The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Cervical Cancer Module

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1 1812 The European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Cervical Cancer Module EORTC QLQ-CX24 Elfriede R. Greimel, PhD 1 Karin Kuljanic Vlasic, MA 2 Ann-Charlotte Waldenstrom, MD 3 Vlatka M. Duric, PhD 4 Pernille T. Jensen, MD, PhD 5 Susanne Singer, PhD 6 Weichu Chie, MD, PhD 7 Andy Nordin, MBBS 8 Vesna Bjelic Radisic, MD 1 Dariusz Wydra, MD, PhD 9 on behalf of the European Organization for Research and Treatment of Cancer Quality-of-Life Group 1 Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria. 2 Department of Gynecology and Obstetrics, University Hospital Center Rijeka, Rijeka, Croatia. 3 Department of Oncology, Sahlgrenska University Hospital, Goteborg, Sweden. 4 National Health and Medical Research Council Clinical Trials Centre, University of Sydney and Gynaecological Cancer Centre, Royal Hospital for Women, Sydney, New South Wales, Australia. 5 Department of Obstetrics and Gynecology, Herlev University Hospital, Copenhagen, Denmark. 6 Department of Social Medicine, University of Leipzig, Leipzig, Germany. 7 Department of Public Health and Institute of Preventative Medicine, National Taiwan University, Taipei, Taiwan. 8 East Kent Gynaecological Oncology Centre, Queen Elizabeth the Queen Mother Hospital, Margate, United Kingdom. 9 Department of Gynecology, Medical University of Gdansk, Gdansk, Poland. 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 a 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%). The module-development process was supported by a grant from the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Group, and a grant from the National Science Council, Taiwan (NSC B , NSC B ). 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. The following are members of the EORTC Gynecological Cancer Group Steering Committee: K. Bergmark (Sweden), C. Creutzberg (the Netherlands), B. DeSouza (Brazil), F. Fehlauer (Germany), L. Incrocci (The Netherlands), J. Routledge (U.K.), T. Swift (U.K.), and H. Y. Yun (Korea). The EORTC QLQ-CX24 is copyrighted by the EORTC QoL Group. The module and the scoring procedure are available on request (Andrew Bottomley, PhD, EORTC Quality of Life Unit; abo@eortc.be). Address for reprints: Elfriede R. Greimel, PhD, Department of Obstetrics and Gynecology, Medical University Graz, Auenbruggerplatz 14, 8036 Graz, Austria; Fax: (011) ; elfriede.greimel@meduni-graz.at Received April 5, 2006; revision received July 25, 2006; accepted July 27, ª 2006 American Cancer Society DOI /cncr Published online 14 September 2006 in Wiley InterScience (

2 The EORTC Cervical Cancer Module/Greimel et al 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;107: Ó 2006 American Cancer Society. KEYWORDS: quality of life, patient-reported outcome, questionnaire development, European Organization for Research and Treatment of Cancer, reliability, validity, cervical cancer. Worldwide approximately half a million women are diagnosed annually with invasive cervical cancer. 1 The 5-year survival rates are >90% for earlystage 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 irradiation 5,6 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. 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 A list of 74 issues related to cervical cancer patients was derived. Issues were excluded if they were too general or if they were

3 1814 CANCER October 15, 2006 / Volume 107 / Number 8 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 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 QoL indicates quality of life; EORTC, European Organization for Research and Treatment of Cancer; QLQ-C30, 30-item core EORTC QoL questionnaire. 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 ¼ lowest relevance and 4 ¼ 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 TABLE 2 Hypothesized Scale Structure of the European Organization for Research and Treatment of Cancer Cervical Cancer Module 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 * These items deleted because of conceptual ambiguity and semantic differences in the translations. 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 Guidelines 11 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.

4 The EORTC Cervical Cancer Module/Greimel et al 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. Twentythree 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 ¼ 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 a coefficient. Values of a 0.70 were considered acceptable for group comparisons. Clinical validity was assessed by using Student t tests to compare different clinical groups (knowngroup 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 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 hos-

5 1816 CANCER October 15, 2006 / Volume 107 / Number 8 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 Australia Austria Brazil Croatia Denmark Germany Korea The Netherlands Poland Sweden Taiwan United Kingdom Total FIGO indicates International Federation of Gynecology and Obstetrics. pital 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 years, respectively; P ¼.048). 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 ¼.002). There were no differences between the treatment modalities of surgery (P ¼.145) and chemotherapy (P ¼.240) 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 ¼.002) compared with patients in Subsample 2. Only patients from the Netherlands received hyperthermia treatment. The incidence of treatmentrelated menopause was significantly greater in Subsample 2 compared with Subsample 1 (P ¼.001), whereas the use of hormone-replacement therapy did not differ statistically between the groups (P ¼.124). The Karnofsky performance status scores were high in both groups (mean score, >90; P ¼.749). 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

6 The EORTC Cervical Cancer Module/Greimel et al TABLE 4 Sociodemographic and Clinical Characteristics Phase III sample (n = 179) Phase IV sample (n = 167) Variable No. of patients % No. of patients % Age (mean 6 SD) Education Compulsory or less Postcompulsory school University level Unknown Employment Full time Part time Homemaker Unemployed Self-employed Retired Other/unknown Living Alone With partner or family With others Unknown Sexual partner Yes No Unknown FIGO disease stage Stage I Stage II Stage III Stage IV Treatment* Surgery Chemotherapy Radiochemotherapy Brachytherapy External beam radiation Hyperthermia Active treatment Yes No Unknown Menopausal status Premenopausal Postmenopausal Treatment related Unknown HRT Yes No Unknown Karnofsky PS (mean 6 SD) 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.

7 1818 CANCER October 15, 2006 / Volume 107 / Number 8 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 During the past week 31. Have you had cramps in your abdomen? Have you had difficulty in controlling your bowels? Have you had blood in your stools (motions)? Did you pass water/urine frequently? Have you had pain or a burning feeling when passing water/urinating? Have you had leaking of urine? Have you had difficulty emptying your bladder? Have you had swelling in one or both legs? Have you had pain in your lower back? Have you had tingling or numbness in your hands or feet? Have you had irritation or soreness in your vagina or vulva? Have you had discharge from your vagina? Have you had abnormal bleeding from your vagina? Have you had hot flushes and/or sweats? Have you felt physically less attractive as a result of your disease or treatment? Have you felt less feminine as a result of your disease or treatment? Have you felt dissatisfied with your body? During the past 4 weeks 48. Have you worried that sex would be painful? Have you been sexually active? Answer these questions only if you have been sexually active during the past 4 weeks 50. Has your vagina felt dry during sexual activity? Has your vagina felt short? Has your vagina felt tight? Have you had pain during sexual intercourse or other sexual activity? Was sexual activity enjoyable for you? * ÓQLQ-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. (n ¼ 179 patients). The exploratory scaling analyses for the hypothesized scale structure revealed satisfying Cronbach a 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 ¼ 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 a >.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 ( ). 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.

8 The EORTC Cervical Cancer Module/Greimel et al 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 a Item-own scale correlation* Item-other scale correlation y Scaling errors (%) Symptom Experience (Items 31 37, 39, 41 43) (2.3) Body Image (Items 45 47) (0) Sexual/Vaginal Functioning (Items 50 53) (0) Lymphoedema (Item 38) NA NA NA Peripheral Neuropathy (Item 40) NA. NA NA Menopausal Symptoms (Item 44) NA NA NA Sexual Worry (Item 48) NA NA NA Sexual Activity (Item 49) NA NA NA Sexual Enjoyment (Item 54) NA NA NA SD indicates standard deviation; NA, not available. * Corrected for overlap. y The opposite value is displayed for negative correlations. 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 Functioning scales Physical Functioning 0.40* 0.28* * 0.17 y 0.30* 0.17 y 0.28 Role Functioning 0.43* 0.31* y 0.36* y 0.29* 0.06 Emotional Functioning 0.47* 0.43* y 0.28* 0.18 y * 0.08 Cognitive Functioning 0.34* 0.31* 0.28* * 0.20* 0.20 y 0.19 y 0.22 Social Functioning 0.48* 0.38* * 0.18 y * 0.16 Global Health/QoL 0.45* 0.41* y 0.32* y Symptom scales Fatigue 0.49* 0.25* * 0.34* 0.25* 0.22* 0.24* 0.10 Nausea and Emesis 0.34* 0.18 y y y Pain 0.44* 0.22* * 0.20* * 0.14 Single item scales Dyspnea 0.39* 0.31* * 0.18 y 0.20* 0.21* 0.23 y Insomnia 0.31* 0.22* * 0.25* 0.43* 0.21* Appetite Loss 0.30* 0.23* * * Constipation 0.26* y 0.14 Diarrhea 0.32* * Financial Difficulties 0.24* 0.25* y y 0.17 y 0.09 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). y P <.05 (<.40 ¼ weak correlation, ¼ moderate >60 ¼ high correlation). 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 Experiencescaleappearedtobecorrelatedmoderatelywith the QLQ-C30 functioning scales (r ¼ ), except cognitive functioning (r ¼ 0.34). The Body Image scale also was correlated moderately with emotional functioning (r ¼ 0.43) and global health/qol (r ¼ 0.41). Clinical Validity Known-group comparisons were used to explore whether the QLQ-C30 and the QLQ-CX24 were able

9 1820 CANCER October 15, 2006 / Volume 107 / Number 8 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 ¼ 0.20; P ¼.010) and the single-item scales Lymphoedema (r ¼ 0.16; P ¼.047) and Sexual Worry (r ¼ 0.16; 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 Multiitem scales Symptom experience 0.20*.010 Body image Sexual/vaginal functioning Single-item scales Lymphoedema 0.16*.047 Peripheral neuropathy Menopausal symptoms Sexual activity Sexual worry 0.16*.044 Sexual enjoyment 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). P ¼.044) (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 ¼.029). 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 ¼.030). These differences also were significant clinically (difference, >10 points). 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 ¼.036). 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 ¼ ). How- 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 Mean ± SD Mean ± SD Mean ± SD EORTC QLQ-CX24 Scale On Treatment (n = 44) Off Treatment (n = 113) P d FIGO Stage I (n = 95) FIGO Stage II-IV (n = 72) P d Recurrence (n = 18) NED (n = 130) P d Multiitem scales Symptom Experience Body Image Sexual/Vaginal < Functioning* Single-item scales Lymphoedema Peripheral Neuropathy Menopausal Symptoms Sexual Activity Sexual Worry Sexual Enjoyment* 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 ¼ 14 patients; off-treatment, n ¼ 62 patients. FIGO stage I, n ¼ 54 patients; FIGO stages II IV, n ¼ 25 patients. Recurrence, n ¼ 4 patients; NED, n ¼ 64 patients.

10 The EORTC Cervical Cancer Module/Greimel et al ever, the number of patients who had recurrent disease was small (n ¼ 16 patients); of those, <50% (n ¼ 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 sitespecific 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

11 1822 CANCER October 15, 2006 / Volume 107 / Number 8 with the women who responded. This is important information that has to be considered when interpreting the results. Theresultsoftheknown-groupcomparisonsdemonstrated 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 samplebeforeconclusionsmaybedrawn.however,inthe 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 diseasespecific 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. REFERENCES 1. Franco EL, Schlecht NF, Saslow D. The epidemiology of cervical cancer. Cancer J. 2003;9: Gusberg SB, Runowiczl CD. Gynecologic cancers. In: HollebAI, FinkDJ, Murphy GP, editors. Textbook of Clinical Oncology. Atlanta: American Cancer Society, 1991; Keys H, Gibbons SK. Optimal management of locally advanced cervical carcinoma. J Natl Cancer Inst Monogr. 1996; Green JA, Kirwan JM, Tierney JF, et al. 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