnosis by the Kaplan-Meier method

8 Study Objective and Methods Retroperitoneal Dedifferentiated Liposarcoma  Objective: To identify factors predictive of outcomes within a cohort exclusively of primary RP DDLPS  A retrospective review of all patients with primary RP DDLPS treated at our institution between 1998 and 2008 was performed (n=119)  Endpoints of interest:  Progression-free survival (PFS)  Local recurrence-free survival (LRFS)  Distant recurrence-free survival (DRFS)  Overall survival (OS)  Survival was calculated from date of diagnosis by the Kaplan-Meier method  Multivariable Cox regression analyses were performed to identify significant prognostic factors

9 Patient Characteristics (n=119) Retroperitoneal Dedifferentiated Liposarcoma Variablen (% or range) Median age, years60.3 (35-84) Gender Female51 (43) Male68 (57) Median size, cm20.5 (0.8-75.0) Multifocality Single tumor88 (74) Multifocal disease25 (21) Unknown6 (5) FNCLCC Grade Intermediate63 (53) High33 (28) Unknown23 (19)

10 Treatment Regimens Retroperitoneal Dedifferentiated Liposarcoma Treatment at Initial Presentation (n=119)n% Surgery119100 Surgery alone10388 + Neoadjuvant chemotherapy + radiation therapy11 + Neoadjuvant chemotherapy43 + Neoadjuvant radiation therapy119 Postoperative chemotherapy108 Intraoperative radiation therapy76 Postoperative radiation therapy1412  Site of initial surgery  Referring institution - 82 patients (69%)  Of these, 19 patients (23%) underwent surgery by urologists or gynecologists  BWH/DFCI – 37 patients (31%)

11 Surgical Outcomes Retroperitoneal Dedifferentiated Liposarcoma Variablen (%) Extent of resection R0/R1 resection95 (80) R2 resection13 (11) Unknown11 (9) Microscopic margins, dedifferentiated component Negative13 (11) < 1 mm with intact fascia0 (0) < 1 mm without fascia14 (12) Positive72 (61) Unknown20 (17) Tumor integrity Tumor intact86 (72) Tumor transected or ruptured 19 (16) Unknown14 (12) Median number of organs resected2 (0-7)

12 All Patients Months (95% CI) R0/R1 resection Months (95% CI) R2 resection Months (95% CI) Median PFS 21.1 (15.0-27.2)22.1 (16.9-27.3)6.6 (1.6-9.3) Median LRFS 21.5 (14.5-28.5)23.9 (19.5-28.3)5.7 (3.8-7.6) Median DRFS 45.8 (29.7-61.8)51.1 (32.3-59.0)17.4 (8.4-27.9) Median OS 59.0 (51.8-66.2)63.2 (55.8-83.3)17.8 (10.0-41.5) Survival Outcomes Retroperitoneal Dedifferentiated Liposarcoma All Patients Months (95% CI) Median PFS 21.1 (15.0-27.2) Median LRFS 21.5 (14.5-28.5) Median DRFS 45.8 (29.7-61.8) Median OS 59.0 (51.8-66.2)

13 High Local Recurrence Rate Retroperitoneal Dedifferentiated Liposarcoma  100/119 patients (84%) had disease recurrence or progression  92/100 (92%) were local recurrences Variablen (%) Number of recurrences 143 (45) 224 (25) 39 (10) 42 (2) Unknown17 (18) Site of recurrence or progression Retroperitoneal92 (92) Intraperitoneal26 (26) Lung14 (14) Liver6 (6) Bone6 (6) Skin/subcutaneous3 (3)

14 High Local Recurrence Rate Retroperitoneal Dedifferentiated Liposarcoma  100/119 patients (84%) had disease recurrence or progression  92/100 (92%) were local recurrences  Recurrence/progression by extent of resection  R0/R1 resection – 82% had disease recurrence  R2 resection – 77% had disease progression Variablen (%) Number of recurrences 143 (45) 224 (25) 39 (10) 42 (2) Unknown17 (18) Site of recurrence or progression Retroperitoneal92 (92) Intraperitoneal26 (26) Lung14 (14) Liver6 (6) Bone6 (6) Skin/subcutaneous3 (3)

15 High Local Recurrence Rate Retroperitoneal Dedifferentiated Liposarcoma  100/119 patients (84%) had disease recurrence or progression  92/100 (92%) were local recurrences  Recurrence/progression by extent of resection  R0/R1 resection – 82% had disease recurrence  R2 resection – 77% had disease progression  Distant metastasis uncommon – 22/119 patients (19%) Variablen (%) Number of recurrences 143 (45) 224 (25) 39 (10) 42 (2) Unknown17 (18) Site of recurrence or progression Retroperitoneal92 (92) Intraperitoneal26 (26) Lung14 (14) Liver6 (6) Bone6 (6) Skin/subcutaneous3 (3)

16 Predictors of Outcomes: Variables Examined Retroperitoneal Dedifferentiated Liposarcoma  Age  Gender  Location of initial surgery (BWH v. OSH)  DDLPS size  Multifocality  FNCLCC grade  Extent of resection (R0/R1 v. R2)  Tumor integrity (fragmented v. intact tumor specimen)  Chemotherapy at initial presentation  Radiation therapy at initial presentation  Number of organs resected

17 Retroperitoneal Dedifferentiated Liposarcoma Predictors of PFS Multivariable Cox Regression Analysis HR95% CIP value 2.271.20-4.290.012 Univariate Analysis Variable Median (months)95% CIP value Multifocality 0.084 Single tumor22.615.8-29.5 Multifocal disease13.16.6-21.4 Extent of Resection 0.041 R0/R122.414.8-29.5 R211.02.7-27.9 Tumor Integrity 0.004 Intact tumor specimen(s)23.917.7-29.9 Fragmented tumor specimen(s)6.63.5-19.4

18 Retroperitoneal Dedifferentiated Liposarcoma PFS: Tumor Integrity at Resection Fragmented tumor specimen Intact tumor specimen

19 Retroperitoneal Dedifferentiated Liposarcoma Predictors of LRFS Multivariable Cox Regression Analysis HR95% CIP value 0.610.38-0.990.045 1.751.01-3.030.047 Univariate Analysis Variable Median (months)95% CIP value Location of Initial Surgery 0.006 OSH15.38.31-22.29 BWH27.911.99-43.81 Multifocality 0.003 Single tumor24.519.29-29.71 Multifocal disease11.46.96-15.84 Extent of Resection 0.018 R0/R123.919.50-28.30 R25.73.83-7.57

20 Retroperitoneal Dedifferentiated Liposarcoma LRFS: Location of Initial Surgery and Multifocality Initial surgery at OSH Initial surgery at BWH/DFCI Multifocal disease Single tumor

21 Retroperitoneal Dedifferentiated Liposarcoma Predictors of DRFS Univariate Analysis Variable Median (months)95% CIP value Gender 0.029 Female57.532.3-98.5 Male31.822.1-51.1 FNCLCC grade 0.064 Intermediate51.132.3-59.0 High26.015.9-42.8 Extent of Resection 0.008 R0/R151.131.8-62.0 R217.43.3-27.9 Tumor Integrity <0.001 Intact tumor specimen(s)53.438.3-62.0 Fragmented tumor specimen(s)10.84.6-21.0 Chemotherapy at Initial Presentation 0.047 No chemotherapy49.731.8-59.0 Received chemotherapy13.88.4-55.1

22 Retroperitoneal Dedifferentiated Liposarcoma Predictors of OS Multivariable Cox Regression Analysis HR95% CIP value 1.831.04-3.210.037 4.001.50-10.670.006 2.201.02-4.740.045 Univariate Analysis Variable Median (months)95% CIP value Gender 0.010 Female77.857.7-111.9 Male49.134.8-60.8 FNCLCC grade 0.019 Intermediate59.349.1-83.3 High38.925.6-60.8 Extent of Resection <0.001 R0/R163.255.8-83.3 R217.810.0-41.5 Tumor Integrity <0.001 Intact tumor specimen(s)64.255.8-91.7 Fragmented tumor specimen(s)21.09.2-46.7

23 Retroperitoneal Dedifferentiated Liposarcoma OS: Grade, Extent of Resection, and Tumor Integrity High grade Intermediate grade R2 resection R0/R1 resection Fragmented tumor specimen Intact tumor specimen

24 Strengths and Limitations Retroperitoneal Dedifferentiated Liposarcoma  Limitations  Single institution retrospective study  Modest sample size  Strengths  Largest published cohort of patients with RP DDLPS  To our knowledge, this is the first study to examine primary RP DDLPS specifically  Thus, this study provides important prognostic information for the clinician evaluating a patient with primary RP DDLPS in the clinic

25 Conclusions  Primary RP DDLPS are large tumors (median size 20.5 cm), typically requiring multi-organ resection  Resections are often macroscopically complete (R0/R1, ~80%) but margins are rarely negative (~10%) Retroperitoneal Dedifferentiated Liposarcoma

26 Conclusions  Primary RP DDLPS are large tumors (median size 20.5 cm), typically requiring multi-organ resection  Resections are often macroscopically complete (R0/R1, ~80%) but margins are rarely negative (~10%)  Rate of recurrence/progression is high (84%)  Local recurrence is common (92%) and often multifocal  Distant recurrence is less common (19%) Retroperitoneal Dedifferentiated Liposarcoma

27 Conclusions – Multivariable Analysis  Initial surgery at BWH/DFCI was associated with better LRFS  Multifocal disease was associated with worse LRFS  High FNCLCC grade and R2 resection were associated with worse OS  Tumor fragmentation during resection was associated with worse PFS and OS  Neither chemotherapy nor radiation therapy at initial presentation was associated with PFS, LRFS, DRFS, or OS Retroperitoneal Dedifferentiated Liposarcoma

28

29 Surgical Treatment of 119 Patients with RP DDLPS at Initial Presentation Retroperitoneal Dedifferentiated Liposarcoma Variablen (%) Organ resected Kidney78 (66) Colon49 (41) Ureter22 (19) Adrenal21 (18) Pancreas19 (16) Spleen18 (15) Small bowel14 (12) Psoas13 (11) Diaphragm13 (11) Iliac vessels11 (9) Stomach8 (7) Bladder8 (7) Uterus3 (3) Ovary7 (6) Variablen (%) Number of organs resected 07 (6) 132 (27) 229 (24) 313 (11) 412 (9) 57 (6) 69 (8) 73 (3) Unknown7 (6)

30 Treatment of DDLPS Recurrence Retroperitoneal Dedifferentiated Liposarcoma Treatment at First Recurrence/Progression (n=100)n% Surgery76 Alone41 + Chemotherapy + radiation therapy22 + Chemotherapy20 + Radiation therapy13 No surgery24 Chemotherapy + radiation therapy11 Chemotherapy14 Radiation therapy11 None88

31 FNCLCC Grading System Retroperitoneal Dedifferentiated Liposarcoma

32 Outcomes of 119 Patients with Primary RP DDLPS Retroperitoneal Dedifferentiated Liposarcoma Variablen (%) Status at last visit (n=119) NED34 (29) Stable disease8 (7) Disease progression75 (63) Unknown2 (2) Last known status (n=119) NED15 (13) AWD13 (11) DOD63 (53) Dead of other cause or cause unknown21 (18) Unknown7 (6) Variablen (%) Number of recurrences (n=79) 143 (45) 224 (25) 39 (9.5) 42 (2.1) Unknown17 (18) Site of recurrence or progression (n=100) Retroperitoneal92 (92) Intraperitoneal26 (26) Lung14 (14) Liver6 (6) Bone6 (6) Skin/subcutaneous3 (3)

33 Retroperitoneal Dedifferentiated Liposarcoma Predictors of LRFS, DRFS, PFS, and OS Among Patients Undergoing R0/R1 Resection: Multivariable Cox Regression Analyses PFS Variable Median (months)95% CIP value Fragmented tumor specimen(s) (v. intact tumor specimen[s])2.131.09-4.160.028 LRFS Variable Median (months)95% CIP value Initial surgery at BWH (v. OSH)0.590.35-0.970.037 Multifocal disease (v. single tumor)2.151.21-3.810.009 OS Variable Median (months)95% CIP value Fragmented tumor specimen(s) (v. intact tumor specimen[s])2.271.20-4.290.012 DRFS Variable Median (months)95% CIP value Fragmented tumor specimen(s) (v. intact tumor specimen[s])3.661.57-8.540.003

34 Retroperitoneal Sarcomas (RPS) Retroperitoneal Dedifferentiated Liposarcoma  Retroperitoneal sarcomas constitute ~10-15% of all soft tissue sarcoma with incidence of 2-5 per million  Surgical resection is the only curative treatment  Local recurrence is common (5-year local recurrence ~70%) and accounts for nearly 90% of disease-related mortality (5-year overall survival ~50%)  Liposarcomas account for the majority of RPS with multiple histologic subtypes:  Well-differentiated  Dedifferentiated  Myxoid/round cell  Pleomorphic Anaya DA, et al. Ann Surg Oncol. 2009;16:667-675. Crago AM, Singer S. Curr Opin Oncol. 2011;23(4):373-378. Mussi C, et al. Cancer. 2008;113:1657-1665.

35 Retroperitoneal Dedifferentiated Liposarcoma (RP DDLPS): The Current Knowledge Deficit Retroperitoneal Dedifferentiated Liposarcoma  To date, studies examining RPS and DDLPS include either multiple histologies and/or disease locations  A few studies have included subsets of patients with RP DDLPS StudyPatient CohortFindings Singer S, et al. Ann Surg. 2003;238:358-70  177 patients w/primary RP LPS  65 (37%) w/RP DDLPS  RP DDLPS - increased risk of death (HR 6.0), local recurrence (HR 3.6), distant recurrence (HR 15.4)  RP DDLPS - 83% local recurrence rate, 30% distant recurrence rate at 3 years Lahat G, et al. Ann Surg Onc. 2008;15:1585-93  77 patients w/DDLPS, 58 w/WDLPS  DDLPS - higher recurrence (82% vs 50%), shorter RFS (13.5 vs 55.5 mo), shorter OS (45.8 mo vs not reached) and worse 5-year survival (37% vs 92%)  No variable significant on univariate analysis for RFS among 77 DD patients Ghadimi M, et al. Ann Surg Onc. 2011;18:3762- 70  40 patients w/DDLPS systemic metastases  29 (73%) had RPS  14% metastatic rate (17% for primary, 9% for secondary DDLPS)  Median survival of metastatic patients was 11.5 mo, 5-year disease- specific survival 5%  Patients who underwent surgery had better 5-year DSS (19%)  No study has been performed examining RP DDLPS alone

36 Conclusions  Nearly 1/4 of patients presenting to referring institutions underwent surgery by urologists or gynecologists  It is important that these surgeons consider RP DDLPS when evaluating patients with an RP mass and be familiar with the management of RP DDLPS Retroperitoneal Dedifferentiated Liposarcoma

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