Nuclear Medicine Imaging
in Pediatric Malignancies
Clare J. Twist, MD
Pediatric Oncology
Lucile Packard Children’s Hospita...
Scintigraphic Studies for Pediatric Malignancies
Gallium Scan –
No longer routinely used
Skeletal Scintigraphy – 99mTc-MDP...
Neuroblastoma
3rd most common pediatric cancer
Most common extra-cranial malignant solid tumor of
infancy
~50% of patients...
Neuroblastoma
Embryonal cancer of the postganglionic
sympathetic nervous system:
Adrenal gland
Sympathetic chain
Neuroblas...
Neuroblastoma:
Biologic features predict prognosis
MYCN gene amplification
DNA ploidy – for infants
1p or 11q LOH
Histolog...
Neuroblastoma: Clinical Heterogeneity
Anatomic stage and age at diagnosis are tightly
correlated with prognosis
Children l...
Low-risk: Achieved 97.4 ± 0.8% OS with elimination of cytotoxic therapy
Intermediate-risk: Achieved 96.0 ± 1.0% OS with re...
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Years
1990-1994 (N=575) 1995-1999 (N=345) 2000-2004 (N=856)
...
Current Risk-Stratification System Is Based on
Powerful Prognostic Markers
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12 ...
“Neuroblastoma:
A disease requiring a multitude of imaging studies”
Kushner, BH J Nucl Med 2004;45:1172
No single modality...
International Neuroblastoma Response Criteria
Site Test CR VGPR PR
Primary CT or MRI No tumor > 90% reduction in tumor
vol...
123I - MIBG imaging study
Semi-Quantitative Scoring System for MIBG response:
Modified Curie Scale
Messina J, et al Pediatr Blood Cancer 2006;47:865...
Is 123I-MIBG imaging alone sufficient for
staging and disease surveillance in NB?
MSKCC study: 162 patients (90 newly diag...
123I-MIBG: Cautionary tales
Intensity of MIBG uptake not necessarily linked to degree of
neuroblastoma differentiation
Som...
Imaging Neuroblastoma with radiolabeled
antibodies: investigational
Anti-GD2 monoclonal antibodies
99mTc-labeled ch14.18 c...
131I-MIBG: Therapeutic modalities
Single agent therapy for palliation of recurrent NB
Response rate 30-40% [Howard et al, ...
131I-MIBG single agent therapy
Phase II study of 131I-MIBG in 164 patients with recurrent NB
[Matthay, K et al, J Clin Onc...
Phase I Study of 131I-MIBG + chemotherapy:
NANT Trial N9901 [Matthay et al, J Clin Oncol 2006 Jan 20;24(3):500]
N=24 patie...
FDG-PET/CT imaging in pediatric malignancies
Advantages
Most pediatric cancers are metabolically active
Experience in adul...
FDG-PET/CT imaging in pediatric malignancies
Disadvantages
False positive sites due to physiologic variations in FDG distr...
FDG-PET imaging: Neuroblastoma
Small studies confirm FDG-avidity in most NB, and generally concordant
with 123I-MIBG imagi...
FDG-PET imaging: Lymphoma
Adult experience has driven rapid acceptance in pediatric lymphomas
Pediatric lymphomas (NHL & H...
FDG-PET imaging: Wilms tumor
Role of FDG-PET in Wilms has not yet been established,
although there are anecdotal reports o...
FDG-PET imaging: Hepatoblastoma
Metabolically active and take up FDG much more reliably than
Hepatocellular carcinoma
Limi...
FDG-PET imaging: Osteosarcoma & Ewing Sarcoma
Role of FDG-PET remains unclear in pediatric bone tumors
May play a role in ...
FDG-PET imaging: Sarcomas
Prospective trial using FDG-PET for staging in pediatric sarcoma
patients [Volker et al, J Clin ...
FDG-PET imaging: Rhabdomyosarcoma
Retrospective review of diagnostic FDG-PET vs CT/MRI
[Klenn et al, J Pediatr Hematol Onc...
Nuclear Medicine Imaging in Pediatric Malignancies:
Future Directions
Prospective studies of utility of FDG-PET vs traditi...
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Nuclear Medicine Imaging in Pediatric Malignancies

  1. 1. Nuclear Medicine Imaging in Pediatric Malignancies Clare J. Twist, MD Pediatric Oncology Lucile Packard Children’s Hospital 1/15/08
  2. 2. Scintigraphic Studies for Pediatric Malignancies Gallium Scan – No longer routinely used Skeletal Scintigraphy – 99mTc-MDP Cortical bone metastases Radiolabeled MIBG – 123I-MIBG +/- SPECT Neuroendocrine tumors FDG-PET/CT Evolving use in pediatrics Radiolabeled antibodies/targeted reagents
  3. 3. Neuroblastoma 3rd most common pediatric cancer Most common extra-cranial malignant solid tumor of infancy ~50% of patients are diagnosed before age 3, nearly all before age 10 ~600 new cases diagnosed each year in U.S.
  4. 4. Neuroblastoma Embryonal cancer of the postganglionic sympathetic nervous system: Adrenal gland Sympathetic chain Neuroblastoma cells may exhibit features of neuronal differentiation Spontaneous or induced differentiation to ganglioneuroblastoma or ganglioneuroma
  5. 5. Neuroblastoma: Biologic features predict prognosis MYCN gene amplification DNA ploidy – for infants 1p or 11q LOH Histologic features– favorable vs unfavorable
  6. 6. Neuroblastoma: Clinical Heterogeneity Anatomic stage and age at diagnosis are tightly correlated with prognosis Children less than 18 months of age have a much more favorable outcome, even when they present with metastatic disease Clinical challenge: reduce therapy for patients with excellent prognosis Improve therapy (intensify, add novel agents, etc) for high risk patients
  7. 7. Low-risk: Achieved 97.4 ± 0.8% OS with elimination of cytotoxic therapy Intermediate-risk: Achieved 96.0 ± 1.0% OS with reduction of cytotoxic therapy (e.g. 75-85% decrease in #days receiving chemotherapy) 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 Years Probability(%) 0.00 0.25 0.50 0.75 1.00 0 .5 1 1.5 2 2.5 3 YEARS A3961 Intermediate-risk N=467 P9641 Low-risk N=903 Biologically Favorable Neuroblastoma is very curable with minimal therapy
  8. 8. 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years 1990-1994 (N=575) 1995-1999 (N=345) 2000-2004 (N=856) High Risk Neuroblastoma: only modest improvement in survival despite dramatic intensification of therapy
  9. 9. Current Risk-Stratification System Is Based on Powerful Prognostic Markers 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years EFSProbability(%) 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Years EFSProbability(%) 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years EFSProbability(%) 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Years EFSProbability(%) Age < 365 days (N = 1339) Age ≥ 365 days (N = 2327) p < 0.0001 Stage 1, 2, 3, 4s (N = 1910) Stage 4 (N = 1522) p < 0.0001 Favorable Histology (N = 894) Unfavorable Histology (N = 665) p < 0.0001 MYCN Not Amplified (N = 2357) MYCN Amplified (N = 520) p < 0.0001
  10. 10. “Neuroblastoma: A disease requiring a multitude of imaging studies” Kushner, BH J Nucl Med 2004;45:1172 No single modality can fully assess extent of disease International Response Criteria are defined by sum of individual modality results Unique biology includes possibility of tumor differentiation Overall response to induction therapy probably predicts for EFS/OS “Kitchen Sink” approach to staging/surveillance: Physical exam, urine VMA/HVA, CT/MRI, Bone scan, MIBG, Bilateral BMA/Bx, ? FDG-PET? ……Q 3 months
  11. 11. International Neuroblastoma Response Criteria Site Test CR VGPR PR Primary CT or MRI No tumor > 90% reduction in tumor volume 50-90% reduction in tumor volume Mets BMA/Bx Bone Scan & MIBG Liver or chest CT Physical exam No tumor No lesions No tumor No tumor No tumor All lesions improved; no new lesions (BS can be residual + but MIBG must be neg) No tumor No tumor No tumor or only 1 side + All lesions improved; no new lesions (BS &/or MIBG must be improved, but both can show residual abnormalities) 50-90% reduction 50-90% reduction Tumor marker VMA/HVA Normal Normal or both decreased > 90% Both decreased 50-90%
  12. 12. 123I - MIBG imaging study
  13. 13. Semi-Quantitative Scoring System for MIBG response: Modified Curie Scale Messina J, et al Pediatr Blood Cancer 2006;47:865 Method 1 Method 2 Method 1 allows additional sector scoring for soft tissue lesions; Method 2 does not Absolute score = sum of all segment scores Relative score = current abs score pre-Rx abs score Major Response= Relative Score <0.5
  14. 14. Is 123I-MIBG imaging alone sufficient for staging and disease surveillance in NB? MSKCC study: 162 patients (90 newly diagnosed) MIBG imaging was discordant with BM Bxs in 12% Falsely negative MIBG scan in 15/38 (39%) pts with + BM Can probably substitute for bone scan surveillance in some patients, since no pts had PD detected by BS alone Urine VMA/HVA may still identify some PD before MIBG So unfortunately, no! [Kushner B, et al, J Clin Oncol 2003; 21:1082]
  15. 15. 123I-MIBG: Cautionary tales Intensity of MIBG uptake not necessarily linked to degree of neuroblastoma differentiation Some mature ganglioneuromas are MIBG-avid False positive uptake in treated patients Liver - ? Radiation or chemotherapy injury, blood product deposition Small sites can be missed on planar imaging Need SPECT to identify and provide anatomic localization
  16. 16. Imaging Neuroblastoma with radiolabeled antibodies: investigational Anti-GD2 monoclonal antibodies 99mTc-labeled ch14.18 chimeric (IgG2a) 131I-3F8 – murine (IgG3) (64) Cu-ch14.18-PET – tumor specific PET reagent for NB & melanoma Xenograft models only Antibodies to other molecules chCEM = chimeric IgG1 against Cellular Adhesion Molecule L1 (L1-CAM) Sensitivity may be superior in small series but practical utility remains limited Limited availability of reagents Cumbersome nature of labeling antibodies
  17. 17. 131I-MIBG: Therapeutic modalities Single agent therapy for palliation of recurrent NB Response rate 30-40% [Howard et al, Pediatr Blood Cancer 2005;44:232] Provides excellent pain control for bone metastases Recurrent, low dose (outpatient) single agent therapy European/Canadian experience Hyperbaric oxygen-enhancement with MIBG therapy Enhances radiation effect Not yet in the US Combined with chemotherapy & stem cell rescue Intensification of therapy for refractory disease Intraoperative mapping with gamma probe 123I-MIBG probe to identify small sites of viable tumor [Iagaru et al, Mol Imaging Biol. 2008 Jan-Feb;10(1):19-23]
  18. 18. 131I-MIBG single agent therapy Phase II study of 131I-MIBG in 164 patients with recurrent NB [Matthay, K et al, J Clin Oncol. 2007;25:1054]. CR/VGPR/PR rate = 36% Additional 34% stabilization of disease for median 6 months Major acute toxicity is myelosuppression, which can be overcome by stem cell rescue (33% of patients) 18 mCi/kg/dose ~ 2.92 Gy median total body dose 12 mCi/kg/dose for pts without stem cells for rescue Late effects? Hypothyroidism 40% despite KI blockade [Brans et al, Med Pediatr Oncol 2002;38:41] Hepatic toxicity: VOD, fibrosis? Second malignant neoplasms/AML/Myelodysplasia?
  19. 19. Phase I Study of 131I-MIBG + chemotherapy: NANT Trial N9901 [Matthay et al, J Clin Oncol 2006 Jan 20;24(3):500] N=24 patients with primary refractory high risk NB Dose escalation of 131I-MIBG with high dose chemotherapy (Carboplatin/Etoposide/Melphalan) with stem cell rescue MTD = 12 mCi/kg 131I-MIBG combined with chemo DLTs included hepatic veno-occlusive disease 6/22 evaluable pts had CR/PR 3 yr estimated EFS rate = 31% Phase II study underway in NANT Will a COG study of 131I-MIBG for refractory NB be feasible?
  20. 20. FDG-PET/CT imaging in pediatric malignancies Advantages Most pediatric cancers are metabolically active Experience in adult malignancies (lymphoma, brain tumors) Excellent spatial resolution Change in FDG uptake/intensity may provide information about tumor response or differentiation
  21. 21. FDG-PET/CT imaging in pediatric malignancies Disadvantages False positive sites due to physiologic variations in FDG distribution in children More extensive distribution of red marrow, exacerbated by G-CSF Thymus, tonsils/adenoids, skeletal growth centers, brown fat Skeletal muscle and vocal cords FDG uptake can be seen in some benign lesions Fibro-osseous defects, osteochondromas Ganglioneuroma Brain/skull may be difficult to image accurately Small metastatic lesions (< 1cm) may not be imaged Need for general anesthesia Not in the trailer!
  22. 22. FDG-PET imaging: Neuroblastoma Small studies confirm FDG-avidity in most NB, and generally concordant with 123I-MIBG imaging (but not 100%) [Shulkin et al, Radiology 1996;199:743] [Kushner et al, J Clin Oncol 2001; 19:3397] Better spatial resolution Useful in MIBG-negative disease Change in FDG uptake/intensity may provide information about tumor response or differentiation? Good sensitivity with low false negative rate (2.5%) when combined with BM bx for surveillance [Kushner B, et al, J Clin Oncol 2001; 19:3397] Superior to bone scan and MIBG for osteomedullary disease Small amounts of bone marrow disease will be missed
  23. 23. FDG-PET imaging: Lymphoma Adult experience has driven rapid acceptance in pediatric lymphomas Pediatric lymphomas (NHL & HD) tend to be high grade, metabolically active May change the disease stage and treatment in 10-20% children Generally older children Less likely to need general anesthesia Has replaced Gallium (67Ga citrate) scanning Provides important information about ‘active’ disease versus ‘inactive’ residual mass No need to biopsy residual anterior mediastinal masses
  24. 24. FDG-PET imaging: Wilms tumor Role of FDG-PET in Wilms has not yet been established, although there are anecdotal reports of FDG-uptake in Wilms Normal excretion of FDG through the kidney may limit utility of imaging this organ May be useful for distinguishing active vs inactive tumor in residual masses after chemotherapy or radiation Case reports describe false negatives [Shulkin et al, 1997 Peds Hematol Oncol 19(4):334]
  25. 25. FDG-PET imaging: Hepatoblastoma Metabolically active and take up FDG much more reliably than Hepatocellular carcinoma Limited data in HB Series of 5 pts compared FDG-PET and MRI/CT [Moody et al, Pediatr Blood Cancer 2006;47:51] In 3/5 patients FDG-PET showed good correlation with MRI or CT 1/5 FDG-PET was superior to CT/MRI at defining residual tumor 1/5 false positive FDG-PET and CT False positives Regenerating liver tissue Necrotizing granulomas False negative Non-fasting state
  26. 26. FDG-PET imaging: Osteosarcoma & Ewing Sarcoma Role of FDG-PET remains unclear in pediatric bone tumors May play a role in assessing extent of disease, monitoring response to therapy, and perhaps predicting long-term outcome? FDG uptake may underestimate the extent of tumor necrosis compared with histologic response May be superior to Bone Scan in detecting metastases in Ewing sarcoma but not in Osteosarcoma [Franzius et al, Eur J Nucl Med 2000; 27:1305]
  27. 27. FDG-PET imaging: Sarcomas Prospective trial using FDG-PET for staging in pediatric sarcoma patients [Volker et al, J Clin Oncol 2007;25:5435] N=46 pediatric patients FDG-PET identified additional lesions beyond MRI/CT/BS imaging In Ewings (but not in OS) pts, FDG-PET was superior in identifying bone lesions compared to bone scan In Rhabdo pts, FDG-PET was superior to CT/MRI in detecting regional LN involvement Low sensitivity (25%) of FDG-PET for detecting pulmonary metastases All false negative lesions were < 7mm size Alterations in therapy based on FDG-PET were much more likely in EWS (41%) and RMS (50%), compared to OS (8%)
  28. 28. FDG-PET imaging: Rhabdomyosarcoma Retrospective review of diagnostic FDG-PET vs CT/MRI [Klenn et al, J Pediatr Hematol Oncol 2007;29:9] N=24 patients at initial diagnosis N=51 sites of disease by CT/MRI 41/51(80%) of sites + by CT/MRI were also + by FDG-PET 10/51 (20%) findings were discordant 9 sites seen on CT/MRI were felt to be ‘real’, ie, false negative FDG-PET results Small lymph nodes, may be obscured by primary mass 1 site that was negative on FDG-PET was deemed to be the ‘true’ result In 1 patient, FDG-PET identified regional LAN that was not seen on CT/MRI and was ultimately determined to be true disease No patients had distant mets identified only on FDG-PET FDG-PET may be most useful in identifying involved regional lymph nodes, which changes the prognosis To be prospectively studied in the next COG intermediate risk Rhabdo study
  29. 29. Nuclear Medicine Imaging in Pediatric Malignancies: Future Directions Prospective studies of utility of FDG-PET vs traditional imaging modalities in particular diseases Funding! General anesthesia! Development of targeted reagents for imaging and therapy Functional imaging Minimize risk to pediatric patients Radiation exposure Number of imaging modalities Number and duration of anesthesia Late effects of therapy

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