FDA’s ODAC Weighs the Reliability and Validity of Using PROs in Pediatric Oncology

The FDA’s Oncologic Drugs Advisory Committee met to discuss the need, validity, and reliability of using patient-reported outcomes measurements linked to the Common Terminology Criteria for Adverse Events in pediatric oncology.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met to discuss the need, validity, and reliability of using patient-reported outcomes (PRO) measurements linked to the Common Terminology Criteria for Adverse Events (CTCAE) in pediatric oncology.

Presentations from physicians who treat pediatric cancers at Children’s National, Duke Health, The Hospital for Sick Children, Comer Children’s, and the Children’s Oncology Group were given. These presentations addressed rationale, clinical trial design, challenges, and the impact of implementing PROs in the pediatric oncology field.

The key topic of discussion was a new pediatric PRO‐CTCAE developed by Childen’s National for use in children aged 7 to 17. The questionnaire is designed to help with the key issue oncologists treating pediatric patients with cancer notice; fatigue, pain, sadness, depression, and worry.

Testing Pediatric PRO‐CTCAE

Pediatric PRO-CTCAE is meant to help more accurately report treatment-related adverse events (AEs) and other conditions experienced by children.

Pediatric Pro-CTCAE was evaluated in a trial of 482 patients ranging from 7 to 18 years old. Of the children, 41.5% were not non-Hispanic white newly diagnosed with cancer and their caregivers. Each patient completed a survey 72 hours preceding treatment initiation and a follow-up questionnaire was completed 7 to 17 days later for chemotherapy and 4 or more weeks after the initiation of radiation. Psychometric analyses examined the relationship between the 62 AEs with Patient-Reported Outcomes Measurement Information System, the Memorial Symptom Assessment Scale, the Lanksy Play-Performance Scale, and medication use. An additional, separate test-retest study included 46 children.2

According to results, the Pediatric PRO-CTCAE and Memorial Symptom assessment Scale were strongly correlated across age groups at the second test, 7-12 years (range, 0.62-0.80 years), 13-15 years (range, 0.44-0.94 years), and 16-18 years (range, 0.65-0.98 years); and over time. The system was also strongly correlated with Patient-Reported Outcomes Measurement Information System Pediatric at the second test as well including in pain interference (95% confidence interval [CI], 0.64-0.76), fatigue severity (95% CI, 0.56-0.69), and depression severity (95% CI, 0.71-0.81). When it came to the Lansky-Performance Scale, children were differentiated by medication use.2

Pediatric PRO-CTCAE is a valid and reliable way of reported AEs reported by children between the ages of 7 and 18, according to the study. Future uses of the system could be helping clinicians know how to respond to identified symptoms and improve CPG-concordant care. Additionally, as many childhood cancer patients go onto have chronic conditions, collecting data on symptoms and AEs now can help address those conditions later.

The Case for PROs from Pediatric Patients With Cancer

Due to the toxicity of treatments, 2 out of every 3 survivors of childhood cancer will develop at least one chronic health condition, which may be either musculoskeletal problems or second cancers. In addition, nearly 60% of pediatric patients who survive cancer experience severe or life-threatening complications in adulthood.

The vast majority, 90%, of ill children do not report symptoms unless directly asked by clinicians about them. The most common toxicities for children include fatigue, pain, sadness, depression, and worry. However, children are not routinely asked about toxicities.

According to a presentation given by Pamela S. Hinds, PhD, RN, FAAN of Children’s National hospital and Bryce B. Reeve, PhD of the Duke Cancer Institute, health care providers should learn how to translate medical jargon into child and adolescent friendly terms. For example, when talking about abdominal pain, refer to it as “stomach pain” or dysphagia as “problems with swallowing.”

“I think this type of information can be incredibly valuable, particularly, I take care of a lot of patients with multiple-relapsed cancers, and a lot of the interventions we might be thinking about may have only a modest impact on event-free survival or a relatively modest response rate, but if I had data that patients on the drug maybe felt better than patients who weren’t on the drug, even if progression-free survival wasn’t much improved, if patents were feeling better… then that might be helpful,” said Steven DuBois, MD, MS, a pediatric hematology oncologist at the Dana-Farber Cancer Institute. 

PROs as A Tool for Pediatric Oncology Physicians

Just as PROs are utilized to aid physicians’ treatment decision in adults with cancer, part of the ODAC meeting focused on how physician will benefit from PROs questionnaires being used in pediatric oncology.

Presenters from the Hospital for Sick Children hypothesized that implementing PROs may help oncologists respond to AEs and improve care to a standard that is concomitant with Clinical Practice Guidelines. Further, it can assist in detection of AEs and clinical trial design.

According to presenters, providers intervene for severely bothersome AEs such as hurt or pain 96% of the time and headache 89% of the time. However, feelings of being scared or worried were addressed 56% of the time and disappointment or sad feelings were addressed 12% of the time.

“I believe both [the] psychological and cognitive impacts of our treatment are grossly underestimated, in that this tool can be very important for uncovering some of those questions that we never get to ask our patients,” said Tobey J. MacDonald, a neuro-oncologist at the Winship Cancer Institute. “And this would be both in the acute setting and of course the long-term setting of what the impact is on those two very critical elements.”

Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee (ODAC). FDA. May 11, 2021. Accessed May 11, 2021.
Reeve BB, McFatrich M, Mack JW, et al. Validity and Reliability of the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events. J Natl Cancer Inst. 2020;112(11):1143-1152. doi: 10.1093/jnci/djaa016.