Pediatric Neuroblastoma - Impact of Nutritional Status on Complications and Outcomes.

Aim: The aim is to study the impact of nutritional status on outcomes and treatment-related complications in patients of neuroblastoma. Materials and
Methods: Anthropometry (height, weight, weight for height [in <5 years], mid-arm circumference [MAC] [in <5 years], and body mass index [BMI]), hemoglobin level, and serum albumin level were recorded.
Results: Twenty-four neuroblastoma patients, 16 males and 8 females, with a mean age of 42.7 months were treated and followed up over a period of 0.03-170 months. Of 24 patients, 16 survived (complete response - 9, partial response - 2, no response - 2, progressive disease - 3). Height <2 standard deviation [SD] was seen in 12.5% (3/24). Mortality and complications were found in 66.7% (2/3) and 100% (3/3), respectively. Weight <2SD was seen in 37.5% (9/24). Mortality and complications were found in 33.3% (3/9) and 67% (6/9), respectively. Weight for height <2 SD was seen in 35% (7/20). Mortality and complications were found in 42.9% (3/7) and 71.4% (5/7), respectively. MAC <2 SD was seen in 15.8% (3/19). Mortality and complications were found in 66.7% (2/3) and 66.7% (2/3). BMI <2SD was seen in 29.2% (7/24). Mortality and complications were found in 42.8% (3/7) and 28.6% (2/7). Anemia was seen in 62.5% (15/24), of which nine survived. Complications were seen in 58.3% (14/24) (P = 0.001). Hypoproteinemia was seen in 20.8% (5/24). Mortality and complications were 40% (2/5) and 80% (4/5).
Conclusion: Neuroblastoma has poor outcome in Indian children, and there does not appear to be a major role played by nutrition in determining the response to treatment and survival. Copyright:

INTRODUCTION

Neuroblastoma is the most common solid tumor of childhood and infancy. It is responsible for 10% of all childhood tumors, with an incidence being 1 in 7500–10,000. It has one of the least favorable outcomes among pediatric cancers, accounting for 15% of all childhood cancer deaths.[1] Even in developed countries, the cure rate does not exceed 40%.[2] The outcome is poor in developing countries like India. Very few centers in India have studied and published the outcomes and prognostic factors.[34567] The factors contributing to poor outcome in India are late presentation, poor nutrition status, poor compliance to treatment, cost, and nonavailability of autologous stem cell transplantation at most centers.[8] Good nutritional status is always warranted; however, the effect of poor nutritional status has not been evaluated by most of the studies.

Therefore, we planned the study to assess the nutritional status using anthropometry, anemia and hypoproteinemia and analyzed its effect on the survival, response to treatment, and complications during treatment.[9] Unlike the other prognostic factors, the nutritional status of the patients can be improved.

MATERIALS AND METHODS

An ambispective study was done to include all consecutive cases of neuroblastoma under 14 years of age, who were registered under the Pediatric Surgery Tumor Clinic from July 2015 to June 2020. Patients who refused consent for participation, who discontinued treatment before receiving 3 weeks of chemotherapy, and with a final diagnosis other than neuroblastoma, ganglioneuroma, and ganglioneuroblastoma were excluded from the study.

Methodology

The ethical clearance was taken from the institutional ethics committee (IECPG-622/22.12.2016, RT-08/16.02.2017). Patient's parents/guardians were informed about the study. Written informed consent for participation in the study was taken. Detailed history including age, gender, clinical features, family history, and residential address was recorded. Physical examination including general physical examination, vitals, systemic examinations, and anthropometry was recorded. The patients were investigated and treated according to the stage of the disease. Investigations done for diagnosis and during management were recorded. The course of therapy including neoadjuvant chemotherapy, surgery, adjuvant chemotherapy, radiotherapy, and Meta-iodobenzylguanidine (MIBG) therapy were noted. Any complications during therapy, survival, and response to treatment were also recorded. All the alive patients were followed up to June 30, 2020. The data were analyzed in detail for the evaluation of outcomes.

Anthropometry was recorded. Standing height (in centimeter up to one-digit) was measured using a stadiometer in children >2 years of age. The recumbent length was measured using an infantometer in children <2 years of age. Weight (in kilograms up to two-digit) was taken using an electronic weighing machine. Mid-arm circumference (MAC, in centimeter up to one digit) was measured for children below 5 years of age. It was measured at mid-point between the acromion process and olecranon while the child holds his arm by his side. Weight for height was determined for all children below 5 years of age using the WHO charts.[9] Body mass index (BMI) was calculated as weight in kilograms/(height in meters)2.

For children <5 years, weight, height, weight for height, MAC, and BMI were assessed. For children >5 years, weight, height, and BMI were assessed. The assessment was done using the Indian Academy of Pediatrics (IAP) guidelines.[10] IAP recommends the use of the WHO Multistandards Growth Reference Study for the assessment of children under the age of 5 years. For the assessment of children older than 5 years, IAP Growth Charts were used.[10] The WHO recommends the use of Z-scores (SDs above or below the mean) for evaluating the anthropometric data to classify individuals with indices below the extreme percentiles.[11] A Z-score of −2 to −3 indicates moderate malnutrition and <−3 indicates severe malnutrition. In our study, we have taken anthropometric indices below 2 SD as an indicator of poor nutritional status.

Hemoglobin and albumin level at presentation were recorded. Those with albumin level <3.5 g/dl were considered to have hypoalbuminemia.[12] Anemia was labeled using the WHO cutoff for different age groups.[13]

Management

Investigations done for diagnosis and treatment were as follows: contrast-enhanced computed tomography scan of primary tumor, histopathology (preoperative and postoperative), MIBG scan, bone marrow aspiration and biopsy, bone scan, skeletal survey, complete blood count, and liver and kidney function test. The diagnosis was established by tumor biopsy along with immunohistochemistry. The staging was done using the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRG).[1415] Treatment was administered according to the stage at presentation. Surgery was done if the tumor was resectable either upfront or following week 17 chemotherapy. Chemotherapy was administered according to the stage of the disease. Stage L1 received 3 weekly courses of cyclophosphamide (150 mg/m2/day × 7 days; weeks 0, 3, 6, 9, 12) and doxorubicin (35 mg/m2/dose; weeks 1, 4, 7, 10, 13) after surgery. Stage MS received 3 weekly courses of cyclophosphamide (5 mg/kg/day) × 3 days and vincristine (0.05 mg/kg) on day 1 for a total of 6 courses. STAGE L2, M received cyclophosphamide (150 mg/m2/day × 7 days; weeks 0, 3, 6, 13, 17, 21, 29), cisplatin (90 mg/m2; weeks 1, 7, 10, 14, 25, 33), doxorubicin (35 mg/m2/dose; weeks 1,7,14,22, 30), and etoposide (100 mg/m2/day × 2 days; weeks 4, 10, 18, 25, 33). For the progressive disease (PD), alternate chemotherapy regimen, ifosfamide, carboplatin, etoposide (ICE) regimen was administered. Metronomic therapy (alternate etoposide and cyclophosphamide, 3 weekly and daily dose of thalidomide and celecoxib for 6 weeks) was administered for progressive stage 4 disease showing no response (NR) to ICE regimen. Radiotherapy was given to those found unresectable at week 17. Radiotherapy to the primary site was given to Stage 3 and 4 abdominal and pelvic tumors. MIBG therapy was given to patients for palliation in PD. The treatment response was assessed according to the International Criteria for Response to Treatment.[14] Response to treatment was categorized as complete response (CR), partial response (PR), NR, and PD. CR is defined as complete absence of primary and metastatic disease. PR is defined as more that 50% reduction in tumor size. NR is defined as <50% reduction, but <25% increase in tumor size. PD is defined as more than 25% increase in any measureable lesion or appearance of any new lesion.

Statistical analysis

Data was analyzed by statistical software STATA 14.0 Stata (StataCorp LLC, College Station TX77845, USA). Categorical data were expressed as frequency and percentage. Chi-square/Fisher's exact test was used to check the association between categorical variables. In time to event data, Kaplan–Meir analysis was carried out. A P < 0.05 was considered statistically significant.

RESULTS

A total of 24 neuroblastoma patients, 16 males and 8 females, were included in the study. They were followed up over a period of 0.03–170 months (mean follow-up - 40.9 months). The mean age at diagnosis was 42.7 months (range-[0.5–144 months]). Of the 24 patients, 29% (n = 7) were <12 months of age.

Site of primary tumor and metastasis at diagnosis

The most common site was adrenal gland (n = 12; 50%), followed by thorax (n = 6; 25%), retroperitoneum (n = 5; 21%), and pelvis (n = 1; 4%). None were located in the neck. The intraspinal extension was seen in 3 of 6 thoracic cases, 2 of 12 adrenal cases, and 2 of 5 retroperitoneal cases. Metastasis at diagnosis was seen in 37.5% (n = 9) of the patients. Bones were the most common site of metastasis. Vertebrae and femur were most commonly involved, followed by pelvic bones, ribs, parietal bone, tibia, and humerus. Other metastatic sites were lymph nodes and liver.

Stage and treatment course

INSS stage - Out of 24 patients, 12.5% (n = 3) were Stage 1, 8.3% (n = 1) were stage 2, 41.7% (n = 10) were Stage 3, 29.2% (n = 7) were Stage 4, and 8.3% (n = 2) were Stage 4S

INRG stage - Out of 24 patients, 20.8% (n = 5) were Stage L1, 41.7% (n = 10) were Stage L2, 29.2% (n = 7) were Stage M, and 8.3% (n = 2) were Stage MS.

On histopathology, 1 had ganglioneuroma, 3 had ganglioneuroblastoma, and 20 had neuroblastoma. Out of 24 patients, 18 received neoadjuvant chemotherapy, and six were operated upfront. In the neoadjuvant chemotherapy group, the tumor became resectable in 6 patients. Postsurgery, they received adjuvant chemotherapy. Twelve remained unresectable following neoadjuvant chemotherapy, but chemotherapy was continued in these patients, and five of these children were given radiotherapy. Three children with PD were given MIBG therapy for palliation. Six children underwent upfront surgery, following which three received chemotherapy, while 3 underwent only surgery [Figure 1].

Figure 1

Treatment course

Survival, response to treatment, and complications during treatment

At the end of our follow-up, 33.3% (n = 8) were dead and 66.7% (n = 16) were alive. The most common cause of death was progression of disease (n = 4; 50%), followed by febrile neutropenia (n = 3; 37.5%) and hypertension and tumor lysis syndrome (n = 1; 12.5%). The 3-year overall survival was 0.6667 ± 0.0962 (95% CI 0.4428–0.8173) [Figure 2]. Of a total of 24 patients, 37.5% (n = 9) had CR, 8.3% (n = 2) had PR, 8.3% (n = 2) had NR, 12.5% (n = 3) had PD, and 33.3% (n = 8) had mortality.

Figure 2

Kaplan–Meier curve for 3-year overall survival

The most common complication that occurred during the treatment course was neutropenia and affected 54.2% of the patients (n = 13). Other complications were acute respiratory distress syndrome (n = 1) and tumor lysis syndrome and hypertension (n = 1).

Nutritional status and its effect on survival, response to treatment, and complications

The nutritional status of the patients at presentation is depicted in Table 1, and its effect on survival and complications are depicted in Table 1 and its effect on response to treatment in Table 2.

Table 1

Effect of nutritional status on survival and complications

Nutritional parameter	n (%)	Survival			Complications
		Died, n (%)	Alive, n (%)	P	Yes, n (%)	No, n (%)	P
Height
<2SD	3 (12.5)	2 (66.7)	1 (33.3)	0.249	3 (100)	0	0.239
>2SD	21 (87.5)	6 (28.6)	15 (71.4)		11 (52.4)	10 (47.6)
Weight
<2SD	9 (37.5)	3 (33.3)	6 (66.7)	0.999	6 (66.7)	3 (33.3)	0.678
>2SD	15 (62.5)	5 (33.3)	10 (66.7)		8 (53.3)	7 (43.7)
Weight for height
<2SD	7 (35)	3 (42.9)	4 (57.1)	0.651	5 (71.4)	2 (28.6)	0.642
>2SD	13 (65)	4 (30.8)	9 (69.2)		7 (53.9)	6 (46.5)
MAC
<2SD	3 (15.8)	2 (66.7)	1 (33.3)	0.523	2 (66.7)	1 (33.3)	0.999
>2SD	16 (84.2)	5 (31.2)	11 (68.8)	10 (62.5)	6 (37.5)
BMI
<2SD	7 (29.2)	3 (42.8)	4 (57.2)	0.647	5 (71.3)	2 (28.6)	0.653
>2SD	17 (70.8)	5 (29.4)	12 (70.6)		9 (52.9)	8 (47.4)
Anemia
Yes	15 (62.5)	6 (40)	9 (60)	0.657	14 (93.3)	1 (6.7)	0.001
No	9 (37.5)	2 (22.2)	7 (77.8)		0	9 (100)
Hypoproteinemia
Yes	5 (20.8)	2 (40)	3 (60)	0.999	4 (80)	1 (20)	0.358
No	19 (79.2)	6 (31.6)	13 (68.4)		10 (52.6)	9 (47.4)

SD: Standard deviation, MAC: Mid-arm circumference, BMI: Body mass index

Table 2

Effect of nutritional status on response to treatment

Nutritional parameter	n	Mortality, n (%)	CR, n (%)	PR, n (%)	PD, n (%)	NR, n (%)	P
Height
<2SD	3	2 (66.7)	0	0	0	1 (33.3)	0.277
>2SD	21	6 (28.6)	9 (42.8)	2 (9.5)	3 (14.3)	1 (4.8)
Weight
<2SD	9	3 (33.3)	1 (11.1)	1 (11.1)	2 (22.2)	2 (22.2)	0.090
>2SD	15	5 (33.3)	8 (53.3)	1 (6.7)	1 (6.7)	0
Weight for height
<2SD	7	3 (42.9)	1 (14.3)	1 (14.3)	1 (14.3)	1 (14.2)	0.297
>2SD	13	4 (30.8)	7 (53.8)	1 (7.7)	0	1 (7.7)
MAC
<2SD	3	2 (66.7)	0	0	1 (33.3)	0	0.140
>2SD	16	5 (31.2)	7 (43.8)	2 (12.5)	0	2 (12.5)
BMI
<2SD	7	3 (42.8)	1 (14.3)	1 (14.3)	2 (28.6)	0	0.283
>2SD	17	5 (29.4)	8 (47.1)	1 (5.9)	1 (5.9)	2 (11.7)
Anemia
Yes	15	6 (40)	3 (20)	1 (6.67)	3 (20)	2 (13.3)	0.147
No	9	2 (22.2)	6 (66.7)	1 (11.1)	0	0
Hypoproteinemia
Yes	5	2 (40)	0	0	2 (40)	1 (20)	0.069
No	19	6 (31.5)	9 (47.4)	2 (10.5)	1 (5.3)	1 (5.3)

SD: Standard deviation, MAC: Mid-arm circumference, BMI: Body mass index, CR: Complete response, PR: Partial response, PD: Progressive disease, NR: No response

Nutritional status parameters

Height below − 2SD was seen in 12.5% (3/24) patients, of which 1 survived (NR - 1). All had complications during treatment. Weight below 2SD was seen in 37.5% (9/24) patients, of which 6 survived (CR - 1, PR - 1, PD - 2, NR - 2). Complications were seen in 66.7% (6/9). Weight for height below 2SD was seen in 35% (7/20) patients, of which 4 survived (CR - 1, PR - 1, PD - 1, NR - 1). Complications were seen in 71.4% (5/7). MAC below 2SD was seen in 15.8% (3/19) patients, of which 1 survived (PD - 1). Complications were seen in 66.7% (2/3). BMI below 2SD was seen in 29.2% (7/24) patients, of which 4 survived (CR - 1, PR - 1, PD - 2). Complications were seen in 28.6% (2/7). Anemia was seen in 62.5% (15/24) patients, of which 9 survived (CR - 3, PR - 1, PD - 3, NR - 2). Complications were seen in 93.3% (14/15) (P = 0.001). Hypoproteinemia was seen in 20.8% (5/24) patients, of which 3 survived (PD - 2, NR - 1). Complications were seen in 4 of 5 (80%).

Among the deranged nutritional status parameters, anemia was most commonly seen, affecting 62.5% of the patients [Table 1]. The next common deranged parameter was weight (37.5%) [Table 1]. Among the patients who had mortality, anemia was seen in 75% of the patients [Table 1]. However, the effect of none of the nutritional status parameters on survival reached statistical significance, because of the small number of patients. When we studied the effect of nutritional status on response to treatment, we found that hypoproteinemia affected response to treatment with P value approaching significance (P = 0.069) [Table 2]. None of the other parameters significantly affected the response to treatment. On studying the effect of nutritional status on complications, we found that complications were significantly high in anemic patients (P = 0.001), with neutropenia being the most common complication [Table 1].

DISCUSSION

Neuroblastoma is the most common solid tumor of childhood and infancy and is responsible for 10% of all childhood tumors.[8] Numerous biological and genetic markers have been identified as prognostic markers of neuroblastoma which includes age and stage at presentation, primary site, metastasis, histopathology, Myc-N amplification, chromosome 1p loss, DNA index, CD44, Trk-A expression, vanillylmandelic acid:homovanillic acid ratio, neuron-specific enolase, lactate dehydrogenase, ferritin, and multidrug resistance.[16] These prognostic factors can help to stratify the patients into different risk groups. The treatment can be administered accordingly. This is important as some of these tumors will undergo spontaneous regression (mostly in young children) or maturation, whereas others will continue to progress despite intensive therapy. The most suitable therapy can be delivered according to a risk-stratified strategy, from observation to megadose chemotherapy with stem cell transplantation. The proper establishment of the most appropriate individual and potential combinations of prognostic markers to be used in clinical practice can thereby improve patient care. However, the majority of hospitals in India do not have the facility to identify molecular markers, and it is costly at centers where the facility is available. It is also difficult to decide which marker should be given more importance.

The impact of nutritional status on outcome in neuroblastoma patients has not been studied well in Indian children. A few studies outside India have tried to assess its impact.[171819] Most of them have studied the role of nutrition in neuroblastoma along with other cancers and have included few patients of neuroblastoma.[2021222324] Thus, the impact of nutritional status on neuroblastoma was not very clear.

Sala et al. assessed the nutritional status at diagnosis of 1787 children and adolescents with cancer (including 30 neuroblastoma cases).[20] They found the survival of the adequately nourished children to be significantly more than the severely depleted (65% vs. 48%) (P < 0.001). However, in our study, 24 neuroblastoma patients were included, and survival and outcome were not significantly affected by the nutritional status of the patients. Donaldson et al. reviewed the nutritional status of 455 children with cancer (including 13 neuroblastoma cases) and found that in children with advanced disease, survival was poorer, regardless of their nutritional status, whereas in children with localized disease, survival improved with good nutritional status.[21] However, in our study, the impact of nutritional status on localized and advanced disease could not be assessed due to the small number of patients.

Lahorra et al. reported that children with neuroblastoma had a significantly lower weight for age at diagnosis when compared with those of Wilms’ tumor.[22] Their weight for height and weight for age at completion were statistically lower (P < 0.05). They spent a greater proportion of their treatment time as hospital-admitted patients and had more frequent hospital admissions, longer delays in therapy, and more complications. Their anthropometric measurements did not correlate with the development of complications during therapy.

In our study, 37.5% (9/24) patients had weight below 2SD and 35% (7/20) patients had weight for height below 2SD. We found no significant correlation of weight for age (P = 0.678), height for age (P = 0.239), weight for height (P = 0.642), and BMI (P = 0.653) with development of complications. The anthropometric impact was not found to be significant due to less number of patients. However, we found a higher incidence of complications in patients with anemia (P = 0.001).

Rickard et al. studied the effect of the state of nutrition in 18 children with Stage IV neuroblastoma.[17] The malnourished children had delayed remission (P < 0.01) and poor survival (P = 0.08). In our study, there were seven patients in Stage IV, 71.4% (5/7) had weight below 2SD, 14.3% (1/7) had height below 2SD, and 28.6% (2/7) had weight for height below 2SD. 42.9% (3/7) died, 42.9% (3/7) had PD, and 14.2% (1/7) had NR. However, the impact of nutritional status on Stage IV disease could not be assessed due to the small number of patients.

Small et al. evaluated BMI status of 154 children with neuroblastoma and reported that BMI at diagnosis did not affect survival.[19] In our study also, BMI did not affect survival (P = 0.647) and outcome (P = 0.283).

Radhakrishnan et al. found that hemoglobin less than 10 g% predicted inferior event-free survival (P = 0.002) and overall survival (P = 0.005) for 85 neuroblastoma patients.[7] In our study, there was no significant effect of anemia on survival (P = 0.657) and outcome (P = 0.147). However, patients with anemia had more complications (P = 0.001).

Navalkele et al. found hypoalbuminemia in 85.7% (30/35) of neuroblastoma patients at presentation.[18] However, in our study, 20.8% (5/24) had hypoalbuminemia at presentation. Elhasid et al. reported hypoalbuminemia in 2.7% of children with solid tumors (50 patients, including 5 cases of neuroblastoma).[24] Merritt et al. showed that patients with normal albumin levels at presentation had a better chance at survival.[23] In our study, no significant impact of hypoalbuminemia on survival (P = 0.067) and outcome (P = 0.069) was there.

The limitation of the study was that no biological marker was used for risk stratification because of nonavailability at our institute. Because of the high cost of the tests for biological markers, most of the patients could not afford them. The number of patients is less and follow-up period is less. Cause, effect, and incidental association cannot be differentiated. Although it is an ambispective study, data of most of the patients were included prospectively. Only a few were studied retrospectively. There does not appear to be a major role played by nutrition on survival as none of the values attained statistical significance.

To conclude, anemic patients have significantly more treatment-related complications. Nutritional status does not appear to have significant impact on survival and response to treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.