Sarcopenia in metastatic cancer patients: results of a prospective non-randomized study.

Background Prognostic factors can impact the quality of life and overall survival in metastatic situations: sarcopenia and nutritional status disorders. Methods We conducted a non-interventional, observational prospective study during 3 consecutive months (SPACE trial, ClinicalTrials.gov identier: NCT04714203). Performance status, lumbar skeletal muscle index (by CT scan), albumin, C-reactive protein, or LDH, were collected from medical records in the classic balance sheet at inclusion and then at 3 and 6 months after the day of inclusion. Results 38 patients were included with a median age of 68 years old and 31 were evaluable for sarcopenia. 58.1% of patients with metastatic cancer were sarcopenic at the diagnosis and 61% at 6 months. At the inclusion, 87.5% of sarcopenic patients were men (p < 0.0002) and sarcopenia status was associated with lung localization (p < 0.0332) and non-operable cancer (p < 0.0069). at


Introduction
Cancer is one of the leading causes of death in the world and despite a great deal of progress in disease detection and treatment, cancer incidence is steadily increasing and particularly in certain localizations like pancreas, lung, brain and stomach [1,2]. Metastatic cancer is rarely curable with the exception of germ cell tumors [3,4]. Palliative care support is then most often offered. The recurring symptoms reported by patients are: pain, fatigue, decreased appetite, nausea, and are directly related to phenomena such as cachexia, loss of autonomy and deterioration of psychological state, resulting in decreased overall survival [5]. Chemotherapies and targeted therapies can provide a bene t in quality of life and survival only in the early phase [6]. Other prognostic factors can impact the quality of life and overall survival in these situations: sarcopenia and nutritional status disorders. Sarcopenia is de ned by a loss of skeletal muscle mass and muscle function (strength and/or physical performance). The European Working Group on Sarcopenia in Older People described the diagnostic criteria in 2010 [7]. It was rst de ned for elderly people then for cancer patients, with a negative prognostic impact on overall survival [8-10, 11-15, 16].
Skeletal muscle mass is usually assessed by CT scan: the L3 level (cross section facing the 3rd lumbar vertebra) was chosen as a reference because it re ects to the quantities of tissue in the whole body. The lumbar muscle mass area (paravertebral muscles, psoas, muscles of the abdominal wall) is divided by body height (cm 2 /m 2 ) to de ne the Lumbar Skeletal Muscle Index (LSMI) of each patient [17,18].
Strength and performance are assessed by clinical tests: handgrip test for strength and Short Physical Performance Battery for performance (SPPB) (balance, walking speed, 5 time sit-to-stand tests) [19,20].
Three categories are described to evaluate the severity [7]: Pre sarcopenia: a loss of muscle mass index is only detected, Sarcopenia: loss of muscle mass and strength or performance, Severe sarcopenia: signi cant decrease of mass, strength and performance Sarcopenia is present in 10 to 70% of cancer patients and depends on the stage of the disease (localized or metastatic). It emerges as an unfavorable prognostic factor in overall survival and has been found correlated with a high comorbidity score, an increase in treatment-related complications and hospital costs [10,[21][22][23][24][25].
The Pronopall score has been validated in a prospective study [26], and also predicts survival according to 4 variables: Performance Status, number of metastatic sites, lactate deshydrogenase level (LDH) and albumin level [27].
We propose here to evaluate the prevalence of sarcopenia and its correlation with the Pronopall score in a prospective non-interventional study concerning cancer patients at the diagnosis of metastatic progression.

Study Design and ethical considerations
The SPACE study (ClinicalTrials.gov number, NCT04714203) is a prospective, non-interventional and

Study population and inclusion criteria
All patients were over 18 years old and suffered from metastatic cancer. Metastases were recently diagnosed (less than 3 months). The size of study population was determined by the inclusion period. Biological analysis and abdominal CT scan had to be performed less than 1 month before the inclusion.

Exclusion criteria
The exclusion criteria were: patients under 18, patients with germinal tumor, hematologic cancer, nonmetastatic cancer and pregnancy.

Primary and secondary objectives
The primary objective was to determine the prevalence of sarcopenia in cancer patients in an early metastatic situation.
The secondary objectives were the prevalence of undernutrition, overall survival, progression-free survival (PFS), event-free survival (EFS), and the correlation between the Pronopall score and sarcopenia.

Sarcopenia measurement method
The CT scans with abdominal sections were performed to assess muscle area (including psoas, rectus abdominus, obliques, erector spinae and quadratus lumborum muscles) at the level of third lumbar vertebrae on a slice showing both transversal processes of the vertebrae. To calculate the cross section of the tissue (cm2), the area of the muscle tissue was chosen according to the CT Houns eld unit (HU), ranging from 29 to 150 for skeletal muscles; this area was divided to body height to calculate the lumbar L3 skeletal muscle index (LSMI). The IMAGEJ software was chosen for the validation of the volumes [18].
LSMI assessment was performed by one trained investigator at the inclusion, and then at 3 and 6 months after inclusion.

Biological analysis
Albumin and LDH levels were recorded for nutritional status assessment and Pronopall score calculation.

Nutritional status
Criteria used to diagnose undernutrition were: a loss of at least 10% of weight in 6 months, a body mass index under 21 and an albuminemia level under 35 g/L, according to HAS guidelines [29].

Data and statistical analysis
The search for correlation with clinical and biological data re ecting the nutritional status and the aggressiveness of the disease was carried out, studying data are as follows: Qualitative data were compared using either the Chi-square or the Fischer Exact test and presented as percentages.
The time-to-event analyses were performed using the Kaplan-Meier method and the estimates were presented as rates with the corresponding 95% CIs.
Correlation between LSMI and Pronopall score was done with the non-parametric Spearman correlation test.
All the analyses were performed using SAS→ 9.3 (SAS Institute Inc. Cary, NC, USA).

Patient characteristics
Thirty-eight patients were included in the study. Seven were non evaluable at inclusion for LSMI (5 CT scans were performed in an other center and data were not available and 2 patients had a thoracic CT scan without lumbar sections). Fifty-four point eight percent (54,8%) of patients were male and median age was 66 years old. The main tumor locations were lung (25,9%), colon (22,7%) and breast (13%). At inclusion, thirty-two patients had synchronous metastatic disease, and for the 6 other patients, metastatic progression occurred 4 months to 9 years after the initial diagnosis of cancer.
Thirty-seven of the thirty-eight patients (97%) received a treatment for metastatic disease and 16% were included in a clinical trial. The characteristics are summarized in Table 1.  The prevalence of sarcopenia in the study population is 58,1%.
Twelve patients were evaluable for weight loss and only one had a 15% weight loss since the inclusion.
Twelve (38,7%) patients died during the study: 7 within 3 months of inclusion, 2 within 6 months and 3 after 6 months. The cause of death was progression.

Discussion
Nowadays, the evaluation of sarcopenia by CT scan at L3 vertebrae in palliative patients is still too scarce despite it's a reference method. Sarcopenia is often underestimated although it is clearly associated with older age, co-morbidities, increased infectious complications and early mortality.
Sarcopenia was diagnosed in 58% of our study population. Median overall survival was 7,5 months without any signi cant difference between sarcopenic and non-sarcopenic group nor correlation with Pronopall Score.
Interpretation of the results is limited by the size of the study sample and missing data (noninterventional study). A prospective study published in 2019 on 334 patients with advanced solid tumors (66% metastatic disease) has shown a signi cant correlation between survival and sarcopenia in palliative situation [30]. Yet they used only clinical tool to evaluate sarcopenia. Perhaps future research on detection of sarcopenia in palliative situation would consider clinical tools with CT scan data as an optimal solution.
Because of the high prevalence in this target population, a prospective larger interventional study combining sarcopenia screening and speci c care (nutritional support and adapted physical activity) is warranted in order to assess its impact on the quality of life and overall survival of these patients. The search for correlation with clinical and biological data re ecting the nutritional status and the aggressiveness of the disease will be carried out in a larger population.

Declarations
Funding: Partial nancial support was received from Elsan SAS group, France. Authors' contributions: All authors contributed to the study conception and design. All authors read and approved the nal manuscript.
Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Consent to participate: Informed consent was obtained from all individual participants included in the study.