Skeletal muscle anabolism in patients with advanced cancer

Skeletal muscle anabolism in patients with advanced cancer Since oncologists have begun to deploy tissue-specifi c measurements of body composition,1 the loss of skeletal muscle—with or w

Only the choice of a PFS endpoint makes the success

of this rationally designed study evident, allowing it to

fi nally add to the therapeutic armamentarium against

osteosarcoma Osteosarcoma is a rare disease, and it is

diffi cult to do a study including 50–100 patients With

the 37 patients that the investigators could accrue to

the trial, the study design chosen could detect only a

large improvement over the result with sorafenib alone

on the basis of their previous trial; accordingly they let

the realities of accrual rather than realistic expectations

drive the extent of improvement they could detect The

study design chose a null hypothesis of 25% 6-month

PFS (sorafenib alone gave 30%) and a target alternative

hypothesis of 50% 6-month PFS Grigani and colleagues

noted a 6-month PFS of 45%, which would lead

statistical purists to still call the study negative because

the target was not reached, but the authors argue

convincingly that the result represents a step forward

Improved study designs are needed for rare tumours

It should not be necessary to double the 6-month PFS to

classify results as positive A simple Bayesian design to

estimate the distribution of the posterior probability of

the 6-month PFS would probably be the best strategy

to deal with the small number of patients available for

study The more patients available for study, the more accurately the distribution is defi ned If exclusion of a lower limit of the desired endpoint is preferred, a lower level of statistical signifi cance should be used in the study of rare tumours or an adjustable target accrual should be used so that if the new treatment seems better after initial accrual is reached, it would be possible

to expand and extend the existing study

Robert S Benjamin

Department of Sarcoma Medical Oncology, The University of Texas

MD Anderson Cancer Centre, Houston, TX, USA

I declare no competing interests.

1 Grignani G, Palmerini E, Ferraresi V, et al Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after

standard treatment: a non-randomised phase 2 clinical trial Lancet Oncol

2015; 16: 98–107.

2 Fox E, Patel S, Wathen JK, et al Phase II study of sequential gemcitabine followed by docetaxel for recurrent Ewing sarcoma, osteosarcoma, or unresectable or locally recurrent chondrosarcoma: results of Sarcoma

Alliance for Research through Collaboration Study 003 Oncologist 2012;

17: 321.

3 Grignani G, Palmerini E, Dileo P, et al A Phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of

standard multimodal therapy: an Italian Sarcoma Group study Ann Oncol

2012; 23: 508–16.

4 Rosen G, Marcove RC, Caparros B, et al Primary osteogenic sarcoma: the

rationale for preoperative chemotherapy and delayed surgery Cancer 1979:

43: 2163–77.

Skeletal muscle anabolism in patients with advanced cancer

Since oncologists have begun to deploy tissue-specifi c

measurements of body composition,1 the loss of

skeletal muscle—with or without loss of fat—has

emerged as the main facet of cachexia that predicts risk

of physical impairment, post-operative complications,

chemotherapy toxicity, and mortality in patients with

cancer Preclinical studies provide evidence in principle

that such muscle loss and the detriments associated

with it can be reversed In laboratory animals,

cancer-associated muscle loss is a pathophysiological entity

involving specifi c signals (eg, MIC-1/GDF15, PTHrP,2

and myostatin3); such muscle loss is preventable—and

reversible—by agents targeting these signals A key

fi nding is that cancer-associated muscle wasting can

be substantially uncoupled from the progression of

the underlying disease Zhou and colleagues3 provide

a case in point: the activin IIB receptor (ActRIIB)

mediates antiproliferative and catabolic eff ects on

muscle and pharmacological blockade of these actions

by a decoy receptor resulted in muscle hypertrophy, enhanced strength, and extended survival, even in the setting of progressive disease Such fi ndings defi ne the rationale for placing muscle as the therapeutic target4

and gain of muscle mass as the fi rst primary outcome4,5

of new cachexia treatments currently in phase 2/3 clinical trials

The question thus arises: do patients with advanced cancer possess exploitable anabolic potential?6

Proponents of anticachexia therapy would say yes, but this complex clinical entity is distant from the controlled setting of the laboratory Equally tenable is the assumption that old age, poor nutritional status, deconditioning, infl ammation, cancer, and comorbid conditions would preclude reversal of muscle wasting

Patients with cancer are typically older and thus have

a propensity to lose muscle mass and function rapidly during periods of inactivity.7 Further catabolic losses of muscle are induced by many types of cancer therapy

December 16, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71185-4

See Articles page 108

However, several reports have shown muscle mass gains in patients with advanced cancer receiving new anticachexia therapeutics José Garcia and colleagues

in The Lancet Oncology5 have presented the combined results of two phase 2 trials of anamorelin (an orally bioavailable, small-molecule ghrelin mimetic with appetite-stimulating and anabolic activities)

as an anticachexia therapy Anamorelin binds to and stimulates the growth hormone secretagogue receptor centrally, mimicking the appetite-stimulating and growth hormone-releasing eff ects of ghrelin

Anamorelin treatment for 12 weeks increased lean body mass detected by dual energy x-ray compared with placebo (least-squares mean diff erence 2·09 kg, 95% CI 0·94–3·25; p=0·0006) Anamorelin also improved appetite, bodyweight, handgrip strength, and Anderson Symptom Assessment Scale scores compared with placebo Anamorelin was well-tolerated with no dose-limiting toxicities identifi ed Their study establishes that a quantitatively important net gain of lean tissue is possible and that this tissue is functional

Thus, treatment with anamorelin may provide palliation

of cachexia, an unmet need in supportive oncology

Other candidate molecules that act in a pleotropic fashion (such as ghrelin) on appetite, energy storage, and the gastrointestinal system could also stand a high chance of success in addressing this issue

Other fi ndings support the contention that robust anabolic responses are possible in cancer patients An earlier phase 2 study of the oral selective androgen

receptor modulator enobosarm induced gain of

lean body mass of median 1·5 kg (range –2·1 to 12·6, p=0·0012) in a group patients of various cancers, whereas placebo-treated controls lost lean mass.4 In a phase 2 study of patients with cholangiocarcinoma,8

selumetinib (AZD6244; ARRY-142886) induced gain

of skeletal muscle detected by CT scans The mean overall gain of total lumbar muscle cross-sectional area was 13·6 cm² (SD 11·9; equivalent to ~2·3 kg of muscle

on a whole-body basis) Muscle protein synthesis

is evidently not shut down in patients with cancer, because several studies suggest that this process is unimpaired and responsive to the dietary supply of aminoacids, albeit a somewhat higher quantity than

in younger, healthy individuals.9,10 Collectively these results refute the notion that patients with cancer of advanced stage categorically lack the potential for net

muscle anabolism This fi nding is an important step

on the path towards the fi rst approved therapy for cachexia and to the end of oncologists’ therapeutic nihilism about this condition

However, other questions need to be answered The

effi cacy of pharmacological agents to provoke gain of muscle mass might be substantially augmented through the tactical application of physical therapy and the provision of optimal nutrition As we further develop and optimise gains of muscle mass, a key outstanding challenge will be to defi ne what manner of clinical benefi t is to be expected from successful cachexia therapy For the moment, in recent trials approved by European and American regulatory authorities, clinical benefi t is defi ne as enhanced physical functioning objectively quantifi ed as either power or speed on a stair climbing test4 or handgrip strength.5 Although

no accepted standard exists to assess quality of life in relation to cachexia, after further consideration we may

fi nd agreement on the most relevant representations of clinical benefi t, from the perspective of patients whose cancer journey is burdened by cachexia

Vickie E Baracos

Department of Oncology, University of Alberta, 11560 University Avenue, Edmonton, Canada T6G1Z2

vickie.baracos@ualberta.ca

I declare no competing interests

1 Prado CM, Lieff ers JR, McCargar LJ, et al Prevalence and clinical implications

of sarcopenic obesity in patients with solid tumours of the respiratory and

gastrointestinal tracts: a population-based study Lancet Oncol 2008;

9: 629–35.

2 Kir S, White JP, Kleiner S, et al Tumour-derived PTH-related protein triggers

adipose tissue browning and cancer cachexia Nature 2014; 513: 100–04.

3 Zhou X, Wang JL, Lu J, et al Reversal of cancer cachexia and muscle wasting

by ActRIIB antagonism leads to prolonged survival Cell 2010; 142: 531–43.

4 Dobs AS, Boccia RV, Croot CC, et al Eff ects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind,

randomised controlled phase 2 trial Lancet Oncol 2013; 14: 335–45.

5 Garcia JM, Boccia RV, Graham CD, et al Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised,

placebo-controlled, double-blind trials Lancet Oncol 2014; published online Dec 16

http://dx.doi.org/10.1016/S1470-2045(14)71154-4

6 Prado CM, Sawyer MB, Ghosh S, et al Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic

potential? Am J Clin Nutr 2013; 98: 1012–19.

7 Kortebein P, Ferrando A, Lombeida J, Wolfe R, Evans WJ Eff ect of 10 days of

bed rest on skeletal muscle in healthy older adults JAMA 2007;

297: 1772–74.

8 Prado CM, Bekaii-Saab T, Doyle LA, et al Skeletal muscle anabolism is a side

eff ect of therapy with the MEK inhibitor: selumetinib in patients with

cholangiocarcinoma Br J Cancer 2012; 106: 1583–86.

9 MacDonald AJ, Johns N, Stephens NA, et al Habitual myofi brillar protein synthesis is normal in patients with upper GI cancer cachexia Clin Cancer Res 2014; published online Nov 4 DOI:10.1158/1078-0432.CCR-14-2004.

10 Winter A, MacAdams J, Chevalier S Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer

cachexia Clin Nutr 2012; 31: 765–73.