Original Article
The Degree of Tumor Volume Reduction During the Early Phase of Induction Chemotherapy Is an Independent Prognostic Factor in Patients With High-Risk Neuroblastoma So Young Yoo, MD, PhD1; Jung-Sun Kim, MD, PhD2; Ki Woong Sung, MD, PhD3; Tae Yeon Jeon, MD1; Joon Young Choi, MD, PhD4; Seung Hwan Moon, MD4; Meong Hi Son, MD3; Soo Hyun Lee, MD, PhD3; Keon Hee Yoo, MD, PhD3; and Hong Hoe Koo, MD, PhD3
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 ¼ .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 ¼ .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 ¼ .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 outC 2012 American Cancer Society. comes. Cancer 2013;119:656-64. V KEYWORDS: neuroblastoma, chemotherapy, metaiodobenzylguanidine score, transplantation, prognosis.
INTRODUCTION 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/123Imetaiodobenzylguanidine (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. Corresponding author: Ki Woong Sung, MD, PhD, Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea; Fax: (011) 82-2-3410-0043;
[email protected] 1 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 4Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
The first 2 authors contributed equally to this article. DOI: 10.1002/cncr.27775, Received: April 11, 2012; Revised: July 12, 2012; Accepted: July 12, 2012, Published online September 5, 2012 in Wiley Online Library (wileyonlinelibrary.com)
656
Cancer
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Tumor Volume Reduction Predicts Outcome/Yoo et al
Table 1. Induction and High-Dose Chemotherapy Regimens
Regimen/Drugs
Dose
Schedule: Treatment Day(s)
60 mg/m2/d 100 mg/m2/d 30 mg/m2/d 30 mg/kg/d
0 2, 5 2 3, 4
1200 mg/m2/d 400 mg/m2/d 100 mg/m2/d
0-4 0, 1 0-4
Carboplatin Etoposide Melphalan
300 mg/m2/d 200 mg/m2/d 140 mg/m2/d
8, 7, 6, 5 8, 7, 6, 5 7
TBI
70 mg/m2/d 3.33 Gy/d
6 3, 2, 1
Induction regimens CEDC Cisplatin Etoposide Doxorubicin Cyclophosphamide
ICE Ifosfamide Carboplatin Etoposide
First HDCT regimens CEM-TBI
CEM 2
Carboplatin Etoposide Melphalan
300 mg/m /d 200 mg/m2/d 140 mg/m2/d
6, 5, 4, 3 6, 5, 4, 3 5
70 mg/m2/d
4
650 mg/m2/d 650 mg/m2/d 1,800 mg/m2/d
7, 6, 5 7, 6, 5 4, 3, 2
250 mg/m2/d 200 mg/m2/d 160 mg/m2/d
6, 5, 4 6, 5, 4 3
3.2 mg/kg/d 120 mg/m2/d
6, 5, 4, 3 2
200 mg/m2/d 60 mg/m2/d 3.33 Gy/d
8, 7, 6 5, 4 3, 2, 1
300 mg/m2/d 60 mg/m2/d
6, 5, 4 3, 2
12 or 18 mCi/kg 200 mg/m2/d 60 mg/m2/d
21 6, 5, 4 3, 2
CEC Carboplatin Etoposide Cyclophosphamide
Second HDCT regimens CTM Carboplatin Thiotepa Melphalan
BM Busulfan, intravenous Melphalan
TM Thiotepa Melphalan
MIBG-TM 131 I-MIBG Thiotepa Melphalan
Abbreviations: 131MIBG, 131I-metaiodobenzylguanidine; Gy, grays; HDCT, high-dose chemotherapy; TBI, total body irradiation.
MATERIALS AND METHODS Patients
From January 1997 to December 2010, all patients with high-risk neuroblastoma who had volumetrically evaluable computed tomography (CT) or magnetic resonance Cancer
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 Local Radiotherapy
TM-TBI Thiotepa Melphalan TBI
(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.
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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 657
Original Article
the periphery of the tumor were partially encased were excluded from tumor volume measurements. Tumor Response Evaluation by Metaiodobenzylguanidine Score
Figure 1. Computed tomography volumetry is shown in a girl aged 30 months who had v-myc myelocytomatosis viralrelated 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.
localized tumors) total-body irradiation or high-dose 131 I-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 658
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 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% Cancer
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Tumor Volume Reduction Predicts Outcome/Yoo et al
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.
Parameter
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. Twentyseven 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. 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 ¼ 3), myocarditis during the first HDCT/autoSCT (n ¼ 1), tumor progression after the first HDCT/autoSCT (n ¼ 1), and refusal of the second HDCT/autoSCT (n ¼ 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 ¼ .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. February 1, 2013
No. of Patients
Tumor Volume (Range), %
P
16 74
23.9 (2.7-67.5) 21.9 (0.6-96.2)
.231
12 78
13.1 (1.7-88.2) 24.6 (0.6-96.2)
.080
40 49 1
33.9 (0.6-86.5) 14.8 (1.1-96.2)
.006
18 65 7
29.1 (7.5-88.2) 16.6 (1.1-86.5)
.066
4 21 38 20 7
83.6 (21.0-88.2) 26.5 (7.8-80.0) 30.6 (1.1-83.5) 7.4 (2.7-70.3)
< .001
27 63
31.6 (1.1-88.2) 19.2 (0.6-96.2)
.235
42 25 22 1
12.5 (1.1-79.7) 26.5 (0.6-88.2) 45.3 (7.2-96.2)
< .001
58 20 12
21.0 (1.7-96.2) 41.5 (0.6-83.5) 11.6 (1.1-57.1)
.066
Age, mo
