Influence of nutritional status and body composition on postoperative events and outcome in patients treated for primary localized retroperitoneal sarcoma

Retroperitoneal sarcomas (RPS) are soft tissue tumours of mesenchymal origin accounting for approximately 15% of all sarcomas and less than 1% of all tumour malignancy.^1,2,3 Most patients develop large tumour mass before diagnosis is clinically confirmed. Imaging techniques, CT and MRI are primarily used in clinical evaluation of RPS.^1,4 Surgical resection with removal of all gross disease is the cornerstone of curative therapy and optimal results are achieved with en bloc resection at the time of primary presentation.^4,5 The role of radiation therapy and chemotherapy in management of RPS is still under investigation. Following the STRASS trial and STREXIT study, it seems that preoperative radiotherapy might influence the local control in liposarcoma (LPS) patients, while the evaluation of chemotherapy remains ongoing for high-grade LPS and leiomyosarcoma.^6,7,8 There are no currently available data supporting the use of routine neoadjuvant or adjuvant chemotherapy for these patients.¹ Optimal management is achieved in specialized sarcoma centres^4,9 with multidisciplinary approach.^10,11,12,13 Institute of Oncology Ljubljana is the only referral sarcoma centre in Slovenia.¹⁴

Body composition changes are related to nutrition status and associated with perioperative outcome and influence management of surgical oncology patients.¹⁵ Ongoing catabolic processes, systemic inflammation, as well as decreased protein synthesis, as part of often presented cancer-associated cachexia, together contribute to loss of lean body mass and pose a risk of malnutrition in sarcoma patients.^16,17,18 Sarcopenia is a clinical syndrome in which involuntary loss of skeletal muscle mass and function is progressive and generalized, together or without increased fat mass.^19,20 Another clinically important body composition abnormality, myosteatosis, is characterized by excess accumulation of adipose tissue within muscle, resulting in impaired muscle strength and physical ability, as well as increased frailty.^21,22 Recent studies demonstrated that both sarcopenia and myosteatosis pose a greater risk for postoperative complications and decrease overall survival (OS) in a variety of different cancers, including soft tissue sarcomas.^{22,23,24,25,26,27} Visceral obesity (VO) is the fat accumulation in visceral adipose tissue and serves as a clinical marker for adiposopathy.²⁸ Number of recent studies reported that VO is more reliable clinical marker for predicting outcome than traditional view on obesity defined by BMI.^{29,30,31,32,33} The useful predictor of VO is visceral-to-subcutaneous adipose tissue area ratio (VSR), and high VSR is associated with poor oncologic outcome.^34,35,36,37 Also, another body composition abnormality, the new concept of sarcopenic obesity (SO), a combination of excess adiposity and sarcopenia, seems to have powerful negative prognostic impact in oncology treatment and is gaining increased attention in cancer research.^38,39 Loss of muscle mass or myopenia is a critical determinant of sarcopenia.

CT has been shown to be a precise and feasible method to evaluate body composition parameters.^40,41,42,43 There is a lack of literature data regarding the impact of body composition on postoperative and oncologic outcome in patients operated on for primary RPS.

The aim of our study is to investigate the impact of low muscle mass or myopenia, myosteatosis, visceral obesity and cancer cachexia on OS, local recurrence-free survival (LRFS) and postoperative morbidity in patients operated for primary localized RPS. Additionally, we aimed to investigate the predictive value of preoperative body composition parameters for OS, LRFS and postoperative morbidity.

Our study provided new insight into the association between preoperative body composition and postoperative and oncologic outcome in primary RPS patients. We focused on evaluation of the significance of preoperative nutrition status-related syndromes. Furthermore, we examined the predictive value of SMI and MRA, measures of muscular quantity and quality, as well as, VATI, SATI and VSR, measures of adiposity, for possible clinical use in preoperative clinical assessment of patients diagnosed with this rare malignancy. To address the lack of literature and inconsistency in used body composition cut points, we used maximally selected rank statistics to defined cohort – specific cut point. This method incorporated follow-up time and time-to-event outcomes, dividing the patients into two groups with the most significant statistics between each other in term of survival.⁵⁶

In our cohort, both myopenia and VO were associated with poorer OS. Patients with myopenia had 5-year OS of 33.7%, compared to significantly higher 78.3% 5-year OS for non-myopenic patients (p = 0.009). SMI predicted LRFS on univariate analysis and lost prognostic value in multivariate analysis.

These findings are in line with knowledge that sarcopenic surgical oncology patients are at greater risk for poor operative outcome because of underlying muscle mass loss which is an integral component of sarcopenia and also facilitates the impairment of muscle function and physical performance.⁵⁷ Therefore we used the cut-off values for diagnosis of myopenia which are the component of diagnostic criteria and tools that define and characterize sarcopenia in EWGSOP2 Revised European Consensus.⁴⁸ Our optimal fitting method analysis for establishing the cut-off value for defining low SMI (used for comparative and descriptive purposes) resulted in slightly different cut-off values: SMI < 49.21 cm²/m² for males and females with BMI < 25, and SMI < 49.9 cm²/m² for males with BMI ≥ 25 and SMI < 50.64 cm²/m² for females with BMI ≥ 25. Both EWGSOP2 criteria for low SMI and our cut-off values were able to predict poor prognosis. It seems, that difference is generated because our cohort consisted of only patients with primary RPS with resectable disease rather than a heterogeneous cohort. We also found that SMI analysed as continuous variable was not able to predict poor outcome. This is another proof that in clinical practice SMI should be evaluated as body composition (myopenia) parameter defined with cut-off values below which the risk of poor prognosis is increased significantly, rather than discretional decrease.⁵⁸

Several studies demonstrated the superior predictive value of myosteatosis to sarcopenia or myopenia for poor survival.^59,60,61 Most of this data is founded on reports about patients operated on for gastrointestinal cancers. In our study cohort myosteatosis was also associated with greater overall complication rate (OR 5.05, 95% CI 1.39–24.41, p = 0.023) in univariate analysis, but it was not confirmed in multivariate analysis. Myosteatosis was not associated with OS, LRFS or postoperative outcome. However, recently a group of authors reported significant association between myosteatosis and major complication rate and OS in retroperitoneal and trunk soft tissue sarcoma.²⁹ They used preoperative MRA as continuous variable to define myosteatosis, not providing any cut-off point for reference. We defined myosteatosis based on optimal cut point analysis for MRA, and determined cut-offs are comparable to most commonly used range of MRA cut-offs for myosteatosis.⁶²

In order to evaluate obesity and the distribution of fat tissue, we calculated VAT, SAT and corresponding height-adjusted indexes VATI and SATI. We also considered BMI. Higher value of BMI (≥ 25) was not associated with oncologic or postoperative outcome. This is in line with number of studies suggesting that BMI is not reliable prognostic parameter for predicting perioperative outcome in cancer patients.^63,64,65 Stratified for myopenia, comparison of the subgroups revealed that body fat and VATI were significantly higher in non-myopenic patients (median 31.1 vs. 28.1%, p = 0.024 and 42.3 vs. 20.6 cm²/m², p = 0.025, respectively) (Table 2). Further on, we used VAT to assess VO applying the ESPEN/EASO criteria.³⁹ VO predicted poorer OS and higher postoperative complication rate. VAT alone had no impact on OS or postoperative outcome. Recent study on soft tissue sarcoma patients reported identical findings.²⁹ We considered VSR into adiposity analysis defining subgroup of patients with normal and high VSR (> 0.26) based on optimal cut-off analysis. In multivariate analysis VSR was an independent predictor for overall complication rate following surgery. High VSR group experienced significantly more complications compared to normal VSR group (33 (89.2%) vs. 4 (10.8%), p = 0.008). These results are comparable with previous reports in which VSR was superior to VAT as independent risk factor for death and local recurrence. ^{34,35,58,66,67} Linear regression analysis showed significant corelation between VSR and both VATI and fat mass (Figure 3 – panels G–H and Supplementaly Figure 5), confirming the importance of balance between visceral and subcutaneous adipose tissue. Recent studies demonstrated that predictive values of VSR for cardiovascular and metabolic disease incidence is superior to VAT.^34,36,37,68 However, to our knowledge, only a few studies investigated the impact of VSR and VAT on survival and postoperative outcome in patients operated on for primary RPS.²⁹ Our study underlined that high VSR is not only superior to VAT but also to BMI in predicting poor oncologic and peri-operative outcome. These findings suggest that VSR better estimates adipose tissue distribution and poses an additional difficulty for performing the surgery itself. High VSR is strong independent predictor for overall postoperative morbidity (multivariable-adjusted OR 5.05, p = 0.05). On the other hand, in the context of survival analysis, the multivariate regression model was not able to confirm the statistical significance of VSR (p = 0.068). This suggests that the impact of VSR on survival of RPS patients may be attenuated when considered alongside the broader set of predictors. One of the reasons may be the fact that, the presence of high VSR, as determined by specific gender-independent cut-off criteria, exhibited a statistically significant gender difference, with females having higher odds (OR = 4.5, p = 0.027) compared to males. Furthermore, we found a statistically significant difference in the distribution of SMI, between the two groups defined by VSR (high VSR vs. low VSR OR = 0.926, p = 0.047). Logistic regression model revealed significant association of SMI with a reduced odds of the specified outcome within the “high VSR” group. Based on our initial hypothesis that “high VSR” has a negative impact on survival, supported by univariate analysis, this implies that SMI (approximation of myopenia) may be a factor that mitigates the negative impact of “high VSR” on patient survival or serves as a positive influence, hence confounding the effect of VSR in multivariate settings. Further prospective studies need to be developed to confirm the importance of preoperative VSR for poor postoperative survival. In contrast to high VAT, low SATI, independently predicted poorer OS (adjusted HR 7.00, p = 0.057). Recent study reported similar protective effect of higher subcutaneous fat in RPS patients²⁹, which confirms the known benefits of SATI in processes of carcinogenesis and metabolism.^30,69,70,71

The multivariate analysis demonstrated that, when assessed as a continuous variable, albumin levels (HR 0.9, 95% CI 0.81–0.98, p = 0.019) and NLR (HR 1.4, 95% CI 1.06–1.75, p = 0.015) were independently associated with overall survival. This finding underscores the pivotal role of these inflammatory biomarkers in clinical practice and management of surgical oncology patients. Our results align with previous findings.^{17,18,72,73,74,75,76,77} Furthermore, our observation suggests that hypoalbuminemia identifies a high-risk cohort that may derive greater benefits from enhanced nutritional support preoperatively. The omission of descriptive statistical analysis for serum albumin and NLR, in term of patients' outcome, limits the depth of our data exploration.

Our study had some limitations. It was a single center report including relatively small number of patients which might influence the power of drown conclusions. Another weakness was the fact that we didn't assess all comorbidities in our analyses, as they were considered negligible in patients with soft tissue sarcoma. However, since our Institution is the only referral sarcoma center in Slovenia, having population of 2.1 million, our study cohort consisted of unique set of primary RPS patients eligible for curative surgery. We reported the most distinguishable, cohort – specific, cut points for CT measured body composition (muscle and adipose tissue) parameters in regard to long term prognosis. And finally, providing a unique and new insight into the association between preoperative body composition and postoperative and oncologic outcome in primary RPS patients was the main strength of the study.

Patients with primary RPS are in a great risk for nutritional disorders for number of reasons such as: requirement for demanding abdominal surgery in their management, long preclinical history and tumour size.^{4,10,18,78,79} In our study cohort there was a high prevalence of myopenia (32.8%) and visceral obesity (36.2%). Myopenia, cancer cachexia and low SATI were strongly associated with poor OS. High VSR was strong independent predictor for overall postoperative morbidity. Additional prospective studies are required to substantiate the role of preoperative VSR as independent prognostic factor for postoperative survival. Our findings suggest that clinical nutrition interventions towards improving visceral adiposity and myopenia may benefit surgical and oncologic outcome in primary RPS patients.