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neuroblastoma

Updated : February 14, 2024





Background

The most prevalent extracranial pediatric tumor is NB (neuroblastoma). It is categorized as a neural crest progenitor cell-derived embryonal NETs (neuroendocrine tumor). Because of this, it can happen anywhere throughout the sympathetic nervous system, such as the celiac ganglia, superior cervical, and paraspinal; nevertheless, the majority of cases start in the adrenals.

The clinical symptoms and signs at appearance might vary widely because of the large degree of variety in the tumor’s presentation, from a benign palpable lump with distension to serious sickness from significant tumor dissemination.

Despite the claimed gains in 5-year event-free survival overall, subgroup-specific analyses of mortality have shown discrepancies between both the higher cure rates for the less dangerous low-risk varieties and the lack of progress in the high-risk classes. The need for targeted therapies in the extreme management of high-risk patients is, therefore, great.

Epidemiology

The average diagnosis age for neuroblastoma, which is 97 percent common among sympathetic nervous system tumors and the most prevalent cancer in infants, is seventeen months. It is responsible for 15 percent of mortality in children from cancer.

With just a small shift (0.4 percent) across time, the annual prevalence of neuroblastoma in the U.s is roughly 650 occurrences, or 10.2 per million kids (65 for every million babies).

A distinct picture is painted by subcategory-specific mortality, despite the fact that a general increase in 5-year mortality has already been recorded between 1975 and 2005.

Anatomy

Pathophysiology

The most significant of the several biochemical indicators of NB is MYCN. Approximately 25 percent of NB patients have overexpression of this oncogene. The gene is frequently discovered in individuals who have advanced malignancies. Patients who carry the MYCN trait frequently experience rapid cancer development and unfavorable prognosis. H-Ras gene expression, on the other hand, is connected to early-stage illness.

Additionally, therapy response is evaluated using the DNA (deoxyribonucleic acid) index. Comparatively to those with a DNA index below 1, those with a deoxyribonucleic acid index higher than 1 typically respond well to cyclophosphamide and doxorubicin. Additional biological indicators associated with a bad prognosis include telomerase RNA levels that are high and a lack of glycoprotein CD44 expression.

Serum neuron-specific enolase, serum ferritin, and high levels of LDH are additional indicators associated with poor outcomes. Nearly 90percent of patients had elevated levels of homovanillic acid and vanillyl mandelic acid in their urine. It has been demonstrated that mass scanning in Japan utilizing urine catecholamines reduces fatalities from high-risk neuroblastoma.

The paraspinal ganglia, adrenal gland, and, less frequently, the cervical, thoracic, and pelvis regions are all potential sites for neuroblastoma development. While older children typically appear with stomach tumors, infants may present with neck or thoracic lumps. The lesion’s mass, which widens the abdomen and creates pain, is mostly to blame for the symptoms. Neurological deficiencies can be a symptom of spinal cord lesions.

Etiology

Although exposures during conceiving and gestation are a subject of inquiry, complications for the development of mutations in crucial genes that cause neuroblastoma have not yet been found. Both spontaneous development and germline transmission are possible with NB. The majority of familial instances of neuroblastoma are caused by the transmission of highly penetrant alterations in the ALK and PHOX2B genomes.

Only a small fraction of familial NB exhibits autosomal dominant heredity. Although ALK mutations can cause NB in up to 15 percent of sporadic instances, polymorphisms in BARD1 (2q35), FLJ22536 (6p22.3), and LIN28B (6q16.3) are more frequently associated with transformative mutations.

The absence of chromosomes 1p and 11q, copy number change in 1q21, and gain of 17q are further examples of cytogenetic abnormalities. Notably, MYCN oncogene amplification is observed in about a 25percent of cases and is linked to the worst prognosis; MYCN amplification is correlated with 17q growth and 1p deletion.

Genetics

Prognostic Factors

Clinical History

Physical Examination

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

Medication

 

doxorubicin

Single drug-treatment:

60 - 75

mg/m^2

Intravenous (IV)

over 3 to 10 minutes every 21 days.
Combination drug treatment: 40 to 75 mg/m^2 IV every 21 to 28 days in combination with other chemotherapeutic agents.



naxitamab 

Indicated as combined with GM-CSF (granulocyte-macrophage colony-stimulating factor) for refractory high-risk neuroblastoma that occurs in the bone marrow of patients
3mg/kg/day intravenously on 1st, 3rd, and 5th day of every cycle as fused with GM CSF subcutaneously
The cycle of treatment goes like this:
5 days before the naxitamab- Administer 250 mcg/m2
GM-CSF subcutaneously
1-5 days- Administer 500 mcg/m2 GM-CSF subcutaneously 1 hour before naxitamab on 1st, 3rd, and 5th day
1st, 3rd, and 5th day- Administer naxitamab at 3 mg/kg/day intravenously
Repeat every 4 weeks until 5 cycles
Later repeat after every 8 weeks
Discontinue the treatment after the disease is progressed



indisulam 

The drug is investigational and currently undergoing phase 2 clinical trials



eflornithine 

For body surface area within 0.75 to 1.5 m2 then take a dose of 576 mg orally two times daily
For body surface area >1.5 m2 then take a dose of 768 mg orally two times daily
Dosage Modifications
If adverse reactions occur, then continue to decrease the dose till reaching up to 192 mg orally daily
If not able to tolerate dose of 192 mg orally daily, then permanently discontinue
Dosing Considerations
Before initiating perform complete blood cell count (CBC), baseline audiogram and liver function tests



indisulam 

The drug is investigational and currently undergoing phase 2 clinical trials



 

doxorubicin

< 12 kg:

0.83

mg/kg

Intravenous (IV)

per day as a continuous infusion on days 1, 2, and 3 of a total dose of 2.49 mg/kg in combination with cyclophosphamide and vincristine with etoposide and cisplatin.
> 12 kg: 25 mg/m^2 per day as a continuous infusion on days 1, 2, and 3 of a total dose of 75 mg/m2 in combination with cyclophosphamide and vincristine with etoposide and cisplatin.



dinutuximab

17.5 mg per m2 per day given IV over 10-20hrs for four days of 5 cycles:
on 4, 5, 6, and 7 days infuse cycles 1, 3, and 5
cycles and 1, 3, and 5 cycles are 24 days in duration
On 8, 9, 10, and 11 days infuse during cycles 2 and 4
cycles 2 and 4 are 32 days in duration
Rate of Infusion:
Initiate 0.875 mg per m2 per hour for 30 minutes
Gradually increase the dose to 1.75 mg per m2 per hour



Dose Adjustments

Renal Dose Adjustments:
No Data available
Liver Dose Adjustments:
No Data available

naxitamab 

Indicated as combined with GM-CSF (granulocyte-macrophage colony-stimulating factor) for refractory high-risk neuroblastoma that occurs in the bone marrow of patients
For more than 1 year-
The cycle of treatment goes like this:
5 days before the naxitamab- Administer 250 mcg/m2
GM-CSF subcutaneously
1-5 days- Administer 500 mcg/m2 GM-CSF subcutaneously 1 hour before naxitamab on 1st, 3rd, and 5th day
1st, 3rd, and 5th day- Administer naxitamab at 3 mg/kg/day intravenously
Repeat every 4 weeks until 5 cycles Later repeat after every 8 weeks



lutetium Lu 177- Diethylenetriamine Pentaacetic acid-omburtamab (FDA Approval Pending) 

FDA approval pending for radioimmunotherapy in pediatric patients with CNS metastasis from neuroblastoma



cisplatin 

Off-label
The recommended dose of cisplatin via IV is 90 mg/m2 every three weeks:



eflornithine 

For body surface area within 0.75 to 1.5 m2 then take a dose of 576 mg orally two times daily
For body surface area >1.5 m2 then take a dose of 768 mg orally two times daily
Dosage Modifications
If adverse reactions occur, then continue to decrease the dose till reaching up to 192 mg orally daily
If not able to tolerate dose of 192 mg orally daily, then permanently discontinue
Dosing Considerations
Before initiating perform complete blood cell count (CBC), baseline audiogram and liver function tests



 

Media Gallary

References

https://www.ncbi.nlm.nih.gov/books/NBK448111/

neuroblastoma

Updated : February 14, 2024




The most prevalent extracranial pediatric tumor is NB (neuroblastoma). It is categorized as a neural crest progenitor cell-derived embryonal NETs (neuroendocrine tumor). Because of this, it can happen anywhere throughout the sympathetic nervous system, such as the celiac ganglia, superior cervical, and paraspinal; nevertheless, the majority of cases start in the adrenals.

The clinical symptoms and signs at appearance might vary widely because of the large degree of variety in the tumor’s presentation, from a benign palpable lump with distension to serious sickness from significant tumor dissemination.

Despite the claimed gains in 5-year event-free survival overall, subgroup-specific analyses of mortality have shown discrepancies between both the higher cure rates for the less dangerous low-risk varieties and the lack of progress in the high-risk classes. The need for targeted therapies in the extreme management of high-risk patients is, therefore, great.

The average diagnosis age for neuroblastoma, which is 97 percent common among sympathetic nervous system tumors and the most prevalent cancer in infants, is seventeen months. It is responsible for 15 percent of mortality in children from cancer.

With just a small shift (0.4 percent) across time, the annual prevalence of neuroblastoma in the U.s is roughly 650 occurrences, or 10.2 per million kids (65 for every million babies).

A distinct picture is painted by subcategory-specific mortality, despite the fact that a general increase in 5-year mortality has already been recorded between 1975 and 2005.

The most significant of the several biochemical indicators of NB is MYCN. Approximately 25 percent of NB patients have overexpression of this oncogene. The gene is frequently discovered in individuals who have advanced malignancies. Patients who carry the MYCN trait frequently experience rapid cancer development and unfavorable prognosis. H-Ras gene expression, on the other hand, is connected to early-stage illness.

Additionally, therapy response is evaluated using the DNA (deoxyribonucleic acid) index. Comparatively to those with a DNA index below 1, those with a deoxyribonucleic acid index higher than 1 typically respond well to cyclophosphamide and doxorubicin. Additional biological indicators associated with a bad prognosis include telomerase RNA levels that are high and a lack of glycoprotein CD44 expression.

Serum neuron-specific enolase, serum ferritin, and high levels of LDH are additional indicators associated with poor outcomes. Nearly 90percent of patients had elevated levels of homovanillic acid and vanillyl mandelic acid in their urine. It has been demonstrated that mass scanning in Japan utilizing urine catecholamines reduces fatalities from high-risk neuroblastoma.

The paraspinal ganglia, adrenal gland, and, less frequently, the cervical, thoracic, and pelvis regions are all potential sites for neuroblastoma development. While older children typically appear with stomach tumors, infants may present with neck or thoracic lumps. The lesion’s mass, which widens the abdomen and creates pain, is mostly to blame for the symptoms. Neurological deficiencies can be a symptom of spinal cord lesions.

Although exposures during conceiving and gestation are a subject of inquiry, complications for the development of mutations in crucial genes that cause neuroblastoma have not yet been found. Both spontaneous development and germline transmission are possible with NB. The majority of familial instances of neuroblastoma are caused by the transmission of highly penetrant alterations in the ALK and PHOX2B genomes.

Only a small fraction of familial NB exhibits autosomal dominant heredity. Although ALK mutations can cause NB in up to 15 percent of sporadic instances, polymorphisms in BARD1 (2q35), FLJ22536 (6p22.3), and LIN28B (6q16.3) are more frequently associated with transformative mutations.

The absence of chromosomes 1p and 11q, copy number change in 1q21, and gain of 17q are further examples of cytogenetic abnormalities. Notably, MYCN oncogene amplification is observed in about a 25percent of cases and is linked to the worst prognosis; MYCN amplification is correlated with 17q growth and 1p deletion.

doxorubicin

Single drug-treatment:

60 - 75

mg/m^2

Intravenous (IV)

over 3 to 10 minutes every 21 days.
Combination drug treatment: 40 to 75 mg/m^2 IV every 21 to 28 days in combination with other chemotherapeutic agents.



naxitamab 

Indicated as combined with GM-CSF (granulocyte-macrophage colony-stimulating factor) for refractory high-risk neuroblastoma that occurs in the bone marrow of patients
3mg/kg/day intravenously on 1st, 3rd, and 5th day of every cycle as fused with GM CSF subcutaneously
The cycle of treatment goes like this:
5 days before the naxitamab- Administer 250 mcg/m2
GM-CSF subcutaneously
1-5 days- Administer 500 mcg/m2 GM-CSF subcutaneously 1 hour before naxitamab on 1st, 3rd, and 5th day
1st, 3rd, and 5th day- Administer naxitamab at 3 mg/kg/day intravenously
Repeat every 4 weeks until 5 cycles
Later repeat after every 8 weeks
Discontinue the treatment after the disease is progressed



indisulam 

The drug is investigational and currently undergoing phase 2 clinical trials



eflornithine 

For body surface area within 0.75 to 1.5 m2 then take a dose of 576 mg orally two times daily
For body surface area >1.5 m2 then take a dose of 768 mg orally two times daily
Dosage Modifications
If adverse reactions occur, then continue to decrease the dose till reaching up to 192 mg orally daily
If not able to tolerate dose of 192 mg orally daily, then permanently discontinue
Dosing Considerations
Before initiating perform complete blood cell count (CBC), baseline audiogram and liver function tests



indisulam 

The drug is investigational and currently undergoing phase 2 clinical trials



doxorubicin

< 12 kg:

0.83

mg/kg

Intravenous (IV)

per day as a continuous infusion on days 1, 2, and 3 of a total dose of 2.49 mg/kg in combination with cyclophosphamide and vincristine with etoposide and cisplatin.
> 12 kg: 25 mg/m^2 per day as a continuous infusion on days 1, 2, and 3 of a total dose of 75 mg/m2 in combination with cyclophosphamide and vincristine with etoposide and cisplatin.



dinutuximab

17.5 mg per m2 per day given IV over 10-20hrs for four days of 5 cycles:
on 4, 5, 6, and 7 days infuse cycles 1, 3, and 5
cycles and 1, 3, and 5 cycles are 24 days in duration
On 8, 9, 10, and 11 days infuse during cycles 2 and 4
cycles 2 and 4 are 32 days in duration
Rate of Infusion:
Initiate 0.875 mg per m2 per hour for 30 minutes
Gradually increase the dose to 1.75 mg per m2 per hour



Dose Adjustments

Renal Dose Adjustments:
No Data available
Liver Dose Adjustments:
No Data available

naxitamab 

Indicated as combined with GM-CSF (granulocyte-macrophage colony-stimulating factor) for refractory high-risk neuroblastoma that occurs in the bone marrow of patients
For more than 1 year-
The cycle of treatment goes like this:
5 days before the naxitamab- Administer 250 mcg/m2
GM-CSF subcutaneously
1-5 days- Administer 500 mcg/m2 GM-CSF subcutaneously 1 hour before naxitamab on 1st, 3rd, and 5th day
1st, 3rd, and 5th day- Administer naxitamab at 3 mg/kg/day intravenously
Repeat every 4 weeks until 5 cycles Later repeat after every 8 weeks



lutetium Lu 177- Diethylenetriamine Pentaacetic acid-omburtamab (FDA Approval Pending) 

FDA approval pending for radioimmunotherapy in pediatric patients with CNS metastasis from neuroblastoma



cisplatin 

Off-label
The recommended dose of cisplatin via IV is 90 mg/m2 every three weeks:



eflornithine 

For body surface area within 0.75 to 1.5 m2 then take a dose of 576 mg orally two times daily
For body surface area >1.5 m2 then take a dose of 768 mg orally two times daily
Dosage Modifications
If adverse reactions occur, then continue to decrease the dose till reaching up to 192 mg orally daily
If not able to tolerate dose of 192 mg orally daily, then permanently discontinue
Dosing Considerations
Before initiating perform complete blood cell count (CBC), baseline audiogram and liver function tests



https://www.ncbi.nlm.nih.gov/books/NBK448111/