Management of Nuroblastoma

1. NEUROBLASTOMA
PRESENTER: DR.MOUMITA PAUL
2NDYEAR PGT
MODERATOR: DR.MOUCHUMEE BHATTACHARYYA
ADDL.PROFESSOR
DEPARTMENTOF RADIATIONONCOLOGY
BBCI

2. Introduction
 The third most common malignancy in children
(after leukemia and brain tumours ).
 Most common extracranial solid tumour in children.
 Most common cancer diagnosed in infants
(accounting for almost half of all cancers in infants).
 Median age at diagnosis : 2 years
 Origin: Cells of the neural crest that form the
adrenal medulla and sympathetic ganglia.
 Constitutes 8-10% of all childhood cancers.

3. Common sites of origin
 Adrenal medulla(30-40%) – M/C site of origin
 Paraspinal ganglia in the abdomen or pelvis
(25%)
 Thorax (15%)
 Head and Neck (15%)

4. Risk Factors
 For familial neuroblastomas-
1) Germline mutations in the anaplastic lymphoma kinase
gene(ALK)
2) Aberrations in PHOX2b
3) Deletion of chromosome arms 1p and 11q
 Amplification of the MYC-N proto-oncogene
 Duplicated segments of the LMO1 gene
 Among younger infants – high birth weight, maternal HTN,
older maternal age, USG were ideas that the risk of NB
development include.
 Among older infants – low birth weight, first born status,
prolonged labour, premature rupture of membranes were
ass.with increased risk.
 Maternal ingestion of diuretics and other anti hypertensives.

5. Natural History
 More than 70% of patients present with metastases.
 Most frequent sites of metastasis are lymph nodes,
bone, bone marrow, skin (or subcutaneous tissues)
and liver.
 Lung and CNS are rare sites of metastases.
 Neuroblastoma has the highest spontaneous
remission rate of any human neoplasm, usually by
maturation to ganglioneuroma.
 May be associated with Neurofibromatosis type 1
and Beckwith-Wiedemann syndrome.

6. Genetics
 Autosomal dominant pattern of inheritance.
*(Knudson and Strong, 1972a; Robertson et al, 1991)
 In familial cases median age decreases to 9 months.
 Hereditary neuroblastoma predisposition gene
chromosome 16p12-13
*(Maris et al, 2002)
 Amplification of the N-MYC oncogene seen in roughly
20%.
*(Look et al,1991; Muraji et al,1993)
 Deletion of short arm of chr 1.
*(Brodeur et al,1992; Caron et al,1996)

7. Cytogenetics and Molecular
genetics
 Amplification of MYC-N oncogene – results in persistently
high levels of MYCN protein, a DNA-binding transcription
factor known to cause malignant transformation.
 Loss of heterozygosity (LOH; loss of one allele) at chr 1p36and
11q occurs in 23% and 34% of tumours respectively.
 Gain of chr 17 or 17q is present in 50-60% cases.
 Elevated expressions ofTrkA orTrkC is seen in low stage
tumours.LowTrk A and elevatedTrkB is seen in advanced
stage MYC-N amplified tumours.
 Disruption of NBPF23 gene is also shown to be highly
associated with NB.
 Common variations in the BRCA1-associated RING domain
protein 1(BARD1) gene have been implicated in the
development of high-risk disease.
 LMO1 is also found to be suggestive of neuroblastoma
oncogene.

8. Clinical Features
 Depends on the site of localisation of the primary tumour.
 Pain- M/C presenting symptom caused by bone, liver, or bone
marrow metastases or low visceral invasion.
 Symptoms of Neuroblastoma in abdomen : Abdominal pain, non-
tender mass under the skin, changes in bowel habits such as
diarrhoea, swelling in legs.
 Symptoms in chest : Chest pain, wheeze, respiratory distress
 Horner’s syndrome may accompany a primary tumour originating
in the neck.
 Other constitutional symptoms :Weight loss, Anorexia, Malaise.
 Orbital mets can present with proptosis and ecchymosis.
 Blueberry muffin sign : Skin metastases with bluish tinge.
 An unusual presentation of localised Neuroblatoma is opsoclonus-
myoclonus syndrome(Kinsbourne syndrome), manifested by
truncal ataxia and cerebellar encephalopathy.

9. Olfactory Neuroblastoma
 An uncommon malignant neuroectodermal nasal tumour.
 Constitutes 2% of all sinonasal tract tumours with an incidence of approx.
0.4 per million population.
 Also k/a esthesioneuroblastoma/olfactory placode tumour/
esthesioneurocytoma /esthesioneuroepithelioma.
 Bimodal age distribution: 2nd and 6th decades
 Locations mostly are– sphenopalatine ganglion, autonomic ganglia of nasal
mucosa, ganglion of Loci(nervus terminalis).
 C/F : U/L nasal obstruction(70%), epistaxis(50%) are the most common.
Others- headache, pain, excessive lacrimation, rhinorrhoea, anosmia and
visual disturbances.
 Stains positive for synaptophysin, chromogranin, CD56, NSE, NFP and S-
100.
 CT Scan : Dumb-bell shaped mass across the cribriform plate with speckled
calcification and bone erosion of lamina papyracea, cribriform plate.
 Treatment : In cases of resectable disease trephination with bicranial-facial
approach followed by RT.
In unresectable cases, palliation with CT(Cyclophosphamide and
Vincristine) .

10. STAGING

11. Pathology
 Small,round, blue cell tumour
composed of dense nests of
hyperchromatic cells.
 HomerWright rosettes-
differentiated tumour cells
surround the neutrophils.
 Areas of necrosis, haemorrhage,
and calcium are frequently
present.
 Characteristically stains positive
for neurofilaments, neuron-
specificc enolase (NSE),
synaptophysin, and
chromograninA.

12. Histologic classification of
Neuroblastic tumours
 Depending on the neural type cells and Schwann
type cells:
 1) Neuroblastoma (Schwannian stroma-poor)
 2) Ganglioneuroblastoma, intermixed
(Schwannian stroma rich)
 3) Ganglioneuroblastoma, nodular (composite
Schwannian stroma rich/stroma dominant or
stroma poor)
 4) Ganglioneuroma (Schwannian stroma
dominant)

13. Shimada et al Pathologic Grading

14. Diagnostic Work-Up
 Biopsy (Excisional if tumour is resesctable/incisional biopsy)
*Bone marrow biopsy frequently show tumour deposits that can establish the
diagnosis.
 Lab investigations:Urinary HVA andVMA(metabolites of norepinephrine and
epinephrine resp.)
*Elevated in >90% cases of stage IV neuroblastoma
 Imaging:
 X-ray – speckled calcifications in 85% of neuroblastomas.
 CT Scan : with iv contrast for better assessment of local extent of primary
tumours, lymph node metastases and also about the resectibility.
 MRI : For better evaluation of blood vessel encasement, intraspinal
extension, diffuse hepatic replacement and bone marrow involvement.
 Bone Scan : Because of predilection for bony metastases, a radionucleide
bone scan is mandatory.
I-123 MIBG(metaiodobenzyl guanidine) plays an important role and is
the first line functional imaging agent for disease assessment, both at
diagnosis and during follow up.(Sensitivity of 88-93% and a specificity of 83-
92%).

15.  The Radiology Diagnostic Oncology Group enrolled
96 children with newly diagnosed Neuroblastoma in
a multicentre prospective cohort study prior to
surgery where CT, MRI and Bone Scan were used to
evaluate tumour stage.
i) In stage 1 tumour, abdominal extent was more
likely to be staged correctly with CT than with MRI,
which often overstaged tumour.
ii) For stage 2 and 3 tumours, both CT and MRI were
more likely to understage than overstage tumour
iii) For stage 2 tumour, understaging was more likely
with CT than MRI.

16. Prognostic Factors
 Prognostic factor Favourable Unfavourable
1) Age <2 years >2 years
2) Stage I,II,IV-S III,IV
3) Pathology(Shimada) Favourable Unfavourable
4) Ferritin <143 ng/ml >143 ng/ml
5) NSE <100 >100
6) Chromogranin <190 ng/ml >190 ng/ml
7) GD2 ganglioside <103 pmol/ml >103pmol/ml
8) UrineVMA/HVA <1 >1
9) N-myc Single copy Amplified
10) DNA index >1.1 <1
11) 1p deletion Absent Present

17. Neuroblastoma Risk Assessment

19. Treatment Types
 1) Surgery
 2) Chemotherapy
 3) Radiotherapy
 4)Stem cell transplant.
 5) Retinoid therapy
 6) Immunotherapy

20. Treatment of Neuroblastoma by
Risk Group
 Low Risk Disease:
 Low stage,resectable tumours (INSS 1,2 or 3 with negative nodes) have excellent
prognosis after complete gross surgical excision.
 If much of the tumour can’t be removed or if it has some unfavourable
features(such as in spinal cord compression or in respiratory insufficiency
caused by hepatomegaly)or recurrence , Chemotherapy is added after
surgery.CommonCT regimen used: Carboplatin, Cyclophosphamide,
Doxorubicin and Etoposide.
 Unresectable low stage tumours (INSS stages 1 to 3 with negative lymph nodes)
may require preoperative CT and occasionally RT if CT does not shrink the
tumour fast enough.
Complete remission can be achieved in almost 2/3rd of previously
unresectable tumours.
 Infants with stage IV-S disease and no symptoms can often be watched carefully
with no treatment , because these cancers typically matures and go away on
their own.
 Routine RT is inappropriate in stage 4-S disease and should be instituted only
when disease progression threatens vital organ function(2-6Gy is sufficient for
reduction of marked symptomatic hepatomegaly).

21.  POG 8104 Phase II trial :Patients with INSS stage 1
(POG) stage A disease, where MYCN amplification
and DNA index were not evaluated uniformly.
Treatment was surgery only. Regardless of the
presence of microscopic residual disease , the 2 year
disease free survival rate was 89% and overall
survival(OS) was 97%.
 CCGTrial 3881 : 4 year event free survival and
overall survival in stage 1 disease for children
treated initially with surgery alone were 93% and
99% respectively.

22. Intermediate Risk Disease
 Locally advanced and regionally metastatic tumours (INSS stage 2b to 3
with positive lymph nodes) requires more intensive therapy.
 Surgery is rarely enough at its own.
 Infants should undergo complete resection of the primary tumour and
receive adjuvant CT.
 Children are typically given 4 to 8 cycles (about 12 to 24 weeks) of
chemotherapy(usually carboplatin, cyclophosphamide, doxorubicin and
etoposide) before or after surgery.
 RT when CT is not effective or clinical deterioration despite CT or surgery
or persistent tumour after CT or second-look surgery.
 If CT is used after surgery, a second-look surgery may be done to see if
there is any cancer remaining and if present , to remove if possible.This
might be followed by RT,if needed.
 Current study : Possibility of not givingCT after surgery in some infants
who are asymptomatic who can just be watched closely after surgery
and would only get further treatment if the tumour begins growing or
causing symptoms.

23.  POG study randomised patients more than 1 year
old with stage C NB to receive post-op CT or CT
with regional RT(24-30 Gy/16-20#).Of 62 eligible
patients in CT arm 45% and 31% achieved
complete remission and remained disease-free,
resp.at a median of 35 months, and in CT and RT
arm 67% and 58% achieved complete remission
and remain disease-free, resp, at a median age of
23 months.
 Patients with favourable Shimada histology
tumours had a 92% event free survival compared
with 58% with unfavourable tumours(p=0.009).

24. High Risk Disease
 Children at high risk require more aggressive treatment
which often includes CT, surgery and RT.
 Therapy for high risk NB is divided into three phases:
1)Intensive induction phase :
 Goal is to achieve maximum reduction of tumour
burden, including reduction of bone marrow tumour.
 Treatment usually starts with CT using alternating
regimens of several drugs (typically cisplatin, etoposide,
vincristine, cyclophosphamide, doxorubiocin and
topotecan) at higher doses than in other risk groups.
 Surgery is usually done after this to try to remove any
tumours that are still visible.

25.  2) Consolidation phase:
 Uses more intensive treatment to try to get rid of any cancer
cells that remain in the body.
 High dose CT is given (sometimes alongwith RT ), followed
by a stem cell transplant and then immunotherapy.
 RT is often given to the primary site after stem cell
transplant and any other part of the body that might have
active disease.
 3) Maintenance phase :
 Goal is to lower the chances of relapse.
 The retinoid drug 13-cis-retinoic acid (isotretinoin) is often
given for 6 months after other treatments are completed.
 Immunotherapy with the monoclonal antibody dinutuximab,
along with immune activating cytokines (GM-CSF and IL-2) is
often given as well.

26.  CCG-3891 trial : Prospective randomised phase 3 trial
showed that there was improvement in 3-year event-
free survival (EFS) for children with high-risk
neuroblastoma treated with ABMT (34%+/-4%) as
compared to continuous CT(CC)(22%+/-4%), p=0.034)
and for those treated with 13-cis-retinoic acid compared
to no post-consolidation therapy (46%+/-6% vs 29%+/-
5%, p=0.027).
 The overall 5-year EFS and OS rates+/- standard
error(SE) for patients with Stage 3 disease were 55%+/-
6% and 59+/-6% , respectively as compared to stage 4
disease patients that was 21%+/-3%(p<0.0001) and
32%+/-3%(p<0.0001), respectively.
 For patients who received 10Gy of EBRT to the primary
site the addition of 10 Gy ofTBI and ABMT resulted in
lower local recurrence rates than CC.

28. High-risk disease
Induction
CT
Surgery
High dose
CT
alongwith
RT
Stem cell
transplant
Retinoid therapy
+
Immunotherapy

29. Radiotherapeutic Management
 EBRT is used—
 To try to shrink tumours before surgery.
 To treat larger tumours that are causing serious symptoms and do
not respond to CT.
 As part of the treatment regimen after stem cell transplant in
children with high-risk neuroblastoma cells that remain
behind.Radiation might involve the primary tumour area and
other areas of the body that might have active disease seen on
MIBG scan.
 To help relieve pain caused by advanced disease.
 TBI has been used in the past for children with high-risk
neuroblastoma before a stem cell transplant.
 It is more common now for radiation only to be given to the
primary tumour site and any other areas of the body that might
have active neuroblastoma cells.

30. Treatment planning and Field Design :
 Neuroblastoma is very radiosensitive.
 3DCRT/IMRT: decreases risk of normal tissue irradiation.
 Radiation therapy portals to a primary tumour site should
treat the gross residual tumour remaining after CT, with
atleast a 2 cm margin from the tumour to block the edge.
 Regional lymph node sites should be covered if nodes are
radiographically or pathologically involved at any time
during the disease course.
 Appropriate radiation dose is debatable.In infants, a dose of
12 Gy appears sufficient for durable local control.
 Tumours in children aged 12-48 months may require doses of
atleast 25 Gy.

31. Radiation treatment field for a child with left adrenal primary neuroblastoma
and para-aortic lymph node metastases.The beam’s eye view display with
digital radiograph allows for adequate coverage of the target volume and
lymph node region with sparing of the ipsilateral kidney and liver while
homogeneously irradiating the adjavent spine.

32. Retinoid therapy
 Known as differentiating agents because they are
thought to help some cancer cells differentiate into
normal cells.
 Retinoid called 13-cis-retinoic acid reduces the risk
of relapse after high dose CT and stem cell
transplant in patients with high-risk neuroblastoma.
 Recommended for a period of 6 months after stem
cell transplant- twice a day for 2 weeks, followed by
2 weeks off.

33. Immunotherapy
 A monoclonal antibody called Dinutuximab
(Unituxin) attaches to GD2, a substance found on
the surface of many neuroblastoma cells.
 Can be given together with cytokines such as GM-
CSF and IL-2 .
 Now a part of routine treatment for many children
with high risk neuroblastoma, often after a stem cell
transplant.

35. Recurrent Neuroblastoma
 For low and intermediate-risk neuroblastomas that
recur in the same primary site, surgery with or
without chemotherapy may be effective.
 For high-risk neuroblastomas or those that recur in
distant parts of the body, treatment is usually more
intense- a combination of surgery, CT and RT.
Intensive treatment with high dose CT/RT
followed by a stem cell transplant might be another
option.

36. Sequelae of treatment
 Acute effects :
 Surgery may cause excess bleeding, infections and
damage to blood vessels, kidneys and other organs, or
nerves.
 General side effects of CT include mouth sores, hair loss,
loss of appetite, nausea and vomiting, diarrhoea or
constipation, fatigue and increased chances of
infection.
 Radiation effects depend on the site.In abdomen RT
may cause nausea or diarrhoea.
 Immunotherapy with Dinutuximab may cause
vomiting,diarrhoea and nerve pain.
 13-cis-retinoic acid causes dry and cracked lips, dry skin
or eyes, nosebleeds, muscle and joint pains occasionally.

37.  Late effects :
 Cyclophosphamide can cause haemorrhagic
cystitis.
 Doxorubicin can cause cardiomyopathies.
 Cisplatin and carboplatin affect the kidneys.
 RT in younger children can cause growth
abnormalities , secondary malignancies.
 RT in chest may cause heart or lung problems
in some children when they grow older.RT to
abdomen in girls may cause damage to
ovaries and thus infertility.

38. Conclusion
 Survival rates in low-risk disease after surgery alone is
found to be about 90%.
 In intermediate-risk disease , children with initially
unresectable tumours often needs primary CT.Children
with unresponsive disease may require EBRT.A second
look operation shows survival rate of 60% to 90%.
 In high-risk disease in children >1 yr of age, poor
prognosis with expected 3 or 4 year survival rates of
<10% to 30%.
 The addition of 13-cis-retinoic acid is associated with 47%
event free survival.
 RT may be considered in patients with metastatic
disease to a local field, fractionated low dose
irradiation(<12 Gy) alongwith minimum CT and
supportive care to achieve a high survival rate.

39. ThankYou