Keywords pediatric - metastatic neuroblastoma - survival - developing country - India
Introduction
Neuroblastoma (NB), the most common pediatric extracranial solid tumor, is one of
the most challenging childhood cancers to treat. In the developing countries, majority
of children with NB present with high-risk and metastatic disease, with frustratingly
low survival even after skillful use of multiple treatment modalities.[1 ] In the high-income countries, the use of advanced therapeutics like high-dose chemotherapy
followed by autologous stem cell transplant (ASCT), surgery, radiotherapy, and immunotherapy
is able to yield around 40% survival in high-risk NB.[2 ] Transplant facilities and anti-GD2 therapy, which form the standard of care in the
developed countries, are not available to majority of the needful patients in the
low-and-middle-income countries (LMICs). In the nontransplant setting like ours, metastatic
NB is treated with conventional chemotherapy combined with local control modalities
like surgery and/or radiotherapy.[3 ] We determined treatment outcome and factors affecting survival of children over
1 year of age with metastatic NB treated at our center with chemotherapy, surgery,
and radiotherapy.
Materials and Method
This is a retrospective study of case records of all children aged 1 to 14years with
stage 4 NB treated at our center over a 10-year period (January 1, 2008 to December
31, 2017). Disease evaluation was done clinically and by blood investigations including
lactate dehydrogenase (LDH) and imaging of the primary site with ultrasound or computed
tomography scan. Metastatic workup included skeletal X-rays and bone marrow biopsy.
Assessment of bone metastases was dependent on skeletal X-rays, as MIBG (metaiodobenzylguanidine)
scintigraphy was not available in our hospital and bone scan could be used only sparsely
because of interruptions in availability of reagent. The diagnosis of NB was established
by histopathology and immunohistochemistry of bone marrow or primary tumor tissue.
N-myc studies were not available in the hospital.
Inclusion and Exclusion Criteria
All patients over 1 year of age diagnosed with metastatic NB and received treatment
at our center were included. Patients who received treatment elsewhere and those who
expired before starting treatment were excluded.
Chemotherapy
Two chemotherapy schemes were in use for treating pediatric NB in the hospital during
this time. Chemo A was a moderately aggressive regimen consisting of vincristine 1.5 mg/m2 , Adriamycin 40 mg/m2 and cyclophosphamide 1500 mg/m2 alternating with cisplatin 100 mg/m2 , and etoposide 450 mg/m2 every 3 weekly for 1 year (maximum cumulative dose of Adriamycin 360 mg/m2 ). Chemo B was the less intensive regimen consisting of six 3-weekly cycles of vincristine,
Adriamycin 30 mg/m2 , and cyclophosphamide 750 mg/m2 . Patients were assigned to receive the chemotherapy regimen by the treating consultant
based on the general condition, extent of metastatic disease, logistic and social
factors, and parental decision.
Response to Chemotherapy
Response assessment was done after four cycles of chemotherapy with bone marrow examination
and skeletal X-rays. MIBG was not available in the hospital and bone scan was not
done universally due to erratic availability of reagent. Disappearance of disease
from metastatic sites as evidenced by a normal bone marrow examination and absence
of lytic bone lesions on skeletal X-rays was considered as good response. Imaging
of the primary site for response assessment was done only for patients who cleared
the disease from metastatic sites. Persistent metastatic disease was considered as
poor response.
Local Treatment and Maintenance Chemotherapy
Surgery was done if safe resection was feasible, followed by further chemotherapy
according to the assigned regimen. Radiotherapy was given for unresectable/residual
disease after completion of treatment regimen, followed by oral metronomic chemotherapy
with cyclophosphamide 50 mg/m2 and etoposide 50 mg/m2 daily for 20 days per month for 6 to 8 months. Patients with disease progression
at any time were assigned to palliative care.
Primary and Secondary Outcome Measures
The primary outcome measure was to estimate the survival of children over 1 year of
age treated for metastatic NB. The secondary outcome was to determine any clinical
or biological factors affecting survival of these patients in the nontransplant setting.
Statistical Methods
The descriptive analysis included the absolute and relative frequency for categorical
variables. Comparison between groups was carried out using the chi-square test or
Fisher's exact test. Variables for the survival analysis were age, primary site, metastatic
site, baseline LDH, chemotherapy regimen, response to chemotherapy, and surgery. The
survival curve was estimated for each variable using the Kaplan–Meier method. The
comparison between curves was obtained by the log-rank test. The Cox regression model
was used to assess the effect of the variables on survival (multivariate analysis
to calculate hazard ratios), which included variables with the following characteristics
according to the Kaplan–Meier analysis with a significant difference (p < 0.05). The level of significance established for all analyses was 5%. All analyses
were performed using the software SPSS 20.0 for Windows (Statistical Package for Social
Sciences, IBM, United States).
Ethics
All procedures performed in studies involving human participants were in accordance
with the ethical standards of the institutional and/or national research committee
and with the 1964 Helsinki Declaration and its later amendments or comparable ethical
standards. The study was carried out according to the regulations established by the
Institutional Clinical Research Review Board and approved by Human Ethics Committee,
Regional Cancer Centre Trivandrum (No. 02/2018/13, dated 22/02/2018, 2 p.m.). Consent
for treatment and use of medical record data for scientific studies were routinely
obtained for all patients.
Results
Patient Demographics
There were 119 children > 1 year of age with metastatic NB, forming 50.2% of the total
noninfant NB patients. Mean age of the patients was 3.5 years (range 1–14 years) and
male:female ratio was 1.1:1. Eighty-nine patients consented for treatment and are
included in the analysis. Out of these, 24 patients were aged < 18 months and 65 patients
were older.
Disease Characteristics
The most common site of primary tumor was suprarenal (n = 66, 55.5%), followed by retroperitoneal (n = 25, 21%), thoracic/mediastinal (n = 7, 5.9%), cervical (n = 8, 6.7%), and multifocal (n = 3, 2.5%). Primary tumor was undetected in 6 patients (5%). The most common site
of metastasis was bone marrow (n = 68, 76.3%), followed by bone (n = 14, 15.9%), lymph nodes (n = 6, 6.2%), and liver (n = 1, 1%). Thirty-six patients (40.4%) had multiple metastatic sites. Baseline LDH
values were available for 79 patients, with mean value of 3724 U/L (range 303–16609
U/L). Fifty-eight patients (65%) had LDH > 750 U/L and 21 patients (23.5%) had LDH < 750
U/L.
Treatment and Response
Thirty-eight patients (42.6%) received Chemo A, out of which 30 patients (78.9%) had
good response to chemotherapy and 6 patients (15.7%) had poor response. Fifty-one
patients (57.3%) received Chemo B, out of which 23 patients (45.09%) had good response
and 24 patients (47.05%) had poor response ([Table 1 ]). In 6 patients, response assessment could not be done because of early clinical
progression or death. Surgery could be attempted in 26 patients (29.2%), with excision
in 16 patients, debulking in 6 patients, and biopsy alone in 4 patients. Only 3 patients
received radiotherapy and 12 patients received metronomic maintenance chemotherapy
(9 patients after Chemo A and 3 patients after Chemo B).
Table 1
Prognostic variables on univariate analysis
Prognostic variable
DFS probability
p -Value
OS probability
p -Value
Hazard ratio
p -Value
Age
< 2 y
19.8
0.96
23.3
0.92
1.02
0.927
> 2 y
15.3
15.2
Primary site
Adrenal
14.7
0.178
17.6
0.07
1.00
0.99
Cervical
30.0
30.0
Posterior mediastinal
50.0
100.0
Paraspinal
13.3
13.3
Abdominal/retroperitoneal
33.3
33.3
Multifocal
25.0
25.0
Metastatic site
Bone marrow
18.0
0.865
20.7
0.87
1.3
0.861
Bones
9.1
9.1
Lymph nodes
25.0
25.0
Multiple sites
16.3
15.9
LDH
< 750 U/L
50.0
0.028
46.9
0.032
2.29
0.013
> 750 U/L
18.6
16.2
Chemotherapy
Chemo A + Metronomic
55.6
55.6
Chemo A
23.6
0.001
27.2
0.001
6.03
0.001
Chemo B
8.3
8.1
Response
Good
27.8
0.001
29.7
0.001
6.96
0.001
Poor
3.3
3.3
Surgery
No surgery
5.7
0.001
7.5
0.001
1.32
0.001
Biopsy only
0.0
0.0
Debulking
66.7
66.7
Excision
43.8
43.8
Abbreviations: DFS, disease-free survival; LDH, lactate dehydrogenase; OS, overall
survival.
[Table 2 ] shows patient outcome by treatment regimen.
Table 2
Response and outcome by treatment regimen
Parameter
Chemo A
(n = 38)
Chemo B
(n = 51)
Metronomic chemo maintenance
9 (23.6%)
3 (5.8%)
RT
2 (5.2%)
1 (1.9%)
Good response
30 (78.9%)
23 (45%)
Poor response
6 (15.7%)
24 (47%)
Recurrence/relapse
27 (71%)
46 (90%)
Patients alive
11 (28.9%)
5 (9.8%)
5-year DFS
23.6%
5.0%
5-year OS
27.2%
8.1%
Abbreviations: DFS, disease-free survival; OS, overall survival; RT, radiotherapy.
Relapse and Death
Overall, 74 patients (86%) developed recurrence/progression of disease. Out of the
53 patients who had good initial response to chemotherapy, 43 patients (81%) relapsed.
The median time to recurrence/progression was 9 months (range 1–120 months). Seventy-three
patients (85.9%) died, the median time to death being 10 months (range 1–123 months).
Cause of death was disease progression in 71 patients and toxicity-related deaths
in 2 patients. Three relapsed patients are lost to follow-up.
[Fig. 1 ] depicts the summary of patient treatment and outcome.
Fig. 1 Flowchart depicting treatment course and outcomes.
Prognostic Factors
In univariate analysis, age < 18 months, LDH > 750 U/L, type of chemotherapy regimen,
response to initial chemotherapy, number of chemotherapy cycles received, and surgery
were found to be statistically significant factors for disease-free survival (DFS)
and overall survival (OS).
Details of prognostic factors on univariate analysis are given in [Table 1 ].
On multivariate analysis, age > 18 months, LDH > 750U/L, less aggressive Chemo B regimen,
and poor response to chemotherapy were statistically significant poor prognostic factors.
Survival
At a median follow-up of 72 months (range 15–135 months), there were 16 survivors.
Five-year DFS was 17.6% and OS was 18.4%. Children < 18 months had significantly better
DFS and OS (35.1 and 38.6%, respectively). Eleven patients out of 38 (28.9%) who received
Chemo A and 5 patients out of 51 (9.8%) who received Chemo B survived. Twelve patients
(9 on Chemo A and 3 on Chemo B) received metronomic chemotherapy, and 5 out of those
12 patients (41.6%) are alive.
[Fig. 2 ] shows the survival curves by the relevant prognostic factors where 9 out of 16 patients
(56.2%) who survived were aged < 18 months at diagnosis. Mean age of survivors was
2.3 years (range 1–9 years) and their mean LDH at presentation was 728 U/L (range
303–1747 U/L).
Fig. 2 Kaplan–Meier survival curves of (A ) overall survival (OS) by lactate dehydrogenase (LDH) > 750 U/L and < 750 U/L. (B ) OS by type of chemotherapy regimen. (C ) OS by response to chemotherapy.
Details of survival cohort are depicted in [Table 3 ].
Table 3
Characteristics of the survivor cohort (n = 16)
Variable
Value
Age
Mean
2.3 y
Range
1–7 y
Gender
Female
10
Male
6
LDH
Mean
728 U/L
Range
303–1747 U/L
Primary site
Adrenal
6
Abdominal
5
Cervical
2
Thoracic
1
Paraspinal
1
Multifocal
1
Metastatic site
Limited metastases
14
Multiple metastases
2
Chemotherapy regimen
Chemo A
12
Chemo B
4
Metronomic chemo
5
Response to treatment
Good
15
Poor
1
Surgery/RT
Debulking/excision
10
No surgery/biopsy only
6
RT
2
Abbreviations: LDH, lactate dehydrogenase; RT, radiotherapy.
Discussion
It is well known that the burden of high-risk and metastatic NB is high in the LMICs
with suboptimal survivals. A previous study of 91 pediatric NB patients from our hospital
some years back had reported around 60% stage 4 disease, with long-term survivors
as low as 9% after multimodality treatment.[1 ] A recent compilation of studies from LMICs which includes several studies from India,
describes survivals of 0 to 45% world-over without ASCT and anti-GD2 antibody.[4 ] Single-institution studies from other developing countries like Brazil and countrywide
outcomes from Turkey have reported 17 and 45% five-year survival, respectively, for
stage 4 NB.[5 ]
[6 ] The overall poor results in LMICs are likely multifactorial such as inadequate diagnostic
facilities, less intense chemotherapy protocols, inability to resect the primary tumor,
limited availability, expertise, and prohibitive cost of transplant facilities and
unavailability of monoclonal antibodies.[2 ] Treatment refusal and abandonment are also high in resource-challenged nations[1 ]
[3 ] as was noted in our study, likely because of social, health system-related, and
financial reasons. Optimization of available resources thus becomes important while
treating these patients in the LMICs.
The significance of clinical and biological prognostic factors like age, metastatic
burden, and LDH in metastatic NB patients treated without transplant was explored
in this study. Data from the International Neuroblastoma Risk Group (INRG) reveals
that older age, involvement of bone marrow, bone, and multiple metastatic sites are
associated with worse outcome.[7 ] The better prognostic value of younger age in noninfant metastatic NB has been proved
historically by the Children's Cancer Group and the European registries.[8 ] Age cutoff of 18 months is utilized as standard for risk stratification of noninfant
NB, but the earlier Children's Oncology Group study has shown that prognostic effect
of age is continuous in nature.[9 ] In our study, children < 18 months had significantly better event-free survival
(EFS) and OS in a nontransplant setting. We understand that some of them would have
had biologically favorable disease and would be considered as nonhigh-risk by the
current international standards had they been properly risk-stratified using N-myc.
Because of lack of facility in the hospital, N-myc study, MIBG scintigraphy, and bone
scans could not be done in all our patients. Under these limitations, the significance
of biomarkers like LDH and ferritin becomes important in risk stratification and prognostication
of these patients. LDH is considered as a surrogate marker for N-myc amplification,
and the International Society for Pediatric Oncology-Pediatric Oncology Developing
Countries has recommended an arbitrary LDH value of 750 U/L as a prognostic marker
when N-myc status is not known.[2 ] In the recently published INRG study, higher LDH at presentation was independently
prognostic for worse DFS and OS in metastatic NB.[10 ] In our study, patients with LDH > 750 U/L demonstrated markedly inferior survival
than those with LDH < 750 U/L (18.2% vs. 46.9%), suggesting that those patients may
have had biologically adverse tumors.
Treatment-related factors analyzed in this study were intensity of chemotherapy, response
to chemotherapy, and impact of surgery. Dose-intensive short-duration chemotherapy
incorporating cisplatin and etoposide is associated with better clinical outcomes
in metastatic NB, and utilized in different chemotherapeutic regimens.[11 ] In the earlier study by Kusumakumary et al from our hospital in a group of NB patients
treated with heterogeneous chemotherapy protocols, one of the reasons explained for
poor outcome of stage 4 NB patients was the less aggressive palliative intent chemotherapy.[1 ] In our study, survival of patients who received the cisplatin-containing regimen
A was far better than those who received the regimen without cisplatin (28.9% vs.
9.8%). Our results may have been confounded by a selection bias, as patients with
multiple metastases and poor general condition were not expected to tolerate aggressive
treatment and inadvertently received the less intensive regimen.
We noted an unusually high response to chemotherapy in our patients, probably because
response evaluation was done with bone marrow examination and skeletal X-rays only.
If MIBG would have been used, the number of responders would have been lesser. However,
good response to initial chemotherapy did not translate to proportionately good EFS
or OS in our patients, because of early relapses, suggesting that conventional chemotherapy
is not able to maintain the remission status. In an earlier analysis from our own
center, 15 out of 17 children with metastatic NB treated with multiagent chemotherapy
had a good initial treatment response, but their 2-year survival was only 11.7%.[11 ] Whether further intensification of chemotherapy in good responders should be considered
in the setting of nonavailability of transplant facility is a question to be addressed.
Recently, Jain et al have reported improved survivals in high-risk NB patients treated
without ASCT or dinutuximab using an intensive consolidation regimen with topotecan,
vincristine, and doxorubicin in India.[4 ] We also observed that patients who underwent tumor excision or debulking had better
outcome, but surgery and radiotherapy could be offered to very less number of patients,
hence the impact of such a finding is doubtful.
Of interest are the characteristics of our survivor cohort. We observed that they
were younger, mostly females, presented with lower baseline LDH, mostly had limited
metastases, received moderately intensive cisplatin-containing chemotherapy, all but
one were good responders, and most underwent excision or debulking. Very few patients
in our cohort were able to reach the maintenance phase of treatment, but this group
had the best survival of 41%.
The limitations of our study are that it is a retrospective study of a cohort of patients
treated with nonuniform chemotherapy protocols. Nonavailability of N-myc testing and
MIBG, selection bias in treatment protocol, and limitation of clinical facilities
and resources for treatment may also be considered as a limitation. Most patients
who attend our center for treatment come from poor socioeconomic status and are not
able to afford costly treatments. Treatment costs were met partially by the center
with the help of government aids and there was always shortage of human resources.
Given the poor prognosis of metastatic NB, during the earlier time period many parents
opted out of the cisplatin-containing regimen because they could not afford to stay
in and around the hospital for frequent monitoring and management of subsequent complications.
Over the years, because of increased government initiatives and support from new voluntary
organizations, new treatment assistance schemes and staff support for pediatric cancer
patients in the hospital were provided, resulting in increase in clinical facilities
and improvements in supportive care, so that overall more number of pediatric patients
could afford cancer treatments. The increased trend in survival may be a reflection
of more number of patients being able to take the aggressive protocol.
Future prospective study may be proposed based on our findings from the present study.
Younger patients and those with lower LDH at presentation may be treated with moderately
intensive platinum-containing chemotherapy and response of metastatic sites after
first few cycles of chemotherapy may be utilized to guide further treatment. Patients
with clearance of metastases may preferably receive intensified chemotherapy, followed
by surgery of primary, radiotherapy to residual tumor, and maintenance chemotherapy.
On the other end of the spectrum, identification of patients with multiple adverse
factors like older age, very high baseline LDH, multiple metastatic sites, or poor
response to chemotherapy which portend poor outcome may allow the focus to be directed
on early provision of palliative care along with less intensive cancer-directed treatment
aiming at reducing the symptom burden, improving the quality of life, and smooth transition
toward end-of-life care.
Conclusion
Our study reveals that improvement in clinical services like chemotherapy and supportive
care can result in a trend toward better survivals in children with metastatic NB
in a resource-limited setting. Selected stage 4 NB patients may survive even without
transplant or immunotherapy, and they can be identified based on simple and affordable
investigations like baseline LDH, ferritin, and good response to initial chemotherapy.
Stratification of these patients on the basis of clinical and biological factors can
facilitate justified allocation of available resources while planning treatment for
metastatic NB patients in the LMICs.
