Cancer-induced muscle wasting: latest findings in prevention and treatment

Background Palliative systemic treatment in patients with advanced or metastatic esophagogastric cancer may result in improved overall survival and quality of life but can also lead to considerable toxicity. In various cancer types, severe muscle mass depletion (sarcopenia) and poor muscle strength are associated with decreased survival and increased chemotherapy‐related toxicity. The aim of this study is to determine the impact of body composition on survival and chemotherapy toxicity in esophagogastric cancer patients treated with first‐line palliative chemotherapy. Methods A total of 88 patients with advanced esophagogastric cancer treated with standard first‐line palliative systemic therapy consisting of capecitabine and oxaliplatin (CapOx) between January 2010 and February 2017 were included. Skeletal muscle index (SMI), reflecting muscle mass, and skeletal muscle density (SMD), associated with muscle strength, were measured using pre‐treatment of all patients and evaluation computed tomography scans after three treatment cycles of 65 patients and were used to determine sarcopenia and sarcopenic obesity (i.e. sarcopenia and body mass index >25 kg/m 2 ). The associations between body composition (SMI, SMD, sarcopenia, and sarcopenic obesity) and survival and toxicity were assessed using univariable and multivariable Cox and logistic regression analyses, respectively. Results Of 88 patients, 75% was male, and median age was 63 (interquartile range 56–69) years. The majority of patients had an adenocarcinoma (83%). Before start of treatment, 49% of the patients were sarcopenic, and 20% had sarcopenic obesity. Low SMD was observed in 50% of patients. During three cycles CapOx, SMI significantly decreased, with a median decrease of 4% (interquartile range −8.6–−0.4). Median progression‐free and overall survival were 6.9 and 10.1 months. SMI, SMD, sarcopenia, and sarcopenic obesity (both pre‐treatment and after three cycles) were neither associated with progression‐free nor overall survival. Pre‐treatment SMD was independently associated with grade 3–4 toxicity (odds ratio 0.94; 95% confidence interval 0.89–1.00) and sarcopenic obesity with grade 2–4 neuropathy (odds ratio 3.82; 95% confidence interval 1.20–12.18). Conclusions Sarcopenia was not associated with survival or treatment‐related toxicity in advanced esophagogastric cancer patients treated with CapOx. Pre‐treatment sarcopenic obesity was independently associated with the occurrence of grade 2–4 neurotoxicity and skeletal muscle density with grade 3–4 toxicity.

Section: Discussionmentioning

confidence: 59%

Association between body composition, survival, and toxicity in advanced esophagogastric cancer patients receiving palliative chemotherapy

Dijksterhuis

Pruijt

Woude

et al. 2019

“…The strong correlations that we have identified between a high relative frequency of EM CD8 + T cells and stronger HGS and chest press capacity in patients with cancer suggest that CD8 + T cell surveillance might continue during cancer recurrence in some patients. Some control of tumour burden might then reduce the detrimental effect that tumour growth has on muscle function resulting in stronger muscle measures . Our data do not address whether the CD8 + EM cells in cancer participants with greater muscle strength contain cancer‐specific cells.…”

Section: Discussionmentioning

confidence: 75%

“…In people with cancer, reduced muscle mass and strength are also negatively associated with disease‐free survival and overall survival . Tumour growth is known to promote loss of muscle mass and function; however, the specific mechanisms mediating this effect are incompletely understood . Cancer‐specific T cell responses that target cancer cells might indirectly protect muscle mass and function by reducing tumour burden .…”

Section: Introductionmentioning

confidence: 99%

Cancer‐driven changes link T cell frequency to muscle strength in people with cancer: a pilot study

Narsale

Moya

et al. 2019

Background Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4 + precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti‐cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer. Methods The frequency of circulating CD4 + and CD8 + naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real‐time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one‐repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual‐energy X‐ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses. Results Our data show significant correlations between (i) higher frequencies of CD8 + naïve ( P = 0.02) and effector memory ( P = 0.003) T cells and lower frequencies of CD8 + central memory T cells ( P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index ( P = 0.04), (iii) lower frequency of CD8 + T cells that express CD95 with greater stair climb power ( P = 0.003), (iv) higher frequency of T cells that co‐express CD197 and CD45RA and greater one‐repetition maximum knee extension strength ( P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment ( P = 0.004) in people with cancer. Conclusions We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow‐up study with a larger cohort to test the validity of the findings.

“…Based on results from murine models, recent clinical trials have aimed to unravel the efficiency of blocking activin signalling in patients with cachexia or muscle dystrophy. Clinical trials involving ACVR2B decoy receptors, however, were terminated due to severe adverse effects, including bleeding . More specific antibodies directed towards the ACVR2B are being tested in clinical trials; however, because ACVR2 are central receptors for multiple TGFβ family members, and our study points to the central role of activin A, specific inhibition of activin A itself may prove less invasive and equally efficient.…”

Section: Discussionmentioning

confidence: 93%

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

Pettersen

Andersen

Veen

et al. 2019

Background The majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development. Methods We investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice. Results We show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005). Conclusions Our data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.