Slipping through the gap: teenage oncology patients miss trial benefits
MedWire reporter Lynda Williams talks to Dr Jeremy Whelan about why clinical trials are failing teenage cancer patients.
Dr Jeremy Whelan is a consultant medical oncologist at University College Hospital, London, UK, specializing in bone and soft tissue sarcoma. He is lead clinician for the hospital's teenage cancer services and was appointed Chair of the National Cancer Research Institute's Teenage and Young Adult Clinical Studies Development Group in April 2005.
Dr Lorna Fern was appointed as research development coordinator of the Teenage and Young Adult Clinical Studies Development Group in October 2006. The position is supported by the Teenage Cancer Trust charity.
Not enough teenagers and young adults are being enrolled into clinical trials for cancer treatment. As a result, survival rates for this group have been almost static, compared with the improvements for children.
The UK’s National Cancer Research Institute has set up a group aimed at increasing enrolment rates among 13–24 year olds. It is called the Teenage and Young Adult Clinical Studies Development Group (TYA CSDG) and is headed by Dr Jeremy Whelan from University College Hospital in London.
The statistics are stark. Over the past 25 years, 5-year survival rates for under-15 year olds have improved by 1.5% a year. The same goes for those over 35 years old. But for the age groups in between, the increase for 15–24 year olds is less than 0.5% a year. For those aged 25–34 years, there has been no increase at all.
So how has this discrepancy arisen? And what can be done to correct it? Whelan acknowledges that they face a complex challenge to ensure the inclusion of teenagers and young adults in future clinical trials and improve their outcome.
Teenage and Young Adult Clinical Studies Development Group
Whelan explained that the TYA CSDG was set up in parallel with the UK’s National Institute for Health and Clinical Excellence Improving Outcomes Guidance for Children and Young People with Cancer, an evidence-based review of all aspects of care.
A key recommendation of the guidance is that teenagers and young adults – those aged 13 to 24 years – should be given access to clinical trials, and part of the remit of the CSDG is to assess trial availability and trial accrual in this population.
The CSDG has now characterized current trial accrual of teenage and young adults with the most common malignancies: leukemia, lymphoma, bone sarcoma, and tumors of the central nervous system, and male germ cells.
“What we have identified is that, in comparison with children, for whom we know that there has been a strong record of inclusion in clinical trials through patterns of care that have built up over 20 years, we can see that quite rapidly, beginning in the mid teenage years, there is a fall off in the inclusion of these patients or teenagers in clinical trials,” Whelan said.
CSDG findings
Whelan explained that the barriers to better accrual of young people into clinical trials include trial availability, as well as clinician choice.
The CSDG is due to publish data showing that between April 2005 and March 2006 almost twice as many 10–14-year-old cancer patients were recruited to trials as patients aged 15–24 years in the tumor types studied, said Dr Lorna Fern, research development co-ordinator for the CSDG.
The data for 2006–2007 show a similar overall accrual to that in 2005–2006, but closer analysis of the data showed that the tumor types of the patients included in trials changed significantly.
The group found a significant decline in the accrual of children, teenagers, and young adults with acute lymphoblastic leukemia (ALL) across the study years. This was mainly due to the closure of the UKALL XII trial of young patients to those with Philadelphia-negative ALL in December 2006.
However, this shortfall was compensated for by accrual of teenagers and young adults, as well as pediatric patients, to the EURAMOS (European and American Osteosarcoma Study Group) trial which opened in the UK in September 2005.
“So although the overall data looks the same, if you look at specific tumor types you see that the contribution changes with the opening and closing of trials,” Fern explained.
Whelan said of the findings: “Absolute numbers are useful to a point but if you don’t have any trials open in a particular disease type then you can’t include any patients.
“So there are different aspects both in terms of availability of clinical trials that are open, and the access to those trials, as well as clinicians actually putting patients into those trials.”
Age-appropriate eligibility criteria
The decision to include young people in clinical trials is not just down to individual researchers.
Clinical trial protocols have traditionally used an age range in their eligibility criteria, which has often been arbitrary and based on whether the trial organizers care for children or adults, with a cut-off age of around 16–20 years.
“If you’re in the group of patients who straddle those overlapping age ranges then of course you can potentially be disadvantaged by being excluded from one trial,” Whelan explained.
“Alternatively, there may be different trials with overlapping age criteria for the same condition and [researchers] would have to choose the most appropriate one.”
Pediatric and adult patients are affected by different cancers, but there is an overlap in diseases that affect the middle range of teenage and young adults.
Some tumors are particularly common in teenagers and young adults such as Ewing’s sarcoma and osteosarcoma. Yet arbitrary age eligibility criteria on trial entry have resulted in 25% of patients with these sarcomas being excluded from some clinical trials because they are over 20 years old.
This gives researchers a “distorted picture of the overall behavior and response to treatment of that disease,” Whelan said.
“And we don’t know whether we should extrapolate the results from one age group of patients to another.”
Broad application of a biology-based trial design
Whelan recommends a more biology-based trial design that takes into consideration the age incidence patterns of the condition.
He noted that teenagers and young adults with cancer may not be the only patient population that could benefit from a disease biology-based approach to clinical trial design.
“What we want to do is to see protocols that are written that cover the biological spectrum of the disease rather than simply by something that is defined by who is going to treat them.”
“Clinical research should not lose sight of the biology of the disease, and one major factor that helps us understand that is age incidence patterns,” Whelan said.
He suggested that the eligibility criteria of all clinical trials should reflect the age incidence patterns of the disease, and advised caution among researchers enrolling just one part of the population with that disease, unless there is a very good reason to do so.
Studies show that teenage and young adult patients with ALL who are treated under adult care have significantly poorer outcomes than those treated by pediatricians, with survival rates of 40% versus 80%.
This disparity is caused by differences in care between the populations rather than age-related disease patterns. As ALL is most common in children, they often receive treatment from pediatricians specializing in leukemia, while patients under adult care are looked after by doctors specializing in adult malignant hematology who may have less experience with ALL. Children receive more aggressive treatment and their oncologists ensure stricter adherence to regimens than oncologists treating adults.
Applying an age-unrestricted, biology-based approach to ALL, could benefit older adults as well as teenagers treated within the adult oncology departments.
“What we want to do is to see protocols that are written that cover the biological spectrum of the disease rather than simply by something that is defined by who is going to treat them,” Whelan said.
Changing trial protocols
The CSDG hopes that its findings on teenage and young adult trial participation will help to improve trial planning and young people accrual.
Whelan believes that increasing dialog between physicians treating adults and children is the next step in improving teenage and young adult care.
“I think there is a role for everybody who is involved in planning clinical trials in this. Often just as a very small part of that planning, to stop and check and say ‘well, how does this meet the needs of young people with cancer?’” he said.
“If you’re planning a trial for prostate cancer, then you really don’t need to hang around on that. But if you’re planning a trial for Hodgkin’s disease, say, actually it’s quite important.”
Whelan added: “We’d like to see those trials coming out, ensuring that there has been dialog between all the treating communities, ensuring that there isn’t a variation in practice that isn’t closely related to the biological behavior and the knowledge of treatment of that particular disease.”
The CSDG has started highlighting the need for teenage and young adult accrual to clinicians running tumor-specific trials and hopes that by raising awareness the trial coordinators will increase accrual of this population to ongoing studies and improve the design of future trials.
Teenage and young adult participation
There are currently no data to show whether gaining consent for trial participation is harder to achieve with teenagers and young adults than for adults or children through proxy of their parents, but Whelan believes it should be no different.
“The problem is not teenagers not wanting to take part in clinical trials but actually teenagers not being offered the chance to participate.”
“My experience of looking after young people is that they are open and positive about the reasons why clinical trials are undertaken. And are perfectly able to consider and make independent decisions with support about their own participation,” he said.
“There are data that have come through from teenagers themselves, through the [UK charity Teenage Cancer Trust’s] Find Your Sense of Tumour conference which shows that actually the problem is not teenagers not wanting to take part in clinical trials but actually teenagers not being offered the chance to participate.”
Future work
As well as determining TYA accrual, the CSDG has also established three working parties, one of which has provided evidence to instigate the creation of a TYA Cancer Registry based at the North West Cancer Intelligence Service in Manchester, UK.
The second, the Late-Effects Working Party, is examining survivorship issues and late effects of cancer in teenagers and young adults, such as morbidity and fertility, and causes of death in this population.
The third, the CSDG’s Health Services Research Party, is investigating delays in teenagers and young adults being referred to an oncologist after symptoms are first noticed and seen by a primary care practitioner.
This party is also determining the impact of place-of-care on patients and whether specialist units provided by the Teenage Cancer Trust affect patient outcomes.
There are no current data to show that teenage and young adult accrual is better in oncology departments with such a specialist unit. But Whelan concluded that Teenage Cancer Trust units are an example of “people prioritizing the need for special provision for young people with cancer, of which appropriate clinical trials and making access to clinical trials is one part of.”
References:
Adolescents and young adults with cancer Cancer 2006; 107 (7 Sppl): 1645–1655
Myths and Lessons from the Adult/Pediatric Interface in Acute Lymphoblastic Leukemia Hematol Jan 2006: 128–132
Web links:
National Cancer Institute
Teenage and Young Adult Clinical Studies Development Group
National Institute for Health and Clinical Excellence
Teenage Cancer Trust
North West Cancer Intelligence Service