Abstract
Background
Clinical trials are often an important component of cancer care but are misunderstood by many patients. Few studies have examined age differences in clinical trial understanding in older versus younger adults, especially among patients with indolent non-Hodgkin lymphoma (NHL), a slowly progressive and not typically curable cancer diagnosed primarily in older adults.
Patients and Methods
Participants aged ≥21 years with a diagnosis of NHL were recruited from a single academic medical center in an urban setting. Age was dichotomized as <65 and ≥65 years. Clinical trial understanding was assessed using a four-item survey of potential goals of a clinical trial, with responses including “yes,” “no,” and “I don’t know.” Survey responses were examined by age using Chi-square tests.
Results
The sample was comprised of 74 patients who were predominantly non-Latino White, with a mean age of 60.4 years (SD=12.27). Compared to younger patients, older patients were more likely to respond “I don’t know” to the clinical trial goals of reducing the lymphoma (41.4% vs 13.3%; P=0.023) and keeping the lymphoma from worsening (41.4% vs 13.3%; P=0.017). Age differences for the remaining goals were not statistically significant. Similar findings emerged when the sample was restricted to patients under active surveillance.
Conclusions
Relative to younger adults, older adults may have a less nuanced understanding of clinical trial goals. Therefore, older adults may benefit from developmentally-tailored interventions to improve clinical trial understanding. Future research should examine the relationship between clinical trial understanding and enrollment by age using validated measures in diverse samples.
Keywords: Non-Hodgkin lymphoma, clinical trials, patient understanding, age
Micro Abstract
Cancer patients often have an inaccurate understanding of the goals of a clinical trial. Up to two-thirds of indolent non-Hodgkin lymphomas (NHL) diagnoses are made in older adults. We examined indolent NHL patients’ understanding of the goals of clinical trials and differences in this understanding by age. Older adults were more likely to endorse “I don’t know” for certain goals than younger adults. Older adults may benefit from additional information to ensure understanding.
Introduction
Difficulty accruing patients into clinical trials is a commonly cited problem, especially in oncology clinical trials.1 In fact, clinical trials often fail to meet their primary endpoint, not because of lack of efficacy or poor study design, but because of an inability to accrue a sufficient sample size. For example, in a review of 2,579 initiated phase 2 and 3 clinical trials that were registered as closed in 2011, 481 (19%) were either terminated for failed accrual or completed with less than 85% of expected enrollment.2 As a result, the resources used to initiate these studies failed to advance research and clinical care.
While accrual into clinical trials is already difficult across patient populations, accrual of older adults is particularly difficult. Older adults are overrepresented among new cancer diagnoses but are underrepresented in clinical trials.3 A review of 55 registration trials of new oncology drugs approved by the United States Food and Drug Administration from 1995 to 2002 found that patients aged 65 and older, 70 and older, and 75 and older represented 36%, 20%, and 9%, respectively, of the studied patient population, despite comprising 60%, 46%, and 31%, respectively, of the US cancer population.4 Separately, a study of 302 ClinicalTrials.gov randomized controlled trials in oncology found a statistically significant age disparity between the trial participant median age and the population-based disease-specific median age with the population age significantly greater than trial participant age. This disparity was particularly notable among industry-funded trials.5 The age difference in patients studied in clinical trials and those treated in real-world settings, reduce the generalizability of clinical trial conclusions to older adults who comprise a large proportion of the cancer patient population. In response, major cancer societies have advocated for research into reasons for these disparities and additional efforts to improve clinical trial accrual in older adults.6,7
Limited understanding of the goals of clinical trials may be one factor that explains low enrollment by older adults. A qualitative study of older cancer patients found that patients expressed confusion regarding clinical trial participation and the goals of clinical trials, with one interviewee even indicating that they had never heard the expression “clinical trial”.8 This research suggests that older adults may have a poor understanding of the goals of clinical trials. However, little is known about older adults’ clinical trial understanding and how it compares to that of younger adults.
Non-Hodgkin lymphomas (NHL) are among the most common cancers in the United States, consisting of approximately 4% of all cancers.9 Like many cancers, the majority of new diagnoses occur in older adults, with over half of incident cases between 2014 and 2018 occurring in patients 65 years and older. However, unlike many other cancers, indolent NHL subtypes are slowly progressive and not typically curable, with median survival often extending to over a decade. Patients may require multiple lines of therapy over their lifetime, and many could benefit from clinical trial participation as novel agents are frequently more effective and/or better tolerated than historical options.10 Although several studies have examined reasons for differential clinical trial accrual between older and younger adults,11–16 few have studied patients with NHL. Furthermore, most of the aforementioned studies included patients with lower 5-year survival rates than in indolent NHLs, limiting generalizability to patients with indolent NHL. The purpose of the present study is to examine age differences in understanding of clinical trial goals in patients with newly diagnosed indolent NHLs. We hypothesized that older adults would have a more limited understanding of the goals of clinical trials compared to younger adults.
Methods
Participants and Procedures
Participants were recruited from May 2016 to November 2018 from a single academic medical center in an urban setting. Participants were identified through self-referral from fliers posted in participating clinics, referrals from oncology providers, and medical chart reviews by study staff. Eligible participants were English-speaking and aged 21 or older with a diagnosis of follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, or Waldenstrom’s macroglobulinemia in the past six months. Patients additionally required a working email address and internet access to participate. Patients were excluded if they were too cognitively impaired to complete study procedures per the treating clinician and/or endorsed active suicidal ideation on study screening measures. Patients who endorsed suicidal ideation were evaluated by a mental health clinician before being referred to the appropriate level of care. The analytic sample was restricted to patients who had complete data on all study measures.
Approval was obtained from the institutional review board (IRB) and informed consent was conducted over the telephone by trained study staff. Consented patients were sent an email that included a link to study measures. Surveys were administered using REDCap, a secure HIPAA-compliant data management system.
Measures
Demographic and disease characteristics.
Patients reported their age, gender (male/female), race (white/other), ethnicity (Latinx/non-Latinx), education (college degree or less/post-graduate), income (≤$199,999/≥$200,000), employment (yes/no), and partner status (partnered/other). Age was dichotomized as <65 and ≥65 years. Disease characteristics were extracted from the medical record and included cancer type (CLL/other) and whether the patient was receiving cancer-directed therapy or was under active surveillance. Performance status was also extracted from the medical record and assessed with the ECOG Performance Status scale, ranging from 0 (Fully Active) to 5 (Dead).
Clinical trial understanding.
Patients’ understanding of the goals of clinical trials was assessed with a four-item measure of potential goals of a clinical trial: curing the lymphoma, reducing the lymphoma, keeping the lymphoma from worsening, and advancing research. Response options for each potential goal were “yes,” “no,” and “I don’t know.”
Statistical Analyses
Descriptive statistics were used to report demographic characteristics of study participants overall and by age. Chi-square analyses were used to examine the relationship between age and baseline descriptive characteristics and the relationship between age and clinical trial understanding. The relationship between age and clinical trial understanding was additionally examined in a subset of patients who had not yet initiated cancer-directed therapy. Statistical tests were two-sided, with a significance level of 0.05. All analyses were performed in statistical software SPSS version 26 (Armonk, NY: IBM Corp).
Results
A total of 74 patients met inclusion/exclusion criteria and had complete data on all study measures (Table 1). The patient population was equally distributed in terms of gender (n=37, 50.0% male vs n=37, 50.0% female) and was predominantly White (n=72, 97.3% White vs n=2, 2.7% non-White) and non-Latinx (n=71, 95.9% non-Latinx vs n=3, 4.1% Latinx). The mean age was 60.4 years (SD=12.3), with 60.8% of patients being <65 years. The majority of patients had a post-graduate education (n=42, 56.8%) and were employed (n=52, 75.4%). Just over half of patients had chronic lymphocytic leukemia (n=38, 53.5%) and the majority had not yet initiated cancer-directed treatment (n=56, 75.7%). Distributions of baseline sample characteristics were not significantly different between patients <65 years and patients ≥65 years, with the exception of employment status. The majority of employed patients were <65 years (n=36, 69.2%) and the majority of unemployed patients were ≥65 years (n=11, 64.7%) (P=0.013).
Table 1.
Baseline sample characteristics by age (n=74)
| Total N (%) | <65 years | ≥65 years | P value | |
|---|---|---|---|---|
| Age, Mean (SD) | 60.41 (12.27) | - | - | - |
| <65 years | 45 (60.8) | - | - | - |
| ≥65 years | 29 (39.2) | |||
| Gender | .48 | |||
| Male | 37 (50.0) | 21 (56.8) | 16 (43.2) | |
| Female | 37 (50.0) | 24 (64.9) | 13 (35.1) | |
| Race | .25 | |||
| White | 72 (97.3) | 43 (59.7) | 29 (40.3) | |
| Non-white | 2 (2.7) | 2 (100.0) | 0 (0) | |
| Ethnicity | .16 | |||
| Latinx | 3 (4.1) | 3 (100.0) | 0 (0) | |
| Non-Latinx | 71 (95.9) | 42 (59.2) | 29 (40.8) | |
| Education | .22 | |||
| College degree or less | 32 (43.2) | 22 (68.8) | 10 (31.3) | |
| Post graduate | 42 (56.8) | 23 (54.8) | 19 (45.2) | |
| Annual household incomea | .15 | |||
| ≤$199,999 | 35 (62.5) | 20 (57.1) | 15 (42.9) | |
| ≥$200,000 | 21 (37.5) | 16 (76.2) | 5 (23.8) | |
| Employed | .013 | |||
| Yes | 52 (75.4) | 36 (69.2) | 16 (30.8) | |
| No | 17 (24.6) | 6 (35.3) | 11 (64.7) | |
| Partner status | .76 | |||
| Spouse/partner | 55 (74.3) | 34 (61.8) | 21 (38.2) | |
| Other | 19 (25.7) | 11 (57.9) | 8 (42.1) | |
| Cancer type | .48 | |||
| CLL | 38 (53.5) | 25 (65.8) | 13 (34.2) | |
| Other | 33 (46.5) | 19 (57.6) | 14 (42.4) | |
| Treatment status | .98 | |||
| Active surveillance | 56 (75.7) | 34 (60.7) | 22 (39.3) | |
| Cancer-directed therapy | 18 (24.3) | 11 (61.1) | 7 (38.9) | |
| ECOG Performance status; M (SD) | .51 (.63) | .44 (.55) | .63 (.74) | .23 |
Note: Sample sizes vary due to missing data.
Approximately one-quarter (24.3%) of the data on income was unavailable because participants actively chose not to answer the question (n=10) or refused to consider the question (n=8).
Regarding clinical trial understanding, 23.0% (n=17) of patients responded affirmatively to the prompt, “To cure the patients in the clinical trial,” compared to 41.9% (n=31) who responded negatively and 35.1% (n=26) who responded “I don’t know” (Table 2). In contrast, 56.8% (n=42) of the sample responded affirmatively to the prompt, “To reduce as much as possible the lymphoma of patients in the trial,” compared to 18.9% (n=14) who responded negatively and 24.3% (n=18) who responded “I don’t know.” Approximately half of the sample (56.8%, n=42) responded affirmatively to the prompt, “To keep the lymphoma of patients in the trial from getting worse,” with 18.9% (n=14) responding negatively and 24.3% (n=18) responding “I don’t know.” A majority of the sample (n=65, 87.8%) responded affirmatively to the prompt, “To advance research on treatments for indolent lymphoma,” compared to 1.4% (n=1) who responded negatively and 10.8% (n=8) who responded “I don’t know.”
Table 2.
Relationship between age and clinical trial understanding (n=74)
| Age; n (%) | ||||
|---|---|---|---|---|
| <65 | ≥65 | Chi-Square | P value | |
| To cure the patients in the clinical trial | 3.65 | .16 | ||
| Yes | 12 (26.7) | 5 (17.2) | ||
| No | 21 (46.7) | 10 (34.5) | ||
| I don’t know | 12 (26.7) | 14 (48.3) | ||
| To reduce as much as possible the lymphoma of patients in the trial | 7.56 | .023 | ||
| Yes | 29 (64.4) | 13 (44.8) | ||
| No | 10 (22.2) | 4 (13.8) | ||
| I don’t know | 6 (13.3) | 12 (41.4) | ||
| To keep the lymphoma of patients in the trial from getting worse | 8.16 | .017 | ||
| Yes | 28 (62.2) | 14 (48.3) | ||
| No | 11 (24.4) | 3 (10.3) | ||
| I don’t know | 6 (13.3) | 12 (41.4) | ||
| To advance research on treatments for indolent lymphoma | 1.05 | .59 | ||
| Yes | 40 (88.9) | 25 (86.2) | ||
| No | 1 (2.2) | 0 (0) | ||
| I don’t know | 4 (8.9) | 4 (13.8) | ||
Compared with patients <65 years, patients ≥65 years more frequently endorsed “I don’t know” to the prompts, “To reduce as much as possible the lymphoma of patients in the trial” (n=12, 41.4% vs n=6, 13.3%; P=0.023) and “To keep the lymphoma of patients in the trial from getting worse” (n=12, 41.4% vs n=6, 13.3%; P=0.017; Table 2). There were no differences by age for the remaining two prompts, with 26.7% (n=12) of patients <65 years responding with “I don’t know” to the prompt of curing patients in the clinical trial (compared to 48.3% [n=14] of patients ≥65 years; P=0.16) and 8.9% (n=4) of patients <65 years responding with “I don’t know” to the prompt of advancing research on treatments for indolent lymphoma (compared to 13.8% [n=4] of patients ≥65 years; P=0.59).
Patients’ experience with cancer-directed treatment may influence their understanding of clinical trials. To account for this, we restricted the sample to patients under active surveillance who had not yet received cancer-directed therapy (n=55). Among these patients, similar results emerged. Patients ≥65 years more frequently endorsed “I don’t know” to the prompts, “To reduce as much as possible the lymphoma of patients in the trial” (n=10, 45.5% vs n=4, 12.1%; P=0.020) and “To keep the lymphoma of patients in the trial from getting worse” (n=10, 45.5% vs n=4, 12.1%; P=0.020; Table 3). There were similarly no differences by age for the remaining two prompts.
Table 3.
Relationship between age and clinical trial understanding in patients who had not initiated cancer-directed therapy (n=55)
| Age; n (%) | ||||
|---|---|---|---|---|
| <65 | ≥65 | Chi-Square | P value | |
| To cure the patients in the clinical trial | 3.93 | .14 | ||
| Yes | 8 (24.2) | 4 (18.2) | ||
| No | 17 (51.5) | 7 (31.8) | ||
| I don’t know | 8 (24.2) | 11 (50.0) | ||
| To reduce as much as possible the lymphoma of patients in the trial | 7.85 | .02 | ||
| Yes | 21 (63.6) | 8 (36.4) | ||
| No | 8 (24.2) | 4 (18.2) | ||
| I don’t know | 4 (12.1) | 10 (45.5) | ||
| To keep the lymphoma of patients in the trial from getting worse | 7.86 | .02 | ||
| Yes | 20 (60.6) | 9 (40.9) | ||
| No | 9 (27.3) | 3 (13.6) | ||
| I don’t know | 4 (12.1) | 10 (45.5) | ||
| To advance research on treatments for indolent lymphoma | .69 | .71 | ||
| Yes | 28 (84.8) | 19 (86.4) | ||
| No | 1 (3.0) | 0 (0) | ||
| I don’t know | 4 (12.1) | 3 (13.6) | ||
Discussion
In this study of 74 patients with NHL, we found that a large proportion of patients were unsure of the goals of clinical trials, with one-quarter to one-third of the sample responding with “I don’t know” to various prompts assessing understanding of the goals of clinical trial. Furthermore, we found statistically significant differences in patients’ understanding of clinical trial goals by age. Specifically, older adults were more likely to indicate uncertainty regarding whether trials reduce and prevent worsening of lymphoma. However, no age differences emerged regarding whether the goals of clinical trials include cure and the advancement of research. These findings suggest that, across ages, patients with lymphoma may not understand the goals of clinical trials, with greater uncertainty among older adults as compared with younger adults.
The results of this study suggest that many patients may be uncertain regarding the goals of clinical trials, highlighting the importance of informed consent prior to trial enrollment. In a recent review of the informed consent process for clinical research, researchers found that only around half of studies found that patients had adequate understanding of the aim of the trial, the process of randomization, voluntarism, withdrawal, and the risks and benefits of treatment among study participants.17 These data, in combination with the present study, suggest that improvements to the informed consent process are needed to ensure that patients entering studies understand the goals and mechanics of clinical trials, the risks and benefits of trial participation, and the important concepts of voluntarism and withdrawal. For example, modifications to the informed consent process, such as decreasing the reading level of consent forms18 and engaging patient and clinician stakeholders in development of informed consent materials,19 may improve patients’ understanding of clinical trials. Furthermore, given the important role of providers in explaining clinical trials to patients, training providers in strategies for communicating clinical trial information clearly may improve patients’ understanding of clinical trials.
In the current study, the two statements that demonstrated differential responses between older and younger adults were 1) “To reduce as much as possible the lymphoma of patients in the trial” and 2) “To keep the lymphoma of patients in the trial from getting worse.” In contrast, there were no differences in responses for 1) “To cure the patients in the clinical trial” and 2) “To advance research on treatments for indolent lymphoma.” These findings suggest that while older patients may have a broad understanding of clinical trial goals, that understanding may lack nuance. Prior research has not directly examined the degree to which older and younger adults understand the goals of clinical trials. However, a study of 110 oncology clinical trial participants found that younger participants were more likely than older participants to directly assess risks and benefits of participation while older adults were more likely to defer to the researcher and value the treatment cost coverage provided by the trial.14 These findings suggest that older and younger adults may approach clinical trials differently, using different processes to decide whether to participate in a clinical trial and relying on different resources to guide their decision-making. Accounting for these differences during the consent process may result in a tailored approach that reduces age disparities in clinical trial understanding.
The majority of patients in our sample had not yet initiated cancer-directed treatment and data on whether patients were presented with clinical trial options by their providers were not available. First-line treatment for patients with indolent NHL is most commonly a standard chemotherapy regimen. Therefore, it is likely that patients under active surveillance had not yet discussed clinical trial options with their oncologists. We conducted subgroup analyses restricted to patients who had not initiated cancer directed therapy and found similar results as in the full sample. These findings suggest that age differences in clinical trial understanding may exist prior to conversations with the oncologist about clinical trials. Oncologists may be able to improve clinical trial understanding and reduce these age disparities with targeted conversations tailored to the needs of older adults.
Clinical trial understanding has previously been studied in women who underwent a definitive surgical operation for early-stage invasive breast cancer (n=545). Women who were more knowledgeable about randomized trials were more likely to respond affirmatively or with “not sure” regarding their willingness to take part in a randomized clinical trial than women who indicated they would not participate in a randomized trial.20 These findings suggest that individuals who are more knowledgeable about clinical trials may be more likely to consent to clinical trial participation than individuals with less knowledge. Longitudinal research is needed to understand the causal relationship between clinical trial understanding and trial enrollment and whether interventions that improve clinical trial understanding have the potential to impact trial enrollment. It is important to note that the seven-item knowledge scale used in this study of breast cancer patients assessed understand of the mechanics of clinical trials (e.g., “In a randomized trial the treatment you get is decided by chance” or “Clinical trials are not appropriate for serious diseases like cancer”), while the four-item survey used in our study assessed understanding of the goals of clinical trials. Future studies that assess patient understanding of the goals and methods of clinical trials are needed to evaluate the relationship between the nuances of clinical trial understanding and enrollment to inform targeted interventions to increase trial accrual.
Given the disparity between rates of cancer in older adults and their enrollment in clinical trials, efforts have been made to increase older adults’ clinical trial enrollment. For example, one randomized clinical trial attempted to increase enrollment of older adults by educating medical oncologists and the clinical research team on the importance of enrolling older cancer patients using geriatric oncology educational materials, educational symposia, and regular communications via mailings and e-mails.21 Despite this intervention, researchers found no significant differences in older patient accrual over two years. However, research suggests that targeting patients’ understanding of a clinical trial directly may increase clinical trial accrual. For example, in initial recruitment for a trial of men with early-stage prostate cancer, 0 of 27 eligible patients approached about the study enrolled. After introduction of group discussions between prospective patients and clinical research associates, prostate cancer survivors, other clinical trial participants, urologists, and radiation oncologists, 34 of 263 eligible patients consented for a one in six consent rate.22 The increase in accrual following the education sessions suggests that targeting patient understanding directly as part of the recruitment process may improve accrual. Our findings suggest that tailoring such interventions for older adults may be important to reducing age disparities in clinical trial enrollment.
Study findings should be interpreted in the context of limitations. This study was conducted at a single site in an urban setting with a largely white, non-Hispanic, and highly educated patient population, limiting the generalizability of our findings to other populations of patients with NHL. Additionally, the patient population was restricted to those diagnosed in the past 6 months, which limits our ability to examine the relationship between time from diagnosis and clinical trial understanding. Furthermore, the surveys were administered over the internet using patients’ personal computers, which may have excluded patients with no access to the internet or poor electronic literacy. However, this limitation may have resulted in a conservative estimate of clinical trial misunderstanding given that patients with poor computer literacy may be at greater risk for poor health literacy.23 In addition, the current study was not conducted in the context of a particular clinical trial and most patients had not initiated cancer-directed treatment. Patients who participated in an informed consent process for a specific trial may have a better understanding than reflected in these results. As such, there may be heterogeneity in the sample regarding exposure to information about clinical trials. Furthermore, this study did not examine differences in the quality of communication about clinical trials across providers, an important factor that is likely to impact patients’ understanding of clinical trials. Finally, our assessment of understanding of clinical trial goals consisted of only four statements and had not previously been validated. As a result, these statements may not be a valid and comprehensive assessment of understanding of clinical trial goals. Future studies are needed to replicate these findings in larger, more diverse population of patients with NHL using validated measures of understanding of clinical trial goals.
Conclusion
The results of this study suggest that many indolent NHL patients are uncertain about the goals of clinical trials and that older patients may have worse understanding than younger patients. Additional research on the relationship between clinical trial understanding and clinical trial enrollment is needed to evaluate whether a causal relationship exists and interventions targeting understanding could be expected to improve enrollment. However, this study suggests that greater examination of age differences in clinical trial understanding may highlight a modifiable factor with the potential to increase accrual of older adults to clinical trials.
Clinical Practice Points.
Cancer patients often have an inaccurate and/or incomplete understanding of the goals of a clinical trial. Older adults comprise a large proportion of the cancer patient population and may be more susceptible to poor understanding of the goals of a clinical trial.
In this study, we examined clinical trial understanding in younger (<65 years) and older adults (≥65 years) with non-Hodgkin’s lymphoma (NHL) using a four-item survey of potential goals of a clinical trial.
Older adults were more likely than younger adults to respond with “I don’t know” to the goals of reducing the lymphoma and keeping the lymphoma from worsening, but not to the goals of curing the patients in the clinical trial and advancing research on treatments for the lymphoma.
Our findings suggest that older adults may have a less nuanced understanding of the goals of a clinical trial compared to younger adults and may benefit from developmentally-tailored interventions to improve their understanding of clinical trial goals.
Acknowledgements:
The authors would like to acknowledge Simon Cohen and David Kwak for their work on recruitment for this study. This research was funded by the National Institute on Aging and American Federation for Aging Research (K23 AG048632, K.M.T.) and the Weill Cornell Medicine Lymphoma Program (J.P.L.).
Footnotes
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