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Keywords:

  • neuroblastoma;
  • chemotherapy;
  • metaiodobenzylguanidine score;
  • transplantation;
  • prognosis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

In patients with high-risk neuroblastoma, the reduction in primary tumor volume was measured during the early phase of induction chemotherapy as an indicator of early tumor response, and the authors investigated whether the degree of tumor volume reduction could predict outcome in these patients.

METHODS:

Primary tumor volumes were measured both at diagnosis and at the first tumor response evaluation (after 2 or 3 cycles of induction chemotherapy) in 90 patients with high-risk neuroblastoma who had volumetrically evaluable computed tomography or magnetic resonance scans. If the tumor volume at the first response evaluation was >40% of the initial tumor volume, then the patient was categorized as a poor responder; otherwise, the patient was categorized as a good responder. Outcomes were compared according to the degree of tumor volume reduction at the first response evaluation.

RESULTS:

The tumor volume reduction was greater in patients who remained relapse free than in patients who had a relapsed tumor (median percentage tumor volume, 21% vs 41.5%; P = .037). The 5-year relapse-free survival rate was higher in the good responders than in the poor responders (83% [95% confidence interval, 72%-94%] vs 51% [95% confidence interval, 31%-71%]; P = .002). In a multivariate analysis of relapse-free survival, a poor early response was identified as an independent, unfavorable prognostic factor (hazard ratio, 4.24; 95% confidence interval, 1.59-11.29; P = .004).

CONCLUSIONS:

A greater reduction in tumor volume reduction the early phase of induction chemotherapy was associated with a better outcome in patients with high-risk neuroblastoma. Tailoring treatment intensity according to the early tumor response to induction chemotherapy may improve patient outcomes. Cancer 2013. © 2012 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

The morphologic response in bone marrow during the early phase of induction chemotherapy is a predictor of outcomes in childhood leukemias.1-4 The degree of tumor necrosis after preoperative chemotherapy also is predictive of event-free survival and overall survival in patients with bone tumors.5, 6 In patients with neuroblastoma, the Children's Cancer Group reported that quantitative tumor content of both bone marrow and blood after a few cycles of chemotherapy was prognostic.7 In addition, researchers observed that early metastatic response, as determined by 131I-metaiodobenzylguanidine/123I-metaiodobenzylguanidine (MIBG) scanning, was correlated with outcome.8-11 However, these measures evaluated only the response of metastatic tumors and were applicable only to patients with bone marrow metastasis or MIBG-avid tumors.

The standard treatment for high-risk neuroblastoma consists of induction treatment, high-dose chemotherapy (HDCT), autologous stem cell transplantation (autoSCT) as a consolidation treatment, and 13-cis-retinoid acid treatment to reduce relapse from minimal residual disease. Induction treatment consists of conventional chemotherapy and surgery with or without radiotherapy. In many patients with high-risk neuroblastoma, the tumor is inoperable at diagnosis, and definitive surgery is postponed until after preoperative chemotherapy.

In the current study, we hypothesized that a better early tumor response to induction chemotherapy may be associated with a better outcome in patients with high-risk neuroblastoma. We measured the degree of tumor volume reduction in the primary tumor during the early phase of induction chemotherapy as an indicator of early tumor response and investigated whether it could predict outcome.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patients

From January 1997 to December 2010, all patients with high-risk neuroblastoma who had volumetrically evaluable computed tomography (CT) or magnetic resonance (MR) scans at both diagnosis and during follow-up were retrospectively reviewed. Patients who had undergone surgery before the initiation of induction chemotherapy were excluded. Patients were staged according to the International Neuroblastoma Staging System.12 Amplification of v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian) (MYCN) was determined using Southern blot analysis or quantitative reverse transcriptase-polymerase chain reaction analysis. Tumors were classified as histologically favorable or unfavorable according to the International Neuroblastoma Pathology Classification.13 Stage 4 tumors in patients aged >1 year and any MYCN-amplified tumors were stratified as high-risk tumors. This retrospective study was approved by the Samsung Medical Center Institutional Review Board. Informed consent was waived by the Institutional Review Board.

Induction Chemotherapy

In the early period of this study (diagnosis by December 2003), patients underwent definitive surgery after 5 cycles of induction chemotherapy.14, 15 The combined cisplatin, etoposide, doxorubicin, and cyclophosphamide (CEDC) regimen was used for induction chemotherapy (Table 1). Overall, patients received 6 to 12 cycles of chemotherapy before HDCT/autoSCT. In the late period (diagnosis from January 2004), patients underwent definitive surgery after 6 cycles of chemotherapy. The CEDC regimen and the ifosfamide, carboplatin, and etoposide regimen were used in an alternating manner. Overall, patients received 9 or 10 cycles of chemotherapy before HDCT/autoSCT.14, 15

Table 1. Induction and High-Dose Chemotherapy Regimens
Regimen/DrugsDoseSchedule: Treatment Day(s)
  1. Abbreviations: 131MIBG, 131I-metaiodobenzylguanidine; Gy, grays; HDCT, high-dose chemotherapy; TBI, total body irradiation.

Induction regimens  
 CEDC  
  Cisplatin60 mg/m2/d0
  Etoposide100 mg/m2/d2, 5
  Doxorubicin30 mg/m2/d2
  Cyclophosphamide30 mg/kg/d3, 4
 ICE  
  Ifosfamide1200 mg/m2/d0-4
  Carboplatin400 mg/m2/d0, 1
  Etoposide100 mg/m2/d0-4
First HDCT regimens  
 CEM-TBI  
  Carboplatin300 mg/m2/d−8, −7, −6, −5
  Etoposide200 mg/m2/d−8, −7, −6, −5
  Melphalan140 mg/m2/d−7
 70 mg/m2/d−6
  TBI3.33 Gy/d−3, −2, −1
 CEM  
  Carboplatin300 mg/m2/d−6, −5, −4, −3
  Etoposide200 mg/m2/d−6, −5, −4, −3
  Melphalan140 mg/m2/d−5
 70 mg/m2/d−4
 CEC  
  Carboplatin650 mg/m2/d−7, −6, −5
  Etoposide650 mg/m2/d−7, −6, −5
  Cyclophosphamide1,800 mg/m2/d−4, −3, −2
Second HDCT regimens  
 CTM  
  Carboplatin250 mg/m2/d−6, −5, −4
  Thiotepa200 mg/m2/d−6, −5, −4
  Melphalan160 mg/m2/d−3
 BM  
  Busulfan, intravenous3.2 mg/kg/d−6, −5, −4, −3
  Melphalan120 mg/m2/d−2
 TM-TBI  
  Thiotepa200 mg/m2/d−8, −7, −6
  Melphalan60 mg/m2/d−5, −4
  TBI3.33 Gy/d−3, −2, −1
 TM  
  Thiotepa300 mg/m2/d−6, −5, −4
  Melphalan60 mg/m2/d−3, −2
 MIBG-TM  
  131I-MIBG12 or 18 mCi/kg−21
  Thiotepa200 mg/m2/d−6, −5, −4
  Melphalan60 mg/m2/d−3, −2

Local Radiotherapy

In the early period, patients received local radiotherapy to the primary site only if gross residual tumor remained after surgery. However, in the late period, all patients received local radiotherapy to the primary site after the second HDCT/autoSCT.14, 15

High-Dose Chemotherapy/Autologous Stem Cell Transplantation

Table 1 lists the HDCT regimens. Briefly, the principal regimens for the first HDCT were combined carboplatin, etoposide, and melphalan with (for metastatic tumors) or without (for localized tumors) total-body irradiation in the early period and combined carboplatin, etoposide, and cyclophosphamide in the late period. The principal regimens for the second HDCT were combined carboplatin, thiotepa, and melphalan or combined busulfan and melphalan in the early period and combined thiotepa plus melphalan with (for metastatic tumors) or without (for localized tumors) total-body irradiation or high-dose 131I-MIBG treatment in the late period.14, 15

Treatment After High-Dose Chemotherapy/Autologous Stem Cell Transplantation

Patients received differentiation therapy with 13-cis-retinoic acid plus immunotherapy using interleukin-2 for 1 year after HDCT/autoSCT to reduce relapse from possible minimal residual tumor cells.14, 15

Tumor Volume Measurement

The primary tumor volume was measured at diagnosis and at the first response evaluation after 2 cycles (in the early period) or 3 cycles (in the late period) of induction chemotherapy. To calculate the tumor volume on CT and MR scans, we used axial, contrast-enhanced CT scans and fat-suppressed, contrast-enhanced, T1-weighted MR images. We viewed the CT scans with a window level of 10 and a window width of 450. By consensus, 2 radiologists defined the tumor areas by manually drawing on each slice of stacked CT and MR images. The tumor volume was then calculated from the sum of the areas on the images multiplied by the slice thickness using computer software (Advantage Workstation, Volume Share version 2.0; GE Healthcare, Madison, Wis). The absolute tumor volume and the percentage tumor volume at the first response evaluation compared with the initial tumor volume were calculated (Fig. 1). Encased vessels within tumors were included in tumor volume measurement in most patients. However, cases in which large vessels and/or other organs (pancreas, kidney, vertebra, etc) present in the periphery of the tumor were partially encased were excluded from tumor volume measurements.

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Figure 1. Computed tomography volumetry is shown in a girl aged 30 months who had v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian) (MYCN)-amplified, undifferentiated, and metastatic neuroblastoma. The tumor is outlined manually on each slice of postcontrast axial scan. The tumor volumes (A) at diagnosis and (B) after 3 cycles of induction chemotherapy were 516.5 mL and 27.0 mL, respectively.

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Tumor Response Evaluation by Metaiodobenzylguanidine Score

MIBG scores were determined as previously described.16 In brief, the body was divided into 9 segments (head, chest, thoracic spine, lumbar spine, pelvis, upper arms, lower arms, femurs, and lower legs) to view osteomedullary involvement and a tenth general sector that included any soft tissue involvement. The extension score was graded as follows: 0 indicated no MIBG involvement; 1, 1 MIBG-avid lesion present; 2, more than 1 MIBG-avid lesion present; and 3, diffuse involvement (>50% of the segment). The absolute score was obtained by adding the scores of all the segments. The relative score was calculated by dividing the absolute score at the tumor response evaluation by the corresponding overall score at diagnosis.

Response Criteria

International response criteria were used to evaluate treatment response.13 Briefly, a complete response was defined as no identifiable tumor with a normal catecholamine level. A very good partial response was defined as a decrease between 90% and 99% in the primary tumor volume with a normal catecholamine level with or without any residual 99Tc bone changes. A partial response was defined as a reduction >50% in the primary and metastatic tumors. A mixed response was defined as a reduction >50% in any measurable lesion with a reduction <50% in any other lesion. Progressive disease (PD) was defined as any new lesion or an increase >25% in any measurable lesion.

Degree of Cytopenia During the First Chemotherapy Cycle

We investigated whether the degree of cytopenia during the first chemotherapy cycle (which was the CEDC regimen in all patients), used as an indicator of intrinsic patient cellular characteristics, also was related to tumor response. We analyzed the relations between various hematologic parameters at the nadir during the first chemotherapy cycle and the degree of tumor volume reduction at the first response evaluation.

Statistics

If the tumor volume at the first response evaluation was >40% of the initial tumor volume, then the patient was categorized as a poor responder; otherwise, the patient was categorized as a good responder. The percentage tumor volume at the first response evaluation was compared between the groups using the Mann-Whitney U test or the Kruskal-Wallis test. The survival rate and 95% confidence interval (CI) were determined using the Kaplan-Meier method. An event was defined as the occurrence of relapse, progression, or treatment-related mortality. Differences in survival rates between the 2 groups were compared using the log-rank test. Multivariate analyses for relapse-free survival and event-free survival were performed using Cox regression analysis. P values < .05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patient Characteristics

In total, 120 patients were newly diagnosed with high-risk neuroblastoma during the study period. Fourteen patients who underwent surgery before initiation of chemotherapy, 12 patients who had CT/MR scans with which volumetry was impossible, 2 patients with unknown primary sites, and 2 patients who were transferred to other hospitals before response evaluation were excluded. Therefore, 90 high-risk patients were included in the study. Twenty-seven of these patients were diagnosed in the early study period, and the remaining 63 patients were diagnosed in the late study period. Table 2 lists the clinical and biologic characteristics of the patients.

Table 2. Percentage Tumor Volume at the First Response Evaluation With Respect to Clinical and Biologic Factors
ParameterNo. of PatientsTumor Volume (Range), %P
  1. Abbreviations: CR, complete response; GNB, ganglioneuroblastoma; INPC, International Neuroblastoma Pathology Classification; INSS, International Neuroblastoma Staging System; MYCN, v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian); NB, neuroblastoma; VGPR, very good partial response.

Age, mo   
 <181623.9 (2.7-67.5) 
 ≥187421.9 (0.6-96.2).231
INSS stage   
 Localized1213.1 (1.7-88.2) 
 Metastatic: Stage 4/4S7824.6 (0.6-96.2).080
MYCN status   
 Not amplified4033.9 (0.6-86.5) 
 Amplified4914.8 (1.1-96.2).006
 Unknown1  
INPC pathology   
 Favorable1829.1 (7.5-88.2) 
 Unfavorable6516.6 (1.1-86.5).066
 Unknown7  
Differentiation   
 GNB483.6 (21.0-88.2) 
 NB, differentiating2126.5 (7.8-80.0) 
 NB, poorly differentiated3830.6 (1.1-83.5) 
 NB, undifferentiated207.4 (2.7-70.3)< .001
 Unknown7  
Treatment era   
 Diagnosis by 20032731.6 (1.1-88.2) 
 Diagnosis from 20046319.2 (0.6-96.2).235
Response to induction   
 CR4212.5 (1.1-79.7) 
 VGPR2526.5 (0.6-88.2) 
 Worse than VGPR2245.3 (7.2-96.2)< .001
 Treatment-related death1  
Overall outcome   
 Event free5821.0 (1.7-96.2) 
 Relapse/progression2041.5 (0.6-83.5) 
 Treatment-related death1211.6 (1.1-57.1).066

Treatment and Outcome

Tumors progressed in 3 patients, and treatment-related mortality occurred in 1 patient during the induction treatment; therefore, 86 patients completed induction treatment. Response evaluation at the end of induction revealed a complete response in 42 patients, a very good partial response in 25, a partial response in 18 patients, and a mixed response in 1 patient. All patients but 1 who refused HDCT/autoSCT proceeded to the first HDCT/autoSCT. However, 12 patients could not proceed to the second HDCT/autoSCT because of treatment-related mortality during the first HDCT/autoSCT (n = 3), myocarditis during the first HDCT/autoSCT (n = 1), tumor progression after the first HDCT/autoSCT (n = 1), and refusal of the second HDCT/autoSCT (n = 7). The remaining 73 patients proceeded to the second HDCT/autoSCT as scheduled at diagnosis. There was no difference in the proportion of patients who completed tandem HDCT/autoSCT between good responders and poor responders (82% vs 78%, respectively; P = .679). Tumors relapsed or progressed in 15 patients after the second HDCT/autoSCT. Treatment-related mortality occurred during the second HDCT/autoSCT in 7 patients and during follow-up after HDCT/autoSCT in 1 patient. Overall, tumors relapsed or progressed in 20 patients, and treatment-related mortality occurred in 12 patients. Therefore, 58 patients remained event free at a median follow-up of 53 months (range, 15-179 months) from diagnosis. The 5-year rates of relapse-free survival, event-free survival, and overall survival in all patients were 72% (95% CI, 62%-83%), 62% (95% CI, 52%-73%), and 65% (95% CI, 54%-76%), respectively.

Tumor Volume Reduction According to Known Prognostic Factors

The median volume of the primary tumor at diagnosis was 310.9 mL (range, 5.9-1298.6 mL). The median volumes after 2 and 3 cycles of chemotherapy were 67.3 mL (range, 0.6-405.8 mL) and 59.2 mL (range, 0.4-1027.8 mL), respectively. Table 2 lists the tumor volumes at the first response evaluation as a percentage of the initial tumor volume according to biologic and clinical factors. It is noteworthy that the reduction in tumor volume was greater in patients who had MYCN-amplified tumors (P = .006) (Fig. 2A) or undifferentiated tumors (P < .001) (Fig. 2B).

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Figure 2. The degree of tumor volume reduction is illustrated according to (A) v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian) (MYCN) amplification status and (B) and tumor differentiation. GNB indicates ganglioneuroblastoma; NB-D, differentiating neuroblastoma; NB-PD, poorly differentiated neuroblastoma; NB-UD, undifferentiated neuroblastoma.

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Tumor Volume Reduction According to Outcome

Tumor volume reduction was greater in patients who achieved a complete response or a very good partial response at the end of induction than in patients who had a response worse than a very good partial response (P < .001) (Fig. 3A). Similarly, the tumor volume reduction was greater in patients who remained relapse free than in patients with relapsed tumors (P = .037) (Fig. 3B). It is noteworthy that the reduction in tumor volume also was greater in patients who died from treatment-related toxicities than in patients who had relapsed tumors (P = .039) (Fig. 3B).

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Figure 3. The degree of tumor volume reduction is illustrated according to (A) response at the end of induction treatment and (B) and final outcome.

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Outcome According to Tumor Volume Reduction

Sixty-two patients (69%) were good responders, and 28 patients (31%) were poor responders. There was no difference in the proportion of poor responders according to the study period (33% in the early period vs 30% in the late period; P = .766). Table 3 lists the clinical and biologic characteristics of the patients according to early tumor responses. There was no difference in the initial tumor volume between good responders and poor responders (median, 293.2 mL vs 330.6 mL, respectively; P = .951). The proportions of MYCN-amplified tumors or undifferentiated tumors were greater in good responders than in poor responders (P = .013 and P = .013, respectively). Although a complete response/very good partial response was achieved at the end of induction in 54 of 61 evaluable good responders (89%), it was achieved in only 13 of 28 poor responders (47%; P < .001). Consistent with these results, tumors relapsed or progressed in 8 of 62 good responders (13%) compared with 12 of 28 poor responders (43%; P = .011). In contrast, treatment-related mortality occurred in 10 of 62 good responders (16%) and in 2 of 28 poor responders (7%; P = .328). In particular, all 8 events of treatment-related mortality during or after the second HDCT/autoSCT occurred in good responders.

Table 3. Patient Characteristics With Respect to Early Tumor Response
 No. of Patients (%) 
ParameterGood Responders, n = 62Poor Responders, n = 28P
  1. Abbreviations: CR, complete response; GNB, ganglioneuroblastoma; INPC, International Neuroblastoma Pathology Classification; INSS, International Neuroblastoma Staging System; MYCN, v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian); NB, neuroblastoma; VGPR, very good partial response.

Sex   
 Male36 (58)19 (68) 
 Female26 (42)9 (32).378
Age, mo   
 <1813 (21)3 (11) 
 ≥1849 (79)25 (89).239
INSS stage   
 Localized11 (18)1 (4) 
 Metastatic: Stage 4/4S51 (82)27 (96).067
Bone metastasis   
 No17 (27)5 (18) 
 Yes45 (73)23 (82).328
Bone marrow metastasis   
 No24 (39)8 (29) 
 Yes38 (61)20 (71).352
MYCN status   
 Not amplified22 (36)18 (64) 
 Amplified39 (64)10 (36).013
 Unknown1  
INPC pathology   
 Favorable11 (20)7 (26) 
 Unfavorable45 (80)20 (74).515
 Unknown61 
Differentiation   
 GNB1 (2)3 (12) 
 NB, differentiating13 (22)8 (32) 
 NB, poorly differentiated25 (43)13 (52) 
 NB, undifferentiated19 (33)1 (4).013
 Unknown43 
Treatment era   
 Diagnosis by 200319 (31)8 (29) 
 Diagnosis from 200443 (69)20 (71).842
Response to induction   
 CR37 (61)5 (18) 
 VGPR17 (28)8 (29) 
 Worse than VGPR7 (11)15 (54)< .001
 Treatment-related death10 
Overall outcome   
 Event free44 (71)14 (50) 
 Relapse/progression8 (13)12 (43) 
 Treatment-related death10 (16)2 (7)< .001

The 5-year relapse-free survival rate was higher in good responders than in poor responders (83% [95% CI, 72%-94%] vs 51% [95% CI, 31%-71%], respectively; P = .002) (Fig. 4A). In a multivariate analysis of relapse-free survival, a poor early response was identified as an independent, unfavorable prognostic factor (hazard ratio, 4.24; 95% CI, 1.59-11.29; P = .004) (Table 4). Similarly, the 5-year event-free survival rate was higher in good responders than in poor responders with borderline significance (70% [95% CI, 58%-82%] vs 47% [95% CI, 27%-66%], respectively; P = .054) (Fig. 4B). In a multivariate analysis of event-free survival, a poor early response also was identified as an independent, unfavorable prognostic factor (hazard ratio, 2.40; 95% CI, 1.13-5.11; P = .023) (Table 4).

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Figure 4. (A) Relapse-free survival and (B) event-free survival are illustrated according to early tumor response.

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Table 4. Univariate and Multivariate Analyses for Relapse-Free and Event-Free Survival
   Multivariate Analysis: RFS Multivariate Analysis: EFS 
Variable5-Year RFS (95% CI), %PHR (95% CI)P5-Year EFS (95% CI), %PHR (95% CI)P
  1. Abbreviations: CI, confidence interval; EFS, event-free survival; HR, hazard ratio; INPC, International Neuroblastoma Pathology Classification; INSS, International Neuroblastoma Staging System; MYCN, v-myc myelocytomatosis viral-related oncogene, neuroblastoma derived (avian); RFS, relapse-free survival.

Age, mo        
 <1878 (55-100)   68 (47-88)   
 ≥1871 (59-83).6880.88 (0.22-3.54).85661 (49-73).9610.83 (0.30-2.26).714
INSS stage        
 Localized92 (76-100)   92 (76-100)   
 Metastatic: Stage 4/4S68 (56-80).1134.00 (0.46-34.46).20857 (46-69).0288.78 (1.13-68.48).038
MYCN status        
 Nonamplified67 (51-83)   64 (48-80)   
 Amplified76 (63-90).4471.34 (0.46-3.95).59163 (49-77).6251.80 (0.78-4.17).171
INPC pathology        
 Favorable77 (55-99)   68 (45-92)   
 Unfavorable70 (57-82).6681.39 (0.37-5.23).62260 (48-73).6431.19 (0.44-3.27).733
Treatment era        
 Diagnosis from 200473 (61-86)   69 (56-81)   
 Diagnosis by 200369 (50-89).4032.11 (0.76-5.87).15448 (29-67).0352.26 (1.05-4.89).038
Tumor volume at first evaluation        
 <40%83 (72-94)   70 (58-82)   
 >40%51 (31-71).0024.24 (1.59-11.29).00447 (27-66).0542.40 (1.13-5.11).023

Association Between Tumor Volume Reduction and Metaiodobenzylguanidine Scores

The median MIBG extension scores at diagnosis in good and poor responders were 18.5 (range, 1-27) and 11 (range, 1-27), respectively (P = .836). The absolute and relative MIBG scores at the first response evaluation were lower in good responders than in poor responders with borderline significance (P = .089 and P = .058, respectively) (Table 5). However, the differences became significant after 5 or 6 cycles of induction chemotherapy (P = .001 and P = .001, respectively) (Table 5).

Table 5. Association Between Tumor Volume Reduction and 131I-Metaiodobenzylguanidine/123I-Metaiodobenzylguanidine Score
 Median Score (Range) 
Evaluation TimeGood RespondersPoor RespondersP
Absolute score   
 At diagnosis18.5 (1-27)11 (1-27).836
 After 2-3 cycles0 (0-27)1 (0-23).089
 After 5-6 cycles0 (0-1)1 (0-1).001
Relative score   
 After 2-3 cycles0 (0-1.00)0.38 (0-1.11).058
 After 5-6 cycles0 (0-1.00)0.17 (0-1.11).001

Cytopenia During the First Chemotherapy Cycle

It is noteworthy that the white blood cell count at the nadir during the first chemotherapy cycle was lower in good responders than in poor responders (median, 220/μL vs 400/μL, respectively; P = .005), although there was no difference in the frequency of bone marrow metastasis between the 2 groups (62% vs 71%, respectively; P = .372). Similarly, the absolute neutrophil count at the nadir was lower in good responders than in poor responders (median, 51/μL vs 160/μL, respectively; P < .001), and the duration of neutropenia (absolute neutrophil count, <500/μL) also was longer in good responders than in poor responders with borderline significance (median, 6 days vs 5 days, respectively; P = .068). However, there were no differences in hemoglobin or platelet counts at the nadir between the 2 groups (P = .170 and P = .796), because erythrocytes and platelets were transfused if hemoglobin and platelet counts fell below 8.0 g/dL and 20,000/μL, respectively.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Several researchers have searched for a sensitive measure of early response to therapy that would be capable of predicting later response and survival in patients with neuroblastoma. Some studies have reported that early metastatic response detected by immunohistochemical examination of bone marrow or MIBG scanning after a few cycles of induction chemotherapy was correlated with outcome.7-11 However, these measures evaluated only the response of metastatic tumors, and not the response of primary tumors. In addition, some patients with stage 4 disease do not have bone marrow metastasis, and approximately 10% of patients have MIBG-nonavid tumors.17, 18 Therefore, a response evaluation using these methods is applicable only to patients who have bone marrow metastasis or MIBG-avid tumors. In contrast, our method also can be applied in patients who have nonmetastatic or MIBG-nonavid tumors, because it evaluates the response of primary tumors, and not the response of metastatic tumors. To our knowledge, this is the first study suggesting that the degree of volume reduction in the primary tumor as an indicator of early tumor response is an independent prognostic factor in patients with high-risk neuroblastoma.

Tailoring treatment intensity according to the early response in bone marrow during induction chemotherapy improved the prognosis of patients with childhood acute lymphoblastic leukemia.19, 20 In some current chemotherapy protocols for childhood acute lymphoblastic leukemia, the treatment intensity after induction chemotherapy is tailored according to the minimal residual disease status of the bone marrow during the early phase or at the end of induction chemotherapy.21 Emerging results from those trials suggest that the adverse prognostic impact of minimal residual disease during the early phases of therapy can be diminished by treatment intensification. However, in neuroblastoma, the same treatment was received by all patients with the same risk after stratification into a certain risk group at diagnosis. In the current study, all patients were assigned to receive tandem HDCT/autoSCT at diagnosis, and >80% of patients completed treatment as scheduled. Our survival rates are very encouraging compared with those in previous studies that used a single HDCT/autoSCT strategy.22, 23 We believe that these encouraging results are generally attributable to further dose escalation with the tandem HDCT/autoSCT strategy. However, many good responders died from treatment-related toxicities, particularly during the second HDCT/autoSCT, although the relapse rate was relatively low in these patients. These findings suggest that good responders may benefit from treatment de-escalation, thus sparing them from treatment-related toxicities. Conversely, the relapse rate remained high in the poor responders even after tandem HDCT/autoSCT; therefore, a more intensified treatment or the addition of another treatment modality may be needed to reduce the relapse rate in these patients. Our results suggest that tailoring treatment intensity according to the early tumor response may further improve the outcomes of patients with high-risk neuroblastoma.

It is very interesting that the degree of tumor volume reduction was higher in MYCN-amplified tumors or undifferentiated tumors than in their counterparts. MYCN amplification and undifferentiated histology are known as independent, unfavorable prognostic factors in neuroblastoma.24, 25 However, these factors may lose their prognostic relevance in high-risk patients who receive intensive treatment, as in our study. Indeed, MYCN amplification and undifferentiated histology were not identified as unfavorable factors for relapse-free survival in the current study. These findings may be explained in part by the better early responses of MYCN-amplified tumors or undifferentiated tumors. Tumors with unfavorable features, such as a high mitotic index, may be more sensitive to chemotherapy than their counterparts.

We hypothesized that the intrinsic cellular characteristics of patients (eg, pharmacogenetic characteristics) that are shared by tumor cells also may affect the tumor response. Therefore, we investigated whether the degree of cytopenia during the first chemotherapy cycle, as an indicator of the intrinsic cellular characteristics of the patients who responded to chemotherapy, was related to tumor response. It is noteworthy that leukopenia and neutropenia during the first chemotherapy cycle were more severe in good responders than in poor responders. These findings suggest that the intrinsic cellular characteristics of patients also may affect tumor response, and treatment needs to be tailored according to the intrinsic cellular characteristics of patients as well as the characteristics of tumor cells.

In summary, our study has certain limitations, in that only patients with high-risk neuroblastoma were analyzed, and the patients received different therapies over the study period. In addition, the timing of the first response evaluation differed among patients. Nonetheless, the current findings suggest that a greater tumor volume reduction during the early phase of induction chemotherapy may be associated with a better outcome in patients with high-risk neuroblastoma. Our findings also suggest that tailoring treatment intensity according to the early tumor response may improve the outcomes of these high-risk patients. Further studies with larger cohorts of patients who receive uniform treatment will be necessary to confirm our findings.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES
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