Examination of accrual to National Cancer Institute (NCI)-sponsored cancer treatment trials from 1988 to 1992 revealed a clear age dependent relationship to accrual. More than 70% of children with cancer, 4.0% of adult patients age 20–49 years with cancer, and only 1.5% of adult patients age ≥ 50 years with cancer were entered on clinical trials.1 These findings were supported further by Trimble and colleagues'2 study of cancer patients age ≥ 65 years who were entered on NCI-sponsored clinical trials compared with the Surveillance, Epidemiology, and End Results (SEER) Program incidence rates for seven disease sites in the United States. With the exclusion of prostate carcinoma, which is overwhelmingly a disease of men age > 65 years, the difference between the proportion of cancer patients with these diagnoses entered on NCI trials and SEER incidence data for those patients with these diagnoses age > 65 years is striking. For men age ≥ 65 years with these diagnoses, the average proportion of patients entered on NCI trials among patients with lung carcinoma, colorectal carcinoma, pancreatic carcinoma, and leukemia is 37.5%, compared with the average SEER incidence rate for these diseases of 63.8%, an under-representation of older male patients in NCI trials of 26.3% (P < 0.001).2 A similar picture emerged for women age ≥ 65 years, with an average proportion of patients entered on NCI trials for lung carcinoma, breast carcinoma, colorectal carcinoma, ovarian carcinoma, and pancreatic carcinoma of 25.9%, compared with the SEER incidence rate for these disease sites of 56.5%, an under-representation of older female patients on trials of 30.6% (P < 0.001).2 For men, the greatest disparity between accrual of older patients to trials compared with disease incidence in the United States was among patients with leukemia (NCI trials, 9.6%; SEER trials, 55.6%); for women, the greatest disparities were among both patients with breast carcinoma (NCI trials, 17.3%; SEER trials, 47.7%) and patients with colorectal carcinoma (NCI trials, 46.2%; SEER, 74.7%).
Similarly, in a study of 16,396 patients with cancer on Southwest Oncology Group (SWOG) trials from 1993 to 1996 involving 15 disease sites, older patients with cancer accounted for 25% of patients on SWOG trials compared with 63% of patients with cancer in the U.S. population, an under-representation of 38% (P < 0.001).3 The greatest disparity occurred for women with breast carcinoma (SWOG, 9%; SEER/U.S. population, 49%).
It was findings like these that prompted our pilot study to determine the barriers to accrual for older patients with breast carcinoma who were eligible to enter treatment trials, controlling for major confounding variables of treating physician, disease stage, comorbidity, and physical functioning.4 Because the three studies discussed above1–3 only posed possible reasons for the disparities in accrual by patients' age, it was important to obtain empiric evidence from both physicians and patients concerning their perceptions of barriers to the participation of older patients in clinical trials, even when it has been determined that patients are eligible to participate. This article presents the findings from a survey of 156 physicians, most of whom were oncologists who treated patients with newly diagnosed carcinoma during the year prior to protocol activation (CALGB 9670), with regard to their perception of the difficulties in entering older patients with cancer on clinical trials.
MATERIALS AND METHODS
The physicians who were surveyed in this study all practiced at 10 institutions in the CALGB that had taken part in the parent pilot study of the barriers to the participation of older patients with breast carcinoma in clinical trials (CALGB 9670).4 For the purposes of this study, the 10 institutions were selected based on the largest accrual of patients with breast carcinoma to treatment trials in the CALGB across all ages. The primary objective of the parent pilot study was to test whether older patients with breast carcinoma who were eligible for an open treatment trial at their institution were placed on trials less frequently than their younger counterparts. The parent trial, CALGB 9670, had a case-control design in which an older patient (age ≥ 65 years) was paired with a younger patient with the same disease stage and the same treating physician. Fifty-one percent of younger patients were offered a trial compared with 35% of their matched cohort of older patients (P = 0.06). However, when race, comorbidity, and functional status were controlled for in a regression analysis, age interacting with disease stage became the most important predictor of whether a patient would be offered a trial by a physician (P = 0.03).4 Specifically, 68% of younger patients with Stage II disease were offered a trial compared with 34% of the remaining patients (P = 0.0004). Thus, older patients who had Stage II disease were at a clear disadvantage with regard to whether they were offered a trial compared with younger patients who had Stage II disease and both older and younger patients who had Stage I disease.
The views of older patients with breast carcinoma, their own treating physicians, and other oncologists at their institution who had treated at least one newly diagnosed woman with breast carcinoma in the year prior to protocol activation were assessed to examine different groups' perceptions of what the significant barriers were in accruing older patients to trials. The results presented here represent the views of oncologists other than the treating physicians. The sample was comprised of 156 physicians who were asked to complete a brief questionnaire about their perceptions of the difficulties in placing older patients with carcinoma on clinical trials. Clinical research associates at each of the participating institutions sent copies of the survey by interoffice or regular mail to physicians who were involved in the treatment of patients with breast carcinoma.
Because all participants in this aspect of the study were physicians, assent, rather than written informed consent, was obtained. The return of the completed questionnaires served as proof of their agreement to participate in the survey. Completed questionnaires were then mailed or sent by facsimile back to the clinical research associates.
Measures: Physicians' Assessment of Barriers to accrual
A brief questionnaire was constructed (by M.K. and A.B.K.) for the purposes of this study to assess physicians' views about why it was difficult to enter older patients with breast carcinoma on clinical trials (see Table 2). Because barriers to accrual of older patients were considered to be multidimensional, items included protocol requirements (e.g., older patients often do not meet the eligibility criteria), treatment specific issues (e.g., treatments are too toxic), social support (assistance at home not available for treatment administration or management of side effects), logistic issues (transportation not available; unable to pay for costs not covered by insurance), physician attitudes about the protocol (e.g., an arm of the protocol is viewed as less effective or unacceptable; best treatment for the patient is not included in the protocol), and medical and cognitive characteristics of older patients (comorbid conditions not excluded by the trial's eligibility criteria that still may affect patients' responses to the trial; difficulty of older patients understanding the trial). Although ageism (which is defined by Butler as a process of systematic stereotyping and discrimination against people due to their age5) may have influenced physicians' responses to many of these items, the only item that most clearly reflected ageism was the idea that the life expectancy of some patients may too short to justify their participation in clinical trials. Physicians could write in additional reasons why they thought it was difficult to accrue older patients to clinical trials.
Physicians were then asked to rank the three most important reasons why it was difficult to accrue older patients with cancer to clinical trials. Finally, physicians were asked to check off which of seven possible interventions they thought may be effective in improving accrual and to rank the three interventions that may be most effective. Examples of items include special educational lectures or materials for physicians concerning older patients with malignant disease, educational materials for patients and/or family members concerning clinical trials, providing the older patient with transportation to and from the clinic, and providing the physician with more personnel in the clinic to help explain the trials to patients (for a complete list of the items, see Table 3). Physicians also were able to write in additional approaches that they thought may be useful in improving accrual.
Separate from the Physician Survey of Barriers to Accrual, a different questionnaire was completed by the patients' own treating physician in the parent trial (CALGB 9670),4 in which the oncologist reported whether the patient had been offered participation in a trial and, if not, why not. The results of this questionnaire are described in the parent trial4 and are referred to briefly below (see Discussion).
Basic characteristics of the physician were measured, including the physician's age, gender, ethnicity, medical specialty (e.g., medical, surgical, radiation oncology, etc.), the setting of their medical practice, and the proportion of their case load that involved patients age > 65 years.
One hundred fifty-six questionnaires were returned. The actual percentage of questionnaires returned from those distributed is unknown, because most institutions had not kept track of the number of questionnaires sent to physicians. The return rate of three institutions ranged from 33% to 100%, indicating a high degree of variability. One-third of the questionnaires were obtained from North Shore University Hospital (n = 50 questionnaires; 32%), with the other institutions contributing completed questionnaires as follows: Duke University Medical Center, n = 25 questionnaires (16%); Washington University Medical Center, n = 22 questionnaires (14%); University of Chicago Medical Center, n = 14 questionnaires (9%); State University of New York Upstate Medical University at Syracuse, n = 14 questionnaires (9%); and others, n = 31 questionnaires (20%).
Physicians participating in this survey were predominantly oncologists (85%) in academic medical centers (71%), and had a patient caseload in which one-third to two-thirds of their patients were age > 65 years (see Table 1). The majority were men (69%), white (87%), and had a median age of 43 years (range, 29–74 years).
Table 1. Characteristics of Physicians (n = 156)
|Gender|| || |
|Age (yrs)|| || |
| < 40||31||46|
|Ethnicity|| || |
| Southeast Asian (Indian)||3||4|
|Medical specialty|| || |
| Medical oncology||48||75|
| Surgical oncology||21||32|
| Radiation oncology||16||25|
| General surgery||12||18|
|Practice setting|| || |
| Academic medical center||71||106|
| Private practice||25||37|
| Community-based hospital||5||7|
|Proportion of patients age > 65 yrs|| || |
| < 1/3||30||46|
Physicians' Assessment of Barriers to the Accrual of Older Patients with Breast Carcinoma to Clinical Trials
There were four reasons endorsed by ≥ 50% of physicians as to why it was difficult to accrue older patients with breast carcinoma to clinical trials: transportation needs (68%); comorbid conditions that were not excluded by the eligibility criteria but that physicians believed would affect how older patients felt or responded to treatment (53%); toxicity of the treatment regimens (51%); and patient difficulty in understanding the trial (50%) (see Table 2). Physicians wrote in other additional barriers to accrual that they felt were not captured in the reasons listed in the questionnaire. Because physicians had written in these barriers, their frequency of endorsement did not reflect the actual proportion of physicians who may have viewed these issues as barriers to accrual, because they had not been included on the list of items in the questionnaire. In fact, in the case-control study in which the patient's treating physicians filled out the parallel questionnaire to the survey regarding why their own patients had not been placed on a trial, even though they had been eligible, 8 of 45 physicians (18%) and 6 of 47 physicians (13%), respectively, reported that they were not aware that an appropriate trial existed for their younger and older patients.4 This was in contrast to the surveys completed by 156 physicians in which only 1 physician had written this in as a reason why the accrual of older patients to clinical trials was difficult.
Table 2. Physicians' Assessment of Barriers to Accrual of Older Patients with Breast Carcinoma to Clinical Trials (Ranked in order of frequency of endorsement)
|1. Transportation often required for clinic visits is difficult, costly, or often not available to the elderly patient||68.0||106||6.0||9||17.0||25|
|2. Elderly often have significant other comorbid conditions, not excluded by protocols but would affect how they would respond or feel||53.0||78||16.0||25||14.0||21|
|3. Elderly patients have difficulty understanding what is required in a complicated clinical trial, resulting in poor compliance||50.0||80||16.0||24||11.0||16|
|4. Treatment regimens are too toxic for elderly||51.0||78||14.0||22||17.0||26|
|5. Assistance required at home for treatment administration or management of side effects often is not available||40.0||63||5.0||7||7.0||11|
|6. Elderly often do not meet eligibility criteria||36.0||56||15.0||23||8.0||12|
|7. Some costs for medical care in clinical trials often are not covered by health insurance||34.0||53||3.0||4||5.0||7|
|8. Physicians feel that an arm of protocol is less effective or is unacceptable||25.0||39||5.0||7||7.0||10|
|9. Best treatments for an elderly patient often are not included in clinical trial||21.0||33||5.0||7||4.0||6|
|10. Life expectancy of some patients is too short to justify participation in clinical trials||17.0||27||0.6||1||3.0||5|
|11. In many trials, likelihood of success is often low||6.0||9||1.0||2||0.7||1|
|12. Other|| || || || || || |
| Patient refusal; not interested in aggressive treatment||5.0||8||—||—||—||—|
| Patient unwilling to be randomized||2.0||3||—||—||—||—|
| Influence of family members||1.0||2||—||—||—||—|
| Patient feels one arm of trial is superior||1.0||2||—||—||—||—|
| Patient lives too far away, making it difficult to manage care||0.6||1||—||—||—||—|
| Trial was not offered to patient||0.6||1||—||—||—||—|
| MD not aware of an available trial||0.6||1||—||—||—||—|
| Additional testing required could be toxic||0.6||1||—||—||—||—|
Three out of four of the most frequently endorsed barriers to accrual were also those that most frequently were ranked as the most important barrier to accrual. Transportation needs was the one exception, in that it was endorsed the most frequently, although it was not considered the most important barrier as frequently. Although elderly often do not meet the eligibility criteria was endorsed less frequently than other barriers, it was one of the top three barriers to accrual rated as most important. However, those that were ranked as the second most important barriers to accrual were transportation needs (17%) and toxic treatment regimens (17%).
When they were asked about various possible methods for improving the accrual of older patients to clinical trials, virtually all methods provided in the questionnaire were endorsed by 45–69% of physicians: having more clinic personnel available to explain trials to older patients (69%), providing patients (63%) and family members (59%) with educational materials about clinical trials, providing physicians with educational lectures and materials about the toxicity of treatments in older patients (45%), and having more protocols available with fewer exclusion criteria related to comorbid conditions (49%). However, only a minority of physicians (19%) felt that educational lectures and materials concerning older patients' physical and mental capabilities would be effective in improving accrual (see Table 3). The need for more clinic personnel to explain trials to older patients was selected most frequently by physicians as the most important method for improving accrual (25%).
Table 3. Physicians' Suggestions for Improving Accrual of Older Patients with Breast Carcinoma to Clinical Trials (Ranked in order of frequency of endorsement)
|1. Make personnel available in the clinic to explain clinical trials to elderly patients and their families||69.0||108||25.0||38|
|2. Provide patients with better educational materials concerning clinical trials||63.0||99||13.0||19|
|3. Provide transportation to make it easier for elderly patients to participate in trials||63.0||98||14.0||21|
|4. Provide family members with better educational materials concerning clinical trials||59.0||92||5.0||7|
|5. Provide protocols with few exclusion criteria related to comorbid conditions||49.0||77||9.0||14|
|6. Provide MDs with lectures, courses, articles concerning toxicity of cancer treatments in the elderly||45.0||70||18.0||27|
|7. Provide MDs with lectures, courses, articles concerning physical and mental capabilities of the elderly||19.0||29||1.0||2|
|8. Other|| || || || |
| Eliminate extra examinations and testing; simplify trials||3.0||4||—||—|
| Reduce extra costs; provide insurance coverage||2.0||3||—||—|
| Provide MDs with lists of available protocols and brief summaries||1.0||2||—||—|
| Provide home care||0.6||1||—||—|
| Use less toxic regimens in protocols||0.6||1||—||—|
| Train MDs in how to present clinical trials to patients||0.6||1||—||—|
| Simplify informed consents||0.6||1||—||—|
The findings in our survey support the original contention that physicians' perceptions of barriers to accrual of older patients with cancer are multidimensional, primarily consisting of those that reflected protocol requirements, treatment specific issues, social support, logistic issues, and the medical and cognitive condition of older patients. Additional barriers that physicians wrote in broadened the types of barriers to include patient attitudes about participating in a research study (e.g., not wanting to be randomized, not wishing to be used as a guinea pig, lack of interest in aggressive treatment), family attitudes (e.g., family advising against the patient's participation), and lack of physician awareness of existing protocols. This latter finding emerged in Siminoff and colleagues' study9 as well, with surgical and medical oncologists significantly more likely to offer clinical trials to patients when they were aware that there was an open trial for which a patient was eligible (P ≤ 0.01).
Many of the barriers to accruing older patients with cancer to clinical trials that were suggested in the literature2, 3 were endorsed frequently by physicians in this survey as well. These included transportation difficulties, treatment toxicity, and significant comorbid conditions that had not eliminated an older patient but were believed to affect how the patient would respond to the treatment trial.
Two issues that appeared to be much more important to physicians when considering a trial for older patients compared with younger patients were the toxicity of the regimen and comorbid conditions. Although these factors did not exclude a patient from the trial, they were believed to affect a patient's treatment response. In the case-control parent study,4 11 of 33 treating physicians (33%) reported that treatment toxicity was one of the three most important reasons for not offering a trial to their older patients; no physician stated this as a reason for not offering a trial to younger patients.4 Furthermore, the finding that younger patients with Stage II disease were offered trials significantly more often than all other remaining patients, including older patients with Stage II disease,4 suggests that treatment toxicity was most likely a major reason for the difference: Protocols for Stage II patients often include chemotherapy.
Six of 33 treating physicians (18%) reported that one of the three most important reasons for not offering a trial to an older patient was that their comorbid conditions, were viewed as affecting patients' responses to the treatment, even though they were not excluded by the protocol. None stated this as a reason for not offering a trial to a younger patient. Although the sample sizes were not large, these findings indicate that treatment toxicity and comorbidity were critically important to oncologists when deciding whether to offer a trial to an older patient.
It was not possible to estimate the degree to which ageism influenced physicians' perceptions of barriers to the accrual of older patients to clinical trials. Two items in the questionnaire were more openly suggestive of ageism: difficulty of older patients understanding the trial and life expectancy too short to justify an older patient's participation in a trial. The former was endorsed by 50% of physicians, whereas the latter was endorsed by only 17% of physicians. The vast majority of physicians did not endorse the most blatant item concerning ageism—short life expectancy—as a significant barrier to accrual. However, difficulty of older patients understanding the trial, which is a more subtle ageist item that clearly would apply to some older patients, was endorsed heavily. Most of the barriers listed in the questionnaire may very well be valid reasons that explain the difficulties in offering trials to older patients with cancer. There are very toxic treatment regimens; older patients have more comorbid conditions that increase their frailty and, thus, may influence their response to treatment; they may need help at home with treatment regimens that is not available, etc. However, a number of items also may have reflected stereotypical attitudes toward older persons, justifying the physician's decision not to offer them a trial: assumptions of transportation needs, other comorbid illnesses that affect patients' responses to treatment, difficulty of older patients understanding a trial, and treatment toxicity. In the case-control parent study, age interacting with disease stage remained the significant predictors of whether patients were offered participation in a trial, after controlling for comorbidity and physical functioning.4 This analysis, which controlled for factors that commonly exclude patients from clinical trials, in conjunction with the finding that there was no significant difference between older patients and younger patients accepting trial participation once it was offered,4 suggested that ageism played a role in whether physicians offered trial participation to their older patients with Stage II disease.
In most cases, the types of barriers that physicians perceived to accruing older patients with cancer to clinical trials have been cited in the literature concerning difficulties in accruing any patient with cancer to clinical trials.6–9 With clinical trial participation of newly diagnosed adult patients with malignant diseases estimated at 2.5% across all adult age groups,10 it is abundantly clear that barriers to accrual to clinical trials are pandemic. Furthermore, barriers that we believed may be especially problematic in the accrual of older patients with cancer have all been mentioned in other studies in relation to difficulties in accruing all adult patients with cancer to clinical trials, irrespective of their age:6, 9, 11 restrictive eligibility criteria due to comorbid conditions, difficulty in patients' understanding and compliance with protocol requirements, and the extra time required to enroll patients in trials and, thus, the need for extra personnel.
Interventions to Improve Accrual
Given the complexity of the problem, a variety of interventions is likely to be needed to improve accrual of older patients with malignant disease to clinical trials. The methods that physicians frequently endorsed for improving accrual of older patients to clinical trials reflected the multidimensional aspect of the problem: educational efforts directed to the physician, patients, and family members; greater resources for the patient (transportation) and physician (more personnel in the clinic to explain clinical trials to older patients); and simpler, less restrictive, and less toxic protocols. Providing oncologists with medical information to help them determine whether a clinical trial should be offered to their older patients with cancer may improve accrual to trials, particularly because not all studies demonstrate that older patients tolerate these regimens as well as younger patients (e.g., see Giovanazzi-Bannon et al.12 and Crivellari et al.13). However, with only a limited number of studies addressing treatment tolerance of older patients with cancer, there is an insufficient body of knowledge to inform physicians adequately regarding this issue.
Based on this survey's findings that physician education would improve the accrual of older patients to clinical trials, an educational intervention is being tested through the CALGB (CALGB 360001) that involves a geriatric symposium combined with monthly E-mail reminders of available CALGB protocols. With 13% of treating physicians in the case-control parent study reporting that they were not aware that an appropriate trial existed for their older patients, it is possible that increasing oncologists' awareness of open trials for their eligible older patients, in itself, may substantially improve the frequency with which trials are offered to older patients with malignant disease.
However, if ageism is a significant underlying barrier to offering a trial to older patients with cancer,14, 15 then an additional type of intervention will be needed to reduce negative attitudes toward older patients. Possible approaches may include increasing knowledge about older patients in conjunction with positive experiences with these patients; funding for additional staff to provide the extra time that often is required to determine whether an older patient is eligible, to describe the study, and to obtain informed consent; development of combined geriatrics/oncology training programs and institutional leadership, with strong encouragement for oncologists to improve clinical, research, and teaching practices related to older patients with malignant disease.
These results were part of the parent study, which was conducted at the 10 institutions with the highest accrual to breast carcinoma treatment trials in the CALGB.4 Consequently, our findings are not based on a representative sample of oncologists who treat patients with breast carcinoma in the United States or oncologists across all specialties. Therefore, our findings may not reflect the true prevalence of oncologists' views of barriers to offering clinical trials to older patients with cancer. Nor did all physicians who treat patients with breast carcinoma at these 10 institutions complete this survey, as indicated by the return rate of three of the institutions ranging from 33% to 100%. This most likely biased the findings. Additional research is necessary to test whether our findings can be replicated. However, our results suggest what oncologists perceive as the major barriers to offering trials to older patients with cancer, thus serving as a springboard for possible interventions.
When the items were developed for this trial (by M.K. and A.B.K.), we focused on areas that had been identified either in the literature or by clinical experience as barriers to the accrual to clinical trials of older patients with cancer. Consequently, the questionnaire did not include all reasons that may serve as barriers to accrual of any patient to a trial, such as patient refusal, their family objecting to their participation, and patient fears of being included in an experimental treatment, among others. Because these are relevant barriers to accrual across all age groups, this questionnaire should be revised to include the full range of reasons why it is difficult to enter older patients with cancer onto trials.
All those involved in clinical trials research fully understand that an accrual of 2.5% of cancer patients to clinical trials is unacceptable for both ethical and scientific reasons. That this rate of accrual may be diminished further by virtue of being an older patient is disheartening. Accrual to clinical trials is a multidimensional problem that requires multidimensional interventions to affect improvement. To the degree that the different barriers outlined above are independent of each other, each intervention may improve accrual incrementally. However, if there are underlying issues that are not addressed adequately, such as insufficient knowledge among physicians about how to treat older patients effectively as well as a lack of awareness about ageist attitudes, then there will be only a minimal improvement in the frequency with which older patients with cancer are offered participation in clinical trials.