Weighing the role of skeletal muscle mass and muscle density in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: a multicenter real-life study

Abstract

Sarcopenia represents one of the hallmarks of all chronic diseases, including cancer, and was already investigated as a prognostic marker in the pre-immunotherapy era. Sarcopenia can be evaluated using cross-sectional image analysis of CT-scans, at the level of the third lumbar vertebra (L3), to estimate the skeletal muscle index (SMI), a surrogate of skeletal muscle mass, and to evaluate the skeletal muscle density (SMD). We performed a retrospective analysis of consecutive advanced cancer patient treated with PD-1/PD-L1 checkpoint inhibitors. Baseline SMI and SMD were evaluated and optimal cut-offs for survival, according to sex and BMI (+/−25) were computed. The evaluated clinical outcomes were: objective response rate (ORR), immune-related adverse events (irAEs), progression free survival (PFS) and overall survival (OS). From April 2015 to April 2019, 100 consecutive advanced cancer patients were evaluated. 50 (50%) patients had a baseline low SMI, while 51 (51%) had a baseline low SMD according to the established cut offs. We found a significant association between SMI and ECOG-PS (p = 0.0324), while no correlations were found regarding SMD and baseline clinical factors. The median follow-up was 20.3 months. Patients with low SMI had a significantly shorter PFS (HR = 1.66 [95% CI: 1.05-2.61]; p = 0.0291) at univariate analysis, but not at the multivariate analysis. They also had a significantly shorter OS (HR = 2.19 [95% CI: 1.31-3.64]; p = 0.0026). The multivariate analysis confirmed baseline SMI as an independent predictor for OS (HR = 2.19 [1.31-3.67]; p = 0.0027). We did not find significant relationships between baseline SMD and clinical outcomes, nor between ORR, irAEs and baseline SMI (data not shown). Low SMI is associated with shortened survival in advanced cancer patients treated with PD1/PDL1 checkpoint inhibitors. However, the lack of an association between SMI and clinical response suggests that sarcopenia may be generally prognostic in this setting rather than specifically predictive of response to immunotherapy.Sarcopenia is the condition of loss of muscle mass, with decreased muscle power, and it is one of the hallmarks of cancer, which negatively affects the most of clinical outcomes such as toxicities and survival 1 . The interactions must recognize also the lack of other adiposity metrics, such as the waist circumference, the waist-to-height ratio, and the body fat percentage. Moreover, the CT imaging analysis was limited by the data availability; indeed, the acquisition protocol was planned according to the presence of previous examination. conclusionOur finding of a significant shorter OS for low-SMI patients treated with PD-1/PD-L1 checkpoint inhibitors, suggests that sarcopenia might have a prognostic role, rather than predictive. However, to properly weighing our results, we must consider the significant association between poorer PS and low-SMI. Without making conclusive considerations, we can assume that after the advent of ICIs, we should give back further relevance to baseline nut...

Unfavorable impact of decreased muscle quality on the efficacy of immunotherapy for advanced non‐small cell lung cancer

“…Assessment tools included the cross‐sectional area of the psoas or lumbar muscles divided by body height squared. However, three of these studies did not assess the effects of PD‐L1 expressions on outcomes 14–16 . Only one study adjusted for the predictive impact of muscle quantity by PD‐L1 expression and reported the absence of an association with PFS, 17 which is consistent with our study, although the assessment tool used for muscle quantity was different.…”

“…While a previous study stated that decreased lumbar muscle density is predictive of inferior PFS in patients with metastatic melanoma treated with ipilimumab, 25 several other studies conducted in patients with metastatic NSCLC treated with PD‐1/PD‐L1 inhibitors were skeptical about its predictive value 10,17 . Cortellini et al retrospectively reviewed the impact of muscle quality on PFS in association with PD‐1/PD‐L1 inhibitor use in a mixed cancer population comprising 46 patients with advanced NSCLC and 54 patients with other advanced cancers including renal cell carcinoma and melanoma 14 . They measured lumbar skeletal muscle density as an indicator of muscle quality and showed no association between muscle quality and PFS or ORR.…”

“…However, results on the predictive impact of quantitative or qualitative skeletal muscle loss, which are hallmarks of cancer cachexia, are inconsistent 12 . Several articles, including ours, 13 have reported that decreased muscle quantity, as evaluated by computed tomography (CT), is correlated with poor clinical outcomes in patients who use a PD‐1/PD‐L1 inhibitor 13–16 . However, the definitions and measurement methods of muscle depletion varied across studies, 14–17 and the association was not always positive 17 .…”

“…12 Several articles, including ours, 13 have reported that decreased muscle quantity, as evaluated by computed tomography (CT), is correlated with poor clinical outcomes in patients who use a PD-1/PD-L1 inhibitor. [13][14][15][16] However, the definitions and measurement methods of muscle depletion varied across studies, [14][15][16][17] and the association was not always positive. 17 While some studies reported a negative correlation between muscle quality and the therapeutic effect of PD-1/PD-L1 inhibitors, 14,17 the results were not definitive.…”

Baseline prognostic nutritional index and changes in pretreatment body mass index associate with immunotherapy response in patients with advanced cancer

“…The predictive value of nutritional status for ICI efficacy is not well-established, which is in contrast with the plethora of data supporting the association between malnutrition and overall survival. [21][22][23] Only one recent study reported that patients with non-small cell lung cancer (NSCLC) with a PNI ≤45.5 had significantly worse ORR, DCR and PFS as compared with patients with PNI >45.5. 24 Yet, there are several reasons that poor nutritional status could impair ICI effectiveness.…”