Milestones in Childhood Cancer Collaborative Research - Part 2

The 21st century has see the emergence of multi-centre collaborative research from low and middle income countries with reports from Central America, Africa, China and India. This is a very welcome development and I will briefly describe some of these initiatives below. But I would like to start with Brazil where cooperative groups for childhood cancer started in the 1980s.

The Brazilian Experience

The Cooperative Groups Initiative in Brazil started in 1980, allowing exchange of expertise and proposals of better care. There are seven well-established cooperative groups with ongoing protocols including the participation in international studies. Among their earliest works which was published in 1991 was the randomised controlled study on Single‐dose versus fractionated‐dose dactinomycin in the treatment of wilms' tumor with no significant difference in overall or relapse‐free survival. Shortly afterwards, they published the Treatment results of three consecutive Brazilian cooperative childhood ALL protocols: GBTLI-80, GBTLI-82 and -85 and were able to examine the role and dose of cranial radiation as well as treatment intensification.

For further reading - Brazilian Society of Pediatric Oncology - SOBOPE: 30 years of history, a lot in the present, full of the future and Pediatric hematology oncology in Brazil

Francophone Africa - The French‐African Pediatric Oncology Group (GFAOP)

The Franco-African Childhood Cancer Group (French acronym, GFAOP) was founded in 2000 with aim of improving the outcomes of children with cancer in Africa. The GFAOP has developed two forms of action. The main form consists of organizing two- to twelve-month training sessions for physicians and nurses in France and Morocco. The other form involves assessing the feasibility of modern treatment protocols for various cancers in Africa. The first feasibility trials were carried out on nephroblastoma and Burkitt's lymphoma in 12 pilot units in North Africa, West Africa, and Madagascar. In the first study from 2001 to 2004, 306 children of Burkitt's lymphoma using French LMB protocols adapted to the African setting and achieved a survival rate of 61% - Treatment of B‐cell lymphoma with LMB modified protocols in Africa—report of the French‐African Pediatric Oncology Group (GFAOP).

For further reading (In French) - Treatment of childhood cancer in Africa. Action of the Franco-African childhood cancer group

The SIOP PODC Africa Wilms Tumour Project

This project is implementing a SIOP PODC adapted treatment guideline for Wilms tumour in several centres in sub-Saharan Africa. This is done as a multi centre prospective clinical trial with uniform outcome evaluation. The project started in 2014. More than 300 patients have been included and treated. End of treatment survival without evidence of disease increased from 52% to 68%. Death during treatment decreased from 21% to 13% and abandonment of treatment from 23% to 13% - Improved outcome at end of treatment in the collaborative Wilms tumour Africa project

For further reading - The Collaborative Wilms Tumour Africa Project; baseline evaluation of Wilms tumour treatment and outcome in eight institutes in sub-Saharan Africa

 Asociación de Hemato‐Oncologiá Pediátrica de Centro América (AHOPCA)

Inspired by the twinning program of Manuel de Jesus La Mascota Hospital in Managua, Nicaragua and the Pediatric Clinic of the University of Milano‐Bicocca in Monza, Italy as well as the subsequent establishment of the Monza International School of Pediatric Hematology‐Oncology (MISPHO), the Asociación de Hemato‐Oncologiá Pediátrica de Centro América (AHOPCA) was formed in 1998. Initially this consisted of Guatemala, Honduras, El Salvador, Nicaragua, and Costa Rica. Panama joined in 2001 and the Dominican Republic in 2006

Their early collaborative research works have been in the area of Nutrition and Retinoblastoma.

For further reading - Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA): a model for sustainable development in pediatric oncology

There are several other regional and national initiatives in pediatric oncology collaborative research in LMIC which have blossomed in recent years e.g. the Turkish Pediatric Oncology Group, The Pediatric Oncology East and Mediterranean (POEM) network and others. We look forward to seeing their work in the future. I would like to now focus on China and India, which together would constitute nearly a third of the childhood cancer burden. And so both of these countries have to strengthen their collaborative research so that they individually and the world collectively can aspire to reach the WHO Global Initiative for Childhood Cancer target of at least 60% survival by 2030.

The Chinese Experience

There are two national collaborative groups within China. The Chinese Children Leukemia Group (CCLG) started the CCLG-ALL 2008 Study. A total of 2231 patients were recruited from 10 hospitals across the country from 2008 to 2013 - Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008: The first nation-wide prospective multicenter study in China. More recently, the Chinese Children Cancer Group (CCCG) which was formed in In 1997 under the China Anti-Cancer Association, has organized one of the largest clinical trials in China, the CCCG-ALL-2015 Study. The study is led by the National Center for Children’s Health (Shanghai) and supported by St Jude Children’s Research Hospital and the VIVA Foundation. Up to January 2019, and 6024 patients were recruited into the study.

 

For further reading - Treatment of childhood cancer in China: Current status and future direction

Indian Pediatric Oncology Group (InPOG)

 

The earliest report of collaboration in the field of pediatric oncology in India was that between Cancer Institute, Chennai and the National Cancer Institute, USA in the early 1980s. Adopting a more intense protocol (MCP841) than that being used at the time, led to an improvement in the event free survival of acute lymphoblastic leukemia from 20% to 40%. This treatment strategy was then adopted by Tata Memorial Hospital, Mumbai in 1986 and All India Institute of Medical Sciences, New Delhi in 1992. With this common protocol, event free survival rates of 40-60% were achieved - Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period.

The need to establish a national cooperative group in order to develop prospective multi-centre clinical trials in India became increasingly apparent. Such a strategy was critical to understand the biological differences in the disease, to assess responses to treatment and ultimately to improve childhood cancer survival in India. Active since 2015, the mission of InPOG is to improve the outcomes of children with cancer in India by collaborative research. At present here are 26 disease and discipline subcommittees with a portfolio of 31 studies.

 

The InPOG-HL-15-01 was amongst the first studies to start recruitment and standardised therapy of children with Hodgkin disease on an ABVD backbone – InPOG-HL-15-01 - Challenges and lessons learnt in setting up the first collaborative multicentre prospective clinical trial in childhood cancer in India.  Initial results are expected to be published next year.

 

For further reading - Indian Pediatric Oncology Group (InPOG) - Collaborative research in India comes of age

The future looks very exciting. May this momentum gather an even greater speed!

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.

Childhood Cancer Awareness Month: increasing survival rates for children with cancer

From UICC

1 September 2020

September marks Childhood Cancer Awareness Month, a moment to reflect on the particular challenges facing children who have cancer and their parents and recall the Global Initiative for Childhood Cancer launched by WHO in 2018.

Childhood Cancer Awareness Month: increasing survival rates for children with cancer

Cancer and Childhood Cancer Care in India – FIVE reasons why I am POSITIVE and MOTIVATED on our 74th Independence day

Today we complete 73 years of our independent existence and celebrate our 74^th Independence day. The strides we have made as a nation are truly enormous and are acknowledged widely. At the same time, the challenges which remain are no less mighty and we need to continue on the path of relentless progress to overcome hunger, poverty, ill health, strife, pollution, among others.

At this time I reflect on the cancer and childhood cancer care in India, and despite the many challenges which we face in this area, I have found FIVE reasons why I as a pediatric oncologist am POSITIVE and MOTIVATED on this day and look forward to the coming year and decade with great anticipation.

REASON ONE – WHO Global Initiative for Childhood Cancer (GICC)

Active involvement of the WHO and launch of the GICC in 2018 (https://www.who.int/cancer/childhood-cancer/en/) has been a landmark development for all stakeholders in pediatric oncology across the world. Work has already started in several countries including Myanmar which is in the South Asian region. Some work has also begun in India last year with meetings with the professional societies and the parent groups. This year, the Ministry of Health and Family Welfare, Government of India along with the WHO SEARO office have selected 4 centres (BBCI Guwahati, Kidwai Hospital Bangalore, Kalawati Saran Hospital New Delhi and Tata Memorial Hospital Mumbai) to be National Centres of Excellence for Childhood Cancer services. Many more activities and initiatives will follow to help India reach the target of 60% survival rate for children with cancer by 2030.

REASON TWO – National Cancer Grid (NCG)

For too long we have had a plethora of national societies in all spheres of medicine including oncology and pediatrics, which seem to exist from meeting to meeting, seminar to seminar. Most professional medical societies in India have not taken up the cause of the patient, and addressed the deficiencies in healthcare in a big way. Enter National Cancer Grid (https://tmc.gov.in/ncg/) in 2012 – today it is a network of >200 major cancer centers, research institutes, patient groups and charitable institutions across India. Led very ably by Dr CS Pramesh it has launched and successfully executed a host of collaborative activities – Disease Management Group specific Virtual Tumour Boards, Online second opinion service through Navya, CRedO Workshop for researchers, are just a few of the many initiatives which are ongoing or in development.

REASON THREE – Indian Pediatric Oncology Group (InPOG)

Multicentre collaborative research is critical if India wants to make progress in the care and outcomes of its children with cancer. InPOG (https://www.phoindia.org/cms/inpog-faqs) has been active since the beginning of 2015 and as of December 2019 (in five years) 5543 patients have been recruited in 15 studies (40% interventional and 60% non-interventional studies) from 90 centres. It now enters into its next phase and promises faster and greater developments.

REASON FOUR – Cankids

Driven by the relentless energy of its founder Poonam Bagai, Cankids (https://www.cankidsindia.org/) has blazed the trail in India as well as globally, showcasing how patients, parents and civil society can contribute to childhood cancer care. They not only provide vital social and psychological support for children with cancer and their families, but are leading engagement with state governments on Change for Childhood Cancer in India (http://childhoodcancerindia.blogspot.com/2017/09/supporting-childhood-cancer-treatment.html) and have done a phenomenal amount of work during COVID-19 ensuring that the treatment of patients is not disrupted.

REASON FIVE – Max Healthcare and Max Institute of Cancer Care

My workplace and my employer (https://www.maxhealthcare.in/) have consistently demonstrated, never more than now in these COVID-19 times, that it is possible to deliver high quality care to cancer patients while balancing social responsibility and driving academics and research in the private sector. Solving India’s healthcare challenges would need partners in all sectors of healthcare and Max has shown the way. Thank you Mr Abhay Soi and Dr Harit Chaturvedi for your inspirational leadership

-->

Childhood cancer survivorship and late effects: The landscape in India in 2020

Cure from childhood cancer is now a justifies expectation and with the right treatment most children would get cured of their cancer and achieve long-term survival. While the goal is that this long-term survival is normal, experience has taught us that some survivors suffer from late side-effects. This has been an area of intense focus in the last few decades and there is now growing evidence on how to prevent and treat these late side-effect.

So far, the information from India has been limited and scattered. We mad an attempt to bring this all together and are happy to share our recent publication on this in the Pediatric Blood Cancer - Childhood cancer survivorship and late effects: The landscape in India in 2020

We highlight not only the steadily increasing work going on with childhood cancer survivors in the hospitals, but also the efforts taken by healthcare providers, and other stakeholders in developing this service, advocating for this cause and providing survivors with a platform. A special mention of two such organisations - Ugam and Cankids - who contributed to this effort.

COVID-19 Pandemic and Childhood Cancer

None of us has ever seen anything like this before. And I am not talking about a viral infection. I am talking about the emergence of a new infection and the global and national response to it which has been without parallel. Over the last few months not only has the infection affected the health of millions and taken the lives of hundreds of thousands, it has brought the world to a HALT! Individuals, businesses and countries have borne the brunt of it and continue to do so.

It will be some time before this comes to pass. Meanwhile children with cancer (like those with many other illnesses) have been caught in this maelstrom with impact on their diagnosis, their treatment and eventually outcomes. In the face of such ongoing challenges, the global and the national pediatric oncology community has got together to respond on multiple fronts in many different ways.

The Global COVID-19 Observatory and Resource Center for Childhood Cancer is one such effort. Developed by SIOP and St Jude Global, this Resource Centre provides all relevant information to those caring for children with cancer including parents and families. The reader is encouraged to browse the website for further information.

Specifically I wanted to highlight two things.

Firstly, are the weekly COVID Conversations - a live webinar to discuss difficult issues, address pressing questions, and hear the experiences of our colleagues when it comes to caring for children with cancer during this pandemic. Several such Conversations have happened with one specifically relating to Experiences in India and Pakistan.

Secondly, is the Global Registry of COVID-19 in Pediatric Cancer which provides a visualisation of the impact of the virus on our patient population.

Podcast on perspectives of caregivers of children with cancer in India on their journey to accessing timely cancer diagnosis and treatment

I am glad to share a podcast https://www.ghccpod.com/22-the-labyrinth/ was conducted by Dr Mark Zobeck based on one our recent pieces of work in trying to understand the experiences of the caregivers of children with cancer in India as they obtain their diagnosis and start treatment.

I quote from his link

How does a child with cancer in India access care?

If you’ve ever had an illness that was difficult to diagnose, you know that navigating the medical system can be incredibly frustrating. Bouncing back and forth between doctors, taking time off of work or school, waiting for hours upon hours, all while you don’t feel well and do not know what is going on with your body is enough to drive anyone crazy. Unfortunately for families of children with cancer, they know this feeling all too well. Childhood cancer can be very difficult to diagnose and the journeys that families undergo to find answers and receive care can be long and grueling. 

To better understand these journeys, Drs. Neha Faruqui, Ramandeep Arora, and their colleagues have studied what they call the “healthcare labyrinth” of accessing childhood cancer care in India. Through discussions with parents and caregivers, they classified the major themes that contribute to difficult or prolonged paths to care. Today on the podcast, we will discuss their findings from their many hours of listening to the families’ stories. 

I would encourage anyone listening to the podcast to also read their paper. As I say in the podcast, it reads more like a novel than a journal article, and I found myself emotionally invested in the way the parents described their journeys. It made me appreciate anew how important it is to establish robust health systems that can rapidly identify patients and refer them to appropriate tertiary care.

Lastly, this discussion is not meant to be a criticism of the Indian healthcare system. It is an enormous system that is responsible for caring for 1.3 billion people! There are many things it does very well! But of course, there are things that can be improved. As Dr. Arora says in the episode, this paper, and our discussion is about listening to the caretakers to discover how providers everywhere can better care for not only the patient during treatment but for the entire family through the entire cancer experience. 

Read the full study here: https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-019-7911-x

Key Information on International Childhood Cancer Day 2020 from WHO and the International Society of Pediatric Oncology