© 2007 European Society for Medical Oncology
hematologic malignancies |
An open, randomized, controlled, phase II, single centre, two-period cross-over study to compare the quality of life and toxicity experienced on PEG interferon with interferon-
2b in patients with multiple myeloma maintained on a steady dose of interferon-2b
Leukaemia and Myeloma Units, Royal Marsden NHS Trust, Surrey SM2 5PT and Clinical Trials and Statistics Unit, Institute of Cancer Research, UK
* Correspondence to: Prof. R. Powles, Parkside Cancer Centre, 49 Parkside, Wimbledon SW19 5NB, UK. Tel: +44-20-8944-7979; Fax: +44-20-8605-9103; E-mail: myeloma{at}clara.co.uk
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Purpose: To compare the effects of pegylated interferon-
2b (P-IFN) and interferon-2b (IFN) on quality of life (QoL) and toxicity in patients with multiple myeloma maintained on a steady dose of IFN. Patients and methods: Consenting, eligible myeloma patients on IFN maintenance therapy for at least 6 weeks were randomly (1:1) allocated to receive P-IFN for 3 months followed by IFN for 3 months, or to continue with IFN for 3 months followed by P-IFN for 3 months (cross-over design). Patients were assessed for toxicity and QoL. Dose of P-IFN was equivalent to IFN.
Results: The study enrolled 60 patients. At enrolment, 35 patients were in complete remission, 20 in partial remission and 5 were minimal responders. P-IFN was associated with significantly better global QoL score (mean difference 8.4; P = 0.0002). There was a significant improvement in functional scales—physical (P = 0.03), emotional (P = 0.04), social (P = 0.0008) with P-IFN. Fatigue (P = 0.0003), pain (P = 0.02) and appetite loss (P = 0.003) symptom scales were less in patients while on P-IFN. There were no statistically significant differences between treatment arms in QoL as measured by QLQ-MY24.
Conclusion: These data suggest that patients on P-IFN have a better QoL. Dose escalation studies are warranted to investigate potential impact on survival.
Key words: maintenance therapy, myeloma, pegylated interferon, quality of life
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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The previously accepted use of unmodified interferon-
(IFN) for treating myeloma has been overshadowed by the use of new and more active biological agents such as thalidomide, lenalidomide, bortezomib or a reduced intensity allogeneic transplant [1–8]. However, it is also increasingly clear that myeloma patients with a median survival in excess of 5 years and with good quality of life (QoL), require all of the above drugs in treatment packages in sequence, in addition to standard treatments such as infusional chemotherapy and autografting [9–11]. Therefore IFN, although weak as a single agent in its activity, potentially would make a useful treatment adjunct for the future. To this end, it is currently being tested in combination with thalidomide as maintenance treatment, as part of the Central Europe Myeloma Study Group (CEMSG) [12].
But such studies would be much more persuasive if the doses of IFN that had been used in the past could be escalated, as has occurred in hepatitis C by the use of pegylated interferon (P-IFN). P-IFN is better tolerated in higher doses, and has (in combination with ribavirin) become standard treatment for this disease [13–16]. We know from meta-analyses that the use of IFN in myeloma produces marginal benefit and it was questioned at the time whether this was worthwhile, but if dose escalation was possible with less toxicity in the same way as seen in hepatitis C, then worthwhile benefit may be obtained [17–18].
This present cross-over study uses a group of patients with myeloma receiving the maximum tolerated doses (MTDs) of IFN as maintenance and at a steady state, and investigates the impact on toxicity and QoL when switched to an equivalent dose of P-IFN. The cross-over design was used because it was impossible to blind this study and by having patients act as their own controls, this mitigated person-to-person inter-variability and perception.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
Patients with multiple myeloma on a steady dose of IFN were recruited to an open, randomized, controlled, phase II, two-period cross-over study to compare QoL and toxicity experienced on P-IFN with that on IFN. The study was approved by the local research ethics committee (Trial number 1871; NCT number NCT00323505 [ClinicalTrials.gov] ).
Eligible, consenting patients were assessed for toxicity and after having completed the baseline QoL questionnaires, were randomized to receive either P-IFN followed by IFN (arm A) or IFN followed by P-IFN (arm B). Patients were randomized centrally by the Clinical Trials and Statistics Unit at the Institute of Cancer Research. Patients received each treatment for 3 months (P-IFN or IFN) and then crossed over to the other arm. At the end of the study, patients randomized to the P-IFN arm for the second period reverted to the original dose of IFN. The study design is shown in Figure 1. Toxicity was assessed throughout the randomized treatment study period as done routinely for patients on IFN.
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doses of IFN and P-IFN
The doses of P-IFN administered in this trial were equivalent to doses of IFN (Table 1). This was calculated based on previously published pharmacokinetic data [19]. At enrolment, 16 (27%) patients were maintained on 1.5 million units (MU) three times a week (tiw), 29 (48%) on 3 MU tiw and 15 (25%) on 5 MU tiw.
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Patients received IFN subcutaneously tiw with multi-dose pen. P-IFN was provided by Schering-Plough as a lyophilized powder in a 50 mg vial. Each vial of P-IFN had to be reconstituted using 0.7 ml sterile water. Patients were taught and given written instructions. Dose modifications were allowed if patients developed grade 3 toxicity (except flu-like symptoms). IFN or P-IFN was restarted at a lower dose level once the toxicity returned to grade 1. If patients developed grade 4 toxicity, IFN or P-IFN was discontinued permanently.
QoL questionnaire
Patients completed the questionnaires EORTC QLQ-C30 and EORTC QLQ-MY24 at baseline, 3 months (at cross-over to the other arm) and 6 months (end of study) [20, 21]. The EORTC QLQ-C30 is a health-related QoL questionnaire with 30 items which assesses QoL mainly during the past week. It is constructed to be cancer specific and multi-dimensional. Scores for each scale were calculated as suggested in the EORTC QLQ-C30 scoring manual. All scales were linearly transformed so that the results range from 0 to 100. For the five functional scales and the single global health and QoL scale, higher scores represent better QoL whereas for symptom scales, high scores represent worsening of symptoms. The psychometric properties and validity of the questionnaire have been found to be satisfactory and test–retest reliability to be high [22].
The EORTC QLQ-MY24 questionnaire is specifically designed for patients with myeloma and consists of 24 questions combined into five scales: disease symptoms and treatment side-effects (treated as symptom scales); social support, future perspective and body image (treated as function scales), which assess QoL during the past week.QLQ-MY24 is currently undergoing international field testing to assess its psychometric properties. Data generated from this study are being used by the Northern and Yorkshire Clinical Trials and Research Unit, Leeds, UK to validate this questionnaire. The EORTC Study Group on QoL has given permission to use both the QLQ-C30 and QLQ-MY24 questionnaires.
toxicity assessment
Patients were evaluable for toxicity even if they received one dose of the drug. Patients were asked to report any toxicity, which was graded by National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2 Grading System [23]. The research team kept in telephone contact with patients on a weekly basis.
data collection procedures
Patients received all the questionnaires at the hospital and completed them whilst waiting for their prescription. Time to complete the questionnaires was recorded by the patients. Patients were withdrawn from the study if they had signs and/or symptoms of disease progression that warranted stopping IFN, had a serious adverse event requiring permanent discontinuation of IFN or at patient request. If patients withdrew from treatment early, they were asked to complete the QoL questionnaire at the time of withdrawal.
statistical considerations
Sample size.
The proposed sample size of 60 patients (30 per sequence) was considered large enough to detect a difference of 10 points in Global Health Status/QoL score between the two treatments with 80% power at the 5% significance level. Ten points in the EORTC questionnaires is considered clinically relevant. An adjustment was made to the sample size calculations to allow for analyses to be carried out using the Wilcoxon signed rank test rather than the paired t-test if the data were non-normally distributed.
Endpoints.
The primary endpoint was to compare the QoL on P-IFN and IFN. The secondary endpoints were to compare toxicity (as measured by the CTC grading system) on P-IFN and IFN, assess early withdrawal rate and reasons for early withdrawal for both treatment arms, assess proportion of patients with dose modifications in both treatment arms and the proportion of patients who complete the QoL questionnaires.
Statistical methods.
All summaries are based on an intention-to-treat basis. Patients baseline characteristics, toxicity and QoL prior to commencing randomized treatment are summarized using descriptive statistics The Mann–Whitney test for equality of medians was used to compare continuous variables, and the 
2 test to compare frequencies. Differences in QoL scales at the end of treatment were analysed using a mixed model with treatment (P-IFN or IFN) and period (1 or 2) included as fixed effects and patient as a random effect. Baseline scores for each scale were also included in the model as a covariate. Results are presented as the mean score on each treatment with the difference, its associated 95% confidence interval and P-value. The changes from baseline to 3 months in the QLQ-C30 domains were analysed using two-sample t-tests. Analyses of the QoL data were implemented using SAS/STAT software (Version 8.2 of the SAS system for Windows, SAS Institute Inc., Cary, NC, USA). The Mann–Whitney non-parametric test was used to assess the change in neutrophils levels and differences per patient were examined using the Wilcoxon signed rank test. The frequencies of toxicities in both arms were compared using 2 tests.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
Sixty patients with myeloma on maintenance IFN therapy were randomized. The median age was 53 years (31–70) and 67% patients had Durie–Salmon Stage III at diagnosis [24]. Before enrolment, the median duration of IFN therapy was 2.5 years (0.12–12.7). At enrolment, 59% patients were in complete remission (CR), 33% in partial remission (PR) and 8% were minimal responders to previous therapy according to criteria described by Blade et al. [25]. There were no statistically significant differences between the treatment groups at randomization (Table 2).
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compliance
Questionnaires.
Fifty-four (90%) patients completed all three QoL questionnaires (baseline, 3 and 6 month) and all patients completed at least two questionnaires. As the EORTC QLQ-MY24 was being validated, the time to complete this questionnaire was recorded; the median time was 5 min (2–30) in the 171 completed questionnaires.
Drug. (i) Dose modifications: reductions.
One patient receiving IFN during first 3 months (arm B) and four patients in the cross-over arm receiving IFN (arm A) required dose reductions compared with no dose reductions in the P-IFN arm (P = 0.02).
(ii) Dose modifications: discontinuations.
A total of 10 patients required discontinuation. Of the six patients discontinuing on IFN (arms A and B), three discontinued due to relapse; one developed autoimmune thrombocytopenia (arm B); one developed deranged liver function tests on the cross-over arm (arm A); and one patient on the IFN cross-over arm (arm A) had severe backache and missed six doses of IFN. Of the patients on P-IFN (arms A and B, n = 4), two discontinued due to relapse (arm A); one patient randomized to P-IFN was not evaluable as she found the reconstitution of the injection cumbersome (arm A); one patient on the P-IFN cross-over arm (arm B) switched to IFN after receiving nine doses as the patient thought the symptoms relating to benign prostrate hypertrophy were related to P-IFN (protocol violation).
comparison of QoL of patients on P-IFN versus IFN
The baseline QoL function and symptom scales at the first treatment received was not significantly different between the two arms (data not shown). The results of the analysis of QLQ-C30 are shown in Table 3. There were no significant differences in any of the baseline scores between patients randomized to arm A or B. P-IFN was associated with a statistically significantly better global QoL score (P = 0.0002). Also there were statistically significant improvements in the following functional scales: physical (P = 0.03), emotional (P = 0.04), social (P = 0.0008) with P-IFN. The fatigue (P = 0.0003), pain (P = 0.02) and appetite (P = 0.003) symptom scale scores were less in patients while they were on P-IFN. However, only the result for fatigue symptoms reached the level considered clinically relevant (>10 points) for the QLQ-C30.
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The mean change from baseline in each domain of the QLQ-C30 is shown in Table 4. P-IFN was significantly better than IFN in terms of global QoL score (P = 0.012), fatigue and appetite loss (P = 0.0037 and P = 0.013, respectively).
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The results of the analysis of QLQ-MY24 are shown in Table 5. There were no statistically significant differences in QoL between treatment arms as measured by this questionnaire.
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There was no evidence of a differing effect of treatment whether a particular arm was given first or second (data not shown). There was no evidence of period or carryover effects.
toxicity
One patient randomized to P-IFN (arm A) was not evaluable for toxicity due to early withdrawal (did not receive the first dose).
Haematological. (i) Neutrophils.
No patient's WBC count fell below 2 x 109/l throughout the study period. There was no difference in the baseline absolute neutrophil count (ANC) between the two arms (Table 2). Median ANC at the end of first 3 months in arm A was 1.85 x 109/l (0.1.–4.8 x 109/l) after P-IFN compared with 1.93 x 109/l (0.27–6.09) in arm B after IFN (P = 0.9). The median ANC at the end of 6 months (post-cross-over) was 2.31 (1.1–4.4) in arm A after IFN compared with 2.11 (0.6–4.5) in arm B after P-IFN (P = 0.5). Table 6 shows changes in ANC over the 6 month period. Overall there was a median increase in ANC of +0.05 with P-IFN and +0.57 with IFN.
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The Mann–Whitney non-parametric test showed that median ANC level changed from 1.94 at baseline to 2.22 after 6 months (P = 0.04 for overall comparison) in the whole group of 60 patients. Differences per patient examined using the Wilcoxon signed rank test confirmed a statistically significant median change of 0.28 (P = 0.025).
(ii) Platelets.
At randomization, nine patients had a platelet count of <100 x 109/l, seven were randomized to arm B to receive IFN and two in arm A to receive P-IFN; five (56%) of these recovered their platelet count to >100 x 109/l whilst on P-IFN (three after cross-over in arm B). The platelet count of one patient randomized to IFN (arm B) dropped from 130 x 109/l to 17 x 109/l and was diagnosed as interferon-induced autoimmune thrombocytopenia which responded to i.v. immunoglobulin therapy and steroids.
Renal/hepatic.
None of the patients developed renal or hepatic dysfunction attributable to the drug. One patient with AL amyloidosis developed deranged liver function tests on the IFN cross-over (arm A); this was due to relapse of disease and the patient responded to high-dose therapy.
Local/systemic reactions.
Seventeen patients on P-IFN had local reactions compared with two on IFN (P < 0.0001) throughout the study period. Systemic reactions were seen in the form of flu-like symptoms (seven on P-IFN and six on IFN), lethargy (10 on P-IFN and 15 on IFN) and dry skin (three on P-IFN and two on IFN). No formal comparisons were made.
Infections.
By the end of 3 months, six patients on P-IFN (arm A) had developed an infection: cough and cold (n = 3), herpes simplex (HSV) (n = 1), diarrhoea (n = 2) compared with eight patients on IFN (arm B; cough and cold n = 5; HSV n = 2; diarrhoea n = 1). After the cross-over, eight patients on P-IFN (arm B) developed similar infections (seven cough and cold, one HSV) compared with two on IFN (arm A; one cough and cold, one diarrhoea).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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For patients with multiple myeloma, the optimum characteristics of a maintenance treatment are that it should improve both progression-free survival (PFS) and overall survival (OS) but most importantly should not impact on QoL. The present study uses a group of patients with myeloma receiving as maintenance the MTD of IFN and at a steady state, and shows that there is statistically reduced toxicity when switched to the equivalent dose of P-IFN.
Interferon has been used for treating myeloma for over a quarter of a century, and it is 15 years since Mandelli et al. reported the results of the first trial of the use of maintenance IFN and shortly afterwards our report of prolongation of complete remission, but thereafter inconsistent results have been reported in the literature in several studies regarding the use of IFN as maintenance therapy [26–33]. However, a recent report of the phase III HOVON-16 trial on 262 patients shows that IFN maintenance prolongs PFS and does not adversely affect QoL, provided the burden of toxicity is not too high [34].
In order to evaluate the overall efficacy of IFN, the Myeloma Trialists' Collaborative Group performed a meta-analysis of randomized trials using individual patient data which compared IFN with control. This analysis showed that OS and PFS were significantly prolonged with IFN treatment by 4 months [18]. Despite this, general use of IFN in myeloma has declined, in part because of its adverse toxicity profile but also because its use has been overshadowed by the cascade in availability of newer agents [1–3]. The current issue relating to IFN is therefore whether the individual patient is prepared to tolerate it for possibly only small benefit. To this end, Ludwig et al. [35] interviewed 355 myeloma patients throughout the United States by telephone without identifying IFN but describing potential adverse events, financial costs, self-injection procedures and potential benefits of four treatment choices, the result being that patients would tolerate a drug with the profile of IFN only if there was at least a 6 month gain in outcome and the question to ask is ‘can we gain additional benefit from IFN by dose escalation without increased toxicity and reduced QoL?’
We were mindful that P-IFN may cause neutropenia as our patients had previously received an autotransplant. We have previously published that post-autotransplant, myeloma patients were robust to the known myelosupressive effects of IFNs but there are data from hepatitis C studies in patients with assumed normal marrow function that suggest that P-IFN may be more neutropenia inducing [13, 36]. Manns et al. [13] have shown in a three-arm study that 18% of the high-dose P-IFN patients were neutropenic, to a point at which they needed a dose reduction versus 10% for the lower dose P-IFN patients and 8% for the unmodified IFN patients. However, only 
1% of patients discontinued treatment for neutropenia. We were reassured to see that the data from our study show no evidence of depression of neutrophil counts (Figure 2).
Other reported side-effects with possible impact on the usage of P-IFN when compared with unmodified IFN relate to the injection site. In the Manns et al. [13] study 58% of patients had an injection site reaction in the high-dose P-IFN arm, 59% in the lower dose P-IFN arm verses 36% in the unmodified IFN arm. In our study, local reactions occurred in 17/60 of those patients receiving P-IFN. The reaction was usually transient, red and with minimum induration. No patient was discontinued from receiving P-IFN because of this effect.
A third side-effect with possible impact on the usage of P-IFN when compared with unmodified IFN relates to depression. We did not have as part of our study assessment of depression. Future studies of P-IFN should have psychological assessment incorporated within the secondary endpoints. It may be argued that if one sticks to the doses of P-IFN used in this trial, patients will have low adverse effects but will probably not improve on the few week median improvement in survival that one gets with IFN; on the other hand, if the dose of P-IFN is increased to get a better outcome, it is possible that we may have the same adverse event profile as seen with IFN. There may be a middle ground of high doses of P-IFN that do not cause significant toxicities.
Our study showed that the patients' QoL improved significantly whilst on P-IFN. Health-related quality of life (HRQoL) has become an increasingly important endpoint in cancer studies, and is most relevant in patients who cannot be cured of disease such as myeloma [37]. Though EORTC scoring system rates 
10 as clinically important, our figures of <10 may reflect the relatively low level of symptoms relating to IFN and are in keeping with the lower dose we have used. The higher function scales and relatively lower symptom scales reflect that the patients were receiving maintenance treatment.
Realistically, the hope of P-IFN becoming a major option in the treatment pathway of myeloma appears small given all the other newer biological agents. Currently, we are not aware of any major trials to test P-IFN. We are aware of the limitations of the study, even with cross-over; without blinding (which was not possible due to the schedule of injections given) QoL estimated can be flawed due to physician or patient bias. It is possible that the QoL benefits may be less impressive if the study was blinded.
The data generated in this study opens the way to a phase I/II study in a group of patients with minimal (near CR) disease to determine the MTD of this drug in myeloma patients after autotransplant. Subsequently, the value of P-IFN as maintenance therapy should be tested in a randomized trial with other biological agents as is currently being undertaken by the CEMSG group using interferon in combination with thalidomide.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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David Adams Leukaemia Fund, Parkside Research Fund, Johnstone Britten Myeloma Fund, Bud Flanagan Leukaemia Fund. The drug pegylated interferon was supplied free by Schering Plough, Wellwyn Garden City, Herts.
Received for publication December 22, 2006. Revision received March 30, 2007. Accepted for publication April 4, 2007.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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