Local Recurrence Growth Rate Predicts OutcomeIn Locally Recurrent Retroperitoneal Liposarcoma

James Park, MD, Li-Xuan Qin, PhD, Francesco Prete, MDMurray Brennan, MD, Samuel Singer, MD

Background: Retroperitoneal Liposarcoma

Retroperitoneal sarcoma (RPS) 15% of soft tissue sarcomas (STS)1

Liposarcoma (LS) most common; 20% of all STS, up to 50% of RPS2

Complete resection feasible in 80% of primary RPLS3

Local recurrence 40~80%; local effects cause of death in 75%1,2

1. Stoeckle. Cancer 2001 2. Lewis. Ann Surg 1998 3. Singer. Ann Surg 2003

Background: Retroperitoneal Liposarcoma

Gross margin, grade, and histologic subtype predict survival1,2

Subtype and contiguous organ resection, predict local recurrence1

No objective consensus to guide re-resection of local recurrence following complete resection

1. Singer. Ann Surg 2003 2. van Dalen. EJSO 2006

Histologic subtype defines grade and

predicts local recurrence and survival in RPLS

1. Singer. Ann Surg 2003

Grade 5-yr DSS (%) 5-yr LRFS (%)

Well-differentiated low 83 45

Dedifferentiated high 20 12

Myxoid (<5% round cell) low 75 40

Round cell (>5% round cell) high 35 NA

Purpose

Determine prognostic factors for survival and recurrence in patients with locally recurrent retroperitoneal liposarcoma

Use these factors to guide therapy and define subset of patients with locally recurrent retroperitoneal liposarcoma most likely to benefit from surgical resection

Methods

Prospective sarcoma database reviewed 7/82~10/05

All STS treated N=6682

All RPS treated N=607

All RPLS treated N=355

Primary RPLS treated N=207

Complete resection N=180 (180/207 87%)

Local recurrence (LR) N=105 (105/180 58%)

Complete resection of LR N=61 (61/105 58%)

Methods

Endpoints:Disease-specific survival (from time of first local recurrence) for all 105 patientsLocal recurrence-free survival for 61 patients re-resected

Statistics: Univariate analysis- Kaplan Meier curve and Log-rank test Multivariate analysis- Cox’s PH model and Score test Cut-point finding- Minimum P value method

Patient/tumor variables Treatment variables

Age Sex Microscopic Margins

Histologic Subtype Grade Contiguous organ resection

Tumor Size (sum largest dimensions) Adjuvant Radiation

Time to LR Adjuvant Chemotherapy

Results: Patient/Tumor Characteristics

Variable Median Range

Age (yrs) 60 24~84

Tumor Size (cm) 27 5~70

Time to LR (mo) 21 2~160

Variable Category N % Total

Sex Female 36 34.3

Histologic Grade High 52 49.5

Histologic Subtype Well-differentiated 48 45.7

Dedifferentiated 49 46.7

Myxoid 4 3.8

Round cell 3 2.9

Variable N % Total

Microscopic Margin Negative 53 51

Contiguous Organ Resection 65 62

Adjuvant Radiation EBRT

Brachy

9

8

8

7

Adjuvant Chemotherapy 10 9

Results: Treatment characteristics

Univariate Analysis of Disease-Specific Survival

for First LR (N=105)

Start time: First LR End point: Dead of disease

LR Growth Rate =

Variable p Variable p

LR Growth Rate <0.00001 Primary Size 0.1

LR Resection <0.00001 Contig Organ 0.1

Primary Grade <0.00001 Age 0.2

Primary Subtype <0.0001 Chemo 0.3

LR Size <0.0001 Micro Margin 0.4

Time to LR 0.01 Radiation 0.6

Sex 0.9

Tumor size (sum of max dimensions on imaging)

Time from primary resection to LR

Multivariate Analysis of Disease-Specific Survival

for First LR (N=105)

Variable p HR LCI 0.95 UCI 0.95

LR Growth Rate 0.015 1.2 1.0 1.4

LR Resection 0.010 0.4 0.2 0.8

Primary Low Grade 0.010 0.4 0.2 0.8

Univariate Analysis of Disease-Specific Survival

for Complete Resection of First LR (N=61)

Start time: LR resection End point: Dead of disease Second recurrence

LR Growth Rate =

Variable p Variable p

LR Growth Rate <0.00001 Micro Margin 0.3

LR Grade <0.0001 Primary Size 0.4

LR Subtype 0.001 Sex 0.4

LR Size 0.009 Age 0.4

Primary Grade 0.02 Radiation 0.7

Primary Subtype 0.1 Chemo 0.9

Time to LR 0.2

Tumor size (sum of max dimensions on pathology)

Time from primary resection to LR

Multivariate Analysis of Disease-Specific Survival

for Complete Resection of First LR (N=61)

Variable p HR LCI 0.95 UCI 0.95

LR Growth Rate 0.002 2.2 1.3 3.6

LR Low Grade 0.020 0.2 0.1 0.8

Primary Low Grade 0.990 1.0 0.4 2.8

LR Size 0.001 1.0 1.0 1.1

LR Low Grade 0.001 0.2 0.1 0.5

Primary Low Grade 0.290 0.6 0.2 1.6

Univariate Analysis of Disease-Free Survival

for Complete Resection of First LR (N=61)

Variable p Variable p

LR Growth Rate <0.00001 Sex 0.2

LR Size 0.002 Micro Margin 0.2

LR Grade 0.06 Primary Subtype 0.7

LR Subtype 0.07 Primary Size 0.8

Age 0.09 Primary Grade 0.8

Time to LR 0.12 LR Resection 1.0

Multivariate Analysis of Disease-Free Survival

for Complete Resection of First LR (N=61)

Variable p HR LCI 0.95 UCI 0.95

LR Growth Rate <0.001 2.7 1.7 4.3

LR Low Grade 0.390 0.7 0.4 1.5

LR Size 0.001 1.1 1.0 1.1

LR Low Grade 0.024 0.5 0.2 0.9

Finding a cutoff for LR growth rate

using the Minimum p value method

0.9

1. Mazumdar. Statist Med 2003

Disease-Specific Survival by LR Growth Rate

All 105 Patients 61 Re-resected

Resection does not improve Disease-specific survival

for LR Growth Rate ≥ 0.9 (N=105)

Summary

LR growth rate and primary grade are independent predictors of disease-specific survival in locally recurrent RPLS

Patients with LR growth rate ≥ 0.9 cm/month had significantly worse disease-specific survival

Re-resection of the recurrence did not alter the poor outcome for patients with LR growth rate ≥ 0.9 cm/month

Conclusion

LR growth rate predicts disease-specific survival and local control following complete resection of locally recurrent RPLS

Patients with LR growth rate ≥ 0.9cm/month did not benefit from aggressive operative management and should be considered for trials of novel targeted therapies