Background
Methods
Patients
Induction treatment
Regimen | Drug | Dose | Schedule | Total dose |
---|---|---|---|---|
Induction regimens | ||||
CEDCa
| Cisplatin | 60 mg/m2/day | Day 0 | 60 mg/m2
|
Etoposide | 100 mg/m2/day | Days 2, 5 | 200 mg/m2
| |
Doxorubicin | 30 mg/m2/day | Day 2 | 30 mg/m2
| |
Cyclophosphamide | 30 mg/kg/day | Days 3, 4 | 60 mg/kg | |
ICEa
| Ifosfamide | 1 200 mg/m2/day | Days 0–4 | 6 000 mg/m2
|
Carboplatin | 400 mg/m2/day | Days 0, 1 | 800 mg/m2
| |
Etoposide | 100 mg/m2/day | Days 0−4 | 500 mg/m2
| |
First HDCT regimen | ||||
CEC | Carboplatin | 650 mg/m2/day | Days −7, −6, −5 | 1 950 mg/m2
|
Etoposide | 650 mg/m2/day | Days −7, −6, −5 | 1 950 mg/m2
| |
Cyclophosphamide | 1 800 mg/m2/day | Days −4, −3, −2 | 5 400 mg/m2
| |
Second HDCT regimens | ||||
131I-MIBG-TM |
131I-MIBG | 18 or 12 mCi/kg | Days −21 | 12 or 18 mCi/kg |
Thiotepa | 200 mg/m2/day | Days −6, −5, −4 | 600 mg/m2
| |
Melphalan | 60 mg/m2/day | Days −3, −2 | 120 mg/m2
| |
TM | Thiotepa | 300 mg/m2/day | Days −6, −5, −4 | 900 mg/m2
|
Melphalan | 60 mg/m2/day | Days −3, −2 | 120 mg/m2
|
Tandem HDCT/auto-SCT
Post-HDCT/auto-SCT treatment
Response criteria
Evaluation of late adverse effects
Survival analysis and statistics
Results
Patient characteristics
Parameters | NB-2004 (n = 50) | NB-2009 (n = 54) |
P value |
---|---|---|---|
Age (months) | 37 (4–129) | 30.5 (1–231) | 0.460 |
Age >18 months, n (%) | 42 (84.0) | 45 (83.3) | 0.927 |
INSS stage, n (%) | 0.116 | ||
Stage 3 | 5 (10.0) | 2 (3.7) | |
Stage 4 | 45 (90.0) | 49 (90.7) | |
Stage 4S | 0 (0.0) | 3 (5.6) | |
MYCN amplification, n (%) | 22 (44.0) | 25 (48.1) | 0.680 |
Unfavorable pathology (INPC), n (%) | 37/43 (86.0) | 39/52 (75.0) | 0.180 |
Serum LDH (IU/L), median (range) | 1766 (505–15 720) | 1746 (416–14 435) | 0.542 |
Serum ferritin (ng/mL), median (range) | 226 (20–3 284) | 266 (25–1491) | 0.972 |
Serum NSE (ng/mL), median (range) | 141.2 (17.9–1 507.1) | 97.6 (10.3–1 815.0) | 0.134 |
24-h urine VMA (mg), median (range) | 15.0 (0.7–100.0) | 9.3 (0.4–92.4) | 0.576 |
Induction treatment
Parameter | CEDC (261 cycles) | ICE (210 cycles) |
---|---|---|
Hematologic toxicity | ||
Duration of neutropenia, day (range) | 6 (0–19) | 9 (0–25) |
No. of platelet transfusions, n (range) | 2 (0–27) | 3 (0–15) |
Neutropenic fever, n (%) | 71 (27.2) | 94 (44.8) |
Positive blood culture, n (%) | 4 (1.5) | 12 (5.7) |
Non-hematologic toxicity | ||
Elevation of liver enzymes, n (%) | 10 (3.8) | 16 (7.6) |
Hyperbilirubinemia, n (%) | 1 (0.4) | 0 (0.0) |
Renal insufficiency, n (%) | 0 (0.0) | 0 (0.0) |
Hyponatremia, n (%) | 7 (2.9) | 4 (1.9) |
Hypokalemia, n (%) | 15 (5.7) | 13 (6.2) |
Tandem HDCT/auto-SCT
First HDCT in NB-2009 (n = 52) | Second HDCT in NB-2009 (n = 47) |
P value | TM-TBI in NB-2004 (n = 42) |
131I-MIBG-TM in NB-2009 (n = 43) |
P value | |
---|---|---|---|---|---|---|
Hematologic toxicity | ||||||
CD34+ cells (×106/kg), median (range) | 2.7 (1.0–14.1) | 2.4 (1.0–14.1) | 0.321 | 1.9 (1.0–16.0) | 2.3 (1.0–14.1) | 0.184 |
Time (days) to reach an ANC 0.5 × 109/La, median (range) | 11 (9–14) | 10 (8–15) | 0.339 | 11 (8–16) | 10 (8–15) | 0.038 |
Time (days) to reach a PLT count 20 × 109/Lb, median (range) | 24 (13–52) | 32 (16–275) | 0.004 | 40 (18–1 248) | 32 (16–275) | 0.041 |
Days of BT ≥38.0 °C, median (range) | 3 (0–16) | 4 (0–11) | 0.221 | 8 (2–27) | 4 (0–11) | <0.001 |
Positive blood culture, n (%) | 3 (5.8) | 3 (6.4) | 0.898 | 2 (4.8) | 3 (7.0) | 0.511 |
Non-hematologic toxicity | ||||||
Vomiting, n (%) | 12 (23.1) | 6 (12.8) | 0.184 | 11 (26.2) | 5 (11.6) | 0.086 |
Stomatitis, n (%) | 9 (17.3) | 18 (38.3) | 0.019 | 28 (66.7) | 15 (34.9) | 0.003 |
Diarrhea (frequency ≥10/day), n (%) | 16 (30.8) | 17 (36.2) | 0.569 | 23 (54.8) | 15 (34.9) | 0.065 |
Elevation of liver enzyme, n (%) | 44 (84.6) | 1 (2.1) | <0.001 | 7 (16.7) | 1 (2.3) | 0.030 |
Hepatic VOD, n (%) | 3 (5.8) | 0 (0.0) | 0.245 | 4 (9.5) | 1 (2.3) | 0.202 |
Renal insufficiency, n (%) | 4 (7.7) | 0 (0.0) | 0.119 | 2 (4.8) | 0 (0.0) | 0.241 |
Hypokalemia, n (%) | 17 (32.7) | 3 (6.4) | 0.001 | 17 (40.5) | 3 (7.0) | <0.001 |
Myocarditis, n (%) | 3 (5.8) | 0 (0.0) | 0.245 | 0 (0.0) | 0 (0.0) | >0.999 |
Intracranial hemorrhage, n (%) | 1 (1.9) | 0 (0.0) | 0.525 | 0 (0.0) | 0 (0.0) | >0.999 |
Toxic death, n (%) | 5 (9.6) | 0 (0.0) | 0.058 | 0 (0.0) | 0 (0.0) | >0.999 |
Time (days) to discharge from day 0 of SCT, median (range) | 17 (12–51) | 18 (12–31) | 0.135 | 19 (15–81) | 18 (12–31) | 0.098 |
Relapse and survival
Late adverse effects
NB-2004 (n = 32) | NB-2009 (n = 27) |
P value | |
---|---|---|---|
Endocrinopathy | |||
Hypothyroidism, n (%) | 12 (37.5) | 11 (40.7) | 0.799 |
Growth hormone deficiency, n (%) | 9 (28.1) | 1 (3.7) | 0.016 |
Glucocorticoid deficiency, n (%) | 1 (3.1) | 0 (0.0) | 0.542 |
Sex hormone deficiency, n (%) | 1/2a (50.0) | 1/3a (33.3) | 0.700 |
Height, Z-score, median (range) | −1.46 (−5.66–0.93) | −0.65 (−2.78–1.40) | 0.004 |
Weight, Z-score, median (range) | −0.84 (−2.91–0.75) | −0.32 (−2.15–2.08) | 0.014 |
BMI, Z-score, median (range) | −0.38 (−2.58–1.62) | −0.42 (−1.86–2.68) | 0.166 |
Hearing loss, n (%) | 24 (75.0) | 16 (59.3) | 0.197 |
Cataract, n (%) | 9 (28.1) | 0 (0) | 0.002 |
Chronic lung disease, n (%) | 2 (6.3) | 0 (0.0) | 0.673 |
Renal | |||
Glomerulopathy, n (%) | 18 (56.3) | 4 (14.8) | 0.001 |
Tubulopathy, n (%) | 20 (62.5) | 17 (63.0) | 0.971 |
Cardiac dysfunction, n (%) | 0 (0.0) | 0 (0.0) | 1.000 |
Presence of grade 3 dysfunction, n (%) | 4 (12.5) | 2 (7.4) | 0.678 |
Number of dysfunctions/patient, median (range) | 3 (0–7) | 2 (0–4) | 0.003 |