5 Types of Paediatric Cancer You Need to Know About

Here is another one I wrote a few years ago on the Max Healthcare platform. This talks about the 5 Types of Paediatric Cancer You Need to Know About

https://www.maxhealthcare.in/blogs/5-types-paediatric-cancer-you-need-know-about

Milestones in Childhood Cancer Collaborative Research - Part 1

September is Childhood Cancer Awareness Month and it is a good time to reflect on the progress we have made in curing childhood cancer and how we got here. An important part has been the ability of all stakeholders to get together and enroll children with cancer on to clinical trails, specially multicentre collaborative research. In this first part I look at some of the earliest works done in North America and Europe and highlight a few studies.

This all started in 1948 when Sidney Farber attempted to use a folate antagonist, Aminopterin to block the function of folic acid in patients with acute leukemia in hopes of achieving remission - Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. Of 16 children, 10 demonstrated clinical, hematological and pathological evidence of improvement for three months. At that time this observation was met with disbelief and also it was felt to be unethical to "experiment" with the life of a child with leukemia when cure was not possible.

Thankfully, he and others like him continued in their efforts. The relative rarity of the disease and the need for shared expertise in management led to the creation of the first pediatric oncology co-perative groups (Cancer and Leukemia Group B Cooperative Group as well as the Acute leukemia Chemotherapy Cooperative Study Group A) in the US in 1955 which were the forerunners of the now well established and respected Children's Oncology Group. For the last 65 years, COG in North America and SIOP in Europe  have increased our knowledge and understanding of childhood cancers and conducted studies which have improved outcomes. Here are some of the earliest studies:

Childhood Leukemia

Published by Heyn et al in 1960, The Comparison of 6-Mercaptopurine with the Combination of 6-Mercaptopurine and Azaserine in the Treatment of Acute Leukemia in Children: Results of a Cooperative Study was the first multi-centre co-operative clinical trial in childhood cancer. In 125 cases of previously untreated acute leukemia in children, no significant difference was seen in the percentage of complete remissions obtained when 6-mercaptopurine was used alone or when 6-mercaptopurine and azaserine were used in combination. The median duration of the complete remissions for the combination therapy was 4.12 months compared to 2.75 months for 6-mercaptopurine alone and the difference was not statistically significant.

At the same time, Freireich et al studied 6-Azauracil in patients with "advanced" acute leukemia, refractory to standard chemotherapy - Evaluation of a New Chemotherapeutic Agent in Patients with "Advanced Refractory" Acute Leukemia. Studies of 6-Azauracil. Under the conditions of the study this compound was found to have no significant antileukemic activity.

Two decades later, in 1980, the first collaborative efforts in childhood ALL from Europe were published on children treated on the BFM 70/76 protocol - The Berlin Childhood Acute Lymphoblastic Leukemia Therapy Study, 1970–1976. The treatment protocol consisted of vincristine, prednisone, daunorubicin, L-asparaginase, cyclophosphamide, cytarabin, 6-mercaptopurine, intrathecal methotrexate, and cranial or craniospinal irradiation. Maintenance therapy was cyclic sequential administration of intravenous methotrexate and oral 6-mercaptopurine with 6-week reinduction pulses of prednisone/vincristine. 56.2% of patients were in complete continuous remission for a median of 67 months.

Childhood Solid Tumours

Following the work on childhood leukemia, cooperative groups simultaneously also started looking at solid cancers. Earliest work was done on Wilms tumour on both sides of the Atlantic.

Published in 1968, maintenance dactinomycin following surgery was found to be superior (continued remission rate of 86%) compared to when no maintenance was given (continued remission rate of 48%) - Single versus multiple dose dactinomycin therapy of Wilms's tumor. A controlled co-operative study conducted by the Children's Cancer Study Group A (formerly Acute Leukemia Co-operative Chemotherapy Group A)

Colleagues in Europe investigated the role of radiotherapy and actinomycin d (dactinomycin) in Wilms tumour - Preoperative versus postoperative radiotherapy, single versus multiple courses of actinomycin d, in the treatment of Wilms' tumor. Preliminary results of a controlled clinical trial conducted by the international society of paediatric oncology (S.I.O.P.). This was the first SIOP study and also the first international randomized trial in Europe. Pre-op radiotherapy reduced the tumour rupture rate at surgery. Also there was no added benefit of post-op radiotherapy after receiving pre-op radiotherapy. 

Childhood CNS Tumours

It was in 1990, that the first multicentre co-operative group studies were published on childhood CNS tumours in North America and Europe, almost at the same time. Both looked at the role of adjuvant chemotherapy in medulloblastoma.

Evans et al from the Children's Cancer study Group (another forerunner of COG) studied the benefit of adjuvant vincristine, CCNU and prednisolone after surgery and radiation in children with medulloblastoma - The treatment of medulloblastoma - Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone.  It is concluded that chemotherapy does not benefit patients with low-stage medulloblastoma, but may benefit those with more advanced stages of disease.

Tait et al from SIOP examined adjuvant vincristine and CCNU in medulloblastoma - Adjuvant chemotherapy for medulloblastoma: The first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Their results were that although there was no overall statistical difference between the two arms of the trial, a benefit for chemotherapy was seen in a number of sub-groups; partial or sub-total surgery, brainstem involvement , and stage T3 and T4 disease. 

Childhood Cancer Survivors

By the end of the 20th century collaborative research in childhood cancer survivors was in flow and the first publication from the Childhood Cancer Survivor Study came out. Marriage in the survivors of childhood cancer: A preliminary description from the childhood cancer survivor study showed a decreased likelihood of marriage among childhood cancer survivors, which may be influenced by gender and/or race

These studies are only a tiny reflection of the huge amount of collaborative work and scientific output which took place in the second half of the 20th century. Noticeably, there was a complete absence of such work from low and middle income countries (LMIC). Health professionals in these settings were also working hard to provide the best possible care to their patients while being hampered by limited resources. They were however unable to translate their efforts into regional or national collaborative efforts. Progress in this area happened much later and in my next blog post I will showcase milestones of childhood cancer collaborative research in LMIC.

Leukaemia mis-diagnosed

We know that childhood cancer is underdiagnosed in resource-limited settings. Patients presenting with leukaemia who have fever and anemia may be misdiagnosed as malaria, those with seizures and space-occupying lesion may be mis-diagnosed as tuberculoma or neurocysticercosis, etc. I have however not found a lot of evidence which investigates this phenomenon.

Then I came across this blogpost on Alex's Lemonade Stand Foundation which talks about Dr Terry Vik's work  While reading 3000 slides for suspected malaria in children in Kenya, a trained technician picked up 5 possible cases of leukaemia. The study is in its early stages yet and I keenly look forward to its conclusion.

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.

Communication in Paediatric Cancer Patients: A Parent's Perspective

Clear and honest communication done sensitively is important in the holistic management of children with cancer and their parents. Little research has been done in India to assess the health information needs of sick children (and their parents). Also the quality and adequacy of information given by health professionals not been looked at.

To address this knowledge gap, Dr Tullika Seth, a haematologist at All India Institute of Medical Sciences has done a pilot study where she interviewed parents of children aged 10 to 18 years with acute lymphocytic leukaemia (Seth T, Indian Journal of Palliative Care, Jan-Apr 2010). The results clearly show that in the Indian context, parents wanted little information to be shared with their children (65% did not want their children to be informed of the diagnosis; 60% did not want the child to be informed about side effects of therapy and especially about long term effects). There was even a stronger opinion about not involving children with decision-making (95% did not want them to involved with making any decision about the treatment; 100% did not want them to involved with making any decision about stopping curative treatment when such a situation arose).

These findings would be useful to health professionals in "forging an alliance with the family to facilitate communication" as Dr Seth says. They also offer us insight into the different attitudes and practices in India compared to the Western context, where patient autonomy is more visible.

Music Therapy Reduces Procedural Pain in Children with Cancer

Repeated procedures like lumbar puncture and bone marrow aspiration are routine part of management of several childhood cancers (in particular acute lymphoblastic leukaemia). Adequate sedation and analgesia for these procedures in a safe environment is desirable and there are guidelines available in Europe and North America in this context. The mainstay of sedation in such settings is general anaesthesia.

A recent survey shows that the practice of sedation and analgesia for lumbar punctures and bone marrow aspiration in children with cancer in India is varied and includes no sedation/analgesia, local anaesthesia or some systemic sedation/analgesia but no general anaesthesia (unpublished data). Further research is needed to identify reasons for these variations.

The recently published report from Vietnam (in collaboration with Swedish investigators) shows reduced pain and anxiety in children aged 7-12 years with leukaemia during and after lumbar puncture who were randomised to receive music therapy compared to no music. (Ref - Nguyen et al, Journal of Pediatric Oncology Nursing, May-June 2010). What makes this clinical trial particularly relevant to the Indian context is the fact that besides music therapy, there was no use of any form of sedation/analgesia for the procedure. Such a practice of lack of any sedation/analgesia during the procedure is standard in Vietnam and also a common occurrence in India. Music therapy is a low cost, safe and easily available option which should be considered (in isolation or as an adjunct) for these procedures.

Proportion of Translocations in Childhood ALL in Pakistan is similar to that in India

TEL gene rearrangement due to the 12;21 chromosome translocation is the most common molecular genetic abnormality in childhood acute lymphoblastic leukemia (ALL) and is seen in around 25% of children with pre-B cell ALL (studies mainly from Europe and North America). In this translocation the 5’ part of the TEL (ETV6) gene fuses with almost the entire AML1 (CBFA2) gene, producing the chimeric transcript ETV6-CBFA2.

Figure from www.kreatech,com

It is associated with a better prognosis in ALL . In contrast to the West, the frequency of the translocation TEL/AML1 in children in India with ALL is around 7% (Ref - Siraj et al, Leukemia, June 2003). Now in a study of 50 children with ALL from two institutes in Lahore, Pakistan the frequency of the TEL/AML1 translocation was a similar 6% (Ref - Faiz et al, Journal of Pediatric Hematology Oncology, April 2010). Interestingly, the frequency of another translocation which confers a poor prognosis, t(9;22) or BCR/ABL, was 24% and is much higher than that reported from India and elsewhere.

Clearly, these results are from a hospital-based case series and further larger studies in Pakistan would be necessary. The fact that 42 of these 50 ALL children with ALL were boys illustrates the limitation of such hospital-based case series.

Addendum (08/06/2010) - A recent report shows that the frequency of TEL/AML1 in Far East Asia (Japan, Korea, China, Hong Kong, Chinese in Singapore, and Taiwan) based on a pooled analysis of 1321 children with ALL was 13.4% (Ref - Liang et al, Pediatr Blood Cancer, 2010). This is lower than that reported from the West but higher than that from the Indian subcontinent.

Treatment Refusal and Abandonment

The outlook of childhood cancer has improved enormously in the developed world with 5 year survival overall ~80%. Unfortunately we have not been unable to translate this success to much of the developing world including India. Treatment related mortality and relapse are important causes of treatment failure. However they are overshadowed by the widespread prevalence of treatment refusal and abandonment which are the main causes of treatment failure. These are as much a social problem as they are a medical problem. Any attempts to improve the outlook of children with cancer in a country like India has to have at its core strategies to deal with this problem. Such successful models are now being increasingly reported from Central and South America. Most notable has been the reduction of treatment abandonment in children with acute leukaemia as a result of the “twinning programs” between St. Jude Children’s Research Hospital in Memphis USA and Instituto Materno Infantil de Pernambuco in Recife, Brazil (see graph below)

Ref - Howard et al, JAMA, May 2004

Attempts have been made in the past to contact the children and families of those who abandon treatment. There are a very few studies looking at this and their dissemination has been limited to scientific proceedings. The recently published paper from Indonesia (Ref - Sitaresmi et al, Psycho-Oncology, April 2010) is the first extensive analysis of child and parent attitudes and behaviour to explain this complex problem. The authors conducted home-visits to interview families of 37 acute leukaemia patients, diagnosed between January 2004 and August 2007, who refused or abandoned treatment. There was no relation of abandonment with age, risk stratification of leukaemia, class of hospitalization (marker of economic status), parental education level and travel time. Girls abandoned slightly more often but this difference did not reach statistical significance.

Financial difficulties and a belief in the incurability of acute leukemia were the leading reasons given by parents for abandoning treatment. Additionally, treatment-related toxicity, painful procedures performed with inadequate analgesia and sedation, inadequate communication provided by health care providers and transportation difficulties were contributing reasons.