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© 2001 American Society for Clinical Oncology Patient Preferences for Adjuvant Interferon Alfa-2b TreatmentFrom the Departments of Health Evaluation Sciences, Internal Medicine, and Surgery, University of Virginia Health System, Charlottesville, VA; Center for Outcomes and Policy Research, Dana-Farber Cancer Institute; Department of Dermatology and Division of Hematology/Oncology, Massachusetts General Hospital; and Division of Hematology/Oncology, Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, MA; Division of Medical Oncology at University of Pittsburgh, Pittsburgh, PA; and Laboratory for Medical Decision Sciences, Washington University, School of Medicine, St Louis, MO. Address reprint requests to Kerry Laing Kilbridge, MD, Department of Health Evaluation Sciences, University of Virginia Health System, HSC P.O. Box 800821, Charlottesville, VA 22908-0821; email: kk4h{at}virginia.edu
PURPOSE: Although trials of adjuvant interferon alfa-2b (IFN  -2b) in high-risk melanoma patients suggest improvement in disease-free survival, it is unclear whether treatment offers improvement in overall survival. Widespread use of adjuvant IFN-2b has been tempered by its significant toxicity. To quantify the trade-offs between IFN-2b toxicity and survival, we assessed patient utilities for health states associated with IFN therapy. Utilities are measures of preference for a particular health state on a scale of 0 (death) to 1 (perfect health).
PATIENTS AND METHODS: We assessed utilities for health states associated with adjuvant IFN among 107 low-risk melanoma patients using the standard gamble technique. Health states described four IFN
RESULTS: Utilities for melanoma recurrence with or without IFN
CONCLUSION: On average, patients rate quality of life with melanoma recurrence much lower than even severe IFN
DESPITE A TREND toward earlier detection of melanoma, patients with high-risk tumors, defined as deep primary melanoma ( > 4 mm) or melanoma metastatic to regional draining lymph nodes, continue to have a poor prognosis. These patients have a relapse rate of 50% to 90% that usually results in death from melanoma.1-4 Because of the activity of interferon alfa-2b (IFN -2b) in patients with metastatic melanoma, there has been considerable interest in its role in the adjuvant setting.5-9 Trials of adjuvant IFN-2b have shown conflicting results,10,11 but one study, Eastern Cooperative Oncology Group (ECOG) trial EST 1684, demonstrated improvement in both recurrence-free and overall survival.11 However, enthusiasm for the widespread adoption of adjuvant IFN therapy has been tempered by concerns for the toxicity of the regimen.
The IFN regimen currently believed to be the most promising is prolonged and toxic. Patients receive intravenous IFN
Thus, concerns arose for the adverse effects of treatment on patients’ quality of life. To address the impact of IFN
These relative values have assumed even greater importance with the early analysis of intergroup trial E1690/S9111/C9190, a follow-up trial of adjuvant IFN. Results of the trial suggest that therapy may provide a benefit in terms of recurrence-free survival but no overall survival advantage.10 In light of these findings, the relative values that patients place on side effects of treatment and melanoma recurrence will ultimately play an important role in the decision whether to use adjuvant IFN. Thus, we interviewed patients to elicit their preferences (utilities) for IFN
Patients Subjects were identified from routine follow-up appointment listings and melanoma patient databases at Massachusetts General Hospital, the University of Virginia Health System, and Beth Israel Deaconess Medical Center. Patients were eligible for study if their melanoma was categorized as low-risk, defined as a tumor too shallow to be considered for elective or sentinel lymph node dissection, and had no clinically palpable lymph nodes. The criteria for low-risk melanoma were institution-specific, and size ranged from  1.0 mm to 1.5 mm. The rationale for interviewing patients with low-risk melanoma was to obtain a study population with the necessary familiarity with melanoma but to avoid ethical conflicts that might arise in unduly influencing a patient’s decision for or against adjuvant IFN-2b therapy (see Discussion). Patients were required to have completed staging and definitive surgical therapy for melanoma before enrollment. Patients unable to speak or read English were excluded. After permission was obtained from the patients’ primary oncologist, patients were contacted either by an introductory letter with an opt-out card or by a scripted telephone call describing the study. If the opt-out card was returned or the patient declined to participate by phone, no further patient contact took place. If subjects agreed to participate, an appointment for the interview was scheduled, usually at the time of follow-up. The study was described in detail a second time at the appointment, and written informed consent was obtained. Fifty patients were contacted by telephone; seven patients declined, and 43 patients agreed to participate. Two hundred twenty-seven patients were initially contacted through the mail, 30 patients returned opt-out cards. Of the remaining 197 patients, 128 patients were then contacted by telephone to schedule an interview; the other 69 were never contacted further because enrollment was achieved. At the time of phone contact, 29 patients subsequently declined to participate. Of the total 142 patients who agreed to participate in the investigation, 107 were interviewed, and 34 could not be interviewed because of scheduling difficulties. Only one patient initiated the interview, but declined to complete the full study, and was excluded from analysis.
Interview: Utilities
The first two scenarios, monocular and binocular blindness, were designed to familiarize the subject with the standard gamble technique and to assess the subject’s understanding of the conceptual task. The next five scenarios captured the range of possible outcomes during and after adjuvant IFN
Following the usual convention, standard gambles for the IFN The standard gambles for the two melanoma recurrence scenarios asked patients what chance of death they would be willing to risk to be free of melanoma recurrence. They were asked to imagine the following two options: (1) living with melanoma recurrence ultimately leading to death from cancer or (2) taking a single pill that would rid them of melanoma recurrence and allow them to die of other causes after the same time interval. Once again, the pill was associated with some risk of instant painless death. The patient was then asked to choose between two alternatives: (1) taking the pill with an uncertain outcome, knowing that this option involved an X% chance of instant painless death and a (1-X)% chance of success (a defined life expectancy without melanoma recurrence and death from noncancer causes); and (2) choosing the certainty of life with melanoma recurrence for the same life expectancy, then death from melanoma. Patients live for the same amount of time if they take the pill "successfully" or live with melanoma recurrence, but they die of different causes. The X% chance of death from the pill was varied in an iterative fashion until the patient was indifferent between the two alternatives. At this point of indifference, the (1-X)% chance of success was equivalent to the patient’s utility for melanoma recurrence. An example of the standard gamble for melanoma recurrence after adjuvant IFN treatment is contained in Appendix B.
Interview: Threshold Questions and Attitudinal Questions
We also asked our subjects a series of 10 attitudinal questions ( Table 4) to search for correlations between their responses and their utility measurements. Some of these questions were designed to synthesize aspects of the decision to undergo adjuvant IFN
Medical Record Abstraction and Statistical Methods Data abstracted from patient records included date of birth, date of melanoma diagnosis, date of definitive melanoma treatment, and confirmation of melanoma pathology and staging. The expected SD of standard gamble utilities assessed using U-Titer is 0.25 (R. Nease, personal communication, May 1997). As a result, a target sample size of 96 subjects was selected to estimate the mean utility of each health state, with a 95% confidence interval of ± 0.05. The Wilcoxon signed rank test was used to compare patient utilities for all health state scenarios.18 Correlations between attitudinal questions, treatment thresholds, age, time since diagnosis, and utilities were measured using the Spearman rank order correlation coefficient.19 The correlation between sex and utilities was measured using the Mann-Whitney U test.20
Study Population Characteristics and Attitudes About the Interview A total of 107 patients were interviewed, 54 (50%) were men and 53 (50%) were women. The mean age was 50 years, with a range in ages of 23 to 93 years. No nonwhite patients were interviewed. The median time since diagnosis was 2 years (range, 1 month to 21 years). The study was well tolerated, as evident by the responses to questions about how subjects felt about the interview. Only sixteen patients (15%) indicated mild agreement with the statement " I was upset by this interview," and no patients indicated strong agreement. One hundred four subjects (97%) said they strongly agreed or mildly agreed with the statement "My answers do a good job showing how I feel about different health conditions." One hundred three subjects (96%) said they agreed that "These questions made me think hard about my personal values, preferences, and feelings." Lastly, one hundred four subjects (97%) mildly or strongly agreed with the statement "This interview could help doctors better understand how patients feel about their health."
Of the 107 subjects, two provided utilities suggesting that they preferred being blind in both eyes rather than being blind in one eye (utility for monocular blindness less than utility for binocular blindness). An additional 10 subjects provided utilities suggesting a misordering of the treatment outcomes (eg, utility for IFN
Standard Gamble Utilities
Threshold Benefit: Melanoma-Free 5-Year Survival Necessary to Tolerate IFN -2bThe mean chance of being melanoma-free at 5 years after adjuvant IFN -2b with mild-to-moderate side effects at which subjects were indifferent between this or skipping IFN (with a baseline 5-year melanoma-free survival of 25%)11 was 32% and the median was 29%, as illustrated in Table 3. In other words, for the average subject, if IFN-2b treatment were certain to cause mild-to-moderate side effects, it would have to offer at least a 32% chance of being melanoma-free at 5 years to be preferred to a side effect-free treatment with a 25% chance of being melanoma-free at five years. This measure of patient preference for avoiding mild-to-moderate side effects of IFN-2b treatment was correlated with the utilities for IFN-2b treatment with mild-to-moderate side effects (Spearman rank order correlation coefficient = -0.24, P = .023).
We performed a similar assessment in which the second option was IFN -2b treatment with severe clinical side effects requiring dose-adjustment (instead of treatment with mild-to-moderate side effects). The mean chance of being melanoma-free at 5 years with IFN-2b treatment and severe side effects at which subjects were indifferent was 40% and the median was 35%, as illustrated in Table 4. This measure of patient preference for avoiding the severe side effects of IFN-2b treatment was correlated with utility for IFN-2b treatment with severe side effects (Spearman rank order correlation coefficient = -0.23, P = .026). We also asked patients directly the minimum reduction in the chance of melanoma recurrence they believed was needed to justify IFN-2b treatment with mild-to-moderate side effects. Table 5 lists the answers of the 95 subjects. These responses were associated with the utilities for IFN-2b with mild-to-moderate side effects (Spearman rank order correlation coefficient = -0.45, P < .0001).
Attitudinal Questionnaire: Correlation With Utilities Table 6 lists Spearman rank correlation coefficients for the association between utilities for treatment outcomes and attitudinal questions. Four items (having melanoma return after toxic treatment being better than having melanoma return without treatment, trade-off between length of life and quality of life, willingness to endure a year of feeling bad to improve the chance of survival, and feeling downhearted and blue during the past month) had statistically significant associations with all four treatment outcomes at a P value of .05 or less. Subjects who agreed with the statement, "If I had a serious disease, I would gladly accept feeling lousy for a year if it meant having a better chance of living longer" had higher utilities than those who disagreed (negative correlation coefficient). Similarly, subjects who agreed with the statement, "Having my cancer return after taking a treatment with bad side effects would be better than having my cancer return without taking that treatment" had higher utilities than those who disagreed. Subjects who had frequently felt downhearted and blue over the past month and subjects who had agreed "I’d rather live a short time in good health than a longer time in very bad health," had lower utilities than those who had not (positive correlation coefficient). Other associations were not consistently statistically significant across all treatment outcomes.
The initial randomized prospective trial of adjuvant IFN -2b for high-risk melanoma patients showed both an overall and a recurrence-free survival benefit for therapy.11 However, the toxicity and lengthy duration of this regimen led to concerns regarding patient quality of life and reluctance to adopt the regimen as standard practice. A more recent investigation continues to suggest a recurrence-free survival benefit but did not show an overall survival benefit for adjuvant therapy.10 In the face of conflicting data on the overall survival benefit of adjuvant IFN-2b, the way that melanoma patients value the toxicity of treatment and melanoma recurrence becomes even more important in the determination of whether to consider adjuvant treatment. Thus, we measured patient preferences for melanoma recurrence and the toxicities of adjuvant IFN-2b in an effort to assist these difficult clinical decisions and measure their impact on patients’ quality of life.
The population of melanoma patients we studied had remarkably high utilities for even the most severe side effects of adjuvant IFN
The most striking finding in our investigation is the significantly lower utilities for melanoma recurrence compared with utilities for the most severe toxicities of adjuvant IFN
Another important finding from our study is the marked variation in utilities from patient to patient, as demonstrated by the large SDs for the utilities for all health states. This variation suggests that patients differ in how they feel about the outcomes of adjuvant IFN
Our investigation has several limitations. Foremost, we did not interview the high-risk melanoma patients who would actually consider adjuvant IFN
Therefore, we chose to interview low-risk melanoma patients. This patient population is also at some risk for recurrent disease and has likely considered how they would feel about this outcome. But because they had not and will not be offered adjuvant therapy for their current treatment, there was no possibility that the study would interfere with their decision-making process. Clearly, though, they are functioning as surrogates for the patients of primary interest here, those with high-risk melanoma who are candidates for adjuvant therapy. We can only speculate about how the utilities of the low-risk patients in our sample might differ from those of high-risk patients facing an actual decision about adjuvant treatment, but it seems likely that patients with low-risk disease would be less accepting of the toxicity of adjuvant treatment because they know they have a better prognosis than the patients described in the scenarios. As a result, any bias introduced by using this surrogate population probably resulted in an under rather than an overestimate of the utilities for IFN Two related limitations of our study are that we cannot address how the utilities of high-risk melanoma patients change over the course of adjuvant IFN treatment nor can we address how the knowledge of such utilities might influence decision-making before treatment. Both questions raise important considerations in the general use of adjuvant therapy throughout the field of oncology. Do the preferences of patients who experience therapy affect the decisions of patients considering therapy? Do patients accommodate to severe side effects? Do patients who have undergone adjuvant therapies experience regret if their tumors recur? Would these patients go through therapy all over again with the benefit of hindsight? Unfortunately, the assessment of utilities in high-risk melanoma patients before, during, and after adjuvant IFN therapy, though critical to our understanding of patient preferences, is beyond the scope of our investigation.
Although disease-free survival may depend on the frequency of follow-up and the degree with which caregivers pursue their suspicions of tumor recurrence, it is frequently reported as a secondary end point in clinical trials. The primary outcome for most clinical oncology trials, however, remains overall survival as a measure of irrefutable benefit. Conflicting results from randomized prospective trials of adjuvant IFN The work by Cole et al12 establishes an important precedent for our current investigation and provides a framework with which to interpret the results reported here. These researchers determined the quality-adjusted benefit of adjuvant IFN treatment based on results of ECOG trial E1684 by accounting for patient utilities for IFN toxicity paired with utilities for melanoma recurrence. They were able to identify utility thresholds above which patients would experience an improvement in quality-adjusted life expectancy even accounting for the toxicity of adjuvant IFN therapy. However, they pointed out that "to use the threshold utility analysis for decision-making it is necessary to obtain an individual patient’s specific utility weights."12 Such weights were not available to the investigators at the time of their analysis but can now be supplied with the results of our current study.
Ultimately, the utilities measured in our study can be applied directly to quality-of-life determinations incorporating more recent trial results than those available to Cole et al12 and any results of subsequent trials in the future. Thus, the net benefit of adjuvant IFN
APPENDIX A: Health State Scenarios After the first month, you will give yourself the interferon 3 days a week (Monday, Wednesday, and Friday) for the remaining 11 months. This means giving yourself a shot under the skin. Your doctor will also ask you to take Tylenol to try to prevent fever. Your doctor will test your blood every week for the first 2 months of your treatment; and then once 3 months, 4 months, 6 months, and 9 months after starting your treatment. This test will require that some blood be drawn from your arm.
A: Interferon Treatment Without Side Effects Getting started on the interferon treatment takes about a month. During that month you will get your interferon by IV (a needle is put into your vein to get the medicine in) every weekday. This means that you will need to drive to and from your doctor’s office. Getting the IV treatment takes about an hour. After the first month, you will give yourself the interferon 3 days a week (Monday, Wednesday, and Friday) for the remaining 11 months. This means giving yourself a shot under the skin. Your doctor will also ask you to take Tylenol to try to prevent fever. Your doctor will test your blood every week for the first 2 months of your treatment; and then once 3 months, 4 months, 6 months, and 9 months after starting your treatment. This test will require that some blood be drawn from your arm. Because you have no side effects from your treatment, you:
You will continue the interferon treatment for a year. At the end of your treatment, you will feel fine and will be able to do all your usual activities.
B: Interferon Treatment With Mild-to-Moderate Side Effects
Side effects of treatment.
You will mostly feel this way on the days after you take your interferon (weekdays during the first month of the treatment; Tuesday, Thursday, and Saturday during the remaining 11 months). When you feel like you have the flu, you:
Although you will feel the worst on the days after you take your interferon treatment, you may feel a little off on the other days as well. You will continue your interferon treatment for a year. At the end of your treatment, you will feel fine and will be able to do all of your usual activities.
C: Interferon Treatment Adjusted Because of Abnormal Blood Tests, Mild-to-Moderate Symptoms
Side Effects of Treatment.
You will mostly feel this way on the days after you take your interferon (weekdays during the first month of the treatment; Tuesday, Thursday, and Saturday during the remaining 11 months). When you feel like you have the flu, you:
Although you will feel the worst on the days after you take your interferon treatment, you may feel a little off on the other days as well. Then, your doctor notices serious abnormalities in your blood tests. Most of the time these abnormalities occur during the first month of IV therapy. These abnormalities do not cause you to have worse symptoms, but they do require that your doctor decrease the dose of your interferon to avoid complications. If the abnormalities continue, your doctor may have you stop your treatment. If the abnormalities improve, you will continue for a full year of interferon treatment. Seven out of 10 patients do not have to stop their treatment and are able to continue interferon. Until you finish your treatment, you will feel like you have the flu. It is important to know that interferon is effective regardless of whether your doctor has had to decrease the dose or stop your treatment. At the end of your treatment, you will feel fine and will be able to do all of your usual activities.
D: Interferon Treatment Adjusted Because of Severe Side Effects
Side effects of treatment. Early in your interferon treatment you feel like you have the flu. Just like the previous descriptions, your symptoms are worst on the days after you take your interferon (weekdays the first month and 3 times a week for the rest of your treatment). During that time, you may have nausea and vomiting, fever, headache, muscle-aches, fatigue, mild depression, or weight loss. When you feel like you have the flu you spend more time than usual resting, may take medicine for aches, are less interested in sex, avoid heavy chores, and avoid strenuous leisure activities. In this scenario, we want you to imagine that part way through the interferon treatment you develop severe side effects. Approximately half of patients with severe side effects will have more than one episode, usually in the first 6 months of treatment. During these episodes (which usually last several days but possibly several weeks), the treatment makes you feel like you have a bad case of the flu. The interferon treatment may severely affect your mood and your ability to think. You will have at least one, and maybe more, of the following symptoms:
You will feel this way most of the time for several days (possibly several weeks) and you:
Because of your side effects, your doctor will lower your dose of interferon. Just over half of patients with severe side effects need dose adjustment during the first month of IV therapy. The rest need dose adjustment during the interferon shots, usually in the first few months. If your side effects continue to be severe, your doctor may stop your treatment. This happens to about four out of 10 patients with severe side effects. If your side effects improve, you will continue for a full year of interferon treatment. Until you finish your treatment, you will feel like you have a mild-to-moderate case of the flu. It is important to know that interferon is effective regardless of whether your doctor has had to decrease the dose or stop your treatment. At the end of your treatment, you will feel fine and will be able to do all of your usual activities.
E: Cancer Returns After Interferon Treatment After the melanoma returns, you may undergo further treatment for the tumor and any symptoms it might cause. This treatment may include more surgery, radiation treatment, or medicines like chemotherapy. Some of these treatments may cause side effects. You will also need to see your doctor more frequently so he can supervise your care closely and minimize any side effects of treatment or symptoms from the melanoma. Early after the melanoma returns you:
Later, after you have been living with your recurrent melanoma for a time, you have progressively more symptoms from your cancer, which eventually causes your death. When you have more symptoms, you:
F: Cancer Returns After No Interferon Treatment After the melanoma returns, you may undergo further treatment for the tumor and any symptoms it might cause. This treatment may include more surgery, radiation treatment, or medicines like chemotherapy. Some of these treatments may cause side effects. You will also need to see your doctor more frequently so he can supervise your care closely and minimize any side effects of treatment or symptoms from the melanoma. Early after the melanoma returns you:
Later, after you have been living with your recurrent melanoma for a time, you have progressively more symptoms from your cancer, which eventually causes your death. When you have more symptoms, you:
G: Disease-Free
Example 1: Standard Gamble for Interferon with Mild-to-Moderate Side Effects as an Example of Side Effect Gambles Imagine that you have just been told that you have high-risk malignant melanoma that has a significant chance of returning and making you sick. Suppose that there are two treatments available to lower the chance that the melanoma will return. Option 1 is described on the card the research assistant just handed to you (Interferon Treatment With Mild-to-Moderate Side Effects). Please take time to read the interferon Treatment With Mild-to-Moderate Side Effects card. Option 2 involves taking a single pill. You only have to take the pill once, and you don’t have to get any more treatments over the next year. Option 2 involves no side effects and is quick and easy, but there is a chance that you will die from the pill. If you die from the pill, it will happen right away, and it will be painless. If you don’t die from the pill, you don’t need any other treatments. Options 1 and 2 are equally good at treating your disease; if you survive option 2, you will avoid any of the hassles and complications of Option 1 and do just as well in the long term. Think about what risks you would take With Option 2 to avoid Option 1.
Example 2: Standard Gamble for Melanoma Returns After Interferon Treatment as an Example of Recurrence Gambles Please take time to read Melanoma Returns After Interferon Treatment, as described on the card the research assistant just handed you. Think about how you would feel about the malignant melanoma returning after your treatment. Now imagine that you can pick between two options. With option 1, you live with melanoma after interferon treatment. With this option, you die from malignant melanoma in about 2 more years. With option 2, you take a pill. If the pill works, you live without melanoma but die from other causes in about 2 more years. If the pill doesn’t work, you die painlessly today. With both options, you live about the same length of time, 2 more years. Think which option you’d rather have.
This study was supported in part by a research grant from Integrated Therapeutics Group, a subsidiary of Schering-Plough, Kenilworth, NJ.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
