No child should die at the dawn of life was the motto of Danny Thomas, the founder of the world-famous St Jude Children’s Research Hospital in Memphis to treat children with cancer and other catastrophic diseases.
In 1962, when St Jude was established, the survival rate of childhood cancers was less than 4%. Today, 80% of the children suffering from cancer survive. The rates hover above 90% in certain types of blood cancer.
Nevertheless, resource-challenged settings, including that in India, are still way behind in their achievements.
Unlike adult-onset malignancy, cancers affecting children have better prognosis thanks to advances made in the treatment of childhood cancers, considered one of the biggest success stories in the field of oncology in the last millennium.
In western societies, the five-year-survival rate of paediatric cancer has dramatically risen to 90%. The outlook, however, remains very hazy and dismal in most parts of the world.
India did make some progress in this area in recent years, and things have started shaping up. Still, it looks way off the mark in almost every aspect —service, research and education in paediatric oncology.
Paediatric cancers are mostly managed by adult oncologists or self-trained paediatricians, except in a few centres. Even a fewer number of hospitals have dedicated beds for paediatric cancer patients, or facilities for platelet transfusion or bone-marrow transplant.
Apart from a lack of expert clinicians and facilities, trained oncology nurses and nutritionists to treat children with cancer, necessary services like immunophenotyping, cytogenetics, nuclear imaging, radiotherapy, blood components and morphine are very limited, experts say.
“Paediatric oncology is neglected by far, in India. Many of the medical colleges still lack dedicated departments for paediatric oncology,” says Dr Muzammil Shaikh, a consultant medical oncologist at the PD Hinduja National Hospital & Medical Research Centre in Mumbai.
Compared to the developed world, the cure rates for childhood cancers in India are abysmally low. One can put the figure to roughly to 30-40% in some centres.
The scenario has started changing slowly. Medical institutions now offer super specialty programmes in paediatric oncology, he adds.
Quality of care
Not all paediatric oncologists concur with Dr Muzammil’s view. Some of them maintain that survival rates are progressively improving in India too. The numbers cannot be as low, they say, preferring to put it around 60%. The 5-years survival rate is as good as 65-70% in specialised centres, which comes close to the 75% of the western standard and 90% in ALL.
Over the decades, long-term survival rates in haematological cancers have greatly improved, including in acute lymphoblastic leukaemia (ALL), Hodgkin disease, non-Hodgkin lymphoma (NHL) and in acute myeloblastic leukaemia (AML).
The survival rate in solid tumours has also risen. However, the numbers are considerably poor in certain types of cancers, such as retinoblastoma, CNS tumours and germ cell tumours. Studies also show a significant disparity in outcomes from centre to centre, with only a few achieving standard results.
Other than the standard of treatment, the outcome of paediatric cancers in a country like India is dependent on a host of factors, including patient compliance, the quality of medicines and so on.
Some haematologic cancers usually have a protracted treatment period with multiple phases. Families tend to stop the treatment as soon as the child gets relieved of acute symptoms during the induction and remissions phases, citing unaffordability and other inconveniences associated with the treatment as reasons.
Non-completion of the treatment or treatment abandonment is a major cause for the low survival rates of children suffering from cancer in India. Earlier, studies have found the ratio of these treatment defaulters to be as high as 45%. More than 90% of them stopped the treatment due to a lack of financial resources.
Even the NGOs working in this area cannot support the cost of the medicines. Treatment is offered free of cost in the public-funded cancer centres. But most of the time, the family of the patients have to travel long distances to reach such specialised facilities that offer free treatment. It can involve additional expenditure, such as travel, food, lodging etc.. Little wonder, then, that thoughts of long queues in OPs and ordeals around the often-painful treatments deter families. A lack of financial resources, coupled with low awareness of the disease, often compels poor villagers to resort local clinics or babas for relief.
Access to treatment depends on two factors. One is availability and the other is affordability. Most of the drugs currently used in treating cancers like leukaemia are old. So, generic versions of these drugs are available. Still, their affordability remains a question. A large section of families with children suffering from cancer are unable to support the cost of the long-drawn treatment. Apart from the cost of the medicines, cancer treatment usually involves other expenses for purchasing blood bags for transfusion and so on.
The quality of drugs is another crucial factor which will have a direct impact on the outcome of the treatment. Therefore, ensuring the quality of the medications used in the treatment of cancer is essential. Presently, there is no mechanism to ascertain the quality of medicines available in the market and quality surveillance is poor.
Child malignancy vs adult cancer
Paediatric malignancies, which are estimated to affect nearly 300,000 children aged 0-19 years, are different from adult cancers in their aetiology and biology.
Leukaemias, followed by central nervous system tumours and lymphomas, are the most frequent cancers in children. Lymphomas come second in certain regions.
More than 60 different cancers occur in children. The number is even higher when considering different molecular types of each cancer. There are, for example, four different subtypes of medulloblastoma, defined by their molecular biology. Each have different prognoses and survival rates and require different approaches. Every cancer in a child is either rare or extremely rare. This creates practical difficulties in clinical research and the way in which new drugs are developed.
So far, little progress has been made in hard-to-treat cancers like medulloblastoma, high-risk sarcoma and high-risk leukaemia. Over the last ten years, these cancers have shown no improvement in survival.
“Paediatric tumours tend to have far fewer genetic changes. In addition, some children are born with cancer or with precancerous cells. In contrast, adult tumours develop after decades of accumulating small changes to the DNA,” says Dr Alix E Seif, Assistant Professor, Perelman School of Medicine, University of Pennsylvania, USA.
Several of the same types of cancer affecting adults also affect young people. However, the ways in which they develop, and the treatment modalities, can be entirely different. Several reasons are attributed for this.
Most cancers affecting children involve a precursor cell, known as a “blast” cell. Blast cells are important in the formation of bodily tissues, including blood and immune cells, bones, eyes and the brain.
“Paediatric cancers are different altogether. They usually grow very fast. They also respond to treatment in a better way,” explains Dr Muzammil.
Paediatric cancer is also different because it affects children — the building blocks of a nation’s future. A child with cancer cannot be equated to a 58 or 60 year-old person suffering from lung cancer. So, the socio-economic cost is also pretty high with paediatric cancers, he avers.
Poor reporting and underdiagnosis
No consolidated epidemiologic data on paediatric cancers are available in India. Though the National Cancer Registry Program (NCRP) was started in 1982, the data on paediatric cancers are still limited and show great variation between different populations in India.
There are no population-based cancer registries in many poor and populous states. Since the follow-up of patients is inadequate, there is no nationwide data on survival or treatment abandonment.
“The biggest problem is that we don’t have a national registry for cancers. We do have some population-based data. But that is too urban-centric. If we start to extrapolate, it could lead to bias,” rues Dr Muzammil, who is also associated with Indian Oncology Study Group (IOSG).
The age-standardized rates of childhood cancers are the highest in metropolitan areas, followed by other urban and rural areas. The numbers can also represent other factors like underdiagnosis and under ascertainment in places with limited availability of diagnostic and clinical facilities.
“Paediatric patients come late on many occasions. This makes the prognosis also poor,” says Poonam Bagai, founder and chairperson of CanKids India, a not for profit organisation working in the field of childhood cancer.
In addition, paediatric oncologists are rare in some regions of the country. Reporting is yet to improve in paediatric cancer, especially in rural India.
The number of cases of paediatric cancer is gradually increasing in semi-urban regions, thanks to early diagnosis and prompt referrals. The cooperation from primary care centres, various specialties and family physicians help to refer more cases to specialty centres.
The percentage of underdiagnoses in paediatric cancers can still be very high in India, experts say, pointing to a recently published study in Lancet Oncology that as much 50% of paediatric cancers are underdiagnosed in South Asian countries.
Criticality of collaborative research
Global data on paediatric oncology indicate that the adoption of uniform protocols and participation in prospective, multicentre clinical trials have been key in significantly enhancing survival and outcome.
In India, clinical trial participation is extremely low. As of April 2018, four studies by Indian Paediatric Oncology Group (InPOG) completed recruitment and another five studies were recruiting, according to the website of the Paediatric Hematology and Oncology (PHO) chapter of the Indian Academy of Paediatrics. While another four trials have completed the registration process, eight studies were listed under provisional registration. InPOG was formed to galvanise collaborative research with 21 disease-specific subcommittees dedicated to different cancers.
“Presently, 29 studies are underway on various paediatric cancers in India,” says Dr Ramandeep Singh Arora, Secretary InPOG. The situation is rapidly changing with the establishment of a cooperative network of paediatric oncologists.
Till recently, there were no such networking societies formed in India and that was the major reason behind the lack of participation in clinical studies, he adds.
Networking is absolutely crucial in paediatric oncology and has been essential to the significant progress that has been made over recent years. The only way to improve care and research is to run trials through co-operative groups at a global level rather than at a national level.
“Since childhood cancer is also far less common than adult cancers, collaboration and sharing of data is essential to deepening our understanding of what is common and relevant,” says Dr Jon Sherlock, Director, Product Management, Oncology, Thermo Fisher Scientific, Massachusetts, USA.
According to him, cooperation in this field will speed up discovery, and, for the first time, consistent results will be obtained due to the use of standardized assays, allowing data comparison across the globe.
Thermo Fisher launched the International Childhood Oncology Network (ICON) with an aim to create a global community spanning academic and clinical researchers who collaborate by sharing data, best practices and experimental protocols to drive a better understanding of childhood and young-adult cancers.
“The biggest contributor to our increased success in curing children of their cancers is the development of collaborative groups. By joining together with colleagues around the country or even around the world, we are able to study enough patients to learn how to improve their care over the past 5 decades,” comments Dr Alix.
Paediatric cancer trials still take a relatively long time to complete, compared to large, adult studies. However, incredible progress has been made “and the idea of collaborative group trials came out of paediatric oncology, out of sheer necessity”, according to her.
Oncologists say that a range of factors, including a paucity of experts and regulatory and policy issues, impede clinical research in paediatric oncology. Funding and facilities are other concerns.
“In India we do have enough expertise in the field of paediatric oncology. But the question is whether we have full-time researchers who can dedicate themselves to clinical research. Most of the physicians are tied up with their professional responsibilities fulltime,” says Dr Ramandeep, who is also a senior consultant paediatric oncologist, Max Super specialty Hospital, New Delhi.
Some estimates indicate that only 4-5% of the affected children are being enrolled in clinical studies in India.
Meanwhile, more than 90% of the children with cancer are participating in trials in west. 95% of the patients in Europe are treated in public and university hospitals or cancer centres by paediatric oncologists. They have integrated clinical trials with routine care in paediatric oncology for many years, which also means that more than 80% are prospectively monitored, based on a standard of care protocols shared by all institutions.
Not only deficiencies with protocols, but several other factors mar the outcome in paediatric cancers. “In places like India, poor standards of hygiene, poor infection control and poor nutrition practices, all compound the problem of overall survival of children affected with cancer,” opines Bagai. She explained how CanKids India has been trying to build a base of nurses trained in managing paediatric patients through its ‘100 Nurses Programme”. 62 of these “nurse practitioners” have completed the training and have already been deployed at various centres. The NGO is also giving a “big push” to cancer care nutrition, apart from enabling better standards of treatment and care by partnering with cancer centres through funding support, by providing social support staff, enhancing capacities and driving quality care, research and impact assessment.
ALL success and inequality gap
Scripting one of the greatest success stories in modern medicine, improved treatments helped to raise the global 5-year survival rate for children diagnosed with ALL, the most common childhood cancer, to 92% in 2012 from a mere 3% in the 60s. Similarly, survival rates in non-Hodgkin’s lymphoma rose to 91% in 2012, according to the National Cancer Institute, US.
As a part of standardising treatment of children with ALL, Tata Translational Cancer Research Centre (TTCRC) has initiated a study using Indian Childhood Collaborative Leukaemia (ICICLe) protocol in five centres across the cities of Mumbai, Delhi, Kolkata and Chennai. The clinical study started in October 2016 and around 2,600 patients have been recruited so far. ICICLe offers a modern-yet-simplified clinical management process for childhood ALL, providing the opportunity to develop new, cost-effective tools for risk stratification.
“The primary objective of the study is to raise the five-year survival rate of ALL patients to 75% from the current 65% and then gradually move to 90% target, which is the international standard,” says Prof Vaskar Saha, Senior Consultant at Department of Paediatric-Haematology & Director of Tata Translational Cancer Research Center (TTCRC), Kolkata.
Despite the tremendous progress made, the survival of young cancer patients, as mentioned, is not essentially the same all over the world. Various organisations working in the field of childhood cancer are trying to address this gap of inequality.
“An enormous amount of good work is going on within the paediatric oncology community in India. That will drive better outcomes, quality of life and care for children with cancer and their families, as well as secure child rights for the health-impaired child with cancer – right to health, education, childhood, pain and palliative care as well as right to be heard,” avers Poonam Bagai.
The Ponte di Legno Working Group statement, issued in December 2003 during the Sixth International Childhood Acute Lymphoblastic Leukaemia meeting held in San Diego, remains the cornerstone of the principle. Representatives from 15 leading study groups and institutions said an improved possibility of survival should be considered among a fundamental right of affected children.
Emphasising the urgency of the priority to correct this inequality in ALL treatment, they called upon international agencies to qualify as essential drugs used in the protocols developed for the children to treat leukaemia and other cancers. The group urged all the authorities concerned “to recognize and support all measures that promote this right to a chance of cure”.
Presently, most of the therapies used in childhood cancer are not of a targeted nature. As a result, a cure is often accompanied by significant acute and long-term toxicities.
Hence, childhood cancer survivors stand the risk of developing complications years after the treatment has ended. Children who were treated for bone cancer, brain tumours and Hodgkin lymphoma, or who received radiation to their chest, abdomen, or pelvis, have the highest risk of serious late effects from their cancer treatment, including second cancers, joint replacement, hearing loss and congestive heart failure.
Data from long-term follow-up analysis of a cohort of survivors of childhood cancer treated between 1970 and 1986 have shown that more than half of cancer survivors have experienced a disabling complication or even death by the time they reach age of 50 years.
Since then, modifications in treatment regimens to reduce exposure to radiotherapy and chemotherapy, increased efforts to detect late effects and improvements in medical care for late effects have reduced the risks. An analysis of over 34,000 five-year childhood cancer survivors in the US published in the New England Journal of Medicine in 2016 showed the rate of death from any cause within 15 years of childhood cancer diagnosis declined by half (from 12% to 6%) among survivors treated in the 1990s compared to those treated in the 1970s. Long-term follow-up guidelines are now available for follow-up care and enhanced medical surveillance of childhood cancer survivors for the rest of their lives.