86 Med J Indones 2023;32(2)

Clinical Research

Prognostic value of neutrophil-to-lymphocyte ratio and fibrinogen levels in ovarian

cancer
Roudhona Rosaudyn1, Faradillah Mutiani2, Indra Yuliati1, Birama Robby Indraprasta1

pISSN: 0853-1773 • eISSN: 2252-8083 ABSTRACT

https://doi.org/10.13181/mji.oa.236880 BACKGROUND High neutrophil-to-lymphocyte ratio (NLR) and fibrinogen levels have
Med J Indones. 2023;32:86–97
been associated with mortality in several malignancies. However, the studies on
Received: March 23, 2023 the association between NLR or fibrinogen levels and ovarian cancer prognosis are
Accepted: September 10, 2023 inconsistent. This study aimed to investigate the prognostic roles of NLR and fibrinogen
Published online: October 02, 2023
in ovarian cancer.
Authors' affiliations:
1
Department Obstetrics and Gynecology,
METHODS A systematic search of electronic databases was performed to analyze
Faculty of Medicine, Universitas
Airlangga, Dr. Soetomo General studies on the association of pre-treatment NLR and fibrinogen levels with overall
Hospital, Surabaya, Indonesia, 2Faculty survival (OS) and progression-free survival (PFS) among patients with ovarian cancer.
of Medicine, Universitas Airlangga, Dr. The hazard ratio (HR) and corresponding 95% confidence intervals [CIs] were analyzed.
Soetomo General Hospital, Surabaya, All statistical analyses were done using RevMan version 5.4 (Cochrane, United
Indonesia
Kingdom).
Corresponding author:
Roudhona Rosaudyn
RESULTS A total of 7,312 patients from 27 studies were included. The median cut-off for
Department Obstetrics and Gynecology,
Faculty of Medicine, Universitas high NLR was 3.6 for OS among 17 studies and 3.23 for PFS among 11 studies reporting
Airlangga, Dr. Soetomo General Hospital, an NLR HR. The median cut-off for fibrinogen levels was 4.0 in 9 studies reporting
Jalan Mayjen Prof. Dr. Moestopo 47, fibrinogen levels HR. High NLR was associated with lower OS (HR 1.35, 95% CI 1.18 to
Surabaya 60131, Indonesia 1.55, p<0.0001, I2 = 76%) and PFS (HR 1.35, 95% CI 1.14 to 1.60, p = 0.0005, I2 = 71%). High
Tel/Fax: +62-31-5501640/
fibrinogen levels were associated with lower OS (HR 1.44, 95% CI 1.14 to 1.82, p = 0.002, I2
+62-31-5012632
E-mail: [email protected] = 81%) and PFS (HR 1.34, 95% CI 1.17 to 1.55, p<0.0001, I2 = 15%). This association occurred
in all ovarian cancer types.

CONCLUSIONS High pre-treatment NLR and plasma fibrinogen levels were related to
poor OS and PFS in ovarian cancer.

KEYWORDS meta-analysis, ovarian cancer, prognosis, progression-free survival,

survival analysis

In 2020, ovarian cancer was the third most common rate of patients with ovarian cancer is approximately
gynecological cancer worldwide. Ovarian carcinoma 49%, mainly because at least half the patients are
accounts for over 90% of all ovarian cancers and is diagnosed with distant-stage disease.3 In patients with
the deadliest gynecological cancer because it is often advanced-stage ovarian cancer (stage IV), the 5-year
diagnosed at an advanced stage.1 It is the foremost survival rate falls to 17%, indicating a poor prognosis.1,4
cause of death in patients with gynecological cancer In women under 65 years of age, the rate is almost
and the fifth most common cause of death in women.2 twice as high (61%) as in those aged 65 years and older
The prognosis of ovarian cancer depends on the (33%).3 However, a better prognosis of ovarian cancer
disease stage at diagnosis. The 5-year relative survival can be predicted by numerous favorable factors,

Copyright @ 2023 Authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://
creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original author and
source are properly cited. For commercial use of this work, please see our terms at https://mji.ui.ac.id/journal/index.php/mji/copyright.

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Medical Journal of Indonesia
 Rosaudyn, et al. | Prognostic role in ovarian cancer 87

including younger age, good performance status, Inclusion and exclusion criteria
histological type other than clear cell or mucinous, Two investigators (RR and MF) independently
well-differentiated tumor, early-stage tumor, smaller identified all the articles. The included studies met
volume before debulking surgery, smaller residual all the following criteria: (1) studies in women with
tumor after primary cytoreductive surgery, BRCA1 or ovarian cancer that reported the prognostic effect of
BRCA2 mutation carrier status, and lack of ascites.5 NLR and/or plasma fibrinogen; (2) NLR and/or plasma
Cancer pathogenesis can be affected by fibrinogen values collected before all treatments; (3)
inflammatory pathways. Hence, identifying the studies investigating the correlation of pretreatment
systemic inflammation status is a high priority.6 NLR and/or fibrinogen levels with overall survival
Inflammation is a significant prognostic risk factor. (OS) and/or progression-free survival (PFS); (4)
Appropriate biological indicators, such as CA125, soluble studies with adequate data to evaluate the hazard
cytokeratin, serum human kallikreins, serum cytokines, ratio (HR) with a 95% confidence interval (CI); and
serum vascular endothelial growth factor, plasma (5) clinical trials, cohort, or case-control studies. The
D-dimer, and fibrinogen, may reflect the inflammatory exclusion criteria were as follows: (1) overlapping or
state.7 The neutrophil-to-lymphocyte ratio (NLR) is a duplicate publications; (2) abstracts, reviews, letters,
marker of systemic inflammation assessed through a case reports, case series, editorials, and comments;
complete blood count examination, providing absolute (3) non-English studies; (4) non-human research;
neutrophil and lymphocyte counts. (5) unpublished trials; (6) studies presenting data
A high pretreatment NLR is primarily associated in graphic form only (e.g., Kaplan–Meier curves)
with poor survival outcomes, based on several meta- without reporting numerical HR values; and (7) full-
analyses of patients with cancer.6,8,9 In recent studies, text unavailability. Disagreements between the two
plasma fibrinogen levels have been associated with researchers were resolved through discussion and
tumor progression and poor prognosis in patients consensus.
with several cancers. For example, increased plasma
fibrinogen levels in hepatocellular carcinoma are Data extraction
independently associated with advanced disease The following characteristics were extracted from
stages and poor prognosis.10 Other studies have also each included study: name of the first author, year
revealed that pretreatment with fibrinogen is a strong of publication, number of patients included in the
predictor of poor survival in gastric and digestive analysis, mean or median age, disease stage, study
cancers with different traits.11,12 Recent studies have design (prospective or retrospective), boundaries used
revealed an association between the NLR or fibrinogen to determine scores, high plasma NLR or fibrinogen
levels and ovarian cancer prognosis. However, these levels, treatment gain, and HR with 95% CI for OS and/
findings are varied. Therefore, this study aimed to or PFS.
investigate the prognostic roles of NLR and fibrinogen
levels in ovarian cancer. Quality assessment of primary study
The quality of the included studies was assessed
using the Newcastle-Ottawa Quality Assessment Scale
METHODS
(NOS). An NOS score of more than five was considered
Search strategy high quality. Disagreements were resolved through
This study followed the Preferred Reporting Items discussion and consensus.
for Systematic Reviews and Meta-Analyses guidelines.
A systematic literature search was performed using Statistical analysis
the PubMed and ScienceDirect databases for relevant The extracted data were collected using the
studies published until July 7, 2023. The subsequent RevMan 5.4 software (Cochrane, United Kingdom).
search phrases used were (“NLR ratio” OR “neutrophil- This analysis was conducted on all included studies for
lymphocyte ratio” OR “Neutrophil to Lymphocyte each relevant outcome. The main outcomes of interest
ratio” OR "fibrinogen") AND (“ovarian cancer” OR were OS and PFS. HR estimates were pooled, weighted
“ovarian malignancy” OR “ovarian carcinoma” OR by generic inverse variance, and calculated using a
“cancer ovary” OR “carcinoma ovary”). random-effects model. Heterogeneity was evaluated

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 88 Med J Indones 2023;32(2)

using Cochran’s Q test and I2 statistics. A random- classified as advanced stage III or IV based on the FIGO
effects model was used if significant heterogeneity was criteria. The studies used different cut-offs to classify
present (I2>50% or Cochran’s Q<0.1). Sensitivity analysis high NLR (range 0.89 to 6.00) and high fibrinogen
was performed to investigate the effect of omitting (range 3.63 to 4.85). The median cut-off for a high
studies that could contribute to data heterogeneity, NLR was 3.6 for OS in 17 studies and 3.23 for PFS in 11
including studies that provided a multivariate HR or in studies that reported an NLR HR. The median cut-off
which NLR or plasma fibrinogen levels were used as for high fibrinogen was 4.0 in nine studies reporting
continuous variables. Predefined subgroup analyses HR fibrinogen levels. The main characteristics of the
were performed according to the disease stage and included studies are summarized in Table 1.13–39
specific treatment. Disease stages were classified as
per the International Federation of Gynecology and Characteristics of high NLR and high plasma fibrinogen
Obstetrics (FIGO) stages (I, II, III, and IV), and advanced The pretreatment NLR and fibrinogen values
stages referred to FIGO stages III and IV. Specific were obtained from blood tests prior to the initial
treatments were classified into surgery, chemotherapy, primary treatment in most studies, except for two
and mixed therapy (surgery and/or chemotherapy). studies¹⁴,²⁴ that included patients with recurrent
Publication bias was assessed by visual inspection of disease and one study²¹ that included patients
funnel plots. All statistical tests were two-sided, and with previous surgical treatment. Patients in eight
statistical significance was defined as p<0.05. studies¹⁵,¹⁸,²³,²⁸,²⁹,³⁷⁻³⁹ underwent surgical intervention or
neoadjuvant chemotherapy (NACT), and patients in 13
studies¹³,¹⁶,¹⁷,¹⁹,²⁰,²⁵⁻²⁷,³¹⁻³³,³⁵,³⁶ underwent primary surgery
RESULTS
(primary staging or debulking surgery) with or without
Extraction process and study characteristics adjuvant chemotherapy as the initial intervention for
A total of 302 studies were identified using the treatment. Four studies¹⁴,²¹,²²,²⁸ included patients who
search strategy. The initial search and study selection were treated with chemotherapy (Table 1).
processes are presented in Figure 1. As a result, 27 studies Of the 5,018 patients in the studies evaluating NLR,
published between 2009 and 2021, which included 7,312 29.5% (1,482 patients) had high NLR levels, 74.0% (1,097
patients, were included in this meta-analysis. patients) were diagnosed with advanced-stage ovarian
The majority of the patients included in the cancer, and the majority had serous carcinoma. Most
studies were above 50 years of age. Most ovarian patients with a high NLR were >50 years of age and
cancers were of epithelial type. However, 15% of the had CA125 levels varying from <35 U/ml to 2,306 U/ml
143 samples in the study by Wang et al13 were non- (Supplementary Table 1). High plasma fibrinogen levels
epithelial ovarian cancers. Most ovarian cancers were were seen in 26.9% (618 of 2,294 patients in plasma

Articles identified (n = 302):

- PubMed (n = 246)
- ScienceDirect (n = 56)

Duplication (n = 50)

Articles screened (n = 252) Exclusion (n = 205):

- Full-text unavailable (n = 38)
- Systematic review or meta-analysis (n = 8)
- Non-English articles (n = 16)
Assessed for eligibility (n = 47) - Not related (n = 143)

Articles excluded because lack of data (n = 20)

Figure 1. Flow chart of the study selection

process Included for meta-analysis (n = 27)

mji.ui.ac.id
 Table 1. Baseline characteristics of the included studies

Duration of follow-up Age (years),

First author, year Study Country Outcomes Cut-off N (months), median/ median/mean FIGO stage, n (%) Treatment strategy NOS
mean (range/SD) (range/SD)
NLR
Prospective
Henriksen,14 2020 Denmark OS ≥4.1 69 19.3 (11.7–33.3) 69 (47–92) NA Chemotherapy 7
cohort
Prospective 1. III: 282 (71.8) 1. PDS: 76 (38.2%)
Marchetti,15 2021 Italy PFS and OS >4 397 24 (4–47) 60.2 (27–89) 7
cohort 2. IV: 111 (28.2) 2. NACT: 123 (61.8%)
1. I: 55 (23.4)
2. I: 28 (11.9)
United
Asher,16 2011 Retrospective OS >4 235 NA 62 (24–90) 3. III: 107 (45.5) Primary surgery 6
Kingdom
4. IV: 34 (14.5)
5. Missing: 11 (4.7)
Primary surgery with/
1. I/II: 189 (54.9)
Komura,17 2018 Retrospective Japan PFS ≥4 344 NA NA without adjuvant 7
2. III/IV: 155 (45.1)
chemotherapy
1. I/II: 54 (38)
Wang,13 2016 Retrospective China PFS and OS >3.43 143 NA 52.27 (14.09) Primary surgery 7
2. III/IV: 89 (62)
Retrospective
Baert,18 2018 Belgium PFS and OS 6 39 NA NA NA PDS and NACT 6
cohort
1. I/II: 168 (48.8) Surgical staging or PDS and
Miao,19 2016 Retrospective China PFS and OS >3.02 344 72 (61–97) 55 (45–84) 7
2. III/IV: 176 (51.2) adjuvant chemotherapy
Surgery and adjuvant
Zhou,20 2018 Retrospective China PFS and OS >3.08 370 >10 years 54.3 (8.7) IIIC 7
chemotherapy
1. I: 61 (19.4)
Badora-Rybicka,21 2. II: 30 (9.5) Platinum-taxane regimen
Retrospective Poland PFS and OS 0.89 315 NA 54 (22–77) 6
2016 3. III: 186 (59) (after previous surgery)
4. IV: 38 (12.1)
Retrospective 1. IIIC: 88 (79.3) NACT 3–4 cycles then with/
Salman,22 2020 Israel OS 6 111 NA NA 6
cohort 2. IV: 23 (20.7) without IDS
1. I: 92 (30.1) 1. NACT: 75 (24.5%)
Jeerakornpassawat,23 2. II: 22 (7.19) 2. Upfront surgery: 231
Retrospective Thailand OS >3.38 306 NA 54.14 (9.72) 6
2020 3. III: 129 (42.2) (75.5%)
4. IV: 18 (5.9) 3. Adjuvant chemotherapy
1. I/II: 59
Retrospective South
Cho,24 2009 OS 2.61 192 20.9 51.8 (12.9) 2. III/IV: 125 Elective surgery 8
cohort Korea
Rosaudyn, et al. | Prognostic role in ovarian cancer

3. Recurrence: 8
89

Table continued on next page

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 Table 1. (continued)
90

Duration of follow-up Age (years),

First author, year Study Country Outcomes Cut-off N (months), median/ median/mean FIGO stage, n (%) Treatment strategy NOS

mji.ui.ac.id
mean (range/SD) (range/SD)
PDS or primary staging
25 1. I/II: 75 (8.6) with/without received
Feng, 2016 Retrospective China PFS and OS >3.24 875 29 (1–115) 56 (30–90) 6
2. III/IV: 800 (91.4) platinum-based adjuvant
chemotherapy
PDS or primary staging
1. I/II: 33 with/without received
Med J Indones 2023;32(2)

Wang,26 2015 Retrospective China PFS and OS 3.77 126 41.3 (3.3–70.4) NA 7
2. III/IV: 93 platinum-based adjuvant
chemotherapy
1. I: 87 (13.3) PDS or primary staging
27 Retrospective 2. II: 34 (5.2) with/without received
Li, 2017 USA OS 5.25 654 49.5 (0.1–175.3) 63 (28–93) 7
cohort 3. III: 416 (63.6) platinum-based adjuvant
4. IV: 117 (17.9) chemotherapy
1. IIIB: 7 (3.6)
3.81 (OS)
28 Retrospective South 2. IIIC: 45 (22.8)
Kim, 2018 PFS and OS and 2.23 197 NA 57 (27–80) NACT then underwent IDS 8
cohort Korea 3. IVA: 89 (45.2)
(PFS)
4. IVB: 56 (28.4)
Retrospective 1. I/II: 28 (30.2)
John-Olabode,29 2021 Nigeria PFS and OS 1.93 93 NA 47.1 PDS and NACT 7
cohort 2. III/IV: 65 (69.8)
1. I: 150 (30)
30 5.7 years (1 month–21 2. II: 44 (9)
Williams, 2014 Retrospective USA OS NA 519 NA NA 6
years) 3. III: 266 (53)
4. IV: 42 (8)
Fibrinogen
1. I: 22
Primary surgical staging
31 2. II: 26
Qiu, 2012 Retrospective China OS 4.0 136 NA 44.42 (12.97) then platinum-based 7
3. III: 81
chemotherapy
4. IV: 7
Retrospective 59.2 1. I/II: 52 (28.0)
Li,32 2019 China OS 3.63 186 NA Primary CRS 7
cohort (51.1–65.9) 2. III/IV: 134 (72.0)
1. I: 88
2. II: 29 Surgery and adjuvant
Polterauer,33 2009 Retrospective Austria OS 4.0 422 29.2 (25.1) 59.9 (13.9) 6
3. III: 252 chemotherapy
4. IV: 53
Retrospective 1. I/II: 23
Hu,34 2020 China PFS and OS 4.0 104 NA 53 (37–81) NA 7
cohort 2. III/IV: 81

Table continued on next page

 Table 1. (continued)

Duration of follow-up Age (years),

First author, year Study Country Outcomes Cut-off N (months), median/ median/mean FIGO stage, n (%) Treatment strategy NOS
mean (range/SD) (range/SD)
Primary staging or
1. I/II: 62 PDS with/without
Feng,35 2016 Retrospective China PFS 4.0 724 29 (1–115) 56 (30–90) 6
2. III/IV: 662 platinum-based adjuvant
chemotherapy
1. I: 22
36 50.6 (11.1), 2. II: 31 CRS and platinum-based
Zhang, 2015 Retrospective China OS and PFS 4.0 190 43 (2–164) 7
(24–76) 3. III: 128 adjuvant chemotherapy
4. IV: 9
1. PDS and adjuvant
1. I/II: 89
Man,37 2015 Retrospective China PFS and OS 4.0 190 48 (2–150) 55 (25–8) chemotherapy 7
2. III/IV: 101
2. NACT
1. CRS then adjuvant
1. I/II: 39
Liu,38 2015 Retrospective China PFS 4.0 125 49 (5–85) 51 (25–73) chemotherapy 7
2. III/IV: 86
2. NACT
1. IIIA: 3 (1.4)
39 Retrospective 2. IIIB: 15 (6.9)
Luo, 2017 NA OS 4.852 217 44.5 (7–167.2) 54.4 (25–84) NACT and non-NACT 7
cohort 3. IIIC: 149 (68.7)
4. IV: 50 (23)

CRS=cytoreductive surgery; FIGO=The International Federation of Gynecology and Obstetrics; IDS=interval debulking surgery; NA=not available; NACT=neoadjuvant chemotherapy; NLR=neutrophil-to-
lymphocyte ratio; NOS=Newcastle-Ottawa Quality Assessment Scale; OS=overall survival; PFS=progression-free survival; PDS=primary debulking surgery; SD=standard deviation
Rosaudyn, et al. | Prognostic role in ovarian cancer
91

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 92 Med J Indones 2023;32(2)

fibrinogen studies), and 81.4% (503 patients) were cancer at all stages and at the advanced stage
diagnosed with advanced-stage ovarian cancer. Almost (Figure 2a). In addition, subgroup analyses based
all the patients had serous epithelial ovarian cancer on the type of therapy administered revealed that
(Supplementary Table 1). patients with a higher NLR who underwent surgery
and chemotherapy had a shorter OS (Supplementary
NLR and OS Figure 1).
Multivariate analysis demonstrated an association
between an NLR greater than the cut-off value and a NLR and PFS
lower OS. In the subgroup analysis, a higher NLR was According to the multivariate analysis, an NLR
associated with lower OS in patients with ovarian higher than the cut-off was associated with a lower

Figure 2. Forest plots showing HR of OS (a) and PFS (b) according to pretreatment NLR. CI=confidence interval; HR=hazard ratio;
NLR=neutrophil-to-lymphocyte ratio; OS=overall survival; PFS=progression-free survival; SE=standard error

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 Rosaudyn, et al. | Prognostic role in ovarian cancer 93

Figure 3. Forest plots showing HR of OS (a) and PFS (b) according to pretreatment fibrinogen level. CI=confidence interval;
HR=hazard ratio; OS=overall survival; PFS=progression-free survival; SE=standard error

PFS. In subgroup analysis, a higher NLR was associated

with shorter PFS in all stages of ovarian cancer (Figure
2b). Subgroup analysis based on the type of therapy
administered revealed that patients with a higher NLR,
both in those who underwent surgery and chemotherapy,
had a lower PFS (Supplementary Figure 2).

Plasma fibrinogen level and OS

Multivariate analysis showed that plasma
fibrinogen levels greater than the cut-off value
were associated with a lower OS. According to the
Figure 4. Funnel plots of HR of plasma fibrinogen according subgroup analysis, higher plasma fibrinogen levels
to the PFS in multivariate analyses (horizontal axis) and the were associated with lower OS in patients with
SE for the HR (vertical axis). Each study is represented by one ovarian cancer at all stages (Figure 3a) and in those
circle. The vertical line represents the pooled effect estimate.
HR=hazard ratio; PFS=progression-free survival; SE=standard
who underwent surgical treatment (Supplementary
error Figure 3).

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 94 Med J Indones 2023;32(2)

Plasma fibrinogen level and PFS to cause the development of malignant tumors,
Fibrinogen levels greater than the cut-off were which increases the probability of and accelerates
associated with lower PFS (Figure 3b) in patients who mutations. Therefore, inflammation can affect the
underwent surgical treatment (Supplementary Figure incidence, tumor stage, and development of cancer.
4). In subgroup analysis, higher plasma fibrinogen Increasing evidence suggests an elevated systemic
levels were associated with lower PFS in patients with inflammatory response as an important indicator of
ovarian cancer at all stages. cancer progression and prognosis.44,45 Recent studies
have shown that the interactions between tumor
Sensitivity analysis cells, immune cells, inflammatory cells, and interstitial
A sensitivity analysis was performed to assess components influence tumor metastasis.43
the effect of each study on the pooled HR. One study Various biochemical or hematological features
included in the pooled meta-analysis was omitted from routinely measured in general blood tests or as ratios
each round of analysis. If the corresponding HR did derived from the measurements can be used to
not change significantly, this suggested that the meta- assess systemic inflammation. Previous studies have
analysis results were credible (data not shown). highlighted several ratios associated with morbidity and
mortality, including NLR, platelet-to-lymphocyte ratio,
Publication bias lymphocyte-to-monocyte ratio, C-reactive protein/
Funnel plots were used to evaluate publication albumin ratio, and systemic immune-inflammation
bias. All NLR analyses exhibited asymmetric funnel index.⁴⁴⁻⁴⁶ However, most of these studies examined
plots, indicating a substantial publication bias. The them as prognostic markers in patients newly
funnel plots of the plasma fibrinogen analyses were diagnosed with cancer, even though this ratio has been
asymmetric, except for the five-study analysis of plasma associated with cancer risk and mortality.44
fibrinogen levels and PFS in ovarian cancer (Figure 4). Lymphocytes, the primary antitumor response
Other funnel plots are shown in Supplementary Figures effectors, have prognostic and predictive values in
5–7. cancer treatment.²²⁻²⁴ The role of neutrophils in cancer
is controversial, as they can either impede or promote
tumor growth.²⁶,²⁷ NLR, a marker of disease burden,
DISCUSSION
was hypothesized to be an independent prognostic
This meta-analysis pooled a large number of studies factor after adjusting for disease stage, metastatic
on the prognostic value of NLR and fibrinogen levels site, and tumor markers.¹⁰–¹² However, data on blood
on OS and PFS in patients with ovarian cancer. Overall, parameters and the mechanical basis for the prognostic
higher NLR or plasma fibrinogen levels were associated value of NLR remain unclear.²³,⁴⁷ NLR is an affordable
with poor prognosis in patients with ovarian cancer. and promising index for cancer prognosis; however,
Patients with low NLR or plasma fibrinogen levels some studies have shown conflicting results.⁷,⁸,⁴⁷⁻⁴⁹
had higher OS and PFS despite heterogeneity. The Other markers of inflammation, such as plasma
prognostic effects of the NLR and plasma fibrinogen fibrinogen, are associated with tumor development
levels were reliable at all stages (FIGO stages I–IV) and and poor prognosis in several patients with cancer.10,50
advanced stages (FIGO stages III–IV). These results For example, studies on hepatocellular carcinoma,10
suggest that decreased NLR or plasma fibrinogen gastrointestinal cancers of different types,11 and gastric
predicts a favorable prognosis in ovarian cancer, in cancer12 have revealed that elevated plasma fibrinogen
agreement with a meta-analysis on pretreatment NLR or levels before treatment are independently associated
plasma fibrinogen and other cancer prognoses.⁸,⁹,¹¹,⁴⁰,⁴¹ with poor prognosis or survival. Tumor growth, invasion,
Analyses of sensitivity and publication bias indicated and distant metastasis are associated with coagulation
that our results were credible. disorders. Several studies have discussed the role of
It is important to identify systemic inflammation fibrinogen in cancer pathogenesis.12–14 Fibrinogens can
status as the inflammatory pathway is known to play a act as a platform to bind to tumor cells and platelets
role in many diseases, including cancer.⁶ Inflammation when they detach from the primary focus into the
is a hallmark of the development and progression of circulation,14 contributing to tumor cell adherence to
cancer.42,43 Chronic inflammation has been suggested distant organs and facilitating tumor angiogenesis.

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 Rosaudyn, et al. | Prognostic role in ovarian cancer 95

Evidence has shown that fibrinogen supplies nutrients This study had several limitations. The varied cut-
and exchanges gases for the proliferation of tumor off values of NLR and plasma fibrinogen in several
cells. Fibrinogen promotes tumor cell migration and studies led to high heterogeneity. Additionally, there
protects cells from the innate immune system by acting was publication bias in the NLR and plasma fibrinogen
as an extracellular matrix.13 Zheng et al51 reported that analyses. Some studies did not explicitly state the
fibrinogen can accumulate and form dense fibrin layers variables included in the multivariate model, thus
around tumor cells, protecting them from natural killer generating uncertainty in interpreting the independent
cell-mediated cytotoxicity. Gropp et al52 also found prognostic value of the NLR. Furthermore, only
that fibrinogen breakup products repress immune English articles were included, leading to language
reactions. and publication biases. Most of the included studies
Based on the present meta-analysis, patients with were retrospective; therefore, additional clinical trials
low NLR and low plasma fibrinogen serum levels had and research are essential to draw more accurate
greater OS and PFS. In a subgroup study of patients with conclusions.
ovarian cancer at any stage who were simultaneously In conclusion, NLR and plasma fibrinogen levels
receiving surgical treatment, those with lower OS were reliable indicators of ovarian cancer prognosis.
and PFS had higher NLR and plasma fibrinogen levels. These affordable tests are widely available at hospitals.
Moreover, multivariate analysis showed that a higher The F-NLR score could also be a prognostic blood
NLR was associated with lower OS and PFS in patients marker. However, these indicators could be affected
with ovarian cancer receiving chemotherapy. These by factors such as disease burden, age, and systemic
results are similar to those of another study involving inflammation. Further research is needed to understand
2,919 patients, in which lower OS and PFS were found the association between prognostic value and the
in the group with high NLR rates in multivariate and combination of NLR and plasma fibrinogen levels.
univariate analyses.53 Luo et al39 also showed that high
Conflict of Interest
plasma fibrinogen levels were associated with poor The authors affirm no conflict of interest in this study.
PFS and OS.
In contrast to the present study, a study on Acknowledgment
None.
preoperative NLR in high-grade serous ovarian cancer
found that high NLR was an independent predictor for Funding Sources
None.
PFS (p = 0.011) but not for OS (p = 0.148) in multivariate
analysis.25 A retrospective study in patients with
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