Malignancy Grade and Histologic Subtype of Primary Retroperitoneal Sarcoma (RPS) are Predictive of...

Malignancy Grade and Histologic Subtype of Primary Retroperitoneal Sarcoma (RPS) are Predictive of Pattern

of Recurrence: a Large Retrospective Study from the Transatlantic RPS Working Group

Gronchi A, Strauss D, Miceli R, Bonvalot S, Swallow CJ, Hohenberger P, Van Coevorden F, Rutkowski P, Callegaro D,

Pollock RE and Raut CP

Disclosures

• No disclosures

Background

Surgery is the primary and only curative treatment of localized disease

Quality of local treatments and biology of the tumor are the major determinants of outcome

Gronchi A and Pollock RE. Ann Surg Oncol 2013; 20(7): 2011-2013

ControversyWhat is the appropriate extent of resection?

Great Debates SSO 2013

Toulemond et al. Ann Oncol 2014; 25: 735-742

Questions

• What are the patterns of recurrence and survival?

• Do different strategies by institution translate into different outcomes?

Methods

Trans-Atlantic RPS Working Group

• 1007 consecutive primary adult-type RPS from 8 centers– Ewing/PNET, alveolar/embryonal rhabdo, desmoid,

GYN sarcoma and GIST excluded

Patient Characteristics• 2002-2011

• M 52%, F 48%

• Median age: 58 (IQR 48-67)

• Median size: 20 cm (IQR 13-30 cm)

• Macroscopic complete resection: 95%– Tumor rupture with spillage in the operative field: 6%– Contamination: 4%

• Multifocality: 9%

• Distance from home > 100km (62 miles): 46%

Patient Characteristics• Postoperative complication ≥3 according to CTCAE: 21%

• Reoperation: 11%

• Median number of resected organs: 2 (IQR 1-4)

• CT done: 18% (Anthracyclin based: 12%)

• RT done: 32% (preoperatory: 20%)

• Median FU: 58 months (IQR 36-90)

• Grading: 1 (34%), 2 (38%), 3 (28%)

WD LPSGII DD LPSGIII DD LPSLEIOSFTMPNSTUPSOTHER

Histology Distribution

Statistical Analysis

• OS estimated with KM curves

• CCI of LR and DM calculated in a competing risk framework

• Multivariable Cox regression analysis of OS, LR and DM

Results

Over

Entire Cohort

5-yr 66.8% (95%CI 63.5-70.2%)8-yr 56.1% (95%CI 52.0-60.6%)10-yr 45.8% (95%CI 39.7-52.8%)

5-yr CCI 25.9% (95% CI 23.1-29.1%)8-yr CCI 31.3% (95%CI 27.8-35.1%)10-yr CCI 35.0% (95%CI 30.5-40.1%)

5-yr CCI 21.0% (95% CI 18.4-23.8%)8-yr CCI 21.6% (95%CI 19.0-24.6%)10-yr CCI 21.6% (95%CI 19.0-24.6%)

0.0

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Time (months)

CC

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0 12 24 36 48 60 72 84 96

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Time (months)

CC

I

0 12 24 36 48 60 72 84 96

Time (months)

OS

0 12 24 36 48 60 72 84 96

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0.8

1.0

Overall Survival

Local Recurrence Distant Metastasis

Current status – overall survival

SEER: Primary 1365 RPS5yr OS – 47% (2010)

Time (months)

OS

0 12 24 36 48 60 72 84 96

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0.2

0.4

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1.0

Transatlantic Sarcoma Group>1000 Primary RPS

5yr OS – 67% (2014)

OS by Histology

WD LPS: 83.4%

SFT: 76.5%

GIII DD LPS: 30.2%

LMS: 43.4%

GII DD LPS: 51.1%

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Time (months)

CC

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LMS 1MPNST 1Other 1SFT 1UPS 1WD-lipo 1DD-lipo-G1-2 1DD-lipo-G3 1

0 12 24 36 48 60 72 84 96

WD LPS: 34.5%

SFT: 14.0%

GIII DD LPS : 38.0%

LMS: 11.6%

GII DD LPS: 49.1%

LR by Histology

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Time (months)

CC

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LMS 2MPNST 2Other 2SFT 2UPS 2WD-lipo 2DD-lipo-G1-2 2DD-lipo-G3 2

0 12 24 36 48 60 72 84 96

DM by Histology

WD LPS: 0.4%

SFT: 12.7%

GIII DD LPS: 32.6%

LMS: 52.6%

GII DD LPS: 9.1%

Results from the Cox proportional hazards models on the three endpoints analyzed.  OS LR DM  HR 95% CI P HR 95% CI P HR 95% CI PAge, years     <0.001     0.004     0.055 67 vs. 48* 1.49 (1.25, 1.77)   1.27 (1.07, 1.50)   1.21 (1.00, 1.47)  Size, cm     0.021     0.115     0.090 30 vs. 13* 1.28 (0.99, 1.66)   1.31 (1.00, 1.71)   0.94 (0.71, 1.25)  Surgical resection     <0.001     <0.001     0.059 Incomplete vs. complete 2.54 (1.61, 4.00)   3.71 (2.35, 5.83)   2.02 (0.97, 4.17)  FNCLCC grade     <0.001     <0.001     <0.001 II vs. I 2.50 (1.44, 4.34)   2.54 (1.52, 4.25)   2.21 (1.26, 3.87)  Multifocality <0.001 <0.001 0.003 Yes vs.no 1.91 (1.34-2.74) 2.16 (1.51-3.09) 1.93 (1.25-2.96)Histological subtype     0.076     0.009     <0.001 WD liposarcoma vs. SFT 1.65 (0.44, 6.18)   2.35 (1.04, 5.32)   0.53 (0.20-1.37)    DD liposarcoma vs. SFT 1.64 (0.80, 3.35)   1.98 (0.92, 4.24)   0.98 (0.45, 2.13)   Leiomyosarcoma vs.SFT 1.98 (0.95, 4.11)   1.06 (0.47, 2.40)   2.62 (1.22, 5.61)   MPNST vs. SFT 1.69 (0.68, 4.19)   1.08 (0.38, 3.04)   0.93 (0.32, 2.70)   Other vs. SFT 2.87 (1.31, 6.29)   1.67 (0.67, 4.15)   2.19 (0.95, 5.03)  CT     0.208     0.175     0.429 Yes vs.no 1.21 (0.90, 1.64)   1.28 (0.90, 1.83)   1.14 (0.82, 1.59)  RT     0.704     0.001     0.200 Yes vs. no 0.95 (0.71, 1.26)   0.55 (0.40, 0.77)   0.82 (0.60, 1.11)  

Abbreviations: HR, hazard ratio; CI, confidence interval; OS, overall survival; LR, local recurrence; DM, distant metastases; WD: well differentiated; DD: dedifferentiated; SFT, solitary fibrous tumor; MPNST, malignant peripheral nerve sheath tumor; RT, radiation therapy; CT, chemotherapy.* The two values are, respectively, the 3rd and 1st quartiles of the variable distribution.

Should the strategy be tailored to histology subtype?

• Extended resection and/or radiation for GII-GIII DD LPS?

• Adjacent uninvolved organ preservation in LMS and SFT?

• WD LPS ?

A closer look at outcome by center

• specific center was not significant on multivariate analysis

but

some differences in strategy and outcomes were observed

1007 consecutive primary adult-type RPS from 8 centers

25%25%14 %

10 %12 %

14 %

1. Focus on WD LiposarcomaPure ALT Sclerosing, inflammatory, myxoid like, cellular

(GI DD)

1. Focus on WD Liposarcoma

tumor size by center number of resected organs by center

Boston London Milano Other Paris Toronto

02

46

810

N. r

esec

ted

orga

ns

Histotype: WD lipo

Abbreviations: IQR, interquartile range

5 (IQR 3-7)

3 (IQR 2-5)

2 (IQR 1-3)

Boston London Milano Other Paris Toronto

020

4060

80

Tum

or s

ize

(cm

)

Histotype: WD lipo

Abbreviations: IQR, interquartile range

26cm(IQR 14-24cm)

26cm(IQR 19-32cm)

24cm(IQR 16-33cm)

1. Focus on WD Liposarcoma

RT administration by center

No 100% 86,5% 28%

Yes 0% 13,5% 72%

Quality of surgery by center

Complete 100% 94% 100%

Incomplete 0% 6% 0%

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Time (months)

CC

I

0 12 24 36 48 60 72 84 96

CCI of LR by center

5%

35%

50%

1. Focus on WD Liposarcoma

1. Focus on WD Liposarcoma

Time (months)

OS

0 12 24 36 48 60 72 84 96

0.0

0.2

0.4

0.6

0.8

1.0 88%

76%

88%

1. Focus on WD Liposarcoma

• Better local control in patients treated by extended resection and RT

• OS apparently unaffected at 8-yr time point

• LR risk seems to flatten out with a combination of extended surgery and RT

2. Focus on Leiomyosarcoma

tumor size by center number of resected organs by center

2. Focus on Leiomyosarcoma

Boston London Milano Other Paris Toronto

020

4060

80

Tum

or s

ize

(cm

)

Histotype: LMS

Boston London Milano Other Paris Toronto

02

46

810

N. r

esec

ted

orga

ns

Histotype: LMS

4 (IQR 3-4)

3 (IQR 2-3)

1 (IQR 0-2)

RT administration by center CT administration by center

2. Focus on Leiomyosarcoma

No 87% 66% 19%

Yes 13% 34% 81%

No 100% 37% 76%

Yes 0% 63% 24%

CCI of LR by center CCI of DM by center

2. Focus on Leiomyosarcoma0.

00.

10.

20.

30.

40.

50.

60.

7

Time (months)

CC

I

0 12 24 36 48 60 72 84 96

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0.3

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0.6

0.7

Time (months)

CC

I

0 12 24 36 48 60 72 84 96

CCI of LR at 5yr7,4% 9,1% 0%

CCI of DM at 5yr38,9% 58,9% 55,9%

2. Focus on Leiomyosarcoma

• Optimal local control with adequate surgery + RT

• New therapies eagerly needed to address the systemic risk, as available ones seems not to help

Limitations

• Retrospective study

• Different case mix, different FU schedules

• No prospective QoL measures

• Similar surgical strategies, but different indication to adjuvant/neoadjuvant therapies

…in brief

After primary optimal surgery histology subtype is one of the major determinant of outcome

• G2-G3 DD LPS – highest LR rate

• G3 DD LPS and LMS – highest DM rate

• WD LPS indolent course but constant risk over time

• Conventional SFT – least LR and DM rate

Different strategies for local therapy

• May lead to different outcomes in low-intermediate grade LPS

125 over 256 patients recruited

Different strategies for local therapy

• May lead to different outcomes in low-intermediate grade LPS

• May be of limited value when the systemic risk is high (Leio, GIII DD LPS). Need new systemic agents to address the systemic risk

This unprecedented collaboration has led to:

• The collection of a large retrospective series which will serve as historical control for all future studies

• An open comparison of outcomes amongst participating centers, which allows to learn what are the best practice patterns at each institution.

• Active recruitment of the ongoing prospective randomized study on preoperative RT in RPS, which will answer to the question of the role of RT in this disease.

• Application for a prospective trans-atlantic registry to create a library of information to use for future therapies

Trans-Atlantic RPS Working Group

… alessandro.gronchi@istitutotumori.mi.it