Background
Esophageal cancer is highly lethal1 and the eighth most common cancer in the world.2 In Australia, in 2007-2011, the five-year relative survival rate at diagnosis was 17.5%.3 Although surgical resection has been the traditionally favored treatment,4 since the 1960s there has been a gradual shift toward the use of neoadjuvant therapy.5-7 For esophageal cancer, neoadjuvant therapy can take the form of chemotherapy (CT), radiotherapy or chemoradiotherapy (CRT) administered before surgical resection to reduce tumor size and spread.4,7 Neoadjuvant radiotherapy without accompanying CT is generally not practiced because it has not been shown to enhance survival over surgical resection alone,8 whereas clinical data suggest that neoadjuvant CT and neoadjuvant CRT both offer a survival benefit.4 Thus, clinical practice guidelines currently advocate the use of CT or CRT before surgery.7,9
In 2007, a meta-analysis of randomized control trial (RCT) data highlighted that neoadjuvant CT offered a two-year absolute survival benefit of 7% in comparison to surgical resection alone.4 When examining how the effectiveness of neoadjuvant CT varies as a function of histological tumor subtype, it was shown to have a significant effect on all-cause mortality for adenocarcinoma, but not for squamous cell carcinoma (SCC).4 In the same meta-analysis, Gebski et al.4 observed a two-year absolute survival benefit of 13% for neoadjuvant CRT in comparison to surgical resection alone (with significant effects for both adenocarcinoma and SCC). An update to this meta-analysis, which included an additional seven studies (i.e. 1255 more patients and 57% more events), found comparable results.10 For example, there was a two-year absolute survival benefit of 8.7% for neoadjuvant CRT and 5.1% for neoadjuvant CT.10 While these results would suggest that neoadjuvant CRT delivers superior survival rates in comparison to neoadjuvant CT, in recent times only three RCTs have directly compared these approaches, and the researchers reported no statistically significant differences in survival benefit.11-13
The conflict in results between the RCTs comparing neoadjuvant CT and CRT and the indirect comparisons derived from meta-analyses could be due to cohort differences and/or publication bias. For example, Gebski et al.'s4 meta-analysis has been criticized for mainly using data from RCTs that were published in the 1980s and 1990s, inevitably confounding variation between trials with differences in surgical techniques, radiation doses, CT regimens, staging methods and imaging techniques.12 Further, Gebski et al.4 in their meta-analysis conducted a formal test of publication bias, calculating an estimated zero unpublished studies for neoadjuvant CT but nine unpublished studies for neoadjuvant CRT. This difference could have inflated the absolute survival rate of patients receiving neoadjuvant CRT compared to surgical resection alone, thus giving the impression that neoadjuvant CRT was superior compared to neoadjuvant CT. However, sensitivity analyses conducted by Sjoquist et al.10 for their updated meta-analysis, with comparable conclusions, indicated that the review was robust to publication bias.
Nonetheless, it is also important to note potential criticisms of the RCTs that reported no difference in survival benefits between CT and CRT. Most importantly, it has been argued that the trials were underpowered to detect differences in absolute survival.12,13 Further data are required to determine whether a clinically significant difference exists for the two neoadjuvant treatments and the conditions that might moderate survival benefit.
Given the currently conflicting results, it is unsurprising that standard clinical practice varies between countries. For example, Crosby and Evans1 highlight that neoadjuvant CRT is predominantly favored in much of North America, whereas neoadjuvant CT is favored in the United Kingdom. Currently, there is no consensus on the optimal neoadjuvant therapy.
With the current evidence not being able to differentiate between neoadjuvant CT and neoadjuvant CRT in terms of mean overall survival (CT - 29 months, CRT - 32 months)12 and survival rates at three years,11,13 it is important to consider other outcome variables to assist in treatment evaluation. The American Society of Clinical Oncology recommends prioritizing patient outcomes over cancer outcomes when evaluating new cancer treatments and developing cancer treatment guidelines.14 Patient outcomes can be collected via PROs, which are defined as "a measurement of any aspect of a patient's health status that comes directly from the patient (i.e. without interpretation of the patient's response by a physician or anyone else)".15(p.1) Patient-reported outcomes (PROs) can encompass health-related quality of life (including psychological and somatic wellbeing and functioning), but also refer to signs and symptoms of disease (e.g. pain and fatigue), and experience of care or health behaviors (e.g. smoking).16,17 Collecting PROs is important given that they are more likely than clinical outcome measures to yield information that is relevant to the daily functioning of a person with esophageal cancer.18 Therefore, the PROs of esophageal cancer patients may provide a means to better determine the effectiveness of neoadjuvant CT and CRT.
The current scoping review seeks to identify, describe and compare the nature and timing of PROs that esophageal cancer patients experience following the two types of neoadjuvant therapy approaches. This will be achieved through the identification and inclusion of published and unpublished studies that use quantitative measures of PROs in esophageal cancer patients who have received either neoadjuvant CT or neoadjuvant CRT followed by surgery. We will also describe the PRO measures used for data collection in this patient group, given the diverse range available to researchers.19,20 This review will not only inform clinicians about the likely impacts of both neoadjuvant CT and neoadjuvant CRT, but also guide researchers and clinicians in the collection of PRO data in the future. Ultimately, both neoadjuvant CT and CRT have potentially adverse short-, medium- and long-term effects,19 which will be addressed by collating and comparing reports of the impact of these treatments on PROs. We aim to provide a focused resource to inform clinicians and other health professionals in their evaluation of adjuvant CT or CRT therapy options and will thus address PROs that specifically address psychological and somatic wellbeing, and symptoms. This review will not include PROs more attuned to longer term postsurgery such as satisfaction with care, economic factors or health behaviors.
The conduct and reporting of this review will adhere to the methodology for scoping reviews set out by Peters et al.21 which is an extension of Arksey and O'Malley's22 original framework. A preliminary search of the literature (i.e. The Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports and TRIP database) demonstrated that no systematic reviews, meta-analyses or scoping reviews have compared neoadjuvant CT and CRT in terms of PROs. Instead, they have either focused on the outcomes of survival or observer-rated toxicity,10 and/or comparing one type of neoadjuvant treatment with surgery alone23-25 or comparing palliative CT with radiotherapy.26
The current planned scoping review will serve multiple purposes. First, it will summarize the current literature in regard to the PROs of neoadjuvant CT and neoadjuvant CRT, highlighting key, existing studies that could be used to inform treatment decisions. This scoping review could also be used as a foundation for the development and/or implementation of interventions to address key PROs at sensitive times following these treatments. Further, this scoping review will be of use to health professionals by highlighting any gaps in the literature regarding the impact of neoadjuvant CT or CRT on PROs and the PRO measures commonly used to do so. Finally, by providing a comprehensive overview of the literature in this field, this scoping review may indicate where potential future systematic reviews may be carried out based upon the best available published evidence.
Inclusion criteria
Types of participants
The current scoping review will include studies that have involved people treated for esophageal cancer with either neoadjuvant CT or neoadjuvant CRT and surgery. No studies will be excluded on the basis of the type of CT or CRT administered (including dosage, duration details or timing of data collection/follow-up) or the surgical resection technique used. Age, gender, ethnicity and comorbidity status will not be used to determine inclusion or exclusion, but will be extracted as potentially relevant data for reporting.
Concept
The concept of interest of the proposed scoping review is the type, timing and characteristics of PROs, specifically psychological and somatic quality of life and symptoms, collected following neoadjuvant CT or CRT. Patient-reported outcomes collected at one or more points in time will be eligible.
Context
Studies eligible for inclusion must have taken place in any hospital or clinical context within which people diagnosed with esophageal cancer are treated. Studies that have been conducted with people following their treatment, such as those that have collected data from community- or hospice-dwelling participants will also be eligible for inclusion. This will include studies conducted in any country.
Types of studies
Studies of any design (e.g. experimental, descriptive and observational) reporting quantitative data will be eligible for inclusion. If identified, where previously published systematic or literature reviews have included relevant studies, the primary studies will be sought to determine eligibility for inclusion. Studies reporting qualitative, text and opinion type data, or economic data will not be eligible for inclusion as such data do not correspond with the review objectives or the concept of interest (PROs) of the proposed review. Due to time and resource constraints, only published studies written in English will be eligible for inclusion.
Search strategy
A three-stage search will be undertaken. First, an initial search will be conducted in MEDLINE (via PubMed). Second, an analysis of the keywords contained in the title and abstracts of relevant papers as well as their index terms will then be used to develop a subsequent search strategy for adaptation and use across the following databases: PubMed (via MEDLINE), PubMed (non-MEDLINE content only), Embase, Cochrane Central Register of Controlled Trials, CINAHL, Scopus and Web of Science. This search strategy will be developed with the assistance of a medical research librarian, ensuring that appropriate truncation, wildcards and keywords are used for each database (including both American and English spellings).
Second, only studies published from the year 2000 will be included, as surgical techniques before this time are likely to be outdated,27 and thus, any reported PROs before this date are likely to be less relevant to contemporary clinical research and practice. Third, the reference lists of included studies will be hand searched for additional potentially relevant studies. The following keywords (plus a comprehensive list of variations of these keywords) will be used: esophageal neoplasms, CRT, CT, neoadjuvant therapy, PROs and quality of life. To maximize the number of relevant studies retrieved, terms relating to PROs will be supplemented with terms relating to quality of life (as they have often been used synonymously) and to specific symptoms. Refer to Appendix I for the search strategy used in MEDLINE, which was translated for use in other databases.
To ensure the scoping review search is as comprehensive as it can be, the search strategy will include a range of gray literature sources. This will include digital thesis repositories, clinical trial registers, clinical practice guideline portals and national library catalogs. We will also identify the key cancer/oncology organizations and review their webpages for additional relevant studies. The main cancer and oncology meetings will also be checked. Finally, we will run a general web search using the Google Advanced search engine. Appendix II provides further detail for the gray literature search.
The eligibility criteria will be piloted by two reviewers on the first 50 titles and abstracts, with any disagreements managed via discussion or with input from a third reviewer. Following the piloting process, each reviewer will independently screen the titles and abstracts of the papers that have been identified by the systematic search strategy. Articles that pass the title/abstract screening stage will be retrieved so that their full text can be reviewed by the two reviewers to ensure that they meet the eligibility criteria. Any disagreements will be managed via the process outlined above. The reference lists of papers fulfilling the eligibility criteria will be hand searched for other relevant studies. The screening and eligibility selection process will be managed using Covidence.28
Data extraction
Relevant data will be extracted from included studies as they correspond with the proposed review objectives using the draft tool (Table 1). The relevant characteristics and details regarding the nature of PROs will be extracted and inputted into this table including, where available, what stage of treatment the PROs have been collected. Descriptive information (e.g. publication date, country of origin, number of participants, details of PRO measurement tools, etc.) will also be included. The table may be adapted during the conduct of the review as required. Where necessary, authors of primary studies will be contacted for clarification or missing information.
Presenting the results
Once all relevant data have been extracted from the included studies, it will be presented in tabular form supplemented by narrative descriptions for the review objectives. To address review objective one, data that identify and describe PROs for esophageal cancer patients following either neoadjuvant CT or neoadjuvant CRT will be synthesized and reported. For the purposes of this review, findings in terms of how neoadjuvant CT or CRT impacts psychological and somatic quality of life, and symptoms, at different times following these treatments will be outlined. Objective two will be answered by presenting all data pertinent to the use of quantitative measures used to assess PROs in this population. Further, simple frequencies will be calculated and presented in a table to demonstrate the types of PRO measures used. A narrative summary of the results will also be developed to explain what can be gathered from considering the extracted data for each of the two review objectives combined.
Appendix I: MEDLINE search strategy
Appendix II: Gray literature search strategy
For each "gray" repository used, the complex database search strategy will be simplified, as appropriate, to run effectively. The most basic version of this will be "(o)esophageal cancer" AND Patient Reported Outcomes OR PROs OR PROMs OR Quality of Life OR QOL. Searching for gray literature will therefore require a more iterative process.
References