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Keywords:

  • multiple myeloma;
  • randomised clinical trial;
  • health-related quality of life;
  • methodological quality;
  • clinical impact;
  • review

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Objectives:  Patients with multiple myeloma (MM) often have pronounced symptoms and substantially reduced quality of life. The aims of treatment are to control disease, maximise quality of life and prolong survival. Hence, health-related quality of life (HRQOL) should be an important end-point in randomised controlled trials (RCTs) in addition to traditional endpoints. We wanted to evaluate whether trials reporting HRQOL outcomes have influenced clinical decision making and whether HRQOL was assessed robustly according to predefined criteria.

Methods:  A systematic review identified RCTs in MM with HRQOL assessment as a study end-point. The methodological quality of these studies was assessed according to a checklist developed for evaluating HRQOL outcomes in clinical trials. The impact of the HRQOL results on clinical decision making was assessed, using published clinical guidelines as a reference.

Results:  Fifteen publications presenting RCTs with HRQOL as a study end-point were identified. In 13 trials, the author stated that HRQOL results should influence clinical decision making. We found, however, that the HRQOL data only had a limited impact on published treatment guidelines for bisphosphonates, high-dose treatment, interferon, erythropoiesis-stimulating agents and novel agents.

Conclusion:  The present review indicates that the there are still few RCTs in MM including HRQOL as a study end-point. Systematic incorporation of HRQOL measures into clinical trials allows for a comparison of treatment arms that includes the patients’ perspective. Before the full impact on clinical decisions can be realised, the quality and methodology of collecting HRQOL data must be further improved and the results rendered more comprehensible to clinicians.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Treatment of multiple myeloma (MM) has improved substantially over the past years as a result of the introduction of high-dose therapy with autologous stem cell rescue (ASCT) and novel agents such as thalidomide, bortezomib and lenalidomide. However, despite significant advances in treatment, MM remains incurable with a median survival of 5 yr (1). At diagnosis, myeloma patients report a pronounced impairment of health-related quality of life (HRQOL) with reduced physical functioning, fatigue and pain as the major problems (2). Typical clinical features are bone pain and bone fractures, recurrent bacterial infections, impaired renal function and anaemia.

Consequently, HRQOL has become increasingly important in addition to traditional end-points such as response to treatment and survival. The question remains, however, whether HRQOL outcomes have had any impact on clinical decision making. Even though thousands of patients have had their HRQOL assessed by a variety of instruments in clinical trials, there are few examples of HRQOL outcomes that have influenced clinical decision making or treatment guidelines (3). One limiting factor is that studies focusing on HRQOL have been of variable quality. Low compliance, lack of prespecified end-points and inadequate reporting of power calculations are common problems. Furthermore, a clear justification for the selection of HRQOL instruments and the time points for measurement is often lacking (4).

Without specific guidelines for interpreting HRQOL assessment in clinical trials, clinicians and health care providers are often uncertain about how to interpret HRQOL scores. While the significance of changes in response rate, response duration and overall survival is immediately apparent to the physician, this is not the case for HRQOL results. P-values indicating statistically significant changes in HRQOL scores do not necessarily indicate that the change is perceived as important by the patients. Determining the clinically important magnitude of change in HRQOL is essential, and is currently the subject of extensive continuing research (5). The minimally important difference is ‘the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patient′s management’ (6). Based on the results by Osoba et al. it is recommended to use 10% of the scale as the cut-off point to define a clinically important change (7). That is, on a 0–100 point scale, a change of 10 points may be regarded as clinically significant.

The purpose of measuring HRQOL in RCTs is to guide future decision making. Within haematology, one recent paper has investigated the quality of HRQOL reporting and the added value in clinical decision making in patients with leukaemia (8). They concluded that the quality of the reported trials seemed fairly robust. However, the number of studies in leukaemia which reported HRQOL was very low as compared to number of studies in solid tumours, possibly denoting a lower emphasis on patient reported outcomes in haematological research.

This review evaluates the methodological quality of HRQOL assessments in RCTs in patients with MM and evaluates the impact of HRQOL findings on treatment recommendations.

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Literature search

We conducted a systematic search of the literature in November 2008, looking for randomised studies incorporating quality of life measurement in patients with MM. Medline, Embase, Cinahl, PsycINFO and the Cochrane Library were searched, using the following Medical Subject Heading search terms: ‘multiple myeloma expl’, combined with ‘quality of life’ and ‘randomised controlled trials’. The search was restricted to publications in English from 1990 through Nov 2008. We selected 1990 as a cut off date for publications because it is in the last 20 yr HRQOL has becoming a research area of interest. Case reports, editorials, letters, commentaries, reviews and overviews were excluded, as was unpublished material. Published conference abstracts were not included because they rarely contain sufficient data to allow for a critical quality review. References cited by the retrieved papers were reviewed according to the criteria below and eligible articles were included. The first author, AKK, reviewed the identified RCTs and classified them according to a ‘Minimum Standard Checklist for evaluating HRQOL outcomes in clinical trials’ developed by Efficace et al. (9). For quality control, a second reviewer (MJH) independently classified the papers. In cases of uncertainty about inclusion, papers were discussed and a final decision was reached.

Criteria for inclusion

For the purpose of this review, articles including patients diagnosed with MM were eligible. Any RCT comparing medical intervention between two or more groups of patients was considered. The search was restricted to RCTs because these represent the gold standard for comparing alternative forms of clinical interventions. A study was eligible for inclusion if it had self-reported HRQOL as a primary or secondary end-point. We only included studies measuring HRQOL as a multidimensional construct. Only trials reporting both clinical and HRQOL outcomes (in the same article or in separate articles) were considered.

Evaluation of methodological design

The CONSORT guidelines (10) help with good reporting of clinical trials, but they fail to address the key issues of clinical trials assessing quality of life. Critical issues such as the selection of quality of life measures, minimal standards of psychometric validity of the instruments, agreed standards of cultural validity, agreement of acceptable levels of missing data and standardised methods of analysis and reporting are not discussed in these guidelines (11). At the present time, there are no agreed international standards for assessing and reporting HRQOL in RCTs, although guidelines have been proposed (12). However, a ‘Minimum Standard Checklist for evaluating HRQOL outcomes in clinical trials’ (MSC) has been developed by Efficace et al. (9). The checklist comprises 11 items grouped into four categories related to the HRQOL assessment: conceptual, measurement, methodology and interpretation. The 11 items were originally selected from the literature by consensus of HRQOL researchers with international expertise in oncology. The checklist items should be answered ‘yes’ or ‘no’ and every ‘yes’ scores one point. Efficace et al. propose that a study can be described as probably robust’ (score between 8 and 11), ‘limited’ (score between 5 and 7) or ‘very limited’ (score between 0 and 4). Three mandatory items of the checklist had to be satisfied for an article to be judged as ‘probably robust’: documentation of baseline compliance, psychometric properties reported and documentation of missing data. Studies that fail to report these mandatory items would not be categorised as ‘probably robust’ even if they satisfied eight or more methodological criteria. It is suggested that only those evaluated as ‘probably robust’ are likely to provide useful data to further facilitate clinical decision making. In addition, we checked whether the authors discussed the issue of statistical vs. clinical significance of the reported differences in HRQOL scores.

Evaluation of impact of HRQOL results on clinical decision making

In absence of a gold standard for evaluating the impact of HRQOL results on clinical decision making, we categorised the articles according to (1) whether the authors claim that HRQOL outcome should influence clinical decision making and (2) whether HRQOL measurement was methodologically evaluated as ‘probably robust’ and likely to provide useful data to influence clinical decision making. Furthermore, based on published guidelines on the treatment of MM (13–17) we evaluated whether the reported HRQOL data has had impact on published treatment recommendations.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

Identified studies

The search yielded 102 citations of which the titles and abstracts were examined. Twenty-seven were duplicate records and therefore excluded. Another 60 citations were excluded because the abstract revealed that the study was not a RCT or because there was no specific HRQOL outcome. Thus, a total of 15 publications were identified that fulfilled the inclusion criteria. The characteristics of the studies including a summary of clinical and HRQOL outcomes are listed in Table 1.

Table 1.   Impact of HRQOL and clinical outcomes in decision making in RCTs in multiple myeloma
AuthorsYear of publicationNo. patients (HRQOL data at baseline)TreatmentsHRQOL end pointHRQOL instrumentMain clinical outcomeHRQOL outcomesHRQOL influenced on clinical decision making –authors statement
  1. HRQOL, health-related quality of life; RCTs, randomised controlled trials; SREs, skeletal-related events; NHP, Nottingham Health Profile; CLAS, Cancer Linear Analogue Scale; FACT, Functional Assessment of Cancer Therapy; IFN, interferon; TTF, time to treatment failure; OS, overall survival; Dex, dexamethasone; EORTC, European Organisation for Research and Treatment of Cancer; TTP, time to progression; PFS, progression-free survival; TFS, transfusion free survival; BP, bendamustine + prednisone; MP, melphalan + prednisone; RSCL, Rotterdam Symptom Checklist; ASCT, autologous stem cell transplantation; EFS, event-free survival.

Berenson JR et al., NEJM1996392 (377)Pamidronate vs. placebo in patients with lytic lesionsSecondarySpitzer’s quality of life index Fewer SREs with pamidronate (P < 0.001)No HRQOL deterioration in pamidronate group. Placebo patients had worsening of HRQOL. HRQOL assessed monthly for 9 mYes, pamidronate recommended based on better clinical outcomes and improved HRQOL
Dammaco F et al., BJH2001145 (138)Epoetin alfa vs. placebo in patients with anaemiaSecondaryNHP and CLAS (LASA)Epoetin alfa reduced transfusions after 12 wk (P = 0.017)No differences between groups. HRQOL measured before start of study + weeks 4, 8, 12Yes, epoetin alfa recommended based on better clinical outcomes and improvement in HRQOL
Hedenus M et al., BJH2003344 (303)Darbepoetin alfa vs. placebo in anaemic patientsSecondaryFACT-fatigueHb higher in darbepoetin alfa group (P < 0.001)Improvement HRQOL in Darbepoetin alfa group. HRQOL assessed every 4 weeks for 12 wkYes, darbepoetin alfa recommended based on better clinical outcomes and less fatigue
Joshua DE et al., BJH1997113 (not reported)Intensive chemotherapy with or without IFNSecondaryMultiple choice + global HRQOL No differences in TTF or OSNo differences. HRQOL measured after each cycle of chemo and every 2 m for 12 mYes, a possible benefit of INF should not be discarded on the basis of impairment of HRQOL
Lee SJ et al., BJH2008669 (642)Bortezomib vs. dex in relapsed MMSecondaryEORTC QLQ-C30 + FACT/GOG-NTXBortezomib group had longer TTP (P < 0.001)Bortezomib associated with better HRQOL. HRQOL measured before start of study + six times until week 42Yes, bortezomib recommended based on clinical benefits of living longer with improved HRQOL
Littlewood TJ et al., JCO2001375 (349)Epoetin alfa vs. placebo in patients with MM and anaemiaSecondaryFACT-An, CLAS (LASA), SF-36Epoetin alfa reduced transfusions after 4 wk (P = 0.0057)Improvement of cancer – and anaemia-specific HRQOL domains in epoetin alfa group. HRQOL assessed before start + three times during studyYes, epoetin alfa recommended based on improved HRQOL and better clinical outcomes
Menssen HD et al., JCO2002198 (not reported)Ibandronate vs. placebo in preventing SREsSecondaryEORTC QLQ-C30No significant differences in SREsNo differences. HRQOL assessed monthly for 24 monthNo, ibandronate (2 mg i.v) was not effective in reducing SREs
Osterborg A et al., JCO2002343 (333)Epoetin beta vs. placebo in anaemic patientsSecondaryFACT-AnTFS higher in epoetin group between weeks 5–16 (P = 0.0012)HRQOL improved in epoetin group after 12 and 16 wk. HRQOL assessed before start of study + weeks 4, 8, 12, 16Yes, epoetin beta recom-mended based on improved HRQOL and better clinical outcomes
Pönisch W et al., J Cancer Res Clin Oncol2006131 (42)BP vs. MP in patients with MMSecondaryEORTC QLC-C30TTF longer in BP group (P < 0.02). No differences in OSHigher global status of health after 4 m in BP-group. HRQOL measured longitudinallyYes, BP recommended based on better clinical outcomes and better HRQOL
Schaar CG et al., Annals of Oncology200590 (not reported)IFN-α-2b vs. no maintenance therapy in plateau phase MMSecondaryRSCLIFN prolonged PFS (P = 0.04), no improved OSNo differences. 1/3 discontinued IFN due to toxicity. HRQOL measured every 3 m up to 3 yrYes, IFN recommended based on clinical outcomes and no reduced HRQOL, provided that the burden of toxicity was not too high
Segeren CM et al., Blood2003261 (not reported)Intensified chemotherapy (IC) + ASCT vs. IC aloneSecondaryEORTC QLQ-C30No difference in EFS (P = 0.28), but longer TTP (P = 0.04)More symptoms and worse functioning after ASCT. HRQOL assessed prior to treatment and every 3 m for 2 yrNo, ASCT recommended based on clinical outcomes, despite worse HRQOL after ASCT
Sirohi B et al., Annals of Oncology200760Pegylated IFN-α2b (P-IFN) vs. IFN-α2b. A cross-over designPrimaryEORTC QLQ-C30 + QLQ-MY24Reduced toxicity when switch from IFN to P-IFNP-IFN associated with better global HRQOL and less fatigue. HRQOL measured at baseline, 3 and 6 mYes, P-IFN recommended based on improved HRQOL and reduced toxicity
Smith A et al., Int J of Pall Nursing200437 (34)Pamidronate given at home vs. in hospitals. A cross-over designSecondaryEORTC QLQ-C3081% preferred home treatment (P < 0.001)No differences. HRQOL assessed at baseline, 3 and 6 mYes, home-treatment recommended based on patients preferences and equal HRQOL
Straus DJ et al., Cancer2006269 (232)Early vs. late treatment with epoetin alfaPrimaryFACT-An total and LASANo difference in transfusion (P = 0.11)Early patients had less fatigue and better functioning. HRQOL assessed longitudinally for 16 wkYes, early treatment with epoetin alfa recommended based on better HRQOL and clinical results
Wisloff et al., BJH1996583 (524)MP vs. MP+ IFN-a in newly diagnosed MM.SecondaryEORTC QLQ-C30 + IFN toxicityPlateau phase duration longer in IFN group (P = 0.03) IFN group reported more symptoms during first 12 m. No differences after 12 m. HRQOL measured at baseline and six times until 4 yrYes, no HRQOL benefit associated with the plateau-phase prolongation, making the importance of the prolongation uncertain

Demographics and trial design

The 15 RCTs involved about 2200 patients and were published from 1996 to 2008, with only three published before 2000. There were 11 studies with myeloma patients only (18–28) and four also including patients with different haematological malignancies (29–32). Eight trials were carried out in Europe, one in USA, one in Australia and five enrolled patients from several continents. Sample sizes ranged from 37 to 669 patients.

HRQOL methodological characteristics

Table 2 presents the MSC (9) and summarises the methodological details of the trial HRQOL assessments. Only four of 15 articles stated an a priori hypothesis or had a predefined HRQOL end-point (21, 26, 30, 32). In most studies (13/15), HRQOL was a secondary end-point. Sample size calculations based on the anticipated differences in HRQOL scores that could be detected between groups were only reported in the two studies that had HRQOL as the primary outcome (26, 32). All studies but one used validated instruments covering the main HRQOL dimensions relevant for a generic cancer population. Joshua et al. only reported that they used multiple-choice quality of life questionnaires and a global HRQOL rating completed by the patients (20). The most frequently used instrument (7/15 studies) was the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) (33) (Table 1). The Functional Assessment of Cancer Therapy (FACT) series of questionnaires (34) was used in five studies, in which four measured the impact of erythropoiesis stimulating agents (ESAs) on anaemia in cancer patients. The rationale for instrument selection was reported in 11 articles. Six studies used more than one HRQOL questionnaire (Table 1). These studies combined a generic instrument with a disease specific or symptom specific questionnaire. Timing of HRQOL assessment was documented in 13 articles and 10 reported baseline compliance. Missing data or compliance was reported in eight trials. However, details of how missing data were analysed were only provided by three papers (21, 28, 32). All articles reported statistical tests for evaluation of differences in scores between treatment arms. However, only six papers discussed whether the reported differences were clinically and not merely statistically significant (Table 3). According to the MSC, three trials were considered ‘very limited’ in terms of methodological design and five were evaluated as being ‘limited’. Seven trials were categorised as ‘probably robust’ (Table 3).

Table 2.   The reporting of HRQOL outcomes in the 15 myeloma trials
HRQOL issueNo of RCTs with criteria (%)References
  1. According to the Minimum Standard Checklist (MSC) for evaluating HRQOL outcomes in cancer clinical trials (9).

Conceptual
 A priori hypothesis stated4 (27)(20, 25, 29, 31)
 Rationale for instrument reported11 (73)(18, 20, 23–31)
Measurement
 Psychometric properties reported14 (93)(17, 18, 20–31)
 Cultural validity verified14 (93)(17, 18, 20–31)
 Adequacy of domains covered14 (93)(17, 18, 20–31)
Methodology
 Instrument administration reported8 (53)(18, 19, 25–30)
 Baseline compliance reported10 (67)(18, 20, 22, 25–31)
 Timing of assessments documented13 (87)(17–20, 22–30)
 Missing data documented8 (53)(20, 23, 25–27, 29–31)
Interpretation
 Clinical significance addresses6 (40)(20, 25–28, 31)
 Presentation of results in general15 (100)(17–31)
Table 3.   Robustness of HRQOL trial design and interpretation of HRQOL results
AuthorsRobust design based on quality reporting according to Efficace et al.Statistically significant differences exploredClinical significance discussed
  1. Probably robust (8–11).

  2. Limited (5–7).

  3. Very limited (0–4).

  4. *The three mandatory criteria are not met; the study could not be judged as high quality.

Berenson JR et al.Very limited 5/11NoNo
Dammaco F et al.Limited * 8/11NoNo
Hedenus M et al.Limited * 9/11YesYes
Joshua DE et al.Very limited 3/11NoNo
Lee SJ et al.Probably robust 10/11YesYes
Littlewood TJ et al.Probably robust 10/11YesNo
Menssen HD et al.Very limited 4/11NoNo
Osterborg A et al.Probably robust 9/11YesNo
Pönisch W et al.Limited 6/11YesNo
Schaar CG et al.Limited 7/11NoNo
Segeren CM et al.Limited 6/11YesNo
Sirohi B et al.Probably robust 11/11YesYes
Smith A et al.Probably robust 10/11NoYes
Straus DJ et al.Probably robust 9/11YesYes
Wisløff F et al.Probably robust 10/11YesYes

Impact of HRQOL results on clinical decision making

The authors’ claims regarding the impact of clinical and HRQOL outcomes on trial results are listed in Table 1. In 13 trials, the reports stated that HRQOL outcomes should influence decision making. In nine of these 13, the authors’ recommendations were based on improved HRQOL and better clinical outcomes (18, 19, 21, 23, 26, 29–32). In two of the trials, the decision was based on improved clinical outcomes and no change in HRQOL (24, 27). Two of the studies were inconclusive due to lack of effect on clinical and HRQOL outcomes (20, 22). One study recommended treatment based on clinical data, despite a worsening of HRQOL (25). In one trial, the improved clinical outcome was associated with an impairment of HRQOL, and the treatment was not recommended by the authors (35).

For the seven trials that were categorised as having a ‘robust’ HRQOL design and as such provided useful data to further facilitate clinical decision making, more details are given below. Three of these related to treatment with ESAs, two to interferon (IFN) treatment, one to bisphosphonates and one to bortezomib treatment in relapsed MM.

Effect of ESAs on HRQOL

Four randomised, double-blind placebo-controlled trials that included myeloma patients receiving chemotherapy showed a statistically significant decrease in transfusion requirements and rise in Hb levels in patients receiving ESAs (19, 29–31). The trials from Littlewood et al. and Osterborg et al., evaluating HRQOL in 349 and 343 patients respectively, were classified as ‘probably robust’ according to the checklist (Table 3). Littlewood et al. assessed HRQOL using three measurement tools: the three-item visual analogue scale (VAS), the symptom specific FACT-An questionnaire, and a generic questionnaire, SF-36 (36). Scores on all three items of the VAS scale and the FACT-An system showed statistically and clinically significant improvement in the ESA group over placebo, but with the SF-36 there were no statistically significant differences. There was a correlation between Hb concentration and changes in HRQOL; however, although all the correlation coefficients were statistically significant, they were low (0.14–0.34). Osterborg et al. reported that after 12 and 16 wk of treatment, the improvement in the total FACT-An and the FACT-G score was statistically significantly greater in the group receiving ESAs compared with the placebo group (P < 0.05). However, according to the criteria suggested by Cella et al., the differences of 6.1 points on a 0–196 scale were too small to be clinically important (37).

In the study by Straus et al. comparing early vs. late treatment with ESAs, the mean Hb increased with 1.2 g/dL [0.98–1.46] in the early treatment group but decreased with 0.2 g/dL [−0.32–0.12] in the late treatment group (32). The mean change in the total FACT-An score favoured early patients (P = 0.003). HRQOL was the primary study end-point and the magnitude of the mean treatment difference was considered clinically significant (37).

IFN treatment in multiple myeloma

Four RCTs measuring HRQOL in trials with IFN treatment were identified (20, 24, 26, 28). Two were categorised as ‘probably robust’ and could influence clinical decision making (Table 3). Data from the Nordic study showed that IFN prolonged relapse-free survival by 6 months but there was only a small and not statistically significant gain in overall survival. During the first year of treatment, patients on IFN reported more chills, fever, fatigue, pain, nausea/vomiting, appetite loss and dry skin than the control patients and a slight reduction of global health and quality of life. However, there were no statistically significant differences in any scores across groups after 12 months (28). The authors concluded that there was no HRQOL benefit associated with the 6 months’ plateau phase prolongation achieved with IFN.

In a cross over study, Sirohi et al. compared pegylated IFN (P-IFN) with IFN-alpha (26). They concluded that patients on P-IFN had an improved HRQOL compared to patients on IFN-alpha, with statistically significant improvement in global HRQOL (P = 0.0002), physical – (P = 0.03), emotional – (P = 0.04) and social functioning (P = 0.0008). Furthermore, patients reported less fatigue (P = 0.0003) and pain (P = 0.02), and improved appetite (P = 0.003) while they were on P-IFN. However, only the differences in the fatigue scale (10.3 points on a 0–100 scale) reach the level considered clinically significant.

Effect of bisphosphonates on HRQOL

Berenson et al. conducted a randomised, double-blind study comparing monthly pamidronate with placebo for the reduction of skeletal events in patients with MM (18). The occurrence of skeletal events was significantly lower in the pamidronate group (24%) than in the placebo group (41%, P < 0.001). The quality of the HRQOL design was, however, ‘very limited’ (4/11), and the sparse data reported was unsuitable as a basis of clinical decision making beyond the clinical results. Menssen et al. found that ibandronate 2 mg IV monthly neither reduced bone morbidity nor prolonged survival compared to placebo (22). They found no difference between the two groups regarding HRQOL. However, the HRQOL design was ‘very limited’ (4/11). The study by Smith at al was the only trial in this category that was ‘probably robust’ (10/11) (27). Patients were randomised to receive 3 months of home treatment with pamidronate followed by 3 months of in-hospital treatment with pamidronate or vice versa. HRQOL was assessed by the EORTC QLQ-C30 questionnaire. Assessment indicated improvements in favour of home care treatment but none of these reached the level of clinical importance as described by Osoba et al. (7). The authors concluded that pamidronate administrated in a home setting appeared feasible and safe and was preferred by 81% of the patients.

Bortezomib in relapsed MM and the effect on HRQOL

In a trial by Richardson et al., patients with relapsed MM who had received one to three previous therapies were randomised to receive either bortezomib or high-dose dexamethasone (38). Patients treated with bortezomib had higher response rates, longer time to progression (primary end-point), and longer survival than patients treated with dexamethasone. HRQOL was prospectively measured during the randomised trial. The results showed that bortezomib was associated with statistically significantly improved HRQOL compared with dexamethasone. Specifically, there was improved global health status (primary HRQOL end-point), improved physical health, role, cognitive, and emotional functioning and less dyspnoea and sleep disturbance (21). The authors stated that there was a clinically significant difference between the two groups regarding global health status. They concluded that compared with patients treated with high-dose dexamethasone, patients treated with bortezomib experienced clinical benefits of living longer and living better.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The main objective of this review was to evaluate the methodological quality of HRQOL assessment in RCTs in patients with MM and to evaluate the impact of HRQOL findings on treatment recommendations. Because MM is associated with severe symptoms and remains incurable, maintaining quality of life should be a major aim of treatment. Still, we were able to identify only 15 RCTs out of about 360 RCTs (from 1990 to 2008) in MM with HRQOL as a primary or secondary study objective. At a critical methodological assessment, only seven of the 15 studies were categorised as ‘probably robust’ regarding HRQOL and potentially useful for influencing clinical decision making. However, six of these were published after 2000, indicating a quality improvement in the HRQOL reporting of RCTs in MM over time. This is comparable to a similar review from 2007 in patients with breast, colorectal, non-small-cell lung cancer and prostate cancer (39). Hundred and fifty-nine RCTs with a HRQOL endpoint and published between 1990 and 2004 were identified and analysed. The authors explored that the quality of HRQOL reports, as measured by the MSC, was independently related to more recently published studies.

We identified five studies looking at the relation between treatment with ESAs and HRQOL. In all trials, the authors recommended ESAs based on improved HRQOL and better clinical outcomes. However, the average HRQOL benefit of ESAs in these trials appears to be of limited subjective importance. Nevertheless, HRQOL data from these trials have been used extensively in the marketing of ESAs.

Four of the 15 studies dealt with IFN treatment in MM. IFNs improve progression-free survival, but the survival benefit is minimal (40). In the study by Sirohi et al., there was a statistically significant reduced toxicity when the patients switched from IFN to the equivalent dose of P-IFN. However, no placebo arm was included in the trial, making difficult the comparison with patients not receiving interferon. The modest clinical effect of this drug, and the reduced quality of life associated with its use, has nearly abolished its use in MM (17).

Bisphosphonates have been found to reduce the incidence of skeletal related events in patients with MM. A Cochrane Review conducted in 2002 concluded that adding bisphosphonates to the treatment of myeloma reduced pathological vertebral fractures and pain, but not mortality (41). Despite the ‘limited’ methodology with respect to HRQOL, the study by Berenson et al. has had great impact on the use of bisphosphonates in patients with MM. Long-term use of bisphosphonates therapy is now recommended by guidelines on management of the disease (13, 42).

We identified only one RCT regarding novel agents in the treatment of MM with HRQOL as a study end-point. The study by Lee et al. showed that bortezomib was associated with significantly improved multidimensional HRQOL compared with high-dose dexamethasone (21). Although there was a higher incidence of gastrointestinal events, thrombocytopenia and peripheral neuropathy in the bortezomib group (38), this was not reflected in overall HRQOL. Bortezomib treatment was recommended on the basis of prolonged survival with a good HRQOL. This study included heavily treated MM patients with a limited survival. No RCTs with HRQOL assessment comparing bortezomib to other treatment options in resistant MM have been reported.

Randomised trials showing prolonged survival with ASCT compared to conventional chemotherapy have been performed in patients aged inline image65 yr with a normal renal function (43, 44). We explored one RCT regarding ASCT which had HRQOL as a study end-point (25). Despite the moderate HRQOL impairment during the short period following ASCT, this treatment modality is considered the standard of care in this population of patients. However, ASCT is currently challenged by the introduction of novel agents and the question is now to determine whether novel agents should replace ASCT as first-line treatment or whether they should be used in combination with ASCT (45).

This review identified 12 different instruments used for measurement of patient-reported HRQOL in MM. Both generic cancer questionnaires and disease specific questionnaires were used in the trials. Seven studies used the EORTC QLQ-C30 questionnaire, which is the most commonly used HRQOL assessment tool in MM patients. This questionnaire is reliable and valid for measuring HRQOL in patients with MM (35). The EORTC has recently developed a myeloma module (EORTC QLQ-MY20) to supplement their core questionnaire (46). The module has been validated and shown to be measuring additional aspects of HRQOL, particularly issues regarding body image and future perspective (47). Four studies used the FACT-An/Fatigue questionnaire which was specifically designed to capture the effect of anaemia and fatigue (34).

Only six of the 15 papers discussed whether the results were clinically significant from a patient’s perspective. With a large sample size, as may be required when survival is the primary end-point, even very small differences in HRQOL could attain statistically significance (48). Thus, it is possible that a difference could be so small that it would be considered clinically trivial and unimportant, even if statistically significant.

Compliance and missing data are important issues. In MM, HRQOL and survival are both important end-points. Patients are often severely ill and it is common for participants to drop out of the study because of illness or death. In such situations, data are not missing at random and may no longer be representative. Thus, in the trial by Ponisch et al. where less than one third of the patients took part in the HRQOL study (23), no firm conclusions may be drawn. This is because we do not know whether the characteristics of the patients enrolled in the HRQOL study are different from the characteristics of the non-participants.

Only four of the 15 RCT papers explicitly stated an ‘a priori hypothesis’ regarding the HRQOL outcomes. This makes interpretation of the results difficult, as it may not be clear whether the authors tested the multiple HRQOL dimensions separately. Multiple significance testing increases the chance of finding a false difference when a true difference does not exist (Type 1 error). Also, performing a large number of statistical tests results in a multitude of results that are difficult to interpret (49).

One possible reason for the inadequate reporting of HRQOL in trials is the word-count constraint imposed by journals. When reported alongside the primary end-points, limited space is available for reporting of HRQOL outcomes. This problem could be alleviated by preparing separate HRQOL publications, thus providing an opportunity for adequate explanation and presentation of what may often be complex results. On the other hand, this may hamper the communication of HRQOL results to clinicians. In our review, only two HRQOL reports were published in a separate publication from the original trial (21, 28).

There are some potential limitations to this review. Despite the search strategy using several literature databases, it cannot be ruled out that some relevant studies have been missed. Published abstracts were not included because of their limited information but most abstracts presenting RCTs are subsequently published. Assessing the quality of HRQOL trials is difficult because there is no single, unified, agreed upon checklist for such evaluation. We used the MSC to evaluate RCTs. Using other criteria, the studies could have been categorised somewhat differently. Assessment of trial quality in the selected articles was also often complicated because only limited details were presented.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

The present review indicates that the there are still few RCTs in MM including HRQOL as a study end-point. In 13 of the 15 studies we identified, the authors gave treatment recommendations based on their HRQOL results. However, we found limited impact of these HRQOL data on published treatment recommendations (bisphosphonates, ASCT, ESAs, bortezomib) probably due to methodological weaknesses and controversies in the interpretation of results. The use of IFN in myeloma has declined, in part because of the reduced quality of life associated with its use, but also because its use has been replaced by the availability of novel agents. In order to make rational treatment choices on the individual as well as group level, HRQOL should be included as an end-point in clinical trials in MM, in addition to response to treatment, plateau phase duration and overall survival. Systematic incorporation of HRQOL measures into clinical trials would make it possible to compare the study treatments taking into account the patients’ perspective. However, the methodological quality of collecting and reporting HRQOL data must be improved before HRQOL results can be expected to exert a major influence on clinical decision making.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References

This project has been financed with the aid of EXTRA funds from the Norwegian Foundation for Health and Rehabilitation.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Acknowledgements
  9. References
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