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Neuroblastoma an overview
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Neuroblastoma an overview

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  • 1. NEUROBLASTOMATREATMENT 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 GANGLIONEUROMAGANGLIONEUROBLASTOMA NEUROBLASTOMA
  • 4. NEUROBLASTOMA
  • 5. ARISES FROMSYMPATHETIC NERVOUS SYSTEM ADRENAL MEDULLA - 40% PARASPINAL GANGLIA – 25% THORASIC – 15 % HEAD & NECK – 5 %
  • 6. 70 % HAVE METASTASISAT TIME OF PRESENTATION LYMPH NODE BONE BONE MARROW SKIN LIVER
  • 7. THORASIC NEUROBLASTOMA AXIAL VIEW
  • 8. THORASIC NEUROBLASTOMACORONAL 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 UPTISSUE DIAGNOSISCT SCANMRI SCANBONE MARROW ASPIRATIONRADIONUCLIDE 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. STAGINGEvans and D ‘ AngioPeadiatric Oncology GroupInternational Staging System
  • 20. ISSSTAGE – 1Localized tumour withcomplete gross excision without microscopic residualdisease, LN negative
  • 21. STAGE 2ALocalized tumour with incomplete grossexcision. Representative ipsilateral nonadherent LN negativeSTAGE 2BLocalized tumour with or with outcomplete gross excision, ipsilateral nonadherent LN positive
  • 22. STAGE 3Unresectable unilateral tumourcrossing the midline , localiszdunilateral tumour with contralateralLN involvement or midline tumourwith bilateral extention by infiltration(unresectable ) or by LN involvement.
  • 23. STAGE 4Any primary tumour with dissemination todistant lymph nodes, bone ,bonemarrow, liver , skin or other organs.STAGE 4SLocalized primary tumour as defined for stage1, 2A, 2B with dissemination limited toskin, liver and or bone marrow. ( limited toinfants < 1 year of age.
  • 24. PROGNOSTIC VARIABLES PROGNOSTIC FACTOR FAVORABLE UNFAVOURABLEAGE < 2 YRS > 2 YRSSTAGE 1 , 11, 1V S 111, 1VPATHOLOGY FAVOURABLE UNFAVOURABLEFERITTIN <143 ng/mL >143 ng/mLNEURON SPECEFIC ENOLASE < 100 100URINE VMA/HVA <1 1N – myc SINGLE COPY AMPLIFIEDDNA INDEX > 1.1 11P DELETION NIL 1 P DELETION
  • 25. INSS STAGE AGE MYCN SHIMADA DNA RISK GROUP STATUS HISTOLOGY PLOIDY1 0 – 21 YRS ANY ANY ANY LOW2A/2B < 365 D ANY ANY ANY LOW >365 D – 21 Y AMP FAV _ LOW >365 D – 21 Y AMP UNFAV _ HIGH3 < 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 PLOIDY4 <365 D NON AMP ANY ANY INTERMEDIATE <365 D AMP ANY ANY HIGH >365 D – 21 Y ANY ANY - HIGH4S < 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 RTRESPIRATORY DISTRESSSPINAL CORD COMPRESSIONPROGRESSIVE DISEASERECURRENT DISEASE
  • 31. INTERMEDIATE RISK Followed byComplete surgical adjuvant resection chemotherapy 12 – 24 weeks Unresectablecases, 5 cycles of Second look surgery chemo
  • 32.  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
  • 33. 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
  • 34. 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 )
  • 35. OPEC REGIMENSVINCRISTINE 1.5 mg/m2 D1CYCLOPHOSPHAMIDE 600 mg/ m2 DICISPLATIN 100 mg/m2 D2TENIPOSIDE (VM 28 ) 150 mg/ m2 D4
  • 36. CADO REGIMENCYCLOPHOSPHAMIDE 300 mg/m2 DI-D 5ADRIAMYCIN 60 mg/m2VINCRISTINE 1.5mg/m2
  • 37. 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.
  • 38. DEFENITIVE INDICATIONS OF RTRespiratory distress secondary to massivehepatoslenomegaly.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.
  • 39. HIGH RISK DISEASECURRENT TREATMENT APPROACHESIntensive induction chemotherapyMyelo ablative consolidation chemo with stem cellrescue.Targeted therapy for residual disease.
  • 40. INTENSIVE INDUCTION CHEMOCISPLATIN 30 mg / m2 D1DOXORUBICIN 30 mg/m2 D2ETOPOSIDE 100 mg/ m2 D2 & D5CYCLOPHOSPHAMIDE 1000 mg/m2 D3 &D45 CYCLES AT 28 DAY INTERVELS.
  • 41.  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.
  • 42. 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
  • 43. MYELO ABLATIVE THERAPYHIGH DOSE OF CARBOPLATIN , MELPHELAN AND ETOPOSIDETOTAL BODY IRRADIATION3 DAILY FRACTIONS3.33 GY PER FRACTIONPURGED AUTOLOGOUS MARROW IS INFUSED WITH GM - CSF
  • 44. 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
  • 45. 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
  • 46. RECURRENT TUMOURS TARGETED PHARMACEUTICALS CYCLOPHOSPHAMIDE + TOPOTECAN IRINOTECAN + TEMOZOLAMIDE TARGETED IMMUNO THERAPY 13 – CIS RETINOIC ACID

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