To the best of our knowledge, this is the first study to evaluate and explore the impact of sarcopenia in patients with NSCLC and pre-existing ILD by quantitatively measuring PMI. The present study showed a correlation between sarcopenia and the incidence of ILD exacerbation and prognosis, with sarcopenia having been identified as an independent predictor of chemotherapy-triggered exacerbation of ILD after adjusting for established prognostic factors of NSCLC and ILD. Furthermore, our findings showed that patients with sarcopenia exhibited a significantly lower median OS compared to those without it. The aforementioned results suggest the importance of monitoring PMI in clinical settings. Furthermore, the management of sarcopenia may prevent exacerbations of ILD and improve prognosis, highlighting a novel therapeutic target among such patients.
Although several studies have investigated the relationship between ILD prognosis and skeletal muscle mass21–24, only one has thus far examined the relationship between ILD exacerbations and skeletal muscle mass. Awano et al. reported that the cross-sectional area of the erector spinae muscles measured at the 12th thoracic vertebral body level predicted the prognosis of patients with IPF but did not contribute to IPF exacerbation23, which diffed from the results presented herein. This could have been attributed to our use of the psoas major muscle instead of the erector spinae muscle. Although all previous studies on ILD have used the erector spinae muscles, lung cancer studies often use the psoas major muscle at the third lumbar spine level17–20, 29 given that the muscle group found at the cranial level 5 cm from the fourth–fifth lumbar vertebra has been considered the most accurate estimate of whole-body muscle mass30. The PMI used in the present study, which can be easily calculated from the psoas major muscle cross-sectional area and height, has been suggested to have a strong correlation with the skeletal muscle index28. Moreover, criteria for low skeletal muscle mass among Asians (6.36 and 3.92 cm2 / m2 for men and women, respectively) have been widely used in lung cancer research as indicators of sarcopenia17,18,29. The present study, which has been the first to utilize the PMI for ILD, found that sarcopenia can predict chemotherapy-triggered ILD exacerbation. As such, we believe that sarcopenia evaluation based on the psoas major muscle may become the standard in the future studies investigating ILD.
ILD exacerbations observed herein had been limited to antineoplastic causes, which could also be another point of difference from a previous report23. Although various chemotherapy regimens had been included, patients with ILD who received the contraindicated chemotherapy in Japan were excluded, which would expectedly decrease the potential impact of chemotherapy on the incidence of ILD exacerbation. Furthermore, after grouping the patients according to the presence or absence of sarcopenia, no significant difference in chemotherapy regimens had been noted, suggesting that sarcopenia can predict ILD exacerbations regardless of the type of anticancer drugs administered.
The reason for the involvement of sarcopenia in the ILD exacerbations and prognosis of lung cancer with ILD remains unclear. However, such involvement may be attributed to myokine, a bioactive substance secreted by skeletal muscle. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional coactivator required for the maintenance and generation of mitochondria, has been identified as an important factor in the relationship between exercise and inflammation31. Patients with sarcopenia have been found to have reduced PGC-1α in their skeletal muscle but enhanced interleukin-6 and tumor necrosis factor-α expression, causing inflammation and muscle proteolysis32,33. Previous studies have suggested that inflammation and undernutrition may contribute to the prognosis and exacerbation of ILD14,34−37. Based the aforementioned findings, anti-inflammatory treatment through myokine supplementation and maintenance of muscle mass through nutrition therapy and rehabilitation may be novel approaches for suppressing ILD exacerbation, as well as improving the prognosis for lung cancer with ILD.
At present, no treatment has been established for ILD exacerbation, which has shown high mortality rates2,7,8. Therefore, patients with lung cancer and ILD often do not receive chemotherapy38,39. On the other hand, given evidence suggesting that chemotherapy may prolong survival, uniformly excluding these populations from chemotherapy may not be appropriate5,6. The present study showed that patients without sarcopenia were less prone to ILD exacerbation and could hence receive aggressive chemotherapy, which may contribute to a better prognosis. On the other hand, patients with sarcopenia may have a worse prognosis due to ILD exacerbation and hence require careful chemotherapy. In some cases, physicians may offer the patient the option to opt out from chemotherapy. Thus, the presence or absence of sarcopenia may be useful in determining treatment approaches for patients with lung cancer and ILD. Considering that these patients undergo whole-body CT for the purpose of staging evaluation, sarcopenia evaluation based on the psoas major muscle can be performed quite easily. Therefore, routine evaluation of sarcopenia upon introducing a chemotherapeutic drug may be better for patients with lung cancer and ILD.
The present study has several limitations worth noting. First, this was a single-center retrospective study with a relatively small sample size, which may introduce bias. However, lung cancer with ILD is a rare disease with a limited number of patients3,4,9,10, 12–14,38,40. The number of patients included herein does not considerably differ from those included in other studies. Moreover, given the absence of large-scale phase III trials in patients with ILD-complicated lung cancer to date, evidence has been largely obtained from retrospective studies. Therefore, despite these limitations, we believe that the results presented herein are of considerable significance. Further studies are required to confirm our observations in other external validation cohorts. Second, diseases (e.g., diabetes, osteoporosis), drugs (e.g., statins, sulfonylureas, glinides, and antifibrotic drugs), and lifestyles (e.g., exercise and diet) that may affect skeletal muscle mass could not be completely assessed. On the other hand, the effects of sarcopenia due to complications can be considered minimal given that patients who had received steroids, had malignant tumors other than lung cancer, and had secondary ILD were excluded. Third, although the total psoas area was used, it might have been better to measure whole-body skeletal muscle mass using bioelectrical impedance or dual-energy X-ray absorption. However, these devices expose the patients to radiation and are considerably costly. Therefore, CT can be considered appropriate from the viewpoint of convenience.
The present study showed that sarcopenia can predict ILD exacerbations and OS in patients with ILD-complicated NSCLC who received chemotherapy. In the future, targeting sarcopenia can be expected to become a novel approach for suppressing ILD exacerbation and improving patient prognosis.