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.

Collaboration - in Africa and in India

Collaboration among colleagues, institutions and indeed countries has been a cornerstone in the successful journey to improving the outcomes of children with cancer. The scientific literature is replete with examples of such collaborations. At the same time, there is also a glaring absence of scientific literature related to childhood cancer on collaboration among individuals and institutions in low and middle income countries till recently. There have been several positive developments in the last decade, most notable among them are AHOPCA (collaboration among Central American countries) and GFAOP (collaboration among several francophone African nations) and the benefits of these collaborations are becoming quickly evident.

Another such collaboration is the Collaborative Wilms Tumour Africa Project, a remarkable initiative by colleagues from 8 institutions in 5 countries in Sub-Saharan Africa (Cameroon, Ethiopia, Ghana, Malawi, Uganda).

Their aim is very simple - take a curable childhood cancer (like Wilms tumour), treat in a standard scientific manner keeping in mind the local support services and at the same time build capacity in terms of guidelines, pathology, radiology, supportive care, etc. Having received funding from several organisations including World Child Cancer and the the International Society of Pediatric Oncology, the project has taken off well and has recruited more than 100 patients into the study. It is truly my honour to be associated as an ambassador to this project. I personally, continue to be inspired by the whole project and the individuals involved including my dear friend Trijn Israels. More information on this can be found on the dedicated website http://paedonc.wix.com/wilmsafricaproject.

And this brings me to India, where we have also suffered from the lack of collaboration among individuals and institutions. This is now rapidly changing and the rejuvenation of Indian Pediatric Oncology Group as well as the start of two multi-centre studies on Hodgkin disease (already recruiting in 11 centres in India) as well as on acute lymphoblastic leukmeia (recruitment to start shortly) under its umbrella are exciting developments. More on this in the future.

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.