Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2022 Dec 1.
Published in final edited form as: Value Health. 2021 Aug 8;24(12):1820–1827. doi: 10.1016/j.jval.2021.06.012

Inclusion of Patient-Reported Outcomes in Adolescent and Young Adult Phase III Therapeutic Trials: An Analysis of Cancer Clinical Trials Registered on ClinicalTrials.gov

Amy M Berkman 1, Karly M Murphy 2, Elizabeth J Siembida 3, Nancy Lau 4,5, Yimin Geng 6, Susan K Parsons 7, John M Salsman 2, Michael E Roth 8
PMCID: PMC8630401  NIHMSID: NIHMS1727188  PMID: 34838280

Abstract

Objectives:

There is a paucity of research on the impact of cancer treatment on the health-related quality of life (HRQOL) of adolescent and young adult (AYA) cancer patients. Patient-reported outcomes (PROs) are self-report measures used to assess HRQOL and symptom burden. The extent to which PROs have been included in trials that include common AYA cancer types has not been previously assessed.

Methods:

Therapeutic phase 3 trials among common AYA cancer types (Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, sarcomas, and germ cell tumors) initiated between 2007 and 2020 were identified on Clinicaltrials.gov. The proportions and characteristics of trials including a PRO endpoint were assessed. For comparison to an older population, the proportion of breast and colorectal therapeutic phase 3 trials including PRO endpoints were assessed.

Results:

Eighty-seven studies met inclusion criteria. Overall, 20.7% of therapeutic phase 3 AYA trials included a PRO endpoint, and only one trial published PRO data. Germ cell tumors (42.9%) and NHL (40%) trials had the highest proportions of PRO inclusion. The EORTC QLQ-C30 was the most commonly used PRO measure; however, the measures utilized varied within and between cancer types. The proportion of trials including a PRO endpoint did not change significantly between 2007-2013 and 2014-2020 (18.6% vs 22.7%, p=0.79).

Conclusions:

Few therapeutic phase 3 AYA cancer trials include PRO endpoints, few publish PRO data, and there is heterogeneity in the measures administered. Therapeutic trials represent an underutilized opportunity to capture PRO data in the AYA population with the goal of improving HRQOL outcomes.

Summary:

Few phase 3 AYA therapeutic clinical cancer trials include PRO endpoints and even fewer publish PRO data.

INTRODUCTION

Patient-reported outcomes (PROs) are self-report measures of a patient’s symptoms and functioning, obtained directly from the patient without interpretation or corroboration by a clinician.[1] Questionnaires are used to measure a broad spectrum of patient experiences, including symptoms of disease and treatment, perceived physical, emotional, and social health, functional outcomes, and multidimensional constructs such as health-related quality of life (HRQOL). Quality of life emerged as a focus in health care practice and research after the World Health Organization put forth a definition of health as “the state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” in 1948.[2] The definition of HRQOL is broad and generally reflects the impact of disease and its treatment on daily functioning, specifically it reflects the impact of an individual’s perceived health as modified by disease impairments on that individual’s ability to lead a fulfilling life.[3] Data from assessment of PROs provides important information that can be used to identify supportive care needs and direct resources to improve the HRQOL of cancer patients. The role of PROs as a key part of care is being increasingly recognized, particularly as these data can provide valuable information regarding tolerability and toxicity of treatment options as well as long-term effects of treatment.[4] Both the National Cancer Institute (NCI) Clinical Trials Network and Consolidated Standards of Reporting Trials have advocated for the inclusion of PRO measurements into clinical trials.[5, 6] As a result, PROs are included as secondary and sometimes primary endpoints in a growing number of cancer clinical trials.[7, 8] However, adolescent and young adult (AYA; ages 15-39 years as defined by the National Cancer Institute) cancer patients are a group that has been consistently underrepresented in cancer clinical trials; thus it is unclear whether AYAs have benefitted from this increased inclusion of PROs.[9, 10]

Few AYAs with cancer enroll in clinical trials. Studies suggest that only 2-14% of all AYAs participate in NCI-supported trials, a significantly lower participation rate than childhood and adult cancer patients.[11, 12] Compared with pediatric patients, AYAs with cancer are more likely to be treated in community settings compared with academic settings, and data has shown that clinical trial enrollment is lower in community settings.[10] Adolescents and young adults with cancer enroll on clinical trials at similar rates as adult cancer patients, though the AYA patient population is much smaller than the adult cancer population.[13] Barriers to clinical trial enrollment, specific to the AYA population include lack of AYA-targeted trials, lack of access to clinical trials, and lack of physician awareness of available AYA trials.[14] Thus, it is essential to learn as much as we can from every patient enrolled to improve care and HRQOL outcomes. The improvement in 5-year survival of AYA cancers to current levels >80%, and recent data suggesting that AYA survival gains are outpacing childhood and adult cancer survival improvements,[15] further supports the importance of collecting PRO data and focusing on patients’ HRQOL, given the anticipated increased length of life. For those cancer types that AYAs continue to have worse survival compared with younger patients, such as soft-tissue sarcoma,[16] collecting PRO data is important to understand symptom burden and treatment impact on HRQOL in efforts to minimize suffering. Knowledge of the HRQOL impacts of diagnosis and treatment can improve care not only during treatment but also into survivorship. In the cancer setting, measurement of PROs has been associated with increased supportive care interventions, improved patient satisfaction, and improved symptom control.[17] Studies among AYA cancer patients and survivors focused only on PRO assessment have found poor HRQOL across multiple domains, including physical (symptom burden/fatigue, sexual function, fertility), emotional (depression, anxiety, body image concerns), social (isolation/loneliness), and occupational (financial hardship, job lock) domains compared with the general population.[18–23] Including PRO measures into AYA cancer clinical trials can provide insight into the timing and specific treatment variables associated with these HRQOL deficits.

The extent to which PRO measurements have been included in AYA-relevant therapeutic clinical trials has not been previously assessed. In addition, there is a lack of data regarding what PRO domains are most commonly assessed and which assessment tools are used in the AYA cancer population.[24] In the current study, we utilized ClinicalTrials.Gov to determine the frequency with which PROs are captured in AYA-relevant phase 3 therapeutic cancer trials as well as identify the HRQOL domains captured and the PRO measures utilized. ClinicalTrials.gov is a mandatory reporting repository maintained by the National Institutes of Health and the National Library of Medicine containing information on clinical trials conducted under United States regulations.[25] For trials that had published their findings, we also assessed whether PRO data included in the trial design was reported in a publication. To compare PRO endpoint inclusion in common AYA cancer types with cancers that occur in AYAs but are more prevalent in older adults, we also assessed PRO endpoint inclusion in therapeutic phase 3 breast and colorectal cancer trials.

METHODS

Procedures

As registered trials typically are open to broad age ranges and are not limited specifically to the AYA ages, we restricted our analysis to trials focused on common AYA cancers identified in the Adolescent and Young Adult Health Outcomes and Patient Experiences (AYA HOPE) study. This important population-based study investigated factors related to gaps in research, care, and outcomes for AYA cancer patients as well as physical and psychosocial functioning, providing some of the earliest data HRQOL data in this population.[26] These cancer types included germ cell tumors, Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), sarcomas, and non-Hodgkin lymphoma (NHL), with the exception of indolent NHL subtypes that primarily affect older adults.

We conducted a search of ClinicalTrials.gov through July 30, 2020. In the context of interventional trials that were initiated January 1, 2007, or later, the following search terms were used: “Hodgkin lymphoma” OR “non-Hodgkin lymphoma” OR “germ cell tumors” OR “acute lymphoblastic lymphoma” OR “Ewing’s sarcoma” OR “osteosarcoma” OR “rhabdomyosarcoma.” Similarly, we used the search terms “interventional studies,” “breast cancer”, “breast neoplasms,” breast carcinomas,” colorectal cancer,” “colorectal neoplasm,” “colorectal tumor,” and “phase 3” to identify phase 3 breast and colorectal clinical trials for comparison. Trials were considered for inclusion if they met the following criteria: (1) trial initiation after 2007 regardless of whether the trial has reached completion, (2) trial registration prior to the search date of July 30, 2020, and (3) the trial age range did not exclude patients age 15-39. Trials were excluded if they did not meet the inclusion criteria or if they: (1) did not include survival and/or cancer response as a primary or secondary outcome, (2) were withdrawn prior to patient recruitment, or (3) were either phase 1 or phase 2 trials. The year 2007 was used as a starting point as it was during this year that therapeutic trial registration became a requirement and it was one year prior that the NCI issued its report “Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer,” that called for inclusion PRO endpoints into clinical trials.[27, 28] Phase 1 and phase 2 trials were excluded from this review because those trial designs and sample sizes are rarely conducive to the inclusion of PROs as secondary or exploratory outcomes and PROs are frequently not approved for inclusion by national funding agencies in early phase trials.

Data were abstracted from ClinicalTrials.gov and trials were reviewed for inclusion in the study by two investigators. For the trials included in the final sample, study initiation year, cancer type, sponsorship (COG, adult cooperative groups, NCI with no associated cooperative group, industry, institution, international cooperative group, combined industry/institution), PRO inclusion and PRO measures utilized were abstracted and analyzed. While trials have many supporters and collaborators, study sponsorship type classification was determined by the group(s) identified on ClinicalTrials.gov in a sponsorship role. In this study, we only considered a trial as including a PRO if that measure was completed by the AYAs themselves. There are measures described as PROs that are reported by clinicians or caregivers rather than patients and these were not included as PROs in the current study. Additionally, Cogstate, a computerized battery of tests aimed to assess neurocognitive function in children, while sometimes designated as a HRQOL measure on ClinicalTrials.gov, did not meet our criteria of AYA PRO measurement and was utilized only in younger children on acute lymphoblastic leukemia trials.[29]

Analyses

First, we calculated the proportion of therapeutic trials that included at least one PRO endpoint in their published trial design. We also calculated this proportion by cancer type, year of trial initiation, and type of study sponsorship. Next, we described the PRO measurement tools utilized and categorized the PRO domains that were assessed, adapting an HRQOL framework recommended for AYA survivors of childhood cancer.[30] Finally, we used the registered clinical trial ID numbers (NCT number) to search PubMed and GoogleScholar for any publications of the trials’ findings. Using these data, we determined the proportion of the trials that published any study data (e.g. survival data, cancer response data, PRO data), and the proportion of trials with a PRO endpoint in their registered trial design that published any PRO data. This information is presented overall and by cancer type. Differences in the proportion of trials that included a PRO endpoint over time was assessed by comparing the first versus the second half of the study period (2007-2013 vs 2014-2020) using a Fisher’s exact test. Differences in the proportion of AYA trials versus breast cancer and colorectal cancer trials that included a PRO endpoint was assessed by the Fisher’s exact test. These results were also confirmed by linear regression with comparison of the slope of the line versus zero. p value <0.05 was considered statistically significant.

RESULTS

Characteristics of Included Trials

Figure 1 shows the ClinicalTrials.gov search results and excluded trials. Initially, 2431 trials were identified. Of these, 1210 were excluded because they were either phase 1 or 2 trials or initiated prior to 2007. An additional 1057 trials were excluded because they included cancer types other than HL, NHL, ALL, germ cell tumors, or sarcomas, or were NHL trials including indolent subtypes exclusively. Finally, 34 trials were excluded because they only included patients aged younger than 15 years or 40 years and older. Of the 99 phase 3 trials remaining, nine were excluded because survival and/or cancer response was not a primary or secondary outcome, and three trials were excluded because they were withdrawn prior to recruitment. The final sample included 87 trials, of which 33 were ALL trials, 23 were HL trials, 10 were sarcoma trials, 10 were NHL trials, 7 were germ cell tumor trials, and 4 were trials with multiple AYA cancer types.

Figure 1.

Figure 1.

Open in a new tab

AYA Phase 3 Clinical Trial Inclusion Approach. Trials were excluded if they were not phase 3, started prior to 2007, included non-AYA cancer types, did not include any participants aged between 15-39 years, were withdrawn prior to recruitment, or did not include a survival/cancer response outcome.

Proportion of therapeutic trials that included PRO endpoints

Overall, 20.7% (n=18) of therapeutic AYA trials included at least one PRO endpoint (secondary or exploratory) in their registered trial design (Table 1). When examining across cancer types, 42.9% of germ cell tumor trials (3/7), 40% of NHL trials (4/10), 18.2% of ALL trials (6/33), 17.4% of HL trials (4/23) and 10% of sarcoma trials (1/10) included at least one PRO endpoint. There were no mixed AYA cancer type trials that included PRO endpoints. Inclusion of PRO endpoints into trial design varied by year (range, 0%-50%). There was no significant change in the proportion of trials that included a PRO endpoint between 2007-2013 and 2014-2020 (18.6% vs 22.7%, p=0.79; Figure 2). Linear regression analysis of the number of trials including a PRO endpoint each year demonstrated a slope of the line that was not significantly different from zero (slope= 0.06, p=0.94). During the study period, 2 of the 14 years (14.3%) did not have any registered phase 3 AYA-relevant trials with a PRO endpoint. Among the four therapeutic AYA trials registered in 2020 through July, none included PRO endpoints.

Table 1.

Inclusion of Patient-Reported Outcomes into trial design and publication in AYA phase 3 clinical trials identified on Clinicaltrials.gov (2007-2020)

Cancer Type(s) Total Number of Trials, n Trials that included PROs, n(%) Trials ending completed by 2020, n(%) Trials that published any data, n(%) Trials that included PROs in design that published PRO data, n(%)
Overall 87 18(20.7) 41(47.1) 25(28.7) 1(6.3)
Acute lymphoblastic leukemia 33 6(18.2) 15(45.5) 10(30.3) 1(16.7)
Hodgkin’s lymphoma 23 4(17.4) 12(52.2) 9(39.1) 0(0.0)
Sarcomas 10 1(10.0) 4(40.0) 2(20.0) 0(0.0)
Non-Hodgkin’s
lymphoma		 10 4(40.0) 6(60.0) 3(30.0) 0(0.0)
Germ Cell 7 3(42.9) 3(42.9) 0(0.0) N/A
Multiple cancer types 4 0(0.0) 1(25.0) 1(25.0) 0(0.0)
Open in a new tab
*

PRO(Patient Reported Outcome)

Figure 2.

Figure 2.

Open in a new tab

Proportion of AYA Phase 3 Clinical Trials Identified on Clinicaltrials.gov Including PRO Endpoints in Trial Design by Year of Trial Initiation. The bar graph demonstrates number of trials that included a PRO into trial design by each year and the line graph shows the two-year average proportion of trials including a PRO into trial design. When splitting the study period, there was no significant difference in proportion of trials including PROs in the first and second half of the study period.

Inclusion of PRO endpoint and study sponsorship

Trial sponsorship varied by cancer type, as seen in Supplemental Table 1. Overall, 31% of trials were sponsored by industry, 20.7% by institutions, 18.4% by international cooperative groups, 17.2% by the Children’s Oncology Group (COG), 4.6% by NCTN adult network groups, 4.6% by combined industry/institution, and 3.5% by the NCI with no cooperative group specified. The most common sponsorship for ALL trials was institutional (27.3%). Industry was the most common sponsor of HL studies (39.1%) and NHL studies (70.0%). Sarcoma trials were primarily sponsored by international cooperative groups (40%). The COG, international cooperative groups, and institutions each sponsored 28.6%of germ cell trials.

There was some variation in PRO endpoint inclusion based on study sponsorship (range, 0%-33.3%). NCI-sponsored trials with no associated cooperative groups had the highest proportion of PRO endpoint inclusion (1 of 3 trials, 33.3%), followed by those with COG (4 of 15 trials, 26.7%) or adult cooperative groups (1 of 4 trials, 25%) sponsorship or collaboration (Figure 3). There was no significant difference between the inclusion of PRO endpoints in NCI sponsored studies compared with non-NCI sponsored studies (27.2% vs 18.5%, p=0.38)

Figure 3.

Figure 3.

Open in a new tab

Proportion of AYA Phase 3 Clinical Trials Including PRO Endpoints by Sponsor Type. There was no significant difference in PRO inclusion between NCI and non-NCI sponsored trials.

PRO Assessment Measures and HRQOL domains assessed

The PRO measures included in trial designs and the PRO domains that they capture are shown in Table 2. The European Organization for Research and Treatment of Cancer generic, cancer-specific quality of life questionnaire (EORTC QLQ-C30) was the most commonly used PRO measure (n=8). Symptom burden, physical function, emotional function, and role function were the most common PRO domains covered by these multi-dimensional measures.

Table 2.

Patient-Reported Outcome measures and domains in AYA phase 3 clinical trials identified on Clinicaltrials.gov (2007-2020)

Inventory Trials Using (N) Global HRQOL Physical Function/Symptoms Emotional Social/Occupational
EORTC QLQ-C30 8 global health status physical functioning, role functioning, cognitive functioning, symptoms emotional functioning social functioning, financial difficulties
Fact-LYM 3 FACT-G total, FACT-LYM total physical well-being, functional well-being, lymphoma sub-scale, trial outcome index, emotional well-being social/family well-being
FACT-GOG-NTX 3 peripheral neuropathy, physical well-being emotional well-being social/family well-being
EQ-VAS 2 overall self-rated health
EQ-5D 2 mobility, self-care, usual activities, pain/discomfort anxiety/depression
EORTC QLQ-TC26 1 Treatment side-effects, treatment satisfaction, physical limitations, infertility, sexual activity, sexual functioning, sexual enjoyment, testicular implant satisfaction body image, future perspective family problems, communication, job and education problems
PedsQL 1 physical functioning emotional functioning social functioning, school functioning
Ped-PRO-CTCAE 1 oral, gastrointestinal, respiratory, cardio/circulatory, cutaneous, neurological, visual/perceptual, attention/memory, pain, sleep/wake, genitourinary, miscellaneous mood
MDASI 1 symptom severity affective interference activity interference
SF-36 1 general health physical functioning, role limitations due to physical health, energy/fatigue, pain role limitations due to emotional problems, emotional wellbeing social functioning
(CHRIs)-Global
Scale		 1 physical functioning, energy emotional functioning role functioning
PROMIS-General 1 global health status physical function, pain, fatigue mood, emotional well-being social functioning
PROMIS-Fatigue 1 fatigue
Open in a new tab

Abbreviations: EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire; Fact-LYM, Functional Assessment of Cancer Therapy – Lymphoma; FACT-GOG-NTX, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity; EQ-VAS, EuroQol-Visual Analogue Scale; EQ-5D, EuroQol Five-Dimensional Questionnaire; EORTC QLQ-TC26, European Organization for Research and Treatment of Cancer Quality of Life Testicular Cancer Questionnaire; PedsQL, Pediatric Quality of Life Inventory; Ped-PRO-CTCAE, Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; MDASI, MD Anderson Symptom Inventory; SF-36, 36-Item Short Form Health Survey; CHRIs-Global Scale, Child Health Ratings Inventories-Global Scale; PROMIS-General, Patient-Reported Outcomes Measurement Information System-General; PROMIS-Fatigue, Patient-Reported Outcomes Measurement Information System-Fatigue

Publication of PROs

Across all 87 reviewed trials, 41 (47.1%) reached the end of their study period and 25 (28.7%) had published any data at the time of study abstraction (Table 1). Of the trials with published data, 5 (20%) included PRO endpoints in their study design, and one of those trials had published the PRO data (Table 3). The trial that published the PRO data was an ALL trial initiated in 2014 that utilized the EORTC QLQ-C30. Overall, only 5.6% of the reviewed trials published PRO data (1 of 18 trials with PRO endpoints). It is important to note that at the time of study abstraction, just under half (47%) of the trials were completed, though there were incomplete trials with publications.

Table 3.

Reporting of AYA phase 3 cancer trials identified on Clinicaltrials.gov (2007-2020) that included assessment of Patient-Reported Outcomes

Trial Active Years Cancer Type Study Participants,
N		 Ages Included Reported PRO Results
(Y/N)		 PRO Assessment Tools
2012-2017 ALL 326 18+ (65% <55 years) N EQ-5D; EQ-5D-VAS; EORTC QLQ-C30
2012-2026 HL 1334 18+ (median 36 years) N EORTC-QLQ-C30
2014-2017 ALL 405 18-80 (median 41 years) Y EORTC QLQ-30
2007-2017 NHL 862 18-80 (median 60 years) N Unknown
2009-2019 Ewing
Sarcoma		 907 4-40 years N Unknown
Open in a new tab

Inclusion of PROs in Breast and Colorectal Cancer Trials

There were 396 breast and 231 colorectal cancer trials that met inclusion criteria (Supplemental Figures 1 and 2). Out of these phase 3 clinical trials, 43.4% of breast and 36.4% of colorectal trials, respectfully, included PRO endpoints in to the clinical design (Supplemental Table 2). Breast cancer trials and colorectal cancer trials were each significantly more likely to include PRO endpoints compared with AYA-focused therapeutic trials (43.4% vs. 20.7%, p<0.001 and 36.4% vs. 20.7%, p=0.007, respectively). European measures, specifically the EORTC QLQ-30, as well as breast (QLQ-BR23) or colorectal (QLQ-CR28/29) specific EORTC measures, and the EQ-5D and EQ-VAS were the most commonly used PRO measures, utilized by 60.5% of breast and 69.0% of colorectal trials that included PRO endpoints (Supplemental Table 2).

DISCUSSION

The current study found that just over 20% of all phase 3 AYA-relevant therapeutic trials registered from January 1, 2007 to July 30, 2020 included the assessment of PROs in the trial design. To-date, only one of those trials has published PRO data. In 2006, the NCI Progress Review Group published its important report “Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer,” which detailed disparities in outcomes and unmet needs of the AYA cancer population,[27] including the importance of assessing and addressing the unique psychosocial needs of the AYA population. Subsequently, there has been a surge in national efforts to identify and address disparities in AYA care and outcomes, including the release of multiple AYA-focused NCI funding announcements and a variety of National Community Oncology Research Program efforts focused on increasing AYA access to cancer clinical trials.[14, 31] Despite this priority, data on the impact of a cancer diagnosis and cancer treatment on AYA HRQOL continue to be limited and our analysis highlights numerous missed opportunities to prioritize the patient experience by measuring AYA HRQOL in late phase therapeutic clinical trials.

Lack of PRO endpoints in cancer clinical trials is not unique to the AYA population. A previous study of all oncologic trials registered from 2007-2013 found that 35% of phase 3 trials included PRO endpoints in their design, though this study did not report whether PRO data were published.[8] In our assessment of breast and colorectal phase 3 trials that included phase 3 trials initiated up until mid-2020, we found that 46% of breast and 36% of colorectal cancer trials included a PRO endpoint, suggesting that not much progress has been made, though larger studies focused primarily on adult cancers are needed. Breast is a common cancer in older AYAs and colorectal cancer incidence is increasing in the AYA population, however, both of these cancer types are primarily found in older populations. These findings suggest that PRO endpoint inclusion is more common in studies that are focused on older populations. Additionally, there were many more breast and colorectal cancer trials that met inclusion criteria (n= 396 and 231), compared with only 87 trials that met inclusion criteria across the 5 common AYA cancer types. Thus, even small differences in PRO endpoint inclusion rate results in significantly more PRO data collected in older populations. To the authors’ knowledge, similar studies assessing the inclusion of PRO endpoints in therapeutic childhood cancer trials have not been performed recently. A study of phase 3 clinical trials from the Pediatric Oncology Group, one of the predecessor groups to the COG, published in 1995 found that only 3% of the 70 trials included quality of life data, whereas toxicity data were included in over 75% of the trials.[32] Inclusion of PRO measures remains uncommon in the childhood cancer population.[33] In a recent analysis assessing inclusion of PRO endpoints in commercial pediatric oncology studies submitted to the FDA for review, 24% of the submitted applications included PRO data, all of which were exploratory endpoints.[34] In the current study, we found that about 25% of phase 3 therapeutic COG affiliated AYA trials included a PRO endpoint.

One of the challenges of incorporating PRO endpoints into cancer clinical trials that predominantly recruit AYAs is lack of assessment tools specifically designed for this population.[35, 36] As seen in the current study, there is a lack of consistency among tools used and PRO domains measured in AYA-relevant cancer clinical trials. Additionally, there are continental differences in implementation of HRQOL measures. For many phase 3 studies sponsored by the NCI or U.S.-based groups, a clear hypothesis and scientific rationale related to the primary PRO is often needed to justify inclusion of PRO endpoints on trials, thus adding additional barriers to including these outcomes and limiting the inclusion of important descriptive and exploratory HRQOL aims. While similar standards apply in therapeutic trials sponsored by European organizations, the European Organization for Research and Treatment of Cancer (EORTC) has created a Quality of Life Study Group aimed to liaise across tumor groups and facilitate the process of HRQOL measurements into trials.[37] This likely contributed to predominance of EORTC assessments seen in the current study.

Lack of validated, AYA-specific PRO measurement tools may be contributing to the low proportion of AYA phase 3 trials including PRO endpoints. The common HRQOL measures currently in use, such as the PedsQL and European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30), were not validated for use across the entire AYA age group.[38, 39] To address this gap, each of these measures has developed a separate age-specific version for young adults. The PedsQL Young Adult measure is designed for patients 18-25 years,[40] while the EORTC AYA-specific measure is designed for patients ages 14-25 years, with plans to extend validation work to age 39. Similarly, while both the pediatric and adult item banks, developed as part of the National Institutes of Health’s Patient-Reported Outcomes Measurement Information System (PROMIS) initiative, have been tested in adolescents and in young adults, neither the development nor validation studies were specific to AYAs with cancer[41, 42] The BRIGHTLIGHT survey, specific to cancer patients aged 13-24 years, has been developed and validated by a National Institute for Health Research project in England that aimed to evaluate cancer and healthcare services from an AYA perspective, however, it is not yet in widespread use and does not cover the full AYA age range.[43] There is also ongoing work to adapt PROMIS for targeted use in the AYA cancer population, as well as to link pediatric and adult PROMIS measures for integrated and longitudinal scoring.[44, 45] The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is another measure that has both adult and pediatric validated versions (Ped-PRO-CTCAE), and work has begun to explore whether the adult version can be used among adolescents, thus capturing the AYA population with a singular version.[46, 47] Until there are new widely used PRO and HRQOL measurement tools specific to the AYA cancer population or currently used tools are modified and validated in this population, comparison of these outcomes between studies remains difficult. Additionally, many of the domains impacted in the AYA population (i.e., sexual function, body image, fertility, financial/educational) are not routinely included in measures currently in use. These AYA-specific domains may not fit into most therapeutic trial endpoints as well as other domains (i.e., symptom burden), which may also explain their rarity. These domains also have a critical developmental component. Taken together, this points to the need for robust AYA-specific HRQOL measures that can be utilized broadly. In addition, as PRO endpoints are more frequently included in AYA cancer clinical trials, there will be a need for standardization and optimization of the analysis and interpretation of this data.[48]

With the vast majority of clinical trials including broad age ranges and the lack of trials that exclusively target AYAs, it is exceedingly difficult to identify all therapeutic phase 3 trials that ended up enrolling a majority AYA population. To overcome this challenge and to keep our focus on AYAs without including an over-representation of younger or older populations, we modeled this analysis on the AYA HOPE study, including cancer types that were included in that seminal work. A limitation to the current study is that our inclusion criteria may have missed some trials that included a large proportion of AYA cancer patients. Similarly, we may have included trials that included AYAs, however, ultimately end up enrolling a predominantly younger or older population.

The current study highlights the lack of PRO endpoints included in late phase AYA-relevant trials, the lack of harmonization across HRQOL domains, and the lack of standardization of measures utilized to measure AYA HRQOL. AYAs with cancer are living longer due to therapeutic advancements, however, without systematic measurement of HRQOL, it is not known if they are living healthy, fulfilling lives. There is an urgent need for coordinated efforts to understand the short and long-term impact of cancer therapies on AYAs’ HRQOL, with on treatment HRQOL data needed to identify initial insults and monitor trajectories. In response to this need, an AYA PRO Task Force has recently been assembled with stakeholders from across the NCTN to identify opportunities to standardize the inclusion of PROs in NCTN AYA trials. The Task Force, which is funded through the Childhood Cancer Data Initiative, is charged with coming to consensus on a core battery of AYA PRO measures which will be recommended for inclusion in AYA trials as well as fostering and monitoring their inclusion into these trials. Additionally, a number of cross-network NCTN AYA therapeutic trials, which include participation from both pediatric and medical oncology, have recently been developed for AYAs with soft tissue sarcoma, Hodgkin lymphoma, and germ cell tumors. These trials represent prime opportunities to assess the impact of cancer therapy on the HRQOL of AYAs as they have enough AYAs to adequately power these important questions. These are promising first steps towards describing the trajectory of HRQOL in AYA cancer patients; however, additional collaborative efforts are needed to identify those AYAs at highest risk for impaired HRQOL and develop timely interventions to mitigate these outcomes.

Supplementary Material

1
2

Supplemental Figure 1. Phase 3 Breast Cancer Trials Inclusion Approach. Trials were excluded if they were not phase 3, started prior to 2007 or after 7/30/2020, included non-breast cancer types, included only participants aged ≥40 years, were withdrawn prior to recruitment, or did not include a survival/cancer response outcome.

3

Supplemental Figure 2. Phase 3 Colorectal Cancer Trials Inclusion Approach. Trials were excluded if they were not phase 3, started prior to 2007 or after 7/30/2020, included non-colorectal cancer types, included only participants aged ≥40 years, were withdrawn prior to recruitment, or did not include a survival/cancer response outcome.

Highlights:

What is known:

Adolescent and young adult (AYA) cancer patients enroll in clinical trials at lower rates than younger cancer patients. There is a paucity of research on patient-reported outcomes (PROs) and health-related quality of life (HRQOL) of AYAs going through cancer treatment.

What does the paper add to existing knowledge:

The current study demonstrates a low proportion of PRO endpoints included in therapeutic phase 3 AYA clinical cancer trials.

What insights does the research provide for informing healthcare-related decision making:

Late-stage clinical trials represent an underutilized opportunity to collect PRO data in the AYA cancer population. This data is needed to inform interventions aimed to improve HRQOL and symptom management among AYAs through cancer treatment and into survivorship.

Funding/Support:

This work was supported by grants U10-CA180886 (MR), P30 CA016672 (MR), R38-HL143612 (AB), UG1-CA189955 (MR, SP), CA193193 (KM), CA122061 (KM), 5K12 HL137940-02 (NL), UG1 CA189828-07S1 (JS), and R01 CA218398 (JS) from the National Cancer Institute at the National Institutes of Health.

Role of Support:

The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflict of Interest Disclosures:

Dr Berkman reported being supported by grant NIH R38-HL143612 during the course of this study. Dr Murphy reported being supported by grant NCI T32 CA193193 and NCI T32 CA122061 from the National Cancer Institute during the course of this study. Dr Lau reported being funded as an Implementation Science Scholar through the National Heart, Lung, and Blood Institute at the National Institutes of Health under grant 5K12 HL137940-02 during the course of this study. Dr Parsons reported receiving consultant fees for Seattle Genetics, receiving grants from the Leukemia & Lymphoma Society, and is on the advisory board for the Dana Farber/Harvard Cancer Center outside the submitted work. Dr Salsman reported receiving funding from the National Cancer Institute under grants UG1 CA189828-07S1 and R01 CA218398 during the course of this study, and being on the advisory board for True North Treks and Team Maggie outside the submitted work. No other conflicts were reported.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of Interest Disclosures:

SP is a consultant for Seattle Genetics and is on the advisory board for Dana-Farber/Harvard Cancer Center. JS is on the advisory board for True North Treks and Team Maggie. The authors do not report any additional conflicts of interest to disclose.

REFERENCES

  • 1.U. S. Department of Health Food and Drug Administration, Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Qual Life Outcomes 2006; 4: p. 79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Huber M, Knottnerus JA, Green L, van der Horst H, Jadad AR, Kromhout D, et al. , How should we define health? British Medical Journal 2011; 343. [DOI] [PubMed] [Google Scholar]
  • 3.Haraldstad K, Wahl A, Andenaes R, Andersen JR, Andersen MH, Beisland E, et al. , A systematic review of quality of life research in medicine and health sciences. Qual Life Res 2019; 28(10): p. 2641–2650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Nyrop KA, Deal AM, Shachar SS, Basch E, Reeve BB, Choi SK, et al. , Patient-Reported Toxicities During Chemotherapy Regimens in Current Clinical Practice for Early Breast Cancer. Oncologist 2019; 24(6): p. 762–771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Bruner DW, Bryan CJ, Aaronson N, Blackmore CC, Brundage M, Cella D, et al. , Issues and challenges with integrating patient-reported outcomes in clinical trials supported by the National Cancer Institute-sponsored clinical trials networks. J Clin Oncol 2007; 25(32): p. 5051–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Basch E, Abernethy AP, Mullins CD, Reeve BB, Smith ML, Coons SJ, et al. , Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology. J Clin Oncol 2012; 30(34): p. 4249–55. [DOI] [PubMed] [Google Scholar]
  • 7.LeBlanc TW and Abernethy AP, Patient-reported outcomes in cancer care - hearing the patient voice at greater volume. Nat Rev Clin Oncol 2017; 14(12): p. 763–772. [DOI] [PubMed] [Google Scholar]
  • 8.Vodicka E, Kim K, Devine EB, Gnanasakthy A, Scoggins JF, and Patrick DL, Inclusion of patient-reported outcome measures in registered clinical trials: Evidence from ClinicalTrials.gov (2007-2013). Contemp Clin Trials 2015; 43: p. 1–9. [DOI] [PubMed] [Google Scholar]
  • 9.Roth ME, O’Mara AM, Seibel NL, Dickens DS, Langevin AM, Pollock BH, et al. , Low Enrollment of Adolescents and Young Adults Onto Cancer Trials: Insights From the Community Clinical Oncology Program. J Oncol Pract 2016; 12(4): p. e388–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Roth ME, Unger JM, O’Mara AM, Lewis MA, Budd T, Johnson RH, et al. , Enrollment of adolescents and young adults onto SWOG cancer research network clinical trials: A comparative analysis by treatment site and era. Cancer Med 2020; 9(6): p. 2146–2152. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Unger JM, Cook E, Tai E, and Bleyer A, The Role of Clinical Trial Participation in Cancer Research: Barriers, Evidence, and Strategies. Am Soc Clin Oncol Educ Book 2016; 35: p. 185–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Parsons HM, Penn DC, Li Q, Cress RD, Pollock BH, Malogolowkin MH, et al. , Increased clinical trial enrollment among adolescent and young adult cancer patients between 2006 and 2012-2013 in the United States. Pediatr Blood Cancer 2019; 66(1): p. e27426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Freyer DR and Seibel NL, The Clinical Trials Gap for Adolescents and Young Adults with Cancer: Recent Progress and Conceptual Framework for Continued Research. Curr Pediatr Rep 2015; 3(2): p. 137–145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Siembida EJ, Loomans-Kropp HA, Trivedi N, O’Mara A, Sung L, Tami-Maury I, et al. , Systematic review of barriers and facilitators to clinical trial enrollment among adolescents and young adults with cancer: Identifying opportunities for intervention. Cancer 2020; 126(5): p. 949–957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Liu L, Moke DJ, Tsai KY, Hwang A, Freyer DR, Hamilton AS, et al. , A Reappraisal of Sex-Specific Cancer Survival Trends Among Adolescents and Young Adults in the United States. J Natl Cancer Inst 2019; 111(5): p. 509–518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Miller KD, Fidler-Benaoudia M, Keegan TH, Hipp HS, Jemal A, and Siegel RL, Cancer statistics for adolescents and young adults, 2020. CA Cancer J Clin 2020. [DOI] [PubMed] [Google Scholar]
  • 17.Kotronoulas G, Kearney N, Maguire R, Harrow A, Di Domenico D, Croy S, et al. , What is the value of the routine use of patient-reported outcome measures toward improvement of patient outcomes, processes of care, and health service outcomes in cancer care? A systematic review of controlled trials. J Clin Oncol 2014; 32(14): p. 1480–501. [DOI] [PubMed] [Google Scholar]
  • 18.Smith AW, Bellizzi KM, Keegan TH, Zebrack B, Chen VW, Neale AV, et al. , Health-related quality of life of adolescent and young adult patients with cancer in the United States: the Adolescent and Young Adult Health Outcomes and Patient Experience study. J Clin Oncol 2013; 31(17): p. 2136–45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ketterl TG, Syrjala KL, Casillas J, Jacobs LA, Palmer SC, McCabe MS, et al. , Lasting effects of cancer and its treatment on employment and finances in adolescent and young adult cancer survivors. Cancer 2019; 125(11): p. 1908–1917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Henderson JR 2nd, Kiernan E, McNeer JL, Rodday AM, Spencer K, Henderson TO, et al. , Patient-Reported Health-Related Quality-of-Life Assessment at the Point-of-Care with Adolescents and Young Adults with Cancer. J Adolesc Young Adult Oncol 2018; 7(1): p. 97–102. [DOI] [PubMed] [Google Scholar]
  • 21.Olsson M, Steineck G, Enskar K, Wilderang U, and Jarfelt M, Sexual function in adolescent and young adult cancer survivors-a population-based study. J Cancer Surviv 2018; 12(4): p. 450–459. [DOI] [PubMed] [Google Scholar]
  • 22.Vani MF, Sabiston CM, Petrella A, Adams SC, Eaton G, Chalifour K, et al. , Body image concerns of young adult cancer survivors: A brief report. J Psychosoc Oncol 2020: p. 1–7. [DOI] [PubMed] [Google Scholar]
  • 23.Young K, Shliakhtsitsava K, Natarajan L, Myers E, Dietz AC, Gorman JR, et al. , Fertility counseling before cancer treatment and subsequent reproductive concerns among female adolescent and young adult cancer survivors. Cancer 2019; 125(6): p. 980–989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Rae C, Shah N, De Pauw S, Costa A, and Barr RD, System Performance Indicators for Adolescent and Young Adult Cancer Care and Control: A Scoping Review. J Adolesc Young Adult Oncol 2020; 9(1): p. 1–11. [DOI] [PubMed] [Google Scholar]
  • 25.U.S. National Library of Medicine. ClinicalTrials.gov Background. Available from: https://clinicaltrials.gov/ct2/about-site/background. [DOI] [PubMed]
  • 26.Smith AW, Keegan T, Hamilton A, Lynch C, Wu XC, Schwartz SM, et al. , Understanding care and outcomes in adolescents and young adult with Cancer: A review of the AYA HOPE study. Pediatr Blood Cancer 2019; 66(1): p. e27486. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.US Department of Health and Human Services, N.I.o.H., National Cancer Institute, LIVESTRONG Young Adult Alliance. Closing the Gap: Research and Care Imperatives for Adolescents and Young Adults with Cancer. Available from: https://www.cancer.gov/types/aya/research/ayao-august-2006.pdf
  • 28.Food and Drug Administration, Amendments Act of 2007. 2007. [Google Scholar]
  • 29.Sands SA, Harel BT, Savone M, Kelly K, Vijayanathan V, Welch JG, et al. , Feasibility of baseline neurocognitive assessment using Cogstate during the first month of therapy for childhood leukemia. Support Care Cancer 2017; 25(2): p. 449–457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Nightingale CL, Quinn GP, Shenkman EA, Curbow BA, Zebrack BJ, Krull KR, et al. , Health-Related Quality of Life of Young Adult Survivors of Childhood Cancer: A Review of Qualitative Studies. J Adolesc Young Adult Oncol 2011; 1(3): p. 124–132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.RFA-CA-20-027, Research to Reduce Morbidity and Improve Care for Pediatric, and Adolescent and Young Adult (AYA) Cancer Survivors (R01 Clinical Trial Option). 2021, National Institutes of Health. [Google Scholar]
  • 32.Bradlyn AS, Harris CV, and Spieth LE, Quality of life assessment in pediatric oncology: a retrospective review of phase III reports. Soc Sci Med 1995; 41(10): p. 1463–5. [DOI] [PubMed] [Google Scholar]
  • 33.Leahy AB, Feudtner C, and Basch E, Symptom Monitoring in Pediatric Oncology Using Patient-Reported Outcomes: Why, How, and Where Next. Patient 2018; 11(2): p. 147–153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Murugappan MN, King-Kallimanis BL, Reaman GH, Bhatnagar V, Horodniceanu EG, Bouchkouj N, et al. , Patient Reported Outcomes in Pediatric Cancer Registration Trials: A U.S. Food and Drug Administration Perspective. J Natl Cancer Inst 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Lazor T, Tigelaar L, Pole JD, De Souza C, Tomlinson D, and Sung L, Instruments to measure anxiety in children, adolescents, and young adults with cancer: a systematic review. Support Care Cancer 2017; 25(9): p. 2921–2931. [DOI] [PubMed] [Google Scholar]
  • 36.Sodergren SC, Husson O, Robinson J, Rohde GE, Tomaszewska IM, Vivat B, et al. , Systematic review of the health-related quality of life issues facing adolescents and young adults with cancer. Qual Life Res 2017; 26(7): p. 1659–1672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.de Haes J, Curran D, Young T, Bottomley A, Flechtner H, Aaronson N, et al. , Quality of life evaluation in oncological clinical trials - the EORTC model. The EORTC Quality of Life Study Group. Eur J Cancer 2000; 36(7): p. 821–5. [DOI] [PubMed] [Google Scholar]
  • 38.Varni JW, Seid M, and Rode CA, The PedsQL: measurement model for the pediatric quality of life inventory. Med Care 1999; 37(2): p. 126–39. [DOI] [PubMed] [Google Scholar]
  • 39.Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. , The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85(5): p. 365–76. [DOI] [PubMed] [Google Scholar]
  • 40.Varni JW and Limbers CA, The PedsQL 4.0 Generic Core Scales Young Adult Version: feasibility, reliability and validity in a university student population. J Health Psychol 2009; 14(4): p. 611–22. [DOI] [PubMed] [Google Scholar]
  • 41.Husson O, Sodergren S, and Darlington AS, The importance of a collaborative health-related quality of life measurement strategy for Adolescents and Young Adults with Cancer. Cancer in press. [DOI] [PubMed] [Google Scholar]
  • 42.EORTC Quality of Life. Adolescents and Young Adults. Available from: https://qol.eortc.org/questionnaire/aya/.
  • 43.Taylor RM, Fern LA, Solanki A, Hooker L, Carluccio A, Pye J, et al. , Development and validation of the BRIGHTLIGHT Survey, a patient-reported experience measure for young people with cancer. Health Qual Life Outcomes 2015; 13: p. 107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Salsman JM, Danhauer SC, Moore JB, Canzona MR, Victorson DE, Zebrack BJ, et al. , Optimizing the measurement of health-related quality of life in adolescents and young adults with cancer. Cancer 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Tulsky DS, Kisala PA, Boulton AJ, Jette AM, Thissen D, Ni P, et al. , Determining a transitional scoring link between PROMIS(R) pediatric and adult physical health measures. Qual Life Res 2019; 28(5): p. 1217–1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Reeve BB, McFatrich M, Mack JW, Maurer SH, Jacobs SS, Freyer DR, et al. , Validity and Reliability of the Pediatric Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events. J Natl Cancer Inst 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Reeve BB, McFatrich M, Pinheiro LC, Freyer DR, Basch EM, Baker JN, et al. , Cognitive Interview-Based Validation of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events in Adolescents with Cancer. J Pain Symptom Manage 2017; 53(4): p. 759–766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Coens C, Pe M, Dueck AC, Sloan J, Basch E, Calvert M, et al. , International standards for the analysis of quality-of-life and patient-reported outcome endpoints in cancer randomised controlled trials: recommendations of the SISAQOL Consortium. Lancet Oncol 2020; 21(2): p. e83–e96. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1
NIHMS1727188-supplement-1.docx (16.4KB, docx)
2

Supplemental Figure 1. Phase 3 Breast Cancer Trials Inclusion Approach. Trials were excluded if they were not phase 3, started prior to 2007 or after 7/30/2020, included non-breast cancer types, included only participants aged ≥40 years, were withdrawn prior to recruitment, or did not include a survival/cancer response outcome.

NIHMS1727188-supplement-2.tif (79.6KB, tif)
3

Supplemental Figure 2. Phase 3 Colorectal Cancer Trials Inclusion Approach. Trials were excluded if they were not phase 3, started prior to 2007 or after 7/30/2020, included non-colorectal cancer types, included only participants aged ≥40 years, were withdrawn prior to recruitment, or did not include a survival/cancer response outcome.

NIHMS1727188-supplement-3.tif (80.5KB, tif)

RESOURCES