Sarcopenia and myosteatosis at presentation adversely affect survival after esophagectomy for esophageal cancer

Constant gradual improvements of operative techniques and perioperative care have reduced the dangers of esophagectomy, the cornerstone of radical treatment of resectable esophageal cancer, but it remains a major procedure burdened with high morbidity and mortality.1 Overall 5-year survival in resectable esophageal cancer has improved in recent years by about 2–3 fold.2 This improvement was attributed to centralization of surgical treatment and introduction of neoadjuvant chemoradiotherapy.3 Advances were also made in perioperative care and better understanding and prevention of the detrimental effects of muscle depletion so typical of esophageal malignancies.4

Further improvement in outcomes can be achieved by tailoring the treatment to patients’ ability to withstand the trauma of surgery and to return to a functional life after treatment. Adequate fitness for treatment has traditionally been assessed from various performance scores, risk scores as well as more basic patients’ characteristics like age and body mass index.5 Body mass index (BMI) at presentation has proven to be an inaccurate predictor of outcomes since it does not correspond to body composition well.6,7 Better methods to assess the most important parameter of body composition, the skeletal muscle content, have been introduced. They include functional tests like muscle strength measurements and measurements of muscle mass with dual energy x-ray imaging (DEXA), bioimpedance analysis or cross-sectional imaging (CT or MRI).8 Cross-sectional imaging (or planimetry) has the advantage of being readily available in cancer patients for staging purposes. This has encouraged many studies to examine the relationship between overall muscle mass, its quality and their effect on outcomes. A reliable relationship between planimetrically determined muscle mass and quality and its function, determined by other methods available, has been established. Muscle area at the level of 3^rd lumbal vertebra, normalized for height (skeletal muscle index (SMI)) is highly correlated with total body skeletal muscle mass.9

Estimating survival chances for a patient presenting with resectable esophageal cancer is important in planning appropriate treatment strategies and interventions aimed at improving survival and quality of life. Pronounced weight loss is a hallmark of malignant disease, especially pronounced in digestive tract tumors, among them in esophageal and pancreatic cancers in particular.10 In their seminal work, the team from University of Alberta have shown that skeletal muscle depletion (sarcopenia and low muscle attenuation) is the real negative predictor of survival regardless of overall body weight in cancer patients.6

Sarcopenia is defined by the European Working Group on Sarcopenia in Older people as the presence of low muscle mass (under the 5th percentile) and low muscle function (strength or performance)11 typically presenting in advanced age but also in cancer and other diseases. It is a well established predictor of poor survival and treatment outcomes in cancer patients.6 Myosteatosis is defined as abnormal fat infiltration in skeletal muscle. It is negatively associated with muscle strength and quality and is brought on by aging12, diabetes13, obesity14 and malignant disease.6,15,16 Radiodensity of human muscle on CT scan (or muscle attenuation, MA) correlates well with its triglyceride content.14 Measuring the attenuation values of muscle tissue corresponds well to the extent of myosteatosis, which is a sign of muscle wasting and again a predictor of poor outcome.17

By assessing muscle mass and quality before treatment an individualized risk assessment for overall survival and complications during treatment can be improved, patients at risk identified and appropriate interventions (mainly directed towards maintaining and gaining muscle mass) undertaken.18 Our aim was to study the impact of muscle depletion (sarcopenia and myosteatosis) on outcomes (overall survival [OS], perioperative mortality and rate of complications) in resectable esophageal cancer.

Our prospective cohort study shows that diminished muscle reserves, measured as sarcopenia (loss of muscle mass) and myosteatosis (infiltration of muscle with fat), are associated with decreased overall survival in patients receiving esophagectomy as part of radical esophageal cancer treatment. A relationship between sarcopenia and myosteatosis and other negative outcomes after esophagectomy (perioperative mortality and incidence of complications) could not be established.

Effects of muscle mass loss have been studied in numerous other malignancies as well as non malignant diseases25,26,27 but studies reporting myosteatosis as well as sarcopenia are still rare.28 Prevalence of sarcopenia in studies on correlation between muscle area and survival in esophageal cancer can range widely from 16%–80%.29,30,31 Choosing the right cutoff values for defining sarcopenia and myosteatosis can be challenging. In keeping with the definition of sarcopenia as absolute muscle mass below the 5th percentile of the population32 we chose recently published cutoff values for a population closely resembling ours. Van der Werf et al have published sex specific percentiles for SMI and MA for a healthy Caucasian population.24 They proposed using the 5th percentile for cutoff values for SMI and MA in non-elderly (age 20–60) to avoid age related muscle loss. These values (SMI 43.1 cm²/m² for men and 32.7 cm²/m² for women) are markedly lower then ones used in most previous studies. Consequently, the prevalence of sarcopenia in our study (16.5%) is also lower than 26–75% reported in other studies in resectable esophageal cancer. Mean SMA and SMI was 157.6 ± 28.0 cm² and 52.1 ± 9.5 cm²/m² in males and 103.9 ± 16.3 cm² and 39.8 ± 6.8 cm²/m² in females (both significantly different between sexes with p < 0.001) which correlates well with studies in similar populations. We believe that choosing the right population with which patients are compared is crucial in determining the real prevalence of sarcopenia (e.g, the study by Nishigori et al in Japanese esophageal cancer patients33 used the cutoff points obtained in Canadian obese patients34 and reported sarcopenia in 75% of patients).

Defining myosteatosis is even more difficult, since the term is not used much yet and reports are scarcer. We chose cutoffs according to the same principle, i.e at the 5th percentile of a healthy population. We did not find a statistically significant difference in muscle attenuation between males and females (31.2 ± 8.3 HU vs 27.8 ± 8.7 HU, p = 0.082), but with small numbers in our groups and the availability of sex-specific cutoff values for attenuation we opted for those. Myosteatosis was present in 51.8% of our patients and there was no significant relationship between sarcopenia and myosteatosis (OR 1.256 (CI 0.510–3.093, p = 0.620)). This is in contrast with the study by Stretch et al where the proportions of patients with sarcopenia and myosteatosis were inverse (40.7% vs 25.2%) but they similarly reported no correlation between muscle mass and muscle radiodensity. A possible reason for this are the higher cutoffs they used for sarcopenia (40th percentile of their patients or 47.7 cm²/m² and 36.5 cm²/m²).28

On univariate analysis sarcopenia and myosteatosis were associated with lower overall survival in our study group (Kaplan Meier log rank p = 0.042 and p = 0.044, respectively). For sarcopenia this is in accordance with previously published data and for myosteatosis this is one of the first published reports. Dijksterhuis et al have published a report on body composition, survival and toxicity in advanced esophagogastric cancer patients receiving palliative chemotherapy where they used BMI-specific cutoff values to define myosteatosis (< 41 HU in non obese (BMI < 25) and < 33 HU in overweight patients). Prevalence of myosteatosis in their group was 50% and they found a lower risk of grade III and IV toxicity in patients with higher muscular density but no association between sarcopenia or myosteatosis and survival was found.35 Tamandl et al published a study with 200 patients receiving an esophagectomy. They stratified patients in low- and high-muscle attenuation groups with a cutoff of 40HU in a population similar to ours. Average MA was 36 HU (31–41) and patients with MA < 40 HU had significantly poorer overall survival.36 The percentage of patients with MA over and under 40 HU is not given, so we cannot compare the prevalence to our results but this definition of reduced muscle attenuation uses a cutoff considerably higher than ours.

On the other hand, a study by Gabiatti et al in patients with locally advanced esophageal cancer receiving definitive chemoradiotherapy demonstrated favorable progression free survival and overall survival in a subgroup of patients with myosteatosis but without systemic inflammation.37

Sarcopenia has been studied extensively as a predictive factor in esophageal cancer. A recently published meta-analysis by Boshier et al reviewed 29 studies with 3193 patients (38% sarcopenic) in which various methods were used to diagnose sarcopenia.38 Sarcopenic patients had more pulmonary complications and lower overall survival. A similar meta-analysis by Deng et al reviewed 11 cohort studies including 1520 patients (52.3% sarcopenic). Patients with sarcopenia had lower 3-year and 5-year survival after resection.39

Complications and perioperative mortality were compared in our study between sarcopenia/no sarcopenia and myosteatosis/no myosteatosis groups and no statistically significant negative effect of muscle depletion was found. This is in concordance with most other studies who failed to show a connection even in studies who showed differences in long term survival.29,40 Insufficient statistical power in most studies including ours to detect a potential difference in complication rates is no doubt a strong factor. For conduit complications however, the incidence in our cohort was significantly lower in the myosteatosis group (5/72 (6.9%) vs 16/67 (23.9%) in patients without myosteatosis, (OR 0.238 (0.082–0.692), p = 0.005). It is difficult to explain the reason for this observation. A higher BMI in patients with myosteatosis could indicate a better nutritional status at presentation. Despite the lower incidence of this dangerous complication perioperative mortality in patients with myosteatosis was not different than in patients without it.

General clinical data in our cohort does not differ significantly from similar published series in resectable esophageal cancer. Patients with myosteatosis were significantly older than patients without it (67.1 ± 7.7 vs 60.5 ± 10.0 (p < 0.001)) whereas in patients with or without sarcopenia age difference didn’t reach statistical significance (67.1 ± 7.8 vs 63.3 ± 9.7 (p = 0.076)). BMI was significantly lower in sarcopenic patients (23.8 ± 5.9 vs 26.7 ± 4.4 (p = 0.006)) but significantly higher in patients with myosteatosis (27.3 ± 4.9 vs 25.2 ± 4.4 (p = 0.006)). 13 patients (9.4%) had both sarcopenia and myosteatosis, their BMI was 25.5 ± 6.1 (range 18.1–37.1). 33.1% of our patients lost 10% or more of their body weight but this did not confer a greater risk of having sarcopenia (OR 2.12 (CI 0.855–5.266), p = 0.100) or myosteatosis (OR 1.165 (CI 0.574–2.366), p = 0.672). As suggested elsewhere28 sarcopenia and myosteatosis are probably two separate entities with different causes and effects reflecting different disturbances in metabolic processes.

Underlying causes of sarcopenia and myosteatosis are most likely overlapping to some extent. Possible mechanisms, through which they negatively affect survival, are various. Diminished food intake due to dysphagia and loss of appetite as well as a chronic inflammation state in esophageal cancer lead to sarcopenia. This in turn causes diminished mobility and rehabilitation after surgery41, respiratory complications33, inferior wound healing42 and diminished tolerance of chemo and radiotherapy.35 Skeletal muscle has been described as an endocrine organ43 and it is the derangement of this function that is also a possible cause of inferior survival. Carefully designed studies are needed to corroborate this hypothesis.

The inclusion of myosteatosis assessment is in our opinion a strength of our study. We see that myosteatosis is more prevalent than sarcopenia and is a more sensitive marker of muscle degradation which precedes muscle mass and overall body mass loss. It is nevertheless at least as detrimental to prognosis as sarcopenia. Our study also uses recently published cut-off values that in our opinion assess the incidence of sarcopenia better than previous studies. However, this hinders the comparability of our results with others. It is not without weaknesses either. All CT images were recorded at staging with approximately half the patients going straight to resection and the other half receiving neoadjuvant treatment first. No repeat CT images were taken after neoadjuvant treatment if there were no clinical signs of progression according to our group’s guidelines. The distribution of intervals from CT to esophagectomy is therefore bimodal and the planimetric data reflects patients’ muscle reserves at beginning of any treatment and not necessarily at esophagectomy. This is a shortcoming when assessing the impact on perioperative mortality and complications since muscle mass loss is a well known process during neoadjuvant therapy.44,45,46,47 The large variation in times between CT and esophagectomy should in our opinion however not be regarded as a weakness when assessing the impact on overall survival of radical esophageal cancer treatment. Our study also lacks statistical power to detect a potential difference in mortality and complications, an issue that has fraught all previous studies as well. With growing numbers of cases in which CT images are available for analysis and with potential pooling of data these statistical issues can be overcome in the future.

Lastly, due to the univariate nature of our analysis no causal effect between survival and muscle depletion markers can be established, but the association shown can serve as an incentive for further research.

In a prospective cohort study from a dedicated database on esophagectomies we studied the association of sarcopenia and myosteatosis with outcomes after curative esophagectomies with or without neoadjuvant chemoradiotherapy. Prevalence of sarcopenia and myosteatosis at presentation was 16.5% and 51.8%, respectively. Both sarcopenia and myosteatosis were associated with decreased overall survival. For sarcopenia this is in accordance with previously published data and for myosteatosis this is one of the first published reports. Identifying novel predictors of outcomes can be beneficial for tailoring treatment options in patients with esophageal cancer as well as for planning intervention strategies targeted at improving functional body reserves.