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.
TUMOURS ARISING FROM SYMPATHETIC GANGLIA GANGLIONEUROMAGANGLIONEUROBLASTOMA NEUROBLASTOMA
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 %
OTHER INVESTIGATIONS Urinary HVA / VMA Complete Blood Count Serum Ferritin Lactate Dehydrogenase Liver Function Tests
STAGINGEvans and D ‘ AngioPeadiatric Oncology GroupInternational Staging System
STAGE 2ALocalized tumour with incomplete grossexcision. Representative ipsilateral nonadherent LN negativeSTAGE 2BLocalized tumour with or with outcomplete gross excision, ipsilateral nonadherent LN positive
STAGE 3Unresectable unilateral tumourcrossing the midline , localiszdunilateral tumour with contralateralLN involvement or midline tumourwith bilateral extention by infiltration(unresectable ) or by LN involvement.
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.
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
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
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
RATIONALE POG TRIAL 8104 patients with stage 1 Treatment surgery only Regardless of microscopic residual disease , 2 yr DFS is 84 %
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 %
INDICATION OF CHEMO OR RTRESPIRATORY DISTRESSSPINAL CORD COMPRESSIONPROGRESSIVE DISEASERECURRENT DISEASE
INTERMEDIATE RISK Followed byComplete surgical adjuvant resection chemotherapy 12 – 24 weeks Unresectablecases, 5 cycles of Second look surgery chemo
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
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
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 )
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.
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.
HIGH RISK DISEASECURRENT TREATMENT APPROACHESIntensive induction chemotherapyMyelo ablative consolidation chemo with stem cellrescue.Targeted therapy for residual disease.
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.
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
MYELO ABLATIVE THERAPYHIGH DOSE OF CARBOPLATIN , MELPHELAN AND ETOPOSIDETOTAL BODY IRRADIATION3 DAILY FRACTIONS3.33 GY PER FRACTIONPURGED AUTOLOGOUS MARROW IS INFUSED WITH GM - CSF
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
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