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Bone Metastasis from Gastric Cancer: The Incidence, Clinicopathological Features, and Influence on Survival

Purpose To evaluate the incidence, clinicopathological characteristics, treatment outcomes, prognostic factors, and survival of gastric cancer patients with bone metastases. Materials and Methods Of 4,617 gastric cancer patients who were treated between 2001 and 2013, 176 patients with bone metastases were analyzed. Results The incidence of bone metastasis was 3.8%. The most common histopathological subtype was adenocarcinoma (79%) with poor differentiation (60.8%). The median interval from the diagnosis to bone metastasis was 11 months. The median survival time after bone metastasis was 5.4 months. Factors that were associated with longer median survival times included the following: isolated bone metastasis (P=0.004), well-differentiated tumors (P=0.002), palliative chemotherapy (P=0.003), zoledronic acid treatment (P<0.001), no smoking history (P=0.007), and no metastatic gastric cancer at the time of diagnosis (P=0.01). On the other hand, high levels of lactate dehydrogenase (LDH) (hazard ratio [HR]: 1.86; P=0.015), carcinoembryonic antigen (CEA) (HR: 2.04; P=0.002), and carbohydrate antigen (CA) 19-9 (HR: 2.94; P<0.001) were associated with shorter survival times. In multivariate analysis, receiving zoledronic acid (P<0.001) and performance status (P=0.013) were independent prognostic factors. Conclusions Smoking history, poor performance status, poorly differentiated adenocarcinoma, and high levels of LDH, CEA, and CA 19-9 were shown to be poor prognostic factors, while receiving chemotherapy and zoledronic acid were associated with prolonged survival in gastric cancer patients with bone metastases.


Introduction
Gastric cancer (GC) is the fourth most common malignancy worldwide, with an estimated 989,600 newly diagnosed cases an-nually, and it is the second leading cause of cancer-related deaths, resulting in 738,000 deaths per year. 1 According to GLOBOCAN 2012, age-standardized incidence rates for GC were 17.9 and 10.9, and mortality rates were 15.5 and 9.3 per 100,000 Turkish men and women, respectively. 2 Most patients have metastatic or locally advanced disease at the time diagnosis, and the overall 5-year survival rate is 7% for stage IV GC. The systemic recurrence rate after curative resection is 60%, and the most common sites are the liver, peritoneum, and lungs. 3,4 Although bone metastasis can be commonly observed in breast, prostate, and lung cancers, it is extremely rare in GC, and consequently, there is limited data available on the clinicopatho-logical features, optimal treatment approaches, and prognostic factors for GC patients with bone metastasis in the existing literature.
The majority of the studies investigating bone metastasis in GC originate from Japan and Korea where GC is endemic. The clinical course of bone metastasis from GC in different ethnic and regional populations is largely unknown. The reported frequency of bone metastasis in GC patients is 13.4% to 15.9% in autopsy series and increases up to 45.3% in bone metastasis screening studies, whereas it has been reported in only 0.9% to 10% of the GC patients in clinical practice. [5][6][7][8][9][10][11][12][13] These findings suggest that asymptomatic bone metastasis is underestimated, and that the rate of bone metastasis in clinical cases may be much higher than is reported. The presence of bone metastasis in GC is a poor prognostic factor, and it is also associated with pain, pathological fractures, paralysis, hypercalcemia, and hematologic complications, all of which have a negative impact on the quality of life and treatment outcomes.
The purpose of this study was to investigate the frequency, demographics, and clinical and pathological features of GC patients with bone metastases. Furthermore, the prognostic factors, treatment outcomes, and survival in these patients were also evaluated.

Study population and data collection
A total of 4,617 patients who were diagnosed gastric adenocarcinoma between 2001 and 2013 were retrospectively reviewed.
Of these, 176 GC patients with radiologically and/or pathologically confirmed bone metastasis were analyzed. Patients with nonadenocarcinoma histology, such as small cell, squamous cell types, as well as those with neuroendocrine carcinoma, gastric lymphoma, and those with other synchronous malignancies were excluded.
Detailed information about treatment initiation/termination dates was obtained from the patients' medical records. Zoledronic acid was administered to patients with normal renal clearance at a dose Data on mortality were obtained from the hospitals' medical records and via linkage with their respective death registries. If death was not evident, patients were censored at their last follow-up.

Statistical analyses
Descriptive statistics were expressed as the mean±standard deviation or median (minimum-maximum) for continuous variables in conjunction with the number of subjects and percentage for categorical variables. The Pearson chi-square test and Student t-test were used to analyze frequencies and means, respectively, to compare the clinicopathological parameters among groups, whereas the Kaplan-Meier analysis with a log-rank test was used to determine cumulative survival curves. Univariate and multivariate Cox pro-portional hazards regression models with 95% confidence intervals (CI) for OS-BM were performed to evaluate the prognostic factors.
To select the factors with an independent significant influence on outcomes, only those factors with clinical significance in univariate analyses were included, and multivariate analyses were carried out in a stepwise Cox regression with backward selection.
Statistical analyses were performed using SPSS software version 15.0 (SPSS Inc., Chicago, IL, USA). All statistical assessments were two-sided, and the significance levels were set at P＜0.05.

Patient and tumor characteristics
A total of 4,617 patients with GC were analyzed, and bone me-  P=0.033) were detected in patients who had both bone and concomitant non-bone metastases. Serum LDH levels were also higher   The median OS-BM was longer in patients who had no smok-    ses. According to their study, the incidence of bone metastasis was only 0.9% after gastric resection and 11.2% in inoperable patients.

Treatments and survival
In a multicenter Italian study, the authors reported an incidence of   bone metastasis in 10% of GC patients. 13 Ahn et al. 10   The most common histopathological subtype in our study was adenocarcinoma (79%) with poor differentiation (60.8%). Most of the previous studies showed relationships between poorly differentiated adenocarcinoma and the risk of bone metastasis in advanced GC patients. 6,[9][10][11][12][13][14][15] In our study, a significant survival benefit (19.3 vs. 4 months) was observed for patients with well-differentiated tumors. It has been suggested that the risk of bone metastasis is associated with lymph node involvement, large tumor size, the depth of the tumor, and the presence of LVI in some studies, whereas no association was reported in others. 8,9,[11][12][13]15 We found no significant associations between survival and the above variables.
Sudo et al. 15 reported that metastatic bone lesions were predominantly seen in the lumbar-thoracic vertebra and in the ribs. Park at al. 9 also showed that bone metastases of GC most commonly occurred in the spine and pelvis. In our study, the most common sites of metastases were in the lumbar vertebra (54.5%), thoracic vertebra (46%), and pelvis (29%), similar to previous reports. [7][8][9][10][11]15 Only the multicenter Italian study indicated long bones as the most com-mon site of bone metastasis (52%) followed by the hip and spine. 13 The underlying pathophysiology of bone metastasis in GC is still controversial, and the suggested pathways include the paravertebral venous plexus, portal vein, lymphatic channels, thoracic duct and gastric mucosal capillaries; 9,12,14,16-18 the paravertebral venous plexus might be the major route of bone metastasis in our cohort.
Skeletal metastatic lesions arising from GC usually occur as many lesions and are of the osteolytic type. [7][8][9][10][11][12][13][14] We observed multiple bone metastases in 66.5% of patients and found no difference between the patients with synchronous and metachronous bone metastases, which is consistent with previous reports. 9,10,13 Higher LDH, CEA, and CA 19-9 levels were detected in patients who had both bone and concomitant non-bone metastases, and they were poor prognostic factors in the present study. Moreover, ECOG performance status was found to be an independent prognostic factor. Sudo et al. 15 9,10,13,19 In an observational study, the median time to the first SRE was 2 months and the median survival after SRE occurrence was 3 months. 13 Pain is the most frequent form of SRE that is treated with non-steroidal antiinflammatory drugs and opioid analgesics. Palliative radiotherapy is also used to control severe pain and to prevent fractures, which was reported as an effective strategy in these patients. 10,12,13 Zoledronic acid, a bisphosphonate, inhibits osteoclast-mediated bone resorption and increases bone mineralization. It also has antitumor and anti-angiogenic effects, and it has been proven effective in preventing SREs in bone metastases of solid tumors. 20  was an independent prognostic factor for these patients (P＜0.001).
These data may support the beneficial effects of zoledronic acid in GC patients with bone metastasis. On the other hand, zoledronic acid was prescribed selectively to the patients who received chemotherapy and who had a good performance status, which must be considered when evaluating these results.
A number of trials have provided evidence for the effect of systemic chemotherapy compared to best supportive care alone for patients with advanced GC. In a meta-analysis, a significant improvement in OS was shown in favor of chemotherapy (HR: 0.37; 95% CI, 0.24~0.55). 21 We observed a significant impact of receiving palliative chemotherapy on survival (HR: 0.59; P=0.003) in our cohort. Ahn et al. 10 reported an improvement in the clinical symptoms and survival time with chemotherapy in these patients.
Although earlier studies showed no clear benefit of chemotherapy in GC patients with bone metastasis, with the development of chemotherapeutic agents such as taxanes and S-1, and targeted therapies such as trastuzumab have been recognized to be an effective management approach. 12 Park et al. 9 suggested that aggressive therapeutic approaches should be reserved for low-risk patients while conservative care is a more desirable option for high-risk patients.
A number of various effective chemotherapy regimens have been described in cases of GC with bone metastases in the literature; however, no prospective randomized trials have been conducted.
Several studies have reported that the presence of bone metastasis in GC is associated with a poor prognosis. The median OS and OS-BM of the entire study population were 13.8 and 5.4 months, respectively. Moreover, the median OS-BM was significantly shorter in patients with a smoking history, metastatic GC at the time of diagnosis and a poor ECOG performance status. Nakanishi et al. 14 found that the mean survival time after a diagnosis of skeletal metastasis was 60 days in their study, which included 48 GC patients. Ahn et al. 10 reported that the mean survival time after the diagnosis of bone metastasis was 3.8±2.6 months and Sudo et al. 15 found that the median survival time was 189 days. Similarly, the median OS-BM was found to be approximately 6 months in two recent studies. 9,13 The survival results of our study are similar to those described in these previous studies.
One of the limitations of our study was that the majority of the bone metastases were not confirmed pathologically. Another limitation was that the impact of bone metastases on the function and quality of life could not be evaluated owing to the retrospective design of the study. Moreover, the current study did not quantify and compare the therapeutic effects of chemotherapy regimens because of the wide range of anti-cancer therapies utilized. Although univariate and multivariate analyses reached the statistical significance threshold (P＜0.05), missing data could lead to some biases.
In conclusion, bone metastasis of GC is often in multiple locations, metachronous, coexisting with visceral metastasis, and most commonly in the lumbar-thoracic vertebrae and pelvis. While smoking history and high levels of LDH, CEA, and CA 19-9 are poor prognostic factors, treatment with chemotherapy is associated with longer survival. According to multivariate analysis, treatment with zoledronic acid and the performance status were found to be independent prognostic factors. Early diagnosis and treatment are crucial to prevent the development of severe morbidity in GC patients with bone metastasis.