Esophageal cancer is a highly lethal malignant tumor, approximately half of patients present with metastases to distant organs such as bone, liver, brain and lung at initial diagnosis15, 16. The incidence rate of esophageal cancer with bone metastasis ranges from 5.2-8.0% in all stage patients6, 17, 18. Furthermore, OS was worst for bone metastases. To establish a comprehensive insight into whether chemotherapy is justifiably being prescribed to esophageal cancer patients with bone metastasis, we performed this retrospective study based on the SEER database. Our research found that chemotherapy was significantly associated with OS and CSS in esophageal cancer patients with bone metastasis. It meant that chemotherapy could reduce the risk of dying from all causes and reduce the risk of dying from esophageal cancer.
Previous studies have mentioned the effect of chemotherapy on survival in esophageal cancer with bone metastasis. Gerald et al. reported that most esophagogastric cancer patients, who underwent curative resections, have bone marrow micrometastases. They further found that a higher percentage of chemoradiotherapy patients were alive at 10 years (28%) compared to surgery alone patients (20%). It indicated a survival advantage with the chemoradiation strategy19, 20. A retrospective study 21 has investigated the clinical features and prognostic factors in esophageal cancer patients with bone metastasis. They found that higher serum CEA levels and no chemotherapy were significant risk factors for poor OS, indicating that bone metastasis patients may benefit from chemotherapy. A multicenter retrospective cohort study suggested that among patients with recurrent or metastatic esophageal squamous cell carcinoma who cannot tolerate or whose tumors are refractory to fluorouracil, platinum and taxane, those receiving active salvage chemotherapy achieved better OS than those receiving best supportive care 22. Consistent with the previous results, our univariate analysis suggests that the non-chemotherapy showed a poorer prognosis than the chemotherapy. In addition, adjusting for clinical and treatment variables, chemotherapy was also an independent prognostic factor for esophageal cancer patients with bone metastasis. Compared to patients who received chemotherapy, the hazard ratios for patients who didn’t receive chemotherapy was 3.082(95% CI: 2.615–3.633).
Our research further explores the association between chemotherapy and survival by stratifying patients by tumor grade and histological subtype. Both in squamous cell carcinoma or adenocarcinoma subgroups, chemotherapy could significantly improve OS and CSS. Chemotherapy was a good prognostic indicator for OS and CSS in both squamous cell carcinoma and adenocarcinoma patients. In patients with grade I esophageal cancer, neither OS nor CSS were significant between the chemotherapy and non-chemotherapy groups. This result means that chemotherapy may not improve the prognosis of grade I esophageal cancer. To date, no common consensus that the necessity of chemotherapy is used for grade I esophageal cancer with bone metastasis has established. Considering the balance of the survival outcomes and the toxicity, chemotherapy is not recommended for grade I esophageal cancer patients. However, due to the small sample size of grade I patients, more prospective and retrospective studies need to be conducted to confirm our results.
Combination chemotherapy consisting of 5-fluorouracil plus cisplatin was recommended to recurrent or metastatic esophageal cancer, but the overall response rate of the included patients was 33.3%23. As the low response rate of chemotherapy and poor prognosis of esophageal cancer, patients with distant organ metastasis also suggest being treated with a multidisciplinary approach, using modalities such as radiotherapy, surgery and various medical treatments that include chemotherapy, hormone therapy, and bone-modifying agents21, 24, 25. Tanaka et al. evaluated the role of multimodality therapy in esophageal squamous cell cancer patients with distant organ metastasis. They found that multimodality therapy, which included chemoradiotherapy, surgery followed by chemotherapy and/or radiation therapy, could improve survival of the esophageal squamous cell cancer patients with distant organ metastasis11. On the basis of the encouraging result, the finding further underscores the need for chemotherapy approaches in this disease.
Patients with bone metastases had significantly poorer OS than those with metastasis to other sites.6 Therefore, to have a more prolonged OS and improved quality of life are the idea expectation for the end-stage cancer patients whose life expectancy is short.26, 27 chemotherapy is the first-line therapy for esophageal cancer with distant metastases12, 28. Nevertheless, a standard first-line treatment for bone metastases has not yet been established. To determine whether all esophageal cancer patients with bone metastasis should undergo chemotherapy, we conducted this study using the SEER database. To our knowledge, this research is the first comprehensive, population-based study evaluating the efficacy of chemotherapy for esophageal cancer with bone metastasis.
In order to minimize the baseline discrepancies and increase the comparability, we conducted 1:1 chemotherapy: the non-chemotherapy PSM analysis. PSM is an analysis of an even distribution of confounders between groups, and there is a tendency for observational studies applied this statistical method because of its advantages29. By performing PSM analysis, we further validated that esophageal cancer with bone metastasis patients undergoing chemotherapy has a promising prognosis with high credibility.
Nevertheless, there were some limitations in the present study. First, detailed information about chemotherapy such as regimens, doses and duration were missing from the database. Consequently, a further conclusion could not be drawn due to insufficient information. Second, since all the dataset was collected from retrospective studies and no randomization of treatment cohorts. It may lead to reporting bias and selection bias. Thirdly, the efficacy of the chemotherapy was evaluated by the OS and CSS in this study. Side effects, cost-effectiveness and performance status, could be included as evaluations in the future study to assess patient status comprehensively.
In conclusion, this study suggested that chemotherapy significantly improved OS and CSS in esophageal cancer patients with bone metastasis, chemotherapy was an independent prognostic factor for esophageal cancer patients with bone metastasis. However, chemotherapy might not improve the prognosis of grade I esophageal cancer. Furthermore, more prospective studies need to be conducted to confirm our results. Despite several limitations, the results ought to provide severe consideration when making a treatment decision for esophageal cancer patients with bone metastasis.