Laquente et al. BMC Palliative Care (2020) 19:103 https://doi.org/10.1186/s12904-020-00610-4 RESEARCH ARTICLE Open Access Quality of life of patients with metastatic pancreatic adenocarcinoma initiating first- line chemotherapy in routine practice Berta Laquente1* , Teresa Macarulla2, Cristina Bugés3, Marta Martín4, Carlos García5, Carles Pericay6, Sandra Merino7, Laura Visa8, Teresa Martín9, Manuela Pedraza10, Beatriz Carnero11, Raquel Guardeño12, Helena Verdaguer2, Alejandro Mut13, David Vilanova13 and Adelaida García12 Abstract Background: Despite advances in surgery, radiotherapy, and chemotherapy, pancreatic adenocarcinoma often progresses rapidly and causes death. The physical decline of these patients is expected to impact their quality of life (QoL). Therefore, in addition to objective measures of effectiveness, the evaluation of health-related QoL should be considered a matter of major concern when assessing therapy outcomes. Methods: Observational, prospective, multicenter study including patients with metastatic pancreatic adenocarcinoma who started first-line chemotherapy in 12 Spanish centers. Treatment and clinical characteristics were recorded at baseline. Patients’ health-related quality of life, ECOG, and Karnofsky index were measured at baseline, at Days 15 and 30, and every four weeks up to 6 months of chemotherapy. Health-related quality of life was measured using the EORTC-QLQ-C30 and EQ-5D questionnaires. Other endpoints included overall survival and progression-free survival. Results: The study sample included 116 patients (median age of 65 years). Mean (SD) scores for the QLQ-C30 global health status scale showed a significant increasing trend throughout the treatment (p = 0.005). Patients with either a Karnofsky index of 70–80 or ECOG 2 showed greater improvement in the QLQ-C30 global health status score than the corresponding groups with better performance status (p ≤ 0.010). Pain, appetite, sleep disturbance, nausea, and constipation significantly improved throughout the treatment (p < 0.005). Patients with QLQ-C30 global health status scores ≥50 at baseline had significantly greater overall survival and progression-free survival (p = 0.005 and p = 0.021, respectively). No significant associations were observed regarding the EQ-5D score. Conclusions: Most metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy showed an increase in health-related quality of life scores throughout the treatment. Patients with lower performance status and health-related quality of life at baseline tended to greater improvement. The EORTC QLQ-C30 scale allowed us to measure the health-related quality of life of metastatic pancreatic adenocarcinoma patients receiving first-line chemotherapy. Keywords: Pancreatic Cancer, Health-related quality of life, Cancer chemotherapy, Performance status, EORTC QLQ-C30 * Correspondence: blaquente@iconcologia.net 1 Institut Catala d’Oncologia, Hospital Duran i Reynals, Hospitalet de Llobregat, Avda. De la Gran Via, 199, 08908 L’Hospitalet de Llobregat, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. Laquente et al. BMC Palliative Care (2020) 19:103 Page 2 of 11 Background centers, who had started first-line chemotherapy. Adult Despite recent advances in chemotherapy treatments, patients (i.e., aged ≥18 years) with a Karnofsky Index metastatic pancreatic adenocarcinoma (mPAC) remains (KI) ≥70 and a life expectancy ≥6 months, who attended incurable and survival rates are still low [1]. In the ab- routine follow-up visits between October 2014 and Oc- sence of treatments achieving long-term survival, tober 2015, were consecutively included in the study. No chemotherapy aims to slow tumor progression and re- other recruitment sources were considered. Patients that lieve symptoms [2, 3]. However, mPAC is an aggressive were pregnant or breastfeeding, participating in a clinical disease, and the burden of physical symptoms, together trial, or unable to understand or answer questions re- with the adverse effects of chemotherapy, lead to pa- lated to their health were excluded from the study. Base- tients’ rapid physical decline and the subsequent deteri- line demographic and clinical data were collected from oration of their quality of life (QoL) [2, 3]. In this the medical records at the initiation visit (i.e., at study scenario, health-related quality of life (HRQoL) becomes entry, before starting the first-line treatment). Assess- a significant concern in the management of patients with ments, which were scheduled to match routine visits, mPAC [4, 5]. were performed at baseline, at Days 15 and 30, and every Given the acknowledged importance of HRQoL, sev- 4 weeks up to 6 months after starting chemotherapy eral clinical trials have reported HRQoL and other QoL- (Treatment Period). After this time, patients were related outcomes in mPAC patients [5, 6]. Typically, followed up every 6 months for up to 18 months to as- trials including mPAC report a remarkable burden of sess survival (Follow-Up Period). toxicities associated with chemotherapy regimens. Nevertheless, some of these trials provide supportive evi- Endpoints, variables and assessments dence that favor chemotherapy in terms of HRQoL, par- The primary endpoint was the evolution of HRQoL in ticularly in patients who responded to it [3, 6]. In line patients with mPAC treated with first-line chemotherapy with these observations, global HRQoL and HRQoL- in a routine clinical practice setting. HRQoL was related outcomes, such as pain and fatigue, were associ- assessed using two self-administered questionnaires: the ated with survival in the clinical trial setting [7–10]. European Organization for Research and Treatment of However, the methodologies used to evaluate HRQoL— Cancer (EORTC) Quality of Life Questionnaire (QLQ- usually introduced as secondary endpoints—were het- C30) (Version 3.0), and the European Quality of Life-5 erogeneous, thus they precluded comparisons between Dimensions (EQ-5D). The QLQ-C30 is a 30-item, studies, often leading to inconsistent results [5, 6]. Fur- cancer-specific multidimensional questionnaire designed thermore, thorough selection criteria from randomized for prospective clinical studies that includes five func- controlled trials (e.g., patients with relatively good phys- tional scales (role, physical, emotional, cognitive and so- ical status) are unlikely to reflect a real-life practice sce- cial functioning), three symptom scales (fatigue, pain, nario. To date, real-world data is limited to a few studies and nausea and vomiting), a global health and quality- proving the association between HRQoL and survival of-life scale, additional specific symptoms commonly re- [11–15], and the positive impact of nab-paclitaxel plus ported by cancer patients (dyspnea, loss of appetite, gemcitabine treatment in HRQoL of patients with partial sleep disturbance, constipation, and diarrhea), and the response or stable disease [16]. perceived financial impact of the disease and treatment The American Society of Clinical Oncology (ASCO) [19]. The EQ-5D is a 5-item generic measure of health defines clinically meaningful outcomes in the clinical status, including five dimensions (mobility, self-care, trial setting as a balance between toxicity and efficacy, usual activities, pain/discomfort and anxiety/depression) stressing the importance of HRQoL measures as indica- and a Visual Analog Scale (VAS) [20]. Both question- tors of toxicity [17]. Similarly, real-life studies recom- naires, which have been translated to Spanish and vali- mend routine assessments of HRQoL to guide treatment dated in the Spanish population [21, 22], were decisions [18]. In this observational prospective study, administered during routine follow-up visits at baseline we describe the evolution of HRQoL in patients with and at each visit during the Treatment Period. mPAC treated with first-line chemotherapy in routine Baseline demographic characteristics considered in the clinical practice, and analyze patients’ clinical character- study included age, sex, and weight loss in the last 3 istics that may influence their HRQoL. months. Clinical and treatment characteristics included relevant concomitant diseases, date of diagnosis of the pri- Methods mary tumor, location of the metastatic disease, previous Study design and population adjuvant treatments for non-metastatic disease (if any)— This was an observational, prospective, multicenter regimen, number of cycles, start and completion dates, study including patients with histologically confirmed and response—, and first-line treatment prescribed mPAC (either recurrent or de novo) from 12 Spanish (schedule and initiation date). Together with the Laquente et al. BMC Palliative Care (2020) 19:103 Page 3 of 11 administration of HRQoL questionnaires, routine assess- the informed consent (n = 1), and withdrawing for not ments were performed at baseline and during the 6- having started treatment (n = 1). The resulting study month Treatment Period, including blood tests, biochem- sample included 116 patients, of which 101 (87.1%) had istry, tumor evaluation, performance status (PS) (ECOG concomitant diseases, with a median (Q1, Q3) age of and KI), treatment modification, and concomitant medica- 65.0 (59.5, 71.5) years and a median (Q1, Q3) Body Mass tion. Other variables were reasons for discontinuation of Index (BMI) of 23.9 (22.2, 26.6) kg/m2. Table 1 summa- chemotherapy, recorded during the Treatment and rizes the demographic and clinical characteristics of Follow-Up Periods, dose modifications and adverse events, study patients at baseline and main treatment recorded during the Treatment Period. Adverse events characteristics. (AE) were classified according to the Common Termin- Of these 116 patients, 113 (97.4%) started chemother- ology Criteria for Adverse Events (CTC-AE, version 4.02) apy in the study setting and were treated for a median of the National Cancer Institute (NCI) (http://ctep.cancer. (Q1, Q3) of 3.9 (1.4, 6.7) months. Median OS was 9.0 gov/reporting/ctc.html). months (95% CI 6.5–11.1) and median PFS was 6.0 months (95% CI 4.6–7.8). ORR was 32.6%, with three Statistical analysis (3.4%) and 24 (27.6%) patients achieving complete and Categorical variables and outcomes were presented as partial responses, respectively; 32 patients (36.8%) had frequencies and percentages, whereas continuous vari- stable disease. The number of patients assessed gradually ables and outcomes were presented as mean and stand- declined during the Treatment Period due to death or ard deviation (SD), or as median and interquartile range disease progression (and subsequent start of second-line (Q1,Q3). Categorical outcomes were compared using the regimens), with 40 (34.2%) study patients remaining at Chi-Square test or the Fisher’s exact test. Correspond- the end of the 6-month treatment, and 22 (19.0%) com- ingly, continuous outcomes were compared using the T- pleting all study visits. Test, the ANOVA, or their non-parametric counterparts Overall, 112 patients (96.6%) had 962 adverse events Wilcoxon or Kruskal-Wallis tests. OS and PFS curves (AEs), of which 111 were serious, 390 were related to were plotted using the Kaplan-Meier estimator, and treatment, and 171 were of grade 3–5. The most fre- compared using the log-rank test. Survival analyses are quent grade 3–5 AEs were neutropenia (32 events), as- described by median and 95% confidence interval (CI). thenia (14 events), thrombocytopenia (7 events), The improvement or deterioration in HRQoL was de- pneumonia (6 events), pyrexia (6 events), febrile neutro- fined as an increase or decrease of ≥5 points in the penia (6 events), diarrhea (5 events), and anemia (5 EORTC QLQ-C30 global health status score with re- events). Table 2 summarizes the frequency of most com- spect to baseline [23]. Overall changes in the score mon treatment-related grade ≥ 3 AEs, classified by Sys- throughout the study visits were assessed using the ad- tem Organ Class. justed linear mixed model. The significance level for all analyses was set at a two-sided α = 0.05. Evolution of HRQoL To estimate the minimum sample size needed, we as- The adjusted linear mixed model revealed a significant sumed a rate of QoL improvement of 5%. The rate of difference in QLQ-C30 global health status scores QoL improvement was defined as a minimum increase throughout the Treatment Period (p = 0.005), with of 5–10 points in EORTC QLQ-C30 global health status scores showing an increasing trend at each visit. Overall, scores with respect to baseline. Based on this assump- mean (SD) scores increased from 53.7 (24.6) at baseline tion, a sample size of 110 patients was deemed necessary to 66.7 (18.1) at the 6-month visit. Furthermore, at each to estimate the proportion of patients with an improve- of the follow-up visits, the percentage of patients with ment in QoL 6 months after starting first-line chemo- better QLQ-C30 global health status scores than at base- therapy with a ± 4.1% precision and a 95% CI. Presuming line was ≥46.8% (Fig. 1). Fifty-seven (65.5%) patients im- that 10% of patients may not complete the EORTC proved their HRQoL in at least one visit, 15 (17.2%) QLQ-C30, the approximate number of patients included showed a decline or a stable score, and 15 (17.2%) in the study was 120. All analyses were performed using showed a decline in all visits. Of the 15 patients showing the statistical SAS software for Windows (version 9.4). only deterioration in HRQoL compared to baseline, 13 (86.7%) had QLQ-C30 global health status scores ≥50 at Results baseline. Overall, HRQoL deterioration was more fre- Patient characteristics and treatment outcome quent in patients with higher QLQ-C30 global health Of the 120 patients recruited, four were excluded for not status scores at baseline: the percentage of patients with having a first-line chemotherapy regimen scheduled (n = deterioration at each study visit ranged from 24 to 50% 1), being enrolled in a clinical trial (n = 1), declining to and from 6 to 15% in patients with baseline QLQ-C30 participate in the study for personal reasons after signing global health status scores ≥50 and < 50, respectively Laquente et al. BMC Palliative Care (2020) 19:103 Page 4 of 11 Table 1 Characteristics of study patients and treatment (p < 0.0001). EQ-5D (dimensions and VAS) did not Demographic characteristics change significantly throughout the Treatment Period. Sex, n (%) (n = 116) Regarding the symptom scales included in the QLQ- Male 70 (60.3) C30, the ones assessing pain, appetite, and sleep disturb- Females 46 (39.7) ance improved throughout the treatment, as shown by a significant decrease in their mean scores (Fig. 2). Mean Clinical characteristics scores for nausea and constipation also decreased, albeit Diagnosis, n (%) (n = 116) modestly, whereas mean scores for fatigue, dyspnea, Metastatic after relapse/progression 25 (21.6) diarrhea and financial impact did not show statistically De novo metastatic 91 (78.4) significant differences throughout the Treatment Period % Weight loss in the last 3 mo (median, Q1, Q3) (n = 74) 9.2 (4.5, 14.1) (p = 0.63, p = 0.64, p = 0.06, and p = 0.22, respectively). Weight loss > 10%, n (%) 33 (44.6) Of all variables analyzed for their influence on CA 19.9 UI/mL (median, Q1, Q3) (n = 90) 725.7 (83.0, 7323.0) HRQoL, baseline PS and treatment response significantly Comorbidities, n (%) (n = 116) influenced QLQ-C30 global health status scores. Patients with either KI of 70–80 or ECOG 2 at baseline showed a Hypertension 48 (41.4) significantly greater improvement in HRQoL than the Diabetes 35 (30.2) corresponding groups with better PS, reaching similar Performance Status QLQ-C30 global health status scores after 2 months of ECOG Performance Status, n (%) (n = 103) chemotherapy (Fig. 3). Regarding treatment response, 0–1 84 (81.6) baseline QLQ-C30 global health status scores were simi- 2 19 (18.4) lar in patients whose best response during first-line Karnofsky Index, n (%) (n = 115) treatment was either partial/complete or stable disease 90–100 60 (52.2) and in patients with progression as best response. How- ever, patients whose best response was partial/complete 70–80 55 (47.8) or stable disease had significantly higher QLQ-C30 glo- Treatment characteristics and outcome bal health status scores at each study visit during the Treatment, n (%) (n = 113) first 3 months than those with progression as best re- Gemcitabine + nab-paclitaxel 73 (64.6) sponse (Fig. 4). No significant associations were ob- Gemcitabine monotherapy 21 (18.6) served with EQ-5D scores. FOLFIRINOX or mFOLFIRINOX 14 (12.4) Other combinations 5 (4.4) Relationship between health status measures and survival Treatment schedule, n (%) (n = 101) Of all baseline parameters analyzed for their potential role as prognosis factors for survival, KI and QLQ-C30 Patients with any change in the dose or schedule 57 (56.4) global health status scores showed a significant associ- Patients with any delay in the treatment 59 (58.4) ation with OS and/or PFS (Fig. 5). Patients with baseline Reasons for treatment discontinuation, n (%) (n = 111)a KI of 90–100 had a significantly higher OS (but not a Progression 60 (54.1) higher PFS) than patients with baseline KI of 70–80. Pa- Toxicity 15 (13.5) tients with baseline QLQ-C30 global health status scores Clinical deterioration 15 (13.5) ≥50 had a significantly higher OS and PFS than those Lost to follow-up 1 (0.9) scoring < 50. Weight loss in the previous 3 months (> Voluntary withdrawal of the study 1 (0.9) 10% vs. < 10%) did not have a significant influence on OS and PFS. Death 3 (2.7) Other reasons 19 (17.1) Discussion Best response obtained in the first-line treatment, n (%) (n = 87) In this observational prospective study, we found that Complete response 3 (3.4) patients receiving any first-line chemotherapy treatment Partial response 24 (27.6) in routine clinical practice experienced positive changes Stable disease 32 (36.8) in various health domains, resulting in an improvement Progression 28 (32.2) of the HRQoL; this improvement was more notorious in a Patients could have more than one reason for treatment discontinuation patients with poorer HRQoL at treatment start ―there- fore, with most room for improvement. Mean scores of the QLQ-C30 global scale and pain, appetite, sleep dis- turbance, nausea, and constipation symptom scales im- proved throughout the chemotherapy treatment, Laquente et al. BMC Palliative Care (2020) 19:103 Page 5 of 11 Table 2 Common treatment-related adverse events (> 1% of While QLQ-C30 showed good responsiveness and was patients) of grade ≥ 3 classified by System Organ Class and sensitive to changes in HRQoL throughout the Treat- Preferred Term, (n = 113) ment Period, EQ-5D (questionnaire and VAS) did not No. (%) reflect any changes in HRQoL. This finding is in line General disorders and alterations related to the administration site with a previous observational study in patients with Asthenia 6 (5.3) mPAC, in which QLQ-C30, but not EQ-5D, enabled to Hematological disorders identify changes in HRQoL [16]. In contrast, another clinical trial reported significant changes in the scores of Neutropenia 21 (18.6) pain symptoms using EQ-5D in patients with advanced Febrile neutropenia 5 (4.4) pancreatic cancer [24]. To our knowledge, very few stud- Thrombocytopenia 5 (4.4) ies on mPAC patients used EQ-5D to assess HRQoL, Anemia 2 (1.8) likely because other cancer-specific tools, such as QLQ- Hemato-toxicity 2 (1.8) C30 and cancer site-specific instruments, are available. Gastrointestinal disorders In fact, the National Cancer Institute of Canada Clinical Trial Group chose QLQ-C30 as a standard questionnaire Diarrhea 3 (2.7) in clinical trials [25]. Even though EQ-5D lacked sensi- Nervous system disorders tivity, its response rates were slightly higher than those Neurotoxicity 2 (1.8) of the QLQ-C30 questionnaire: mean response rate throughout study visits was 79.0 and 76.1% for EQ-5D dimensions and VAS, respectively, and 70.3% for the whereas scores from the EQ-5D questionnaire (dimen- complete QLQ-C30 questionnaire. The EORTC QLQ- sions and VAS) remained unchanged. The evolution of C30 global health status score, used to investigate corre- HRQoL throughout the first-line treatment, measured lations with baseline PS, treatment response and progno- using the QLQ-C30 global health status score, was sig- sis, reached a mean response rate of 78.6% throughout nificantly influenced by patients’ PS and treatment re- the study. While a consensus on acceptable response sponse. Baseline QLQ-C30 global health status scores rates for patient-reported outcomes remains unestab- influenced OS and PFS, suggesting a prognostic value lished, a 70–80% response rate can be considered rea- for this factor. sonable to good [26]. Although assessing the validity of In this study, two instruments were used to measure these questionnaires was out of the scope of our study, HRQoL: the EORTC QLQ-C30 scale and the EQ-5D. the sensitivity observed with the QLQ-C30 questionnaire Fig. 1 Qualitative changes in QLQ-C30 global health status scale scores at each of the study visits throughout the treatment period. The number of patients experiencing improvement, stability or deterioration in their HRQoL is presented as a percentage over the total of patients attending each of the visits Laquente et al. BMC Palliative Care (2020) 19:103 Page 6 of 11 Fig. 2 Evolution of the mean EORTC QLQ-C30 scores for fatigue, nausea, pain, dyspnea and sleep disturbance (A); and appetite loss, constipation, diarrhea and financial impact (B) throughout the treatment period suggests it is suitable for measuring changes in HRQoL 14 studies reporting changes in HRQoL compared to of mPAC patients undergoing first-line chemotherapy. baseline, five observed an improvement in at least one Despite the importance of assessing HRQoL to evalu- treatment arm, three observed worsening in at least one ate the balance between toxicity and effectivity of treatment arm, and the remaining seven reported no chemotherapy, studies focusing on changes in HRQoL change [6]. Our results, showing a statistically significant of mPAC patients treated with chemotherapy are scarce, 13-point increase in mean QLQ-C30 global health status heterogeneous, and have often reported conflicting re- scores from baseline to Month 6, are in line with the five sults. Kristensen et al. systematically reviewed 23 clinical studies reporting an improvement in HRQoL in the trial trials in advanced pancreatic cancer, which included the setting [7, 9, 27–29]. Likewise, the decrease in pain assessment of HRQoL as a secondary endpoint. Of the scores during the Treatment Period in our cohort, which Laquente et al. BMC Palliative Care (2020) 19:103 Page 7 of 11 Fig. 3 Evolution of the mean QLQ-C30 global health status scale scores according to the baseline Karnosfky Index (A) and ECOG (B) throughout the treatment period indicates an improvement of this symptom, are in line show an improvement throughout the Treatment Period with the seven studies (out of eight clinical trials report- than those with better HRQoL at baseline. ing on the evolution of pain scores) showing an im- Asides from assessing the evolution of HRQoL in real- provement in pain [9, 28, 30–34]. Even though the mean life patients receiving first-line chemotherapy, we inves- QLQ-C30 global health status score improved in our tigated the prognostic value of baseline HRQoL in our study population throughout the Treatment Period, 17% study population. Previous clinical trials and real-life of patients showed only deterioration. Interestingly, pa- studies have demonstrated that baseline HRQoL and tients with worse HRQoL at baseline were more likely to subsequent changes during treatment (global and Laquente et al. BMC Palliative Care (2020) 19:103 Page 8 of 11 Fig. 4 Evolution of the mean QLQ-C30 global health status scale scores according to the best response to first-line treatment. No evaluable patients remained in the progression group beyond month 3 of treatment. SD: stable disease, PR: partial response, CR: complete response subscales) are associated with survival of patients with In addition to the general limitations of observational pancreatic cancer [8, 9, 11–14, 35]. Our results con- designs, such as the uneven sample size across variables firmed this trend in a real-life setting, with patients scor- due to missing data, the results of this study must be ing ≥50 in the QLQ-C30 global health status scale and interpreted in the context of the risk of bias associated showing higher OS and PFS. with a decrease in the study sample over time. This limi- Remarkably, besides low QLQ-C30 global health status tation, also observed in previous studies assessing scores at treatment start, low baseline PS was signifi- HRQoL [6], implies that patients who discontinue treat- cantly associated with a greater improvement in HRQoL ment because of disease progression or death—and, throughout the treatment, presumably because of the therefore, are likely to have poorer HRQoL—are not greater room for improvement in these patients. Thus, followed up any longer. Consequently, the study popula- although QLQ-C30 global health status scores at base- tion is gradually biased towards a better HRQoL as the line were lower in patients with poorer PS (18- and 21- follow-up progresses. Nevertheless, our overall purpose point differences compared to patients with better PS was to describe the changes in HRQoL during first-line for KI and ECOG, respectively), PS scores of both chemotherapy, making it necessary to interrupt follow- groups of patients were consistent after 2 months of up in patients initiating second-line chemotherapy. Fu- chemotherapy. This finding encourages priority assess- ture studies investigating the evolution of HRQoL ment of HRQoL in patients with poorer PS. Regarding throughout further treatment lines shall follow up pa- treatment response, patients with stable disease, or par- tients during larger periods, irrespective of the treatment tial or complete response had persistently higher QLQ- outcome. Furthermore, since a specific questionnaire for C30 global health status scores than those who pro- assessing HRQoL in patients with pancreatic adenocar- gressed during the first 3 months of treatment. Of note, cinoma has been validated [36], its use in future studies HRQoL assessment was restricted to patients receiving may be more adequate. first-line treatment, thus gradually reducing the number of patients in the progression subgroup. The observed Conclusions trend was consistent with data from clinical trials, indi- In summary, our study shows that most patients starting cating a relationship between HRQoL and disease pro- first-line chemotherapy improve their HRQoL throughout gression [3, 5, 6]. the treatment, although this trend might not be applicable Laquente et al. BMC Palliative Care (2020) 19:103 Page 9 of 11 Fig. 5 Overall survival (A,B,C) and progression-free survival (D,E,F) depending on baseline EORTC QLQ-C30 global score (A,D), baseline Karnofsky Index (B,E), and weight loss in the previous 3 months (C,F). Survival is presented as median (95% CI); p-values correspond to the Log-rank test for inter-curve differences to patients who interrupt treatment early in the first few Authors’ contributions months due to progression or toxicity. Unlike clinical tri- BL, AM and DV conceived and designed the study. BL, TM1, CB, MM, CG, CP, SM, LV, TM2, MP, BC, RG, HV and AG acquired, BL, AM and DV analyzed, and als, which usually exclude patients with low PS, our study all authors interpreted the data. All authors revised the manuscript drafts revealed that these patients—which are likely to have critically for important intellectual content and reviewed and approved the poorer HRQoL—may benefit more from chemotherapy in final version of the paper. terms of HRQoL. In line with the psychometric properties reported in validation studies of the EORTC QLQ-C30, in Funding This study was promoted, sponsored, and funded (including statistical and our experience, the administration of the questionnaire medical writing support) by Celgene. The funding body contributed to study during routine follow-up visits of patients with mPAC was design, data analysis, and revision of the manuscript drafts; all members of feasible. Taken together, our results suggest that, in the funding body involved in this work have been included in the author list. addition to PS, the EORTC QLQ-C30 global health status score may help to identify mPAC patients that are more Availability of data and materials likely to benefit from chemotherapy., and that HRQoL Additional data used in this study are available from the corresponding may be a useful factor to stratify patients in clinical trials. author on reasonable request. Finally, our study shows that the EORTC QLQ-C30 scale is a responsive tool for identifying changes in HRQoL of Ethics approval and consent to participate mPAC patients who have started first-line chemotherapy. All study participants signed the corresponding informed consent before their inclusion in the study. Participation in the study was voluntary and patients did not receive honoraria for signing the informed consent. The Abbreviations study was conducted in accordance with the Helsinki Declaration and the mPAC: Metastatic pancreatic adenocarcinoma; HRQoL: Health-related quality local Personal Data Protection Law (LOPD 15/1999); the study protocol was of life; PS: Performance status; OS: Overall survival; PFS: Progression free approved by the Clinical Research Ethics Committee of the Bellvitge survival; VAS: Visual analog scale; KI: Karnofsky index Biomedical Research Institute (IDIBELL) (approval ref. EPA035/14). Acknowledgements The authors would like to thank BioClever 2005 SLU for providing statistical Consent for publication medical writing support. Not applicable. Laquente et al. BMC Palliative Care (2020) 19:103 Page 10 of 11 Competing interests 16. Picozzi V, Narayanan S, Henry Hu X, Vacirca J. Health-related quality of life in T. Macarulla has received honoraria for consultancy from Celgene; A. García patients with metastatic pancreatic Cancer. J Gastrointest Cancer. 2017;48: has received non-financial support from Celgene. A. Mut and D. Vilanova are 103–9. employees of Celgene. The authors declare no other conflicts of interest re- 17. Ellis LM, Bernstein DS, Voest EE, Berlin JD, Sargent D, Cortazar P, et al. garding either this work or its funding body. American Society of Clinical Oncology perspective: raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol. 2014; Author details 32:1277–80. 1 Institut Catala d’Oncologia, Hospital Duran i Reynals, Hospitalet de 18. Moningi S, Walker AJ, Hsu CC, Reese JB, Wang J-Y, Fan KY, et al. Correlation Llobregat, Avda. De la Gran Via, 199, 08908 L’Hospitalet de Llobregat, of clinical stage and performance status with quality of life in patients seen Barcelona, Spain. 2Vall d’Hebrón University Hospital and Vall d’Hebrón in a pancreas multidisciplinary clinic. J Oncol Pract. 2015;11:e216–21. Institute of Oncology (VHIO), Barcelona, Spain. 3Institut Català d’Oncologia 19. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. (ICO) – Hospital Germans Trias i Pujol, Badalona, Spain. 4Hospital de Sant Pau, The European organization for research and treatment of cancer QLQ-C30: Barcelona, Spain. 5Complejo Hospitalario de Burgos, Burgos, Spain. a quality-of-life instrument for use in international clinical trials in oncology. 6 Corporació Sanitaria Parc Taulí, Sabadell, Spain. 7Hospital Sant Joan de Reus, J Natl Cancer Inst. 1993;85:365–76. Reus, Spain. 8Hospital del Mar, Barcelona, Spain. 9Hospital Universitario de 20. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Salamanca, Salamanca, Spain. 10Complejo Asistencial Universitario de León, group. Ann Med. 2001;33:337–43. León, Spain. 11Hospital El Bierzo, Ponferrada, Spain. 12Institut Català 21. Arraras JI, Arias F, Tejedor M, Pruja E, Marcos M, Martínez E, et al. The EORTC d’Oncologia (ICO), Girona, Spain. 13Celgene S.L.U, Madrid, Spain. QLQ-C30 (version 3.0) quality of life questionnaire: validation study for Spain with head and neck cancer patients. Psychooncology. 2002;11:249–56. Received: 24 January 2020 Accepted: 30 June 2020 22. Badia X, Roset M, Montserrat S, Herdman M, Segura A. The Spanish version of EuroQol: a description and its applications. European Quality of Life scale. Med Clin (Barc). 1999;112(Suppl):79–85. 23. Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of References changes in health-related quality-of-life scores. J Clin Oncol. 1998;16:139–44. 1. Society AC. Cancer. Facts & Figures 2017. American Cancer Society: Atlanta; 2017. 2. Carrato A, Falcone A, Ducreux M, Valle JW, Parnaby A, Djazouli K, et al. A 24. Romanus D, Kindler HL, Archer L, Basch E, Niedzwiecki D, Weeks J, et al. systematic review of the burden of pancreatic Cancer in Europe: real-world Does health-related quality of life improve for advanced pancreatic cancer impact on survival, quality of life and costs. J Gastrointest Cancer. 2015;46: patients who respond to gemcitabine? Analysis of a randomized phase III 201–11. trial of the cancer and leukemia group B (CALGB 80303). J Pain Symptom 3. Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. Manag. 2012;43:205–17. Pancreatic cancer. Nat Rev Dis Prim. 2016;2:16022. 25. Osoba D, Bezjak A, Brundage M, Pater J, National Cancer Institute of Canada 4. Laquente B, Calsina-Berna A, Carmona-Bayonas A, Jiménez-Fonseca P, Peiró Clinical Trials Group. Evaluating health-related quality of life in cancer I, Carrato A. Supportive care in pancreatic ductal adenocarcinoma. Clin clinical trials: the National Cancer Institute of Canada Clinical Trials Group Transl Oncol. 2017;19:1293–302. experience. Value Health. 2007;10(Suppl 2):S138–45. 5. Lewis AR, Pihlak R, McNamara MG. The importance of quality-of-life 26. Mundy D. A question of response rate. Sci Ed. 2002;25:25–6. management in patients with advanced pancreatic ductal adenocarcinoma. 27. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Buckels JAC. A Curr Probl Cancer. 2018;42:26–39. double-blind placebo-controlled, randomised study comparing gemcitabine 6. Kristensen A, Vagnildhaug OM, Grønberg BH, Kaasa S, Laird B, Solheim TS. and marimastat with gemcitabine and placebo as first line therapy in Does chemotherapy improve health-related quality of life in advanced patients with advanced pancreatic cancer. Br J Cancer. 2002;87:161–7. pancreatic cancer? A systematic review. Crit Rev Oncol Hematol. 2016;99: 28. Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost 286–98. A, et al. Randomized phase III trial of gemcitabine plus cisplatin compared 7. Bernhard J, Dietrich D, Glimelius B, Hess V, Bodoky G, Scheithauer W, et al. with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol. 2006; Estimating prognosis and palliation based on tumour marker CA 19-9 and 24:3946–52. quality of life indicators in patients with advanced pancreatic cancer 29. Maisey N, Chau I, Cunningham D, Norman A, Seymour M, Hickish T, et al. receiving chemotherapy. Br J Cancer. 2010;103:1318–24. Multicenter randomized phase III trial comparing protracted venous infusion 8. Diouf M, Filleron T, Pointet A-L, Dupont-Gossard A-C, Malka D, Artru P, et al. (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable Prognostic value of health-related quality of life in patients with metastatic pancreatic cancer. J Clin Oncol. 2002;20:3130–6. pancreatic adenocarcinoma: a random forest methodology. Qual Life Res. 30. Ciuleanu TE, Pavlovsky AV, Bodoky G, Garin AM, Langmuir VK, Kroll S, et al. A 2016;25:1713–23. randomised phase III trial of glufosfamide compared with best supportive 9. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, Ychou M, Bouché O, care in metastatic pancreatic adenocarcinoma previously treated with Guimbaud R, et al. Impact of FOLFIRINOX compared with gemcitabine on gemcitabine. Eur J Cancer. 2009;45:1589–96. quality of life in patients with metastatic pancreatic cancer: results from the 31. Kindler HL, Niedzwiecki D, Hollis D, Sutherland S, Schrag D, Hurwitz H, et al. PRODIGE 4/ACCORD 11 randomized trial. J Clin Oncol. 2013;31:23–9. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo 10. Vickers MM, Lee C, Tu D, Wheatley-Price P, Parulekar W, Brundage MD, et al. in patients with advanced pancreatic cancer: phase III trial of the Cancer Significance of baseline and change in quality of life scores in predicting and leukemia group B (CALGB 80303). J Clin Oncol. 2010;28:3617–22. clinical outcomes in an international phase III trial of advanced pancreatic 32. Moore MJ, Hamm J, Dancey J, Eisenberg PD, Dagenais M, Fields A, et al. cancer: NCIC CTG PA.3. Pancreatology. 2016;16:1106–12. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor 11. Braun DP, Gupta D, Staren ED. Longitudinal health-related quality of life BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of assessment implications for prognosis in stage IV pancreatic cancer. the pancreas: a phase III trial of the National Cancer Institute of Canada Pancreas. 2013;42:254–9. clinical trials group. J Clin Oncol. 2003;21:3296–302. 12. Deng Y, Tu H, Pierzynski JA, Miller ED, Gu X, Huang M, et al. Determinants 33. Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ, et al. Phase and prognostic value of quality of life in patients with pancreatic ductal III study comparing gemcitabine plus cetuximab versus gemcitabine in adenocarcinoma. Eur J Cancer. 2018;92:20–32. patients with advanced pancreatic adenocarcinoma: southwest oncology 13. Lis CG, Gupta D, Grutsch JF. Patient satisfaction with quality of life as a group-directed intergroup trial S0205. J Clin Oncol. 2010;28:3605–10. predictor of survival in pancreatic cancer. Int J Gastrointest Cancer. 2006;37: 34. Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, et al. 35–44. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in 14. Sugimoto H, Kawashima H, Ohno E, Hayashi D, Kuwahara T, Morishima T, patients with advanced pancreatic cancer: an open-label randomised phase et al. The prognostic factors and trajectory of HRQOL in patients with II study. Lancet. 2008;371:2101–8. pancreatic cancer who received psychiatric intervention. J Gastroenterol 35. Anwar S, Tan W, Yu J, Hutson A, Javle M, Iyer R. Quality-of-life (QoL) as a Hepatol. 2016;31:685–90. predictive biomarker in patients with advanced pancreatic cancer (APC) 15. Velanovich V. The association of quality-of-life measures with malignancy and receiving chemotherapy: results from a prospective multicenter phase 2 survival in patients with pancreatic pathology. Pancreas. 2011;40:1063–9. trial. J Gastrointest Oncol. 2014;5:433–9. Laquente et al. BMC Palliative Care (2020) 19:103 Page 11 of 11 36. Eaton AA, Karanicolas P, Johnson MChir CD, Bottomley A, Allen PJ, Gonen M. Psychometric validation of the EORTC QLQ-PAN26 pancreatic Cancer module for assessing health related quality of life after pancreatic resection. JOP J Pancreas. 2017;18:19–25. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.