Cancer cachexia

Cancer anorexia-cachexia (CACS) is defined as a multifactorial syndrome characterized by ongoing loss of skeletal muscle mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment [1]. Cancer cachexia occurs across a continuum, varying in severity and stage; according to new classification we have pre-cachexia (early clinical signs of cachexia, low-grade weight loss), which may progress to cachexia (weight loss >5% in the last 6 months or a combination of >2% weight loss with low muscle or low BMI), and refractory cachexia (occurs due to rapidly progressing disease, and is unresponsive to anti-cancer therapy) [2-4]. CACS cannot be reversed by conventional nutritional support. The highest prevalence of this syndrom is seen in patients suffering from gastrointestinal and head and neck cancers (up to 90% of cases) [3-5].

(;Chapter 1) EnvoLuntary weight Boss, evenrualBy Beading to cachexia, is a clinimcally Urighly relevant mmplication of cancer (13 that negatively influences quality of life, survival (2-51, and treatment, rmpanse (6,7).Although it might wcur in any type of cancer, ills incidence is particularly high in malignancies of the lung, pancreas and gastroirzrestinal @act (2,8>. The pathophysiology of this weight loss is complex and only partly understclod.Predominantly based on studies in experimental models, several ~niechanisms are thought to play a major role: an increased systemic inflammatory state (91, the circullntion of tumor-derived (noncytokine) lipolytic and pcoteolytic factors [10,1 I), increased Cori cycle activity (1231, and a decreased f d intake (8).
Despite the f a ~t that in the past decade many agents have been tested for their ability to reverse cancer-related weight loss, the number of therapies presently recomlmendable for use in daily clinical practice is still disappointingly limited.
(Chapter 2) As nearly all tissues that are vital for a normal functioning of the body are part of the body-cell-mass (BCM) (13), it is evident that particularly wasting of this body compartment can be expected to be responsible for the negative effects of wciglzt loss on performance status and survival.If so, BCM-wasting sE~ould become a specific target for Lherapeukical intervention.However, Lo develop such specific treatment strategies it is mandatory to have a maximum of insight in its underlying pathophysiology.
Particularly studies in experimental models revealed that the developmenc of cancer cachexia is for an important part related to a clrronic, low-grade, tumor-induced activation of the host immune system (9).Until the start of our studies, however, confirmatory data were scarce in h u m n cancer (14,15), and particularly the specific pathophysiology of cancer-related BCM-wasting had nor been investigated, To explore these issues, we investigated in 20 male lung cancer patients tire relationship between both weight loss and BCM-wwtiarg, and the putative presence of systemic inflammation (sTNF-M5, sTNF-RTSS, 1L-61, increased acute-phase response (LBP, allbumin), anorexia, hypcrmetzlbolism and changes in circulating levels of catabolic (cortisol) and anabolic (testosterone, IGF-I) hormones.In addition, LO obtain more ia~sighl in the specific clinical relevance of canoes-related BGM-wasting, the relatlonahip between height-adjusted BCM (BCM-ix) and Karnofsky performance status was msesscd.
Karnofsky performance score was shown to be expl~citly oorralated with BCM-ix.Severe weight loss was significantly correlated wit11 high sTNF-R55 levels, low levels of the "negative" acute-phase protein albumin, and low IGF-I.In addition, BCM.was;ting was specifically correlated with high circulalt~ng levels of sTWF-R55 and srll'NF-U75, high plasma levels of LBP, low serum afbum~n and high BCbd-adjustfd resting energy expenditure I(REE/DCM).Furthermore, a trend towards a (positive) correlation bemeen BCM-lx and IGF-f was obiserwedl.sTNF-U5.9Ievels correlated negatively with albumin and pesitiwely wirh REE/BGM, and there were trends towards a posltive mudation with LRP and a negative ~orrelaL~on with appetite.
B m d on these resulu, we eoncludd that human lung eaunwr-related weight loss and BCM-wmting are msociatwl with systemic inflammation, increased hepatic acute-phase protein production and, in e a e of BCM-wasting, hypermetabolism.In addition, we were able ltca show that, although not evidently related to systemlc inflammation, also decrmed ICF-I levels might lue involved.
(Chapter 33.Leptin, the product of the adipocyte ob gene, is a recently identified hormone that is thought to represent the afferent signal in a feedback mechanism regulating fat mass (16).After release by the adipocyte, leptsn is assumed to bind to a specific receptor in the hypothalamus (17-19), the brain nucleus that pBays a ceneal role in the regwlation of feeding behaviour and energy balance (20,21).In animal models, the result of this interaction is a decrease in food intake and an increase in energy expenditure (18,19,22,23).In view of the fact that anorexia and hypermetabolism frequently play a sole in the development of cancer cachexia, underlying abnormalities in the leptin feedback mechanism might, in hypothesis, be present.In particular, elevated levels of circulating leptin or, on the contrary, a hypothalamic ~nsensitivity to a fall in leptin levels might be invalvled.As there is evi~de~ice from studies in i ~! vitm and iin vivo experimental models that oh gene expression may be up-regulated by substances like cortisol and proinflammatory cytokines such as TNF and IL-1 (24-271, substances that also seem to be involved i n the pathophysiology af cancer caclvexia (15,281, particularly the passibility OF high leptiu levels playing a role in infectnon-and malignancy-related cachexia has been suggcsled in llleralwre (26,271.'I'o clarity this issue, wc ~nvesrigated the relationship between total plasma leptln, wcigl% loss, body compasituon, appetite aaid REE in lung cancer.
Twenty-one male paticnts were studied.These subjects were on average clraraeterzzed by a wvle~gElt loss of approximately 10% and a body weight of 94% of ideal.In only 6 of these patients plasma leptin was detectatable, with Bevels within the normal range.These subjects were characterized by iess weight loss, by less underweight, and by a higher h e Inass tha~a the patients wirh non-detectable leptin levels, arid sign~ficant between-group differences in appetite and REE were lacking.
Based on these results, we co~lcluded that in cancer patients, in analogy to rrormal and obese individuals (29,3O), leptin levels are directlly related to the amowrrt of body fat.being compatible with a normal function of the afferent Imp of the lepti~r feedback mechanism.We were therefore not able to confirm the hypothesis 1(26,23) tl~at elevated leptin levels may be involved in the pathophysiology af cancer cachexia.As low roh1 leptin levels were not refleaed in decreased energy expenditure and increased appetite, i t was hypothesized that in cancer cachexia the Jeptin feedback mechulism dysfunctions at the hypothalamic level.Wether turnor-or host-derived cycokines or other tunzor-or hosrderived substances are responsible for this overruling of normal weight kaomeostasis still has to be further clarified.
(Chapter 4) As wasting of fat-free mass (FFM) and BCM may hare substantively mare impact on performance status, quality of life and prognosis of cancer patients than wasf ng of fat, a far more differentiated diagnosis of cancer cachexia can be made whcn not only the amount of weight loss and the degree of underweigl~t are taken into account, but also body composition.Furthermore, body composition data can be used in the decision to start a specifically tailored therapeutical intervention, and to evaluate iu resunts.Also in clinical trials, body composition analysis is indispensa'ble for a reliable interpretation of the efficacy of anti-cachectic interventions.
Apart from skinfold anthropometry with its known limitations, bioelectrical impedance analysis (BIA) is probably the only b d y composition analysis rechnique tirat ~s inexpensive, can be performed without specific operator skills, and forms no burden on the measured subject.This makes BBA potervlially suitable for body cornposiaron atzalysis in "daily" clinical practice, as well as in large-scale clinical trials, i~~clnllding multicenter studies.
Wheream the reliability of B1A (in particular the parameter Irt2/R) to predict ~otal body waber (TBW) and its derivative FFM has been proven in many studies i ~a heallY~y indi~iduals (311-39, few studies investigated the applicability of BIX to assess 'I'BW and EFM in non-healthy individuals, especially those with cachexia, To clarify this issue, the applicability of single-frequency 50-kHz BlA to predict deuterium dilution-derived TBW was assessed In 16 underweight and 25 normal-weight cancer patien&. Although ht'JR proved lo be a strong single predictor of TBW in both groups, rle was shown that TBW would be significantly over-estimated in lthe underwelgFit group wlren the prediction formula developed in the normal-welght group was used (bliss 1.67 L 15%]).A systematic over-esrimatuon of TBW in the underweight paltents was also found whera TBW was predicted by several previously published BIA forunulas developed in normal-TBW or FFM is alculated.Unfortunately, however, this is moo at alk conumoa practice in prospective clinical studies to date.
(Chapter 61 In view of the negative effects of weight loss oar quality of life% survival and treatment response, several agents have been tested far their abulity to reverse the process of cancer cachexia.While agents like corticosteroids, cyproheptadii~ and hydrazine sulfate failed to influence weight loss i ~u controlled human studies, synthetic progestagem -MA and MPAwere shown to improve appetite and weight, independent of tumor response, when used in the treatment of disseminated breast cancer (46,4.7).Subsequently, also several double-blind, placebo-controlled trials in non-hormonesensitive cancer observed a favorable effect of MA on appetite (48-52).Soma of t h s e studies, though not ail, also found a significant beneficial effect on weight (48,49.51).This weight effect was however only seen in a subgroup of patien~ts, wl~ile a significant beneficial influence on average weight was not dernonstmted.In addition, the effects of MA on quality of life were hardly investigated, at least nor with the use of standard, wellvalidated quality of life iinstruments.
To generate ffurther evidence regarding the usefulness of synthetic progesragens in the treatment of cancer cachexia, we conducted a multicenter, double-blind, placebooontrolled study in 206 patienits suffering from advanced-stage, incurable, no8~-hormonesensitive cancer.In this study, we investigated the effects af MPA (lOO0 rngJday) on appetite, weight and quality of life.
A beneficial effect of MPA on appetite was observed after both 6 weeks and 12 weeks of treatment.After 12 weeks, a mean weight gain of 0.6 kg was seen iol the MPA group, versus an ongoing, mean weight loss of 1.4 kg in the placebo group.This difference was statistically significant.Tl~e results of a subgroup analysis suggested that patients wllo are weight losing but not yet cachectic rnay bcnel'nt inost from MPA Ireeanment.During the study, several arcas of quality of life deter~orateel rru the lolal group of pat8ent.s.With the exception of an ilrnprovernent of appetite and possibly also a reduction in nausea and vomiting, no measurable beneficial effects of MPA on quali~y of life could however be demonstrated.The ssdc effects profile of MPA was favorable.a~aly a rend toward an increase in [usually mild) perrpl.~eraledema was observed.Surv~val analysis, based on the subset of patients that fully compUeled the 12 week study, indicated a mednan sunrtval advantage of 3.4 months for patients who were treated ~8 t h MPA.However, this finding dld nor, reach shtistlcal signficance In the relatively small group or patients investigated.
Based on these results, we concluded than in advanced-stage, ruon-lrormone-sens~llive cancer MPA exhibrfrt a mild side effects profile, har; a b~enefieial effect on appetite, and prevemb further weigh,r loss.General quality of Irfe was however not ellearly influenred.Several explamtions far thh negative finding might nevertheless be given.First, the magnitude of weight changes might have been lo, small to influence general quality of life, especially when the major part was fat (see chapter 7).Second, 1n many cancer patients overall quality of life might be affected more by factors related ilo tumor extension and progression per se, than by anorexra and weight lass.Third, the daily dose of lOOa rng MPA might have been to Pow to have an effect on, m d . in a recent study by Beller ed a[., MA in a daily dose of 480 mg significantly improved mood and "overall qwallty of lifeM independent of weight change, while Lhls (glucmrticoid-like?) effect was not absesved when a daily dose of 160 mg (equivalent to MPA 1W mg) was used (52).
Further smdies &re needed to investigate whether progestagensl may prevent further weight loss anld improve quality of life when the treatment is initiated earlier (i.e., from the moment a patient experiences involuntary weight loss), and continued longer.This design would also be appropriate to further clarify the effects of MPA on survival.
(Chapter 7) To investigate whether an MPA-induced improvement of appetite also results in an increa~~e ~F I f d intake and whether the observed weight gain represents tissue mass and nor.just fluid retention, which is a reported side effect of synthetic progestagens (48,51,53), we collducted an additional study in 54 patients io investigate the effecls of MPA on food intake and body composition, 111 addition, also the effects of MPA on REE were assessed.
In contrast with placebo treatment, 12 weeks of MPA led to an increase in energy intake that was significantly associated with an increase in fat mass.The increase in energy intake was the result of a significantly improved intake of both protein, fat and catbolrydrates.FFM was not significttnlly influenced.In addition, MPA-treatment was associalled wid? an increase in REE.
Based on these results, we concluded that MPA is able to significantly increase f d inuke and to co~tcomitanlly reverse fat loss in weight-lasing patients with non-hormonesetlsltlve cancer.However.we were no1 able to show a beneficial effect on FFM.