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