Susanne Blauwhoff-Buskermolen

Loss of Muscle Mass During Chemotherapy Is Predictive for Poor Survival of Patients With Metastatic Colorectal Cancer

PURPOSE Low muscle mass is present in approximately 40% of patients with metastatic colorectal cancer (mCRC) and may be associated with poor outcome. We studied change in skeletal muscle during palliative chemotherapy in patients with mCRC and its association with treatment modifications and overall survival. PATIENTS AND METHODS In 67 patients with mCRC (mean age ± standard deviation, 66.4 ± 10.6 years; 63% male), muscle area (square centimeters) was assessed using computed tomography scans of the third lumbar vertebra before and during palliative chemotherapy. Treatment modifications resulting from toxicity were evaluated, including delay, dose reduction, or termination of chemotherapy. Multiple regression analyses were performed for the association between change in muscle area and treatment modification and secondly overall survival. RESULTS Muscle area of patients with mCRC decreased significantly during 3 months of chemotherapy by 6.1% (95% CI, -8.4 to -3.8; P < .001). Change in muscle area was not associated with treatment modifications. However, patients with muscle loss during treatment of 9% or more (lowest tertile) had significantly lower survival rates than patients with muscle loss of less than 9% (at 6 months, 33% v 69% of patients alive; at 1 year, 17% v 49% of patients alive; log-rank P = .001). Muscle loss of 9% or more remained independently associated with survival when adjusted for sex, age, baseline lactate dehydrogenase concentration, comorbidity, mono-organ or multiorgan metastases, treatment line, and tumor progression at first evaluation by computed tomography scan (hazard ratio, 4.47; 95% CI, 2.21 to 9.05; P < .001). CONCLUSION Muscle area decreased significantly during chemotherapy and was independently associated with survival in patients with mCRC. Further clinical evaluation is required to determine whether nutritional interventions and exercise training may preserve muscle area and thereby improve outcome.

Aiming for a Better Understanding and Management of Cancer-Related Fatigue

Cancer-related fatigue (CRF) is a serious symptom of patients with cancer and deteriorates their daily quality of life. Whereas fatigue is a common problem in the general population, with a prevalence of about 30%, up to 99% of patients with cancer have fatigue of more intense severity. CRF is directly related to the biology of cancer, but it can also be caused by anticancer treatment. We reviewed current evidence about the potential pathophysiological mechanisms causing CRF. Clinical methods to determine the presence and severity of CRF and potential treatment options to reduce CRF will be discussed. After reading this review, the reader will have knowledge of the current understanding of CRF and will be able to give evidence-based advice to patients with CRF.

Identifying the Barriers and Enablers to Nutrition Care in Head and Neck and Esophageal Cancers An International Qualitative Study

BACKGROUND The goal of this work was to identify barriers and enablers to the implementation of nutrition care in head and neck and esophageal (HNE) cancers and to prioritize barriers to help improve the nutrition care process. MATERIALS AND METHODS This study used a multimethod qualitative study design (including semistructured interviews, focus group). Interviews (n = 29) were conducted at 5 European sites providing care and treatment to patients with HNE cancers. A focus group (n = 21) reviewed and corroborated interview findings and identified priorities for nutrition care. Participants were healthcare providers and researchers with direct experience in the field of HNE cancer. RESULTS Five themes with accompanying barriers and enablers were identified related to nutrition care: (1) evidence for the benefit of nutrition interventions, (2) implementation of nutrition care processes (assessment, intervention, and follow-up), (3) characteristics of healthcare providers, (4) site factors, and (5) patient characteristics. Focus group discussions identified 2 priorities that must be acted on to improve nutrition care: (1) improve the evidence base and (2) develop standardized nutrition care pathways. CONCLUSION Themes related to nutrition care in HNE cancers were similar between sites, but barriers and enablers differed. Interview and focus group participants agreed the following actions will result in improvements in nutrition care: (1) enhance the evidence base to test the benefit of nutrition interventions, with a focus on resolving specific controversies regarding nutrition therapy, and (2) establish a minimum data set with a goal to create standardized nutrition care pathways where roles and responsibilities for care are clearly defined.

The influence of different muscle mass measurements on the diagnosis of cancer cachexia

Progressive loss of muscle mass is a major characteristic of cancer cachexia. Consensus definitions for cachexia provide different options to measure muscle mass. This study describes the effect of different methods to determine muscle mass on the diagnosis of cancer cachexia. In addition, the association of cachexia with other features of cachexia, quality of life, and survival was explored.

‘Pre-cachexia’: a non-existing phenomenon in cancer?

We read with great interest the article by Blum et al. [1] who reported an important validation study on the diagnostic framework of cancer cachexia. For patients with cancer, cachexia is a major problem associated with reduced physical functioning [2], tolerance to anti-cancer therapy [3] and survival [2]. Despite the growing knowledge on the pathophysiology of cachexia, assessment in clinical practice is limited due to lack of adequate diagnostic criteria. The past years, experts developed a diagnostic framework [4] but validation studies were still awaited. Blum et al. reported that differentiation of cachexia from no cachexia using the proposed framework worked out successfully with significant and clinically relevant differences in laboratory values, food intake, performance status and survival [1]. With limited treatment options for cancer cachexia, focus has been shifting to pre-cachexia, a potential early stage of cachexia, in which (multi-modal) interventions may slow down the process of cachexia [4]. Blum et al. defined pre-cachexia as weight loss >1 kg but <5% of usual body weight/6 months [1] and found that, by using these criteria, survival rates were not different from those of patients without cachexia. The authors state that ‘the pre-cachexia stage might be better defined by additional factors representing the cachexia domain, for instance CRP and appetite loss’ [1]. In our cancer centre, we assessed these additional factors and weight loss in 200 patients before start of treatment with (combination) chemotherapy in a prospective study. Pre-cachexia was defined as:

Plasma Ghrelin Levels Are Associated with Anorexia but Not Cachexia in Patients with NSCLC

Background and Aims: The ghrelin receptor is one of the new therapeutic targets in the cancer anorexia-cachexia syndrome. Previous studies revealed that plasma ghrelin levels were high in patients with anorexia nervosa and low in obese subjects. We studied to what extent ghrelin levels are related with anorexia and cachexia in patients with cancer. Materials and Methods: Fasted ghrelin levels were determined as well as anorexia and cachexia in patients with stage III/IV non-small cell lung cancer before chemotherapy. Total plasma ghrelin was measured by radioimmunoassay. Anorexia was measured with the FAACT-A/CS questionnaire (cut-off value ≤ 37). Cachexia was determined as >5% weight loss (WL) in 6 months or >2% WL in 6 months in combination with low BMI or low muscle mass. The Kruskal-Wallis test was performed to assess differences in plasma ghrelin levels between four groups: patients with (+) or without (−) anorexia (A) or cachexia (C). Multiple regression analyses were performed to assess differences in plasma ghrelin levels between patients C+ and C− and patients with A+ and A− (adjusted for age and sex). Results: Forty patients with stage III (33%) or stage IV (68%) were recruited, of which 50% was male. Mean age was 59.6 ± 10.3 years. Sixteen patients had no anorexia or cachexia (A−C−), seven patients had both anorexia and cachexia (A+C+), ten patients had anorexia without cachexia (A+C−) and seven patients had cachexia without anorexia (A−C+). The levels of total plasma ghrelin were significantly different between the four groups of patients with or without anorexia or cachexia (p = 0.032): the A+C− patients had significantly higher ghrelin levels [median (IQR): 1,754 (1,404–2,142) compared to the A−C+ patients 1,026 (952–1,357), p = 0.003]. A+ patients had significantly higher ghrelin levels compared A− patients (C+ and C− combined, β: 304, p = 0.020). Plasma ghrelin levels were not significantly different in C+ patients compared to C− patients (A+ and A− combined, β: −99, p = 0.450). Conclusions: Patients with anorexia had significantly higher ghrelin levels compared to patients without anorexia. We therefore hypothesize that patients with cancer anorexia might benefit from treatment with a ghrelin receptor agonist to prevent WL and deterioration in physical functioning.

Percentiles for skeletal muscle index, area and radiation attenuation based on computed tomography imaging in a healthy Caucasian population

Background/objectivesMuscle mass is a key determinant of nutritional status and associated with outcomes in several patient groups. Computed tomography (CT) analysis is increasingly used to assess skeletal muscle area (SMA), skeletal muscle index (SMI) and muscle radiation attenuation (MRA). However, interpretation of these muscle parameters is difficult since values in a healthy population are lacking. The aim of this study was to provide sex specific percentiles for SMA, SMA and MRA in a healthy Caucasian population and to examine the association with age and BMI in order to define age- and BMI specific percentiles.Subjects/methodsIn this retrospective cross-sectional study CT scans of potential kidney donors were used to assess SMA, SMI and MRA at the level of the third lumbar vertebra. Sex specific distributions were described and, based on the association between age/BMI and muscle parameters, age, and BMI specific predicted percentiles were computed. The 5th percentile was considered as cut-off.ResultsCT scans of 420 Individuals were included (age range 20–82 years and BMI range 17.5–40.7 kg/m2). Sex specific cut-offs of SMA, SMI and MRA were 134.0 cm2, 41.6 cm2/m2 and 29.3 HU in men and 89.2 cm2, 32.0 cm2/m2 and 22.0 HU in women, respectively. Correlations were negative between age and all three muscle parameters, positive between BMI and SMA/SMI and negative between BMI and MRA, resulting in age- and BMI specific percentiles.ConclusionsThis study provides sex specific percentiles for SMA, SMI, and MRA. In addition, age- and BMI specific percentiles have been established.

The effect of individualized NUTritional counseling on muscle mass and treatment outcome in patients with metastatic COLOrectal cancer undergoing chemotherapy: a randomized controlled trial protocol

BackgroundA low muscle mass is prevalent in patients with metastatic colorectal cancer (mCRC) and has been associated with poor treatment outcome. Chemotherapeutic treatment has an additional unfavorable effect on muscle mass. Sufficient protein intake and physical activity are known to induce muscle protein anabolism in healthy individuals, however it is unclear whether optimal nutrition is effective to preserve muscle mass in patients with mCRC during first-line chemotherapy as well. We hypothesize that individual nutritional counseling by a trained dietitian during first-line chemotherapy is effective in preserving muscle mass and may improve clinical outcomes in patients with mCRC.Methods/DesignIn this multi-center single-blind randomized controlled trial, patients with mCRC scheduled for first-line combination chemotherapy consisting of oxaliplatin and fluoropyrimidine, with or without bevacizumab (n = 110), will be randomized to receive either individualized nutritional counseling by a trained dietitian to achieve a sufficient dietary intake and an adequate physical activity level, or usual care. Outcome measures will be assessed at baseline and after two and four months of treatment. The primary endpoint will be the change in skeletal muscle area (measured by CT-scan) at the first treatment evaluation. Secondary endpoints will be quality of life, physical functioning, treatment toxicity, treatment intensity and survival. Statistical analyses include one-sided t-tests for the primary endpoint and mixed models and the Kaplan-Meier method for secondary endpoints.DiscussionThis randomized controlled trial will provide evidence whether individualized nutritional counseling during chemotherapy is effective in preventing loss of muscle mass in patients with mCRC.Trial registrationClinicalTrials.gov NCT01998152; Netherlands Trial Register NTR4223.

Muscle mass as a target to reduce fatigue in patients with advanced cancer

Cancer‐related fatigue (CRF) reduces quality of life and the activity level of patients with cancer. Cancer related fatigue can be reduced by exercise interventions that may concurrently increase muscle mass. We hypothesized that low muscle mass is directly related to higher CRF.

Reply to L.E. Daly et al

We thank Daly et al for providing valuable comments regarding our recent paper on the prognostic role of muscle loss during anticancer treatment in patients with metastatic colorectal cancer. We have found that muscle mass decreased significantly during chemotherapy and a decrease in muscle mass was independently associated with poor survival in patients with metastatic colorectal cancer. Daly et al correctly note that we observed no associations between a low skeletal muscle index at baseline and reduced survival, in contrast to some but not all previous studies. In our article, we provide some explanations for this discrepancy, for example, the heterogeneity regarding treatment regimens and follow-up time. Daly et al add a possible explanation as there may be a possible difference in body composition reference values between a North American (Canadian) and European population. Daly et al suggest that extrapolating cutoff points from a Canadian population to a cohort of Dutch patients may have been a suboptimal approach to identify the true prevalence of low SMI and the relationship between low SMI and survival within this cohort. We acknowledge the importance of differences in body composition between countries. For example, the Dutch population, on average, is taller and the prevalence of overweight and obesity is lower compared with the Canadian population. Although a large percentage of the Canadian population consists of (European) immigrants, we agree that it would be better to compare our study data with normative values derived from a European, or even a Dutch, population. Although we did find a new publication with cutoff values for an Asian population, normative data for a European population are not available yet. There are several options to consider to overcome the question of ethnic variation in body composition in the near future. Data on body composition measured with computed tomography scans from recent European studies could be pooled to build a database with reference values for the European population. Another approach is to derive normative values from a healthy population, which is what our group is working on at the moment. It would then be interesting to repeat the statistical analyses of our study and to investigate whether our population truly displayed a low skeletal muscle index compared with European reference values. Only then we will be able to understand why skeletal muscle index was not associated with survival in our cohort and whether this may have been caused by choosing the wrong reference group. In the meantime, while we await reference values for different countries and/or ethnic groups, we recommend that future studies on body composition display patient characteristics with regard to ethnicity, especially when cutoff values or reference values are being used. This does not apply to Europe alone, but also to other regions across the world.