million l, terezakis s, donaldson s, anderson j, randall rl, hayes- jordan a, laurie f, coffin c,...
TRANSCRIPT
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)