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© 2000 American Society for Clinical Oncology Impact of Quality of Life on Patient Expectations Regarding Phase I Clinical TrialsFrom the Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; Departments of Medicine and Psychiatry and the School of Nursing, Georgetown University, Washington, DC; and Divisions of Medical Science and Population Science, Fox Chase Cancer Center, Philadelphia, PA. Address reprint requests to Neal J. Meropol, MD, Divisions of Medical Science and Population Science, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; email nj_meropol@ fccc.edu.
PURPOSE: Quality of life (QOL) is increasingly recognized as a critical cancer-treatment outcome measure, but little is known about the impact of QOL on the patient decision-making process. A pilot study was conducted in an effort to (1) measure the expectations of patients, physicians, and research nurses regarding the potential benefits and toxicities from experimental and standard therapies, and (2) determine the relationship of QOL to patient perceptions regarding treatment options. METHODS: Thirty cancer patients enrolling in phase I clinical trials, their physicians, and their research nurses were administered questionnaires that assessed demographics, QOL, and treatment expectations. RESULTS: Compared with their physicians, patients overestimated potential benefits and toxicities from experimental therapy (mean expected benefit, 59.8% v 23.8%, P < .01; mean expected toxicity, 29.8% v 16.0%, P < .01). Patients estimated a greater potential for benefit (59.8% v 36.8%, P < .01) and less potential for toxicity (29.8% v 45.6%, P = .01) for experimental therapy, compared with standard therapy. Short Form- 36 general health perception correlated with patient perception of potential benefit from experimental therapy (r = .48, P = .01). CONCLUSION: Participants in phase I clinical trial have high expectations regarding the success of experimental therapy and discount potential toxicity. Patient QOL may affect the expectation of benefit from experimental therapy and, ultimately, treatment choice. Understanding the interactions between QOL and patient expectations may guide the development of improved strategies to present appropriate information to patients considering early-phase clinical trials.
PHASE I TRIALS ARE the first step in the clinical development of new drugs or modalities. Because the primary end point of phase I trials is generally the determination of toxicity, rather than antitumor effectiveness, subjects for phase I trials are usually patients for whom there is no standard therapy of known benefit. Thus the participants in these studies are particularly vulnerable. Understanding how patients derive and weigh perceptions of treatment alternatives is critical to improving the consent process in this context. Many influences on patient decision-making regarding cancer treatment have been described. These can be broadly grouped into physician, nurse, and patient factors. Examples of physician influences include information framing,1-3 the physician-patient relationship,4 and trust in the physician.5 Although patients wish to actively participate in the decision-making process, many patients feel that the physician should be the primary decision maker for cancer treatment.6 The research nurse often functions as an educator by reinforcing, interpreting, and clarifying information.7-10 Patients receive much of their information about the trial from the nurses and will often direct their questions toward nurses rather than toward their physicians.11 The role of nurses in the decision-making process has largely been unexplored. Examples of patient factors include the perception of potential benefit and toxicity,5 prognosis,12 age,13 education,14 social support,15 trust in the treating institution,5 hope,16,17 and altruism.5 Quality of life (QOL) outcomes have emerged with increasing prominence as clinical trial end points, particularly in new drug studies.18-20 A large number of QOL measures have gained widespread acceptance,21,22 allowing for a reliable and valid quantification of a patient’s multidimensional functional status. QOL evaluations have been used to compare treatment groups,23,24 to quantify the toxicities of a new treatment,25,26 and to predict survival outcomes.27,28 QOL also correlates with patient performance status, both of which decline over the course of the disease.29 However, few QOL studies have focused on the interaction of QOL measures with patient factors that are known to be important in the decision-making process. Although previous studies have explored how patients derive their perceptions of the risks and benefits of experimental treatments, little is known about how these perceptions are integrated into a treatment choice. We have developed a theoretical model, the Health Stock Risk Adjustment model,30 to explain how patients with life-threatening illnesses derive and weigh treatment options. This model predicts that as one’s perception of future health, relative to baseline health, declines, a patient will tend to overvalue potential benefits and undervalue potential risks in deciding whether to choose an experimental treatment. The pilot study presented here was an initial attempt to obtain data that could inform the development of tools to be used in a later empiric validation of the Health Stock Risk Adjustment model. The impact of health care providers in shaping patient perceptions of various treatment options was obtained by surveying patients, physicians, and nurses regarding treatment expectations. In addition, we explored the relationship between QOL and patient expectations.
Subjects Thirty patients who chose to enroll in a phase I clinical trial at Roswell Park Cancer Institute (RPCI) participated in this study. Common eligibility requirements for phase I trials include the ability to provide written informed consent, incurable malignancy for which there was no standard therapy or for which standard therapy had failed, age greater than 18 years, life expectancy greater than 3 months, and Cancer and Leukemia Group B performance status of 0 to 2 (ambulatory > 50% of waking hours). Six medical oncologists and six research nurses involved in phase I clinical trials at RPCI also participated in this trial.
Questionnaires Patient questionnaires consisted of 69 items (123 questions) in seven sections. Section I involved sociodemographic information. Section II inquired about the patient’s cancer history and other past medical history or comorbid conditions. Section III addressed potential factors important in the patient’s decision-making process, focusing on the patient’s relationships with the physician and research nurse, using survey instruments developed by CARES33 and Daugherty et al.5 Section IV used the FACT-G Social/Family well-being subscale31 to determine the patient’s social support structure. Section V used the Medical Outcomes Study SF-3632 to assess the patient’s QOL. Section VI obtained perceptions of predicted survival with various treatments and at various time points. The patient’s predicted survival was determined on a scale ranging from 6 months to more than 8 years. Section VII obtained perceptions of benefits and toxicities from experimental and standard therapies. Physician questionnaires were given to the oncologists of all patients participating in this study. The questionnaire consisted of 26 items in three sections. Section I inquired about the physician’s demographic information, educational background, and phase I clinical trial experience. Section II involved physician perceptions of benefits and toxicities from experimental and standard therapies. Section III addressed the patient’s cancer history, physician-predicted survival, treatment options offered, and reasons for choosing to participate in phase I studies. Nurse questionnaires were given to the research nurses involved in the phase I trial consent process for all patients. The questionnaire consisted of 33 items in three sections. Section I pertained to the research nurse’s demographic information, educational background, and phase I clinical trial experience. Section II inquired about the research nurse’s perceptions of benefits and toxicities from experimental and standard therapies. Section III pertained to the patient’s cancer history, nurse-predicted predicted survival, and reasons for choosing to participate in phase I studies.
Statistical Analyses
Patient, Physician, and Nurse Characteristics Thirty patients (20 men and 10 women) were enrolled onto this study. Patient characteristics are listed in Table 1. Patients’ mean age was 57.8 years. Ninety-three percent were Caucasian, with 43% having attended college. Eleven different tumor types were represented. Physician and nurse demographics are listed in Table 2. Various types of phase I trials were active during the study period, including new chemotherapy agents, chemotherapy doublets, new cytokines plus established chemotherapy regimens, and immunotherapies.
Response Rate to the Questionnaire Thirty patients were asked 123 questions in each questionnaire. There were 3,591 items completed (97.3% overall). The most difficult question was "Did you experience tumor shrinkage with chemotherapy?" (23.3% unanswered). Section VI (Health Stock Expectations, eight items) and section VII (Perception of Benefit and Adverse Impact, four items) each had a response rate of 86.7%. The most difficult questions were "With standard chemotherapy, how long do you think you would survive?" (43.4% unanswered) and "With investigational therapy, how long do you think you would survive?" (20% unanswered).
Patient, Physician, and Nurse Expectations
Assessments of benefit and toxicity from standard therapies were also compared (Fig 2). Patient expectations of benefit from standard therapy (36.8% ± 27.8%) were higher than the expectations of physicians (20.8% ± 21.9%, P < .01) and neared statistical significance when compared with those of nurses (22.5% ± 21.5%, P = .06). As in the case of experimental therapy, patient expectations of toxicity from standard therapy (45.6% ± 28.4%) were higher than the expectations of physicians (18.3% ± 12.2%, P < .01) and nurses (19.2% ± 20.7%, P = .02). There were no statistically significant differences between physician and research nurse responses in any of the above comparisons.
When experimental therapy was compared with standard therapy, patients perceived a greater probability for benefit from experimental therapy (59.8% ± 26.1% v 36.8% ± 27.8%, P < .01) and less probability for severe toxicity (29.8% ± 14.7% v 45.6% ± 28.4%, P = .01). Research nurses also perceived experimental therapy as having a greater probability of benefit, compared with standard therapy (29.3% ± 15.7% v 22.5% ± 21.5%, P = .04), but no difference in the probability for toxicity (21.4% ± 21.2% v 19.2% ± 20.7%, P = .12). No differences in the estimations of the probability of benefits or toxicities for experimental and standard therapies were seen in physician responses. There was a positive correlation between a patient’s expectation of benefit from experimental therapy and the expectation of benefit from standard therapy (r = .49, P = .01) (Fig 3). There was an inverse correlation between a patient’s expectation of benefit from experimental therapy and the patient’s expectation of toxicity from experimental therapy (r = .50, P < .01) (Fig 4).
Impact of QOL on Treatment Valuations The mean score (± SD) from the SF-36 general health scale was 52.4 ± 25.0. There was a strong correlation between the general health score and patient prediction of survival (r = .85, P < .01) (Fig 5). A lesser correlation with predicted survival was seen with the physical functioning (r = .44, P = .04) and pain (r = .46, P = .03) scales of the SF-36. There was also a correlation between the SF-36 general health scale and patient expectation of benefit from experimental therapy (r = .48, P = .01) (Fig 6). An analysis of the SF-36 general health scale and patient expectation of toxicity from experimental therapy showed no significant correlation (r = -.31, P = .12). No significant correlation was seen between patient expectations and the other scales of the SF-36 (Table 4). No correlation was seen between the FACT-G social/family well-being scale and patient expectation of benefit (r = .26, P = .19) or toxicity (r = -.30, P = .14).
In an effort to understand the decision-making of patients who choose to participate in phase I clinical trials, we evaluated the perceptions of patients, their physicians, and their research nurses regarding different treatment options. In contrast to prior studies, we also explored the effect of QOL on patient perceptions of experimental therapy. Our findings demonstrate that patients perceive potential benefits and toxicities differently than do physicians and research nurses and that QOL may be an important determinant of patient expectations regarding the potential benefit of experimental therapy. Compared with their providers, patients overestimated treatment benefit. Interestingly, patients also overestimated toxicity from experimental therapy. They perceived a greater potential for benefit and less potential for toxicity of experimental therapy, compared with standard therapy. These observations point to an optimistic mindset in this group of patients for whom standard therapy is inadequate or has failed. Unrealistic expectations and false hope in patients who consider phase I studies may need to be addressed in the informed-consent process. The treatment response rates for patients in phase I trials have consistently been reported in the literature as less than 5%.34-37 The likelihood of life-threatening toxicity is similarly low, with toxic deaths reported to be 0.5%.36 The reason for the discrepancy between patient and health care provider expectations is unclear. Mackillop et al14 and Siminoff et al38 showed that patients often have inaccurate perceptions of their cancers, with differing expectations of treatment outcome compared with their physicians. Daugherty et al39 reported discrepancies between physician and patient assessment of goals and toxicities from phase I trials. We confirmed these differences between patient and physician expectations, showing that patient estimation of the probability of benefit from experimental treatment was much higher than the estimation of their treating physician. We also showed that differing expectations of toxicity are present, because patients overestimated the toxicities of both standard and experimental therapy, compared with their physicians. Furthermore, we showed that research nurses, who play an integral and often overlooked role in the informed-consent process, have treatment expectations that are similar to those of physicians, rather than patients. Clearly, the disparities we observed between patients and providers raise concern for the effectiveness of the informed-consent process for this vulnerable population. We observed a positive correlation between patient expectations of benefit from experimental and standard therapy. Those who were most optimistic regarding the potential benefits of experimental therapy tended to feel that standard therapy would also be of benefit. There was also an inverse correlation between a patient’s expectation of benefit from experimental therapy and the possibility of an adverse reaction from the therapy. Those who felt that experimental therapy had the greatest chance of benefiting them tended to feel that they were less likely to experience adverse reaction from the experimental therapy, compared with patients who were less optimistic about the benefits of experimental therapy. This again points to an optimistic mindset regarding the potential of experimental research in patients who take part in phase I clinical trials. A patient’s health status is known to affect the decision-making process. For example, AIDS patients’ desires to be resuscitated are related to their current health status.40 The health status of patients also affects patient preferences for chemotherapy.2 Social well-being has also been shown to play an important role in predicting patient willingness to accept aggressive cancer treatment,15 as have patient estimates of their survival.12 QOL may therefore significantly impact a patient’s treatment choice. There was a strong correlation between patient QOL, as measured by the SF-36 general health scale, and expectation of survival (r = .85, P < .01) (Fig 5). Patients with excellent QOL perceive themselves as relatively healthy and would therefore predict themselves to have a longer overall survival. Conversely, those with poor QOL may consider themselves to be more ill and therefore may predict a shorter overall survival. There was also a positive correlation between the patient SF-36 general health score and the expectation of benefit from experimental therapy (Fig 6). This implies that QOL may affect patient expectation of benefit from experimental therapy and, ultimately, their treatment choice. Our study suggests that patient QOL may affect the decision of whether to enter into an investigational treatment, namely through modulation of the expectation of benefit from the experimental therapy. Patients who enroll in phase I trials typically have incurable malignancies for which standard therapy either does not exist or has failed. Therefore, these patients represent a particularly vulnerable population, given the threat of physical debility and short-term mortality. These characteristics may distinguish patients who consider phase I studies from other cancer patients and suggest the need for increased research in order to better understand how to protect patients from the potential risks of clinical trials. Patient vulnerability is highlighted by the observation by Daugherty et al5 that patients enter onto phase I studies primarily with the goal of therapeutic benefit, despite the fact that the primary study objective is dose-finding. Altruism was identified as a factor by only 33% of patients, whereas the possibility of medical benefit was identified as important by 100% of subjects. Penman et al4 also reported that only 6% of patients listed altruism as a major factor for entering clinical trials. The informed-consent process is a mechanism to afford patient protection.41 Understanding the interactions between QOL and patient perceptions of benefit as presented in our study may allow one to focus on particular issues in the informed-consent process for patient subgroups with disparate decision-making profiles. QOL may be an important aspect of the decision-making process, influencing patient perceptions of benefit from investigational therapy. A framework affording additional insight into how patient perceptions are integrated into a treatment choice may permit tailoring of the informed-consent process to individual perceptions of treatment risks and benefits. The overall questionnaire response was high, with a mean of 97.3% items completed. Questionnaire compliance in multi-institutional studies typically ranges from 85% to 94%.42-44 The administration of our questionnaire by trained interviewers eliminated many of the logistic difficulties, such as unreturned surveys, and aided in clarification of ambiguous questions. However, it is notable that several patients had difficulty with questions dealing with predicted survival. A number of patient factors contributing to item nonresponse have been identified.44,45 These include deteriorating health, lower educational level, advancing age, and questions concerning areas of sensitivity (eg, sexual functioning). The experience with our questionnaire suggests that additional areas of patient sensitivity relate to predicted survival and prior response to therapy. Patients may consciously or subconsciously avoid dwelling on their potentially limited survival, or lack of response to therapy, as a means of coping with their cancer. The study presented here is limited by its small sample size from a single institution. Furthermore, the correlations seen in this study do not necessarily indicate causation. Although patient expectations of benefits and toxicities from investigational therapy are well-known influences in patient decision-making, the suggestive correlation with QOL seen in our study does not definitively demonstrate its causative role in decision-making. To address this issue, a multi-institutional study of decision-making by patients who participate in phase I studies, as well as those who decline to participate, has been initiated. Further insight into how the factors that bear on patient decision-making are weighed may enhance our ability to communicate effectively with patients and facilitate the informed-consent process.
Supported by National Cancer Institute Grant R01-CA82085.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
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ABSTRACT
INTRODUCTION
