Ifosfamide/carboplatin/etoposide (ICE) as front‐line, topotecan/ cyclophosphamide as second‐line and oral temozolomide as third‐line treatment for advanced neuroblastoma over one year of age

Abstract

Children affected by advanced neuroblastoma have a discouraging prognosis, but intensive induction chemotherapy may increase the complete response rate. The combination of ifosfamide, carboplatin and etoposide (ICE) was used for the first time as front‐line regimen in patients with stage 4 neuroblastoma over the age of 1 y. Similarly, second‐line treatment for children with relapsed neuroblastoma, particularly after high‐dose chemotherapy, has been unsatisfactory. The combination of topotecan and cyclophosphamide was studied in resistant or relapsed solid tumors. Furthermore, there is a need for effective palliative treatment in patients failing therapy. Temozolomide, a new dacarbazine analog with optimal oral bioavailability, is being used in an ongoing phase II study as an alternative to oral etoposide. Seventeen patients with stage 4 neuroblastoma have entered the ICE study; 15/16 (94%) major responses after induction were observed and 6/16 (37%) evaluable patients are disease free after a median of 51 mo. Twenty‐one patients with relapsed/refractory disease (of whom 13 neuroblastomas) entered the topotecan/cyclophosphamide study: 7/21 (33%) patients responded. Forty‐one patients entered the temozolomide study (of whom 16 had neuroblastomas): stable disease and symptom relief were obtained in 15/30 (50%) evaluable patients. Intensive induction with ICE resulted in a faster response with high response rate; a larger study with longer follow‐up is needed to confirm a survival advantage. Second‐line treatment was effective in obtaining remissions, some of them long lasting. Third‐line treatment did not elicit measurable responses in neuroblastoma, but achieved prolonged freedom from disease progression and excellent palliation in several patients.

Overview and recent advances in the treatment of neuroblastoma

“…Disease regression was achieved in 14 of 17 patients (82%) with a new relapse, 13 of 26 patients (50%) with refractory neuroblastoma, and 12 of 34 patients (35%) who were treated for progressive disease during chemotherapy [111]. The ICE regimen also demonstrated responses in 37% of patients with relapsed or refractory high-risk neuroblastoma, with an additional 17% of patients having stable disease [112], while 15 of 16 patients receiving ICE as front-line treatment for patients older than one year of age with stage 4 neuroblastoma had major responses, with a 37% disease-free survival rate [113], suggesting a role for ifosfamide-based chemotherapy regimens for both frontline and relapsed neuroblastoma treatment.…”

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

“…Furthermore, the survival of patients with advanced disease without N-myc amplification (o10 copies) is not much greater (Kaneko et al, 2002). Cytotoxic therapies (doxorubicin, cyclophosphamide, etoposide, irinotecan and cisplatin) still play a major role in neuroblastoma treatment (Furman et al, 1999;Thompson et al, 1999Thompson et al, , 2001Houghton and Santana, 2002;Castel and Canete, 2004;Donfrancesco et al, 2004). Bone marrow or peripheral blood stem cell transplants appear to have some value increasing relapse-free survival, at least in some studies (Matthay et al, 1999;Valteau-Couanet et al, 2000;Imaizumi et al, 2001;Goldsby and Matthay, 2004).…”

Ifosfamide, carboplatin, and etoposide for neuroblastoma

“…ICE in lower dosages has activity against various solid tumors, [18][19][20][21][22][23][24][25][26][27][28][29][30][31] but it may be particularly suitable for treating NB. Thus, NB is sensitive to all 3 components, whereas other major pediatric solid tumors (eg, Ewing sarcoma) are relatively resistant to platinum compounds.…”

“…27 The studies pointed to a better response rate of refractory or recurrent sarcomas to this ICE regimen compared with lower dose ICE or 2-drug carboplatin-etoposide or ifosfamide-etoposide regimens. 27 Recently, ICE at dosages higher than in preceding phase 1 studies a) was used as salvage, with major responses in 24/64 (36%) patients treated for primary refractory or progressive NB 28 ; and b) was included in induction regimens for patients with newly diagnosed NB with responses defined according to International Neuroblastoma Response Criteria [29][30][31] (Table 3). In previously untreated patients, ICE achieved a >70% major response rate.…”

“…In previously untreated patients, ICE achieved a >70% major response rate. 19,29 Elsewhere, ICE was incorporated into induction after other combinations had been administered. 30,31 Thus, Sung et al initially reserved ICE for NB that was resistant to combined cisplatin, etoposide, doxorubicin, and cyclophosphamide (CEDC) for 5 cycles.…”