DISCUSSION:
In the developing countries, a large number of children with NB present
with metastatic disease , with frustratingly low survival even after
skilful use of multiple treatment modalities. Many years back, in a
study of 91 pediatric NB patients from our own centre, as high as 60%
children had Stage 4 disease, with long term survivors as low as 9%
after chemotherapy, surgery and radiotherapy.[1]. Contemporary
Indian studies by Bansal et al [2] and Agarwala et al [3] have
also reported higher proportion of patients with advanced disease and
poor survivals in NB treated with conventional non-myeloablative
chemotherapy. Studies from other developing countries like Brazil and
Turkey have reported 17% and 6.5% 5-year survival respectively for
stage 4 NB under similar circumstances. [4],[5] In the
high-income countries, accurate risk-stratification based on molecular
diagnostics and advanced treatment facilities like high-dose
chemotherapy followed by ASCT with excellent supportive care, surgery,
radiotherapy and immunotherapy is able to yield around 40% survival in
high-risk NB.[6] But limited availability and prohibitive cost of
transplant facilities render them inaccessible to majority of the
patients in resource-constrained settings like ours. The present study
shows a trend towards improved survival over the years in children with
metastatic NB treated without transplant, attributable to improvement in
treatment facilities and supportive care.
Identifying clinical prognostic factors in this cohort of non-infant
metastatic NB could guide us to develop a risk-adapted approach for
treating these patients. Data from the International Neuroblastoma Risk
Group (INRG) database reveal that clinical parameters like older age,
involvement of bone marrow, bone and multiple metastatic sites are
associated with worse outcome in metastatic NB. [7] The earlier
studies from Children’s Cancer Group had reported better outcome of
Stage 4NB in children under 2 years of age and those with extraskeletal
metastases alone. [8] In our study, children <2 years
showed a trend towards better survival, but impact of age or the number
of metastatic sites on survival was not statistically significant. Other
well-known prognostic factors in metastatic NB supported by research are
baseline LDH, ferritin and N-Myc amplification status.[6],[9]
N-myc study was not done in our patients because of lack of facility
within the institution. Ferritin could be estimated in only a few
patients, and hence was not considered for analysis. LDH is a surrogate
marker for N-myc amplification,[6] and in the recently published
INRG study, higher LDH at presentation had independent prognostic
ability for worse DFS and OS in metastatic NB. [9] The SIOP PODC has
recommended an arbitrary LDH value of 750 U/L as a prognostic marker
when N-myc status is not known. [6] In our cohort, patients with LDH
>750 U/L demonstrated markedly inferior survival than those
with LDH<750 U/L (18.2% vs 46.9%), and we plan to study
prospectively its prognostic value in children with metastatic NB in our
setting.
The question of whether intensity of chemotherapy improves survival in
metastatic NB is a subject of various clinical trials. A retrospective
analysis of 44 clinical trials by Cheung and Heller revealed that
chemotherapy dose-intensity, particularly of cisplatin and teniposide,
strongly correlated with clinical outcomes in metastatic NB.[10] In
the present study, survival of patients who received the moderately
intensive cisplatin-containing regimen A was far better than those who
received the less aggressive regimen B (28.9% vs 9.8%), and the small
group of patients who received 6-8 months of oral metronomic
chemotherapy after the intensive regimen had prolonged survivals when
compared to the whole cohort (41% vs 18.4%). However, a selection bias
may have confounded the results, as patients with multiple metastases
and poor general condition inadvertently received the less intensive
chemotherapy regimen. Since cisplatin administration required staying in
and around the hospital for frequent monitoring and subsequent
supportive care, causing financial and social difficulties when cure was
less likely, many parents opted out of this regimen during the earlier
period of our study. Over time, with improvements in clinical
facilities, human resources and availability of treatment assistance
schemes, we were able to provide intensive chemotherapy and supportive
care services for more patients, with minimal treatment-related
mortality. This heterogeneity in selection of treatment regime may have
influenced our results.
The relevance of good response to chemotherapy in metastatic NB in the
non-transplant setting is uncertain because relapses occur early if not
consolidated with ASCT.[3] In an earlier analysis from our own
centre,15 out of 17children with metastatic NB treated with multiagent
chemotherapy had a favourable response, but their 2-year survival was
only 11.7%[11].In the present study, chemosensitivity was
demonstrated in majority of the patients, but most of them relapsed and
died within a short period (median 9 months and 10 months respectively)
while continuing on the same chemotherapy regimen or soon after
completing treatment. Whether further intensification of chemotherapy
after getting a good initial response would have translated into more
favourable outcomes in some of these patients is a matter worthy of
consideration. A recently published study from India has reported
survivals of around 30% in high-risk NB patients treated without ASCT
using an intensive consolidation regimen with topotecan, vincristine and
doxorubicin[12]
The impact of surgery on survivals of metastatic NB is debated. Several
studies have demonstrated that radical resection of the primary tumour
does not influence local control or outcome in non-infant metastatic NB,
[13] nevertheless, safe resection with or without local radiotherapy
continues to be the accepted practice. In our study, patients who
underwent tumour excision or debulking had significantly better outcome,
but surgery and radiotherapy could be offered to very less number of
patients.
Of interest are the characteristics of our survivor cohort. We found
that they were younger(around 2 years of age), mostly female and
presented with lower baseline LDH and mostly had limited metastases.
Most of them received moderately intensive cisplatin-containing
chemotherapy and all but one were good responders, and most underwent
excision or debulking. This shows that interplay between multiple
clinically demonstrable favourable prognostic factors may be
contributory to better survival in children with metastatic NB treated
without ASCT.
In conclusion, this study points out that outcome of metastatic NB
patients remains suboptimal in a non-transplant setting, but there is a
definite trend towards better survival over the years contributed by
improvement in supportive care. Setting up enough transplant facilities
to cater to the large numbers of metastatic NB patients in developing
countries may not be practical because of the huge burden on resources.
Under such circumstances, simple and affordable investigations like
baseline LDH and response to initial chemotherapy may be useful in
identifying selected patients who may have the chance of survival even
without transplant. Younger patients with lower LDH at presentation may
attain prolonged survival with moderately intensive cisplatin-containing
chemotherapy, local treatment and metronomic maintenance chemotherapy.
This knowledge may be utilised for justified allocation of the available
resources so that patients with favourable prognostic factors are
treated aggressively while those with adverse prognostic factors are
spared the burden of treatment toxicity. Identification of patients
expected to have poor survival 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 towards end-of-life
care.
Acknowledgements: Nil
Conflict of interest: Nil