The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life questionnaire cervical cancer module

EORTC QLQ-CX24^†

Abstract

BACKGROUND

The authors report on the development and validation of a cervical cancer module for the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QoL) questionnaire (QLQ), which was designed to assess disease-specific and treatment-specific aspects of QoL in patients with cervical cancer.

METHODS

The cervical cancer module (EORTC QLQ-CX24) was developed in a multicultural, multidisciplinary setting to supplement the EORTC QLQ-C30 core questionnaire. The QLQ-C30 and the cervical cancer module were administered to 346 patients with cervical cancer who underwent radical hysterectomy and received radiotherapy and chemotherapy. Psychometric analyses were performed by using data from 2 independent samples.

RESULTS

The QLQ-CX24 consists of 3 multiitem scales and 5 single-item scales. Multitrait scaling analyses revealed high internal consistencies for the subscales with Cronbach α coefficients ranging from .72 to .87 (Symptom Experience, .72; Body Image, .86; Sexual/Vaginal Functioning, .87). Convergent and discriminant validity were fulfilled with scaling errors below 3%. The QLQ-CX24 was capable of discriminating between clinical subgroups. All items exhibited good compliance with <3% missing values. Most patients completed the EORTC QLQ-C30 and the QLQ-CX24 in <15 minutes (86%), and many did not require any assistance to complete the questionnaires (65%).

CONCLUSIONS

The current psychometric analyses supported the content and construct validity and the reliability of the EORTC QLQ-CX24 module. This newly developed module is a useful instrument for assessing the QoL of patients who are treated for cervical cancer both in clinical trials and in clinical practice. Cancer 2006. © 2006 American Cancer Society.

Worldwide approximately half a million women are diagnosed annually with invasive cervical cancer.1 The 5-year survival rates are >90% for early-stage cervical cancer in developed countries and <10% for more advanced stages.2 The treatment of patients with cervical cancer has changed significantly over the last few years. Various new therapeutic options are applied according to tumor stage. Patients with disease of limited volume usually undergo radical hysterectomy. For patients with locally advanced disease, extensive radiotherapy, including external pelvic irradiation and brachytherapy, has been the standard treatment for several years.3 More recently, concurrent chemoradiotherapy has become the treatment of choice for patients with locally advanced cervical cancer and has produced promising results in terms of survival.4 Neoadjuvant chemotherapy followed by radical surgery has been suggested as an alternative to irradiation5, 6 and currently is being investigated in a randomized European Organization for Research and Treatment of Cancer (EORTC) trial (Protocol 55994). The decision regarding the choice of therapeutic method is based on an interdisciplinary consultation process. This process involves the consideration of the stage of the disease, patient age, side effects of the different therapies, personal circumstances, and the quality of life (QoL) during and after treatment. With a growing emphasis on the need for evidence-based practice and for involving patients in treatment decision-making, patient-reported QoL outcomes have become important. QoL assessment in randomized clinical trials for cervical cancer remains rare.7 Multicenter studies require cross-culturally validated measures that cover the whole range of disease-related and treatment-related issues.

The 30-item EORTC QoL questionnaire (QLQ-C30) is a psychometrically robust, cross-culturally accepted questionnaire that was designed to be applicable to a broad spectrum of cancer patients as a core questionnaire.8 This instrument consists of 5 function scales (physical, role, emotional, cognitive, and social), 3 symptom scales (fatigue, nausea/emesis, and pain), 6 single-item scales (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global QoL scale. The EORTC QoL Group measurement strategy is to supplement the generic QLQ-C30 with disease-specific and/or treatment-specific modules. In this article, we report on the development of a questionnaire module that supplements the EORTC QLQ-C30 in the assessment the QoL of women with cervical cancer in clinical trials (EORTC QLQ-CX24). The objective of this study was to investigate the scale structure of this new cervical cancer module and to determine its reliability, validity, and cross-cultural applicability.

MATERIALS AND METHODS

The EORTC cervical cancer module was developed in a multicultural setting that included 9 European countries, Australia, Brazil, Korea, and Taiwan. The module was developed by following the guidelines of the EORTC QoL Group.9 According to the guidelines, cancer site-specific modules are supplements to the core questionnaire (EORTC QLQ-C30). Modules address additional relevant areas of QoL that are not covered sufficiently by the core instrument. Because modules are designed to assess treatment outcomes in clinical trials, issues related to symptoms and treatment should be included. The development process, which includes 4 phases, is presented in Table 1.

Table 1. Phases in the Development of the Supplemental 24-Item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire

QoL indicates quality of life; EORTC, European Organization for Research and Treatment of Cancer; QLQ-C30, 30-item core EORTC QoL questionnaire.

Phase I: Generation of QoL issues

Literature search

Review of QoL instruments related to cervical cancer

Interviews with health care professionals and patients

Selection of issues

List of potentially relevant QoL items

Phase II: Operationalization

Construction of questions for the provisional module

Items worded to be compatible with the QLQ-C30 format

Translation process using forward-backward procedure

Formal report submitted to the EORTC QoL Group

Approval by the EORTC QoL Group (Module Development Committee)

Phase III: Pretesting

Testing the translations in a pilot sample

Patients complete the module and undergo debriefing questions

Data analysis according to preset criteria

Formal report submitted to the EORTC QoL Group

Approval by the EORTC QoL Group (Module Development Committee)

Phase IV: Testing the psychometric properties

Evaluation of reliability, validity and cross-cultural acceptability

Phase I: Generation of QoL Issues

In Phase I of module development, the objective was to identify issues relevant to the QoL of patients with cervical cancer by using 3 sources: literature, patients, and health care professionals. In accordance with the EORTC QoL Group questionnaire-development policy, members of the EORTC Gynecology Clinical Trials Group were consulted.10 Literature searches were conducted using the MEDLINE, Psychinfo, and Cinahl data bases from 1992 to 2002. A list of 74 issues related to cervical cancer patients was derived. Issues were excluded if they were too general or if they were covered by the EORTC QLQ-C30. Each issue was rated for relevance and priority by patients and health care providers. Sixty-eight patients who were diagnosed with various stages of cervical cancer according to the International Federation of Gynecology and Obstetrics (FIGO) (26 women with Stage I disease, 22 women with Stage II disease, 11 women with Stage III disease, and 4 women with Stage IV disease) and 132 health care professionals (51 gynecologists, 29 medical and radiation oncologists, 31 nurses, 7 psychologists, 7 social workers, and 7 others) participated in Phase I of development. Each issue was rated on a 4-point Likert scale (1 = lowest relevance and 4 = highest relevance). Issues with high relevance ratings (mean score ≥2) and high priority ratings for inclusion in the module (ratings by ≥30%) were considered. The list of issues also was presented to the EORTC Gynecologic Cancer Group at their biannual meeting. Twenty members of the group provided feedback on the appropriateness of content and breath of coverage to achieve content validity. The health care professional ratings largely were in agreement with the patient ratings during the module development Phase I.

Phase II: Construction of Items and Translation

The module was comprised of issues pertaining to symptoms of cervical cancer, treatment-related issues, and any additional dimensions of QoL that are relevant for patients with cervical cancer. In Phase II of module development, for the 26 identified issues, questions were generated, and a provisional module was established. The items were compatible with the EORTC QLQ-C30 in terms of response format and time frame. The module included gastrointestinal symptoms, genitourinary symptoms, vaginal symptoms, body image, issues related to sexual functioning, and several additional issues. Table 2 shows the content and hypothesized scale structure. The provisional cervical cancer module was developed in English and then translated according to the EORTC Translation Guidelines11 into Croatian, Chinese (Taiwan), Danish, Dutch, French, German, Korean, Norwegian, Polish, Portuguese (Portugal), Portuguese (Brazil), and Swedish. The translation process followed a forward-backward procedure. It was coordinated by the EORTC QoL Unit and was supervised by the collaborators in the participating countries.

Table 2. Hypothesized Scale Structure of the European Organization for Research and Treatment of Cancer Cervical Cancer Module

* These items deleted because of conceptual ambiguity and semantic differences in the translations.

Sexual functioning

Vaginal dryness

Short vagina

Tight vagina

Pain during intercourse

Enjoying sexual activities

Importance of sexual intimacy*

Uneasy about sexual intimacy*

Body image

Decreased feeling of attractiveness

Less feminine

Dissatisfied with body

Gastrointestinal symptoms

Abdominal cramps

Difficulty controlling bowels

Blood in stools

Urologic symptoms

Frequent urination

Pain or burning feeling when urinating

Incontinence

Difficulty in emptying bladder

Vaginal symptoms

Irritation/soreness around vagina

Vaginal discharge

Abnormal bleeding

Single items

Lymphoedema

Pain in the lower back

Tingling and numbness

Menopausal symptoms

Worry about sex being painful

Sexual enjoyment

Phase III: Pretesting

In Phase III of module development, the provisional module was pretested in 12 languages. In this phase, the objectives were to identify and solve potential problems in the translations (e.g., phrasing of questions) and to determine the need for additional items or the elimination of items. During the pretest, a sample of 216 patients completed the questionnaires (EORTC QLQ-C30 and QLQ-CX24) and underwent cognitive debriefing. Wording problems of 3 sexuality items were identified after interviewing the first 37 patients. This required rephrasing of the problematic items (“To what extent were you sexually active?”, “To what extent were you interested in being sexually intimate?”, and “To what extent was sex enjoyable for you?”). The wording ‘to what extent’ was considered problematic, and the items were rephrased (e.g., “Was sexual activity enjoyable for you?”) The linguistically modified version was pretested further on 179 patients. According to the cognitive debriefing results from those 179 patients, the module was revised slightly. The modifications were minor linguistic changes mainly in the English version, which did not affect the other translations. Two sexuality items were excluded because of conceptual ambiguity and semantic differences in the translations. These items were not included in Phase IV of module development and were deleted from the final version. One of those items (“Have you felt uneasy about being sexually intimate?”) had a very high nonresponse rate of 72%. In Phase III, a total of 179 patients (Subsample 1) provided complete data, and a preliminary scaling analysis was performed.

Phase IV: Testing the Psychometric Properties

In Phase IV, the psychometric properties of the modified 24-item module were tested on a cross-cultural sample. One hundred ninety patients with histologically confirmed FIGO Stages I through IV cervical cancer completed the EORTC QLQ-C30 (version 3.0), the QLQ-CX24 module, and debriefing questions. Twenty-three patients were excluded (21 women had missing FIGO stage information, and 2 women had not completed the QLQ-CX24 module). The psychometric analysis in Phase IV was based on 167 patients (Subsample 2).

Statistical Analysis

The sample size calculation was based on 5 to 10 patients per questionnaire item to generate stable reliability and validity estimates.12 All statistical analyses were performed using the data from Phase IV of module development (n = 167 patients). Descriptive statistics were used for the sociodemographic and clinical data to characterize the sample. The scale scores were transformed to a scale from 0 to 100. In instances of missing responses, the following procedure was applied: If >50% of items were missing, then no scale score was computed. For reliability analyses, the scale score was computed only from valid responses.12 Multitrait scaling analyses were employed to examine correlations between items and the hypothesized scales within the EORTC QLQ-CX24. Convergent validity for each scale was assessed by calculating the correlation between each item and its own scale corrected for overlap. The correlation values were then compared for the correlation of each item with other scales to examine discriminant validity. A scaling error for an item was obtained when the correlation between an item and its own scale was lower than its correlation with any other scale.13 Correlations were determined by using the Pearson product-moment coefficient. Because the cervical cancer module contained optional items (sexuality items), pair-wise deletion of individuals with missing values was used in the multitrait analysis. The internal consistency of the multiitem scales was calculated by using the Cronbach α coefficient. Values of α ≥ 0.70 were considered acceptable for group comparisons.

Clinical validity was assessed by using Student t tests to compare different clinical groups (known-group comparisons) and Pearson correlations for metric scales for Karnofsky performance status and the QLQ-CX24 scales. Student t tests for independent samples were used to test differences in the QLQ-CX24 scales by stage of disease as follows: early stage (FIGO Stage I) versus advanced stages (FIGO Stages II-IV), disease status (no evidence of disease vs. recurrent disease), and treatment status (on-treatment vs. off-treatment, surgery alone vs. combined treatment). A significance level of P < .05 was considered acceptable. The Cohen d was computed as a measure for the effect size.14 According to the classification of effect sizes, an effect is small when d is ≥0.20, an effect is medium-sized when d is ≥0.50, and an effect is large when d is ≥0.80. If d is <0.20, then the effect is very small and practically negligible.

RESULTS

Patients with various stages of cervical cancer from 12 countries were recruited for the validation study. The cross-cultural distribution shown in Table 3 indicates a well balanced number of patients per country/language. Patients with different stages of cancer also were represented well. The Institutional Review Board or Ethical Committee at the investigators' hospital reviewed and approved the study. Patients provided informed consent to participate in the study. In Phase III of module development, 179 patients (Subsample 1) completed the 26-item version of the cervical cancer module. Based on the results of the cognitive debriefing, this version of the module was refined further and revised. In Phase IV, 167 patients (Subsample 2) completed the 24-item version. Sociodemographic and clinical characteristics are shown in Table 4. Concerning demographic variables, there were no statistically significant differences between the subgroups except for age. The patients in Subsample 1 were significantly older compared with the patients in Subsample 2 (51.4 years vs. 48.6 years, respectively; P = .048). In both samples, >50% of women had compulsory or postcompulsory school education, and >33% of women were employed either full time or part time. The majority of women lived with their partner or family and had a sexual partner. Patients with different stages of cancer who were receiving various treatment regimens were represented well. The incidence of advanced-stage disease (Stage III) was significantly greater in Subsample 1 compared with Subsample 2 (P = .002). There were no differences between the treatment modalities of surgery (P = .145) and chemotherapy (P = .240) between the 2 groups. In Subsample 1, significantly fewer patients received radiochemotherapy (P < .001), significantly more patients were receiving active treatment (P < .001), and significantly more patients received external beam radiation (P < .001) or hyperthermia (P = .002) compared with patients in Subsample 2. Only patients from the Netherlands received hyperthermia treatment. The incidence of treatment-related menopause was significantly greater in Subsample 2 compared with Subsample 1 (P = .001), whereas the use of hormone-replacement therapy did not differ statistically between the groups (P = .124). The Karnofsky performance status scores were high in both groups (mean score, >90; P = .749).

Table 3. Cross-Cultural Distribution by Stage

Country	Total No.	FIGO stage: No. of patients
		Phase III, sample 1 (n = 179)				Phase IV, sample 2 (n = 167)
		Stage I	Stage II	Stage III	Stage IV	Stage I	Stage II	Stage III	Stage IV
FIGO indicates International Federation of Gynecology and Obstetrics.
Australia	11	4	0	1	0	13	2	1	1
Austria	26	9	6	0	1	3	4	3	1
Brazil	19	0	1	4	1	3	10	1	0
Croatia	28	9	3	3	1	7	3	3	0
Denmark	22	5	6	3	1	0	6	2	0
Germany	56	3	4	6	4	28	8	1	2
Korea	27	11	5	0	1	5	5	0	0
The Netherlands	32	3	7	16	0	2	3	1	0
Poland	41	23	7	1	0	9	1	0	0
Sweden	24	9	4	2	0	6	2	1	0
Taiwan	26	7	3	1	0	10	4	1	0
United Kingdom	23	3	4	1	0	9	4	1	1
Total	346	86	50	38	5	95	52	15	5

Table 4. Sociodemographic and Clinical Characteristics

Variable	Phase III sample (n = 179)		Phase IV sample (n = 167)
	No. of patients	%	No. of patients	%
SD indicates standard deviation; FIGO, International Federation of Gynecology and Obstetrics; HRT, hormone-replacement therapy; PS, performance status. * Some patients may have received >1 treatment.
Age (mean ± SD)	51.4 ± 14.28		48.6 ± 12.20
Education
Compulsory or less	78	43.6	62	37.1
Postcompulsory school	80	44.7	74	44.3
University level	19	10.6	28	16.8
Unknown	2	1.1	3	1.8
Employment
Full time	45	25.1	49	29.3
Part time	22	12.3	27	16.2
Homemaker	36	20.1	37	22.2
Unemployed	16	8.9	9	5.4
Self-employed	6	3.4	4	2.4
Retired	40	22.3	28	16.8
Other/unknown	14	7.8	13	7.8
Living
Alone	29	16.2	20	12.0
With partner or family	138	77.1	139	83.2
With others	6	3.4	6	3.6
Unknown	6	3.4	2	1.2
Sexual partner
Yes	116	64.8	111	66.5
No	60	33.5	37	22.2
Unknown	3	1.7	19	11.4
FIGO disease stage
Stage I	82	48.0	95	56.9
Stage II	50	27.9	52	31.1
Stage III	38	21.2	15	9.0
Stage IV	3	2.8	5	3.0
Treatment*
Surgery	111	62.0	116	69.5
Chemotherapy	64	35.8	70	41.9
Radiochemotherapy	11	5.6	46	27.5
Brachytherapy	71	39.7	77	46.1
External beam radiation	97	54.2	9	5.4
Hyperthermia	10	5.6	0	0
Active treatment
Yes	91	50.8	44	26.3
No	84	46.9	113	67.7
Unknown	4	2.2	10	6.0
Menopausal status
Premenopausal	61	34.1	36	21.6
Postmenopausal	68	38.0	51	30.5
Treatment related	46	25.7	77	46.1
Unknown	4	2.2	3	1.8
HRT
Yes	27	15.1	31	18.6
No	145	81.0	122	73.1
Unknown	7	3.9	14	8.4
Karnofsky PS (mean ± SD)	90.1 ± 12.93		90.6 ± 12.76

The majority of the women (86%) completed the QLQ-C30 and the QLQ-CX24 module in <15 minutes, and 65% did not require any help. Most patients (90%) reported that the questions were clear and easy to understand. Only 2 patients (1%) reported that some items were upsetting. Item compliance was assessed among patients who completed the QLQ-C30 and the cervical cancer module. All items except the conditional items exhibited good compliance with <3% of missing values. The sexuality items, as expected, were completed only by patients who were active sexually. Greater than 60% of women had not been sexually active and, thus, were unable to respond to these items. Among these women, 34% in Subsample 1 and 22% in Subsample 2 had no sexual partner. In addition, more nonresponding women were receiving active treatment compared with women who responded to the sexuality questions.

Exploratory Scaling Analyses

In phase III of module development, a preliminary, multitrait scaling analysis of the 26-item version was carried out with data from the first subsample (n = 179 patients). The exploratory scaling analyses for the hypothesized scale structure revealed satisfying Cronbach α coefficients for the Sexual Functioning scale (.67) and for the Body Image scale (.81). For the symptom scales, the internal consistencies were poor (Gastrointestinal Symptoms, .39; Genitourologic Symptoms, .51; Vaginal Symptoms, .52).

Internal Consistency: Item Convergent and Discriminant Validity

In Phase IV, all symptom items were combined into 1 multiitem scale, and the scale structure was reanalyzed in the second subsample (n = 167 patients). The postulated scale structure was Symptom Experience (items 31–37, 39, and 41–43), Body Image (items 45–47), Sexual/Vaginal Functioning (items 50–53), and 5 single-item scales: Lymphoedema (item 38), Peripheral Neuropathy (item 40), Menopausal Symptoms (item 44), Sexual Worry (item 48), Sexual Activity (item 49), and Sexual Enjoyment (item 54). The final version of the EORTC QLQ-CX24 is shown in Table 5. The scale structure was analyzed for scaling errors by using tests for item convergent and discriminant validity. The results are shown in Table 6. The internal consistency was satisfactory in all scales with Cronbach α > .70 (Symptom Experience, .72; Body Image, .86; Sexual/Vaginal Functioning, .87). All scales showed good convergent validity, because all item-own scale correlations were >.40 except for Symptom Experience (0.24–0.50). There were no scaling errors for the Body Image scale or the Sexual/Vaginal Functioning scale. The scaling error for the Symptom Experience scale of 2.3% also was low.

Table 5. The Supplemental 24-Item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-CX24): Sample*

Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you have experienced these symptoms or problems during the past week : Please answer by circling the number that best applies to you	Not at all	A little	Quite a bit	Very much
* ©QLQ-CX24 Copyright 2003 EORTC Quality-of-Life Group. All rights reserved. This table is being used with permission from the EORTC Quality-of-Life Group.
During the past week
31. Have you had cramps in your abdomen?	1	2	3	4
32. Have you had difficulty in controlling your bowels?	1	2	3	4
33. Have you had blood in your stools (motions)?	1	2	3	4
34. Did you pass water/urine frequently?	1	2	3	4
35. Have you had pain or a burning feeling when passing water/urinating?	1	2	3	4
36. Have you had leaking of urine?	1	2	3	4
37. Have you had difficulty emptying your bladder?	1	2	3	4
38. Have you had swelling in one or both legs?	1	2	3	4
39. Have you had pain in your lower back?	1	2	3	4
40. Have you had tingling or numbness in your hands or feet?	1	2	3	4
41. Have you had irritation or soreness in your vagina or vulva?	1	2	3	4
42. Have you had discharge from your vagina?	1	2	3	4
43. Have you had abnormal bleeding from your vagina?	1	2	3	4
44. Have you had hot flushes and/or sweats?	1	2	3	4
45. Have you felt physically less attractive as a result of your disease or treatment?	1	2	3	4
46. Have you felt less feminine as a result of your disease or treatment?	1	2	3	4
47. Have you felt dissatisfied with your body?	1	2	3	4
During the past 4 weeks
48. Have you worried that sex would be painful?	1	2	3	4
49. Have you been sexually active?	1	2	3	4
Answer these questions only if you have been sexually active during the past 4 weeks
50. Has your vagina felt dry during sexual activity?	1	2	3	4
51. Has your vagina felt short?	1	2	3	4
52. Has your vagina felt tight?	1	2	3	4
53. Have you had pain during sexual intercourse or other sexual activity?	1	2	3	4
54. Was sexual activity enjoyable for you?	1	2	3	4

Table 6. Multitrait Scaling Analyses with Pearson Correlations between Scales Items on the Supplemental 24-Item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire

Scale	Mean ± SD	Cronbach α	Item-own scale correlation*	Item-other scale correlation†	Scaling errors (%)
SD indicates standard deviation; NA, not available. * Corrected for overlap. † The opposite value is displayed for negative correlations.
Symptom Experience (Items 31–37, 39, 41–43)	14.06± 13.05	.72	0.24–0.50	0.00–0.36	2 (2.3)
Body Image (Items 45–47)	27.61± 29.49	.86	0.65–0.79	0.00–0.33	0 (0)
Sexual/Vaginal Functioning (Items 50–53)	25.98± 27.98	.87	0.61–0.81	0.01–0.67	0 (0)
Lymphoedema (Item 38)	20.04± 32.61	NA	NA	0.01–0.31	NA
Peripheral Neuropathy (Item 40)	18.18± 27.90	NA.	NA	0.06–0.33	NA
Menopausal Symptoms (Item 44)	26.15± 31.07	NA	NA	0.03–0.41	NA
Sexual Worry (Item 48)	25.21± 29.90	NA	NA	0.01–0.49	NA
Sexual Activity (Item 49)	30.50± 37.26	NA	NA	0.02–0.69	NA
Sexual Enjoyment (Item 54)	59.49± 32.32	NA	NA	0.09–0.49	NA

Relation between the Core Questionnaire and the Cervical Cancer Module

Most scales in the cervical cancer module were weakly correlated with the QLQ-C30 scales (correlation coefficient [r] < 0.40) (Table 7). However, the Symptom Experience scale appeared to be correlated moderately with the QLQ-C30 functioning scales (r = 0.40–0.48), except cognitive functioning (r = 0.34). The Body Image scale also was correlated moderately with emotional functioning (r = − 0.43) and global health/QoL (r = − 0.41).

Table 7. Correlations between the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Core Cervical Cancer Questionnaire and the Supplemental 24-Item Cervical Cancer Module of the EORTC Quality-of-Life Questionnaire

	EORTC QLQ-CX24 scales
EORTC-QLQ-C30	Symptom experience	Body image	Sexual/Vaginal functioning	Lymphoedema	Peripheral neuropathy	Menopausal symptoms	Sexual worry	Sexual activity	Sexual enjoyment
EORTC QLQ indicates European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire; CX24, the supplemental 24-item Cervical Cancer Module of the EORTC QLQ; QLQ-C30, 30-item core EORTC QLQ; QoL, quality of life. * P < .01 (2-tailed). † P < .05 (<.40 = weak correlation, .40−.60 = moderate >60 = high correlation).
Functioning scales
Physical Functioning	−0.40*	−0.28*	−0.12	−0.11	−0.37*	−0.17†	0.30*	−0.17†	0.28
Role Functioning	−0.43*	−0.31*	−0.18	−0.19†	−0.36*	−0.15	0.19†	−0.29*	0.06
Emotional Functioning	−0.47*	−0.43*	−0.11	−0.16†	−0.28*	−0.18†	0.14	−0.25*	0.08
Cognitive Functioning	−0.34*	−0.31*	−0.28*	−0.04	−0.25*	−0.20*	0.20†	−0.19†	0.22
Social Functioning	−0.48*	−0.38*	−0.17	−0.06	−0.23*	−0.18†	0.15	−0.26*	0.16
Global Health/QoL	−0.45*	−0.41*	−0.06	−0.16†	−0.32*	−0.12	0.17†	−0.12	0.00
Symptom scales
Fatigue	0.49*	0.25*	0.12	0.27*	0.34*	0.25*	−0.22*	0.24*	−0.10
Nausea and Emesis	0.34*	0.18†	−0.08	0.09	0.20†	0.04	−0.20†	−0.02	−0.09
Pain	0.44*	0.22*	0.20	0.21	0.21*	0.20*	−0.12	0.22*	0.14
Single item scales
Dyspnea	0.39*	0.31*	0.06	0.14	0.29*	0.18†	−0.20*	0.21*	−0.23†
Insomnia	0.31*	0.22*	0.19	0.26*	0.25*	0.43*	−0.21*	0.12	−0.10
Appetite Loss	0.30*	0.23*	−0.12	−0.09	0.21*	0.00	−0.25*	0.14	−0.09
Constipation	0.26*	0.02	−0.11	0.12	0.08	0.12	−0.09	0.20†	0.14
Diarrhea	0.32*	0.09	0.08	0.02	0.07	0.06	−0.22*	−0.01	0.05
Financial Difficulties	0.24*	0.25*	0.18	0.12	0.18†	0.11	−0.17†	0.17†	−0.09

Clinical Validity

Known-group comparisons were used to explore whether the QLQ-C30 and the QLQ-CX24 were able to discriminate between subgroups of patients who differed in terms of their clinical status. The Karnofsky performance status scores were correlated significantly with the Symptom Experience scale (r = − 0.20; P = .010) and the single-item scales Lymphoedema (r = − 0.16; P = .047) and Sexual Worry (r = 0.16; P = .044) (Tables 8, 9). The QLQ-CX24 module discriminated well between patients with early-stage disease (FIGO Stage I) and patients with advanced-stage disease (FIGO Stages II-IV). On the Symptom Experience scale, patients who had FIGO Stage I cancer had significantly less symptoms compared with patients who had FIGO Stage II through IV disease (P = .029). Similarly, on the Body Image scale, patients with FIGO Stage I disease had significantly lower impairments than patients with FIGO Stage II through IV disease (P = .030). These differences also were significant clinically (difference, >10 points).

Table 8. Correlations between the Supplemental 24-Item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire and Karnofsky Performance Status

EORTC QLQ-CX24	Karnofsky PS	P
EORTC QLQ-CX24 indicates the supplemental 24-item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire; PS, performance status. * P < .05 (2-tailed).
Multiitem scales
Symptom experience	−0.20*	.010
Body image	−0.02	.831
Sexual/vaginal functioning	0.01	.961
Single-item scales
Lymphoedema	−0.16*	.047
Peripheral neuropathy	−0.05	.560
Menopausal symptoms	−0.06	.465
Sexual activity	−0.06	.449
Sexual worry	0.16*	.044
Sexual enjoyment	0.06	.637

Table 9. Differences in the 24-Item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Scales by Treatment Status, Stage, and Disease Status

EORTC QLQ-CX24 Scale	Mean ± SD		P	d	Mean ± SD		P	d	Mean ± SD		P	d
	On Treatment (n = 44)	Off Treatment (n = 113)			FIGO Stage I (n = 95)	FIGO Stage II-IV (n = 72)			Recurrence (n = 18)	NED (n = 130)
SD indicates standard deviation; FIGO, International Federation of Gynecology and Obstetrics; SD, standard deviation, EORTC QLQ-CX24, the supplemental 24-item Cervical Cancer Module of the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire; NED, no evidence of disease; SD, standard deviation; d, effect size (Cohen d); NED, no evidence of disease. * On treatment, n = 14 patients; off-treatment, n = 62 patients. FIGO Stage I, n = 54 patients; FIGO Stages II-IV, n = 25 patients. Recurrence, n = 4 patients; NED, n = 64 patients.
Multiitem scales
Symptom experience	17.55 ± 12.31	12.85 ± 12.61	.036	−.34	12.05 ± 10.93	16.73 ± 15.09	.029	.36	15.04 ± 17.14	13.14 ± 11.65	.553	−.10
Body image	25.00 ± 29.07	27.63 ± 28.80	.609	.08	23.16 ± 25.97	33.49 ± 32.86	.030	.35	27.78 ± 39.83	26.58 ± 28.57	.903	−.03
Sexual/Vaginal functioning*	8.33 ± 7.31	31.09 ± 29.40	<.001	.67	23.92 ± 27.62	30.44 ± 28.81	.338	.22	12.50 ± 10.76	28.04 ± 30.25	.313	.25
Single-item scales
Lymphoedema	14.39 ± 24.27	22.22 ± 34.91	.116	.22	19.15 ± 31.49	21.26 ± 34.29	.685	.06	25.93 ± 35.34	20.63 ± 33.43	.534	−.10
Peripheral neuropathy	15.91 ± 25.40	18.15 ± 27.90	.644	.07	14.89 ± 25.22	22.54 ± 30.74	.090	.28	16.67 ± 28.58	20.05 ± 28.78	.641	0.08
Menopausal symptoms	26.52 ± 31.81	26.55 ± 30.91	.995	.00	23.16 ± 28.80	30.09 ± 33.64	.154	.22	27.78 ± 34.77	26.67 ± 31.45	.890	−.02
Sexual activity	26.67 ± 34.76	33.02 ± 39.09	.369	.15	31.03 ± 36.23	29.80 ± 38.84	.840	−.03	21.43 ± 38.36	33.33 ± 38.65	.277	.19
Sexual worry	15.00 ± 24.98	29.01 ± 30.60	.006	.43	30.00 ± 30.42	18.69 ± 28.12	.019	−.38	15.56 ± 24.77	26.50 ± 30.59	.185	.23
Sexual enjoyment*	47.62 ± 31.25	60.75 ± 32.24	.170	.32	64.81 ± 32.00	48.00 ± 30.55	.031	−.50	75.00 ± 31.91	59.90 ± 33.16	.379	−.22

Concerning treatment status, statistically significant differences were observed between patients who were on treatment and patients who were off treatment on the Symptom Experience scale and the Sexual/Vaginal Functioning scale. Women who were receiving active treatment reported significantly more symptoms compared with patients who were off treatment (P = .036). On the Sexual/Vaginal Functioning scale, patients who were receiving active treatment had significantly lower scores compared with patients who had completed treatment (P < .001).

Concerning disease status, there were no differences between patients who had no evidence of disease and patients with recurrent disease on the multiitem scales or on the single-item scales (P = .195-.890). However, the number of patients who had recurrent disease was small (n = 16 patients); of those, <50% (n = 7 patients) were receiving active treatment. Effect sizes for statistically significant group differences ranged from low to medium.

DISCUSSION

For patients with cervical cancer, the objective of new treatment approaches is to improve their survival without compromising QoL. Valid assessment of QoL requires well designed and validated instruments. Generic QoL measures do not adequately assess disease-specific and treatment-specific issues that affect the QoL of women who are treated for cervical cancer. Therefore, a cervical cancer questionnaire module was developed to supplement the widely used EORTC QLQ-C30. In the current study, the QLQ-CX24 module was tested in a heterogeneous sample of patients with cervical cancer.

An extensive process of literature review and international consultation with specialists and patients assured content validity of the newly developed cervical cancer module. Collaboration with the EORTC Gynecological Cancer Group and the Australian New Zealand Gynaecological Oncology Group as well as with different medical centers in Europe, Taiwan, Brazil, and Korea ensured that issues of cross-cultural relevance were addressed appropriately. Particular care was given to achieve wording that would be widely understood, socially acceptable, and equivalent across countries and cultures. Sensitivity was required in the translation of questions about sexuality. Sexual items were identified as most difficult to translate and adapt across cultures. Both patients and health care providers believed that the wording ‘to what extent’ in some sexuality items (e.g., ‘To what extent were you sexually active?’) was insensitive; it also caused translation problems and, thus, was revised. Two sexuality items were omitted, because the expression ‘sexual intimacy’ was too difficult to translate, and conceptual misunderstandings could not be eliminated. All other questions were easy to understand and did not require revision.

The module proved to be acceptable to a large, heterogeneous sample of patients. The 2 subsamples differed in terms of disease stage and treatment. In Subsample 1, more patients were diagnosed with Stage III disease and were receiving active treatment, and fewer patients had received radiochemotherapy. In Phase IV, the objective was to include more patients who received chemoradiotherapy, because this has become a promising treatment option for patients with advanced cervical cancer.4 The majority of patients completed the EORTC QLQ-C30 and the cervical cancer module in less than 15 minutes. The initial exploratory scale analysis did not confirm the hypothesized scale structure. Psychometric analyses of the revised scale structure confirmed a 3 multiitem scale structure (Symptom Experience, Body Image, and Sexual/Vaginal Functioning) with high internal consistency within the scales. Known-group comparisons confirmed differences in the predicted direction within the scales structure. In the Symptom Experience scale, we included a variety of symptom items that were specific to patients who are treated for cervical cancer. The inclusion of symptom items in a site-specific QoL module seems justified, even if symptoms also may be assessed objectively. There is evidence that patient self-reports are not in agreement with physician judgments. Calhoun et al. reported that physicians rated chemotherapy-associated nephrotoxicity health states more favorably than patients.15 The objective of cancer therapies is to eliminate symptoms; conversely, treatment-related symptoms may occur as short-term or long-term side effects. In clinical trials, symptom experience may be an important study endpoint. The QLQ-CX24 can be used for symptom evaluation from the patients' point of view. In the current study, patients reported a variety of symptoms that affected their QoL. The prevalence rates of 2 symptoms (“Have you had blood in your stools?” and “Have you had abnormal bleeding from your vagina?”) were lower compared with the prevalence rates of issues in other subscales. However, those 2 items were included because patients who suffer late effects of radiotherapy or who develop recurrent tumor may experience these symptoms, which can have a marked effect on their QoL.16 Items in the Symptom Experience scale lend themselves to be used in 2 ways: as a subscale representing cumulative treatment effects or as single items that assessing individual symptoms.

Concerning sexuality, 2 single items (“Have you worried that sex would be painful?” and “Have you been sexually active?”) are intended for completion by all patients. Therefore, these items were analyzed separately from the Sexual/Vaginal Functioning subscale, which includes items that should be completed only by patients who are sexually active. The item “Was sexual activity enjoyable for you?” also was retained as a single item, because it differs from the items included in the Sexual/Vaginal Functioning scale. Sexual enjoyment includes emotional aspects rather than physical aspects of sexuality. The sexuality items had the highest rates of nonresponders (>60%). For almost 33% of study participants, the sexuality items were not applicable, because those women did not have a sexual partner at the time of QoL assessment. Among the nonresponders, more women were receiving active treatment compared with the women who responded. This is important information that has to be considered when interpreting the results.

The results of the known-group comparisons demonstrated that the QLQ-CX24 module is able to discriminate between subgroups of patients who differ in terms of their clinical status. The Symptom Experience scale and the Body Image scale discriminate best when comparing patients with different cancer stages. The subscales (Sexual Experience and Sexual/Vaginal Functioning) also were able to discriminate between patients who were receiving treatment compared and patients who were off treatment. However, the scales did not reveal differences in patients who had no evidence of disease versus patients who had recurrent disease. This observation should be interpreted with caution, because there were only 16 patients in the study who had a recurrence. The sensitivity of the QLQ-CX24 needs to be tested further in a larger sample before conclusions may be drawn. However, in the presence of symptom items that are likely to be causal variables of QoL, classic psychometric properties are less relevant.17, 18 Content validity or the breadth of coverage is satisfactory and is important for a disease-specific or symptom-specific instrument.

Limitations of this study are that test-retest analyses and the responsiveness over time were not performed. Future research on the QLQ-CX24 module should include further exploration of its sensitivity to treatment effects in different settings or clinical changes over time. Including the current module in randomized trials would allow further testing of these issues.

The EORTC-CX24 has been developed according to the formal guidelines of the EORTC QoL Group. The questionnaire should be used in its entirety, including 3 multiitem scales and 5 single-item scales. The psychometric analyses revealed a robust measure. The module should be scored according to the EORTC conventions, i.e., the average of the items that contribute to each scale is taken as the raw score.18 The module has undergone psychometric testing in a multicultural setting. The results confirmed a 3-subscale structure with high construct validity and reliability. Based on psychometric grounds, the QLQ-CX24 module can be recommended for assessing the QoL of patients with cervical cancer in clinical trials.

Acknowledgements

We thank the following individuals who took part in various stages of the module-development process: V. Boyadjian (Russia), T. Conroy (France), C. L. Graham (U.K.), B. Holzner (Austria), K. Kapp (Austria), E. Mautner (Austria), M. Stead (U.K.), and A. Visser (The Netherlands). We also thank F. Daghofer (Austria) for the psychometric analyses of the data and the EORTC Module Development Committee for reviewing the different phases of the project (G. Velikova, J. Ramage, M. Stead, J. Arraras, and J. Blazebey) and Karen West (EORTC Quality-of-Life Unit) for coordinating the translation of the questionnaire module. The authors thank the EORTC Gynecological Cancer Group and the Australian New Zealand Gynaecological Oncology Group (N. H. Hacker) for supporting the module development. Special thanks go to the study participants and recruiting clinicians for their time and effort.