1. 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

2. ACRIN 6660: Whole-Body MRI in the Evaluation of Pediatric Malignancies Biostatisticians: Brad Snyder, MS & Vincent Girardi, MS Lead Data Manager: Jamie Downs

3. 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

4. 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

5. 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

6. 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

7. Fast WBMRI Techniques Whole Body Imaging Vertex to toes Coronal plane images Body Coil Scans performed on a 1.5 T STIR

8. STIR MR-Ewing Sarcoma

9. Rhabdomyosarcoma Renal Metastasis CT MRI Mass

10. 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

11. 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

12. 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)

13. AUC for ROC analysis 70 cases (35-, 35+) WBMRI 0.8291 empirical, 0.8436 parametric Conventional imaging 0.8676 empirical, 0.8896 parametric

14. 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

15. 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

16. WBMRI Reader experience: Empirical AUC MRI reader pairs (5 each) WBMRI AUC Convent- ional AUC WBMRI – Conventional 95% CI Experienced0.84410.8895-0.0455(-0.1452, 0.0542) Less experienced 0.81420.8456-0.0314(-0.1357, 0.0730) The experienced MRI readers did better on both WBMRI and conventional imaging readings.

17. AUC as per tumor type Empirical AUC #WBMRI Average AUC Conventional Average AUC WBMRI – Conven- tional 95% CI Lymphoma310.70600.8177-0.1117(-0.2305, 0.0070) Solid tumor390.91160.90780.0038(-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.

18. Average sensitivity Tumor typeImagingEstimate95% CI LymphomaWBMRI0.5156(0.4158, 0.6142) Conv.0.6308(0.5444, 0.7095) Solid tumorWBMRI0.8652(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).

19. Average specificity Average specificity of WBMRI tended to be better than conventional imaging for solid tumors but not significantly Tumor typeImagingEstimate95% CI LymphomaWBMRI0.8323(0.7523, 0.8902) Conv.0.8673(0.7711, 0.9270) Solid tumorWBMRI0.8746(0.8023, 0.9229) Conv.0.8588(0.7578, 0.9220)

20. Age of patient vs. WBMRI reading Age of patient# of patients Average WBMRI Sensitivity Average WBMRI Specificity Age < 2 yrs170.76730.8856 Age > 2 yrs530.72820.8378 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.

21. Weighted averages of false negatives (FN) for WBMRI reading (all missed lesions were <1 cm) FN locationLymphomaSolid tumor Lung52.38%36.67% Liver12.69%33.33% Lymph node7.94%43.33% Other53.97%20.00%

22. False negative (FN) cases missed by >5 of 10 readers by WBMRI or conventional imaging among 35 positive cases Advanced Stage Location FN Cases >5 WBMRI readers FN Cases >5 conventional Lung52 Pleura10 Chest wall22 Lymph nodes21 Liver22 Skeletal only13 CSF by LP21

23. 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 Lung3918 Pleura61 Chest wall1614 Lymph nodes1412 Liver17 Skeletal only1322

24. 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)

25. 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

26. 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 diffusion-weighted imaging for staging malignant lymphoma in children. Whole-body MR imaging, bone diffusion imaging: how and why? Jaramillo D. Pediatr Radiol. 2010 Jun;40(6):978-84.Whole-body MR imaging, bone diffusion imaging: how and why?