Skeletal muscle is independently associated with grade 3-4 toxicity in advanced stage pancreatic ductal adenocarcinoma patients receiving chemotherapy

Merel R Aberle; Mariëlle M E Coolsen; Gilles Wenmaekers; Leroy Volmer; Ralph Brecheisen; David van Dijk; Leonard Wee; Ronald M Van Dam; Judith de Vos-Geelen; Sander S Rensen; Steven W M Olde Damink

doi:10.1016/j.clnesp.2024.11.004

Skeletal muscle is independently associated with grade 3-4 toxicity in advanced stage pancreatic ductal adenocarcinoma patients receiving chemotherapy

Clin Nutr ESPEN. 2024 Nov 30:65:134-143. doi: 10.1016/j.clnesp.2024.11.004. Online ahead of print.

Affiliations

¹ Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; Department of Surgery, Maastricht University Medical Center+, Maastricht, the Netherlands.
² Department of Surgery, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of General, Visceral- and Transplantation Surgery, RWTH Aachen University, Germany.
³ Department of Surgery, Maastricht University Medical Center+, Maastricht, the Netherlands.
⁴ GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of Radiotherapy (MAASTRO), Maastricht University Medical Centre+, Maastricht, the Netherlands.
⁵ GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of Radiotherapy (MAASTRO), Maastricht University Medical Centre+, Maastricht, the Netherlands; Clinical Data Science, Maastricht University, Maastricht, the Netherlands.
⁶ Department of Surgery, Maastricht University Medical Center+, Maastricht, the Netherlands; GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of General, Visceral- and Transplantation Surgery, RWTH Aachen University, Germany.
⁷ GROW School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands; Department of Medical Oncology, Maastricht University Medical Center+, Maastricht, the Netherlands.
⁸ Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands. Electronic address: [email protected].
⁹ Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands; Department of Surgery, Maastricht University Medical Center+, Maastricht, the Netherlands; Department of General, Visceral- and Transplantation Surgery, RWTH Aachen University, Germany.

PMID: 39577693
DOI: 10.1016/j.clnesp.2024.11.004

Abstract

Background: Patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) are regularly treated with FOLFIRINOX, a chemotherapy regimen based on 5-fluorouracil, irinotecan and oxaliplatin, which is associated with high toxicity. Dosing of FOLFIRINOX is based on body surface area, risking under- or overdosing caused by altered pharmacokinetics due to interindividual differences in body composition. This study aimed to investigate the relationship between body composition and treatment toxicity in advanced stage PDAC patients treated with FOLFIRINOX.

Methods: Data from patients treated at the Maastricht University Medical Centre + between 2012 and 2020 were collected retrospectively (n = 65). Skeletal muscle-, visceral adipose tissue, subcutaneous adipose tissue-, (SM-Index, VAT-Index, SAT-Index resp.) and Skeletal Muscle Radiation Attenuation (SM-RA) were calculated after segmentation of computed tomography (CT) images at the third lumbar level using a validated deep learning method. Lean body mass (LBM) was estimated using SM-Index. Toxicities were scored and grade 3-4 adverse events were considered dose-limiting toxicities (DLTs).

Results: Sixty-seven DLTs were reported during the median follow-up of 51.4 (95%CI 39.2-63.7) weeks. Patients who experienced at least one DLT had significantly higher dose intensity per LBM for all separate cytotoxics of FOLFIRINOX. Independent prognostic factors for the number of DLTs per cycle were: sarcopenia (β = 0.292; 95%CI 0.013 to 0.065; p = 0.013), SM-Index change (% per 30 days, β = -0.045; 95%CI -0.079 to -0.011; p = 0.011), VAT-Index change (% per 30 days, β = -0.006; 95%CI -0.012 to 0.000; p = 0.040) between diagnosis and the first follow-up CT scan, and cumulative relative dose intensity >80 % (β = -0.315; 95 % CI -0.543 to -0.087; p = 0.008).

Conclusion: Sarcopenia and early muscle and fat wasting during FOLFIRINOX treatment were associated with treatment-related toxicity, warranting exploration of body composition guided personalized dosing of chemotherapeutics to limit DLTs.

Keywords: Chemotherapy; Pancreatic cancer; Personalized medicine; Systemic therapy; Toxicity.