6660: Whole-Body MRI in the Evaluation of Pediatric

MalignanciesMarilyn J. Siegel, MD (Principle Investigator)Fredric Hoffer, MD Suddhasatta Acharyya, PhDBrad Wyly, MD Berry Siegel, MD Alison Friedmann, MD, MSc

ACRIN 6660: Whole-Body MRI in the Evaluation of Pediatric

Malignancies

• 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

• Whole Body Imaging

• Vertex to toes

• Coronal plane images

• Body Coil

• Scans performed on a 1.5 T

• STIR

STIR MR-Ewing Sarcoma

Rhabdomyosarcoma

Renal Metastasis

CTMRI

MassMass

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

• 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 AUC

Convent-ional

AUC

WBMRI –Conventional

95% CI

Experienced 0.8441 0.8895 -0.0455 (-0.1452, 0.0542)

Less experienced

0.8142 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

Empirical

AUC

# WBMRI

Average

AUC

Conventional

Average AUC

WBMRI –

Conven-tional

95% CI

Lymphoma 31 0.7060 0.8177 -0.1117 (-0.2305, 0.0070)

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 0.5156 (0.4158, 0.6142)

Conv. 0.6308 (0.5444, 0.7095)

Solid tumor WBMRI 0.8652 (0.8055, 0.9087)

Conv. 0.8864 (0.8370, 0.9222)

The average sensitivity for advanced stage lymphoma was lower than stage 4 solid tumors for both WBMRI & conventional imaging (p<0.0001).

Average specificity

• Average specificity of WBMRI tended to be better than conventional imaging for solid tumors but not significantly

Tumor type Imaging Estimate 95% CI

Lymphoma WBMRI 0.8323 (0.7523, 0.8902)

Conv. 0.8673 (0.7711, 0.9270)

Solid tumor WBMRI 0.8746 (0.8023, 0.9229)

Conv. 0.8588 (0.7578, 0.9220)

Age of patient vs. WBMRI reading

Age of patient # of patients

Average WBMRI Sensitivity

Average WBMRI Specificity

Age < 2 yrs 17 0.7673 0.8856

Age > 2 yrs 53 0.7282 0.8378

Significance of age difference

(p=0.5331) (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 casesAdvanced Stage Location

FN Cases >5 WBMRI readers

FN Cases >5 conventional

Lung 5 2

Pleura 1 0

Chest wall 2 2

Lymph nodes 2 1

Liver 2 2

Skeletal only 1 3

CSF by LP 2 1

False negative (FN) WBMRI & conventional readings in a subset of 13

of 35 + cases missed by >5 readers

Advanced Stage Location

WBMRI FN reads

Conventional FN reads

Lung 39 18

Pleura 6 1

Chest wall 16 14

Lymph nodes 14 12

Liver 17 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

• CT is the major source of radiation in diagnostic radiology

• Children are more susceptible than adults to cancer after radiation exposure

•www.imagegently.org

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.