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Enrollment of Older Patients in Cancer Treatment Trials in Canada: Why is Age a Barrier?

Karen W.L. Yee, Joseph L. Pater, Lam Pho, Benny Zee, Lillian L. Siu

From the Princess Margaret Hospital, University Health Network, Toronto; and National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, Ontario, Canada.

Address reprint requests to Lillian L. Siu, MD, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, 610 University Ave, 5-210, Toronto, Ontario M5G 2M9, Canada; email: lillian.siu{at}uhn.on.ca.

	ABSTRACT

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Purpose: To evaluate the enrollment of older patients ( 65 years) in Canadian cancer treatment trials and compare accrual of older patients in Canada and the United States.

Patients and Methods: A retrospective analysis of the number of older patients enrolled in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) treatment trials between 1993 and 1996 was performed. These rates were compared with the corresponding rates in the general population of patients who were 65 years old and had cancer, obtained from Statistics Canada, and those published by the Southwest Oncology Group (SWOG) in the United States.

Results: Between 1993 and 1996, 4,174 patients were enrolled onto 69 NCIC CTG trials of 16 tumor types. Older patients accounted for 22% of trial enrollees, compared with 58% of the Canadian population with cancer. This discrepancy existed in all cancer types except for multiple myeloma. The percentages of older patients enrolled were also analyzed by study type: 15% in adjuvant trials, 25% in metastatic trials, 29% in investigational new drug trials, 24% in phase I trials, and 21% in supportive care trials. The overall proportion of older patients enrolled onto Canadian trials (22%) was slightly lower than that in SWOG trials (25%).

Conclusion: Age remains a barrier for accrual onto cancer treatment trials, even when reimbursement is not an issue. Strategies to overcome this barrier, including the implementation of trials specifically tailored to patients aged 65 years, are prudent in light of our aging population.

	INTRODUCTION

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AS THE POPULATION ages and life expectancy increases, diseases in individuals 65 years of age and older will have an increasing impact on the Canadian healthcare system. In 1996, the life expectancy at birth for Canadians was 78.6 years (ie, 75.7 years for men and 81.4 years for women).¹ Unfortunately, since 1981, the incidences of cancer have continued to increase with increasing age. In the year 2000, 60,300 new cases of cancer (46%) and 38,200 cancer deaths (59%) were estimated to have occurred in Canadians 70 years of age or older. However, despite the increasing incidence of cancers in the older population, the age-related physiologic changes in organ function, the potential differences in cancer biology in this cohort, and the higher likelihood of not receiving standard therapy, the representation of older patients in clinical trials has been poorly evaluated.^2–4 A recent Southwest Oncology Group (SWOG) study determined that older ( 65 years) patients were substantially underrepresented in cancer treatment studies conducted between 1993 and 1996.⁵ Only 25% of enrollees in SWOG cancer treatment trials consisted of patients 65 years of age or older, even though such patients represent 63% of the population with cancer during that period. Possible explanations for this low accrual rate may include lack of appropriate trials, study-imposed restrictions, high burden of comorbidity, physician attitudes and knowledge, patient preferences, and social, geographic, or financial barriers.

Although Canada and the United States share many cultural similarities, there are significant differences between their healthcare and social programs. The Canadian healthcare system, unlike the American system, provides reimbursement for healthcare costs regardless of whether they are incurred while the patient is participating in a clinical trial. Therefore, we examined in this retrospective study the accrual of older patients in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) cancer treatment trials in Canada and compared the Canadian and United States practices of enrollment of older patients in such trials. Because the NCIC CTG sponsors a high proportion of the cancer clinical trials conducted in Canada, these findings are likely to reflect the representation of cancer patients in clinical trials nationally.

	PATIENTS AND METHODS

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NCIC CTG Cancer Treatment Clinical Trials
A retrospective analysis was performed on all NCIC CTG cancer treatment trials conducted between 1993 and 1996. The period from 1993 to 1996 was chosen because this matched the period previously examined by SWOG. The information obtained included a brief description of the trials, the cancer sites involved, the type of study (phases I, II, or III or investigational new drugs), and the total number of patients, including the number of older (age 65 years) patients, enrolled onto the trials. The trials (adjuvant and metastatic) involved the following cancer sites: cancers of the bladder, breast, cervix, colon and rectum, endometrium and uterus, head and neck, lung, ovary, pancreas, and prostate, in addition to leukemia, lymphoma, melanoma, myeloma, and sarcoma. The number of trials restricted to premenopausal patients or to patients younger than 65 years was determined, and these trials were excluded from this analysis.

Canadian Population of Patients With Cancer
The total number of patients diagnosed with cancer in the Canadian population for the period from 1993 to 1996 was obtained from Statistics Canada. The incidences of all cases of cancer with the International Classification of Disease diagnostic codes corresponding to the aforementioned tumor types and diagnosed between 1993 and 1996 also were obtained from Statistics Canada. The proportions of older patients (age 65 years) among the entire Canadian population, as well as within each tumor type, were defined for that specified time period.

Comparison of Canadian NCIC CTG and United States SWOG Rates
For each type of cancer, the percentage of patients 65 years of age or older was compared with the corresponding percentage in the Canadian population with cancer enrolled onto NCIC CTG trials and with the percentage enrolled onto SWOG trials as reported by Hutchins et al.⁵

Statistical Analysis
The ² test was used to evaluate the differences in proportions of older patients between NCIC CTG trials and the Canadian population of patients with cancer. A two-sided P value of .05 was used in the analysis. Similarly, ² tests were used for other comparisons between two groups of patients.

	RESULTS

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NCIC CTG Cancer Treatment Clinical Trials
During the period from 1993 to 1996, the NCIC CTG conducted 75 cancer treatment trials of 16 tumor types. Six trials had restrictions on the basis of age or menopausal status and were therefore excluded from analysis. The remaining 69 trials involved the following types or sites of cancer: breast (n = 11), gastrointestinal (n = 8), genitourinary (n = 6), gynecologic (n = 6), head and neck (n = 3), hematologic (n = 9), lung (n = 10), skin (n = 3), soft tissue or bone (n = 4), and other sites (n = 5). Four remaining trials examined supportive care in cancer. Of the 69 trials, 29 (42%) involved investigational new drugs. Overall, 4,174 patients were enrolled onto these 69 studies, of whom 22% were 65 years of age or older.

Enrollment of Older Patients
Patients who were 65 years of age or older accounted for 22% of patients in NCIC CTG trials compared with 58% of the Canadian population of patients with cancer (P < .0001) from 1993 to 1996. This discrepancy existed for all cancer types except multiple myeloma (Fig 1). Older patients accounted for 15% of the patients enrolled onto adjuvant trials, 25% of patients enrolled onto metastatic trials, 29% of patients enrolled onto investigational new drug trials, 24% of patients enrolled onto phase I trials, and 21% of patients enrolled onto supportive care trials (Table 1). The overall Canadian accrual of older patients (22%) in adjuvant and advanced cancer treatment trials was lower than that in the SWOG cancer trials in the United States (25%) from 1993 to 1996 (P = .0002; Table 2).¹ The SWOG trials as reported by Hutchins et al⁵ included both adjuvant (27 of 164 trials) and advanced (137 of 164 trials) cancer treatment trials (L. Hutchins and J. Unger, personal communications, June 2002). Nineteen percent of the patients enrolled onto adjuvant trials were 65 years of age or older, whereas 30% of patients enrolled in advanced cancer trials were 65 years of age or older (L. Hutchins and J. Unger, personal communications, June 2002). The Canadian NCIC CTG enrollment rates of older patients in adjuvant or advanced disease trials were comparable to those of the United States SWOG enrollment rates.

View larger version (24K): [in this window] [in a new window]   Fig 1. Proportion of older patients (age 65 years) enrolled in National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) cancer treatment trials compared with the proportion of older patients in the Canadian population of patients with cancer, according to the type of cancer (1993 to 1996).

	DISCUSSION

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Enrollment rates according to disease sites, phase of trial (ie, phase I, II, or III), and treatment types (ie, adjuvant v metastatic) were examined to determine whether the participation rates of older patients were consistently low. The proportion of older patients enrolled onto NCIC CTG cancer treatment trials was significantly lower than the proportion of older patients in the Canadian population with cancer for all types of cancer except for endometrium and/or uterine cancers (which had a small number of patients enrolled) and multiple myeloma. This exception in multiple myeloma might be due to the existence of active clinical trial(s) from 1993 to 1996 that were appropriate and attractive, onto which physicians would enroll their older patients and, similarly, in which older patients could enthusiastically take part. Specifically, MY.7 is an NCIC CTG clinical trial that started accrual in June 1995 and compared dexamethasone to prednisone as induction therapy in multiple myeloma.⁷ Of 119 patients who were accrued onto this trial from June 1995 through December 1996, 77 (65%) were 65 years of age and older (Table 2). The accrual rates in the NCIC CTG trials were lower in studies involving colorectal cancer, lung cancer, prostate cancer, lymphoma, and melanoma and higher in trials involving breast cancer, myeloma, and leukemia compared with those in SWOG trials. This is in part due to differences in the number and types of studies that were available in the two countries at the time (L. Hutchins and J. Unger, personal communications, June 2002).

The proportions of older patients enrolled onto phase I or other investigational new drug trials and supportive care trials were comparable to their enrollment in other types of cancer trials and are consistently low. In general, enrollment of older patients in adjuvant trials was lower than their enrollment in advanced disease trials. This concurs with the observations by Hutchins and Unger (L. Hutchins and J. Unger, personal communications, June 2002). This may arise because older patients often have more advanced tumors at the time of diagnosis.^8–10 Physicians may be reluctant to offer adjuvant therapy to older patients after they have undergone recent curative treatments because of (1) the slower recovery of older patients from curative procedures (eg, surgery or radiotherapy) such that participation in adjuvant trials may not be physically desirable or feasible, (2) hesitation on the part of physicians or patients to enroll in adjuvant trials after recovering from curative treatments when there is no active evidence of disease, and (3) a perception that the likelihood of significantly prolonging life expectancy in this older patient population is low. In contrast, chemotherapy for advanced-stage disease may be more acceptable given the potential to improve quality of life in these patients by decreasing tumor burden and thereby relieving symptoms.

This retrospective analysis may underestimate the proportion of older patients enrolled onto cancer treatment trials because many cancer patients in Canada participate in trials sponsored by groups other than the NCIC CTG, such as those funded by pharmaceutical and biotechnology companies, nonprofit organizations, and individual Canadian universities and hospitals. However, because the NCIC CTG sponsors a high proportion of the cancer clinical trials conducted in Canada, these findings are likely to reflect the representation of cancer patients in clinical trials nationally. Another potential confounding factor that may influence these results is the type of trials offered during the time period under analysis. For example, if a large number of trials are offered in disease sites that are more common in younger patients, enrollment rates for this age group may be increased. Despite the probable differences in the types of trials open during the period under analysis, the accrual of older cancer patients onto clinical trials has been consistently low during the last three decades. Therefore, the low accrual of older patients onto cancer treatment trials is unlikely to be a reflection of age restrictions imposed by the trials or the type of trials active during those periods. In addition, because Statistics Canada gathers information from the provinces, which in turn obtain information from the health services sector, there is a potential for inaccurate coding in claims-based analysis. Despite these limitations, the findings in this study are consistent with results from other countries (including the United States) and with results obtained over various time intervals in Canada.^5,6,8

Possible impediments to enrollment and participation in clinical studies may be secondary to barriers imposed by the patient, physician, institution, protocol design, or health insurance system. Financial barriers have been considered a major obstruction to accrual onto clinical trials.¹¹ Canada and the United States share many cultural similarities but have significant differences in their healthcare and social programs. In the United States, the distribution of healthcare services is based on the ability to pay, whereas in Canada, there is equal and universal access to comprehensive medical care irrespective of the individual’s economic status.¹² Voluntary employment-based private healthcare plans are the primary sources of health insurance coverage for most of the population in the United States. The remainder of the American population receives financial assistance from the governmentally administered programs, Medicare and Medicaid. Medicaid is a federally aided, state-operated and -administered program for individuals with low income. The federal Medicare program provides health insurance to the majority of the United States population 65 years of age and older. Before June 2002, Medicare provided reimbursement only for costs incurred during standard care but not for those incurred during participation in clinical trials.¹³ In contrast, the federal- and provincially funded Canadian healthcare system provides reimbursement for healthcare costs to individuals 65 years of age and older with minimal or no copayments regardless of whether costs are incurred while participating in a clinical trial. Despite this difference in medical coverage, the overall proportion of older patients enrolled onto NCIC CTG adjuvant and advanced-stage trials (ie, 15% and 25%, respectively) from 1993 to1996 was similar to that in SWOG trials (ie, 19% and 30%, respectively).⁵ This indicates that differences in healthcare systems are unlikely to be the major cause for the consistent exclusion of older patients from clinical trials.

Previous studies have shown that physician refusal to enroll patients onto trials is among the top reasons for low protocol participation.^4,14–22 However, only one survey has addressed factors that may affect accrual of older female patients onto breast cancer treatment trials.¹⁹ Therefore, a pilot survey of 40 physicians attending the NCIC CTG Spring 2000 meeting (Toronto, Ontario, Canada) was conducted to examine Canadian physicians’ perspective regarding factors that may affect enrollment of older patients onto cancer treatment trials. The 14-question pilot survey instrument was a self-administered, anonymous questionnaire containing (1) six closed-ended questions to determine the physicians’ demographics (ie, background, type of practice, and patient population), (2) two open-ended questions to ascertain the major deterrents to entering older patients onto trials (eg, protocol requirements, toxicities, logistics, and so on), (3) four closed-ended questions to assess whether physicians actively sought trials for their older patients, and (4) two closed-ended questions to determine what benefit-to-risk ratio would be required for enrollment of older patients onto trials. This brief questionnaire was constructed to expand on previous information available regarding potential barriers to enrollment of cancer patients, in general, onto trials.^3,23 Physicians were at liberty to provide written comments about the topics mentioned in the questionnaire.

Survey respondents included 28 hematologists and medical oncologists (70%), nine radiation oncologists (22%), two surgeons (5%), and one palliative care physician (3%). Because the returned questionnaire was largely blank for the palliative care physician, his or her responses were not included in the data analysis. Most physicians (80%) were affiliated with a university. The majority of cancer specialists had practices that comprised a large proportion ( 25%) of older patients; however, only 10% of physicians enrolled more than 15% of their older patients onto clinical trials. Most physicians expressed reluctance to enroll older patients onto clinical trials. The main reasons for such reluctance were underlying comorbidities in older patients (28%), the concern for possible increased toxicity (50%), and the patient’s and/or family member’s preferences (25%). Other concerns included the inconvenience for patients, the lack of social support, the excessive time required for patient enrollment and follow-up studies, and the physician’s preference for conventional therapy. A higher benefit-to-risk ratio was desired by physicians to enter older patients onto adjuvant trials as opposed to metastatic trials.

The older patient may be at increased risk for therapy-related toxicity²⁴ given the normal age-associated deteriorations in biologic and physiologic functions^25–31 and the higher proportion of older individuals who are likely to have underlying comorbidities.³² Physicians’ concern with regard to administering chemotherapy to cancer patients with comorbidities may be justified. Women with breast cancer who had three or more underlying medical illnesses had a 20-fold increased risk of death from causes other than breast cancer compared with women without coexisting conditions, even after adjustment for disease stage and type of therapy.³³

However, there is inadequate evidence to indicate that older cancer patients who are otherwise fit will have increased treatment-related toxicities compared with their younger counterparts. Some studies indicate that for certain tumors, such as breast and lung cancers, given the same treatment regimen and dose-intensity, older patients have no increased toxicity and similar survival rates compared with younger patients,^34–37 whereas for other cancers, such as acute myeloid leukemia, increased toxicity and poorer overall survival rates were observed.^38,39 In contrast, evidence indicates that failure to provide full treatment to older patients may lead to inferior outcomes.^40–44 At present, given the paucity of information concerning the benefit-to-risk ratio of administering chemotherapy in older cancer patients, it may be helpful to use a decision analysis model to guide medical decision making.⁴⁵

Older cancer patients have been consistently underrepresented in cancer treatment trials both in the United States and Canada, irrespective of differences in healthcare systems. Strategies to improve the quality of care for older cancer patients will require increased research on the age-related changes in organ function, the impact of comorbidities on baseline function and tolerance to chemotherapy, the pharmacology of drugs in this population given the changes in pharmacokinetics and pharmacodynamics with age, the role of supportive modalities such as administration of granulocyte colony-stimulating factor to reduce the incidence of febrile complications, and the impact of age on the biology of the disease. Increased participation of older patients in clinical trials is also required to improve quality of care. This can be achieved by educating both physicians and patients about the toxicities and benefits of treatment regimens, increasing the number of trials targeted to this population using the National Cancer Center Network guidelines for the use of chemotherapy in older patients as a framework,⁴⁶ and streamlining the amount of time and paperwork required to enroll patients onto studies.

In 1998, the United States NCI and the National Institute on Aging jointly started a program to fund NCI trials in older individuals and a program on cancer pharmacology and treatment to accurately define the burden of comorbidity in older cancer patients and to devise optimal therapy for these patients with age-associated health problems.⁴⁷ In 2000, the United States NCI introduced several initiatives designed to make participation in clinical trials easier for oncologists, including the Expanded Participation Project (http://spitfire.emmes.com/study/epp/), which will let oncologists participate in trials conducted by several cooperative groups and provide centralized data management, and the Cancer Trials Support Unit (http://www.ctsu.org/), which will allow members of cooperative groups in North America to register for any Cancer Trials Support Unit trial; download protocols, case report forms, and other documents; and receive reimbursement for research costs.⁴⁸

These are essential and fundamental steps toward improved care and, it is hoped, increased survival in older cancer patients. However, additional and consistent efforts are required to ensure that the representation of older patients in trials will translate into changes in clinical practice, enabling an improvement in their survival and quality of life.

	ACKNOWLEDGMENTS

 
We thank L. Hutchins and J. Unger for providing more detailed information about the enrollees in the SWOG studies and S. Marlin for data on enrollment of older patients onto NCIC CTG trials during the period from 1974 to 1993.

	NOTES

 
Presented in part at the Thirty-Seventh Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001.

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Submitted December 11, 2001; accepted January 22, 2003.

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