Abstract
Background
To evaluate the ability of individuals with metastatic cancer to provide informed consent to research participation, we used a structured vignette-based interview to measure 4 consenting standards across 3 participant groups.
Methods
Participants included 61 individuals diagnosed with brain metastasis, 41 individuals diagnosed with non-CNS metastasis, and 17 cognitively intact healthy controls. All groups were evaluated using the Capacity to Consent to Research Instrument (CCRI), a performance-based measure of research consent capacity. The ability to provide informed consent to participate in research was evaluated across 4 consent standards: expressing choice, appreciation, reasoning, and understanding. Capacity performance ratings (intact, mild/moderate impairment, severe impairment) were identified based on control group performance.
Results
Results revealed that the brain metastasis group performed significantly lower than healthy controls on the consent standard of understanding, while both metastatic cancer groups performed below controls on the consent standard of reasoning. Both metastatic cancer groups performed similar to controls on the standards of appreciation and expressing choice. Approximately 60% of the brain metastasis group, 54% of the non-CNS metastasis group, and 18% of healthy controls showed impaired research consent capacity.
Conclusions
Our findings, using a performance-based assessment, are consistent with other research indicating that the research consent process may be overly cumbersome and confusing. This, in turn, may lead to research consent impairment not only in patient groups but also in some healthy adults with intact cognitive ability.
Keywords: cancer, consent capacity, informed consent, metastasis, research participation
The spread of cancer through the bloodstream or lymphatic system to distant organ sites significantly complicates treatment and reduces prognosis of survival.1,2 Known as metastatic cancer, this condition is associated with cognitive changes across all stages of treatment (ie, at diagnosis, during treatment, and in the years following treatment) and both in CNS and non-CNS disease sites.3–5 Although declines in executive function and memory appear to be the most prominent cognitive changes in metastatic cancer, attention, processing speed, and reasoning abilities may also be affected.6–8 In fact, one review9 found that up to 30% of patients with non-CNS cancer show cognitive impairment before chemotherapy treatment. This estimate increased to 75% during treatment with 35% experiencing cognitive issues in the years following treatment. Cognitive impairment is even more prevalent when cancer is detected in the brain. For example, up to 90% of individuals with brain metastasis show at least some level of cognitive impairment,5,10,11 with affected domains and the magnitude of impairment primarily determined by metastatic lesion volume and tumor location.5
Research consent capacity describes the mental ability of a person to make an informed and rational decision about participation in research.12–14 Derived from the legal standards for competence,15 performance-based research consent capacity is composed of 4 parallel standards: expressing choice, appreciating the situation and its consequences, reasoning provided in support of the choice, and understanding relevant information necessary for making a choice.16 Impairment in the ability to consent to research is associated with impairment in cognitive function and has been observed in samples of individuals with psychiatric illness and dementia.17,18 In the oncology setting, the impaired ability to consent to research has been documented in patients with malignant glioma, with approximately one-quarter to one-third of this group performing in the impaired range on 3 of the 4 capacity standards.16 Although general cognitive impairments were common in this sample, deficits in verbal episodic memory, attention, semantic knowledge, executive functions, and expressive language were most predictive of impaired ability to consent to research participation.
Given the increased risk of cognitive impairment in people with metastatic cancer, it is likely rates of research consent capacity impairment are also elevated in other cancer groups. However, research on the ability of individuals with cancer to consent to research participation is limited. To address this gap in the research literature, the present study evaluated research consent capacity in 3 groups: individuals with brain metastasis, individuals with non-CNS metastasis, and cognitively intact healthy controls. We hypothesized that both cancer groups would perform significantly lower than healthy controls on the research consent standards of appreciation, reasoning, and understanding. We further hypothesized that the brain metastasis group would perform worse than the non-CNS metastasis group on these standards.
Methods
Participants
All study procedures were approved by the institutional review board at the University of Alabama at Birmingham (UAB). Written informed consent was obtained by all participants prior to enrollment in the study. The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) was used as a minimal consenting standard for participant inclusion. Only one participant failed to pass the UBACC and this participant selected to withdraw from further consideration.
In total, 61 individuals with brain metastasis and 41 individuals with non-CNS metastasis were recruited from UAB’s Department of Radiation Oncology and Division of Hematology Oncology between August 2011 and December 2018 as this study was sponsored by 2 grant-funded projects over 7 years. All cancer diagnoses were made by board-certified radiation oncologists. Eligible participants were age 18 years or older and English speaking. We excluded patients with prior history of brain tumor or cranial radiation (ie, recurrent disease), leptomeningeal disease, prior/existing neurological or psychiatric illness, substance abuse history, or other serious medical illness that could adversely affect cognition.
Demographically similar healthy adult volunteers were recruited from the community to serve as controls. Controls were screened over the telephone to exclude potential participants with a history of cancer or other medical or psychiatric conditions that could impair cognition. Controls were age 18 years or older, English speaking, and neurologically intact (based on neuropsychological testing results). Twenty participants were recruited and evaluated; 3 participants were excluded because of cognitive deficits on neuropsychological testing, resulting in a control group of 17 neurologically intact healthy controls.
Data Collection
Study staff identified potentially eligible patients through physician referrals and/or discussions of cases at weekly radiation oncology treatment rounds. Patient data were collected after all postoperative visits (as applicable) and either before or within 1 week of starting whole- or focal brain radiation treatment. The following treatments for brain metastasis were used: conventional surgery, single-fraction radiosurgery with Gamma Knife or linear accelerator (LINAC) technology (15-24 Gy) for tumors 4 cm or smaller, hypofractionated focal radiation with LINAC for tumors larger than 3 to 4 cm (5-6 Gy × 5 fractions for 25-30 Gy total), and whole-brain radiation therapy (with LINAC) (30 Gy in 10 fractions to 37.5 Gy in 15 fractions). Off-study guidelines for radiosurgical treatment at UAB followed maximum tolerated doses outlined in Radiation Therapy Oncology Group (RTOG) 9005.19
Full-time psychometrists trained in the administration of standardized neuropsychological tests and with routine patient contact in the department of neurology evaluated participants on all standardized measures. Testing required approximately 2 hours to complete. Medical and treatment data for patients with metastatic cancer were extracted from medical records. Medical and treatment data for controls were collected through self-report.
Measures
Capacity to Consent to Research Instrument
The Capacity to Consent to Research Instrument (CCRI)16 is a structured, hypothetical, vignette-based interview designed to evaluate a person’s ability to consent to research participation. Capacity-to-consent standards on the CCRI were derived from 4 well-established legal standards as described by Appelbaum and Grisso.15These standards include the following: expressing a choice to participate or not participate (expressing choice); appreciating the personal consequences associated with that choice (appreciation); providing rational reasons in support of the choice (reasoning); and demonstrating understanding/comprehension of the information presented in the simulated consenting procedure (understanding). On the CCRI, the participant assumes the role of a potential research candidate and is asked to consider his or her involvement in a hypothetical drug trial for the treatment of memory loss. The CCRI includes a written consent document modeled on routine informed consenting procedures used in human participant research protocols. Specifically, the informed consent document includes (a) the purpose and plan of study, (b) description of study procedures, (c) study evaluations, (d) early treatment discontinuation, (e) risks, (f) benefits, (g) alternative medications and treatments, (h) new research findings, (i) confidentiality, (j) payment for participation, (k) payment for research related injuries, (l) voluntary participation, and (m) other information. The consent document is provided in writing and reviewed orally with the participant. After the simulated consenting process, the participant responds verbally to a series of 36 questions designed to evaluate understanding and comprehension of the informed consent material. The participant is allowed to refer to the written consent form when responding to questions. Participant responses are recorded in writing and scored by the examiner according to predefined criteria (item responses are scored as 0, 1, or 2 points). Points are totaled for each of the four consenting standards.
University of California, San Diego Brief Assessment of Capacity to Consent
The UBACC20 is a 10-item structured interview designed to evaluate a potential participant’s understanding and appreciation of the most important aspects of the consenting process. Responses are graded on a 0-, 1-, or 2-point Likert-type scale assessing comprehension of each item. Ambiguous responses are queried for clarification. Six of the items require a full, 2-point response to qualify for participation. Suboptimal responses on these items result in review of relevant information and follow-up questioning. A participant who fails to provide a 2-point response after 3 attempts is deemed incapable of consenting. The UBACC was used to exclude potential participants who could not meet a minimal standard of consent.
KPS
The KPS21 is a measure of functional ability for patients diagnosed with cancer.
Neurocognitive testing
Each participant’s neurocognitive status was assessed using a neuropsychological test battery assessing attention, working memory, processing speed, executive functioning, language fluency, and memory. Tests included Wechsler Adult Intelligence Test—Third Edition (selected subtests), Trail Making Test Parts A and B, Controlled Oral Word Association Test, and Hopkins Verbal Learning Test—Revised. Control participants were classified as cognitively impaired if performance on more than one subtest fell in the borderline or impaired range based on conventional neuropsychological practice standards (ie, 1.5 SD below the population mean).22 Because neurologically healthy adults may occasionally perform in the impaired range on standardized neuropsychological testing,23 we required at least 2 subtest scores to fall in the impaired range for a control group participant to be classified as impaired. Neurocognitive testing was used to establish a control group of cognitively intact participants.
Statistical Analysis
Earlier capacity studies support the assignment of psychometric cut scores derived from control group performance to determine functional impairment.24–26 In our study, each participant was assigned an impairment rating based on standard scores (z scores) derived from the control group mean and SD. For the consent standards of appreciation, reasoning, and understanding, an intact outcome was defined as a z score greater than –1.5. The following z scores were used to classify level of impairment: mild/moderate impairment –1.5 or less but greater than –2.5 and severe impairment –2.5 or less. For expressing choice, an intact rating was defined as a score of 2, a mild/moderate impairment rating as a score of 1, and a severe impairment rating as a score of 0. For each standard’s total score, the percentage of individuals falling into the intact, mild/moderate impairment, and severe impairment ranges was calculated.
Demographic variables were analyzed using ANOVA for age and Pearson chi-square tests for race, sex, and education (< 12 years, ≥ 12 years). Differences on CCRI consent standards were also investigated using ANOVA. Significant group differences were further evaluated with a post hoc analysis using Tukey-Kramer tests. Owing to multiple comparisons, an adjusted alpha using the Bonferroni correction (α = 0.017) was used for all analyses.
Results
Demographics and Clinical Characteristics
Demographic characteristics are reported in Table 1. Study groups did not significantly differ according to age, sex, race, or education (P > .017 with Bonferroni correction). Clinical characteristics and treatment information are presented in Table 2. On average, individuals with brain metastasis and those with non-CNS metastasis reported similar levels of functional ability on the KPS. For participants with brain metastasis, 31% were currently receiving chemotherapy treatments; for participants with non-CNS metastasis, 44% were currently receiving chemotherapy treatments. Groups did not differ according to chemotherapy and radiotherapy status.
Table 1.
Demographic Characteristics
| Variable | Range | Controls (n = 17) | Patients With Brain Metastasis (n = 61) | Patients With Non-CNS Metastasis (n = 41) | P |
|---|---|---|---|---|---|
| Age, mean (SD), y | 24-81 | 51 (13.1) | 59 (10.3) | 60 (12.2) | .031 |
| Sex, n (%) | .617 | ||||
| Female | 6 (35.3) | 29 (47.5) | 20 (48.8) | ||
| Male | 11 (64.7) | 32 (52.4) | 21 (51.2) | ||
| Race, n (%) | .166 | ||||
| African American | 0 (0.0) | 13 (21.3) | 11 (26.8) | ||
| White | 17 (100.0) | 47 (77.0) | 30 (73.2) | ||
| Other | 0 (0.0) | 1 (1.6) | 0 (0.0) | ||
| Education, n (%), y | .288 | ||||
| < 12 | 0 (0.0) | 8 (13.3) | 5 (12.2) | ||
| ≥ 12 | 17 (100.0) | 52 (86.6)a | 36 (87.8) |
Age evaluated with ANOVA; mean (SD). Sex, race, and education evaluated with Pearson chi-square test; n (%). Statistical significance was established at P = .017 following Bonferroni correction.
Table 2.
Functional Status, Clinical Characteristics, and Treatment Information for Participants With Brain Metastasis and Participants With Non-CNS Metastasis
| Variable | Patients With Brain Metastasis (n = 61) | Patients With Non-CNS Metastasis (n = 41) |
|---|---|---|
| KPS, mean | 80 | 80 |
| 100 | 9 (14.8) | 12 (29.3) |
| 90 | 11 (18.0) | 3 (7.3) |
| 80 | 27 (44.3) | 14 (34.1) |
| 70 | 10 (16.4) | 10 (24.4) |
| ≤ 60 | 4 (6.5) | 2 (4.8) |
| Primary cancer location | ||
| Lung | 32 (52.5) | 8 (19.5) |
| Breast | 10 (16.4) | 6 (14.6) |
| Melanoma | 5 (8.2) | 4 (9.8) |
| Gynecological | 5 (8.2) | 3 (7.3) |
| Gastrointestinal | 3 (4.9) | 10 (24.4) |
| Renal | 2 (3.3) | 2 (4.9) |
| Prostate | 1 (1.6) | 5 (12.2) |
| Testicular | 1 (1.6) | 0 (0.0) |
| Other | 2 (3.3) | 3 (7.3) |
| No. of brain metastases, median | 2 | 0 |
| 1 | 26 (42.6) | NA |
| 2-3 | 19 (31.1) | NA |
| > 3 | 16 (26.2) | NA |
| Tumor location/hemisphere | ||
| Right | 14 (25.9) | NA |
| Left | 21 (38.9) | NA |
| Both | 19 (35.2) | NA |
| Cancer treatments | ||
| Surgery | 9 (14.8) | 2 (4.9) |
| Type of radiation | ||
| Focal | 51 (83.6) | NA |
| Whole brain | 8 (13.1) | NA |
| None | 2 (3.3) | NA |
| Past chemotherapy use | 23 (37.7) | 32 (78.0) |
| Current chemotherapy use | 8 (31.1) | 18 (43.9) |
| AED use | 10 (16.4) | NA |
| Corticosteroid use | 37 (60.7) | 8 (19.5) |
| Hormone therapy | 5 (8.2) | 7 (17.1) |
Abbreviations: AED, antiepileptic drug; NA, not available.
Age evaluated with ANOVA; sex, race, and education evaluated with Pearson chi-square test. Unless otherwise indicated, values are n (%).
Capacity to Consent to Research Instrument Performance
Table 3 lists CCRI performances by group. Significant group differences were observed on the CCRI standards of reasoning and understanding but not appreciation or expressing choice. Post hoc analyses revealed that the brain metastasis and non-CNS metastasis groups scored significantly lower than controls on reasoning. In contrast, only the brain metastasis group performed lower than controls on understanding, whereas the non-CNS metastasis group performed similarly to controls on this standard.
Table 3.
Group Comparisons on Capacity to Consent to Research Instrument Consent Standards
| Variable | Range | Healthy Controls (n = 17) | Patients With Brain Metastasis (n = 61) | Patients With Non-CNS Metastasis (n = 41) | F | df | P |
|---|---|---|---|---|---|---|---|
| Expressing choice | 1-2 | 2.0 (0.00) | 1.98 (0.13) | 1.93 (0.26) | 1.56 | 2 | .214 |
| Appreciation | 0-4 | 3.41 (0.87) | 2.74 (1.22) | 2.56 (1.26) | 3.09 | 2 | .049 |
| Reasoning | 0-12 | 5.41 (2.62) | 2.86 (2.09)a | 3.21 (2.06)a | 9.31 | 2 | < .001 |
| Understanding | 13-87 | 66.47 (13.02) | 54.00 (15.57)a | 56.97 (14.8) | 4.60 | 2 | .012 |
Unless otherwise indicated, values are mean (SD).
aSignificantly different from controls at P = .017 following Bonferroni correction.
Pearson product-moment correlations evaluated the effects of neurocognitive testing on CCRI outcomes (data not reported) to help characterize the cognitive deficits associated with poorer performance on the CCRI. Lower cognitive flexibility was associated with impairments on the CCRI consent standards of appreciation, reasoning, and understanding, whereas aspects of verbal learning and memory were associated with impairments on consent standards of appreciation and reasoning.
CCRI impairment outcomes are listed in Tables 4 and 5. In total, 60.7% of the brain metastasis group was impaired on at least one CCRI consent standard (42.6% on appreciation, 26.2% on reasoning, 31.1% on understanding, and 1.6% on expressing choice). For the non-CNS metastasis group, 53.7% were impaired on at least one consent standard (43.9% on appreciation, 17.1% on reasoning, 24.4% on understanding, and 7.3% on expressing choice). Of healthy controls, 17.6% demonstrated impairment on at least one consent standard (11.8% on appreciation, 5.9% on reasoning, 5.9% on understanding, and 0.0% on expressing choice).
Table 4.
Capacity Outcomes on Capacity to Consent to Research Instrument Consent Standards
| Standards | Intact | Mild/Moderate Impairment | Severe Impairment |
|---|---|---|---|
| Expressing choice | |||
| Controls | 17 (100.0) | 0 (0.0) | 0 (0.0) |
| Brain metastasis | 60 (98.4) | 1 (1.6) | 0 (0.0) |
| Non-CNS metastasis | 38 (92.7) | 3 (7.3) | 0 (0.0) |
| Appreciation | |||
| Controls | 15 (88.2) | 1 (5.9) | 1 (5.9) |
| Brain metastasis | 35 (57.4) | 16 (26.2) | 10 (16.4) |
| Non-CNS metastasis | 23 (56.0) | 11 (26.8) | 7 (17.1) |
| Reasoning | |||
| Controls | 16 (94.1) | 1 (5.9) | 0 (0.0) |
| Brain metastasis | 45 (73.8) | 16 (26.2) | 0 (0.0) |
| Non-CNS metastasis | 34 (82.9) | 7 (17.1) | 0 (0) |
| Understanding | |||
| Controls | 16 (94.1) | 1 (5.9) | 0 (0.0) |
| Brain metastasis | 42 (68.9) | 13 (21.3) | 6 (9.8) |
| Non-CNS metastasis | 31 (75.6) | 6 (14.6) | 4 (9.8) |
Values are n (%).
Table 5.
Overall Capacity Outcomes—Impairment on any Standard
| Standards | Intact | Impaired |
|---|---|---|
| Overall capacity | ||
| Controls | 14 (82.4) | 3 (17.6) |
| Brain metastasis | 24 (39.3) | 37 (60.7) |
| Non-CNS Metastasis | 19 (46.3) | 22 (53.7) |
Values are n (%).
Discussion
In this study, we evaluated research consent capacity across 3 groups: (a) individuals with brain metastasis, (b) individuals with non-CNS metastasis, and (c) healthy controls. Intact consent capacity requires that an individual be able to adequately appreciate, reason, understand, and express a choice to voluntarily participate in experimental research. When compared to neurologically intact healthy controls, people with brain metastasis demonstrated impairment on the CCRI standards of reasoning and understanding, whereas the non-CNS metastasis group showed impairment on the CCRI standard of reasoning. When considering impairment on any CCRI standard, more than half of both cancer groups demonstrated at least some level of impaired ability to provide informed consent to participate in research. These findings have important implications for researchers and clinicians working with patients with cancer.
In total, 60% of our sample of individuals with brain metastasis and more than 50% of our sample of participants with non-CNS metastasis showed impairment on at least one CCRI consent standard. Impaired consent standards were predominantly associated with deficits in cognitive flexibility, new verbal learning, and delayed recall of newly learned information. Given that informed consent includes the review of multiple consenting considerations with highly detailed specifications and the application of these details to personal decision making, it is not surprising that impaired aspects of executive and memory functioning would result in inadequate consenting performance. The impairment rates from our study are comparable to previous estimates in cancer and other patient groups. In a survey-based study, 74% of individuals with cancer failed to recognize the experimental treatment as nonstandard, 63% failed to appreciate the potential for increased risk, and only 25% understood that the benefits of participation would primarily affect future patients.27 In a meta-analysis composed of data from samples of patients undergoing surgery and participating in clinical trials, 54% adequately understood the primary aims of a study, 47% understood the voluntary nature of participation, and 50% understood the risks associated with participation.28 These estimates are interesting given that 90% of participants in the Joffe et al study27 and 80% of clinical trial participants from the Falagas and colleagues study28 reported being satisfied with the level of information provided in the informed consent process, thus illustrating a discrepancy between the performance and perception of research participants.
Participants with brain metastasis demonstrated significantly poorer understanding than controls. Although the mean understanding score for the non-CNS metastasis group fell below that of the control group, this difference did not reach statistical significance. However, participants from both metastatic cancer groups demonstrated lower reasoning scores compared to healthy controls. Although controls were more likely to provide multiple reasons based directly on details presented in the informed consent process, both cancer groups provided limited and/or indirect reasons in support of their choice. Similar to individuals with malignant glioma,16 differences were not observed for either cancer group on the CCRI standard of appreciation despite high rates of impairment on this standard. This finding may be due to a number of related factors. First, the range of scores (ie, 0-4) for this standard is small, thereby limiting variability of performances. Second, one participant in the control condition scored particularly low on this standard, but not so low as to represent a statistical outlier. Taken together, group differences on appreciation in the present samples were not statistically significant. As expected, no group differences were found on the consent standard of expressing choice.
In most university-based research studies, the only consent standard explicitly evaluated in the consenting process is expressing choice to participate or not participate (ie, by verbally agreeing to participate and signing the informed consent document). However, our results indicate that reasoning and/or understanding is more likely to be impaired than expressing choice. This discrepancy shows that many participants may be included in research studies yet do not possess an adequate ability to understand and thoroughly evaluate important personal and clinical implications of their choice. Under these conditions, and despite the best intentions of researchers and participants alike, the full ethical standard of informed consent remains unmet for many participants engaging in clinical research.14,29
We also found that nearly 1 in 5 (18%) healthy controls demonstrated impairment on at least one CCRI standard despite being neurologically intact. This finding likely indicates that the informed consent procedures routinely used in clinical research are so cumbersome that even some cognitively intact community-dwelling adults are unable to fully appreciate, reason through, and understand important aspects of the research in which they agree to participate. Although surprising, this finding is consistent with prior studies that reported that some healthy volunteers fail to understand basic information about study participation, such as study aims, side effects, and prior use of the experimental procedure.30
Previous research has indicated that extended discussion related to informed consent and specific modifications to the language and length of informed consent documents significantly improve participant understanding of research involvement.31,32 In a review of 54 interventions aimed at improving participant understanding of research participation, enhanced consent documentation and extended discussion between researchers and prospective participants significantly improved the ability to provide informed consent to participate in research.31 Specifically, informed consent documentation with simplified language (eg, seventh-grade reading level)33 and revised layout and text styling had the greatest effect on increasing the comprehension of information included in informed consent documents.34 Although showing a small effect, extended discussion between researchers and potential participants also improved comprehension of information pertaining to research participation.31
The present study has some limitations. First, the sample size was limited. Thus, our results may not generalize to other samples of individuals with cancer and healthy controls. Second, our healthy control group was on average 8 to 9 years younger than both metastatic cancer groups, although these age differences were not statistically significant in this evaluation. Third, although our findings are consistent with previous studies,27,30 hypothetical performance-based consenting procedures may not fully reflect the real-world consenting process. Third, it is important to note that our psychometrically referenced impairment ratings are not synonymous with clinical capacity or legal competency outcomes. Instead, our rating standards are offered as a guide for evaluating performance impairments in consent capacity using parametric statistical approaches.
In conclusion, the present research represents an extension of performance-based empirical investigation into research consent capacity in cancer. Compared to healthy controls, both metastatic cancer groups demonstrated impairments in the cognitively demanding research consent capacity standard of reasoning. In addition, our brain metastasis group demonstrated impairment in the ability to understand/comprehend information about participation in research. A majority of our sample of participants with metastatic cancer (ie, 60% of the brain metastasis group and more than 50% of the non-CNS metastasis group) and a notable minority (ie, 18%) of neurologically intact healthy controls demonstrated impairment on at least some aspect of the ability to consent to research participation. Despite these impairments, a vast majority of all participants (97%) demonstrated intact performance on the only consent standard routinely assessed in university-based clinical research (ie, expressing choice). In combination with previous research,27,30 the current findings suggest that commonly used research consent procedures are not only confusing but may inadequately evaluate the ability of potential research participants to provide informed consent. Incorporating empirically supported modifications to informed consent documentation and procedures are recommended to mitigate risk to research participants, including individuals with metastatic cancer.
Funding
This work was supported by the American Cancer Society [Mentored Research Scholar Grant MRSG-14-204-01-PCSM to K.T.], the National Institutes of Health National Center for Advancing Translational Sciences [KL2 TR000166 to K.T.], UAB’s Cancer Research Experiences for Students (CaRES) Program [5R25CA076023] funded by the National Cancer Institute.
Conflict of interest statement. None declared.
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