Introduction
Neuroblastoma (NB) originates from the sympathetic nerve cells and can occur in any parts of the sympathetic nervous system, including adrenal glands, pelvis, abdomen, chest and neck. NB also is one of the most common types of extracranial solid tumors in children, which constitutes about 11% of pediatric tumors [
1,
2]. The prognosis of NB is quite variant; patients with low-risk NB (age at diagnosis < 18 months or non-metastatic NB) generally have a favorable prognosis and merely require intensified anti-cancer treatments, while children with high-risk NB (age at diagnosis ≥ 18 months with metastatic NB) mostly show an unfavorable prognosis, regardless of improvements in multimodal anti-NB therapy, including surgery, chemotherapy, radiotherapy, hematopoietic stem cell transplantation and immunotherapy [
3], with 3-year and 5-year overall survival (OS) rates being 60% [
4] and 50% [
5], respectively. In China, the 3-year and 5-year OS rates are often lower than 60% and 50% owing to some therapeutic limitations and racial differences. For instances, the CAR-T therapy and anti-GD2 immunotherapy are often hard to obtain and costly in China; moreover, the OS rates of Asian NB patients are reported to be lower than that of black and white ones [
1]. With the refined stratification definition for low-risk NB patients putting into effect, "middle low-risk NB" subgroup could be well-identified from low-risk NB group [
6], the prognosis of children with high-risk NB still remained heterogeneous [
7], and there is lack of agreement on the term of “ultra high-risk NB” (a subgroup that has the highest risk of death within 3 or 5 years). Thus, it is necessary to develop a refined stratification system for early screening the subgroup of “ultra high-risk NB” at the time of diagnosis.
Currently, there are two main stratification systems for NB,
i.e., International Neuroblastoma Staging System (INSS) [
8] and International Neuroblastoma Risk Group Staging System (INRGSS) [
9]. However, INSS and INRGSS are both mainly used for guiding the intensity of the anti-NB therapy, they are unable to help in predicting the OS of high-risk NB individually at the time of diagnosis. On the basis of INSS and INRGSS, Children’s Oncology Group (COG) risk stratification system, including age of diagnosis,
MYCN status, DNA ploidy, tumor histologic classification and INSS/INRGSS stages, was following established [
10]. However, this risk stratification system is used for all risk types of NB, there is no specific stratification system solely used for high-risk NB group to identify “ultra high-risk NB” children with the poorest outcome. On the other hand, although many researchers using novel omic-related technologies to develop stratification systems for high-risk NB group, none of them have been validated clinically and applied for clinical use [
11].
Nomogram is a powerful predictive model and widely used in forecasting outcomes of many human cancers due to its objectivity, accuracy and visualization [
12]. To date, some nomograms using NB prognosis-related biomarkers, such as age at diagnosis
, MYCN status, DNA ploidy and tumor histology, have been already reported in NB [
1‐
3]. However, there is only one prognostic nomogram applied specifically for high-risk NB, this study based on the International Neuroblastoma Risk Group (INRG) public database reported a nomogram for the prognosis prediction of 3-year OS in high-risk NB patients [
3]. However, the study was only used for predicting 3-year OS, and only incorporated patients enrolled on trials at Europe, United States and Japan. To the best of our knowledge, there is no prognostic nomogram reported concretely based on Chinese high-risk NB population or applied to predict 1-, 3- and 5-year OS rates for high-risk NB children from developing countries or regions. Thus, we were preparing this article, a single-center study based on Chinese population generated a user-friendly prognostic nomogram for high-risk NB. We took advantage of these easily obtainable and common biochemical blood-derived indicators, developing a nomogram model especially for developing countries or regions to evaluate the precise risk in high-risk NB children.
Discussion
High-risk NB is the main risk type of NB with the high degree of cancer mortality rate [
17]. It is needed to develop a readily available, low-cost and easy-to-use tool for clinical application to identify ultra high-risk NB patients, a subgroup of high-risk NB with the worst prognosis, and help guide novel and intensive front-line treatments earlier for them. In current study, we successfully constructed a nomogram based on Chinese population for predicting 1-, 3- and 5-year OS for the first time, and to identify those newly diagnosed high-risk NB individuals who are at the highest risk of death within the 5 years, by combining pretreatment blood-derived biochemical indicators, including LDH and ALB. ROC curve was performed to evaluate the prognostic accuracy of the nomogram model in training and validation cohorts. Model discriminatory ability was also assessed through calibration plot, Kaplan–Meier analysis and DCA curve in both cohorts, and the results revealed that the nomogram model had powerful prognostic potential and high-risk NB patients could make use of it clinically to predict their 3- and 5-year OS rates, enabling them to further understand their survival condition within the first 3 or 5 years of diagnosis before initiation of anti-cancer therapy. Most importantly, clinicians could apply it to identify potential ultra high-risk NB children at the time of diagnosis, offering them access to innovative anti-NB treatments early in their following course of multimodal therapies and aiding their clinical decision-making.
Currently, multiple efforts are attempting to improve our understanding of the tumorigenesis of NB and its upstream genomic aberrations [
18]. For examples,
MYCN amplification, genetic aberrations of chromosomes 1p, 11q and 17q, DNA ploidy and
ALK mutation are the main known upstream genomic aberrations that play key roles in the NB tumorigenesis and are highly associated with NB prognosis. Therefore, these upstream genomic aberrations had been successfully utilized in risk stratification. Unfortunately, hospitals in many low- and middle-income countries or regions such as western provinces of China, where professional tumor pathologic examination may be unavailable, and technical or financial resources may be also not enough to perform genomic analysis of ploidy, genetic aberrations of chromosomes and
MYCN status. Thanks to the heterogeneity of NB biology that provides us a large number of clinical and biological indicators with potential prognostic values, including not only upstream factors of genomic aberrations, but also downstream indicators of clinical manifestations, opening the door for consideration and testing of many candidate downstream clinical biofactors. That is a great opportunity to apply these easy-to-obtain and low-cost downstream clinical biofactors especially in low- and middle-income countries or regions to predict survival outcome of high-risk NB.
In the current study, incorporated prognostic variables—LDH and ALB—are all easily obtained and low-cost downstream clinical biofactors known for the vast majority of patients in the world. Among them, serum LDH is a common biomarker of tissue damage and has been found to be involved in multiple tumor biological processes, including cancer initiation [
19], cancer cell invasion and tumor metastasis [
20]. LDH also has been known as a prognostic biofactor in NB since 1992 [
21], and its prognostic strength was emphasized recently by Moroz et al. [
22], based on a large NB cohort. These studies have indicated that high level of LDH in serum could play as an independent prognostic biofactor for NB patients in predicting OS, and was highly associated with poor OS, which was also reflected in our study. Nutritional status has been found to be highly related to tumor initiation and development in children [
23]. Serum ALB, one of the important nutrition-related indicators, was listed in our nomogram. Hypoalbuminermia is a common clinical event in cancer children and correlated with poor survival in many types of cancers [
24]. In our study, we demonstrated that decreased ALB in serum was an independent prognostic indicator in high-risk NB for predicting OS. This might be due to the high aggressiveness and early extensive metastatic characteristics of high-risk NB, especially peritoneum metastasis with severe ascites. We therefore propose a hypothesis that ALB infusion may have therapeutic effects for improving the survival of high-risk NB children with severe hypoalbuminermia. However, Due to lack of prospective clinical study, whether an apparent increase in serum ALB levels could improve prognosis of high-risk NB children with severe hypoalbuminermia still remains undetermined. We hope our findings in this study will stimulate future prospective clinical studies on exploring the use of ALB infusion in anti-NB treatments for high-risk NB children with severe hypoalbuminermia.
On the other hand, the main reasons why we did not add
MYCN status or chromosomes 11q aberration to classify ultra high-risk NB in this study can be summarized as follows: (1) Firstly, this study mainly aimed to develop a survival prediction nomogram that could be used for high-risk NB children in developing countries or regions that lack of necessary technical or financial resources to perform genomic analysis. Based on this point, it seems that there is no need to add
MYCN status or chromosomes 11q aberration indictors to construct prognostic nomograms in current research. (2) Secondly, from the patients' view, many patients' parents, including many recruited patients' parents in this study, are unwilling to choose these genomic tests (detections of
MYCN status and 11q aberration) due to the expensive costs of fluorescence in situ hybridization (FISH) technology and relatively hard-to-obtain sample requirements (fresh tumor specimens or bone marrow samples). Consequently, the
MYCN status or chromosomes 11q aberration of many patients in current study were unknown or unavailable before treatment, which obviously affected the predictive performances of these genomic analysis indicators in our cohort. (3) Finally, there have already been a study designed by Moreno L et al., which included
MYCN status indicator to construct a survival prediction nomogram for high-risk NB children [
3]. Based on their study, it is meaningful for us to develop a nomogram without genomic indicators and explore the predictive difference between their nomogram model and ours. The nomogram we established and validated based on the real-world population might represent a promising survival prediction tool for high-risk NB children at their pretreatment stage. According to the 3-year OS nomogram of high-risk NB constructed by Moreno L et al. [
3], using indicators of
MYCN status, serum LDH and presence of bone marrow metastases, the AUC value of their validation cohort from SIOPEN HR-NBL1 trails was reported to be 0.629, while the AUC of our 3-year OS nomogram in current training and validation sets was 0.758 and 0.825, respectively. Our model showed enhanced prognostic accuracy in predicting 3-year OS for high-risk NB children when compared with the nomogram model created by Moreno L et al., although the numbers of individuals enrolled in current research was relatively small that could cause unpredictable bias. Therefore, a larger patient population from other cancer center should be included to further validate our nomogram. Besides that, our prognostic nomogram was based on a retrospective analysis. How it acts in prospective researches remained to be further evaluated. Moreover, our nomogram model demonstrated specificity for Chinese high-risk NB patients, whether it could also be applied to other risk types of NB and other race of high-risk NB remained to be further determined.
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