Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study

发布时间:2011-02-15 来源:Annals of Oncology

J. Beck1, G. Procopio2, E. Bajetta2, U. Keilholz3, S. Negrier4, C. Szczylik5, C. Bokemeyer6, S. Bracarda7, D. J. Richel8, M. Staehler9, U. P. Strauss10, S. Mersmann10, K. Burock11 & B. Escudier12*

1Johannes Gutenberg University Medical Center, Mainz, Germany; 2Medical Oncology Unit 2, Fondazione IRCCS, National Cancer Institute, Milan, Italy; 3Department of  ,Medicine, Charite Berlin, Germany;4Le´on Be´rard Multidisciplinary Center, Lyon Cedex, France; 5Central Clinical Hospital, Warsaw, Poland; 6University Medical Center; Hamburg-Eppendorf, Hamburg, Germany; 7S.C. Medical Oncology, San Donato Hospital, Arezzo, Italy; 8Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 9Department of Urology, University of Munich, Munich, Germany; 10Bayer Vital GmbH, Leverkusen, Germany; 11Bayer Schering Pharma AG, Wuppertal, Germany; 12Immunotherapy Unit, Institut Gustave Roussy, Villejuif, France

Background: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access studyprovided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed.The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-basedpatient population across 11 countries in Europe.

Patients and methods: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. Endpoints included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroupanalyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, andnumber and sites of metastases.

Results: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverseevents (AEs) of any grade, with the most common grade ≥3 AEs including hand–foot skin reaction (13%), diarrhea(7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups wassimilar to that in the overall population. Median PFS was 6.6 months; DCR at ≥8 and ≥12 weeks was 85% and 78%,respectively.

Conclusions: The sorafenib safety profile in European community-based practice settings was similar to thatreported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessmentof sorafenib in important subpopulations of advanced RCC patients.

Key words: expanded access trials, protein kinase inhibitors, renal cell carcinoma, sorafenib, tolerability


Sorafenib is an orally active multitargeted tyrosine kinase inhibitor (TKI) approved by the USA Food and Drug Administration in 2005 and the European Medicines Agency in 2006 for the treatment of advanced renal cell carcinoma (RCC) [1]. The efficacy of sorafenib was demonstrated in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a large phase III study in patients with advanced RCC who had received one prior systemic therapy [2, 3]. In TARGET, sorafenib doubled progression-free survival (PFS) [5.5 months versus 2.8 months; P < 0.001; hazard ratio (HR) = 0.51] as shown by a planned interim analysis and had a manageable safety profile in patients in whom prior cytokine therapy had failed [2]. Based on these data, patients originally randomized to placebo could cross over to the sorafenib arm. Although this crossover confounded the long-term overall survival (OS) results for this study, a subsequent analysis in which censored patients had crossed over revealed a significant survival advantage with sorafenib (17.8 months versus 14.3 months; P = 0.029; HR = 0.78) [3].  

Treatment strategy for advanced RCC changed dramatically with the availability of sorafenib in 2005 and additional TKIs in subsequent years. These targeted agents have substantially improved the prognosis of advanced RCC patients. Data describing use of targeted agents in advanced RCC patients treated in clinical practice are limited [4] because stringent clinical trial eligibility criteria, such as those in TARGET, excluded patients with certain characteristics to ensure a homogeneous cohort. In clinical practice, the advanced RCC population is heterogeneous; many patients present with disease characteristics or demographic factors that may affect survival and treatment tolerability.   

Treatment-associated adverse events (AEs) are considered in the selection of therapies for individual patients. RCC is frequently diagnosed in older patients; ~25% of newly diagnosed patients in the United States are >74 years of age [5]. Elderly patients can be more affected by some AEs than younger patients, e.g. dehydration due to diarrhea [6]. A subset analysis of the younger (

An expanded-access program with sites in North America [8] and Europe provided sorafenib before regulatory approval to advanced RCC patients in whom previous systemic therapy had failed and who had no access to, or were ineligible for, other sorafenib clinical trials. These large open-access studies permitted comprehensive subanalyses evaluating the tolerability and efficacy of sorafenib in patients frequently excluded from clinical trials because of stringent inclusion criteria. We present the findings of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study. EU-ARCCS was an open-label study assessing sorafenib safety and limited data for efficacy in a large varied community- based patient population across 11 countries in Europe with different practice patterns. Safety and efficacy results from this trial offer general insights for sorafenib treatment in a broad range of advanced RCC patients in real-world settings.


Patients aged ≥18 years with advanced RCC and life expectancy >2 months in whom one or more lines of systemic therapy had failed or who were unsuitable for or unable to tolerate cytokine therapy were eligible for the study (Figure 1). Patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2 who were likely to benefit from single-agent sorafenib treatment were included in the study. Inclusion criteria permitted patients with active or progressive brain metastases who had prior therapy for the lesions and patients who had metastatic brain lesions surgically removed. Patients who received systemic and local therapies, including treatment of brain metastases, had to have completely recovered from any toxicity associated with these treatments before study entry.

All patients provided written informed consent before enrollment and any study procedure, including screening, was carried out. The study was conducted in accordance with the International Conference on Harmonization for Good Clinical Practice, Bayer’s Standard Operating Procedures, and Declaration of Helsinki guidelines. Documented approval from appropriate ethics committees and institutional review boards was obtained for all participating centers or countries before the start of the study according to good clinical practice, local laws, regulations, and organizations.

study design
In the noncomparative, open-label EU-ARCCS study, advanced RCC patients were treated with single-agent oral sorafenib (400 mg b.i.d.) on a continuous basis. Dose increases were not permitted. Treatment was discontinued if the patient had progressive disease (PD), was unlikely to benefit from further sorafenib treatment as judged by the investigator, was intolerant of the dose, withdrew consent, was transferred to an alternative sorafenib program or treatment extension protocol, or was switched to commercially available sorafenib once it was approved in the patient’s country of residence.

study assessments: safety and efficacy

Sorafenib safety and tolerability were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. All AEs in this report are drug related, unless otherwise specified. Baseline evaluations were conducted within 28 days before start of therapy. Timing of subsequent tumor evaluations during sorafenib treatment was based on local practice patterns but occurred at least every 3 months. The efficacy of sorafenib was characterized by PFS (defined as the time from start of sorafenib therapy to death or disease progression, whichever occurred first), time to progression (TTP; defined as time from start of sorafenib therapy to progression), and disease control rate [DCR; the proportion of patients who achieved a complete response (CR), partial response (PR)/unconfirmed PR (uPR), or stable disease (SD) maintained for at least 8 or 12 weeks from first demonstration of response]. Disease progression was evaluated using the RECIST or by clinical assessment by the treating physician. The uPR category included patients who had PR by a single radiological measurement and no confirmatory assessment. Patients with disease that had not progressed or who had not died by the time of analysis were censored at their last nonprogressive assessment date. statistical analysis The population for safety analysis included all patients who received at least one dose of sorafenib and at least one safety assessment after the start of sorafenib treatment. All drug-related AEs were recorded, as well as all grade ≥3 AEs and all serious AEs (SAEs), regardless of causal relationship to study drug.   

Patient demographic data and baseline characteristics were analyzed using summary statistics for quantitative variables and frequency tables for qualitative variables. Efficacy analysis was carried out on the intent-to-treat (ITT) population, made up of patients who received at least one dose of sorafenib. Efficacy analyses of overall best response were carried out on the ‘assessable-for-response’ population, i.e. patients with one radiological tumor evaluation at baseline and at least one such evaluation after the start of study drug. Summary statistics were shown for CR, PR, uPR, SD, and PD separated by radiological and clinical evaluation. Kaplan–Meier analyses were carried out for PFS and TTP. Post hoc analyses of safety and efficacy were carried out across patient subgroups, including age (

baseline patient characteristics in the overall (ITT) patient population

From October 2005 to January 2007, 1159 patients diagnosed with advanced RCC in 11 European countries (Belgium,Denmark, France, Germany, Italy, The Netherlands, Poland,  Spain, Sweden, Switzerland, and UK) were enrolled in EU-  ARCCS (Figure 1). Of the 1159 enrolled, 1150 received  sorafenib treatment and were included in the ITT population.  The baseline patient characteristics of the ITT population are  shown in Table 1. The majority of patients were men (75%)  and had an ECOG PS 0 or 1 (85%). The median age was 62  years, and 23% of the patients were ≥70 years. Approximately  half the patients (47%) presented withthree or more tumor  sites at baseline (supplemental Table S1, available at Annals of  Oncology online). The lung was the most common site of  metastasis at baseline (73%), although patients also had  metastases to the bone (32%), liver (28%), and brain (2%). The  majority of patients had received prior therapy including  nephrectomy (89%), systemic anticancer therapy (71%), and/  or cytokine therapy (67%).


Figure 1. Patient disposition.

safety results in the overall patient population

A total of 1145 patients were included in the safety analysis;  94% of patients experienced drug-related AEs of any grade,  45% of whom (519 patients) experienced grade ≥3 AEs  (Table 2). The most common grade ≥3 AEs were hand–foot  skin reaction (HFSR; 13%), diarrhea (7%), fatigue (7%),  hypertension (6%), and rash/desquamation (5%).

Table 1. Baseline patient characteristics

Table 1. Baseline patient characteristics (Continued)

ECOG PS, Eastern Cooperative Oncology Group performance status.

Table 2. Drug-related adverse eventsa by age, ECOG PS, and histology

Table 2. Drug-related adverse eventsa by age, ECOG PS, and histology (Continued)

a Drug-related adverse events occurring in ≥10% of patients.
b Includes oral cavity (clinical exam and functional/symptomatic).
ECOG PS, Eastern Cooperative Oncology Group performance status.

Treatment-emergent SAEs were experienced by 45% of the  overall study population. However, most of these were not  associated with sorafenib, as drug-related SAEs were reported  for 170 patients (15%). The most common drug-related SAEs  included fatigue (1.2%), rash/desquamation (1.2%), and  cardiac ischemia (0.9%). There were 256 deaths within the  safety population during the study; 224 deaths (88%) were  attributed to PD, 6 deaths (2%) to study drug (one each  associated with bowel perforation after radiotherapy [9], blood  infection, gastrointestinal hemorrhage, renal failure, pulmonary  hemorrhage, and hypoxia), and 25 deaths (10%) to other  reasons.

Overall, 537 patients (47%) in the safety population  underwent dose reductions because of AEs of any grade. HFSR  (7%) and diarrhea (3%) were the most common grade ≥3 AEs  leading to dose reduction. Treatment with sorafenib was  generally well tolerated; of the 1145 patients included in the  safety analysis, 211 (18%) discontinued treatment because  of AEs.

efficacy results in the overall (ITT) patient population

Because of the open-label, noncomparative design of this trial, efficacy data collected (including PFS and TTP) are limited. PFS and TTP analyses were based on 835 and 717 events (progression or death), respectively; 27% of patients were censored for PFS and 38% for TTP. The median PFS in the ITT population (n = 1150) was 6.6 months [95% confidence interval (CI) 6.1–7.4] (Figure 2), and the median TTP was 7.9 months (95% CI 7.2–8.6). 

The overall confirmed response rate in EU-ARCCS was 4% (response population, n = 1048), with 1 patient (<1%) achieving CR and 45 patients (4%) achieving PR. Inclusion of uPRs resulted in an overall response rate (CR + PR/uPR) of 17%. Stable disease was reported for 713 patients (68%) at ≥8 weeks and 633 patients (60%) at ≥12 weeks, and primary PD was reported for 101 patients (10%). DCRs at 8 and 12 weeks were 85% and 78%, respectively.

subgroup analysis: safety and efficacy

The large number of patients participating in the EU-ARCCS trial allowed for additional analyses of specific subgroups of patients who may be underrepresented in or excluded from large randomized, controlled trial populations. Safety and efficacy data for patient subgroups were analyzed according to baseline patient characteristics and known prognostic variables including age, ECOG PS, histology, and prior therapies, as well as number of tumor sites and the sites of metastasis (bone, lung, liver, or brain). The data analyzed include baseline characteristics (Table 1 and supplemental Table S1, available at Annals of Oncology online), safety (incidence rates of treatment- emergent drug-related AEs; Tables 2–4), PFS (Figure 3), and DCR (Figure 4). Subgroup analyses by tumor histology, by number of tumor sites, and by the sites of metastases are described in the supplemental information (available at Annals of Oncology online).

subgroup analysis by age and ECOG PS

Patient age can influence treatment strategy, and PS is a known prognostic factor in RCC [10, 11]. Patient data were analyzed according to the following subgroups: age (

Figure 2. Kaplan–Meier analyses of PFS and TTP. CI, confidence interval;PFS, progression-free survival; TTP, time to progression.

Sorafenib treatment was generally well tolerated in patients in EU-ARCCS, independent of age and ECOG PS. The incidence and severity of AEs across patient subgroups were comparable with those in the overall EU-ARCCS safety population, with some notable differences. Fatigue was more common in the older than in the younger patients (44% versus 31%), and patients with baseline ECOG PS 2 had higher incidence rates than those with ECOG PS 1 to 2 of any grade HFSR (66% versus 50%), diarrhea (64% versus 49%), or hypertension (25% versus 16%), while experiencing less vomiting (6% versus 14%). Drug-related SAEs were reported in 14% and 16% of patients

Although there was a trend for longer PFS in older than in younger patients (8.0 versus 6.4 months, respectively), DCRs at 8 and 12 weeks were similar across age-groups and similar to the overall ITT study population. PFS and DCR decreased with worsening ECOG PS: PFS rates for patients with ECOG PS 0, 1 and 2 were 9.2, 6.1, and 3.2 months, respectively; DCRs at 8 weeks were 91%, 85%, and 70%, and at 12 weeks 85%, 77%, and 56%, respectively.

subgroup analysis by prior therapies: cytokines, systemic therapy, and/or nephrectomy

The treatment paradigm for RCC is currently shifting, and many patients are being treated with a sequence of multiple therapeutic modalities. All patients in the ITT population had received at least one other therapy before sorafenib in EU- ARCCS, including nephrectomy (89%; n = 1020), cytokine treatment (33%; n = 375), cytokine in addition to other systemic therapies (34%; n = 390), and noncytokine systemic anticancer therapy (4%; n = 50). To evaluate the safety and efficacy of sorafenib in previously treated patients, analyses were carried out on subpopulations who had or had not undergone prior nephrectomy, cytokine treatment (67%; n = 765), or systemic anticancer treatment, which included prior cytokine and noncytokine therapies (71%; n = 815). 

Table 3. Drug-related adverse eventsa by prior nephrectomy, systemic, or cytokine therapy

a Drug-related adverse events occurring in ≥10% of patients.
b Includes oral cavity (clinical exam and functional/symptomatic).
Table 4. Drug-related adverse eventsa by number of tumor sites and sites of metastases

a Drug-related adverse events occurring in ≥10% of patients.
b Includes oral cavity (clinical exam and functional/symptomatic).

Figure 3. Median PFS for patient subgroups. The median PFS for the overall population is 6.6 months. CI, confidence interval; ECOG PS, Eastern
Cooperative Oncology Group performance status; PFS, progression-free survival.

The baseline characteristics of patients who received prior systemic anticancer and cytokine therapies were generally similar to each other and to the overall ITT study population, as were the characteristics of patients who had undergone nephrectomy, with the exception of ECOG PS, history of cytokine therapy, and number of tumor sites. Compared with patients who received a prior nephrectomy and patients in the overall ITT study population, at baseline, patients who had not received prior nephrectomy were more likely to be of ECOG PS 2 (13% and 15% versus 27%, respectively), less likely to have received prior cytokine therapy (69% and 67% versus 44%, respectively), and more likely to have three or more tumor sites (43% and 47% versus 78%, respectively). The sorafenib safety and efficacy profiles in these subgroups were similar to that in the overall ITT study population (supplemental material, available at Annals of Oncology online).    

Figure 4. DCR at 8 and 12 weeks for patient subgroups (%; 95% CI). The DCR for the overall population is 85% and 78%, respectively. CI, confidence interval; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status.


The EU-ARCCS expanded-access study provided sorafenib, before regulatory approval, to advanced RCC patients in whom prior systemic therapy had failed and who had no access to or were ineligible for other clinical trials with sorafenib. This study collected safety and limited efficacy data from sorafenib therapy in patients who are representative of the general European population in community-based settings with different practice patterns across Europe. This broad heterogeneous population permitted valuable subgroup analyses based on age, ECOG PS, histological features, prior therapy, and the number and sites of metastases. 

Similar to the large expanded-access study of sorafenib conducted in parallel in North America (NA-ARCCS) [8], the inclusion criteria for EU-ARCCS were more liberal than those for previous randomized, controlled trials of sorafenib in RCC. The EU-ARCCS patient population was similar to that of NA- ARCCS, with a comparable median age and distribution of males and sites of metastases. More patients in EU-ARCCS than in NA-ARCCS had three or more tumor sites (47% versus 30%, respectively) and had prior cytokine therapy (67% versus 49%, respectively), which may reflect the different treatment practices common to the respective regions [8]. A recent expanded-access study of sunitinib in clinical settings also enrolled a broad patient population, with substantial proportions of patients with two or more metastatic sites (80%) and prior cytokine therapy (68%) as well as patients with brain metastases (7%) and with intermediate (44%) or poor (9%) Memorial Sloan Kettering Cancer Center (MSKCC) risk scores [12]. The RCC patient population may be more diverse than that frequently enrolled in randomized, controlled trials, highlighting the value of evaluating drug safety and treatment outcomes in expanded-access and open-access studies.

Even with these differences in patient characteristics, the safety profile of sorafenib remained generally consistent with the findings of NA-ARCCS [8] and the pivotal phase III trial, TARGET [2]. The most commonly reported AEs in EU- ARCCS, NA-ARCCS [8], and TARGET [2] were HFSR, diarrhea, fatigue, rash/desquamation, hypertension, and alopecia, and AEs occurred with similar frequency in all three studies. Two exceptions were the incidence of moderate HFSR, which was somewhat higher in EU-ARCCS and NA-ARCCS than in TARGET (13% and 10% grade ≥3 HFSR versus 2% grade 3/4 HFSR, respectively), and the incidence of moderate diarrhea, which was higher in EU-ARCCS than in the NA- ARCCS and TARGET (7% versus 2% grade ≥3 diarrhea and 2% grade 3/4 diarrhea, respectively).

The characteristics chosen for subanalyses of the EU-ARCCS patient population were based on the current clinical landscape of advanced RCC patients. Patient PS (Karnofsky or ECOG) consistently correlates with OS; poor PS predicts poor survival [10, 11]. The age of the patient is also a concern because the impact and prevalence of comorbidities are greater in older patients [6]. Histological subtypes are prognostic for OS; patients with pure clear-cell advanced RCC tend to have better survival than patients with tumors with sarcomatoid features [10, 11]. In subanalyses of patients in EU-ARCCS by these categories, baseline characteristics were mostly similar across subgroups. The few differences were that patients ≥70 years tended to have worse ECOG PS, as did patients with tumors with sarcomatoid features compared with other histological subtypes, although the small number of patients with non- clear-cell RCC limits the strength of the conclusions that can be drawn from this subanalysis.
Another factor prognostic for survival in patients with advanced RCC is prior treatment. A recent retrospective analysis found that patients who had undergone nephrectomy before receiving anti-vascular endothelial growth factor therapy had longer survival than patients who did not receive nephrectomy, although the selection of patients for the procedure may have created a bias for healthier patients with better PS [11]. A similar bias may have been in effect when therapies were selected for patients before their enrollment in EU-ARCCS. In each subanalysis by treatment history, more patients who had prior therapy had ECOG PS 0 than did patients who did not have prior therapy: 42% versus 36% of patients who did or did not receive prior systemic anticancer therapy, 42% versus 35% of patients who did or did not receive prior cytokine therapy, and 41% versus 30% of patients who did or did not have prior nephrectomy, respectively.

Subanalysis of the patient population by the number and sites of metastases revealed that many baseline characteristics were generally similar in these groups. One exception was in patients with bone metastases, which included more patients with ECOG PS 1 or 2 than did the EU-ARCCS population (51% and 21% versus 45% and 15%, respectively). Bone metastases can be painful [13] and may affect the activity level of the patient [14].

Frequency of AEs was similar in all subpopulations analyzed, with a few notable exceptions. Patients with ECOG PS 1 or 2 experienced slightly more nausea and vomiting than those with ECOG PS 0 (20% and 14% versus 14% and 6%, respectively); this pattern may reflect the poorer health status of the patients with ECOG PS 1 or 2. Patients ≥70 years (n = 265) and those with tumors with sarcomatoid features (n = 53) experienced fatigue more frequently than patients

In TARGET, sorafenib doubled the PFS of advanced RCC patients in whom previous cytokine therapy had failed compared with placebo, demonstrating a clear benefit. The median PFS for the ITT population of EU-ARCCS was 6.6 months and was 8.3 months in NA-ARCCS [8]; both studies support the findings in the more homogeneous patient population enrolled in TARGET (5.5 months) [2].

Treatment outcomes did not vary substantially between patient subgroups in EU-ARCCS. As expected, patients with poor ECOG PS or other indicators of risk, such as three or more metastases, had shorter PFS than those with ECOG PS score of zero or one tumor site. Similarly, the DCR indicated substantial tumor response in all populations. Although limited conclusions can be drawn regarding the efficacy of sorafenib in the EU-ARCCS patient population, the consistency of the median PFS and DCR data among these clinically relevant subpopulations suggests that sorafenib is broadly beneficial in advanced RCC patients, regardless of clinical presentation.

The EU-ARCCS study was an expanded-access, noncomparative study, and so it is important to note that these findings are not directly comparable with those from randomized, controlled trials; EU-ARCCS lacked a comparator arm and there are limitations associated with the operation of a large expanded-access study, such as the absence of an independent, centralized reviewer to confirm progression. Gathering data about sorafenib in a real-world setting, however, is essential for developing a full picture of the efficacy and safety of the drug. Moreover, EU-ARCCS enrolled patients frequently excluded from randomized, controlled trials, permitting assessment of the tolerability of sorafenib in relevant populations. All subanalyses demonstrated that sorafenib was consistently well tolerated in advanced RCC patients, regardless of age, PS, histology, prior treatment, or the site or number of metastases. AEs were mild to moderate and were medically manageable. The broad tolerability of sorafenib shown in this study suggests that prospective trials could be cautiously designed in these patient populations to obtain controlled data.


We acknowledge the contributions of other investigators for this study. We thank Ogilvy Healthworld for assisting with manuscript preparation and revision.


Bayer HealthCare and Onyx Pharmaceuticals.


JB received consulting and/or lecture fees from Bayer HealthCare, Pfizer, and Roche; GP received consulting fees from Bayer HealthCare; UK received research funding from Bayer HealthCare; SN received research funding and lecture fees from Bayer HealthCare; CB received consulting and lecture fees from Bayer HealthCare; SB has received consulting fees and/or honoraria from Bayer HealthCare, Pfizer, Roche, Wyeth, and Novartis; DJR indicates no conflicts of interest. MS received consulting fees and research funding from Bayer HealthCare; UPS, KB, and SM are employees of Bayer HealthCare AG; and BE received consulting fees from Bayer HealthCare, Roche, GlaxoSmithKline, and Novartis. The academic investigators (JB, GP, EB, UK, SN, CS, CB, SB, DJR, MS, BE) were responsible for the decision to publish, had unrestricted access to the final data, and vouch for the completeness and accuracy of the data and data analyses. Bayer Healthcare and Onyx Pharmaceuticals funded writing assistance in the form of preparation of the manuscript, references, figures, tables, collation of author comments, editing, and administrative support. The corresponding author had full access to the data in the study, final responsibility for interpretation of the data, and made the decision to submit for publication.


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