Published Online: September 19, 2014
Surabhi Dangi-Garimella, PhD
A recent report, the result of a collaboration among the National Cancer Institute (NCI), the CDC, and the North American Association of Central Cancer Registries, estimated that 15,780 children and adolescents through age 19 years will be diagnosed with cancer in 2014, of whom 1960 will not survive. That 1 in 285 children will be diagnosed with cancer before they reach 20 years of age is a devastating statistic.1
According to the National Comprehensive Cancer Network (NCCN), only about 10% of 15- to 19-year-old patients, and 1% to 2% of 20- to 39-yearold patients, enroll in clinical trials (CTs) in the United States. This is in stark contrast to the statistics observed in young children: more than 90% of children <15 years of age diagnosed with cancer participate in CTs.2
This could be the primary reason for the lack of improvement observed in cure rates in adolescent and young adult (AYA) oncology patients (15 to 39 years of age) compared with very young patients.3 AYAs, especially those transitioning into adulthood, are overlooked in cancer CTs, and are increasingly being recognized as a neglected population that should be accounted for by researchers.
Recent Updates on Trial Enrollment
Several studies have examined the deficit of adolescents in trials and identified various factors that influence recruitment patterns. A survey conducted by the NCI revealed that between 1997 and 2003, NCI-sponsored trials recruited only about half of the adolescents as patients <15 years of age, and this was observed to be a global phenomenon.4 Several reasons were identified as possible causes of this phenomenon: overlapping age criteria, cancer type, and geographic accessibility.
“With pediatric clinical trials, patient enrollment decreases with age—a 17-year-old is less likely to be enrolled than a 2-year-old,” said Karen Albritton, MD, medical director, Adolescent and Young Adult Program, Cook Children’s Hematology and Oncology Center, in conversation with Evidence-Based Oncology. Albritton pointed out that not just age, but the site of care—pediatric institution versus an adult institution—determines participation in trials. “The AYA patient, who could be seen at either site, is more likely to be enrolled at a pediatric institution, where the culture prioritizes clinical trial availability and enrollment.”
Evaluation of data from a Surveillance, Epidemiology, and End Results Program, which examined CT enrollment and time to treatment among 1358 AYA cancer patients, showed that only 14% of patients in the 15- to 39-year age group had enrolled in a CT, with certain cancer type–specific trends observed—patients with acute lymphoblastic leukemia (ALL) and sarcoma demonstrated the highest participation. While the reason for non-enrollment for more than 60% of patients was not documented, 16% of patients noted that no CT was open for registration. The report indicated that uninsured older patients (35 to 39 years), and those treated by nonpediatric oncologists, were the least likely to participate in trials. When the authors evaluated the time to treatment from diagnosis, especially in the older AYA population, they discovered that efficient referral mechanisms to tertiary care facilities—such as comprehensive cancer centers or children’s hospitals that offer specialized cancer treatment or trial participation— could prove extremely important for achieving earlier access to care. The study’s conclusion was that improved access to trials for this age group could result in better survival outcomes.5
Several studies have indicated that AYA patients have better outcomes when treated with pediatric-based protocols than when treated with protocols for adults (18 years and older).5 On this premise, a multicenter trial sponsored by the NCI is evaluating a pediatric chemotherapy regimen administered by adult hematologists/oncologists in
AYA patients (16 to 39 years of age) with acute ALL.6
According to Albritton, the medical oncology community should be engaged in the design of clinical trials for AYAs to ensure the feasibility of enrollment and compliance of AYAs treated in the medical oncology community. “All the stakeholders—the patient, the primary care provider, and the oncologist—need to be educated about and advocates for the importance of clinical trials in this age group. Patients should be aware and ask if the hospital has AYA-appropriate care, including AYA clinical trials,” said Albritton.
Barriers to Treatment
In the year 2012, the CDC’s Division of Cancer Prevention and Control convened a working group to understand and address the barriers and challenges that discourage the participation of adolescents in CTs. The participants included research scientists across the spectrum of care (pediatric and adult oncology, health informatics, behavioral science, CTs) working at clinical, academic, and government institutions as well as nonprofit organizations. Together, they identified 5 major barriers to AYA recruitment in trials:
• low referral rates of adolescent patients with cancer to pediatric cancer centers
• limited availability of CTs for certain cancers
• physician-related barriers that limit CT accrual
• institutional barriers that impede collaboration between pediatric and adult oncologists on CTs
• unique psychological needs of adolescent patients with cancer.7
The working group posited that the adolescent population has some unique issues associated with the transition to adulthood that can significantly impact recruitment into trials. Addressing these matters would therefore require a coordinated effort from the various stakeholders in this domain.
Age restrictions prove a major barrier to the recruitment of AYAs. Some pediatric hospitals do not enroll young adults older than 18 years while others have an upper age restriction of 21 years. Some pediatric centers will enroll older patients only if the tumor is deemed to be of pediatric origin or if there is an open treatment protocol. Unfamiliarity of the family practice physician, who refers the young patient for treatment, with pediatric oncology programs can also influence choice of treatment site.8
“Age restrictions are not usually a barrier in adult hospitals; however, some pediatric hospitals do have an upper age limit. Some may have an upper age limit of 18 years, while others may enroll young adults up to 29 years of age,” Albritton informed EBO. “However, federal regulations necessitate appropriate credentials for the institute and staff, which could influence the ability of a hospital to admit (and then offer age-appropriate CTs to) AYAs,” she said.
“The place of care does make a difference,” agreed Eric Tai, MD, MS, medical officer with the Comprehensive Cancer Control Branch, Division of Cancer Prevention and Control, CDC. Speaking with EBO, Tai said, “Pediatric and adult cancer trials usually have age restrictions; so a 20-year-old patient will be considered an adult and may lose out on participating in a pediatric trial, and an 18-year-old may not be able to participate in an adult trial. What we need is more collaboration and dialogue between medical oncologists and pediatric oncologists,” so the patient stands at an advantage.
“The lack of communication between medical oncologists and pediatric oncologists has been an issue,” acknowledged Gregory Reaman, associate director, Office of Hematology and Oncology Products, FDA, in a conversation with EBO. “Specific efforts over the past decade by the NCI and the Cooperative Groups, the American Society of Clinical Oncology, and the American Association for Cancer Research have drawn attention to AYAs as an under-researched population that falls in between pediatric
and adult specialists. Adult oncologists may not be familiar with some of the diseases that adolescents have, and so the patient may not have access to trials for these cancers which are usually conducted by pediatric oncologists.”
The Children’s Oncology Group (COG), an NCI-supported CT organization with global research partnerships, conducts CTs exclusively for childhood and adolescent cancers for an improved understanding of the underlying disease biology and to evaluate new treatments, supportive care, and survivorship.9 COG, in order to maintain impeccable research standards, has stringent regulations in place for its member institutions that have also proved a hindrance for recruiting younger patients, especially AYAs. For example, COG members need to have a pediatric intensive care unit—not an easy requirement to fulfill for hospitals that primarily treat adult patients. COG requires that the radiation oncologist who renders treatment be a COG member, even if the site (which needs to be approved by the Quality Assurance Review Center) is a non-COG treatment site.8 However, according to Reaman—who is past chairman of COG—the organization has amended age eligibility requirements on studies to accommodate adolescents as well as young adults, especially for studies in leukemia and in soft tissue and bone sarcomas.
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