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

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

Berlin

LOCAL CONTROL AMONG YOUNG PATIENTS WITHNON-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 toreceive 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 forunresected 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 tumorexcised incontinuity

withperiosteum/fascia

Ifos

Boost

Margin + 10.8 Gy

Gross 19.4 Gy

Surgery

Week 1

RT 55.8 Gy / 31 Fx

Adria/Ifos

Surgery

Week 1

RT 55.8 Gy / 31 Fx

Week 1

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

Adria/Ifos

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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

Local Failures

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

.61

Sex

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

Survivors

Years

Negative (72%)

Microscopic + (64%)

p=0.21

Years

Survivors

Event Free Survival

Local Failure

Microscopic + (29%)

n=29

Negative (3%)

n=54

p=0.0015

Treatment Arm D

# patients

Total eligible

121

Surgery

98 (81%)

Negative margins (R0)

Microscopic margins (R1)

Gross residual

Unknown

No Surgery

23 (19%)

“Off study” before week 13

Unresectable at week 13

Poor prognosis

Parent/patient preference

Results: Arm D characteristics of week 13 surgery

Results: Arm D margin status

Survivors

Years

p=0.21

Negative (62%)

Microscopic + (72%)

p=0.63

Years

Survivors

Local Failure

Event Free Survival

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)

In field (1)

Arm C (91)

In field (6)

Out of field (3)

Arm D (121)

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 marginnegative tumors

The reasons for higher LF rate in >5 cm microscopic positive margin requiresfurther 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 incombination with chemotherapy

Whether boost for microscopic positive margin (total dose 55.8 Gy) is necessaryrequires 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 % necrosisin surgical specimen at week 13

0-50% necrosis (n=34)

60-80% necrosis (n=21)

90-100% necrosis (n=32)

Years

Survivors

p=0.11

Radiation Therapy: Target volumes

Paraspinal synovial sarcoma

> 5cm, high grade

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

Years

Local failures

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

Survivors

p=0.35

QARC

Results: EFS by margin status

Survivors

Years

Negative margin

Microscopic +

p=0.21

Negative margin

Microscopic +

p=0.63

Years

Survivors

ARM C

ARM D

Radiation Therapy: Dose

Total 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 Gy

55.8 Gy

64.8 Gy

45 Gy

10.8 Gy (week 16)

19.8 Gy (week 16)

Results: Histologic subtypecumulative incidence of local failure

MPNST (22%)

Unclassified

Undifferentiated

Embryonal sarcoma liver

other NRSTS

Synovial sarcoma (6%)

Local Failures

Years

p=0.09

Arm B

Arm C

Arm D

Evaluable

102

141

RT given

112

No Rt given

Included in this analysis

121

No Rt given in this analysis

All receivedRT

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) progressivedisease (3) patient (1)