Ten Challenges in the Management of Neuroblastoma
Ten Challenges in the Management of Neuroblastoma
Accurate staging for a patient with neuroblastoma is essential. It has implications for prognosis and guides the treatment required for individuals with the disease. In 2009, the INRG project published a proposed new staging system for neuroblastoma – the INRGSS – as discussed in Challenge 2. The benefit of this international staging system and classification via the INRG involves the standardization and facilitation of risk-based clinical trials across different areas of the world, in order to improve understanding and ultimately outcome for patients with neuroblastoma.
The INRG have published guidelines on the imaging and staging of neuroblastic tumors with the aim of optimizing imaging and uniform reporting for staging of neuroblastomas according to the new INRGSS. Children presenting with an abdominal or pelvic mass are often initially investigated with ultrasonography due to its noninvasive nature and widespread availability. However, ultrasonography does have limitations and the INRG recommends that an MRI or CT scan should be obtained at diagnosis for accurate staging of the primary tumor.
Functional imaging plays an important role in neuroblastoma, from diagnosis and staging to response evaluation and follow-up. The majority of children with neuroblastoma, >90%, take up the guanethidine derivative mIBG. This is most frequently labeled with I for imaging (Figure 4), but can be labeled with I for treatment with molecular radiotherapy (see Challenge 6). Metastatic disease from neuroblastoma is most frequently located in the bone or bone marrow and distant metastases are best imaged by mIBG scintigraphy. There is no physiological uptake of mIBG in bone or bone marrow, making mIBG an accurate method of detecting bone metastases. Owing to its high sensitivity and specificity, I-mIBG has been recommended as the standard element of staging and response evaluation for neuroblastoma. The INRG task force has recently published criteria guidelines and standardized procedures for mIBG scintigraphy and semiquantitative scoring of the scans, which should facilitate consistency in the interpretation of scans.
(Enlarge Image)
Figure 4.
Anterior whole-body I-meta-iodobenzylguanidine scintigraphy showing uptake in multiple bone metastases: International Neuroblastoma Risk Group stage M, International Neuroblastoma Staging System stage 4.
It is unclear whether the initial mIBG score is of prognostic significance and this is an area of ongoing international research. I-mIBG has been evaluated for its prognostic value in high-risk patients undergoing induction chemotherapy. Most recently, this was evaluated in the German neuroblastoma trial NB97, in which positive metastatic disease on I-mIBG imaging after four or six cycles of chemotherapy was associated with a poor outcome. The I-mIBG response in the primary tumor had no impact on the outcome.
A disadvantage of imaging with I-mIBG is its limited spatial resolution. Very small amounts of bone marrow disease can go undetected by I-mIBG scintigraphy and therefore bilateral bone marrow aspirate and trephine biopsy are also recommended. For patients with mIBG-negative disease, a Tc MDP bone scan has been historically recommended. This test has a lower specificity than I-mIBG and is often difficult to interpret in young children with growing bones. In recent years the development of other functional imaging modalities, such as PET, has been observed. The role and timing of, for example, F-fluorodeoxy glucose (FDG) PET/CT, F-dopa PET/CT and somatostatin receptor scintigraphy or PET/CT studies in neuroblastoma remain unclear.
There are limited reports in the literature on the use of F-FDG PET/CT in neuroblastoma and questions remain with regard to the optimal patient group and timing of scans. Two recent studies have compared I-mIBG and F-FDG PET in neuroblastoma patients at diagnosis. Melzer et al. compared I-mIBG scintigraphy/single photon emission CT and F-FDG PET in 19 patients with suspected neuroblastic tumors. They found a sensitivity of 50% with I-mIBG versus 78% with F-FDG PET and a specificity of 75% with I-mIBG and 92% with F-FDG PET. They concluded that F-FDG PET may be a valuable imaging modality for patients with discrepant or inconclusive findings on I-mIBG single photon emission CT/scintigraphy. Sharp et al. retrospectively compared 113 paired I-mIBG and F-FDG PET scans at diagnosis. They found F-FDG PET to be superior for depicting neuroblastoma stages 1 and 2. F-FDG PET was valuable for those patients weakly accumulating I-mIBG. F-FDG PET was better at defining disease in the chest, abdomen and pelvis but I-mIBG was superior overall for high-risk disease because of the better detection of bone or bone marrow disease.
Papathanasiou et al. compared I-mIBG and F-FDG PET/CT and found I-mIBG imaging to be superior to F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, F-FDG PET/CT had significant prognostic implications in these patients. Tumoral metabolic activity or maximum standardized uptake value and extent of F-FDG-avid bone–bone marrow disease (F-FDG skeletal scores) were identified as poor prognostic factors associated with decreased survival. Taggart et al. compared I-mIBG scans with F-FDG PET to evaluate response in patients with relapsed neuroblastoma treated with I-mIBG. They found the I-mIBG scans to be significantly more sensitive for individual lesion detection in this cohort of relapsed neuroblastoma patients. F-FDG PET demonstrated a trend towards increased sensitivity for soft tissue lesions; however, CR on F-FDG PET did not always correlate with CR on I-mIBG scans.
PET/CT with radiolabeled somatostatin analogs such as Ga-DOTA-TOC PET and Ga-DOTATATE PET have in recent years been proven to be superior to planar scintigraphy, with agents such as In-octreotide used for the evaluation of metastatic somatostatin-positive neuroendocrine tumors. Many neuroblastomas express somatostatin receptor type 2 and Ga-DOTA-TOC PET has recently been compared with I-mIBG in a small cohort of neuroblastoma patients.
F-dopa is the radiolabeled form of dopa, which is a precursor of dopamine and other catecholamines. Neuroblastoma cells retain the ability to accumulate and decarboxylate amine precursors such as dopa. F-dopa PET/CT has been used with success in catecholamine-secreting neuroendocrine tumors. Piccardo et al. prospectively evaluated 28 paired I-mIBG and F-dopa PET/CT scans in 19 neuroblastoma patients: four at diagnosis and 15 when relapse of disease was suspected. There was a statistically significant increase in sensitivity for the F-dopa PET/CT (95%) compared with the I-mIBG scans (68%). There was no significant difference in specificity.
I-mIBG scintigraphy remains the gold standard form of imaging modality for diagnosis, staging and response evaluation in neuroblastoma. The exact role for other forms of functional imaging remains unclear and their evaluation, in large prospective clinical trials via translational studies, is warranted.
The existence of residual disease is predictive of a poor outcome. Being able to accurately and sensitively detect this would be advantageous in guiding decisions on treatment. Cytology and histology have limited sensitivity and cannot reliably detect MRD. The INRG have published standardized operating procedures for detecting MRD by immunocytology using disialoganglioside GD2 and quantitative reverse transcriptase-PCR using tyrosine hydroxylase mRNA and other markers. The publication of these standardized operating procedures should facilitate the use of these techniques across different treatment centers and countries and facilitate the comparison of results.
Challenge 5
Disease Assessment & Response Assessment
Accurate staging for a patient with neuroblastoma is essential. It has implications for prognosis and guides the treatment required for individuals with the disease. In 2009, the INRG project published a proposed new staging system for neuroblastoma – the INRGSS – as discussed in Challenge 2. The benefit of this international staging system and classification via the INRG involves the standardization and facilitation of risk-based clinical trials across different areas of the world, in order to improve understanding and ultimately outcome for patients with neuroblastoma.
The INRG have published guidelines on the imaging and staging of neuroblastic tumors with the aim of optimizing imaging and uniform reporting for staging of neuroblastomas according to the new INRGSS. Children presenting with an abdominal or pelvic mass are often initially investigated with ultrasonography due to its noninvasive nature and widespread availability. However, ultrasonography does have limitations and the INRG recommends that an MRI or CT scan should be obtained at diagnosis for accurate staging of the primary tumor.
Functional imaging plays an important role in neuroblastoma, from diagnosis and staging to response evaluation and follow-up. The majority of children with neuroblastoma, >90%, take up the guanethidine derivative mIBG. This is most frequently labeled with I for imaging (Figure 4), but can be labeled with I for treatment with molecular radiotherapy (see Challenge 6). Metastatic disease from neuroblastoma is most frequently located in the bone or bone marrow and distant metastases are best imaged by mIBG scintigraphy. There is no physiological uptake of mIBG in bone or bone marrow, making mIBG an accurate method of detecting bone metastases. Owing to its high sensitivity and specificity, I-mIBG has been recommended as the standard element of staging and response evaluation for neuroblastoma. The INRG task force has recently published criteria guidelines and standardized procedures for mIBG scintigraphy and semiquantitative scoring of the scans, which should facilitate consistency in the interpretation of scans.
(Enlarge Image)
Figure 4.
Anterior whole-body I-meta-iodobenzylguanidine scintigraphy showing uptake in multiple bone metastases: International Neuroblastoma Risk Group stage M, International Neuroblastoma Staging System stage 4.
It is unclear whether the initial mIBG score is of prognostic significance and this is an area of ongoing international research. I-mIBG has been evaluated for its prognostic value in high-risk patients undergoing induction chemotherapy. Most recently, this was evaluated in the German neuroblastoma trial NB97, in which positive metastatic disease on I-mIBG imaging after four or six cycles of chemotherapy was associated with a poor outcome. The I-mIBG response in the primary tumor had no impact on the outcome.
A disadvantage of imaging with I-mIBG is its limited spatial resolution. Very small amounts of bone marrow disease can go undetected by I-mIBG scintigraphy and therefore bilateral bone marrow aspirate and trephine biopsy are also recommended. For patients with mIBG-negative disease, a Tc MDP bone scan has been historically recommended. This test has a lower specificity than I-mIBG and is often difficult to interpret in young children with growing bones. In recent years the development of other functional imaging modalities, such as PET, has been observed. The role and timing of, for example, F-fluorodeoxy glucose (FDG) PET/CT, F-dopa PET/CT and somatostatin receptor scintigraphy or PET/CT studies in neuroblastoma remain unclear.
There are limited reports in the literature on the use of F-FDG PET/CT in neuroblastoma and questions remain with regard to the optimal patient group and timing of scans. Two recent studies have compared I-mIBG and F-FDG PET in neuroblastoma patients at diagnosis. Melzer et al. compared I-mIBG scintigraphy/single photon emission CT and F-FDG PET in 19 patients with suspected neuroblastic tumors. They found a sensitivity of 50% with I-mIBG versus 78% with F-FDG PET and a specificity of 75% with I-mIBG and 92% with F-FDG PET. They concluded that F-FDG PET may be a valuable imaging modality for patients with discrepant or inconclusive findings on I-mIBG single photon emission CT/scintigraphy. Sharp et al. retrospectively compared 113 paired I-mIBG and F-FDG PET scans at diagnosis. They found F-FDG PET to be superior for depicting neuroblastoma stages 1 and 2. F-FDG PET was valuable for those patients weakly accumulating I-mIBG. F-FDG PET was better at defining disease in the chest, abdomen and pelvis but I-mIBG was superior overall for high-risk disease because of the better detection of bone or bone marrow disease.
Papathanasiou et al. compared I-mIBG and F-FDG PET/CT and found I-mIBG imaging to be superior to F-FDG PET/CT in the assessment of disease extent in high-risk neuroblastoma. However, F-FDG PET/CT had significant prognostic implications in these patients. Tumoral metabolic activity or maximum standardized uptake value and extent of F-FDG-avid bone–bone marrow disease (F-FDG skeletal scores) were identified as poor prognostic factors associated with decreased survival. Taggart et al. compared I-mIBG scans with F-FDG PET to evaluate response in patients with relapsed neuroblastoma treated with I-mIBG. They found the I-mIBG scans to be significantly more sensitive for individual lesion detection in this cohort of relapsed neuroblastoma patients. F-FDG PET demonstrated a trend towards increased sensitivity for soft tissue lesions; however, CR on F-FDG PET did not always correlate with CR on I-mIBG scans.
PET/CT with radiolabeled somatostatin analogs such as Ga-DOTA-TOC PET and Ga-DOTATATE PET have in recent years been proven to be superior to planar scintigraphy, with agents such as In-octreotide used for the evaluation of metastatic somatostatin-positive neuroendocrine tumors. Many neuroblastomas express somatostatin receptor type 2 and Ga-DOTA-TOC PET has recently been compared with I-mIBG in a small cohort of neuroblastoma patients.
F-dopa is the radiolabeled form of dopa, which is a precursor of dopamine and other catecholamines. Neuroblastoma cells retain the ability to accumulate and decarboxylate amine precursors such as dopa. F-dopa PET/CT has been used with success in catecholamine-secreting neuroendocrine tumors. Piccardo et al. prospectively evaluated 28 paired I-mIBG and F-dopa PET/CT scans in 19 neuroblastoma patients: four at diagnosis and 15 when relapse of disease was suspected. There was a statistically significant increase in sensitivity for the F-dopa PET/CT (95%) compared with the I-mIBG scans (68%). There was no significant difference in specificity.
I-mIBG scintigraphy remains the gold standard form of imaging modality for diagnosis, staging and response evaluation in neuroblastoma. The exact role for other forms of functional imaging remains unclear and their evaluation, in large prospective clinical trials via translational studies, is warranted.
The existence of residual disease is predictive of a poor outcome. Being able to accurately and sensitively detect this would be advantageous in guiding decisions on treatment. Cytology and histology have limited sensitivity and cannot reliably detect MRD. The INRG have published standardized operating procedures for detecting MRD by immunocytology using disialoganglioside GD2 and quantitative reverse transcriptase-PCR using tyrosine hydroxylase mRNA and other markers. The publication of these standardized operating procedures should facilitate the use of these techniques across different treatment centers and countries and facilitate the comparison of results.
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