Million L, Terezakis S, Donaldson S, Anderson J, Randall RL, Hayes- Jordan A, Laurie F, Coffin C, McCarville MB, Hawkins D, Spunt SL CTOS October 17, 2014.

Million L, Terezakis S, Donaldson S, Anderson J, Randall RL, Hayes-Jordan A, Laurie F, Coffi n C, McCarville MB, Hawkins D, Spunt SL

CTOS October 17, 2014

Berlin

LOCAL CONTROL AMONG YOUNG PATIENTS WITH NON-RHABDOMYOSARCOMA SOFT TISSUE SARCOMA

(NRSTS) FOLLOWING RISK-BASED TREATMENT: RESULTS FROM CHILDREN’S ONCOLOGY GROUP (COG)

STUDY ARST0332

Nothing to disclose

Disclosures

Primary: Evaluate local failures for non-metastatic NRSTS assigned to

receive radiation therapy (RT) on Children’s Oncology Group (COG) Trial ARST0332

Secondary: Evaluate potential predictors of local failure Analyze local control rates after neoadjuvant chemo/RT for

unresected NRSTS

Objective

All eligible non-metastatic NRSTS Include only patients assigned to RT <30 years of age Conducted from 2007 - 2012 56 institutions Overall trial results reported at ASCO 2014 (Spunt)

Materials and MethodsCOG ARST0332

Trial Design

Definition of Negative Surgical Margin

> 5mm

*or if tumor excised in continuity with periosteum/fascia

IfosIfos

BoostMargin + 10.8 Gy

Gross 19.4 Gy

Surgery

Week 1 4 7 10 13 16

RT 55.8 Gy / 31 Fx

Adria/Ifos

Surgery

Week 1 4 7 10 13 16

RT 55.8 Gy / 31 Fx

Week 1 4 7 10 13 16

RT 45 Gy / 25 Fx

Arm B = post-op RT only

Arm C = post-op RT/chemo

Arm D = neoadjuvant RT/chemo

Treatment regimens

Surgery

Adria/Ifos Ifos Ifos

Adria/Ifos

Adria/Ifos

Radiation Therapy: Conformal Target Volumes

Gross tumor volume (GTV)

Clinical Target volume (CTV) = GTV + 1.5 cm

Planning Target Volume (PTV) = CTV + .5 cm

Results: Clinical Characteristics

Results: 4 yr Cumulative Incidence of Local Failure

Years

Loca

l Fai

lure

s

Arm B = 9%

Arm C = 13%

Arm D = 14%

p=0.664

Results: Potential prognostic factors for LF (Cox model)Prognostic factor Categories P-value

Age 0-14; 15+ years .61Sex male; female .08

Race white; black; other .17

Tumor characteristics

Site body wall; head and neck;lower extremity;upper extremity; viscera

.49

Type SS; MPNST; ES liver; UDS;Unclassified; ”other NRSTS”

.16

Size <5; > 5cm .89

Depth superficial; deep .94

Invasiveness non-invasive; invasive .21

Status of surgical margins (arm B/C only)

negative; positive .02

Results: Arm C margin status

Prop

ortio

n

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

Status of margins of surgical resection: CENSOR FAIL TOTALMEDIANPositive 20 9 29 .

Negative 44 10 54 .

Test: p=0.21

Event-free survival ARST0332, eligible Arm C patientsby margin status, excluding problem patients

Surv

ivor

s

Years

Negative (72%)

Microscopic + (64%)

p=0.21

Years

Surv

ivor

s

Event Free Survival Local Failure

Prop

ortio

n Loc

al Fa

ilure

s

0.00

0.05

0.10

0.15

0.20

0.25

0.30

Years

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

Log-Rank, p=0.0015

Cumulative incidence of local site failure, ARST0332 Arms C, by margins

Status of margins of surgical resection: Positive Negative

Microscopic + (29%) n=29

Negative (3%)n=54

p=0.0015

Treatment Arm D # patients

Total eligible 121

Surgery 98 (81%)

Negative margins (R0) 71

Microscopic margins (R1) 19

Gross residual 2

Unknown 6

No Surgery 23 (19%)

“Off study” before week 13 16

Unresectable at week 13 5

Poor prognosis 1

Parent/patient preference 1

Results: Arm D characteristics of week 13 surgery

Results: Arm D margin statusSu

rviv

ors

Years

p=0.21

Prop

ortion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

w13stat CENSOR FAIL TOTALMEDIANGR, margin+ 15 4 19 .GR, margin- 52 19 71 .

Test: p=0.63

Event-free survival ARST0332, eligible Arm D patients (no problems) with week 13 surgeryby week 13 status

Negative (62%)

Microscopic + (72%)

p=0.63

Years

Surv

ivor

s

Local Failure Event Free Survival

Prop

ortion

Loca

l Fail

ures

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

Years

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

Log-Rank, p=0.5817

Cumulative incidence of local site failure, ARST0332 Arms Dby status if surgical margin

Status of margins of surgical resection: Positive Negative

Microscopic + (7%) n=19

Negative (3%) n=71

p=0.58

Eligible patients Local failures Received RT In field/out field failures* Arm B (11) 1 1 In field (1)

Arm C (91) 12 9 In field (6)Out of field (3)

Arm D (121) 17 11 In field (11)

Results: Where are local failures after RT?

*In field - 95-100% isodose Out of field - <5-20% isodose

Conclusions Overall cumulative incidence of LF for non-metastatic high grade NRSTS: <15%

Surgical margins status is predictive of LF for initially resected high grade NRSTS: > 5cm; margin negative = 3% vs. microscopic positive = 29% 55.8 Gy in combination with chemotherapy is effective for > 5cm margin

negative tumors The reasons for higher LF rate in >5 cm microscopic positive margin requires

further analysis

After neoadjuvant chemo/RT over 80% high grade NRSTS underwent surgical resection: >90% had R0/R1 resection Local failure rates are low regardless of margin status:

negative = 3% vs microscopic positive = 7% Lower dose (45 Gy) and PTV (2 cm) is effective in the neoadjuvant setting in

combination with chemotherapy Whether boost for microscopic positive margin (total dose 55.8 Gy) is necessary

requires further analysis

Regardless of tumor size and local control there is no difference in EFS.

Compliance with Rt excellent

Study Chair ARST 0332: Sheri Spunt, MD Chair of Soft Tissue Sarcoma COG: Doug Hawkins, MD Statistician: James Anderson, Ph.D COG research coordinator: Ellen Tsan, MPH COG protocol coordinator: Uhma Ganesan Radiation Oncology: Sarah Donaldson, MD; Stephanie Terazakis, MD Pediatric Oncology: Alberto Pappo, MD; Steve Skapek, MD Surgery: R. Lor Randall, MD; Andrea Hayes-Jordan, MD Radiology: Beth McCarville, MD; Simon Kao, MD Pathology: Cheryl Coffin, MD; David Parham, MD IROC (formerly QARC): Fran Laurie; Karen Morano, MPH, CMD

Acknowledgments

Results: EFS based on % necrosis in surgical specimen at week 13

0-50% necrosis (n=34)

60-80% necrosis (n=21)

90-100% necrosis (n=32)

Years

Surv

ivor

s

p=0.11

Radiation Therapy: Target volumes Paraspinal synovial sarcoma > 5cm, high grade

Results: Multi-variate analysis Arms B/C surgical margins prognostic factor

Years

Loca

l fai

lure

s

Negative

Microscopic + (23%) n=40

Negative (3%) n=54

p=0.005

Results: 4 year EFS by Treatment Arm

Arm D = 65% Arm C = 70% Arm B = 73%

Years

Surv

ivor

s

p=0.35

QARC

Results: EFS by margin statusPr

opor

tion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

Status of margins of surgical resection: CENSOR FAIL TOTALMEDIANPositive 20 9 29 .

Negative 44 10 54 .

Test: p=0.21

Event-free survival ARST0332, eligible Arm C patientsby margin status, excluding problem patients

Surv

ivor

s

Years

Negative margin

Microscopic +

p=0.21Pr

oport

ion

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

w13stat CENSOR FAIL TOTALMEDIANGR, margin+ 15 4 19 .GR, margin- 52 19 71 .

Test: p=0.63

Event-free survival ARST0332, eligible Arm D patients (no problems) with week 13 surgeryby week 13 status

Negative margin

Microscopic +

p=0.63

Years

Surv

ivor

s

ARM C ARM D

Radiation Therapy: DoseTotal dose PTV PTV boost

Arm B: Post-operative RT Microscopic margin 55.8 Gy 45 Gy 10.8 Gy

Arm C: Post-operative RT Negative margin/or Microscopic margin

55.8 Gy 45 Gy 10.8 Gy

Arm D: Pre-operative RT Negative margin Microscopic margin Macroscopic margin

45 Gy55.8 Gy64.8 Gy

45 Gy45 Gy45 Gy

010.8 Gy (week 16)19.8 Gy (week 16)

Results: Histologic subtype cumulative incidence of local failure

MPNST (22%)

UnclassifiedUndifferentiated

Embryonal sarcoma liver

other NRSTSSynovial sarcoma (6%)

Loca

l Fai

lure

s

Years

p=0.09

Arm B Arm C Arm D

Evaluable 20 102 141

RT given

18 75 112

No Rt given 2 27 27

Included in this analysis 11 91 121

No Rt given in this analysis All received RT

16 - 27 9-27

Results: Compliance with RT guidelines

No Radiation Therapy Reasons for withholding RT

Arm B (2) Age, parent preference

Arm C (27) Liver (11) age ( 4) physician (3) parent/patient (2) progressive disease (2) no reason (1) RT at non-COG facility (1) wrong arm (1)

Arm D (27) off study Liver (11) physician (9) age (3) progressive disease (3) patient (1)