Nuclear Medicine Imagingin Pediatric Malignancies

Clare J. Twist, MDPediatric Oncology

Lucile Packard Children’s Hospital

1/15/08

Scintigraphic Studies for Pediatric Malignancies

Gallium Scan –No longer routinely used

Skeletal Scintigraphy – 99mTc-MDPCortical bone metastases

Radiolabeled MIBG – 123I-MIBG +/- SPECTNeuroendocrine tumors

FDG-PET/CT Evolving use in pediatrics

Radiolabeled antibodies/targeted reagents

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.

Neuroblastoma

Embryonal cancer of the postganglionic sympathetic nervous system:

Adrenal glandSympathetic chain

Neuroblastoma cells may exhibit features of neuronal differentiation

Spontaneous or induced differentiation to ganglioneuroblastoma or ganglioneuroma

Neuroblastoma:Biologic features predict prognosis

MYCN gene amplification

DNA ploidy – for infants

1p or 11q LOH

Histologic features– favorable vs unfavorable

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 prognosisImprove therapy (intensify, add novel agents, etc) for high risk patients

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)

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A3961 Intermediate-risk N=467

P9641 Low-risk N=903

Biologically Favorable Neuroblastoma is very curable with minimal therapy

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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

Current Risk-Stratification System Is Based on Powerful Prognostic Markers

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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

“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 individualmodality 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, BilateralBMA/Bx, ? FDG-PET? ……Q 3 months

International Neuroblastoma Response CriteriaSite 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%

123I - MIBG imaging study

Semi-Quantitative Scoring System for MIBG response: Modified Curie ScaleMessina 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 scorepre-Rx abs score

Major Response=

Relative Score <0.5

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]

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 patientsLiver - ? Radiation or chemotherapy injury, blood product deposition

Small sites can be missed on planar imagingNeed SPECT to identify and provide anatomic localization

Imaging Neuroblastoma with radiolabeledantibodies: investigational

Anti-GD2 monoclonal antibodies99mTc-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 moleculeschCEM = chimeric IgG1 against Cellular Adhesion Molecule L1 (L1-CAM)

Sensitivity may be superior in small series but practical utility remains limited

Limited availability of reagentsCumbersome nature of labeling antibodies

131I-MIBG: Therapeutic modalities

Single agent therapy for palliation of recurrent NBResponse 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 therapyEuropean/Canadian experience

Hyperbaric oxygen-enhancement with MIBG therapyEnhances radiation effectNot yet in the US

Combined with chemotherapy & stem cell rescueIntensification of therapy for refractory disease

Intraoperative mapping with gamma probe123I-MIBG probe to identify small sites of viable tumor

[Iagaru et al, Mol Imaging Biol. 2008 Jan-Feb;10(1):19-23]

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 dose12 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?

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 chemoDLTs included hepatic veno-occlusive disease

6/22 evaluable pts had CR/PR3 yr estimated EFS rate = 31%

Phase II study underway in NANTWill a COG study of 131I-MIBG for refractory NB be feasible?

FDG-PET/CT imaging in pediatric malignancies

AdvantagesMost 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

FDG-PET/CT imaging in pediatric malignancies

DisadvantagesFalse positive sites due to physiologic variations in FDG distribution in children

More extensive distribution of red marrow, exacerbated by G-CSFThymus, tonsils/adenoids, skeletal growth centers, brown fatSkeletal muscle and vocal cords

FDG uptake can be seen in some benign lesionsFibro-osseous defects, osteochondromasGanglioneuroma

Brain/skull may be difficult to image accurately

Small metastatic lesions (< 1cm) may not be imaged

Need for general anesthesiaNot in the trailer!

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 resolutionUseful 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

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 childrenLess 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

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]

FDG-PET imaging: HepatoblastomaMetabolically active and take up FDG much more reliably than Hepatocellular carcinoma

Limited data in HBSeries 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 CT1/5 FDG-PET was superior to CT/MRI at defining residual tumor1/5 false positive FDG-PET and CT

False positivesRegenerating liver tissueNecrotizing granulomas

False negativeNon-fasting state

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]

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 imagingIn Ewings (but not in OS) pts, FDG-PET was superior in identifying bone lesions compared to bone scanIn 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%)

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 diagnosisN=51 sites of disease by CT/MRI

41/51(80%) of sites + by CT/MRI were also + by FDG-PET10/51 (20%) findings were discordant

9 sites seen on CT/MRI were felt to be ‘real’, ie, false negative FDG-PET resultsSmall 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 diseaseNo 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

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 therapyFunctional imaging

Minimize risk to pediatric patientsRadiation exposureNumber of imaging modalitiesNumber and duration of anesthesiaLate effects of therapy