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Introduction
Neuroblastoma is one of the most common malignant extracranial solid tumors in children aged less than 1 year up to 15 years.13 Neuroblastoma arises from the primitive neural crest cells which give rise to the sympathetic chains. The sympathetic chains, which are the fundamental part of sympathetic nervous system, locate in any parts of the body: head, chest, abdomen, spine. The most common site of neuroblastoma was in the abdomen, where 50-70% was located at the adrenal glands.46
The presentation of disease depends on a primary location, for example neck mass, abdominal mass, abdominal pain, chest discomfort whereas others present with symptoms of metastatic disease e.g. fever, anemia and bleeding from bone marrow suppression, bone pain or pathologic fracture.1,4
Unfortunately, more than half of the patients presented with metastatic disease (stage 4) at diagnosis, of whom were considered as high-risk group.2,4 Outcome of high-risk neuroblastoma was poor with high mortality rate.4,5,7,8 One study reported data of 27 patients with neuroblastoma of stage 3 (4%) and stage 4 (96%) who were treated during 1990-1995 in Khon Kaen University.7 The median survival time was 9 months with 1-year, 2-year, and 3-year overall survival rates of 33.3% 18.5% and 14.8%, respectively.7
Multimodality of treatment were given to high risk group patients. The line of treatment included: induction phase (includes chemotherapy and surgical resection), consolidation phase (tandem cycles of myeloablative therapy and stem cell transplantation) and post-consolidation/ maintenance phase (radiation therapy to the site of the primary tumor and residual metastatic sites, immunotherapy, and retinoid therapy).9 The role of surgery for this particular group of patients had been a controversy regarding an advantage of primary tumor resection after chemotherapy.912 In Thailand, data from Queen Sirikit National Institute of Child Health found that 70% of the patients had stage 4 neuroblastoma; 55% of them had tumor resection.13
This research aimed to study survival outcome of patients with stage 4 neuroblastoma who were treated in Srinagarind Hospital, Khon Kaen University. Prognostic factors of the patients were also studied.
Materials and Methods
This was a retrospective cohort study which was approved by the Khon Kaen University Ethics Committee for Human Research (HE601132). The study was conducted based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines.
All patients aged between 1 and 15 years old who had a diagnosis of stage 4 neuroblastoma and treated in Srinagarind Hospital, Khon Kaen University from January 1st, 2006 to December 31st, 2015 were included. The patients who had incomplete data recorded were excluded. Stage of disease was assigned according to the International Neuroblastoma Staging System (INSS).14 Data collected included patients age at the time of diagnosis, first presentation, primary tumor site, metastatic sites, bone marrow status at diagnosis, induction chemotherapy, surgical resection of primary tumor, intraoperative and post-operative complications, survival outcome, and status of disease after treatment.
Treatment for patients with stage 4 neuroblastoma was approached according to Thai-POG protocol15 which include chemotherapy, tumor resection, local radiotherapy, and retinoid therapy. An unresectable tumor was defined from the first imaging study or intra-operative findings. Complete resection was defined as total tumor resection without any gross residual diseases whereas an incomplete resection defined as subtotal, near total, or partial resection as described in the operative records.
Data were summarized as using percentage for categorical data and using means and standard deviation for continuous data. In addition, non-parametric Wilcoxon rank-sum test and Fisher's exact test were used for continuous and categorical variables, respectively. For the survival analysis, KaplanMeier analyses were used to estimate overall survival (OS) comparing between resectable and unresectable groups. Cox-regression analyses were performed to determine the prognostic factor that associated to survival outcomes. A p-value less than 0.05 were considered significant. The statistical analyses were conducted using STATA software (StataCorp, Texus, USA).
Results
Sixty-three patients, who had diagnosis of stage 4 neuroblastoma, were identified during the study period. Two patients were excluded due to incomplete medical record. The median age of patients at diagnosis was 3.7 years (min-max; 1-14.7 years); 52.5% (n = 31) were male and 47.5% (n =28) were female. Majority of patients presenting with a primary abdominal tumor, being non-adrenal (n=24, 40.7%) followed by adrenal tumors (n=22, 37.3%). The other sites of tumor were thoracic (n=6, 10.2%), head and neck (n=4, 6.8%), and spinal (n=2, 3.4%). One patient had unrevealed primary site of tumor in which the diagnosis of neuroblastoma was made from bone marrow tissue sampling.
For the clinical presentations, more than half of patients presented with two symptoms or more. Mass lesion was the most common symptom (of abdomen, neck and scalp), followed by fever, bone pain and anemia. Other infrequent symptoms included abdominal pain, proptosis, raccoon eye and paraplegia. The data showed that approximately three-quarters of patients had more than single site of metastasis. The location most frequently metastasis was bone, followed by bone marrow, lymph node, lung and liver and brain, respectively. Basic characteristic features of the patients and tumors are shown in Table1.
Table1 Demographic data
|
Demographic data |
Number (59) |
|
Sex (%) |
|
|
Male |
31 (52.54) |
|
Female |
28 (47.48) |
|
Age (years) |
|
|
Mean (SD) |
4.06 (2.45) |
|
Median (min-max) |
3.67 (1 14.67) |
|
Primary tumor site (%) |
|
|
Thoracic |
6 (10.17) |
|
Abdomen (intra- and retroperitoneum) |
24 (40.68) |
|
Head and neck |
4 (6.78) |
|
Adrenal gland |
22 (37.29) |
|
Spine |
2 (3.39) |
|
Unknown |
1 (1.69) |
|
Clinical presentation |
|
|
Mass
Abdominal mass
Neck mass
Scalp mass |
22
5
1 |
|
Abdominal pain |
8 |
|
Bone pain |
15 |
|
Fever |
29 |
|
Anemia |
12 |
|
Proptosis |
7 |
|
Raccoon eyes |
3 |
|
Paraplegia |
1 |
|
Metastatic site |
|
|
Lung |
12 |
|
Liver |
4 |
|
Bone |
43 |
|
Brain |
4 |
|
Lymph node |
20 |
|
Bone marrow |
37 |
After induction chemotherapy, surgical resection of the primary tumor was performed in 38 patients (64.41%) whereas other 21 patients (35.59%) still had unresectable tumors. Among the resectable group, complete resection was achieved in 25 patients (65.79%) and incomplete resection in 13 patients (34.21%). Surgical complications occurred in 10 patients, including massive intra-operative blood loss (1.64%), adjacent organ and/or great vessels injury (13.12%), normal organ removal with the tumor (6.56%). Post-operation, one case died due to severe pulmonary edema.
After the median follow-up time of 24.03 months, the mortality rate of the unresectable, complete resection and incomplete resection groups were 2.7%, 2.36% and 1.6%, respectively. The corresponding median survival time were 11.43, 23.1 and 35.87 months. The 5-year overall survival of all patients in the study was 23.43% (95% CI: 12.93% -35.72%) (Figure1).
Figure 1 Overall survival (OS) outcome of stage 4 neuroblastoma
Survival outcomes between the unresectable, complete resection and incomplete resection groups were compared (Figure2). There were no significant differences of survival of the resectable group compared to unresectable group (p = 0.239), complete resection compared to unresectable groups (p = 0.524), and incomplete resection and unresectable groups (p = 0.149). The recurrence of disease occurred in 17 patients among the complete resection group.
Figure2 The overall 5-year survival outcome between unresectable, incomplete resection, and complete resection group.
We performed the bivariate analysis to evaluate prognostic factors which impacted survival outcome of the patients (Table2). The primary tumor locating at spine had a significant worst outcome (crude HR = 28.1, 95%CI: 4.14-190.83, p = 0.001). No significant differences of survivals by the factors of age, sex, primary tumor site, number of metastasis and site of metastasis. All factors from bivariate analysis were performed the multivariate analysis, and the results showed that age group (>18 month) (adjusted HR [95%CI]: 10.05 [1.34 75.58, p =0.025), positive urine VMA (adjusted HR [95%CI]: 0.96 [0.92 0.99], p =0.020) and presence of liver metastasis (adjusted HR [95%CI]: 3.57 [1.17 10.86], p =0.025) were significant independent prognostic factors for survival (Table3).
Table2 Bivariate analysis: Cox regression analysis
|
Factors |
Crude HR (95%CI) |
p-value |
|
Sex |
|
0.509 |
|
Male |
1 |
|
|
Female |
1.22 (0.67 2.23) |
|
|
Age |
|
0.188 |
|
≤ 18 months |
1 |
|
|
> 18 months |
2.04 (0.63 6.59) |
|
|
Urine VMA |
0.97 (0.94-1.00) |
0.052 |
|
Primary tumor site |
|
|
|
Abdomen |
2.14 (0.72 6.30) |
0.170 |
|
Head |
1.52 (0.34 6.82) |
0.585 |
|
Adrenal |
1.37 (0.45 4.15) |
0.574 |
|
Spine |
28.10 (4.14 190.83) |
0.001 |
|
Metastatic site |
|
|
|
Lung |
0.96 (0.46-2.01) |
0.915 |
|
Liver |
2 (0.69-5.79) |
0.239 |
|
Lymph node |
1.17 (0.62-2.21) |
0.634 |
|
Brain |
0.98 (0.35-2.75) |
0.972 |
|
Bone |
0.61 (0.32-1.18) |
0.154 |
|
Bone marrow |
0.69 (0.37-1.27) |
0.236 |
|
Number of metastasis |
|
0.358 |
|
1 site |
1 |
|
|
2 sites |
0.65 (0.32 1.33) |
|
|
≥ 3 sites |
0.56 (0.25 1.27) |
|
Table 3 Multivariate analysis: Cox regression analysis
|
Factors |
Crude HR
(95%CI) |
p-value |
Adjusted HR
(95%CI) |
p-value |
|
Age (months) |
|
0.188 |
|
0.025 |
|
≤ 18 |
1 |
|
1 |
|
|
> 18 |
2.04 (0.63 6.59) |
|
10.05 (1.34 75.58) |
|
|
Urine VMA |
0.97 (0.94 1.00) |
0.052 |
0.96 (0.92 0.99) |
0.020 |
|
Metastatic site |
|
|
|
|
|
Liver |
2.00 (0.69 5.79) |
0.239 |
3.57 (1.17-10.86) |
0.025 |
Discussion
Neuroblastoma is one of the most common malignant neoplasms in children which mostly presents with stage 4 at the first time of diagnosis.4,7,8 Treatment for this advanced stage is still a challenge and requires a multidisciplinary approach. The 5-year overall survival outcome in patients with stage 4 neuroblastoma was 23-55%.6,8,11,12 Our study found that the 5-year overall survival rate of stage 4 neuroblastoma patients was 23.43% which appears to be in the lower range than from the previous report.7
The role of primary tumor resection, which is typically performed at or near the end of induction chemotherapy, for advanced staged neuroblastoma had been a controversy. Adkins et al.11 found that the resectability for high-risk neuroblastoma was improved after pre-operative chemotherapy, and they showed that there was no statistically significant different in the complication rates between complete and incomplete tumor resection. In 2015, Englum et al.10 studied the outcome of tumor resection in high-risk neuroblastoma children, they suggested that the patient who had been received more than 90% of tumor removal associated with higher overall survival rate compare to those who received less than 90% of tumor removal. In addition, Mullassery et al.9 showed that the gross total tumor resection had significantly increased in 5-year disease-free survival compared to the subtotal tumor resection patients. However, Simon et al.16 found that the extent of tumor resection of first operation had no impact on the event-free survival and overall survival rate in the stage 4 neuroblastoma with age older or equal 18 months at diagnosis. Additionally, Yeung et al.12 categorized the tumor resection of high-risk neuroblastoma into three groups, including complete gross tumor resection, gross total resection (more than 95% of tumor) and subtotal tumor resection. Among three groups, there were no statistically significant difference of 5- year event-free and overall survival rate. Likewise, our studies found that there was no impact of tumor resection to survival outcome of stage 4 neuroblastoma. For the complications associated with surgical removal, Adkins et al.11 found that complete tumor resection was not increase complications while Lei du et al.17 the gross total resection group appeared to have more severe surgical complications, consistent with this study.
Neuroblastoma with intraspinal extension has high burden of long-term health problems as the bivariate analysis showed that the primary tumor at spine had a significant worse survival than that of other locations (crude HR = 28.1, 95%CI: 4.14-190.83, p = 0.001). Plantaz et al.18 found that in most cases of patient with intraspinal extension needed emergent surgery to relieve neurologic deficits. The timing of specific therapy initiation had a great effect on determining the neurological outcome. Early diagnosis may prevent permanent disability in children with malignant cord compression.19 According to the International Neuroblastoma Risk Group (INRG) classification system,20,21 over 18 months of age is one of the factors involved in the classification of stage 4 neuroblastoma into a high-risk group, consistent with the multivariate analysis found that age group (>18 month) (adjusted HR (95%CI): 10.05 (1.34 75.58), p =0.025).
Being a retrospective study was one of the limitations of our study. The other limitations included lacking of other post-operative complications and the amplification of MYCN data which is the one of the important factors for risk classification.2022 Further prospective randomized studies might be required.
Conclusion
The 5-year overall survival rate of stage4 neuroblastoma patients appeared likely to be improved from our previous report, however, our study found no significant differences of survival outcome between resectable and unresectable group in stage 4 neuroblastoma. Tumor location at spine, age group (>18 month), positive urine VMA, and presentation of liver metastasis might be used for the poor prognostic prediction.
References
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