Associations between severe co-morbidity and muscle measures in advanced non-small cell lung cancer patients.

BACKGROUND: Studies show that low skeletal muscle index (SMI) and low skeletal muscle density (SMD) are negative prognostic factors and associated with more toxicity from systemic therapy in cancer patients. However, muscle depletion can be caused by a range of diseases, and many cancer patients have significant co-morbidity. The aim of this study was to investigate whether there were associations between co-morbidity and muscle measures in patients with advanced non-small cell lung cancer. METHODS: Patients in a Phase III trial comparing two chemotherapy regimens in advanced non-small cell lung cancer were analysed (n = 436). Co-morbidity was assessed using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G), which rates co-morbidity from 0 to 4 on 14 different organ scales. Severe co-morbidity was defined as having any grades 3 and 4 CIRS-G score. Muscle measures were assessed from baseline computed tomography slides at the L3 level using the SliceOMatic software. RESULTS: Complete data were available for 263 patients (60%). Median age was 66, 57.0% were men, 78.7% had performance status 0-1, 25.9% Stage IIIB, 11.4% appetite loss, 92.4% were current/former smokers, 22.8% were underweight, 43.7% had normal weight, 26.6% were overweight, and 6.8% obese. The median total CIRS-G score was 7 (range: 0-16), and 48.2% had severe co-morbidity. Mean SMI was 44.7 cm2 /m2 (range: 27-71), and the mean SMD was 37.3 Hounsfield units (HU) (range: 16-60). When comparing patients with and without severe co-morbidity, there were no significant differences in median SMI (44.5 vs. 44.1 cm2 /m2 ; 0.70), but patients with severe co-morbidity had a significantly lower median SMD (36 HU vs. 39 HU; 0.001), mainly due to a significant difference in SMD between those with severe heart disease and those without (32.5 vs. 37.9 HU; 0.002). Linear regression analyses confirmed the association between severe co-morbidity and SMD both in the simple analysis (0.001) and the multiple analysis (0.037) adjusting for baseline characteristics. Stage of disease, gender, and body mass index (BMI) were significantly associated with SMI in both the simple and multiple analyses. Age and BMI were significantly associated with SMD in the simple analysis; and age, gender, and BMI were significantly associated in the multiple analysis. CONCLUSIONS: There were no significant differences in SMI between patients with and patients without severe co-morbidity, but patients with severe co-morbidity had lower SMD than other patients, mainly due to severe heart disease. Co-morbidity might be a confounder in studies of the clinical role of SMD in cancer patients.

A comparison of CT based measures of skeletal muscle mass and density from the Th4 and L3 levels in patients with advanced non-small-cell lung cancer.

BACKGROUND: Muscle mass and density assessed from CT-images at the L3 level are prognostic for survival and predict toxicity in cancer patients. However, L3 is not always included on routine CT-scans. We aimed to investigate whether images at the Th4 level may be used instead. METHODS: Patients from three chemotherapy trials in advanced NSCLC were eligible (n = 1305). Skeletal muscle area (cm2), skeletal muscle index (SMI, cm2/m2) and skeletal muscle density (SMD) at Th4 and L3 levels were assessed from baseline CT-scans. SMI and SMD at the Th4 and L3 level were transformed into z-scores and the agreement between scores was investigated by Bland-Altman plots and estimated by intra-class correlation analyses. Linear regression was used to test if Th4 SMI and SMD z-scores predicted L3 SMI and SMD z-scores. RESULTS: CT-images from 401 patients were analysable at both levels. There was a moderate agreement between Th4 and L3 SMI z-scores with an intra-class correlation of 0.71 (95% CI 0.64-0.77) for men and 0.53 (95% CI 0.41-0.63) for women. Regression models predicting L3 SMI z-scores from Th4 SMI z-scores showed coefficients of 0.71 (95% CI 0.62-0.80) among men and 0.53 (95% CI 0.40-0.66) among women. R-squares were 0.51 and 0.28, respectively, indicating moderate agreement. A similar, moderate agreement between Th4 and L3 SMD z-scores was observed. CONCLUSION: There was only moderate agreement between muscle measures from Th4 and L3 levels, indicating that missing data from the L3 level cannot be replaced by analysing images at the Th4 level.

Muscle mass and association to quality of life in non-small cell lung cancer patients.

BACKGROUND: Cancer wasting is characterized by muscle loss and may contribute to fatigue and poor quality of life (QoL). Our aim was to investigate associations between skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) and selected QoL outcomes in advanced non-small cell lung cancer (NSCLC) at diagnosis. METHODS: Baseline data from patients with stage IIIB/IV NSCLC and performance status 0-2 enrolled in three randomized trials of first-line chemotherapy (n = 1305) were analysed. Associations between SMI (cm2 /m2 ) and SMD (Hounsfield units) based on computed tomography-images at the third lumbar level and self-reported physical function (PF), role function (RF), global QoL, fatigue, and dyspnoea were investigated by linear regression using flexible non-linear modelling. RESULTS: Complete data were available for 734 patients, mean age 65 years. Mean SMI was 47.7 cm2 /m2 in men (n = 420) and 39.6 cm2 /m2 in women (n = 314). Low SMI values were non-linearly associated with low PF and RF (men P = 0.016/0.020, women P = 0.004/0.012) and with low global QoL (P = 0.001) in men. Low SMI was significantly associated with high fatigue (P = 0.002) and more pain (P = 0.015), in both genders, but not with dyspnoea. All regression analyses showed poorer physical outcomes below an SMI breakpoint of about 42-45 cm2 /m2 for men and 37-40 cm2 /m2 for women. In both genders, poor PF and more dyspnoea were significantly associated with low SMD. CONCLUSIONS: Low muscle mass in NSCLC negatively affects the patients' PF, RF, and global QoL, possibly more so in men than in women. However, muscle mass must be below a threshold value before this effect can be detected.

Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From Carboplatin-Doublet Chemotherapy in Advanced Non-Small-Cell Lung Cancer.

BACKGROUND: Variations in lean body mass (LBM) have been suggested to explain variations in toxicity from systemic cancer treatment. We investigated if drug doses per kilogram of LBM were associated with severe hematologic toxicity (HT) in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) enrolled onto randomized trials comparing first-line carboplatin-doublets. PATIENTS AND METHODS: Patients received carboplatin (AUC [area under the plasma concentration vs. time curve] = 5) plus either pemetrexed 500 mg/m2, gemcitabine 1000 mg/m2, or vinorelbine 60 mg/m2. LBM was estimated from the cross-sectional muscle area at the third lumbar vertebra on computed tomographic scans. Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Primary outcome was Common Terminology Criteria for Adverse Events version 3.0 grade 3/4 HT after cycle 1. RESULTS: Data from 424 patients were analyzed. Mean age was 65 years, 57% were men, and 78% had stage IV disease. Despite dose individualization by body surface area for the nonplatinum drugs, mean (range) doses expressed as mg/kg LBM showed ∼3-fold range: gemcitabine 38.0 (22.5-61.7) mg/kg LBM, pemetrexed 19.1 (8.1-27.9) mg/kg LBM, and vinorelbine 2.4 (1.4-3.6) mg/kg LBM. For these drugs, dose per kilogram of LBM was associated with HT in adjusted multivariate models (P = .004). Taking mean dose per kilogram LBM for each drug as reference, a 1% increase (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.01-1.06) or 1% decrease (OR = 0.97; 95% CI, 0.95-0.99) was associated with altered risk of grade 3/4 HT. For doses > 20% above and below mean (14% and 15% of patients, respectively) the risk of grade 3/4 HT was almost doubled (OR = 1.93, 95% CI, 1.21-3.10) and halved (OR = 0.52; 95% CI, 0.32-0.83), respectively. CONCLUSION: Dose per kilogram of LBM varied considerably and was an independent predictor of HT. Computed tomography-defined LBM may provide a future basis for better dose individualization.

Skeletal muscle radiodensity is prognostic for survival in patients with advanced non-small cell lung cancer.

BACKGROUND & AIMS: Recent research indicates that severe muscular depletion (sarcopenia) is frequent in cancer patients and linked to cachexia and poor survival. Our aim was to investigate if measures of skeletal muscle hold prognostic information in advanced non-small cell lung cancer (NSCLC). METHODS: We included NSCLC patients with disease stage IIIB/IV, performance status 0-2, enrolled in three randomised trials of first-line chemotherapy (n = 1305). Computed tomography (CT) images obtained before start of treatment were used for body composition analyses at the level of the third lumbar vertebra (L3). Skeletal muscle mass was assessed by measures of the cross sectional muscle area, from which the skeletal muscle index (SMI) was obtained. Skeletal muscle radiodensity (SMD) was measured as the mean Hounsfield unit (HU) of the measured muscle area. A high level of mean HU indicates a high SMD. RESULTS: Complete data were available for 734 patients, mean age 65 years. Both skeletal muscle index (SMI) and muscle radiodensity (SMD) varied largely. Mean SMI and SMD were 47.7 cm2/m2 and 37.4 HU in men (n = 420), 39.6 cm2/m2 and 37.0 HU in women (n = 314). Multivariable Cox regression analyses, adjusted for established prognostic factors, showed that SMD was independently prognostic for survival (Hazard ratio (HR) 0.98, 95% CI 0.97-0.99, p = 0.001), whereas SMI was not (HR 0.99, 95% CI 0.98-1.01, p = 0.329). CONCLUSION: Low SMD is associated with poorer survival in advanced NSCLC. Further research is warranted to establish whether muscle measures should be integrated into routine practice to improve prognostic accuracy.

Low muscle mass is associated with chemotherapy-induced haematological toxicity in advanced non-small cell lung cancer.

BACKGROUND: Recent research suggests a significant relationship between lean body mass (LBM) and toxicity from chemotherapeutic agents. We investigated if higher drug doses per kg LBM were associated with increased toxicity in stage IIIB/IV non-small cell lung cancer (NSCLC) patients receiving a first-line chemotherapy regimen dosed according to body surface area (BSA). METHODS: Data from patients randomised to receive intravenous gemcitabine 1000 mg/m(2) plus orally vinorelbine 60 mg/m(2) days 1 and 8 in a phase III trial comparing two chemotherapy regimens were analysed. LBM was estimated from assessment of the cross-sectional muscle area at the third lumbar level (L3) on computed tomography images obtained before chemotherapy commenced. Common terminology criteria for adverse events (CTCAE) grade 3-4 haematological toxicity and dose reduction and/or stop of treatment after the first course of chemotherapy were defined as primary and secondary toxicity outcomes. RESULTS: The study sample included 153 patients, mean age was 66 years, 55% were men, 87% had disease stage IV and 75% had performance status (PS) 0-1. Gemcitabine doses per kg LBM varied from 23.2 to 53.1 mg/kg LBM, and vinorelbine doses from 1.5 to 3.3 mg/kg LBM. Higher doses of gemcitabine per kg LBM were significantly associated with grade 3-4 haematological toxicity in bivariate (OR=1.12, 95% CI 1.03-1.23, p=0.008) and multivariate analyses (OR=1.15, 95% CI 1.01-1.29, p=0.018), as were also higher doses of vinorelbine per kg LBM. No significant association was found between drug doses per kg LBM and dose reduction and/or stop of treatment. CONCLUSION: The study showed that dose estimates according to BSA lead to a substantial variation in drug dose per kg LBM, and higher doses per kg LBM are a significant predictor for chemotherapy-induced haematological toxicity. The results indicate that taking LBM into account may lead to a better dose individualisation of chemotherapy.