neuroblastoma an overview
DESCRIPTION
TRANSCRIPT
NEUROBLASTOMATREATMENT GUIDELINES
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
NEUROBLASTOMA
GANGLIONEUROBLASTOMA
GANGLIONEUROMA
NEUROBLASTOMA
ARISES FROM SYMPATHETIC NERVOUS
SYSTEMADRENAL MEDULLA - 40%
PARASPINAL GANGLIA – 25%
THORASIC – 15 %
HEAD & NECK – 5 %
70 % HAVE METASTASISAT TIME OF PRESENTATION
LYMPH NODE
BONE
BONE MARROW
SKIN
LIVER
THORASIC NEUROBLASTOMAAXIAL VIEW
THORASIC NEUROBLASTOMA
CORONAL
SAGITTAL
BONE MARROW INVOLVEMENT
BONE MARROW INVOLVEMENT
MRI of 2 month old infant showing skull vault and orbital metastasis
DIAGNOSTIC WORK UP
TISSUE DIAGNOSIS
CT SCAN
MRI SCAN
BONE MARROW ASPIRATION
RADIONUCLIDE BONE SCAN
CT OR MRI ??
CT OR MRI ??
CT OR MRI ??
MIBG SCAN
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
STAGING
Evans and D ‘ Angio
Peadiatric Oncology GroupInternational Staging System
ISS
STAGE – 1
Localized tumour with complete gross excision with out microscopic residual disease, LN negative
STAGE 2ALocalized tumour with incomplete gross excision. Representative ipsilateral non adherent LN negative
STAGE 2BLocalized tumour with or with out complete gross excision, ipsilateral non adherent LN positive
STAGE 3Unresectable 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.
STAGE 4Any primary tumour with dissemination to distant lymph nodes, bone ,bone marrow, liver , skin or other organs.
STAGE 4SLocalized 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.
PROGNOSTIC VARIABLESPROGNOSTIC 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
INSS STAGE
AGE MYCN STATUS
SHIMADA HISTOLOGY
DNA PLOIDY
RISK GROUP
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
STAGE AGE MYCN STATUS
SHIMADA HISTOLOGY
DNA PLOIDY
RISK GROUP
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
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 RT
RESPIRATORY DISTRESS
SPINAL CORD COMPRESSION
PROGRESSIVE DISEASE
RECURRENT DISEASE
INTERMEDIATE RISK
Complete surgical
resection
Followed by adjuvant
chemotherapy 12 – 24 weeks
Unresectable cases, 5 cycles
of chemo
Second look surgery
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 )
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
CADO REGIMEN
CYCLOPHOSPHAMIDE 300 mg/m2 DI -D 5
ADRIAMYCIN 60 mg/m2
VINCRISTINE 1.5mg/m2
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 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.
HIGH RISK DISEASE
CURRENT TREATMENT APPROACHES
Intensive induction chemotherapy
Myelo ablative consolidation chemo with stem cell rescue.
Targeted therapy for residual disease.
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.
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 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
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
RECURRENT TUMOURS
TARGETED PHARMACEUTICALS CYCLOPHOSPHAMIDE + TOPOTECAN IRINOTECAN + TEMOZOLAMIDE TARGETED IMMUNO THERAPY 13 – CIS RETINOIC ACID