Clinical Comparison of Surgical Treatment and Complications in Pediatric Patients with Neuroblastoma at Stage 4

doi:10.21203/rs.3.rs-2101737/v1

OBJECTIVE: To compare the surgical methods and complications in pediatric patients with neuroblastoma (NB) at International neuroblastoma staging system (INSS) stage 4 in the adrenal site.

METHODS: Thirty-four patients, 21 males and 13 females, with NB at INSS stage 4 underwent radical surgery (RS) from May 2018 to May 2021, and were retrospectively included. Patients were divided into three groups, namely RS group (group A), tumor biopsy + chemotherapy + RS group (group B), and bone marrow biopsy + chemotherapy + RS group (group C) depending on the particular treatment protocol. The total survival rate, factors related to surgical resection, and surgical complications in each group were analyzed.

Results: 5 cases were enrolled in group A, 9 cases in group B, and 20 cases in group C. The number of Encasement of Vessels (EVS) was higher in the (CR+MR) group compared to the IR group (P=0.039). The operative time was shorter when EVS was present (P=0.022). RS complications mainly included bleeding (73.5%), celiac leakage (70.6%) and intestinal obstruction (26.5%). A total of 29 cases (85.3%) were graded by CDC as grade II, 2 cases as grade IIIa, 1 case as grade IIIb, 1 case as grade IVa and 1 case as grade IVb.By comparing patients who developed grade II and grade III complications or higher, it was observed that neuron-specific enolase (NSE) (P<0.0001), primary EVS (P<0.0001), RS preoperative EVS (P<0.0001), Lactate dehydrogenase (LDH) (P=0.005), Ki67 (P=0.012), primary tumor maximum diameter (P=0.018), primary IDRFs (P=0.022), and preoperative IDRFs for RS (P=0.043) were statistically different.

CONCLUSION: In this study, it is concluded that pre-operative biopsy in patients with NB at INSS stage 4 located in the adrenal glands allows for a clear diagnosis, and that subsequent RS does not increase the risk of surgical complications. Moreover, EVS is proved an important factor for surgical resection and surgical complications.

Neuroblastoma

Biopsy

Surgery

complications

Neuroblastoma (NB) is one of the most common malignant solid tumors that affects children, and accounts for 7–10% of pediatric tumors (1). The incidence rate of domestic NB is approximately 0.3 to 5.5 in 100,000 children, accounting for 8–10% of malignant tumors in children under 15 years old, and 80% of which occur in children under 5 years old (2). In 2015, the Pediatric Oncology Committee of the Chinese Anti-Cancer Association and the Surgical Oncology Group of the Pediatric Surgery Branch of the Chinese Medical Association published an expert consensus on the treatment of pediatric NB, which divided the tumors into low-risk, intermediate-risk, and high-risk according to COG grouping. For children with NB in the low-risk group, surgical treatment can result in good prognosis. For pediatrics in the high-risk group, comprehensive treatment protocols are not ideal for long-term patient survival (3, 4). Therefore, it is crucial to explore the treatment of NB more deeply.

Patients diagnosed with NB showed great clinical diversity in various clinical characteristics, such as age, tumor size and location, tumor stage, risk of tumor, and surgical difficulties (5). Pediatric patients aged below 1 year with INSS stage 4 and MYCN gene-negative were placed in the intermediate-risk group, while others were placed in the high-risk group. Surgery before or during chemotherapy was recommended for the intermediate-risk group, while for the high-risk group, surgery after chemotherapy was recommended (6). Moreover, NB located at adrenal sites tends to be extensive, which significantly increases the difficulty of biopsy before surgery. In this condition, bone marrow biopsy with the indication of distant metastasis may provide strong support to the diagnosis and treatment of NB.

This study is designed as a retrospective, single-center, observational clinical investigation aimed at comparing three treatment protocols, namely surgery, biopsy and/or chemotherapy among pediatric patients with NB staged at INSS 4 located at adrenal sites. Unlike traditional studies, we included the “gold-standard” protocol using tumor biopsy or bone-marrow biopsy pre-surgery, as well as the empirical treatments through a retrospective study, to explore improvement in the clinical efficacy and safety of treatment regimens in pediatric NB cases.

2.1 Ethnical statement

The study was approved by the Medical Ethics Committee of the Children's Hospital of Nanjing Medical University (No. 201901014). Written informed consent was obtained from all parents and/or guardians of the pediatric patients. The procedures in our study were undertaken in accordance with the ethical standards set by the Declarations of Helsinki and Istanbul.

2.2 Study design

The objective of this single-center, retrospective study is to compare the clinical efficacy of chemotherapy and surgical treatment in Schwannian mesenchymal paucibacillary type of Neuroblastoma (NB) sited at adrenal gland sites, which was graded as stage 4 based on International Neuroblastoma Staging System (INSS). Pediatric patients underwent chemotherapy or/and surgical treatment from May 2018 to May 2021 in the Department of Urology of the Children's Hospital of Nanjing Medical University.

2.3 Inclusion and exclusion criteria

The inclusion criteria of patients enrolled in this study were as follows: 1) children who underwent RS in the Children's Hospital of Nanjing Medical University; 2) tumors must be diagnosed as NB at adrenal sites after or before surgery; 3) NB tumors must be graded as INSS stage 4; and 4) patients must be willing to be enrolled in the study.

In addition, the exclusion criteria was as follows: 1) history of surgical treatment at other centers; 2) children did not undergo surgical treatment in our center; 3) children only took biopsy examination; 4) NB located at non-adrenal sites or combined with NB from other areas; 5) bilateral adrenal NB; 6) NB graded as other than INSS stage 4.

2.4 Treatment

Patients were retrospectively enrolled for comparison and extensive analysis and divided into three groups. The surgery group (group A) had 5 patients who did not undergo preoperative chemotherapy and RS, and whose diagnoses were confirmed by post-operative pathology examination. The biopsy group (group B) had 9 patients who firstly underwent ultrasound-guided Fine Needle Aspiration Biopsy (FNAB) or Open Incisional Biopsy (OIB) of the primary tumor. The chemotherapy group (group C) had 20 patients who were admitted to the hospital, and their diagnosis of NB confirmed by undergoing relevant examinations, and subsequently taking chemotherapy, followed by RS.

Detailed RS procedures were summarized as below:

The chemotherapy protocols

2.5 Data collection

Basic information of enrolled patients, including gender, age, history of hypertension, and primary symptoms, was collected. Laboratory tests [Hemoglobin (Hb), Lactate dehydrogenase (LDH), Neuron-specific enolase (NSE), Nmyc gene of tumor tissue].

Tumor-related data were also reviewed, such as maximum tumor diameter, predicted volume (estimated by length*width*height*π/6), INPC and International neuroblastoma risk group staging system (INRGSS) staging, histological type, immunohistochemistry results of Ki67, imaging risk by Image-Defined Risk Factors (IDRFs), Encasement of vessels EVS, and Children's Oncology Group (COG), and lymph node metastasis. Based on the imaging examination and surgical records, EVS was defined as 100% of the vessels encircled by the tumor.

Importantly, chemotherapy protocols (course of treatment, change in tumor size before RS surgery) and surgical treatment, as well as post-surgery complications were collected.

The International Neuroblastoma Surgical Report Form (INSRF) [1] was used as an index for RS, and the extent of resection was defined in four categories: Complete Resection (CR), Minimal Residue (MR), Incomplete Resection (IR), and others. According to the classification of surgical complications (Clavien-Dindo classification of surgical complications, CDC) by Dindo [2] and Katayama [3], they are classified as grade I, II, IIIa, IIIb, IVa, IVb, V. Surgical complications were defined as: 1) bleeding: perioperative bleeding with a decrease in erythrocyte pressure volume of more than 20% or requiring blood transfusion within 5 days of surgery [4]; 2) celiac leakage requiring more than 10 days of abdominal, retroperitoneal or pelvic drainage with drainage > 30 ml/day; 3) intestinal obstruction involving persistent abdominal pain and distension with difficulty in defecation or requiring more than 10 days of total parenteral nutritional support.

2.6 Statistical analysis

Qualitative data were expressed as a proportion of the case number and the chi-square test was adopted (four-grid Fisher's exact probability calculation method was adopted in case the conditions of the chi-square test were not met). Continuous data were expressed as mean ± standard deviation (SD), and Student t-test was used for comparison between two groups. Welch's correction was used to evaluate uneven variance, and one-way ANOVA test (Brown-Forsythe and Welch ANOVA tests) were used to review variance discrepancies for comparison among multiple groups. Pearson correlation analysis was adopted for correlation analysis of continuous variables, and Spearman correlation analysis was adopted for correlation analysis of continuous and ordered categorical variables. P < 0.05 was considered a statistically significant difference. SPSS version 16.0 software was used for statistical analysis.

3.1 Basic characteristics of patients

Baseline information of enrolled patients is presented in Table 1. A total of 34 pediatric patients fulfilled the inclusion criteria, and they were divided into three groups according to their therapeutic protocol. Their ages ranged from 8 months to 10 years, with a mean age of (45.2±26.3) months and a mean weight of (16.8±7.1) kg. A total of 16 out of 34 cases were on the left side, while 18 cases were on the right side.

Among them, group A had 5 cases, two of which were evaluated to be INSS stage 2 with regard to the tumor limited within the midline of abdomen, while the staging were converted into INSS stage 4 post-surgery with minimal residual disease (MRD) positive. Meanwhile, two cases in group A were determined to be INSS stage 3 before surgery, with tumors exceeding the midline of abdomen, one having liver metastasis and the other having distant lymph node metastasis after surgery. Group B had 9 cases, six of which were diagnosed with suspected NB and were not included in stage 4 in the preoperative evaluation. One of them had liver metastasis intraoperative, four were found to have bone metastasis by postoperative Positron emission tomography (PET), and one was found to have bone metastasis and distant lymph node metastasis by postoperative PET. In group C, 20 cases were positive for MRD with elevated NSE of (318.5±74.1) ng/ml, among which 11 cases were > 370 ng/ml.

For preoperative chemotherapy, 4 cases (44.4%) in group B used the standard protocol of the 2015 Expert Consensus on the Treatment of Childhood Neuroblastoma [5], and 12 cases (60.0%) in group C used the standard protocol. The main reasons for not following the standard protocol were incomplete preoperative evaluation for temporary inclusion in the intermediate-risk group, significant tumor liquefaction, and intolerance of some chemotherapy drugs or adverse side effects. A total of 33 cases (97.1%) received postoperative chemotherapy, as only one case in group A that did not receive chemotherapy.

Additionally, 33 (97.1%) of 34 cases underwent open surgery and one underwent laparoscopic surgery. Mean operation time was (394.4±158.4) min, and mean intraoperative blood transfusion was (1.3±1.8) U. CR was observed in 5 cases (14.7%), while MR and IR were observed in 24 cases (70.6%) and 5 cases (14.7%), respectively. Postoperative fasting was performed for (11.2±14.1) days, and drainages of abdominal, pelvic, and retroperitoneal cavities were performed for a maximum of (16.3±12.6) days. Three cases (8.8%) of ipsilateral kidney of the tumor were intraoperatively removed due to renal hilum vascular encirclement and hilar invasion.

3.2 Univariate analysis of clinical outcomes of three treatment protocols

Univariate analysis was performed to compare preoperative and postoperative changes in NSE, Hb, LDH, Ki67, tumor volume, number of IDRFs and EVS, time to second surgery, blood transfusion, number of lymph node biopsies, days of drainage, and days of fasting among three groups undergoing different treatment protocols.

It was found that preoperative NSE and pathological ki67 were statistically different (NSE, P=0.002; Ki67, P<0.0001; Table 2) among the three groups, and both NSE and LDH were significantly statistically different preoperatively and postoperatively (NSE, P<0.0001; LDH, P=0.002; Table 2). There was no statistical difference recorded in RS/(CR+MR) ratio, proportion of surgical complications (P > 0.05; Table 2). There were 23 cases (67.6%) with varying degrees of vascular wrapping, with a mean of (1.6±1.6) vascular wraps. Among them, 12 cases were wrapped with left renal artery, while 10 cases, 11 cases and 3 cases were wrapped with left renal vein, right renal artery and right renal vein, respectively. Furthermore, 8 cases of abdominal aorta, 1 case of inferior vena cava, 5 cases of superior mesenteric artery, 1 case of inferior mesenteric artery, and 3 cases of abdominal trunk were observed. Among all cases, renal vascular wraps were the most prevalent (66.7%) among all cases. The operative times in EVS cases were significantly longer than cases without EVS (436.7 ± 157.1 min vs. 360.0 ± 125.9 min; P = 0.022), and no differences were observed in surgical transfusion (1.6 ± 1.9 U vs. 0.8 ± 1.2 U; P = 0.18).

3.3 Risk factor analysis of surgical resection and surgical complications

To further explore risk factors influencing surgical resection selection, we divided patients into IR group and (CR+MR) group depending on surgical resection procedures. It was statistically found that patients with high EVS were less likely to be surgically resected, compared with those having primary EVS (P = 0.03; Table 3) and pre-RS EVS (P = 0.039; Table 3). Besides, no significant risk factors were reported for other clinical variables.

RS complications such as bleeding (73.5%), celiac leakage (70.6%) and intestinal obstruction (26.5%) were mainly reported. Cases with bleeding required a mean intraoperative blood transfusion of (1.8±1.8) U. No case underwent secondary operation due to persistent bleeding. 29 cases (85.3%) suffered from CDC grade II, and all required parenteral nutrition for a mean of (10.6±14.4) days; while 2 cases were diagnosed as grade IIIa (1 case of pleural effusion requiring drainage tube under local anesthesia and 1 case of celiac leakage requiring drainage tube under local anesthesia), 1 case as grade IIIb (intestinal necrosis requiring reoperative treatment under general anesthesia), 1 case as grade IVa (renal dysfunction), and 1 case as grade IVb (multiple organ dysfunction). Detailed complications observed after performance of RS are presented in Table 4.

For the analysis of risk factors influencing surgical complications, CDC grade II was compared with CDC grade above III, suggesting that NSE values (P<0.0001), EVS (P<0.0001), pre-RS EVS (P<0.0001), LDH (P=0.005), Ki67 (P=0.012), maximum diameter of primary tumor (P=0.018), primary IDRFs (P=0.022), and pre-RS IDRFs (P=0.043) were statistically related to the degree of complications (Table 3).

3.4 Follow-up outcomes

The follow-up duration ranged from 5 to 41 months, with a mean follow-up of (15.2±10.0) months. Among the three groups, 2 cases in group A suffered from recurrence at 20 and 30 months, respectively, and 1 patient died at 2 months postoperatively. In group B, 1 case suffered from recurrence at 4 months, and 1 patient died at 3 months postoperatively. In addition, recurrence was observed in 3 cases in group C at 10, 10 and 24 months, respectively. In this study, the overall recurrence rate was 17.6% and the mortality rate was 5.9%.

In this study, we have retrospectively reviewed various treatment protocols of NB at INSS stage 4 in our single-center, and divided enrolled cases into three groups based on the treatment protocol. It is concluded that biopsy before surgery is strongly recommended since there were no significant differences in the total surgical risks between patients with or without pre-operative biopsy. In addition, EVS was observed to be significantly correlated to surgical resection procedures and surgical complications, so great caution should be taken during pre-operative evaluation of tumors and patients.

It is recommended that for patients with IDRFs, RS should be postponed and be performed after the risk of surgical complications has been reduced by chemotherapy (7, 8). In this study, there were 31 cases (91.2%) in the high-risk group, 2 cases (5.9%) in the intermediate-risk group, and 1 case that was unclear. In the high-risk group, 83.9% were treated with chemotherapy before undergoing RS. The statistical analysis suggested that there were no differences in surgical resection rates and complications among cases in groups A, B, and C. However, the number of cases in group A was low and preoperative evaluation was inadequate, so the authors suggest that it would be more appropriate to follow the expert consensus to administer chemotherapy first after adequate preoperative evaluation. IDRFs and EVS followed by chemotherapy were both present in the intermediate-risk group.

The expert consensus considered two criteria for confirming the diagnosis of NB: (1) a definite pathological diagnosis; (2) a bone marrow smear or biopsy for neuroblastoma with NSE or elevated urinary catecholamine metabolites. In this paper, patients in group C all met the second diagnostic criteria, and were all included in the high-risk group, in which chemotherapy was administered before surgery. Biopsy was performed for cases in group B mainly because: (i) MRD was negative, the tumor diagnosis was unclear, and NB was only suspected and not regarded as stage 4; (ii) the tumor was not confined to the adrenal region and was accompanied by renal and hepatic infiltration. In this study, we did not observe any significant differences in surgical risks among the three groups, indicating that biopsy would not contribute to RS complications. Therefore, to determine the pathological diagnosis, biopsy before surgery is strongly recommended for pediatric patients with INSS stage 4.

Asim et al (9) reported that the sensitivity and specificity of FNAB for the diagnosis of malignant small round cell tumors (SRCT) were 97% and 100%, respectively. Similarly, Das et al (10) indicated that the sensitivity and specificity of FNAB for asymptomatic retroperitoneal masses were 98.02% and 72.22%, respectively. Furthermore, Koshy et al (11) pointed out that FNAB can identify pNT well. Research has also proved the important role FNAB plays in recurrent NB and in guiding clinical surgery and treatment of pediatric solid abdominal tumors (12, 13). In this paper, the sensitivity and specificity of biopsy were 88.9% and 100%, respectively, as expected for surgery. It is worth noting that, in this study, we excluded cases with postoperative pathology of FNAB as GN and final pathology as GNB. Campagna et al (14) concluded that FNAB multi-stitch sampling is sufficient for complete diagnosis and can replace OIB. To minimize misdiagnosis, the combination of pathology immunohistochemistry and molecular biology diagnosis is recommended to identify pNT and the rest of SRCT (15-17). Unfortunately, none of the nine cases in group B underwent further molecular biology diagnosis due to limitations of current technology. Lack of Nmyc gene information led to unclear COG grading, while lack of 11q results led to unclear INRG grading (18). The routine biopsy modalities include OIB, FNAB, and laparoscopic-assisted biopsy, but only the first two biopsy modalities were adopted in the cases involved. We have concluded that FNAB can be the first choice for most cases, and OIB or laparoscopic-assisted biopsy can be adopted for cases with deeper mass location, rich peripheral blood supply, and obscured important organs. Previous studies have reported that the postoperative complication rate of FNAB is low and the risk is manageable (18, 19). In this study, cases in group B had accurate postoperative pathological diagnosis, all CDCs were regarded as grade I, and no significant complications occurred. Moreover, there were no statistical differences between groups A and C in terms of surgical resection rates and surgical complications, indicating that biopsy still has an important diagnostic value in NB cases with suspected INSS stage 4 in the adrenal glands, and it does not increase the risk of surgery.

The impact of surgical resection rate on the prognosis of NB is a controversial topic, especially for patients in the high-risk group, and it is uncertain whether this group of patients can benefit from CR. Meta-analysis has suggested that RS significantly improves OS in the high-risk group of NB patients, but there was no significant difference in EFS (20). The International Society of Paediatric Oncology Europe Neuroblastoma Group (SIOPEN) also suggested that, for stage 4 high-risk NB patients who respond to induction therapy, complete sarcomerectomy of the primary tumor resection was associated with improved survival and local control after high-dose chemotherapy, local radiotherapy and immunotherapy (21). Contrarily, no significant relationship was observed between surgical resection and survival (22). The main reason for the difference in conclusions is that high-risk group patients often undergo a combination of surgery, chemotherapy, radiotherapy, and immunotherapy, of which surgery is only one part. Again, for the high-risk group, the number of patients who undergo direct RS is low, and cases in group A are due to inadequate preoperative evaluation. For surgeons, although CR is the goal to pursue, MR is still a perfectly acceptable outcome as it does not affect prognosis but reduces associated complications and preserves organ and neurological functions. Meanwhile, it is necessary to consider whether the family can accept more serious complications, especially those above CDC grade IIIb or even grade V (death). In this paper (CR+MR) accounted for 85.3% of the cases, and surgery achieved better expected outcomes.

Subsequently, statistical analysis suggested that the only factor associated with (CR+MR) resection was EVS, but it was not significantly different before and after preoperative chemotherapy for RS. Brisse (23) identified the main tumor-vessel relationships in IDRFs as contact, encapsulation, and infiltration, with the first two being assessable through imaging. Contact means <50% of circumference connected to the tumor, and encapsulation means 50% of circumference connected to the tumor. In this paper, EVS refers to vessels that are 100% encircled by the tumor, especially in the renal artery (42.6%), renal vein (24.1%), and abdominal aorta (13.0%). When encircled, the renal vessels on the side of the lesion tend to be longer in length, while the contralateral renal vessels, superior mesenteric artery, inferior mesenteric artery, and abdominal trunk tend to only encircle the starting segment. The EVS did not change significantly after chemotherapy, and only some of the EVS wrapped around the starting segment disappeared when the tumor shrank significantly. Mühling (24) stated that vascular infiltration is a major challenge for surgical resection of NB and is associated with poor treatment outcomes, which is consistent with our study results which show that patients with less EVS are more likely to achieve (CR+MR) resection and that patients without EVS have shorter operative times. The majority of EVS can be predicted in preoperative ancillary examinations, but the vena cava and renal vein portions are not clearly wrapped preoperatively due to significant compression. As for the superior mesenteric artery, inferior mesenteric artery, and abdominal trunk, they are often wrapped at the beginning only, which needs to be confirmed intraoperatively. Therefore, EVS has greater application potential for preoperative assessment of RS.

Our oncologic surgery team has accumulated surgical experience with >50 pNT surgeries/year. Most of the CDCs in RS were grade II, and main complications included bleeding, celiac leakage and intestinal obstruction. 2 patients died after 30 days postoperatively. We have suggested that patients with higher NSE, LDH, higher number of IDRFs and EVS to undergo imaging, but those with larger tumors can have surgical complications. Warmann (25) considered vascular wrapping as part of IDRF as an important factor in risk stratification of NB. Renal vascular wrapping and stenosis, excretion delay and tumor invasion of the kidney, especially pelvis and perinephric invasion, were closely associated with partial or total nephrectomy for NB surgery (26). Consistent with these findings, patients with more EVS show a higher grade of surgical complications, and the presence of EVS requires extra attention in cases where EVS is not significantly reduced after chemotherapy. All intraoperative nephrectomy and postoperative renal ischemia are associated with renal vascular wrapping. This requires the operator: to fully assess the renal vascularity preoperatively; not to blindly ligate intra-tumor vessels intraoperatively; to reduce damage when separating vessels; and to pay attention to the presence or absence of renal branch supply vessels in order to reduce the occurrence of complications.

Overall, this study has several limitations. Firstly, only INSS stage 4 NB patients were enrolled for the study, and the number of cases was relatively small. Secondly, the follow-up time of some cases was short, and full chemotherapy courses were not completed. Finally, patients with radiotherapy immunotherapy were not enrolled for the study, so postoperative outcomes were not analyzed. Therefore, it is necessary to conduct a large-scale, long-term, well-designed prospective study to enrich research on the clinical efficacy and safety of treatment regimens in pediatric NB cases.

In conclusion, this study reported that pre-operative biopsy in patients with NB at INSS stage 4 located in the adrenal glands, allowed for a clear diagnosis and subsequent RS did not increase the risk of surgical complications. Moreover, EVS has been affirmed as an important factor for surgical resection and surgical complications.

We declare that there was no conflict of interest.

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Table 1. Basic Characteristics of patients in this study.

Variables	Group A	Group B	Group C
Case number	5	9	20
Gender (n)
Boys	4	5	12
Girls	1	4	8
Age（months; mean±SD）	62.6±36.0	34.8±30.2	45.6±20.3
Weight（kg; mean±SD）	23.5±13.5	14.0±6.2	16.3±4.1
Hypertension (n)	2	4	10
Side (n)
Left	3	3	10
Right	2	6	10
Histology (n)
Undifferentiation	1	0	0
Less differentiation	2	1	2
Differentiation	2	0	0
N/A	0	8	18
INRGSS stage (n)
M	5	8	20
Ms	0	1	0
COG grade (n)
High-rsik	5	6	20
Intermediate-risk	0	2	0
N/A	0	1	0
Distant metastasis (n)	1	3	5
Kidney
Liver	2	5	2
Bone marrow	3	3	20
Bone	2	5	6
Lymphatic metastasis (n)
Positive	3	6	18
Negative	1	2	1
N/A	1	1	1
MYCN gene (n)
Positive	1	4	4
Negative	2	3	12
N/A	2	2	4
Symptom before initial clinic visit (n)
Mass	1	3	5
Abdominal pain	2	2	5
Osteodynia	0	0	5
Fever	1	1	1
No symptom	0	2	1
Emesis	0	0	1
Abdominal distention	1	0	1
Anemia	0	1	0
Orbital edema	0	0	1
Death after surgery (n)	1	1	0
Surgical treatment
CR	1	2	2
MR	2	6	16
IR	2	1	2
Complication grade (n)
II	4	6	19
IIIa	0	2	0
IIIb	0	0	1
IVa	0	1	0
IVb	1	0	0
Ⅴ	0	0	0

Abbreviations: SD, standard deviations; CR, complete resection; MR, minimal residue; IR, incomplete resection; INRGSS, International neuroblastoma risk group staging system; N/A, not available;

Table 2. Results of Univariate analysis among three groups

Variables	Group A	Group B	Group C	P value
N	5	9	20
NSE（ng/ml; mean ± SD）
Pre-surgery	141.2±133.0	280.9±108.0	321.0±73.0	0.002
Post-surgery	90.0±108.2	59.5±117.8	19.7±9.6	0.31
LDH（U/L; mean ± SD）
Pre-surgery	491.8±317.2	1984.01±2216.5	1586.7±2200.9	0.43
Post-surgery		359.0±236.3	261.9±89.1	0.12
Ki-67（%; mean ± SD）	62.0±8.4	62.2±14.2	11.7±9.9	<0.0001
Tumor volume（ml; mean ± SD）
Primary	263.1±350.5	438.4±303.9	309.5±445.3	0.66
Before RS	263.1±350.5	103.7±82.8	165.9±452.8	0.69
IDRFs（n）	3.0±2.5	3.9±0.8	3.8±1.6	0.66
Primary
Before RS	3.0±2.5	3.7±0.7	3.7±1.5	0.77
EVS（n）	1.0±1.4	2.7±1.7	1.3±1.4	0.054
Primary
Before RS	1.0±1.4	2.4±1.4	1.3±1.4	0.095
Operative time（min; mean ± SD）	307.0±165.4	439.4±169.2	396.0±151.0	0.33
Transfusion during RS（U; mean ± SD）	2.1±3.4	1.6±1.7	1.1±1.2	0.74
Number of lymph node biopsies（n; mean ± SD）	4.8±8.5	14.4±12.5	17.2±16.9	0.27
Drainage days（d; mean ± SD）	11.0±8.2	20.9±13.5	15.6±12.8	0.35
Fasting days（d; mean ± SD）	8.0±9.8	15.6±13.5	10.1±15.4	0.56
Surgical treatment (n)
CR+MR	3	8	18	0.51^a
IR	2	1	2	>0.99^b
Complication grade (n)
II	4	6	19	>0.99^a
III-IV	1	3	1	0.076^b

Abbreviations: SD, standard deviations; RS, radical surgery; CR, complete resection; MR, minimal residue; IR, incomplete resection; IDRF, Image-Defined Risk Factors; EVS, Encasement of vessels; LDH, Lactate dehydrogenase; NSE, neuron-specific enolase.

a, compared between group A and group B; b, compared between group B and group C.

Table 3.Risk factors analysis of surgical resection and complications.

	Surgical treatment			Complication after RS
Group	CR+MR	IR	P value	II	III+IV	P value
Age（months; mean±SD）	43.9±26.0	53.0±29.6	0.48	47.1±27.7	34.4±12.7	0.326
Weight（kg; mean±SD）	16.4±7.3	19.0±6.1	0.45	17.3±7.5	13.8±1.9	0.32
Operative time（min; mean±SD）	397.2±167.7	378.0±99.3	0.807	381.9±160.6	467.0±136.9	0.274
Blood transfusion（U; mean±SD）	1.2±1.4	2.5±3.2	0.416	1.2±1.4	2.4±3.1	0.431
Primary IDRFs（n; mean±SD）	3.6±1.5	4.6±1.8	0.181	3.4±1.5	5.2±1.1	0.022
IDRFs before RS（n; mean±SD）*	3.4±1.4	4.6±1.8	0.093	3.3±1.4	4.8±1.5	0.043
Primary EVS（n; mean±SD）	1.3±1.4	3.0±1.9	0.03	1.2±1.2	4.0±1.4	<0.0001
EVS before RS（n; mean±SD）*	1.3±1.4	2.8±1.8	0.039	1.1±1.2	3.8±1.3	<0.0001
Primary maximum diameter of the tumor（cm; mean±SD）	9.0±3.9	9.4±4.2	0.849	8.4±3.8	12.8±1.5	0.018
Primary tumor volume（ml; mean±SD）	327.9±406.4	388.5±351.3	0.756	282.4±383.1	652.1±332.3	0.051
Maximum diameter of the tumor before RS（cm; mean±SD）*	6.6±3.3	6.4±3.8	0.909	6.4±3.3	7.2±3.3	0.646
Tumor volume before RS（ml; mean±SD）*	155.4±375.2	212.0±376.9	0.758	152.3±376.1	229.9±366.7	0.672
NSE（ug/ml; mean±SD）	285.4±107.1	275.7±135.4	0.858	269.1±112.0	370.0±0.0	<0.0001
Hb（g/L; mean±SD）	95.4±21.7	88.8±31.9	0.56	97.4±21.9	77.2±23.6	0.068
LDH（U/L; mean±SD）	1513.9±2084.8	1629.2±2079.0	0.91	1138.4±1723.8	3806.8±2523.8	0.005
ki67（%; mean±SD）	30.0±27.0	45.0±29.2	0.273	27.7±24.5	60.0±29.2	0.012

Abbreviations: SD, standard deviations; RS, radical surgery; CR, complete resection; MR, minimal residue; IR, incomplete resection; IDRF, Image-Defined Risk Factors; EVS, Encasement of vessels; LDH, Lactate dehydrogenase; NSE, neuron-specific enolase.

*data in group A was included.

Table 4. Complications of RS surgery reported in this study.

Complications	n	%
Haemorrhage	25	73.5
Celiac leakage	24	70.6
Intestinal obstruction	9	26.5
Partially resection of tumors	5	14.7
Ipsilateral nephrectomy	3	8.8
Renal ischaemia	2	5.9
Renal insufficiency	1	2.9
Multiple organ failure	1	2.9
Injury of blood vessel	1	2.9
Bowel necrosis	1	2.9
Pleural effussion	1	2.9
Urinous infiltration	1	2.9

No competing interests reported.

Clinical Comparison of Surgical Treatment and Complications in Pediatric Patients with Neuroblastoma at Stage 4

Status:

Version 1

Abstract

1. Introduction

2. Population And Methods

2.1 Ethnical statement

2.2 Study design

2.3 Inclusion and exclusion criteria

2.4 Treatment

2.5 Data collection

2.6 Statistical analysis

3. Results

Discussion

Declarations

References

Tables

Additional Declarations

Status:

Version 1