Preoperative thrombocytosis is a predictor of poor prognosis in patients with resectable non-small-cell lung cancer: a retrospective randomized controlled study

doi:10.21203/rs.3.rs-3310556/v1

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Preoperative thrombocytosis is a predictor of poor prognosis in patients with resectable non-small-cell lung cancer: a retrospective randomized controlled study

https://doi.org/10.21203/rs.3.rs-3310556/v1

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Background: Operable non-small-cell lung cancer (NSCLC) has highly variable biological behavior. Blood markers cannot accurately predict its prognosis. Previous studies have shown that preoperative thrombocytosis is associated with poor prognosis in several cancers. The purpose of this study is to evaluate the prognostic significance of preoperative thrombocytosis in patients with NSCLC.

Methods: We conducted a retrospective study on patients with NSCLC who underwent radical resection from May 2016 to December 2017. Platelet count was measured before each operation to evaluate the relationship between platelet count and clinicopathological factors and prognosis.

Results: compared with patients with normal platelet count, patients with elevated platelet count had an increased risk of disease progression and death. The hazard ratio for disease progression was 1.585 (95% [CI] 1.159–2.166, P = 0.001), and the ratio for death was 1.385 (95% [CI] 1.041–1.843, P = 0.025).

Non-small-cell lung cancer

Platelet count

Thrombocytosis

Prognosis

Recurrence

Survival

Lung cancer is one of the most common tumors and the main cause of cancer-related death in the world. The year 2020 saw about 2.21 million new cases and 1.8 million deaths [1]. Most cases of lung cancer (80–90%) are non-small-cell lung cancer (NSCLC), and most patients are diagnosed at an advanced stage (65%). Improvements in treatment technology have greatly improved the prognosis of lung cancer, but its 5-year overall survival rate is still only about 18% [2]. There have been recent advancements in the field of cancer treatment, and current treatments for lung cancer include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Among them, surgery has the best efficacy, but some patients still experience relapse and metastasis, which affect patient prognosis. In the past few decades, a large number of studies have tried to find molecular biomarkers to predict the metastasis and recurrence of non-small-cell lung cancer [3, 4]. However, most of these markers have been controversial and have not been proven to be sufficiently effective in clinical applications.

In the 1960s, Richard et al. proposed that platelet could be associated with cancer [5]. Platelets play an important role in the growth, progression, and metastasis of cancer cells [6, 7]. They significantly affect the survival, growth, migration, and epithelial mesenchymal transformation (EMT) of circulating tumor cells. Some tumor cells, such as hepatoblastoma and ovarian cancer, can produce thrombopoietin (TPO), which is considered the most important factor in platelet formation. Other cytokines also play a role in platelet production. Interleukin-6 can activate platelets and affect thrombosis, and lung cancer cells can directly produce interleukin-6 [8]. Platelets activated by cancer cells have numerous precancerous effects, such as stimulating tumor growth, preparing metastatic niches, and helping metastatic cells survive in circulation. Activating platelets can activate the paracrine signaling pathway, which is mediated by epithelial cell cyclooxygenase-2 (COX-2) and adenoma stromal cells. In this way, activating platelets could induce subsequent cancer cells to exhibit a more aggressive phenotype [9]. Studies have shown that thrombocytosis can predict prognosis in a variety of cancers, such as esophageal cancer, gastric cancer, and colorectal cancer [10–13]. In lung cancer, a relationship between platelets and lung cancer prognosis has also been reported [14–16], but most of these studies covered only small cell lung cancer or had small samples. To our knowledge, there have been few studies exploring the relationship between platelets and the prognosis of operable non-small-cell lung cancer. In this study, 554 patients with operable non-small-cell lung cancer were analyzed retrospectively to explore the relationship between platelet count, clinical characteristics, and prognosis.

This study included 554 patients diagnosed with non-small-cell lung cancer in Shaoxing People's Hospital, Zhejiang Province, China, from 2016 to 2017. All patients were newly diagnosed and had not received any treatment before. Patients with the following characteristics were excluded from this study: patients with any coexisting or previous cancer other than non-small-cell lung cancer; patients with suspected elevated serum platelet concentration, including severe hypertension, spleen disease, or coagulation dysfunction; and patients who had taken aspirin or other acetylsalicylic acid drugs during the month before treatment. This study was approved by the institutional review committee of Shaoxing People's Hospital in Zhejiang Province. All patients provided informed consent before surgery. Blood was taken by peripheral venous puncture before breakfast, and 3 ml blood samples were taken from each patient for detection. The best cut-off value was determined using X-Tile software. Platelet counts greater than 263×109/L were considered indicative of thrombocytosis.

All patients received standardized follow-up, occurring at 3‑month intervals for two years, at 6‑month intervals in the third year, and yearly thereafter. The evaluation included physical examination, hematologic tumor index, chest computed tomography (CT), brain magnetic resonance imaging, bone ECT, and abdominal ultrasound. Whenever possible, histological examination was performed to confirm the metastasis.

Statistical analysis

The chi square test was used to evaluate the correlation between clinicopathological variables and platelet count. Disease-free survival (DFS) was defined as the period from the date of surgery to the date of local or distant progression. Overall survival (OS) was calculated from lung surgery to death or amputation. The Kaplan–Meier curve was used to estimate the distribution of DFS and OS, and the bilateral log-rank test was used to compare the differences in survival. All statistical calculations were performed with SPSS 22.0 for Windows (SPSS, Chicago, IL, USA). P < 0.05 was considered to indicate a statistically significant difference.

1. Correlation between platelet count and characteristics of patients with operable NSCLC

A total of 554 patients with stage I-III primary NSCLC were included in this study. Table 1 summarizes the clinical and pathological features of these patients. According to the new IASLC staging system, among these patients, 222 were stage I patients, 149 were stage II patients, and 183 were Stage III patients. There were 299 cases of squamous cell carcinoma, 250 cases of adenocarcinoma, and 5 other cases. 298 cases were highly differentiated and 256 were poorly differentiated. There was no significant correlation between the platelet count and patient age, drinking status, cancer cell differentiation, or family history. There were statistically significant correlations between the platelet count and gender, smoking state, clinical stage, and tumor histological type. The frequency of thrombocytosis was higher in male patients (28.1%) than in female patients (18.3%), (P < 0.05). This correlation was also detected in the squamous cell subgroup (30.8%), but not in patients with adenocarcinoma cell histology (20.4%) or others (20.0%) (P < 0.05). Thrombocytosis was significantly more frequent in smokers (28.3%) than in non-smokers (20.0%) (P < 0.05). The incidence of thrombocytosis gradually elevated with increasing cancer stage (I-II-III stage, 36 (16.2%) vs. 43 (28.9%) vs. 65 (35.5%), P < 0.05).

2. Association of platelet count with DFS and OS

Univariate and multivariate analyses for DFS and OS are shown in Table 2 and Table 3. The patients' gender (P = 0.686), age (P = 0.306), family history (P = 0.537), smoking status (P = 0.521), drinking state (P = 0.357), and tumor histology (P = 0.122) were not found to be related to disease-free survival in the univariate analysis. The later the stage, the worse the DFS (P = 0.001). The poorly differentiated tumor cells exhibited worse disease-free survival than the well or moderately differentiated groups (P = 0.01). The lower platelet count group showed better disease-free survival than the thrombocytosis group (median disease-free survival time: 49.8 months vs. 37.9 months, P = 0.001). Patients with thrombocytosis had lower 5-year overall survival rates than those with normal platelet counts (43.7% vs. 59.6%), as shown in Table 3.

The Kaplan–Meier survival curves indicated that patients with thrombocytosis had worse disease-free survival (Fig. 1) and overall survival (Fig. 2) than patients with normal platelet counts. Multivariate analyses indicated that platelet count was an independent prognostic factor in these NSCLC patients. Patients with thrombocytosis had an elevated risk of disease progression and death than those with normal platelet counts. The hazard ratio was 1.585 (95% confidence interval [CI] 1.159–2.166) for disease progression and 1.385 (95% CI 1.041–1.843) for death (Table 2 and Table 3).

Our research suggests that preoperative thrombocytosis is significantly associated with an increased risk of death and disease recurrence in patients with resectable NSCLC. To the best of our knowledge, this is the largest sample study to reveal the correlation between platelet count and prognosis in patients with operable NSCLC.

In this study, platelet counts were significantly correlated with tumor clinical stage and prognosis. The increases in platelet counts were found to be related to poorer prognosis. Multivariate analysis of the Cox proportional hazards model showed preoperative platelet count to be an independent prognostic factor in patients with operable NSCLC. Patients with elevated platelet counts had a 1.58-fold higher risk of disease progression than patients with lower platelet counts. These findings were similar to previous studies [17]. The sample size of this study was relatively small. The 5-year survival rates of patients with normal and elevated platelet counts were 55.3% and 39.2%, respectively.

In 1872, Reiss et al. first reported the relationship between elevated platelet count and malignant tumors [18]. Recently, in a nested case-control study, elevated platelet counts were found to be associated with an increased risk of cancer in several sites (colon, lung, ovary, and stomach) [19]. Studies have shown that thrombocytosis occurs in different solid tumors in 10–57% of cancer patients [20]. In our study, 26% of patients with resectable non-small-cell lung cancer had thrombocytosis. Several mechanisms have been proposed to explain the association between high platelet count and cancer, including platelet aggregation of cancer cells, increased extravasation or basement membrane permeability, and protection of cancer cells from immune attack in the bloodstream [21–23]. Other possible mechanisms include iron deficiency, bleeding (in patients with colon cancer) [24], abnormal platelet count, and infiltration of diffuse cancer cells in the bone marrow [25]. However, the relationship between elevated platelet count and local non-small-cell lung cancer and the exact mechanism underlying this relationship are not fully understood. Studies have shown that platelets can secrete a large number of growth factors, such as transforming growth factor β (TGF-β), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), from alpha granules, dense granules, and lysosomes. These cytokines are related to tumor cell proliferation and angiogenesis [26, 27].

The main advantages of this research are as follows. First, the cutoff value for thrombocytopenia was redefined using the software package X-Tile. It may be more suggestive of prognosis in patients with non-small-cell lung cancer. Second, a large number of patients with non-small-cell lung cancer were enrolled to study the prognostic value of platelet count. The large size of the study may have allowed us to avoid bias and heterogeneity. The highly standardized procedures for data collection were another advantage. Patients with acute inflammatory diseases (e.g., acute cholecystitis and acute appendicitis) or other diseases (splenomegaly and hypersplenism) that might cause a transient increase in platelet count were excluded at enrollment. However, our research also had limitations. This study was retrospective. Insufficient information on recurrence after treatment may affect the survival of patients going forward.

Our study showed preoperative thrombocytosis to be an independent marker of recurrence and poor prognosis in operable non-small-cell lung cancer. It could be a target for the treatment of lung cancer. However, the specific molecular mechanism underlying elevated platelet count promoting the recurrence and metastasis of lung cancer remains to be explored. This may be a suitable direction for further research.

Acknowledgements

None.

Funding

No funding.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the

article and its additional file.

Authors’ contributions

Haiyong Wang and Guangmao Yu designed the study, Bin Wang and Zhupeng Li wrote the article, Ting Zhu collected the data, Jianyi Ding analyzed the data, and Jiandong Zhang and Junjun Zhao were responsible for the follow-up.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The present study was carried out in accordance with the ethical standards

of Helsinki Declaration II and approved by the Shaoxing peoples’ Hospital

Ethics Committee. Informed consents were provided for all patients before

surgery.

Author details

1 Department of Thoracic Surgery, Shaoxing People’s Hospital, 568

Zhongxin Road, Shaoxing, Zhejiang, 312000,China.

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Tables 1 to 3 are available in the Supplementary Files section.

No competing interests reported.

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Preoperative thrombocytosis is a predictor of poor prognosis in patients with resectable non-small-cell lung cancer: a retrospective randomized controlled study

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