Prognostic value of the Glasgow prognostic score in colorectal cancer: a meta-analysis of 9,839 patients

Xin Lu; Wanying Guo; Wei Xu; Xuelei Zhang; Zhijie Shi; Leizhen Zheng; Wenzhao Zhao

doi:10.2147/CMAR.S185350

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Original Research

Prognostic value of the Glasgow prognostic score in colorectal cancer: a meta-analysis of 9,839 patients

Authors Lu X, Guo W, Xu W, Zhang X, Shi Z, Zheng L, Zhao W

Received 26 August 2018

Accepted for publication 16 November 2018

Published 24 December 2018 Volume 2019:11 Pages 229—249

DOI https://doi.org/10.2147/CMAR.S185350

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Rituraj Purohit

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Xin Lu,¹ Wanying Guo,² Wei Xu,¹ Xuelei Zhang,¹ Zhijie Shi,¹ Leizhen Zheng,¹ Wenzhao Zhao¹

¹Department of Gastrointestinal Surgery, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; ²Department of Breast Surgery, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China

Purpose: The aim of this study was to perform a systematic review and meta-analysis to evaluate the value of the Glasgow prognostic score (GPS) or modified Glasgow prognostic score (mGPS) in patients with colorectal cancer (CRC).
Methods: A comprehensive medical literature search was performed using the online databases PubMed, Embase, Web of Science, and the Cochrane Library. After extracting basic characteristics and prognostic data from the included studies, overall survival (OS) and cancer-specific survival (CSS) were pooled as primary outcomes. Subgroup analyses were performed according to therapeutic strategies, models, cutoff values, regions, tumor, node, metastasis stages, sample size, and ages.
Results: Forty-three independent cohorts from 41 studies with 9,839 CRC patients were included in the present study. Correlation between GPS or mGPS and OS was analyzed in 32 cohorts of 7,714 patients, and 23 independent cohorts of 5,375 patients focused on the correlation between GPS or mGPS and CSS. The overall outcomes showed that patients with elevated GPS or mGPS were associated with poor OS (HR: 2.20, 95% CI: 1.88–2.57, P<0.001). Elevated GPS or mGPS also resulted in worse CSS (HR: 1.86, 95% CI: 1.59–2.17, P<0.001). The results of the subgroup analyses confirmed the overall outcomes.
Conclusion: GPS or mGPS is an accurate prognostic predictor in patients with CRC. Patients with elevated pretreatment GPS or mGPS have a poor prognosis. Subgroup analyses confirmed the overall outcomes. Pretreatment GPS is a useful biomarker in the management of CRC.

Keywords: colorectal cancer, Glasgow prognostic score, modified Glasgow prognostic score, systematic review, meta-analysis

Introduction

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies and the fourth leading cause of cancer-related mortality worldwide.^1,2 CRC accounts for ~10% of all newly diagnosed cancers each year.³ Although diagnostic technologies and therapeutic strategies for CRC have markedly improved, the prognosis of patients remains poor, which is attributed to the high rate of tumor recurrence and metastasis.^2,4 The treatment strategies for CRC are based on the biological characteristics of the tumor and the systemic condition of patients. Surgery remains the optimal curative treatment for resectable cancer and the optional strategy for many patients with advanced cancer,⁵ while chemotherapy, immunotherapeutic strategies, and targeted therapy are optional for unresectable cancers.^4,5 Therefore, an accurate prediction model which can predict the prognosis of CRC patients would be useful for the selection of therapeutic modalities.

In previous studies, the tumor, node, metastasis (TNM) stage, which was proposed by the American Joint Committee on Cancer, was considered an effective system for predicting CRC recurrence and patient prognosis.^6,7 However, the TNM stage alone was demonstrated to be inadequate in evaluating prognostic outcomes as tumor progression may be determined by the tumor characteristics as well as systemic inflammation and nutritional status.^8,9 Recently, an increasing number of studies have focused on the prognostic role of inflammation biomarkers in predicting the prognosis of malignancies.^10–12 The Glasgow prognostic score (GPS), an inflammation-based model, has been shown to be an accurate predictor of prognosis in CRC patients in several studies.^13–17 This score is based on the combination of C-reactive protein (CRP) and serum albumin (ALB) levels. It was first reported by Forrest et al in 2003 for its prognostic value in non-small-cell lung cancer.¹⁸ GPS was defined based on the presence of hypoalbuminemia (<35 g/L) and elevated CRP (>10 mg/L): if both were abnormal, the score was 2; if either was abnormal, the score was 1; if neither was abnormal, the score was 0.^19–21 Subsequently, more studies have evaluated the prognostic role of the GPS in a variety of cancers, such as pancreatic cancer, esophageal cancer, and hepatocellular carcinoma.^12,22,23 In addition, some centers applied the modified Glasgow Prognostic Score (mGPS) to evaluate the prognostic outcomes of CRC patients. mGPS is also calculated using CRP and ALB levels. Patients with CRP <10 mg/L were scored 0, those with CRP >10 mg/L were scored 1, and those with CRP >10 mg/L and ALB <35 g/L were scored 2.²⁰ However, the role of the GPS in CRC remains controversial. Ishizuka et al verified the accurate predictive value of GPS,²⁴ while other researchers showed no association between the GPS and the prognosis of CRC patients.^13,19,25,26

In this study, we investigated the prognostic value of pretreatment GPS in CRC patients by searching available relevant studies and conducting a meta-analysis. We also investigated the predictive role of the GPS in patients in different subgroups by subgroup analysis.

Methods

Literature search strategy

A comprehensive medical literature search was performed in May 2018 using the online databases PubMed, Embase, Web of Science, and the Cochrane Library. Studies which focused on the association between GPS and the prognostic outcomes of CRC patients were retrieved. There were no restrictions on language, publication region, and type. Search terms were confined to the following free-text words and Medical Subject Headings: ((C-reactive protein) or (CRP) or (albumin) or (Glasgow prognostic score) or (GPS)) and ((colorectal) or (colon) or (rectum) or (rectal)) and ((cancer) or (cancers) or (tumor) or (tumors) or (carcinoma)). A backward search was also conducted using cross-references from the bibliographies of primary selected studies and relevant studies to ensure a comprehensive search. Two reviewers (Lu X and Guo WY) completed searching for titles and abstracts independently.

Inclusion and exclusion criteria

Two reviewers (Lu X and Guo WY) selected eligible studies independently based on the prespecified inclusion and exclusion criteria. When there were disagreements, a final decision was made by a senior reviewer (Zhao WZ). Inclusion and exclusion criteria were established by all authors.

The inclusion criteria were as follows: 1) studies evaluating patients with CRC; 2) studies evaluating either GPS or mGPS in patients prior to treatment; and 3) studies with a clear presentation of the main outcomes including overall survival (OS) and cancer-specific survival (CSS).

The exclusion criteria were as follows: 1) studies not focusing on the prognosis of CRC patients; 2) studies without survival data; 3) studies not focusing on either pretreatment GPS or mGPS; 4) review articles/editorials; and 5) conference abstracts/case reports.

For duplicate publications by the same authors or departments, only the publications with most representative patient cohorts were included in this meta-analysis. If two or more independent sample sets such as training cohorts and validation cohorts were analyzed in the same study, the cohorts were analyzed independently. Moreover, if the researches were repetitive, only one was included. A flow diagram of study retrieval and selection is shown in Figure 1.

Figure 1 Flow diagram showing study retrieval and selection process.

Abbreviations: CRC, colorectal cancer; GPS, Glasgow prognostic score; mGPS, modified Glasgow prognostic score.

Data management and statistical analyses

EndNote software (version X7, Thomson Reuters, USA) was used for sorting and preliminary screening. Data from the included studies were extracted by two authors (Xu W and Zhang XL) by reading the full text independently. Baseline information including the full list of authors, year of publication, regions of the research, research centers, sample size, follow-up period, TNM stages, and therapeutic strategies was summarized. The endpoints of OS and CSS were characterized by HRs with 95% CIs.

Data were extracted from tables or the text of the included studies. In some studies, the HRs and 95% CIs were not presented in the tables or text. These values were then computed from the Kaplan–Meier graph using the Engauge Digitizer software (version 4.1, M Mitchell, Engauge Digitizer, http://digitizer.sourceforge.net).^27,28 All data from the included studies were pooled using the Cochrane Collaboration’s Review Manager 5.3 (Cochrane Collaboration, Oxford, UK). A fixed effects model was used when there was no obvious heterogeneity (I²=0); otherwise, a random effects model was used. Statistical heterogeneity among the studies was determined using the chi-squared test with a significance level of P=0.10, and heterogeneity was quantified using the I² statistic. A sensitivity analysis of OS was performed using Stata software (version 12.0; StataCorp LP, College Station, TX, USA).²⁹ Funnel plots were used to evaluate publication bias. Symmetry of the funnel plots was analyzed using Egger and Begg tests (Stata, version 12.0).

Risk of bias assessment

All the included studies were critically assessed for methodological quality by two researchers independently (Lu X and Guo WY) by using the Quality In Prognosis Studies tool.³⁰ Each study was graded for the following domains: study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, and statistical analysis and reporting. The risk of bias for each domain is graded as low (−), moderate (±), or high (+).

Subgroup analyses

Subgroup analyses were performed according to the models used to predict the prognostic outcomes of CRC patients as the scoring of the GPS and mGPS models was different. Subgroups were set according to therapeutic strategies, score cutoff values, sample size, region of publication, and TNM stages of patients in the included studies. The treatment modalities included surgical resection (SR) and chemotherapy. The cutoff value for sample size in the studies was a total of 300 patients. The region subgroups were defined as Asian countries and countries out of Asia taking into consideration the differences between the epidemiologic features and clinicopathological characteristics of CRC. Subgroups of TNM stages were divided into patients with advanced tumors of TNM stage IV and patients with TNM stage 0–III.

Results

Characteristics of the included studies

The comprehensive literature search identified a total of 14,359 studies from the above four databases. A flow diagram of study identification and selection is shown in Figure 1. Of these studies, 3,138 were duplicates. The titles and abstracts of the remaining 11,221 studies were then screened. Among the 11,125 studies excluded, 4,732 were not related to CRC, 3,192 were irrelevant studies, 268 were case reports, 71 were reviews or editorials, and 2,862 did not evaluate GPS or mGPS. The full texts of the remaining 96 articles were carefully reviewed, 56 articles were excluded, and 41 articles were finally included in the present study. Of the 56 excluded studies, 18 studies were published by the same center, 18 included duplicate sample sets, 14 did not include survival outcomes, and six were conference abstracts. Two studies were published by the same author in the same year.³¹ However, the patients enrolled in these studies received different treatment modalities (SR and chemotherapy). As a result, both studies were included in this meta-analysis. Two other studies were published by the same center^13,24 and both were included as independent cohorts due to their different endpoints. Patient cohorts in these studies were analyzed independently. Hence, 43 independent cohorts from 41 studies were included in this study.^{13–17,19–21,24–26,31–59} The methodological quality of the included studies is summarized in Table S1.

The characteristics of the included studies are summarized in Table 1. A total of 9,839 patients were enrolled. Thirty-three independent cohorts of 8,006 CRC patients analyzed the correlation between GPS or mGPS and OS, and 26 independent cohorts of 7,616 patients focused on the correlation between GPS or mGPS and CSS. The overall outcomes showed that patients with elevated GPS or mGPS were associated with poor OS (HR: 2.20, 95% CI: 1.88–2.57, P<0.001). In addition, higher GPS or mGPS resulted in worse CSS (HR: 1.86, 95% CI: 1.59–2.17, P<0.001).

Table 1 Characteristics of included studies

Note: Age and follow-up periods were expressed as mean ± SD or median (range).

Abbreviations: CSS, cancer-specific survival; GPS, Glasgow prognostic score; mGPS, modified Glasgow prognostic score; N/A, not available; OS, overall survival; R, resectable; T, training; TNM, tumor, node, metastases; U, unresectable; V, validation.

Subgroup analysis

The results of the subgroup analyses are shown in Table 2. In the model subgroups, elevated GPS resulted in worse OS (HR: 2.08, 95% CI: 1.69–2.55, P<0.001) and CSS (HR: 2.38, 95% CI: 1.63–3.46, P<0.001). Patients in the mGPS subgroup with elevated mGPS were associated with a worse OS (HR: 2.23, 95% CI: 1.79–2.78, P<0.001) and CSS (HR: 1.73, 95% CI: 1.47–2.03, P<0.001) (Figure 2). Patients with increased GPS or mGPS who underwent SR had a poor OS (HR: 2.30, 95% CI: 1.90–2.79, P<0.001) and CSS (HR: 2.06, 95% CI: 1.67–2.53, P<0.001). The chemotherapy subgroup confirmed that elevated GPS or mGPS was associated with a worse OS (HR: 1.95, 95% CI: 1.46–2.62, P<0.001) and CSS (HR: 1.47, 95% CI: 1.24–1.74, P<0.001) (Figure 3). The pooled outcomes of studies which used 1 as the cutoff value demonstrated that CRC patients with elevated GPS or mGPS had a worse OS (HR: 1.85, 95% CI: 1.58–2.16, P<0.001) and CSS (HR: 1.74, 95% CI: 1.48–2.05, P<0.001). Studies which used 2 as the cutoff value also demonstrated that elevated GPS resulted in poor OS (HR: 3.02, 95% CI: 2.21–4.13, P<0.001) and CSS (HR: 2.34, 95% CI: 1.61–3.40, P<0.001) (Figure 4). The pooled outcomes of 21 independent cohorts published in Asia showed that increased GPS or mGPS was associated with worse OS (HR: 2.44, 95% CI: 1.98–3.02, P<0.001) and CSS (HR: 2.01, 95% CI: 1.65–2.44, P<0.001) (Figure 5). The subgroup analysis based on geographical regions showed that Asian patients with increased GPS or mGPS level had a poor OS (HR: 2.44, 95% CI: 1.98–3.02, P<0.001) and CSS (HR: 2.01, 95% CI: 1.65–2.44, P<0.001) (Figure 6). For elderly patients with a mean/median age >65 years, elevated GPS or mGPS was also associated with worse OS (HR: 2.46, 95% CI: 1.93–3.13, P<0.001) and CSS (HR: 1.73, 95% CI: 1.34–2.24, P<0.001) (Figure 7). The subgroup of patients with CRC TNM stage 0–III demonstrated the prognostic value of GPS or mGPS in predicting OS (HR: 2.13, 95% CI: 1.66–2.73, P<0.001) and CSS (HR: 2.01, 95% CI: 1.57–2.58, P<0.001) (Figure 8). The subgroup of patients with CRC TNM stage IV indicated that elevated GPS or mGPS was associated with poor OS (HR: 1.95, 95% CI: 1.56–2.42, P<0.001) and CSS (HR: 1.80, 95% CI: 1.43–2.27, P<0.001).

Table 2 Results of subgroup analyses of overall survival and cancer-specific survival

Abbreviations: df, degrees of freedom; GPS, Glasgow prognostic score; H, high group; L, low group; mGPS, modified Glasgow prognostic score; TNM, tumor, node, metastases.

Figure 2 Subgroup analysis showing correlation between GPS and prognosis of CRC patients according to models.