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Salvage chemotherapy regimens with arsenic trioxide for relapsed or refractory neuroblastoma: a promising approach

BMC Cancer volume 24, Article number: 1140 (2024) Cite this article

Abstract

In patients with relapsed or refractory neuroblastoma (NB), the limited efficacy of conventional chemotherapies necessitates the exploration of new treatment options. Previous studies have highlighted the anti-tumor properties of arsenic trioxide (ATO) in high-risk NB (HR-NB). This study aims to assess the effectiveness and safety of ATO combined with salvage chemotherapy regimens, featuring cyclophosphamide and topotecan, as a foundational treatment for children with relapsed or refractory NB. Eleven patients (four relapsed, seven refractory NB) were retrospectively analyzed for efficacy and treatment relevance. Salvage treatments, incorporating ATO (0.18 mg/kg daily for 8 h intravenously on days 1 to 10), were administered upon disease progression or relapse, with assessments conducted every two cycles. Treatments had 63.6% efficacy, with six cases of partial response, one case of stable disease, and four cases of disease progression. The overall response rate was 54.5%, and the disease control rate was 63.6%. Importantly, the systemic toxicity experienced by patients following salvage chemotherapy with ATO was mild. Salvage chemotherapy regimens featuring ATO demonstrated potential for prolonging disease stabilization for relapsed or refractory HR-NB patients, exhibiting both favorable efficacy and safety profiles. This suggests further clinical exploration and promotion of this therapeutic approach in the treatment of NB.

Clinical perspectives summary

Point 1. The inadequate effectiveness of traditional chemotherapy in individuals with recurrent or resistant neuroblastoma (NB) necessitates the investigation of novel therapeutic approaches.

Point 2. Arsenic trioxide (ATO)-based salvage treatments are both effective and less toxic in relapsed or refractory NB.

Point 3. Salvage chemotherapy regimens incorporating ATO have shown promise in extending disease stabilization in relapsed or refractory high-risk NB patients, with favorable efficacy and safety profiles, which suggests further clinical exploration and promotion of this therapeutic approach in the treatment of NB.

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Introduction

Neuroblastoma (NB) is the prevailing extracranial solid tumor observed in pediatric patients, arising from primitive neuroblasts and manifesting at various locations within the sympathetic nervous system [1]. It constitutes approximately 7–8% of the prevalence of childhood malignancies and contributes to 15% of cancer-related mortality in the pediatric population [2]. NB demonstrates significant biological and clinical heterogeneity, as children classified as low-risk exhibit a favorable prognosis, and in certain instances, tumors may exhibit spontaneous regression [3]. However, nearly half of patients are diagnosed with high-risk NB (HR-NB), a condition characterized by the prevalence of bone or bone marrow metastasis in individuals older than 18 months or MYCN amplification regardless of age [4]. Despite the implementation of a multidisciplinary sequential comprehensive treatment regimen encompassing chemotherapy, radiotherapy, surgery, immunotherapy, and hematopoietic stem cell transplantation (HSCT), the five-year survival rate for patients with HR-NB continues to be below 50% [5]. Treatment failure is predominantly attributed to the presence of multiple drug resistance (MDR), which poses a significant obstacle in achieving successful curative chemotherapy [6]. The mechanisms underlying resistance to NB cells are intricate and diverse, encompassing factors such as tumor burden and growth kinetics, tumor heterogeneity, untargetable cancer drivers, the immune system and the microenvironment, and physical barriers, among others [7]. The occurrence and development of NB have been shown to be influenced by aberrant mutations in genes such as MYCN, as well as dysregulation of signaling pathways including PI3K/AKT/mTOR, WNT/β-catenin, P53-MDM2, and RAS-MAPK [8]. These genetic and signaling abnormalities have also been identified as mechanisms contributing to chemoresistance in NB. The prognosis for patients diagnosed with relapsed or refractory NB is unfavorable, owing to the restricted availability of efficacious conventional chemotherapeutic treatments. Consequently, it is crucial to formulate novel therapeutic regimens for these patients with the aim of enhancing response rates.

Arsenic trioxide (ATO), a traditional Chinese medicine with a long-standing history of over 2,400 years, has been utilized for the treatment of acute promyelocytic leukemia and has also been investigated for its potential efficacy against various solid tumors, such as NB [9]. The anti-tumor mechanisms of ATO encompass a range of actions, including the inhibition of cell proliferation, induction of cellular differentiation, down-regulation of B-cell lymphoma 2 protein expression, suppression of tumor angiogenesis, and inhibition of telomerase activity. In a similar vein, our research team has been diligently investigating the potential therapeutic efficacy of ATO against NB. Our previous research has demonstrated that ATO functions as a chemotherapeutic potentiator, effectively enhancing its cytotoxic effects when combined with mitotic-specific antitumor agents (vincristine or docetaxel) or non-mitotic-specific antitumor agents (etoposide or cisplatin) [10]. This potentiation is achieved by inducing cell cycle arrest in NB cells in the G2/M phase. ATO has the potential to impede the expression of drug-resistant proteins, such as p-gp proteins, thereby counteracting chemoresistance [11]. Furthermore, Chen S et al. [12] have reported promising findings indicating that ATO can restore the functionality of structurally mutated p53 through cryptic ectopic sites. Our previous clinical studies have also revealed that the combination of ATO and chemotherapy yields a substantial enhancement in the terminal induction response among patients diagnosed with high-risk NB, which can be considered a viable alternative treatment for HR-NB, presenting novel prospects for patients to extend their survival [13, 14]. As previously stated, the utilization of ATO either independently or in conjunction with chemotherapeutic agents presents a potentially encouraging therapeutic approach for addressing relapsed or refractory NB. The present study aims to assess the effectiveness and safety of ATO combined with a salvage chemotherapy regimen based on cyclophosphamide and topotecan for the treatment of relapsed and refractory NB in children.

Patients and methods

Eligibility

Patients under 18 years of age diagnosed with HR-NB, as confirmed by the revised neuroblastoma classification established by the Children’s Oncology Group (COG) in 2021 [15], were deemed eligible for inclusion if they exhibited one of the following responses to prior chemotherapy: either relapsed disease or refractory disease, defined as progressive disease (PD) or stable disease (SD) following a minimum of four induction courses.

Patients with previous total body irradiation, allogenic transplant, pregnancy, breastfeeding, active or uncontrolled infection, previous noncatheter-associated deep venous thrombosis, or active diarrhea were excluded.

Study design and treatment

This retrospective, single-center case series was conducted between January 2021 and July 2022, involving 11 pediatric patients with relapsed or refractory HR-NB. No randomization was planned for this study. The study received approval from both the protocol review committee and the institutional review board of Sun Yat-sen Memorial Hospital. Each patient obtained written consent approved by the Ethics Committee of Sun Yat-sen Memorial Hospital from their legal guardian. No blinding was applied.

In this study, patients enrolled underwent the compulsory baseline examination, including a complete physical examination, serum neuron-specific enolase (NSE), urinary vanillylmandelic acid/creatinine (VMA/Cr) ratio, serum lactate dehydrogenase (LDH), computed tomography (CT), and magnetic resonance imaging (MRI) or positron emission tomography (PET) CT, at the time of initial admission. Patients underwent gene sequencing if necessary.

All eligible patients received salvage therapy containing ATO (regimen A or regimen B) for a total of six courses, with arm 1 and arm 2 alternating sequentially in each. Regimen A was the first option to be considered. Patients who failed to achieve complete response (CR) or partial response (PR) after four cycles of regimen A chemotherapy would receive regimen B. Notably, standard hematologic criteria for initiating chemotherapy were met when the patients’ neutrophil count exceeded 1.0 × 109/L and platelet count exceeded 1.0 × 1011/L. Courses of chemotherapy were spaced 28 days apart (counting from day 1 of chemotherapy).

In regimen A (Table 1) and regimen B (Table 2), ATO was administrated at a dose of 0.18 mg/kg per day for 10 days. The ATO injection was administrated at a constant rate over 8 h in 250–500 ml of normal saline or a 5% glucose solution through a central vein. Regimen A further included topotecan (Topo), vincristine (VCR), and cyclophosphamide (CTX) in arm 1, and Topo, CTX, and etoposide (VP-16) in arm 2. Regimen B included Topo, CTX, and vinorelbine (VNL) in arm 1, and Topo, doxorubicin liposomes, and VNL in arm 2. The specific medication regimens are detailed in Tables 1 and 2. Patients also received 0.5–1.0 g ascorbic acid along with 5% 100- to 250- ml glucose injection in another vein channel.

Table 1 Dose and usage of chemotherapeutics of regimen A
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Table 2 Dose and usage of chemotherapeutics of regimen B
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Definition of outcomes

The response were assessed after two, four, and six courses. This study assessed response using RECIST 1.1 criteria [16]. Efficacy of target lesions was defined as: (1) CR: all target lesions disappeared, and pathological lymph nodes reduced to < 10 mm. (2) PR: target lesion diameters reduced by at least 30% from baseline. (3) SD: target lesions did not decrease enough for PR or increase enough for PD, falling between PR and PD. (4) PD: an increase of at least 5 mm and 20% in the total diameter of target lesions compared to the smallest recorded value (or baseline if it’s the smallest), or the emergence of new lesions.

The endpoints were objective response rate (ORR) and disease control rate (DCR) based on bone/bone marrow examination and general imaging examinations such as CT, MRI, or PET. ORR was defined as CR and PR, while DCR was defined as CR, PR, and SD.

Meanwhile, we monitored tumor markers, including serum NSE, VMA/Cr ratio, and LDH, every two chemotherapy courses. In addition, we monitored common adverse events (AEs) after ATO administration, such as myelosuppression, cardiotoxicity, and allergic reactions. According to the criteria of CTCAE 4.03 [17], the adverse effect severity was classified as grades 0, I, II, III, IV, and V, showing a positive correlation between toxicity and grading.

Statistical analysis

Statistical analysis and mapping were performed using GraphPad Prism 9.5 in this study. Testing for normality was performed by Shapiro-Wilk. Then, paired t tests or paired Wilcoxon rank sum tests were used to test significance. A P-value of less than 0.05 is considered significant.

Results

Patients

Between January 2021 and July 2022, 11 eligible patients were enrolled. All patients were classified as high risk on the basis of the the revised neuroblastoma classification by COG in 2021 [15]. Four patients (36.4%) had relapsed HR-NB, and the remainder had refractory disease (n = 7, 63.6%; Table 3). In patients, the primary NB sites were the retroperitoneal space (n = 8, 72.7%) and the mediastinum (n = 3, 27.3%). Of 11 patients < 18 years of age, 5 (45.4%) had MYCN-amplified tumors, 4 (36.4%) had concomitant bone marrow metastases, and all of them had bone metastases (n = 11, 100.0%). Before receiving salvage chemotherapy regimens containing ATO, patients were heavily pre-treated with different regimens, including COG chemotherapy regimen in four (36.4%), ATO combined with conventional chemotherapy regimen in six (54.5%), and CCCG-NB regimen (modified N7 regimen) in three (27.3%).

The disease type, previous chemotherapy strategy, MYCN amplifications, chromosome deletions, and gene sequencing results for all 11 patients are shown in Table 4. Genes commonly associated with poor prognoses in NB, such as MYCN, ALK, RB1, and PIK3CA, were included. In terms of gene type, patients responding to salvage chemotherapy as PD carried genes associated with poor NB prognosis in 75% (3/4) compared with non-PD patients (28.6%, 2/7). Likewise, 50% (2/4) of PD patients had chromosomal deletions compared with 14.3% (1/7) of non-PD patients.

Table 3 Baseline patient characteristics
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Table 4 Disease type, previous chemotherapy strategy, genotypes, and responses of 11 relapsed/refractory patients
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Response

All patients were evaluated for treatment response. A total of 11 patients underwent salvage chemotherapy regimens containing ATO for two to five courses. The ORR of CR and PR using INSS criteria for all eligible patients was 54.5% (6/11), including no CR and six PR (Table 5; Fig. 1). The DCR of CR, PR and SD was 63.6% (7/11), including no CR, six PR, and one SD (Table 5; Fig. 1).

Table 5 Overall response to salvage chemotherapy regimens in patients with relapsed/ refractory NB
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Fig. 1
figure 1

Overall response to salvage chemotherapy regimens in patients with relapsed (n = 4) or refractory (n = 7) NB

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Toxicity

Full-course AEs are shown in Table 6. In total, 11 patients in the safety analysis set reported 56 AEs. There were no treatment-related deaths reported. The most common AEs of the salvage chemotherapy regimens used in this study were grade IV myelosuppression (n = 11) and grade II gastro-intestinal symptoms (n = 11), according to to the criteria of CTCAE 4.03. Remarkably, the next most common AEs were infection and hepatotoxicity (Table 6). Eight (72.7%) patients had secondary infections due to bone myelosuppression and gastrointestinal symptoms, six (54.5%) of which were grade I and two (18.2%) grade II. Nine (81.8%) patients reported grade II hepatotoxicity. Five (45.5%) patients developed grade II diarrhea and grade II cardiac adverse reactions. In addition, three (27.3%) patients reported abdominal pain, including two grade I (18.2%) and one (9.1%) grade II case. Oral mucositis of grade II was observed in three (27.3%) patients. Allergic reactions (grade II) were the least frequent, occurring in only one (9.1%) patient. The AEs above were relieved after symptomatic treatment or gradually disappeared after drug withdrawal.

Table 6 Times of adverse events in full-length salvage chemotherapy containing ATO
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Tumor markers

The serum NSE, 24-h urinary VMA/Cr, and serum LDH levels were evaluated at the initial admission and every disease assessment, as shown in Table 7; Fig. 2. The purpose was to investigate the relationship between NSE, VMA/Cr, and LDH levels in patients with relapsed or refractory HR-NB and the changes before and after the adoption of the salvage chemotherapy regimens containing ATO. The levels of NSE, VMA/Cr, and LDH in patients before and after treatment with this regimen did not exhibit statistically significant changes, with P-values of 0.58, 0.46, and 0.10, respectively.

Table 7 Comparison of serum NSE, 24-h urinary VMA/Cr, and serum LDH levels in children with NB before and after treatment
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Fig. 2
figure 2

Variation between serum NSE (A), 24-h urinary VMA/Cr (B) and serum LDH (C) before and after salvage chemotherapy regimens containing ATO in patients with relapsed or refractory HR-NB. ns, P > 0.05

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Discussion

Significant advances have been achieved in clinical treatment strategies as a result of comprehensive investigations into the biological characteristics and pathogenesis of NB. However, despite the implementation of multiple treatments within a multidisciplinary combined diagnostic model, HR-NB remains susceptible to recurrence or progression among patients. This phenomenon significantly impacts the prognosis of affected children, leading to suboptimal long-term survival outcomes. The emergence of MDR and minimal residual disease (MRD) during the advanced stages of chemotherapy diminishes the effectiveness of hematopoietic stem cell transplantation (HSCT) and immunotherapy, resulting in a relapse rate of up to 80% within a span of two years [18]. Despite the numerous advances in the treatment of NB, the persistence of relapsed or refractory disease continues to pose a significant barrier to achieving a cure. The chemotherapy combinations administered to patients with relapsed or refractory NB are typically different from those initially employed. Fiona Herd et al. [19] provided a comprehensive summary of different salvage regimens and their respective ORR, which included CT with a response rate of 63%, CTE with a response rate of 61%, and CTV with a response rate of 52%. Recent research also indicate that patients diagnosed with relapsed or refractory NB may derive advantages from intensified therapeutic interventions aimed at attaining a comprehensive remission, subsequently followed by consolidation therapy, such as HSCT, which leads to a sustained remission or complete eradication of the ailment [20]. Thus, we attempted to combine ATO with a more efficacious salvage chemotherapy regimen, with the aim of enhancing the overall outcome and prognosis for patients afflicted with relapsed or refractory NB. Here we present the anti-tumor and safety activity of the ATO combined salvage chemotherapy regimens in children with relapsed or refractory NB. In this study, the primary aims were to evaluate the anti-tumor activity of these modified salvage chemotherapy regimens by determining the ORR and DCR. Secondary aims were to determined the safety and toxicity of salvage chemotherapy regimens containing ATO by the incidence of AEs.

Our results indicate that salvage chemotherapy regimens containing ATO are both efficacious and well tolerated in patients with relapsed or refractory HR-NB. From an efficacy standpoint, out of the 11 patients included in our study who had relapsed or refractory conditions, 7 experienced PR or maintained SD, while the remaining 4 unfortunately experienced PD. The ORR among patients who underwent relapsed or refractory chemotherapy was slightly lower (54.5% vs. 52.0-63.0%) than reported in existing research [21,22,23,24]. Theoretically, salvage chemotherapy regimens containing ATO would be a promising treatment option for patients with relapsed or refractory NB. On one hand, we speculated that all 11 patients recruited in this study were treated with multiple second-line chemotherapy regimens and may have developed MDR to salvage chemotherapy regimens. The mechanisms underlying resistance in NB cells are intricate and diverse, encompassing factors such as tumor load and growth kinetics, tumor heterogeneity, incurable cancer drivers, the immune system, and physical barriers [7]. The up-regulation of ATP-binding cassette transporters, namely P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance protein 1 (MRP1), has been demonstrated to enhance drug efflux, which serves as a significant resistance mechanism in HR-NB [25, 26]. On the other hand, previous research on relapsed or refractory NB has incorporated notably smaller proportions of patients with MYCN amplification, specifically 27.3% [23], 20.0% [22], and 33% [24]. In contrast, the patients included in this study exhibited a higher rate of bone metastasis (100%) and MYCN amplification (45.4%), which are significantly higher than the population characteristics of similar studies. Bone is the most common site of NB metastasis and recurrence, and studies have shown that NB patients with bone metastases respond poorly to chemotherapy and have a poorer prognosis [27, 28]. MYCN amplification is widely recognized as the predominant genetic modification in HR-NB, and its etiology involves the abnormal activation of the PI3K/AKT/mTOR pathway, resulting in the excessive expression of the MYCN protein, indicating an unfavorable prognosis [29]. Furthermore, this study revealed that genes linked to unfavorable prognosis, such as ALK, MYCN, EGFR, and CHD6, were detected in 55.6% (n = 5) of the nine patients who underwent gene sequencing, surpassing the prevalence reported in the Ashraf study (26%) [23]. This study reveals that patients who received ATO in combination with salvage chemotherapy exhibited notable rates of ORR (54.5%) and DCR (63.6%), thereby reinforcing the significance of ATO in the treatment of HR-NB patients. However, it was observed that there was no significant decrease in the relevant tumor markers of the patients following treatment. This observation indicates that children with relapsed or refractory NB encounter significant challenges in attaining CR. This difficulty may be attributable to the persistence of central lesions in some patients, which impede the efficacy of pharmacological treatments by obstructing drug passage through the blood-brain barrier [30]. Additionally, it is important to note that the sample size of this cohort was insufficient, leading to considerable variability and fluctuations in the overall data. Simultaneously, it is encouraging to note that the systemic toxicity of chemotherapy observed in all participants of our study exhibited a resemblance to previous research, primarily characterized by prevalent myelosuppression and gastrointestinal symptoms, while the remaining AEs were predominantly mild. This finding demonstrates a notable similarity to the toxicities commonly associated with traditional chemotherapy treatment protocols.

In general, the utilization of the ATO-based chemotherapy salvage regimen exhibits the potential to extend the duration of disease stabilization in patients diagnosed with relapsed or refractory HR-NB, demonstrating favorable effectiveness and safety. Consequently, this treatment approach warrants further consideration for widespread implementation in clinical practice. Nevertheless, it is important to acknowledge certain limitations within our study, notably the inclusion of a relatively small cohort of relapsed refractory NB patients. Overall, the ATO-based chemotherapy salvage regimen can prolong the time of disease stabilization in patients with relapsed-refractory HR-NB with good efficacy and safety, which is worthy of further promotion in clinical treatment. However, there are some limitations in our study, such as the number of relapsed refractory NB patients included in this study being too small. In the next step, we will try to expand the study time frame to recruit as many eligible patients as possible, and we will also encourage other centers to join us. We look forward to more teams joining our ATO clinical study in the future and contributing to the cure of more patients with relapsed or refractory NB.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AEs:

Adverse events

ATO:

Arsenic trioxide

CAV:

Cyclophosphamide, doxorubicin and vincristine

CCCG:

Chinese Children’s Cancer Group

COG:

The Children’s Oncology Group

CR:

Complete response

CT:

Computed tomography

CTE:

Cyclophosphamide, topotecan, and etoposide

CTX:

Cyclophosphamide

DCR:

Disease control rate

HR-NB:

High-risk neuroblastoma

HSCT:

Hematopoietic stem cell transplantation

ICE:

Ifosfamide, carboplatin, and etoposide

INSS:

International Neuroblastoma Staging System

LDH:

Lactate dehydrogenase

MDR:

Multidrug resistance

MRD:

Minimal residual disease

MRI:

Magnetic resonance imaging

NB:

Neuroblastoma

NSE:

Neuron-specific enolase

ORR:

Objective response rate

PD:

Progressive disease

PET:

Positron emission tomography

PR:

Partial response

PVP:

Cisplatin and etoposide

SD:

Stable disease

TC:

Topotecan and cyclophosphamide

Topo:

Topotecan

TOTEM:

Temozolomide and topotecan

TVC:

Topotecan, vincristine and cyclophosphamide

TVD:

Topotecan, vincristine and doxorubicin

VCR:

Vincristine

VMA/Cr:

Vanillylmandelic acid/creatinine

VNL:

Vinorelbine

VP-16:

Etoposide

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Acknowledgements

Not applicable.

Funding

This work was supported by the Guangzhou Area Clinical Specialty Technology Program (Grant 2023P-TS39), the Sun Yat-Sen Medical–Industrial Integration Cultivating Program (Grant YXYGRH202203), and Heilongjiang Harbin Yida Pharmaceutical Co. (Grant 7670020013).

Author information

Author notes

  1. Xiaoshan Liu and Xiaomin Peng contributed equally to this work.

Authors and Affiliations

  1. Pediatric Oncology, Children’s Medical Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No.107, Yanjiang West Road, Yuexiu District, Guangzhou, 510120, Guangdong, China

    Xiaoshan Liu, Xiaomin Peng, Shu Yang, Yuhan Ma, Yu Wu, Zhixuan Wang, Wenjun Weng & Yang Li

  2. Department of Pediatric Surgery, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, 341000, Jiangxi, China

    Haijin Liu

  3. Department of General Surgery, Jiangxi Provincial Children’s Hospital, Nanchang, 330006, Jiangxi, China

    Shouhua Zhang

  4. Department of Surgical Oncology, Children’s Hospital Zhejiang University School of Medicine, Hangzhou, 310052, Zhejiang, China

    Jinhu Wang

Authors
  1. Xiaoshan Liu
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  2. Xiaomin Peng
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  3. Shu Yang
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  4. Haijin Liu
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  5. Shouhua Zhang
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  6. Jinhu Wang
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  7. Yuhan Ma
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  8. Yu Wu
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  9. Zhixuan Wang
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  10. Wenjun Weng
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  11. Yang Li
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Contributions

Conceptualization: Yang Li; Methodology: Yang Li, Xiaoshan Liu, Xiaomin Peng; Writing—original draft: Xiaoshan Liu, Xiaomin Peng; Writing—review and editing: Yang Li; Data curation: Xiaomin Peng, Shu Yang, Xiaoshan Liu, Yuhan Ma, Yu Wu, Zhixuan Wang; Formal analysis: Xiaoshan Liu; Visualization: Xiaoshan Liu, Xiaomin Peng; Supervision: Wenjun Weng; Validation: Haijin Liu, Shouhua Zhang, Jinhu Wang; Project administration: Yang Li; Funding acquisition: Yang Li.

Corresponding author

Correspondence to Yang Li.

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Ethics approval and consent to participate

The Ethics Committee of Sun Yet-sen Memorial hospital of Sun Yat-sen University (China, Guangzhou) approved this study (ID SYSKY-2023-678-01). All individual patients provided informed written consent to participate in this study. This study was performed in accordance with the Declaration of Helsinki.

Competing interests

The authors declare no competing interests.

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Liu, X., Peng, X., Yang, S. et al. Salvage chemotherapy regimens with arsenic trioxide for relapsed or refractory neuroblastoma: a promising approach. BMC Cancer 24, 1140 (2024). https://doi.org/10.1186/s12885-024-12884-5

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  • DOI: https://doi.org/10.1186/s12885-024-12884-5

Keywords

BMC Cancer

ISSN: 1471-2407

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