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© 1999 American Society for Clinical Oncology Health-Related Quality of Life in Men With Metastatic Prostate Cancer Treated With Prednisone Alone or Mitoxantrone and PrednisoneFrom the Department of Medicine, University of British Columbia, Vancouver, British Columbia; Princess Margaret Hospital and University of Toronto, Ontario; Tom Baker Cancer Centre and University of Calgary, Calgary; and Hamilton Regional Cancer Centre and McMaster University, Hamilton, Canada. Address reprint requests to David Osoba, MD, Quality of Life Consulting, 4939 Edendale Court, West Vancouver, British Columbia, Canada V7W 3H7; email david_osoba{at}bc.sympatico.ca
PURPOSE: A combination of mitoxantrone plus prednisone is preferable to prednisone alone for reduction of pain in men with metastatic, hormone-resistant, prostate cancer. The purpose of this study was to assess the effects of these treatments on health-related quality of life (HQL). PATIENTS AND METHODS: Men with metastatic prostate cancer (n = 161) were randomized to receive either daily prednisone alone or mitoxantrone (every 3 weeks) plus prednisone. Those who received prednisone alone could have mitoxantrone added after 6 weeks if there was no improvement in pain. HQL was assessed before treatment initiation and then every 3 weeks using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (EORTC QLQ-C30) and the Quality of Life Module–Prostate 14 (QOLM-P14), a trial-specific module developed for this study. An intent-to-treat analysis was used to determine the mean duration of HQL improvement and differences in improvement duration between groups of patients. RESULTS: At 6 weeks, both groups showed improvement in several HQL domains, and only physicalfunctioning and pain were better in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. After 6 weeks, patients taking prednisone showed no improvement in HQL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life (P = .009), four functioning domains, and nine symptoms (.001 < P < .01), and the improvement (> 10 units on a scale of 0 to100) lasted longer than in the prednisone-alone group (.004 < P < .05). The addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life (.001 < P < .003). CONCLUSION: Treatment with mitoxantrone plus prednisone was associated with greater and longer-lasting improvement in several HQL domains and symptoms than treatment with prednisone alone.
IN A RANDOMIZED STUDY conducted in multiple Canadian institutions, therapy with a combination of mitoxantrone and prednisone was shown to be preferable to treatment with prednisone alone for the palliation of pain in men with hormone-resistant, metastatic prostate cancer.1 A palliative response was defined as a decrease in pain on a self-assessment pain scale without an increase in analgesic medication, which was maintained for two consecutive evaluations at least 3 weeks apart. A secondary end point was a decrease in analgesic use without an increase in pain, and other health-related quality-of-life (HQL) parameters were evaluated by patient self-assessment using the Prostate Cancer–Specific Quality-of-Life Instrument (PROSQOLI),1,2 the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire C30 (QLQ-C30),3,4 and a trial-specific module of questions (Quality of Life Module–Prostate 14 [QOLM-P14]) designed for this study. In the previous report, the emphasis was placed on the primary and secondary end points, and the quality-of-life results were described only briefly.1 As shown by changes in the PROSQOLI Linear Analog Self-Assessment scores and the QLQ-C30 scores, treatment with mitoxantrone plus prednisone was favored over prednisone alone for pain relief, physical activity or function, constipation, and mood. Patients in both treatment arms who met the criteria for a palliative response had improvement in most HQL domains, but details of the nature of the improvements and their duration were not described. Here we present a detailed analysis of HQL as measured by the QLQ-C30 and the trial-specific module. Analysis of quality-of-life data was performed to obtain information about the following questions: (1) Was there a difference in HQL between the patients treated with mitoxantrone plus prednisone compared with prednisone alone at 6 weeks of therapy, ie, before patients treated with prednisone were eligible for the addition of mitoxantrone? (2) Was HQL improved in patients who continued on treatment with mitoxantrone and prednisone, and if so, which domains continued to show improvement and for how long? (3) Was HQL maintained in patients who continued treatment with prednisone alone? (4) Was there an improvement in HQL in patients in whom mitoxantrone was added after the failure of prednisone alone?
Patient Characteristics and Treatment The characteristics of the patient population were described previously.1 Briefly, 161 men with metastatic adenocarcinoma of the prostate, who had symptoms that included pain and disease progression despite standard hormonal therapy, were randomized to receive mitoxantrone (12 mg/m2 given intravenously every 3 weeks) and prednisone (5 mg orally twice daily) (80 patients) or prednisone alone (81 patients). In addition to other eligibility criteria, the patients had to be willing and able to complete pain and HQL questionnaires. The treatment of the patients in the study was described in detail previously.1 Briefly, patients continued their primary androgen ablation therapy, and most patients had discontinued additional antiandrogen treatment. Midway through the study, flutamide withdrawal response was recognized; thereafter, patients were monitored for at least 4 weeks after stopping flutamide before being entered onto the study. Two responding patients who entered earlier in the study discontinued flutamide less than 4 weeks before entry. Patients were examined in the clinic every 3 weeks. Analgesic medication was adjusted to give optimum pain control before entry and throughout the study. All analgesic medications were recorded by the patients in a diary, which was used to compute an analgesic score representing mean daily analgesic use during the previous week. Use of dexamethasone and other corticosteroids was not allowed for antiemetic medication. Dosages of mitoxantrone were adjusted according to granulocyte and platelet nadirs. Patients with no improvement in pain or those with progressive symptoms after treatment with prednisone alone at 6 weeks were eligible to have mitoxantrone added to the prednisone. The study was not blinded because it was deemed inappropriate to give control patients sham injections of colored fluid.
Primary End Point
Quality-of-Life Questionnaires The QLQ-C30 was supplemented by the QOLM-P14, which consisted of 14 items related to symptoms from metastatic prostate cancer and side effects of analgesics and chemotherapy that are not covered by the QLQ-C30 (Appendix). These items were derived by interviewing 10 men with advanced prostate cancer who were attending a support group to obtain information about their concerns. A semistructured format was used to ask what was of importance to their HQL and to list their issues. Twenty issues, many related to each other but not covered by the QLQ-C30, were identified. From these issues, 12 items were written and reviewed by oncologists who care for patients with prostate cancer. An item on difficulty passing urine and one on the extent to which having to pass urine at night disturbed sleep were added to the questionnaire halfway through the study, after it was discovered that they had been inadvertently left out at the beginning. As a first step, before an analysis of the HQL data was performed, an evaluation of the psychometric properties of the original 12 QOLM-P14 items was conducted on the data set of responses obtained in the trial. Questionnaire structure and scaling errors were examined by a principal components factor analysis, including orthogonal varimax rotation,6 and by a multitreat scaling analysis.7 Three scales (impact of pain on mobility, pain relief, and drowsiness) and two single items (hair loss and change in taste) were identified. Internal consistency estimates as assessed by Cronbach's alpha coefficient were 0.88 for impact on pain mobility, 0.72 for pain relief, and 0.68 for drowsiness. The two items added during the study (nocturia and effect of nocturia on sleep) were not included in the factor analysis and were analyzed as single items.
The QLQ-C30 was scored according to previously described methodology.4,8 The raw scores were transformed to provide a range between 0 and 100; higher scores for the functioning and global quality-of-life scales indicated better functioning, whereas higher scores for the symptom scales and items indicated more of each symptom. After factor and scaling analysis of the QOLM-P14, the scoring of the resulting scales and single items was performed in a similar fashion to that of the QLQ-C30. Patients also completed a nine-item linear analog self-assessment instrument, the PROSQOLI.1,2 A comparison of this assessment method with the QLQ-C30 was reported elsewhere.2
HQL Analyses The proportions of patients in each treatment group who had a change of at least 10 units in either domain or item scores (possible range, 0 to 100) on at least two successive measurements were calculated.9 This degree of change is probably meaningful to patients because it is easily perceptible to them and may therefore be clinically important. Another study using different methodology10 also supports the contention that a change of greater than 10 units in QLQ-C30 domain scores is clinically important, and studies in other illnesses indicate that changes of this magnitude are clinically meaningful.11-13 The mean duration of change (± 2 SE) for each group was determined by an intent-to-treat analysis. To calculate the duration of change, each patient who experienced a change of greater than 10 units lasting for at least two treatment cycles (6 weeks) was counted only once, and data from patients who experienced a change at any cycle followed by no further data (off treatment or death) were excluded. The mean duration of change was calculated by summing the duration of change for all patients and dividing by the number of patients randomized to the group. Statistical comparisons for the mean duration of change between the intent-to-treat groups were not attempted because the data were not normally distributed. We did not use nonparametric methods for these analyses because it seemed unreasonable to assign median values of zero to a group in which the majority of patients did not have an improvement of greater than 10 in a given HQL score. In addition to assessing the mean duration of change in HQL scores for the treatment groups on an intent-to-treat basis, we also assessed the duration of a change of greater than 10 only in patients who experienced it. This was accomplished by plotting the proportions of patients who were still experiencing this degree of change as a function of time, rounded to 3-week intervals (the timing of the assessments), and comparing the resulting curves by the log-rank test in a manner analogous to that used for comparison of survival curves. Participating investigators were unaware of individual HQL scores while the study was being conducted, and the analysis of HQL data was performed only after the study was closed to accrual.
Characteristics at Baseline The characteristics of the 161 men who participated in the trial that are of importance for the quality-of-life assessment are listed in Table 1. Most characteristics were well balanced, except that there was a trend for patients who had been randomized to the mitoxantrone-plus-prednisone arm to have a higher analgesic score than those treated with prednisone alone. Details of the baseline QLQ-C30 and QOLM-P14 scores indicated no apparent differences between the groups in any of the functioning scales, global quality-of-life scale, and symptoms (Table 2).
Intergroup Comparison of HQL After 6 Weeks of Therapy Of the 81 patients randomized to the prednisone arm, 62 remained in this arm after 6 weeks, compared with 71 of the 80 patients randomized to the combined treatment arm. The difference in attrition rates (23% v 11%) creates bias when attempting a between-groups analysis in the conventional manner, because the patients who were doing well were more likely to remain on study. Therefore, a statistical analysis of these differences was not attempted, but a description of the HQL results in patients who completed 6 weeks of prednisone or of mitoxantrone plus prednisone (two cycles) is provided, using two different methods. In the first method, the mean scores were calculated for each treatment group. The mean values for each score in both groups were similar, although patients who received mitoxantrone plus prednisone apparently experienced more distress from hair loss (mean scores ± SD, 9.0 ± 19.6 v 1.1 ± 6.0) and a change in taste (mean scores ± SD, 24.6 ± 28.4 v 12.5 ± 22.6), whereas those who received only prednisone had more difficulty with insomnia (mean scores ± SD, 28.0 ± 28.4 v 19.2 ± 25.6). In the second method, we examined the differences in the change in scores from baseline to the 6-week time point in both groups. The baseline scores for each patient were subtracted from the scores at 6 weeks and the means of differences were calculated for each group. Thus, each patient served as his own control. The advantage of this method over the previous one is that it accounts for variations in individual baseline values between patients (whether or not the group baseline values are statistically significantly different between groups). Compared with the prednisone-only group, the mitoxantrone-plus-prednisone group apparently showed improvement in physical functioning (mean change from baseline ± 2 SE, +8.4 ± 2.3 v -1.1 ± 3.2) but greater hair loss (+6.8 ± 2.5 v –0.6 ± 1.4) and greater nocturia leading to sleep disturbance (+4.6 ± 4.6 v -9.0 ± 3.5).
Changes in HQL as Compared With Baseline In the following analysis, the differences between the baseline scores and scores after each even-numbered (second, fourth, and sixth) cycle of treatment were calculated for each of the three treatment groups, ie, patients who started and continued on prednisone alone or on mitoxantrone plus prednisone and those who had mitoxantrone added (the cross-over group). The comparison between baseline and each treatment cycle assesses the degree and duration of improvements in HQL at specific time points in patients who continued on treatment. Thus, it is not a comparison between groups by intent to treat but, rather, a comparison of scores within the groups of patients remaining on study and their own pretreatment scores. Of the patients who remained on treatment after 6 weeks of therapy (two cycles), the group treated with prednisone alone (n = 62) showed improvements in social functioning, global quality of life, nausea and vomiting, anorexia (.003 < P < .007), and the impact that pain had on their mobility (P = .01) compared with baseline scores (Fig 1). The group treated with mitoxantrone plus prednisone (n = 71) showed an improvement in physical functioning, social functioning, global quality of life, pain, anorexia, constipation, the impact of pain on mobility, the degree of pain relief, and drowsiness (.0001 < P < .009). This group experienced an increase in hair loss as the only statistically significant deleterious effect (P = .009; Fig 1). Six weeks after the addition of mitoxantrone, the cross-over group (n = 35) experienced an improvement in pain, insomnia, and the impact of pain on mobility (.0001 < P < .01; Fig 1). Only comparisons with differences reaching a significance level of P = .01 are emphasized, although several other comparisons of differences, particularly in the mitoxantrone-plus-prednisone and cross-over groups, showed P values of .01 < P < .05.
After 12 weeks of therapy (four completed cycles), there was no statistically significant improvement, as compared with baseline, in any of the HQL scores in the group still being treated with prednisone (n = 42), although there was an insignificant decrease in pain (P = .05; Fig 1). However, the group that continued to be treated with mitoxantrone plus prednisone from randomization (n = 54) showed continuing improvement over baseline in four functioning scores (.0001 < P < .004), global quality of life (P = .009), and nine symptoms (.0001 < P < .01). The only deterioration was in hair loss (P = .001). The cross-over group (n = 25) had an improvement in global quality of life (P = .003) as well as in pain relief (P = .0001). After 18 weeks of therapy (six completed cycles), the small number of patients still receiving prednisone (n = 19) had improvement only in the impact of pain on mobility (P = .004) as compared with baseline (Fig 1). Those receiving mitoxantrone plus prednisone (n = 43) continued to have an improvement in 11 of the 14 function and symptom scales that had improved after cycle 4. The small number of cross-over patients (n = 17) still remaining on study after 18 weeks of mitoxantrone therapy continued to have improvement in pain, impact of pain on mobility, and pain relief (.001 < P < .003) but had significantly greater hair loss (P = .01).
Duration of Change in HQL Scores In the mitoxantrone-plus-prednisone group, duration of improvement in several domains and symptoms ranged from 11 to 19 weeks, whereas duration of improvement in the same domains and symptoms in the group treated with prednisone alone ranged from 3 to 7 weeks (Table 3). In patients who had mitoxantrone added to prednisone after worsening of symptoms on prednisone alone, duration of improvement ranged from 4 to 26 weeks after the addition of mitoxantrone. Hair loss lasted longer in the mitoxantrone-plus-prednisone group than in the prednisone-alone group. Although some patients experienced deterioration in their taste, it was noted that some patients (23.5%) who received mitoxantrone plus prednisone had an improvement in taste.
When duration of improvement (> 10 points) was assessed by the log-rank test, a longer duration of improvement was found in social functioning, pain, impact of pain on mobility, pain relief, insomnia, and drowsiness (.004 < P < .048) in patients treated with mitoxantrone plus prednisone compared with prednisone alone (Fig 2). In the cross-over patients, a longer duration of improvement was found in pain, pain relief, and drowsiness compared with the prednisone-alone group.
The Canadian study of mitoxantrone plus prednisone versus prednisone alone for men with symptomatic hormone-resistant prostate cancer has provided a valuable database for analyzing HQL during treatment.1 The purpose of the present report is to provide a more detailed analysis of the HQL data obtained from administration of the QLQ-C30 and QOLM-P14. Our approach was to address questions about the extent, if any, to which HQL improved in the treatment arms, which domains showed improvement, how long improvement lasted, and whether patients in whom mitoxantrone was added after failure of prednisone alone derived benefit in HQL after the addition of mitoxantrone. A general limitation of the analyses of HQL that compared groups of patients with unequal attrition rates was that the resulting missing data led to difficulties in the interpretation of any differences between the groups. Unequal rates of attrition in each group may lead to bias, usually in favor of the group with the largest proportion of patients remaining on study. Thus, the comparison of mean values during the treatment and follow-up periods is particularly subject to bias. An analysis based on the last recorded observation suffers from the same criticism.11 The use of mean change scores between baseline and a later time to compare groups is advantageous because it is not influenced directly by attrition because each patient acts as his own control; however, this approach is limited because it can be applied only to patients who are still undergoing treatment or follow-up. Thus, there may still be some apparent selection bias because patients who experience some benefit from treatment are more likely to remain on it longer. Another potential bias is that better HQL at pretreatment also leads to patients remaining on treatment longer. However, this is less important when each patient acts as his own control because the patients with the highest pretreatment HQL scores are also the ones with the least room for showing improvement with time. To avoid these biases, some investigators have used various imputation methods12 and growth curve analysis/mixed effects analysis of variance models13 in attempts to make optimal use of serial HQL data with missing observations. However, these latter sophisticated methods are based on making assumptions about the values to be assigned to the missing data, are complex to perform, and are not intuitively appealing. In attempting to determine differences in duration of changes from baseline between groups with unequal attrition rates, some of the aforementioned difficulties may be overcome by an intent-to-treat analysis in which the mean duration of a predetermined amount of change (eg, > 10 on a scale of 0 to 100) is calculated by summing the length of all individual changes for each group and then dividing by the number of patients randomized to that group. This approach is commonly used to compare duration of tumor response and survival between groups in oncology clinical trials. It addresses the important question of whether the patients assigned to a particular treatment protocol benefit from it regardless of subsequent censoring. Thus, a longer period of improvement in HQL scores in one group would constitute strong evidence for better HQL in that group. The limitation of this method in our study is that most of the patients in the group that began on prednisone alone had mitoxantrone added after prednisone failure. This cross-over group necessitated a separate analysis. Thus, each patient who began treatment with prednisone only and then had mitoxantrone added could be considered as part of the prednisone-alone group only as long as he stayed in that group. This cutoff point is considered to be reasonable because patients would be censored as prednisone treatment failures at this time. In addition, careful attention to the attrition rates in the treatment groups being compared provides important, complementary information and should not be ignored. After 6 weeks of treatment, there were few differences in either mean scores or mean change scores (difference from baseline) between the prednisone-alone and mitoxantrone-plus-prednisone treatment arms. However, the number of patients in the prednisone arm had decreased from 81 to 64, whereas the number of patients in the mitoxantrone-plus-prednisone arm had decreased from 80 to 71, and three patients in the prednisone arm had already crossed over to have mitoxantrone added to their treatment. Thus, although prednisone seemed to benefit patients who were still on treatment at 6 weeks, the high attrition rate compared with that in the mitoxantrone-plus-prednisone arm probably indicates a higher likelihood of treatment failure in the prednisone-alone group. Patients who were initially randomized to mitoxantrone plus prednisone and who continued on this treatment derived the greatest improvement in HQL scores compared with baseline. This benefit was still evident at 18 weeks after randomization, although the number of patients in the mitoxantrone-plus-prednisone group was now approximately half of the original number (43 of 80). In the mitoxantrone-plus-prednisone group, HQL scores improved in global quality of life and all functioning domains except role and cognitive functioning. Several symptoms, ie, pain, fatigue, insomnia, anorexia, drowsiness, and constipation (the latter two presumably as a result of a decrease in analgesic intake), also improved significantly. By using an intent-to-treat analysis, we found that the mean duration of improvement in these domain and symptom scores ranged from 11 to 19 weeks in the mitoxantrone-plus-prednisone group compared with 3 to 7 weeks in the prednisone-alone group. In addition, when patients who experienced an improvement were analyzed separately, the duration of improvement was significantly longer in those treated with mitoxantrone plus prednisone. Thus, the analyses indicate a better HQL in patients who were treated with mitoxantrone and prednisone rather than prednisone alone after randomization. The only deleterious effects in patients treated with mitoxantrone plus prednisone were greater concern about hair loss and a temporary increase in an unpleasant taste. However, it is possible that this group did have deleterious effects in the first 2 weeks after each chemotherapy cycle, but this would not have been evident because the QLQ-C30 and QOLM-P14, which ask about the past week, were not administered at these times. There was improvement in HQL in the group that had mitoxantrone added to the prednisone after treatment failure on prednisone alone. However, the improvement was in fewer domains and symptoms than in the group that began on mitoxantrone plus prednisone, which might have been a result of selection bias because prednisone, given for at least 6 weeks, had failed to control symptoms, and these patients would be unlikely to benefit from continuing the prednisone as part of the combination. Nevertheless, mitoxantrone added to prednisone produced a reduction in pain that lasted from 14 to 26 weeks in approximately one half of these patients. This implies that mitoxantrone alone may be effective in producing pain relief. It is evident that mitoxantrone plays an important role not only in pain relief but also in the improvement of several HQL domains and symptoms. Whether such improvement is a secondary effect attributable to pain relief is uncertain. A decrease in constipation and drowsiness would be expected with a decrease in analgesic use, but a decrease in pain might also result in increased physical, role, emotional, and social functioning. An improvement in these domains together with a decrease in fatigue, insomnia, and anorexia would be expected to lead to an improvement in global quality-of-life scores, as was demonstrated by the data. This was most evident in the mitoxantrone-plus-prednisone and cross-over groups after the completion of 12 and 18 weeks of treatment with mitoxantrone, respectively. Attending physicians were expected to add mitoxantrone to prednisone for patients who did not have an improvement in pain or a decrease in analgesic consumption while taking prednisone alone after 6 weeks. An examination of the QLQ-C30 and QOLM-P14 scores at the observation before cross-over confirms that there was no statistically significant improvement in pain among the patients who received prednisone alone. However, there was a decrease in the impact of pain on physical activity. This group also experienced improvement in anorexia, social functioning, and global quality of life. Although these benefits were evident at 6 weeks, they were no longer evident by 12 weeks of treatment in those who remained on prednisone. There was also a more rapid attrition of patients over time in this group than in the other two groups. These data suggest that treatment with prednisone is likely to give only short-term benefits. In our study, better HQL provides strong evidence for therapeutic benefit from the administration of mitoxantrone plus prednisone in men with advanced, hormone-resistant cancer of the prostate. Moreover, it is evident that there were substantial HQL benefits in the group who had mitoxantrone added to prednisone after the failure of prednisone alone. However, it should be emphasized that multiple comparisons were performed, and despite setting a P value of .01 as the level at which differences were considered significant, some of these differences may still have occurred due to chance alone. Nevertheless, the data are congruent within themselves and are in keeping with the clinical experience of the investigators participating in the study. Recently, the results of a survey of international investigators who are experts in the field of hormone-resistant metastatic prostate cancer showed that 94% considered survival to be the most important end point.14 Other outcomes, such as tumor response, time to progression, response duration, a prostate-specific antigen level decrease, or quality-of-life improvement, were considered to be less important than survival. Given that significant prolongation of survival in this stage of prostate cancer is not achievable with currently available therapies, it would seem likely that quality-of-life outcomes would be of prime importance. However, questions to elucidate this possibility apparently were not asked in the survey. Nevertheless, 88% of the investigators ranked quality-of-life end points second after survival. The study reported here shows that despite failure to achieve prolongation of survival,1 HQL can be improved in hormone-resistant metastatic prostate cancer by prednisone and mitoxantrone. This finding adds another palliative approach that will preserve or improve HQL (improved functioning with decreased symptoms) in patients with end-stage prostate cancer.
Supported by Lederle Laboratories, Immunex Corporation, Seattle, WA.
1. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative end points. J Clin Oncol 14:1756-1764, 1996 2. Stockler MR, Osoba D, Goodwin P, et al: Responsiveness to change in health-related quality of life: A comparison of the Prostate Cancer Specific Quality of Life Instrument (PROSQOLI) with analogous scales of the EORTC QLQ-C30 and a trial specific module. J Clin Epidemiol 51:37-45, 1998[Medline] 3. Melzack R: The McGill Pain Questionnaire: Major properties and scoring methods. Pain 1:277-299, 1981
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Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international trials in oncology. J Natl Cancer Inst 85:365-376, 1993 5. Osoba D, Zee B, Pater J, et al: Psychometric properties and responsiveness of the EORTC Quality of Life Questionnaire (QLQ-C30) in patients with breast, ovarian and lung cancer. Qual Life Res 3:353-364, 1994[Medline] 6. Morrison DF: Multivariate Statistical Methods (ed 2). New York, NY, McGraw-Hill, 1976 7. Hays RD, Hayashi T, Carson S, et al: User's Guide for the Multitrait Analysis Program (MAP). Santa Monica, CA, Rand Corporation, 1988 8. Fayers P, Aaronson N, Bjordal K, et al: EORTC QLQ-C30 Scoring Manual. Brussels, Belgium, Quality of Life Unit, EORTC Data Centre, 1995
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Osoba D, Rodrigues G, Myles J, et al: Interpreting the significance of health-related quality-of-life scores. J Clin Oncol 16:139-144, 1998 10. King MT: The interpretation of scores from the EORTC quality of life questionnaire QLQ-C30. Qual Life Res 5:555-567, 1996[Medline] 11. Little R, Yau L: Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics 52:1324-1333, 1996[Medline] 12. Fairclough DL: Multiple imputation for missing data in longitudinal studies of quality of life. Qual Life Res 6:642, 1997 (abstr) 13. Zee B, Pater J: Statistical analysis of trials assessing quality of life, Osoba D (ed):Effects of Cancer on Quality of Life113-124Boca Raton, FL, CRC Press, 1991 14. Dawson NA: Apples and oranges: Building a concensus for standardized eligibility criteria and end points in prostate cancer clinical trials. J Clin Oncol 16:3398-3405, 1998[Abstract] Submitted August 10, 1998; accepted January 21, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), prednisone plus mitoxantrone (
), and mitoxantrone added to prednisone (
). Changes were calculated from baseline to treatment cycles 2 (first bar in each triplet of bars), 4 (second bar), and 6 (third bar). Improvements in scores are above the 0 horizontal line. Asterisks indicate P values 
.01 for the change from baseline.
