Understanding the quality of life (QOL) issues in survivors of cancer: towards the development of an EORTC QOL cancer survivorship questionnaire

Understanding the quality of life (QOL) issues in survivors of cancer: towards the development of... Backround: The number of cancer survivors is growing steadily and increasingly, clinical trials are being designed to include long-term follow-up to assess not only survival, but also late effects and health-related quality of life (HRQOL). Therefore it is is essential to develop patient-reported outcome measures (PROMs) that capture the full range of issues relevant to disease-free cancer survivors. The objectives of this project are: 1) to develop a European Organisation for Research and Treatment of Cancer (EORTC) questionnaire that captures the full range of physical, mental and social HRQOL issues relevant to disease-free cancer survivors; and 2) to determine at which minimal time since completion of treatment the questionnaire should be used. Methods: We reviewed 134 publications on cancer survivorship and interviewed 117 disease-free cancer survivors with 11 different types of cancer across 14 countries in Europe to generate an exhaustive, provisional list of HRQOL issues relevant to cancer survivors. The resulting issue list, the EORTC core questionnaire (QLQ-C30), and site-specific questionnaire modules were completed by a second group of 458 survivors. Results: We identified 116 generic survivorship issues. These issues covered body image, cognitive functioning, health behaviors, negative and positive outlook, health distress, mental health, fatigue, sleep problems, physical functioning, pain, several physical symptoms, social functioning, and sexual problems. Patients rated most of the acute symptoms of cancer and its treatment (e.g. nausea) as no longer relevant approximately one year after completion of treatment. Conclusions: Compared to existing cancer survivorship questionnaires, our findings underscore the relevance of assessing issues related to chronic physical side effects of treatment such as neuropathy and joint pain. We will further develop a core survivorship questionnaire and three site-specific modules for disease-free adult cancer survivors who are at least one year post-treatment. Keywords: Cancer survivor, Disease-free, Health- related quality of life, Survivorship questionnaire, Disease-free, Oncology * Correspondence: m.v.leeuwen@nki.nl Division of Psychosocial Research & Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 2 of 15 Background objective of developing a HRQOL assessment approach With continuing improvement in early detection and that captures the full range of issues relevant to disease- treatment, and an aging population, the number of can- free cancer survivors, both in general and for specific cer survivors is increasing steadily. This has resulted in a cancer sites. Many definitions of cancer survivorship growing interest in evaluating the health-related quality have been used in the literature [14]. We use the term of life (HRQOL) of cancer survivors [1]. Increasingly, “cancer survivor” to describe any person who has been clinical trials and comparative effectiveness studies are diagnosed with cancer who has completed treatment being designed to include long-term follow-up to assess, with curative-intent (with the exception of maintenance in addition to survival, late effects of treatment and treatment) and is disease-free (no evidence of active HRQOL. In order to integrate HRQOL in such studies, cancer). Since The EORTC QLG’s current portfolio of it is essential to develop patient-reported outcome mea- measures has been primarily designed to assess patients’ sures (PROMs) that capture the full range of issues rele- HRQOL during treatment and shortly after completion vant to disease-free cancer survivors. of treatment, it makes sense to begin use of survivorship Many of the cancer-related HRQOL questionnaires that measures once the acute symptoms of the disease and are available today, including the European Organisation its treatment have resolved. An important secondary for Research and Treatment of Cancer core questionnaire objective of this project is to determine the most appro- (EORTC QLQ-C30) [2] and the Functional Assessment of priate minimum time since end of primary treatment for Cancer Therapy – General (FACT-G) [3], with their commencing use of survivorship HRQOL measures. supplementary site-specific modules, may not be entirely The conceptual framework we employed for the devel- appropriate for assessing the experiences of disease-free opment of the questionnaire followed the World Health cancer survivors. These questionnaires include items asses- Organization (WHO) definition of health, dating from sing acute and treatment-related symptoms (e.g., vomiting) 1948, as “a state of complete physical, mental, and social that are typically no longer relevant in the post-treatment well-being and not merely the absence of disease or infirm- survivorship period. Conversely, they may not adequately ity”. Combined with the Medical Outcomes study (MOS) address physical and psychosocial health problems particu- framework it delineates three key dimensions of health: larly relevant to cancer survivors (e.g., fear of recurrence, physical, mental and social [15]. These three dimensions return to work). can be assessed by several types of indicators (see Fig. 1). Questionnaires that have been developed specifically for Some of these indicators reflect primarily one of the three use among (long-term) cancer survivors include the Cancer dimensions (e.g., physical functioning) and others reflect Problems in Living Scale (CPILS) [4, 5], Impact of Cancer two or three dimensions (e.g., fatigue) [15]. (IOC/IOCv2) [6–8], QualityofLifein Adult Cancer In terms of measurement strategy, this project follows Survivors (QLACS) [9, 10], Quality of Life Cancer the tradition within the EORTC QLG of involving patients Survivors (QoL-CS) [11] and Satisfaction with Life from a range of countries, cultures and languages at every Domains Scale for Cancer (SLDS-C) [12]. These ques- step in the developmental process. Additionally, given the tionnaires focus primarily on psychosocial aspects of goal of addressing both generic and cancer site-specific survivorship and pay relatively little attention to asses- survivorship issues, the project encompasses a broad sing chronic physical effects of cancer and its treatment range of diagnostic groups. We follow the EORTC QLG’s [13]. Additionally, while they assess generic (e.g., fear of four- phase process of questionnaire development [16]: 1) recurrence) HRQOL issues relevant to the survivorship generation of relevant HRQOL of issues; 2) conversion of period, these questionnaires do not include condition- HRQOL issues into a set of questionnaire items; 3) ques- specific issues which may persist or arise as a long-term tionnaire pre-testing; and 4) large-scale international field consequence of treatment (e.g., genitourinary problems testing. In the current paper we report on the results of in prostate cancer survivors or lymphedema problems the first phase of this project. in breast cancer survivors). Also, they often have been based on investigations of a limited number of cancer Methods sites and on survivors living in the United States [4–8, Phase I had two aims: 1) to determine the full range of 12], thus limiting their generalizability to other survivor issues relevant to disease-free cancer survivors, both in populations in other countries. Finally, for most of general and for specific cancer sites; and 2) to determine these questionnaires, there is only limited information the most appropriate minimum time since end of pri- available about their psychometric properties, or the mary treatment for commencing use of survivorship psychometrics have been based on only a small number HRQOL measures. It consisted of two sub-phases: In of cancer survivor populations [13]. phase 1a we generated an exhaustive list of HRQOL is- For this reason, the EORTC Quality of Life Group sues, drawing upon two primary sources: the literature (QLG) has embarked on a project with the primary and cancer survivors. In phase 1b we asked a sample of van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 3 of 15 Fig. 1 Three-dimensional theoretical framework of health. In this framework health is assessed by multiple health indicators cancer survivors to rate the QLQ-C30 to determine at Health”[Major] OR “Physical Fitness/psychology”[Major] which time after treatment completion the acute symp- OR “Physical Fitness/physiology”[Major] OR “Health Sta- toms and side-effects related to cancer and its treatment tus”[Major] OR “late effects”)AND adults. Weincluded are no longer relevant. We considered the diminishing only original articles published in English that investigated prevalence of these symptoms an indicative of the need HRQOL in adult, disease-free cancer survivors. Articles to shift to the assessment of longer term survivorship is- reporting only scale scores without reference to specific sur- sues. In addition, the survivors participating in phase 1b vivorship issues were excluded. Two of the authors (MVL rated the list of HRQOL issues developed in phase 1a to and OH) screened references independently, and disagree- identify the issues relevant to disease free-survivors. In ments were resolved by consensus. this phase only quantitative data analyses were applied. The workflow of the study is also presented in Fig. 2. Study sample Literature search For phase 1a & b we recruited cancer survivors from hos- In October 2014, we performed a literature search in pitals from four geographic regions: the United Kingdom, PubMed and PsycINFO, the goal of which was to identify Northern Europe (Denmark, Germany, the Netherlands, the full range of HRQOL issues relevant to all adult disease- Norway, Sweden), Southern Europe (Cyprus, France, free cancer survivors, irrespective of their specific diagnosis. Greece, Israel, Italy, Spain), and Central Europe (Austria, We used the following search terms: (“Survivors”[Major] Poland). Inclusion of participants for phase 1b took place OR “Survivors/psychology”[Major]) AND (“neoplasms”[Ma- after completion of phase 1a. Eligible patients were those jor] OR “Carcinoma”[Major]) AND (“Quality of Life”[Mesh] aged 18 years or older at the time of diagnosis who had OR “patient-reported outcomes” OR “health-related quality sufficient command of their native language and did not of life” OR “wellbeing” OR “well-being” OR “Mental have severe psychological or cognitive problems. van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 4 of 15 Fig. 2 Work flow of phase I. TST time since completing last treatment To ensure that the survivorship questionnaire would approximately equal distribution of patients across diag- be generic in nature, we recruited survivors with a range noses and time since treatment (see below). of cancer diagnoses, selected on the basis of their preva- Basic sociodemographic data collected at study entry lence and/or survival rates. This included 11 diagnoses: included: age, sex, education, employment status, and breast, colorectal, prostate, bladder, gynecological (ovar- living arrangement. Clinical data collected included pri- ian, cervix and endometrial), head and neck, lung, and mary diagnosis, stage of disease, type of treatment, date testicular cancer, lymphoma, melanoma, and glioma. Eli- of diagnosis, date of start of primary treatment, date of gible patients had completed their treatment with cura- completing primary treatment, recurrences, date of com- tive intent (both primary treatment and treatment of pletion of treatment for last recurrence, and comorbidity recurrent disease) at least 6 months earlier and were using the Charlson Index [18]. disease-free (no evidence of disease). They could be re- ceiving maintenance therapies (e.g., hormonal treatment Phase 1a survivor interviews: issue generation for primary breast cancer). Although low-grade glioma We conducted semi-structured interviews with an initial patients are not treated with curative intent and are not sample of survivors in order to generate an exhaustive disease-free, they were included in the study because list of relevant HRQOL issues. The goal was to complete they have a median survival of between 4.7 and 9.8 years 10 interviews per diagnostic group, equally distributed [17]. We employed purposive sampling to ensure an over the four geographical regions [16]. First, the van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 5 of 15 respondents were asked open-ended questions about diagnostic groups * 3 time periods (6 months – 2 years / their survivorship experience. Subsequently, respondents 2–5 years / > 5 years since completing primary treatment) were shown the EORTC core questionnaire (QLQ-C30) [16]. The sample was also stratified according to geograph- and, if available, the relevant site-specific questionnaire ical region. The respondents were asked to complete the module [19–32]. These cancer site-specific modules provisional issue lists, using a 4-point response scale (not at assess the HRQOL issues most relevant to each of the all, alittlebit, quiteabit, or verymuch) to indicatethe specific patient populations. These modules range in extent to which they had experienced each issue. The length from 13 to 35 items. Instead of completing these provisional issue lists consisted of a generic survivor issue questionnaires, the respondents were asked to rate the list, and the sex- and cancer site-specific issues. In addition, relevance of the items on a 4-point scale (not at all, a they were also asked to complete the QLQ-C30 and, if little bit, quite a bit, or very relevant). The respondents available, the relevant site-specific module using the were also asked to identify survivorship issues that they same response scale. This was followed by a debrief- believed to be important that were not included in the ing interview about any relevant issues missing from QLQ-C30 and, where relevant, site-specific module. the provisional issue lists. Relevance ratings of the EORTC core questionnaire Definition of the minimal time since end of treatment for (QLQ-C30) assessing survivorship issues We evaluated the relevance ratings by composing scales To determine the minimum time since end of treatment that were in accordance with the QLQ-C30 scale structure: for which the survivorship questionnaire would be rele- 5 multi-item functioning scales (physical, role, emo- vant, we divided the Phase 1b sample into three time- tional, cognitive, and social functioning), three multi- since-completion-of-last-treatment (TST) groups: (1) 0.5 item symptom scales (fatigue, pain, nausea/vomiting), to 1 years; (2) 1 to 2 years; and (3) 2 years or more since and 6 single items (dyspnea, insomnia, appetite loss, treatment completion. For each TST group we investi- constipation, diarrhea, and financial difficulties). All gated which items of the QLQ-C30 were rated as rele- scores were linearly transformed to a 0 to 100-points vant for that specific group: an item was considered scale. A higher score on a scale means that the survi- relevant if at least 30% of the respondents in a group vors considered the items of this particular scale more endorsed an item (i.e., had experienced the issue at least relevant. We compared the following survivor groups: “a little bit”). We were particularly interested in compar- 0.5 to 2 years since diagnosis, 2 to 5 years since diag- ing responses to the QLQ-C30 items between the three nosis, and 5 years or more since diagnosis. TST groups, as the QLQ-C30 contains a number of acute symptom and side-effect items. Our objective here Issue extraction from literature and interviews was to determine at what point in time these relatively Phase 1a interviews were transcribed and translated in acute issues were no longer relevant for the majority of English by the interviewers. We employed thematic ana- respondents, and thus it would be appropriate to begin lysis [33]using NVivo 10 [34], a software program for using survivorship measures. qualitative data analyses, to extract a list of relevant sur- vivorship issues from the articles included in the literature review and from the transcribed semi-structured phase 1a interviews. Literature and interviews were analyzed simul- Criteria for issue selection in phase 1b taneously using the coding system that evolved during the In this phase, the provisional issue list was reviewed to thematic analyses. Items of the existing questionnaires generate one comprehensive list of generic issues that and the issues described in the qualitative studies were was relevant to all groups of cancer survivors, regardless coded in issues that were organized into hierarchical trees. of specific diagnosis. In addition, site-specific issue lists Cancer site or sex-specific issues were extracted in separ- and sex-specific issues were generated. As indicated ate coding trees, and kept separately to avoid survivors in above, we coded an issue as being endorsed by a re- phase 1b having to rate too many issues. All issues were spondent if it was scored “a little bit” or higher. An issue consolidated into a provisional list which included generic, needed to be endorsed by at least 30% of the survivors site-specific, and sex-specific issues to be completed by a in any given diagnostic group to be regarded as an issue second group of survivors in phase 1b. relevant to that group. If an issue was endorsed by survi- vors from 6 or more diagnostic groups, it was then con- Phase 1b survivor interviews: defining minimal time since sidered to be a generic survivorship issue; otherwise it treatment completion and issue selection was deemed to be a cancer-site specific issue. This In the second round of interviews, our goal was to recruit resulted in 12 consolidated survivorship issue lists: one 330 survivors: 10 interviews per survivor group * 11 generic list and 11 cancer-site specific lists. van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 6 of 15 Sub-analyses in the younger age groups Previous research has shown that younger adult survi- vors can be particularly impacted by the cancer experi- ence [35–41]. For this reason, we performed post-hoc, age-related subgroup analyses to identify issues that are particularly relevant to survivors younger than 50 years. We divided the total sample into five age groups (< 40; 40–50; 50–60; 60–70; 70+ years). Issues endorsed as relevant by at least 30% of respondents under the age of 50 years that would otherwise have been excluded on the basis of ratings by respondents above the age of 50 (i.e. low endorsement in the older sample causing the endorsement in the total sample to be below 30%) were retained in the generic list as being particularly relevant for younger cancer survivors. Our expectation was that we would retain issues likely to be specifically relevant to younger cancer survivors such as problems in obtain- ing a mortgage or family planning. Results Literature review The literature search identified 1494 publications, of which 134 were retained for issue extraction (for details see Fig. 3). The list of 134 articles included in the review can be found in Additional file 1. Research articles included in the review were most commonly qualitative studies, studies developing cancer survivor specific mea- sures, or studies reporting the use of a self-constructed study-specific measure. Fig. 3 Prisma flow chart of the literature review Semi-structured interviews phase 1a: issue generation For phase 1a, 117 survivors were interviewed between around physical exams” were combined into “fear of recur- August 2014 and May 2015 in nine different European rence”. Issues reflecting states like “being retired” were not countries (Table 1). The average age of the survivors was included, as they cannot be assessed on a 4-point scale, and 57 years (SD = 13.6 years), and 54% had received their would not be informative for an assessment of HRQOL. cancer diagnosis between 2 and 5 years ago. Issues stating a change in physical symptoms were not included. General issues like “emotional problems” were Issue extraction from literature and interviews notincludedaswebelievedthattheywerebettercaptured In the first step, we identified 1555 issues from the 117 by more informative issues, for example, “being worried”, interviews and the first 75% of the research articles. These “fear of dying”, “anxiousness”, “feeling stressed”, “feeling issues were classified into 11 themes: mental health, phys- depressed”. This resulted in 197 generic, 62 cancer site-spe- ical symptoms, cognitive changes, role functioning (includ- cific (e.g. pain during urination), and 8 sex-specific (e.g. ing work), meaning of cancer, health behaviors, spirituality, feeling less feminine) issues. social functioning (including feelings of belonging), finan- cial issues, body image, and sexuality. In the next step we Relevance ratings of the EORTC core questionnaire reduced this list to 718 issues by combining issues that (QLQ-C30) were very similarorformedacontinuous scale(e.g. “de- The relevance ratings are presented in Fig. 4. The figure pression” and “feeling depressed” were combined into “feel- shows that the functioning scales were still considered ing depressed”). The remaining 25% of studies was coded relevant by the survivors, with the perceived relevance using this 718 issues coding system. We did not identify increasing with longer time since diagnosis. A number new issues in these studies. In the last step, the total of the symptom items and scales were considered less number of issues was further reduced. Issues that were very relevant, especially when more time had passed since specific were combined. For example, “fear of recurrence diagnosis. Two years after diagnosis, nausea/ vomiting, when having physical symptoms” and “fear of recurrence appetite loss, constipation, and diarrhoea were seldom van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 7 of 15 Table 1 Number of cancer survivors per cancer site and per We started our analyses by defining the post-treatment region included in phase 1a and 1b survivorship period in the complete phase 1b sample by Phase 1a Phase 1b comparing the three subgroups (0.5–1year, 1to 2years, and 2 years or more post-treatment). The following QLQ- Cancer site C30 items were rated as being relevant in the 0.5–1year Bladder 7 32 post-treatment survivors subgroup, but no longer so in Breast 17 53 the other two TST subgroups: needing to stay in bed or a Colorectal 12 46 chair during the day, pain interfering with daily activities, Glioma 10 36 physical condition or treatment interfering with family life Gynecological 12 49 and social activities, and physical condition or treatment causing financial difficulties. Scores on the functional and Head & neck 10 44 symptom scales of the QLQ-C30 showed an increase in Lung 8 41 physical, role emotional and social functioning one year Lymphoma 9 38 after completion of treatment, and a decrease in fatigue Melanoma 11 38 (Fig. 5). After this first year these scores tended to Prostate 11 44 stabilize. Based on these findings we decided to Testicular 10 37 employ the one year post-treatment mark as the threshold for recommending transitioning to the use Total 117 458 of survivorship measures. Region Additionally, the analyses of the QLQ-C30 data Northern Europe 30 147 showed that the following items were of low relevance Southern Europe 46 126 to all of the TST survivor subgroups: “Do you have any English speaking 13 98 trouble taking a short walk outside of the house?”, “Do Central Europe 28 87 you need help with eating, dressing, washing yourself or using the toilet?”, and those items assessing appetite, Time since diagnosis nausea, vomiting, and gastrointestinal symptoms. 0.5 to 2 years 21 111 For the subsequent selection of issues to be included 2 to 5 years 63 189 in the survivorship questionnaire, only the 386 respon- more than 5 years 33 158 dents who were at least 1 year post-treatment were Time since completing last treatment included. Table 3 displays the 116 issues that were re- 0.5 to 1 year – 72 ported as being relevant by respondents in at least 6 of the diagnostic groups. Thirty-four percent of these con- 1 to 2 years – 105 sisted of issues covering physical functioning (e.g. pain, 2 to 5 years – 172 neuropathy, muscle cramp), 32% were mental function- more than 5 years – 109 ing issues (e.g. body image, anxiety, positive affect), 19% For phase 1b only, also the number of survivors per time since completion of issues were related to social and role functioning (e.g. last treatment category is reported For phase 1a only information was available regarding date of diagnosis and sexual problems, feelings of belonging) and 16% involved date of recurrence general health perceptions (e.g. negative health outlook and health behavior). Of the 116 issues, 106 were not rated as being relevant. The ratings showed that particu- included in the QLQ-C30. Table 3 shows which issues larly insomnia was considered highly relevant by the are overlapping with the QLQ-C30, which were identi- survivors less than 2 years after diagnosis and fatigue by fied from the literature, and which from the interviews. the survivors who were less than 5 years since diagnosis. In addition to generic issues, we also identified sur- vivorship issues that were cancer site-specific. On average, 26 (range 7–48) issues were considered as Phase 1b interviews: defining minimal time since cancer-site specific per diagnostic group. We intend to treatment completion and issue selection use these issues for the future development of cancer Between November 2015 and August 2016, we inter- site-specific survivorship modules. Among these can- viewed 458 survivors from 23 centers in 14 countries for cer site-specific survivorship issues, we observed the phase 1b (Table 1). The mean age of the sample was following trends: body image issues were frequently 59 years, and 46% was female. Sixty percent had been endorsed by bladder, breast, colorectal, and head & diagnosed with stage I or II cancer, and 16% had experi- neck cancer survivors. Cognitive functioning problems enced disease recurrence in the past. The average time were rated as highly relevant by glioma, lymphoma, since last treatment was 3.6 years (Table 2). lung, bladder, breast, and head and & neck cancer van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 8 of 15 Fig. 4 Relevance ratings of the functional and symptom scales of the QLQ-C30 per time since diagnosis group. The y-axis shows the relevance ratings of the QLQ-C30. A higher score on a scale means that the survivors considered the items of a particular scale more relevant survivors. Lung cancer and glioma survivors reported Discussion having a negative health outlook as highly relevant. In this first phase of our cancer survivorship questionnaire Bladder and head & neck cancer survivors frequently development project, we identified 116 generic survivor- endorsed role functioning issues. Lung, lymphoma, ship issues. Additionally, on average, we identified 26 and colorectal cancer survivors more often endorsed site-specific survivorship issues per tumor site, which only work-related issues than the other survivor groups. partially overlapped with the existing EORTC site-specific Glioma and lymphoma survivors more frequently modules. We also observed that, approximately one year rated issues related to a negative impact on feelings of following completion of cancer treatment, most of the belonging as relevant. acute disease- and treatment-related symptoms have Based on the 94 survivors below the age of 50 years, resolved themselves in the large majority of survivors. we identified 10 issues that were relevant for younger Based on these findings, we will move forward with survivors and for which relevance declined with age (see the development of a core survivorship questionnaire for Table 3). Three issues were related to body image; the disease-free adult survivors who are at least one year others were related to the ability to have children, being post-treatment. This questionnaire will retain many of treated differently by people because of having had can- the original items and scales from the QLQ-C30, delet- cer, difficulties talking about cancer, negative personality ing only those items that assess acute symptoms (nau- change, needing psychological support, loss of future life sea/vomiting, appetite loss, constipation, and diarrhea). plans, and financial problems. Additional survivorship issues will be added to expand van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 9 of 15 Table 2 Basic demographics, disease and treatment characteristics Table 2 Basic demographics, disease and treatment characteristics of the survivors included in phase 1b of the survivors included in phase 1b (Continued) Survivors Phase 1a Phase 1b Survivors Phase 1a Phase 1b N = 117 Total Subsample N = 117 Total Subsample a a N = 458 N = 386 N = 458 N = 386 Age current maintenance 861 47 therapy Mean ± SD (years) 57 (13.6) 59 (13.8) 59 (13.7) Percentages are given in the cases that categories are mutually exclusive Sex (%) N number, SD Standard deviation subsample of phase 1b that consists of the survivors who are at least 1 year male 58 (50%) 246 (54%) 207 (54%) after treatment completion b b Partner status categories are not mutual exclusive, e.g. one can be a widower and have a new relationship in relationship 90 367 313 c for glioma survivors in Phase 1b tumor grading was used, we included per tumor grade: grade 1: 2 survivors; grade 2: 8 survivors; grade 3: 14 survivors; widower/ divorced/ 961 49 grade 4: 1 survivor separated single 14 50 43 Education (%) the scope of issues addressed by the questionnaire. To improve the measurement precision of some of the none or primary 15 (13%) 59 (13%) 47 (12%) school only existing scales of the QLQ-C30, we will collaborate with the EORTC CAT team [42] to select the issues of the high school 46 (39%) 167 (36%) 140 (36%) generic issue list and the items of the EORTC QLG item college or university 53 (45%) 222 (48%) 190 (49%) library assessing these issues. This survivorship ques- missing 3 (3%) 10 (2%) 9 (2%) tionnaire can be complemented by cancer-site specific Work status (%) survivorship modules based on and adapted from the working 59 (50%) 205 (45%) 180 (47%) existing EORTC cancer site-specific modules. retired 43 (37%) 185 (40%) 157 (41%) The period after treatment completion is often de- scribed by survivors as more difficult than the treatment unemployed 4 (3%) 24 (5%) 17 (4%) itself [43]. The end of the phase of transition from being a homemaker 4 (3%) 22 (5%) 17 (4%) patient to resuming normal life [44] can be very positive, disabled 5 (4%) 10 (2%) 7 (2%) but also brings with it feelings of uncertainty about the other or missing 2 (2%) 12 (2%) 10 (3%) future and fear of cancer recurrence. During this early Disease recurrence (%) 11 (9%) 75 (16%) 66 (17%) survivorship period, patients often begin to process the Tumor stage (%) emotions related to the diagnosis, to find meaning in their experience of having had cancer, and to deal with the stage I 19 (16%) 101 (23%) 88 (24%) lingering effects of treatment. The end of this turbulent stage II 45 (38%) 131 (30%) 108 (28%) immediate post-treatment period appears to represent an stage III 29 (25%) 113 (25%) 95 (25%) appropriate starting point for assessing survivorship is- stage IV 3 (3%) 40 (9%) 34 (9%) sues, as both physical and psychosocial health begin to stage unknown 13 (11%) 47 (11%) 40 (10%) stabilize. This was corroborated by the increase in phys- no stage determined 8 (7%) ical, role, and social functioning and the decline in fatigue observed in our study sample after the first post-treatment Time since completing primary treatment year. We did not observe a further decline in the acute Mean (SD) (years) – 4.2 (4.0) 4.8 (4.0) symptoms of cancer treatment, as the prevalence of acute Time since completing last treatment symptoms was already low a half year after treatment Mean (SD) (years) – 3.6 (3.2) 4.4 (3.2) completion. The chronic side effects of treatment Therapy (pain, dyspnea, insomnia, and fatigue) continued to be surgery 98 342 326 relevant for all survivor groups into the longer post- treatment phase. chemotherapy 77 254 222 In accordance with the existing cancer survivorship radiotherapy 54 238 209 questionnaires [4–12] our results indicate that feelings of hormonal therapy 15 49 48 uncertainty about the future, fears related to recurrence of monoclonal antibodies 2 21 18 cancer, fears and worries concerning family members, cell transplantation 6 6 feelings of depression and anger, feelings that others do active surveillance 7 66 59 not understand the impact of cancer, positive impact on social relationships, positive changes in (perception of) van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 10 of 15 Fig. 5 Functional and symptom scales of the QLQ-C30 per time since last treatment category. The y-axis shows the scores on QLQ-C30. On the functional scales a higher score represents a better level of functioning and on the symptom scales a higher score represents a higher level of symptoms life, negative body image, cognitive problems, fatigue, the existing survivorship questionnaires may reflect both sleeping problems, pain, sexual problems, and dealing culture (including differences between the American and with the chronic physical consequences of cancer are all European health care systems) and the fact that we in- relevant issues for cancer survivors. However, our results cluded a wider range of diagnostic groups in our study, also indicate that other issues often included in survivor- and placed relatively less emphasis on breast cancer and ship questionnaires may be less relevant when rated by a non-solid cancer survivors, as has typified the develop- wider range of cancer survivors in an international mental phase of other survivorship questionnaires. context. This includes issues related to feelings of guilt, Another important finding from our study is that there fears related to starting new (romantic) relationships, and is not only a fairly large number of condition-specific feelings of pride about having survived cancer. Also, physical health issues in cancer survivorship, but also compared to existing questionnaires, our findings under- differences in the extent to which various psychosocial score the relevance of assessing issues related to chronic issues are perceived as relevant by specific cancer diag- side effects of treatment such as neuropathy and joint pain nostic groups. These differences in perceived relevance [4–12]. Over 30% of the issues were related to physical of survivorship issues may reflect differences in sur- functioning, including chronic physical effects of cancer vival rates between the cancer types, the average age at and its treatment, like Raynaud symptoms, neuropathy, diagnosis, thenatureofthe chronicsideeffects of the joint pain, and muscle cramps. These issues receive rela- various treatments, and whether a cancer diagnosis is tively little attention in the existing cancer survivorship sex-specific. For example, glioma and lung cancer sur- questionnaires. The differences between our findings and vivors reported issues related to the negative impact of van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 11 of 15 Table 3 Consolidated issue list with generic survivorship issues Body Image b, c � feeling unattractive � feeling old b, c � feeling satisfied with your physical appearance b, c � feeling you could not trust your body Cognitive functioning a,b, c � difficulties with concentration b, c � forgetfulness a,b, c � memory problems b, c � problems with multi-tasking b, c � difficulty gathering your thoughts (together) b, c � ability to think (to process information) has slowed down Health behaviors b, c � being alert for symptoms that may signal a return of my cancer � going quickly to my GP due to having (had) cancer b, c � drinking less alcohol due to having (had) cancer b, c � listening to my body due to having (had) cancer b, c � eating healthily due to having (had) cancer b, c � avoiding the sun or protecting my skin due to having (had) cancer b, c � exercising (more) due to having (had) cancer b, c � avoiding stress in my life due to having (had) cancer b, c � cutting down smoking due to having (had) cancer (not applicable option) b, c � taking better care of yourself due to having (had) cancer Meaning of cancer b, c � other issues not related to cancer bother me more than having had cancer b, c � cancer is a learning experience b, c � having (had) cancer has made me accept my own mortality a, b, c � overall quality of life b, c � being (more) emotional due to having (had) cancer � seeking a deeper meaning in having (had) cancer Negative outlook b, c � concerned with long term effects of cancer treatment b, c � feeling that my life has been suspended because of having (had) cancer b, c � difficulties adapting my life to the physical consequences of having had cancer b, c � still feeling like a cancer patient b, c � experiencing uncertainty about the future Positive outlook b, c � appreciating life (more) due to having (had) cancer b, c � being psychologically strong(er) due to having (had) cancer b, c � my personality has changed for the better due to having (had) cancer � having (had) cancer has given me a purpose in life b, c � because of having (had) cancer I have reconsidered my priorities in life b, c � standing up for myself (more) due to having (had) cancer b, c � having (had) cancer has given me a reason to make changes in my life b, c � willing to help others (more) due to having (had) cancer b, c � due to having (had) cancer, being (more) understanding of what other people feel Mental health Depression/behavioral-emotional control Health distress a, b, c b, c � feeling depressed � fear of recurrence or spread cancer b, c b, c � feeling angry or frustrated � worried about health b, c b, c � feeling stressed � fear of dying b, c b, c � mood swings � fear of new cancer b, c b, c � needing psychological support � fear family members will develop cancer a, b, c � feeling irritable b, c � feeling upset about having (had) cancer Anxiety a, b, c � being worried b, c � feeling anxious Physical symptoms b, c � altered hair structure van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 12 of 15 Table 3 Consolidated issue list with generic survivorship issues (Continued) b, c � weight gain � feeling ill or unwell � acid reflux a, b, c � overall health Fatigue Sleep problems b, c b, c � feeling constantly tired � problems falling asleep c b, c � needing more sleep to function � waking up frequently at night b, c a,b, c � feeling exhausted � trouble sleeping a, b, c b � feeling tired � waking up too early � needing time to recover from normal activities a, b, c � feeling weak � needing to take naps b, c � sudden attacks of tiredness Physical functioning/ mobility Leg problems b b, c � difficulty carrying something in both hands while climbing stairs � difficulty standing for a long time a,b, c c � difficulty taking a long walk � restless legs b, c b, c � difficulty running fast � swollen feet or legs b, c � difficulty carrying something weighing 5 kg b, c � difficulty hiking for 3 km b, c � difficulty walking up a flight of stairs � difficulty doing strenuous activities like carrying a heavy shopping bag or a a, b suitcase Pain Skin Problems b, c b, c � headaches � dry and or scaly skin c b, c � joint pain � thin skin b, c � muscle pain Raynaud Neuropathy c b, c � hands and/or feet sensitive to hot and cold � tingling in hands and/or feet b, c � cold or pale fingers or toes Muscle problems Temperature b, c b, c � muscle cramps � night sweats S b, c � muscle weakness � hot flushes b, c � feeling cold Role functioning a,b, c � limited in recreational activities Work b, c � difficulties returning to work since having (had) cancer b, c � having (had) cancer decreased work performance b, c � career interrupted due to cancer Feelings of belonging Positive impact Negative impact b, c � family relationships are close(r) due to having (had) cancer � feeling that others do not understand the impact of having (had) b, c � having (had) cancer has a positive impact on the relationship with my cancer b, c b, c partner � not wanting to burden family members b, c b, c � feeling close(r) to friends since having (had) cancer � worried about the impact of my cancer on my children b, c � friends and family are (more) important since having (had) cancer Sexual problems � feeling guilty for not fulfilling sexual needs of partner Sex-specific sexual problems Sexual frequency b, c b, c � vaginal dryness � low interest in sex b, c b, c � problems getting or maintaining erection � sexually active with or without intercourse � avoiding sex Sexual pleasure � difficulty becoming sexually aroused � feeling uneasy with sex � problems enjoying sex � problems having an orgasm van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 13 of 15 Table 3 Consolidated issue list with generic survivorship issues (Continued) b, c � problems with sexual intimacy Sub-analyses: issues relevant to younger cancer survivors b, c � upset with appearance of scar b, c � feeling angry towards body b, c � feeling embarrassed about body b, c � concerned about the ability to have children b, c � having problems with people treating me differently because I have (had) cancer b, c � difficulties talking about cancer b, c � my personality has changed for the worse due to having (had) cancer � having (had) cancer has made me lose my future life plans or goals b, c � financial problems caused by problems with getting a loan, mortgage, or insurance Issues in this list were endorsed by 30% of the survivors in at least 6 of the included cancer sites issues which are also included in the QLQ-C30 issues identified in the literature issues identified in the survivor interviews cancer on their lives and issues related to struggles with strategy with site-specific survivor modules ensures that family and friends as being very relevant; lung, lymphoma, relevant chronic physical symptoms are included. Fur- and colorectal cancer survivors more frequently rated thermore, the retention of the items and scales of the work-related issues; and bladder and head & neck cancer QLQ-C30 that are still relevant for disease-free survi- survivors more frequently endorsed role functioning vors will ensure continuity in the evaluation of HRQOL issues. Most of these site-specific survivorship issues over time, from diagnosis through the long-term sur- are currently not included in the existing site-specific vivorship phase. modules of the EORTC. A possible limitation of our work is that those cancer The literature consistently shows that younger cancer survivors in our sample who were more than 5 years survivors report a higher impact of their cancer experi- post-treatment were drawn primarily from hospital ence on HRQOL [45, 46], including higher levels of dis- registries. Many patients who are 5 years or longer post- tress, than older cancer survivors. This is likely related to treatment may no longer be in active follow-up, and the fact that relatively younger survivors are confronted those who are may be those with more serious, chronic with a life-threatening illness at a time when many are in health problems. This could cause some degree of over- the midst of forming relationship bonds, starting and rais- estimation of the relevance of various survivorship issues ing families, and trying to establish a workable balance be- in this subgroup of longer term survivors. Also, our tween career and family life. During this period of young sample was somewhat younger than one might expect adulthood, a serious illness such as cancer is less expected, based on the median age of the general population at and may therefore be more disruptive. Also, younger can- cancer diagnosis (66 years) [47]. cer patients and survivors may perceive themselves as hav- ing more to lose in terms of future perspective, and may Conclusions have fewer opportunities for peer support (i.e., having con- We identified 116 generic survivorship issues, and on temporaries with whom they can share their common ex- average, 26 site-specific survivorship issues per tumor perience of having had cancer). Conversely older survivors site. Compared to existing cancer survivorship question- have more life experience, which might lead to better cop- naires, our findings underscore the relevance of asses- ing strategies, and they may face fewer work-related and sing issues related to chronic physical side effects of social demands. This is supported by the findings from treatment such as neuropathy and joint pain in addition our study that younger survivors are more likely than to the psychosocial aspects of survivorship. older survivors to rate issues related to having children, fi- In the next phase of this project, we will further develop nancial difficulties, loss of future life plans, and lack of and test the core survivorship questionnaire, and we will support as being relevant to them. Although some of these also develop survivorship modules for breast, prostate, issues appear to be more relevant to younger survivors, in and colorectal cancer survivors. The choice of these three the interest of parsimony (i.e., not having to create two disease sites was based on the incidence, survival rates, versions of a core survivorship questionnaire), we have and the number of survivorship studies conducted in decided to include them in our consolidated issue list. these disease sites. In the longer term, we intend to A strength of our study is that we included a relatively develop survivorship modules for a much broader set of large number of survivors from 11 cancer diagnosis cancer sites. Ultimately, this will yield a comprehensive groups from a total of 14 European countries. This en- suite of survivorship questionnaires that will yield both a hances the generalizability of our findings. Also, our common data set for comparison of results across tumor van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 14 of 15 sites, and unique information about the survivorship Neurology, Leiden University Medical Center, Leiden, The Netherlands. Department of Neurology, Haaglanden Medical Center, The Hague, the experience of specific groups of cancer survivors. Netherlands. Division of Epidemiology and Health Services Research at Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Mainz, Germany. Department of Otolaryngology Head and Neck Surgery, Additional file Sahlgrenska University Hospital, Göteborg, Sweden. Department of Psychiatry and Psychotheraphy, Division of Psychooncology, Innsbruck Additional file 1: The list of 134 articles included in the review. Medical University, Innsbruck, Austria. University Surgical Unit, University (PDF 118 kb) Hospitals Southampton, Southampton, UK. Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece. Unit of Survivorship Research, Danish Cancer Society Abbreviations Research Center, Copenhagen, Denmark. Oncology Institute, Chaim Sheba CPILS: Cancer Problems in Living Scale; EORTC: European Organisation for Medical Center, Tel-Hashomer, Israel. Department of Psychosomatic Research and Treatment of Cancer; FACT-G: Functional Assessment of Cancer Medicine Center for Internal Medicine and Dermatology, Charité - Therapy – General; HRQOL: Health-related quality of life; IOC/IOCv2: Impact Universitätsmedizin Berlin, Berlin, Germany. East Kent Gynaecological of Cancer; MOS: Medical Outcomes study; N: Number; PROMs: Patient- Oncology Centre, Margate, UK. Neuroncology Unit, National Cancer reported outcome measures; QLACS: Quality of Life in Adult Cancer Institute Regina Elena, Rome, Italy. Rehabilitation Unit, Department of Survivors; QLG: Quality of Life Group; QLQ: Quality of life questionnaire; QLQ- Supportive Care, Istituto Nazionale Tumori – IRCCS- Fondazione G. Pascale, C30: EORTC core questionnaire; QOL: Quality of life; QoL-CS: Quality of Life Naples, Italy. Evangelische Kliniken Gelsenkirchen, Gelsenkirchen, Germany. Cancer Survivors; SD: Standard deviation; SLDC-C: Satisfaction with Life Department of Gastroenterology and Hepatology, Hampshire Hospitals Domains Scale for Cancer; TST: Time-since-completion-of-last-treatment; NHS Foundation Trust, Basingstoke, UK. Department of Neurology and WHO: World Health Organization Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. Unit of Psychoncology - Breast Unit, Istituto Oncologico Funding Veneto (IOV)-IRCCS, Padua, Italy. Health Outcomes Research Unit, This study was funded by the a grant from the European Organisation for Department of Geriatrics, Gerontology, and Social Work, Faculty of Education, Research and Treatment of Cancer Quality of Life Group (003/2014). Ignatianum Academy, Krakow, Poland. Department of Radiation Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus. Department of Availability of data and materials Otolaryngology / Head & Neck Surgery, VU University Medical Center, The data that support the findings of this study are available from the Amsterdam, The Netherlands. Department of Gynecology and Obstetrics, Division of Psychosocial Research and Epidemiology of the Netherlands Sorlandet Hospital Kristiansand, Kristiansand, Norway. Lynda Jackson Cancer Institute (contact person: L.V. van de Poll-Franse), but restrictions Macmillan Centre, East & North Hertfordshire NHS Trust including Mount apply to the availability of these data due to an agreement between the Vernon Cancer Centre, Northwood, UK. Comprehensive Cancer Centre Netherlands Cancer Institute and the European Organisation for Research South (CCCS), Eindhoven Cancer Registry, Eindhoven, The Netherlands. and Treatment of Cancer Quality of Life Group, and so they are not publicly Tilburg University, Tilburg, The Netherlands. available. 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Medicine & Public Health; Quality of Life Research; Quality of Life Research
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Abstract

Backround: The number of cancer survivors is growing steadily and increasingly, clinical trials are being designed to include long-term follow-up to assess not only survival, but also late effects and health-related quality of life (HRQOL). Therefore it is is essential to develop patient-reported outcome measures (PROMs) that capture the full range of issues relevant to disease-free cancer survivors. The objectives of this project are: 1) to develop a European Organisation for Research and Treatment of Cancer (EORTC) questionnaire that captures the full range of physical, mental and social HRQOL issues relevant to disease-free cancer survivors; and 2) to determine at which minimal time since completion of treatment the questionnaire should be used. Methods: We reviewed 134 publications on cancer survivorship and interviewed 117 disease-free cancer survivors with 11 different types of cancer across 14 countries in Europe to generate an exhaustive, provisional list of HRQOL issues relevant to cancer survivors. The resulting issue list, the EORTC core questionnaire (QLQ-C30), and site-specific questionnaire modules were completed by a second group of 458 survivors. Results: We identified 116 generic survivorship issues. These issues covered body image, cognitive functioning, health behaviors, negative and positive outlook, health distress, mental health, fatigue, sleep problems, physical functioning, pain, several physical symptoms, social functioning, and sexual problems. Patients rated most of the acute symptoms of cancer and its treatment (e.g. nausea) as no longer relevant approximately one year after completion of treatment. Conclusions: Compared to existing cancer survivorship questionnaires, our findings underscore the relevance of assessing issues related to chronic physical side effects of treatment such as neuropathy and joint pain. We will further develop a core survivorship questionnaire and three site-specific modules for disease-free adult cancer survivors who are at least one year post-treatment. Keywords: Cancer survivor, Disease-free, Health- related quality of life, Survivorship questionnaire, Disease-free, Oncology * Correspondence: m.v.leeuwen@nki.nl Division of Psychosocial Research & Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 2 of 15 Background objective of developing a HRQOL assessment approach With continuing improvement in early detection and that captures the full range of issues relevant to disease- treatment, and an aging population, the number of can- free cancer survivors, both in general and for specific cer survivors is increasing steadily. This has resulted in a cancer sites. Many definitions of cancer survivorship growing interest in evaluating the health-related quality have been used in the literature [14]. We use the term of life (HRQOL) of cancer survivors [1]. Increasingly, “cancer survivor” to describe any person who has been clinical trials and comparative effectiveness studies are diagnosed with cancer who has completed treatment being designed to include long-term follow-up to assess, with curative-intent (with the exception of maintenance in addition to survival, late effects of treatment and treatment) and is disease-free (no evidence of active HRQOL. In order to integrate HRQOL in such studies, cancer). Since The EORTC QLG’s current portfolio of it is essential to develop patient-reported outcome mea- measures has been primarily designed to assess patients’ sures (PROMs) that capture the full range of issues rele- HRQOL during treatment and shortly after completion vant to disease-free cancer survivors. of treatment, it makes sense to begin use of survivorship Many of the cancer-related HRQOL questionnaires that measures once the acute symptoms of the disease and are available today, including the European Organisation its treatment have resolved. An important secondary for Research and Treatment of Cancer core questionnaire objective of this project is to determine the most appro- (EORTC QLQ-C30) [2] and the Functional Assessment of priate minimum time since end of primary treatment for Cancer Therapy – General (FACT-G) [3], with their commencing use of survivorship HRQOL measures. supplementary site-specific modules, may not be entirely The conceptual framework we employed for the devel- appropriate for assessing the experiences of disease-free opment of the questionnaire followed the World Health cancer survivors. These questionnaires include items asses- Organization (WHO) definition of health, dating from sing acute and treatment-related symptoms (e.g., vomiting) 1948, as “a state of complete physical, mental, and social that are typically no longer relevant in the post-treatment well-being and not merely the absence of disease or infirm- survivorship period. Conversely, they may not adequately ity”. Combined with the Medical Outcomes study (MOS) address physical and psychosocial health problems particu- framework it delineates three key dimensions of health: larly relevant to cancer survivors (e.g., fear of recurrence, physical, mental and social [15]. These three dimensions return to work). can be assessed by several types of indicators (see Fig. 1). Questionnaires that have been developed specifically for Some of these indicators reflect primarily one of the three use among (long-term) cancer survivors include the Cancer dimensions (e.g., physical functioning) and others reflect Problems in Living Scale (CPILS) [4, 5], Impact of Cancer two or three dimensions (e.g., fatigue) [15]. (IOC/IOCv2) [6–8], QualityofLifein Adult Cancer In terms of measurement strategy, this project follows Survivors (QLACS) [9, 10], Quality of Life Cancer the tradition within the EORTC QLG of involving patients Survivors (QoL-CS) [11] and Satisfaction with Life from a range of countries, cultures and languages at every Domains Scale for Cancer (SLDS-C) [12]. These ques- step in the developmental process. Additionally, given the tionnaires focus primarily on psychosocial aspects of goal of addressing both generic and cancer site-specific survivorship and pay relatively little attention to asses- survivorship issues, the project encompasses a broad sing chronic physical effects of cancer and its treatment range of diagnostic groups. We follow the EORTC QLG’s [13]. Additionally, while they assess generic (e.g., fear of four- phase process of questionnaire development [16]: 1) recurrence) HRQOL issues relevant to the survivorship generation of relevant HRQOL of issues; 2) conversion of period, these questionnaires do not include condition- HRQOL issues into a set of questionnaire items; 3) ques- specific issues which may persist or arise as a long-term tionnaire pre-testing; and 4) large-scale international field consequence of treatment (e.g., genitourinary problems testing. In the current paper we report on the results of in prostate cancer survivors or lymphedema problems the first phase of this project. in breast cancer survivors). Also, they often have been based on investigations of a limited number of cancer Methods sites and on survivors living in the United States [4–8, Phase I had two aims: 1) to determine the full range of 12], thus limiting their generalizability to other survivor issues relevant to disease-free cancer survivors, both in populations in other countries. Finally, for most of general and for specific cancer sites; and 2) to determine these questionnaires, there is only limited information the most appropriate minimum time since end of pri- available about their psychometric properties, or the mary treatment for commencing use of survivorship psychometrics have been based on only a small number HRQOL measures. It consisted of two sub-phases: In of cancer survivor populations [13]. phase 1a we generated an exhaustive list of HRQOL is- For this reason, the EORTC Quality of Life Group sues, drawing upon two primary sources: the literature (QLG) has embarked on a project with the primary and cancer survivors. In phase 1b we asked a sample of van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 3 of 15 Fig. 1 Three-dimensional theoretical framework of health. In this framework health is assessed by multiple health indicators cancer survivors to rate the QLQ-C30 to determine at Health”[Major] OR “Physical Fitness/psychology”[Major] which time after treatment completion the acute symp- OR “Physical Fitness/physiology”[Major] OR “Health Sta- toms and side-effects related to cancer and its treatment tus”[Major] OR “late effects”)AND adults. Weincluded are no longer relevant. We considered the diminishing only original articles published in English that investigated prevalence of these symptoms an indicative of the need HRQOL in adult, disease-free cancer survivors. Articles to shift to the assessment of longer term survivorship is- reporting only scale scores without reference to specific sur- sues. In addition, the survivors participating in phase 1b vivorship issues were excluded. Two of the authors (MVL rated the list of HRQOL issues developed in phase 1a to and OH) screened references independently, and disagree- identify the issues relevant to disease free-survivors. In ments were resolved by consensus. this phase only quantitative data analyses were applied. The workflow of the study is also presented in Fig. 2. Study sample Literature search For phase 1a & b we recruited cancer survivors from hos- In October 2014, we performed a literature search in pitals from four geographic regions: the United Kingdom, PubMed and PsycINFO, the goal of which was to identify Northern Europe (Denmark, Germany, the Netherlands, the full range of HRQOL issues relevant to all adult disease- Norway, Sweden), Southern Europe (Cyprus, France, free cancer survivors, irrespective of their specific diagnosis. Greece, Israel, Italy, Spain), and Central Europe (Austria, We used the following search terms: (“Survivors”[Major] Poland). Inclusion of participants for phase 1b took place OR “Survivors/psychology”[Major]) AND (“neoplasms”[Ma- after completion of phase 1a. Eligible patients were those jor] OR “Carcinoma”[Major]) AND (“Quality of Life”[Mesh] aged 18 years or older at the time of diagnosis who had OR “patient-reported outcomes” OR “health-related quality sufficient command of their native language and did not of life” OR “wellbeing” OR “well-being” OR “Mental have severe psychological or cognitive problems. van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 4 of 15 Fig. 2 Work flow of phase I. TST time since completing last treatment To ensure that the survivorship questionnaire would approximately equal distribution of patients across diag- be generic in nature, we recruited survivors with a range noses and time since treatment (see below). of cancer diagnoses, selected on the basis of their preva- Basic sociodemographic data collected at study entry lence and/or survival rates. This included 11 diagnoses: included: age, sex, education, employment status, and breast, colorectal, prostate, bladder, gynecological (ovar- living arrangement. Clinical data collected included pri- ian, cervix and endometrial), head and neck, lung, and mary diagnosis, stage of disease, type of treatment, date testicular cancer, lymphoma, melanoma, and glioma. Eli- of diagnosis, date of start of primary treatment, date of gible patients had completed their treatment with cura- completing primary treatment, recurrences, date of com- tive intent (both primary treatment and treatment of pletion of treatment for last recurrence, and comorbidity recurrent disease) at least 6 months earlier and were using the Charlson Index [18]. disease-free (no evidence of disease). They could be re- ceiving maintenance therapies (e.g., hormonal treatment Phase 1a survivor interviews: issue generation for primary breast cancer). Although low-grade glioma We conducted semi-structured interviews with an initial patients are not treated with curative intent and are not sample of survivors in order to generate an exhaustive disease-free, they were included in the study because list of relevant HRQOL issues. The goal was to complete they have a median survival of between 4.7 and 9.8 years 10 interviews per diagnostic group, equally distributed [17]. We employed purposive sampling to ensure an over the four geographical regions [16]. First, the van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 5 of 15 respondents were asked open-ended questions about diagnostic groups * 3 time periods (6 months – 2 years / their survivorship experience. Subsequently, respondents 2–5 years / > 5 years since completing primary treatment) were shown the EORTC core questionnaire (QLQ-C30) [16]. The sample was also stratified according to geograph- and, if available, the relevant site-specific questionnaire ical region. The respondents were asked to complete the module [19–32]. These cancer site-specific modules provisional issue lists, using a 4-point response scale (not at assess the HRQOL issues most relevant to each of the all, alittlebit, quiteabit, or verymuch) to indicatethe specific patient populations. These modules range in extent to which they had experienced each issue. The length from 13 to 35 items. Instead of completing these provisional issue lists consisted of a generic survivor issue questionnaires, the respondents were asked to rate the list, and the sex- and cancer site-specific issues. In addition, relevance of the items on a 4-point scale (not at all, a they were also asked to complete the QLQ-C30 and, if little bit, quite a bit, or very relevant). The respondents available, the relevant site-specific module using the were also asked to identify survivorship issues that they same response scale. This was followed by a debrief- believed to be important that were not included in the ing interview about any relevant issues missing from QLQ-C30 and, where relevant, site-specific module. the provisional issue lists. Relevance ratings of the EORTC core questionnaire Definition of the minimal time since end of treatment for (QLQ-C30) assessing survivorship issues We evaluated the relevance ratings by composing scales To determine the minimum time since end of treatment that were in accordance with the QLQ-C30 scale structure: for which the survivorship questionnaire would be rele- 5 multi-item functioning scales (physical, role, emo- vant, we divided the Phase 1b sample into three time- tional, cognitive, and social functioning), three multi- since-completion-of-last-treatment (TST) groups: (1) 0.5 item symptom scales (fatigue, pain, nausea/vomiting), to 1 years; (2) 1 to 2 years; and (3) 2 years or more since and 6 single items (dyspnea, insomnia, appetite loss, treatment completion. For each TST group we investi- constipation, diarrhea, and financial difficulties). All gated which items of the QLQ-C30 were rated as rele- scores were linearly transformed to a 0 to 100-points vant for that specific group: an item was considered scale. A higher score on a scale means that the survi- relevant if at least 30% of the respondents in a group vors considered the items of this particular scale more endorsed an item (i.e., had experienced the issue at least relevant. We compared the following survivor groups: “a little bit”). We were particularly interested in compar- 0.5 to 2 years since diagnosis, 2 to 5 years since diag- ing responses to the QLQ-C30 items between the three nosis, and 5 years or more since diagnosis. TST groups, as the QLQ-C30 contains a number of acute symptom and side-effect items. Our objective here Issue extraction from literature and interviews was to determine at what point in time these relatively Phase 1a interviews were transcribed and translated in acute issues were no longer relevant for the majority of English by the interviewers. We employed thematic ana- respondents, and thus it would be appropriate to begin lysis [33]using NVivo 10 [34], a software program for using survivorship measures. qualitative data analyses, to extract a list of relevant sur- vivorship issues from the articles included in the literature review and from the transcribed semi-structured phase 1a interviews. Literature and interviews were analyzed simul- Criteria for issue selection in phase 1b taneously using the coding system that evolved during the In this phase, the provisional issue list was reviewed to thematic analyses. Items of the existing questionnaires generate one comprehensive list of generic issues that and the issues described in the qualitative studies were was relevant to all groups of cancer survivors, regardless coded in issues that were organized into hierarchical trees. of specific diagnosis. In addition, site-specific issue lists Cancer site or sex-specific issues were extracted in separ- and sex-specific issues were generated. As indicated ate coding trees, and kept separately to avoid survivors in above, we coded an issue as being endorsed by a re- phase 1b having to rate too many issues. All issues were spondent if it was scored “a little bit” or higher. An issue consolidated into a provisional list which included generic, needed to be endorsed by at least 30% of the survivors site-specific, and sex-specific issues to be completed by a in any given diagnostic group to be regarded as an issue second group of survivors in phase 1b. relevant to that group. If an issue was endorsed by survi- vors from 6 or more diagnostic groups, it was then con- Phase 1b survivor interviews: defining minimal time since sidered to be a generic survivorship issue; otherwise it treatment completion and issue selection was deemed to be a cancer-site specific issue. This In the second round of interviews, our goal was to recruit resulted in 12 consolidated survivorship issue lists: one 330 survivors: 10 interviews per survivor group * 11 generic list and 11 cancer-site specific lists. van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 6 of 15 Sub-analyses in the younger age groups Previous research has shown that younger adult survi- vors can be particularly impacted by the cancer experi- ence [35–41]. For this reason, we performed post-hoc, age-related subgroup analyses to identify issues that are particularly relevant to survivors younger than 50 years. We divided the total sample into five age groups (< 40; 40–50; 50–60; 60–70; 70+ years). Issues endorsed as relevant by at least 30% of respondents under the age of 50 years that would otherwise have been excluded on the basis of ratings by respondents above the age of 50 (i.e. low endorsement in the older sample causing the endorsement in the total sample to be below 30%) were retained in the generic list as being particularly relevant for younger cancer survivors. Our expectation was that we would retain issues likely to be specifically relevant to younger cancer survivors such as problems in obtain- ing a mortgage or family planning. Results Literature review The literature search identified 1494 publications, of which 134 were retained for issue extraction (for details see Fig. 3). The list of 134 articles included in the review can be found in Additional file 1. Research articles included in the review were most commonly qualitative studies, studies developing cancer survivor specific mea- sures, or studies reporting the use of a self-constructed study-specific measure. Fig. 3 Prisma flow chart of the literature review Semi-structured interviews phase 1a: issue generation For phase 1a, 117 survivors were interviewed between around physical exams” were combined into “fear of recur- August 2014 and May 2015 in nine different European rence”. Issues reflecting states like “being retired” were not countries (Table 1). The average age of the survivors was included, as they cannot be assessed on a 4-point scale, and 57 years (SD = 13.6 years), and 54% had received their would not be informative for an assessment of HRQOL. cancer diagnosis between 2 and 5 years ago. Issues stating a change in physical symptoms were not included. General issues like “emotional problems” were Issue extraction from literature and interviews notincludedaswebelievedthattheywerebettercaptured In the first step, we identified 1555 issues from the 117 by more informative issues, for example, “being worried”, interviews and the first 75% of the research articles. These “fear of dying”, “anxiousness”, “feeling stressed”, “feeling issues were classified into 11 themes: mental health, phys- depressed”. This resulted in 197 generic, 62 cancer site-spe- ical symptoms, cognitive changes, role functioning (includ- cific (e.g. pain during urination), and 8 sex-specific (e.g. ing work), meaning of cancer, health behaviors, spirituality, feeling less feminine) issues. social functioning (including feelings of belonging), finan- cial issues, body image, and sexuality. In the next step we Relevance ratings of the EORTC core questionnaire reduced this list to 718 issues by combining issues that (QLQ-C30) were very similarorformedacontinuous scale(e.g. “de- The relevance ratings are presented in Fig. 4. The figure pression” and “feeling depressed” were combined into “feel- shows that the functioning scales were still considered ing depressed”). The remaining 25% of studies was coded relevant by the survivors, with the perceived relevance using this 718 issues coding system. We did not identify increasing with longer time since diagnosis. A number new issues in these studies. In the last step, the total of the symptom items and scales were considered less number of issues was further reduced. Issues that were very relevant, especially when more time had passed since specific were combined. For example, “fear of recurrence diagnosis. Two years after diagnosis, nausea/ vomiting, when having physical symptoms” and “fear of recurrence appetite loss, constipation, and diarrhoea were seldom van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 7 of 15 Table 1 Number of cancer survivors per cancer site and per We started our analyses by defining the post-treatment region included in phase 1a and 1b survivorship period in the complete phase 1b sample by Phase 1a Phase 1b comparing the three subgroups (0.5–1year, 1to 2years, and 2 years or more post-treatment). The following QLQ- Cancer site C30 items were rated as being relevant in the 0.5–1year Bladder 7 32 post-treatment survivors subgroup, but no longer so in Breast 17 53 the other two TST subgroups: needing to stay in bed or a Colorectal 12 46 chair during the day, pain interfering with daily activities, Glioma 10 36 physical condition or treatment interfering with family life Gynecological 12 49 and social activities, and physical condition or treatment causing financial difficulties. Scores on the functional and Head & neck 10 44 symptom scales of the QLQ-C30 showed an increase in Lung 8 41 physical, role emotional and social functioning one year Lymphoma 9 38 after completion of treatment, and a decrease in fatigue Melanoma 11 38 (Fig. 5). After this first year these scores tended to Prostate 11 44 stabilize. Based on these findings we decided to Testicular 10 37 employ the one year post-treatment mark as the threshold for recommending transitioning to the use Total 117 458 of survivorship measures. Region Additionally, the analyses of the QLQ-C30 data Northern Europe 30 147 showed that the following items were of low relevance Southern Europe 46 126 to all of the TST survivor subgroups: “Do you have any English speaking 13 98 trouble taking a short walk outside of the house?”, “Do Central Europe 28 87 you need help with eating, dressing, washing yourself or using the toilet?”, and those items assessing appetite, Time since diagnosis nausea, vomiting, and gastrointestinal symptoms. 0.5 to 2 years 21 111 For the subsequent selection of issues to be included 2 to 5 years 63 189 in the survivorship questionnaire, only the 386 respon- more than 5 years 33 158 dents who were at least 1 year post-treatment were Time since completing last treatment included. Table 3 displays the 116 issues that were re- 0.5 to 1 year – 72 ported as being relevant by respondents in at least 6 of the diagnostic groups. Thirty-four percent of these con- 1 to 2 years – 105 sisted of issues covering physical functioning (e.g. pain, 2 to 5 years – 172 neuropathy, muscle cramp), 32% were mental function- more than 5 years – 109 ing issues (e.g. body image, anxiety, positive affect), 19% For phase 1b only, also the number of survivors per time since completion of issues were related to social and role functioning (e.g. last treatment category is reported For phase 1a only information was available regarding date of diagnosis and sexual problems, feelings of belonging) and 16% involved date of recurrence general health perceptions (e.g. negative health outlook and health behavior). Of the 116 issues, 106 were not rated as being relevant. The ratings showed that particu- included in the QLQ-C30. Table 3 shows which issues larly insomnia was considered highly relevant by the are overlapping with the QLQ-C30, which were identi- survivors less than 2 years after diagnosis and fatigue by fied from the literature, and which from the interviews. the survivors who were less than 5 years since diagnosis. In addition to generic issues, we also identified sur- vivorship issues that were cancer site-specific. On average, 26 (range 7–48) issues were considered as Phase 1b interviews: defining minimal time since cancer-site specific per diagnostic group. We intend to treatment completion and issue selection use these issues for the future development of cancer Between November 2015 and August 2016, we inter- site-specific survivorship modules. Among these can- viewed 458 survivors from 23 centers in 14 countries for cer site-specific survivorship issues, we observed the phase 1b (Table 1). The mean age of the sample was following trends: body image issues were frequently 59 years, and 46% was female. Sixty percent had been endorsed by bladder, breast, colorectal, and head & diagnosed with stage I or II cancer, and 16% had experi- neck cancer survivors. Cognitive functioning problems enced disease recurrence in the past. The average time were rated as highly relevant by glioma, lymphoma, since last treatment was 3.6 years (Table 2). lung, bladder, breast, and head and & neck cancer van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 8 of 15 Fig. 4 Relevance ratings of the functional and symptom scales of the QLQ-C30 per time since diagnosis group. The y-axis shows the relevance ratings of the QLQ-C30. A higher score on a scale means that the survivors considered the items of a particular scale more relevant survivors. Lung cancer and glioma survivors reported Discussion having a negative health outlook as highly relevant. In this first phase of our cancer survivorship questionnaire Bladder and head & neck cancer survivors frequently development project, we identified 116 generic survivor- endorsed role functioning issues. Lung, lymphoma, ship issues. Additionally, on average, we identified 26 and colorectal cancer survivors more often endorsed site-specific survivorship issues per tumor site, which only work-related issues than the other survivor groups. partially overlapped with the existing EORTC site-specific Glioma and lymphoma survivors more frequently modules. We also observed that, approximately one year rated issues related to a negative impact on feelings of following completion of cancer treatment, most of the belonging as relevant. acute disease- and treatment-related symptoms have Based on the 94 survivors below the age of 50 years, resolved themselves in the large majority of survivors. we identified 10 issues that were relevant for younger Based on these findings, we will move forward with survivors and for which relevance declined with age (see the development of a core survivorship questionnaire for Table 3). Three issues were related to body image; the disease-free adult survivors who are at least one year others were related to the ability to have children, being post-treatment. This questionnaire will retain many of treated differently by people because of having had can- the original items and scales from the QLQ-C30, delet- cer, difficulties talking about cancer, negative personality ing only those items that assess acute symptoms (nau- change, needing psychological support, loss of future life sea/vomiting, appetite loss, constipation, and diarrhea). plans, and financial problems. Additional survivorship issues will be added to expand van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 9 of 15 Table 2 Basic demographics, disease and treatment characteristics Table 2 Basic demographics, disease and treatment characteristics of the survivors included in phase 1b of the survivors included in phase 1b (Continued) Survivors Phase 1a Phase 1b Survivors Phase 1a Phase 1b N = 117 Total Subsample N = 117 Total Subsample a a N = 458 N = 386 N = 458 N = 386 Age current maintenance 861 47 therapy Mean ± SD (years) 57 (13.6) 59 (13.8) 59 (13.7) Percentages are given in the cases that categories are mutually exclusive Sex (%) N number, SD Standard deviation subsample of phase 1b that consists of the survivors who are at least 1 year male 58 (50%) 246 (54%) 207 (54%) after treatment completion b b Partner status categories are not mutual exclusive, e.g. one can be a widower and have a new relationship in relationship 90 367 313 c for glioma survivors in Phase 1b tumor grading was used, we included per tumor grade: grade 1: 2 survivors; grade 2: 8 survivors; grade 3: 14 survivors; widower/ divorced/ 961 49 grade 4: 1 survivor separated single 14 50 43 Education (%) the scope of issues addressed by the questionnaire. To improve the measurement precision of some of the none or primary 15 (13%) 59 (13%) 47 (12%) school only existing scales of the QLQ-C30, we will collaborate with the EORTC CAT team [42] to select the issues of the high school 46 (39%) 167 (36%) 140 (36%) generic issue list and the items of the EORTC QLG item college or university 53 (45%) 222 (48%) 190 (49%) library assessing these issues. This survivorship ques- missing 3 (3%) 10 (2%) 9 (2%) tionnaire can be complemented by cancer-site specific Work status (%) survivorship modules based on and adapted from the working 59 (50%) 205 (45%) 180 (47%) existing EORTC cancer site-specific modules. retired 43 (37%) 185 (40%) 157 (41%) The period after treatment completion is often de- scribed by survivors as more difficult than the treatment unemployed 4 (3%) 24 (5%) 17 (4%) itself [43]. The end of the phase of transition from being a homemaker 4 (3%) 22 (5%) 17 (4%) patient to resuming normal life [44] can be very positive, disabled 5 (4%) 10 (2%) 7 (2%) but also brings with it feelings of uncertainty about the other or missing 2 (2%) 12 (2%) 10 (3%) future and fear of cancer recurrence. During this early Disease recurrence (%) 11 (9%) 75 (16%) 66 (17%) survivorship period, patients often begin to process the Tumor stage (%) emotions related to the diagnosis, to find meaning in their experience of having had cancer, and to deal with the stage I 19 (16%) 101 (23%) 88 (24%) lingering effects of treatment. The end of this turbulent stage II 45 (38%) 131 (30%) 108 (28%) immediate post-treatment period appears to represent an stage III 29 (25%) 113 (25%) 95 (25%) appropriate starting point for assessing survivorship is- stage IV 3 (3%) 40 (9%) 34 (9%) sues, as both physical and psychosocial health begin to stage unknown 13 (11%) 47 (11%) 40 (10%) stabilize. This was corroborated by the increase in phys- no stage determined 8 (7%) ical, role, and social functioning and the decline in fatigue observed in our study sample after the first post-treatment Time since completing primary treatment year. We did not observe a further decline in the acute Mean (SD) (years) – 4.2 (4.0) 4.8 (4.0) symptoms of cancer treatment, as the prevalence of acute Time since completing last treatment symptoms was already low a half year after treatment Mean (SD) (years) – 3.6 (3.2) 4.4 (3.2) completion. The chronic side effects of treatment Therapy (pain, dyspnea, insomnia, and fatigue) continued to be surgery 98 342 326 relevant for all survivor groups into the longer post- treatment phase. chemotherapy 77 254 222 In accordance with the existing cancer survivorship radiotherapy 54 238 209 questionnaires [4–12] our results indicate that feelings of hormonal therapy 15 49 48 uncertainty about the future, fears related to recurrence of monoclonal antibodies 2 21 18 cancer, fears and worries concerning family members, cell transplantation 6 6 feelings of depression and anger, feelings that others do active surveillance 7 66 59 not understand the impact of cancer, positive impact on social relationships, positive changes in (perception of) van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 10 of 15 Fig. 5 Functional and symptom scales of the QLQ-C30 per time since last treatment category. The y-axis shows the scores on QLQ-C30. On the functional scales a higher score represents a better level of functioning and on the symptom scales a higher score represents a higher level of symptoms life, negative body image, cognitive problems, fatigue, the existing survivorship questionnaires may reflect both sleeping problems, pain, sexual problems, and dealing culture (including differences between the American and with the chronic physical consequences of cancer are all European health care systems) and the fact that we in- relevant issues for cancer survivors. However, our results cluded a wider range of diagnostic groups in our study, also indicate that other issues often included in survivor- and placed relatively less emphasis on breast cancer and ship questionnaires may be less relevant when rated by a non-solid cancer survivors, as has typified the develop- wider range of cancer survivors in an international mental phase of other survivorship questionnaires. context. This includes issues related to feelings of guilt, Another important finding from our study is that there fears related to starting new (romantic) relationships, and is not only a fairly large number of condition-specific feelings of pride about having survived cancer. Also, physical health issues in cancer survivorship, but also compared to existing questionnaires, our findings under- differences in the extent to which various psychosocial score the relevance of assessing issues related to chronic issues are perceived as relevant by specific cancer diag- side effects of treatment such as neuropathy and joint pain nostic groups. These differences in perceived relevance [4–12]. Over 30% of the issues were related to physical of survivorship issues may reflect differences in sur- functioning, including chronic physical effects of cancer vival rates between the cancer types, the average age at and its treatment, like Raynaud symptoms, neuropathy, diagnosis, thenatureofthe chronicsideeffects of the joint pain, and muscle cramps. These issues receive rela- various treatments, and whether a cancer diagnosis is tively little attention in the existing cancer survivorship sex-specific. For example, glioma and lung cancer sur- questionnaires. The differences between our findings and vivors reported issues related to the negative impact of van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 11 of 15 Table 3 Consolidated issue list with generic survivorship issues Body Image b, c � feeling unattractive � feeling old b, c � feeling satisfied with your physical appearance b, c � feeling you could not trust your body Cognitive functioning a,b, c � difficulties with concentration b, c � forgetfulness a,b, c � memory problems b, c � problems with multi-tasking b, c � difficulty gathering your thoughts (together) b, c � ability to think (to process information) has slowed down Health behaviors b, c � being alert for symptoms that may signal a return of my cancer � going quickly to my GP due to having (had) cancer b, c � drinking less alcohol due to having (had) cancer b, c � listening to my body due to having (had) cancer b, c � eating healthily due to having (had) cancer b, c � avoiding the sun or protecting my skin due to having (had) cancer b, c � exercising (more) due to having (had) cancer b, c � avoiding stress in my life due to having (had) cancer b, c � cutting down smoking due to having (had) cancer (not applicable option) b, c � taking better care of yourself due to having (had) cancer Meaning of cancer b, c � other issues not related to cancer bother me more than having had cancer b, c � cancer is a learning experience b, c � having (had) cancer has made me accept my own mortality a, b, c � overall quality of life b, c � being (more) emotional due to having (had) cancer � seeking a deeper meaning in having (had) cancer Negative outlook b, c � concerned with long term effects of cancer treatment b, c � feeling that my life has been suspended because of having (had) cancer b, c � difficulties adapting my life to the physical consequences of having had cancer b, c � still feeling like a cancer patient b, c � experiencing uncertainty about the future Positive outlook b, c � appreciating life (more) due to having (had) cancer b, c � being psychologically strong(er) due to having (had) cancer b, c � my personality has changed for the better due to having (had) cancer � having (had) cancer has given me a purpose in life b, c � because of having (had) cancer I have reconsidered my priorities in life b, c � standing up for myself (more) due to having (had) cancer b, c � having (had) cancer has given me a reason to make changes in my life b, c � willing to help others (more) due to having (had) cancer b, c � due to having (had) cancer, being (more) understanding of what other people feel Mental health Depression/behavioral-emotional control Health distress a, b, c b, c � feeling depressed � fear of recurrence or spread cancer b, c b, c � feeling angry or frustrated � worried about health b, c b, c � feeling stressed � fear of dying b, c b, c � mood swings � fear of new cancer b, c b, c � needing psychological support � fear family members will develop cancer a, b, c � feeling irritable b, c � feeling upset about having (had) cancer Anxiety a, b, c � being worried b, c � feeling anxious Physical symptoms b, c � altered hair structure van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 12 of 15 Table 3 Consolidated issue list with generic survivorship issues (Continued) b, c � weight gain � feeling ill or unwell � acid reflux a, b, c � overall health Fatigue Sleep problems b, c b, c � feeling constantly tired � problems falling asleep c b, c � needing more sleep to function � waking up frequently at night b, c a,b, c � feeling exhausted � trouble sleeping a, b, c b � feeling tired � waking up too early � needing time to recover from normal activities a, b, c � feeling weak � needing to take naps b, c � sudden attacks of tiredness Physical functioning/ mobility Leg problems b b, c � difficulty carrying something in both hands while climbing stairs � difficulty standing for a long time a,b, c c � difficulty taking a long walk � restless legs b, c b, c � difficulty running fast � swollen feet or legs b, c � difficulty carrying something weighing 5 kg b, c � difficulty hiking for 3 km b, c � difficulty walking up a flight of stairs � difficulty doing strenuous activities like carrying a heavy shopping bag or a a, b suitcase Pain Skin Problems b, c b, c � headaches � dry and or scaly skin c b, c � joint pain � thin skin b, c � muscle pain Raynaud Neuropathy c b, c � hands and/or feet sensitive to hot and cold � tingling in hands and/or feet b, c � cold or pale fingers or toes Muscle problems Temperature b, c b, c � muscle cramps � night sweats S b, c � muscle weakness � hot flushes b, c � feeling cold Role functioning a,b, c � limited in recreational activities Work b, c � difficulties returning to work since having (had) cancer b, c � having (had) cancer decreased work performance b, c � career interrupted due to cancer Feelings of belonging Positive impact Negative impact b, c � family relationships are close(r) due to having (had) cancer � feeling that others do not understand the impact of having (had) b, c � having (had) cancer has a positive impact on the relationship with my cancer b, c b, c partner � not wanting to burden family members b, c b, c � feeling close(r) to friends since having (had) cancer � worried about the impact of my cancer on my children b, c � friends and family are (more) important since having (had) cancer Sexual problems � feeling guilty for not fulfilling sexual needs of partner Sex-specific sexual problems Sexual frequency b, c b, c � vaginal dryness � low interest in sex b, c b, c � problems getting or maintaining erection � sexually active with or without intercourse � avoiding sex Sexual pleasure � difficulty becoming sexually aroused � feeling uneasy with sex � problems enjoying sex � problems having an orgasm van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 13 of 15 Table 3 Consolidated issue list with generic survivorship issues (Continued) b, c � problems with sexual intimacy Sub-analyses: issues relevant to younger cancer survivors b, c � upset with appearance of scar b, c � feeling angry towards body b, c � feeling embarrassed about body b, c � concerned about the ability to have children b, c � having problems with people treating me differently because I have (had) cancer b, c � difficulties talking about cancer b, c � my personality has changed for the worse due to having (had) cancer � having (had) cancer has made me lose my future life plans or goals b, c � financial problems caused by problems with getting a loan, mortgage, or insurance Issues in this list were endorsed by 30% of the survivors in at least 6 of the included cancer sites issues which are also included in the QLQ-C30 issues identified in the literature issues identified in the survivor interviews cancer on their lives and issues related to struggles with strategy with site-specific survivor modules ensures that family and friends as being very relevant; lung, lymphoma, relevant chronic physical symptoms are included. Fur- and colorectal cancer survivors more frequently rated thermore, the retention of the items and scales of the work-related issues; and bladder and head & neck cancer QLQ-C30 that are still relevant for disease-free survi- survivors more frequently endorsed role functioning vors will ensure continuity in the evaluation of HRQOL issues. Most of these site-specific survivorship issues over time, from diagnosis through the long-term sur- are currently not included in the existing site-specific vivorship phase. modules of the EORTC. A possible limitation of our work is that those cancer The literature consistently shows that younger cancer survivors in our sample who were more than 5 years survivors report a higher impact of their cancer experi- post-treatment were drawn primarily from hospital ence on HRQOL [45, 46], including higher levels of dis- registries. Many patients who are 5 years or longer post- tress, than older cancer survivors. This is likely related to treatment may no longer be in active follow-up, and the fact that relatively younger survivors are confronted those who are may be those with more serious, chronic with a life-threatening illness at a time when many are in health problems. This could cause some degree of over- the midst of forming relationship bonds, starting and rais- estimation of the relevance of various survivorship issues ing families, and trying to establish a workable balance be- in this subgroup of longer term survivors. Also, our tween career and family life. During this period of young sample was somewhat younger than one might expect adulthood, a serious illness such as cancer is less expected, based on the median age of the general population at and may therefore be more disruptive. Also, younger can- cancer diagnosis (66 years) [47]. cer patients and survivors may perceive themselves as hav- ing more to lose in terms of future perspective, and may Conclusions have fewer opportunities for peer support (i.e., having con- We identified 116 generic survivorship issues, and on temporaries with whom they can share their common ex- average, 26 site-specific survivorship issues per tumor perience of having had cancer). Conversely older survivors site. Compared to existing cancer survivorship question- have more life experience, which might lead to better cop- naires, our findings underscore the relevance of asses- ing strategies, and they may face fewer work-related and sing issues related to chronic physical side effects of social demands. This is supported by the findings from treatment such as neuropathy and joint pain in addition our study that younger survivors are more likely than to the psychosocial aspects of survivorship. older survivors to rate issues related to having children, fi- In the next phase of this project, we will further develop nancial difficulties, loss of future life plans, and lack of and test the core survivorship questionnaire, and we will support as being relevant to them. Although some of these also develop survivorship modules for breast, prostate, issues appear to be more relevant to younger survivors, in and colorectal cancer survivors. The choice of these three the interest of parsimony (i.e., not having to create two disease sites was based on the incidence, survival rates, versions of a core survivorship questionnaire), we have and the number of survivorship studies conducted in decided to include them in our consolidated issue list. these disease sites. In the longer term, we intend to A strength of our study is that we included a relatively develop survivorship modules for a much broader set of large number of survivors from 11 cancer diagnosis cancer sites. Ultimately, this will yield a comprehensive groups from a total of 14 European countries. This en- suite of survivorship questionnaires that will yield both a hances the generalizability of our findings. Also, our common data set for comparison of results across tumor van Leeuwen et al. Health and Quality of Life Outcomes (2018) 16:114 Page 14 of 15 sites, and unique information about the survivorship Neurology, Leiden University Medical Center, Leiden, The Netherlands. Department of Neurology, Haaglanden Medical Center, The Hague, the experience of specific groups of cancer survivors. Netherlands. Division of Epidemiology and Health Services Research at Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), Mainz, Germany. Department of Otolaryngology Head and Neck Surgery, Additional file Sahlgrenska University Hospital, Göteborg, Sweden. Department of Psychiatry and Psychotheraphy, Division of Psychooncology, Innsbruck Additional file 1: The list of 134 articles included in the review. Medical University, Innsbruck, Austria. University Surgical Unit, University (PDF 118 kb) Hospitals Southampton, Southampton, UK. Department of Nutrition & Dietetics, School of Health Sciences and Education, Harokopio University, Athens, Greece. Unit of Survivorship Research, Danish Cancer Society Abbreviations Research Center, Copenhagen, Denmark. Oncology Institute, Chaim Sheba CPILS: Cancer Problems in Living Scale; EORTC: European Organisation for Medical Center, Tel-Hashomer, Israel. Department of Psychosomatic Research and Treatment of Cancer; FACT-G: Functional Assessment of Cancer Medicine Center for Internal Medicine and Dermatology, Charité - Therapy – General; HRQOL: Health-related quality of life; IOC/IOCv2: Impact Universitätsmedizin Berlin, Berlin, Germany. East Kent Gynaecological of Cancer; MOS: Medical Outcomes study; N: Number; PROMs: Patient- Oncology Centre, Margate, UK. Neuroncology Unit, National Cancer reported outcome measures; QLACS: Quality of Life in Adult Cancer Institute Regina Elena, Rome, Italy. Rehabilitation Unit, Department of Survivors; QLG: Quality of Life Group; QLQ: Quality of life questionnaire; QLQ- Supportive Care, Istituto Nazionale Tumori – IRCCS- Fondazione G. Pascale, C30: EORTC core questionnaire; QOL: Quality of life; QoL-CS: Quality of Life Naples, Italy. Evangelische Kliniken Gelsenkirchen, Gelsenkirchen, Germany. Cancer Survivors; SD: Standard deviation; SLDC-C: Satisfaction with Life Department of Gastroenterology and Hepatology, Hampshire Hospitals Domains Scale for Cancer; TST: Time-since-completion-of-last-treatment; NHS Foundation Trust, Basingstoke, UK. Department of Neurology and WHO: World Health Organization Brain Tumor Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. Unit of Psychoncology - Breast Unit, Istituto Oncologico Funding Veneto (IOV)-IRCCS, Padua, Italy. Health Outcomes Research Unit, This study was funded by the a grant from the European Organisation for Department of Geriatrics, Gerontology, and Social Work, Faculty of Education, Research and Treatment of Cancer Quality of Life Group (003/2014). Ignatianum Academy, Krakow, Poland. Department of Radiation Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus. Department of Availability of data and materials Otolaryngology / Head & Neck Surgery, VU University Medical Center, The data that support the findings of this study are available from the Amsterdam, The Netherlands. Department of Gynecology and Obstetrics, Division of Psychosocial Research and Epidemiology of the Netherlands Sorlandet Hospital Kristiansand, Kristiansand, Norway. Lynda Jackson Cancer Institute (contact person: L.V. van de Poll-Franse), but restrictions Macmillan Centre, East & North Hertfordshire NHS Trust including Mount apply to the availability of these data due to an agreement between the Vernon Cancer Centre, Northwood, UK. Comprehensive Cancer Centre Netherlands Cancer Institute and the European Organisation for Research South (CCCS), Eindhoven Cancer Registry, Eindhoven, The Netherlands. and Treatment of Cancer Quality of Life Group, and so they are not publicly Tilburg University, Tilburg, The Netherlands. available. Data are available pending approval of both the Netherlands Cancer Institute and the EORTC. Received: 20 December 2017 Accepted: 30 April 2018 Authors’ contributions Study conception and design: ML, OH, JA, AC, ASD, LD, BH, CJ, OM, JR, JCR, KT, IVL, TY, NA, LPF. Acquisition of data: ML, OH, PA, JA, OC, AC, ASD, LD, ME, References EH, BH, CJ, MK, TK, OM, SN, AN, AP, MP, KP, JR, JCR, SS, KT, VV, IVL, SV, TY. 1. Ayanian JZ, Jacobsen PB. Enhancing research on cancer survivors. J Clin Analysis and interpretation of data: ML, OH, NA, LPF. Drafting of manuscript: Oncol Off J Am Soc Clin Oncol. 2006;24:5149–53. ML, NA, LPF. Critical revision: ML, OH, JA, ASD, LD, ME, TK, SN, AN, AP, MP, JR, 2. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, JCR, KT, IVL, SV, TY, NA, LPF. All authors read and approved the final Filiberti A, Flechtner H, Fleishman SB, De Haes JC. The European manuscript. 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Health and Quality of Life OutcomesSpringer Journals

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