Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 https://doi.org/10.1186/s41687-019-0161-y Journal of Patient- Reported Outcomes RESEARCH Open Access BOMET-QoL-10 questionnaire for breast cancer patients with bone metastasis: the prospective MABOMET GEICAM study A. Barnadas1,2* , M. Muñoz3, M. Margelí4, J. I. Chacón5, J. Cassinello6, S. Antolin7, E. Adrover8, M. Ramos9, E. Carrasco10, M. A. Jimeno10, B. Ojeda1, X. González11, S. González12, M. Constenla13, J. Florián14, A. Miguel15, A. Llombart16, A. Lluch2,17, M. Ruiz-Borrego18, R. Colomer19, S. Del Barco20 and On behalf of GEICAM, Spanish Breast Cancer Group Abstract Background: Bone metastasis (BM) is the most common site of disease in metastatic breast cancer (MBC) patients. BM impacts health-related quality of life (HRQoL). We tested prospectively the psychometric properties of the Bone Metastasis Quality of Life (BOMET-QoL-10) measure on MBC patients with BM. Methods: Patients completed the BOMET-QoL-10 questionnaire, the Visual Analogue Scale (VAS) for pain, and a self-perceived health status item at baseline and at follow-up visits. We performed psychometric tests and calculated the effect size of specific BM treatment on patients´ HRQoL. Results: Almost 70% of the 172 patients reported symptoms, 23.3% experienced irruptive pain, and over half were receiving chemotherapy. BOMET-QoL-10 proved to be a quick assessment tool performing well in readability and completion time (about 10 min) with 0–1.2% of missing/invalid data. Although BOMET-QoL-10 scores remained fairly stable during study visits, differences were observed for patient subgroups (e.g., with or without skeletal- related events or adverse effects). Scores were significantly correlated with physician-reported patient status, patient-reported pain, symptoms, and perceived health status. BOMET-QoL-10 scores also varied prospectively according to changes in pain intensity. Conclusions: BOMET-QoL-10 performed well as a brief, easy-to-administer, useful, and sensitive HRQoL measure for potential use for clinical practice with MBC patients. Trial registration: NCT03847220. Retrospectively registered on clinicaltrials.gov (February the 20th 2019). Keywords: Metastatic breast cancer, Bone metastasis, Quality of life, Psychometric, Treatment, Assessments Introduction therapeutic agents to cancer treatment and a better dis- Breast cancer represents 25% of all cancer cases worldwide ease management, the median survival has increased in [1]. Between 6% and 10% of them will present as meta- patients with advanced disease over the years. Patients live static breast cancer (MBC) at diagnosis [2]. Between 30% longer and health-related quality of life (HRQoL) becomes and 40% of those receiving adjuvant or neoadjuvant a great outcome of interest in MBC-related research [3, 4]. chemotherapy for early-stage disease will eventually de- Bone metastasis (BM), the most common site of dis- velop MBC [3, 4]. Thanks to the incorporation of new ease in MBC patients [5], greatly impacts HRQoL due to its high morbidity [6–9]. In addition, treatment-related * Correspondence: ABarnadasM@santpau.cat toxicities are generally under-reported by physicians 1 Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, C/Sant when compared to patients´ reports [10]. Surprisingly, Antoni Maria Claret, 167, 08041 Barcelona, Spain how and to what extent MBC symptoms, MBC-related 2 Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain treatments, or palliative care may affect patients´ Full list of author information is available at the end of the article HRQoL remains understudied [11–14]. © The Author(s). 2019 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. Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 2 of 10 Better understanding of the disease’s overall impact on MBC patients with BM have disease-specific complica- HRQoL requires questionnaires designed to assess pa- tions with particular impacts on HRQoL. Thus, the main tients’ perception of their pain and other potentially life- objective of the present study was to evaluate the aplic- limiting symptoms. The questionnaire designed by the ability of BOMET-QoL-10 in this patient population, re- European Organization for Research and Treatment of gardless of treatment received. Secondary objectives Cancer (EORTC), QLQ-C30, and the functional assess- included: 1) Evaluating the differences on BOMET-QoL- ment of cancer therapy (FACT-G) assess general cancer- 10 scoring when patients have skeletal-related events related HRQoL issues. The corresponding breast cancer (SREs) and BM symptoms; 2) Exploring the association modules focus on image and sexual life issues, lymph- between BOMET-QoL-10 scores and other measures of edema of the arm, and surgery incision pain, i.e., chal- self-perceived health status and pain such as ECOG PS lenges found in both metastatic and non-metastatic and Visual Analog Scale (VAS); and 3) Assessing patients. However, 50–70% of patients with BM present whether the magnitude of the effect of BM treatment on with bone pain and related threats to HRQoL [15]. The patients´ HRQoL reaches clinical significance. Quality of Life Questionnaire-Bone Metastasis-22 (QLQ- BM22), a 22-item submodule of QLQ-C30 [15], and Materials and methods Bone Metastasis Quality of Life (BOMET-QoL), a 25- This was a prospective, observational, multicenter study item questionnaire [16], were designed to fill this gap by of MBC patients who received systemic therapy accord- targeting cancer patients with BM. ing to local guidelines. MBC patients were eligible for in- BOMET-QoL was later reduced to 10 items (BOMET- clusion with age above 18 and diagnosed with BM, QoL-10) and validated using a similar population of pa- ability to understand and complete the questionnaires, tients with BM. In that validation study, factorial ana- estimated life expectancy of at least 8 months, and ab- lyses identified a single dimension which accounted for sence of co-morbidities. 45.8% of explained variance. The disease’s impact on Study visits were pre-specifed in the protocol as a first HRQoL did not vary significantly across clinical variables baseline visit and 6 follow up visits at 4, 8, 12, 16, 20 and such as number and location of bone metastases and 24 months after baseline visit. time since diagnosis. However, it did vary significantly Figure 1 shows the study timeline. The following data by presence, number, and duration of irruptive pain cri- were collected: 1) Basic socio-demographic data: age at ses, pain management index (PMI), and Eastern Co- study entry and family support; 2) Clinical data: date of operative Oncology Group Performance Status (ECOG diagnosis, stage of disease at diagnosis, site(s) and date PS) [17]. Reported impact on HRQoL was lower with of diagnosis of BM and visceral metastases at baseline; fewer irruptive pain crises when pain control was satis- SREs, MBC-related symptoms, type of irruptive pain cri- factory (PMI = 0) or when ECOG PS score was between ses if any, treatments for breast cancer and for BM, 0 and 1 [18]. chronic osteoarticular comorbidities and their treatment, In most cases, BOMET-QoL-10 questionnaire scores other chronic diseases, and ECOG PS score were col- correlated statistically significantly, and at least moder- lected by the physician at baseline and throughout the ately, with EORTC QLQ-30 and BOMET-QoL dimen- study; 3) Safety measures: clinically-relevant adverse sions, confirming convergent validity. Also, BOMET- events (AE) and their grades and blood tests (especially QoL-10 scores experienced a statistically significant in- creatinine, calcium, and albumin) were collected during crease (i.e., improved HRQoL) throughout the study each follow-up visit. [18]. The effect size between the baseline visit and the 6- To assess HRQoL and perceived health data partici- month follow-up was 0.841. BOMET-QoL-10 showed pants completed the BOMET-QoL-10 questionnaire the capacity to detect changes in perceived health status (Additional file 1) and the VAS for pain at study visits in (between 3 and 6 months), pain perception, and ECOG the hospital. The questionnaire was administered to the PS score throughout the study. This indicates that patients on paper by trained study site personnel. In the BOMET-QoL-10 is able to detect changes in relevant BOMET-QoL-10 patients were asked to respond to conditions. The instrument also exhibits good internal questions based on a 5-point Likert scale ranging from consistency (Cronbach’s α =0.93) and good test-retest “never” (4) to “always” (0). The VAS for pain was a con- reliability (Intraclass Correlation Coefficient = 0.94). The tinuous 10 cm line where the patients have to mark the result is a useful 10-item measure of HRQoL easy-to-use pain they were experiencing at that moment (left side of in both clinical trial interventions and in regular clinical the line was no pain and the other end was unbearable practice [18]. Previously, Adrover and colleagues (2005) pain). Perception of general health status was collected were unable to evaluate the psychometric properties and at baseline and reports of changes in perceived health clinical utility for specific types of cancer, such as MBC, status (compared to that at baseline) were collected at due to sample size limitations [16]. follow-up visits. General health status was based on both Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 3 of 10 Fig. 1 Study timeline patient’s and health professional’s responses ranging patients receiving any specific medical intervention for from “very good” to “very bad” on a 7-point Likert scale. BM, at any visit(s) during the study, versus patients who did not. The minimum effect size (d) for the difference Statistical analysis between groups to be considered a clinically significant Initially, we calculated the need to recruit 241 patients improvement in HRQoL was set at d ≥ 0.20. The effect based on the following assumptions: a standard deviation size was calculated using the standardized mean differ- (SD) of 23 points for BOMET-QoL-10 scores (same as ence, defined in this case as the ratio of the difference in BOMET-QoL), a 20% patient drop-out rate, an estima- mean scores between baseline and last follow-up and the tion of HRQoL with a precision of ±3.25, and having at standard deviation of scores at baseline. least 80% power to detect a difference ≥ 0.20 SD between To evaluate the correlation between the reduction in BOMET-QoL-10 scores at baseline and at last follow-up pain (according to pain VAS) and the HRQoL on the (visit 7) with a 0.05 level of significance. However, due BOMET-QoL questionnaire, we compared the difference to recruitment limitations, we recalculated the target re- of mean values of those parameters between baseline cruitment to 174 by slightly lowering our precision in es- and last follow-up visit.. We categorized this as: “Gets timating QoL to a ± 3.75 instead, while keeping the worse” if the difference was negative, “Stays the same” if other parameters the same. the difference was zero and “Improves” if the difference Categorical variables were described using frequencies was positive. and their differences were tested using Chi-square (χ2) Finally, to evaluate the evolution of BOMET-QoL-10 or Fisher exact tests. Associations between ordinal vari- scores, when explicitly mentioned, certain analyses only ables were described using Kendall’s Tau. We used included those questionnaires with no missing data. All means, standard deviations, medians, and ranges (mini- tests were two-tailed with an α = 0.05. Analyses were mum and maximum) to describe continuous variables. conducted using SPSS version 17.0 (SPSS Inc., Chicago Depending on variables’ distributions either Student t- IL, 2008). tests or Mann–Whitney U-tests were used for compari- sons. Likewise, we used Pearson r coefficients or Results Spearman’s rank correlation coefficients (ρ) to assess as- From October 2007 to May 2010, 174 patients were re- sociations between variables of interest. Relationships cruited at 15 GEICAM hospitals distributed throughout between BOMET-QoL-10 scores and ECOG PS scores, Spain. One hundred seventy-two were eligible and en- perceived health status, and presence of SREs and AEs rolled in the study. Only 83 of them completed the last were analyzed. follow-up visit at 24 months. Missing data for specific To assess the BOMET-QoL-10 scores we calculated questions or instruments varied across assessments, as the mean score value in every visit for every item and a reflected in in Tables 1 and 2. global standardized mean score of the whole question- Patients’ median age was 59 years (range: 30–89) and naire. This value was performed taking into account only 14% lived alone. The median time between breast those questionnaires completely fulfilled (10 questions). cancer diagnosis and study enrollment was 4.4 years The higher the BOMET-QoL-10, the higher quality of (Range: 0–36.8). Over half of the patients (52.7%) were life (HRQoL). stage IV at diagnosis. The most common BM sites were To assess the clinical usefulness of our results we cal- the spine (76.2%), pelvis (53.5%), and ribs (45.3%). In culated the effect size of the questionnaire’s scores for addition, visceral metastases were present in 40.7% of Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 4 of 10 Table 1 Baseline patient characteristics (n = 172) comorbidities. (Table 1). More than half of the patients Characteristics Value had a baseline ECOG PS score of 1 (51.2%) and 37.3% Age (years), median (Range) 58 (30–89) had a score of 0. Bone metastasis site, n (%) At baseline 54.7% of patients were receiving chemo- therapy, 58,1% were on hormone therapy, and 12.2% re- Spine 131 (76.2) ceived other treatments including bisphosphonates, Ribs 78 (45.3) palliative radiotherapy for bone metastasis or orthopedic Pelvis 92 (53.5) surgery (Additional file 2). Patients could be receiving Upper limbs 24 (14.0) more than one treatment concurrently and they contin- Lower limbs 48 (27.9) ued receiving treatments during follow-up visits. Overall, Skull 37 (21.5) at each follow-up the proportion of patients receiving any one treatment grew smaller, except hormone Other 48 (27.9) therapy, but still with a marked downward trend. For Visceral metastasis, n (%) 70 (40.7) instance, at the 24-month follow up, only 16.9% were Patients with skeletal related events, n (%) 32 (18.6) receiving chemotherapy, 1.2% radiotherapy, 20.5% Pathologic fractures 8 (25.0) endocrine therapy, and 4.8% other treatments (anal- Hypercalcemia 1 (3.1) gesic, anti-inflamatory therapy and some rehabilita- Medullar compression 1 (3.1) tion). Patients were also treated for BM with bisphosphonates (79.1%) and pain relievers (37.8%) As Need for surgery 8 (25.0) with MBC treatment, the proportion of patients re- Need for radiation therapy 21 (65.6) ceiving treatment for BM tended to decrease at each Patients with symptoms, n (%) 119 (69.2) follow-up (Additional file 3). Lower back pain 44 (37.0) The vast majority of patients (80%) completed the Hip pain 32 (26.9) BOMET-QoL-10 in less than 10 min in all visits, with a Rib pain 27 (22.7) high completion rate. The small proportion of un- answered items throughout the entire follow-up ranged Asthenia 39 (32.8) between 0% and 1.2%. Based on fully-completed ques- Arthromyalgia 7 (5.9) tionnaires, we calculated the global average score for Other bone pain 8 (6.7) each visit from baseline (n = 172) to the 24-month Other 23 (19.3) follow-up (n = 83). There was no significant trend in Patients with Irruptive Pain, n (%) 40 (23.3) BOMET-QoL-10 scores over the 7 visits. In fact, base- Incidental 29 (72.5) line and last follow-up global average scores (25.6 [SD 8.0] and 25.9 [SD 8.2], respectively) were were not statis- Spontaneous 9 (22.5) tically significant different (Additional file 4). Similarly, Other 3 (7.5) there were no a regular behavior for each of the 10 items Patients with non-osteoarticular comorbidities, n (%) 59 (34.3) of the questionnaire across visits and there were no Chronic Obstuctive pulmonary disease (COPD) 1 (7) items more likely to be skipped than others. However, Dislipemia 18 (30,5) there were two items with a tendency to receive lower Cardiovascular disease 7 (11.9) scores, reflecting worse HRQoL, than the rest: “I feel tired” and “I have pain in some areas of my body such as Arterial hypertension 35 (59.3) my back, legs, hips, … that affect my life” and two items Diabetes mellitus 11 (18.6) that tended to get higher scores reflecting better Other 25 (42.4) HRQoL, than other items: “I avoid family activities” and “I have an intense pain that doesn’t leave me alone.” Further, as expected, BOMET-QoL-10 lower scores patients. SREs were reported in 18.6% of patients, the were negatively correlated with the number of BM- most common one being pathologic fractures (25.0%). related symptoms (ρ = − 0.410, p < 0.001) (Add- Almost 70% of patients presented symptoms, mostly itional file 5) as well as with VAS pain global standard- lower back pain (37.0%) and weakness (32.8%). Further, ized mean scores (ρ = − 0.542, p < 0.01). These patterns 23.3% of patients presented irruptive pain, of whom, of correlations held true for the scores reported in every 72.5% reported the pain to be incidental and clearly visit (Table 2). In addition, 32 patients whose pain im- linked to oncological and neuropathic pain. Over 50% of proved between baseline and last follow-up visit (visit 1 patients presented chronic conditions, 19.2% were vs 7, Table 2) reported significantly higher BOMET- osteoarticular and 34.3% were non-osteoarticular QoL-10 average scores compared to those whose pain Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 5 of 10 Table 2 Relationship between HRQoL according to BOMET-QoL-10 and pain VAS Bomet-QoL-10 HRQoL questionnaire Visits Pain VAS Gets worse No change Improves Correlation (Kendall’s Tau-b) p-value 1 vs 2 Gets worse 33 5 19 0.232 0.003 n = 133 No change 7 4 5 Improves 19 7 34 2 vs 3 Gets worse 37 6 13 0.466 < 0.0001 n = 106 No change 3 1 2 Improves 8 4 32 3 vs 4 Gets worse 23 6 9 0.271 0.002 n = 97 No change 5 1 7 Improves 15 5 26 4 vs 5 Gets worse 28 6 11 0.348 < 0.0001 n = 92 No change 5 1 2 Improves 12 0 27 5 vs 6 Gets worse 24 0 11 0.373 0.001 n = 72 No change 1 4 2 Improves 8 2 20 6 vs 7 Gets worse 25 3 8 0.432 < 0.0001 n = 69 No change 1 4 1 Improves 7 2 18 1 vs 7 Gets worse 31 0 12 0.464 < 0.0001 n = 79 No change 1 1 2 Improves 13 1 18 HRQoL Health Related Quality of Life remained at the same level or worsened (29.4, SD = 7.7 follow-up. As expected, BOMET-QoL-10 global mean vs.24.0, SD = 7.8; p = 0.003). for these highly stable patients was unchanged between Most patients (85.5%) reported ECOG PS scores be- baseline and visit 7 (26.4, SD = 8.8 and 26.4, SD = 7.0, re- tween 0 and 1. We compared BOMET-QoL-10 scores spectively) (p = 0.956). Thus, BOMET-QoL-10 scores for for each visit between two groups formed by patients highly stable patients were consistently stable through- with ECOG PS scores 0–1 versus those with ECOG PS out the study. scores > 1, to assess the differences in QoL within these In addition we compare the BOMET-QoL-10 scores groups. The former reported significantly higher between patients with SREs and/or AEs and patients BOMET-QoL-10 scores (range: 26.5 to 28.0) than the with neither, as well as the questionnaire’s power of dis- latter (range: 17.3 to 22.9). Differences between patients crimination between these two groups, we compared with ECOG PS 0–1 and > 1 were statistically significant their average scores for each visit (Fig. 2). Results show overall and for every visit, except in visit 3 (Table 3). that the average score for each group remained fairly The BOMET-QoL-10 and perceived health status scores stable (range: 21.8 to 24.0 for the former and range: 26.1 were also moderately inversely correlated for all 7 visits to 28.5 for the latter). The mean differences between the (range: − 0.6 to − 0.3; p < 0.001 for all). two groups were in the expected direction and statisti- We also evaluated the values of BOMET-QoL-10 cally significant in 4 of the 7 visits while approaching scores for those patients (up to 42 patients between significance in the other 3 visits. Further, we tested the visits 4 and 5) reporting their perceived health status be- difference between the overall average score (all 7 visits) tween visits remaining “more or less the same.” As ex- between patients ever reporting SREs and/or AEs at any pected, their corresponding BOMET-QoL-10 scores did of the visits during the 2 year-follow up (n = 111; mean = not vary between consecutive visits either. There were 24.1, SD = 7.2) and that for patients reporting neither 26 highly stable patients who reported the same per- SREs nor AEs at any of the visits during the same period ceived health status from baseline all throughout the last (n = 61; mean = 26.8, SD = 7.4). The average score for the Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 6 of 10 Table 3 BOMET-QoL-10 scores throughout the study by ECOG first group was significantly lower than that of the sec- PS ond group (p ≤ 0.007) (data not shown). Mean SD p Finally, MBC patients receiving specific treatment Visit 1 (n = 166) for BM reported a clinically significant improvement in ECOG 0–1 26.5 7.6 0.003 HRQoL throughout the study compared to those patients who did not. The magnitude of the treatment’s ECOG > 1 19.8 9.2 effect for BM was calculated as the difference between Visit 2 (n = 143) the BOMET-QoL-10 mean values at visit 7 in these two ECOG 0–1 26.5 7.9 0.002 groups divided by a combined standard deviation. The ECOG > 1 18.0 8.6 relative overall study variability yielded an effect size of Visit 3 (n = 120) 0.203 in BOMET-QoL-10 scores, which is greater than ECOG 0–1 26.7 7.4 0.111 our pre-set value for clinical significance (0.200) (Table 4)). ECOG > 1 22.9 7.2 Visit 4 (n = 115) ECOG 0–1 27.2 7.6 0.000 Discussion ECOG > 1 17.3 7.3 With increasing rates of survival after a breast cancer Visit 5 (n = 95) diagnosis a growing number of patients are at risk for ECOG 0–1 28.0 7.5 0.004 MBC [1, 19]. For MBC patients, whose treatments are essentially palliative, an accurate and clinically valid as- ECOG > 1 18.9 10.6 sessment of HRQoL is particularly important. Thus, in- Visit 6 (n = 76) struments should be comprehensive enough to capture ECOG 0–1 27.8 7.3 0.036 the key aspects of a patients´ quality of life, though still ECOG > 1 19.0 8.9 easy to understand and brief. This could remain as a Visit 7 (N = 76) feasible tool to be used in clinical practice [20, 21]. ECOG 0–1 27.3 7.6 0.005 Aside from BOMET-QoL, QLQ-BM22, a widely used tool, is the only other HRQoL instrument designed spe- ECOG > 1 17.3 8.1 cifically for BM patients. QLQ-BM22 is a useful and reli- ECOG PS Eastern Cooperative Oncology Group Performance Status SD Standard Deviation able instrument especially when administered in combination with the QLQ-C30 [22, 23]. Several studies Fig. 2 BOMET-QoL-10 mean scores for each visit over time reported by patients with AEs and/or SREs versus patients with neither. Higher scores indicate better Health Related Quality of Life.*Mean scores are statistically different between patient groups (p < 0.05) Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 7 of 10 Table 4 Effect size of the global BOMET-QoL-10 mean values at (about 10 min); and presenting very low levels of missing visit 7 in patients receiving specific treatment for BM vs those or invalid data (0–1.2%) throughout all 7 follow-up who did not visits. Quick completion is important in the context of BM Visit 7 clinical practice not only because of the inherent time intervention Mean SD N = 83 % D limitations but also because it reduces response burden No 27.08 7.24 24 28.9% 0.203 in patients who may be experiencing chronic pain and/ Yes 25.41 8.61 59 71.1% or who may fatigue easily during assessments. Thus, sin- Abbreviations: D Effect size gle instruments are preferred over two or more [27]. Whereas succinctness is important, items highly relevant to the patient’s experience are also key to keeping sub- have evaluated and validated the QLQ-BM22 module ject burden low [21]. Our results convey low administra- with male and female patients of a variety of primary tion burden and high content relevancy. Acceptable cancers and BM, and/or residing in a variety of countries subject burden is a key factor for achieving high comple- as summarized below. However, despite its satisfactory tion and response rates as well as high data quality [28]. psychometric properties, caution is warranted when BOMET-QoL-10 scores for overall HRQoL remained comparing certain items by gender or country as they stable over time for the sample as a whole. This lack of may function differently [24]. Raman and colleagues variability may reflect the influence of aspects other than (2016) [23] validated the module based on a sample of the socio-demographic and clinical factors assessed here. 204 men and women diagnosed with one of at least six However, when patients were grouped by disease status different cancers and BM. Patients were assessed at (e.g., with or without SRE and/or AE) BOMET-QoL-10 baseline and at a 42 day-follow-up. Another international scores reflected the differences in group wellness one study evaluated the module’s performance based on two would expect at each visit and throughout the study administrations—1 month apart— to 59 patients from 6 (had SREs and/or AEs at any of the visits vs. not). Fur- different countries [9]. A larger 7-country study adminis- ther, the instrument’s scores were significantly correlated tered the module twice—1 month apart—to 400 male with physician-reported patient status, patient-reported and female patients diagnosed with at least 9 different pain, symptoms, and perceived health status. Perceived cancers with BM [25]. Recently, Lin and Pakpour (2016) pain was directly proportional to HRQoL and VAS [24] performed a psychometric evaluation of QLQ- scores and BOMET-QoL-10 scores also varied accord- BM22 based on a pre-treatment single administration of ingly as patient’s pain improved or worsened. As ex- a pooled sample of 573 BM patients from 8 countries. pected, the BOMET-QoL-10 and ECOG PS scores were Miki-Rosário and colleagues (2016), [26] validated the inversely proportional throughout the study. This sup- Brazilian Portuguese translation of the QLQ-BM22 ports previously reported results based onQLQ-C30 and based on a sample of 95 men and women with BM de- QLQ-BM22 [23, 25, 29]. We should highlight that in rived from 9 different cancers. Reliability, face and con- some of the categories, the effect was the opposite, but tent validity were assessed based on 40 patients over this was most likely due to the low number of patients three administrations of the module. The use of other in those categories. Overall, these results suggest that tools not designed specifically for BM patients (e.g., Brief the BOMET-QoL-10 is a reliable and useful, tool to Pain Inventory, the QLQ-C30 alone, the QLQ-C15 PAL, measure of HRQoL in this patient population. the Net pain relief concept, and the Spitzer’s QOL Finally, we assessed the instrument’s sensitivity to Index) to assess QOL in patients with BM has been change by calculating the effect size for patients who reviewed by McDonald and colleagues [8]. had received BM-specific medical intervention versus BOMET-QoL-10 has been shown to closely reflect those who had not. We then compared it to an a priori variations in relevant pain and wellness measures, having value we considered to be minimum clinically relevant good internal consistency, and being highly reliable effect. The BOMET-QoL-10 effect size was greater than among cancer patients with BM [18, 22]. Our objective the pre-set value. Thus, MBC patients receiving specific in this study was to evaluate whether the BOMET-QoL- treatment for BM reported a clinically relevant improve- would be a valuable tool to use for breast cancer patients ment in HRQoL throughout the study compared to with BM. The questionnaire was tested at baseline on a MBC patients who did not. This confirms that the in- MBC patient population in which 70% of individuals re- strument is sensitive to changes independently of the ported symptoms, close to a quarter experienced irrup- statistical significance of other results [16]. tive pain, over half presented chronic conditions, and The study presents limitations which should be con- more than half were receiving chemotherapy. BOMET- sidered when interpreting our results. First, a majority of QoL-10 proved to be a quick assessment tool perform- patients (71.5%) were recruited by 5 of the 15 participant ing well in terms of readability and completion time research centers. As palliative care populations tend to Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 8 of 10 be highly heterogeneous, a limited number of recruiting dimensions of HRQoL are subjective and may be af- centers may have resulted in a less diverse sample of fected by gender, site of original tumor [16], type of participants than expected. This may have introduced an therapy administered or cultural norms and expecta- unknown bias [30] and reduced the generalizability of tions in unknown ways. Our results minimize this po- the results. However, it is not uncommon for samples to tential negative interaction by using a fairly be drawn from one or a handful of medical facilities [29, homogenous patient sample (female MBC patients 31]. Second, due to feasibility concerns the study is residing in Spain). In contrast, many of the studies based on a non-probability sample which removes the evaluating or using QLQ-BM22 or BOMET-QoL-10 possibility of estimating sampling variability or to ascer- are based on patients of both genders, diagnosed with tain potential biases. Research centers such as Statistics different primary cancers, and/or recruited across Canada, nonetheless, use non-probability sampling for countries with different cultures and languages [9, 16, questionnaire testing [32]. 18, 23, 26, 29]. A third limitation is the small number of patients completing the entire 24-month study. This is the result of an initial small sample size compounded by a much Conclusions higher lost-to-follow-up rate (51.7%) than anticipated The regular surveillance of HRQoL issues in patients (20%). However, recent adaptation and validation studies with advanced disease and receiving palliative care of HRQoL instruments as well as HRQoL assessments of can be used to guide pain management therapy [34] palliative care patients have been based on small samples and other symptoms and choose the best course of followed for short periods of time ranging from 1 to 6 palliative action for patients [26]. The development of months [9, 23, 26]. quality easy-to-administer tools such as BOMET- Unfortunately, the lower numbers limited the evalu- QoL-10 will facilitate such needed surveillance. Al- ation of the study’s secondary objectives and actual dif- though, not as comprehensive as other assessments, ferences may have gone undetected given the low BOMET-QoL-10’s brevity and relevancy allow the statistical power of some of our comparisons. For in- clinician to accurately and efficiently assess some rele- stance, even though BM-associated pain is quite com- vant quality of life aspects in patients with breast can- mon and often undertreated in MBC patients [33], cer and BM. In only 10 min and without burdening BOMET-QoL-10 failed to statistically differentiate the symptomatic frail patients, this reliable and useful tool HRQoL of patients with AEs and/or SREs versus those identifies key quality of life aspects in a regular clin- with neither one in 3 of the 7 visits even when they were ical setting. substantial in magnitude and clearly of clinical signifi- This instrument exhibits longitudinal and cross- cance. These differences, which approached significance, validation, construct validity, as well as feasibility and it most likely would have reached significance in a larger is sensible to detect some changes related with the dis- sample. In fact, when we compared patients ever report- ease evolution and their treatment. BOMET-QoL-10 is ing SREs and/or AEs during the 2-year study (n = 111) sensitive to the number of symptoms, pain level, ECOG to those who did not report either during the study (n = PS, presence of SREs and/or AEs, and the effects of BM- 61) their overall average scores were significantly differ- specific treatment. ent (p < 0.007). Further research is needed to test this tool in larger The study also has some important strengths. First, samples of breast cancer patients with BM as well as in the longitudinal administration of the same tool to other homogenous cancer populations with BM, e.g., patients with BM in seven occasions over a 2-year prostate or lung cancer patients with BM. Further steps period represents a solid assessment of the user- would involve translation and cross-cultural adaptation acceptance, respondent burden of the tool, and stabil- of the tool to other languages and countries. ity of the measurement. As aforementioned, this con- trasts with other studies which include just one or two follow-ups over periods of time under 1 year [9, Supplementary information 16, 18, 23, 26], with the exception of Jordhøy and Supplementary information accompanies this paper at https://doi.org/10. colleagues who followed 395 patients for 2 years [29]. 1186/s41687-019-0161-y. Second, our main overall outcome, patients´ HRQoL, was assessed by three methods in addition to Additional file 1. BOMET-QoL 10 points items BOMET-QoL-10: the doctor’s perception, the patient’s Additional file 2. Breast Cancer Treatments at baseline perception, and the VAS score. These assessments Additional file 3. Treatments for bone metastasis per visit were highly associated suggesting that BOMET-QoL- Additional file 4. BOMETQoL items evolution through study visits and mean standardized global score 10 has a high construct validity. Third, certain Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 9 of 10 Additional file 5. Correlation between the number of symptoms at visit Manresa, C/ Dr. Joan Soler, s/n, 08243 Manresa, Barcelona, Spain. 16Medical 7 and the BOMET-QoL global score Oncology Department, Hospital Arnau de Vilanova, Avda. Alcalde Rovira Roure, 80, 25198 Lleida, Spain. 17Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain. 18Medical Oncology Abbreviations Department, Hospital Virgen del Rocío, Avda. Manuel Siurot, s/n, 41013 AE: Adverse Events; BM: Bone Metastasis; BOMET: Bone Metastasis Quality of Sevilla, Spain. 19Medical Oncology Department, Hospital Universitario La Life; ECOG PS: Eastern Cooperative Oncology Group Performance Status; Princesa, C/ Diego de León n° 62, 28006 Madrid, Spain. 20Medical Oncology EORTC: European Organization for Research and Treatment of Cancer; Department, Hospital U. Josep Trueta, Avda. De França s/n, 17007 Gerona, FACT: Functional Assessment of Cancer Therapy; HRQoL: Health Related Spain. Quality of Life; MBC: Metastatic Breast Cancer; PMI: Pain Management Index; SD: Standard Deviation; SREs: Skeletal-Related Events; VAS: Visual Analog Received: 29 May 2019 Accepted: 15 November 2019 Scale Acknowledgements References We thank the investigators, the participating patients, local research and 1. Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J., & Jemal, A. GEICAM staff. We thank Hosanna Soler-Vila, PhD for her contribution as med- (2015). Global cancer statistics, 2012. CA: a Cancer Journal for Clinicians, 65(2), ical writer and GOC Networking for the statistical analysis. 87–108. 2. Network MBC. 13 Facts About Metastatic Breast Cancer 2016 [Available Authors’ contributions from: http://www.mbcn.org/13-facts-about-metastatic-breast-cancer/. AB, EA, MRB and RC participated in the design and coordination of the 3. Cardoso, F., Harbeck, N., Fallowfield, L., Kyriakides, S., Senkus, E., & Group study, data analysis and data interpretation. An external CRO (GOC EGW. (2012). Locally recurrent or metastatic breast cancer: ESMO clinical Networking) carried out the statistical analysis; All authors participated in the practice guidelines for diagnosis, treatment and follow-up. Annals of data acquisition, were involved in drafting the manuscript and revising it Oncology, 23(Suppl 7), vii11–vii19. critically for important intellectual content and they all gave final approval of 4. Yu, H. H., Tsai, Y. Y., & Hoffe, S. E. (2012). Overview of diagnosis and the version to be published. management of metastatic disease to bone. Cancer Control, 19(2), 84–91. 5. Hagberg, K. W., Taylor, A., Hernandez, R. K., & Jick, S. (2013). Incidence of Funding bone metastases in breast cancer patients in the United Kingdom: Results This work was sponsored by GEICAM and Novartis. Roche funded the of a multi-database linkage study using the general practice research publication fees for this article. database. Cancer Epidemiology, 37(3), 240–246. 6. Caissie, A., Culleton, S., Nguyen, J., Zhang, L., Zeng, L., Holden, L., et al. Availability of data and materials (2012). EORTC QLQ-C15-PAL quality of life scores in patients with advanced The datasets used and/or analyzed during the current study are available cancer referred for palliative radiotherapy. Support Care Cancer, 20(4), 841– from the corresponding author on reasonable request. 848. 7. Costa, L., Badia, X., Chow, E., Lipton, A., & Wardley, A. (2008). Impact of Ethics approval and consent to participate skeletal complications on patients' quality of life, mobility, and functional The study followed the International Guidelines for Ethical Review of independence. Support Care Cancer, 16(8), 879–889. Epidemiological Studies and the guidelines of the Spanish Epidemiological 8. McDonald, R., Chow, E., Rowbottom, L., Bedard, G., Lam, H., Wong, E., et al. Society. The protocol was approved by the Institutional Review Board of (2015). Quality of life after palliative radiotherapy in bone metastases: A each participating institution. Written informed consent was obtained before literature review. Journal Bone Oncology, 4(1), 24–31. enrolling in the study. 9. Zeng, L., Chow, E., Bedard, G., Zhang, L., Fairchild, A., Vassiliou, V., et al. (2012). Quality of life after palliative radiation therapy for patients with Consent for publication painful bone metastases: Results of an international study validating the Not applicable. EORTC QLQ-BM22. International Journal of Radiation Oncology, Biology, Physics, 84(3), e337–e342. Competing interests 10. Di Maio, M., Gallo, C., Leighl, N. B., Piccirillo, M. C., Daniele, G., Nuzzo, F., et al. The authors declare that they have no competing interests. (2015). Symptomatic toxicities experienced during anticancer treatment: Agreement between patient and physician reporting in three randomized Author details trials. Journal of Clinical Oncology, 33(8), 910–915. 1 Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, C/Sant 11. Osoba, D. (2000). Health-related quality-of-life assessment in clinical trials of Antoni Maria Claret, 167, 08041 Barcelona, Spain. 2Centro de Investigación supportive care in oncology. Support Care Cancer, 8(2), 84–88. Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain. 3Medical 12. Porter, G. A., & Skibber, J. M. (2000). Outcomes research in surgical oncology. Oncology Department, Hospital Clinic i Provincial, C/ Villarroel n° 170, 08036, Annals of Surgical Oncology, 7(5), 367–375. Barcelona, Spain. 4Medical Oncology Department, Ctra, Hospital Germans 13. Roila, F., & Cortesi, E. (2001). Quality of life as a primary end point in Trias i Pujol, Canyet s/n, 08916 Badalona, Barcelona, Spain. 5Medical oncology. Annals of Oncology, 12(Suppl 3), S3–S6. Oncology Department, Hospital Virgen de la Salud, Avda. Barber, n° 30, 14. Schwartz, C. E., & Sprangers, M. A. (2002). An introduction to quality of life 45005 Toledo, Spain. 6Medical Oncology Department, Hospital General de assessment in oncology: The value of measuring patient-reported Guadalajara, C/ Donantes de Sangre, s/n, 19002 Guadalajara, Spain. 7Medical outcomes. The American Journal of Managed Care, 8(18 Suppl), S550–S559. Oncology Department, Complejo Hospitalario U. A Coruña, C/ Xubias de 15. Chow, E., & Bottomley, A. (2009). Understanding the EORTC QLQ-BM22, the Abaixo s/n, 15006 A Coruña, Spain. 8Medical Oncology Department, module for patients with bone metastases. Expert Review of Complejo Hospitalario Universitario de Albacete, C/ Hermanos Falcó n° 37, Pharmacoeconomics & Outcomes Research, 9(5), 461–465. 02006 Albacete, Spain. 9Medical Oncology Department, Centro Oncológico 16. Adrover, E. A. J., Sureda, A., Domine, M., Barnadas, A., Constela, M., Lluch, A., de Galicia, C/ Doctor Camilo Veiras s/n, 15009 A Coruña, Spain. 10GEICAM Ruiz, M., Piera, J., Mayordomo, J. I., Morales, A., Muñoz, M., Alcover, J., (Spanish Breast Cancer Group), Avda. de los Pirineos n° 7, 28703 San Colomer, R., Llombart, A., Massutti, B., Carballido, J., Garrido, P., García, R., Sebastián de los Reyes, Madrid, Spain. 11Medical Oncology Department, Badia, X., Lizan, L., & Gilabert, M. (2005). Development of a questionnaire to Hospital General de Catalunya, Carrer de Pedro Pons 1, 08195 Sant Cugat del measure health related quality of life (HRQoL) in patients with bone Valles, Barcelona, Spain. 12Medical Oncology Department, Hospital Mutua de metastases (BM) (BOMET-QoL). Journal Outcomes Research, 9, 15–28. Terrassa, Barcelona, Plaza del Dr. Robert n°5, 08221 Terrassa, Barcelona, Spain. 17. Oken, M. M., Creech, R. H., Tormey, D. C., Horton, J., Davis, T. E., McFadden, E. 13 Medical Oncology Department, Complejo Hospitalario De Pontevedra, Calle T., et al. (1982). Toxicity and response criteria of the eastern cooperative Mourente s/n, 36071 Pontevedra, Galicia, Spain. 14Medical Oncology oncology group. American Journal of Clinical Oncology, 5(6), 649–655. Department, Hospital Comarcal de Barbastro, Ctra. Nacional 240, s/n, 22300 18. Sureda, A., Isla, D., Cózar, J., Ruiz, M., Domine, M., Margelí, M., Adrover, E., Barbastro, Huesca, Spain. 15Medical Oncology Department, Hospital Althaia Ramos, M., Pastor, M., Martín, A., Llombart, A., Massuti, B., Muñoz, M., Barnadas et al. Journal of Patient-Reported Outcomes (2019) 3:72 Page 10 of 10 Barnadas, A., Fernández, J., Colomer, R., Allepuz, C., Gilabert, M., & Badia, X. (2007). Final development and validation of the Bomet-QoL questionnaire for assessing quality of life in patients with malignant bone disease due to neoplasia (BOMET-QoL). Journal of Medical Economics, 10, 41–53. 19. Irvin Jr., W., Muss, H. B., & Mayer, D. K. (2011). Symptom management in metastatic breast cancer. Oncologist., 16(9), 1203–1214. 20. Converse JMP, S. (1986). In S. P. Ltd (Ed.), Quantitative applications in the social sciences: Survey questions. 21. Rolstad, S., Adler, J., & Rydén, A. (2011). Response burden and questionnaire length: Is shorter better? A review and meta-analysis. Value in Health, 14, 1101–1108. 22. Bedard, G., Zeng, L., Poon, M., Lam, H., Lauzon, N., & Chow, E. (2014). Comparison of the EORTC QLQ-BM22 and the BOMET-QOL quality of life questionnaires in patients with bone metastases. Asia-Pacific Journal of Clinical Oncology, 10, 118–123. 23. Raman, S., Ding, K., Chow, E., Meyer, R. M., Nabid, A., Chabot, P., et al. (2016). A prospective study validating the EORTC QLQ-BM22 bone metastases module in patients with painful bone metastases undergoing palliative radiotherapy. Radiotherapy and Oncology, 119(2), 208–212. 24. Lin, C. Y., & Pakpour, A. H. (2016). Assessing the EORTC QLQ-BM22 module using Rasch modeling and confirmatory factor analysis across countries: A comprehensive psychometric evaluation in patients with bone metastases. Asian Pacific Journal of Cancer Prevention, 17(3), 1405–1410. 25. Chow, E., Nguyen, J., Zhang, L., Tseng, L. M., Hou, M. F., Fairchild, A., et al. (2012). International field testing of the reliability and validity of the EORTC QLQ-BM22 module to assess health-related quality of life in patients with bone metastases. Cancer., 118(5), 1457–1465. 26. Miki-Rosário, N. G. F. R., Garcia, J. G., Dini, G. M., Bottomley, A., Chow, E., & Sabino, N. M. (2016). Translation into Portuguese, cross-cultural adaptation and validation of "the European Organization for Research and Treatment of cancer-quality of life questionnaire-bone Metastases-22". Palliative Medicine, 5, 190–195. 27. Snyder, C. F., Watson, M. E., Jackson, J. D., Cella, D., Halyard, M. Y., & Mayo FDAP-ROCMG. (2007). Patient-reported outcome instrument selection: Designing a measurement strategy. Value in Health, 10(Suppl 2), S76–S85. 28. Diehr, P., Chen, L., Patrick, D., Feng, Z., & Yasui, Y. (2005). Reliability, effect size, and responsiveness of health status measures in the design of randomized and cluster-randomized trials. Contemporary Clinical Trials, 26(1), 45–58. 29. Jordhoy, M. S., Fayers, P., Loge, J. H., Saltnes, T., Ahlner-Elmqvist, M., & Kaasa, S. (2001). Quality of life in advanced cancer patients: The impact of sociodemographic and medical characteristics. British Journal of Cancer, 85(10), 1478–1485. 30. Hearn, J., & Higginson, I. J. (1998). Do specialist palliative care teams improve outcomes for cancer patients? A systematic literature review. Palliative Medicine, 12(5), 317–332. 31. Lee, J., Hodgson, D., Chow, E., Bezjak, A., Catton, P., Tsuji, D., et al. (2005). A phase II trial of palliative radiotherapy for metastatic renal cell carcinoma. Cancer., 104(9), 1894–1900. 32. Canada S. Non-Probability Sampling [updated 2013-07-23. Available from: http://www.statcan.gc.ca/edu/power-pouvoir/ch13/nonprob/5214898-eng.htm. 33. Patrick, D. L., Cleeland, C. S., von Moos, R., Fallowfield, L., Wei, R., Ohrling, K., et al. (2015). Pain outcomes in patients with bone metastases from advanced cancer: Assessment and management with bone-targeting agents. Support Care Cancer, 23(4), 1157–1168. 34. Puetzler, J., Feldmann Jr., R. E., Brascher, A. K., Gerhardt, A., & Benrath, J. (2014). Improvements in health-related quality of life by comprehensive cancer pain therapy: A pilot study with breast cancer outpatients under palliative chemotherapy. Oncology Research Treatment, 37(9), 456–462. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.