Radiol Oncol 2019; 53(3): 337-347. doi: 10.2478/raon-2019-0047 337 research article Health-related quality of life in Croatian general population and multiple myeloma patients assessed by the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires Sanja Ledinski Ficko1,2, Vlatko Pejsa3, Vesna Zadnik4 1 University of Applied Health Sciences, Department of Nursing, Zagreb, Croatia 2 University of Ljubljana, Interdisciplinary Doctoral Study of Biomedicine, Ljubljana, Slovenia 3 Clinical Hospital Dubrava, Institut of Hematology, Zagreb, Croatia 4 Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Ljubljana, Slovenia Radiol Oncol 2019; 53(3): 337-347. Received 23 July 2019 Accepted 9 August 2019 Correspondence to: Assoc. Prof. Vesna Zadnik, M.D., Ph.D., Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Zaloška cesta 2, SI-1000 Ljubljana, Slovenia. Phone: + 386 1 5879 451; E-mail: vzadnik@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. The impact of disease and treatment on the patient’s overall well-being and functioning is a topic of growing interest in clinical research and practice. The aim of this study is to obtain reference data on quality of life of Croatian general population. Further, we aim to assess the impact of the disease and its primary systemic treatment on their health related quality of life (HrQoL) in multiple myeloma (MM) patients. Patients and methods. Participants for the first part of the study were randomly selected from adult Croatian population. In the clinical part of the study MM patients were included as prospectively diagnosed within two years in two major Croatian haematological centres. The EORTC QLQ-C30 in both trials and QLQ-MY20 in MM patients only were applied for HrQoL assessment. Results. Gender, age and place of residence have great impact on quality of life scores in Croatian population. The MM patients at the time of diagnosis have lower QLQ-C30 scores for global quality of life, functional and symp- tom scale scores, as well as single items. The type of disease followed by the choice of therapy options are important HrQoL determinants. Conclusions. The norm values available now for Croatian population will help to interpret HrQoL for clinicians and aid in planning cancer care interventions. This study identified treatment effect consistent with those from other observa- tional studies and provided new data on HrQoL across two different treatment choices for MM patients. Key words: health-related quality of life; multiple myeloma; EORTC QLQ-C30; EORTC MY-20; reference data; Croatian population Introduction Cancer incidence is increasing both in devel- oped and developing countries. According to the Croatian Institute for Public Health, in Croatia can- cer incidence has been steadily rising from 1990 on. In 2016, there were 23,650 newly diagnosed cancer cases, less than 1 percent are younger than 20 years at diagnoses. Among adult patients 3 to 4 percent are diagnosed before the age of 40.1 Statistic data of the International Agency for Research on Cancer show that the incidence of multiple myeloma (MM) in Croatia for men is 4.0 with mortality of 2.1 in 100,000 citizens, and for women the incidence is 3.4 with mortality of 2.1 in 100,000 citizens. This means that every year we have 225–260 new MM cases in Croatia. MM is more frequent in males; the incidence increases with age.1 In 2016, there were Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma338 no case of MM before the age of 40 in Croatia, and most patients are aged 70 years or more at the time of diagnosis.1 Given the number of patients, there is a great need for assessing the health-related qual- ity of life (HrQoL) to improve the care of oncology patients. Therefore, quality of life assessment is be- coming more common in oncology.2 Health is one of the most important variables affecting well-being.3 World Health Organisation defines quality of life as the individuals’ percep- tion of their position in life in the context of the culture and value system in which they live and in relation to their goals, expectations, standards and concerns.4 The impact of disease and treatment on the patient’s overall well-being and functioning is a topic of growing interest in clinical research and practice.5 Indicators of quality of life can provide evidence that is based on comparable and stand- ardized measures and that can be used to improve the health care system. Conducting studies using various health-related quality of life measures is a basis for improvement of health care delivery.6 In the last decades, the measurement of health- related quality of life has gained acceptance as a primary or secondary endpoint in cancer research worldwide.7 Evaluation of quality of life is conducted by using standardized questionnaires.8 European Organization for Research and Treatment of Cancer (EORTC) has purposed a development of an inte- grated, modular approach for evaluating the qual- ity of life of cancer patient. They have launched a core EORTC quality of life questionnaire for can- cer patients that consists of 30 questions (EORTC QLQ-C30). The EORTC QLQ-C30 is one of the most widely used instrument for assessing health- related quality of life in cancer patients9 and has been used so far in more than 3000 studies world- wide. The core questionnaire is supplemented by disease-specific modules.10 So far disease specific modules were developed for 13 different malig- nant conditions. The EORTC QLQ-MY20 is specific questionnaire adjusted for patients with multiple myeloma. The EORTC QLQ questionnaires have been translated and validated into 81 languages. The EORTC QLQ-C30 and EORTC QLQ-MY20 ex- ist also in Croatian language.11,12 The normative (reference) values of QLQ-C30 questionnaire for general healthy population are already available for some countries, for example Germany5, the Netherlands13, Denmark7, Sweden14 and Slovenia.15 Typically, they demonstrate the decrease of HrQoL on all levels with age in both sexes. On the contrary, some symptoms such as pain and fatigue increase with age. The population norms are applied in clinical practice as an aid to the clinical assessment of an individual patient and in research to assist in the overall interpretation of results from clinical studies of HrQoL. The knowledge on HrQoL in MM patients is scarce. The findings of the recent European cohort study provide a better understanding on how to improve the treatment of patients with MM in or- der to improve their QoL. The data indicated that there is a need for better management of the treat- ment of fatigue and bone related symptoms since those are the strongest HrQoL predictors. The study also suggested that specific QoL aspects can be notably improved by treatment which targets specific symptoms.16 The aim of this study is to obtain reference da- ta on quality of life in a representative sample of Croatian general population older than 40 years, and obtaining data on quality of life in MM patients with the aid of EORTC QLQ-C30 and QLQ-MY20 questionnaires. The norm values will help to inter- pret health-related quality of life data for clinicians, and aid in planning interventions for symptoms in the early stages of the disease. In MM patients, we aim to assess the impact of the disease and its pri- mary systemic treatment on their HrQoL. Patients and methods Population sample The study was conducted in the second half of 2016 and during 2017. For the initial part of our study, eligible respondents were adults, aged over 40 at the entry, residents of Croatia with no history of a malignant disease. A random sample of adult inhabitants in all six regions of Croatia: Dalmatia, Slavonia, Istria, Podravina, Zagreb region and Medimurje has been obtained. The EORTC QLQ-C30 questionnaire supplemented by a demographic inquiry was personally delivered to randomly selected individuals. The data collection was carried out by specially trained medical nurs- es in health centres, homes for the elderly, in the street and in other highly frequented places. For any randomly chosen adult we firstly determined their age and health status, and, in the case of not having a malignant disease and being older than 40, we continued with collecting the quality of life data. From the 362 initially contacted, 310 respond- ents were included in our population sample. Of 51 not included respondents, 35 had cancer, while 16 of them chose not to participate for different Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma 339 personal reasons. The Survey Monkey Sample Size Calculator17 was used to estimate that such a sam- ple size is sufficient for our study to reach adequate power. Multiple myeloma patient sample In the second part of the study MM patients older than 40 were included. A prospective study was conducted in the second half of 2016, 2017 and the first half of 2018. EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires were filled in by re- spondents before and three months after treatment with chemotherapy and stem cell transplantation in two major haematological centres in Croatia: Clinical Hospital Dubrava and Clinical Hospital Merkur. Questionnaires were distributed to the respondents during their stay in hospital, at the moment when transplantation or chemotherapy is determined as a therapeutic procedure. The sec- ond evaluation was conducted three months after therapeutic procedures. The sample consisted of 25 respondents before and after stem cell trans- plantation and 26 respondents before and after chemotherapy, which corresponds to a similar Czech research which evaluated the quality of life among malignant lymphoma and MM patients un- dergoing autologous stem cell transplantation.16 Additional five people were invited to the study but they chose not to participate. Questionnaires In both samples we used the EORTC QLQ-C30 questionnaire which contains 30 questions. The of- ficial Croatian translation of the questionnaire was used in assessing individual HrQoL during previ- ous week. Respondents were offered four response alternatives: 1 “not at all”, 2 “a little”, 3 “quite a bit” and 4 “very much”. In the last two questions the range was 1 to 7 in which 1 is “very poor” and 7 is “excellent”. The EORTC QLQ-C30 questionnaire consists of a general health/quality of life scale, and five functional scales: physical functioning, role functioning, cognitive functioning, emotional functioning and social functioning, and 13 symp- tom items. Functional scale includes cognitive, emotional, physical, role and social functioning dimension. Symptom scale includes fatigue, nau- sea or vomiting and pain, and single items include loss of appetite, constipation, diarrhoea, dyspnoea, financial impact and sleep disturbance. For general quality of life and functional scale, higher scores mean better quality of life while higher scores for symptom scale and single items mean lower qual- ity of life.18 In addition to EORTC QLQ-C30 all the participants also responded to a questionnaire on their demographic data including age, gender and place of residence. The EORTC QLQ-MY20 is specific questionnaire adjusted for patients with multiple myeloma. The official Croatian translation of the questionnaire was used in assessing individual HrQoL during the previous week. It consists of functional scales which include future perspective and body image, and symptom scale which includes disease symp- toms and side effects of treatment. Respondents were offered four response alternatives: 1 “not at all”, 2 “a little”, 3 “quite a bit” and 4 “very much”. The higher the number of an item means poorer functioning.18 Internal consistency Some dimensions are composed of more than one answer, and the others include only one categorical answer. Internal consistency of multiple answers within single dimension was proved by using the Cronbach alpha coefficient of reliability. The high value of the Cronbach alpha coefficients suggests a very high reliability. The coefficients were as fol- lows: general health status/quality of life (0,87), physical functioning (0,84), role functioning (0,86), emotional functioning (0,87), cognitive functioning (0,70), social functioning (0,88), fatigue (0,83), nau- sea/vomiting (0,69) and pain (0,81). In case of a lack of response to a question, the average of the other answers was used, but only if at least half of the questions were answered.19-21 To investigate if there is a correlation between EORTC QLQ-C30 and QLQ-MY20 scores, Pearson correlation coefficient calculations were performed. Statistical analysis Demographic characteristics were analysed as categorical variables and are represented in num- bers and relative frequencies. Four age categories (40-49, 50-59, 60-69 and 70+) and six geographical regions were applied. The chi-square test was ap- plied for determining the statistical significance of difference in demographical characteristics among groups of individuals in the sample. The answers, which were recorded in the EORTC QLQ-C30 and EORTC QLQ-MY20 were converted into dimen- sions, which evaluate the quality of life associated with health. Dimensions are ranged from 0–100 according to the EORTC scoring instructions.18 Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma340 Dimensions are described by the arithmetic mean and standard deviation. As suggested by Nielsen et al.22 Mann-Whitney U test was used to compare the dimensions within two groups (gender, treat- ment). Where there were more than two groups for comparison (age, region) we used the Kruskal- Wallis test. For testing the statistical significance of the change in dimensions before and after treat- ment Wilcoxon signed rank test was used. Furthermore, for the first time to the best of our knowledge, the QLQ-C30 summary score of the EORTC QLQ-C30 was calculated for the popula- tion reference scores. QLQ-C30 summary score is a single higher-order model based on 27 of the 30 items of the QLQ-C30, excluding global qual- ity of life and financial difficulties proposed by Giesinger et al.23 In our study we investigated the ability of the QLQ-C30 summary score to distin- guish between groups formed according to treat- ment choice (chemotherapy, transplantation) and general population. The values of p < 0.05 were evaluated as sta- tistically significant. Statistical analysis was per- formed using the 24.0 SPSS Inc., Chicago, IL, SAD software. Compliance with ethical standards The data collection, preparation, implementation and presentation were in accordance with legal requirements for protecting the confidentiality of personal information: in Croatia non-drug trials are reviewed by ethics committees at an institu- tional level. Approval for the study was obtained from the Medical Ethics Committee of the Clinical Hospital Dubrava and Clinical Hospital Merkur (03/1-6234). All participants were fully informed about the aims of the study and provided written informed consent for participation in the study. TABLE 1. Mean score (MS) and standard deviations (SD) for all EORTC QLQ-C30 dimensions and scales by age for general population 40–49 50–59 60–69 70 and older p* MS SD MS SD MS SD MS SD Global health status/quality of life 69.1 18.6 71.1 20.7 67.4 19.9 56.9 23.9 .035 Physical functioning 86.2 12.9 83.9 16.9 81.8 21.7 61.2 30.2 .000 Role functioning 86.1 20.6 85.9 20.2 80.8 28.6 69.1 37.2 .128 Emotional functioning 71.9 22.4 78.2 19.7 78.6 19.7 66.7 26.4 .034 Cognitive functioning 80.6 21.7 85.7 17.8 85.6 17.4 80.8 26.3 .402 Social functioning 86.8 20.1 90.6 15.5 88.5 20.8 76.5 31.0 .049 Fatigue 33.7 20.8 28.0 22.7 29.5 22.8 43.8 29.2 .014 Nausea/vomiting 6.9 14.2 4.9 11.3 4.6 10.4 10.3 20.1 .276 Pain 25.8 24.3 23.3 24.5 24.1 27.8 40.2 32.3 .028 Dyspnoea 18.8 24.6 17.3 23.6 22.1 25.9 26.5 30.6 .362 Insomnia 24.4 28.7 26.3 30.2 30.7 30.5 41.2 37.7 .094 Appetite loss 6.9 15.2 5.3 13.7 8.2 15.6 24.5 34.1 .001 Constipation 8.2 18.0 8.3 19.2 13.8 21.9 14.7 28.7 .164 Diarrhoea 7.9 15.8 6.5 13.9 6.2 13.0 13.7 26.1 .595 Financial difficulties 7.6 17.7 7.4 17.7 14.4 26.9 22.5 33.6 .009 Summary score 83.1 12.5 85.8 12.2 82.9 15.0 72.6 23.7 .030 *p = Kruskal-Wallis test 0 10 20 30 40 50 60 70 80 90 general population initial testing post-testing Summary score chemotherapy transplantation FIGURE 1. Summary score for EORTC QLQ-C30 in general population, initial testing and post-testing. Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma 341 Results From the general population there were 310 ques- tionnaires eligible for analysis; 68.4% women (212 persons) and 31.6% men (98 persons). The largest number of the respondents were in the age range of 50–59 years, at 36.8% (114 persons). Most of the respondents were from the Zagreb region, at 33.9% (105 persons). Furthermore, 51 MM patients were included in the second part of the research. The largest number of the MM respondents were in the age range of 60–69 years, 20 patients. 25 of the re- spondents were treated with chemotherapy while 26 of the respondents underwent transplantation. Supplement table 1 shows how the groups differ in their demographic characteristics. Scale and item scores Results illustrate the transformed values of general quality of life, functional and symptom scales in the range 1–100. Table 1 shows the results for the EORTC QLQ-C30 for all scales, single items, as well as the summary score in general population according to age. In many dimensions there is a statistically significant difference in age in our sam- ple. The scores for general health status are highest for the respondents aged 50–59 and lowest for the respondents who are 70 and older. Furthermore, there is also a statistically significant difference ac- cording to age for physical functioning, emotional functioning and social functioning. The scores are significantly lower for respondents aged 70 and older. EORTC QLQ-C30 summary scores also in- dicate that there is a statistically significant differ- ence according to age, where scores are lower with increasing age. Supplement Figure 1 shows mean scores of EORTC QLQ-C30 scores for all scales and items in general population according to age and gen- der. Men reported better general quality of life, as well as better physical and emotional functioning. There is a statistically significant difference if we compare the results for symptom scale and single items for fatigue, pain, dyspnoea and insomnia by gender, where the ranges are higher for women. Men reported better functioning for all items on the symptom scale. If we compare the results for single items, women reported less constipation, diarrhoea and financial problems. Supplement Figure 2 shows EORTC QLQ-C30 summary score in Croatian general population according to age and gender. Supplement Table 2 shows results for the EORTC QLQ-C30 for all scales and sin- gle items according to a place of residence. There is a statistically significant difference in general health status according to a place of residence; the scores are higher for respondents from Istria and Medimurje, and lowest for respondents from Dalmatia. Furthermore, there is a statistically sig- nificant difference in physical functioning, role functioning, emotional functioning, cognitive func- tioning and social functioning according to a place of residence; the scores are again the highest for respondents from Istria and Medimurje. Table 2 presents the comparison between gen- eral population and multiple myeloma patients for all EORTC QLQ-C30 dimensions. There is a statistically significant difference for global health status, physical functioning, physical functioning, role functioning, social functioning, fatigue, pain, appetite loss and financial difficulties. The values for global health status, physical functioning, role functioning and social functioning are higher in general population while values for fatigue, pain, appetite loss and financial difficulties are higher in MM patients. There is a statistically significant difference in physical functioning, cognitive functioning, social TABLE 2. Mean score (MS) and standard deviation (SD) for all EORTC QLQ-C30 dimensions and scales in general population and multiple myeloma (MM) patients at diagnosis at the time of setting the diagnosis MM patients at diagnosis General population MS SD MS SD P* Global health status/ quality of life 58.9 19.4 68.2 20.6 .003 Physical functioning 63.0 26.2 81.7 20.1 .000 Role functioning 52.6 38.6 83.1 25.1 .000 Emotional functioning 75.8 21.7 75.1 21.6 .820 Cognitive functioning 82.0 22.0 83.5 20.1 .725 Social functioning 60.1 34.0 87.4 20.6 .000 Fatigue 41.0 24.3 31.9 23.4 .014 Nausea/vomiting 7.5 13.9 6.2 13.3 .346 Pain 38.2 33.4 26.1 26.5 .020 Dyspnoea 27.5 29.6 19.7 25.2 .078 Insomnia 31.4 32.9 28.3 30.9 .556 Appetite loss 21.6 34.5 8.5 18.7 .010 Constipation 13.7 25.9 10.1 20.8 .392 Diarrhoea 9.8 20.3 7.7 16.2 .712 Financial difficulties 39.2 36.9 10.6 22.6 .000 Summary score 72.9 17.8 83.0 14.8 .000 *p = Mann-Whitney test Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma342 functioning, fatigue, pain, insomnia and financial difficulties in the measurements before and af- ter chemotherapy where the results are worse in measurements after chemotherapy. Furthermore, there is statistically significant difference for global health status, role functioning, social functioning, nausea and vomiting, diarrhoea and financial dif- ficulties in measurements after transplantation. For global health status in post-testing positive ranks in 15 cases were observed which means that they indicate better results. For role functioning posi- tive ranks in 15 cases were observed while in so- cial functioning positive ranks in 14 cases were observed which means that they indicated worse results. While for nausea and vomiting in 8 cases, constipation in 7 cases, diarrhoea in 7 cases and fi- nancial difficulties in 12 cases negative ranks were observed which means that they indicate better re- sults (Table 3). When analysing QLQ-MY20 questionnaire, there is a statistically significant difference for body image and disease symptoms in measurements be- fore and after chemotherapy. In post-testing nega- tive ranks in 7 cases for body image were observed which means that they indicate better results. For disease symptoms in post-testing positive ranks in 16 cases were observed which means that the values were higher in post-testing in accordance to initial TABLE 3. Mean score (MS) and standard deviation (SD) for all EORTC QLQ-C30 dimensions and scales in multiple myeloma (MM) patients before and after chemotherapy and transplantation MM–before chemotherapy MM–after chemotherapy p* MM–before transplantation MM–after transplantation p* MS SD MS SD MS SD MS SD Global health status/ quality of life 53.3 21.4 49.7 22.5 .283 64.4 15.7 74.7 18.0 .008 Physical functioning 53.9 26.3 38.9 21.3 .011 71.8 23.4 71.8 19.1 .955 Role functioning 50.7 39.8 46.7 31.9 .458 54.5 38.2 77.6 24.5 .009 Emotional functioning 73.3 27.6 78.0 21.9 .776 78.2 14.5 84.3 23.3 .107 Cognitive functioning 78.0 27.1 57.3 28.1 .007 86.0 14.9 91.0 14.3 .083 Social functioning 57.3 37.6 787 26.6 .007 62.8 30.7 78.0 26.1 .026 Fatigue 43.1 27.3 64.0 22.3 .001 39.1 21.5 40.2 24.6 .782 Nausea/vomiting 7.3 15.3 5.3 13.4 .603 7.7 12.7 0.0 0.0 .010 Pain 39.3 36.9 54.7 25.2 .039 37.2 30.3 31.4 28.0 .323 Dyspnoea 28.0 32.9 33.3 30.4 .590 26.9 26.7 17.9 23.5 .100 Insomnia 40.0 36.0 14.7 23.7 .010 23.1 27.9 20.5 31.4 .637 Appetite loss 28.0 38.1 21.3 35.8 .463 15.4 30.2 7.7 17.1 .286 Constipation 16.0 32.1 20.0 28.9 .564 11.5 18.7 1.3 6.5 .011 Diarrhoea 9.3 22.6 6.7 19.2 .414 10.3 18.3 1.3 6.5 .035 Financial diffuclities 41.3 41.1 14.7 28.9 .005 37.2 33.1 20.5 29.9 .018 Summary score 69.6 19.5 67.7 14.5 .181 76.0 15.7 83.3 9.7 .097 *p = Wilcoxon signed rank test TABLE 4. Mean score (MS) and standard deviation (SD) for all QLQ-MY20 scales in multiple myeloma (MM) patients before and after chemotherapy and transplantation MM–before chemotherapy MM–after chemotherapy p* MM–before transplantation MM–after transplantation p* MS SD MS SD MS SD MS SD Future perspective 2.2 0.7 2.0 0.7 .285 2.2 0.7 1.8 0.7 .036 Body image 1.9 1.3 1.4 0.9 .023 1.4 0.6 1.4 0.6 1.00 Disease symptoms 1.9 0.6 2.2 0.6 .039 1.7 0.6 1.8 0.7 .571 Side effects of treatment 2.1 0.7 1.8 0.4 .361 1.9 0.6 1.5 0.3 .144 *p = Wilcoxon signed rank test Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma 343 testing. Furthermore, there is a statistically signifi- cant difference for future perspective in measure- ments before and after transplantation (Table 4). We investigated the ability of the QLQ-C30 summary score to distinguish between groups formed according to treatment choice (chemo- therapy, transplantation) and general population status. Using the treatment choice as a variable, the QLQ-C30 summary score showed the chang- es from the initial testing to post-testing. For MM patients on chemotherapy, results showed that in comparison to general population and trans- planted patients, their functional scale was worse in the initial testing and it further deteriorated in post-testing. For transplanted patients the results showed worse results in comparison to general population but better when compared to patients on chemotherapy. In post-testing the results were improved. Three months after treatment the sum- mary score was comparable to general population and significantly better when compared to patients on chemotherapy. Correlation between EORTC QLQ-C30 and QLQ-MY20 in MM patients before treatment The correlations between the EORTC QLQ-C30 di- mensions and scales and 4 items of the QLQ-MY20 before treatment are shown in Table 5 for patients on chemotherapy, and Table 6 for transplanted pa- tients. The strongest positive correlation was found for pain (0.779) and disease symptoms, and strong- est negative correlation for fatigue (-0.808) and physical functioning for patients on chemotherapy. Furthermore, for transplanted patients the strong- est positive correlation was found for pain (0.707) and disease symptoms, and strongest negative cor- relation for physical functioning (-0.710) and side effects of treatment. Discussion Quality of life is now widely recognized as a cen- tral outcome of many clinical trials.3 It is a multi-di- mensional concept based on a holistic view of hu- man well-being. It considers a number of domains of people’s lives and the interplay between these dimensions. The principal domains include: sub- jective well-being, health, income and standard of living, relationship with family and friends, work and quality of jobs, sense of inclusion in one’s local community, and personal safety.24 In this study we presented the reference data of the EORTC QLQ-C30 quality of life dimensions for the general Croatian population. This study begun with the aim of obtaining reference data of the EORTC QLQ-C30 quality of life dimension in a sample of Croatian adults older than 40 years who were not suffering from a malignant disease. In Croatia, there is around 30% of population younger than 40 years, however there are only around 4% of cancer patients that are diagnosed below this age.1 The collected data are transformed into expected mean HRQL scores for distinctive demographic population groups. Our results illustrate that mean scores vary with age, gender and place of residence. Men reported better general health status as well as physical and emotional functioning. On the symptom scale they reported less symptoms when compared to wom- en. Women reported significantly higher scores for fatigue, pain, dyspnoea and insomnia. These find- ings are similar to those of the Norwegian study, which was the first to be conducted in a general population. Their study also showed that men re- ported fewer symptoms and better quality of life on all scales.25 Moreover, a study conducted in German general population showed that men re- ported better quality of life on all scales and few- er symptoms in comparison to women.5 The first study conducted on a South-eastern European population was in neighbouring Slovenia, also showed that men report better quality of life on the majority of specific scales and that they report fewer symptoms, but the results were mostly not statistically significant.15 Our study also highlights that all scores dete- riorated with age and older respondents reported more symptoms present. Scores were statistically higher for respondents 70 and more years old for physical, emotional and social functioning. The study conducted in the Norwegian population also showed that increasing age influences the scores; both QoL scales and all functional scales, except for emotional, showed a gradual decline in mean scores with increasing age for both sexes.25 The study conducted in Slovenia also showed that old- er participants report more symptoms.15 For gener- al health status the ranges are interestingly highest for the age group 50–59 in the Croatian population. The results indicate that place of residence has great impact on quality of life. Two of the ar- eas in Croatia report better global functioning and less symptoms present. The ranges for physical, emotional, cognitive and social functioning are the highest for the respondents from Istria and Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma344 TABLE 5. Correlation between dimensions and scales in the EORTC QLQ-C30 and QLQ-MY20 (chemotherapy) FP BI DS SET GHS PF RF EF CF SF F NV P D I AL C DIA FD FP 1 .369 .330* .395* -.213 -.254 -.443 -.478 -.057 -.410 .086 .149 .322* .119 -.104 .309* .004 .017 .264 BI .369 1 .208 .586 -.135 -.155 -.333* -.428 -.101 -.396 131 .299* .164 -.044 .107 .186 -.074 .229 .270 DS .330* .208 1 .669 -.459 -.678 -.429 -.369 -.545 -.400 .642 .289* .779 .255 -.127 .512 .150 .274 .243 SET .395* .586 .669 1 -.277 -.513 -.462 -.579 -.577 -.568 .560 .599 .482 .116 .305 .644 -.121 .451 .469 GHS -.213 -.135 -.459 -.277 1 .427 .341* .503 .336* .468 -.399 -.205 -.332* -.283* .013 -.528 -.033 -.489 -.335* PF -.254 -.155 -.678 -.513 .427 1 .588 .367 .524 .430 -.807 -.277 -.725 -.337* .165 -.389 -.156 -.136 -.147 RF -.443 -.333* -.429 -.462 .341* .588 1 .384 .359* .491 -.564 -.373 -.554 -.376 -.094 -.449 -.113 -.259 -.316* EF -.478 -.428 -.369 -.579 .503 .367 .384 1 .329* .692 -.266 -.616 -.408 .115 .048 -.596 -.117 -.424 -.414 CF -.057 -.101 -.545 -.577 .336* .524 .359* .329* 1 .176 -.625 -.383 -.502 -.170 -.088 -.424 .043 -.349* -.262 SF -.410 -.396 -.400 -.568 .468 .430 .491 .692 .176 1 -.225 -.498 -.353* -.134 .007 -.589 .064 -.304* -.534 F .086 .131 .642 .560 -.399 -.807 -.564 -.266 -.625 -.225 1 .272 .717 .456 .066 .374 .127 .369 .119 NV .149 .299* .289* .599 -.205 -.277 -.373 -.616 -.383 -.498 .272 1 .227 -.139 .083 .605 .125 .361* .317* P .322* .164 .779 .482 -.332* -.725 -.554 -.408 -.502 -.353* .717 .227 1 .350* -.178 .389 .161 .222 .182 D .119 -.044 .255 .116 -.283* -.337* -.376 .115 -.170 -.134 .456 -.139 .350* 1 .204 .078 -.187 .206 .160 I -.104 .107 -.127 .305 .013 .165 -.094 .048 -.088 .007 .066 .083 -.178 .204 1 .238 -.186 .271 .194 AL .309* .186 .512 .644 -.528 -.389 -.449 -.596 -.424 -.589 .374 .605 .389 .078 .238 1 .000 .329* .375 C .004 -.074 .150 -.121 -.033 -.156 -.113 -.117 .043 .064 .127 .125 .161 -.187 -.186 .000 1 -.089 -.133 DIA .017 .229 .274 .451 -.489 -.136 -.259 -.424 -.349* -.304* .369 .361* .222 .206 .271 .329* -.089 1 .517 FD .264 .270 .243 .469 -.335* -.147 -.316* -.414 -.262 -.534 .119 .317* .182 .160 .194 .375 -.133 .517 1 AL = appetite loss; BI = body image; C = constipation; CF = cognitive functioning; D = dyspnoea; DIA = diarrhoea; DS = disease symptoms; EF = emotional functioning; F = fatigue; FD = financial difficulties; FP = future perspective; GHS = global health status; I = insomnia; NV = nausea/vomiting; P = pain; PF = physical functioning; RF = role functioning; SET = side effects of treatment; SF = social functioning; * Correlation is significant at the 0.05 level (2-tailed) TABLE 6. Correlation between dimensions and scales in the EORTC QLQ-C30 and QLQ-MY20 (transplantation) FP BI DS SET GHS PF RF EF CF SF F NV P D I AL C DIA FD FP 1 .451** .029 .289 -.383 -.246 -.203 -.499 -,106 -.333* .287* .238 -.035 .145 .296* .371 .309* .049 .053 BI .451 1 -.142 .026 -.109 -.047 -.009 -.083 ,105 .016 .038 -.006 -.151 -.048 .333* .109 .053 -.029 -.195 DS .029 -.142 1 .447 -.312* -.589 -.449 -.339* ,228 -.397 .527 -.051 .707 .406 .145 .035 -.060 -.072 .188 SET .289 .026 .447 1 -.615 -.710 -.627 -.397 -,299 -.455 .570 .597 .519 .642 .377* .523 .470 .485 .337* GHS -.383 -.109 -.312* -.615 1 .629 .518 .349* ,159 .498 -.436 -.467 -.423 -.443 -.071 -.192 -.429 -.371 -.370 PF -.246 -.047 -.589 -.710 .629 1 .562 .403 ,147 .506 -.645 -.375 -.643 -.447 -.379 -.325* -.232 -.171 -.443 RF -.203 -.009 -.449 -.627 .518 .562 1 .346* -,015 .580 -.563 -.341* -.626 -.403 -.194 -.200 -.209 -.127 -.421 EF -.499 -.083 -.339* -.397 .349* .403 .346* 1 ,188 .378 -.347* -.217 -.146 -.191 -.395 -.120 -.123 -.054 -.258 CF -.106 .105 .228 -.299 .159 .147 -.015 .188 1 .024 -.002 -.348* .023 -.041 -.105 -.033 -.304* -.143 -.250 SF -.333* .016 -.397 -.455 .498 .506 .580 .378 ,024 1 -.539 -.245 -.376 -.178 -.188 -.078 -.158 -.080 -.292* F .287* .038 .527 .570 -.436 -.645 -.563 -.347* -,002 -.539 1 .299* .563 .294* .423 .441 .154 .266 .336* NV 238 -.006 -.051 .597 -.467 -.375 -.341* -.217 -,348* -.245 .299* 1 .258 .263 .197 .587 .660 .464 .299* P -.035 -.151 .707 .519 -.423 -.643 -.626 -.146 ,023 -.376 .563 .258 1 .563 .077 .182 .188 .143 .376 D .145 -.048 .406 .642 -.443 -.447 -.403 -.191 -,041 -.178 .294* .263 .563 1 .149 .346* .190 .356 .178 I .296* .333* .145 .377* -.071 -.379 -.194 -.395 -,105 -.188 .423 .197 .077 .149 1 .398 .123 .264 .288* AL .371** .109 .035 .523 -.192 -.325* -.200 -.120 -,033 -.078 .441 .587 .182 .346* .398 1 .271 .363 .148 C .309* .053 -.060 .470 -.429 -.232 -.209 -.123 -,304* -.158 .154 .660 .188 .190 .123 .271 1 .540 .152 DIA .049 -.029 -.072 .485 -.371 -.171 -.127 -.054 -,143 -.080 .266 .464 .143 .356 .264 .363 .540 1 .104 FD .053 -.195 .188 .337* -.370 -.443 -.421 -.258 -,250 -.292* .336* .299* .376 .178 .288* .148 .152 .104 1 AL = appetite loss; BI = body image; C = constipation; CF = cognitive functioning; D = dyspnoea; DIA = diarrhoea; DS = disease symptoms; EF = emotional functioning; F = fatigue; FD = financial difficulties; FP = future perspective; GHS = global health status; I = insomnia; NV = nausea/vomiting; P = pain; PF = physical functioning; RF = role functioning; SET = side effects of treatment; SF = social functioning; * Correlation is significant at the 0.05 level (2-tailed) Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma 345 Medimurje. It is hard to define what is the predic- tor for this result because one area is continental and the other is a coastal area. Both areas are devel- oped and it could be that socio-economic circum- stances in these areas have influenced the results. Development index is a composite indicator cal- culated as a customized average of standardized values of socio-economic indicators for measur- ing the degree of development in a given period. In Croatia, the following indicators are used to calculate the development index: average income per capita, average source income per capita, the average unemployment rate, movements of gen- eral population, degree of education of the popula- tion (tertiary education) and the aging index. Local self-government units are classified into categories considering development index. Third and fourth level represent above-average ranking units. Istria currently belongs to the forth level and Medimurje to the third level, which means that they are above- average developed.26,27 For global health status the ranges are the lowest for respondents from Dalmatia. In addition, in this study we also aimed to as- sess the impact of the disease and its primary sys- temic treatment on their HrQoL in a prospective cohort of multiple myeloma patients older than 40 years at the time of diagnosis. If we compare the results for general population and MM patients which were obtained using the EORTC QLQ-C30 questionnaire, it can be seen that during the initial testing patients suffering from multiple myeloma have lower scores for global health status, physical functioning, role functioning and social function- ing, while they have higher scores for fatigue, pain, appetite loss and financial difficulties. It can be concluded that they have more symptoms present. According to Delforge et al., about 70% of the patients suffer from pain at the time of diagnosis.28 Our results indicate that pain is a great predictor of global health status in general population, as well as in MM patients. In general population, pain and fatigue were the most expressed symptoms, while in MM patients pain, fatigue, insomnia, dyspnoea and appetite loss were the most expressed symp- toms. Severity, type of disease, symptoms and treatment are important determinants of HrQoL in patients with multiple myeloma. Advanced dis- ease and treatment related symptoms are associ- ated with lower HrQoL.16 Our descriptive and exploratory analysis sug- gests a beneficial effect of transplanted patients three months after therapy on HrQoL. HrQoL scores were higher among transplanted patients, compared to those who underwent chemotherapy. Respondents who underwent chemotherapy were mostly older than 70 years with a different co- morbidity. They also indicate that approximately 9 months passed from the occurrence of the first symptoms and diagnosis, due to the attribution of symptoms to other diseases, most commonly to spi- nal diseases. Also, patients starting treatment for the first time are affected by the psychological bur- den of their recent diagnosis and experience treat- ment related toxicities which they have not previ- ously been exposed to.29 Furthermore, the period of three months was sufficient for transplanted pa- tients to recover from high doses of chemotherapy that preceded transplantation. On the other hand, patients who underwent chemotherapy, regardless of the small dosage of therapy, noticed that they have deterioration in symptoms. The Netherlands study, also conducted on 51 transplanted patients during the treatment and 12 months after, shown that after 12 months the results were better for physical, role, emotional, cognitive and social functioning. Additionally, for symp- toms, the results were better for fatigue, pain and appetite loss while nausea/vomiting and diarrhoea deteriorated in results.30 Our results illustrate that scores for global health status, physical function- ing, role functioning and cognitive functioning are higher three months after transplantation, while results for fatigue, pain, dyspnoea and constipa- tion are higher after chemotherapy. Patients who underwent chemotherapy had more symptoms present three months after therapy in comparison to patients who underwent transplantation. An additional valuable output from our study is the correlation analysis of the EORTC QLQ-C30 scores and 4 items of the EORTC QLQ-MY20. This method can provide reliable, accurate descriptions of the HrQoL of patients with multiple myeloma.29 Correlation analysis for patients on chemotherapy from our study shows that side effects of treat- ment strongly correlate with body image and dis- ease symptoms; furthermore, physical functioning strongly correlates with disease symptoms, side effects of treatment and role functioning, while emotional functioning correlates with side effects of treatment and social functioning. Cognitive functioning strongly correlates with disease symp- toms, side effects of treatment and physical func- tioning. When symptoms are taken into consid- eration fatigue correlates with disease symptoms, side effects of treatment, physical functioning and cognitive functioning, while pain strongly corre- lates with disease symptoms, physical functioning, Radiol Oncol 2019; 53(3): 337-347. Ledinski Ficko S et al. / Quality of life in Croatian patients with multiple myeloma346 role functioning, cognitive functioning and fatigue. Appetite loss strongly correlates with disease symptoms, side effects of treatment, global health status, emotional functioning, social functioning, and nausea/vomiting. Correlation analysis for transplanted patients from our study shows that global health status strongly correlates with side effects of treatment; furthermore, physical functioning strongly corre- lates with disease symptoms, side effects of treat- ment and global health status but also with role functioning; while role functioning and physi- cal functioning correlate with social functioning. When symptoms are taken into consideration the pain strongly correlates with the largest number of items. Pain strongly correlates with disease symp- toms, side effects of treatment, physical function- ing, role functioning and fatigue. Other symptoms correlate only with one item as follows: dyspnoea with side effects of treatment, appetite loss with nausea/vomiting, constipation with nausea/vomit- ing and diarrhoea with constipation. The study conducted in France shows the strongest correlation between EORTC QLQ-C30 global health status and QLQ-MY20 disease symp- toms. They also highlight that information such as this may be useful in studies of HrQoL in multiple myeloma by helping to establish the factors that have greatest influence on the global health status score.29 These data do not represent the course of an individual patient’s disease. Nonetheless, they offer a basis for hypotheses regarding the factors that could influence HrQoL throughout the disease course.29 Improvements in overall survival achieved in recent years with new therapies for MM patients are a great achievement. Data from clinical tri- als suggest that the benefits of multiple myeloma treatment may outweigh the negative effects of toxicities and disease progression.29 Quality of life is influenced by the ability to adapt to unfortunate conditions or it can be said that that changes in HQL scores are subordinate to the individual sub- jective assessment of life situations which they con- sider to be important.31,32 However, the updating and improving QoL measure is essential to remain relevant in new treatments.33,34 Quality of life could be monitored objectively, excluding the impact of important socio-demographic factors.15 In conclusion, this study is the first to present Croatian general population reference values for the EORTC QLQ-C30 questionnaire. Age, gender and place of residence are important predictors of quality of life in Croatian population. For MM patients, our study identified treatment effects consistent with those from other observational studies and provide new data on HrQoL across two different treatment choices for patients with multiple myeloma treated in Croatian clinical cen- tres. According to available information there has been no research on MM patients before and after transplantation using the combination of EORTC QLQ-C30 and EORTC MY-20 questionnaires. It was recognized once again, that there is a need to compare the patient’s quality of life to the quality of life in the general population. Similarly as in the same research in our neigh- bouring Slovenia,15 our results are applicable to more than 95% of the entire pool of Croatian can- cer patients. Still, the HrQoL in Croatian general population could be further explored on larger sample sizes, and also with a wider range of age groups, where younger respondents could also be included. 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