Tumour markers are poor predictors for relapse or progression in neuroblastoma

doi:10.1016/S0959-8049(03)00376-9

European Journal of Cancer

Volume 39, Issue 13, September 2003, Pages 1899-1903

https://doi.org/10.1016/S0959-8049(03)00376-9 Get rights and content

Abstract

The value of the tumour markers vanillylmandelic acid (VMA) and homovanillic acid (HVA) in urine (u) and serum (s), neurone-specific enolase (NSE), and lactate dehydrogenase (LDH) in the early prediction of relapse/progression in neuroblastoma is not known. We analysed the data of neuroblastoma patients who had successfully completed first-line treatment and had laboratory results available from their initial diagnosis and from relapse/progression (n=196). Patients’ overall survival from relapse or progression was 21.5±4.2% (mean±standard deviation). At diagnosis, we found abnormal results in 75% for VMA and/or HVA (s), 92% for VMA and/or HVA (u), 90% for NSE, and 81% for LDH. We found a lower incidence of abnormal results at relapse or progression with 40% for VMA and/or HVA (s), 54% for HVA and/or VMA (u), 61% for NSE, and 48% for LDH. Sensitivity of all markers was higher for metastatic compared with local recurrence. NSE was the best, being able to detect 42% of the localised relapses, 77% of the combined local/metastatic relapses, and 69% of the metastatic recurrences. Relapse or progression in neuroblastoma cannot be detected reliably by monitoring tumour markers alone. Therefore, follow-up of neuroblastoma patients must include clinical assessment and imaging studies.

Introduction

Vanillylmandelic acid (VMA) and homovanillic acid (HVA) levels in serum (s) and urine (u) and the serum levels of neurone-specific enolase (NSE) and lactate dehydrogenase (LDH) are considered characteristic tumour markers of neuroblastoma. These parameters are well described at the initial diagnosis 1, 2, 3 and during the response assessment of neuroblastoma 4, 5. Therefore, tumour markers are commonly monitored in the follow-up of neuroblastoma survivors. However, the value of these markers in the early prediction of relapse or progression in neuroblastoma is not known. We analysed our data to learn more about the incidence of abnormal tumour markers at the time of progression or relapse of neuroblastoma.

Section snippets

Patients and methods

The data of 1764 consecutive patients of the Cooperative Neuroblastoma Treatment Trials NB90 and NB97 were reviewed retrospectively. All data were collected with the informed consent of the patients/parents. The initial diagnosis was established by histology, by typical bone marrow metastasis in combination with abnormal catecholamines according to the International Neuroblastoma Staging System (INSS) criteria [3], or in seriously ill children by typical tumour localisation with a distinct ¹²³I

Results

Among 1764 patients, 77 patients (4.4%) were lost to follow-up. The median observation time of all surviving patients was 4.7 years (range 23 days–13.0 years). We observed a total of 506 relapses or progressions. 104 recurrences occurred during treatment and were excluded from this analysis. 402 recurrences occurred after complete initial treatment. Of these, 196 children were evaluable for this analysis having one or more tumour markers available from the initial diagnosis and from recurrence

Discussion

Tumour markers are widely used in the initial assessment of neuroblastoma patients. They are considered a good tool for the follow-up of neuroblastoma patients, but there has been no data which demonstrate their value for the follow-up of neuroblastoma survivors.

In our series, the sensitivity of the tumour markers in relapse or progression was found to be low. Many recurrences were diagnosed by routine ultrasound, MRI, MIBG scintigraphy, or when the patient became symptomatic. Only in 14% of

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To assess the predictive ability of an ¹⁸F-FDG PET/CT-based radiomics nomogram for bone marrow involvement in pediatric neuroblastoma.
A total of 241 neuroblastoma patients who underwent ¹⁸F-FDG PET/CT at two medical centers were retrospectively evaluated. Data from center A (n = 200) were randomized into a training cohort (n = 140) and an internal validation cohort (n = 60), while data from center B (n = 41) constituted the external validation cohort. For each patient, two regions of interest were defined using the tumor and axial skeleton. The clinical factors and radiomics features were derived to construct the clinical and radiomics models. The radiomics nomogram was built by combining clinical factors and radiomics features. The area under the receiver operating characteristic curves (AUCs) were used to assess the performance of the models.
Radiomics models created from tumor and axial skeleton achieved AUCs of 0.773 and 0.900, and the clinical model had an AUC of 0.858 in the training cohort. By incorporating clinical risk factors and axial skeleton-based radiomics features, the AUC of the radiomics nomogram in the training cohort, internal validation cohort, and external validation cohort was 0.932, 0.887, and 0.733, respectively.
The axial skeleton-based radiomics model performed better than the tumor-based radiomics model in predicting bone marrow involvement. Moreover, the radiomics nomogram showed that combining axial skeleton-based radiomics features with clinical risk factors improved their performance.
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To construct and validate a combined model based on axial skeleton radiomics of ¹⁸F-FDG PET/CT for predicting event-free survival in high-risk pediatric neuroblastoma patients.
Eighty-seven high-risk neuroblastoma patients were retrospectively enrolled in this study and randomized in a 7:3 ratio to the training and validation cohorts. The radiomics model was constructed using radiomics features that were extracted from the axial skeleton. A univariate Cox regression analysis was then performed to screen clinical risk factors associated with event-free survival for building clinical model. Radiomics features and clinical risk factors were incorporated to construct the combined model for predicting the event-free survival in high-risk neuroblastoma patients. The performance of the models was evaluated by the C-index.
Eighteen radiomics features were selected to build the radiomics model. The radiomics model achieved better event-free survival prediction than the clinical model in the training cohort (C-index: 0.846 vs. 0.612) and validation cohort (C-index: 0.754 vs. 0.579). The combined model achieved the best prognostic prediction performance with a C-index of 0.863 and 0.799 in the training and validation cohorts, respectively.
The combined model integrating radiomics features and clinical risk factors showed more accurate predictive performance for event-free survival in high-risk pediatric neuroblastoma patients, which helps to design individualized treatment strategies and regular follow-ups.
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Citation Excerpt :
Approximately 40% of patients with high-risk neuroblastoma occur in older children with the 11q aberration and are usually susceptible to BMI (39). The urine levels of VMA and serum levels of NSE are considered characteristic tumor markers for neuroblastoma, and are well described at the initial diagnosis and during the response assessment of neuroblastoma (40). It can assess the condition of children with neuroblastoma and predicts the outcome of treatment (41).
To develop and validate an ¹⁸F-FDG PET/CT-based radiomics nomogram and evaluate the value of the ¹⁸F-FDG PET/CT-based radiomics nomogram for the diagnosis of bone marrow involvement (BMI) in pediatric neuroblastoma.
A total of 144 patients with neuroblastoma (100 in the training cohort and 44 in the validation cohort) were retrospectively included. The PET/CT images of patients were visually assessed. The results of bone marrow aspirates or biopsies were used as the gold standard for BMI. Radiomics features and conventional PET parameters were extracted using the 3D slicer. Features were selected by the least absolute shrinkage and selection operator regression, and radiomics signature was constructed. Univariate and multivariate logistic regression analyses were applied to identify the independent clinical risk factors and construct the clinical model. Other different models, including the conventional PET model, combined PET-clinical model and combined radiomics model, were built using logistic regression. The combined radiomics model was based on clinical factors, conventional PET parameters and radiomics signature, which was presented as a radiomics nomogram. The diagnostic performance of the different models was evaluated by receiver operating characteristic (ROC) curves and decision curve analysis (DCA).
By visual assessment, BMI was observed in 80 patients. Four conventional PET parameters (SUVmax, SUVmean, metabolic tumor volume, and total lesion glycolysis) were extracted. And 15 radiomics features were selected to build the radiomics signature. The 11q aberration, neuron-specific enolase and vanillylmandelic acid were identified as the independent clinical risk factors to establish the clinical model. The radiomics nomogram incorporating the radiomics signature, the independent clinical risk factors and SUVmean demonstrated the best diagnostic value for identifying BMI, with an area under the curve (AUC) of 0.963 and 0.931 in the training and validation cohorts, respectively. And the DCA demonstrated that the radiomics nomogram was clinically useful.
The ¹⁸F-FDG PET/CT-based radiomics nomogram which incorporates radiomics signature, independent clinical risk factors and conventional PET parameters could improve the diagnostic performance for BMI of pediatric neuroblastoma without additional medical costs and radiation exposure.
An 18F-FDG PET/CT radiomics nomogram for differentiation of high-risk and non-high-risk patients of the International Neuroblastoma Risk Group Staging System
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Citation Excerpt :
An NSE increase in serum may have some utility for gathering prognostic information about the overall survival of neuroblastoma patients in advanced stages of the disease [35]. NSE has high sensitivity in predicting recurrence in patients with neuroblastoma, detecting 42% of local recurrences, 77% of combined local/metastatic recurrences, and 69% of metastatic recurrences [36]. NSE has been shown to be prognostic in patients with neuroblastoma [37].
To develop and validate an ¹⁸F-FDG PET/CT radiomics nomogram for non-invasive differentiation of high-risk and non-high-risk patients of the International Neuroblastoma Risk Group (INRG) Staging System (INRGSS).
One hundred thirty-nine neuroblastoma patients were retrospectively enrolled and classified into a training set (n = 84) and validation set (n = 55). Radiomics features were extracted from ¹⁸F-FDG PET/CT images, a radiomics signature was constructed, and a radiomics score (Rad score) was calculated. Then, univariate and multivariate logistic regression analyses were used to screen out the independent clinical factors and construct the clinical model. A radiomics nomogram was developed based on the Rad score and independent clinical factors. The performance of the clinical model, Rad score, and nomogram was assessed by receiver operating characteristic (ROC) curves, calibration curves, and decision curves analysis (DCA).
Seven radiomics features were selected to build the radiomics signature. The age at diagnosis, the INRG stage, neuron-specific enolase (NSE) and Rad score showed a significant difference between the high-risk and non-high-risk patients. The radiomics nomogram incorporating the Rad score and the above clinical factors demonstrated favorable predictive value for differentiating high-risk from non-high-risk, yielded AUCs of 0.988 and 0.971 in the training and validation sets, respectively. The calibration curves showed that the radiomics nomogram had the goodness of fit, and the DCA demonstrated that the radiomics nomogram was clinically useful.
The radiomics nomogram, which incorporates the Rad score and clinical factors can well predict high-risk and non-high-risk patients of the INRGSS. It may help the disease follow-up and management in clinical practice and assist in personalized and precise treatment of neuroblastoma.
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European Journal of Cancer

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

References (13)

Serum vanillylmandelic acid/homovanillic acid contributes to prognosis estimation in patients with localised but not with metastatic neuroblastoma

Eur. J. Cancer

Mass fragmentographic determination of homovanillic and 4-hydroxy-3-methoxy mandelic acids in 50 μl plasma

Clin. Chim. Acta

Clinical significance of catecholamine excretion levels in diagnosis and treatment of neuroblastoma

Arch. Dis. Child.

Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment

J. Clin. Oncol.

Evaluation of catecholamine metabolites, mIBG scan, and bone marrow cytology as response markers in stage 4 neuroblastoma

Med. Ped. Oncol.

Neuron-specific enolase evaluation in patients with neuroblastoma

Tumour Biol.

Cited by (55)

<sup>18</sup>F-FDG PET/CT-Based Radiomics Nomogram for Prediction of Bone Marrow Involvement in Pediatric Neuroblastoma: A Two-Center Study

Axial Skeleton Radiomics of <sup>18</sup>F-FDG PET/CT: Impact on Event-Free Survival Prediction in High-Risk Pediatric Neuroblastoma

Diagnostic Value of <sup>18</sup>F-FDG PET/CT-Based Radiomics Nomogram in Bone Marrow Involvement of Pediatric Neuroblastoma

An <sup>18</sup>F-FDG PET/CT radiomics nomogram for differentiation of high-risk and non-high-risk patients of the International Neuroblastoma Risk Group Staging System

Laboratory testing in pediatric cancer patients

Serum cholesterol level as a predictive biomarker for prognosis of Neuroblastoma