Accrual of adolescents and young adults with cancer to clinical trials

Cancer is the most common disease-related cause of death in 15to 29-year-olds in Canada, with more than 2000 new cancer cases and more than 300 deaths per year1. Between 1996 and 2005, the cancer incidence in that population rose by approximately 1%1. Although mortality rates have declined1, rates of improvement have been less than those observed in younger and in older patients2. Statistics alone are an inadequate reflection of the personal and societal impact of cancer in the young adult age group. Statistics Canada estimated that, in 2004, 16,000 potential life-years were lost to cancer in individuals 15–29 years of age1. Accrual to clinical trials has been a major contributor to the steadily increasing 5-year survival rates in cancer. Compared with children and older adults, adolescents and young adults (ayas) have been enrolled on clinical trials at a much lower rate in Canada3,4 and internationally5,6, leading to the plausible postulate that lower trial participation accounts at least in part for lesser survival gains in that age group7,8. Improving access to clinical trials for ayas is a priority6,9.

Group, the U.S. National Cancer Institute convened a Progress Review Group focused uniquely on a population (ayas) rather than on a disease and partnered for the first time with a nongovernmental organization (livestrong) 9 . International Society of Paediatric Oncology symposia on aya oncology have focused on the challenges of accruing ayas to cancer clinical trials, as reflected in national initiatives in Australia 10 , Italy 11 , the United Kingdom 12 , and the United States 13 . Recognizing that cancer is the leading cause of death from disease for ayas, the American Society of Clinical Oncology launched their Focus Under Forty initiative (http://university.asco.org/focus-under-forty) and, in collaboration with philanthropic and professional organizations, designed education programs to increase awareness of the unique biology and care issues associated with cancer in this age group, including clinical trials.
In Canada, early interest in aya oncology was driven by the Pediatric Oncology Group of Ontario 14

Importance of Cancer Clinical Trials
Medical practice has been transformed and tremendous advances for patients realized through randomized clinical trials 18,19 . In childhood cancers, survival rates have quadrupled since the mid-1970s and now exceed 80% 19 . As stated in the Canadian Cancer Research Alliance report on the state of cancer clinical trials in Canada, "without clinical trials, the outcomes of cancer patients will not continue to improve" 20 .
Generalizability is key to ensuring that clinical trial results can be reliably extrapolated and used to guide health policy and health care for the general population. In the United States, more than 60% of children with cancer are enrolled on clinical trials 19 ; accrual drops to 2%-4% of those 20-29 years of age 21 , raising real concerns about the generalizability of clinical trial results within the wider population of young adults with cancer. Differences in cancer subtype, disease biology, and patient physiology limit the applicability to young adults of research conducted in children. For instance, relative to younger patients, ayas experience increased treatment-related toxicity 22 .
Defining the aya age range is important. The lower bound is uncontested, given that the international registration of children with cancer encompasses the group 0-14 years of age. Furthermore, there is growing acceptance that, for this purpose, "adolescence" comprises the teenage (15)(16)(17)(18)(19) years. Much less agreement exists on the upper bound for ayas. It has been argued that the boundary will vary according to circumstance-for example, 24 years for active care, 29 for epidemiology, and 39 for "long-term" follow-up 23 . However, the U.S. National Cancer Institute's Surveillance, Epidemiology, and End Results Program has adopted 29 years for the upper age limit 24 , as has the Canadian Cancer Society.
The debate is not artefactual. The classification system proposed for cancer in ayas 25 and adopted by the Surveillance, Epidemiology, and End Results Program is pertinent to the 15-29 age range. It is also clear that the distribution and biology of malignant diseases in ayas varies appreciably not only from the nosologically same diseases in children and older adults 26 , but also across the aya age range. Focused translational and clinical research is required to understand the malignancies prevalent across the age groups that constitute this young population.

The Landscape in Canada
The Canadian Task Force on Adolescents and Young Adults with Cancer established a Clinical Trial Accrual Working Group in 2013. As a prerequisite to addressing barriers to enrolment and improving recruitment, that group, comprising oncologists in pediatric and adult practice, with representation from the Canadian Cancer Society and academic clinical trial cooperative groups, was charged with determining national accrual rates for ayas to clinical trials. Obtaining data about clinical trial accrual for ayas in Canada has proved to be a greater challenge than anticipated. There is no single, national, comprehensive, and accurate source of such information, because the databases that include age as a variable reside with the numerous sponsors of clinical trials or represent fragments of the population.
Health Canada, the federal department responsible for the review of clinical trial applications, recently created an online database of Canadian clinical trials involving human pharmaceutical and biologic drugs (http://www. hc-sc.gc.ca/dhp-mps/prodpharma/databasdonclin/ index-eng.php). Health Canada does not collect information about accrual.
The Canadian Cancer Trials Group (previously the ncic Clinical Trials Group) is an adult cooperative group that conducts academic clinical trials for individuals with cancer across Canada. A retrospective review of enrolment to Canadian Cancer Trials Group trials between 2000 and 2013, which accounted for disease incidence by age, revealed that individuals 18-29 years of age were, overall, underrepresented by a factor of almost 2 when compared with individuals 30 years of age and older 3 . However, aya accrual in certain disease types, including non-Hodgkin lymphoma and breast and cervical cancers, was greater than expected.
The U.S. National Cancer Institute's Cancer Therapy Evaluation Program records age at time of accrual for the small proportion of Canadian patients enrolling on National Clinical Trials Network (nctn) studies in the United States. Pharmaceutical sponsors of clinical trials hold detailed data about patients enrolled on their studies, but collating such information from those sources is impractical; numerous individual data-sharing agreements would be required.
Recently launched, with the aim of supporting researchers conducting academic-sponsored multicentre clinical trials that will benefit patients, the Canadian Cancer Clinical Trials Network (http://w w w.3ctn.ca) will collect data about accrual to academic clinical trials across Canada. Currently, collection of individual patient characteristics (such as age) and of data about accrual to studies sponsored by the pharmaceutical industry and to single-institution trials is not planned (Dancey J. Personal communication).
The Cancer Care Ontario used accrual to clinical trials as a quality indicator until 2011, but no longer does.
The Childhood, Adolescent, and Young Adult Cancer Survivors research program records accrual of patients 15-24 years of age to clinical trials in British Columbia 27 . As detailed in Table i, clinical trial enrolment declines with increasing age. Good accrual in the early 1990s has not been maintained over subsequent years.
Table i and Figure 1 summarize provincial data, including those from CancerCare Manitoba and Cancer-Control Alberta. Notably, the age range and disease types included vary from one database to the next.
At an institutional level, major systemic barriers hinder clinical trial accrual across the aya spectrum. Dichotomous pediatric and adult approaches to patient care and clinical research have evolved over decades and become established. Even in institutions in which care is provided within the same hospital, the infrastructure, funding model, and clinical trial research office are completely separate for children and young adults. In institutions that are geographically separated, additional challenges are present.

Opportunities for Progress
Collaboration is key to increasing the opportunities for ayas with cancer to participate in clinical trials and the uptake to available trials. An aya working group has been established that bridges the U.S. National Cancer Institute's nctn cooperative groups: the Children's Oncology Group, the Alliance for Clinical Trials in Oncology, swog (formerly the Southwest Oncology Group), nrg Oncology, and the ecog-acrin Cancer Research Group in the United States, and the Canadian Cancer Trials Group in Canada. Goals include identification of gaps in which clinical trials are needed, systematic change in age eligibility requirements for aya-relevant trials, monitoring of aya accrual patterns over time on nctn trials, and development of nctn-wide strategies to promote and facilitate aya accrual 6 .
Within Canada, the C 17 Council (pediatric) and the Canadian Cancer Trials Group (adult) have partnered to span the arbitrary age divide by developing a unified platform that enables children and adults to use a single clinical trials application from Health Canada to enrol on clinical trials. A harmonized approach for all aspects of clinical trial conduct, including monitoring and safety reporting, is being piloted in a clinical trial for patients 2 years of age and older with sarcoma (NCT02180867). The approach will continue to evolve as more trials are made available through that mechanism.
The Ontario Cancer Research Ethics Board, which has conducted ethics reviews of multicentre adult cancer trials since 2004, began reviewing pediatric submissions in 2015. Streamlining the ethics review system will make it easier to initiate cancer clinical trials at multiple centres for multiple patient age groups. Individual institutions in which treatment and research for ayas is divided between pediatric and adult services are beginning to explore opportunities for closer working relationships between the associated clinical trial research offices and for minimization of duplicated workload. Effective operationalization of a unified platform for aya clinical trial accrual will require major systemic change and drivers to champion institutional buy-in. The Clinical Trials Working Group of the Canadian Taskforce on Adolescents and Young Adults with Cancer, having established indicators of poor national clinical trial accrual, continues to seek opportunities to develop a more robust and encompassing record, with the goal of developing a national source for clinical trial accrual data and using it as a benchmark for improvement. Acknowledging the time pressures affecting physicians and the financial constraints under which hospital clinical trial units operate, progress must be efficient and affordable. Discussion with the Canadian Association of Provincial Cancer Agencies will continue to explore whether provincial cancer agencies can work with their regional cancer centres to obtain the requisite data at the level of individual clinical trial units, where the raw information resides. Engagement of ayas who have cancer is crucial to ensure that new clinical trials are acceptable, available, and accessible to them 28 .
In the United Kingdom, a national focus 29 on ayas with cancer has resulted in improved participation in clinical trials for that group. Factors contributing to the U.K. success include the establishment of a Teenage and Young Adult Clinical Studies Group, an increase in the profile of ayas among researchers conducting clinical trials, expansion of the age eligibility criteria for clinical trials, and increased collaboration between the pediatric and adult communities 12 . Through the ongoing collaboration of relevant stakeholders in Canada, the effort to better understand the hindrances to clinical trial participation and to actively develop strategies and systems to overcome those hindrances continues, in pursuit of the ultimate goal of improved survival and quality of life for ayas with cancer.