Neuroblastoma 187

35. Neuroblastoma

35.1 General considerations

International Neuroblastoma Staging System (INSS)

Stage Characteristics

1 Complete gross resection + microscopic residuals (removed

adherent lymph nodes may be positive)

2 Unilateral tumor

a) incomplete gross resection

b) ipsilateral nonadherent lymph nodes positive for tumor +

incomplete gross resection

3 Bilateral tumor

Tumor and/or lymph nodes infiltrating across the midline

(opposite site of vertebral column)

4 Distant metastases(bone marrow, bone, lymph nodes, skin,CNS

4S Primary tumor as in stage 1 or 2 + dissemination limited to

skin, liver,bone marrow(bone marrow < 10% of nucleated

cells); age< 1 year

For practical reasons, patients may be categorized as “low risk”(observation), “Standard-risk”or “high-risk”.

The use of cytotoxic drugs can be omitted in a substantial proportion of

low-risk patients who only need surgery.”Mild”chemotherapy is adequate

for most patients with standard-risk disease to achieve a tumor remission

or at least a better resectability of the primary tumor.For high-risk patients

intensive polychemotherapy (also including consolidative megatherapy

With autologous stem cell support) represents the basis and the backbone

of treatment among other modalities like repeated surgical tumor

resections, radiotherapy, and immunotherapy.

The complex biology of neuroblastoma and the resulting risk-adapted use of all currently available treatment modalities demand that each patient must be treated according to the guidelines of a modern protocol. The selected schedules therefore only represent illustrating examples for therapy elements and no treatment recommendations!

Literature: for review

BERTHOLD and HERO,Drugs 59(2000):1261-1277 (current drug

therapy recommendation as part of the total treatment approach)

CASTLEBERRY,Eur.J.Cancer 33(1997):1430-1437

PINKERTON et al, Eur.J.Cancer 36(2000):1808-1815(dose-

reponse relationship)

35.2 “Low-risk”

(incl. Patients with stage 1 and infants with asymptomatic stage 4S

neuroblastoma.No uniform recommendation for patients with stage 2

or 3 neuroblastoma.)

Initial treatment with surgery.

35.3 “Standard-risk”

(incl.patients>1 year of age with unresectable tumors that are not MYCN amplified and infants with significant tumor-related symptoms from stage

2,3 and 4S neuroblastoma),e.g.

188 Neuroblastoma

35.3.1 Children’s Cancer Croup Study CCG-3881

____________________________________________________________

Induction

week0 week4 week7 week11 week 15

CDEC CPM CPM CDDP CPM

DOX CDDP ETOP CDDP

DOX DOX

Consolidation

week 18 week 19 week 19 week 20 week 21

Surgery CPM Radiation Radiation Radiation

ETOP

Maintenance

week 22 week 26 week 30 week 34 week 38

CPM CDDP CPM CDDP Surgery if

DOX ETOP DOX ETOP residual tumor

CDEC

Cisplatin 60mg/m² i.v.(6 h inf) d0

Doxorubicin 30mg/m² i.v. d2

Etoposide 100mg/m² i.v.(1 h inf) d2+5

Cyclophosphamide 900mg/m² i.v. d3+4

CPM / DOX

Cyclophosphamide 150mg/m² i.v.or p.o. for7d

Doxorubicin 35mg/m² i.v. d1

CPM / CDDP / DOX

Cyclophosphamide 150mg/m² i.v. or p.o. for 7 d

Cisplatin 90mg/m² i.v.(8 h inf) d1

Doxorubicin 35mg/m² i.v. d1

CDDP / ETOP

Cisplatin 90mg/m² i.v.(8 h inf) d1

Etoposide 150mg/m² i.v.(cont inf) over 3 d

CPM / ETOP

Cyclophosphamide 150mg/m² i.v. or p.o. for 7 d

Etoposide 150mg/m² i.v.(cont inf) over 3 d

Literature:

MATTHAY et al,J.Clin.Oncol.16(1998):1256-1264

Neuroblastoma 189

35.3.2 German Society of Pediatric Oncology and Hematology(GPOH)study N97

Block N4

Doxorubicin 0.5mg/kg i.v.(30 min inf) d1,3,5

Vincristine 25mg/kg i.v.(bolus) d1,3,5

Cyclophosphamide 10mg/kg i.v.(5 min inf) d1-7

For patients<6 months of age 2(in case of stage 4S)to 3 cycles

Block N5

Cisplatin 40mg/m² i.v.(96h inf) d1-4

Etoposide 100mg/m² i.v.(96 h inf) d1-4

Vindesine 3mg/m² i.v.(1 h inf) d1

With G-CSF support from d8 until WBC>10/nl

Followd by

Block N6

Vincristine 1.5mg/m² i.v.(1 h inf ) d1+8

Dacarbazine 200mg/m² i.v.(1 h inf) d1-5

Ifosfamide 1500mg/m² i.v.(120 h inf) d1-5

With mesna uroprotection

Doxorubincin 30mg/m i.v.(4 h inf) d 6+7

With G-CSF support from d 9 until WBC >10/nl.For patients> 6months of

age

Two blocks of N5 alternatingly with two blocks of N6.

Literature:

BERTHOLD and HERO,Drugs 59(2000):1261-1277

35.4.1 " High-risk "

(incl.stage 4 and stages 1,2,3,4S MYCN amplified),e.g.

35.3.3 Children’s Cancer Group Study CCG 3891

Induction

week 0 week4 week 8 week12 week 13

CDEC CDEC CDEC BM harvest CDEC

Week 17 week18 week 21

Surgery CDEC Radiation

Randomization

Consolidation/ABMT
week22 week 26 week 30 week 34

CIDE CIDE CIDE Randomization

CEM-TBI+

ABMT

190 Neuroblastoma

Biotherapy/Follow-up

Week 34 week 46 week 58

____________________________________________________________

13-CRA 13-CRA Follow-up

Follow-up Follow-up Follow-up

____________________________________________________________

CDEC

Cisplatin 60mg/m² i.v.(6 h inf ) d0

Doxorubicin 30mg/m² i.v. d2

Etoposide 100mg/m² i.v.(1 h inf) d2+5

Cyclophosphamide 900mg/m² i.v. d3+4

CIDE

Cisplatin 40mg/m² i.v.(cont inf) d0-3

Ifosfamide 2500mg/m² i.v.(1 h inf) d0-3

With mesna uroprotection

Doxorubicin 10mg/m² i.v.(cont inf) d0-3

Etoposide 125mg/m² i.v.(cont inf) d0-3

CEM-TBI

Carboplatin 250mg/m² i.v.(cont inf) d8 to-5

Etoposide 160mg/m² i.v.(cont inf) d8 to-5

Melphalan 140mg/m² i.v. d-7 and

70mg/m² i.v. d-6

Total body irradiation day-3 to – 1.Purged autologous bone marrow infusion d 0 .

13-CRA

____________________________________________________________

13-cis-retinoic acid 160mg/m²/d divided twice daily on d0-13 of each 28 d for a total of 3 cycles per course for 2 courses

Literature:

MATTHAY et al, J.Clin.Oncol.16(1998):1256-1264 and

N.Engl.J.Med.341 (1999): 1165-1173

35.4.2 SFOP Study NB 87

CADO

Cyclophosphamide 300mg/m² i.v. or p.o. d1-5

Vincristine 1.5mg/m² i.v. d1+5

(max 2mg)

Doxorubicine 60mg/m² i.v.(3h inf) d5

Courses 1 and 3

CVP

Cisplatin 40mg/m² i.v.(bolus or cont inf) d1-5

Etoposide 100mg/m² i.v.(1 h inf) d1-5

Courses 2 and 4

Neuroblastoma 191

Four alternating courses on a 21-day schedule (with G-CSF support).

Literature:

COZE et al, J.Clin.Oncol.15(1997):3433-3440

MICHON et al, Eur.J.Cancer 34 (1998): 1063-1069

35.4.3 German Society of Pediatric Oncology and Hematology(GPOH) study

N97

Block N5

Cisplatin 40mg/m² i.v.(96 h inf) d 1-4

Etoposide 100mg/m² i.v.(96 h inf) d 1-4

Vindesine 3mg/m² i.v.( 1 h inf) d 1

With G-CSF support from d 8 until WBC>10/nl

Block N6

Vincristine 1.5mg/m² i.v.(1 h inf) d 1+8

Dacarbazine 200mg/m² i.v.(1 h inf) d 1-5

Ifosfamide 1500mg/m² i.v.(120 h inf) d 1-5

with mesna uroprotection

Doxorubicin 30mg/m² i.v.(4 h inf) d 6+7

With G-CSF support from d 9 until WBC > 10/nl

Three blocks of N5 alternatingly with three blocks of N6 (every 3 weeks)

Block N7

Cyclophosphamide 150mg/m² p.o. d1-8

with mesna uroprotection

Four cycles as maintenance therapy(alternatively consolidation with megatherapy)

Literature:

BERTHOLD and HERO,Drugs 59(2000): 1261-1277

35.4.4 OPEC/OJEC

Vincristine 1.5mg/m² i.v. d1

Cisplatin 80mg/m² i.v. d1

Etoposide 200mg/m² i.v. d1

Cyclophosphamide 600mg/m² i.v. d1

Alternating every 3 weeks with

Vincristine 1.5mg/m² i.v. d1

Carboplatin 500mg/m² i.v. d1

Etoposide 200mg/m² i.v. d1

Cyclophosphamide 600mg/m² i.v. d1

Literature:

TWEDDLE et al,Med.Pediatr.Oncol.36(2001):239-242

192 Neuroblastoma

35.4.5 Megatherapy

Myeloablative consolidation therapy based e.g. melphalan ± busulfan or

total body irradiation with autologous stem cell support (see also 34, 4, 1

CEM-TBI).

Literature:

GRUPP et al, J. Clin. Oncol. 18 (2000): 2567-2575 (tandem high-

dose therapy)

McELWAIN et al, Exp. Hem. 7 (1979 – 360 – 371

PRITCHARD et al, Eur. J. Cancer 31 (1995): 134 – 136

PHILIP et al,Eur. J. Cancer 33 (1997): 2130 – 2135 (experience from

1070 megatherapy procedures )

VALTEAU-COUANET et al, Bone Marrow Transplant , 25 (2000):

937 – 942 (busulfan-melphalan-containing regimens)

35.5 [ 131 I ] metaiodobenzylguanidine

Radiotherapy-based strategy for managing large regional tumors and

disseminated disease. Alone or in combination with chemotherapy.

Literature:

CASTELLANI et al, Q. J. Nucl. Med. 44 (2000): 77 – 87

HOEFNAGEL et al, Q. J. Nucl. Med 39 (1995): 61 – 64

MAIRS, Eur. J. Cancer 35 (1999): 1171-1173

MASTRANGELO et al, Br. J. Cancer 84 (2001): 460 – 464

MATTHAY et al, J. Nucl. Biol. Med. 35 (1991): 244-247

TEPMONGKOL and HEYMAN, Med. Pediatr. Oncol. 32 (1999):

427- 432

35.6 Salvage chemotherapy

E.g.

Cyclophosphamide 250 mg/m² i.v. (30 min inf) d 1-5

Topotecan 0.75 mg/m² i.v. (30 min inf) d 1-5

To be repeated every 3-4 weeks with G-CSF support

Literature:

SAYLORS et al, J. Clin. Oncol. 19 (2001): 3463 – 3469