The LMCE5 unselected cohort of 25 children consecutively diagnosed with untreated stage 4 neuroblastoma over 1 year at diagnosis

Abstract

The Lyon-Marseille-Curie-Est (LMCE) of France cooperative group has previously reported successive series of unselected stage four children older than 1 year at diagnosis with metastatic neuroblastoma (LMCE 1 and 3). The goal of LMCE 5 study was to increase progression free survival rate as compared to LMCE 1 and 3. Based on improvements reported with post induction chemotherapy, the LMCE 5 used post induction for all children, but omitted total body irradiation and immunomagnetic purging in megatherapy regimen for all children. Twenty-five sequentially diagnosed children received an induction regimen which compared with previous induction included an increased dose of etoposide and cyclophosphamide, delivered similar dose of cisplatinum, and deleted doxorubicin and vincristin. After surgery treatment was stratified based on response and eligible children received etoposide carboplatin (LMCE 5A : n=10)+doxorubicin (LMCE 5B -C n=13) followed by megatherapy (melphalan without total body irradiation and unpurged peripheral blood stem cell rescue). The increase in drug doses during induction did not improve remission rate. The progression free survival at 6 years is 8%. It is significantly worse than LMCE 3, and equivalent to LMCE 1 study though toxic death rate has decreased with increasing experience. Failure to improve the response rate during induction and reducing the megatherapy regimen may be the main factors in this disappointing result. Modified strategies for induction, non toxic alternative to total body irradiation, and post megatherapy regimen should be developed.

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

“…These studies evaluated megatherapy vs continuing intensive chemotherapy (Matthay et al, 1999), or maintenance chemotherapy (Berthold et al, 1990;Castel et al, 2001), or no treatment (Pritchard et al, 2005). Combined with the other experiences including megatherapy, they reliably support the conviction that this consolidation treatment modality offers an advantage in terms of survival probability (McCowage et al, 1995;Kushner et al, 2001;Frappaz et al, 2002;Kaneko et al, 2002;Kletzel et al, 2002;De Bernardi et al, 2003).…”

2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors

“…It is commonly accepted, but has not yet been convincingly confirmed within randomized trials, that rapid induction chemotherapy is more effective because the risk for neuroblastoma cells acquiring chemoresistance is considered to be lower. Chemotherapy regimens of the major US, European, Japanese and German neuroblastoma trial groups differ [9,10,24,30,33,40,50,82,102,105,126,148,149,151,155,195,198]. While data from controlled clinical trials comparing different induction chemotherapies are not yet available, response and outcome data from the previous GPOH high-risk neuroblastoma trials are similar to, or in some cases better than, those reported by other national neuroblastoma trial groups [9,123,149,154].…”

“…The number of available cytotoxic drugs effective for neuroblastoma is limited. Induction therapy for high-risk neuroblastoma patients worldwide consists of combinations of drugs including cisplatin, carboplatin, cyclophosphamide, ifosfamide, doxorubicin, etoposide, teniposide, vincristine and vinblastine [9,10,24,30,40,50,102,105,126,149,151,155,195,198]. One European randomized phase III trial compared rapid COJEC induction chemotherapy, which administers cytotoxic drugs every 10 days, to standard chemotherapy cycles administered every 21 days.…”

Intensified External-Beam Radiation Therapy Improves the Outcome of Stage 4 Neuroblastoma in Children > 1 Year with Residual Local Disease

“…Intensive induction chemotherapy, myeloablative high-dose chemotherapy with autologous stem cell transplantation (ASCT), and surgery are accepted as important elements in the treatment of high-risk neuroblastoma [4,9,10,16,22,29]. External-beam radiation therapy (EBRT) proved effective in small series of localized neuroblastoma [7] and infants' neuroblastoma [24] but data in high-risk neuroblastoma are still limited [5,13,19].…”