D-dimer levels predict the treatment efficacy and prognosis of esophageal squamous cell carcinoma treated with PD-1/PD-L1 inhibitors

Abstract

Objectives

This study aimed to explore the value of D-dimer levels in predicting the treatment efficacy and prognosis of advanced esophageal squamous cell carcinoma (ESCC) treated with programmed cell death protein-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors.

Methods

The study retrospectively analyzed 233 ESCC patients who received PD-1/PD-L1 inhibitors. The optimal cut-off values for platelets, fibrinogen, and D-dimer were calculated based on maximally selected rank statistics for patients’ overall survival. Univariate and multivariate analyses of progression-free survival and overall survival were conducted by Cox proportional hazards regression model. Subgroup analyses of D-dimer levels in different fibrinogen levels were performed by log-rank test.

Results

The multivariate Cox regression analyses demonstrated that ESCC patients with D-dimer levels > 236 ng/mL exhibited both poorer progression-free survival (P = 0.004) and overall survival (P < 0.0001) compared to those with low D-dimer levels. The subgroup analyses further indicated that in the group of low fibrinogen levels, the higher D-dimer levels of ESCC patients exhibited significantly shorter progression-free survival (P = 0.0021) and overall survival (P < 0.0001).

Conclusions

The study revealed that the D-dimer levels possess predictive value for the treatment efficacy and prognosis of ESCC patients treated with PD-1/PD-L1 inhibitors.

Keywords

Esophageal carcinoma immune checkpoint inhibitors D-dimer efficacy survival

Introduction

According to data released by the Global Cancer Report in 2020, esophageal carcinoma (EC) ranked seventh in the incidence of all cancers and the total mortality rate ranked sixth.¹ The burden of EC in China is extremely heavy, with the incidence and death rates accounting for nearly half of the global total.² Esophageal squamous cell carcinoma (ESCC) is the majority pathological type (90%–95%).³ The prognosis of EC is poor, and the 5-year survival rate is approximately 30% in China.⁴ Furthermore, the 5-year survival rate is less than 20% in patients with unresectable advanced or metastasis EC.⁵ In recent years, immunotherapy has been successfully applied as a new method for treating solid tumors. As the most used immunotherapy drugs, immune checkpoint inhibitors (ICIs) were confirmed to possess encouraged benefits in the treatments of EC.^6,7 Programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) are the most targeted checkpoints in ICIs. However, the treatment efficacy of anti-PD1/PD-L1 treatment varies, with most patients not responding well and only a small portion benefiting. The overall response rate of immunotherapy in EC patients is less than 30%, and most patients initially receiving PD-1/PD-L1 inhibitors may develop acquired resistance over time.⁸ Given the narrow treatment time window and the high cost of ICIs therapy, it is particularly essential to determine reliable biomarkers before initiating ICIs treatment to predict the treatment efficacy and prognosis. As far as we know, the expression levels of PD-1 and PD-L1, mismatch repair deficiency, microsatellite instability status, and anti-inflammatory cytokine levels have been used to predict the outcomes of ICIs.^9,10 Nevertheless, these items are not routine clinical initiatives, with complex testing procedures and without the ability to fully predict the therapeutic effects of ICIs. Consequently, there is currently a lack of simple and efficient ideal biomarkers for assessing the efficacy and prognosis of ESCC patients treated with PD-1/PD-L1 inhibitors.

Cancer patients often exhibit coagulation and fibrinolysis abnormalities. The coagulation and fibrinolysis systems are closely associated with the progression of malignant tumors.¹¹ Studies have reported that a hypercoagulable state is associated with poor prognosis in various cancers.^12–14 As we all know, platelets, fibrinogen, and D-dimer are the most basic blood biomarkers reflecting the coagulation and fibrinolysis status of patients’ physiological system in clinical practice. Hematological biomarkers are usually convenient to measure, have low costs, and are easy to implement, especially for pre-treatment detection and application, which to some extent improves the efficiency of disease diagnosis and treatment. The value of certain coagulation-fibrinolysis-related biomarkers in predicting the outcomes of ESCC patients has been indicated.^15–20 However, there are limited reports on the value of those biomarkers for assessing the treatment efficacy and prognosis of ESCC patients treated with PD-1/PD-L1 inhibitors.

This study conducted a retrospective analysis of ESCC patients treated with PD-1/PD-L1 inhibitors, aiming to explore the value of D-dimer levels in predicting the efficacy and prognosis.

Materials and methods

General information and inclusion criteria

A total of 233 patients with EC were treated in Zhejiang Cancer Hospital from July 2017 to May 2021 were collected and included. Inclusion criteria are as follows: (a) Patients with advanced or metastatic EC who were not candidates for curative surgery or curative radiotherapy; (b) patients with pathologically confirmed ESCC; (c) patients who received PD-1/PD-L1 inhibitors treatment for ≥ 2 cycles; (d) patients without a history of other malignancies or blood disorders; (e) patients who have not received anticoagulant therapy; and (f) patients with complete clinical data. All data collection in this study was approved by the Ethics Committee of Zhejiang Cancer Hospital and informed consent was obtained from the patients.

Data collection

Clinical data of patients, including gender, age, smoking history, alcohol history, tumor primary location, treatment lines, treatment regimens, and previous treatments were collected through the hospital information system. Based on clinical and pathological data, tumor node metastasis (TNM) staging was rigorously performed for all patients according to the 8th Edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual.²¹ Preoperative relevant hematological markers were collected from all involved patients, including platelet count, fibrinogen levels, and D-dimer levels. Blood samples were collected in a fasting state within 1 week before the patients received PD-1/PD-L1 inhibitors and were tested strictly according to the instructions of the testing equipment and reagents. Fibrinogen and D-dimer were determined using the Werfen^® ACL TOP 700 LAS fully automated coagulation analyzer (Barcelona, Spain) and the Werfen HemosIL^® original reagents, using the Clauss method (fibrinogen) and immunoturbidimetric method (D-dimer). Platelets were determined using the Mindray^® BC-6800/BC-6900 fully automated blood cell analyzer (Shenzhen, China) and the Mindray^® original reagents, with the methodology being electrical impedance method. The clinical reference ranges for each hematological parameter are as follows: FIB: 2.00 g/L–4.00 g/L; D-dimer: 0.00 ng/mL–232.00 ng/mL (DDU); PLT: 125 × 10^9 /L–359 × 10^9 /L.

Follow-up data

According to the Response Evaluation Criteria in Solid Tumors RECIST 1.1,²² we assessed the treatment response of ESCC patients after receiving PD-1/PD-L1 inhibitors. An increase of ≥20% in the sum of the maximum diameters of target lesions or the appearance of new lesions was considered as progressive disease (PD). Progression-free survival (PFS) was defined as the time from the initiation of PD-1/PD-L1 inhibitors therapy to the PD. Overall survival (OS) was defined as the time from the initiation of anti-PD-1/PD-L1 therapy to death from any cause or the end of follow-up. PFS and OS were measured in months. Patients were followed up via telephone or hospital information systems until death or the end of follow-up. The final follow-up date for this study was May 6, 2023.

Statistical analysis

In this study, normally distributed continuous data were represented as mean ± SD (x ± s), while non-normally distributed continuous data were presented as the median (25th percentile, 75th percentile). The optimal cut-off values for platelets, fibrinogen, and D-dimer were calculated using the “survminer” package in R 4.3.1 (R Project for Statistical Computing, Vienna, Austria) based on maximally selected rank statistics for patients’ OS. These cut-off values were subsequently employed to categorize the aforementioned markers into high-level and low-level groups. The relationship between dichotomous clinical factors and D-dimer levels was examined using Fisher's exact test, while the relationship between multicategory clinical factors and D-dimer levels were evaluated through the chi-square test. The univariate and multivariate analyses of PFS and OS were conducted using the Cox proportional hazards regression model. Multivariate analysis employed the stepwise forward (likelihood ratio) method. Subgroup analyses of D-dimer levels in different fibrinogen levels were performed by log-rank test. All Fisher's exact tests, chi-square tests and Cox proportional hazards regression analyses were performed by SPSS 25.0 (IBM Corp., Armonk, NY, USA). Kaplan–Meier survival curves were generated using the “survival”, “ggplot2”, and “survminer” packages in R 4.3.1. Significance was attributed to statistical results when P-values were <0.05 in two-tailed tests.

Results

The optimal cutoff values of platelets, fibrinogen, and D-dimer

Following the maximally selected rank statistics principle, the optimal cut-off values for platelets, fibrinogen, and D-dimer were determined to be 243 × 10⁹ /L, 3.9 g/L, and 236 ng/mL, respectively. Their statistics were 2.274303, 2.645864, and 4.300744, respectively (Figure S1). Utilizing these established cut-off values, a noticeable disparity in OS was evident between the high and low groups for platelets, fibrinogen, and D-dimer (P < 0.05).

The clinical data of 233 ESCC patients and their relationship with D-dimer levels

A total of 233 patients diagnosed with ESCC were included in the study, consisting of 215 (92.27%) males and 18 (7.73%) females, with an average age of 61.89 ± 7.71 years, ranging from 43 to 79 years. The median of blood biomarkers levels were as follows: platelets at 198.00 (158.50, 254.50), fibrinogen at 3.85 (3.36, 4.39), and D-dimer at 240.00 (160.50, 412.50). Among the 233 patients who underwent ICIs therapy, 229 (98.28%) received PD-1 inhibitors, while 4 (1.72%) received PD-L1 inhibitors. Also, among the patients, 83 (36.24%) received first-line treatment, 117 (51.09%) received second-line treatment, and 29 (12.66%) received third-line treatment. Also 171 patients (74.67%) concurrently received radiotherapy and/or chemotherapy. Based on the 8th Edition of the AJCC Cancer Staging Manual, the patients were classified as follows: 35 cases (15.28%) in stage ⅢB, 13 (5.68%) in stage ⅣA, and 181 (79.04%) in stage ⅣB. Additional baseline details are presented in Table S1.

The findings revealed the correlation between D-dimer levels and fibrinogen levels among various clinical factors. The patients who had elevated fibrinogen levels had a higher prevalence of high D-dimer levels (P = 0.008).

The univariate and multivariate analyses of PFS and OS

Up to the termination of the follow-up period, among the 233 patients with ESCC, 214 experienced PD while 19 did not. Among the 19 patients without progression, 11 achieved partial responses, and 8 maintained stable disease. Additionally, 194 patients passed away, while 39 patients survived. The median PFS was 6.0 months (range 0.7–44.2 months), and the median OS was 14.5 months (range 1.7–61.7 months).

The univariate Cox regression analysis of clinical factors showed that third-line treatment (P = 0.020), absence of concurrent radiotherapy or/and chemotherapy (P = 0.001), lower primary location (P = 0.036), fibrinogen > 3.90 g/L (P = 0.023), and D-dimer levels > 236 ng/mL (P = 0.003) were associated with shorter PFS in ESCC patients treated with PD-1/PD-L1 inhibitors (Table 1). Meanwhile, lower primary location (P = 0.017), fibrinogen levels > 3.90 g/L (P = 0.008), D-dimer levels > 236 ng/mL (P < 0.0001), and platelets > 243 × 10⁹ /L (P = 0.017) were associated with shorter OS in ESCC patients treated with PD-1/PD-L1 inhibitors (Table 2). The multivariate Cox regression analysis demonstrated that D-dimer levels > 236 ng/mL (P = 0.004, hazard ratio (HR) = 1.524, 95% confidence interval (CI) = 1.145, 2.030), concurrent radiotherapy or/and chemotherapy (P = 0.001; HR = 1.746, 95% CI = 1.095, 2.784), and lower primary location (P = 0.019; HR = 0.553; 95% CI = 0.396, 0.772) were independent factors influencing PFS in ESCC patients (Table 3). Furthermore, D-dimer levels > 236 ng/mL (P < 0.0001; HR = 2.046; 95% CI = 1.518, 2.757) and lower primary location (P = 0.013; HR = 1.948; 95% CI = 1.153, 3.292) were identified as independent factors affecting OS in ESCC patients (Table 4). Worth noting is that ESCC patients with high D-dimer levels, treated with PD-1/PD-L1 inhibitors, exhibited both poorer PFS and OS compared to those with low D-dimer levels. (Figure 1)

Figure 1.

The Kaplan–Meier survival curves of ESCC patients with different D-dimer levels. (a) DFS of ESCC patients. (b) OS of ESCC patients.

Table 1.

The univariate Cox regression analysis of PFS in ESCC patients.

Characteristics		Univariate analysis
Characteristics		HR	95% CI	P value
Gender	Male	Ref.
	Female	1.025	0.624, 1.683	0.923
Age	≤ 60y	Ref.
	> 60y	0.936	0.712, 1.230	0.635
Alcohol history	Never	Ref.		0.833
	Former	0.901	0.643, 1.262	0.545
	Current	0.937	0.652, 1.348	0.727
Smoking history	Never	Ref.		0.618
	Former	0.873	0.631, 1.206	0.410
	Current	1.008	0.721, 1.411	0.962
Lines of treatment	1st	Ref.		0.066
	2nd	1.120	0.836, 1.500	0.447
	≥3rd	1.662	1.083, 2.549	0.020
Combined chemoradiotherapy	No	Ref.
	Yes	0.570	0.413, 0.787	0.001
Previous treatment	Never	Ref.		0.694
	Chemotherapy or/and radiotherapy	1.124	0.790, 1.599	0.516
	Surgery	1.154	0.823, 1.618	0.405
Location	Upper	Ref.		0.103
	Middle	1.441	0.860, 2.413	0.165
	Lower	1.639	1.033, 2.600	0.036
TNM stages	III B	Ref.		0.097
	IV A	0.704	0.354, 1.402	0.318
	IV B	0.221	0.866, 1.863	0.221
Fibrinogen	≤3.90 g/L	Ref.
	>3.90 g/L	1.368	1.045, 1.792	0.023
D-dimer	≤236 ng/mL	Ref.
	>236 ng/mL	1.509	1.149, 1.983	0.003
Platelets	≤243 × 10⁹ /L	Ref.
	>243 × 10⁹ /L	1.249	0.930, 1.679	0.140

CI: confidence interval; ESCC: esophageal squamous cell carcinoma; HR: hazard ratio; PFS: progression-free survival; Ref.: reference; TNM: tumor node metastasis.

Table 2.

The univariate Cox regression analysis of OS in ESCC patients.

Characteristics		Univariate analysis
Characteristics		HR	95% CI	P value
Gender	Male	Ref.
	Female	1.043	0.615, 1.767	0.877
Age	≤60y	Ref.
	>60y	1.043	0.783, 1.390	0.744
Alcohol history	Never	Ref.		0.902
	Former	0.924	0.649, 1.316	0.662
	Current	0.933	0.638, 1.365	0.722
Smoking history	Never	Ref.		0.889
	Former	1.079	0.767, 1.516	0.663
	Current	1.008	0.705, 1.440	0.965
Lines of treatment	1st	Ref.		0.213
	2ed	1.114	0.819, 1.517	0.491
	≥3rd	1.492	0.955, 2.330	0.079
Combined chemoradiotherapy	No	Ref.
	Yes	0.854	0.607, 1.201	0.364
Previous treatment	Never	Ref.		0.587
	Chemotherapy or/and radiotherapy	1.087	0.753, 1.570	0.655
	Surgery	0.915	0.641, 1.306	0.624
Location	Upper	Ref.		0.058
	Middle	1.762	0.994, 3.122	0.052
	lower	1.888	1.120, 3.183	0.017
TNM stages	III B	Ref.		0.223
	IV A	0.796	0.385, 1.645	0.538
	IV B	1.264	0.840, 1.903	0.261
Fibrinogen	≤3.90 g/L	Ref.
	>3.90 g/L	1.468	1.107, 1.947	0.008
D-dimer	≤236 ng/mL	Ref.
	>236 ng/mL	1.896	1.420, 2.531	< 0.0001
Platelets	≤243 × 10⁹ /L	Ref.
	>243 × 10⁹ /L	1.448	1.067, 1.965	0.017

CI: confidence interval; ESCC: esophageal squamous cell carcinoma; HR: hazard ratio; OS: overall survival; Ref.: reference; TNM: tumor node metastasis.

Table 3.

The multivariate Cox regression analysis of PFS in ESCC patients.

Characteristics		HR	95% CI	P value	Beta	Standard error	Wald	Degrees of freedom
Location	Upper	Ref.		0.042			6.326	2
	Middle	1.370	0.812, 2.311	0.238	0.315	0.267	1.395	1
	Lower	1.746	1.095, 2.784	0.019	0.557	0.238	5.475	1
Combined chemoradiotherapy	No vs. Yes	0.553	0.396, 0.772	0.001	−0.592	0.170	12.094	1
D-dimer	≤236 ng/mL vs. > 236 ng/mL	1.524	1.145, 2.030	0.004	0.422	0.146	8.326	1

CI: confidence interval; HR: hazard ratio; Ref.: reference.

Table 4.

The multivariate Cox regression analysis of OS in ESCC patients.

Characteristics		HR	95% CI	P value	Beta	Standard Error	Wald	Degrees of Freedom
Location	Upper	Ref.		0.043			6.289	2
	Middle	1.716	0.967–3.047	0.065	0.540	0.293	3.406	1
	lower	1.948	1.153–3.292	0.013	0.667	0.268	6.21	1
D-dimer	≤ 236 ng/mL vs. > 236 ng/mL	2.046	1.518–2.757	< 0.0001	0.716	0.152	22.102	1

ESCC: esophageal squamous cell carcinoma; CI: confidence interval; HR: hazard ratio; PFS: progression-free survival; Ref.: reference.

Subgroup analysis of different fibrinogen levels

Considering the correlation between D-dimer levels and fibrinogen levels in ESCC patients (Table S1), we conducted subgroup analyses based on different fibrinogen levels. The results revealed that among ESCC patients with low fibrinogen levels (≤3.90 g/L), those with high D-dimer levels (>236 ng/mL) experienced significantly shorter PFS (P = 0.0021, Figure S2A) and OS (P < 0.0001, Figure S2B). Conversely, for ESCC patients with high fibrinogen levels (>3.90 g/L), D-dimer levels showed no significant differences in terms of PFS (P = 0.66, Figure S2C) and OS (P = 0.15, Figure S2D).

Discussion

Previous studies have already validated the utility of D-dimer levels for assessing the prognosis of surgically resectable ESCC patients¹⁹ and the treatment efficacy of chemotherapy in unresectable EC patients.²³ Nevertheless, there is currently no research report on the role of D-dimer levels in relation to the efficacy and prognosis of ESCC patients who underwent ICIs treatment. Immunotherapy checkpoint inhibitors are gradually being accepted and incorporated into the treatment regimens for EC patients.²⁴ If potential biomarkers affecting the efficacy and prognosis of ICIs treatment can be identified from blood indicators, it could assist clinical practitioners in predicting the effectiveness of ICIs in a cost-effective and straightforward way. This, in turn, would enable timely adjustments to treatment plans to improve patients’ outcomes. This study represents the first investigation into the relationship between coagulation-fibrinolysis-related biomarkers and the effectiveness as well as post-treatment survival of anti-PD-1/PD-L1 treatment in ESCC patients. It provides initial evidence of the value of plasma D-dimer levels in assessing the efficacy and post-treatment survival of advanced or metastatic EC patients who underwent anti-PD-1/PD-L1 treatment.

Table S1 shows that there is a higher proportion of ESCC patients with elevated D-dimer levels in the groups with high fibrinogen levels. It is known that the higher fibrinogen levels are indicative of a hypercoagulable state in the body. The result of a positive correlation between fibrinogen levels and D-dimer levels is highly acceptable. Previous research has established that D-dimer levels in the body tend to increase with age.²⁵ However, this study did not show a significant correlation between D-dimer levels and age. The probable explanation lies in the coagulation-fibrinolysis abnormalities experienced by advanced ESCC patients, arising from factors such as the tumor itself or cancer treatments, which exert a more pronounced influence on D-dimer levels than age-related baseline disparities.

Compared to the upper and middle portions of the esophagus, EC is more frequently observed in the lower esophagus, accounting for approximately 69% of cases.²⁶ There is ongoing debate regarding whether the location of EC impacts the patients’ outcomes. Some studies have suggested that tumors originating in the lower esophagus carry a higher risk of mortality.^27,28 Conversely, some researchers argue that tumor location does not significantly impact the prognosis of ESCC patients.²⁹ Through the Cox proportional hazards regression model, this study has revealed that the primary location of ESCC significantly influences the efficacy and prognosis of anti PD-1/PD-L1 treatment. Obviously, lower primary location cases exhibit markedly poorer treatment response and prognosis in comparison to upper/middle primary location cases (Table 3, Table 4). We hypothesize that these findings could be related to variations in the lymph node drainage regions in different parts of the esophagus. In contrast to the upper esophagus, the lymphatic vessels of the lower esophagus follow the path of the left gastric artery to reach the gastric and abdominal lymph nodes. Lymph nodes involvement near the abdominal aorta is more commonly observed in patients with lower EC. Studies have reported that those with such lymph node metastasis exhibit a significantly worse prognosis with the outcomes akin to patients with advanced EC characterized by distant metastasis.³⁰ However, the results of this study may be influenced by the differences in the population selected for this research.

Furthermore, we have discovered that D-dimer is the only independent factor among the mentioned coagulation-fibrinolysis-related biomarkers that affects both the PFS and OS of ESCC patients treated with PD-1/PD-L1 inhibitors. Notably, high D-dimer levels exhibit the highest impact for OS (HR = 2.046) (Table 4). This discovery underscores the value of D-dimer levels as a predictive biomarker for the efficacy and prognosis of anti-PD-1/PD-L1 therapy. Elevated D-dimer levels in cancer patients indicate the presence of a hypercoagulable state and secondary fibrinolytic hyperactivity.³¹ Research has reported that in patients with a hypercoagulable state, plasma fibrinogen can interact with platelets to form microthrombi that cover the surface of cancer cells. These microthrombis act as physical barriers to protect tumor cells from being eliminated by natural killer cells.³² We speculate that upon formation, these barriers might obstruct the immune checkpoint receptors on the surface of tumor cells. This hindrance could impede the specific immune response of T cells activated by ICIs, thereby assisting tumor cells in evading immune attacks and reducing the effectiveness of PD-1/PD-L1 inhibitors. We observed that in the study by Ma et al.,³³ D-dimer levels were identified as an independent predictor of objective response rate (ORR) in EC patients following neoadjuvant immunotherapy, demonstrating a positive correlation. However, our research indicates that D-dimer levels are negatively correlated with PFS and OS in ESCC patients. We propose that these conclusions are not contradictory but rather reflect differences in the study populations. D-dimer levels often indicate tumor burden, and a higher tumor burden may render the tumor more responsive to immunotherapy, thus leading to an initially higher ORR. In contrast, in patients with more advanced, unresectable esophageal cancer, elevated D-dimer levels likely reflect changes in the tumor microenvironment, such as angiogenesis and stromal remodeling.³⁴ These changes can facilitate tumor invasion and metastasis and increase the likelihood of developing drug resistance, thereby diminishing treatment efficacy and adversely affecting PFS and OS.

Our study also revealed that combined chemoradiotherapy resulted in a longer PFS compared to the monotherapy of PD-1/PD-L1 inhibitors, although there was no significant difference in OS. D-dimer, as a widely-used hematological biomarker, offers the advantage of non-invasive collection and rapid detection, making it a valuable tool for assessing the efficacy and prognosis of PD-1/PD-L1 inhibitors in ESCC patients before treatment initiation. Unfortunately, this study was unable to eliminate the influence of chemotherapy or radiotherapy on PD-1/PD-L1 inhibitors treatment efficacy, and there were variations in the specific medications used by each patient. To address this issue, further research with larger sample sizes and more refined treatment regimens are needed to establish and validate our findings.

Subgroup analysis based on different fibrinogen levels reveals that D-dimer levels are more valuable for predicting the treatment efficacy and prognosis of PD-1/PD-L1 inhibitors in ESCC patients whose fibrinogen levels are ≤ 3.90 g/L (Figure S2). Elevated fibrinogen levels indicate that the patients are in a hypercoagulable state. In ESCC patients, this state can result from factors other than the tumor itself, such as inflammation, pain, or treatment medications, etc. Therefore, patients with elevated fibrinogen levels may also exhibit changes in D-dimer levels due to non-tumor factors such as inflammation and pain. This could potentially reduce the accuracy of using D-dimer levels to assess the treatment efficacy and prognosis of anti-PD1/PD-L1 therapy. Consequently, when using D-dimer levels to predict PFS and OS before anti-PD1/PD-L1 treatment, it is advisable to consider the patients’ fibrinogen levels to enhance the accuracy of the assessment.

Of course, this study has certain limitations. First, ESCC is a complex and highly variable disease, and each patient exhibits individualized differences in their conditions and treatments. Therefore, it is challenging to completely eliminate potential confounding factors that could affect the results. Second, this study is retrospective and based on a single medical institution, which means that selection bias and outcome bias were not entirely eliminated. To address these limitations, further research with larger sample sizes and multicenter prospective studies are needed.

Conclusion

A retrospective study involving 233 ESCC patients revealed that the D-dimer levels possess predictive value for the treatment efficacy and prognosis of anti-PD1/PD-L1 therapy.

Supplemental Material

sj-docx-1-jbm-10.1177_03936155241262045 - Supplemental material for D-dimer levels predict the treatment efficacy and prognosis of esophageal squamous cell carcinoma treated with PD-1/PD-L1 inhibitors

Supplemental material, sj-docx-1-jbm-10.1177_03936155241262045 for D-dimer levels predict the treatment efficacy and prognosis of esophageal squamous cell carcinoma treated with PD-1/PD-L1 inhibitors by Yuchen Wu, Xin Liu, Huihui Li, Wenjing Wang, Lisha Ye, Yun Zhou and Da Chen in The International Journal of Biological Markers

Footnotes

Author contributions

Yuchen Wu analyzed the data and wrote the manuscript. Xin Liu and Huihui Li organized and analyzed the data. Wenjing Wang, Lisha Ye, and Yun Zhou collected the data. Da Chen conceptualized and revised the manuscript. Yuchen Wu, Xin Liu, and Huihui Li have contributed equally to this work as co-first authors. All authors contributed to the article and approved the submitted version.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethics statement

This study was performed according to the Helsinki Declaration. The Ethics Committees of Zhejiang Cancer Hospital approved this study, and the approval number is NO:IRB-2023-203.

Funding

This work was supported by funding from the Medical Science and Technology Project of Zhejiang Province (2022KY691, 2024KY840).

ORCID iD

Yuchen Wu

Supplemental material

Supplemental material for this article is available online.

References

Sung

Ferlay

Siegel

, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209–249.

GBD 2017 Oesophageal Cancer Collaborators.

The global, regional, and national burden of oesophageal cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020; 5: 582–579.

Lin

Totsuka

, et al. Epidemiology of esophageal cancer in Japan and China. J Epidemiol 2013; 23: 233–242.

Zeng

Chen

Zheng

, et al. Changing cancer survival in China during 2003-15: a pooled analysis of 17 population-based cancer registries. Lancet Glob Health 2018; 6: e555–e567.

Kelly

. Emerging multimodality approaches to treat localized esophageal cancer. J Natl Compr Canc Netw 2019; 17: 1009–1014.

Smyth

Lagergren

Fitzgerald

, et al. Oesophageal cancer. Nat Rev Dis Primers 2017; 3: 17048.

Yap

DWT

Leone

Wong

NZH

, et al. Effectiveness of immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma: a meta-analysis including low PD-L1 subgroups. JAMA Oncol 2023; 9: 215–224.

Fang

Zhou

Liang

, et al. Immunotherapy resistance in esophageal cancer: possible mechanisms and clinical implications. Front Immunol 2022; 13: 975–986.

Hynes

Kwon

Vadlamudi

, et al. Programmed death ligand 1: a step toward immunoscore for esophageal cancer. Ann Thorac Surg 2018; 106: 1002–1007.

10.

Yao

Jia

, et al. Factors affecting tumor responders and predictive biomarkers of toxicities in cancer patients treated with immune checkpoint inhibitors. Int Immunopharmacol 2020; 85: 106628.

11.

Wang

, et al. Coagulation- and fibrinolysis-related genes for predicting survival and immunotherapy efficacy in colorectal cancer. Front Immunol 2022; 13: 1023908.

12.

Falanga

Marchetti

Vignoli

. Coagulation and cancer: biological and clinical aspects. J Thromb Haemost 2013; 11: 223–233.

13.

Marchetti

Falanga

. Hemostatic biomarkers in occult cancer and cancer risk prediction. Thromb Res 2020; 191: S37–S42.

14.

Falanga

Marchetti

Russo

. Hemostatic biomarkers and cancer prognosis: where do we stand? Semin Thromb Hemost 2021; 47: 962–971.

15.

Liu

Gao

, et al. The association of plasma fibrinogen with clinicopathological features and prognosis in esophageal cancer patients. Oncotarget 2017; 8: 93029–93038.

16.

Wang

Huang

Wang

, et al. Pretreatment plasma fibrinogen and serum albumin levels predict therapeutic efficacy of concurrent radiochemotherapy for esophageal squamous cell cancer. Front Oncol 2022; 12: 1021214.

17.

Zhang

Lei

Cai

, et al. Preoperative serum fibrinogen is an independent prognostic factor in operable esophageal cancer. Oncotarget 2016; 7: 25461–25469.

18.

Ishibashi

Tsujimoto

Kouzu

, et al. Impact of antiplatelet and anticoagulant therapies on platelet-related prognostic markers in patients with esophageal cancer. In Vivo 2020; 34: 1941–1949.

19.

Feng

Yang

Chen

, et al. Prognostic value of plasma D-dimer in patients with resectable esophageal squamous cell carcinoma in China. J Cancer 2016; 7: 1663–1667.

20.

Diao

Zhu

Wang

, et al. Prognostic value of the D-dimer test in oesophageal cancer during the perioperative period. J Surg Oncol 2013; 108: 34–41.

21.

American Joint Committee on Cancer. AJCC cancer staging manual. 8th ed. New York: Springer, 2017.

22.

Watanabe

Okada

Kaji

, et al. New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1). Gan To Kagaku Ryoho 2009; 36: 2495–2501.

23.

Shibutani

Kashiwagi

Fukuoka

, et al. The significance of the D-dimer level as a prognostic marker for survival and treatment outcomes in patients with stage IV colorectal cancer. In Vivo 2023; 37: 440–444.

24.

Wang

Liu

Chen

, et al. Recent advances in combination of immunotherapy and chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. Cancers (Basel) 2022; 14: 5168.

25.

Olson

. D-dimer: an overview of hemostasis and fibrinolysis, assays, and clinical applications. Adv Clin Chem 2015; 69: 1–46.

26.

Rice

Rusch

Apperson-Hansen

, et al. Worldwide esophageal cancer collaboration. Dis Esophagus 2009; 22: 1–8.

27.

Amin

Parikh

Gangireddy

, et al. Early esophageal cancer specific survival is unaffected by anatomical location of tumor: a population-based study. Can J Gastroenterol Hepatol 2016; 2016: 6132640.

28.

Eloubeidi

Desmond

Arguedas

, et al. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002; 95: 1434–1443.

29.

Yang

Hou

Liu

, et al. Tumor location does not impact long-term survival in patients with operable thoracic esophageal squamous cell carcinoma in China. Ann Thorac Surg 2012; 93: 1861–1866.

30.

Tanaka

Yano

Motoori

, et al. The significance of abdominal para-aortic lymph node metastasis in patients with lower thoracic esophageal cancer. Dis Esophagus 2012; 25: 146–152.

31.

Weitz

Fredenburgh

Eikelboom

. A test in context: D-dimer. J Am Coll Cardiol 2017; 70: 2411–2420.

32.

Elinav

Nowarski

Thaiss

, et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 2013; 13: 759–771.

33.

Yuan

, et al. Factors affecting the ORR after neoadjuvant therapy of TP regimen combined with PD-1 inhibitors for esophageal cancer. Sci Rep 2023; 13: 6080.

34.

Tran

HCM

Mbemba

Mourot

, et al. The procoagulant signature of cancer cells drives fibrin network formation in tumor microenvironment and impacts its quality. Implications in cancer cell migration and the resistance to anticancer agents. Thromb Res 2024; 238: 172–183.

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