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      Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation

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          Abstract

          Background

          A standard therapy for locally advanced rectal cancer (LARC) includes fluoropyrimidine (FP)-based neoadjuvant chemoradiation (nCRT). Previous studies have inconsistently demonstrated that baseline neutrophil- and platelet-to-lymphocyte ratios (NLR and PLR) are predictive of response to nCRT or prognostic of outcomes in LARC.

          Methods

          We reviewed patients with LARC undergoing nCRT followed by surgery from 2005 to 2013 across 8 Canadian cancer centres. Outcome measures of interest were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to assess for associations between baseline hematologic variables and outcomes.

          Results

          Of 1527 identified patients, 1237 (81%) were included in the DFS/OS analysis. Median age was 62 (range 23–88), 69% were male, and 80% had performance status (PS) 0–1. Twenty-six percent had elevated NLR (≥ 4), and 66% had elevated PLR (≥ 150). Ninety-seven percent of patients received FP-based nCRT, with 96% receiving ≥44 Gy. 81% completed neoadjuvant chemotherapy and 95% completed neoadjuvant radiotherapy, with a pCR rate of 18%. After a median follow-up time of 71 months, 8% developed local recurrence, 22% developed distant recurrence and 24% died. 5-year DFS and OS were 69% (95% CI 66–72%) and 79% (95% CI 77–82%), respectively. In multivariate analyses, elevated baseline NLR and PLR were neither prognostic for DFS and OS nor predictive of pCR.

          Conclusions

          NLR and PLR were not found to be independently prognostic for DFS or OS and did not predict for pCR in patients with LARC undergoing nCRT followed by surgery.

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          Most cited references24

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          Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.

          There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic renal cell carcinoma (RCC) treated with vascular endothelial growth factor (VEGF) -targeted therapy. Baseline characteristics and outcomes on 645 patients with anti-VEGF therapy-naïve metastatic RCC were collected from three US and four Canadian cancer centers. Cox proportional hazards regression, followed by bootstrap validation, was used to identify independent prognostic factors for OS. The median OS for the whole cohort was 22 months (95% CI, 20.2 to 26.5 months), and the median follow-up was 24.5 months. Overall, 396, 200, and 49 patients were treated with sunitinib, sorafenib, and bevacizumab, respectively. Four of the five adverse prognostic factors according to the Memorial Sloan-Kettering Cancer Center (MSKCC) were independent predictors of short survival: hemoglobin less than the lower limit of normal (P < .0001), corrected calcium greater than the upper limit of normal (ULN; P = .0006), Karnofsky performance status less than 80% (P < .0001), and time from diagnosis to treatment of less than 1 year (P = .01). In addition, neutrophils greater than the ULN (P < .0001) and platelets greater than the ULN (P = .01) were independent adverse prognostic factors. Patients were segregated into three risk categories: the favorable-risk group (no prognostic factors; n = 133), in which median OS (mOS) was not reached and 2-year OS (2y OS) was 75%; the intermediate-risk group (one or two prognostic factors; n = 301), in which mOS was 27 months and 2y OS was 53%; and the poor-risk group (three to six prognostic factors; n = 152), in which mOS was 8.8 months and 2y OS was 7% (log-rank P < .0001). The C-index was 0.73. This model validates components of the MSKCC model with the addition of platelet and neutrophil counts and can be incorporated into patient care and into clinical trials that use VEGF-targeted agents.
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            The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer.

            Since the initial work, a decade ago that the combination of C-reactive protein and albumin, the Glasgow Prognostic Score (GPS), had independent prognostic value in patients with cancer, there have been more than 60 studies (>30,000 patients) that have examined and validated the use of the GPS or the modified GPS (mGPS) in a variety of cancer scenarios. The present review provides a concise overview of these studies and comments on the current and future clinical utility of this simple objective systemic inflammation-based score. The GPS/mGPS had independent prognostic value in (a) unselected cohorts (4 studies, >19,400 patients) (b) operable disease (28 studies, >8,000 patients) (c) chemo/radiotherapy (11 studies, >1500 patients) (d) inoperable disease (11 studies, >2,000 patients). Association studies (15 studies, >2,000 patients) pointed to an increased GPS/mGPS being associated with increased weight and muscle loss, poor performance status, increased comorbidity, increased pro-inflammatory and angiogenic cytokines and complications on treatment. These studies have originated from 13 different countries, in particular the UK and Japan. A chronic systemic inflammatory response, as evidenced by the GPS/mGPS, is clearly implicated in the prognosis of patients with cancer in a variety of clinical scenarios. The GPS/mGPS is the most extensively validated of the systemic inflammation-based prognostic scores and therefore may be used in the routine clinical assessment of patients with cancer. It not only identifies patients at risk but also provides a well defined therapeutic target for future clinical trials. It remains to be determined whether the GPS has prognostic value in other disease states. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Association of the Lung Immune Prognostic Index With Immune Checkpoint Inhibitor Outcomes in Patients With Advanced Non–Small Cell Lung Cancer

              Question Are pretreatment derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level associated with resistance to immunotherapy in patients with advanced non–small cell lung cancer (NSCLC)? Findings In this cohort study evaluating 466 patients with advanced NSCLC, the Lung Immune Prognostic Index (LIPI), combining baseline dNLR and LDH, was associated with the outcomes of immunotherapy but not chemotherapy. Meaning Poor baseline LIPI, combining dNLR greater than 3 and LDH greater than upper limit of normal, was correlated with worse outcomes for immune checkpoint inhibitor treatment in patients with NSCLC, but not with chemotherapy. This cohort study investigates whether the pretreatment derived neutrophils/(leukocytes minus neutrophils) ratio and lactate dehydrogenase level are associated with resistance to immunotherapy in patients with advanced non–small cell lung cancer. Importance Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma. Objective To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non–small cell lung cancer (NSCLC). Design, Setting, and Participants Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors). Main Outcomes and Measures The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR). Results In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio [HR] 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached [NR]), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P  < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort. Conclusions and Relevance Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.
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                Author and article information

                Contributors
                (403) 521-3166 , shaan.dudani@gmail.com
                hmarginean@toh.ca
                patricia.tang@ahs.ca
                jose.monzon@ahs.ca
                soundouss.raissouni@ahs.ca
                tiasmis@toh.ca
                rgoodwin@toh.ca
                jgotfrit@toh.ca
                winson.cheung@ahs.ca
                mvickers@toh.ca
                Journal
                BMC Cancer
                BMC Cancer
                BMC Cancer
                BioMed Central (London )
                1471-2407
                5 July 2019
                5 July 2019
                2019
                : 19
                : 664
                Affiliations
                [1 ]ISNI 0000 0000 9606 5108, GRID grid.412687.e, The Ottawa Hospital Cancer Centre/University of Ottawa, ; Ottawa, Ontario Canada
                [2 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Alberta Health Services/University of Calgary, ; Calgary, Alberta Canada
                [3 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Alberta Health Services/University of Calgary, ; Medicine Hat, Alberta Canada
                [4 ]ISNI 0000 0001 0702 3000, GRID grid.248762.d, British Columbia Cancer Agency, ; Vancouver, British Columbia Canada
                [5 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Present address: Division of Medical Oncology, Tom Baker Cancer Centre, , University of Calgary, ; 1331 29 St NW, Calgary, AB T2N 4N2 Canada
                Author information
                http://orcid.org/0000-0003-4958-381X
                Article
                5892
                10.1186/s12885-019-5892-x
                6612202
                31277604
                d82ed149-b46b-47a9-b7ee-9a90ac2a1d71
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 9 February 2019
                : 28 June 2019
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                biomarkers,survival,pathologic complete response,inflammatory response,personalized medicine

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