Clinicopathologic features and prognosis of 71 patients with gastric cancer and disseminated intravascular coagulation

Introduction

Diffused intravascular coagulation (DIC) is a clinical illness characterized by microcirculatory failure and bleeding. DIC is a pathological process in which pathogenic factors harm the vascular system and trigger coagulation activation, systemic microvascular thrombosis, large consumption of coagulation factors, and secondary hyperfibrinolysis. Severe infection, malignant tumors, pathological obstetric diseases, surgery, trauma, severe poisoning and immune responses are the most common underlying diseases that contribute to DIC (Levi & ten Cate, 1999). DIC is also a common hemostatic complication of malignant tumors. According to Sallah et al. (2001), the incidence of DIC was 6.8% among 1117 individuals with solid tumors. Yamashita et al. (2014) reported that the incidence of DIC in 478 patients with advanced malignant diseases was 13.2%. Coagulation and fibrinolytic activity are biological characteristics of tumor cells. In patients with malignant tumors, various coagulation factors such as tissue factor and fibrinogen are increased, the physiological anticoagulation pathway is weakened, and fibrinolytic ability is decreased. DIC occurs when the dynamic balance in the hypercoagulable state is disrupted by the inducing factors of DIC, such as radiotherapy, chemotherapy, surgery, and infection (Donati, 1995; Nadir, Vlodavsky & Brenner, 2008; Milsom et al., 2008; Kwaan & McMahon, 2009; Rodeghiero & Castaman, 1994). DIC has been frequently found in patients with gastric cancer, breast cancer, hepatic cell carcinoma and hematopoietic malignancies. Gastric cancer consists of solid tumors with a tendency for DIC, but there have been few studies on this condition. The majority of these studies (Chao et al., 2000; Hironaka et al., 2000; Therasse et al., 2000; Tokar et al., 2006; Huang et al., 2008; Hwang et al., 2014) are case reports and small-sample studies of 6–68 individuals. DIC can occur in both advanced and early gastric cancer; however, all of the above studies evaluated DIC in advanced gastric cancer (AGC) patients. Seventy-one patients with stomach cancer and DIC were included (60 AGC patients and 11 early gastric cancer (EGC) patients) in this study. The clinical data of these patients were retrospectively analyzed to observe clinical characteristics and prognostic factors.

Materials and Methods

Results

Survival analysis

The five-year survival of 71 patients was 2.8%. The median OS was 57.0 days (95% confidence interval [CI] [33.1– 80.9]) (Fig. 1). Tumor status (P = 0.000) and treatment (P = 0.003) were found to be significant variables linked with OS by univariate analysis (Table 3). The median OS in the with-tumor group was significantly shorter than that in the tumor-free group (37 vs. 396 days, P = 0.000) (Fig. 2). The median OS was significantly shorter in the BSC group than in the chemotherapy group (28 vs. 106 days, P = 0.003) (Fig. 3). Univariate analysis showed no significant correlations between OS and sex, age, histological category, bleeding symptoms, comorbidities or metastatic patterns. Multivariate analysis showed that tumor status (P = 0.000) and treatment (P = 0.000) had independent effects on OS (Table 4).

Table 3:

Results of the univariate analysis to identify factors predicting the survival time of gastric cancer patients with DIC.

Clinicopathological factors	Median OS days [95% CI]	P value
Sex		0.152
Male	67.0 [33.8–100.2]
Female	37.0 [8.9–65.1]
Age (years)		0.648
<65	42.0 [14.9–69.1]
≥65	62.0 [49.2–74.8]
Histological category		0.157
Highly differentiated	112.0 [96.6–127.4]
Poorly differentiated	37.0 [10.9–63.1]
Uncertain	67.0 [15.4–118.6]
Tumor status		0.000
With tumor	37.0 [5.4–68.6]
Tumor free	396.0 [0.0–922.5]
Bleeding symptoms		0.881
Positive	53.0 [27.0–79.0]
Negative	57.0 [17.6–96.4]
Comorbidities		0.352
Negative	82.0 [36.6–127.4]
Positive	37.0 [10.0–64.0]
Metastatic patterns		0.089
Uncertain	13.0*
Locoregional metastasis	83.0 [42.3–123.7]
Hematogenous metastasis	58.0 [55.4–60.6]
Peritoneal implantation	28.0 [0.0–61.3]
Multiple metastatic patterns	37.0 [10.0–64.0]
Negative	15.0Δ
Treatment		0.003
BSC	28.0 [11.2–44.8]
Chemotherapy	106.0 [61.1–150.9]

DOI: 10.7717/peerj.16527/table-3

Notes:

*Only one patient’s metastatic pattern was uncertain.

Δ, Only two patients’ metastatic pattern were negative.

CI, confidence interval.

Table 4:

Results of the multivariate analysis to identify factors predicting the survival time of gastric cancer patients with DIC.

Fators	B	SE	Wald	df	P	Exp(B)	95.0% CI
Tumor status	−1.964	0.464	17.893	1	0.000	0.140	[0.056–0.349]
Treatment	−1.020	0.288	12.529	1	0.000	0.360	[0.205–0.634]

DOI: 10.7717/peerj.16527/table-4

Note:

B, regression coefficient; SE, standard error; df, degree of freedom; Exp(B), odds ratio; CI, confidence interval.

Discussion

The incidence of DIC has been reported to be 1.6–1.7% in AGC patients (Rhee et al., 2010; Takashima et al., 2010). In this study, between June 2006 and March 2020, 14016 patients at Fujian Cancer Hospital were diagnosed with stomach cancer; DIC was detected in 105 of these individuals, for an incidence of 0.75%. This incidence rate is lower than that in the above studies. The reason for this difference is that our study calculated the incidence of DIC in AGC and EGC patients who could be treated surgically, while previous studies reported the incidence of DIC in AGC patients only. After excluding patients who were lost to follow-up, 71 patients were enrolled in this study. The histological category was poorly differentiated gastric cancer in 58 patients (81.7%), highly differentiated in seven patients (9.9%), and uncertain in six patients (8.4%). These data suggest that patients with poorly differentiated gastric cancer are more likely to develop DIC, and this result is similar to the findings of other studies (Yeh & Cheng, 1998; Huang et al., 2008). This suggests that more attention should be given to monitoring coagulation function in patients with poorly differentiated gastric cancer. Fifty-one patients (71.8%) had bleeding symptoms, with gastrointestinal bleeding as the most common. Forty-three (60.6%) patients had comorbidities at the time of DIC diagnosis, with simultaneous infection as the most common. Among the 71 patients, 42 (59.2%) had multiple metastatic patterns, which was the most frequently observed pattern. The above three findings suggest that gastrointestinal bleeding, multiple metastatic patterns and comorbidities at diagnosis with DIC are common in patients with gastric cancer complicated with DIC.

In the MAGIC study, individuals with operable illness who were given perioperative chemotherapy had a 36% 5-year survival rate (Cunningham et al., 2006). However, the median OS for AGC patients is less than one year, with a 5-year survival rate of approximately 5–20% (Kamangar, Dores & Anderson, 2006; Cunningham et al., 2005). In our study, the 5-year survival rate of 71 patients was 2.8%. The median OS was 57.0 days (95% CI: [33.1–80.9] days) in this study, which is consistent with previous studies (Rhee et al., 2010; Hwang et al., 2014). The results of multivariate analysis showed that tumor status (P = 0.000) and treatment (P = 0.000) had independent effects on OS. In this study, 11 patients (15.5%) developed DIC after curative gastric resection, at which time the patients had a tumor-free status. DIC was caused by severe infection and anastomotic leakage. In sepsis, DIC is associated with increased plasma D-dimer and decreased plasma fibrinogen, thrombin-antithrombin complex (TAT), and plasminogen activator inhibitor type 1 (PAI-1) levels (Koyama et al., 2014). Although bacterial infections are the most prevalent cause of DIC, the underlying mechanisms are not completely understood. Wang et al. (2019) reported that outer membrane vesicles (OMVs), which are membrane-enclosed microvesicles released by a variety of bacteria, contribute to the pathogenesis of DIC during gram-negative bacterial infection. The possibility of postoperative DIC after tumor removal should be considered. Early monitoring and early detection and treatment of infection can reduce the occurrence of this type of DIC. Through etiological treatment, such as the use of antibiotics, DIC can be corrected after achieving infection control, and patients can survive for a long time.

In this study, 60 patients (84.5%) had DIC at the initial presentation of gastric cancer or developed DIC as the tumor progressed during treatment. Patients with this type of DIC have a poor prognosis, and the majority of these patients die within 16–58 days (Rhee et al., 2010; Hwang et al., 2014). Among the 60 patients, only 20 (33.3%) patients received chemotherapy. This study showed that chemotherapy prolongs OS more than BSC. Our finding is consistent with the results of previous studies (Rhee et al., 2010; Hwang et al., 2014). Therefore, early chemotherapy should be considered in this population to improve their prognosis. In clinical practice, most of these patients have a poor performance status, severe thrombocytopenia and bleeding tendencies, meaning that chemotherapy would have high risks. Therefore, it is necessary to fully communicate the risks and possible benefits of chemotherapy with the patients and their families before the start of treatment. Paclitaxel every week was the most common chemotherapy regimen, with 10 of 21 (47.6%) patients receiving this regimen. For patients with a poor performance status (PS) and high risk for chemotherapy, we consider single-agent chemotherapy to be a safe and efficient treatment option. After the patient’s physical condition improves, combination with other chemotherapy drugs can be considered to improve the curative effect. This opinion has also been confirmed in some studies. Yeh & Cheng, 1998 have suggested that 5-FU and leucovorin (HDFL) is an ideal initial chemotherapy regimen for gastric cancer patients with DIC. According to Hwang et al. (2012), first-line single-agent palliative chemotherapy showed relatively good clinical efficacy in AGC patients with a poor PS. Wu et al. (2019) reported that liposome-paclitaxel was given to AGC patients with a poor PS and that S-1 was also given after improvement of the patient’s physical condition. These outcomes demonstrate that this treatment can extend patients’ OS and progression-free survival (PFS), with manageable toxicity.

Data from one center were retrospectively analyzed in this research, and data collected from medical records has limitations. We enrolled 71 gastric cancer patients with DIC. This sample is still considered small although it is larger than those in earlier studies that only assessed DIC in AGC patients. Our patients included 60 AGC patients and 11 EGC patients. To obtain more reliable results in the future, prospective studies using larger patient cohorts that collect more detail about patients’ clinicopathologic characteristics and treatment are needed.

Conclusions

Gastrointestinal bleeding, multiple metastatic patterns and comorbidities at diagnosis with DIC are common in patients with gastric cancer complicated with DIC. Patients with poorly differentiated gastric cancer are more likely to develop DIC. This suggests that more attention should be given to monitoring coagulation function in patients with poorly differentiated gastric cancer. Treatment and tumor status are separate risk variables for survival in gastric cancer patients with DIC. DIC patients without tumors have a good prognosis and can be cured by appropriate etiological correction and symptomatic treatment. Chemotherapy can improve the prognosis of DIC patients with tumors.

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