neuroblastoma my lecture 2011

Neuroblastoma

ByWael H Elsawy

Professor of Clinical OncologyFaculty of Medicine, Zagazig University

Egypt

Neuroblastoma is:

A cancer of the sympathetic nervous system It is derived from neural crest cells and is a neuroendocrine tumor.

The most common solid tumor of infancy and the most common extra-cranial solid tumor of childhood.

One of the few cancers known to undergo spontaneous regression from an undifferentiated state to a benign tumor.

– Neuroblastoma can be very difficult to cure in older children.– Neuroblastoma accounts for 8 - 10% of childhood

malignancies. However, it accounts for 15% of cancer deaths in children.

Epidemiology

Epidemiology

− Neuroblastoma accounts for 8 - 10% of childhood malignancies and 15% of cancer deaths in children.

− Incidence (USA) in children younger than 15 years:

10.4 per million per year in white children 8.3 per million black children Uniform throughout the world for industrialized

countries

Epidemiology (Cont.)

− Prevalence (USA) - 1 case per 7,000 live births or 800 new cases per year

− Male: female ratio of 1.2:1 − Neuroblastoma is the most frequent tumor to be diagnosed

in children less than one year of age (50% of cases are diagnosed within the first year of life) but is extremely rare in children over 10 years of age.

Etiology

Etiology

− The etiology is unknown.− The following factors have been implicated but not proven

to cause neuroblastoma:o Paternal exposure to electromagnetic fieldso Prenatal exposure to alcohol, pesticides, phenobarbital

Genetic Predisposition

Genetic Predisposition

• A subset of patients exhibits a predisposition to develop neuroblastoma:

o Familial cases- 1% of all cases.

o Median age of diagnosis for familial neuroblastoma is 9 months (younger than median).

o Analysis of neuroblastoma pedigrees have revealed the short arm of chromosome 16 (16p12-13) is a likely predisposition locus.

o Mutations in PHOX2B (a key regulator of normal development of the autonomic nervous system) have been noted in a subset of patients with hereditary neuroblastoma.

o Heritable mutations in the anaplastic lymphoma kinase (ALK) gene are an important cause of familial neuroblastoma.

Associated Conditions

Hirschsprung disease Congenital central hypoventilation syndrome (CCHS or

Ondine’s curse) Neurofibromatosis type I

By studying the genetics of these disorders, perhaps genes will be identified as possible candidate genes for neuroblastoma

Disease Spread and location

Disease Spread and location

Neuroblastoma may originate anywhere along the sympathetic chain

Table 1: Location of Primary Neuroblastoma

Disease Spread and location

− Babies less than 1 year old have a higher proportion of thoracic tumors compared to older children.

− Roughly 50% of infants and 70% of older children present with metastatic disease.

− The most common sites of metastases are Lymph nodes (regional and disseminated) Bone marrow Bone Liver Subcutaneous tissue.

Presentation

Presentation

Depends on:

1. The site of the primary tumor:o Neuroblastoma may originate anywhere along the sympathetic

chaino Majority of primary tumors arise from the abdomeno Infants have more thoracic and cervical primary tumors

compared to children.

2. Disease Extent (presence of metastatic disease)

3. Presence of paraneoplastic syndromes

* 1% of patients will have no detectable primary tumor.

Abdominal Tumors

• 65% of primary tumors• Most originate from the adrenal gland• Potential symptoms include:– Sense of fullness or abdominal pain– Palpable mass that is firm, irregular, and may cross the

midline.

Paraspinal Tumors

• Occurs in 5-15% of patients• Can cause cord compression

Cervical Tumors

• Occurs in 5% of patients• May present with Horner Syndrome

Thoracic tumors

• May be found coincidentally on CXR• May cause respiratory symptoms• Cervical adenopathy may be palpable • Heterochromia iridis (depigmented iris on the side of the

lesion)• Horner’s syndrome • Babies less than 1 year old have a higher proportion of

thoracic tumors compared to older children.

Associated Syndromes

Associated Syndromes

These syndromes are secondary to neuroblastoma: These syndromes are secondary to neuroblastoma:

Opsoclonus-myoclonus

Acute cerebellar ataxia Rapid random eye movements May present years prior to the neuroblastoma itself Autoimmune disorder (caused by IgG and IgM

antibodies) Associated with thoracic, localized disease Good disease free survival 80% have permanent neurological sequelae

Pepper Syndrome

Massive involvement of liver with metastatic disease May have Respiratory distress

Horner Syndrome

Unilateral ptosis, myosis, anhydrosis Associated with thoracic and cervical tumors Does not resolve with tumor resection

Hutchinson Syndrome

Limping and irritability in young child Associated with bone and bone marrow metastases

Kerner-Morrison Syndrome

Intractable secretory diarrhea Due to vaso-intestinal peptide (VIP) secretion Generally associated with favorable tumors.

Metastatic Disease

Metastatic spread occurs in lymphatic and hematogenous patterns.

Regional lymph node metastases are noted in 35% of patients with apparently localized tumors.

The most common sites for hematogenous spread are to the bone marrow, bone, liver, and skin. Infrequently, it may spread to the brain or lung.

Signs and symptoms include:

− Respiratory problems due to enlarged liver. Seen especially in babies with stage IVS disease.

− Skin or subcutaneous nodules are seen almost only in infants- non-tender, bluish and mobile - “blueberry muffin sign”

− Bone disease can cause: o Pain and limping. o Sphenoid bone and retrobulbar tissue involvement causes orbital

ecchymoses swelling and proptosis (raccoon face).

o Infants present as irritable and fussy

− Bone marrow involvement may result in pancytopenia.

Differential Diagnosis

Investigation

Blood work

Routine blood work and urinalysis including:− CBC – may have normochromic, normocytic anemia − Liver and kidney function studies− Coagulation screen (clotting problems associated with liver

metastases)

Blood work (Cont.)

– Urinary catecholamines - vanillylmandelic acid (VMA) and homovanillic acid (HVA) o Excreted into the urine in large quantities o Levels are elevated in 90% of neuroblastoma patients.o The absolute values of VMA and HVA are not significant, but

the VMA: HVA ratio in patients with disseminated disease correlates with outcome (the higher the value the better the prognosis - VMA: HVA ratio greater than or equal to 1.5 do

better than if this ratio is less than 1.5).

Ferritin

Produced by neuroblastoma cells in vitro Levels increased in about 50% of patients with Stage III or IV

disease at diagnosis. In Stage III disease an elevated ferritin level is a poor prognostic

feature.

Biopsy

– Surgery is important to establish the diagnosis and obtain enough tissue for pathology, molecular studies etc.

– Biopsy may be obtained using a laparoscope or at limited laparotomy with incisional biopsy.

– Only rarely is it possible to resect a neuroblastoma completely at diagnosis.

– If tumor appears localized, every effort should be made to resect as much of the tumor as possible.

Biopsy (Cont.)

– At the operation, as well as removal of the primary, extent of disease should be assessed. Local lymph nodes should be biopsied and neural foramina inspected when relevant.

– At present, open biopsies are preferred rather than needle biopsies if the risks of open biopsies can be minimized. Criteria for neuroblastoma diagnosis are described in Table 3.

Staging Investigations

Pathology

Pathology

– Neural crest cells give rise to the adrenal medulla, sympathetic ganglia, thyroid medullary C cells, meninges, Schwann cells, melanocytes and membranous bone.

– The neural crest contains primitive stem cells which differentiate into sympathoblasts.

– Neuroblastoma is most likely derived from these cells.

Origin of Neuroblastomas

Pathology (Cont.)

– Neuroblastoma is one of the "small blue round cell tumors” of childhood (others include lymphoma, Ewing's sarcoma, germ cell tumors, embryonal rhabdomyosarcoma and PNETs).

– There are dense nests of undifferentiated cells separated by fibrillar bundles. Hemorrhage, necrosis and calcification are usually present. Tumor cells often form rosettes around a pink fibrillar center.

Ganglioneuroblastoma

– As maturation occurs tumor cells differentiate towards ganglion cells and increasing amounts of fibrillar material are present (may not be a uniform process).

– A ganglioneuroblastoma consists of maturing or mature ganglion cells together with neuroblasts. Tumors are less aggressive than neuroblastoma.

– A ganglioneuroma is composed of well differentiated ganglion cells and is benign.

Ganglioneuroblastoma (Cont.)

– Electron microscopy shows neurosecretory dense core granules in the peripheral cytoplasm and neural processes containing microtubules.

– Immunodiagnosis using the antibody to NSE is helpful in differentiating this tumor from other small blue cell tumors.

Neurotrophin Receptors

– Neurotrophic factors and their receptors have been implicated in the pathogenesis of neuroblastoma.

– There is a correlation between the expression of the nerve growth factor TRKA and clinical outcome (TRKs are tyrosine kinase receptor genes).

– Tumors that had no N-myc amplification showed high TRKA expression.

– High TRKA expression was associated with 86% 5 year survival and low TRKA expression with 14% survival.

– ? TRKA and nerve growth factors cause differentiation in neuroblastoma.

Shimada index

• Shimada reviewed the pathology and his classification is used as a prognostic indicator. o Age is taken into account. o This has a strong prognostic significance for stages 1, 3

and 4 and 4S.

Shimada index

o Several criteria are used :-

1. Tumor is defined as being either "stroma rich" or "stroma poor". Stroma rich have more fibrillar material and therefore tend to be more mature.

2. Tumor cell differentiation

3. The nuclear morphology is evaluated by a mitosis- karyorrhexis index (MKI). The total number of mitosis and karyorrhectic cells is determined among 5000 tumor cells in randomly selected fields (less than 100 / 5000 = low and do well, more than 200 / 5000 = high).

Biologic Factors

o Once the tumor is identified, several key tests must be performed on the specimen in order to stratify the patient according to risk as outlined below.

1. Shimada index

2. DNA index

3. N-MYC Amplification

4. Cytogenetics

5. Neurotrophin Receptors

Shimada index

− Hiroyuki Shimada et al developed a histologic classification system, which can be used as a prognostic indicator. Age is taken into account.

− Classifies tumors as favorable or unfavorable

• Favorable

o Stroma-rich, all ages

o Stroma poor, age 1-1.5 yr, differentiated, MKI<100

o Stroma poor, age < 1.5 yr, MKI < 200

Shimada index (Cont.)

• Unfavorable

o Stroma rich, all ages, nodular pattern

o Stroma poor, age > 5 yr

o Stroma poor, age 1.5-5 yr, undifferentiated

o Stroma poor, age < 1.5 yr, MKI > 200

Shimada index (Cont.)

− Stroma- rich/stroma poor refers to presence or absence of Schwannian components

− Differentiation refers to maturity of tumor

− MKI is the mitosis-karyorrhexis index [number of mitoses (cell division) and karyorrhexis (degeneration of the nucleus) per 5,000 cells]

DNA index

− DNA index refers to the amount of DNA in the tumor cell,

which is prognostically important. DNA ploidy probably has

the most prognostic significance in infants.

• Hyperdiploid or near-triploid

o Whole chromosome gains without structural genetic aberrations

o associated with localized tumors and favorable prognosis

o respond better to chemotherapy

DNA index (Cont.)

• Aneuoploidy or near diploid

o Associated with unfavorable prognosis

o Usually have other genetic aberrations (N-MYC, chromosomal losses, etc)

N-MYC Amplification

− N-MYC- is a normal oncogene (promotes cell division)

− Amplification (increased copies) of N-MYC is associated with advanced stages of disease and poorer outcome

− Present in 25-35% of neuroblastoma

− N-MYC gene amplification is more frequent in near-diploid than in hyperdiploid tumors

Cytogenetics

− Cytogenetic analysis of neuroblastoma cell lines has revealed other abnormalities.

− Chromosome 1p (short arm of chromosome 1)

o Is a tumor suppressor gene (prevents amplification of N-MYC)

o 1p deletions usually associated with N-MYC amplification

o Found in 25-35% of neuroblastoma tumors

o Most commonly in patients with advanced disease.

Cytogenetics (Cont.)

− Gains of chromosome 17q is associated with more aggressive

tumors

o Occurs in 60% of neuroblastomas

− Deletion of 11q

o Present in approximately 35-45% of newly diagnosed

tumors

o Rarely occurs in combination with N-MYC

o Associated with high risk disease because it is associated

with older age, advanced stage, and unfavorable pathology

Neurotrophin Receptors

o Signal cell to differentiate

o A neurotrophin receptor, TRKA (a tyrosine kinase) expression associated with younger age at diagnosis, lower stage and absence of N-MYC amplification

o High TRKA expression was associated with 86% 5 year survival and low TRKA expression with 14%survival.

Radiology

Radiology

− Thoracic Tumors

− Plain films:

Below is a chest X-ray showing a mediastinal mass (A) - this was a thoracic neuroblastoma.

Radiology

− Thoracic Tumors

CT scan: Preferred for posterior mediastinal tumors.

MR may be preferred to evaluate paraspinal tumors.

This CT scan of the posterior mediastinal neuroblastoma shown on previous plain film. The SVC is visible on this axial image immediately anterior to the

mass and is not compressed.

The sagittal image of the same tumor shows fingers of tumor extending into the intervertebral exit foramina - common for neurogenic tumors in

this region to do this.

Coronal CT scan cut below showing this intrathoracic neuroblastoma (M) and relationship to the airway.

Radiology

• Abdominal Tumors

• CT scan:

The axial CT scan below shows an intrabdominal neuroblastoma. The mass (M) contains dystrophic calcification, crosses the midline and is associated

with extensive adenopathy.

The coronal CT scan below shows a large primary neuroblastoma arising from the adrenal (Mass). The kidney is displaced down and the liver is

pushed up

The axial CT above shows multiple metastatic nodules within the liver (M) in an infant who has Stage 4S neuroblastoma. The adrenal primary is shown

by 1ry adrenal.

Above is an coronal CT of the same patient, where the adrenal primary is seen and M refers to liver metastatic deposits and Kid. points to the

kidneys.

Radiology

• Nuclear Medicine

• Bone scan: Used to evaluate distant skeletal metastases.

Reliable to evaluate osteolytic lesions

Bone scan below shows extensive diffuse and focal uptake throughout the skeleton consistent with multiple bone deposits in a case of neuroblastoma. The skull is

especially involved as is the proximal humeri and the spine.

Radiology

• Nuclear Medicine

• MIBG scan:I-Meta-Iodo-Benzyl Guanidine is taken up by adrenergic secretory vesicles and is handled by the cells in the same way as norepinepherine. It is radiolabelled using I-131. In most neuroblastoma patients it is taken up both in the primary site and metastatic deposits.

o MIBG scan has better sensitivity and specificity than a bone scan.

o Used in diagnosis and to monitor response to therapy

o However 10% of neuroblastoma patients do not have MIBG avid tumors.

MIBG shows extensive disease with multiple focal and diffuse increased areas of activity involving the skull, long bones, the whole spine and the pelvis in the same patient. There is

also a large area of increased activity in the mid abdomen. This is his primary tumor.

MIBG scan showing diffuse skull metastases

Radiology

• Nuclear Medicine

• PET scan:− There is uptake of a radioactive glucose analogue 18-fluoro-2-

deoxyglucose (FDG) by rapidly proliferating cells undergoing anaerobic glycolysis.

− In the future PET scan is likely to be an important investigation to stage and monitor response to therapy in neuroblastoma.

The PET scan below shows avid FDG uptake in a primary neuroblastoma within upper abdomen and the normal bladder.

PET scan shows FDG avidity in a metastatic deposit from neuroblastoma involving the pubic ramus.

Staging

International Neuroblastoma Staging System (INSS):

Staging

1. Multifocal primary tumors (e.g., bilateral adrenal primary tumors) should be staged according to the greatest extent of disease, as defined above, and followed by a subscript “M” (e.g. 3M).

2. The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite side of the vertebral column.

3. Marrow involvement in Stage 4S should be minimal, i.e., less than 10% of total nucleated cells identified as malignant on bone marrow biopsy or marrow aspirate. More extensive marrow involvement would be considered to be Stage 4. The MIBG scan (if performed) should be negative in the marrow.

4. Proven malignant effusion within the thoracic cavity if it is bilateral or the abdominal cavity upstages the patient to INSS 3.

Stage 4S

Special assignment to children less than 1 year of age

Metastases limited to skin, liver, and bone marrow biopsy

May spontaneously regress

Associated with good prognosis

Stage is an important predictor of outcome.

Risk Categories

Risk Categories

– Patients are stratified into different prognostic categories or risk groups.

– Therapy design is based on the patient’s risk status.

– Risk categories depend on: Pathology

o Histology

o N-MYC status

o DNA ploidy Diagnostic imaging results.

Risk Categories

− The risk group classification determines the treatment for each individual patient.

− More than half the children diagnosed with neuroblastoma will have high risk disease with a poor prognosis.

− Recent studies suggest that toddlers aged 12-18 months with:

Stage 4 disease with N-MYC non-amplified, hyperdiploid, favorable histology have an event free survival of 90%

Stage 3 disease with N-MYC non-amplified, unfavorable histology have an event free survival of 100%

− For this reason, this cohort of patients will now be treated according to the intermediate risk protocol.

− Age and stage are major prognostic factors in neuroblastoma.

Neuroblastoma Risk Categories

Simplified overview of Neuroblastoma Risk Categories

Treatment Overview

Treatment Overview

− Treatment depends on the risk stratification.

− May involve surgery, chemotherapy, bone marrow transplant and radiation.

− Chemotherapy is the major modality of treatment for most patients.

− CCG-3881 regimen was a study that showed improved survival and used four of the most active agents in neuroblastoma

Cyclophosphamide

Doxorubicin

Carboplatin

Etoposide

Treatment Overview (Cont.)

− In patients with localized unresectable disease combination chemotherapy and second look surgery has a good chance of achieving local control.

− Infants with disseminated disease may be cured by chemotherapy alone.

− For older children with disseminated disease it can produce partial and complete remissions, but relapse is very common.

Simplified overview of Therapy for the different Neuroblastoma Risk Categories

Low Risk Category

Low Risk Category

− Complete or even partial resection may be sufficient

− Curative resection is usually possible for Stage 1 disease and sometimes for Stage 2A.

− If biologically favorable and localized tumor which is incompletely resected (stage 2A and stage 2B) - treat with surgery alone

− Overall survival rate greater than 95%.

Low Risk Category (Cont.)

− One course of chemotherapy consists of four 3 week cycles

− Each cycle has different combination of 4 drugso Carboplatin

o Etoposide

o Doxorubicin

o Cyclophosphamide

Low Risk Category (Cont.)

− One course of chemotherapy indicated for:o Life or organ-threatening symptoms at diagnosis

o Progressive or recurrent disease

o < 50% of tumor resected

o Disease recurs or progresses after observation and has favorable histology

− Give 2 courses if:o Recurs or progresses with unfavorable histology

Intermediate Risk Category

Intermediate Risk Category

− Survival greater than 95% for those with favorable characteristics

o Even if older than 1 year of age

− Chemotherapy used includes:o Carboplatin

o Doxorubicin

o Etoposide

o Cyclophosphamide

Intermediate Risk Category

− XRT for patients older than 1 year with positive lymph nodes is associated with improved survival.

− Newer studies looking to further risk stratify within intermediate risk

o Patients who have early response versus those who do not

o Attempt to give less chemo and reduce late effects of chemotherapy

o Patients with 1p or 11q abnormalities (will be upgraded to high-risk)

High Risk Category

High Risk Category

– Overall survival of 20-35%– Chemo responsive, but has a high relapse rate– Four components of treatment

o Induction - Aggressive multiagent chemotherapy (cyclophosphamide, topotecan, cisplatin, etoposide, doxorubicin, vincristine).

o Local Control - surgery and radiation.

o Consolidation - autologous bone marrow transplant.

o Biologic agents - isotretinoin (cis-RA)

High Risk Category (Cont.)

– Current COG high risk study is ANBL0532. To improve event free survival (EFS), this protocol uses: Dose intensification of the induction

chemotherapy (with addition of dose-intensive topotecan and cyclophosphamide into induction)

Tandem transplant using marrow support Escalation of radiotherapy dose for local control

Stage 4S

Stage 4S

− This disease pattern occurs only in infants.

− These patients tend to have Small Stage 1 or 2 primaries Disseminated disease restricted to the liver, skin, bone

marrow or any combination of these. No skeletal involvement.

− The role of surgery is controversial. Generally it is agreed that the primary tumor should be removed - because there is a risk of late relapse. Surgery may take place initially or after chemotherapy.

Stage 4S (Cont.)

Hepatomegaly The liver may become grossly enlarged leading to problems

with compression of abdominal viscera, respiratory embarrassment or coagulopathy.

May require treatment with chemotherapy or low dose XRT (150 cGy x 3 doses to whole abdomen using lateral fields sparing the kidneys and ovaries).

Neither of these treatments appears to affect survival. In a POG study chemotherapy did seem to accelerate tumor regression.

Stage 4S (Cont.)

Prognosis Some of these babies will have spontaneous resolution of their disease

without treatment. Prognosis is generally good with 2 year survivals of 70 - 90%, regardless of

treatment. Prognosis correlates with degree of organ compromise e.g. gastric outlet

obstruction or respiratory compromise. Favorable subgroups within 4S are

o 2 weeks - 12 months old o With skin metastases, with or without liver or bone marrow

involvemento Low N-Myc amplification number o Favorable histology.

Role of Surgery in Neuroblastoma

Surgery

At the operation as well as removal of the primary, extent of disease should be assessed. Local lymph nodes should be biopsied and neural foramina inspected when relevant.

Complete or even partial resection may be sufficient therapy and is the treatment of choice for patients with a favorable outlook or low risk disease. When the tumor is localized (20 - 40%) then an attempt at resection should be made. Sacrifice of a major organ should be avoided.

It is easiest to remove tumors arising from the side of the sympathetic chain in the neck, thorax and pelvis. Most abdominal tumors involve the retroperitoneal ganglia and so excision is difficult.

Surgery (Cont.)

Curative resection is usually possible for Stage 1 disease and sometimes for Stage 2A.

Delayed resection after chemotherapy is frequently performed for tumors that were initially unresectable with or without widespread metastases.

Second look surgeries are also commonly performed after chemotherapy and XRT. This approach has shown benefit for stage 2 and 3 patients. In stage 4 there is an improvement in local control, but not for overall survival.

Role of Radiation Therapy in Neuroblastoma

Radiation Therapy

Low doses of fractionated radiotherapy with total doses in the range of 15 - 30 Gy have been shown to reduce the risk of local recurrence.

Radiation Therapy (Cont.)

High Risk Disease

The current COG investigational study for high risk disease is ANBL0532

The aim of this study is to improve event free survival for children with high-risk neuroblastoma. The study assesses the value of tandem, or dual-cycle, stem cell transplant (HSCT) in therapy. After transplant, local RT is given and the dose is increased to reduce the risk of local relapse.

Neuroblastoma patients receiving 2100 cGy in 150 cGy fractions after incomplete resection of the primary tumor have a local control rate of just over 80% at 5 years. The aim of ANBL0532 is to improve this. The RT outline for this protocol is as follows:

Radiation Therapy (Cont.)

RT Guidelines:

RT is given following myeloablative stem cell transplant (no earlier than 28 days post transplant but within 42 days is best).

Dose:

After gross total resection: Primary site is always given RT on this protocol The dose is 2160 cGy in 12 fractions with no boost.

Radiation Therapy (Cont.)

After incomplete surgical resection: RT dose is 2160 cGy in 12 fractions (180 cGy per fraction)

plus a boost of 1440 cGy in 8 fractions to areas of gross residual disease.

2160 cGy is given to the post-induction chemotherapy, pre-operative primary tumor volume.

Boost follows of 1440 cGy to the gross residual volume. Total dose is 3600 cGy in 20 fractions.

Radiation Therapy (Cont.)

RT Guidelines:

RT given to the primary tumor and metastatic sites.

• GTV = tumor volume before attempted surgical resection (on CT, MRI, and/or MIBG scans). Not the pre-chemotherapy volume or the post-surgical volume. Uninvolved LNs not included.

• Boost GTV volume = Gross-residual disease after surgical resection. Sometimes disease can extend into a body cavity (for example lung) or displace a normal structure. If after surgery the normal structure moves to space previously occupied by the tumor, the normal structure doesn't have to be included in the GTV (as long as it was not infiltrated by disease).

Radiation Therapy (Cont.)

CTV = Clinical Target Volume = GTV with a 1.5 cm margin.

PTV = Planning Target Volume = CTV + a margin for set up error or patient movement (depends on immobilization methods and patient cooperation)

Should be at least 0.5 cm.

3D conformal technique used with 4, 6 or 10 MV photons.

Use wedges, compensators to make the dose distribution more uniform.

Entire PTV should be encompassed within the 95% isodose surface.

No more than 10% of the PTV should receive greater than 110% of the prescription dose (evaluated by DVH).

Radiation Therapy (Cont.)

Often a 3 field technique is used. Portals should be designed as far as possible to

Spare the kidneys &/ remaining kidney. Spare liver to prevent veno-occlusive disease. Because sparing the kidney is a priority, the vertebral

body is not always evenly irradiated as in Wilm’s. In the long term scoliosis due to uneven spinal growth is more of a problem in these patients.

Radiation Therapy (Cont.)

Metastatic sites – Given RT if persistent active disease (MIBG positive) on the

pre-HSCT evaluation (after 6 cycles of induction chemotherapy).

– If negative on the pre-HSCT scans will NOT be given RT.– Persistent active metastatic disease is given RT

concurrently with primary site– Dose of 2160 cGy given in 12 fractions.

Radiation Therapy (Cont.)

Off study, the total dose of radiotherapy for high risk neuroblastoma is generally 2100 - 2160 cGy.

− Radiotherapy can be used to treat emergencies such as Cord compression. Tracheal compression. Expanding retro-orbital tumor. Imminent bone fracture. Rapidly enlarging liver.

− However there is evidence that prompt treatment with chemotherapy is also very effective in these situations.

Tolerances/Dose Modifications for different sites of spread

Autologous Bone Marrow Transplant

Autologous Bone Marrow Transplant

High risk neuroblastoma is incurable in at least 70% of patients.

Autologous bone marrow transplant is used so that higher doses of chemotherapy (i.e.- myeloablative) can be used.

Without a transplant, the bone marrow would be suppressed for a dangerously long time

After myeloablative chemotherapy is give, the patient’s own bone marrow cells or stem cells are returned. This way, patient’s can receive high doses of chemotherapy directed towards the neuroblastoma without prolonged bone marrow suppression

Autologous Bone Marrow Transplant (Cont.)

− The chemotherapy used: Carboplatin Melphalan Etoposide

− Trials have shown that this does reduce the relapse rate.− To improve event free survival (EFS), tandem (or dual-

cycle) transplant regimens with PBSC support are being used after a dose intensified induction regime. The current COG high risk study ANBL0532 is assessing this approach.

Vitamin A Analogues

Vitamin A Analogues

− In studies, a vitamin A analogue, retinoic acid, has activity against minimal residual neuroblastoma (disease that cannot be identified by routine methods).

− May work even in tumors that are resistant to chemotherapy and/or radiation.

− Retinoic acid works by: Decreasing proliferation Decreasing expression of N-MYC Causing morphologic differentiation (from immature

Neuroblastoma to the more mature form)

Vitamin A Analogues

− Toxicities include: Cheilitis Dry skin Hypertriglyceridemia Hypercalcemia

− In a randomized trial (CCG-3891), patients with high risk neuroblastoma were randomly assigned to receive a 6 month course of isotretinoin versus observation alone (after chemotherapy and autologous bone marrow transplant). The 3 year event free survival, for the patients who received isotretinoin was about 50% vs 35% for those who did not. The difference was not statistically significant, but there was a strong trend towards improved survival with isotretinoin.

− Retinoic Acid has now been incorporated into the standard treatment for high risk neuroblastoma.

New Agents

New Agents

− Because the overall survival for high risk Neuroblastoma is still poor, newer agents are constantly being sought to help improve the outcome.

− One of the newest agents currently in trial is a monoclonal antibody. Monoclonal antibody directed against neuroblastoma-

specific antigen, gangliosidase (GD2) May kill neuroblastoma by antibody dependent cellular

cytotoxicity (i.e.- priming the patient’s own immune system to attack the residual neuroblastoma cells)

New Agents (Cont.)

Antigen has limited expression in normal human tissueso Therefore, would expect few side effects

Therapeutic responses have been demonstrated in patients with refractory disease

Studies are underway to see if effective in front-line therapy for patients with high risk disease after chemotherapy, surgery, autologous bone marrow transplant, and radiation.

Prognosis

Prognosis

Age Age at diagnosis is an important prognostic factor. The majority of children diagnosed at 12 months or

younger will survive. Children less than one year with localized tumors have a

five year survival greater than 90%, whereas in older children with advanced disease the long term survival is less than 30%, even with intensive therapy.

Younger patients do tend to present with earlier stage disease.

Stage

StageStage is an important predictor of outcome.

Prognosis

MYCN Oncogene Amplification Genomic amplification of N-myc (or MYCN) is directly

correlated with prognosis. If MYCN oncogene is amplified, patients tend to have

advanced stage and rapid tumor progression. MYCN amplification is only rarely detected in localized

neuroblastoma

Prognosis

Histopathology Shimada analyzed in CCG-3881 data and showed that

unfavorable pathology was associated with advanced disease and less favorable outcome (except for StageI disease).

Prognosis

DNA Ploidy Flow cytometric techniques measure cellular DNA content or ploidy

or cytogeneticanalysis of metaphase chromosomes.

A number of genetic abnormalities correlate with prognosis. Ploidy seems to override favorable clinical features. Hyperdiploid tumors do better than diploid tumors and respond

better to chemotherapy. In infants with disseminated neuroblastoma, DNA ploidy accurately discriminated between good and poor responders to chemotherapy.

MYCN gene amplification is more frequent in diploid than in hyperdiploid tumors.

Risk grouping for patients with neuroblastoma stratifies them into different prognostic categories.

Thank You