Neuroblastoma is the third most common childhood cancer and arises from sympathetic nervous system. Staging involves evaluating tumor size, spread and biomarkers. Treatment ranges from observation to intensive chemotherapy and stem cell transplant depending on risk factors like age, stage, genetics and response to initial treatment. Targeted therapies are being studied in recurrent and high risk disease.

1. NEUROBLASTOMA
TREATMENT GUIDELINES

2. NEUROBLASTOMA
 Enigmatic malignant neoplasm.
 Third most common malignancy in
children.
 Most common cancer diagnosed in infants.
 Median age of diagnosis is 2 years.
 Has highest spontaneous remission rate.
 Usually by progression to mature
ganglioneuroma.

3. TUMOURS ARISING FROM
SYMPATHETIC GANGLIA
GANGLIONEUROMA
GANGLIONEUROBLASTOMA
NEUROBLASTOMA

4. NEUROBLASTOMA

5. ARISES FROM
SYMPATHETIC NERVOUS SYSTEM
ADRENAL MEDULLA - 40%
PARASPINAL GANGLIA – 25%
THORASIC – 15 %
HEAD & NECK – 5 %

6. 70 % HAVE METASTASIS
AT TIME OF PRESENTATION
LYMPH NODE
BONE
BONE MARROW
SKIN
LIVER

7. THORASIC NEUROBLASTOMA
AXIAL VIEW

8. THORASIC NEUROBLASTOMA
CORONAL SAGITTAL

9. BONE MARROW INVOLVEMENT

10. BONE MARROW INVOLVEMENT

11. MRI of 2 month old infant showing skull
vault and orbital metastasis

12. DIAGNOSTIC WORK UP
TISSUE DIAGNOSIS
CT SCAN
MRI SCAN
BONE MARROW ASPIRATION
RADIONUCLIDE BONE SCAN

13. CT OR MRI ??

14. CT OR MRI ??

15. CT OR MRI ??

16. MIBG SCAN

17. MIBG SCAN
 Meta Iodo Benzyl Guanidine
 Concentrated by neurosecretory granules.
 Used to image primary and metastatic sites
of neuroblastoma.
 MIBG is labelled with I 131 or I 123
 Sensitivity 85 – 90 %
 Specificity 90 %

18. OTHER INVESTIGATIONS
 Urinary HVA / VMA
 Complete Blood Count
 Serum Ferritin
 Lactate Dehydrogenase
 Liver Function Tests

19. STAGING
Evans and D ‘ Angio
Peadiatric Oncology Group
International Staging System

20. ISS
STAGE – 1
Localized tumour with
complete gross excision with
out microscopic residual
disease, LN negative

21. STAGE 2A
Localized tumour with incomplete gross
excision. Representative ipsilateral non
adherent LN negative
STAGE 2B
Localized tumour with or with out
complete gross excision, ipsilateral non
adherent LN positive

22. STAGE 3
Unresectable unilateral tumour
crossing the midline , localiszd
unilateral tumour with contralateral
LN involvement or midline tumour
with bilateral extention by infiltration
(unresectable ) or by LN involvement.

23. STAGE 4
Any primary tumour with dissemination to
distant lymph nodes, bone ,bone
marrow, liver , skin or other organs.
STAGE 4S
Localized primary tumour as defined for stage
1, 2A, 2B with dissemination limited to
skin, liver and or bone marrow. ( limited to
infants < 1 year of age.

24. PROGNOSTIC VARIABLES
PROGNOSTIC FACTOR FAVORABLE UNFAVOURABLE
AGE < 2 YRS > 2 YRS
STAGE 1 , 11, 1V S 111, 1V
PATHOLOGY FAVOURABLE UNFAVOURABLE
FERITTIN <143 ng/mL >143 ng/mL
NEURON SPECEFIC ENOLASE < 100 100
URINE VMA/HVA <1 1
N – myc SINGLE COPY AMPLIFIED
DNA INDEX > 1.1 1
1P DELETION NIL 1 P DELETION

25. INSS STAGE AGE MYCN SHIMADA DNA RISK GROUP
STATUS HISTOLOGY PLOIDY
1 0 – 21 YRS ANY ANY ANY LOW
2A/2B < 365 D ANY ANY ANY LOW
>365 D – 21 Y AMP FAV _ LOW
>365 D – 21 Y AMP UNFAV _ HIGH
3 < 365 D NON AMP ANY ANY INTERMEDIATE
< 365 D AMP ANY ANY HIGH
>365 D – 21 Y NON AMP FAV - INTERMEDIATE
>365 D – 21 Y NON AMP UNFAV - HIGH
>365 D – 21 Y AMP FAV - HIGH

26. STAGE AGE MYCN SHIMADA DNA RISK GROUP
STATUS HISTOLOGY PLOIDY
4 <365 D NON AMP ANY ANY INTERMEDIATE
<365 D AMP ANY ANY HIGH
>365 D – 21 Y ANY ANY - HIGH
4S < 365 D NON AMP FAV >1 LOW
< 365 D NON AMP ANY =1 INTERMEDIATE
< 365 D NON AMP UN FAV ANY INTERMEDIATE
< 365 D AMP ANY ANY HIGH

27. LOW RISK GROUP
 Complete gross surgical excision
 Adjuvant chemo and RT has not improved
the out come.
 If surgical margins positive or microscopic
disease is left behind
 Favourable biology - no adjuvant therapy
 Unfavourable biology - 6- 12 weeks of
chemo

28. RATIONALE
 POG TRIAL
 8104 patients with stage 1
 Treatment surgery only
 Regardless of microscopic residual disease , 2
yr DFS is 84 %

29. RATIONALE
 CCG TRIAL
 3881 patients with stage 1 & 2
 Stage 1
4 yr EFS 93 %
OS 99 %
 Stage 2
4 yr EFS 81 %
OS 98 %

30. INDICATION OF CHEMO OR RT
RESPIRATORY DISTRESS
SPINAL CORD COMPRESSION
PROGRESSIVE DISEASE
RECURRENT DISEASE

33. INTERMEDIATE RISK
Followed by
Complete surgical adjuvant
resection chemotherapy
12 – 24 weeks
Unresectable
cases, 5 cycles of Second look surgery
chemo

34.  Followed by second look surgery
 Radiation therapy was given to gross viable
residual tumour on second look surgery.
 Children age 12 – 24 months received 24 Gy in 1.5
Gy per fraction.
 Older children received 30 Gy in 1.5 Gy per
fraction.
 Target volume includes viable microscopic or
gross residual tumour determined by CT , MRI or
MIBG scan with 2 cm margins

35. POG TRIALS
 EFS of completely resected tumours at
diagnosis - 85 %
 EFS of incompletely resected tumours at
diagnosis - 70 %
 Maximum safe surgical excision followed by
5 cycles of chemo

36. CHEMO SCHEDULE
 POG 8742 they received cisplatin and
etoposide alternating with
cyclophosphamide and doxorubicin
 POG 9244 received alternating cycles of
OPEC (vincristine , cisplatin, etoposide and
cyclophosphamide ) and OJEC (vincristine,
carboplatin , etoposide and
cyclophosphamide )

37. OPEC REGIMENS
VINCRISTINE 1.5 mg/m2 D1
CYCLOPHOSPHAMIDE 600 mg/ m2 DI
CISPLATIN 100 mg/m2 D2
TENIPOSIDE (VM 28 ) 150 mg/ m2 D4

38. CADO REGIMEN
CYCLOPHOSPHAMIDE 300 mg/m2 DI
-D 5
ADRIAMYCIN 60 mg/m2
VINCRISTINE 1.5mg/m2

39. ROLE OF RADIATION THERAPY
 CONTROVERSIAL
 In older children with LN metastasis adjuvant
radiation to primary and regional LN has
improved DFS & OS.
 RCT showed that DFS is 31 % in chemo arm
and 58 % in chemo RT arm.
 De Bernadi et al trials failed to show benefit
from adjuvant RT.

40. DEFENITIVE INDICATIONS OF RT
Respiratory distress secondary to massive
hepatoslenomegaly.
4.5 Gy to liver in 3 daily fractions.
Spinal cord compression
< 3 yrs 9 Gy in 5 daily fractions.
Older children 21.6 Gy in 12 daily fractions.

43. HIGH RISK DISEASE
CURRENT TREATMENT APPROACHES
Intensive induction chemotherapy
Myelo ablative consolidation chemo with stem cell
rescue.
Targeted therapy for residual disease.

44. INTENSIVE INDUCTION CHEMO
CISPLATIN 30 mg / m2 D1
DOXORUBICIN 30 mg/m2 D2
ETOPOSIDE 100 mg/ m2 D2 & D5
CYCLOPHOSPHAMIDE 1000 mg/m2 D3 &D4
5 CYCLES AT 28 DAY INTERVELS.

45.  This was followed by second look surgery
 Radiation therapy is given to patients with
persistent disease at primary or metastatic
sites.
 21.6 Gy in 12 daily fractions to post induction
chemo, pre op tumour volume followed by
boost of 14.4 GY to gross residual volume to a
total dose of 36 Gy.

46. IORT
 Single fraction 10 Gy to primary tumour bed
was associated with local control rate of 100
% where as IORT was unable to control any
patients with gross residual disease

47. MYELO ABLATIVE THERAPY
HIGH DOSE OF CARBOPLATIN , MELPHELAN AND ETOPOSIDE
TOTAL BODY IRRADIATION
3 DAILY FRACTIONS
3.33 GY PER FRACTION
PURGED AUTOLOGOUS MARROW IS INFUSED WITH GM - CSF

48. TARGETED THERAPY
 INVESTIGATIONAL PHASE
 I 131 – MIBG
 REFRACTORY DISEASE
 AS A PART OF MYELO ABLATIVE REGIMEN
 MAX. MARROW NON ABLATIVE DOSE – 444 MBq Kg
 MAX. PRACTICAL HIGH DOSE – 666 MBq/ Kg
 US AND EUROPEAN STUDIES SHOWED 30-40 %
RESPONSE RATE

49. TARGETED IMMUNO THERAPY
 HUMAN MOUSE CHIMERIC MONO CLONAL
ANTIBODY ch.14.8
 TARGETS TUMOUR ASSOCIATED ANTIGEN.
 ANTI GD 2 MURINE MONOCLONAL
ANTIBODY 3F8 AND GD 2a

50. RECURRENT TUMOURS
 TARGETED PHARMACEUTICALS
 CYCLOPHOSPHAMIDE + TOPOTECAN
 IRINOTECAN + TEMOZOLAMIDE
 TARGETED IMMUNO THERAPY
 13 – CIS RETINOIC ACID