Factors of Recurrence After Complete Response in Children with Neuroblastoma: A 16-Year Retrospective Study of 179 Cases

Figures & data

Figure 1 Treatment protocol.

Table 1 Clinical Features of the Entire Cohort

	Total (n=179)
Age (months) [n (%)]
≥18	135 (75.4)
<18	44 (24.6)
Gender [n (%)]
Male	94 (52.5)
Female	85 (47.5)
INSS stage [n (%)]
2	10 (5.6)
3	65 (36.3)
4	98 (54.7)
4S	6 (3.4)
Pathological type [n (%)]
Neuroblastoma	104 (58.1)
Ganglioneuroblastoma (nodular)	47 (26.3)
Ganglioneuroblastoma (intermixed)	26 (14.5)
Ganglioneuroma	2 (1.1)
Primary site [n (%)]
Adrenal glands/Retroperitoneum	139 (77.7)
Mediastinum	34 (19.0)
Pelvis	4 (2.2)
Cervical soft tissue	1 (0.6)
Spinal canal	1 (0.6)
Distant metastasis site [n (%)]
Bone marrow	70 (39.1)
Bone	69 (38.5)
Distant lymph node	39 (21.8)
Liver	14 (7.8)
Lung	4 (2.2)
Central nervous system	3 (1.7)
Other sites (skin, scrotum and ascites)	3 (1.7)
MYCN status [n (%)]
Amplified	33 (18.4)
Not amplified	58 (32.4)
Unknown	88 (49.2)
Serum NSE level (ng/mL) [n (%)]
≥100	89 (49.7)
<100	90 (50.3)
Serum LDH level (U/L) [n (%)]
≥1400	11 (6.1)
<1400	168 (93.9)

Abbreviations: INSS, International Neuroblastoma Staging System; NSE, serum neuron-specific enolase; LDH, serum lactate dehydrogenase.

Table 2 Overall Survival of Each Group in Children with Neuroblastoma After Initial Complete Response

	n (%)	1-Year OS (%)	3-Year OS (%)	5-Year OS (%)	P value
Total	179 (100.0)	98.9	88.9	81.9
Recurrence group	86 (48.0)	97.7	86.0	66.2	<0.001
Non-recurrence group	93 (52.0)	100.0	98.7	98.7
High-risk group	120 (67.0)	99.2	85.3	75.7	0.01
Intermediate-risk group	49 (27.4)	98.0	95.9	95.9
Low-risk group	10 (5.6)	100.0	100.0	100.0

Abbreviation: OS, overall survival.

Figure 2 (A) Overall survival (OS) of 179 children with complete response; (B) Comparison of OS between recurrence group and non-recurrence group; (C) Comparison of OS in different COG risk groups. (Kaplan–Meier method, P value shown for Log rank test among variables).

Table 3 Comparison of RFSs in 179 Children with Neuroblastoma After Initial Complete Response

	n (%)	1-Year RFS (%)	3-Year RFS (%)	5-Year RFS (%)	P value
Total	179 (100.0)	94.4	60.1	47.3
COG risk group
High risk	120 (67.0)	90.8	47.9	31.2	<0.001
Intermediate risk	49 (27.4)	93.9	85.1	85.1
Low risk	10 (5.6)	100.0	88.9	88.9
Age (months)
≥18	135 (75.4)	91.9	53.4	36.4	<0.001
<18	44 (24.6)	93.2	81.4	81.4
Gender
Male	94 (52.5)	88.3	59.3	43.7	0.380
Female	85 (47.5)	96.5	61.2	52.7
INSS stage
2,3,4S	81 (45.3)	87.7	70.7	60.3	0.005
4	98 (54.7)	95.9	51.6	37.0
Histological type
Unfavorable histology	100 (55.9)	90.0	46.8	27.0	<0.001
Favorable histology	79 (44.1)	94.9	77.4	77.4
Primary site
Adrenal glands/Retroperitoneum	139 (77.7)	91.4	58.3	45.7	0.467
Others	40 (22.3)	95.0	66.7	53.2
Bone marrow metastasis
Yes	70 (39.1)	95.7	50.4	36.1	0.009
No	109 (60.9)	89.9	66.7	54.6
Osseous metastasis
Yes	69 (38.5)	97.1	49.3	33.9	0.009
No	110 (61.5)	89.1	67.3	56.3
Hepatic metastasis
Yes	14 (7.8)	92.9	77.9	64.9	0.129
No	165 (92.2)	92.1	58.6	45.7
Distant lymph node metastasis
Yes	39 (21.8)	94.9	53.6	40.8	0.254
No	140 (78.2)	91.4	62.0	49.1
MYCN status
Amplified	33 (36.3)	90.9	60.6	49.9	0.090
Not amplified	58 (63.7)	98.3	75.5	66.9
Serum NSE level (ng/mL)
≥100	89 (49.7)	91.0	45.8	32.3	<0.001
<100	90 (50.3)	93.3	74.8	64.4
Serum LDH level (U/L)
≥1400	11 (6.1)	72.7	9.1	9.1	<0.001
<1400	168 (93.9)	93.5	63.6	49.8

Abbreviations: RFS, recurrence-free survival; INSS, International Neuroblastoma Staging System; NSE, serum neuron-specific enolase; LDH, serum lactate dehydrogenase.

Figure 3 (A) Recurrence-free survival (RFS) of 179 children with complete response; (B) Comparison of RFS in different COG risk groups. (Kaplan–Meier method, P value shown for Log rank test among variables).

Figure 4 Comparisons of recurrence-free survival by (A) age, (B) gender, (C) INSS stage, (D) histological type, (E) primary site, and (F) bone marrow metastasis in 179 children with neuroblastoma. (Kaplan–Meier method, P value shown for Log rank test among variables).

Figure 5 Comparisons of recurrence-free survival by (A) osseous metastasis, (B) hepatic metastasis, (C) distant lymph node metastasis, (D) MYCN status, (E) serum NSE level, and (F) serum LDH level in 179 children with neuroblastoma. (Kaplan–Meier method, P value shown for Log rank test among variables).

Table 4 Cox Proportional Hazard Model for the Unadjusted and Adjusted Risk Factors of Post-Remission Recurrence in 179 Children with Neuroblastoma

	n	Unadjusted			Adjusted
		HR	95% CI	P value	HR	95% CI	P value
Age (months)
≥18	135	4.094	1.969−8.511	<0.001	3.017	1.411−6.454	0.004^a
<18	44	1			1
INSS stage
2, 3, 4S	81	1		0.006	1		0.593^b
4	98	1.897	1.206−2.983		0.809	0.373−1.757
Histological type
Unfavorable histology	100	4.156	2.441−7.077	<0.001	2.813	1.581−5.006	<0.001^c
Favorable histology	79	1			1
Bone marrow metastasis
Yes	70	1.736	1.135−2.653	0.011	1.025	0.566−1.858	0.935^d
No	109	1			1
Osseous metastasis
Yes	69	1.749	1.142−2.679	0.010	1.086	0.598−1.972	0.788^e
No	110	1			1
MYCN status
Amplified	33	1.809	0.900−3.635	0.096	1.966	0.832−4.646	0.123^f
Not amplified	58	1			1
Serum NSE level (ng/mL)
≥100	89	2.468	1.564−3.896	<0.001	1.462	0.872−2.451	0.149^g
<100	90	1			1
Serum LDH level (U/L)
≥1400	11	4.740	2.420−9.284	<0.001	3.644	1.760−7.547	<0.001^h
<1400	168	1			1

Notes: ^aAdjusted for INSS stage, histological type, bone marrow metastasis status, osseous metastasis status, serum NSE level, and serum LDH level; ^bAdjusted for age, histological type, bone marrow metastasis status, osseous metastasis status, serum NSE level, and serum LDH level; ^cAdjusted for age, INSS stage, bone marrow metastasis status, osseous metastasis status, serum NSE level, and serum LDH level; ^dAdjusted for age, INSS stage, histological type, osseous metastasis status, serum NSE level, and serum LDH level; ^eAdjusted for age, INSS stage, histological type, bone marrow metastasis status, serum NSE level, and serum LDH level; ^f Adjusted for age, INSS stage, histological type, bone marrow metastasis status, osseous metastasis status, serum NSE level, and serum LDH level; g Adjusted for age, INSS stage, histological type, bone marrow metastasis status, osseous metastasis status, and serum LDH level; h Adjusted for age, INSS stage, histological type, bone marrow metastasis status, osseous metastasis status, and serum NSE level;

Abbreviations: HR, hazard ratio; CI, confidence interval; INSS, International Neuroblastoma Staging System; NSE, serum neuron-specific enolase; LDH, serum lactate dehydrogenase.

Table 5 Comparison of RFSs in 120 Children with High-Risk Neuroblastoma After Initial Complete Response

	n (%)	1-Year RFS (%)	3-Year RFS (%)	5-Year RFS (%)	P value
Age (months)
≥18	107 (89.2)	90.7	46.1	27.3	0.095
<18	13 (10.8)	92.3	61.5	61.5
Gender
Male	68 (56.7)	88.2	53.3	33.2	0.519
Female	52 (43.3)	94.2	40.9	29.1
INSS stage
2,3,4S	29 (24.2)	72.4	44.6	22.6	0.188
4	91 (75.8)	96.7	48.9	33.6
Histological type
Unfavorable histology	94 (78.3)	89.4	45.5	24.0	0.016
Favorable histology	26 (21.7)	96.2	56.3	56.3
Primary site
Adrenal glands/Retroperitoneum	99 (82.5)	90.9	48.3	32.8	0.396
Others	21 (17.5)	90.5	45.9	22.9
Bone marrow metastasis
Yes	68 (56.7)	95.6	48.8	34.5	0.439
No	52 (43.3)	84.6	46.8	23.9
Osseous metastasis
Yes	66 (55.0)	98.5	48.5	33.4	0.442
No	54 (45.0)	81.5	47.4	27.9
Hepatic metastasis
Yes	9 (7.5)	100.0	77.8	58.3	0.053
No	111 (92.5)	90.1	45.4	28.9
Distant lymph node metastasis
Yes	37 (30.8)	94.6	51.1	37.5	0.608
No	83 (69.2)	89.2	46.5	28.4
MYCN status
Amplified	28 (52.8)	89.3	57.1	44.0	0.757
Not amplified	25 (47.2)	100.0	61.7	45.0
Serum NSE level (ng/mL)
≥100	76 (63.3)	92.1	42.9	27.0	0.262
<100	44 (36.7)	88.6	56.4	38.4
Serum LDH level (U/L)
≥1400	9 (7.5)	88.9	11.1	11.1	0.006
<1400	111 (92.5)	91.0	51.0	32.9
Radiotherapy
Yes	35 (29.2)	91.4	37.1	25.0	0.246
No	85 (70.8)	90.6	52.6	33.9
APBSCT
Yes	26 (21.7)	88.5	38.5	19.2	0.176
No	94 (78.3)	91.5	50.8	35.7

Abbreviations: RFS, recurrence-free survival; INSS, International Neuroblastoma Staging System; NSE, serum neuron-specific enolase; LDH, serum lactate dehydrogenase; APBSCT, autologous peripheral blood stem cell transplantation.

Figure 6 (A) Comparisons of recurrence-free survival by (A) age, (B) histological type, (C) hepatic metastasis, and (D) serum LDH level in 120 children with high-risk neuroblastoma. (Kaplan–Meier method, P value shown for Log rank test among variables).

Table 6 Cox Proportional Hazard Model for the Unadjusted and Adjusted Risk Factors of Post-Remission Recurrence in 120 Children with High-Risk Neuroblastoma

	n	Unadjusted			Adjusted
		HR	95% CI	P value	HR	95% CI	P value
Age (months)
≥18		2.115	0.853−5.243	0.106	1.887	0.714−4.988	0.200^a
<18		1			1
Histological type
Unfavorable histology		2.148	1.130−4.082	0.020	1.863	0.964−3.600	0.064^b
Favorable histology		1			1
Hepatic metastasis
Yes		1		0.068	1		0.114^c
No		2.939	0.924−9.350		2.563	0.797−8.235
Serum LDH level (U/L)
≥1400		2.671	1.273−5.605	0.009	2.803	1.280−6.140	0.010^d
<1400		1			1

Notes: ^aAdjusted for histological type, hepatic metastasis status, and serum LDH level; ^bAdjusted for age, hepatic metastasis status, and serum LDH level; ^cAdjusted for age, histological type, and serum LDH level; ^dAdjusted for age, histological type, and hepatic metastasis status.

Abbreviations: HR, hazard ratio; CI, confidence interval; LDH, serum lactate dehydrogenase.

Table 7 The New Recurrence Risk Stratification System and Previous Risk Classification Systems in Predicting Post-Remission Recurrence in Children with Neuroblastoma

	n (%)	5-Year RFS (%)	P value	AUC (95% CI)
COG risk stratification
Low risk	10 (5.6)	88.9	0.705 (low vs intermediate)	0.729 (0.654−0.804)
Intermediate risk	49 (27.4)	85.1
High risk	120 (67.0)	31.2	<0.05 (others)
INRG risk classification
Very low risk	31 (17.3)	86.2	0.571 (very low vs low)	0.700 (0.623−0.777)
Low risk	13 (7.3)	83.9	0.056 (low vs intermediate)
Intermediate risk	37 (20.7)	42.3	0.376 (intermediate vs high)
High risk	98 (54.7)	33.6	<0.01 (others)
New recurrence risk stratification
Low risk	32 (17.9)	93.5	<0.01	0.773 (0.704−0.842)
Intermediate risk	55 (30.7)	66.4
High risk	92 (51.4)	22.5

Abbreviations: RFS, recurrence-free survival; AUC: area under the ROC curve; COG, Children’s Oncology Group; INRG, International Neuroblastoma Risk Group.

Figure 7 Recurrence-free survival of 179 children with neuroblastoma based on (A) COG risk stratification, (B) INRG classification system, and (C) the new recurrence risk stratification; (D) Comparison of ROC curves among the three stratification systems.