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!

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.

It is not what you say, but how you say it that matters

So says Hanan El Malla, a psychologist at the Children’s Cancer Hospital, Cairo, Egypt. And very rightly so.  We as doctors are often guilty of so many basic communication errors when dealing with our patients. We don't talk enough, don't talk early enough, don't listen, don't simplify and then there are all the nuances of the way we talk - condescending, impatient, impersonal, lack of empathy. Traditionally, we in India have not paid attention to our communication skills (and have never been trained) and there are still many non-believers among us that remain to be convinced about the importance of communication. This becomes all the more relevant in children with cancer, where a treating physician will have to make several conversations (some difficult ones) with the child and the family over the period of their treatment.

In a study of 304 parents of children with cancer treated at the Children's Cancer Hospital in Cairo, Hanan and her colleagues looked at PARENTAL TRUST IN HEALTHCARE during treatment as a function of the communication with them at the beginning. There were six independent variables which were significantly related to parental trust.

1. Information received about the child’s disease
2. Information received about the child’s treatment
3. Opportunity to communicate with the child’s physicians
4. Being satisfied with the conversational style of the child’s physicians
5. Perception that the child’s physicians were sensitive to the parent’s emotional needs
6. Considering that the child’s physicians had met the parents with care

Further, parental trust in the physician and the medical care was NOT RELATED to the amount of information given to the parents of children with cancer.

Why is all this important? Because communication and trust are so inextricably linked with treatment abandonment. As part of initiatives to prevent and tackle treatment abandonment, one has to address communication.

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.

Why should there be a focus on children with cancer in resource-limited countries?

This is an often asked question in the context of much of the developing world. And the question should not be surprising; after all neonatal and child mortality from inadequate perinatal care and infectious diseases continue to be the main challenges in these settings. When resources are limited, and needs are many, then often the "less deserving" miss out. Over 5000 children die in India EVERY DAY before they reach the age of 5 years, most of them from prematurity and low birthweight ; neonatal infections; birth asphyxia and birth trauma; pneumonia; and diarrhoeal diseases. In comparison, the total number of children less than 15 years of age with cancer EVERY YEAR in India is around 50,000. So it is not difficult to do the maths and work our areas of focus.

Nevertheless, the life of every child is important and those of us involved in looking after children with cancer in resource-limited settings are well aware of the challenges of access to care, treatment abandonment, etc. The recently published report of the Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries titled "Closing the Cancer Divide: A Blueprint to Expand Access in Low and Middle Income Countries" is an essential read for all the stakeholders involved in delivering care to children with cancer in developing countries. The global task force is composed of leaders from the cancer and global health communities and is an initiative convened by Harvard Global Equity Initiative, The Harvard Medical School, The Harvard School Of Public Health And The Dana-Farber Cancer Institute.

The report highlights some very important facts which I think are relevant for us

1. More than 85% of all newly diagnosed children with cancer and 95% of deaths in children with cancer occur in low and middle income countries.
2. For children aged 5-14, cancer is the third leading cause of death
   in upper-middle, fourth in lower-middle, and eighth in low income countries.
3. A child diagnosed with cancer who lives in one of the poorest countries has an 80% probability of dying, compared to less than 30% in one of the wealthiest countries

The report identifies a set of candidate cancers and compelling  Cancer Care and Control   opportunities for immediate action to expand prevention and/or treatment. Among these are cancers in children which are ideal targets for advocacy and action in low and middle income countries.

Abandonment of treatment for childhood cancer: A Position Statement by the SIOP PODC Working Group

When I look at the outcomes of children with cancer in developing countries including India and try to understand the survival gap with that seen in the developed world, the one fact which strikes me most is the high level of children with cancer who abandon treatment. This is as much a social issue as it is a medical one. There is a need to recognise this, measure it, report it and then tackle it. In this regard, I would like to bring to your attention, the recently published position statement of the SIOP PODC Abandonment of Treatment of Working Group (Mostert et al, 2011).

"Almost 80% of children with cancer in resource-rich countries can be cured by timely, intensive multimodality treatment and robust supportive care. However, only 20% of the world's children with cancer live in these countries; the remaining 80% reside in resource-poor nations and have a substantially lower chance of survival. Abandonment of treatment is a major cause of therapeutic failure in these resource-poor countries, affecting up to 50—60% of cases.4 Abandonment constitutes failure to start or complete curative treatment (except in situations when such treatment is contraindicated for medical reasons—eg, the patient is too ill).

At the 2010 Congress of the International Society of Pediatric Oncology (SIOP), the Abandonment of Treatment Working Group was established as one of 12 new working groups within the Pediatric Oncology in Developing Countries (PODC) structure. Its aims are to: heighten awareness of abandonment as a major cause of treatment failure in resource-poor countries; to elucidate the contributing factors; and to identify and widely disseminate effective solutions. To enable comparisons of studies worldwide, the international paediatric oncology community must adopt consistent terminology and reliably identify and document abandonment. Only in this way can the magnitude of the global problem be measured accurately, the underlying causes ascertained, and solutions devised.

For these reasons, the Working Group offers five recommendations. First, we recommend that abandonment of treatment be documented as an adverse event in childhood cancer studies in resource-poor countries. Patients who do not begin or complete treatment should not be excluded from survival analyses. Event-free survival should be analysed in two ways: by treating abandonment as an adverse event and by censoring cases at the time of abandonment. Because some children might be cured if they abandon treatment after completing most of their planned therapy, these two estimates will reflect the upper and lower bounds of the true event-free survival estimate. Second, we propose that abandonment of treatment be defined as failure either to begin (conventionally termed refusal) or to continue the planned course (abandonment), because both are likely to have related underlying causes and could benefit from similar interventions. However, the timing of abandonment should be documented to help to identify related factors. Third, treatment in resource-poor settings might be interrupted for various reasons, including financial and transportation difficulties. When such interruptions herald full abandonment and what the effect on outcomes will be are difficult to predict. We suggest that abandonment of treatment be defined as a hiatus of 4 or more weeks in the scheduled treatment; this period is based on empirical evidence and on anecdotal observations that, after an absence of this length, patients are unlikely to return. In the rare event that patients do return after a prolonged interruption, the treatment options might be limited in the setting of refractory disease or imminent death. Further research will help to establish whether this 4-week working definition needs revision. Fourth, we recommend that abandonment of treatment should be used only in the context of treatment given with the intention of cure. However, if palliation is the only achievable goal because of disease factors or poor socioeconomic conditions (particularly relevant in resource-poor countries), these children must be documented carefully, tracked, and analysed to elucidate the reasons underlying the administration of solely palliative, symptomatic, or end-of-life care to children with curable cancers. Finally, the Working Group recognises that some might perceive the term abandonment of treatment as implying that the patients and their parents are solely responsible; we emphasise that this is not the case. Abandonment of treatment is as much a socioeconomic issue as a medical one, and is often the result of various factors beyond the control of the patients and parents.

Abandonment of treatment can no longer be ignored by the international paediatric oncology community. The members of our Working Group offer these recommendations in the belief that all children with cancer have the right to an equitable chance of survival."

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.

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.

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.