Rationale and Objectives
To explore whether the sarcopenia body type can help predict response to interleukin-2 (IL-2) therapy in metastatic renal cell carcinoma (RCC).
Materials and Methods
Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective cohort study of 75 subjects with metastatic RCC who underwent pretreatment contrast-enhanced computed tomography within 1 year of initiating IL-2 therapy. Cross-sectional area and attenuation of normal-density (31–100 Hounsfield units [HU]) and low-density (0–30 HU) dorsal muscles were obtained at the T11 vertebral level. The primary outcome was partial or complete response to IL-2 using RECIST 1.1 criteria at 6 weeks. A conditional inference tree was used to determine an optimal HU cutoff for predicting outcome. Bonferroni-adjusted multivariate logistic regression was conducted to investigate the independent associations between imaging features and response after controlling for demographics, doses of IL-2, and RCC prognostic scales (eg, Heng and the Memorial Sloan Kettering Cancer Center [MSKCC]).
Results
Most subjects had intermediate prognosis by Heng (65% [49 of 75]) and the MSKCC (63% [47 of 75]) criteria; 7% had complete response and 12% had partial response. Mean attenuation of low-density dorsal muscles was a significant univariate predictor of IL-2 response after Bonferroni correction ( P = 0.03). The odds of responding to treatment were 5.8 times higher for subjects with higher-attenuation low-density dorsal muscles (optimal cutoff: 18.1 HU). This persisted in multivariate analysis ( P = 0.02). Body mass index ( P = 0.67) and the Heng ( P = 0.22) and MSKCC ( P = 0.08) clinical prognostic scales were not significant predictors of response.
Conclusions
Mean cross-sectional attenuation of low-density dorsal muscles (ie, sarcopenia) may predict IL-2 response in metastatic RCC. Clinical variables are poor predictors of response.
Introduction
Sarcopenia is a recently explored body type that is diagnosable by data routinely acquired with computed tomography (CT) and is associated with a range of negative outcomes including the following: postoperative infectious and noninfectious complications , mortality following liver transplantation , adrenocortical carcinoma mortality , and truncated disease-free survival in stage III melanoma managed with systemic interleukin-2 (IL-2) , among others . In short, sarcopenia is the combination of low core muscle volume and density—characterized by diminutive psoas and dorsal muscles—and high core muscle adiposity. Sarcopenia has been shown repeatedly to outperform common clinical markers of general health such as age and body mass index in predicting patient outcomes .
Sarcopenia has been shown to be prognostic in stage III melanoma and predictive of response to ipilimumab in stage IV melanoma . We were interested to know whether the sarcopenia body type also could be used to predict outcome in patients with metastatic renal cell carcinoma (RCC) treated with IL-2, as both melanoma and RCC are responsive to immunotherapies . A small subset (7%–8%) of patients with metastatic RCC treated with IL-2 experience a complete response to therapy that tends to be durable , with some patients alive and without disease for more than 10 years. However, the majority of patients do not respond at all, and reliable pretreatment prediction of which patients are most likely to benefit using clinical criteria has been elusive. Because of the high cost, potential toxicity, and low response rate (~20%) associated with IL-2 therapy, sparing patients from therapy who are least likely to benefit is desirable .
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Methods
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Subjects
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TABLE 1
Patient Demographic Data
Characteristic All Subjects ( n = 75) Median age (years) 54 (IQR: 50–58) Male 51 (67%) Body mass index (kg/m 2 ) 29 (IQR: 26–33) Systemic therapy prior to IL-2 (all single agent) 8 (11%) Days from RCC diagnosis to first IL-2 12 (IQR: 4–45) Days from CT to first IL-2 dose 24 (IQR: 12–35) Total IL-2 doses out of 28 possible 13 (IQR: 10–16) Response at 6 weeks by RECIST 1.1 Any response 14 (19%) Complete response 5 (7%) Partial response 9 (12%) Progression 40 (53%) Stable disease 21 (28%) Overall subject health Karnofsky performance status 100 (IQR: 90–100) Charlson comorbidity index 8 (IQR: 8–9) RCC Fuhrman nuclear grade 3 (IQR: 3–4) Distribution of metastatic disease Lung 65 (87%) Liver 12 (16%) Renal/nephrectomy bed 22 (29%) Adrenal 11 (14%) Other abdominal 13 (17%) Bone 13 (17%) Central nervous system 1 (1%) Other nonabdominal 5 (7%) MSKCC prognostic score High (worst prognosis) 3 (4%) Intermediate 47 (63%) Low (best prognosis) 25 (33%) Heng prognostic score High (worst prognosis) 6 (8%) Intermediate 50 (66%) Low (best prognosis) 19 (26%)
CT, computed tomography; IL-2, interleukin-2; MSKCC, Sloan Kettering Cancer Center; RCC, renal cell carcinoma; RECIST, Response Evaluation in Solid Tumors.
Continuous variables are presented as medians and interquartile ranges (IQR).
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Imaging and Patient-Level Data
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Interleukin-2 Therapy
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CT Morphomics
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Treatment Response
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Statistical Analysis
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Results
Subject Data
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CT Data
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TABLE 2
CT Examination Parameters
Characteristic All Subjects ( n = 75) Year of CT 2000–2002 7 (9%) 2003–2005 14 (18%) 2006–2008 19 (25%) 2009–2011 15 (20%) 2012–2014 20 (28%) CT scanner Aquilion 2 (4%) Brilliance 64 1 (1%) Discovery HD750 16 (21%) Emotion 16 1 (1%) Genesis HiSpeed 3 (4%) LightSpeed Power 1 (1%) LightSpeed Pro 16 8 (11%) LightSpeed QX/i 5 (7%) LightSpeed Ultra 15 (20%) LightSpeed VCT 15 (20%) LightSpeed 16 6 (8%) SOMATOM Definition 2 (3%) kVp 120 74 (99%) 110 1 (1%) Tube current (mAs) 288 ± 112 Slice thickness 1.25 mm 5 (7%) 2.5 mm 4 (5%) 3 mm 3 (4%) 5 mm 59 (79%) 7.5 mm 3 (4%) 10 mm 1 (1%) Contrast material Noncontrast 0 (0%) 300 mgI/mL 56 (75%) 320 mgI/mL 9 (12%) 370 mgI/mL 2 (3%) Unknown 8 (11%) Contrast dose (mL) mL 119 ± 21 mgI 36,408 ± 6,584
CT, computed tomography.
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TABLE 3
Population-Level Morphomics Data (Median, Interquartile Range) Assessed on a Single Axial Image at the T11 Vertebral Body Level
Morphometric Characteristic Any Response ( n = 14) No Response ( n = 61) Mean CT number of low-density dorsal muscles 18.3 (17.5–18.6) HU 17.3 (16.5–18.1) HU Cross-sectional area of low-density dorsal muscles 684 (389–899) mm 2 726 (399-1,001) mm 2 Mean CT number of normal-density dorsal muscles 59 (56–62) HU 60 (56–62) HU Cross-sectional area of normal-density dorsal muscles 2,786 (2,786–3,648) mm 2 2,347 (1,927–2,950) mm 2 Mean CT number of visceral fat −94 (−91 to −100) HU −100 (−90 to −105) HU Cross-sectional area of visceral fat 8,860 (3,050–11,744) mm 2 7,284 (5,350–14,253) mm 2 Mean CT number of subcutaneous fat −103 (−101 to −108) HU −105 (−101 to −109) HU Cross-sectional area of subcutaneous fat 8,887 (6,470–12,093) mm 2 12,295 (6,452–16,911) mm 2 Total body circumference 1,002 (935–1,039) mm 1,015 (972−1,088) mm Total body area 76,767 (65,873–82,193) mm 2 79,634 (72,279–90,943) mm 2
CT, computed tomography; HU, Hounsfield units.
Low density, 0 to 30 Hounsfield units; Normal density, 31 to 100 Hounsfield units.
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Univariate and Multivariate Analyses
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TABLE 4
Variables Tested in the Univariate and Multivariate Analyses
Predictor Univariate P Value Multivariate P Value Demographics Sex 0.68 Age 0.79 Body mass index 0.67 Clinical information Total number of IL-2 doses 0.08 0.10 MSKCC prognostic score 0.15 0.08 Heng prognostic score 0.22 Morphomics data Mean CT number in low-density dorsal muscles 0.03 0.02 Cross-sectional area of normal-density dorsal muscles 0.08 Mean CT number of visceral fat 0.11 Cross-sectional area of visceral fat 0.17 Cross-sectional area of subcutaneous fat 0.20 Mean CT number of subcutaneous fat 0.46
CT, computed tomography; IL-2, interleukin 2; MSKCC, Memorial Sloan Kettering Cancer Center.
Low density, 0 to 30 Hounsfield units; normal density, 31 to 100 Hounsfield units.
CT morphomics measurements were made on axial CT images at the T11 vertebral body level.
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Discussion
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Compliance with Ethical Standards
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