The purpose of the current study was to evaluate the clinical significance of the four MRPs (i.e., SMI, SMMA, PMI, and PMMA) at the L3 level in stage I through III GC patients who underwent R0 resection. In this study, using a multivariate Cox model, the PMMA was the only MRP that proved to be a significant determinant of OS and DFS.
In this study, the SMA at the L3 level was correlated with height, as in Yoshizumi's previous study. [43]. Therefore, we calculated the SMI, the SMA normalized for height squared, for use as an indicator of muscle mass. Although the most frequent cutoffs of SMI were 52–55 cm2/m2 for men and 39–41 cm2/m2 for women in the literature [19], we determined the cutoffs based on our patient cohort. As the SMI was sex-dependent, it was dichotomized as low and high groups with sex-specific cutoffs (i.e., 46.48 cm2/m2 for men and 40.77 cm2/m2 for women). However, it was not an important determinant of OS or DFS when using the Cox model. In addition, even when SMI was dichotomized as low and high groups with sex-specific cutoffs according to Martin et al. (i.e., 53 cm2/m2 for men with BMI of 25 cm2/m2 or higher, 43 cm2/m2 for men with a BMI lower than 25 cm2/m2, and 41 cm2/m2 for women, irrespective of BMI), it was still not an important determinant of OS or DFS [29]. Thus, the results of the current study were somewhat inconsistent with previous studies that found that the SMI is an important determinant of OS in GC patients who underwent gastrectomy [22-26]. However, in a recent study by Hacker et al., encompassing 761 advanced stage GC patients, the SMI was also not a prognostic factor for OS [31]. In addition, in Zhuang et al.’s study, encompassing 937 stage I GC patients, it was not associated with OS [25]. The reason for the discrepancies between studies is unclear, but the differences in cutoffs, pathologic stage, ethnicity, and variation in CT acquisition parameters (e.g., type of CT examination, slice thickness, and administration of contrast media) and image analysis software may have possibly caused these [19]. Because only a limited number of studies have been performed on CT-based SMI measurements in GC patients, further studies are needed to validate the prognostic role of the SMI.
In addition to the SMA, we measured the PMA at the L3 level as another marker of muscle mass. In our study, the group of muscles, including the erector spinae, multifidus, psoas, and quadratus lumborum, was defined as the paraspinal muscle, as had been reported previously [29, 34, 44, 45]. Since the PMA correlated with height, we calculated the PMI, the PMA normalized for height squared for statistical analysis. As PMI was sex-dependent, PMI was dichotomized as low and high groups with sex-specific cutoffs (26.78 cm2/m2 for men and 23.80 cm2/m2 for women). Using the multivariate Cox model, PMI was not an important determinant of OS or DFS in our study. Similarly, in Hacker's recent study on advanced gastric and gastroesophageal junction cancer, while the PMI was an important determinant of OS (p=0.003), DFS was not significant using a multivariate Cox model [31]. Therefore, our findings are in line with previous studies in terms of DFS, but not OS. The reason for the inconsistent findings between studies is not certain; however, the differences in definition of paraspinal muscles (i.e., with or without the psoas muscle), cutoffs, stage of the tumor (i.e., stage I to III vs. stage IV), tumor location, and ethnicity (i.e., Asian vs. international) may have affected the differences in outcomes between studies.
Fat in the skeletal muscles is present in the form of intermuscular adipose tissue, intramuscular adipose tissue, or intramyocellular lipids [46]. The MA, which is calculated using CT images, is a radiologic index of muscle fat content; the values of the mean MA are inversely correlated with muscle fat content [27]. Under physiological conditions, the values of the MA are considered dependent on sex, age, and ethnicity [47]. Excess fat deposition in skeletal muscle, a pathological variation in the MA, is observed in patients with malignant tumors [27].
In previous studies on gastrointestinal malignancies, the SMMA was usually measured within the total abdominal wall musculature at the L3 level with predefined HU ranges of -29 HU to +150 HU. Therefore, in our study, the SMMA was dichotomized using sex-specific cutoffs (i.e., 40.56 HU for men and 26.39 HU for women), and the adjustment for age was performed by including age as a covariate at entry [48]. In this study, while the SMMA was found to be an important determinant of OS and DFS in the univariate Cox model, but not in the multivariate model. Similarly, in Tamandl et al.'s study, the SMMA was a determinant of OS in patients with resected esophageal or gastroesophageal junction cancer by applying the univariate Cox model, but was no longer true in the multivariate Cox model; therefore, their findings are consistent with our findings [30]. On the other hand, in other studies, using the multivariate Cox model, the SMMA was a significant prognostic factor for determining OS in patients with GC who underwent gastrectomy, patients with various gastrointestinal malignancies, and patients with gastric or gastroesophageal junction cancer. Therefore, the results of these studies were inconsistent with our findings [28, 29, 31].
In our study, the PMMA was measured in a group of skeletal muscles (i.e., erector spinae, multifidus, quadratus lumborum, and psoas muscle) at the L3 level with predefined HU ranges of -29 HU to +150 HU. Before statistical evaluation, this was dichotomized with sex-specific cutoffs (48.12 HU for men and 34.24 HU for women), and the adjustment for age was performed by including age as a covariate at entry. Using the multivariate Cox model, the PMMA was a significant determinant of both OS and DFS. The results of this study were consistent with our group's previous study that enrolled only stage I and II GC without including SMMA as a covariate [34]. Similarly, in Dohzono's study of patients with gastrointestinal cancers, including GC at 25%, the PMMA was a significant determinant of survival. However, discrepancies in terms of the cutoffs, paraspinal muscle definition, tumor stage, and tumor histology limit the exact comparison between studies [33].
As a subgroup analysis, the multivariate Cox model with or without the PMMA was applied. When applying multivariate Cox analysis while excluding the PMMA as a covariate in this study, the SMMA was an independent determinant of OS (p=0.008) and DFS (p=0.008). In addition, Harrell’s C-index for the multivariate Cox model excluding PMMA was 0.816 and 0.810 for OS and DFS, respectively. In comparison, when the PMMA was included as a covariate, Harrell's C-index increased to 0.822 for OS and 0.817 for DFS. Therefore, the SMMA is considered a significant determinant of OS and DFS, and its statistical significance was attenuated by adding the PMMA as a covariate to the multivariate Cox model. Therefore, these findings show that the PMMA rather than the SMMA may be a more accurate determinant of survival in GC patients undergoing gastrectomy. It is also a time-saving strategy because the ROIs for the PMMA are apparently smaller than those of the SMMA. In addition, while the PMMA was an important determinant of OS and DFS, upon application of the multivariate Cox model, the PMI was not a determinant of survival. Thus, muscle quality (i.e., PMMA) appears to be a more powerful factor in determining survival in our patient cohort compared to muscle mass (i.e., PMI). Similarly, in Dohzono et al.’s study, while the PMMA was an important determinant of OS, the PMI was not an important determinant of OS, using the multivariate Cox model [33]. In addition, Hacker et al. found that, although the SMMA was an important determinant of OS, the SMI was not an important determinant of OS, upon application of the multivariate Cox model [31]. On the other hand, in studies by Zhuang [28] and Martin [29], both the SMI and SMMA were significant determinants of OS. Therefore, the results of these studies were inconsistent with our finding, which suggests that muscle quality may be a stronger determinant than muscle mass. Since studies on MA, including PMMA along with SMMA, are rare, more studies are needed to verify the clinical significance of MA as a survival determinant.
In our study, multivariate Cox analysis revealed that total gastrectomy was an important determinant of OS and DFS. Compared with subtotal gastrectomy, total gastrectomy is a technically difficult surgery associated with poor prognosis due to high postoperative complications, infection rates, and hospitalization rates [49, 50]. Therefore, our findings confirmed the current trend. In this study, we also found that perineural invasion was an independent determinant of survival by applying a multivariate Cox model. The prognostic value of perineural invasion has been reported previously [51]. In the present study, the PNI, which is calculated based on serum albumin levels and peripheral ALC, was an important determinant of OS and DFS in the multivariate Cox model [40]. The clinical role of PNI as an indicator of nutritional and immunological status in cancer patients has been validated. Several previous studies on GC have confirmed that the PNI is associated with the depth of invasion, lymph node metastasis, pathological stage, and lymph and vascular infiltration and that low PNI was an adverse prognosticator for survival [51-53].
The strengths of our study are as follows: First, this was the first study to assess the prognostic significance of the PMMA, along with the SMMA as a covariate, in patients with stage I to III GC undergoing curative gastrectomy. In this study, we found that the PMMA was the only MRP capable of predicting OS and DFS by applying a multivariate Cox model. Thus, skeletal muscle quality (i.e., PMMA) compared to skeletal muscle mass (i.e., SMI or PMI) appears to be a more important determinant of survival. Second, for MRP measurements, we used CT images taken as a part of standard cancer staging to avoid additional costs and radiation exposure. Finally, for consistency, we included only those patients who underwent curative gastrectomy by a gastroenterology expert.
However, since this study had several limitations, the results of the study should be interpreted carefully. First, this study was performed retrospectively; therefore, omission of data including CT images is inevitable and may have affected the results. Second, although random errors and potential biases were controlled from the study design to implementation, the lack of external validation was another limitation of our study. For verification, public databases were investigated in domestic and global databases, but there were no CT images suitable for measuring the MRPs. However, based on the results of this study, it is possible to conduct a prospective study with an independent external validation group at the next stage of this study, which could be an essential step for the clinical use of PMMA. Third, since it was a retrospective study, there was no opportunity to provide special interventions to improve postoperative outcomes in patients with PMMA below the threshold. Finally, the cutoffs for dichotomization of MRPs in our cohort were determined using receiver operating characteristic curve analysis. As such, the cutoffs presented in this study may not be applicable to patients with malignant tumors other than GC.
In conclusion, we found that the PMMA was a significant determinant of OS and DFS. Since the PMMA is a newly characterized determinant of survival in GC, its prognostic importance requires further validation prior to clinical application. In addition, measurements of muscle mass and MA using CT require standardization for comparison between studies.