neuroblastoma an overview

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