Transcript Primary Study Results (ACRIN 6660)

6660: Whole-Body MRI in the
Evaluation of Pediatric Malignancies
Marilyn J. Siegel, MD (Principle Investigator)
Fredric Hoffer, MD
Suddhasatta Acharyya, PhD
Brad Wyly, MD
Berry Siegel, MD
Alison Friedmann, MD, MSc
ACRIN 6660: Whole-Body MRI in
the Evaluation of Pediatric
Malignancies
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Biostatisticians:
Brad Snyder, MS &
Vincent Girardi, MS
Lead Data Manager:
Jamie Downs
6660: Primary Aim
• Establish non-inferior diagnostic accuracy of
whole body MRI compared with conventional
imaging studies for detecting metastatic
disease for use in staging of common
pediatric tumors
ACRIN 6660: Study Overview
• Patients to undergo conventional studies
including:
– Scintigraphy (Bone, MIBG or gallium)
– Abdominal/Pelvic CT or MRI
– Chest CT (optional for neuroblastoma)
– FDG-PET (optional)
• Experimental Studies
– Whole-Body Fast MRI
Inclusion Criteria
• Male or female gender
• 21 years or younger
• Suspected soft tissue sarcoma, Ewing’s
sarcoma family of tumors, neuroblastoma,
Hodgkin’s disease, and non-Hodgkin’s
lymphoma.
• Initial imaging completed in a timely fashion
• Final analysis only included above proven tumor
types
Materials
• 192 patients enrolled
– 140 evaluable
• 51 with distant disease (or stage IV)
• 89 with lesser stage
• 70 selected for multi-reader study (35 with
stage 4 solid tumor or advanced stage
lymphoma)
• 21 FDG PET’s were included in
conventional imaging of the reader study
Fast WBMRI Techniques
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Whole Body Imaging
Vertex to toes
Coronal plane images
Body Coil
Scans performed on a 1.5 T
STIR
STIR MR-Ewing Sarcoma
Rhabdomyosarcoma
MRI
CT
Mass
Mass
Renal Metastasis
Central Image Interpretation
• 10 readers for pretreatment conventional
CT/MRI, experimental WBMRI
• 10 readers for pretreatment scintigraphy
– FDG-PET, bone scans, MIBG
• Readers initially blinded to & had washout
period between conventional & experimental
imaging
• 10 pairs of readers of conventional scintigraphy
& cross sectional imaging had combined reports
• All pretreatment studies assessed for distant
tumor extent
Proof of truth committee determined
distant disease (usually stage 4)
• 4 oncologists, 1 pediatric radiologist
• Conventional imaging findings from
primary readers
• Bone marrow biopsy
• CSF aspirates when available
• Additional confirmatory imaging
• Additional confirmatory biopsy
• 6 months of data to determine initial
stage
Determining the Primary Aim
• Reader study: accuracy as area under
ROC curve (AUC)
• Average AUC whole-body MRI (WBMRI)
vs. average AUC conventional imaging
• To declare non-inferiority of WBMRI vs.
conventional imaging for detecting distant
disease, the expected 95% lower bound of
the confidence interval for AUC (WBMRI
minus conventional imaging) must be
above –0.03 (closer to zero)
AUC for ROC analysis
• 70 cases (35-, 35+)
• WBMRI
0.8291 empirical, 0.8436 parametric
• Conventional imaging
0.8676 empirical, 0.8896 parametric
Results for primary aim
• The difference in AUC between the
modalities [The 95% confidence interval
(CI)] for WBMRI – Conventional Imaging =
• -0.0384 [-0.1091, 0.0323] empirically
• -0.0461 [-0.1195, 0.0274] parametrically
• The lower bound CI was not above -0.03
• WBMRI could not be declared non-inferior
to conventional imaging
Search for reasons that WBMRI
failed to achieve non-inferiority
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WBMRI reader experience
Lymphoma vs. other tumors
Sensitivity
Specificity
Patient age
Distant tumor size & locations
WBMRI Reader experience:
Empirical AUC
MRI reader
pairs
(5 each)
WBMRI Convent- WBMRI –
95% CI
AUC
ional
Conventional
AUC
Experienced 0.8441
0.8895
-0.0455
(-0.1452,
0.0542)
Less
0.8142
experienced
0.8456
-0.0314
(-0.1357,
0.0730)
• The experienced MRI readers did better on both
WBMRI and conventional imaging readings.
AUC as per tumor type
WBMRI Conventional WBMRI – 95% CI
Average Average AUC Conventional
AUC
Lymphoma 31 0.7060 0.8177
-0.1117
(-0.2305,
0.0070)
Empirical
AUC
#
Solid tumor 39 0.9116
0.9078
0.0038
(-0.0694,
0.0772)
There was a trend toward non-inferiority for WBMRI
to detect stage 4 solid tumors but the sample size
was not sufficient for statistical significance.
Average sensitivity
Tumor type
Imaging
Estimate
95% CI
Lymphoma
WBMRI
Conv.
WBMRI
Conv.
0.5156
0.6308
0.8652
0.8864
(0.4158, 0.6142)
(0.5444, 0.7095)
(0.8055, 0.9087)
(0.8370, 0.9222)
Solid tumor
The average sensitivity for advanced stage
lymphoma was lower than stage 4 solid tumors for
both WBMRI & conventional imaging (p<0.0001).
Average specificity
Tumor type
Imaging
Estimate
95% CI
Lymphoma
WBMRI
Conv.
WBMRI
Conv.
0.8323
0.8673
0.8746
0.8588
(0.7523, 0.8902)
(0.7711, 0.9270)
(0.8023, 0.9229)
(0.7578, 0.9220)
Solid tumor
• Average specificity of WBMRI tended to be
better than conventional imaging for solid tumors
but not significantly
Age of patient vs. WBMRI reading
Age of patient
# of
Average
patients WBMRI
Sensitivity
Age < 2 yrs
17
0.7673
Age > 2 yrs
53
0.7282
Significance of
(p=0.5331)
age difference
Average
WBMRI
Specificity
0.8856
0.8378
(p=0.2404)
• This trend failed to suggested that the red
marrow of patients under age 2 was confused
with bone marrow tumor on WBMRI.
Weighted averages of false negatives
(FN) for WBMRI reading
(all missed lesions were <1 cm)
FN location
Lymphoma
Solid tumor
Lung
52.38%
36.67%
Liver
12.69%
33.33%
Lymph node
7.94%
43.33%
Other
53.97%
20.00%
False negative (FN) cases missed by >5
of 10 readers by WBMRI or conventional
imaging among 35 positive cases
Advanced Stage
Location
Lung
Pleura
Chest wall
Lymph nodes
Liver
Skeletal only
CSF by LP
FN Cases >5
WBMRI readers
5
1
2
2
2
1
2
FN Cases >5
conventional
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2
1
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3
1
False negative (FN) WBMRI &
conventional readings in a subset of 13
of 35 + cases missed by >5 readers
Advanced
Stage Location
Lung
Pleura
WBMRI
FN reads
39
6
Conventional
FN reads
18
1
Chest wall
16
14
Lymph nodes
Liver
14
17
12
17
Skeletal only
13
22
Conclusion
•ACRIN 6660 failed to demonstrate that WBMRI
with STIR coronal imaging is not inferior to
conventional imaging for determining metastatic
pediatric malignancy
•WBMRI had more false negatives than
conventional imaging due to lung metastases &
other lesions < 1 cm
•WBMRI trended to be as accurate & more specific
than conventional imaging for determining solid
tumor metastases (but not for advanced lymphoma)
Image Gently
•www.imagegently.org
• CT is the major source of radiation in
diagnostic radiology
• Children are more susceptible than adults to
cancer after radiation exposure
Diffusion weighted Whole Body MRI
• Whole-body diffusion-weighted imaging for
staging malignant lymphoma in children.
Kwee TC, Takahara T, Vermoolen MA,
Bierings MB, Mali WP, Nievelstein RA.
Pediatr Radiol. 2010 Oct;40(10):1592-602.
• Whole-body MR imaging, bone diffusion
imaging: how and why? Jaramillo D.
Pediatr Radiol. 2010 Jun;40(6):978-84.