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Complementary and Alternative Medicine Among Advanced Cancer Patients Enrolled on Phase I Trials: A Study of Prognosis, Quality of Life, and Preferences for Decision Making

Fay J. Hlubocky, Mark J. Ratain, Ming Wen, Christopher K. Daugherty

From the Department of Medicine, Section of Hematology/Oncology, MacLean Center for Clinical Medical Ethics, the Cancer Research Center, The University of Chicago, Chicago, IL; and Department of Sociology, University of Utah, Salt Lake City, UT

Address reprint requests to Christopher K. Daugherty, MD, University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637; e-mail: cdaugher{at}medicine.bsd.uchicago.edu

	ABSTRACT

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Purpose: We sought to describe complementary and alternative medicine (CAM) usage among phase I trial participants and to describe these patients' treatment decision-making preferences, awareness of prognosis, survival, and quality of life.

Patients and Methods: Advanced cancer patients enrolling onto phase I trials were surveyed regarding biologically based CAM use. Decision-making preferences and awareness of prognosis were assessed using validated and/or standardized instruments. The Functional Assessment of Cancer Therapy–General instrument was used to assess quality of life. Univariate and multivariate analyses were performed to detect differences between CAM users and nonusers.

Results: Of 212 interviewed patients, 34% (n = 72) described taking biologically based CAM. Median age of those taking biologically based CAM was 55 years, compared with 62 years for nonusers (P < .005). There were no statistically significant differences found between CAM usage and preferences for degree of patient involvement in medical decision making. Those patients who acknowledged that their deaths were likely to occur within 1 year were more likely to admit to prior CAM use (70% v 34%; P = .02). CAM users had poorer overall quality of life compared with nonusers (87.0 ± 12.4 v 91.2 ± 14.7; P = .007). No differences in survival were identified.

Conclusion: Prior CAM use among phase I cancer trial patients studied was common and associated with age, stated acknowledgment of prognosis, and quality of life. Patients enrolling onto early-phase trials should be questioned about CAM use. Additional study is needed to determine the frequency of use of those biologically based CAM agents that threaten the accuracy of early-phase cancer trial data.

	INTRODUCTION

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The use of complementary and alternative medicine (CAM) is the use of unproven interventions by individuals in conjunction with, or in place of, traditional or conventional means of treatment of various diseases or disease-related symptoms. The National Institutes of Health's National Center for Complementary and Alternative Medicine has divided CAM into five categories.¹ Biologically based therapies is the category of compounds found in nature, or are natural products considered as unconventional means of treatment. Examples of biologically based modalities include the use of vitamins, minerals, herbal remedies, and diet. Documented trends of all forms of CAM usage for the general population in the United States range from approximately 34% to 42%.^2,3 With regard to use of CAM among cancer patients, some reports have described as many as 83% using some form of CAM.^4-17

Prior studies have focused on general aspects pertaining to CAM use in cancer care, including which patients may be more likely to use CAM therapies, and their perceptions and motivations toward use.^6-19 Other studies have attempted to examine the relationships of CAM use with decision-making behavior, survival, and quality of life (QOL).^4,5,19-28 Recent studies have also attempted to examine the safety and efficacy of various CAM therapies and some (such as shark cartilage or certain dietary supplements) have been found to cause severe toxicity.^{5,7,9-11,16-18,28-41} Still others have been identified as reducing chemotherapy efficacy.^31,34-46

Although the study of CAM use among the general patient population is relatively widespread, less attention has been given to the study of CAM use (and biologically based CAM use, in particular) among patients enrolled onto clinical trials.^47-49 Such research is needed, especially given that clinical trials have been designed to collect information in a controlled setting, and trial outcomes are presumed to be related solely and exclusively to the experimental agent(s) under study. Phase I trials in particular are likely to be very sensitive to the issue of biologically based CAM use among trial participants because of the relatively small sample sizes involved and the fact that the aim of these trials is to identify an agent's toxicity and/or identify an optimal biologic dose. Thus, CAM use in a phase I trial has the potential to cast doubt on any resulting toxicity data. Only one previous report has described CAM use among phase I trial participants.⁴⁹ In this study, 80% to 90% of approximately 100 phase I trial patients surveyed at Mayo Clinic (Rochester, MN) admitted to using some form of CAM, including both nonbiologically and biologically based agents.

Given these issues, we studied advanced cancer patients enrolling onto phase I trials at our institution seeking to describe the general usage rates of biologically based CAM. Secondary objectives were to explore social and demographic factors associated with CAM use, describe potential differences in treatment decision-making preferences among CAM users and nonusers, and to investigate associations of CAM use with awareness of prognosis and QOL.

	PATIENTS AND METHODS

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Patients
Institutional review board approval was obtained before initiation of the study. Potential participants who had recently provided informed consent to participate in a phase I trial were selected from the University of Chicago's Advanced Solid Tumor Clinic. Approximately 7 to 10 days after providing informed consent for a phase I trial and within 1 week of first receiving an investigational agent(s), patients were approached for the interview. The interview occurred either that same day or on their next scheduled visit. Eligibility requirements for phase I trials at our institution traditionally has included the ability to give informed consent, age 18 years, a prognosis of at least 3 months, a Karnofsky performance status 60%, and a documented diagnosis of advanced cancer that has either proven refractory to standard therapy or for which no identifiable standard therapy is available. Given the goals of the phase I trials, as a routine, cancer patients enrolling in phase I trials at our institution are informed of the need to avoid use of any and all ingested compounds, agents, and medicines unless medically indicated and/or discussed with the involved phase I investigators.

Survey Methods
Interview. Patient information was obtained via semistructured, face-to-face interviews lasting approximately 45 minutes. Questions were those either used or adapted from prior research.^50-55All questions were read from a standardized survey form. Patients' responses were hand written on the survey form by the interviewers.

Interviewer. Two interviewers conducted all interviews. Interviewers had prior training in either the behavioral sciences or medical ethics, and had prior experience obtaining medical histories and conducting surveys of advanced cancer patients. All interview data were entered into a secure database using available statistical software (STATA version 8.0; STATA Corp, College Station, TX). Missing responses, responses that did not fit into one of the specific item responses, and items in which patients provided more than one response to a survey item were all considered missing.

Survey instruments. The survey information obtained included sociodemographic and clinical information. With a focus on biologically based CAM, questions pertaining to patients' prior usage of CAM were open ended: "Have you ever taken what are sometimes called unorthodox therapies?" A series of examples were provided for clarification. If a patient responded that he or she had used CAM, the specific names or types of CAM were recorded. If the patient had not used CAM, and especially given a clinical trial patients' potential unwillingness to volunteer use due to the phase I program's stated prohibitions, they were then asked: "Have you ever considered taking such therapies?" We did not ask these individuals if they were actively taking or planning on taking these unproven compounds because they had all been instructed specifically not to take them, and we were concerned that patients still taking CAM might not honestly reveal their consumption.

Preferences for medical decision making were assessed using a validated instrument that elicits preferences for shared, patient-centered, or physician-centered decision making.⁵⁶ Patients were also asked questions pertaining to their awareness of prognosis adapted from work by Hinton.⁵⁷ These questions asked patients to estimate the likelihood of death occurring from cancer within no specified timeframe and within 1 year, with possible responses as follows: "It is certain that it (death) will occur"; "It is probable that it will occur"; "It is not probable it will occur"; or "It is not possible it will occur."

All patients completed the Functional Assessment of Cancer Therapy–General (FACT-G) QOL instrument.⁵⁸ Data on patients' subsequent length of survival were obtained from the phase I program's deceased record database or from the Social Security Database Index.⁵⁹

Statistical Methods
A two-sample t test was used to examine age differences between CAM users and nonusers. ² testing was used to examine whether stated CAM use was associated with sex, race/ethnicity, education, diagnosis, decision making, and prognostic awareness (likelihood of dying within 1 year or an open-ended timeframe). A multiple logistic regression model was constructed to examine the effect of demographic factors on CAM use and to explore the association between CAM use and perceptions about dying. Wilcoxon rank sum tests were performed to describe the associations between CAM use and QOL measures. Fisher's exact tests were performed where needed.

	RESULTS

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Two hundred twenty advanced cancer patients who had recently provided consent to enroll onto a phase I trial were approached for our interview study, with a total of 212 patients consenting and completing an interview (95% response rate). During approximately 18 months of the study, 275 patients enrolled onto a phase I trial at the University of Chicago. Although it was a sample of convenience, our interviewed population represented 80% of the overall enrolled phase I population. Of the 212 interviewed patients, 34% (n = 72) admitted to having taken biologically based CAM and an additional 30% admitted to having at least considered the possibility of taking these agents.

Characteristics of Phase I CAM Users and Nonusers
Demographic and clinical characteristics for users, nonusers, and the population as a whole are listed in Table 1. Those describing CAM use had a median age of 55 years, compared with 62 years for nonusers (P = .009). After controlling for sex, race, and education, multivariate analyses demonstrated that age was inversely associated with the likelihood of reporting CAM use (odds ratio [OR], 0.95; P < .000). Thus, with each increasing year there was a 5% lower chance of using CAM. In an exploratory analysis, there was a trend for marriage to be associated with a higher chance of CAM usage (OR, 2.2; P = .06). There were no significant differences in usage based on sex or race, although the population included few nonwhites. With regard to education, no differences in reported CAM use were identified.

Awareness of Prognosis Among CAM Users and Nonusers
Awareness of prognosis was assessed as described. Of note, advanced cancer patients enrolling onto phase I trials have been described previously as having a median prognosis of 6 months.⁶⁰ Responders were assigned to two categories: more aware or pessimistic (those responding "certain" or "probable") or less aware or optimistic (those responding "not probable" or "not possible"). Those who did not respond directly to the question (ie, either refused to answer the question or provided open-ended responses) were coded as having missing values. Although the results were not statistically significant, self-described CAM users tended to be more aware that their deaths were "certain" to occur in some point in the future (70% v 54%; P = .06). This association became statistically significant when we analyzed responses to inquiries about the likelihood of death occurring within 1 year, with 70% of CAM users being certain their death would occur versus 34% of nonusers being certain (P = .02). These data suffer from potentially significant nonresponder bias, given that approximately half of the interviewed patients (53%) clearly felt too threatened or were too visibly upset by the prognosis question to provide a quantifiable response.

Median length of survival for the total population was 7.3 months (range, 0.23 to 48.7 months). No differences in overall survival were found between self-described CAM users and nonusers (median, 7.4 v 7.3 months, respectively). Survival was undetermined for 22 patients and five patients were still alive at the time of analyses.

QOL Assessment
Two hundred eleven patients completed the FACT-G. The total FACT-G and subscale means for the population as a whole, as well as for users and nonusers, are listed in Table 3. One patient did not complete any portion of the instrument and this was included as missing data. Those describing CAM use had a poorer overall QOL compared with nonusers (87.0 ± 12.4 v 91.2 ± 14.7; P = .007). Analysis of FACT-G subscales revealed that CAM users had lower social well-being scores (23.9 ± 4.0 v 25.1 ± 3.8; P = .008) and lower emotional well-being (EWB) scores (14.4 ± 3.9 v 16.1 ± 3.5; P = .002) than nonusers.

	DISCUSSION

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We believe our results have potentially serious consequences with regard to the reliability of early-phase trial results, given that small cohorts of patients are enrolled sequentially in a phase I trial (eg, three patients at a time) and they are each given a uniform dose and schedule of the agent under study. This small cohort is then used to describe any toxicity associated with that dose. Particularly troublesome unproven therapies taken by patients could adversely affect the reliability of toxicity data. For example, St John's wort and high-dose vitamin C were used by patients and are known to have potentially significant interactions with chemotherapy.⁴² Thus, biologically based CAM use could result in an investigational agent's toxicity to be overestimated or underestimated—with subsequent cohorts being underdosed or overdosed with the agent.

Previous studies have found that CAM users are more likely to be female, younger, and educated.^{2,6,9-11,14-16} Although patients admitting to CAM usage in our study were primarily male, this is likely reflective of the fact that most phase I patients were male at our institution (Table 1). Consistent with prior research, younger age was associated with CAM usage in our study.^{6,7,9-11,14,49} However, as opposed to other studies, we did not find education to be associated with CAM use.^{6,7,9-11,14,49}

As mentioned, only one prior report has described CAM use among phase I trial cancer patients and described a significantly higher percentage of CAM use than found within our population.⁴⁹ These differences in self-described CAM use between the two populations are not clear, but may relate to differences in the type and rigor of phase I trials being conducted between the two involved institutions, selection bias in the types of patients enrolling at the respective institutions, and methods used to query patients about CAM use.

Although a statistically significant result was not observed, an interesting finding in our study is that patients with preferences for shared patient-physician medical decision making were more likely to report CAM usage. Although the majority of patients enrolled onto a phase I trial stated a preference for shared decision making, several patients preferred to either be the sole decision maker or defer decision making to their physician. Of these 17 individuals who did not prefer shared decision making, only three reported CAM use. We believe that this is likely to be more than just a random event, and additional research examining potential relationships between preferences for involvement in medical decision making and CAM use is warranted. Although previous studies have shown that CAM users have been described as preferring shared decision making,^4,5,15 our results suggest that patients who state a preference for making decisions exclusively by themselves may be just as unlikely to use CAM as those patients who defer decision making exclusively to their physician. One possible hypothesis to explain why patients who prefer to defer decision making to their physician would be unlikely to use CAM is that they would not ingest any substance without direct guidance or prescription by a physician. More perplexing is a hypothesis to explain why patients who prefer to be the sole decision maker are less likely to use CAM. It is possible that these individuals are more likely to have educated themselves and/or be more evidenced based in their medical decision making and, thus, understand that CAM should not be used in a phase I trial for the same reasons that physicians themselves would not support its use.

Patients who were more pessimistic regarding their prognoses were more likely to report CAM use. However, given the lack of statistical significance and the great potential for nonresponder bias in our data, caution must be advised in attempting to interpret these findings. As reviewed elsewhere,⁵³ given the noted difficulties in attempting to obtain quantifiable responses from advanced cancer patients about their understanding of their prognosis, it is difficult (at best) to draw any firm conclusions from these data. Yet, we do believe that these issues warrant additional study.

Our correlation between CAM usage and poorer QOL is consistent with other studies of cancer patients not enrolled onto clinical trials.^{4,5,12,14,15,22-24,68} CAM users were less likely to report feeling supported by family or friends, and had lower EWB scores than nonusers. In fact, the mean EWB score for CAM users is significantly lower than EWB scores reported for the general cancer population.⁵⁷ Our own prior research findings have indicated that phase I cancer patients as a group generally maintain a slightly higher EWB than the general cancer patient population, and are no more likely to report emotional distress.^50,51,53,57 Given these data, those advanced cancer patients enrolling onto phase I trials who report using CAM may be at particularly greater risk for emotional and psychological distress.

Although the differences in overall QOL scores between CAM users and nonusers are relatively modest (approximately 5% difference between the two groups), these differences clearly are statistically significant and we believe they are clinically significant. Prior QOL research has been able to show that even minimal differences in QOL scores are clinically relevant.^69-73 Some of these modest differences have been due to specific differences in isolated domains of QOL (eg, pain or poor functional status). Thus, we believe the differences in QOL scores between CAM users and nonusers are clinically significant, particularly if one considers the significantly lower EWB scores for CAM users.⁵¹

In conclusion, although overall respect for the decision-making preferences of patients enrolling onto a clinical trial should be maintained, physician-investigators need to be fully aware of their patients' potential CAM use to both effectively care for these patients and conduct scientifically sound clinical trials. Patients participating in early-phase trials should be questioned intensively (yet sensitively) about current or planned CAM use. Those who are younger or those identified as having poorer QOL may be more likely to use CAM. Patients who are known to be using biologically based CAM should be excluded from trials of experimental agents because they create unknown risks to themselves and other potential trial participants, and lead to potentially unreliable clinical trial data.

We believe additional research regarding cancer patients' use of CAM should include studying patients' preferences for decision making involvement and perceptions about the terminal nature of their disease. Additional study is also needed to determine more specifically the frequency of use of those (biologically based) forms of CAM that pose the most significant potential threat to the reliability of early-phase trial data.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Fay J. Hlubocky, Christopher K. Daugherty

Administrative support: Mark J. Ratain

Provision of study materials or patients: Mark J. Ratain

Collection and assembly of data: Fay J. Hlubocky, Christopher K. Daugherty

Data analysis and interpretation: Fay J. Hlubocky, Ming Wen, Christopher K. Daugherty

Manuscript writing: Fay J. Hlubocky, Mark J. Ratain, Christopher K. Daugherty

Final approval of manuscript: Fay J. Hlubocky, Mark J. Ratain, Ming Wen, Christopher K. Daugherty

	ACKNOWLEDGMENTS

 
We thank David Cella, PhD, for very helpful comments and expertise regarding the interpretation of the QOL data that appear in this article.

	NOTES

 
Supported by grants from the Soros Foundation Project on Death in America (Faculty Scholar Program [C.K.D.] and the National Institutes of Health [C.K.D.; Grant No. RO1 CA 087605-01A1]).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted January 30, 2006; accepted November 22, 2006.

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