1. 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
One of the primary objectives of his study is assess failure patterns of patients enrolled on this trial.
Goal of this analysis is to look at local failure among non-mets NRSTS patients assigned to receive RT.
Secondary goal
No standard of care for RT dose and volume in pediatric /yng adults heterogenous grp of NRSTS.

2. Disclosures Nothing to disclose
One of the primary objectives of his study is assess failure patterns of patients enrolled on this trial.
Goal of this analysis is to look at local failure among non-mets NRSTS patients assigned to receive RT.
Secondary goal
No standard of care for RT dose and volume in pediatric /yng adults heterogenous grp of NRSTS.

3. Objective
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
One of the primary objectives of his study is assess failure patterns of patients enrolled on this trial.
Goal of this analysis is to look at local failure among non-mets NRSTS patients assigned to receive RT.
Secondary goal
No standard of care for RT dose and volume in pediatric /yng adults heterogenous grp of NRSTS.

4. Materials and Methods COG ARST0332
All eligible non-metastatic NRSTS
Include only patients assigned to RT
<30 years of age
Conducted from
56 institutions
Overall trial results reported at ASCO 2014 (Spunt)

5. Trial Design
For those grossly resected at study entry, only high grade tumors received RT.
For smaller tumors (< 5 cm) Arm B: limit toxicity by using moderate dose/conformal RT volume in margin +
Arm C/D: larger tumors maximize efficacy of local and systemic control using adjvant chemo RT with larger tumors

6. Definition of Negative Surgical Margin
> 5mm
Around entire tumor
*or if tumor excised in continuity
with periosteum/fascia

7. Treatment regimens Arm B = post-op RT only Arm C = post-op RT/chemo
Surgery
RT 55.8 Gy / 31 Fx
Week 1 4 7 10 13 16
Arm C = post-op RT/chemo
Surgery
RT 55.8 Gy / 31 Fx
Ifos
Adria/Ifos
Adria/Ifos
Ifos
Week 1 4 7 10 13 16
Graphically depicts the treatment regimens
Arm B: RT only
Arm C: Included margin – and + patients and received combination 55. 8Gy with ifos
Arm D: chemo followed by 45 Gy pre-op dose with ifos. Boost were given for margin + post surgery week 13.
RT at discretion of treating physician
Liver primary : post-op (arm C)
Age <24 months
All RT data was centrally reviewed for compliance with guidelines
Arm D = neoadjuvant RT/chemo
Boost
Margin Gy
Gross Gy
RT 45 Gy / 25 Fx
Surgery
Adria/Ifos
Adria/Ifos
Ifos
Ifos
Week 1 4 7 10 13 16

8. Radiation Therapy: Conformal Target Volumes
Gross tumor volume (GTV)
Clinical Target volume (CTV) =
GTV cm
Planning Target Volume (PTV) = CTV + .5 cm
Conformal target volumes using ct based treatment planning was required. All radiation was centrally reivewed for compliance to guidelines

9. Results: Clinical Characteristics
Points: 223 eligible patients (few pts arm B)
Age - 2/3 yng
Site:Arm C = 46% visceral (n= 42 of which 21 liver) Rt at discretion of treating physician
Arm D= 21% visceral (n=25 of which 13 liver) No RT
Tumor size = by design all arm B 5 cm or less and arm C > 5 cm. Arm D - 10% (13 patients) , 5 cm tumors
Path: SS most common equal distribution of MPNST in each arm

10. Results: 4 yr Cumulative Incidence of Local Failure
Arm D = 14%
Arm C = 13%
Local Failures
Arm B = 9%
Note arm D steep increase in LF before week 13 but don’t know if PD or many went off study prior to week 13 surgery .
p=0.664
Years

11. Results: Potential prognostic factors for LF (Cox model)
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

12. Results: Arm C margin status
Local Failure
Event Free Survival
Microscopic + (29%)
n=29
Negative (72%)
Microscopic + (64%)
Survivors
Survivors
Negative (3%)
n=54
but margin status did not influence EFS
Disportante tumor factors size, #mpnst/liver, RT: dose/volume adeuqate? Complaince with guidelines, contourign more difficlt, hypoixc tumor bed
p=0.0015
p=0.21
Years
Years

13. Results: Arm D characteristics of week 13 surgery
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
LC for entire cohort is 14%.
80% went to week 13 surgery and majority had R0/R1 resection.

14. Results: Arm D margin status
Event Free Survival
Local Failure
p=0.63
p=0.58
p=0.21
Microscopic + (72%)
Negative (62%)
Survivors
Survivors
Reason for margin + lower LF then arm c: patient characteristics: younger age, tumor factors: such # synovial sarcoma’s chemo sensitive, included smaller < 5cm, RT perspective: compliance with guidelines better lower dose, contouring easier more reliable, not recovering surgery with hypoxia.
Microscopic + (7%) n=19
Negative (3%) n=71
Years
Years

15. Results: Where are local failures after RT?
Eligible patients
Local failures
Received RT
In field/out field failures*
Arm B (11) 1
In field (1)
Arm C (91) 12 9
In field (6)
Out of field (3)
Arm D (121) 17 11
In field (11)
Reasons for no rt RT could be embryonal sarcoma of liver
Look at where failed when did receive RT: MRI reformat with RT CTP to identify where local failures occurec within field or out. a;lthough we know where local failures are we don’t know if they were in compliance with Rt guidliens
Out of field : contouring more diffiuclt
*In field % isodose
Out of field - <5-20% isodose

16. 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
Why is higher risk for failure in margin + >5cm? Tumor factors: higher proportion of visceral tumors including liver where Rt optional, or more mpnst higher LF. RT factors, include adequate dose or margins wide enough in post-op setting contouring more challenging in post-op setting open to greater variability among Rad Onc and possible compliance problems? Hypoxia in post op setting influence chemo and RT effectiveness?
Final recommendations will depend on our findings. Encouraging 45 Gy seems to to effective in majority of resected patients with advantage of lower dose, smaller volumes and resect irradiated tumor bed which may translate into fewer potential secondary malignancies.
Why was LF so much better for microscopic + arm D then C. May be disporportinate chemo sensitive tumors: synovial sarcomas, smaller tumors (incloude several >5 cm tumor)

17. Acknowledgments 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

18. Results: EFS based on % necrosis in surgical specimen at week 13
0-50% necrosis (n=34)
90-100% necrosis (n=32)
Survivors
60-80% necrosis (n=21)
Reviewed whether % necrosis or treatment effect – a reflection of margin status – was relevant for arm D.
p=0.11
Years

19. Radiation Therapy: Target volumes
Paraspinal synovial sarcoma
> 5cm, high grade
Sagittal images define clinical target volume

20. Results: Multi-variate analysis Arms B/C surgical margins prognostic factor
Microscopic + (23%) n=40
Local failures
Negative (3%) n=54
Negative
All received 55.8 Gy regardless of tumor size or margin status as- arm C with larger tumors and recieved chemo
p=0.005
Years

21. Results: 4 year EFS by Treatment Arm
Arm B = 73%
Arm C = 70%
Arm D = 65%
Survivors
p=0.35
Years

23. QARC

24. Results: EFS by margin status
ARM C
ARM D
Negative margin
Microscopic +
Microscopic +
Negative margin
Survivors
Survivors
p=0.21
p=0.63
Years
Years

25. 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
Arm D: Pre-operative RT
Negative margin
Macroscopic margin
64.8 Gy
10.8 Gy (week 16)
19.8 Gy (week 16)

26. Results: Histologic subtype cumulative incidence of local failure
MPNST (22%)
Local Failures
Unclassified
Undifferentiated
Embryonal sarcoma liver
other NRSTS
Not potential px factors
Interest to grp
Synovial sarcoma (6%)
p=0.09
Years

27. Results: Compliance with RT guidelines
Arm B
Arm C
Arm D
Evaluable 20
102
141
RT given 18 75
112
No Rt given 2 27
Included in this analysis 11 91
121
No Rt given in this analysis
All received RT
9-27
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)
(over 2/3 dev. related to boost)