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Barriers to Clinical Trial Participation by Older Women With Breast Cancer

From the Cancer and Leukemia Group B and the University of Chicago Medical Center, Chicago, IL; Cancer Center of Queens, Queens Hospital Center/Mt Sinai School of Medicine, Jamaica; Roswell Park Cancer Institute, Buffalo, NY; Cancer and Leukemia Group B Statistical Center, Cancer and Leukemia Group B Data Management Center, and Duke University Medical Center, Durham, NC; Dana-Farber Cancer Center, Boston, MA; Vermont Cancer Center, Burlington, VT; and Washington University Medical Center, St. Louis, MO.

Address reprint requests to M. Margaret Kemeny, MD, 82-68 164th St, Jamaica, NY 11432; email: kemenym{at}nychhc.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS REFERENCES

 
Purpose: Although 48% of breast cancer patients are 65 years old or older, these older patients are severely underrepresented in breast cancer clinical trials. This study tested whether older patients were offered trials significantly less often than younger patients and whether older patients who were offered trials were more likely to refuse participation than younger patients.

Patients and Methods: In 10 Cancer and Leukemia Group B institutions, using a retrospective case-control design, breast cancer patients eligible for an open treatment trial were paired: less than 65 years old and ≥ 65 years old. Each of the 77 pairs were matched by disease stage and treating physician. Patients were interviewed as to their reasons for participating or refusing to participate in a trial. The treating physicians were also given questionnaires about their reasons for offering or not offering a trial.

Results: Sixty-eight percent of younger stage II patients were offered a trial compared with 34% of the older patients (P = .0004). In multivariate analyses, disease stage and age remained highly significant in predicting trial offering (P = .0008), when controlling for physical functioning and comorbidity. Of those offered a trial, there was no significant difference in participation between younger (56%) and older (50%) patients (P = .67).

Conclusion: In a multivariate analysis including comorbid conditions, age and stage were the only predictors of whether a patient was offered a trial. The greatest impediment to enrolling older women onto trials in the setting of this study was the physicians’ perceptions about age and tolerance of toxicity.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS REFERENCES

 
ALTHOUGH THE incidence of cancer increases with age, and in the United States 60% of cancers occur in people older than 65 years,¹ there are significantly fewer older cancer patients entered onto clinical trials than younger patients.^2–5 The clinical usefulness of the results of a trial are dependent on the sample being representative of the patient population. The consequences of the underrepresentation of the older cancer patient in randomized trials has resulted in insufficient data on treatment toxicity and efficacy in the elderly.

The experience in the Cancer and Leukemia Group B (CALGB) reflects this underrepresentation of older people in trials. In a review of patient accrual to three recently completed breast cancer adjuvant chemotherapy trials in CALGB, none of which had an upper age limit that excluded older women, only 8% of patients were older than 65 years and only 4% were older than 70 years. In an examination of age representation in clinical trials in the United States, only 17.3% of women with breast cancer entered on clinical trials were older than 65 years, compared with 48% of breast cancer patients older than 65 years in the United States population (based on the Surveillance, Epidemiology, and End-Results data).³ In an analysis of patients enrolled in Southwest Oncology Group Trials from 1993 to 1996, 9% of breast cancer patients more than 65 years old had been enrolled in trials as compared with the 49% of breast cancer patients more than 65 years old in the United States population (Surveillance, Epidemiology, and End-Results data).⁵

Although there has been little empirical evidence, a range of potential barriers of older cancer patients participating in trials have been postulated by several investigators to be significant factors in the under -enrollment of older cancer patients.^4–6 The issues include protocol-specific factors, such as restrictive eligibility requirements, comorbid conditions that often eliminate the older patient from being eligible, and toxic treatments. Patient-related issues that may reduce enrollment of older patients include less education of the older patients, who may be less likely to seek out clinical trials, logistic problems such as less access to transportation, which is necessary for clinic appointments, and extra financial costs that may be incurred by the trial. Oncologist-related issues hypothesized to reduce accrual of the elderly include attitudes that older patients are less likely to benefit from aggressive therapy than younger patients, additional paperwork required for clinical trials, and lack of time.

The current study was designed to test the extent to which eligible older breast cancer patients were offered participation in clinical trials compared with patients who were younger than 65 years, using a case-control design to control for confounding factors of individual differences between oncologists and disease stage (CALGB 9670). Once patients had been offered a trial, the differential participation rate between younger and older patients was tested. Patient’s comorbidity and physical functioning, two major factors that might explain differential enrollment of older versus younger patients were assessed so that they could be statistically controlled. In addition to testing the effect of age on a patient’s being offered a trial, this study assessed both oncologists’ reasons as to why they chose not to offer a trial to their older patients and why patients chose to or refused to participate.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS REFERENCES

 
Sample
The 10 institutions selected to participate in this study had the highest accrual rate to breast cancer protocols in the CALGB. Each institution was asked to contribute 10 pairs of patients (20 patients). The pairs consisted of one woman younger than 65 years and one woman 65 years old or older who were matched as to their disease stage (stage I, II, or IV) and to their physician, who could either be a surgical, medical, or radiation oncologist. The patients, who were identified retrospectively, had to have been treated within 2 years of the institutional start date of this protocol and be eligible for enrollment in at least one open breast cancer treatment trial in their institution. The method for obtaining the matched pair can be seen in Figure 1. Once a matched pair was obtained and informed consent was given, a trained research coordinator at each institution administered a questionnaire, usually over the telephone but sometimes in person, to those who had been offered a trial. These patients were asked why they chose to participate or refused participation in the trial. The patients’ physicians were also given a written questionnaire as to the reasons why their patients had not been offered participation in the trial. If they had been offered a trial but had refused participation, physicians were asked why they thought the patient had refused participation.

View larger version (60K): [in this window] [in a new window]   Fig 1. 9670 Procedural Flow Chart.

Physician’s reasons for not offering a patient a trial. Physicians were asked to check the reasons that their eligible patients had not been offered a clinical trial, using a list of 14 reasons (Appendix 2). Among the reasons included were issues related to treatment toxicity, comorbid conditions (which were not excluded by the trial but were considered to affect the patient’ s treatment tolerance or response), one treatment arm was not considered to be adequate, the patient’s lack of assistance at home for administration of the treatment, lack of available transportation, and the patient having difficulty understanding what was required for the trial. As with patients, physicians were then asked to rate the three most important reasons that a patient was not offered a clinical trial. Last, physicians were asked to select from a brief list of reasons why an eligible patient who had been offered a trial chose not to participate. This list was parallel to the items included in the patients’ reasons for nonparticipation.

Comorbid conditions. A modified list of 14 common serious medical conditions in addition to depression was used to measure comorbid conditions that older cancer patients might have.⁷ Each condition was then rated on a 3-point scale from "not at all" to " a great deal" to assess the degree to which it interfered with daily functioning. Two total scores were created from this measure: the total number of comorbid conditions and their interference with daily functioning.

Revised functional limitations scale. A modified version of the Revised Rand Functional Limitations Scale was used to assess physical functioning.^8,9 It consisted of eight items covering the need for help in self-care, mobility, physical activity, and work activities, with items rated on a 5-point Likert scale from "never" to "all the time." A total score was created, with higher scores indicative of greater limitations in physical functioning.

CALGB background information form. Standard questions concerning patients’ sociodemographic characteristics are included in the CALGB background information form, including the highest educational grade achieved, marital status, household composition, employment status, and occupation.¹⁰ Information regarding patients’ age and ethnicity was obtained at the time of registration.

Statistical Methods The study was designed to use the McNemar Test to test the equality of the proportion of younger and older patients offered participation in a clinical trial. One hundred young/old pairs matched on stage of disease and physician gives 80% power for detection of a difference of 40% versus 60% in the rates that older versus younger patients are offered participation in a clinical trial. Because time and resources were not sufficient for all institutions, the trial was stopped early after 77 pairs had been enrolled. Because younger (< 65 years old) and older (≥ 65 years old) women were pair-matched by physician and stage of disease, the McNemar test was initially used to test the association of age with being offered a trial. In all further analyses, however, repeated measures logistic regression (fit with Generalized Estimating Equations) was used to test the univariate and multivariate association of being offered a trial with age and other potential predictors, including race (non-Hispanic white v other), education (some college or more v high school graduate or less), marital status (married v not), number of comorbidities, interference of comorbidities with functioning, and the Functional Limitations Scale total score. Because only four patients had stage IV disease, these patients were grouped with the stage II patients. The consequences of this grouping had minimal impact on the results.

The ² test was used to test the association of age group (younger v older) with whether or not patients who were offered a trial accepted trial participation. Reasons physicians gave for not offering a trial to an eligible patient and reasons for patients accepting or rejecting trial participation were tabulated by age group. A two-sided type I error of 0.05 was used for all statistical tests.

RESULTS
Sample Seventy-seven matched pairs of younger (less than 65 years old) and older (65 years old or older) women with breast cancer were compared, for a total of 154 patients. Accrual was stopped early before 100 pairs were obtained, because of insufficient time and resources at some of the institutions. The mean ages of the younger and the older groups, were 48 and 74 years, respectively (Table 1). Whether younger or older, the majority of patients were white and diagnosed with either stage I or II disease at an interval of not more than 2 years from the start of this study. For both younger and older patients, the sample was evenly split in educational level (high school or less v having some college or more). Age-related differences emerged in terms of marital status (49% of older v 5% of younger patients were widows), retirement (81% of older v 8% of younger patients were retired), and various functional limitations, most noticeably the ability to do the vigorous activities that they used to do (35% of older v 55% of younger patients).

Being Offered a Trial as a Function of Age As shown in Table 3, among the 77 matched pairs, 67 pairs provided complete data on whether both the younger and older member of the pair were offered a trial. Eight other pairs provided these data on only one member, whereas two pairs provided no data on trial offering. Table 4 shows that in 19 of the 67 pairs, the younger member was offered a trial, whereas the older member was not; in nine pairs, the older member was offered a trial, whereas the younger was not. The remaining 39 of 67 pairs were concordant. Thus, there was a trend toward older patients being offered a trial less frequently than younger patients (McNemar; P = .06).

Among the 33 younger patients eligible for but not participating in a trial, the most frequently selected reasons that their treating physicians gave for not offering them a trial were as follows: unaware that a trial was open (30%); thought the patient was not eligible (15%); thought the best treatment was not included in the trials (15%); and thought one arm in a randomized trial would be less effective (15%).

Among the 33 older patients eligible for but not participating in a trial, the most frequently selected reasons that their treating physicians gave for not offering them a trial were as follows: treatment was too toxic for the patient (33%); the best treatment was not included in the available clinical trials (27%); unaware that a trial was available (21%); thought the patient was not eligible (18%); and concerned that the patient’s comorbid conditions might influence her response to treatment, even though the comorbidity had not excluded the patient from being eligible for the trial (18%).

Age as a Predictor of Participation in a Trial, After Patients Were Offered a Trial Sixty-one of 142 patients reported that they were offered participation in a trial; information was available on all but one of these 61 patients as to whether they chose to participate in a trial. Among 36 younger patients offered a trial, 20 (56%) of them participated; among 24 older patients offered a trial, 12 (50%) participated (P = .67). Thus, age was not a significant predictor as to whether a patient would participate, once they had been offered a trial.

When younger patients (n = 20) were asked what their reasons were for choosing to participate in a trial, the three most frequently endorsed reasons were as follows: they expected their health to improve (85%); they wanted to help find a cure for cancer (75%); and they wanted the latest treatment (55%). The three most frequently stated reasons for accepting participation among the 12 older patients who had been offered a trial were as follows: it was the best treatment available (67%); they expected their health to improve (67%); and they wanted to help find a cure for cancer (50%).

The primary reason for not participating among the 16 younger patients who had refused participation was that they wanted to choose their own treatment (69%). In addition, 25% of younger patients also said that they wanted a treatment that was not offered, that they did not want to be in an experiment, and that they felt that the treatment would be life-threatening. The three most frequently endorsed reasons of the 12 older patients who had refused participation were similar to those of the younger group: they wanted to chose their own treatment (75%); they wanted a treatment that was not offered (33%); and they did not want to be in an experiment (25%).

Treating physicians were asked for their opinion as to why their patients who had been offered participation in a trial had refused to participate. The two major reasons physicians gave were the same for both age groups: the patient did not want to be in a study with an experimental treatment, and the patient did not wish to be randomized. These reasons were offered approximately 30% of the time for both the younger and older patients.

DISCUSSION
Why older cancer patients do not participate in clinical trials at the rate of younger patients is more complex than initially anticipated. In this retrospective case-controlled study, older patients with stage II disease were offered participation in a trial significantly less often than younger patients with stage II disease and than patients of any age with stage I disease. This finding was maintained in the multivariate logistic regression analysis, even after controlling for comorbidity and physical functioning, highly relevant factors that might influence a patient being offered a trial. However, although older stage II patients were significantly less likely to be offered a trial than younger patients, there was no significant difference between younger and older patients accepting participation in a trial, once it had been offered. Consequently, the principal barriers to accruing older patients to trials in this pilot study are physician and not patient-related issues.

Treatment toxicity has been suggested by others^4,5 as one of the reasons oncologists do not enter older patients on a trial. In a study by Crivellari et al,¹¹ breast cancer patients older than 65 years had significantly higher grades of toxicity and received less than their expected dose on cyclophosphamide, methotrexate, fluorouracil therapy than younger patients. However, a number of studies have shown that older patients can tolerate adjuvant therapy equally as well as those who are younger^12–16. As the knowledge base grows concerning which treatment regimens older patients tolerate well, treatment toxicity may diminish as an unnecessary barrier to offering older patients trials. Thus, it is critical that as the newer agents and regimens are developed, older cancer patients are included in all phases of treatment trial development so that treatment tolerance can be analyzed for this age group and results disseminated to the oncology community.

Eighteen percent of the treating physicians stated that they had not offered their older patients a clinical trial because of comorbid conditions that might have affected their response to treatment, even though they had met the eligibility criteria for the trial. Little is known about how older patients’ comorbid conditions might affect their response to different cancer treatments. Because of this lack of information, physicians may be more reluctant to put older patients on trials.

It is likely that lack of knowledge regarding older patients’ treatment tolerance and the impact of comorbid conditions on treatment response have both been important factors in oncologists offering trials to older patients at a lower rate than their younger patients. However, it is also possible that stereotypical attitudes toward the elderly have resulted in assumptions about their treatment response.⁵ In a survey of American oncologists, 51% indicated that they excluded patients on the basis of age alone.¹⁷ From our data, it was not possible to determine the extent to which ageism¹⁸ influenced oncologists’ decisions concerning offering a trial to their older stage II patients. However, it remains a credible hypothesis that physicians’ stereotypical assumptions concerning older patients’ treatment tolerance, comorbid conditions influencing treatment response, ability to stay the full course of the trial, and need for aggressive treatment "at their age," may underlie the differential offering of a trial between younger and older stage II patients, much as the findings from Benson¹⁷ suggest.

Although treatment toxicity and comorbid conditions emerged as age-related problems influencing oncologists’ offering older patients a trial, there were a range of issues affecting accrual of both younger and older cancer patients. Two issues of particular interest that appeared in these data were as follows: the physician was unaware that a trial was open, and patient was thought to be ineligible. With the increase in physicians’ caseloads, and in academic centers where there are multiple protocols to consider, it has become extremely hard for oncologists to match available protocols to eligible patients without additional staff. Advanced technology, such as the one developed by Breitfeld et al,¹⁹ might be a simple solution. A portable hand-held computer was programmed so that patient information could be easily matched to eligibility criteria of existing trials. It is possible that the use of this technological device might dramatically increase oncologists offering trials to their older as well as younger patients.

Given that only 2.5% of all newly diagnosed cancer patients go on clinical trials,²⁰ it is clear that barriers to accrual are multidimensional, affecting both younger and older patients.^{3,5,6,21–23} Those barriers to accrual that are more likely to be age sensitive because of worsening physical functioning (transportation problems) and more limited income (paying for any extra costs for being on a trial) might also be the focus of institutional interventions to increase resources for older patients to encourage participation in trials.

Methodologic Limitations This was a pilot study, designed to examine barriers to the accrual of older breast cancer patients, from the perspectives of both oncologists and patients. Only 10 of 30 main member CALGB institutions were involved in this pilot study, specifically selected for having the highest accrual to breast cancer trials in the CALGB. Therefore, these results may not be representative of all oncologists involved in the treatment of breast cancer patients in the CALGB or nationwide. Additionally, the results might not be generalizable to patients with other cancer diagnoses and their oncologists.

The second methodologic issue that emerged was that we were unable to obtain equal numbers of patients with early and advanced stage disease because of the lack of availability of suitable protocols for patients with stage IV disease. Only four patients with stage IV disease were accrued to this study. Therefore, the question as to whether older patients with stage IV disease would be offered a trial significantly less often than their younger counterparts remains unanswered.

Although all our pairs did not have complete data and we did not accrue 100 pairs, we have no evidence to indicate that the pairs with complete data were different from the pairs with incomplete data. Furthermore we found our hypothesized effect in this smaller number of patients was strong enough to show significance even with the incomplete accrual.

The physician in common for the pairs could be either the surgeon, medical oncologist, or radiation oncologist. This means that the same physician may not have been the presenter of breast cancer protocols to the younger/older pair of patients, although any of these physicians could have presented an open protocol to the patients.

This was a retrospective study of patients who were no more than 2 years since diagnosis of their breast cancer. The accuracy of the patients’ and physicians’ recollections of how they felt about studies given that period of time could be questioned. Although every effort was made to avoid bias in the selection of patients into this study (Appendix 1), data are not available to confirm that we were successful. There may have been an ordering effect with the way the questions were asked, but it was not possible to test for this.

In conclusion, given the complexity of the issue as to why there is a significantly lower accrual of older patients compared with younger ones, it is likely that there are multiple reasons that explain this phenomena. However, the finding that older patients with stage II disease were offered trials significantly less often than younger stage II patients and all stage I patients suggests that treatment toxicity is a key issue to oncologists when they consider a trial for an older patient. Less than one third of the stage I patients were offered trials regardless of their age, which may reflect the fact that for more limited disease, physicians in general may not think putting patients on a protocol is warranted. When patients have node-positive disease, physicians may think protocols are more worthwhile, but only for the younger patients. So the level of offering trials to the older patients stays the same. The uncertainty about these issues underscores the necessity to perform prospective clinical trials. Increasing the knowledge base concerning treatment toxicity and comorbidity in the elderly may effectively guide oncologists toward offering trials to older patients, thus helping to rectify the age imbalance.

Another possible interventional approach would be to increase patients’ knowledge of clinical trials, as suggested by Ellis et al.²¹ Although Ellis et al’s study focused on increasing patients’ knowledge about trials so that they would be better able to understand the positive value of participating and thus agree to participate, these results also suggest that increasing older patients’ knowledge about trials might increase the frequency of their requesting a trial from their oncologist. With the older patient initiating the discussion of an available clinical trial with the oncologist, and requesting the physician to look for an appropriate protocol, another barrier to accrual might be reduced. Because multidimensional problems usually require multidimensional solutions, all of the techniques mentioned in this article may need to be used so that there can truly be equal access to care for the older cancer patient.

APPENDIX

	REFERENCES

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3. Trimble EL, Carter CL, Cain D, et al: Representation of older patients in cancer treatment trials. Cancer 74:2208–2214, 1994[CrossRef][Medline]

4. Tejeda HA, Green SB, Trimble EL, et al: Representation of African-Americans, Hispanics, and whites in National Cancer Institute cancer treatment trials. J Natl Cancer Inst 88:812–816, 1996[Abstract/Free Full Text]

5. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer treatment trials. N Engl J Med 341:2061–2067, 1999[Abstract/Free Full Text]

6. Ellis PM: Attitudes toward and participation in randomised clinical trials in oncology: A review of the literature. Ann Oncol 11:939–945, 2000[Abstract/Free Full Text]

7. Fillenbaum GG. Multidimensional Functional Assessment of Older Adults: The Duke Older Americans Resources and Services Procedures. Hilldale, NJ, Lawrence Erlbaum, 1988

8. Brook RH, Ware JE Jr, Davies-Avery A, et al. Conceptualization and Measurement of Health for Adults in the Health Insurance Study: Overview (vol VIII). Santa Monica, CA, Rand, October 1979

9. Kornblith AB, Hollis DR, Zuckerman E, et al: Effect of megestrol acetate upon quality of life in a dose-response trial in women with advanced breast cancer. J Clin Oncol 11:2081–2089, 1993[Abstract/Free Full Text]

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19. Breitfeld PP, Weisburd M, Overhage JM, et al: Pilot study of a point-of-use decision support tool for cancer clinical trials eligibility. J Am Med Inform Assoc 6:466–477, 1999[Abstract/Free Full Text]

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Submitted September 25, 2002; accepted March 28, 2003.

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