Measured and perceived effects of audit and feedback on nursing performance: a mixed methods systematic review protocol

Émilie Dufour
Arnaud Duhoux
Jolianne Bolduc
Measured and perceived effects of audit and feedback on nursing performance: a mixed methods systematic review protocol
10.1186/s13643-019-0956-1P R O T O C O L Open Access
Background: The use of audit and feedback (A&F) interventions in health care has been demonstrated to generally be effective on medical teams. However, literature suggests that the response of nurses to this type of intervention may differ from that of other types of health professionals, in relation to their roles, power, and to the configuration of nursing care activities. To our knowledge, no review has been conducted on A&F interventions with nurses. The objective of this systematic review is to examine the evidence of measured and perceived effects of A&F interventions on nurses' performance. Methods: A mixed methods systematic review design with thematic and narrative synthesis is used. Studies reporting quantitative and qualitative data on the effects of A&F interventions specific to nursing care are considered for inclusion. Studies will be appraised for quality using the Mixed Methods Appraisal Tool. Quantitative and qualitative data will be summarized in narrative and tabular form and will be synthetized using a segregated methodologies approach. Discussion: Results will describe the characteristics of A&F with nurses, as well as the measured and perceived effects specific to nursing care. The associations between the characteristics and the effects as well as the concordance between measured and perceived effects will be presented. We anticipate that combining the evidence from qualitative and quantitative studies will allow us to provide relevant insight that can inform the design of better suited A&F interventions for nurses. Audit and feedback interventions demonstrate potential for improving the performance of nursing care. As their effectiveness varies greatly depending on the context and the professionals involved, a better understanding of the associations between its characteristics and the measured and perceived effects is valuable for improving the effectiveness of A&F. Systematic review registration: PROSPERO CRD42018104973

Background

Scientific literature on quality improvement in healthcare highlights the effectiveness of audit and feedback (A&F) [1][2][3][4][5]. A&F is an intervention comprising of two components: (1) evaluation of the performance (audit) and (2) feedback to the professionals. Most of the literature pertaining to A&F involves physicians [1,[5][6][7]. However, some authors suggest that the response of nurses to this type of intervention may differ from that of other types of health professionals [8] in relation to their roles, power, and the configuration of nursing care activities [9][10][11]. Since nurses often work in teams, quality improvement involves changes both at individual and collective levels. Collective improvements, requiring communication, cohesion, and coordination within the nursing team [11,12], make interventions with this group of professionals particularly challenging.

A&F should focus on elements of practice over which professionals perceive to have control and to be accountable for [1,4], which has been suggested to be a current limitation in A&F interventions involving nurses [9][10][11]. Although many studies report the development and use of nursing-sensitive indicators, the access to measurable process indicators is currently lacking [13][14][15][16]. The use of process indicators, as they are more actionable and proximal to nursing care activities, could result in higher improvement rates of nursing performance [16]. The nature of the indicators reported to nurses could therefore influence the overall effectiveness of A&F. In order to design A&F interventions that are suitable for nursing activities, it is relevant to gather the current state of evidence on A&F targeting nurses.

To our knowledge, no systematic review has been conducted on A&F interventions with nurses. Mixed methods systematic reviews are a method of synthesizing knowledge which aims to combine several types of data concerning the same subject in order to present an integrated synthesis of the results produced through different methodologies [17]. A better understanding of how A&F unfolds in nursing practice settings could allow us to implement design elements according to the care settings and professionals involved. Given the paucity of literature on the effectiveness of A&F interventions with nurses [5] and the difficulty of quantitatively measuring nursing-specific effects [14,18], it is relevant to study both the measured and perceived effects of this type of intervention. Performance, in the current paper, is addressed in a comprehensive way [19] and refers to dimensions of quality, effectiveness, and security.

Characteristics of A&F interventions

Although the efficacy of A&F interventions has been well demonstrated, it is well acknowledged that it has large variations depending on certain characteristics [1,20,21]. Some authors have identified A&F characteristics which are more likely to modify its delivery and would therefore explain those variations [1,2]. These characteristics relate to the form, content, and frequency of interventions [2]. Until now, no consensus has been established to provide best practices for developing A&F interventions. The effectiveness of A&F may also be influenced by, among other things, the type of professional, the context of the intervention, and levels of baseline performance [5].

Measured effects

The effects of A&F interventions are usually assessed using quantitative benchmarks in the form of indicators, which monitor the action around the dimensions of performance [5]. As such, the structure-process-outcome triad developed by Donabedian [22] is a quality of care assessment framework designed to include all dimensions of performance of a health organization. To Donabedian [22], the structure component refers to all the elements relating to the framework in which care is provided, including both elements related to environment and those related to staff characteristics. The process component encompasses all the acts performed by the professional in their care delivery activities as well as the way these activities are performed. The outcome component refers not only to the effects of care on the health status of populations [22], but also to organizational outcomes, including the volume of care provided by a health facility [23]. In this review, this triad will be used to extract and analyze data from quantitative studies.

Perceived effects

Quantitative evaluation of these three categories of indicators requires access to data [24]. In nursing, access to data that are both valid and reliable that allows nursing indicators' measurement is an issue [18,[25][26][27]. At present, the measurable effects of A&F interventions on nursing performance have some limitations, such as variable access to reliable nursing-specific indicators [14][15][16]. Hence, it seems highly relevant to review the perceived effects associated with this type of intervention, which are generally evaluated through qualitative studies. Given the small amount of literature related to nurse-specific effects of AF [5], the inclusion of perceived effects is intended to provide a better understanding of how this type of intervention unfolds with nurses influences the perception of their performance. Murray et al. [28] proposed a framework for describing and evaluating the effects of implementing a complex intervention, such as A&F, within a health organization from the perspective of the professionals involved. We believe this framework provides a global and relevant perspective to better understand the actions of the professionals involved in the implementation of a complex intervention. According to this approach, the effects perceived by professionals when implementing an intervention in their practice relate to four areas. The first area, that of coherence, relates to the meaning and value that participants place on intervention [28]. The second area, that of cognitive participation, refers to the commitment and motivation that the implementation of the intervention entails for participants. The third area, that of collective action, refers to the actions that intervention requires in participants' practice changes, for example, in terms of time and training. The last area, the reflexive domain, refers to the perceived effects of changes in practice, for example, in improving the care provided [28]. The assessment of these domains makes it possible to consider the context of implementation of the intervention and its effects on the response of the participants [28]. This framework will be used in this review to ensure the systematic nature of the data extraction and analysis from qualitative studies.

Objective and research questions

The main objective of this review is to identify and appraise the existing evidence on the effects of A&F on nursing performance. It aims to answer the following questions:

1-What are the main features of A&F with nurses? 2-What are the measured effects of A&F on nurses' performance? 3-What are the perceived effects of A&F on nurses' performance? 4-What are the associations between the features of A&F and the measured and perceived effects? 5-What is the concordance between the measured and perceived effects of A&F with nurses?

Methods

Considering mixed methods reviews' approaches are still emerging, we will conduct the data extraction, analysis, and synthesis using a various range of guidelines [17,[29][30][31][32][33].

The specific contributions and applications of these guidelines are presented in each section of the method. The Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) grid [34] will be used as a reference for the preparation and writing of this review. This mixed methods systematic review is registered with the International Prospective Register of Systematic Reviews (PROSPERO) CRD42018104973.

Outcomes

The primary outcome will include any measured or perceived effect of the AF intervention on nursing-related dimensions of performance, such as quality and security of care and effectiveness. A measured effect is defined as any variable that is reported objectively and assessed through quantitative methods. A perceived effect is defined as any variable that is subjectively reported and assessed through qualitative methods.

Eligibility criteria

Criteria have been developed to specifically address the research questions. Thus, studies that meet the following criteria will been included: (1) A&F intervention corresponding to a feedback of the performance to nurses over a given period of time [1], (2) focusing on an A&F intervention with nurses or health professionals including nurses and with specific effects on nurses, (3) describing characteristics of the A&F intervention, and (4) presenting an A&F intervention related to at least one effect related to a dimension of performance. The literature that will meet the following criteria will be excluded: (1) providing feedback to nursing students and (2) focusing on an A&F intervention targeting patients.

Information sources

The strategy will be carried out in three stages. First, an initial search will be performed from CINAHL and MED-LINE to test the identified keywords and descriptors [17]. Then, a second search will be carried out based on the keywords and descriptors identified in all the selected databases. Then, the list of references of identified studies will be analyzed to identify additional articles. Authors recognized as experts in the field will be contacted by email to obtain any additional relevant study related to the research topic [35]. Online periodicals relevant to the area of interest will be identified and searched for additional and non-indexed articles in the databases [35]. Publications in English and French will be considered with no time restriction. The following databases will be used: CINAHL, Cochrane Controlled Register of Trials, Embase, MEDLINE, PubMed, Scopus, Web of Science, PsycINFO, and Global Health. The ProQuest database will be considered for tracking unpublished studies. Quantitative studies will include randomized controlled trials, nonrandomized studies, and descriptive studies [36]. Qualitative studies will include phenomenological studies, grounded theorization, ethnography, action research, case studies, and descriptive qualitative research [36]. Mixed methods studies, if any, will be considered.

Search strategy

Data screening and extraction process

The lead review author (ED) will upload the search results and remove duplicates using EndNoteX8 (Clarivate Analytics). Search results will then be imported into Covidence (https://www.covidence.org), an online systematic review software, to conduct screening, data extraction and quality assessment. Two independent reviewers (ED and JB) will then screen titles and abstracts and classify studies (1) possibly meeting the eligibility criteria, (2) not meeting the eligibility criteria. Studies possibly meeting the inclusion criteria will then be obtained in full-text format. Two review authors will independently complete the full-text screening process (ED and JB). Any disagreement will be discussed and resolved with a third reviewer (AD). A PRISMA flow-chart diagram [34] will be used to report study selection process. Data extraction will be performed by two independent reviewers (ED and JB). For all studies, a grid will be used to extract data on the design, the geographic location, the context, the participants, and the objective of the included studies. For all studies, a table inspired by the questioning formula what, why, who, when, and how that Colquhoun et al. [2] used to classify the characteristics of AF interventions with medical teams will serve the same purpose in our review. Since the object of interest constitutes a heterogeneous field of research [5], we chose to proceed with the steps of extraction, analysis, and presentation of results using reference frameworks previously selected by the research team to ensure a systematic process. Evidence from quantitative studies will be classified in a systematic way following the Donabedian's quality of care triad [22]. Evidence from qualitative studies will be classified in a table inspired by Murray et al.'s framework [28]. This framework will be used to identify themes and classify perceived effects. Data on measured and perceived effects will be extracted from the results and discussion sections of the studies. Data will include statistical analyses, verbatim quotations, and narrative descriptive summaries of results. The extraction will draw on the method proposed by Sandelowski et al. [31] in order to preserve the methodological context of the findings.

Quality assessment of included studies

The quality assessment of included studies will be carried out using the tool Mixed Methods Appraisal Tool (MMAT) [37]. This tool was developed specifically to assess the quality of items with a quantitative, qualitative, or mixed methods design [37]. The quantitative studies will be first categorized according to their characteristics and then assessed according to their respective characteristics, including the sampling strategy, the measuring instruments, and the response rate. For qualitative studies, the assessment criteria will include context, data sources, and data analysis. The evaluation criteria for the mixed methods studies will include the integration of the methods and the limitations presented. Two reviewers (ED and JB), for each of the criteria, will independently assign a score based on "yes," "no," "unspecified," or "not applicable" responses. Any disagreement between the reviewers will be resolved by discussion or by requesting the assessment of a third reviewer (AD).

Data analysis

Given the expected heterogeneity of quantitative data, the evidence on measured effects will be reported in a narrative form following a thematic analysis [38] based on Donabedian's quality of care triad [22]. Qualitative data will be analyzed through the areas described in Murray et al. [28] framework. Data analysis of evidence from quantitative and qualitative studies will be conducted following the three-step narrative approach proposed by Popay et al. [33]. This approach is suited for inclusion of a wide range of research designs that generate both quantitative and qualitative findings on the effects of an intervention [33]. This approach encompasses (1) developing a preliminary synthesis, (2) exploring relationships in the data, and (3) assessing the robustness of the synthesis product [33]. A primary synthesis describing the patterns of direction and size of the effects will be undertaken from the extraction stage and considering the context and characteristics of the included studies [33]. This first synthesis will allow for an in-depth exploration of relationships between contexts, processes, and outcomes [33]. Patterns across studies will be identified by the reviewers in order to synthesis how characteristics and contexts influence the effects of A&F. Following this in-depth synthesis, its robustness will be assessed by considering the methodological quality of the included studies based on the MMAT [36].

Data synthesis

Based on the segregated methodologies proposed by The Joanna Briggs Institute [17,30] and based on Sandelowski et al. [29], an individual synthesis of quantitative and qualitative data will be performed. In this approach, a clear distinction between quantitative and qualitative evidence is required prior to the mixed method synthesis [17]. This first individual synthesis will be conducted following the approach proposed by Popay et al. [33] as previously described.

A mixed method synthesis including all the generated findings will be then be conducted in order to study (1) the association between the A&F features and the measured or perceived effects and (2) the concordance between the measured effects and the perceived effects of A&F interventions with nurses. The combined findings will either support, contradict, or add to the quantitative and qualitative evidence [17]. This mixed method synthesis will follow a configuration approach [32,39]. Using a configuration will allow to make connections between the evidence from both the quantitative and qualitative individual syntheses without merging them [17]. In this review, quantitative data are used to inform measured effects while qualitative data are used to inform perceived effects. Considering both types of effects have different implications for nursing performance, the findings will be used to complement rather than confirm each other [32]. Figure 1 presents the data analysis plan for this mixed method systematic review.

Assessing confidence in the evidence

An assessment of the confidence in the evidence will be conducted from the recommendations made by The Joanna Briggs Institute [40][41][42]. These recommendations have been formulated in a complementary approach to that of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool [42] and are based on the assessment of the coherence of the evidence according to the study specifications [42]. Given the heterogeneity of approaches to evaluating the effects of A&F interventions [5] as well as the inclusion of qualitative studies, this approach is favored in order to make appropriate recommendations. The levels of evidence proposed by The Joanna Briggs Institute [42], in a similar approach to that of GRADE, include the feasibility, relevance, effectiveness, and meaningfulness of the intervention under study. The latter relates more particularly to the evidence assessment for qualitative studies [42].

Discussion

The primary objective of this mixed methods systematic review is to gather evidence on the measured and perceived effects of A&F interventions on nursing performance. Although systematic reviews on measured effects of A&F have been conducted on professionals' practice and health outcomes [5], no review has focused on gathering effects specific to nursing practice. Furthermore, no review has aimed to assess evidence from qualitative as well as quantitative studies. We anticipate that combining these findings to qualitative studies will be highly relevant in providing insight on nurses' perceptions on A&F and therefore to provide recommendations that can improve its design. This review will be valuable to health professionals interested in designing better suited A&F interventions for nurses. The strengths and the limits of the review, as well as recommendations for the implementation of A&F in nursing care will be discussed. One of the main limitations of this review is the heterogeneity in the literature regarding A&F in nursing. We anticipate A&F studies will take place in many different health settings, as well as in various forms and on different topics. We address this potential limitation by using frameworks specific to each type of data. The heterogeneity of the evidence will also be considered for the recommendations made following the evidence assessment.

Search strategy for CINAHL. (DOCX 24 kb) Abbreviations A&F: Audit and feedback; GRADE: Grading of Recommendations Assessment, Development and Evaluation; MMAT: Mixed methods appraisal tool; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses
AcknowledgementsWe would like to thank Assia Mourid, librarian at the paramedical library of the University of Montreal, for the support in developing the search strategy.FundingThis review did not receive any specific funding from financing of the public, commercial or non-profit sector.Availability of data and materials Not applicable.Authors' contributions ED designed the review and the article under the supervision of AD. ED wrote the article. ED, AD, and JB have revised the content of the article. All authors have read and approved the manuscript.Authors' information Not applicable.Ethics approval and consent to participate Not applicable.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.[17]
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Phase II study of oxaliplatin combined with S-1 and leucovorin (SOL) for Chinese patients with metastatic colorectal cancer
2016

Zhi-Qiang Wang
Dong-Sheng Zhang
Nong Xu
De-Yun Luo
Yan-Hong Deng
Feng-Hua Wang
Hui-Yan Luo
Miao-Zhen Qiu
Yu-Hong Li
Rui-Hua Xu
Phase II study of oxaliplatin combined with S-1 and leucovorin (SOL) for Chinese patients with metastatic colorectal cancer

Chin J Cancer
358201610.1186/s40880-015-0061-3ORIGINAL ARTICLEColorectal cancerOxaliplatinS-1Leucovorin
Background: Fluoropyrimidine and oxaliplatin are widely used for patients with colorectal cancer. This phase II study was conducted to evaluate the efficacy and safety of the combination of S-1, oxaliplatin, and leucovorin (SOL) in the treatment of Chinese patients with metastatic colorectal cancer (mCRC).Methods:Eligible patients with untreated mCRC from four hospitals in China received intravenous oxaliplatin (85 mg/m 2 ) on day 1, oral S-1 twice daily (80-120 mg per day) on day 1-7, and leucovorin twice daily (50 mg per day) simultaneously with S-1, every 2 weeks.Results and discussion: Forty patients were enrolled in our study. In total, 296 cycles of SOL were administered. The overall response rate was 50.0%. At a median follow-up of 27 months, progression-free survival and overall survival were 7.0 months (95% confidence interval [CI] 6.0-10.6 months) and 22.2 months (95% CI 15.1-29.3 months), respectively. The most common grade 3/4 non-hematological adverse events were diarrhea (n = 8, 20.0%), nausea (n = 3, 7.5%), and vomiting (n = 3, 7.5%). The most common grade 3/4 hematological toxicities were thrombocytopenia (n = 3, 7.5%), neutropenia (n = 1, 2.5%), and abnormal alanine transaminase/aspartate transaminase levels (n = 1, 2.5%). There was one treatment-related death.Conclusions:The data indicate that the SOL regimen is effective and moderately tolerated in Chinese patients with mCRC.Trial registration: Clinical trial information: ChiCTR-TNRC-100000838

Background

In 2010, colorectal cancer was the fifth most common cancer in men and the third most common cancer in women in China [1]. At present, the combination of oxaliplatin with infusional 5-fluorouracil (5-FU) and leucovorin (known as the FOLFOX regimen) or the combination of irinotecan with infusional 5-FU and leucovorin (known as the FOLFIRI regimen) are considered the standard first-line chemotherapeutic regimens for the treatment of patients with metastatic colorectal cancer (mCRC) [2][3][4]. However, the FOLFOX and FOLFIRI regimens are less desirable because 5-FU must be continuously infused via vascular access. To overcome the inconvenience of continuous infusion of 5-FU, oral fluoropyrimidines, such as capecitabine, have been substituted for infusional 5-FU/leucovorin. Previous studies have shown that capecitabine plus oxaliplatin (CapeOX) was not inferior to the FOLFOX regimen [5].

S-1, a novel dihydropyrimidine dehydrogenase-inhibitory oral fluoropyrimidine, has been prescribed widely for patients with gastric cancer in eastern Asia [6][7][8].

In phase II studies, S-1, as a single agent, resulted in an Open Access *Correspondence: email@example.com; firstname.lastname@example.com † Zhi-Qiang Wang and Dong-Sheng Zhang contributed equally to this work 2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, 510060 Guangzhou, Guangdong, P. R. China Full list of author information is available at the end of the article overall response rate (ORR) of 19%-40% after first-line treatment of mCRC [9][10][11]. Fluoropyrimidines are integral components of the treatment regimen for patients with mCRC. A meta-analysis by Thirion et al. [12] demonstrated that 5-FU plus leucovorin improved the ORR and prolonged overall survival (OS) of patients with mCRC compared with single-agent 5-FU. A Japanese study [13] indicated that S-1 combined with leucovorin (2 weeks on and 2 weeks off ) showed good efficacy in the first-line treatment of mCRC; however, patients in this study who received S-1 and leucovorin (2 weeks on and 2 weeks off ) had a high occurrence rate of diarrhea, anorexia, and stomatitis. The result of a phase II study showed that patients who received S-1 plus leucovorin (1 week on and 1 week off ) had a high ORR and a low occurrence rate of adverse reactions [14].

In an effort to achieve higher efficacy than S-1 and leucovorin (1 week on and 1 week off ) alone and evaluate the safety, we carried out a phase II clinical trial with a regimen of oxaliplatin combined with S-1 and leucovorin (SOL; 1 week on and 1 week off ) in previously untreated Chinese patients with mCRC.

Patients and methods

Eligibility

This study was approved by the ethics committee of Sun Yat-sen University Cancer Center. The reference number is YP2010031. Eligible patients met the following criteria: presence of unresectable, metastatic, and histologically confirmed colorectal adenocarcinoma; adequate oral intake; older than 20 years; Eastern Cooperative Oncology Group performance status of 0-1; estimated life expectancy of more than 3 months; no prior chemotherapy or only fluoropyrimidine adjuvant chemotherapy that was administered more than 6 months before enrollment, or oxaliplatin-based adjuvant chemotherapy that was administered more than 1 year before enrollment; and at least one measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.0). Also, patients had to have adequate hematological, renal, and hepatic functions, as defined by a white blood cell count of 4.0 × 10 9 -12.0 × 10 9 /L, absolute granulocyte count ≥2.0 × 10 9 /L, platelet count ≥100 × 10 9 /L, hemoglobin level ≥90 g/L, serum creatinine level less than the upper limit of normal, serum bilirubin level less than 1.5 times the upper limit of normal, serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels no more than 2.5 times the upper limits of normal (for patients with liver metastasis, less than five times). Finally, they had to provide written informed consent.

Patients were excluded from this study if they had a history of serious hypersensitivity to fluoropyrimidine, oxaliplatin, or leucovorin; an active infection; serious concomitant diseases or conditions (such as intestinal obstruction, bleeding, pulmonary fibrosis, heart failure, renal failure, or liver failure); severe ascites or pleural effusion; extensive bone metastasis; brain metastasis or symptoms of brain metastasis; diarrhea; or another synchronous cancer. We also excluded patients who participated in another clinical study less than 4 weeks previously; women who were pregnant, nursing, possibly pregnant, or planning to become pregnant; and men intending to conceive children.

Treatment plan

Oxaliplatin 85 mg/m 2 mixed with 500 mL of dextrose solution was administered intravenously over 3 h on day 1. The dosage of S-1 was determined according to the patient's body surface area (BSA) as follows: BSA <1.25 m 2 , 40 mg; 1.25 m 2 ≤ BSA < 1.50 m 2 , 50 mg; BSA ≥1.50 m 2 , 60 mg. Leucovorin was given at a fixed dose of 25 mg. S-1 and leucovorin were administered together orally, twice daily from day 1 to 7, followed by a 7-day rest period. The treatment was repeated every 2 weeks until progression of the disease, the development of unacceptable toxicity, or patient withdrawal from the study.

Dose modifications

The doses of oxaliplatin and S-1 were adjusted when severe toxicities occurred. When both agents caused toxicities, the doses of both were reduced. The dose of leucovorin did not need to be reduced. Treatment was interrupted in the case of grade 2 or higher toxicity (except alopecia) and was not resumed until the toxicity had been resolved or alleviated to grade 0 or 1. The dose of oxaliplatin was reduced to 65 mg/m 2 for related grades 3-4 toxicity (or grade 2 peripheral neuropathy). The dose of S-1 was reduced by 20 mg/day for related grade 3 toxicity. The dose of oxaliplatin was reduced to 50 mg/m 2 if the same grade 3 toxicity occurred a second time. The dose of S-1 was reduced by 40 mg/day if the same grade 3 toxicity occurred a second time. No dose increasing was permitted. Treatment was discontinued if the same grade 3 toxicity occurred a third time or the same grade 4 toxicity occurred a second time, despite dose reduction. In addition, if the toxicity was not alleviated to grade 0 or 1 after 4 weeks, the patient was excluded from the study. RECIST 1.0 criteria were used to evaluate tumor response, and the National Cancer Institute-Common Toxicity Criteria for Adverse Events version 3.0 were used to assess toxicity. Tumor responses were evaluated every three cycles by three-dimensional computed tomography or magnetic resonance imaging. All complete and partial responses were assessed and confirmed no less than 4 weeks after the criteria for response were first met. After completion of the study, patients were followed up every 3 months until disease progression or death.

Response and toxicity evaluation

Statistical analysis

The primary endpoints of this study were ORR and progression-free survival (PFS). The secondary endpoints were safety and OS. PFS was defined as time from the initiation of treatment to the first documentation of disease progression or death from any cause. OS was measured from the start of treatment to the last follow-up or death. PFS and OS were estimated based on Kaplan-Meier plots and are presented as median values with a 95% confidence interval (CI).

Simon's optimal two-stage design was used to test the null hypothesis (80% statistical power and 5% significance), the true ORR was less than 20%, against the alternative hypothesis, the true response rate was greater than 40%. As predefined by the protocol, at least six responses were required among the first 17 assessable patients for the study to continue. In the second stage, 21 additional patients were enrolled to achieve a target sample size of 38 assessable patients. Assuming a dropout rate of 5%, 40 patients were initially required for the study.

Results

Patient characteristics

Between March 2010 and October 2012, 40 patients from four hospitals were enrolled. Patient characteristics are listed in Table 1. The median age was 56 years (range 21-79 years), and most patients were men (n = 27, 67.5%). Twenty-three (57.5%) patients had colon cancer. All patients were histologically confirmed as having adenocarcinoma. The majority (72.5%) had moderately differentiated tumors. Thirty-three patients (82.5%) had resected primary tumors. Sixteen patients (40.0%) had previously received adjuvant chemotherapy. The most common metastatic site was the liver (n = 24). The median number of metastatic organs was two (range 1-5). PFS, OS, and safety were assessed for all patients. Five patients were unavailable for the response analysis due to severe adverse events (n = 1) and withdrawing the informed consent (n = 4).

Response to therapy and survival

A total of 296 treatment cycles were delivered to patients. The median number of treatment cycles was nine (range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. No patient had a complete response, but 20 patients had partial responses, 12 had stable disease, and three had progressive disease. The ORR was 50.0% (95% CI 33.8%-66.2%). Tumor response rates are listed in Table 2.

Safety

Safety was assessed in 40 patients based on a total of 296 treatment cycles. Adverse events are listed in Table 3. Diarrhea, which was experienced by 20.0% of the patients, was the most common grade 3/4 adverse event. Neuropathy, which was experienced by 12.5% of the patients, was the second most common grade 3/4 toxicity. Thrombocytopenia, nausea, and vomiting, which were experienced by 7.5% of the patients,  were the third most common grade 3/4 toxicities. Other non-hematologic toxic effects were usually mild (mostly grade 1/2) and manageable. In total, 160 (54.0%) treatment cycles were delayed. Sixty (21.0%) cycles required a dose reduction of oxaliplatin. The causes of dose reduction of oxaliplatin included neuropathy, thrombocytopenia, and diarrhea. S-1 was reduced in 56 (19.0%) cycles because patients experienced diarrhea, hand-foot syndrome, thrombocytopenia, and stomatitis. During the first cycle of treatment, one patient died because of grade 3 diarrhea and febrile neutropenia with lung infection.

Table 2 The responses of 40 Chinese patients with mCRC to the SOL regimen

SOL the combination of S-1, oxaliplatin, and leucovorin regimen. Other abbreviation as in Table 1 a 95% confidence interval of overall response rate is 33.8%-66.2%

Response No. of patients [cases (%)]

Discussion

This phase II study evaluated the efficacy and safety of SOL in the first-line treatment of Chinese patients with mCRC. The ORR was 50.0%, median PFS was 7.0 months, and median OS was 22.2 months. The common adverse events were diarrhea, neuropathy, thrombocytopenia, nausea, and vomiting. FOLFOX and CapeOX are the standard regimens in the first-line treatment of patients with mCRC. In previous studies, the ORR of FOLFOX or CapeOx was determined to be 37%-55%, the median PFS was 6-9.5 months, and the median OS was 16.2-20.8 months with these first-line treatments [2][3][4][5][15][16][17][18][19][20][21]. In recent years, capecitabine and 5-FU can be substituted by S-1 in the treatment of mCRC patients in Japan [22]. A phase II study evaluated the efficacy of the combination of oxaliplatin and S-1 (SOX) in the first-line treatment of mCRC. In this study, the ORR was 54%, the median time to progression (TTP) was 8.5 months, and the median OS was 27.2 months [23]. A phase III study also evaluated the efficacy of SOX and CapeOX in the first-line treatment of mCRC. In this study, the ORR was 47% and 36%, the median PFS was 8.5 and 6.7 months, and the median OS was 21.2 and 20.5 months, respectively [24]. Collectively, the efficacy data from all the previous studies are similar to the efficacy data of the SOL regimen in our study.

Mechanistically, the anti-tumor activity of 5-FU is considered to result from the formation of a ternary complex of 5-fluoro-2′-deoxyuridine-5′-monophosphate (metabolite of 5-FU), thymidylate synthase, and 5,10-methylenete terahydrofolate (metabolite of leucovorin). This complex inhibits thymidylate synthase, thereby blocking DNA synthesis [25]. In a phase II study, the anti-tumor activity of S-1 was enhanced by oral leucovorin due to this mechanism [13]. This study showed an ORR of 57%, a median TTP of 6.7 months, and a median OS of 24.3 months in patients with mCRC treated with the combination of S-1 and leucovorin (2 weeks on and 2 weeks off ). The most common grade 3/4 toxicities were diarrhea (32%), anorexia (21%), mucositis (20%), and neutropenia (14%). The toxicities first occurred during the 2nd week of treatment. Given these data, the combination of S-1 and leucovorin (1 week on and 1 week off ) may have the same efficacy and lower toxicity. The results of a recent phase II study showed that S-1 and leucovorin (1 week on and 1 week off ) produced an ORR of 53.5%, a median TTP of 6.5 months, and a median OS of 24.3 months in the first-line treatment of Mcrc [14]. It showed that the efficacy of S-1 and leucovorin (1 week on and 1 week off ) was similar to that of FOLFOX or CapeOX [2-5, 11-13, 15-18]. The most common grade 3/4 toxicities of S-1 and leucovorin (1 week on and 1 week off ) were diarrhea (8.3%), anorexia (2.8%), mucositis (8.3%), and neutropenia (9.4%), which were less common than the toxicities observed during the treatment with the S-1 and leucovorin (2 weeks on and 2 weeks off ) regimen [13,14].

We hypothesized that the efficacy might be improved when S-1 and leucovorin were combined with oxaliplatin. Therefore, the current study was designed to test the efficacy and safety of the SOL regimen for the first-line treatment of Chinese patients with mCRC.

In our study, diarrhea was the most common grade 3/4 toxicity, which occurred in eight of 40 patients (20.0%). The high occurrence rate of diarrhea was unexpected. One patient died because of grade 3 diarrhea and febrile neutropenia with lung infection after the first cycle. Previous data showed that the occurrence rate of grade 3/4 diarrhea was about 10% when patients received S-1 and leucovorin or SOL (1 week on and 1 week off ) [14]. The reason for the high occurrence rate of diarrhea in our study was unknown. It may be related to the small sample size or the expression of the fluoropyrimidine metabolic enzymes, such as dihydropyrimidine dehydrogenase. Although peripheral neuropathy was commonly observed (95.0%), most cases were grade 1 and grade 2. The occurrence rates of other common grade 3/4 toxicities, such as neutropenia, anorexia, and fatigue, were lower than those observed in a Japanese study [26]. In our study, approximately 54.0% of the treatment cycles Table 3 The adverse events in the 40 Chinese patients with mCRC treated with the SOL regimen NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Events, ALT/AST alanine transaminase/aspartate transaminase. Other abbreviations as in Tables 1 and 2   Event  NCI-CTCAE grade,  Abnormal ALT/AST 7 (17.5) 3 (7.5) 1 (2.5) had to be delayed due to the toxicities. The dose of oxaliplatin was reduced in 21.0% of the cycles, and the dose of S-1was reduced in 19.0% of the cycles due to diarrhea and other toxicities. A Japanese randomized phase II study compared SOL with FOLFOX in patients with untreated mCRC [26]. In this study, the median PFS was 9.6 months in the SOL group and 6.9 months in the FOLFOX group (hazard ratio [HR], 0.83; 95% CI 0.49-1.40), and the median OS was 28.5 and 25.9 months, respectively (HR, 0.91; 95% CI 0.55-1.49). The efficacy shown in our study seemed to be worse than that in the Japanese study. This may be due to the limited sample size, the high rate of toxicities, and low dose density in our study.

In conclusion, the SOL regimen seems to be an effective, moderately tolerated, and convenient therapeutic strategy for the first-line treatment of Chinese patients with mCRC. A phase III study is necessary to validate the clinical outcomes of the SOL regimen.

Authors' contributions

RHX and YHL designed the study. ZQW and DSZ drafted the manuscript, participated in patient selection and implementation of the study. NX, DYL, YHD and FHW assisted in patient selection and helped collect the data. HYL and MZQ performed the statistical analysis. All authors read and approved the final manuscript.

Fig. 1
1Kaplan-Meier curves of progression-free survival and overall survival for 40 Chinese patients with metastatic colorectal cancer. a The estimated progression-free survival was 7.0 months (95% confidence interval [CI] 6.0-10.6 months). b The estimated overall survival was 22.2 months (95% CI 15.1-29.3 months)

Author details 1
1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, 510060 Guangzhou, Guangdong, P. R. China. 2 Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, 510060 Guangzhou, Guangdong, P. R. China. 3 Department of Medical Oncology, The First Affiliated Hospital of College of Medicine, Zhejiang University, 310003 Hangzhou, Zhejiang, P. R. China. 4 Department of Medical Oncology, West China Hospital of Sichuan University, 610041 Chengdu, Sichuan, P. R. China. 5 Department of Medical Oncology, The Sixth Affiliated Hospital of Sun Yat-sen University, 510655 Guangzhou, Guangdong, P. R. China.

Table 1
1Baseline demographic and clinical characteristics of enrolled patients with mCRC mCRC metastatic colorectal cancer, ECOG Eastern Cooperative Oncology Group, PS performance statusCharacteristic
No. of patients [cases (%)]

Sex

Male
27 (67.5)

Female
13 (32.5)

ECOG PS

0
15 (37.5)

1
25 (62.5)

Primary disease site

Colon
23 (57.5)

Rectosigmoid colon
1 (2.5)

Rectum
16 (40.0)

Primary tumor resection

AcknowledgementsThe authors thank the patients who enrolled in this study and their families. They also thank the staff members in the Department of Medical Oncology at Sun Yat-sen University Cancer Center; the staff members in the Department of Medical Oncology at the First Affiliated Hospital of College of Medicine, Zhejiang University; the staff members in the Department of Medical Oncology at the West China Hospital of Sichuan University; and the staff members in the Department of Medical Oncology at the Sixth Affiliated Hospital of Sun Yat-sen University for their helpful suggestions and assistance. Additionally, they thank Dr. Fu-Gen Li, Dr. Yi-Zhou Ye, and Dr. Ming Yao for their valuable writing advice.Competing interestsThe authors declare that they have no competing interests.
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