Wilms Tumour in India

Carl Max Wilhelm Wilms was a German pathologist and surgeon who worked extensively on renal tumours towards the end of the 19th century. One of the most common solid tumours in children, nephroblastoma, is also known as Wilms tumour in recognition of his work. In resource-rich countries, the five-year survival for this cancer is 90% and the focus now is on reducing the treatment-related morbidity while maintaining similar outcomes.

Despite being a relatively common childhood cancer, there have been no published studies from India on the outcome of this cancer for over a decade. It is for this reason, that the recently published report from PGI Chandigarh (Trehan et al, JPHO, 2011) is so timely. 23 children with Wilms tumour were seen over a five year time period (1999 to 2003). Three did not start treatment and abandoned after diagnosis. In the remaining 20 treatment was based on the SIOP philosophy of neoadjuvant or preoperative chemotherapy. There was one treatment related mortality (5%), three relapses (15%) and one abandonment on therapy (5%) leading to a five-year event-free survival of 75%.

Detailed analysis of causes of treatment failure would be needed to further improve outcomes. What is noteworthy is that the three relapses happened in two Stage II patients and one Stage III patients. Staging of the chest was done by x-ray which would be standard practice in many centres in India. I wonder whether a CT Chest may have upstaged these patients at diagnosis and consequently they might have received more intensive chemotherapy leading to reduced risk of relapse. I think it is a question worth answering in the future.

How does this compare to other centres in India? The difficulty is the lack of published and peer-reviewed literature. Nevertheless, long term event-free survival of 73% and 77% have been reported from Tata Memorial Hospital (SIOP 2005) and AIIMS (SIOP 2009) based on data obtained from scientific presentations of annual SIOP congresses.

My highlights of SIOP 2010 in Boston

I hope that all those of you who had a chance to attend this year's SIOP meeting in Boston at the Hynes Convention Centre had a great time. It was a personal pleasure to meet so many of my old friends and make new ones. There was a good representation of the paediatric oncology community from India as well as many from the Indian diaspora.

There were 45 presentations (8 oral and 37 poster) from India and I had a chance to hear and see several of them. My personal highlight was Dr Kurkure's presentation on L0w cost rationally designed protocol for treatment of pediatric acute lymphoblastic leukemia in developing countries which was used in motivated families below poverty line at Tata Memorial Hospital. This protocol had a 3 drug induction (VCR, L-Asp, Dex) and 91% of children were in clinical remission at the end of induction. The event-free survival for standard risk patients was 63% (median follow-up 22 months) and for high risk patients was 48% (median follow-up 31 months). Remarkably, only 3% of children abandoned treatment during induction and 1% following induction.

The other presentation I really enjoyed was by Dr Vinay Jain on Building capacity in pediatric oncology in India: efforts of Jiv Daya Foundation 2008-2010 which gave a summary of the excellent work that he and his foundation have done over the last few years in several centres in India. More details of their work can be found on www.jivdayafound.org.

Finally, I heard with great interest two related presentations by Paola Freidrich-Medina who is a fellow at the Dana-Farber Cancer Institute. She was presenting the work done by AHOPCA (Asociacion de Hemato-Oncologica Pediatrica de Centro America) which is collection of seven resource-limited countries from Central America. The presentations were Current barriers for successful treatment of children with sarcomas in low-income countries and High tumor burden, high rate of abandonment and fear of disabling surgery are among the innermost barriers to treatment of pediatric sarcomas in resource-limited settings.

I welcome your thoughts and your highlights of the meeting. If there are any photographs that you want to share from the meeting on this blog, you can email them to me.

In India, should we treat children with High Risk Neuroblastoma (HR NB)?

At the outset, let me clarify two things. Firstly, by no means am I advocating not giving treatment to children with HR NB in India. My only purpose is to generate debate and learn from the more experienced and learned clinicians in India who manage children with this cancer. Secondly, every child irrespective of the type of disease or cancer (including HR NB) has a right to palliation including pain relief and this treatment option should not be denied. So, I guess the question I am really asking is "In India, should we treat children with HR NB with a curative intent?"

Around 50% of all children with NB have HR disease (essentially Stage IV i.e. metastatic NB or NB with mycn gene amplification with some caveats for age and histology). A study from the Children's Oncology Group published last month (Yu et al, 2010) reports a 2-year overall survival of 86% and event-free survival of 66% in children with HR NB who were treated with multi-drug induction + stem cell transplantation + isotretinoin + immunotherapy. Prior to the introduction of immunotherapy, the event-free survival in the developed world had plateaued at less than 50%. Thus, this new report of further improvement in outcomes is significant.

This brings me to the situation in India. As far as I am aware, while multi-drug induction (followed by surgery and radiotherapy) is standard treatment for children with HR NB, use of stem cell transplantation is not standard and immunotherapy has not been tried. In such a setting, what are the outcomes of HR NB? It is difficult to answer this question precisely, because assessment of mycn amplification is not standard practice in India either. Outcome of children with Stage IV i.e. metastatic NB can give us some indication, although very few institutes from India have published their outcomes. This includes 3 long term survivors out of 32 children with Stage IV neuroblastomas reported from Thiruvanathapuram (Kusumakumary et al, 1998); 1 out of 27 reported from Chandigarh (Bansal et al, 2008); and 0 out of 38 reported from Mumbai (Bhatnagar et al, 2007, SIOP).

Based on these reported outcomes i.e. less than 10% reported long-term survivors of HR NB, is there an argument for not offering curative treatment to the above group of patients in India? Has anybody reported better outcomes from India?

What is the outcome of children with Acute Lymphocytic Leukemia (ALL) in India?

The answer to this question, depends on whose asking it and to what purpose. At an individual level (when access to treatment is not a barrier), currently the standard 5-year survival in most of the developed world is 80-90% with that for low-risk ALL even higher than 90%. The best published results from India are 59% 5-year survival for children with ALL treated from 1985 to 2003 in CMC Vellore (Bajel et al, 2008), and of 57% in those treated from 1990 to 1993 in Tata Memorial Hospital, Mumbai (Advani et al, 1999). For low-risk ALL, these survival figures are around 73-77%. It is important to point out, that these results from India are calculated after censoring (removing) those children with ALL who refused to start treatment or abandoned ongoing active treatment. There are some unpublished data suggesting better outcomes - 70% 4-year survival of children with ALL treated at Sir Ganga Ram Hospital in Delhi (Sachdeva et al, SIOP 2007); and 94% survival after median follow-up of two years of children with ALL treated at Apollo Hospital in Delhi (Mahajan et al, SIOP 2008). A more accurate reflection of outcomes of children with ALL in India can be obtained when we include all those who refused and abandoned treatment and then calculate the survival. This is particularly relevant to clinicians, epidemiologists and health planners. To my knowledge, the recent paper from PGI in Chandigarh is the only one to publish such data. It shows a 4-year overall survival of 33% and a 10-year overall survival of 30% for children with ALL diagnosed at that institute from 1990 to 2006 (Kulkarni et al, 2009). Other sources of such information are the population-based cancer registries. Only two reports have ever been published looking at population-based 5-year survival in children with cancer and these were 35% from Bangalore for the period 1982 to 1987 (Nandakumar et al, 1996); and 39% for Chennai for the period 1990 to 2001 (Swaminathan et al, 2008). In a nutshell, 6 out of 10 children with ALL in India will have long term survival (and cure) if they are compliant with their treatment. If treatment uptake and compliance is variable, only 1 out of 3 children in such settings would be cured. These outcomes apply only to those treated in specialist tertiary centres in urban areas. For those in rural areas or non-specialist centres, the outlook is certain to be worse.

Childhood Cancer Survival in Philippines (and India) lags by >30 years than in Developed Countries

Survival of childhood cancer has enormously improved in the developed world with current 5-year survival for leukemia and lymphoma now around 80% and 90% respectively. An interesting recent paper shows that for the period 2001-2005 the 5-year survival of children with these cancers in Philippines is much lower (32.9% for leukemias and 47.7% for lymphomas) (Redaniel et al, Br J Cancer, 2010). These figures are even less than the survival seen in USA during 1976-1980 (57.7% for leukemias and 60.9% for lymphomas). These observations although not unexpected, do highlight the enormous gap in the outlook of children with cancer in the developing world.

What about India? There is limited population-based childhood cancer survival data. The most recent data from Madras Metropolitan Tumour Registry shows that for the period 1990-2001 the 5-year survival of children with leukemias in Chennai was 36.3% and lymphomas was 55.3% respectively (Swaminathan et al, Int J Cancer, June 2008). In this study, a combination of completeness of treatment and type of hospital emerged as significant prognostic factors for survival.

CNS disease at presentation in childhood ALL

Hi all,

Recently, management experience of CNS disease at presentation in childhood ALL from PGIMER, Chandigarh, India was published (Ref - Marwaha et al, Leukemia and Lymphoma, Feb 2010). The summary is as below

The spectrum of central nervous system (CNS) disease at diagnosis, traumatic lumbar puncture (TLP), role of cranial irradiation, prognostic parameters, and survival outcome in patients with CNS involvement amongst 747 patients with acute lymphoblastic leukemia managed at PGIMER was analysed. The overall outcome and management experience has been described elsewhere (Ref - Kulkarni et al, Pediatric Blood Cancer, Aug 2009).

25 and 6 patients out of these had CNS disease and TLP, respectively. Patients with CNS disease had significantly higher mean presenting leukocyte count and incidence of hyperleukocytosis compared to those without it. Contemporary immunophenotyping and molecular data was unavailable in majority of the patients especially managed in the 1990s. Other usual prognostic parameters were not significantly associated with CNS disease at presentation. The outcome was poor with three patients in continuous complete-remission, nine relapsers, eight deaths, and eight therapy defaulters.

Despite the fact that the percentage of pateints with CNS disease was lower than published literature, outcome was not inkeeping with the contemporary outcomes. Once again this highlights the difficulties faced by a pediatric Oncologist in the developing world in holistic management of ALL. CNS involvement was significantly associated with inferior survival. CNS involvement was thus a high-risk indicator. Poor outcome in this cohort indicated the need for the revaluation of our treatment protocols with the inclusion of risk-stratified systemic therapy, categorization of CNS involvement according to published criteria into CNS 1, 2 and 3 which is also often difficult in resource limited settings. The rate of traumatic lumbar puncture was however very low. Problably reflecting the fairly good skills of the operators given the large number of patients managed.

Dismal Outcome of Diffuse Intrinsic Pontine Glioma

Around 10-15% of all childhood tumours of the brain are in the brain-stem. A majority of these are diffuse and infiltrating lesions of the pons called Diffuse Intrinsic Pontine Glioma (DIPG). Surgical removal of these tumours is not feasible and focal radiation in combination with experimental chemo/biologic therapeutic agents is the mainstay of treatment. Current outcomes across the world are dismal overall survival less than 10 to 15%.

In a recently published report from Tata Memorial Hospital in Mumbai, clinicians describe the outcome of 20 children with DIPG who were treated with focal radiotherapy (54 Gy in 30 fractions over 6 weeks) along with oral temozolomide during and after radiotherapy (Ref - Jalali et al, Int J Radiat Oncol Biol Phys, May 2010). This was done as a phase 2 feasibility clinical trial. Although the treatment was generally fairly well tolerated, only 35% of children were alive at 12 months after diagnosis and only 6% after 18 months.

In summary, this is one of the very few case-series on DIPG from India and the dismal outcome of these children is similar to that reported from rest of the world. I am fascinated by the complete absence of treatment refusal and abandonment in these group of patients. In a cancer, where treatment is intense and the outcome generally fatal, refusal/abandonment of treatment should theoretically be a relatively common occurrence.

Ovarian Germ Cell Tumours in Children

Tumours of the ovaries represent around 4% of tumours overall in females and around 2% of all tumours in children less than 15 year of age. In children and adolescents, germ cell tumours of the ovary are by far the most common pathology (around 70%) among ovarian tumours while in adults, carcinoma of the ovarian epithelium accounts for 85-90% of the ovarian tumours.

Dr Biswajit and his colleagues from a tertiary cancer centre from Chennai have recently published outcomes of 40 girls less than 18 years of age with ovarian germ cell tumours who were managed in their institute from 1990 to 2002 with cisplatin-based chemotherapy and surgery (Ref - Biswajit et al, Journal of Pediatric Hematology Oncology, March 2010). Nearly 2/3^rd of the patients presented in Stage III-IV. Delays in diagnosis and treatment could have been due to patient-related factors or due to healthcare-related delays although this was not specifically studied. The 5 years disease-free survival was 72.8% (mainly because of relapses in 25% of patients) and overall survival was 94.9%. Similar results were reported from Tata Memorial Hospital in Mumbai nearly 15 years ago although they had less relapses (Ref - Kapoor et al, Journal of Pediatric Hematology Oncology, November 1995).

Extraocular Retinoblastoma in India

Retinoblastoma is the most common cancer of the eye in children and accounts for 2.5 to 4% of all childhood cancers. When a child is diagnosed with retinoblastoma, the cancer may be limited to the eye globe (intraocular) or have spread beyond the eye globe (extraocular). The spread may be local (to the orbit and local lymph nodes) or more distant i.e metastatic. Delays in presentation in India lead to more than half of the children with retinoblastoma having the cancer spread outside the globe at diagnosis.

Ref - Sahu et al, Pediatric Hematology Oncology, Nov-Dec, 1998

Sameer Bakhshi and his colleagues describe the treatment and outcome of 25 children with extraocular but non-metastatic retinoblastoma over a 5 year period (2003 to 2008) from one of the premier treatment centres in India. The overall survival figures are not given but at a median follow up of 28.5 months (nearly 2½ years) 13 of the 25 children had progressed/relapsed.

Ref - Bakhshi et al, Journal of Pediatric Hematology Oncology, Mar 2010

All those who progressed or relapsed, either refused or did not respond to second line treatment which implies that they would all ultimately die of the cancer. One also needs to consider that there were 51 children with extraocular non-metastatic retinoblastoma during this time period but only 25 opted for treatment. Many if not all of those who did not opt for treatment for various reasons are also likely to have succumbed to the cancer. These poor outcomes are all the more significant as majority of the children in India with retinoblastoma present late and the disease has spread locally or systemically. Hence, it is not surprising that the five year overall survival of children with retinoblastoma (all stages combined) is less than 50% while that in Europe and North America is 95% and above.

Ref – Swaminthan et al, International Journal of Cancer, June 2008

Childhood Cancer in India: An Introduction

Globally, it is estimated that 250,000 children under the age of 15 years develop cancer every year. Around 50,000 (20% or 1/5th) of these children are in India.
Both the above estimates are based on the incidence of childhood cancer being 125 to 150 per million per year.

We do not know, how many of these 50,000 children with cancer in India get diagnosed. Of those who are diagnosed, we do not know how many of them seek treatment. A significant proportion of those who do seek treatment, either refuse treatment when it is offered or abandon treatment within the first few weeks. Based on information derived from published studies and presentations at scientific meets we know that treatment refusal and abandonment rates vary from 17 to 62% depending on the type of cancer and treatment center.
Ref – Arora et al, Pediatric Blood Cancer, Dec 2007

Currently, nearly 8 out of 10 children with cancer get cured in resource-rich countries like those in North American and Europe. If we exclude those who refuse or abandon treatment, comparable outcomes for specific cancers are achieved in India in those treated at tertiary institutes like the Tata Memorial Hospital in Mumbai. However, at a population level, the five-year overall survival for all childhood cancers combined has been reported to be 37-40% from Bangalore and Chennai. This cancer registry data is a much more accurate representation of cancer outcomes across India although as it is from urban areas, it is also likely to be an over-estimate of the true survival.
Ref – Arora et al, Indian Journal of Cancer, Oct-Dec 2009