Abstract
Background/Aim: Skeletal muscle mass (SMM) is often depleted in patients with gastric cancer undergoing gastrectomy. Using a novel method, we evaluated the effect of SMM depletion after gastrectomy on disease prognosis. Patients and Methods: The maximum cross-sectional area of the psoas-muscle (MCA-PM) was measured before surgery and at 1 year after in 233 patients with gastric cancer who underwent radical gastrectomy to determine the ratio (MCA-PMR) as an indicator of SMM depletion. Results: The MCA-PMR cutoff value was set at 90%, and patients were divided into the groups with <90% and ≥90%. MCA-PMR <90% was an independent prognostic factor for all patients. In 88 patients who received adjuvant chemotherapy including S-1, the 5-year cancer-specific survival rate was significantly better for those with MCA-PMR ≥90% than for those with MCA-PMR <90% (84.1% vs. 59.1%; p=0.010; hazard ratio=2.974; 95% confidence interval=1.241-7.124). Conclusion: SMM depletion after gastrectomy can be measured using the MCA-PMR. This novel measurement can be easily implemented in the clinical setting.
Loss of skeletal muscle mass (SMM) and skeletal muscle strength is triggered by aging and disease. In addition to evidence supporting a low muscle mass, sarcopenia is diagnosed in the presence of low muscle strength or physical function, and it carries the risk of adverse consequences such as disability, poor quality of life, and death (1). Martin et al. reported that a low SMM is an independent prognostic factor for poorer survival in patients with lung or gastrointestinal cancer (2). Preoperative SMM has been reported to be associated with sarcopenia and is an independent predictive factor for poor prognosis in patients with cancer undergoing surgery (3-5). Although low preoperative SMM is a negative prognostic factor, there is no clear method for quantification. Postoperative SMM depletion is often observed in patients with gastric cancer (6, 7). Additionally, adjuvant chemotherapy may confound SMM depletion after gastrectomy (8, 9). In other words, secondary SMM following treatment for gastric cancer, such as surgery and chemotherapy, may worsen prognosis. Moreover, in patients with weak postoperative immunity, even a low SMM that does not meet the requirements for sarcopenia may worsen the prognosis of those with cancer. Postoperative chemotherapy with tegafur/gimeracil/oteracil (S-1) or multidrug combination including S-1 has considerably contributed to the prolongation of prognosis (10-13).
SMM, in addition to computed tomography (CT), is measured using a dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) (14-16). However, DXA, BIA, and magnetic resonance imaging are not always required for examination after surgery for gastric cancer, and CT is widely used. According to the current Japanese guidelines for gastric cancer treatment, CT is useful for follow-up surveillance (17). Thus, CT appears to be the most suitable approach for measuring SMM, especially in the surgical field.
In the present study, we investigated SMM determined from the maximum cross-sectional area of the psoas muscle mass (MCA-PM), which was calculated based on CT imaging data, and focused on SMM depletion. This method is particularly convenient in that the standard function of the image viewer software implemented in electronic medical charts can be used at clinical facilities where medical information has been computerized. Moreover, the dynamic change in the MCA-PM in the first year after surgery has not been investigated. In this study, we investigated whether depletion of SMM has a negative impact on prognosis and the completeness of postoperative chemotherapy after radical surgery for gastric cancer.
Patients and Methods
Patients. Data of patients who underwent surgery for gastric cancer at the Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School from April 2010 to March 2014 were retrospectively reviewed. The inclusion criteria were (i) gastric adenocarcinoma diagnosed according to the 14th edition of the Japanese Gastric Cancer guidelines issued by the Japan Gastric Cancer Association, histologically verified as clinical stages I-III, and radical surgery performed (18); (ii) patients with an American Society of Anesthesiologists grade of I-II with good tolerance for surgery; (iii) patients underwent elective surgery; and (iv) patients aged 20-80 years. The exclusion criteria were (i) secondary malignancies; (ii) severe comorbidities such as chronic heart failure, chronic respiratory failure, chronic renal disease, and connective tissue disease; and (iii) clinical course that was not followed-up.
This study was performed in accordance with the Declaration of Helsinki. The study protocol was approved by the Ethics Review Committee of Nippon Medical School (Tokyo, Japan, approval number: B-2020-163). Informed consent was obtained by providing a means to opt out.
Surgery, clinical follow-up, and adjuvant therapy. Gastrectomy was performed with D1 plus or D2 lymph node dissection according to the then-latest Japanese Gastric Cancer Treatment Guidelines (17). Reconstructive methods following gastrectomy were selected at the discretion of each surgeon. Data were collected for the following variables: Age, sex, Eastern Cooperative Oncology Group Performance Status, preoperative body mass index (BMI), approach, total gastrectomy or non-total gastrectomy, surgical procedures (surgery length, blood loss, blood transfusion, D1+ or D2 lymph node dissection, and combined resection with splenectomy and/or distal pancreatectomy). Postoperative complications were diagnosed as grade 2 or higher according to the Clavien–Dindo classification within 4 weeks after surgery (e.g. pancreatic fistulae, ileus, intra-abdominal abscess, anastomotic leakage, and surgical site infection) (19). Pathological findings for gastric adenocarcinoma were diagnosed according to the 14th edition of the Japanese Gastric Cancer Association's Japanese Classification of Gastric Carcinoma (18). We also recorded patients' compliance with adjuvant chemotherapy. All patients visited the outpatient clinic, and carcinoembryonic and carbohydrate antigen 19-9 levels were measured every 6 weeks. CT imaging of the chest and abdomen was performed at 5-mm intervals every 6 months after surgery, or immediately, if carcinoembryonic antigen or carbohydrate antigen 19-9 levels increased.
On the basis of postoperative pathological results, patients with stage II or III disease, excluding those with T1 and T3N0, received adjuvant chemotherapy with S-1 alone or in combination with other drugs (e.g. cisplatin, paclitaxel, or docetaxel). S-1 was started within 8 weeks postoperatively, and the dose ranged from 80-120 mg/day according to the patient's body surface area. S-1 treatment schedules were 4-week administration, 2-week rest, or 2-week administration and 1-week rest cycle. This treatment cycle was repeated for the first year after surgery (10, 11) unless an unacceptable adverse drug event or recurrence was observed. Further anticancer drugs were added with S-1 at the discretion of the primary care physician.
Measurement of SMM. We measured the right-side MCA-PM (mm2) on multidetector CT images and used this as an alternative indicator of SMM. In most patients, MCA-PM has a maximum area of 2-5 cm close to the head in relation to the iliac crest. This is larger than the cross-sectional area of the psoas muscle at the L3 level (Figure 1).
We measured the volume of the psoas major and the SMM preoperatively and confirmed their correlation with MCA-PM. MCA-PM and the psoas muscle volume were measured in 20 patients randomly selected from the patient group. The images were analyzed with a volume analyzer, Synapse Vincent (Fuji Film, Tokyo, Japan), and the contours of the psoas muscle were set using Hounsfield units (20). In addition, we measured SMM weight using a BIA (InBody 720; Biospace, Tokyo, Japan) from 30 patients randomly selected from the patient group. The data obtained by the BIA system were compared with the total psoas muscle area, as measured by CT scan images. The measurements with the BIA system in each patient were taken after at least 3 hours of fasting and voiding.
Abdominal CT images taken within the 4 weeks leading up to surgery and 1 year after surgery were used for calculating the MCA-PM. We measured the MCA-PM by CT scans undertaken at two time points: pre-surgery and 1 year after surgery. Firstly, we compared MCA-PM by sex and compared changes from pre-surgery to 1 year after surgery. Secondly, we defined the MCA-PMR as postoperative MCA-PM/preoperative MCA-PM ×100 (%). We evaluated the correlation between MCA-PMR and patient clinicopathological backgrounds and gastric cancer-specific prognosis. Thirdly, we investigated the influence of changes in MCA-PMR in patients with stage II and III disease, especially post-chemotherapy.
Statistical analysis. All statistical analyses were performed using Statistical Package for the Social Sciences version 22.0 (IBM Inc., Armonk, NY, USA). Comparisons between pre- and post-gastrectomy MCA-PM results were examined using Wilcoxon's rank-sum test and the paired t-test for normally distributed data. The cancer-specific survival (CSS) rate was calculated using the Kaplan–Meier method from the day of surgery. To define the optimal cutoff value for MCA-PMR as a predictor of cancer-specific death, the median and the receiver operating characteristic curve were examined. The means and standard deviations were calculated, and the differences were analyzed using Student's t-test. Differences between the categories of each clinicopathological feature were analyzed using the chi-squared test. We determined the optimal cutoff levels for BMI, surgery length, and blood loss using the respective medians. Risk factors for SMM depletion among the clinicopathological factors were analyzed by logistic regression.
Comparisons of CSS secondary to MCA-PMR differences were examined by the log-rank test. Multivariate analysis of the prognostic factors related to CSS was performed using a Cox proportional hazards model and the variables that were significant in the univariate analysis. In all analyses, a value of p<0.05 was considered statistically significant.
Results
A total of 292 patients underwent surgery for gastric cancer during the study. Of these patients, 233 were included in the study after excluding 32 who underwent nonradical resection, 15 who received preoperative chemotherapy, four who were diagnosed with other carcinomas, and eight who were not followed up or examined (Figure 2). In the 233 patients, the 5-year CSS rate was 99.1%, 88.6%, and 54.7% at stages I, II, and III, respectively.
Measurement of the right side of the maximum cross-sectional area of the psoas muscle (MCA-PM) by computed tomography. This figure shows the MCA-PM at the cranial level approximately 3 cm from the level of the L3 vertebral body.
Flow diagram of the selection of the final 233 patients.
MCA-PM correlated with psoas major volume and SMM weight in randomly selected patients (R=0.939, p<0.0001 and R=0.855, p<0.001, respectively) (Figure 3). Before surgery, in a sex-based comparison, MCA-PM was significantly larger in men (1138.5±257.5 mm2) than women (688.5±152.5 mm2) (p<0.001). In both men and women, MCA-PM before surgery was significantly larger than that after surgery (men: 1138.5±257.5 mm2 vs. 1050.9±251.7 mm2; women: 688.5±152.5 mm2 vs. 622.8±149.6 mm2; p<0.001).
The median MCA-PMR was 91.8% (range=55.7-119.7%) (Figure 4), and the cutoff value on the receiver operating characteristic curve was 89.0% (area under the curve: 0.675) (data not shown). Therefore, the cutoff value for this study was set at 90% for an easy-to-use value in clinical practice, and patients were divided into two groups: MCA-PMR <90% and MCA-PMR ≥90%.
Correlation of maximum cross-sectional area of the psoas muscle (MCA-PM) with psoas muscle volume (A) volume and psoas muscle weight (B),
Histogram of the distribution of maximum cross-sectional area-psoas muscle ratio (MCA-PMR) data.
Eighty-nine patients (38.2%) constituted the group with MCA-PMR <90%, and the remaining 144 patients (61.8%) constituted that with ≥90%. Table I shows the background characteristics for all patients in the two groups. No significant differences were observed in regard to age, Eastern Cooperative Oncology Group Performance Status, or BMI, which reflects the patients' preoperative status. Only surgical approaches (e.g. laparoscopic or laparotomy) differed between the two groups, and the MCA-PMR ≥90% group included significantly more laparoscopic surgeries (p=0.021). Furthermore, there was no difference in the final pathological results such as histological type, depth of invasion (T factor), presence or absence of lymph node metastases (N factor), and pathological stage between the two groups. Finally, the rate of postoperative chemotherapy was significantly higher in the group with MCA-PMR <90% than in that with ≥90% group (p=0.006).
Comparison of clinicopathological factors between patients with maximum cross-sectional area-psoas muscle ratio (MCA-PMR) <90% and MCA-PMR ≥90% at 1 year after surgery.
Logistic regression analysis showed that the surgical approach was not a statistically significant factor (p=0.050), and that adjuvant chemotherapy alone was an independent risk factor for SMM depletion after gastrectomy (p=0.009; Table II). Univariate and multivariate analyses showed that age and MCA-PMR were significant risk factors for CSS, especially MCA-PMR (p=0.003; Table III).
Eighty-eight patients received adjuvant chemotherapy, and the relationship between MCA-PMR and chemotherapy is shown in Table IV. All 88 patients received chemotherapy including S-1. The chemotherapy completion rate in the MCA-PMR <90% group was significantly lower than that of the group with MCA-PMR ≥90% (p=0.006). The recurrence rate in the group with MCA-PMR <90% (50.0%) was significantly higher than that of the group with MCA-PMR ≥90% (13.6%; p<0.001). In addition, 5-year CSS was significantly poorer at 59.2% versus 84.1%I respectively (p=0.010) (Figure 5).
Logistic regression analysis of depletion factors related to maximum cross-sectional area-psoas muscle ratio.
Discussion
In this study, we evaluated the impact of SMM depletion on the prognosis of patients with gastric cancer who underwent curative surgery, using MCA-PMR, which is especially convenient to measure and use. We clearly demonstrated three valuable findings. Firstly, SMM decreased in patients who underwent gastrectomy, and this depletion was measurable using MCA-PMR. Secondly, SMM depletion after gastrectomy was an independent prognostic factor in patients with gastric cancer. Finally, SMM depletion was a risk factor for discontinuation of adjuvant chemotherapy and had a negative impact on the prognosis of patients with stage II or III gastric cancer. This study had a single-center design but the treatment outcome was comparable to that other institutions and was strictly validated (21, 22).
Some studies have shown that gastrectomy reduces SMM (5-10%) (6, 7). Total gastrectomy is also a risk factor that interferes with the continuity of postoperative treatment in addition to reduction of SMM (8). Firstly, we were able to show that MCA-PM measured using our method reflected the SMM of each patient and that the method was reasonable and simple to perform. In this study, we calculated MCA-PMR, which is the reduction in SMM after surgery, and this calculation differs from the method in which SMM is simply compared between patients. This is because the method of this study calculated the rate of change before and after surgery for each individual. Therefore, this method can be verified by eliminating individual differences in SMM.
After surgery for gastric cancer, both men and women showed a loss in MCA-PM of nearly 10% compared with preoperative values. When comparing the two groups with respect to MCA-PMR, which is a patient background factor, the group with ≥90% had more patients with stage I early gastric cancer than the other group. This is because laparoscopic surgery is the standard surgical treatment choice for patients with early gastric cancer according to the Japanese Gastric Cancer Treatment Guidelines (17). Conversely, several patients in the <90% group received adjuvant chemotherapy. Nevertheless, MCA-PMR was a significant independent risk factor for CSS in the results of logistic analysis for each factor. Originally, tumor depth of invasion and lymph node metastasis were prognostic factors. Although the present study analyzed data from a single institution only, radical surgery and postoperative adjuvant therapy with S-1 alone or a combination of S-1 and docetaxel were strictly performed and a favorable prognosis was obtained. Recently, adjuvant therapy with S-1 plus docetaxel has been reported to be effective for advanced gastric cancer with lymph node metastasis (12, 13).
Univariate and multivariate Cox proportional hazards analysis.
A decrease in MCA-PMR after gastrectomy reflects SMM depletion and is an independent prognostic factor for patients with gastric cancer. Some studies reported that patients with gastric cancer who underwent gastrectomy with low SMM have a poor prognosis (23, 24) or a high rate of morbidity (8, 25, 26). In patients with malignancies other than gastric cancer, low SMM can worsen short- or long-term outcomes (3-5). In the present study, which included over 200 patients, we clearly demonstrated that SMM depletion after gastrectomy had a negative impact on survival. Furthermore, MCA-PMR was calculated as the altered ratio after surgery for each patient in this study; therefore, the ratio reflects a realistic clinical condition after gastrectomy when handling ‘big data’.
Adjuvant chemotherapy was the only independent risk factor for SMM depletion. To the best of our knowledge, this study is the first study focusing on the association of adjuvant chemotherapy and SMM depletion. SMM depletion was a risk factor for discontinuation of adjuvant chemotherapy and had a negative impact on the prognosis of patients with stage II or III gastric cancer. The completion rate of adjuvant chemotherapy was worse the recurrence rate was higher in the group with MCA-PMR <90%.
Maximum cross-sectional area-psoas muscle ratio (MCA-PMR) of patients with stage II or III gastric cancer treated with postoperative adjuvant chemotherapy including S-1.
Prado et al. reported that a low SMM before starting chemotherapy was a prognostic factor for 5-fluorouracil toxicity (27). Williams et al. reported similar findings in colorectal cancer (28). Furthermore, Aoyama et al. (7) and Yamaoka et al. (8) reported that postoperative body weight loss was an important independent risk factor for discontinuation of treatment in gastric cancer, and a meta-analysis showed that SMM may affect the clearance of 5-fluorouracil (29). Thus, there are several reports evaluating the relationship between chemotherapy and sarcopenia before starting chemotherapy. These results indicate that SMM preservation is associated with the achievement of adjuvant chemotherapy completion and that SMM preservation has an impact on the prognosis of patients with stage II or III gastric cancer.
Cancer-specific survival in 88 patients treated with adjuvant chemotherapy according to maximum cross-sectional area-psoas muscle ratio (MCA-PMR) at 1 year after surgery. CI: Confidence interval; HR: hazard ratio.
MCA-PMR, which is particularly convenient in that the standard function of image viewer software is implemented in electronic medical charts, has three major advantages. Firstly, this ratio can be measured easily without specialized equipment. In Japan, abdominal CT is routinely performed during cancer treatment but BIA or instruments measuring total muscle cross-sectional area require additional staff effort and there are increased costs associated with each device. Surveillance with CT follows the recommended guidelines (17). Secondly, retrospective data are available, and we can use data from daily clinical practice because abdominal CT is routinely performed for patients with gastric cancer after surgery. Various SMM cutoff values have been reported; however, SMM is strongly influenced by individual differences. Conventionally, L3 has been used as the standard landmark for determination of cross-sectional area of the psoas muscle in many studies (4, 20, 25). However, the thickness of the L3 vertebra is approximately 5 cm; therefore, the measurement at the level of L3 has 10 different values (when CT is taken at 5-mm intervals). In contrast, MCA-PM and MCA-PMR examined in this study had unique values.
Several limitations were associated with the present study. Firstly, this was a retrospective analysis performed at a single institution, and our results need to be confirmed in another cohort or in a prospective multicenter study. Secondly, we evaluated SMM at only two time points (pre-surgery and 1 year after surgery). Thus, the impact of SMM depletion at 3 or 6 months after surgery is unknown. The rate of psoas muscle area decrease, including in the early postoperative period (e.g. 3 and 6 months postoperatively), should be verified. Finally, lifestyle, total calorie intake, muscle strength, and physical activity after surgery were not evaluated in this study. Therefore, the effect of interventions to preserve SMM in the perioperative period remains unknown.
After gastrectomy for gastric cancer, SMM depletion with a decrease of 10% or more preoperatively compared to 1 year after surgery negatively impacts the prognosis of patients with gastric cancer. Therefore, the measurement of psoas muscle area as a substitute for SMM is useful as a prognostic surrogate marker in gastric cancer treatment.
Acknowledgements
The Authors would like to thank Editage (www.editage.com) for English language editing.
Footnotes
Authors' Contributions
Conception or design of the work: Kanazawa Y and Yamada T. Data acquisition: Kakinuma D, Matsuno K, Ando F, Fujita I, Kanno H, and Kato S. Writing the article: Kanazawa Y. Data analysis: Kanazawa Y and Yamada T. Data interpretation: Kanazawa Y. Supervision or mentorship: Yoshida H.
Conflicts of Interest
The Authors have no conflicts of interest to disclose.
- Received June 4, 2020.
- Revision received June 28, 2020.
- Accepted July 1, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.