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Early skeletal muscle loss during target therapy is a prognostic biomarker in metastatic renal cell carcinoma patients.

ABSTRACT: Skeletal muscle depletion is common in patients with advanced cancer and may be associated with a poor outcome. To investigate whether the changes in skeletal muscle in metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy are associated with clinical outcome, we undertook an observational cohort study using data from a number of randomized clinical trials previously conducted at the Fudan University Shanghai Cancer Center. The muscle mass was evaluated by comparing computed tomography images obtained at baseline with those obtained after 3-4 months of treatment. A total 101 patients were included in the study. The mean skeletal muscle area reduced from 41.6?cm2/m2 to 39.9?cm2/m2 after 3-4 months of targeted therapy. In multivariable analyses adjusted for the number of baseline covariates, muscle loss ?5% was shown to be a significant prognostic factor for both progression-free (hazard ratio [HR]: 1.744, 95% confidence interval [CI]: 1.077-2.826, P?=?0.024) and overall survival (HR: 2.367, 95%CI: 1.253-4.469, P?=?0.008). The addition of muscle loss to the Heng model significantly improved its discriminative ability. In summary, early skeletal muscle loss is frequently observed in mRCC patients and can add prognostic information to current clinical risk scores.

SUBMITTER: Gu W

PROVIDER: S-EPMC5548774 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Early skeletal muscle loss during target therapy is a prognostic biomarker in metastatic renal cell carcinoma patients.

Gu Weijie W Wu Junlong J Liu Xiaohang X Zhang Hailiang H Shi Guohai G Zhu Yao Y Ye Dingwei D

Scientific reports 20170808 1

Skeletal muscle depletion is common in patients with advanced cancer and may be associated with a poor outcome. To investigate whether the changes in skeletal muscle in metastatic renal cell carcinoma (mRCC) patients receiving targeted therapy are associated with clinical outcome, we undertook an observational cohort study using data from a number of randomized clinical trials previously conducted at the Fudan University Shanghai Cancer Center. The muscle mass was evaluated by comparing computed ...[more]

PMID: 28790354

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Project description:The purpose of the study was to identify a comprehensive prognostic system of pretreatment clinical parameters in 425 patients (pts) with metastatic renal-cell carcinoma treated with different subcutaneous (s.c.) recombinant cytokine-based home therapies in consecutive trials. Treatment consisted of (A) s.c. interferon-alpha 2a (INF-alpha), s.c. interleukin-2 (IL-2) (n=102 pts), (B) s.c. IFN-alpha 2a, s.c. IL-2, and i.v. 5-fluorouracil (5-FU) (n=235 pts) or (C) s.c. IFN-alpha 2a, s.c. IL-2, and i.v. 5-FU combined with p.o. 13-cis-retinoic acid (13cRA) (n=88 pts). Kaplan-Meier survival analysis, log-rank statistics, and Cox regression analysis were employed to identify risk factors and to create a multiple risk factor model. The following pretreatment risk factors were identified by univariate analysis: (1) three and more metastatic sites, (2) presence of liver, lymph node or bone metastases, (3) neutrophil count > or = 6500 cells microl(-1), (4) serum lactate dehydrogenase level (LDH) > or = 220 U l(-1), and (5) serum C-reactive protein level (CRP) > or = 11 mg l(-1). Cox regression analysis with forward stepwise variable selection identified neutrophil count as the major prognostic factor (hazard ratio=1.9, P<0.001), while serum levels of LDH and CRP, time between diagnosis of tumour and onset of metastatic disease, number of metastatic sites, and bone metastases were significant but somewhat less important prognostic variables within the multiple risk factor model (hazard ratio < or = 1.5). Patients were assigned to one of the three risk groups according to cumulative risk defined as the sum of simplified risk s.c.ores for six pretreatment variables. Low-, intermediate-, and high-risk patients achieved a median overall survival of 32+ months (95% CI 24, 43; 5-year survival of 27%), 18+ months (95% CI 15, 20; 5-year survival of 11%), and 8+ months (95% CI 6, 10; 5-year survival of 5%), respectively. These prognostic categories are helpful both in individual patient care and in the assessment of patients entering prospective clinical trials.

Project description:BACKGROUND:Increasing evidence suggests that severe skeletal muscle index (SMI) loss (sarcopenia) is associated with poor overall survival in metastatic colorectal cancer patients, but its mechanisms are unknown. We recently found, using data of the randomized phase 3 CAIRO3 study, that SMI loss was related with shorter time to disease progression and overall survival during first-line maintenance treatment with capecitabine + bevacizumab (CAP-B) or observation and during more intensive capecitabine + oxaliplatin + bevacizumab (CAPOX-B) reintroduction treatment. As a potential risk factor for reduced survival, we explored whether sarcopenia and SMI loss were associated with dose-limiting toxicities (DLTs) during CAP-B and CAPOX-B. METHODS:Sarcopenia status and SMI loss were assessed by using consecutive computed tomography scans. DLTs were defined as any dose delay/reduction/discontinuation of systemic treatment because of reported CTCAE (version 3.0) toxicities at the start or during treatment. Poisson regression models were used to study whether sarcopenia and body mass index (BMI) at the start of treatment and SMI and BMI loss during treatment were associated with DLTs. RESULTS:One hundred eighty-two patients (mean age 63.0 ± 8.8 years, 37% female) received CAP-B, and 232 patients (mean age 63.0 ± 9.0 years, 34% female) received CAPOX-B. At the start of CAP-B and CAPOX-B, 54% and 46% of patients were sarcopenic, respectively. Mean BMI was lower in sarcopenic patients, although patients were on average still overweight (sarcopenic vs. non-sarcopenic at the start of CAP-B 25.0 ± 3.9 vs. 26.7 ± 4.1 and CAPOX-B 25.8 ± 3.8 vs. 27.1 ± 3.8 kg/m2 ). Sarcopenia at the start of CAP-B was not associated with DLTs [relative risk 0.87 (95% confidence interval 0.64-1.19)], whereas patients with >2% SMI loss had a significantly higher risk of DLTs [1.29 (1.01-1.66)]. At the start of subsequent CAPOX-B, 25% of patients received a dose reduction, and the risk of dose reduction was significantly higher for patients with preceding SMI loss [1.78 (1.06-3.01)] or sarcopenia [1.75 (1.08-2.86)]. After the received dose reductions, sarcopenia or SMI loss was not significantly associated with a higher risk of DLTs during CAPOX-B [sarcopenia vs. non-sarcopenic: 0.86 (0.69-1.08) and SMI loss vs. stable/gain: 0.83 (0.65-1.07)]. In contrast, BMI (loss) at the start or during either treatment was not associated with an increased risk of DLTs. CONCLUSIONS:In this large longitudinal study in metastatic colorectal cancer patients during palliative systemic treatment, sarcopenia and/or muscle loss was associated with an increased risk of DLTs. BMI was not associated with DLTs and could not detect sarcopenia or SMI loss. Prospective (randomized) studies should reveal whether normalizing chemotherapeutic doses to muscle mass or muscle mass preservation (by exercise and nutritional interventions) increases chemotherapeutic tolerance and improves survival.

Dataset Information

Early skeletal muscle loss during target therapy is a prognostic biomarker in metastatic renal cell carcinoma patients.

Publications

Early skeletal muscle loss during target therapy is a prognostic biomarker in metastatic renal cell carcinoma patients.

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