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.

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.

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.

Materials and Methods COG ARST0332 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)

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

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

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 + 10.8 Gy Gross 19.4 Gy RT 45 Gy / 25 Fx Surgery Adria/Ifos Adria/Ifos Ifos Ifos Week 1 4 7 10 13 16

Radiation Therapy: Conformal Target Volumes Gross tumor volume (GTV) Clinical Target volume (CTV) = GTV + 1.5 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

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

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

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

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

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.

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

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 - 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 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)

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

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

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

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

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

QARC

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

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)

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

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 16 - 27 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)