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European Journal of Integrative Medicine 3 (2011) e233–e236

Review article

Integrative nutritional approaches to loss of weight and appetite in patientswith advanced cancer

Richa Sood a, Aminah Jatoi b,∗a Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA

b Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Received 22 November 2010; accepted 6 June 2011

bstract

Loss of weight and appetite are common in patients with advanced cancer, and yet palliative options for treating this sign and symptom remain

imited. This article reviews the integrative approaches that have proven most effective to date for this sign and symptom and also discusses somef the challenges of proving efficacy of palliative therapy.

2011 Published by Elsevier GmbH.

eywords: Weight loss; Cancer; Loss of appetite

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oss of weight and appetite in cancer patients

The convergence of nutrition and cancer constitutes an impor-ant topic for patients with advanced cancer, and multiplerevious studies bear witness to this claim. Providing a majorontribution to the oncology literature, Dewys et al. pointed outhat weight loss predicts a poor prognosis for patients with can-er [1]. Whether the cancer type had been breast cancer, colonancer, prostate cancer, small-cell lung cancer, or non-small-ell lung cancer, patients who lost weight manifested a curtailedurvival compared to those who were able to maintain theireight. Importantly, this study included a multivariate analysishich demonstrated that this prognostic effect occurred inde-endently of patients’ performance status and the extent of theirumor burden. For example, among patients with non-small-cellung cancer, the difference in survival between weight-losingnd weight-maintaining patients was six weeks, but, amongatients with other cancer types, this difference was even larger.he critical threshold that defined this prognostic effect was

atient-reported weight loss of greater than 5% over the pre-eding 2 months. Although the study from Dewys and otherss important because it encompassed a dozen prospectively

∗ Corresponding author.E-mail address: jatoi.aminah@mayo.edu (A. Jatoi).

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876-3820/$ – see front matter © 2011 Published by Elsevier GmbH.oi:10.1016/j.eujim.2011.06.002

onducted clinical trials which in total included 3041 can-er patients, subsequent studies have demonstrated this sameowerful association between weight loss and poor clinical out-omes.

Why does weight loss have such a critical role that is so reveal-ng of shortened survival? Referring back to the paper above, wend that Dewys and others provided the comment, “Malnutritionould affect survival. . . by muscle wasting and susceptibility tonfections. . . much of the weight loss would be drawn from leanody tissue. . .” This statement is important because it alludeso the pathophysiological changes that occur in patients withdvanced cancer. Specifically, patients with advanced cancerisproportionately erode lean tissue. Whereas the fat compart-ent does also contract, this erosion of lean tissue is a seminal

eature of cancer-associated weight loss. It appears to be thisrosion of lean tissue that is so tightly associated with a dimin-shed survival perhaps not just from a prognostic but also a

echanistic standpoint. Kotler et al. showed that, among AIDSatients, lean tissue erosion is directly associated with a poorurvival [2]. In fact, when patients appear to have lost 40% ofheir lean tissue, it appears that they have reached a point whereife is no longer sustainable and death quickly ensues. Even

rior to reaching this threshold, patients manifest a progressiveecline in their overall functional status, struggling with per-orming a variety of otherwise simple activities of daily living.ecause lean tissue is considered a highly metabolically active

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234 R. Sood, A. Jatoi / European Journal o

ody compartment, it seems plausible that the attrition of thisody compartment would be associated with compromised func-ional status and other morbidity often observed in patients withdvanced cancer.

Although weight loss has an incontrovertibly important prog-ostic and functional effect, it is also relevant to comment uponhe importance of loss of appetite among cancer patients. If onexamines almost any list of end-of-life cancer-related symp-oms, poor appetite is on that list, and it is often near the top.ranmer et al. looked at 66 patients at the end of life, andbserved that 61% of these patients were troubled by a poorppetite [3]. Loss of appetite was among the five most dis-ressing symptoms suffered by cancer patients preceded onlyy other symptoms such as lack of energy, dry mouth, pain, andausea. Again, this line-up of symptomatology is not uniqueo the specific study from Tranmer and others; other studiesave confirmed the high prevalence of cancer-associated loss ofppetite.

In addition and very much analogous to weight loss, lossf appetite also predicts a poor prognosis. Quinten et al.xamined 1314 cancer patients and assessed appetite as wells survival [4]. Patients with better appetite scores livedonger. In fact, patients could be stratified with respect tourvival based on their appetite scores. Admittedly, many fac-ors, including changes in metabolic rate, contribute to weightoss in cancer patients, not just loss of appetite. Thus, theact that loss of appetite also predicts a poor prognosis isoteworthy.

In short, this sign of weight loss and this symptom of lossf appetite are two nutrition-related features that carry sober-ng ramifications among patients with advanced cancer. Inhe patient with advanced, treatment-refractory cancer, loss ofeight and appetite are common, and both factors lead to a wors-

ning of quality of life and a decreased survival. Saliently, thisituation is not the same as starvation, as suggested by the follow-ng four distinctions. First, in starvation one sees predominantlyloss of fat; whereas, again, in the setting of cancer-associatedeight loss, not only do patients lose fat but they also lose of aotable degree of lean tissue. Secondly, starvation is associatedith hunger; but in the setting of cancer, the exact opposite hap-ens: patients lose their appetite, and in fact this loss of appetites a notable characteristic of this whole process. Thirdly, rest-ng energy expenditure drops in the setting of starvation, but thexact opposite sometimes occurs with cancer-associated weightoss. With some cancer types, one can observe a revving up ofesting energy expenditure. Finally, in classical starvation, spe-ific mediators have not been cited, but in cancer-associated lossf weight and appetite, inflammation appears to play a criticalole and the inflammatory cytokines of tumor necrosis factor,nterleukin-1 beta, and interleukin-6 have been cited. The impor-ance of such distinction are not limited to academic interest;ancer patients and their families can derive some degree ofolace in knowing that poor oral intake does not represent aeclining will to live or a shortcoming on the part of familyembers to provide good care to the patient. It is really the

ancer that is the driving force and that explains this sign andymptom.

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grative Medicine 3 (2011) e233–e236

alliative therapy

What is the standard of care for treating cancer-associatedoss of weight and appetite? In our experience, there are too fewnstances where a patient’s advanced cancer responds favorablyo chemotherapy, but such responses are sometimes associatedith weight gain and better appetite. Unfortunately, a large per-

entage of patients with advanced cancer do not have cancershat shrink with chemotherapy and respond to the extent thate would like. Under these circumstances, the most impor-

ant aspect of patient management entails educating patients andamily members about the etiology of such end of life symptoms.uilt often permeates: guilt on the part of family members that

he prepared food does not seem good enough for the patient toat, guilt on the part of the patient because he/she is not meet-ng the family’s expectations for food intake, and guilt on theart of family members that the patient appears to be giving upecause loved ones have not been able to keep him eating andunctional. Sadly, these issues can sometimes lead to conflictithin households, compounding grief and compounding antic-

pated grief even further. Patients and family members need toe made aware that loss of weight and appetite are the fault ofhe cancer, not their own efforts. Although from afar, this con-ept appears simple to grasp, when one is in the throes of griefnd challenging family dynamics, it can be challenging for allnvolved to view this situation objectively. An extensive, hon-st discussion that involves patients and families and healthcareroviders plays an important role in helping everyone cope.

In terms of agents that may help boost appetite, two classesf agents carry proven, albeit modest, benefit: progestationalgents and corticosteroids. Multiple placebo-controlled trialsemonstrate that these agents do in fact improve appetite.ut how effective are they? After an extensive discussion that

ncludes patients, their families, and the healthcare provider,ome patients voice the opinion that they would like to try a drugo improve their appetite. In the largest placebo-controlled trialso test one of these agents, megestrol acetate, the North Centralancer Treatment Group (NCCTG) examined 133 patients withdvanced cancer and found that megestrol acetate led to appetitetimulation in 70%, whereas placebo did the same in 44% [5].

This NCCTG study illustrates several points. The first ishat megestrol acetate does work to improve appetite, as indi-ated by the statistically significant difference between groups inatient-reported appetite stimulation. The second point is that ineality, effects were modest, as suggested by 44% improvementn appetite among patients who received only placebo. If onedjusts for this placebo effect, the 70% improvement with mege-trol acetate dwarfs, appearing far less convincingly efficacious.imply put, it seems that only a minority of patients who receiveegestrol acetate achieve an improvement in appetite that occurs

s a direct result of this progestational agent. At the sameime, although megestrol acetate-treated patients did demon-trate weight gain, the use of this agent has not been associatedith an improvement in survival, particularly among patients

gents appear to augment fat and not lean tissue. In essence,he prognostic effect of loss of weight and appetite are not

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ltered by the use of such appetite-boosting agents. Finally,f one assesses global quality of life, previous studies do notemonstrate that this patient-reported endpoint is improved withegestrol acetate or with other appetite stimulants. From a clin-

cal standpoint, it is an extremely rare situation when a patienteturns after having started megestrol acetate for appetite stim-lation and declares, “I feel 100% better now.” In effect, webserve an improvement in only a single symptom, namely, lossf appetite and little more.

Thus, three tenets might be utilized to dictate the use ofuch appetite stimulants in patients with advanced cancer. Therst is the decision to prescribe an appetite stimulant must beatient driven. As reviewed above, the benefits of such agentsre quite limited; a patient must perceive a real need to achieven improvement in appetite and must realize that these benefitsre confined to an improvement in this one symptom. Secondly,hese agents should not be used if a patient truly requires nutri-ional support. Under certain circumstances, in which a patients markedly malnourished or at risk for becoming so and inhich it appears there is a large chance of tumor response

rom therapy, there may be a clear need for caloric supple-entation. Under such circumstances, resorting to an appetite

timulant to meet such caloric requirements represents an inap-ropriately indirect approach. If a patient needs calories, he orhe should be prescribed calories – either enterally or parenter-lly. Thirdly, in our opinion, the use of megestrol acetate shouldot be pursued if a patient has a history of thrombophlebitisecause this class of agents is thrombogenic, and thereforehe risk/benefit ratio appears such that the use of megestrolcetate is to high and unjustified. Other risks of megestrol acetatenclude withdrawal bleeding, impotence, and adrenal compro-

ise with abrupt discontinuation; and risks of corticosteroidsnclude adrenal compromise with abrupt withdrawal, proximaluscle weakness, risk of infection, and upper gastrointestinalucosal irritation. Taken together, such risks – although rela-

ively minor – should nonetheless prompt thought and discussionrior to prescribing such agents.

earching for better agents and circumventing pitfallshen evaluating integrative approaches

The foregoing makes an important point: we need to do bet-er in providing advanced cancer patients, who have loss ofppetite and weight, improved therapeutic options. We also needo remain committed to testing such agents to gain a handle onheir efficacy.

What are the pitfalls of evaluating therapeutic agents? Severaluch pitfalls need to be recognized. Perhaps a classic examplehat illustrates the challenges of testing new agents can be seenith the use of eicosapentaenoic acid (EPA), a fish oil derived

ntervention.Indeed, a recent perusal of the internet reveals the state-

ent, “Studies show that 2 g of EPA addresses the metabolic

hanges that cause cancer-induced weight loss” [6]. EPA hadeen considered a good remedy for a cancer-associated weightoss because this agent is thought to carry anti-inflammatoryffects and because cancer-associated weight loss appears to be

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grative Medicine 3 (2011) e233–e236 e235

riven by inflammation. In keeping with testing this hypothesis,arber et al. examined 18 pancreatic cancer patients over seveneeks as a single-arm study in which all patients received fish oil

7]. Remarkably, these patients appeared at first glance to man-fest an improvement in weight as well as an improvement inean body mass with the use of EPA. However, closer scrutinyf results suggests a need for caution. First, a notable patientrop out rate may have contributed to favorable results, makinghe point that study results can potentially appear more favorablever time if the sicker patients are not included in final analy-es. Secondly, the absence of a control arm that would allowor benchmarking outcomes can also lead to results that per-aps appear to project the intervention in a more favorable light.hirdly, in general, the genuine desire of healthcare providers

o help patients might lead to our putting a greater emphasisn favorable results from pilot studies, thus blinding us to theeed to seek rigorous outcome data. Importantly, the Barbernd others were both rigorous and cautious in presenting theirtudy results, stating that “a randomized-controlled trial woulde required to confirm the observed anticachectic effect.” Hence,lthough the results of this trial seemed promising, there is nouestion that these study results called for further testing of thisntervention – despite the internet quote provided above.

Since the study by Barber and others, well over 1000 patientsave participated in randomized trials only to show that EPAoes not provide a major positive impact in palliating cancer-ssociated loss of weight and appetite. A recent Cochraneeview went so far as to claim that there are insufficient data

o establish whether oral EPA is better than placebo [8]. Thus,lthough a variety of other palliative approaches such as mela-onin, l-carnitine, and even simple dietary counseling appearromising, the pitfalls of testing such integrative approacheshould be recognized, particularly given the grave implicationsf this sign and symptom. In our efforts to want to help canceratients, it remains important to sustain rigor in our generationnd interpretation of study results.

ummary

The convergence of nutrition and cancer is an important topicecause it affects so many patients, carries such negative ramifi-ations, and yet remains perplexing from a palliative standpoint.he existing palliative treatment options to improve appetite andurvival are discouraging. Despite the foregoing, it behooves uso remain rigorous in our assessment of candidate integrative,alliative interventions and to remain honest and forthcoming asatients and family members struggle with this distressing signnd symptom.

eferences

1] Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss priorto chemotherapy in cancer patients. Eastern Cooperative Oncology Group.

Am J Med 1980;69:491–7.

2] Kotler DP, Tierney AR, Wang J, Pierson RN. Magnitude of body cell massdepletion and the timing of death from wasting in AIDS. Am J Clin Nutr1989;50:444–7.

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80–6.[8] Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic

236 R. Sood, A. Jatoi / European Journal o

3] Tranmer JE, Heyland D, Dudgeon D, et al. Measuring the symptom expe-rience of seriously ill cancer and noncancer hospitalized patients near theend of life with the memorial symptom assessment scale. J Pain SymptomManage 2003;25:420–9.

4] Quinten C, Coens C, Mauer M, et al. Baseline quality of life as a prognosticindicator of survival: a meta-analysis of individual patient data from EORTC

clinical trials. Lancet Oncol 2009;10:865–71.

5] Loprinzi CL, Ellison NM, Schaid DJ, et al. Controlled trial of megestrolacetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst1990;82:1127–32.

grative Medicine 3 (2011) e233–e236

6] http://prosure.com/FAQ/Using-Prosure.aspx [last accessed 18.06.2010].7] Barber MD, Ross JA, Voss AC, Tisdale MJ, Fearon KC. The

effect of an oral nutritional supplement enriched with fish oil onweight loss in patients with pancreatic cancer. Br J Cancer 1999;81:

acid for the treatment of cancer cachexia. Cochrane Database Syst Rev2007;1:CD004597.