Loss of skeletal muscle mass during palliative chemotherapy is a poor prognostic factor in patients with advanced gastric cancer

Cancer causes muscle mass loss, which is associated with a poor prognosis. Chemotherapy may also reduce muscle mass. We investigated skeletal muscle mass change during palliative chemotherapy for advanced gastric cancer (AGC) and its association with treatment outcomes. We retrospectively reviewed 111 consecutive AGC patients who underwent first-line palliative chemotherapy. Skeletal muscle area was measured before and after chemotherapy at the third lumbar vertebra level using computed tomography scans. We compared skeletal muscle index (SMI), body mass index (BMI), and body weight changes to chemotherapy response and survival. The 80 male and 31 female patients’ median age was 65 (range 31–87) years, and 46.8% had sarcopenia at baseline. Median pre-chemotherapy to post-chemotherapy SMI, BMI, and body weight decreases were − 4.5 cm2/m2 (− 11.3%) (P < 0.001); − 0.7 kg/m2 (− 3.2%) (P < 0.001); and − 2.0 kg (− 3.5%) (P < 0.001), respectively. Median SMI decreases for patients with objective response, stable disease, and disease progression were − 4.0 cm2/m2 (range − 20.1 ~ 9.5); − 4.5 cm2/m2 (range − 19.8 ~ 0.8); and − 3.8 cm2/m2 (range: − 17.6 ~ 0.1), respectively. Response to chemotherapy was not associated with SMI decrease (P = 0.463). In multivariable analysis, sarcopenia at baseline (HR 1.681; 95% CI 1.083–2.609, P = 0.021), decreased SMI (HR 1.620; 95% CI 1.041–2.520; P = 0.032) were significant poor prognostic factors for survival. Skeletal muscle mass decreased significantly during chemotherapy in AGC patients, but was not associated with chemotherapy response. Decreased SMI was a poor prognostic factor in AGC patients during first-line palliative chemotherapy.

www.nature.com/scientificreports/ Chemotherapy may also reduce skeletal muscle mass 14,15 . Chemotherapeutic agents appear to be taken up by skeletal muscle cells and induce proteolytic and oxidative damage, mitochondrial dysfunction, cellular energy depletion and apoptotic cell death 16,17 . Omega 3 fatty acids have been shown to reduce the muscle loss associated with cisplatin chemotherapy 16 . We hypothesized that not only low skeletal muscle at the time of diagnosis (sarcopenia), but also continued decreases in skeletal muscle mass during chemotherapy would have a prognostic effect on survival. Therefore, we aimed to investigate changes of body composition including weight loss, change of body mass index (BMI) and change of skeletal muscle mass during chemotherapy, and their association with treatment outcomes and survival in patients with advanced gastric cancer (AGC) who received first-line palliative chemotherapy.

Results
Patients. From September 2010 through December 2019, 194 patients received chemotherapy for AGC.
As of June 2020, 33 patients had disease recurrence during adjuvant chemotherapy or within 6 months after adjuvant chemotherapy, 13 had not received first-line palliative chemotherapy in our hospital, and 37 patients did not have APCT at the time diagnosis of progression. Thus, 111 patients met the inclusion criteria and were included in the analyses. The baseline characteristics of the patients are described in Table 1. The median age was 65 years (range 31-87 years). Among them, 57 (51.4%) patients were over 65 years old and 57 (51.4%) were male. The incidence of sarcopenia at time of diagnosis was 46.8% (52 patients), including 44 men and 8 women. At baseline, half of the patients (54.1%) had normal BMI.  1).
Change in skeletal muscle index in patients according to response to treatment. The overall response rate during palliative first-line chemotherapy was 27.0% in patients with AGC. Among patients with response, the median SMI decrease was − 4.0 cm 2 /m 2 (range: − 20.1-9.5 cm 2 /m 2 ). This median SMI decrease was − 4.5 cm 2 /m 2 (range: − 19.8-0.8 cm 2 /m 2 ), in those with stable disease and − 3.8 cm 2 /m 2 (range: − 20.1-9.5 cm 2 / m 2 ) in those with progression. The response to chemotherapy was not associated with decrease in skeletal muscle mass (P = 0.463) as illustrated in Fig. 2.

Discussion
This study presented a decrease in muscle mass during the whole first line chemotherapy period for patients with AGC. We found that decreased SMI during chemotherapy and low skeletal muscle at diagnosis (sarcopenia) were poor prognostic factors in patients with gastric cancer who received palliative first-line chemotherapy. However, a decrease in skeletal muscle mass was not associated with response to chemotherapy. Loss of muscle mass, not weight loss or BMI reduction, was a significant prognostic factor in gastric cancer patients during palliative chemotherapy.
Using baseline CT before palliative chemotherapy and at time of disease progression, we showed decreased skeletal muscle mass (− 11.3%) during chemotherapy in patients with gastric cancer. Similar to our study, decreased SMI during systemic chemotherapy has been found in other studies of colon cancer 14 , NSCLC 15 and pancreatic cancer 18 . In colon cancer patients, muscle loss was 6.1% during 3 months of chemotherapy 14    It was suggested that the involvement of digestive organs in gastric cancer makes it more difficult for patients to eat, resulting in a further decrease in muscle mass. Low skeletal muscle at diagnosis (sarcopenia) is a poor prognostic factor in various cancers 13 . We also found that sarcopenia at baseline was a significant prognostic factor for survival in gastric cancer patients. Using baseline CTs, we showed that sarcopenia is common in patients with gastric cancer (46.8%). This is consistent with another study, where the prevalence of sarcopenia was 47.9% in patients with gastric cancer before palliative first-line chemotherapy and patients with sarcopenia had a significantly shorter OS after chemotherapy 9 .
Sarcopenia was a significantly poor prognostic factor for the decreased SMI group. In our study, we found that an SMI decreased group was associated with significantly shorter OS in patients with gastric cancer. Similarly, a previous study revealed that SMI decreases of more than 9% during chemotherapy were associated with a shorter overall survival in colon cancer 14 . The rate of cancer cachexia in gastric cancer patients was also higher than that in other cancers, and the rate of SMI decrease in gastric cancer was 13.0%. This suggests that we need to improve the prognosis of cancer patients by conducting further studies on various therapies, including exercise and high protein diets to prevent the decreased SMI during chemotherapy.
In our study, SMI, BMI, and body weight were significantly reduced during palliative chemotherapy in gastric cancer. The chemotherapy regimens in metastatic colorectal cancer, involved oxaliplatin, occurred skeletal muscle loss 14,20 . Our studies also suggested that sarcopenia and skeletal muscle loss occurred during chemotherapy because most patients underwent platinum based chemotherapy. Decrease in skeletal muscle mass showed a poor prognostic factor. BMI and body weight change were not significantly poor prognostic factors. Other studies have also shown no prognostic significance for changes in BMI, however, one study reported that an SMI decrease during palliative chemotherapy in biliary cancer was a poor prognostic factor 21 .
In conclusion, the present study showed skeletal muscle mass decreased significantly during chemotherapy in patients with AGC and this skeletal muscle loss during chemotherapy was independently associated with poor survival. However, response to chemotherapy was not associated with decrease in skeletal muscle mass. Further studies are required to improve sarcopenia and muscle loss through interventions such as exercise and high protein diet during chemotherapy and may lead to improved clinical outcomes.

Methods
Patients. This retrospective study assessed patients who underwent chemotherapy for gastric cancer in Chung-Ang University College of Medicine between September 2010 and December 2019. The inclusion criteria for analysis were as follows: pathologically confirmed gastric adenocarcinoma; underwent first-line palliative chemotherapy; had enhanced abdominopelvic computed tomography (APCT) within 4 weeks of initiation of first-line chemotherapy and at the time of diagnosis of progression, and an Eastern Cooperative Oncology Group (ECOG) score of 0-2. Exclusion criteria were disease recurrence during adjuvant chemotherapy or within 6 months after adjuvant chemotherapy; palliative first-line chemotherapy not received in Chung-Ang University College of Medicine, and no APCT at the time of diagnosis of progression. This study was approved by the Institutional Review Board of Chung-Ang University Hospital (No. 1909-003-16278). All methods were performed in accordance with the relevant guidelines and regulations. A waiver for the need for informed consent was obtained as part of the IRB approval for this retrospective study.
Measurements. Skeletal muscle area was measured using APCT scans at baseline (within 4 weeks of initiation of first-line chemotherapy) and at the time of diagnosis of progression. We evaluated skeletal muscle area using the third lumbar vertebra (L3) muscle index, one of the international standards for measuring the ratio of skeletal muscle area (cm 2 ) divided by height (m 2 ) 22,23 . The cutoff of a decreased SMI was defined approximately lowest tertile according to Blauwhoff-Buskermolen et al. study 14 . We also divided the patients into three groups were categorized into tertiles the muscle change. Therefore, in our study, SMI decreased group was defined a www.nature.com/scientificreports/ decrease SMI of − 6.5 cm 2 /m 2 or more based on approximately lowest tertile. Sarcopenia defined as < 31 cm 2 / m 2 for females and < 49 cm 2 /m 2 for males on the L3 skeletal index by Korean specific range 13,24,25 . BMI was calculated as weight divided by height squared (kg/m 2 ). BMI were divided as underweight (< 20.0 kg/m 2 ), normal (20.0-25.0 kg/m 2 ), overweight (> 25.0 kg/m 2 ) 26 . Body weight during chemotherapy was obtained from medical records within 2 weeks of the date of the APCT. SMI change during palliative chemotherapy was calculated between baseline and the time diagnosis of progression. Clinicopathological data included age, ECOG performance status, sex, height, weight, BMI, SMI, hemoglobin, serum albumin, chemotherapy regimen, chemotherapy response, and survival status. Response evaluation was performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 using follow-up CT obtained every 6 to 8 weeks during chemotherapy. Overall response rate (ORR) was defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period.
Statistics. Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 24.0 (IBM Corp., Armonk, NY, USA). Statistical significance was defined at P < 0.05. Overall survival (OS) was defined as the time from the first day of treatment to death by any cause. Kaplan-Meier method was used to estimate OS. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CI) were stratified using Cox proportional hazards regression model. For continuous variables, normality of date was tested using Kolmogorov-Smirnov test. Statistical analyses were performed using Student t test to compare means and the 2-paired sample Wilcoxon signed rank test.
Ethical approval. This study was approved by the Institutional Review Board of Chung-Ang University Hospital.