Influence of Nutritional Status on Oncologic and Operative Outcome in Patients Operated for Retroperitoneal Sarcoma

This is a retrospective, observational study in consecutive patients operated on for primary RPS in the Institute of Oncology Ljubljana (Slovenia) between September 1999 and June 2020. This study aims to investigate the impact of preoperatively assessed body composition parameters on the perioperative outcomes of patients operated on for primary RPS. The impact of preoperative malnutrition, sarcopenia, sarcopenic obesity and myosteatosis to the oncologic and postoperative outcome in patients operated on for primary RPS will be examined. Additionally, the aim is to evaluate the prognostic role of preoperative immune and inflammatory markers (serum albumin level, C-reactive protein, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, high-sensitivity modified Glasgow prognostic score) and prognostic nutritional index in primary RPS patients undergoing surgery. Patient outcome will be evaluated in terms of overall survival (OS), local-recurrence free survival (LRFS), postoperative intrahospital length of stay, overall and major postoperative morbidity.

Retroperitoneal sarcomas (RPS) are rare neoplasms of mesenchymal origin with estimated crude incidence of 0.3 cases per 100000 inhabitants per year. The most common histologic subtypes are well-differentiated and dedifferentiated liposarcoma and leiomyosarcoma, accounting for 42% and 26% of cases, respectively. RPS are optimally managed in multidisciplinary settings in specialized sarcoma centers. Surgical resection with an adequate margin of normal tissue is the cornerstone of curative therapy and en bloc surgical resection of localized tumors is the recommended surgical approach. This "extended" surgical approach (including resection of adjacent organs), is optimal for reducing local recurrence and improving overall survival.

Cancer patients undergoing surgical treatment face number of challenges which negatively impact their nutritional status. Patients are usually in catabolic state, which together with ongoing proteolysis and lipolysis as well as decreased protein synthesis contribute to development of cancer - associated cachexia. Most important nutritional disorders in these patients are malnutrition, sarcopenia, cancer cachexia. On the other side, often under-recognized, sarcopenic obesity is gaining attention in clinical and research settings.

The association of malnutrition and poor postoperative outcome has been demonstrated in patients with various cancer locations. Malnourished patients reportedly have longer length of postoperative stay (LOS), higher rates of 30-day mortality, infection rate, sepsis, reoperation, increased number of cardiopulmonary complications. Diagnostic process of malnutrition has been a topic of debate considering inconsistency in diagnostic methodology and criteria. Global Leadership Initiative on Malnutrition (GLIM) addressed this problem and recommended a new diagnostic scheme for malnutrition, in form of consensus report incorporating previous finding and recommendations from world leading clinical nutrition societies. To our knowledge, no study validated GLIM criteria in patients with primary RPS.

Sarcopenia is clinical syndrome characterized by generalized skeletal muscle mass loss, loss of strength and function (performance). Sarcopenia has been associated with lower survival rate and proved to be an independent predictor of survival in patients with breast cancer, pancreatic adenocarcinoma, hepatocellular carcinoma, and melanoma. There is a lack of studies investigating the impact of sarcopenia on survival and postoperative outcome in patients with soft-tissue sarcoma (STS), including retroperitoneal sarcoma. Similarly to malnutrition diagnosis, there is an evident inconsistency and confusion in diagnostic criteria and tools used to define and characterize sarcopenia in clinical practice and research. However, recently the European Working Group on Sarcopenia in Older People (EWGSOP2) published updated findings in form of Revised European Consensus. The Working Group proposed new recommendation, among which are those related to establishing specific cut-off points for body composition (primarily skeletal muscle quantity and quality) measures that identify and characterize sarcopenia.

Sarcopenic obesity (SO) is co-existence of sarcopenia and excess adiposity. Recent expert consensus of The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) will be followed for definition and diagnostic criteria for SO.

Myosteatosis is ectopic adipose tissue infiltration in skeletal muscle. Intermuscular adipose tissue can be quantified using CT scans by low muscle radiodensity. CT-derived myosteatosis contributes to impaired glucose metabolism, including insulin resistance, type 2 diabetes mellitus, and inflammation. Additionally, it may increase the risk for dyslipidemia. Myosteatosis may predict oncologic and postoperative outcome in primary RPS patients.

Patients with primary RPS are in a great risk for malnutrition, sarcopenia and cachexia for the number of reasons: requirement for demanding abdominal surgery in their management, catabolic tumor effects, long period before diagnosis of RPS and tumor size (approximately 15 cm). Due to their rarity, it is still unclear how preoperative nutritional status and body composition impact outcome of patients with primary RPS.

STUDY DESIGN DATA COLLECTION Patient's histories including the anaesthetician's preoperative reports, surgeon's operative reports, hospital records, and follow-up data will be collected. Paper and electronic data archive of Institute of Oncology Ljubljana Patient Data Information System will be used.

The following preoperative clinical data will be acquired: age, sex, preoperative weight, height, significant weight loss, appetite loss and weakness. CT reports will be also acquired for analysis as well as histopathological diagnosis (subtype), stage, grade and tumor size.

The preoperative laboratory data, including absolute counts of leukocytes, neutrophils, lymphocytes, monocytes and platelets, CRP, and albumin levels will be assessed. Data will be deidentified and whenever possible all measures to conceal patient identifiers and maintain patient confidentiality will be taken.

STATISTICAL CONSIDERATIONS The data will be presented using appropriate summary statistics: mean, median, standard deviation for continuous variables and percentages and frequencies for categorical variables. Kaplan-Meier method will be used for survival curves analysis and differences between survival rates compared using the log-rank test. The independent prognostic variables for survival (OS and LRFS) will be identified using Cox proportional hazard model (hazard ratio, 95% confidence interval, p value).

ETHICS The study was approved by Slovenian National Medical Ethics Committee, Institute of Oncology Ljubljana Review Board and Institute of Oncology Ljubljana Ethical Committee. The need to obtain informed consent from participants was waived.

Eligibility Criteria:
Inclusion Criteria:

* Patients aged above 18 years old
* Patients with primary localized RPS or pelvic sarcoma operated at Surgical Department of Institute of Oncology in Ljubljana

Exclusion Criteria:

* Patients with Gastrointestinal Stromal Tumors (GISTs) and Retroperitoneal desmoid-type fibromatosis (DF)
* Patients with visceral sarcomas (arising from visceral organ i.e., gastrointestinal, and genitourinary tracts sarcoma)
* Patients with benign retroperitoneal / pelvic tumors
* Patients with residual RPS operated at another hospital
* Patients with present recurrent, secondary, and metastatic RPS
* Unable to access patients' data