br This study also showed that
This study also showed that the presence of three higher-frequency metastatic sites (within the chest cavity, bone, and brain) was not associated with OS in patients with lung cancer. Similar results have been reported in patients with
stage IV NSCLC [7,9]. However, a study using a large amount of data obtained from the nationwide Swedish Cancer Registry linked bone metastases to poor survival . In another study using “big data” obtained from the Surveillance Epidemiology and End Results database, patients with NSCLC coded as present in either the Cell Counting Kit or bone without other metastases had improved OS relative to all other patients . The present study also suggests that bone metastasis is associated with better OS in patients with an M1b status. Either way, the impact of these metastatic sites (within the chest cavity, bone, and brain) on prognosis might be not very large.
However, several past studies as well as the present anal-ysis showed poorer survival in patients with liver metastasis than in patients with other metastases [2, 6e8,11]. Among patients with NSCLC with only one EPMS, the median OS was worst in patients with liver metastasis (2 months) . In the above analysis of the nationwide Swedish Cancer Registry, liver metastasis conferred the worst prognosis (3 months) . In patients with extensive-stage SCLC, isolated liver metas-tasis had the worst OS among all metastatic sites . Among patients with NSCLC harboring EGFR mutations who under-went gefitinib treatment, PFS and OS were shorter among those with liver metastasis than in those without .
In contrast to liver metastasis, the prevalence of muscle metastasis and its significance in the prognosis and treatment response have been rarely reported because of its lower fre-quency [12e14]. In the present study, muscle metastasis was found in 19 (4.8%) of the 400 patients at the time of diagnosis of lung cancer, which is a much higher frequency than that re-ported previously . 18F-FDG PET was performed in all pa-tients in the present study. All had NSCLC (11 adenocarcinoma,
Please cite this article as: Kanaji N et al., Association of specific metastatic organs with the prognosis and chemotherapeutic response in patients with advanced lung cancer, Respiratory Investigation, https://doi.org/10.1016/j.resinv.2019.06.004
4 squamous cell carcinoma, 2 not otherwise specified, 1 ade-nosquamous cell carcinoma, and 1 pleomorphic carcinoma). These patients with muscle metastasis had higher numbers of other metastatic organ sites than did patients with liver metastasis. Although the reason for the higher frequency of muscle metastasis in the present patient series is unclear, one possibility is that many patients had extensively progressed disease, and muscle metastasis usually appears after the lung cancer has progressed to a very advanced stage. Patients with skin metastasis also had many other metastatic organs, but the multivariate analysis did not show that skin metastasis was an independent poor prognostic factor; this result might have been due to the small number of patients with skin metastasis (n¼12).
Several mechanisms by which tumor cells metastasize to specific organs have been proposed . An important factor is the anatomy of the vascular and lymphatic drainage routes from the primary tumor sites (the anatomical-mechanical hypothesis) . The liver is the organ at which a tumor from the gastrointestinal tract first arrives via the portal venous system. Muscle contractions may prevent metastatic cancer cell survival by inducing high tissue pressure and variable local blood flow . Biomechanical destruction of cancer cells injected into the muscle was observed following electrical stimulation of the muscle . Blood flow is highly variable when a muscle is in the con-tractile state, and it may destroy circulating cancer cells [13,17]. Another mechanism of metastasis to specific organs is the “seed and soil” hypothesis [13,18]. Some tumor cells (seeds) grow preferentially in the selected organs (soil) in which a suitable microenvironment is provided. In this re-gard, many factors including cytokines, growth factors, and other molecules are involved in a complex manner. Hepa-tocyte growth factor (HGF)/c-Met signaling has an important role not only in the maintenance of the homeostasis of the liver by hepatocytes but also in the progression of cancers, including lung cancer. HGF overexpression is a mechanism of acquisition of EGFR-TKI resistance . HGF produced by fibroblasts enhances lung cancer progression . Muscles provide a special microenvironment that includes elevated lactic acid production, hypoxia, local pH instability, and reactive oxygen species generation, and this microenviron-ment differs from those in more frequent metastatic sites such as the bone and liver. This may result in unfavorable conditions for cancer cell survival and the subsequent development of detectable metastatic lesions [13,21].