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Clinical Trial Participation among Patients Enrolled in the Glioma Outcomes Project Susan M. Chang, M.D.1 Fred G. Barker II, M.D.2 Meic H. Schmidt, M.D.1 Andrew E. Sloan, M.D.3 Rachel Kasper4 Leslie Phillips5 Karen Shih1 Subramanian Hariharan, M.D.6 Mitchel S. Berger, M.D.1 The Glioma Outcomes Investigators 1
Department of Neurological Surgery, University of California-San Francisco, San Francisco, California.
2
Brain Tumor Center, Massachusetts General Hospital, Boston Massachusetts.
3
Department of Neurosurgery, Wayne State University, Detroit, Michigan.
4
Glioma Outcomes Project, University of Massachusetts Medical School, Worcester, Massachusetts.
5
Department of Neurology, Harborview Medical Center, University of Washington, Seattle, Washington.
6
Neuro-Oncology, John F. Kennedy Neuroscience Institute, Edison, New Jersey. Presented in part at the 5th Annual Meeting of the Society of Neuro-Oncology, Chicago, Illinois, Nov 9 –13, 2000.
BACKGROUND. Patient participation in well-designed and conducted clinical trials enables researchers to test new therapies. An understanding of the variables that possibly influence patient enrollment may help in patient recruitment for future trials. The authors evaluated factors that influenced patient enrollment in clinical trials using a prospective, large, multi-institutional registry of patients with malignant glioma. METHODS. Data were examined from 708 patients who underwent first or second surgery for a malignant glioma who were enrolled in the Glioma Outcomes Project, which is a prospective observational data base that captures clinical practice patterns. The frequency of clinical trial participation and the variables that may have been associated with trial participation were evaluated. These variables included age, gender, race, household income, educational level, first versus second craniotomy, histology, and whether the patient was treated at an academic institution. RESULTS. One hundred fifty-one of 708 patients (21.3%) participated in a clinical trial, which was higher than the participation reported typically for patients with other types of primary malignancies. In univariate analysis, race, histology, and first craniotomy were significant between the two groups, with Caucasian patients and patients with glioblastoma histology showing higher participation rates. In a multivariate logistic regression model, significant predictors included young age and glioblastoma multiforme histology. CONCLUSIONS. The authors present information on factors that may influence clinical trial participation among patients with malignant glioma and compare their data with information described previously on patients with other types of malignant disease. The percent of participation among the patients in the current study was greater than among patients with other primary tumor sites. Strategies should be implemented to improve recruitment to neuro-oncology trials, especially in elderly and minority populations. Cancer 2002;94:2681–7. © 2002 American Cancer Society. DOI 10.1002/cncr.10536
Supported by an unrestricted educational grant from Guildford Pharmaceuticals, Inc.
KEYWORDS: glioblastoma multiforme, glioma, clinical trials participation, outcomes.
At the time the current research was conducted, Dr. Leslie Phillips was being supported by a grant from Aventis Pharmaceuticals.
A
Address for reprints: Susan M. Chang, M.D., Department of Neurological Surgery, University of California-San Francisco, 400 Parnassus Avenue, A808, San Francisco, CA 94143-0372; Fax: (415) 353-2167; E-mail:
[email protected] Received September 10, 2001; revision received November 5, 2001; accepted December 3, 2001. © 2002 American Cancer Society
lthough they are relatively rare, primary brain tumors contribute significantly to disease-attributable death and disability. Of the 29,000 new primary brain tumors diagnosed annually, about 20,000 are gliomas.1 Malignant glioma is more prevalent in the older population, and the incidence in the elderly appears to be increasing.2 The median survival for patients with glioblastoma multiforme is 10 –12 months, whereas, for patients with anaplastic astrocytoma, the median survival is 3.5 years.3,4 Despite clinical research efforts in neurooncology, survival for patients with malignant glioma has not changed significantly over the last 20 years. Many new approaches to
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the management of these patients are being explored in experimental trials. Patient participation in well-designed, well-conducted clinical trials enables us to answer questions about the value of new therapies. By standardizing treatment, often in collaboration with specialized centers, multicenter controlled clinical trials offer higher survival rates, especially for patients with less common malignancies.5–10 The systematic evaluation of new treatments also prevents the widespread use of unproven, potentially toxic therapies. Clinical trials also can avoid the inappropriate use of scarce resources, protect future patients from unnecessary morbidity, and allow for the determination of appropriate expectations from therapies. Despite studies showing that many patients generally are willing to take part in clinical trials, actual participation rates are low (range, 3–20%).11–16 Only 1.0 –1.5% of available patients with breast carcinoma, 0.5% of patients with rectal carcinoma, and 1% of patients with colon carcinoma actually are recruited to clinical trials.15 To enhance the level of patient involvement in clinical trials in neuro-oncology, we must gain some understanding about the frequency of participation and the factors that appear to influence patient enrollment. We used data from the Glioma Outcomes (GO) Project to examine these aspects among patients with malignant glioma.
MATERIALS AND METHODS The GO Project, which started in 1997, is a prospective longitudinal data base that tracks patterns of clinical practice and outcomes among North American patients with malignant glioma.17 The data base is based on patient and physician questionnaire forms that are completed at 3-month intervals. The data are stored at a data coordinating center established at the Center for Outcomes Research at the University of Massachusetts Medical Center. The major objective of the GO Project is to provide prospectively captured benchmark data to enable comparison of individual practice patterns and outcomes. Fifty-five clinical sites across North America participate in the GO Project. The enrollment criteria include patients with primary brain tumors of Grade 3 and 4 histology who are undergoing a first or second operation for diagnosis or treatment. Patients must be age ⱖ 18 years and must be able to provide informed consent. The data collection instruments include questionnaire forms at enrollment, during the perioperative period, and at follow-up intervals. Patients are followed prospectively at intervals of 3 months either until death or for 24 months. One hundred sixty-one physicians had enrolled 788 patients as of September
TABLE 1 Univariate Analysis of Factors Associated with Clinical Trial Participation Factor
Trial (%)
Nontrial (%)
P value
% Missing data
No. of patients (%) Median age (yrs) Male gender Caucasian Glioblastoma First craniotomy Teaching hospital CAM use
151 (21.3) 53 82 (59.9) 131 (92.9) 114 (77.6) 104 (71.2) 64 (42.4) 79 (58.5)
557 (78.7) 55 246 (56.9) 389 (83.8) 369 (69.2) 321 (61.4) 206 (38.1) 208 (50.7)
— 0.17 0.55 0.0001 0.05 0.03 0.33 0.12
— — 20 15 4 6 2 23
CAM: complementary and alternative medicine.
30, 2000; and, as of March 2001, 10.9% of patients continued to be followed actively, 59.8% of patients had died, 21.5% of patients were either lost to followup or dropped out, and 7.9% of patients were able to complete 24 months of follow-up. The primary outcome measures include treatment management, morbidity, and survival. Sociodemographic and related patient characteristics also are collected. Self-reported changes in functional capacity, quality of life, and satisfaction with care are captured. Practice variation and resource utilization also may be evaluated. All patients who were enrolled in the GO Project were included in the analysis. Clinical trial participation was documented by the treating physician. We evaluated several potential predictors of trial participation, such as age, gender, Karnofsky performance status, race, household income, educational level, and the use of complementary and alternative medicine (CAM). Other factors evaluated included tumor histology, academic versus nonacademic treatment center, and first versus second craniotomy. Factors predictive of clinical trial participation were assessed using Student t tests, chi-square tests, Fisher exact tests, and logistic regression modeling.
RESULTS Seven hundred eighty-eight patients were enrolled in the study from 1997 to 2000, and 708 patients were analyzed in this study. The clinical characteristics of these patients are summarized in Table 1. Data were relatively complete for most variables, although, for some covariates, there were missing responses (Table 1). Insurance status, educational level, and performance status at 12 months were covariates with the highest rate of missing data (⬎ 45%). This information was not captured initially and was added subsequently to later forms, accounting for the high percentage of missing data.
Clinical Trials and Patients with Glioma/Chang et al. TABLE 2 Multivariate Analysis of Factors Associated with Clinical Trial Participation Factor
Odds ratio
95%CI
P value
Male gender Caucasian Glioblastoma First craniotomy Age
1.05 1.61 1.75 1.07 0.98
0.68–1.62 0.68–3.83 1.01–3.00 0.61–1.87 0.967–0.996
0.83 0.28 0.045 0.82 0.038
95%CI. 95% confidence interval.
The overall rate of physician-reported trial participation was 21.3% (151 of 708 patients). The median age of participants was 53 years compared with 55 years for nonparticipants (0.17). Univariate logistic regression analysis showed that three covariates were related significantly to the chance of trial participation (Table 1). These included race, glioblastoma multiforme histology, and first craniotomy. Patient age, gender, type of treatment setting (academic vs. nonacademic), and the use of CAM were not significant predictors of trial participation. In multivariate analysis, younger age and glioblastoma histology were related significantly to increased likelihood of clinical trial participation (Table 2).
DISCUSSION The predominant population group included in cancer treatment trials has been well-educated, middleclass, married, white males.16,18 –20 Despite studies showing that many patients are willing to participate in clinical trials, only 3–20% of patients with malignant disease actually are enrolled onto studies. Many barriers to clinical trial participation have been described.21–24 These barriers can be characterized broadly as patient-related, physician-related, and protocol-related factors. Patient concerns about participation in clinical trials can be separated into three categories. These include time and inconvenience of treatment, negative personal and family attitudes about clinical trials (e.g., that the clinical investigator is more concerned about the trial than the patient), and the perceived lack of personal benefit from clinical trial participation.13,14,25–29 For randomized clinical trials, uncertainty of the treatment arm assignment and the individual’s attitude are also factors.30,31 Clinician-related barriers to participation most commonly are related to concerns for the patient, the conduct of the study, and the physician’s role. Major barriers previously identified include the time and inconvenience for both the patient and the physician,
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the concern about the interference in the physicianpatient relation, and the conflict between the physician’s role as caregiver versus scientist.32–35 The protocols themselves may discourage clinical trial participation because of an insufficiently interesting question, the toxicity associated with the treatment, the complexity and difficulty of the protocol, and the specialized interventions that can be administered only at specific institutions.36 Other general barriers include the financial aspect of conducting clinical trials and the impact of the health care system.37– 42 Negative publicity about the conduct of trials also fuels mistrust in the clinical research enterprise and can have an adverse impact on clinical trial participation. Factors that predict clinical trial participation have not been described previously in the field of neuro-oncology. The unique characteristics of this patient population may influence the frequency of participation and may provide insight into improving recruitment to trials. About 20% of patients enrolled in the GO Project participated in clinical trials. This relatively high percentage, compared with patients who had tumors at other disease sites, may be due in part to the rarity of this disease and the multidisciplinary approach often chosen for patient management. Patients enrolled in the GO Project may have a higher rate of participation in other clinical trials because both the patient and their treating physician have demonstrated interest in clinical research by participating in the GO Project. It is interesting to note that there was no significant difference in trial participation between patients who were treated in an academic setting or a nonacademic setting. This is in contrast to some indication in the nononcologic literature that recruitment rates in nonacademic practices may be better than those at academic sites.43 Caucasian race was a significant variable in our univariate analysis. Racial and ethnic minority groups are under-represented in clinical trials for many reasons. These include the lack of opportunities to participate, the minimal information available about the trials, and potential distrust of white majority groups conducting the studies.44 –50 Many efforts to increase recruitment of minorities have been mandated by the National Cancer Institute.16,51–55 Compared with other reports about the under-representation of women in clinical trials, there was no significant impact of gender on clinical trial participation in the current study.19,20 In univariate and multivariate analyses, patients with glioblastoma histology were more likely to participate in trials than patients with less aggressive tumors. The poor prognosis of patients with glioblas-
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toma multiforme and the lack of progress in improving their survival may influence both physicians and patients to favor enrollment in a clinical trial. This is consistent with Verheggen et al., who have reported that the perception of a threat was a factor that favored trial participation.25 Another possible explanation may be that patients with aggressive tumors are more likely to participate in clinical trials. A previous study suggested that trial participants tended to be more severely ill compared with nonparticipants.56 There are no data on patients with malignancies that are associated with a similarly short expected survival, such as pancreatic carcinoma; however, for patients with other types of solid tumors, the clinical trial participation rate is lower (⬍ 5%). Age was a significant factor for clinical trial participation, with younger patients more likely to enroll. This is consistent with what has been shown repeatedly in the literature for other disease sites.57–59 Despite the increasing number of older people in the population and the greater frequency of malignant disease in this age group,60 substantial under-representation of patients age ⱖ 65 years in cancer treatment trials has been demonstrated.18,61,62 Both older patients and their physicians may choose standard treatments because of the perceived increased toxicity of experimental treatments in this patient population. In a survey of American oncologists, 50% felt that some patients were not suitable for clinical trials based on age alone.63 There are little data to support the possibility that fit, older patients may not be able to tolerate or benefit from treatment in clinical trials. Giovanazzi-Bannon et al. showed that there was no significant difference between elderly patients and younger patients for several clinical trial end points, such as treatment delays and toxicities.64 Those authors concluded that elderly patients should not be denied access to cancer clinical trials based on age alone. Since that publication, several cooperative groups have designed studies to specifically address the older population.65,66 This aspect is particularly relevant among patients with glioblastoma multiforme. These patients tend to be older, and age is an important adverse prognostic factor for survival.4,67,68 Only recently has this been addressed specifically with regard to age specific therapies for older patients with glioma.69 –72 Understanding the molecular cytogenetic and biologic factors that may be correlated to age and that may influence outcome may help target specific agents to the older population.73 Evaluating how well older patients tolerate treatments also may be valuable in understanding the generalizability of clinical trial results to the general population.56,74 Thus, there is a definite need
to improve accrual rates for older patients with glioblastoma multiforme as well as to develop more protocols designed specifically for older patients. The use of CAM did not differ between participants and nonparticipants and occurred in a surprisingly high percentage of patients (⬎ 50%). This suggests that patients do not view clinical research and CAM treatments as exclusive of one another. It also emphasizes the importance of considering the use of CAM in evaluating trial participants.75–77 CAM has the potential to affect toxicity, drug interactions, and pharmacokinetic and pharmacodynamic profiles of the investigational agent as well as clinical outcome. Despite its prospective nature, one of the limitations of using a large registry data base is the limited assurance of compliance in the completion of the questionnaire forms. The effect of patient education and type of access to health care could not be addressed in this report. Both of these factors have been described in the literature on clinical trial participation.41,78 – 82 Also, because clinical trial participation was not a primary outcome for the GO Project, details about the number and type of trials available and the timing of participation relative to the course of the patient’s illness were not assessed. Ideally, a prospective evaluation of the potential barriers to clinical trial participation through physician-based and patientbased questionnaires, as reported recently by Lara et al., would address this issue more directly.21 Nevertheless, we believe that insight into important aspects of this particular patient population with malignant glioma and clinical trial participation has been gained. Although the extent of patient participation was greater in this study compared with the participation reported in most other previous studies of patients with other types of malignancies, it remains suboptimal. Strategies to improve recruitment to clinical trials have been described in the literature.83– 87 Positive publicity through support groups or in the lay press can help educate patients and families about the potential benefits of clinical trial participation.88 Expanding neuro-oncology clinical trials to community settings, as accomplished successfully by cooperative cancer groups, may be another strategy to disseminate information about clinical trials and increase accrual rates to studies. Cooperative groups have shown that the quality of data and clinical outcomes are comparable between academic and community hospital settings.89,90 Recognition of the time, cost, and training necessary to recruit patients into clinical trials is the first step in addressing some barriers to clinical trial participation.16 Research on improving physician communication skills suggests that physicians who talk about study procedures and side effects and who
Clinical Trials and Patients with Glioma/Chang et al.
respond to patient concerns are more likely to accrue patients into studies.91 Overall, there is much work to be done in the field of neuro-oncology to improve patient participation in clinical trials. It is the responsibility of all principal investigators to examine their programs and try to address some of these barriers to recruitment. An effort to improve accrual rates will help determine the value of new therapies as expeditiously as possible.
CONCLUSIONS We present for the first time information on factors that may influence clinical trial participation among patients with malignant glioma and contrast the data with what has been described previously for patients with other types of malignancies. The percentage of trial participation for this group was greater than the reported ⬍ 5% participation among patients with other types of primary tumors. Strategies should be implemented to improve recruitment of patients to neuro-oncology trials, especially among elderly and minority populations.
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