Cancer Trials Face a Shortage of Teen, Young Adult Enrollees

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.

One solution, recommended by 2 leading pediatric oncologists in the field, is to increase referrals to centers that have higher rates of enrollment of AYAs, such as pediatric cancer centers, AYA oncology programs, and NCI-designated cancer centers. They suggest that the centralization of services to institutes with high rates of accrual can improve the current dismal outcomes in AYAs with cancer.¹⁰Additionally, pediatric treatment centers should be encouraged to be more flexible on their age restrictions for enrollment, based on resources and outcomes.

Albritton and Tai both emphasized the use of NCI’s Central Institutional Review Board (CIRB), versus using separate IRBs at the individual pediatric and adult institutions may alleviate some of the barriers to opening clinical trials. According to Albritton, the study should ideally be formulated by medical and pediatric oncologists together, considering even subtle differences in approach between an adult oncology treatment model and a pediatric treatment model. “An example would be the starting criteria

for initiating a round of chemotherapy—a pediatric oncologist might be more comfortable starting at a lower white blood count level than a medical oncologist. So successful implementation of a common IRB protocol would require improved collaboration and communication between the medical and pediatric oncologists. “Additionally, barriers to physically getting the patients and enrolling them at each site need to be overcome. Once the trial sites are open, ensuring that they are presented to the patient is also important,” she said.

Added Reaman, “NCI’s CIRB is a testament to improving recruitment. There is an adult and pediatric CIRB and a memorandum should be issued to improve understanding between them.”

What Are the Steps Being Implemented?

As a relatively new discipline, says Tai, research being conducted and resources made available to study the AYA population are a bit lagging. However, he believes identifying this population is important to determine the involvement of specific institutions as well as to pinpoint funding sources.

NCCN, in collaboration with the NCCN Foundation, the LIVESTRONG Foundation, and Critical Mass, released specific guidelines with the aim of providing support and counseling to AYAs with cancer. In addition to basic information on cancer as a disease, treatment options, and more, the NCCN provides information on websites and

support groups (eg, www.stupidcancer.org) as well as suggestions to cope with the stress of transitioning back to a “normal” life with friends and peers.¹¹

The LIVESTRONG Foundation’s website emphasizes the importance of social and emotional support for teenagers, who may have developed adult-onset cancers and may have a specific need for social and emotional support different from what’s needed by younger children with cancer. The website underscores the fact that teenagers,

transitioning into adulthood, could develop cancers usually found in adults—and they could receive medical treatment that is similar to an adult’s, complemented by age-appropriate social and emotional support.¹²

The Knight Cancer Institute at the Oregon Health and Science University has a specific AYA oncology program to support the treatment of patients in this cohort, one of a few in the United States. In collaboration with the Lance Armstrong Foundation, the AYA team—which includes pediatric oncologists, a psychosocial researcher, and a social worker—provides specific services tailored to young cancer patients, including fertility preservation and connecting with support groups.¹³

Cancer Centers at the University of Chicago (for 15- to 30-year-olds)¹⁴ and at Northwestern University (15- to 39-year-olds)15 have programs in place specifically for the AYA population.

Reaman added that publications, monographs, and journals focused on AYAs with cancer have evolved to draw attention to this underserved patient population. Additionally, “Training programs have developed mechanisms to cross-train both pediatric and medical oncologists. Some medical oncologists are taking the initiative to train in pediatric cancers,” he said, to enhance their abilities to treat those patients.

As for the FDA’s role in improving the situation for AYAs, Reaman informed EBO that although the FDA does not necessarily have jurisdiction over patient recruitment, the

FDA is committed to facilitating pediatric cancer drug development and has recently taken the position that AYAs may be eligible to participate in certain adult trials. “So we are in the process of developing a pediatric oncology product development guidance that states that in certain diseases—such as melanoma, Hodgkin lymphoma, sarcoma—where the age at presentation overlaps (both adult and pediatric populations), the trial could enroll patients down to the age of 12 years if there is reasonable evidence of the prospect for direct clinical benefit from preclinical and early clinical data.”

AYAs and the ACA

Some of the health insurance barriers, especially among younger adults with childhood cancer who may have been denied coverage due to preexisting conditions, will now be eased thanks to the stipulations of the Affordable Care Act (ACA). Specific provisions within the Act ease follow-up care for some of the adult survivors:

1. No denial or cancellation of insurance coverage due to preexisting condition or development of a new condition.

2. Mandatory coverage allowed up to age 26 years on parents’ private insurance plan.

3. States can decide to raise the Medicaid minimum eligibility to 133% of federal poverty level.

4. Insurance companies can no longer set annual or lifetime coverage limits for medical services.

5. Each state will have a marketplace to purchase health insurance, with subsidies for qualifying individuals.¹⁶

Reaman emphasized that the ACA provides “a major opportunity to improve enrollment because one of the barriers to enrollment is the fact that many of the young adults are uninsured. There are frequently added costs associated with CTs, some of which are covered by third-party carriers, which makes it difficult or impossible to enroll in CTs.” He added that for most pediatric cancers, the aim is “cure.” So side effects and toxicities in the long term, following cancer therapy, can impact the quality of life of the patient. Reaman emphasized that long-term survivorship coverage is, therefore, extremely important among the AYAs.

EBO

Albritton agreed that the ACA, although in its early stages, might prove a tremendous boost for the AYA population, “The 18-25 year old AYA population has traditionally been the most uninsured and underinsured age group, limiting their access to treatment options and perhaps even making some hospital administrations hesitant to invest in programs to attract more of this age group. Hopefully more AYAs will be covered because of the ACA and have equal access.” References

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2. NCCN announces new guidelines for adolescent and young adult oncology. NCCN news website. http://www.jnccn.org/content/10/5/xv.extract#. Published May 2012. Accessed July 7, 2014.

3. Bleyer WA, Tejeda H, Murphy SB, et al. National cancer clinical trials: children have equal access; adolescents do not. J Adolesc Health. 1997;21(6):366-373.

4. Ferrari A, Montello M, Budd T, Bleyer A. The challenges of clinical trials for adolescents and young adults with cancer. Pediatr Blood Cancer. 2008;50(5 suppl):1101-1104.

5. Parsons HM, Harlan LC, Seibel NL, Stevens JL, Keegan TH. Clinical trial participation and time to treatment among adolescents and young adults with cancer: does age at diagnosis or insurance make a difference? J Clin Oncol. 2011;29(30):4045-4053.

6. Clinical trials. Combination chemotherapy in treating young patients with newly diagnosed acute lymphoblastic leukemia. National Cancer Institute website. http://www.cancer.gov/clinicaltrials/search/view?cdrid=574230&version=HealthProfessional. Accessed July 17, 2014.

7. Tai E, Buchanan N, Eliman D, Westervelt L, Beaupin L, Lawvere S, Bleyer A. Understanding and addressing the lack of clinical trial enrollment among adolescents with cancer. Pediatrics. 2014;133(suppl 3):S98-S103.

8. Felgenhauer, J, Hooke MC. Regulatory barriers to clinical trial enrollment of adolescent and young adult oncology patients. Pediatrics. 2014;133(suppl 3):S119-S122.

9. Children’s Oncology Group website. http://www.childrensoncologygroup.org/index.php/aboutus. Accessed July 28, 2014.

10. Albritton KH, Coccia P. Influencing referral of adolescents and young adults with cancer to sites with higher rates of trial enrollment. Pediatrics. 2014;133(suppl 3):S104-S108.

11. New NCCN guidelines for patients available for adolescents and young adults with cancer. NCCN website. http://www.nccn.org/patients/ foundation/newsdetail.aspx?NewsID=330. Accessed July 25, 2014.

12. Childhood cancer. LIVESTRONG Foundation website. http://www.livestrong.org/we-canhelp/childhood-cancer/. Accessed July 24, 2014.

13. AYA oncology program. OHSU Knight Cancer Institute website. http://www.ohsu.edu/xd/health/services/cancer/getting-treatment/services/aya-program/. Accessed July 28, 2014.

14. Adolescent and Young Adult (AYA) Oncology Program. University of Chicago hospitals website. http://www.uchospitals.edu/specialties/cancer/young-adult/. Accessed August 5, 2014.

15. Adolescent and Young Adult Oncology (AYAO) Program. Northwestern University website. http://cancer.northwestern.edu/ayao/. Accessed August 5, 2014.

16. Mueller EL. What the Affordable Care Act means for survivors of pediatric cancer. J Clin Oncol. 2014;32(7):615-617.