Challenges Identified With Low Clinical Trial Accrual for AYA Patients With Sarcoma

R. Lor Randall, MD

Adolescent and young adult (AYA) patients with advanced soft tissue sarcoma are likely to have low accrual to clinical trials, with the commonly identified reasons of insufficient funding, lack of study awareness or interest, competing studies, safety concerns, and more, according to R. Lor Randall, MD, who added that the patient subgroup requires a particular approach for optimal care.

A survey examined the opening and enrollment barriers of results of the phase 2/3 ARST1321 trial (NCT02180867) for AYA patients with soft tissue sarcoma.¹ In the trial, investigators were examining radiation with or without combination chemotherapy or pazopanib (Votrient) prior to surgery in patients with newly diagnosed resectable non-rhabdomyosarcoma soft tissue sarcoma. Patients eligible for enrollment were aged 15 to 39 years. Due to slower than anticipated enrollment, cohorts were closed to further patient accrual in October 2017.²

The survey had a response rate of 31% (n = 50/161) and a completion rate of 70%. Almost 50% of all respondents were medical oncologists (n = 24/50), while 6% (n = 3/50) were pediatric, 24% were general or orthopedic surgeons, and 22% (n = 11/50) were radiation oncologists.

Survey results showed that the known barriers with this trial was due to disagreement with proposed treatment backbone and toxicity concerns; lack of interest, awareness and/or support for the trial or competing studies; logistical issues including regulatory and infrastructure barriers; funding concerns at the local and consortia level; and patient preference.

Randall, an author on the study, explained that the survey is not only a collaboration between both pediatric and adult medical oncologists, but also demonstrates the key challenges in this specific sarcoma population.

“The issue is, if you're a medical or pediatric oncologist, and you have a patient at the age of 15 to 39 years, hit the pause button for a moment and think about some of the other issues that these patients may be facing,” Randall said. “Their medical oncologist doesn't necessarily need to take those on, but they can refer them to the right resources: fertility clinic, social work, [resources about] childcare, jobs, college about a variety of things that they're not used to thinking about with someone who's more established in life.”

In an interview with OncLive, Randall, The David Linn Endowed Chair for Orthopaedic Surgery and professor and chair of the Department of Orthopaedic Surgery, University of California Davis Health, discussed these survey results in detail and what the sarcoma community can do to overcome these enrollment barriers for AYA patients.

OncLive: Why is the AYA patient population of soft tissue sarcomas a challenging one?

Randall: They really are an underserved demographic. They're not really pediatric patients, and so they don't necessarily go to a pediatrician, who then would not refer them to a pediatric oncologist. Yet they more or less have a pediatric disease, right? They will see an adult provider who's very well intended, but not knowledgeable in it. Sometimes [these patients] don't get the right chemotherapy and they don't get some of the issues, such as fertility issues and psychosocial things that aren't necessarily on the radar, addressed. Therefore, it becomes a real challenge for them both medically, socially, and economically.

What is exciting about this paper is that it is a survey that we sent out. The authors are representatives from the National Clinical Trials Network. In the [ARST1321] study, there were chemotherapy arms, which was conventional chemotherapy, and pazopanib for soft tissue sarcomas. In certain areas, the accrual was not as robust as we thought it would be, and we were a bit surprised by this. Now, this is the first study in soft tissue sarcoma in the United States, where numerous cooperative groups have come together: the Children's Oncology Group, the Sarcoma Alliance for Research Through Collaboration is involved not in the trial, but involved in this paper, and then the adult cooperative groups, as well.

What's nice is all of us are coming together around the AYA issue and the perspective from the Children's Oncology Group, but also then the adults/medical oncology group are coming together to say, "Why did this trial not accrue in certain arms?" and really look into it.

Regarding the most common reported barriers to AYA enrollment in ARSC1321, there were issues with institutional funding, competing trials, lack of interest, logistical issues, disagreement about therapy backbone—that's a controversial one, probably the center[s] didn't necessarily agree with the design of the trial itself.

Then, regarding some of the non-accrual to the non-chemotherapy arm, there were 26 sites that we looked into. We found that there were competing trials, eligibility or patient considerations, logistical issues, funding concerns, and premature closure.

We know that clinical trials don't enroll particularly well in certain areas. But, this was the first time in a children's clinical trial that we had some low numbers, so we were really surprised by it. It just shows you that we're dealing with a little bit of a different patient population, as we can see, because they're AYA patients, and many of the adolescents are potentially emancipated. Therefore, they don't have that parent advocate, who is reading the fine line, who is looking at why this trial is potentially a good thing for their child. They don't have that support network. Therefore, we were excited to get this published.

For soft tissue sarcoma, this is the first time in the United States that a medical oncology cooperative group and a pediatric oncology group have come together to design a trial to answer a question. As importantly, the other medical oncology groups that weren't involved with the execution of the trial itself were interested enough to the fact that the accrual was low that they got on board with doing the survey, and reaching out and finding out why we weren't getting AYAs enrolled and it affirms the issue that AYA patients have so many challenges. Many of them are young parents; they're not financially secure yet, and they just need the treatment. They don't have time to get enrolled in clinical trials and all that goes along with it.

Of all the reasons for low accrual that were noted here, did any of them surprise you?

Nothing surprised us. However, we really hadn't ever been able to show it; it had been very much sort of "level five, ask the expert," on why these patients are challenged. That's the beauty of this; through this survey, we actually were able to scientifically document these challenges rather than just know them because of the empiricism of being in the clinics with the patients.

What can the soft tissue sarcoma community do to try and overcome these challenges for the AYA population?

Most of the larger centers have AYA programs; UC Davis has one, and I helped start one in Utah [at Huntsman Cancer Institute]. You can drill down on the challenges with the programs themselves, because, again, [there are challenges such as] funding within the institution, who is going to support it, is it going to come from the coffers of the pediatric group or the adult group, etc. There are lots of challenges around getting these programs up and running, which is sort of a reflection on the overall paradigm that all of health care, whether it's in a clinical trial domain, or the just the day-to-day experience of patient care that the AYA patients, at least in oncology, fall between the cracks.

What are the key takeaways from this publication for the community oncologist?

Be very sensitive to the challenges facing AYA patients, and by convention that is defined as 15 to 39 years. We can make arguments all day about what age [constitutes AYA] exactly, right? That's not the point here.

Message number one is put the pause on to think about some of the other things besides the cancer in these patients' lives. Number two is reach out to other AYA centers for engagement. If you're in the community practicing oncology, this is a potential patient you might want to refer into a comprehensive cancer center. Three, be aware that if they do get in clinical trials, there's going to be some real challenges with keeping them in and giving them the support they need to get through the clinical trial.

References

1. Avutu V, Weiss AR, Reed DR, et al. Identified enrollment challenges of adolescent and young adult patients on the nonchemotherapy arm of Children’s Oncology Group Study ARST1321. J Adolesc Young Adult Oncol. Published online September 9, 2021. doi:10.1089/jayao.2021.0103.
2. Radiation therapy with or without combination chemotherapy or pazopanib before surgery in treating patients with newly diagnosed non-rhabdomyosarcoma soft tissue sarcomas that can be removed by surgery. ClinicalTrials.gov. Updated August 5, 2021. Accessed September 23, 2021.