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Quality-of-Life–Adjusted Survival Analysis of High-Dose Adjuvant Interferon Alfa-2b for High-Risk Melanoma Patients Using Intergroup Clinical Trial Data

From the University of Virginia, Charlottesville, VA; Dartmouth Hitchcock Medical Center, Lebanon, NH; University of Pittsburgh, Pittsburgh, PA; Massachusetts General Hospital, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute, Boston, MA; Moffitt Cancer Center, Tampa, FL; and Washington University, St. Louis, MO.

Address reprint requests to Kerry Laing Kilbridge, MD, Department of Health Evaluation Sciences, University of Virginia Health System, HSC PO Box 800821, Charlottesville, VA 22908-0821; email: kk4h{at}virginia.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: High-dose adjuvant interferon alfa-2b (IFN2b) for high-risk melanoma is a 1-year regimen that improves relapse-free and overall survival but has significant toxicity. A quality-of-life–adjusted survival (QAS) analysis analysis of two cooperative group phase III trials, E1684 and E1690/S9111/C9190, was performed, incorporating patient values (utilities) for the toxicity of IFN2b treatment and melanoma recurrence.

PATIENTS AND METHODS: Quality-Adjusted Time Without Symptoms or Toxicity methodology was used with melanoma patient utilities and trial data to estimate the effect of IFN2b on QAS. The increase or decrease in QAS that patients could expect from treatment was estimated based on their utilities. Eleven utility predictor questions were tested to identify patients with utilities that result in decreased QAS.

RESULTS: Using E1684 data, IFN2b would result in an increase in QAS for all sets of patient utilities. This benefit was significant (P < .05) for 16% of patients. Using E1690/S9111/C9190 data, 77% of patients would experience a benefit in QAS from IFN2b and 23% would experience a decrease in QAS; neither of these effects was statistically significant. Using utility predictors and the E1690/S9111/C9190 analysis, a decision rule was formulated that helps identify patients in whom IFN2b may detract from QAS.

CONCLUSION: Most patients experienced improvement in QAS in both trials, but this benefit was statistically significant in only 16% of patients in E1684. Change in QAS depends more on the utility for IFN2b toxicity than on the utility for melanoma recurrence. Cancer patients probably have higher utilities for IFN2b toxicity than members of the general population and will tend to favor IFN2b treatment as a result.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PATIENTS WITH THICK primary melanomas (T4) and those with pathologic or clinical evidence of regional nodal metastasis (N1) have a high risk of tumor recurrence after definitive surgical treatment. The rate of recurrence ranges from 40% to approximately 90% and usually results in death as a result of melanoma.^1-3 In 1996, the pivotal Eastern Cooperative Oncology Group trial E1684 demonstrated that adjuvant high-dose interferon alfa-2b (IFN2b) administered intravenously and subcutaneously for 1 year to high-risk melanoma patients significantly prolonged their relapse-free survival (RFS) and overall survival (OS). In the trial, patients received intravenous induction five times a week for 4 weeks, then subcutaneous maintenance therapy three times a week for 11 months. At least 78% of trial patients experienced grade 3 or worse toxicities, 50% required treatment delay or dose reduction for grade 2 to 4 toxicities, and 23% of patients had to discontinue treatment.⁴ Hence, many clinicians who care for patients with melanoma have expressed the fear that the survival benefits of treatment with IFN2b may not compensate patients for the degree and duration of toxicity they are likely to experience. Thus, interest arose in the impact of treatment on patients’ quality of life (QOL).

In response to this concern, Cole et al⁵ performed an analysis of Eastern Cooperative Oncology Group E1684 by means of the Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) method to evaluate the benefit of adjuvant IFN2b as a function of relative values (utilities)⁶ for QOL associated with toxicity of IFN2b treatment and melanoma relapse. Although the investigators did not measure actual patient preferences, they assigned hypothetical values to utilities and described the range of benefit in QOL-adjusted survival (QAS). In a subsequent study, Kilbridge et al⁷ interviewed melanoma patients to elicit their utilities for IFN2b toxicity and melanoma recurrence but did not apply these findings to clinical trial data.

The recent results of Intergroup trial E1690/S9111/C9190 have heightened the interest in how patients weigh the tradeoffs between length of life and QOL. Although this trial found a modest benefit in RFS for high-dose IFN2b, no improvement in OS was observed, and IFN2b toxicity was as severe as in E1684. No improvement in either RFS or OS was observed for low-dose IFN2b. As a result, the relative values that patients place on high-dose IFN2b toxicity and melanoma recurrence have assumed an even greater potential role in the decision whether to use adjuvant IFN2b. To further explore the complicated QOL issues surrounding adjuvant IFN2b, we combined utility data obtained from melanoma patients⁷ with outcomes from the E1684 and E1690/S9111/C9190 trials.^4,8 We have incorporated patient preferences (utilities) for toxicity and relapse into our assessment of high-dose adjuvant IFN2b to quantify the QAS benefit of treatment.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The primary results and trial design of E1684 and E1690/S9111/C9190 are reported elsewhere.^4,8 These randomized controlled trials were designed to evaluate the efficacy of high-dose IFN2b as adjuvant therapy for high-risk resected cutaneous melanoma compared with observation alone in E1684 and compared with observation and low-dose IFN2b in E1690/S9111/C9190. Only the data from the high-dose IFN2b and observation arms are considered in the analysis of E1690/S9111/C9190 because low-dose IFN2b did not result in a statistically significant improvement in RFS or OS. Patients were evaluated for relapse and survival. A total of 280 patients were randomized in E1684 and a total of 427 patients were randomized in E1690/S9111/C9190, respectively, to observation or high-dose IFN2b.

The QAS analysis was performed by means of Q-TWiST methodology^9-12 in which treatments were compared according to the amount of time that trial patients spent in three different health states: (1) time without toxicity from IFN2b treatment and without tumor recurrence (TWiST); (2) time with toxicity from high-dose IFN2b (TOX); and (3) time with tumor relapse or progression (REL). Time with toxicity from high-dose IFN2b was further subdivided according to four severity categories: (1) no toxicity; (2) mild to moderate toxicity; (3) severe clinical toxicity requiring dose reduction or discontinuation of IFN2b per E1690/S9111/C9190 or E1684 protocol (severe toxicity); and (4) severe myelosuppression, hepatotoxicity, or renal dysfunction requiring dose reduction or discontinuation of IFN2b per protocol (laboratory toxicity). On the basis of extensive record review, all participants included in respective trial analyses were assigned to toxicity categories according to the highest level of toxicity experienced at any time on treatment. Although patients experienced waxing and waning toxicities, the highest level of IFN2b toxicity was used to characterize the entire duration of the patient’s IFN2b therapy. This approach ensured that any bias in the analysis was against adjuvant therapy. By definition, patients randomized to observation experienced no IFN2b toxicity and spent no time in the TOX health state.

The duration of each patient’s TWiST health state was defined as the duration of RFS less the duration of treatment with IFN2b, if any. The duration of a patient’s REL health state was defined as the interval after melanoma relapse until death or last follow-up (OS-RFS). Mean health-state durations within the median follow-up interval were calculated by the Kaplan-Meier method.¹³ To account for QOL effects, duration in each health state was then weighted by the utility for that health state, u_TOX, u_TWiST, and u_REL. QAS was calculated as QAS = [(u_TOX x TOX) + (u_TWiST x TWiST) + (u_REL x REL)], where TOX, TWiST, and REL represent health-state durations. Treatment comparisons were performed for all possible sets of utility values for TOX and REL. Ninety-five percent confidence intervals (CIs) and two-sided P values were calculated based on observed differences in respective trial data between IFN2b treatment and observation, with standard errors calculated by the bootstrap method.¹¹ A threshold utility analysis was performed for each trial to determine the range of u_TOX and u_REL values for which QAS was greater with high-dose IFN2b treatment and the range of values for which it was greater for observation.¹¹

The utility weights for the Q-TWiST analysis were obtained in a separate study involving interviews of 95 low-risk melanoma patients after surgical resection of their primary tumors. 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 IFN2b therapy. The standard gamble technique was used to elicit utilities for the seven health states associated with adjuvant IFN2b treatment on a scale of 0 (instant, painless death) to 1 (current health).⁷ For each patient, a weighted TOX utility (u_TOX) was determined by multiplying the probabilities of each toxicity health state in Table 1 by that patient’s utility for the respective health state and summing the products. The REL utility weight for each patient (u_REL) was elicited for the health state describing melanoma recurrence. By convention, the utility of TWiST (u_TWiST) is defined as 1. The pair of utility weights for each patient, (u_REL, u_TOX), then determined the (x,y) coordinates for each patient’s values in relation to the Q-TWiST threshold analysis that reflects the QAS benefit of adjuvant IFN2b for each patient on the basis of clinical trial data. In other words, on the basis of each patient’s individual values for IFN2b toxicity and melanoma recurrence, we estimated the increase or decrease in QAS that a patient could expect, on average, if he/she had enrolled in E1684 or E1690/S9111/C9190 and had been treated with IFN2b.

View this table: [in this window] [in a new window]   Table 1.  Mean Duration for IFN2b Toxicity According to Trial

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Health-State Durations
The median follow-up period was 7 years for E1684 and 52 months for E1690/S9111/C9190. The mean duration in months for IFN2b toxicity according to trial is listed in Table 1. Treatment regimens and drug dosage of IFN2b were identical in both trials. As expected, the toxicity profile of IFN2b was similar in both trials; however, the criteria for dose reduction were slightly different in each protocol.^4,8 The majority of patients experienced severe clinical or laboratory toxicity requiring dose reduction or discontinuation of treatment—74% in E1684 and 81% in E1690/S9111/C9190. A minority experienced clinically mild to moderate toxicity, and only one patient who received IFN2b experienced no toxicity. Four patients randomized to IFN2b in E1690/S9111/C9190 received no IFN2b and therefore had a TOX duration of 0.

The mean time intervals in the TOX, TWiST, and REL health states according to treatment group are listed in Tables 2 and 3. A mean of 7.4 and 7.5 months was spent in the TOX health state in E1684 and E1690/S9111/C9190, respectively. Because patients in the observation arm did not undergo IFN2b treatment, they spent no time in the TOX state. Patients in the IFN2b group in E1684 spent a mean of 31.5 months in the TWiST state compared with patients in the observation group, who spent a mean of 30.0 months. In contrast, patients in the IFN2b group in E1690/S9111/C9190 spent a mean of 23.9 months in the TWiST state, and patients in the observation group spent a mean of 28.7 months. The mean period after tumor relapse or progression was 10.4 months in the IFN2b group and 12.4 months in the observation group in E1684. A similar 2-month difference in the mean period after tumor relapse was observed in E1690/S9111/C9190.

View larger version (26K): [in this window] [in a new window]   Fig 1. E1684 Q-TWiST threshold analysis superimposed on patient utilities. The solid line labeled 0.0 is the threshold above which interferon results in improved QAS. Only the lighter region (top left) is a statistically significant improvement in QAS. Each point represents the (uREL,uTOX) utility pair of one of 95 melanoma patients interviewed.

The Q-TWiST threshold analysis for E1690/S9111/C9190 superimposed on the utility data from interviews of the 95 melanoma patients⁷ is illustrated in Fig 2 with the same axes and scales as Fig 1. The solid line labeled 0 represents the threshold above which IFN2b treatment results in improved QAS. In this case, however, the darker region (bottom right) represents the lower bound of the 95% CI around the threshold, below which IFN2b results in a statistically significant (P < .05) worsening in QAS. The upper bound of the 95% CI, above which IFN2b would result in statistically significant improvement in QAS, does not fall within the range of possible utilities and is therefore not captured on the threshold plot.

View larger version (28K): [in this window] [in a new window]   Fig 2. E1690/S9111/C9190 Q-TWiST threshold analysis superimposed on patient utilities. Above the solid line, IFN2b improves QAS. Below the solid line, IFN2b detracts from QAS. Only the darker region (bottom right) is a statistically significant decrease in QAS. Each point represents the (uREL,uTOX) utility pair of one of 95 melanoma patients interviewed.

Utility Predictors
Along with utilities, we asked the 95 melanoma patients a set of utility predictor questions.⁷ We found that five of 11 utility predictors in Table 4 helped discriminate between patients who would experience improved QAS with adjuvant IFN2b (utility pairs above the E1690/S9111/C9190 Q-TWiST threshold) and those who would not (P < .05). Using these five questions, we created a decision rule composed of the most parsimonious combination of questions that would predict patients with utility pairs below the Q-TWiST threshold, indicating that IFN2b would detract from their QAS compared with observation (although not in a statistically significant range).

Review of the information presented in Table 5 demonstrates that the combination of these two questions successfully avoids treating patients (nontrial participants) who may suffer a decrease in QAS from IFN2b with a high positive predictive value of 97%. Thirty-eight of the 39 patients who should receive IFN2b according to the decision rule have utility pairs above the Q-TWiST threshold, whereas only one of 39 patients predicted to benefit from treatment has a decreased QAS. Similarly, the rule correctly predicted 21 of 22 patients with utility pairs would fall below the Q-TWiST threshold, for a specificity of 96%. In contrast, these two questions have a sensitivity of only 53%. Even though the decision rule recommends withholding IFN2b pending discussion with a physician, 34 of 55 patients actually have utilities above the Q-TWiST threshold, indicating that IFN2b would improve their QAS.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

We have examined the results of E1684 and E1690/S9111/C9190 together to synthesize available QAS data. The trials shared the same inclusion criteria and IFN2b doses, although E1690/S9111/C9190 included more patients with stage T4 melanoma, a subset with a slightly more favorable prognosis.⁸ Both trials found that IFN2b resulted in a statistically significant improvement in RFS, but only E1684 noted an improvement in OS.^4,8 We consider both trials informative to explore the range of possible QAS benefit for adjuvant IFN2b. If E1684 is considered as defining the upper bound for the benefits of adjuvant therapy, then our results suggest that at best, all patients would experience an improvement in QAS with adjuvant IFN2b, and 16% of melanoma patients might expect an improvement in the statistically significant range. And if E1690/S9111/C9190 is considered as the lower bound of possible benefit for adjuvant IFN2b, our results suggest that at worst, 77% of patients would experience improved QAS, while 23% of patients would experience worse QAS with treatment, although not in a statistically significant range.

In both analyses, we found that the Q-TWiST thresholds are nearly horizontal. For any given toxicity utility, large differences in the utility for relapse have a negligible impact on QAS, although the converse is not true. Thus, change in QAS depends more on the utility for toxicity than the utility for melanoma recurrence. Regardless of their utility for recurrence, patients with a utility of 0.85 for even the most severe toxicity of IFN2b are likely to experience improved QAS according to either trial. Most importantly, we found that no patient experienced a statistically significantly worse QAS with adjuvant IFN2b treatment on the basis of data in either trial.

Our current analysis highlights the importance of understanding patient values that are not captured in the standard measures of RFS and OS. Choosing treatment based only on consideration of OS involves the implicit assumption that all survival is equally valued, regardless of whether it is spent with good QOL or with the morbidity of treatment or disease recurrence (upper right-hand corners of Figs 1 and 2, u_TOX = u_REL = u_TWiST = 1). Similarly, the traditional end point of RFS makes the assumption that time with tumor relapse is as bad as death, and time with IFN2b toxicity is valued equivalently to time without treatment or melanoma recurrence (upper left hand corner of Figs 1 and 2, u_REL = 0 and u_TOX = 1). Our analysis reveals the wide variation in patient values and also how few patients would maximize their QAS by choosing treatment exclusively on consideration of OS or RFS. The majority of patients we interviewed have preferences that are unaccounted for by standard clinical end points. Optimal clinical decision making for these patients necessarily requires that treatment choice be tailored to their preferences.

Because E1690/S9111/C9190 forms the lower bound for the possible benefits of adjuvant therapy when considering both clinical trials together, patients with utility pairs that fall below the E1690/S9111/C9190 Q-TWiST threshold are least likely to benefit and most likely to be harmed by adjuvant IFN2b. We focused on the prospective identification of patients with utilities below the Q-TWiST threshold in an effort to help clinicians identify and avoid treating patients least likely to benefit from IFN2b. The stratification of patients above or below this threshold hinges on patient utilities for IFN2b toxicity and melanoma recurrence. In practice, however, elicitation of utilities is cumbersome and time-consuming, ill suited for use in a doctor’s office to assist with decision making at the time that adjuvant IFN2b is actually being considered. Thus, we developed a decision rule using utility predictors that maximized the identification of patients with utilities below the E1690/S9111/C9190 Q-TWiST threshold.

It is important to note that we present only the formulation of the decision rule. It is our hope that the decision rule may be validated in future investigations and developed as a decision aid to screen for those patients least likely to experience an improvement in QAS from adjuvant IFN2b. Ultimately, this decision rule may be used as a set of screening questions to identify patients who require further consultation with their primary oncologist regarding adjuvant IFN2b therapy. When the decision rule recommends that patients should be treated with IFN2b, 97% of those patients maximize QAS according to their utilities and the results of E1690/S9111/C9190. When the decision rule recommends holding IFN2b, however, 62% of patients still have utilities above the E1690/S9111/C9190 Q-TWiST threshold and may benefit from treatment. Thus, patients should not be denied therapy solely on the basis of their answers to utility predictor questions. Instead, their responses should serve as a flag to the treating oncologist that adjuvant IFN2b may not improve their QOL and that a more detailed discussion of the risks and benefits of adjuvant IFN2b is required. Indeed, aside from their correlation with the E1690/S9111/C9190 Q-TWiST threshold, answers to these questions are important in their own right. Patients who expect to get more than a 10% improvement in 5-year RFS with adjuvant IFN2b should have further discussions with their oncologists: E1690/S9111/C9190 demonstrated a 9% improvement in 5-year RFS with IFN2b,⁸ and E1684 demonstrated an 11% improvement.⁴ Similarly, patients unprepared for a year of flulike side effects from adjuvant treatment need to have further discussions with their oncologists before beginning therapy.

Our study has two important limitations. First, the gains and losses in QAS determined from Q-TWiST analysis and patient utilities are calculated on the basis of the mean time spent in various health states in both clinical trials. Thus, the results of our investigation rely on the average experience of clinical trial participants. The reality of any adjuvant therapy, however, is that there are winners (those who never experience tumor recurrence) and losers (those who experience tumor recurrence and cancer death). Winners do not have the "average" experience; they gain more than the mean time in RFS. The second important limitation in our analysis lies in the use of utilities from low-risk melanoma patients. Although the descriptions of IFN2b toxicity are detailed and explicit in the utility elicitation, it is known that cancer patients are willing to assume enormous risks and treatment toxicities for relatively small improvements in survival.^20-27 As a result, the use of utilities from cancer patients rather than from the general population may bias the analysis in favor of IFN2b treatment. We believe that patient utilities will be informative nevertheless, because our analysis is meant to assist in clinical decision making with cancer patients and not for health-policy decisions. As a related issue, we cannot say how utilities from low-risk melanoma patients who will not actually undergo IFN2b treatment may differ from those of high-risk patients. Recent data in breast cancer patients suggest that utilities from low-risk melanoma patients may underestimate the benefit of treatment. Stiggelbout et al²⁸ observed that breast cancer patients who will undergo adjuvant chemotherapy have higher utilities for treatment side effects than breast cancer patients who will not undergo adjuvant therapy.

We have not included the recent results of E1694/S9512/C509801 in our investigation because data are still being analyzed.²⁹ E1694/S9512/C509801 is a randomized prospective Intergroup trial comparing the benefit of high-dose adjuvant IFN2b to the ganglioside GM2 vaccination in high-risk melanoma patients. The trial was halted early at 16-month median follow-up because IFN2b was demonstrated to be significantly more effective than vaccination and it was felt to be unethical to continue the investigation. Early analysis demonstrated that IFN2b prolonged both RFS and OS, as it did in E1684. Although it is arguable whether the three trials are analogous because an observation arm was not included in E1694/S9512/C509801, some comparison is still possible. When considering all three trials in aggregate, outcomes from adjuvant IFN2b appear best in E1694/S9512/C509801. Thus, results of E1690/S9111/C9190 would still provide the lower bound of possible benefit from IFN2b in terms of QAS and would remain crucial to the identification of patients least likely to benefit from treatment.

In summary, QAS analysis of E1684 suggests that all patients will benefit from adjuvant IFN2b, but in only 15 out of 95 patients would this benefit be statistically significant. Analysis of E1690/S9111/C9190 finds that IFN2b may improve QAS for many patients, but none of 95 patients would experience a benefit in the statistically significant range. More notably, IFN2b may detract from QAS in the 22 out of 95 patients who have relatively low values for IFN2b toxicity, although not in a statistically significant range. In both trials, change in QAS depends more on the utility for IFN2b toxicity than on the utility for melanoma recurrence. That is, for any given utility for IFN2b toxicity, large differences in the utility for relapse have a negligible impact on QAS benefit. These results may be helpful to doctors and patients weighing E1690/S9111/C9190 and E1684 in the decision to undergo adjuvant IFN2b. Ultimately, the proposed decision rule may prove to be a valuable, clinically relevant tool, although formal utility assessment is not currently available.

	ACKNOWLEDGMENTS

 
Supported in part by an unrestricted research grant from Schering-Plough. The Intergroup trials were coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, MD, chair) and supported in part by Public Health Service grant nos. CA23318, CA66636, CA21115, CA39229, CA12449, CA80775, CA73590, and CA32291; the National Cancer Institute; National Institutes of Health; and the Department of Health and Human Services.

	NOTES

 
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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Submitted February 16, 2001; accepted November 5, 2001.

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