Sarcopenia is associated with poor prognosis after chemoradiotherapy in patients with stage III non-small-cell lung cancer: a retrospective analysis

We intended to investigate whether muscle and adipose masses were associated with prognosis among patients with stage III non-small-cell lung cancer (NSCLC) who were undergoing chemoradiotherapy (CCRT). We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. We examined the relationship of overall survival (OS) with body mass index (BMI), skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose tissue index (VAI), subcutaneous adipose tissue index (SAI), and visceral-to-subcutaneous adipose tissue area ratio (VSR) using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Overall, 16, 32, and 12 patients had stage IIIA, IIIB, and IIIC NSCLC, respectively. The total radiotherapy dose ranged from 60 Gy/30 fractions to 66 Gy/33 fractions. In the univariate analysis, the performance status (PS), BMI, and SMI were associated with OS, whereas the PMI, VAI, SAI, and VSR were not. In the multivariate analysis, the PS and SMI were associated with OS. The hazard ratios and 95% confidence intervals were 2.91 and 1.28–6.64 for PS, and 2.36 and 1.15–4.85 for SMI, respectively. The 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively. The SMI correlated with prognosis in our study population, whereas adipose mass did not. Therefore, sarcopenia should be considered while predicting the OS in such patients.


Scientific Reports
| (2021) 11:11882 | https://doi.org/10.1038/s41598-021-91449-z www.nature.com/scientificreports/ adverse health effects, including falls, disability, hospitalization, long-term care placement, poor quality of life, and mortality has been confirmed 6 . Sarcopenia is also associated with poor prognosis after treatment for malignancies, including lung cancer [7][8][9][10][11][12][13] . Further, an association between sarcopenia and poor prognosis in surgical cases, especially those involving early-stage lung cancer, has been demonstrated in many studies 12,13 . In a study by Baracos et al.,46.8% of the patients with stage III-IV non-small-cell lung cancer (NSCLC) were diagnosed with sarcopenia 14 . Concurrent chemoradiotherapy (CCRT) is among the standard treatments for stage III lung cancer 15,16 . Few studies have focused on the association between prognosis and sarcopenia in patients with NSCLC who were treated with chemoradiotherapy. Bowden et al. demonstrated that muscle attenuation, and not muscle mass, was associated with long-term survival in patients with lung cancer, including those with small-cell lung cancer and NSCLC, who underwent chemoradiotherapy 17 . Kiss et al. did not identify an association between muscle mass or muscle attenuation and OS in patients with NSCLC who underwent CCRT 18 . Existing evidence on the association between sarcopenia and OS in patients treated with CCRT for stage III NSCLC is insufficient. Body mass index (BMI)-determined obesity is a poor prognostic factor after treatment in most cancer types 19,20 . However, the relationship between obesity and OS after treatment in patients with lung cancer is controversial 19,20 . In a meta-analysis, Gupta et al. showed that patients with obesity and overweight had lower lung cancer mortality rates than those with normal BMI 21 . Dahlberg et al. showed that patients with advanced NSCLC and obesity who received chemotherapy had better OS than those without obesity in the early stages of their study 22 . In locally advanced NSCLC settings, Lam et al. showed that the OS of patients who were obese was better than that of those who were normal-weight 23 . In the aforementioned studies, obesity was assessed based on BMI alone without using computed tomography (CT). In recent years, sarcopenia and adiposity have been measured based on muscle and fat masses using CT, which is necessary for diagnosing and staging cancer 7,11,17,18,[24][25][26] . Although BMI is not a poor prognostic factor, the visceral-to-subcutaneous adipose tissue mass, in addition to muscle mass, is an independent poor prognostic factor in patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma 25,26 . Because weight includes components besides muscles, the measurement of fat mass in addition to muscle mass using CT is desirable. However, no studies to date have examined the association between fat mass and OS in patients with NSCLC who were treated with CCRT.
The identification of the level of risk before treatment and provision of appropriate interventions for sarcopenia and obesity may improve patient prognosis. Therefore, we intended to investigate whether CT-determined muscle and fat masses were prognostic factors in patients with stage III NSCLC who have undergone CCRT.

Patients and methods
Patients and treatment. We retrospectively explored data of patients with stage III NSCLC who underwent definitive CCRT (≥ 60 Gy) between January 2004 and March 2018 at our hospital. This study included patients for whom pre-CCRT digital plain CT of the third lumbar vertebra (L3) was available in the picture archiving and communication systems. Patients who underwent treatment for NSCLC before CCRT and those who received preoperative CCRT with chest surgery before recurrence were excluded. Staging was determined using the tumor-node-metastasis classification, 8th edition. We examined the patients' histology, smoking history, performance status (PS), location, laterality, and forced expiratory volume in 1 s. The indication of CCRT was determined by consensus of board-certified respiratory physicians and radiation oncologists. The chemotherapy regimen was determined by board-certified respiratory physicians, and details regarding radiotherapy were finally determined by board-certified radiation oncologists. Chemotherapy mainly involved the administration of cisplatin plus docetaxel; tegafur/gimeracil/oteracil was used for vulnerable patients. All patients were treated with three-dimensional conformal radiotherapy. Details regarding the three-dimensional radiotherapy which was employed have been described elsewhere 27 . The gross tumor included the primary tumor and the clinically diagnosed metastatic lymph node. The margin for the clinical target volume was 5-10 mm, and subcarinal and ipsilateral hilar nodal stations were included in cases of elective nodal irradiation. The internal margin was determined using fluoroscopic images, and the planning target volume margin was 5-10 mm. We used a 10 MV photon beam generated from a linear accelerator (Primus or ONCOR, or Mevatron, Canon Medical Systems, Tochigi, Japan).
All procedures were performed according to the ethical standards set out in the 1964 Declaration of Helsinki and subsequent amendments. This study was approved by our institutional review board of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital (approval number 1809-018). Written informed consent for CCRT was obtained from all patients before treatment. The choice to opt out was provided through notifications displayed on the hospital's website and in the outpatient ward before starting the study. Image analysis. Abdominal CT data, which were obtained from the institution's picture archiving and communication systems, were transferred to a workstation computer (SYNAPSE VINCENT version 5.5, FUJIFILM Medical Co., Ltd., Tokyo, Japan). Plain CT was used to examine the vertebra at the L3 level, and contours were extracted automatically by setting the Hounsfield unit (HU) thresholds within a certain range. According to previous studies, the HU thresholds were set from − 29 to + 150 for the skeletal and psoas muscles, − 150 to − 50 for visceral adipose tissues, and − 190 to − 30 for subcutaneous adipose tissues 7,24 . Skeletal muscles included all muscles at the L3 level. Areas that were not obviously targeted muscle or adipose tissues were deleted by manual manipulation. Figure 1A-D illustrate an example for each of the muscle and adipose tissues. These four areas (cm 2 ) were divided by the square of height (m) to obtain the skeletal muscle index (SMI), psoas muscle index (PMI), visceral adipose index (VAI), and subcutaneous adipose index (SAI) 25,28 . Muscle attenuation (MA), as a measure of muscle quality, was defined as the mean of the HU value of the SMI; furthermore, the visceral-tosubcutaneous adipose ratio (VSR) was calculated 7 29 . According to previous reports 26 , we calculated the cutoff values for men and women and divided them into two groups. The survival curves were obtained using the Kaplan-Meier method. We examined the relationship between the aforementioned parameters and OS using log-rank tests for the univariate analysis and Cox proportional hazard models for the multivariate analysis. Statistical significance was determined at p-values < 0.05 (two-sided). R software version 3.5.1 and additional package of survival ROC version 1.0.3 (R Foundation for Statistical Computing, Vienna, Austria) were used for all statistical analyses.

Results
This study included 60 eligible patients.  Table 2 shows the relationship between clinicopathologic factors and sarcopenia (low SMI). Sarcopenia was significantly associated with lower BMI (p = 0.017). Table 3 shows the cutoff values and the results of the univariate and multivariate analyses of factors associated with OS. The female/male cutoff BMI, SMI, PMI, MA, VAI, SAI, and VSR values determined from the time-dependent receiver operating characteristic curve were 17/25 kg/ m 2 , 24/43 cm 2 /m 2 , 4.7/7.3 cm 2 /m 2 , 9/36 HU, 97/40 cm 2 /m 2 , 127/28 cm 2 /m 2 , and 0.8/0.6, respectively. The PS, SMI, and BMI were significant prognostic factors associated with OS in the univariate analysis (p = 0.004, 0.01, and 0.03), whereas the PMI, MA, VAI, SAI, and VSR were not (p = 0.4, > 0.99, 0.1, 0.09, and 0.1, respectively). In the multivariate analysis, the PS and SMI were significant prognostic factors associated with OS (p = 0.011 and 0.020, respectively). The hazard ratios and 95% confidence intervals (CIs) were 2.91 and 1.28-6.64 for the PS, 2.36 and 1.15-4.85 for the SMI, respectively. Since BMI and SMI are significantly correlated, we excluded BMI from the multivariate analysis according to previous reports 30, 31 . www.nature.com/scientificreports/ Figure 2 shows OS curve for all patients. The 1, 3, and 5-year OS rates were 81.7%, 57.9%, and 37.8%, respectively, for all patients. Further, the 1, 3, and 5-year OS rates were 92.1%, 59.6%, and 51.0% in patients with high SMI, and 63.6%, 53.8%, and 17.9% in patients with low SMI, respectively (Fig. 3). Details of the OS rates for  25,26 . In terms of lung cancer, several systematic reviews and meta-analyses have focused on the association between sarcopenia and OS after treatment for lung cancer. Buentzel et al. conducted an analysis of 15 studies on patients with lung cancer (including all stages of NSCLC and small-cell lung cancer), and based on the findings of multivariate analysis, reported that patients with lung cancer and sarcopenia had a three-fold greater risk of death than those without sarcopenia 8 . Yang et al. who conducted an analysis of thirteen studies showed that sarcopenia was an independent prognostic factor for poor OS in patients with stage III-IV NSCLC 9 . www.nature.com/scientificreports/ from our study with respect to the following aspects: it included sequential chemotherapy cases and CCRT cases, patients with small-cell lung cancer, and patients with all disease stages. In addition, the treatment strategies for stage III disease vary across institutions, with our institution prioritizing preoperative CCRT plus surgery. Therefore, we cannot rule out the possibility that the extent of progression and general condition in our patients may have significantly differed from those in patients in the aforementioned reports. In our study, we included patients with stage III NSCLC who had CT data pertaining to the L3 level, with no restrictions on the chemotherapy regimen. Thus, our results may have differed from those of previous studies. In our study, the PMI was also not a prognostic factor. Hamaguchi et al. reported that in 541 adult liver donors (living donor liver transplantation), the PMI was positively correlated with the SMI 28 . Theoretically, if the SMI is significantly associated with OS, similar results should have been obtained for the PMI; however, it is not clear    32 ; therefore, the PMI may not be an important parameter in lung cancer. Data on the association of the SMI and PMI with OS in patients with NSCLC are scarce in the setting of CCRT compared with surgery, and thus, further studies are warranted. Muscle loss is a major symptom of cancer cachexia, along with anorexia, weight loss, anemia, and altered carbohydrate, lipid, and protein metabolism. Cancer cachexia is recognized as a paraneoplastic syndrome in 60-80% of the patients with advanced-stage disease. More than 30% of the patients with cancer die due to cachexia, and more than 50% of them die in the presence of cachexia, which is associated with adverse prognosis and shorter survival times 33,34 . Sarcopenia may be a marker to preemptively predict the development of cancer cachexia. Recently, skeletal muscle has been identified as a secretory organ, which secretes myokines that may affect the growth of cancer cells 35 . Hojman et al. reported that myokines, which are released from muscles during exercise inhibit the growth of breast cancer cells and induce apoptosis of these cells 36 . Therefore, as muscle mass decreases, myokine levels and responses may decrease, making it easier for cancer to progress.
In our study, a higher BMI was correlated with a higher OS rate in the univariate analysis. A high BMI is correlated to poor OS after cancer treatment 19 ; however, there is some controversy regarding the same in patients with lung cancer. In their meta-analysis, Gupta et al. showed that patients who were obese in the pre-treatment stage had lower lung cancer mortality rates than those with normal weight; our results showed the same trend. In gastrointestinal cancers, high VAI, SAI, and VSR have been shown to be associated with poor OS rates 25,26 ; however, no correlation was found in our study that examined data of patients with lung cancer following CCRT. The reason for this is that despite difficulties in the performance of simple comparisons, the median VAI and SAI values were 31.8 cm 2 /m 2 and 41.4 cm 2 /m 2 , respectively, in the study by Fujiwara et al., which are higher than the values of 27.0 cm 2 /m 2 and 28.7 cm 2 /m 2 , respectively, observed in our study. This may be largely attributed to differences in patients' backgrounds. Regarding OS, the result observed in patients with lung cancer may differ from that in those with other carcinomas with respect to adipose mass, as with BMI. In patients undergoing CCRT for stage III NSCLC, adipose mass reductions are not given high priority, with efforts primarily driven toward increasing or maintaining patients' muscle mass. To the best of our knowledge, our study was the first to examine the association between post-treatment OS rates for lung cancer and the VAI, SAI, and VSR, as assessed using CT. In our study, the BMI scores (median 21.7) of all patients were normal, unlike that in the study by Martin et al., in which the average BMI scores were 26.0 for men and 25.1 for women 7 . Among patients with lung cancer and normal BMI, adipose mass may not be related to prognosis; although, further studies on adipose mass are warranted.
In the study of Bowden et al., a PS ≥ 2 was associated with poor OS 17 . Similarly, in our study, the PS was a predictor of prognosis, which is a reasonable result.
Exercise is effective in counteracting the catabolic effects of muscle by increasing the protein synthesis rate and decreasing the proteolysis rate owing to its anti-inflammatory effects 37,38 . Exercise training can attenuate or reverse the process of muscle wasting through anti-inflammatory and antioxidant effects that can attenuate the signaling pathways of proteolysis and activate protein synthesis molecules 38 . Gould et al. stated in their review that exercise successfully improved muscle strength and physical function in patients with cachexia in noncancer-related diseases and that exercise interventions provided at various stages of treatment may improve the protein synthesis rate and help patients recover from low body weight and reverse proteolysis 37 . Delrieu et al. reported that participation in a 6-month personalized walking program resulted in significant improvements in the 6-min walking distance test (+ 7%) and isometric quadriceps strength (+ 22%) among patients with metastatic breast cancer 39 . Exercise interventions may aid in increasing or maintaining the muscle strength in patients with lung cancer. Future clinical trials are warranted to determine whether improvements in muscle strength can lead to OS enhancements.
Our study has some limitations. Since this study was conducted at a single center with a short follow-up period, and CCRT is not the only treatment option for stage III NSCLC, the presence of an unmeasured bias cannot be ruled out. According to the European Working Group on Sarcopenia in Older People guidelines, the diagnosis of sarcopenia requires low muscle strength or low physical performance in addition to low muscle mass; however, because of the retrospective nature of the study, muscle strength measurements could not be performed.
In conclusion, we demonstrated that the SMI is correlated with prognosis in patients with stage III lung cancer undergoing CCRT, whereas adipose mass is not. The additional consideration of sarcopenia improved the predictability degree for OS in our settings, and therefore, could aid in early intervention to maintain muscle mass and improve prognosis.