Defining and measuring tolerability in pediatric, adolescent, and young adult oncology: The essential voices

Susan K Parsons; Kathleen E Montgomery; Julienne Brackett; Katie A Devine; Leanne M Embry; Katie A Greenzang; Philip J Lupo; Michelle M Nuño; Abby R Rosenberg; Michael E Roth; Sue M Zupanec; Pamela S Hinds

doi:10.1002/cncr.35947

. 2025 Oct 22;131(Suppl 2):e35947. doi: 10.1002/cncr.35947

Defining and measuring tolerability in pediatric, adolescent, and young adult oncology: The essential voices

Susan K Parsons ^1,^2,³, Kathleen E Montgomery ⁴, Julienne Brackett ⁵, Katie A Devine ⁶, Leanne M Embry ⁷, Katie A Greenzang ^8,⁹, Philip J Lupo ¹⁰, Michelle M Nuño ^11,¹², Abby R Rosenberg ^13,^14,¹⁵, Michael E Roth ¹⁶, Sue M Zupanec ¹⁷, Pamela S Hinds ^18,^19,^✉

^¹Department of Medicine, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA

^²Department of Pediatrics, Tufts University School of Medicine, Tufts Medical Center, Boston, Massachusetts, USA

^³Department of Medicine, Division of Hematology/Oncology, Institute for Clinical Research and Health Policy Studies, Boston, Massachusetts, USA

^⁴University of Wisconsin‐Madison School of Nursing, Madison, Wisconsin, USA

^⁵Section of Hematology‐Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

^⁶Department of Pediatrics, Rutgers Cancer Institute, New Brunswick, New Jersey, USA

^⁷Pediatric Hematology/Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

^⁸Department of Pediatrics, Dana‐Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

^⁹Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA

^¹⁰Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

^¹¹Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA

^¹²Children’s Oncology Group, Monrovia, California, USA

^¹³Department of Psychosocial Oncology and Palliative Care, Dana‐Farber Cancer Institute, Boston, Massachusetts, USA

^¹⁴Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA

^¹⁵Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA

^¹⁶Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

^¹⁷Department of Nursing, The Hospital for Sick Children, Toronto, Ontario, Canada

^¹⁸Department of Nursing Science, Professional Practice & Quality, Children's National Hospital, Washington, District of Columbia, USA

^¹⁹Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA

Correspondence , Pamela S. Hinds, Department of Nursing Science, Children's National Hospital, 111 Michigan Avenue NW, Washington DC 20010, USA. Email: pshinds@childrensnational.org

^✉

Corresponding author.

PMCID: PMC12619136 PMID: 41123581

Abstract

In this review on the status of tolerability in pediatric oncology, the authors address the relevance and meaning of this important concept and offer a definition to represent treatment tolerability experiences of pediatric, adolescent, and young adult oncology patients. The authors acknowledge the incomplete progress of tolerability research in pediatric oncology clinical trials while describing the recent advances in validating relevant measures and embedding these in pediatric oncology clinical trials to document the symptom burden of specific cancer treatments. They advocate for the consistent use of three voices—patient, caregiver, and clinician—in pediatric oncology to achieve accurate and comprehensive estimates of treatment tolerability while recognizing that a primary voice may be necessary to match the main aim or goal of the proposed research. Future steps include establishing the validity of tolerability measures and methods in patients younger than 7 years and a careful examination of tolerability issues into survivorship.

Keywords: adolescent and young adult (AYA); caregiver‐reported outcomes; cooperative group, measurement; patient‐reported outcomes; pediatric oncology; tolerability

Short abstract

Three voices—patient, caregiver, and clinician—in pediatric oncology are essential to achieving accurate and comprehensive estimates of treatment tolerability. Currently, the voice that is missing in pediatric oncology regarding treatment tolerability is the voice of the young child (younger than 7 years).

INTRODUCTION

Tolerability of cancer treatment is the extent to which adverse events affect the ability and willingness of patients to continue cancer treatment. Treatment tolerability, therefore, plays an important role in determining disease outcomes for all patients, including children and adolescents and young adults (AYAs). Cancer treatment tolerability for pediatric/AYA patients differs according to the unique characteristics of individual patients and groups of patients, adding importance to the essential roles of: (1) patients to speak to the effect of their cancer treatments, (2) their family caregivers to speak to how their child has been affected by cancer treatment, and (3) their clinicians to address how this patient is affected by treatment at the specific time point in treatment compared with all other patients receiving the same treatment. Together, these three voices discern the true and complete effect of the therapies being delivered. The essential roles of caregivers and clinicians depend on believing and respecting the reports of children and AYAs regarding the treatment effect they experience. The combined reports of all three voices—patient, caregiver, and clinician—are critical to translate tolerability reports into the clinical care of patients to support and improve their well‐being during treatment for cancer.

Decades of research and clinical trial outcomes document the immediate, short‐term, and longer term adverse events; lifelong effects experienced by children and AYAs resulting from cancer therapies, ¹ , ² and their ability to report these experiences. ³ , ⁴ Because we in pediatric and AYA oncology now have this knowledge, we must use it to advance our research and clinical practices by consistently addressing tolerability from these essential voices in our patient care and in our scientific efforts. In this report, we address the challenges of defining, measuring, and applying the meaning of treatment tolerability clinically in pediatric and AYA oncology, with a particular focus on the inclusion of tolerability measures in the clinical trials of the Children's Oncology Group (COG). For purposes of brevity, we use the term pediatric/AYA patients to refer to children, adolescents, and young adults.

Defining tolerability in pediatric/AYA oncology

The definition of tolerability of treatment in pediatric/AYA oncology is embedded in the context of pediatric/AYA cancer as a rare collection of diseases with incidence and prevalence data reported in diverse and overlapping age groups (i.e., aged birth to 19 years, 1–21 years, and 15–39 years). Approximately 15,000 children and adolescents younger than 19 years and approximately 84,000 AYAs aged 15–39 years are diagnosed annually with cancer in the United States. ⁵ , ⁶ The incidence of cancer in children has increased steadily over several decades, particularly for some cancer types. ⁷ Among AYAs, statistically significant increases in cancer incidence recently have been reported, ⁶ , ⁸ as have differences in incidence and survival by race, ethnicity, and socioeconomic status. ⁹ , ¹⁰ , ¹¹ These contextual factors influence the evolving definition of tolerability in pediatric/AYA oncology and how treatment tolerability is measured and analyzed in pediatric oncology.

Historically, tolerability of cancer treatments in pediatric/AYA oncology clinical trials was defined solely by clinician assessments. Clinicians reported acute toxicities and severe adverse events (typically grade ≥3) and documented rates of treatment discontinuation or the implementation of protocol‐stipulated dose modification. Efforts to expand this sole reliance on clinician assessment and documentation to include patient and caregiver reports in clinical trials within the COG did not fare well until recent years. The lag was because of a lack of consensus about the value of the information gleaned from patient‐reported outcomes (PROs) and/or proxy reports in clinical trials relative to the time, expense, and perceived burden of collecting, managing, and analyzing resulting data. Consequently, embedding PROs to assess tolerability in COG clinical trials are not yet at the level of PRO use in adult oncology cooperative groups, and a definition of treatment tolerability has not been formalized in pediatric oncology.

The adult oncology groups participating in the National Cancer Institute's Cancer Moonshot Tolerability Consortium have adopted the definition of tolerability from the Friends of Cancer Research Group ¹² : “The tolerability of a medical product is the degree to which symptomatic and nonsymptomatic adverse events associated with the product’s administration affect the ability or desire of the patient to adhere to the dose or intensity of therapy. A complete understanding of tolerability should include direct measurement from the patient on how they are feeling and functioning while on treatment” (p. 4). Recent refinements from the Cancer Moonshot Tolerability Consortium address patient preference regarding willingness to stay on treatment while enduring symptoms and patient attitudes toward the treatment. ¹³ , ¹⁴

There are key distinctions between children/AYAs and older adults regarding cancer therapies, disease and treatment outcomes, and developmentally considered care. In brief, younger patients with cancer generally have better survival outcomes compared with older adults, such that the adverse effect of therapy may be accepted by one or more of the three voices as an acceptable trade‐off for an anticipated ultimate overall survival benefit. An older patient considering a proposed treatment that could extend life for months to years but that has numerous side effects may prioritize quality of remaining life differently than for a young person with high likelihood of survival. These differences need to be reflected in a definition of tolerability in pediatric/AYA oncology

Adherence to treatment, treatment discontinuation, and treatment decision making in children and younger adolescents are commonly influenced by caregivers and clinicians. Rarely are these determined by the ill child or adolescent. During late adolescence and young adulthood, the locus of decision making slowly moves away from the caregiver to include the patient or in conjunction with the AYA's spouse/partner—often in addition to parental caregivers. Caregivers' hope for treatment outcomes, ability to manage uncertainty, ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ and trust in care providers ²⁰ influence treatment adherence, acceptance of randomization in a clinical trial, and treatment discontinuation. The effect of partner/spousal caregivers among AYAs relative to these issues has been much less well studied.

Although direct measurement of the pediatric/AYA patient's subjective feelings and functioning during cancer treatment involves a triadic assessment, patients and caregivers in pediatric oncology tend not to spontaneously report treatment burdens unless prompted by clinicians. ³ Directly asking pediatric/AYA oncology patients and their caregivers to report is not yet a standard part of clinical practice or research, thereby risking the underestimation of the effect of cancer treatment.

Considering these important differences in pediatric/AYA oncology from adult oncology, we offer the following alteration to the Friends of Cancer Research definition of treatment tolerability for pediatric/AYA oncology ¹² :

The tolerability of a cancer treatment is the degree to which symptomatic and nonsymptomatic adverse events associated with the treatment affect the willingness and/or ability of the patient and/or the patient's caregiver to adhere to the dose or intensity of therapy and the degree to which toxicities disrupt current and future functioning and quality of life. A complete understanding of tolerability should include direct measurement from the pediatric/AYA patient to the extent possible, the caregiver(s), and the clinician regarding the subjective and objective effect of the cancer treatment on the patient's feelings and functioning during and after treatment. (Figure 1).

Depicting pediatric cancer treatment tolerability (informed by the works of Basch et al. ¹² and Peipert et al. ¹⁴ ). CTCAE indicates Common Terminology Criteria for Adverse Events; PRO‐CTCAE, Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events.

Conceptual and empirical factors influencing tolerability in pediatric/AYA oncology

The essential voices in pediatric/AYA oncology make defining, understanding, and measuring tolerability quite complex; however, having multiple voices complete PRO measures is supported both conceptually and empirically.

Conceptual sources of support

Mainstream symptom theories ⁴ , ²¹ , ²² and formal guidance from the US Food and Drug Administration ²³ maintain that the patient's report of symptoms is essential for understanding the symptom experience but that, in certain situations like pediatrics, family members may provide their perspective in addition to or in place of the reports of the ill individual’s symptoms.

In pediatric oncology, family‐centered care is a conceptual approach to care that guides clinicians to focus on, understand, and respond to the patient and family responses to cancer. ²⁴ With the patient and family at the center, care involves co‐dependency between the patient and the family and between the family and clinicians across cancer‐related care tasks. The intersection of symptom theory plus the care model of family‐centered care provides the conceptual basis for eliciting the multiple essential voices to comprehensively assess tolerability in pediatric/AYA oncology.

Pediatric/AYA oncology patients embody diverse developmental stages, ranging from infancy to young adulthood. When developmentally able, theirs is the valid voice to report the effect of cancer and its treatment using age‐based PRO measures. ²⁵ The caregiver provides a distinct second perspective by reporting the patient’s response to cancer in the context of baseline effect and behavior. The clinician provides a third perspective by assessing the tolerability to the cancer and treatment and benchmarking it across a broader pediatric/AYA oncology population. All three unique voices, when combined, provide the most comprehensive assessment of the patient experience to inform treatment decision making, particularly if treatments of equal efficacy but different toxicity profiles are available. In addition, the three voices combined guide the selection and timing of supportive care interventions to address the adverse effects of treatment.

Developmental stages influencing relevance and outcomes

Our understanding of patient toxicity and tolerability using PROs is deeper in school‐aged, adolescent, and young adult patient groups compared with younger age groups. ²⁶ Challenges exist in eliciting the voices of very young patients and patients who may be nonverbal or too ill to provide self‐reported information. ²⁷ , ²⁸ The developmental stage of a patient is particularly relevant given that certain cancers commonly occur in very young patients, whereas other cancers extend over a broader age distribution. In general, pediatric care incorporates the full range of patients from infancy to young adulthood. Researchers conceptualize developmental diversity as individual cognitive, psychosocial, and physiologic differences. ²⁶ Developmental diversity affects how pediatric patients assess their illness and their willingness or ability to communicate their perspectives. Researchers have demonstrated the feasibility of collecting symptom information using self‐report questionnaires and interviews from pediatric oncology patients as young as 4–6 years, ²⁶ , ²⁹ although self‐report from patients aged 7 years and older has been more typically used. ³⁰ , ³¹ , ³² With the advances in defining and measuring tolerability in pediatric oncology come new questions, such as, “if developmental stage may influence one’s toxicity, how do we interpret data from participant samples with wide age ranges?” These interpretations will be critical to applying tolerability data from the three essential voices to actual clinical care in pediatric oncology.

Empirically, clinician‐reported adverse events have disproportionately shaped our understanding of treatment toxicity in the context of pediatric cancer clinical trials. ³³ , ³⁴ Clinician‐reported adverse events using the Common Terminology Criteria for Adverse Events (CTCAE) have provided important information for product labeling, including expected severe side effects, but have been silent regarding the subjective effect of treatment and the association with treatment adherence. The result was an incomplete toxicity profile for treatment regimens, focused primarily on severe symptoms and ignoring lower grade symptoms with potentially functional consequences. In parallel to cooperative group clinical trials, researchers studied single‐symptom and multiple‐symptom experiences of patients during cancer treatment and into survivorship. ²⁷ , ³⁵ , ³⁶ , ³⁷ Research findings indicate that pediatric oncology patients experienced and reported up to 16 psychological and physical symptoms during treatment. ³⁸ , ³⁹ , ⁴⁰ The heterogeneity of study samples further highlighted that some degree of symptom suffering was a common experience across diagnoses. Early symptom research was limited by the availability of validated self‐report measures, underrepresentation of certain racial and ethnic groups and non‐English‐speaking participants, and limited understanding of co‐occurring symptoms over time. In addition, symptoms were most often elicited from the caregiver and, less often, directly from the child. ³⁷

Important advances in soliciting and understanding the pediatric/AYA patient's experience with cancer treatment include the use of standardized measures to screen for and measure the presence, intensity, and interference of symptoms ⁴¹ , ⁴² an evaluation of symptoms in pediatric/AYA patients over time ³⁷ , ⁴³ , ⁴⁴ and in an early phase clinical trial ⁴⁵ ; and living with advanced cancer ⁴⁶ or experiencing end‐of‐life care. ⁴⁷ , ⁴⁸ These advances provided substantive evidence to support the feasibility of eliciting pediatric/AYA oncology voices regarding the toxicity of their cancer treatment and legitimatized their perspective as augmenting the voices of caregivers and clinicians.

The triad of voices makes possible the accurate and comprehensive capture of pediatric oncology patient symptoms and toxicity. ⁴⁹ The three voices differ commonly in their symptom and toxicity reports in terms of presence and intensity ⁵⁰ , ⁵¹ and even within one voice, such as different caregivers having divergent reports. ⁵² These divergent reports are a clinical care opportunity for clinicians to discuss, listen, reflect, and support patients and caregivers during the experience of treatment toxicity. These discussions can guide collaborative planning to optimize evidence‐based supportive care. ⁵³ Often, it is the clinician who assumes the role of the convener and who reiterates the perspectives of the essential voices with the goal of achieving consensus.

Types of measures and inclusion of multiple voices

Quite recently, although not universally, patient reports of treatment toxicity in pediatric oncology are being collected through the age‐based Pediatric PRO‐CTCAE items (Ped‐PRO‐CTCAE) ⁵⁴ , ⁵⁵ or PRO‐CTCAE for older adolescents/young adults. ⁵⁶ , ⁵⁷ Measurement models of treatment effect in pediatric oncology have included general and disease‐specific indices of quality of life ⁵⁸ , ⁵⁹ completed by pediatric oncology patients and/or their caregiver.

Recent reviews of pediatric oncology applications for US Food and Drug Administration approval and AYA trials registered on ClinicalTrials.gov confirm that PROs are rarely incorporated into pediatric and AYA cancer trials. A recent estimate of PRO embeddedness was 8.2% of pediatric oncology clinical trials ³⁴ and 20.7% in AYA clinical trials, ⁵⁶ despite efforts calling for their inclusion. ³³ We join with others to advocate for the embedding of PROs in pediatric oncology trials and the concurrent solicitation of toxicity and tolerability reports from the three essential voices of patients, caregivers, and clinicians.

Given the multiple available pediatric PRO measures validated in pediatric oncology, it is critical to carefully select the measure(s) based on study goals and research questions while attending to issues of feasibility and patient burden. A recent review emphasizes that the incorporation of PRO aims and measures must be clearly defined from the study concept development phase. ⁶⁰ A clearly articulated PRO aim, with an a priori specified analytic plan, helps determine which PRO measure(s) to include and the frequency of administration. PROs from the essential voices may be particularly useful when evaluating a novel therapy with unknown toxicities or in trials that compare toxicity burden without compromising treatment outcomes. The timing of assessment should be carefully considered in terms of the anticipated timing of the likely toxicities. Patient and caregiver burden must be considered when deciding upon the number and timing of PRO assessments.

Integrating multiple voices

Across studies, clinicians tend to identify fewer adverse events than children, with poor to fair agreement across symptom domains. Children and caregivers demonstrate moderate agreement across most domains, with a range from fair to good, depending on the symptom. ⁵⁰ , ⁵¹ , ⁶¹ , ⁶² , ⁶³ , ⁶⁴ These divergent ratings need to be anticipated and not disputed because the ratings represent different symptom experiences for each of the three voices.

Also to be anticipated in measuring tolerability are missing responses. Several statistical methods have been used to reduce bias associated with missing patient responses. These include direct imputation of proxy reports when patient reports are not available, the use of proxy reports to build imputation models for missing data, and inverse probability weighting methods. ⁶⁵ , ⁶⁶ These methods may reduce, but not eliminate, bias. Because of this, we recommend putting a plan into place at the study design stage to reduce missing data as much as possible. When missing data cannot be prevented, it is important to collect information regarding the reasons for missingness. ⁶⁷

Although all three voices are considered essential when estimating tolerability, and no one voice is preferred over the other, ⁴⁹ the voice selected for the primary analysis needs to match the goal of the study and the feasibility of data collection. For symptoms that are subjective or unobservable, the primary end point would prioritize the patient response. If it is not feasible to collect information from pediatric oncology patients in certain situations, the primary PRO end point would prioritize the caregiver response.

Most pediatric oncology trials to date have focused on the use of PROs in conjunction with clinical end points to understand the profiles of different treatments. In these clinical trials, tolerability aims tend to be included as secondary or exploratory aims. Because PRO end points provide invaluable information regarding the patient experience, they need to be given as much importance as more traditionally used clinical end points. This includes ensuring that the study is powered to answer the PRO objectives and that measures are taken to ensure quality of the data while minimizing patient and site burden.

Tolerability and PROs in pediatric oncology/AYA cooperative group clinical trials

The inclusion of PROs in pediatric cooperative group clinical trials is important to understand disease‐specific and treatment‐specific patient experiences, including tolerability during and after cancer treatment. Noteworthy progress has been made in recent years in the incorporation of PROs in clinical trials for AYA patients. Quite recently, COG‐led investigators empaneled a task force spanning the National Cancer Institute Clinical Trials Network to develop a consensus‐based recommendation for a core set of PRO measures and best practices for integrating PROs into AYA trials. ⁶⁸ Recommendations for assessment of treatment tolerability and toxicity included the PRO‐CTCAE or Ped‐PRO‐CTCAE to assess four study‐specific adverse events and up to eight additional symptomatic adverse events that are commonly experienced by AYAs across disease groups and trials. There is opportunity to extend this work to provide guidance for trials involving younger pediatric oncology patients.

Despite a past lag in adopting PROs for use in clinical trials, the feasibility of collecting PROs in cooperative group pediatric clinical trials has now been demonstrated. ⁶⁴ , ⁶⁹ , ⁷⁰ Furthermore, important patterns of symptoms and toxicities comprising tolerability have emerged, demonstrating the crucial role of PROs. For example, in COG trial AAML1031, a greater number of clinician‐reported toxicities was significantly associated with patient‐reported and caregiver‐reported impairments in physical health and increased fatigue. ⁷¹ In a second COG trial (AALL0932), parent reports conveyed that many patients experienced early and persistent impairments in physical and emotional functioning. ⁷² In the recent reports from AHOD1331,^64,70 patient and parent reports of peripheral neuropathy were closely aligned and correlated strongly with clinician gradings. Significant decrements in quality of life also were demonstrated among those with worse toxicity. These examples indicate the feasibility of collecting essential information for estimating tolerability and the clinical meaningfulness of the resulting data.

PROs are now embedded in several open, COG‐led clinical trials, as well as cross‐National Cancer Institute Clinical Trials Network trials in which COG is participating (e.g., the Southwest Oncology Group‐led S1826 trial). ⁷³ Cross‐network AYA trials in osteosarcoma (AOST2031) and Hodgkin lymphoma (AHOD2131) include the recommended complement of PROs to assess functional consequences and PRO‐CTCAE or Ped‐PRO‐CTCAE to assess symptom reports from the COG AYA PRO initiative. Electronic data capture is primarily being used in these studies instead of paper‐and‐pencil approaches to meet the needs and preferences of AYA patients while optimizing efficiency and data quality and minimizing site burden. Clinical trials for diagnoses that disproportionately affect younger children or that span the age ranges are also collecting PROs, although a standardized approach to measurement has not yet been undertaken.

Ideally, a standard approach would be a combination of clinical indicators and patient reports of toxicity with tolerability scores declared before the opening of a clinical trial. Without this standardized approach, clinicians may not explore symptoms that matter to patients and/or to their caregivers.

Despite recent progress, further work still is needed. Ongoing efforts should: (1) determine key aspects of treatment tolerability for children across the age ranges; (2) implement data‐collection strategies, such as electronic data capture, that honor the needs and preferences of the three essential voices; (3) determine the analytic and data display methods that effectively summarize tolerability data from the essential voices; and (4) ensure that we are optimally capturing the experiences of the youngest patients and those unable to validly provide self‐report.

Summary PRO and tolerability analysis strategies used in medical oncology also could be explored and potentially adapted for pediatric cancer clinical trials. For example, in adults with cancer, studies have found that symptom bother is associated with an increased number and grade of physician‐rated toxicities, poorer physician‐reported functional status, and a greater likelihood of treatment discontinuation. ⁷⁴ , ⁷⁵ , ⁷⁶ , ⁷⁷ Although the relation between patient‐reported toxicities and symptom bother is relatively unknown in pediatric oncology, it is actively being explored in several ongoing clinical trials of AYA‐aged trial participants. Summary measures of frequency, severity, and persistence of toxicities using strategies, such as those used in adult oncology trials that are associated with meaningful clinical outcomes or treatment decisions, ⁷⁸ , ⁷⁹ need to be established similarly in pediatric oncology.

With the initiation of the COG's Project:EveryChild (APEC14B1), investigators can directly contact children treated at COG institutions (and their families) to conduct remote‐based surveys and administer various questionnaires. Project:EveryChild is the COG patient registration protocol that also includes a component for the storage of biospecimens. As of spring 2024, there are over 40,000 children enrolled in Project:EveryChild. The option to contact these individuals and the availability of biospecimens provide unique and innovative opportunities to conduct novel tolerability assessments for both patients in treatment and survivors of childhood cancer.

Tolerability and clinical practice in pediatric/AYA oncology

Clinical practice in pediatric oncology is evidence‐based, so the incorporation of PRO measures in pediatric oncology clinical trials is a foundational step to understanding and improving patient experience and health outcomes in clinical practice. Here, we identify the opportunities, barriers, and next steps needed to advance translation of PRO science into pediatric oncology clinical care. Translating PRO results into pediatric oncology clinical practice requires understanding the purpose of PROs, how they are measured, and what their scores indicate. It also likely requires communication skills to discuss the scores with the reporting child, adolescent, and young adult patients and their caregivers. How consensus is attempted and achieved, particularly when there is disagreement among the three essential voices, remains a research gap.

With refinement and dissemination of electronic health records, routine screening of patient‐reported symptoms, such as fatigue, pain, and distress, are increasingly common, typically at the point of care. ⁸⁰ , ⁸¹ Most of these symptom reports are single items using a numerical rating scale. Less common in pediatric practice is the use of full PROs embedded in the health records, although the technology and the validated measures exist and are widely used in adult practices.

The very promising initiative to create a standardized approach to measure tolerability put forth by the COG‐led AYA PRO Task Force has achieved expert consensus and is currently guiding PRO selection for certain COG trials. ⁶⁸ As noted above, the recommended PRO battery includes measures to assess physical function, social function, psychological outcomes, and selected items from the PRO‐CTCAE/Ped‐PRO‐CTCAE item libraries that assess regimen‐specific tolerability/toxicity and symptom burden. Recommendations also include time points of assessment from study initiation throughout treatment and extending into survivorship to monitor both short‐term and long‐term concerns. This advance has positive implications for creating a similar standardized approach for younger age groups as well as informing clinical practice beyond clinical trials alone. This approach of standardizing PRO measures to assess tolerability will significantly support clinician efforts to inform their clinical care of pediatric oncology patients and their families.

CONCLUSION

Despite the challenges in assessing, measuring, and managing tolerability for children and AYAs, considerable progress has been made through improved assessment tools and a growing consensus about the importance of the essential voices of patients, caregivers, and clinicians. Although much of this progress has been evinced in frontline clinical trials, we recognize that future work is needed to understand the patient experience beyond active treatment into survivorship. Several issues complicate the inclusion of the three essential voices outside of active cancer treatment, which limits our understanding of the patient experience beyond the delivery of frontline therapy. Specifically, across several trials, follow‐up care participation rates have dropped precipitously after the completion of planned therapy. Off‐treatment assessments have had lower completion rates and thus raise concerns about potential bias in data being reported. This is problematic both for children and AYAs treated in clinical trials. Our failure to capture their voices beyond frontline therapy is of particular concern given the growing numbers of children and AYAs surviving cancer.

Future steps are also needed to address the issues of tolerability among our younger patients, notably those younger than 7 years, who have largely been excluded from our measures to date. ⁶⁰ Innovative approaches are needed to elicit and incorporate their experience and inform their care.

The challenges to ensuring the inclusion of the essential voices in addressing treatment tolerability in pediatric/AYA oncology patients are notable, but the addition here of the definition of tolerability will help guide resolutions of these challenges. The benefits of monitoring and addressing treatment tolerability for children, adolescents, and young adults in treatment and survivorship, as well as for their families and clinicians, are innumerable.

AUTHOR CONTRIBUTIONS

Susan K. Parsons: Conceptualization, formal analysis, writing–review and editing, and writing–original draft. Kathleen E. Montgomery: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Julienne Brackett: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Katie A. Devine: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Leanne M. Embry: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Katie A. Greenzang: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Philip J. Lupo: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Michelle M. Nuno: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Abby R. Rosenberg: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Michael E. Roth: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Sue M. Zupanec: Conceptualization, writing–original draft, writing–review and editing, and formal analysis. Pamela S. Hinds: Conceptualization, writing–original draft, writing–review and editing, formal analysis, and project administration.

CONFLICT OF INTEREST STATEMENT

Michael E. Roth reports grants/contracts from Hebecell Corporation, the National Cancer Institute, and Pfizer; and gifts from the Archer Foundation and LyondellBasell Industries outside the submitted work. The remaining authors disclosed no conflicts of interest.

ACKNOWLEDGMENTS

We acknowledge the thoughtful input of Sarah L. Vargas, PhD, Senior Director of Research Operations, Complex Projects Administrator, Children's Oncology Group National Cancer Institute Community Oncology Research Program (Research Base of the Children’s Oncology Group), and the support and guidance for this work by Douglas Hawkins, MD, Chair of the Children's Oncology Group.

Parsons SK, Montgomery KE, Brackett J, et al. Defining and measuring tolerability in pediatric, adolescent, and young adult oncology: the essential voices. Cancer. 2025;e35947. doi: 10.1002/cncr.35947

We thank the members of the Tolerability Consortium and its working groups for their contributions. We also thank ICF International for supporting the Tolerability Consortium activities, including this supplement.

The findings and conclusions in this Supplement are those of the authors and do not necessarily reflect the official position of the American Cancer Society, John Wiley & Sons, Inc., or the opinions of the journal editors.

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PERMALINK

Defining and measuring tolerability in pediatric, adolescent, and young adult oncology: The essential voices

Susan K Parsons, MD, MRP

Kathleen E Montgomery, PhD, RN, PCNS‐BC

Julienne Brackett, MD, MS

Katie A Devine, PhD, MPH

Leanne M Embry, PhD

Katie A Greenzang, MD, EdM

Philip J Lupo, PhD

Michelle M Nuño, PhD

Abby R Rosenberg, MD, MS, MA

Michael E Roth, MD

Sue M Zupanec, MN, NP

Pamela S Hinds, PhD, RN

Abstract

Short abstract

INTRODUCTION

Defining tolerability in pediatric/AYA oncology

FIGURE 1.

Conceptual and empirical factors influencing tolerability in pediatric/AYA oncology

Conceptual sources of support

Developmental stages influencing relevance and outcomes

Types of measures and inclusion of multiple voices

Integrating multiple voices

Tolerability and PROs in pediatric oncology/AYA cooperative group clinical trials

Tolerability and clinical practice in pediatric/AYA oncology

CONCLUSION

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Defining and measuring tolerability in pediatric, adolescent, and young adult oncology: The essential voices

Susan K Parsons, MD, MRP

Kathleen E Montgomery, PhD, RN, PCNS‐BC

Julienne Brackett, MD, MS

Katie A Devine, PhD, MPH

Leanne M Embry, PhD

Katie A Greenzang, MD, EdM

Philip J Lupo, PhD

Michelle M Nuño, PhD

Abby R Rosenberg, MD, MS, MA

Michael E Roth, MD

Sue M Zupanec, MN, NP

Pamela S Hinds, PhD, RN

Abstract

Short abstract

INTRODUCTION

Defining tolerability in pediatric/AYA oncology

FIGURE 1.

Conceptual and empirical factors influencing tolerability in pediatric/AYA oncology

Conceptual sources of support

Developmental stages influencing relevance and outcomes

Types of measures and inclusion of multiple voices

Integrating multiple voices

Tolerability and PROs in pediatric oncology/AYA cooperative group clinical trials

Tolerability and clinical practice in pediatric/AYA oncology

CONCLUSION

AUTHOR CONTRIBUTIONS

CONFLICT OF INTEREST STATEMENT

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

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