A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China

Abstract

Objective

Recent therapeutic advances have greatly enhanced the survival rates of patients with neuroblastoma (NB). However, the outcomes of neuroblastoma patients in China, particularly those with high-risk (HR) NB, remain limited.

Method

We retrospectively analyzed the clinical data and outcomes of NB patients who were treated at a tertiary pediatric cancer facility in China between January 2013 and October 2021.

Results

A total of 117 NB patients were recruited. Patients with very low-risk (VLR), low-risk (LR), intermediate-risk (IR), and HR-NB patients made up 4%, 27%, 15%, and 54% of total patient population, respectively. Patients diagnosed between 2013 and 2018 were treated according to the protocol of Sun Yat-Sen University Cancer Center and those diagnosed between 2019 and 2021 were treated according to the COG ANBL0531 or ANBL0532 protocol with or without autologous stem cell transplantation (ASCT). The 5-year EFS and OS of all risk groups of patients were 67.29% and 77.90%, respectively. EFS and OS were significantly decreased in patients with higher risk classifications (EFS: VLR/LR vs IR vs HR: 97.22% vs 67.28% vs 51.83%; ***P = .001; OS: VLR/LR vs IR vs HR: 97.06% vs 94.12% vs 64.38%; *P = .046). In HR-NB patients treated according to the COG protocol between 2019 and 2021, the 3-year OS of patients who received tandem ASCT was significantly greater than those who did not receive ASCT (93.33% % vs 47.41%; *P = .046; log-rank test). EFS was not significantly different between patients with and without ASCT (72.16% vs 60.32%).

Conclusion

Our findings show that patients with lower risk classification have a positive prognosis for survival. The prognosis of patients with HR-NB remains in need of improvement. ASCT may enhance OS in HR-NB patients; however, protocol adjustment may be necessary to increase EFS in these patients.

Keywords

neuroblastoma pediatric solid tumor autologous stem cell transplantation cancer survival prognosis

Introduction

Neuroblastoma (NB) is the most prevalent extracranial malignancy in children originating from the retroperitoneal gland or paravertebral sympathetic ganglia.¹ In China, the exact incidence of neuroblastoma in children remains unknown. According to previous reports, the incidence of NB ranges from 1.9 to 14.1 cases per million population per year worldwide.² The prognosis of individuals with NB varies significantly based on their risk categorization^3-5. In certain cases, tumor lesions are reversible without therapy.⁶ Despite diverse therapy, the majority of patients with high-risk neuroblastoma (HR-NB) had a heterogeneous disease onset and distant metastases at the time of diagnosis, resulting in disastrous outcomes.^7,8

Recent advancements in the treatment of NB, such as immunotherapy, targeted therapy, and novel cell therapy, have greatly improved patients’ survival.⁹ Patients who have traditionally depended heavily on conventional treatment strategies, such as surgery, high-dose chemotherapy, and radiation therapy, are beginning to embrace protocols employing advanced therapeutic strategies.^10,11 In certain underdeveloped countries, the survival rates of NB patients with low (LR) to intermediate-risk (IR) disease may be comparable to those in the developed countries. However, the survival rate of patients with high-risk (HR) NB in developing countries ranges from 20% to less than 50%, which is much lower than newly released statistics from the Europe and North America, which indicate a survival rate of 60% or more.^1,11 In addition, whether the adoption of these protocols can enhance the life expectancies of patients with NB in countries with limited resources, it is worthwhile to investigate their results.

In this study, we retrospectively reviewed the clinical data and compared the outcomes of patients with NB treated with a protocol based on multidisciplinary approaches including conventional surgery, chemotherapy, and radiation therapy with those of patients treated with a newer Children’s Oncology Group (COG) protocol ANBL0531 or ANBL0532 in a pediatric oncology center in China.^12,13

Methods

Patients

One hundred and seventeen patients aged 0 to 156 months (median 30 months) were diagnosed and treated for NB in a tertiary pediatric cancer center in China between January 2013 and October 2021, and their clinical data were evaluated retrospectively (Supplementary 1).¹⁴ This study excluded patients who were diagnosed but treated elsewhere. The median patient follow-up duration was 1009 ± 579 days (160–3342 days). All patients were de-identified and were given project numbers before data analysis. This study was conducted in accordance with the Declaration of Helsinki and with the approval of the Institutional Ethics Committee (approval number SEY-XJS-522). Informed written consent was obtained from the patients’ parents or legal guardians.

Diagnosis, Staging, and Risk Classification of NB

The diagnostic criteria for NB have been confirmed by international consensus.^15,16 Bilateral bone marrow aspiration and trephine biopsies; computed tomography (CT) or magnetic resonance imaging (MRI) of the cranial, neck, chest, and abdomen; pelvic ultrasound were utilized to evaluate primary tumor and metastases of NB. In addition, 18F-fluorodeoxy-D-glucose positron emission computed tomography (FDG PET/CT) was used to evaluate metastases of NB, particularly the metastases of the bones, distant lymph nodes, and soft tissues, because metaiodoenzylguanidine (MIBG) evaluation was unavailable during the study period. Using the International Neuroblastoma Pathology Classification, a pathological evaluation was conducted.¹⁷ MYCN gene amplification was assessed by fluorescence in situ hybridization. For patients diagnosed between 2013 and 2018, the International Neuroblastoma Staging System (INSS) was used to classify tumor staging. For patients diagnosed between 2019 and 2020, the International Neuroblastoma Risk Group Staging System (INRGSS) was used to classify disease stage and risk.⁵ In this retrospective study, we did data analysis using the INRGSS system for statistical reasons.

Treatment of patients with NB

Chemotherapy and ASCT

Various procedures were utilized over the course of the investigation. Depending on disease staging, risk stratification, and clinical assessment, treatment options range from observation without specific therapeutic intervention to multidisciplinary approaches, including surgical resection of the tumor, systemic chemotherapy, radiotherapy, and autologous stem cell transplantation (ASCT).

Patients diagnosed between 2013 and 2018 received chemotherapy in accordance with the protocol of the Sun Yat-Sen University Cancer Center. Patients with LR- and IR-NB received chemotherapy consisting of alternating CAV/EP-based regimens (cyclophosphamide, Adriamycin, vincristine, etoposide, and cisplatin). The treatment approach for HR-NB comprised an alternating CAV/VIP-based regimen (cyclophosphamide, vincristine, cisplatin, Adriamycin, ifosfamide, and etoposide) followed by oral metronomic as maintenance therapy.¹⁸ Patients diagnosed between 2019 and 2020 were administered chemotherapy according to the COG ANBL0531 protocol (carboplatin, cyclophosphamide, etoposide, and doxorubicin) for patients with LR and IR-NB^13,19 and the COG ANBL0532 protocol for patients with HR-NB (cyclophosphamide, topotecan, cisplatin, etoposide, doxorubicin, and vincristine)^12,20 with or without ASCT. For patients that did not receive ASCT, oral 13-cis-retinoic acid was administered as maintenance treatment after completion of all cycles of high-dose chemotherapy and radiotherapy.

Surgery

The initial tumor was surgically excised for diagnostic or therapeutic purposes. In general, total or partial resection of the primary tumor was performed on patients with LR and IR-NB at the time of diagnosis or after four to six cycles of chemotherapy. Although surgical resection might be performed in patients with HR-NB at the time of diagnosis, excision of the tumor often occurred after four to six cycles of chemotherapy. In patients in whom removal of the primary tumor at the time of diagnosis is not possible, an ultrasound-guided percutaneous biopsy can be performed for diagnostic purposes.

ASCT, Chimeric Antigen Recombinant T Cell (CART)Therapy, and Immunotherapy

Twenty-four patients with HR-NB who were treated according to the COG protocol underwent ASCT in addition to the previously described high-dose chemotherapy. A carboplatin/etoposide/melphalan-based regimen was administered to single ASCT recipients. Patients receiving tandem transplantation received a cyclophosphamide/thiotepa-based regimen, followed by a reduced dose of the carboplatin/etoposide/melphalan-based regimen. The infusion of CD34⁺ cell included more than 1 × 10⁶ cells/kg. Four patients with HR-NB received CART cell therapy targeting GD-2 and PSMA antigen as maintenance therapy after radiotherapy as part of a phase I/II clinical trial (NCT04637503). GD-2 immunotherapy was not officially assessable during the duration of the research. However, five patients received two to four courses of naxitamab (humanized 3F8) anti-GD2 antibody in a pilot trial in Hainan, China. One patient received naxitamab therapy overseas.

Radiotherapy

Patients received 20–30 Gy of radiation for the primary tumor and metastatic tumor. During the study period, MIBG treatment was not available. Nonetheless, four patients received MIBG therapy in Hong Kong or overseas.

Toxicity Monitoring and Treatment Outcomes

All patients were followed for toxicities associated with chemotherapy, including hematologic, hepatic, renal, and cardiac toxicities, according to the Common Terminology Standard for Adverse Event (CTCAE) version 4.03. Patient response to treatment was assessed every two cycles as follows: complete remission (CR)—absence of primary and metastatic tumors with normal catecholamine levels; very good partial response (VGPR)—90 to 99% volume reduction of the primary tumor, clearance of metastatic tumor with exception of remaining of the bone lesions, and normal catecholamine levels; partial response (PR)—over 50% volume reduction of primary and metastatic tumor; stable disease (SD)—less than 50% reduction of primary and metastatic tumor or less than 25% increase of new lesion; progressive disease (PD)—over 25% increase in a preexisting primary or metastatic tumor, or new lesions.

The outcomes of survival, including overall survival (OS) and event-free survival (EFS), were assessed. OS was defined as survival from the date of diagnosis to the date of the last follow-up visit (31^st August 2022), with events including death, disease progression, and complications. EFS was defined as survival status at the last follow-up visit with no occurrence of events.

Statistical Analysis

GraphPad Prism software version 9.1.2 (225) (GraphPad Software, San Diego, CA, USA) or SPSS software version 28.0.0.0 (IBM Corp., Armonk, NY, USA) was utilized to conduct statistical analyses. The chi-square test was utilized to calculate categorical variables between groups. We investigated group differences using Welch’s ANOVA test. The Kaplan–Meier estimator was utilized to calculate OS and EFS. The log-ranked test was used to calculate OS and EFS group differences. The Cox regression model was used to determine risk variables and prognostic factors. At a P-value less than .05, results were considered statistically significant.

Results

Patient Characteristics

The clinical characteristics of the patients are summarized in Table 1. This research involved 117 patients (46 females and 71 males). The median age at diagnosis was 35 ± 28 m (range 0–157 months). Patients with NB were categorized according to the INRG staging system as L1 (21%, n = 25), L2 (23%, n = 26), M (54%, n = 63), and MS (2%, n = 2) and subsequently categorized as very low-risk (VLR, 4%, n = 5), LR (27%, n = 32), IR (15%, n = 17), and HR (54%, n = 63) groups. Primary tumors were found in the adrenal/retroperitoneal, thoracic, and pelvic regions in 61% (n = 72), 20% (n = 23), and 2% (n = 2) of patients, and in other sites including the cervical, orbital, intraspinal, and intracranial regions in 6% (n = 7) of patients, respectively. In 11% (n = 13) of the patients, primary tumors were observed at more than two sites.

Table 1.

Patient Characteristics.

	Number of patients	VLR	LR	IR	HR
Total patients	117	5 (4%)	32(27%)	17 (15%)	63 (54%)
Age at diagnosis (months, mean±SD)	35 ± 28 (range 0–157)	83 ± 32 (range 40–126)	28 ± 25 (range 0–93)	27 ± 37 (range 3–157)	37 ± 22 (range 6–122)
<18 months	37 (32%)	0	14 (53%)	12 (70%)	11 (17%)
18–60 months	65 (55%)	1 (20%)	15 (47%)	3 (19%)	46 (73%)
>60 months	15 (13%)	4 (80%)	3 (9%)	2 (12%)	6 (10%)
Gender
Female	46 (39%)	2 (40%)	11 (34%)	4 (24%)	29 (46%)
Male	71 (61%)	3 (60%)	21 (66%)	13 (76%)	34 (54%)
Primary tumor sites
Retroperitoneal*	72 (61%)	3 (60%)	16 (50%)	10 (59%)	43(68%)
Thoracic	23 (20%)	2 (40%)	13 (41%)	4 (25%)	4 (6%)
Pelvic	2 (2%)	0	1 (3%)	0	1 (2%)
≥ 2 sites	13 (11%)	0	0	2 (12%)	11 (18%)
Other sites¹	7 (6%)	0	2 (6%)	1 (6%)	4 (6%)
Metastasis
Bone marrow*
Yes	46 (39%)	0	0	7 (41%)	39 (62%)
No	64 (55%)	5 (100%)	32 (100%)	9 (53%)	20 (32%)
Unknown	7 (6%)	0	0	1 (6%)	4 (6%)
Distant lymph nodes
Yes	36 (31%)	0	2 (6%)	8 (47%)	28 (44%)
No	76 (65%)	5 (100%)	29 (91%)	8 (47%)	32 (51%)
Unknown	5 (4%)	0	1 (3%)	1 (6%)	3 (5%)
Bones*
Yes	53 (45%)	0	0	6 (35%)	45 (71%)
No	59 (51%)	5 (100%)	31 (97%)	10 (59%)	15 (24%)
Unknown	5 (4%)	0	1 (3%)	1 (6%)	3 (5%)
MYCN gene amplification*
Yes	18 (16%)	0	0	0	18 (29%)
No	94 (80%)	5 (100%)	32 (100%)	17 (100%)	40 (63%)
Unknown	5 (4%)	0	0	0	5 (8%)
NSE level (ng/mL, mean±SD)*	263.5 ± 560.9	26.88 ± 7.40	76.59 ± 182.3	371.4 ± 559.6	357.0 ± 688.7
LDH level (IU/L, mean±SD)*	935.0 ± 1543.0	354.0 ± 313.5	372.1 ± 215.0	356.4 ± 89.09	2094.0 ± 319.4
INRG staging
L1	25 (21%)	3 (60%)	22 (69%)	0	0
L2	26 (23%)	3 (40%)	9 (28%)	7 (41%)	7 (11%)
M	63 (54%)	0	0	9 (53%)	56 (89%)
MS	2 (2%)	0	1 (3%)	1 (6%)	0

¹Other sites including cervical, orbital, intraspinal, and intracranial regions.

*P < .05.

NSE—neuron-specific enolase; INRG—International Neuroblastoma Risk Group; VLR—very low-risk; LR—low-risk; IR—intermediate-risk; HR—high-risk.

Metastases of bone marrow and bones were found only in IR and HR-NB patients. 41% (n = 7) of IR patients and 62% (n = 39) of HR patients had metastases in the bone marrow. 35% (n = 6) of IR patients and 71% (n = 45) of HR patients were diagnosed with bone metastases. In addition, the proportions of patients with bone marrow and bone metastases correlated strongly with risk classification (*P < .05, chi-square test). Patients with distant lymph node metastases were observed in 6% (n = 2) of IR patients, 47% (n = 8) of IR patients, and 44% (n = 28) of HR patients. There were no significant differences in the proportion of NB patients with lymph node metastases between risk categories. Amplification of the MYCN gene was accounted for 29% (n = 18) of HR patients. Patients’ neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels were also evaluated. Both NSE and LDH were significantly greater in patients with higher risk classifications (***P < .001, Kruskal–Wallis test).

Treatment outcomes of patients with NB

The median patient follow-up duration was 1009 ± 579 days (range 160–3342 days) for all patients. Patients with NB were treated in accordance with above-described risk classifications, and the details and treatment outcomes are summarized in Table 2. VLR and the majority of the LR-NB patients only had surgical excision of their primary tumors. One LR patient that was diagnosed with ultrasound-guided percutaneous biopsy underwent observation alone and had regular follow-ups at the outpatient clinics. The majority of patients with IR- (88%) and HR-NB (84%) underwent systemic chemotherapy prior to surgical resection of the primary and/or metastatic tumors. The remaining patients (12% of IR and 17% of HR) underwent chemotherapy alone. Radiotherapy was administered to 21% of all patients, including 6% of IR patients and 35% of HR patients. Four patients (3%) were treated with MIBG. Six patients (5%) were treated with anti-GD-2 immunotherapy and four patients (3%) were treated with CART cell therapy. After induction chemotherapy, ASCT was administered to a total of 24 HR patients (38%). Ten patients (16%) received a single ASCT, whereas fourteen patients (22%) received tandem ASCTs.

Table 2.

Treatment and Outcomes of Patients With Neuroblastoma by Risk Stratification.

	Number of Patients	VLR	LR	IR	HR
Total patients	117	5 (4%)	32 (27%)	17 (15%)	63 (54%)
Treatment period
2013–2018	31 (26%)	0	9 (28%)	5 (29%)	17 (27%)
2019–2020	86 (74%)	5 (100%)	23 (72%)	12 (71%)	46 (73%)
Treatment
Observation only	2 (2%)	0	1 (4%)	0	0
Surgery only	35 (30%)	4 (80%)	27 (84%)	0	0
Chemotherapy only	9 (7%)	1 (20%)	2 (6%)	2 (12%)	11 (17%)
Surgery + chemotherapy	71 (60%)	0	2 (6%)	15 (88%)	53 (84%)
Radiotherapy	25 (21%)	0	0	1 (6%)	22 (35%)
MIBG	4 (3%)	0	0	0	4 (6%)
CART	4 (3%)	0	0	0	4 (6%)
Anti-GD-2 antibody	6 (5%)	0	0	0	6 (9%)
Autologous stem cell transplantation	24 (21%)	0	0	0	24 (38%)
Single transplant	10 (9%)	0	0	0	10 (16%)
Tandem transplant	14 (12%)	0	0	0	14 (22%)
Treatment response		5	32	17	63
CR*	58 (50%)	2 (40%)	27 (84%)	9 (53%)	20 (32%)
VGPR	7 (6%)	0	0	1 (6%)	6 (10%)
PR	24 (20%)	3 (60%)	4 (13%)	1 (6%)	16 (25%)
SD	1 (1%)	0	0	1 (6%)	0
PD	6 (5%)	0	0	0	6 (10%)
Relapsed	20 (17%)	0	1 (3%)	5 (29%)	14 (22%)
Unknown	1 (1%)	0	0	0	1 (1%)
Death*	13 (11%)	0	1 (3%)	1 (6%)	11 (17%)
Follow-up (days)	1009 ± 579	659 ± 68	999 ± 555	1011 ± 540	1024 ± 630

*P < .05.

CART cell therapy—chimeric antigen receptor T cell therapy; CR—complete response; MIBG—metaiodoenzylguanidine; PD—progression of disease; PR—partial response; VGPR—very good partial response; VLR—very low-risk; LR—low-risk; IR—intermediate-risk; HR—high-risk.

The treatment response was evaluated at the last follow-up visit. Patients with a higher risk classification had a lower probability of achieving a complete response (CR) or very good partial response (VGPR) (***P < .001, chi-square test) and a greater risk of the relapse of disease (*P = .020, chi-square test). There were no significant differences between the risk categories in the proportion of patients with partial response (PR) or disease progression (PD). During the course of follow-up, 13 patients (11%) died among which 11 of them were HR patients.

Survival

The 5-year projected EFS and OS rates for all patients were 67.29% ± 5.69% and 77.90% ± 6.78%, respectively (Kaplan–Meier estimator). Patients with a higher risk classification had significantly lower EFS (VLR/LR 97.22% ± 2.74% vs IR 67.38% ± 12.20% vs HR 51.83% ± 8.43%; ***P = .001, log-rank test) and OS rates (VLR/LR: 97.06% ± 2.90% vs IR: 94.12 ± 5.71% vs HR: 64.38% ± 11.01%; *P = .010, log-rank test) (Figure 1). Using the INRG staging system, patient survival rates were also calculated (Figure 2). The 5-year EFS was significantly lower for stage M patients (L1 vs L2 vs M: 100% vs 71.14% ± 12.10% vs 53.17% ± 26.85%; *P = .022, log-rank test). The OS rates of patients with stages L1, L2, and M disease did not differ significantly (L1 vs L2 vs M: 100% vs 68.73% ± 20.29% vs 71.64% ± 9.13%). Only two stage MS patients were included in this study, and at the last follow-up visit, neither patient reported any adverse effects. Patients with MYCN gene amplification had a significantly lower 5-year EFS (38.89% vs 77.95%; *P = .04, log-ranked test) and OS (51.85% vs 83.76%; **P = .001, log-ranked test) (Figure 3). In addition, Cox regression analysis of the variables revealed no significant correlation between unfavorable prognostic factors such as age, gender, primary tumor site, and disease metastasis with EFS or OS (Supplementary 2).

Figure 1.

Kaplan–Meier survival analysis of patients with very low-risk (VLR)/low-risk (LR), intermediate-risk (IR), and high-risk (HR) neuroblastoma (NB). (A) Significant differences were seen in event-free survival (EFS) among patients with LR-, IR-, and HR-NB (VLR/LR 97.22% ± 2.74% vs IR 67.38% ± 12.20% vs HR 51.83% ± 8.43%; ***P = .001, log-rank test). (B) There were significant differences in overall survival (OS) between HR and LR and IR patients (VLR/LR: 97.06% ± 2.90% vs IR: 94.12 ± 5.71% vs HR: 64.38% ± 11.01%; *P = .010, log-rank test).

Figure 2.

Kaplan–Meier survival analysis of patients with neuroblastoma (NB) classified by the INRG staging system. Patients were staged into stages L1, L2, M, and MS according to the INRG staging system. (A) Patients with stage M NB had a significant lower 5-year EFS (L1 vs L2 vs M: 100% vs 71.14% ± 12.10% vs 53.17% ± 26.85%; *P = .022, log-rank test) than patients with stage L1 and L2 diseases. (B) The 5-year OS did not significantly differ between patients with stage L1, L2, and M diseases (L1 vs L2 vs M: 100% vs 68.73% ± 20.29% vs 71.64% ± 9.13%). The 5-year EFS and OS of patients with stage MS disease were not calculated since this study only included two patients with stage MS disease.

Figure 3.

Kaplan–Meier survival analysis of patients with and without MYCN gene amplification. Patients with MYCN gene amplification had a significantly lower 5-year EFS (38.89% vs 77.95%; *P = .04, log-ranked test) and OS (51.85% vs 83.76%; **P = .001, log-ranked test) than those without MYCN gene amplification.

HR-NB patients diagnosed after 2019 were treated according to the COG ANBL0532 protocol with or without ASCT, and their survival rates were calculated. The OS of patients who received ASCT was significantly greater than that of patients who did not undergo ASCT (93.33% ± 6.44% vs 47.41% ± 22.76%; *P = .046; log-rank test) (Figure 4). However, the EFS at 3 years did not change significantly between patients who received ASCT and those who did not (72.16% ± 10.78% vs 60.32% ± 13.03%). The results of single and tandem ASCT recipients were investigated. Patients who undergone tandem ASCT had a higher OS; however, the difference was not statistically significant (100% vs 88.89% ± 10.48%). There were no statistically significant changes between patients who received a single or tandem ASCT. In addition, Cox regression analysis did not reveal any predictive risk variables in patients with or without ASCT.

Figure 4.

Kaplan–Meier survival analysis of high-risk neuroblastoma (HR-NB) patients with and without autologous stem cell transplantation (ASCT). The event-free survival (EFS, A) and overall survival (OS, B) of HR-NB patients with and without ASCT did not differ significantly. (A) The 3-year OS of patients who received ASCT was significantly greater than that of patients who did not undergo ASCT (93.33% ± 6.44% vs 47.41% ± 22.76%; *P = .046; log-rank test. The 3-year EFS was not significantly different between patients with and without ASCT (72.16% ± 10.78% vs 60.32% ± 13.03%). (B) Patients who got tandem ASCT had a higher but not significantly better 3-year OS than those who had single ASCT (100% vs 88.89% ± 10.48%). Both single and tandem ASCT recipients exhibited similar 3-year EFS (88.89% ± 10.48% vs 85.71% ± 13.23%).

Discussion

In this research, we describe the clinical outcomes of pediatric patients with NB who were assessed at a large tertiary pediatric oncology hospital in China between 2013 and 2022. Patients with NB exhibited heterogeneous manifestations, and their outcomes were very variable according to risk classification and therapy. In the present investigation, children with VLR- and LR-NB had favorable outcomes, consistent with the recent published data from the COG and the International Society of Pediatric Oncology (SIOP).^13,21 Surgical excision of primary tumors continues to be the therapy of choice for the majority of patients with VLR/LR-NB. However, similar with observations in previously published research, one patient younger than one year old had resolution of tumor spontaneously without particular anti-tumor treatment in the current study. Moreover, in LR patients with partially inoperable primary tumors, it might be difficult to decide whether to provide chemotherapy after surgery.²² IR-NB patients also achieve satisfactory OS rates in this study. However, we observed a much lower EFS rate in IR-NB patients. This was probably due to a small number of patients in this classification group. Thus, further observation with more patients and longer follow-up time is required to reveal the definite outcomes of these patients.

The treatment of individuals with HR-NB remains difficult despite maximum comprehensive approaches. The COG recently reported that the 5-year EFS and OS of patients with HR-NB using an earlier version of the protocol were 50.8% ± 1.4% and 61.9% ± 1.3%, respectively. Using a later version of the protocol, these values, respectively, increased to 51.2% ± 1.4% and 62.5% ± 1.3%.²¹ In countries with limited resources, the prognosis for patients with HR-NB is less acknowledged. In a research on the treatment outcomes of patients with NB conducted by Beijing Children’s Hospital in China, the 5-year EFS and OS of patients with HR-NB were 37.7% and 48.9%, respectively. In a research conducted by the Sun Yat-Sen University Cancer Center, 117 patients with HR-NB who did not undergo ASCT or immunotherapy had an overall EFS of 42.7% ± 4.8%.¹⁸ Our survival rates were somewhat higher than these studies conducted in China, and our results were comparable to those of COG studies, where the EFS and OS were 51.83% ± 8.43% and 64.38% ± 11.01%, respectively.

According to more recent studies, the use of high-dose chemotherapy followed by ASCT, which can later be enhanced with GD-2 immunotherapy, has been an advancement in prolonging the life of patients with HR-NB.^23-25 Nevertheless, the choice between a single or tandem ASCT remains debatable in light of the toxicity of chemotherapy drugs and the increased risk of second malignancies following many cycles of intensive chemotherapy. The 3-year EFS increased considerably from 48.4% to 61.6% in a randomized COG analysis of patients younger than 30 y with HR-NB who got tandem ASCT without fatal effects.¹² In addition, combinations of high-dose drugs influence patient outcomes across trials. In the present investigation, only 24 patients received ASCT. In tandem ASCT, the high-dose chemotherapy comprised cyclophosphamide and busulfan, followed by a reduced dose of carboplatin–etoposide–melphalan-based regimen. Carboplatin, etoposide, and melphalan were administered to patients who underwent single ASCT. Although ASCT significantly enhanced OS of patients in the present study, ASCT did not appear to enhance EFS. The International Society of Pediatric Oncology European Neuroblastoma Group (SIOPEN) compared the clinical outcomes of patients who underwent a single ASCT with a busulfan–melphalan-based regimen to those who received a carboplatin–etoposide–melphalan-based regimen, followed by radiotherapy and maintenance therapy with or without immunotherapy.²⁶ In this randomized study, individuals receiving the busulfan–melphalan-based regimen had considerably greater 3-year EFS (50% vs 38%) and less life-threatening toxicities than those that received the carboplatin–etoposide–melphalan-based regimen. Moreover, a recent COG ANBL12P1 trial demonstrated a mean 3-year EFS of 55.6% ± 4.2% with well-tolerated toxicities when adopting a busulfan–melphalan-based consolidation regimen. Therefore, switching to chemotherapy based on high-dose busulfan and melphalan may increase EFS and reduce toxicities for future patients.

In recent years, the introduction of anti-GD2 antibodies, which considerably raised EFS by around 10%, was a notable advancement in increasing the survival of patients with HR-NB.²⁷ The use of immunotherapy using anti-GD2 antibodies as maintenance treatment after chemotherapy and ASCT has been recommended by recent studies. Although ASCT considerably increases OS, a Spanish study found that patients who had ASCT in combination with anti-GD2 antibody did not have a longer EFS than those who received anti-GD-2 antibody alone.²⁵ Nonetheless, anti-GD-2 drugs were unavailable in China during most of the research period. In the present study, only six patients received GD-2 immunotherapy, and it remains to be determined what their results will be. Four patients were enrolled in a phase I/II clinical trial and received CART cell treatment after ASCT. Despite the fact that CART cell treatment has demonstrated antitumor effects in studies involving a small number of patients, the long-term safety and effectiveness of CART cell therapy in NB need more exploration.^28-30 The availability of dinutuximab and naxitamab anti-GD-2 antibodies in China will hopefully increase patient survival in the future.

The prognosis of patients with HR-NB is primarily determined by a number of variables. In this study, NSE and LDH levels upon diagnosis were found to be linked with the risk categorization of NB patients. In addition, this indicates that the NSE and LDH levels are important in the early evaluation of patients with NB. MYCN amplification has been correlated negatively with the prognosis of NB patients and has been connected with very poor outcomes. An earlier COG study revealed that high-dose chemotherapy followed by ASCT might enhance the prognosis for HR-NB patients with MYCN amplification.³¹ However, there is presently no specialized or targeted treatment with promising results for HR-NB patients with MYCN amplification.

This study has several limitations. First, it was a retrospective study in which the majority of patients had HR-NB. Second, only patients diagnosed and treated at our facility were included in this study; those treated elsewhere or discharged without treatment were excluded. Therefore, when combined with the remaining patients, the survival analysis might be biased. Thirdly, the patient population included in this study was relatively small, particularly the ASCT cohort. Therefore, further research is required to discover if these patients may benefit from ASCT. Lastly, the duration of follow-up for patients diagnosed after 2019 is relatively short, and their long-term patient outcomes have not yet been extensively examined.

Conclusion

In conclusion, we observed comparable outcomes in all risk groups of NB patients with limited access to more advanced treatment options, such as immunotherapy and MIBG therapy, compared to the COG studies. The combination of high-dose chemotherapy and ASCT may extend the lives of HR-NB patients. To increase EFS, however, it may be necessary to modify the current chemotherapeutic treatment to reduce drug-related toxicities. In the future, we hope that the incorporation of immunotherapy into treatment protocols will enhance the survival rate of HR-NB patients.

Supplemental Material

Supplemental Material - A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China

Supplemental Material for A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China by Uet Yu, Huanli Xu, Senmin Chen, Meng Yi, Chao Liu, Xiaoling Zhang, Chunjing Wang, Jianming Song, Yungen Gan, Jianyao Wang, Yuanxiang Wang, Qing Zhang, Junjie Sun, Bei Xia, Gongwei Zhang, Changgang Li, Feiqiu Wen, Sixi Liu, and Xiuli Yuan in Cancer Control.

Footnotes

Acknowledgments

We would like to thank the patients and families who participated in this study and recognize A/Prof. Ronald Grant from the Hospital for Sick Children in Toronto, Canada, for his help with patient care through the Sanming Project.

Author Contribution

UY and HX drafted and revised this manuscript. SC, MY, and CL contributed to the data collection and analysis of this manuscript. XZ and CW participated in data collection and statistical analysis of ASCT patients. JS, YG, JW, YW, QZ, JS, BX, and GZ helped with patient recruitment, revised, and gave critical review to this manuscript. CL and FW helped to revise the original draft. SL contributed to the design of this study. XY provided conception and supervised the conduction of this study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This study was supported by Sanming Project of Medicine in Shenzhen (SZSM 201512033), Shenzhen Fund for Guangdong Provincial High-level Clinical Key Specialties (SZGSP012), Shenzhen Key Medical Discipline Construction Fund (SZXK034), Shenzhen Science and Technology Innovation Commission (RCBS20200714114858018), Shenzhen High-level Hospital Construction Fund, and Shenzhen Children’s Hospital Research Grant (ynkt2020-zz01 and ynkt2021-zz26).

Ethical approval and consent to participate

This study was approved by the Shenzhen Children’s Hospital Ethics Committee (7019 Yitian Road, Futian, Shenzhen, China 518038, approval number SEY-XJS-522). Informed written consent to participate in this study was obtained from the patient’s parents or legal guardians.

ORCID iD

Uet Yu

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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