Quality of Life Research

, Volume 23, Issue 3, pp 825–836 | Cite as

International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24

  • Fabio Efficace
  • Michele Baccarani
  • Massimo Breccia
  • Susanne Saussele
  • Gregory Abel
  • Giovanni Caocci
  • Francois Guilhot
  • Kim Cocks
  • Adel Naeem
  • Mirjam Sprangers
  • Simone Oerlemans
  • Weichu Chie
  • Fausto Castagnetti
  • Felice Bombaci
  • Giora Sharf
  • Annarita Cardoni
  • Lucien Noens
  • Stephan Pallua
  • Marzia Salvucci
  • Ourania Nicolatou-Galitis
  • Gianantonio Rosti
  • Franco Mandelli
Article

Abstract

Background

Health-related quality of life (HRQOL) is a key aspect for chronic myeloid leukemia (CML) patients. The aim of this study was to develop a disease-specific HRQOL questionnaire for patients with CML to supplement the European Organization for Research and Treatment of Cancer (EORTC)-QLQ C30.

Patients and methods

The process followed a predefined and systematic stepwise iterative process as defined by the EORTC guidelines for questionnaire development. The process was divided into 3 phases: (1) generation of relevant HRQOL issues, (2) operationalization of the HRQOL issues into a set of items, and (3) pretesting the questionnaire for relevance and acceptability. Descriptive statistics and psychometric analyses were also performed.

Results

Overall, 655 CML patients were enrolled in 10 countries including the USA and countries in Europe and Asia. Interviews with health-care professionals experienced in CML (n = 59) were also conducted. Results from the interviews, clinical experiences, and statistical analyses were used to develop the EORTC QLQ-CML24. The final module consists of 24 items assessing the following aspects: symptom burden, impact on daily life and on worry/mood, body image problems, and satisfaction with care and with social life. Internal consistency, assessed with Cronbach’s alpha coefficients, ranged from 0.73 to 0.83 for the proposed scales.

Conclusion

The EORTC QLQ-CML24 is an internationally developed HRQOL questionnaire for CML patients, and its implementation in clinical research and practice can provide important information to facilitate clinical decision-making.

Keywords

Quality of life Chronic myeloid leukemia Questionnaire 

Introduction

The development of tyrosine kinase inhibitors (TKI) to treat chronic myeloid leukemia (CML) is one of the great triumphs of modern oncology. In less than three decades, the 5-year overall survival rate for CML has considerably increased [4]. Imatinib was the first TKI the United States food and drug administration approved treatment for CML. While its success in extending survival in CML is undeniable, it seems that a substantial amount of patients will need lifelong treatment. This has turned CML into a chronic disease in which patients need to both tolerate and adhere to continuing treatment many years after diagnosis [22, 24]. As a result, assessing health-related quality of life (HRQOL) and managing side effects of TKI, such as imatinib, have become a key issue for CML patients and their physicians [16, 21].

The so-called, second-generation TKI include both nilotinib and dasatinib [7]. These were initially approved for use as salvage therapies among imatinib-resistant and/or imatinib-intolerant patients, but both second-generation drugs have recently been approved for first-line therapy as well, based on two large randomized trials [20, 28].

With three effective drugs (i.e., imatinib, nilotinib, and dasatinib) that can be used frontline in newly diagnosed CML patients, treatment decision-making for individual patients in daily clinical practice has become challenging. Despite the nilotinib and dasatinib have been shown to have higher rates of cytogenetic and molecular responses (compared to imatinib), none of these three drugs are considerably better than the others with regard to progression-free and overall survival [18, 19]. Nevertheless, physician-reported toxicity data suggest that these drugs have different toxicity profiles [21]. While a wealth of biomedical and laboratory data exists on clinical efficacy of TKI in general, the impact of these from the patients’ perspective, in terms of HRQOL and symptom burden, has been poorly investigated [12].

The few studies available show that although TKI result in less toxicity than previous interferon-based therapies [14], patients’ HRQOL is impaired in many respects and chronic symptoms, such as fatigue, greatly affect daily life [10]. CML patients receiving TKI have been shown to have more depression, anxiety fatigue, and symptom burden compared to the general population [26]. Also, HRQOL impairments are particularly evident in younger CML patients (i.e., below 60 years) [9].

The inclusion of HRQOL and other types of patient-reported outcomes (PROs) are supported by major stakeholders [2, 23, 29] and are highly recommended in comparative effectiveness research in adult oncology [3]. While standard generic cancer HRQOL measures such as the EORTC QLQ-C30 are often used, disease-specific questionnaires have the potential to be more precise, reliable, and responsive to HRQOL changes. Although a questionnaire to evaluate HRQOL in leukemia patients has been recently published [6], no HRQOL measure has been developed and validated specifically for CML patients. We thus aimed to develop a rigorous and internationally applicable questionnaire as a supplement to the EORTC QLQ-C30 to assess HRQOL in CML patients.

Patients and methods

Study design and patients

We undertook an international research effort following the EORTC Quality of Life Group (QLG) guidelines for developing questionnaire modules [5, 17]. These guidelines consist of four phases: (1) generation of relevant HRQOL issues, (2) operationalization of the HRQOL issues into a set of items, (3) pretesting the questionnaire module, and (4) large-scale international field-testing. This paper reports results up to phase 3. The CML Advocates Network was involved providing logistic and administrative support and in key steps of the development process and participated in the investigators’ meetings.

Eligibility criteria included adult patients with a confirmed diagnosis of CML who were able to understand and speak the local language. Patients with psychiatric disorders or major cognitive dysfunctions hampering a self-reported evaluation were excluded. Ethics committee permissions from each participating center were obtained, and all patients provided written informed consent.

Phase 1: Generation of relevant HRQOL issues

To devise an initial list of HRQOL issues potentially relevant to CML patients, an extensive literature search was performed. This list was evaluated in semi-structured interviews with health-care professionals (HCPs) treating CML patients and with patients themselves to clarify whether further issues should be included. Face-to-face interviews with patients were conducted in hospitals. HCPs included physicians, nurses, and other clinicians who directly treat patients with CML. HCPs and patients rated each issue according to the following: (a) Relevance, which refers to the frequency with which a problem or symptom occurs and the trouble it may cause, was rated on a four-point scale ranging from “not at all relevant” (1 point) to “very much relevant” (4 points); (b) priority for inclusion (yes vs. no) to identify those issues that affect patients’ HRQOL most and that should definitely be included in the final questionnaire; and (c) breadth of coverage was investigated by asking patients and HCPs to suggest any relevant issues, which were not included in the item list and should therefore be added.

Phase 2: Construction of the provisional questionnaire

The list of “issues” derived from phase 1 was then operationalized into “items” with a response format and time frame compatible with the EORTC QLQ-C30. If available, items were taken from the EORTC Quality of Life Group Item Bank (covering all items from all EORTC modules).

Phase 3: Testing of the questionnaire for relevance and acceptability

The provisional questionnaire was tested in a new, much larger sample of CML patients from 10 countries to identify problems related to wording, comprehensiveness and to identify the need for new items or to delete redundant or confusing items. At this stage, patients were asked to complete the general EORTC QLQ-C30 and the provisional CML-specific module followed by a semi-structured interview. Face-to-face interviews with patients were conducted in hospitals. Patients were explicitly asked to comment on each question and whether items were annoying, confusing, intrusive, or upsetting. They were also asked whether they felt that any aspect relevant to their HRQOL was missing. These interviews led to the final CML questionnaire. All translations were performed according to the EORTC translation procedure guidelines [8].

In phases 1 and 3, an additional sample of patients also completed the survey online, and such data were used for supportive analyses. Patients were asked to complete basic socio-demographic and clinical information on disease and treatment. For each issue (in phase 1) or item (in phase 3), patients had to indicate the extent to which he/she found it relevant. The online survey, with an invitation letter explaining the purpose of the project, was posted on the CML Advocates Network website. Patients were also asked whether there were other areas of concern not included in the list, and thus, an open question was put at the end of the online survey (in this section, patients were allowed to make any additional comment).

Statistical analysis

Results from phases 1 and 3 interviews were analyzed using descriptive statistics, according to the EORTC QLG guidelines [5, 17]. Phase 1 items were retained if three of the following criteria were fulfilled: mean score at least 1.5 (possible range 1–4), prevalence 30 % (number of patients scoring 2, 3 or 4, divided by the total number who completed the item), range of responses at least two points (1–3 or 2–4), and at least 33 % of patients or HCPs prioritizing the item. Items were scored as follows: (1) “not at all,” (2) “a little,” (3) “quite a bit,” and (4) “very much.” In phase 3, recommendations for item retention are that five of seven criteria should be met: mean score >1.5, prevalence ratio >30 % or prevalence of scores 3 or 4 > 50 %, range >2 points, no floor/ceiling effect (responses in categories 3 and 4 or 1 and 2 > 10 %), no concerns expressed by patients (e.g., upsetting, confusing, irrelevant, or intrusive), at least 95 % response to the item and consistency across languages and cultures. During phase 2 of development, multiple items related to the same scale were generated. Scales were hypothesized based on clinical relevance and discussed at investigators’ meetings. Preliminary psychometric testing of the hypothesized scales was conducted during phase 3. Internal consistency was assessed using Cronbach’s alpha coefficient. As recommended by Nunnally [25], estimates of 0.70 or greater were considered acceptable for multi-item scales. Full psychometric testing requires larger patient numbers and will be carried out in phase 4 of the module development. The construct validity was also examined by correlation of the core questionnaire using Pearson’s product moment correlation coefficients. We expected that those scales that are conceptually related would show moderate or high correlations of one another (Pearson’s r ≥ 0.40 or > 0.60, respectively). Conversely, those scales that were unrelated were expected to yield lower correlations (Pearson’s r < 0.40). Clinical validity was assessed with known-group comparisons to assess the extent to which questionnaire scores were able to discriminate between subgroups of patients known to differ in terms of Karnofsky performance status and complete cytogenetic response (CCyR) to therapy. Group differences were assessed for significance using the Wilcoxon rank sum test. Main analysis reported in this study was conducted on patients interviewed face-to-face in participating hospitals. Data stemming from online completion were used for supportive analysis and to better inform decisions taken throughout the development process. All analyses were performed with SAS version 9.2 (SAS Institute Inc).

Results

Phase 1: Generation of issues

A preliminary list of 74 HRQOL issues potentially relevant for CML patients was identified through phase 1. Additional details on searching strategy and issues identified were previously reported [11, 13]. The 74-item initial list was used as a basis to conduct semi-structured interviews with 137 patients recruited in seven hospitals from five countries. Forty-three percent of patients were in treatment with first-line imatinib and 46 % were in second line treatment with TKI. In addition, 99 surveys were completed online through the CML Advocates Network. Patient characteristics of those recruited in hospital and those completing the survey online are provided in Table 1. Fifty-nine HCPs from Australia, Austria, Czech Republic, Germany, Greece, Italy, the Netherlands, Norway, Russia, Switzerland, Taiwan, and UK were also interviewed. The selection of HCPs was performed to cover a broad spectrum of experience in problems in CML, and the majority (83 %) was hematologists. Based on quantitative analysis on both patient and HCP samples, 24 issues were deleted. A further 9 issues were excluded based on redundancy with issues already covered by the EORTC QLQ-C30. One new issue (i.e., eye problems such as burning or dryness) was added as it was raised by 8 % of patients interviewed. Investigators’ meeting discussion led to combine 10 issues into four and to delete additional six issues (Fig. 1).
Table 1

Characteristics of patient samples (N = 655), phases 1 and 3

 

Phase 1 (N = 236)

Phase 3 (N = 419)

Face-to-face interviews in hospitals (N = 137)

Online surveya (N = 99)

Face-to-face interviews in hospitals (N = 312)

Online surveya (N = 107)

Age (years)

    

 Mean (SD)

56.72 (14.76)

46.67 (11.95)

53.30 (14.34)

47.40 (11.33)

 Median

59.00

45.00

53.00

47.00

 Range

20–92

24–74

21–83

25–73

Gender (%)

    

 Male

79 (57.7)

49 (49.5))

158 (50.6)

51 (47.7)

 Female

58 (42.3)

50 (50.5)

154 (49.4)

56 (52.3)

Disease phase (%)

    

 Chronic phase

134 (97.8)

95 (96.0)

309 (99.0)

106 (99.1)

 Other

3 (2.2)

4 (4.0)

3 (1.0)

1 (0.9)

Comorbidities (%)

    

 Yes (at least 1 or more)

61 (44.5)

22 (22.2)

97 (31.1)

25 (23.4)

 No

76 (55.5)

77 (77.8)

215 (68.9)

82 (76.6)

Karnofsky performance status (%)

    

 0–40

0 (0.0)

7 (2.2)

 50–70

19 (13.9)

42 (13.5)

 80–100

118 (86.1)

263 (84.3)

Living arrangements (%)

    

 Living alone

21 (15.3)

6 (6.0)

31 (9.9)

8 (7.5)

 Living with partner or family or others

116 (84.7)

93 (94.0)

255 (81.9)

99 (92.5)

 Unknown

0 (0.0)

0 (0.0)

26 (8.2)

0 (0.0)

Employment (%)

    

 Employed (full time/part time or homemaker)

63 (46.0)

68 (68.7)

181 (58.0)

82 (76.6)

 Unemployed

31 (22.6)

5 (5.1)

45 (14.4)

3 (2.8)

 Training/education

4 (2.9)

3 (3.0)

13 (4.2)

2 (1.9)

 Retired

38 (27.8)

18 (18.1)

62 (19.9)

17 (15.9)

 Other

1 (0.7)

5 (5.1)

11 (3.5)

3 (2.8)

Educational level (%)

    

 Compulsory school education or less

63 (46.0)

18 (18.2)

76 (24.4)

14 (13.1)

 High school

40 (29.2)

42 (42.4)

146 (46.8)

53 (49.5)

University

31 (22.6)

39 (39.4)

66 (21.1)

40 (37.4)

 Unknown

3 (2.2)

0 (0.0)

24 (7.7)

0 (0.0)

Patients’ surveys by country

    

 Austria

13 (4.2)

 Belgium

8 (2.6)

 France

36 (11.5)

 Germany

45 (32.9)

29 (9.3)

 Greece

7 (5.1)

3 (1.0)

 Iraq

8 (5.8)

44 (14.1)

 Italy

67 (48.9)

127 (40.6)

 Taiwan

10 (7.3)

4 (1.3)

 The Netherlands

18 (5.8)

 USA

30 (9.6)

Treatment (%)

    

 First-line treatment with imatinib

59 (43.1)

182 (58.3)

72 (67.3)

 First-line treatment with 2nd generation TKIs

10 (7.3)

35 (11.2)

8 (7.5)

 Second or greater lines of treatment with TKIs

63 (46.0)

92 (29.5)

26 (24.3)

 Other

5 (3.6)

3 (1.0)

1 (0.9)

Duration of therapy (%)

    

 ≥5 years

73 (53.3)

141 (45.2)

36 (33.6)

 <5 years

64 (46.7)

171 (54.8)

71 (66.4)

Complete cytogenetic response (CCyR) (%)

    

 Yes

122 (89.0)

228 (73.1)

 No

15 (11.0)

84 (26.9)

TKIs tyrosine kinase inhibitors, SD standard deviation

aThese data stemmed from the completion of online surveys posted on the website of the CML Advocates Network. These data were used for supportive analyses only

Fig. 1

EORTC QLQ-CML24, summary of questionnaire development

Phase 2: Construction of the provisional questionnaire

The 30 issues resulting from phase 1 were formatted into specific questions (i.e., items) within the EORTC format. Items that covered the content in full were available from the EORTC QLG Item Bank for 9 items. Phases 1 and 2 development process report was peer-reviewed and formally approved by the EORTC QLG module development committee (MDC) before starting with phase 3.

Phase 3: Testing of the provisional questionnaire for relevance and acceptability

The provisional CML module (containing 30 items) and the EORTC QLQ-C30 [1] were completed and face-to-face debriefing interviews were held with 312 patients at fourteen centers in ten countries. Main socio-demographic and clinical characteristics of this sample are similar to that reported in the literature [15] (Table 1). In addition, 107 surveys were completed online through the CML Advocates Network.

The mean score of the 30 module items was higher than 1.5 for 25 items. Compliance with item completion ranged between 96 and 100 %. No ceiling effect was found, but a floor effect was present with item no. 21 (i.e., concerns about ability to have children). All items, statistical results, and patients’ comments from all countries were subject to round table discussions during investigators’ meetings. Five items were deleted due to overlap with QLQ-C30 or other CML items (n = 2) or were conceptually difficult (n = 3). An additional item (i.e., concerns about ability to have children) did not meet the statistical criteria (see Fig. 1; Table 2) The resulting final items included in the EORTC QLQ-CML24 questionnaire are reported in Fig. 2. Supportive analysis conducted on the 107 patients completing the survey online confirmed results obtained with patients interviewed in hospitals (data not shown).
Table 2

The 30 issues used in phase 3 analyses and results of phase 3 interviews

List of issues resulting from phase 1

Mean

Compliance (%)

Prevalence ratio (%)

Deletion vs. retention

Main reason for deletion

Item no. in the QLQ-CML24

1. Abdominal pains or cramps

1.5

99

39

Retained

31

2. Dry mouth

1.7

100

47

Retained

32

3. Problems of weight changing

1.6

99

41

Retained

33

4. Skin problems (e.g., color changes, itchy, dry, or flaking skin)

1.8

98

54

Retained

34

5. Headaches

1.6

99

39

Retained

35

6. Aches or pains in your muscles or joints

2.1

99

67

Retained

36

7. Feeling lethargic

1.7

97

47

Deleted

Overlap with other items

 

8. Hair loss

1.5

100

32

Retained

37

9. Sweating problems

1.5

100

36

Retained

38

10. Acid indigestion or heartburn

1.6

99

44

Retained

39

11. Feeling drowsy

1.9

99

64

Retained

40

12. Swelling in certain parts of the body (e.g., ankles, legs, or around the eyes)

1.8

99

56

Retained

41

13. Urinate frequently

1.8

100

52

Retained

42

14. Problems with eyes (e.g., burning, watery, irritated, or dry)

1.9

100

57

Retained

43

15. Muscle cramps

2.0

100

60

Retained

44

16. Losing interest in activities that one normally enjoy

1.5

99

36

Deleted

Overlap with other items

 

17. Emotional ups and downs

1.8

99

59

Retained

45

18. Worry about health in the future

2.1

99

70

Retained

46

19. Difficulties in conducting a normal life because of getting tired easily

1.8

99

47

Retained

47

20. Worry about picking up an infection

1.6

99

42

Retained

48

21. Concerns about your ability to have children

1.3

96

15

Deleted

Meeting too few criteria

 

22. Dissatisfaction with own’ s body as result of the disease or treatment

1.7

99

44

Retained

49

23. Burden of treatment

2.0

99

69

Retained

50

24. Need of social support (e.g., family, friends or relatives) to undergo the therapy or to cope with the disease

1.6

99

33

Retained

51

25. Understanding all aspects of the therapy you are undergoing (if any)

2.7

96

77

Deleted

Patients’ comments

 

26. Feeling dependent on the treatment schedule

2.1

97

61

Deleted

Patients’ comments

 

27. Satisfaction in continuing with the current treatment

3.1

96

92

Deleted

Patients’ comments

 

28. Satisfaction with the care received

3.3

98

95

Retained

52

29. Satisfaction with the amount of information received (e.g., on remedies to alleviate side effects or details of treatment schedule)

3.4

99

93

Retained

53

30 Satisfaction with the quality of your family and social life

3.1

99

91

Retained

54

In phase 3, recommendations for item retention are that five of seven criteria should be met: mean score >1.5, prevalence ratio >30 % or prevalence of scores 3 or 4 > 50 %, range >2 points, no floor/ceiling effect (responses in categories 3 and 4 or 1 and 2 > 10 %), no concerns expressed by patients (e.g., upsetting, confusing, irrelevant or intrusive), at least 95 % response to the item and consistency across languages and cultures

Fig. 2

Items included in the EORTC QLQ-CML24. Item numbers of the EORTC QLQ-CML24 start from item#31 as the EORTC QLQ-C30 (which should be used in conjunction with this questionnaire) has 30 items. This questionnaire (free of charge for academic studies) can be requested at: http://groups.eortc.be/qol/

Psychometric analysis

Four multi-item scales were proposed for the QLQ-CML24, based on their content and clinical relevance; symptom burden, impact on worry/mood, impact on daily life, and satisfaction with care and information. Two single items were suggested: body image problems and satisfaction with social life. Internal consistency, assessed with Cronbach’s alpha coefficients, ranged from 0.73 to 0.83 for the proposed scales, indicating good internal consistency (Table 3).
Table 3

Scale structure and internal consistency, Cronbach’s alpha

Scale

Item no. in the EORTC QLQ-CML24b

Cronbach’s alpha

Symptom burdena

13 items (31, 32, 34–44)

0.83

Impact on worry/mood

4 items (33, 45, 46, 48)

0.74

Impact on daily life

3 items (47, 50, 51)

0.73

Body image problems

1 item (49)

N/A

Satisfaction with care and information

2 items (52,53)

0.83

Satisfaction with social life

1 item (54)

N/A

a The “symptom burden” scale does not include fatigue as it is already covered by the EORTC QLQ-C30 (we note that for a comprehensive assessment of HRQOL in CML patients, the QLQ-CML24 should always be used in conjunction with the EORTC QLQ-C30)

b For item list, see Fig. 2; N/A: not applicable

Construct validity was investigated by correlations between scales of the QLQ-CML24 and the QLQ-C30 core questionnaire (Table 4). The satisfaction with care and information and satisfaction with social life scales were weakly correlated with the scales from the QLQ-C30 (ranging between 0.01 and 0.37), indicating that they are assessing aspects not currently covered by the core questionnaire. As expected, the symptom burden and impact on daily life scales from the module and the fatigue scale from the core questionnaire were highly correlated (0.64 and 0.65, respectively). There were high correlations between impact on worry/mood scale of the QLQ-CML24 and emotional functioning scale from the QLQ-C30 questionnaire (−0.69) and between impact on daily life scale from the module and two of the QLQ-C30 scales (emotional functioning and social functioning, −0.63 and −0.64, respectively). Additional details are provided in Table 4.
Table 4

Correlation between EORTC QLQ-CML24 and the EORTC QLQ-C30 scales

EORTC QLQ-C30

EORTC QLQ-CML24

Symptom burdena

Impact on worry/mooda

Impact on daily lifea

Body image problemsa

Satisfaction with care and informationb

Satisfaction with social lifeb

Global health status/QoL

−0.49

−0.54

−0.59

−0.42

0.14

0.32

Functioning scale

Physical functioning

−0.60

−0.49

−0.56

−0.45

0.13

0.15

Role functioning

−0.57

−0.47

−0.57

−0.45

0.13

0.21

Emotional functioning

−0.55

−0.69

−0.63

−0.57

0.11

0.28

Cognitive functioning

−0.54

−0.51

−0.53

−0.41

0.09

0.24

Social functioning

−0.53

−0.60

−0.64

−0.49

0.10

0.37

Symptoms

Fatigue

0.64

0.54

0.65

0.48

−0.09

−0.23

Nausea/vomiting

0.42

0.44

0.45

0.30

−0.06

−0.14

Pain

0.60

0.54

0.57

0.45

−0.15

−0.13

Dyspnoea

0.37

0.31

0.31

0.28

−0.06

−0.18

Insomnia

0.46

0.43

0.52

0.32

−0.10

−0.25

Appetite loss

0.39

0.36

0.47

0.23

−0.10

−0.15

Constipation

0.27

0.18

0.22

0.30

0.01

−0.07

Diarrhea

0.30

0.27

0.28

0.21

0.02

−0.09

a Higher scores indicate worse outcomes (i.e., high symptom burden, high impact on worry/mood, high impact on daily life, and higher problems with body image)

b Higher scores indicate better outcomes (i.e., higher levels of satisfaction with care and information and with social life)

With respect to clinical validity, Table 5 displays comparisons of the mean scale scores between patients with low (<80) versus those with high (≥80) Karnofsky performance status and those with or without a CCyR. There were statistically significant differences in all scales in the expected directions with regard to analysis on performance status. Comparisons between responders and non-responders (i.e., reaching at least a CCyR) showed better HRQOL outcomes for patients responding to therapy on all scales. Statistically significant differences were found in four out of the six scales. Supportive analysis conducted on patients who completed the survey online confirmed psychometric characteristics except for analysis on CCyR and performance status as these were not collected in this patient sample (data not shown). Likewise the previous step, a phase 3 development process full report was peer-reviewed and formally approved by the EORTC QLG MDC.
Table 5

QLQ-CML24 group comparisons by performance status and response to therapy

QLQ-CML24 scales

Karnofsky Performance status

Response to therapy (CCyR)

<80 (N = 49) Mean (SD)

≥80 (N = 263) Mean (SD)

Wilcoxon rank sum P value

No (N = 84) Mean (SD)

Yes (N = 228) Mean (SD)

Wilcoxon rank sum P value

Symptom burdena

32.25 (21.47)

23.62 (15.77)

0.0124

27.67 (19.00)

23.98 (16.19)

0.1495

Impact on worry/mooda

38.78 (25.77)

23.65 (20.61)

0.0001

36.57 (27.40)

22.14 (18.46)

<0.0001

Impact on daily lifea

46.83 (32.79)

21.88 (20.94)

<0.0001

37.96 (30.82)

21.31 (20.60)

<0.0001

Body image problemsa

37.41 (37.04)

20.31 (28.51)

0.0013

31.75 (35.81)

19.76 (27.80)

0.0086

Satisfaction with care and informationb

65.99 (31.17)

81.61 (25.66)

0.0003

70.24 (30.51)

82.45 (25.08)

0.0004

Satisfaction with social lifeb

59.86 (35.99)

72.18 (30.85)

0.024

66.67 (35.47)

71.56 (30.55)

0.409

CCyR, complete cytogenetic response

aHigher scores indicate worse outcomes (i.e., high symptom burden, high impact on worry/mood, high impact on daily life, and higher problems with body image)

bHigher scores indicate better outcomes (i.e., higher levels of satisfaction with care and information and with social life)

Discussion

The EORTC QLQ-CML24 has been developed through a predefined and systematic stepwise iterative process involving a large sample of patients, and it is intended for use in conjunction with the EORTC QLQ-C30 to assess HRQOL in CML patients.

Clinicians are now confronted with a number of challenges in the management of CML patients. These include, for example, the best first-line treatment strategy to use and the best treatment option when first-line imatinib therapy fails [7]. We thus expect our questionnaire to raise quality standards of future studies by allowing assessment of the burden of treatment directly from the patients’ perspective. To our knowledge, this is the only internationally developed patient-reported questionnaire to assess HRQOL in CML patients. Recently, however, another questionnaire to assess “symptom burden” in CML has been developed at the MD Anderson Cancer Center [30].

The development of our questionnaire might have major implications for clinical research and clinical practice. As current treatment options have similar clinical efficacy, the availability of a solid patient-reported HRQOL measure, and its implementation in comparative effectiveness studies, will provide invaluable information to help guide clinical decision-making. While TKI-based therapies may not greatly differ with regard to clinical and laboratory outcomes, they might have a different impact on patients’ HRQOL. In addition, future studies aiming to assess the benefits to patients of treatment interruption or even cessation can now include a rigorous assessment of the impact of such strategies in terms of HRQOL.

It has been suggested that the selection of a TKI as initial therapy for chronic phase CML is not as important as switching therapy promptly when a TKI impacts patients’ HRQOL [21]. Now, clinicians have a standard tool to rely on to make such HRQOL assessment. Also, the application of the common terminology criteria for adverse events to define intolerance in case of lifelong TKI therapies has been called into question, and patient-reported HRQOL has been suggested to potentially provide a better indication of true intolerance [27]. The use of the EORTC QLQ-CML24 could thus help better inform physicians of a true intolerance to a given therapy by providing the unique patient’s perception of the burden of treatment overtime. This could potentially help provide patients with more personalized interventions by tailoring treatment on specific patients’ needs and individual characteristics.

Our new questionnaire identifies various areas of concern ranging from a key set of symptoms to more general aspects, such as satisfaction with social life. Symptoms included in the final questionnaire were broadly in-line with other studies reporting PROs in CML patients. Previous studies [9] showed that while symptom prevalence (with any level of concern) ranged from 28 to 82 %, one-fourth to one-third of CML patients reported long-term severe symptoms such as musculoskeletal pain. Other symptoms, such as skin problems and itching, swelling of arms and legs and drowsiness were also shown to be of greater distress in CML patients receiving various TKI [26] compared to patients without cancer. Incidentally, we note that although fatigue is a key aspect for CML patients, it is not included in our symptom burden scale as fatigue is already covered by the EORTC QLQ-C30.

In addition, although TKI have provided major HRQOL improvements over previous interferon-based therapies [14], important limitations in performing daily activities due to physical and emotional problems have been found in these patients [9]. To this end, we note that our questionnaire has two scales measuring both the impact on daily life and the impact on worry and mood.

This study has limitations. As with any questionnaire development, we could only rely on the input of patients who agreed to participate possibly introducing participation bias. Also, a prospective validation is needed to provide additional psychometric data and fully confirm subscale structure. These limitations notwithstanding, this questionnaire can already be used in clinical research and practice to help physicians and patients making more informed treatment decisions and facilitate a more patient-centered approach in the management of CML.

This questionnaire also has a number of strengths. First, it was developed in accordance with the highest quality standards of PRO measure development, and patients’ input was strongly considered from the very beginning of the development process [5, 17, 29]. Second, it was developed simultaneously at fourteen centers in ten different countries, thus ensuring robust content validity. This has major implications particularly for multicenter international studies for which the use of cross-culturally developed measures should be recommended. Finally, we also incorporated an additional sample of patients who completed the questionnaires online, and whose data were used for supportive analyses throughout the development process.

In conclusion, we have developed a new CML-specific HRQOL questionnaire for use in research and clinical practice. The EORTC QLQ-CML24, in conjunction with the EORTC QLQ-C30, will provide key data, complementary to a wealth of clinical and laboratory outcomes already available, to facilitate clinical decision-making.

Notes

Acknowledgments

This study was supported by a research grant from the EORTC Quality of Life Group. Also, additional support for the conduct of the study was provided by the Italian Group for Adult Hematologic Diseases (GIMEMA). We are grateful to all the patients who participated in this study. We also thank Felice Bombaci and Giora Sharf (from the CML Advocates Network) for their invaluable help in representing the unique patients’ perspective throughout the development process. We also thank Dagmara Kulis from the EORTC Quality of Life Department (Brussels) for support in coordinating language translations. Finally, we also express our gratitude to Bernhard Holzner and Marianne Hjermstad for reviewing the module development report on behalf of the EORTC Quality of Life Group. Dr. Susanne Saussele is supported by DJCLS R 10/20.

Conflict of interest

Consultancy: F. E (Novartis Pharma, Bristol Myers Squibb), Honoraria: F. C (Novartis Pharma, Bristol Myers Squibb), and Speaking fees: F. G (Novartis Pharma, Bristol Myers Squibb, Ariad).

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Fabio Efficace
    • 1
  • Michele Baccarani
    • 2
  • Massimo Breccia
    • 3
  • Susanne Saussele
    • 4
  • Gregory Abel
    • 5
  • Giovanni Caocci
    • 6
  • Francois Guilhot
    • 7
  • Kim Cocks
    • 8
  • Adel Naeem
    • 9
  • Mirjam Sprangers
    • 10
  • Simone Oerlemans
    • 11
  • Weichu Chie
    • 12
  • Fausto Castagnetti
    • 2
  • Felice Bombaci
    • 13
  • Giora Sharf
    • 14
  • Annarita Cardoni
    • 1
  • Lucien Noens
    • 15
  • Stephan Pallua
    • 16
  • Marzia Salvucci
    • 17
  • Ourania Nicolatou-Galitis
    • 18
  • Gianantonio Rosti
    • 2
  • Franco Mandelli
    • 1
  1. 1.Italian Group for Adult Hematologic Diseases GIMEMAData Center and Health Outcomes Research UnitRomeItaly
  2. 2.Department of Hematology-Oncology, S. Orsola-Malpighi HospitalUniversity of BolognaBolognaItaly
  3. 3.Department of Cellular Biotechnologies and HematologyUniversity of Rome “Sapienza”RomeItaly
  4. 4.Medizinische Fakultät MannheimUniversität HeidelbergMannheimGermany
  5. 5.Division of Population Sciences, Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA
  6. 6.Department of Internistic Medical SciencesUniversity of CagliariCagliariItaly
  7. 7.Oncologie Hématologique et Thérapie Cellulaire, Centre Hospitalier Universitaire de PoitiersInserm CIC 0802PoitiersFrance
  8. 8.York Trials Unit, Department of Health SciencesUniversity of YorkYorkUK
  9. 9.Department of HematologyBaghdad Teaching HospitalBaghdadIraq
  10. 10.Department of Medical PsychologyUniversity of AmsterdamAmsterdamThe Netherlands
  11. 11.Comprehensive Cancer Centre SouthEindhovenThe Netherlands
  12. 12.Department of Public Health, Graduate Institute of Preventive Medicine, College of Public HealthNational Taiwan UniversityTaipeiTaiwan
  13. 13.Gruppo AIL Pazienti LMC (Italian Member of CML Advocates Network)TurinItaly
  14. 14.CML Advocates NetworkTel AvivIsrael
  15. 15.Department of HematologyGhent University HospitalGhentBelgium
  16. 16.Department for Psychiatry and PsychotherapyInnsbruck Medical UniversityInnsbruckAustria
  17. 17.Hematology UnitAzienda Usl RavennaRavennaItaly
  18. 18.Clinic of Hospital Dentistry, Dental Oncology Unit Dental SchoolUniversity of AthensAthensGreece

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