Measurement of skeletal muscle in oncology

The three most commonly used methods to measure body composition in patients with cancer are bioelectrical impedance analysis, dual-energy x-ray absorptiometry and CT. Each technique has its advantages and disadvantages, and methods differ in terms of cost, reliability, validity, availability and training required⁽Reference Prado and Heymsfield²¹⁾. CT images are considered a gold standard method for body composition assessment, and allow the precise quantification of tissue area, volume and attenuation. Unlike bioelectrical impedance analysis or dual-energy x-ray absorptiometry, CT can measure body composition at a tissue-organ level, particularly total and regional adipose and skeletal muscle tissues. The use of CT for body composition assessment in non-cancer populations is limited by the high radiation dose, high cost and lack of availability. However, in oncology, CT scans are obtained routinely during diagnostic and surveillance purposes, and therefore represent a unique and exploitable opportunity to assess body composition within this patient group.

Measuring muscle mass by CT is usually done by measuring total skeletal muscle area (SMA) at the third lumber vertebra (L3). Using a commercially available image analysis software (e.g. Sliceomatic (TomoVision), OsiriX (Pixmeo), Image J (National Institutes of Health), among others), muscle and adipose tissues can be evaluated based on Hounsfield unit (HU) thresholds. Muscles in this area include the psoas, paraspinal muscles (erector spinea, quadratus lumborum) and the abdominal wall muscles (transversus abdominus, external and internal oblique, rectus abdominus). Measurements are commonly taken at the third lumber vertebra, as the SMA obtained at this level is a good correlate for whole body muscle in healthy individuals (r 0·92)⁽Reference Shen, Punyanitya and Wang²²⁾. From this skeletal muscle index (SMI; total SMA (cm²)/height (m²)) can be calculated and patients are often compared on this basis. Mean MA is typically derived by averaging HU of the SMA at the third lumber vertebra. Although SMI and MA are continuous variables and could be modelled as such to predict survival/outcome, many clinicians find the interpretation of continuous prognostic covariates difficult, and prefer categorical or binary covariates based on a threshold/cut point to stratify patients into distinct risk groups when making treatment decisions.

Defining low muscle mass (sarcopenia) in patients with cancer

Many oncological studies define sarcopenia based solely on low muscle mass, and studies often lack information on muscle strength or physical function. Therefore, the criteria to define sarcopenia in this group differ from those proposed in geriatric populations⁽Reference Cruz-Jentoft, Baeyens and Bauer^23, Reference Fielding, Vellas and Evans²⁴⁾. In the oncology setting, consensus-based cut points to define low muscle mass or sarcopenia are lacking, and a variety have been devised. Studies⁽Reference Prado, Lieffers and Bowthorpe^25–Reference Tamandl, Paireder and Asari²⁸⁾ have defined sarcopenia based on cut points developed by Baumgartner et al. ⁽Reference Baumgartner, Koehler and Gallagher⁷⁾ in elderly individuals (2-sd below a healthy reference population), by converting the original dual-energy x-ray absorptiometry cut points (<7·26 kg/m² for men and <5·45 kg/m² for women) to corresponding CT cut points using published regression equations⁽Reference Mourtzakis, Prado and Lieffers²⁹⁾. These cut points are SMI <55·4 cm²/m² for men and <38·9 cm²/m² for women⁽Reference Mourtzakis, Prado and Lieffers²⁹⁾, and are those used in the cancer cachexia consensus definition⁽Reference Fearon, Strasser and Anker⁸⁾. To date, no healthy population reference values for muscle mass obtained from CT exist.

Studies have employed a statistical technique known as optimal stratification, which is used to identify threshold values associated with elevated risk of poor outcome (e.g. mortality) to define sarcopenia. Using this technique, Prado et al. ⁽Reference Prado, Lieffers and McCargar¹⁹⁾ identified cut points for SMI that best predicted survival in a cohort of 250 obese (BMI >30 kg/m²) cancer patients. These cut points are <52·4 cm²/m² for men and <38·5 cm²/m² for women⁽Reference Prado, Lieffers and McCargar¹⁹⁾, and have been widely applied in the literature. In 2013, Martin et al. ⁽Reference Martin, Birdsell and Macdonald¹⁾ identified both sex and BMI-specific cut points for SMI that best predicted survival (men: <43 cm²/m² if BMI ≤24·9 kg/m² and <53 cm²/m² if BMI ≥25 kg/m²; women: <41 cm²/m²)⁽Reference Martin, Birdsell and Macdonald¹⁾ in a large cohort of 1473 patients with lung and gastrointestinal (GI) cancer, which are more applicable to non-obese cohorts. More recently, in 2017, Caan et al. ⁽Reference Caan, Meyerhardt and Kroenke³⁰⁾ identified sex, BMI and cancer-specific cut points for survival in a very large cohort of early-stage colorectal cancer patients (n 3262; men: <52·3 cm²/m² if BMI <30 kg/m² and <54·3 cm²/m² if BMI ≥30 kg/m²; women: <38·6 cm²/m² if BMI <30 kg/m² and <46·6 cm²/m² if BMI ≥30 kg/m²)⁽Reference Caan, Meyerhardt and Kroenke³⁰⁾.

In addition to sex and BMI, ethnicity should be considered when applying cut points to a specific cohort. Fujiwara et al. ⁽Reference Fujiwara, Nakagawa and Kudo³¹⁾ defined CT-derived cut points for a large (n 1257) homogenous cohort of Japanese patients with mixed stage (I–IV) hepatocellular carcinoma that best predicted survival (<36·2 cm²/m² for men and <29·0 cm²/m² for women), providing a reference population for these individuals. Notably, these cut points are lower⁽Reference Fujiwara, Nakagawa and Kudo^31, Reference Iritani, Imai and Takai³²⁾ compared with those derived from large Caucasian populations⁽Reference Martin, Birdsell and Macdonald^1, Reference van Vugt, Braam and van Oudheusden^3, Reference Coelen, Wiggers and Nio³⁴⁾.

Using optimal stratification methodology, several other studies have reported cut points for SMI associated with mortality in a number of cancer cohorts (see Table 1), these range 36–55·8 cm²/m² for men and 29–46·6 cm²/m² for women. Several factors influence patient's muscularity (ethnicity, age, sex, physical activity and magnitude of adiposity)⁽Reference Heymsfield, Gonzalez and Lu³⁵⁾; hence, published cut points may not be applicable to all cancer populations. For example, cut points published by Prado et al. ⁽Reference Prado, Lieffers and McCargar¹⁹⁾ were devised in a cohort of obese patients with cancer, and may have limited relevance when applied to populations with varying prevalence of obesity, but have subsequently been used in studies comprised of predominantly non-obese individuals⁽Reference Dalal, Hui and Bidaut^36–Reference Elliott, Doyle and Murphy⁴⁰⁾.

Table 1. Cut points for skeletal muscle index (SMI) at the third lumber vertebra (L3) associated with mortality in patients with cancer

GI, gastrointestinal.

* Obese individuals only (BMI >30 kg/m²).

Other studies have defined sarcopenia based on more data-orientated approaches, dichotomizing SMI based on predetermined percentiles, such as quartiles⁽Reference Miyamoto, Baba and Sakamoto⁴¹⁾, tertiles⁽Reference van Dijk, Bakens and Coolsen^17, Reference Harada, Ida and Baba⁴²⁾ or based on the median⁽Reference Rutten, van Dijk and Kruitwagen^43, Reference Boer, de Graaff and Brusse-Keizer⁴⁴⁾. Studies focused solely on one muscle group, the psoas muscle, generating a psoas muscle index, often considered patients within the lowest quartile of psoas muscle index to be sarcopenic⁽Reference Amini, Spolverato and Gupta^45–Reference Peng, Hyder and Firoozmand⁴⁷⁾. However, no studies have related psoas muscle area to whole body measures, and it has only been weakly correlated with total lumbar muscle area⁽Reference Rutten, Ubachs and Kruitwagen⁴⁸⁾. Therefore, it has been argued that the use of the psoas muscle as a sentinel muscle for the diagnosis of sarcopenia is flawed⁽Reference Baracos⁴⁹⁾. Other investigations have included additional measures of physical function (hand grip strength and/or gait speed) in conjunction with skeletal muscle from CT scan analysis when defining sarcopenia in patients with cancer⁽Reference Huang, Zhou and Wang^50, Reference Fukuda, Yamamoto and Hirao⁵¹⁾. The rationale for including the measures of both muscle mass and function is that muscle strength does not depend solely on muscle mass, and the relationship between muscle strength and mass is not linear⁽Reference Goodpaster, Park and Harris⁶⁾. Hence, several expert groups have proposed the use of both muscle mass and function to define sarcopenia in older adults⁽Reference Cruz-Jentoft, Baeyens and Bauer^23, Reference Fielding, Vellas and Evans^24, Reference Chen, Liu and Woo⁵²⁾.

Prevalence of low muscle mass (sarcopenia) in patients with cancer

As discussed previously, comparison among studies reporting the prevalence of sarcopenia is often difficult because of inconsistent methodology used to evaluate body composition (dual-energy x-ray absorptiometry, bioelectrical impedance analysis, CT), and diagnostic criteria/cut points used to define sarcopenia. Table 2 summarises the prevalence of sarcopenia among patients with cancer using the same methodology (CT defined SMI) but using varying published cut points. The prevalence of sarcopenia is highly variable across primary cancer sites, and has been shown to range from 11 to 90 %⁽Reference Fujiwara, Nakagawa and Kudo^31, Reference Auclin, Bourillon and De Maio⁵³⁾. Of note is the heterogeneity in the prevalence of sarcopenia among cohorts of the same primary cancer site and stage, e.g. 19–71 % in advanced colorectal cancer⁽Reference van Vledder, Levolger and Ayez^54, Reference Barret, Antoun and Dalban⁵⁵⁾, 33–90 % in metastatic kidney cancer⁽Reference Auclin, Bourillon and De Maio^53–Reference Cushen, Power and Teo⁵⁶⁾ and 21–89 % in advanced pancreatic cancer⁽Reference Choi, Oh and Kim^57, Reference Wesseltoft-Rao, Hjermstad and Ikdahl⁵⁸⁾. This large variability could be attributed to the varying cut points used to define sarcopenia; limitations related to sample size; or patient characteristics such as age, sex, ethnicity, BMI and concurrent co-morbidities, thus limiting the ability to draw conclusions as to the true prevalence according to the cancer site. Sarcopenia appears to be the most prevalent in patients with any stage of pancreatic or lung cancer, while in other cancer types (e.g. gastric and breast), it appears to be more frequent in advanced stage disease compared with earlier loco regional disease. Sarcopenia can be present at any given BMI, and the prevalence of sarcopenic obesity (sarcopenia and obesity (BMI ≥30 kg/m²)) has been shown to vary between 1 and 29 % in studies including individuals from all BMI categories, and between 15 and 36 % in studies including obese individuals only⁽Reference Carneiro, Mazurak and Prado⁵⁹⁾.

Table 2. Prevalence of sarcopenia according to cancer site, country and definition used

NSC, non-small cell; SC, small cell; GI, gastrointestinal; NR, not recorded; GIST, gastrointestinal stromal tumour.

* Prevalence of sarcopenia in both sexes combined.

† Sarcopenia definitions stratified as follows:

1: Skeletal muscle index (SMI) <52·4 cm²/m² for males; <38·5 cm²/m² for females⁽Reference Prado, Lieffers and McCargar¹⁹⁾.

2: SMI <55·4 cm²/m² for males; <38·9 cm²/m² for females (Baumgartner sarcopenia cut points for elderly healthy subjects⁽Reference Baumgartner, Koehler and Gallagher⁷⁾ converted to CT cut points using regression equations⁽Reference Mourtzakis, Prado and Lieffers²⁹⁾.

3: SMI <43 cm²/m² BMI ≤24·9 kg/m² and <53 cm²/m² for BMI >25 kg/m² for males; <41 cm²/m² for females⁽Reference Martin, Birdsell and Macdonald¹⁾.

4: SMI <43·75 cm²/m² for males; <41·1 cm²/m² for females⁽Reference van Vledder, Levolger and Ayez⁵⁴⁾.

5: SMI <55·8 cm²/m² for males; <38·9 cm²/m² for females⁽Reference Lanic, Kraut-Tauzia and Modzelewski³³⁾.

6: SMI <49·5 cm²/m² and for women <42·1 cm²/m² (lowest quartile)⁽Reference Miyamoto, Baba and Sakamoto⁴¹⁾.

7: SMI <42·2 cm²/m² for males; <33·9 cm²/m² for females⁽Reference Choi, Oh and Kim⁵⁷⁾.

8: SMI <36·2 cm²/m² for males; <29·0 cm²/m² for females⁽Reference Fujiwara, Nakagawa and Kudo³¹⁾.

9: SMI ≤36·0 cm²/m² for males; ≤29·0 cm²/m² for females⁽Reference Iritani, Imai and Takai³²⁾.

10: SMI <41·5 cm²/m² (median) for females⁽Reference Rutten, van Dijk and Kruitwagen⁴³⁾.

11: SMI <46·8 cm²/m² for males; <39·1 cm²/m² for females⁽Reference Coelen, Wiggers and Nio³⁴⁾.

12: SMI <52·3 cm²/m² for men and <38·6 cm²/m² for men with a BMI <30 kg/m² and <54·3 cm²/m² for men and <46·6 cm²/m² for women with a BMI ≥30 kg/m²⁽Reference Caan, Meyerhardt and Kroenke³⁰⁾.

Low muscle attenuation in patients with cancer

Similar to the measures of SMI, no widely agreed upon cut points are available for defining low MA. Martin et al. ⁽Reference Martin, Birdsell and Macdonald¹⁾ provided the first set of cut points for low MA (using optimal stratification) that related to poor survival in a large cohort of lung and GI cancer patients (n 1473; <41 HU for BMI <25 kg/m² and <33 for BMI ≥25 kg/m²)⁽Reference Martin, Birdsell and Macdonald¹⁾. Since then, cancer-specific cut points for low MA that relate optimally to survival have been reported for lung⁽Reference Sjøblom, Grønberg and Wentzel-Larsen^18, Reference Bowden, Williams and Simms⁶⁰⁾, ovarian⁽Reference Kumar, Moynagh and Multinu^61, Reference Aust, Knogler and Pils⁶²⁾, periampullary⁽Reference Van Rijssen, van Huijgevoort and Coelen¹⁶⁾, pancreatic⁽Reference Okumura, Kaido and Hamaguchi⁶³⁾, gastro-oesophageal⁽Reference Tamandl, Paireder and Asari²⁸⁾ and large B-cell lymphoma⁽Reference Chu, Lieffers and Ghosh¹⁵⁾. These range from <28·0 to 44·1 HU in men⁽Reference Van Rijssen, van Huijgevoort and Coelen^16, Reference Sjøblom, Grønberg and Wentzel-Larsen^18, Reference Bowden, Williams and Simms⁶⁰⁾ and <23·8 to 40·5 HU in women⁽Reference Van Rijssen, van Huijgevoort and Coelen^16, Reference Sjøblom, Grønberg and Wentzel-Larsen^18, Reference Bowden, Williams and Simms^60–Reference Aust, Knogler and Pils⁶²⁾. Other studies have defined low MA based on the sample sex-specific median⁽Reference Boer, de Graaff and Brusse-Keizer^44, Reference Antoun, Lanoy and Iacovelli⁶⁴⁾, tertile⁽Reference van Dijk, Bakens and Coolsen¹⁷⁾ or quartile⁽Reference Akahori, Sho and Kinoshita⁶⁵⁾.

The prevalence of low MA among patients with cancer varies greatly, and is dependent on the cohort under investigation and cut point used, but has been shown to range from 10 to 86 %⁽Reference Sjøblom, Grønberg and Wentzel-Larsen^18, Reference Cushen, Power and Murphy⁶⁶⁾. Using the cut points devised by Martin et al. ⁽Reference Martin, Birdsell and Macdonald¹⁾, which have been applied most widely in the literature, the prevalence of low MA has been reported to be between 46 and 53 % in two large cohorts of patients with cancer (mixed tumour sites and stages (I–IV))⁽Reference Martin, Birdsell and Macdonald^1, Reference Ní Bhuachalla, Daly and Power⁶⁷⁾. In the setting of advanced disease, the prevalence of low MA has been reported to be 33 % in melanoma⁽Reference Daly, Power and O'Reilly⁴⁾, 55 % in pancreatic⁽Reference Rollins, Tewari and Ackner⁶⁸⁾, 59 % in gastric⁽Reference Hayashi, Ando and Gyawali¹³⁾, 60 % in breast⁽Reference Rier, Jager and Sleijfer¹⁴⁾ and 86 % in prostate cancer⁽Reference Cushen, Power and Murphy⁶⁶⁾, while in patients with operable colorectal cancer, low MA is present in 58–78 % of patients⁽Reference McSorley, Black and Horgan^69, Reference Malietzis, Currie and Athanasiou⁷⁰⁾.

Muscle abnormalities and tolerance to chemotherapy

Chemotherapy can often be associated with severe toxicity (grades III–IV) that can result in dose delays, dose reductions and treatment termination, referred to as dose-limiting toxicities (DLT). DLT may lead to hospitalisations and can be life threatening. Exploratory studies provided the initial evidence of an association between low muscularity and increased incidence of severe toxicity/DLT to chemotherapy, and subsequent work has confirmed these observations in multiple cancer sites and treatments (Fig. 1). In advanced disease, low muscularity has been associated with poorer tolerance to chemotherapy in patients with breast⁽Reference Prado, Baracos and McCargar^71, Reference Shachar, Deal and Weinberg⁷²⁾, renal⁽Reference Cushen, Power and Teo^56, Reference Antoun, Baracos and Birdsell^73, Reference Huillard, Mir and Peyromaure⁷⁴⁾, liver⁽Reference Mir, Coriat and Blanchet⁷⁵⁾, lung⁽Reference Sjøblom, Grønberg and Benth⁷⁶⁾, colorectal⁽Reference Barret, Antoun and Dalban^55, Reference Chemama, Bayar and Lanoy⁷⁷⁾, thyroid⁽Reference Massicotte, Borget and Broutin⁷⁸⁾ and melanoma skin cancer⁽Reference Daly, Power and O'Reilly^4, Reference Valentine, François and Nora⁷⁹⁾. Sarcopenia, in patients with peritoneal metastasis from colorectal cancer, was associated with significantly more chemotherapy toxicities (57 v. 26 %, P = 0·004) and particularly neutropenia (36 v. 17 %, P = 0·04) in a cohort of 97 patients receiving hyperthermic intraperitoneal chemotherapy.

Fig. 1. Sarcopenic patients experience more dose-limiting toxicities (DLT) to flurouracil (5-FU) in colon cancer⁽Reference Prado, Baracos and McCargar⁸⁰⁾; capecitabine in breast cancer⁽Reference Prado, Baracos and McCargar⁷¹⁾; sorafenib in renal cell carcinoma⁽Reference Antoun, Baracos and Birdsell⁷³⁾; 5-flurouracil, epirubicin, cyclophosphamide (FEC) in breast cancer⁽Reference Prado, Lima and Baracos⁹⁰⁾; sorafenib in hepatocellular carcinoma⁽Reference Mir, Coriat and Blanchet⁷⁵⁾; sunitunib in renal cell carcinoma⁽Reference Huillard, Mir and Peyromaure⁷⁴⁾; vantetanib in medullary thyroid cancer⁽Reference Massicotte, Borget and Broutin⁷⁸⁾; fluropyramidine in colorectal cancer⁽Reference Barret, Antoun and Dalban⁵⁵⁾; phase I drugs in mixed cancer types⁽Reference Cousin, Hollebecque and Koscielny¹⁷⁷⁾; imatinib in gastrointestinal stromal tumours (grade I–II toxicity)⁽Reference Moryoussef, Dhooge and Volet¹⁷⁶⁾; epirubicin, cisplatin, capecitabine (ECX) and cisplatin, 5-flurouracil (CF) in oesophagogastric cancer⁽Reference Tan, Brammer and Randhawa⁸⁴⁾; taxane-based chemotherapy (placitaxel, docetaxel, nab-paclitaxel) in breast cancer⁽Reference Shachar, Deal and Weinberg⁷²⁾; hyperthermic intraperitoneal chemotherapy (oxaliplatin and irrinotecan) in colorectal cancer⁽Reference Chemama, Bayar and Lanoy⁷⁷⁾, neoadjuvant chemotherapy (NACT) (mixed types) in gastric cancer⁽Reference Palmela, Velho and Agostinho⁸¹⁾; ipilimumab in metastatic melanoma⁽Reference Daly, Power and O'Reilly⁴⁾.

Even in early-stage disease (stages I–III), sarcopenia is associated with poorer tolerance to chemotherapy⁽Reference Cespedes Feliciano, Lee and Prado^2, Reference Prado, Baracos and McCargar^80–Reference Tan, Brammer and Randhawa⁸⁴⁾. Interestingly, in patients with early-stage breast cancer (n 151) and receiving anthracycline- and taxane-based chemotherapy, with every five-unit decrease in SMI, the risk of any grade III–IV toxicity increased by 27 % (relative risk 1·27 (95 % CI 1·09, 1·49), P = 0·002)⁽Reference Shachar, Deal and Weinberg⁸²⁾. In a large study of patients with non-metastatic colon cancer (n 533) treated with adjuvant FOLOX treatment, patients with low muscle mass (lowest sex-specific tertile) were twice as likely to experience dose reductions (OR 2·28, P = 0·01), dose delays (OR 2·24, P = 0·002) and early discontinuation of treatment (OR 2·34, P = 0·03)⁽Reference Cespedes Feliciano, Lee and Prado²⁾. Although the majority of studies have consistently demonstrated an association between low muscle mass and increased incidence of severe toxicity/DLT (twenty-six of thirty-two studies; see Supplementary material for summary of each study), fewer small studies found contradictory findings⁽Reference Yip, Goh and Davies^85–Reference Blauwhoff-Buskermolen, Versteeg and de van der Schueren⁸⁸⁾.

Emerging data suggest low MA to be also associated with poorer tolerance to antineoplastic agents⁽Reference Daly, Power and O'Reilly^4, Reference Cushen, Power and Murphy^66, Reference Shachar, Deal and Weinberg⁸²⁾. In metastatic melanoma patients (n 84), we have previously shown that patients with low MA more frequently experienced high-grade toxicities (75 v. 31 %, P = 0·001) and immune-related toxicities to ipilimumab (54 v. 23 %, P = 0·017) compared with those without low MA. More importantly, these patients were more susceptible to experience a DLT (37·5 v. 10·4 %, P = 0·011)⁽Reference Daly, Power and O'Reilly⁴⁾. In patients with metastatic prostate cancer treated with docetaxel (n 63), a combination of both low muscle mass and low MA was associated with an increased risk of DLT (59 v. 29 %, P = 0·021)⁽Reference Cushen, Power and Murphy⁶⁶⁾. Similarly, in early-stage disease, Shachar et al. ⁽Reference Shachar, Deal and Weinberg⁸²⁾ demonstrated that in breast cancer (n 151), the risk of hospitalisations due to chemotherapy toxicity increased 19 % with every five-unit decrease in MA (relative risk 1·19 (95 % CI 1·00, 1·43), P = 0·05).

Increased toxicity in patients with sarcopenia may be attributed to alterations in the distribution, metabolism and clearance of systemic chemotherapy drugs⁽Reference Prado, Baracos and McCargar⁸⁰⁾. The practice of administration of cytotoxic chemotherapy based on body surface area, and targeted therapy as a flat dose, ignores several sources of inter-individual variation. Using body surface area as the only method to individualise chemotherapy drug dose is insufficient to avoid severe toxicity, but the continued use mainly relies on the lack of other more precise methods for dose individualisation⁽Reference Felici, Verweij and Sparreboom⁸⁹⁾. It is recently acknowledged that variability in body composition (lean mass, fat mass and total body water) of cancer patients may be a source of disparities in the metabolism of cytotoxic agents resulting in increased toxicity⁽Reference Antoun, Baracos and Birdsell^73, Reference Prado, Baracos and McCargar^80, Reference Prado, Lima and Baracos⁹⁰⁾. The rationale is that body weight comprises two major compartments, lean mass and fat mass, which may be the two major sites of distribution of hydrophilic and lipophilic drugs, respectively⁽Reference Prado, Baracos and McCargar^80, Reference Prado, Baracos and Xiao⁹¹⁾. Therefore, changes in body composition may lead to changes in the volume of distribution and adversely impact the effectiveness and tolerance of cancer therapies.

Administration of hydrophilic chemotherapy drugs that are mainly distributed to the lean mass compartment in sarcopenic patients would result in a disproportionally small volume of the drug distribution in relation to their body weight or body surface area⁽Reference Prado, Baracos and McCargar^71, Reference Prado, Baracos and McCargar⁸⁰⁾. This has been hypothesised to lead to considerable variation in milligram of chemotherapeutic agent per kg lean mass, and a higher dose per kg lean mass is associated with more frequent severe toxic side effects⁽Reference Sjøblom, Grønberg and Benth^76, Reference Prado, Baracos and McCargar^80, Reference Ali, Baracos and Sawyer^92, Reference Sjøblom, Benth and Grønberg⁹³⁾. In patients with advanced non-small-cell lung cancer (n 424), when the dose of non-platinum drugs was expressed as mg/kg lean mass, a 3-fold range was observed, and the dose of non-platinum chemotherapeutic agent per kg lean mass was a significant predictor of haematologic toxicity. Every 1 % increase in drug dose per kg lean mass above the mean was associated with a 3 % increased risk of grade III–IV haematologic toxicity, while patients with doses >20 % above the mean were at almost double the risk of experiencing a grade III–IV haematologic toxicity⁽Reference Sjøblom, Benth and Grønberg⁹³⁾. Pharmacokinetic data have supported this hypothesis, with sarcopenic patients experiencing higher plasma concentrations of antineoplastic drugs, and experiencing more toxicity⁽Reference Mir, Coriat and Blanchet^75, Reference Massicotte, Borget and Broutin⁷⁸⁾. The same hypothesis holds true for toxicity to lipophilic drugs. In a study of ovarian cancer patients receiving doxorubicin and trabectedin, the risk of DLT decreased with increased fat mass:lean mass ratio. As lipophilic drugs are mainly distributed in the adipose tissue, leaner individuals would present with reduced volume of distribution for the drug and consequently increase their risk for DLT⁽Reference Prado, Baracos and Xiao⁹¹⁾.

In addition to the pharmacokinetic hypothesis to explain the increased toxicity in sarcopenic patients, other mechanisms have been suggested. Low levels of lean mass and altered concentration of plasma proteins (e.g. albumin) may affect the distribution of highly protein-bound drugs, and may explain the increased toxicity of the vandetanib⁽Reference Massicotte, Borget and Broutin⁷⁸⁾, sorafenib⁽Reference Mir, Coriat and Blanchet⁷⁵⁾ and epirubicin⁽Reference Prado, Lima and Baracos⁹⁰⁾. Systemic inflammation is known to inhibit hepatic enzymes and may contribute to higher drug exposure, and subsequently excess toxicity in patients with sarcopenia⁽Reference Mir, Coriat and Blanchet^75, Reference Massicotte, Borget and Broutin⁷⁸⁾. In addition, sarcopenic patients are generally more susceptible to acute medical events and perhaps chemotherapy toxicity may be an additional generalised intolerance⁽Reference Antoun, Borget and Lanoy⁹⁴⁾. Whether altered chemotherapy dosing based on lean mass in patients receiving treatment is effective in preventing toxicity is currently being investigated (ClinicalTrials.gov identifier: NCT01624051).

Sarcopenia and survival

The impact of sarcopenia on survival in oncology was first identified in a cohort of 250 obese lung and GI cancer patients by Prado et al. in 2008⁽Reference Prado, Lieffers and McCargar¹⁹⁾. Within this study, sarcopenic obese patients had a lower median overall survival compared with their non-sarcopenic counterparts (11·3 v. 21·6 months, P < 0·001), and sarcopenic obesity independently predicted survival when adjusted for known prognostic covariates (hazard ratio (HR) 4·2 (95 % CI 2·4, 7·2), P < 0·0001)⁽Reference Prado, Lieffers and McCargar¹⁹⁾. Since then, sarcopenia has repeatedly been shown to be independently prognostic of reduced survival in a number of cancer sites and stages including pancreatic⁽Reference Tan, Birdsell and Martin⁹⁵⁾, kidney⁽Reference Sharma, Zargar-Shoshtari and Caracciolo^96, Reference Fukushima, Nakanishi and Kataoka⁹⁷⁾, liver⁽Reference Meza-Junco, Montano-Loza and Baracos^98–Reference Levolger, van Vledder and Muslem¹⁰⁰⁾, lung⁽Reference Kim, Kim and Park¹⁰¹⁾, oesophageal⁽Reference Tamandl, Paireder and Asari²⁸⁾, colorectal⁽Reference Miyamoto, Baba and Sakamoto^41, Reference van Vledder, Levolger and Ayez^54, Reference Malietzis, Currie and Athanasiou⁷⁰⁾, urothelial⁽Reference Psutka, Carrasco and Schmit^102, Reference Fukushima, Yokoyama and Nakanishi¹⁰³⁾ and lung and GI cancers⁽Reference Martin, Birdsell and Macdonald¹⁾. Its important prognostic ability was reported in a study of 196 patients following resection for colorectal cancer liver metastases, whereby sarcopenic patients had a median survival of 24 months, which was in stark contrast to 60 months in those without sarcopenia (P < 0·001)⁽Reference van Vledder, Levolger and Ayez⁵⁴⁾. In patients with hepatocellular carcinoma (n 116), similar results were obtained with a median survival of 16 months in patients with sarcopenia compared with 28 months in those without sarcopenia (P = 0·003)⁽Reference Meza-Junco, Montano-Loza and Baracos⁹⁸⁾. More recently, a large cohort of stage I–III colorectal cancer patients (n 3262) showed that sarcopenic patients had a 27 % higher risk of overall mortality than their non-sarcopenic counterparts⁽Reference Caan, Meyerhardt and Kroenke³⁰⁾.

The impact of sarcopenia on survival has been extensively reviewed previously⁽Reference Shachar, Williams and Muss^104–Reference Gibson, Burden and Strauss¹⁰⁶⁾ and of note is a recent systematic review and meta-analysis⁽Reference Shachar, Williams and Muss¹⁰⁴⁾, which examined the prognostic value of sarcopenia in 7843 patients with solid tumours from a total of thirty-eight studies. Sarcopenia was found to be associated with poor overall survival (HR 1·44 (95 % CI 1·32, 1·56), P < 0·001), the effect of which remained in various tumour types and across disease stages. Additionally, sarcopenia was associated with cancer-specific survival (HR 1·93 (95 % CI 1·38, 2·70), P < 0·001), as well as disease-free survival (HR 1·16 (95 % CI 1·00, 1·30), P = 0·014). However, it is noteworthy to mention the limitations of this study. The authors included several studies in the review that contained duplicated data, and this is prohibited in a meta-analysis as it may lead to overestimation of an effect⁽Reference Tramèr, Reynolds and Moore¹⁰⁷⁾. In addition, the studies were largely heterogeneous in terms of the tumours considered, stage of disease, treatments and cut points used to define sarcopenia, which ranged from 29 to 42·1 cm²/m² in women and 36 to 55·4 cm²/m² in men⁽Reference Shachar, Williams and Muss¹⁰⁴⁾.

In spite of the abundance of evidence supporting the role of sarcopenia as an important and independent prognostic factor in cancer, this finding has not always been consistently reported and several studies have reported no impact on survival⁽Reference Van Rijssen, van Huijgevoort and Coelen^16–Reference Sjøblom, Grønberg and Wentzel-Larsen^18, Reference Stene, Helbostad and Amundsen^37, Reference Rollins, Tewari and Ackner^68, Reference Blauwhoff-Buskermolen, Versteeg and de van der Schueren⁸⁸⁾. It is possible that the impact of sarcopenia may vary depending on cancer diagnosis, treatment and overall prognosis. For example, in colorectal cancer patients, sarcopenia was shown to be predictive of survival in patients undergoing curative resection⁽Reference Miyamoto, Baba and Sakamoto⁴¹⁾, but not in patients with unresectable disease receiving chemotherapy⁽Reference Miyamoto, Baba and Sakamoto¹⁰⁸⁾. Alternatively, this may be a consequence of the choice of cut points to define sarcopenia in many of these studies. As discussed earlier, cut points obtained in different studies are highly dependent on the methodology and the population from which they were devised, and when used in dissimilar populations, they may represent a suboptimal approach in identifying the true prevalence of low muscle mass and its relationship to survival within these cohorts.

Muscle quality v. quantity

Low MA, often referred to as myosteatosis, is emerging as an important prognostic indicator in patients with cancer and in some cases more superior to predicting survival compared with muscle mass alone⁽Reference Chu, Lieffers and Ghosh^12–Reference Sjøblom, Grønberg and Wentzel-Larsen¹⁸⁾. The first report by Sabel et al. ⁽Reference Sabel, Lee and Cai¹⁰⁹⁾ in melanoma patients showed poorer disease-free survival (P = 0·04) and distant disease-free survival (P = 0·0002) in patients with the lowest tertile of psoas MA. Antoun et al. ⁽Reference Antoun, Lanoy and Iacovelli⁶⁴⁾ corroborated these findings in a cohort of metastatic renal cell carcinoma patients, and reported that the median survival of patients with a MA below the median (<38 HU in men; <36 HU in women) was half that of those with MA above the median (29 v. 14 months, P = 0·001). In a large cohort of 1473 patients with lung and GI cancer, Martin et al. ⁽Reference Martin, Birdsell and Macdonald¹⁾ reported that patients with a MA below the identified cut point (<41 HU for BMI <25 kg/m² and <33 HU for BMI ≥25 kg/m²) were at a 36 % increased risk of mortality (HR 1·36 (95 % CI 1·19, 1·55), P < 0·001). Recently, low MA has been shown to be prognostic of reduced survival in a variety of different tumours, including lung⁽Reference Sjøblom, Grønberg and Wentzel-Larsen^18, Reference Bowden, Williams and Simms⁶⁰⁾, kidney⁽Reference Antoun, Lanoy and Iacovelli⁶⁴⁾, breast⁽Reference Rier, Jager and Sleijfer¹⁴⁾, gastric⁽Reference Hayashi, Ando and Gyawali¹³⁾, pancreatic⁽Reference van Dijk, Bakens and Coolsen^17, Reference Akahori, Sho and Kinoshita⁶⁵⁾, periampullary⁽Reference Van Rijssen, van Huijgevoort and Coelen¹⁶⁾, cholangiocarcinoma⁽Reference Rollins, Tewari and Ackner⁶⁸⁾, lymphoma⁽Reference Chu, Lieffers and Ghosh^12, Reference Chu, Lieffers and Ghosh¹⁵⁾ and melanoma⁽Reference Sabel, Lee and Cai¹⁰⁹⁾. In a cohort of 734 patients with advanced lung cancer, Sjøblom et al. ⁽Reference Sjøblom, Grønberg and Wentzel-Larsen¹⁸⁾ reported that even minor changes in MA are associated with mortality risk. An incremental increase of 1 HU was associated with a 2 % reduction in the risk of death (HR 0·98 (95 % CI 0·97, 0·99), P < 0·001). Accordingly, the mortality risk reduction of a 5 HU and 10 HU increase in MA were 8 % and 16 %, respectively⁽Reference Sjøblom, Grønberg and Wentzel-Larsen¹⁸⁾.

Sarcopenia, low muscle attenuation and post-operative outcomes

Sarcopenia has also been identified as a predictor of post-operative infections, complications, readmissions, longer length of hospital stay and higher health care costs⁽Reference van Vugt, Braam and van Oudheusden^3, Reference Levolger, van Vledder and Muslem^100, Reference Lieffers, Bathe and Fassbender^110–Reference Sharma, Zargar-Shoshtari and Caracciolo¹¹⁴⁾. Elliott et al. ⁽Reference Elliott, Doyle and Murphy⁴⁰⁾ demonstrated that sarcopenia, in a cohort of 252 patients with oesophageal cancer undergoing resection, was independently associated with increased risk of major postoperative complications (grade ≥IIIb; OR 5·30 (95 % CI 1·94, 14·45), P = 0·001) and pulmonary complications (OR 2·17 (95 % CI 1·12, 4·23), P = 0·023). Similarly, in patients with colorectal cancer undergoing cytoreductive surgery for peritoneal carcinomatosis (n 206), sarcopenia was associated with severe post-operative complications, and sarcopenic patients underwent significantly more reoperations (26 v. 12 %, P = 0·012)⁽Reference van Vugt, Braam and van Oudheusden³⁾. Consequently, length of hospital stay has shown to be significantly longer in patients with sarcopenia⁽Reference Elliott, Doyle and Murphy^40, Reference Joglekar, Asghar and Mott^46, Reference Sharma, Zargar-Shoshtari and Caracciolo^96, Reference Lieffers, Bathe and Fassbender^110, Reference Peng, van Vledder and Tsai^111, Reference van Vugt, Buettner and Levolger¹¹⁵⁾. Following colorectal cancer surgery (n 234), the length of hospital stay for sarcopenic patients was 15·9 d compared with 12·3 d in patients without sarcopenia (P = 0·038)⁽Reference Lieffers, Bathe and Fassbender¹¹⁰⁾. Ultimately, adverse post-operative outcomes in patients with sarcopenia lead to increased health care costs. In a Western-Europe healthcare system, sarcopenia was independently associated with increased hospital costs of €4061 per patient (P = 0·015) in a study of 452 patients who underwent cancer surgery of the alimentary tract⁽Reference van Vugt, Buettner and Levolger¹¹⁵⁾.

Akin to sarcopenia, low MA is emerging as a predictor of poor post-operative outcomes⁽Reference Van Rijssen, van Huijgevoort and Coelen^16, Reference Boer, de Graaff and Brusse-Keizer^44, Reference Sabel, Lee and Cai^109, Reference Margadant, Bruns and Sloothaak¹¹⁶⁾. In patients with colon cancer undergoing open resection (n 91), low MA was an independent risk factor for one or more complications (P < 0·001)⁽Reference Boer, de Graaff and Brusse-Keizer⁴⁴⁾. Van Rijssen et al. ⁽Reference Van Rijssen, van Huijgevoort and Coelen¹⁶⁾ reported similar findings, whereby patients with low MA experienced significantly more major post-operative complications (58 v. 37 %, P = 0·005) following resection for periampullary cancer (n 166) compared with those without low MA. Examining MA as a continuous variable, Sabel et al. ⁽Reference Sabel, Lee and Cai¹⁰⁹⁾ reported that a 10 HU decrease in psoas MA was associated with an 8·1 % increase in complication rate in patients with stage III melanoma (n 101). In line with this, low MA was associated with prolonged length of hospital stay following colorectal cancer surgery in a large cohort of 805 patients (7 v. 6 d (P = 0·034))⁽Reference Malietzis, Currie and Athanasiou⁷⁰⁾, and to a greater extent following pancreatic cancer resection, whereby patients with low MA (post-neoadjuvant chemoradiotherapy) had a mean length of stay of 42 d compared with 23 d in those without low MA (P = 0·001)⁽Reference Akahori, Sho and Kinoshita⁶⁵⁾.

Muscle loss during chemotherapy

The precision associated with CT analysis of body composition (1–1·5 %) has allowed recent investigations to focus on the nature and magnitude of changes in body composition during the disease trajectory in patients with cancer. Studies have consistently shown that losses in muscle mass and MA are exacerbated by antineoplastic treatment⁽Reference Palmela, Velho and Agostinho^81, Reference Blauwhoff-Buskermolen, Versteeg and de van der Schueren^88, Reference Prado, Sawyer and Ghosh^117–Reference Reisinger, Bosmans and Uittenbogaart¹¹⁹⁾. In oesophagogastric cancer patients, neoadjuvant chemotherapy treatment which is typically delivered over a 6–8-week period can decrease SMA by 9·59 cm² (P < 0·0001), which is the equivalent to a loss of 2·9 kg of lean mass⁽Reference Awad, Tan and Cui¹¹⁸⁾. These results have been corroborated in a study of 252 oesophageal cancer patients, whereby the prevalence of sarcopenia almost doubled (15·9–30·8 %) during a course of neoadjuvant chemotherapy⁽Reference Elliott, Doyle and Murphy⁴⁰⁾.

In patients with cancer, muscle is lost at a very high rate of 3–5 % per 100 d during systemic chemotherapy⁽Reference Daly, Power and O'Reilly^4, Reference Dalal, Hui and Bidaut^36, Reference Rutten, van Dijk and Kruitwagen^43, Reference Tan, Birdsell and Martin⁹⁵⁾, and losses are exponentially increased with progressive disease and proximity to death⁽Reference Prado, Sawyer and Ghosh^117, Reference Lieffers, Mourtzakis and Hall¹²⁰⁾. In a recent study of metastatic colorectal cancer patients (n 63), on average patients lost muscle at a rate of 6·1 % during 3 months of chemotherapy⁽Reference Blauwhoff-Buskermolen, Versteeg and de van der Schueren⁸⁸⁾; it is noteworthy that the rate of decline is 24-fold more rapid than that observed in healthy ageing adults who tend to lose muscle at a rate of 1–1·4 % per year⁽Reference Goodpaster, Park and Harris^6, Reference Frontera, Hughes and Fielding¹²¹⁾.

Alterations in muscle mass may be a consequence of some cancer-directed therapies. Sorafenib, a multi-kinase inhibitor, has been shown to provoke muscle wasting in metastatic renal cell carcinoma patients, through the downstream suppression of PI3K, AKTm and mTOR, key mediators in activating muscle protein synthesis by amino acids and other stimuli⁽Reference Antoun, Birdsell and Sawyer³⁸⁾. Abiraterone⁽Reference Pezaro, Mukherji and Tunariu¹²²⁾ and MK-0646 (anti-insulin-like growth factor 1 receptor)⁽Reference Fogelman, Holmes and Mohammed¹²³⁾ have also been reported to stimulate muscle loss through maximal androgen suppression and inhibition of anti-insulin-like growth factor 1 receptor, respectively. In contrast, two chemotherapy agents (vandetanib and selumetinib) have resulted in significant muscle gain in patients with advanced cancer⁽Reference Massicotte, Borget and Broutin^78, Reference Prado, Bekaii-Saab and Doyle¹²⁴⁾.

Loss of muscle during systemic anti-cancer treatment is associated with increased mortality in patients with pancreatic⁽Reference Dalal, Hui and Bidaut^36, Reference Cooper, Slack and Fogelman¹²⁵⁾, lung⁽Reference Stene, Helbostad and Amundsen^37, Reference Nattenmüller, Wochner and Muley¹²⁶⁾, colorectal⁽Reference Blauwhoff-Buskermolen, Versteeg and de van der Schueren^88, Reference Miyamoto, Baba and Sakamoto¹⁰⁸⁾, ovarian⁽Reference Rutten, van Dijk and Kruitwagen⁴³⁾, melanoma⁽Reference Daly, Power and O'Reilly⁴⁾ and foregut cancer⁽Reference Daly, Ní Bhuachalla and Power¹²⁷⁾ (see Table 3 for a summary of available studies reporting that muscle loss during treatment is prognostic of reduced survival). Loss of muscle >2 %/100 d was independently associated with reduced survival in ovarian cancer patients receiving neoadjuvant chemotherapy (n 123; HR 1·77 (95 % CI 1·02, 3·09), P = 0·043)⁽Reference Rutten, van Dijk and Kruitwagen⁴³⁾, and we have previously reported that in patients with advanced cancers of the foregut, those with a skeletal muscle loss >6 %/100 d are at more than double the risk of mortality (HR 2·66 (95 % CI 1·42, 4·97), P = 0·002)⁽Reference Daly, Ní Bhuachalla and Power¹²⁷⁾. Importantly, skeletal muscle depletion during chemotherapy has also been associated with reductions in physical function in elderly patients with advanced non-small-cell lung cancer ⁽Reference Naito, Okayama and Aoyama¹²⁸⁾.

Table 3. Summary of studies reporting muscle loss during treatment as prognostic of reduced survival

IQR, interquartile range; NSC, non-small cell; SM, skeletal muscle; SMA, skeletal muscle area; HR, hazard ratio; SMI, skeletal muscle index; se, standard error; OS, overall survival.

Nutritional interventions

A meta-analysis of oral nutritional interventions in malnourished patients with cancer identified thirteen randomised controlled trials and included 1414 patients. The analysis, conducted by Baldwin et al. ⁽Reference Baldwin, Spiro and Ahern¹³³⁾, concluded that oral nutritional interventions had no significant effect on body weight, energy intake or mortality compared with standard care. Given the wide range of pathophysiological alterations that occur in cancer, complex and individualised targeted strategies incorporating modulations of the metabolic components of cachexia (e.g. inflammation) may be required to allow nutrition interventions to be more effective⁽Reference Arends, Baracos and Bertz¹³⁴⁾. To date, n-3 fatty acids, such as EPA have received a lot of attention for the treatment of cancer cachexia due to their potent anti-inflammatory properties. In cancer, plasma n-3 fatty acid levels appear to be depleted in patients with sarcopenia and may contribute to accelerate muscle mass⁽Reference Murphy, Mourtzakis and Chu¹³⁵⁾. The results of several small clinical trials suggested that using EPA supplements or oral nutritional supplements containing EPA in patients with advanced cancer improved appetite, energy intake, body weight, lean mass and/or physical activity⁽Reference Silva, Trindade and Fabre^136–Reference Ryan, Reynolds and Healy¹³⁹⁾. The n-3 fatty acid supplementation has also been shown to be effective in reducing intramuscular adipose tissue while maintaining muscle mass (compared with standard care) in a small cohort of patients with non-small-cell lung cancer⁽Reference Murphy, Mourtzakis and Chu¹³⁸⁾, supporting what is observed in preclinical experimental animal models⁽Reference Almasud, Giles and Miklavcic¹⁴⁰⁾. However, the clinical evidence supporting n-3 fatty acids remain inconclusive. Three systematic reviews published in 2007, 2009 and 2012 concluded that there was insufficient evidence to support a recommendation for n-3 fatty acids to treat muscle depletion and cancer cachexia⁽Reference Ries, Trottenberg and Elsner^141–Reference Arends, Bachmann and Baracos¹⁴⁴⁾. Due to the inconsistencies in the reported effects of n-3 fatty acids⁽Reference Fearon, Barber and Moses^145, Reference Jatoi, Rowland and Loprinzi¹⁴⁶⁾, the ESPEN oncology nutrition guidelines issue only a weak recommendation for their use to stabilise or improve appetite, food intake, lean mass and body weight⁽Reference Arends, Bachmann and Baracos¹⁴⁴⁾.

Achieving adequate protein intake is an essential component to achieving muscle anabolism; however, no optimal amino acid and protein requirements have been established to prevent or treat sarcopenia in patients with cancer. Current recommendations suggest intakes of 1–1·5 g/kg/d in patients with cancer⁽Reference Arends, Bachmann and Baracos¹⁴⁴⁾; however, many patients fail to reach these requirements⁽Reference Prado, Lieffers and Bergsten¹⁴⁷⁾. Moreover, recent research has suggested that protein requirements should be based on the measures of lean mass as opposed to body weight⁽Reference Geisler, Prado and Müller^148, Reference Prado, Cushen and Orsso¹⁴⁹⁾.

Physical activity

A recent meta-analysis⁽Reference Padilha, Marinello and Galvão¹⁵⁰⁾ has shown resistance exercise to be effective in increasing muscle strength and mass in cancer patients undergoing neoadjuvant and adjuvant therapy, with mean increases in lower limb strength of 26·2 kg (P = 0·00001) and lean mass by 0·8 kg (P < 0·00001)⁽Reference Padilha, Marinello and Galvão¹⁵⁰⁾. In a study of early-stage breast cancer patients receiving adjuvant chemotherapy, resistance exercise resulted in the reversal of sarcopenia and dynapenia in 43 and 59 % of patients, respectively⁽Reference Adams, Segal and McKenzie¹⁵¹⁾. To date, most studies have been conducted in early-stage breast and prostate cancer and evidence of the effect of physical activity on muscle mass and strength in patients with advanced disease and cancer cachexia is lacking⁽Reference Stene, Helbostad and Balstad^152, Reference Grande, Silva and Maddocks¹⁵³⁾. A recent Cochrane systemic review⁽Reference Grande, Silva and Maddocks¹⁵³⁾, which aimed to examine the impact of exercise on lean mass in patients with cancer cachexia, showed disappointing results. The authors screened more than 3000 individual articles, but found no trials that met the inclusion criteria for analysis⁽Reference Grande, Silva and Maddocks¹⁵³⁾. Initial findings indicate that exercise is safe and well tolerated in patients with advanced disease⁽Reference Heywood, McCarthy and Skinner¹⁵⁴⁾ and improves physical performance and several domains of quality of life⁽Reference Salakari, Surakka and Nurminen¹⁵⁵⁾, but further work is needed. Evidence of interventions aimed at improving MA in patients with cancer are scarce; however, evidence in older adults suggests that exercise may represent a counter measure to improve MA, as studies have shown that muscle fatty infiltration is amenable to change after 12 weeks of thrice-weekly resistance training⁽Reference Marcus, Addison and Kidde¹³⁰⁾.

Recently, a few studies have demonstrated that exercise interventions are capable of improving cancer outcomes. Cho et al. ⁽Reference Cho, Yoshikawa and Oba¹⁵⁶⁾ reported that preoperative exercise significantly improved operative risk factors and decreased the frequency of serious postoperative complications in gastric cancer patients. In breast cancer, a supervised moderate- to high-intensity exercise programme during adjuvant chemotherapy was associated with a beneficial effect on chemotherapy completion rates with a significantly smaller proportion of patients requiring dose adjustments compared with usual care (12 v. 34 %)⁽Reference van Waart, Stuiver and van Harten¹⁵⁷⁾. The impact of exercise prehabilitation on cancer outcome warrants further investigation.

Pharmacological agents

To date, no pharmacotherapies have been approved to specifically treat the cancer cachexia syndrome. Non-steroidal anti-inflammatory drugs have been suggested as a potential treatment for cancer cachexia, with the aim of reducing systemic inflammation. In a recent systematic review of thirteen studies, eleven showed either improvement or stabilisation in weight or lean mass in patients with cancer⁽Reference Solheim, Fearon and Blum¹⁵⁸⁾; however, the evidence is still insufficient to recommend non-steroidal anti-inflammatory drugs to treat cancer cachexia outside of clinical trials. Promising results have been obtained for anamorelin (a ghrelin receptor agonist); phase III trials (ROMANA 1 and ROMANA 2) have shown that anamorelin significantly increases lean mass and improves anorexia/cachexia symptoms compared with placebo over a 12-week intervention period. However, muscle function (measured by hand grip strength) failed to improve during the intervention⁽Reference Temel, Abernethy and Currow¹⁵⁹⁾. Food and drug administration regulators generally require improvements in lean mass and functional outcomes as co-primary endpoints for the approval of new medications to treat cancer cachexia. As a result, anamorelin has not received the food and drug administration's approval to date. Phase III trials have recently been completed for enobosarm, a selective androgen receptor modulator (NCT01355484), and MABp1, an anti Il-1 α monoclonal antibody (NCT01767857), the results of which are yet to be published.

Multimodal interventions

Results so far suggest that single-agent therapies may be insufficient to counteract cancer cachexia and that early multimodal interventions may be necessary to combat its multifactorial and complex pathogenesis. A multimodal approach including the use of individualised nutritional interventions to promote energy balance and ensure optimal protein intake, decreasing inflammation and hyper metabolic stress with the aid of anti-inflammatory agents (non-steroidal anti-inflammatory drugs s and EPA) and increasing physical activity to stabilise/increase muscle mass, strength and physical performance has been recommended⁽Reference Arends, Baracos and Bertz¹³⁴⁾. One such intervention currently under investigation is the MENAC trial (Multimodal Exercise/Nutrition/Anti-inflammatory treatment for Cachexia), whereby phase II feasibility studies have yielded encouraging results and suggest multimodal interventions are feasible and safe in patients with cancer⁽Reference Solheim, Laird and Balstad¹⁶⁰⁾. The phase III trial (NCT02330926) is currently being conducted across a number of international sites.