Progestagens and Corticosteroids in the Management of Cancer Cachexia

Chapter 10.11 Progestagens and Corticosteroids in the Management of Cancer Cachexia

Davide Tassinari, Marco Maltoni

Introduction rect clinical research can be hard in palliative care, because of the peculiar characteristics of patients Over the past few years, many authors have with advanced or terminal disease. The treatment approached the problem of the treatment of can- of cancer cachexia with corticosteroids or prog- cer cachexia focusing on either the knowledge of estagens is based on a quite solid evidence of the main pathogenetic events, or the outcomes of activity. However, despite the large number of tri- the treatment in terms of symptoms or improve- als supporting their use in clinical practice, some ment in quality of life [1–8]. The relevance of clini- aspects still remain undefined and deserve to be cal investigations of cancer anorexia-cachexia has looked at in more depth. epidemiological and clinical roots, considering that it is very frequent in advanced and terminal disease (up to 40% of patients with advanced dis- Biological Rationale of Medical Treatment of ease, and more than 80% of terminal patients), and Cancer Cachexia that its clinical manifestations often represent a source of great concern for both patients and rela- Recently, many authors have investigated the dif- tives [1–5]. The clinical approach to cancer ferent pathogenetic events responsible for the clin- anorexia-cachexia has been directed towards dif- ical behaviour of cancer cachexia, and suggested a ferent targets, and it can be aetiological, patho- role for both tumour cells and immuno-mediated genetic or symptomatic according to the attention responses to tumour growth, as important events paid to tumour growth, the main pathogenetic in the pathogenesis of the syndrome [1, 7, 9–41]. events, or the clinical behaviour of the syndrome. Although the main pathogenetic events are not However, it is mandatory to define both the biolog- fully understood and the relationship between ical and clinical rationale of the different thera- tumour factors and host inflammatory cytokines peutic options, and the outcomes of every thera- still remains undefined, a role of different tumour peutic approach, using an evidence-based model. products and an immuno-mediated action of the There are two main questions concerning clinical monocyte-macrophage system seem to be involved research in cancer anorexia-cachexia: in the pathogenesis of cancer cachexia (Fig. 1). – Does a treatment exist that could act against Besides the speculative value of the biological the main pathogenetic events and influence the knowledge about the role of host and tumour clinical outcome behaviour of cancer cachexia? cytokines, the efforts of clinical researchers have – What are the main outcomes of a treatment been addressing the possibility of down-regulating against cancer cachexia, and are these out- the pro-cachectic action of cytokines, favouring a comes actually based on evidence-based tools? control of the clinical manifestations of the syn- The need for an evidence-based palliative med- drome. To this end, progestagens and corticos- icine represents one of the main topics of palliative teroids (and also non-steroidal anti-inflammatory care, as it would be incorrect to avoid an evidence- drugs, eicosapentaenoic acid, melatonin and based model when making decisions in clinical thalidomide) have been evaluated and proposed as practice. On the other hand, methodologically cor- active options in the treatment of cachexia-related 654 Davide Tassinari, Marco Maltoni

TUMOUR Aetiological approach

HOST

CACHECTIC CYTOKINES UNKNOWN FACTORS MECHANISMS

ACUTE PHASE PROTEIN INCREASE

HYPERMETABOLISM NEUROHORMONAL ALTERATION IN AND MUSCLE CONTROL OF FOOD ANABOLIC PROTEOLYSIS INTAKE HORMONES

ANOREXIA Pathogenetic approach

LOSS OF MUSCLE MASS AND FUNCTION

LOSS OF FAT Symptomatic Fig. 1. Main pathogenetic approach events and sites of action of therapeutic options

symptoms [24–26, 42–57]. Two considerations can ease represents one of the main topics of modern be made, coupling the biological dimension and oncology, and some different models of clinical the clinical approach: research and clinical practice support the activity – Besides representing a pathogenetic treatment, and effectiveness of such an approach in the treat- a treatment addressed towards one or more ment of solid and haematological cancers [58–66]. steps in the pathogenesis of the clinical syn- There are two fields that might represent an inter- drome might also be considered a kind of ‘tar- esting dimension in the pathogenetic approach to get treatment’ in palliative care [42–44, 46, 47] the palliative treatment of cancer cachexia: – The different sites of action of the different – The use of biological markers to select the molecules might represent the starting point patients with the highest probability of for a poly-pharmacotherapy against different response to the treatment (predictive value of steps in the same cascade [55–57]. the marker) The concept of a treatment designed on the – The use of biological markers as surrogate end- basis of the biological characterisation of the dis- points of response. 10.11 Progestagens and Corticosteroids in the Management of Cancer Cachexia 655

This kind of approach has recently been evalu- sent the primary end-point of a trial in palliative ated in clinical research, and some preliminary care. However, although quality of life can surely results seem promising, but it would be hasty to represent the main end-point whenever an state that the treatment of cancer cachexia as a improvement in survival is not reasonably expect- ‘target approach’ is possible [57, 67]. Indeed, the ed, the way by which quality of life should be reasons limiting a ‘target approach’ are various, assessed in clinical research and in daily clinical and not well known. Besides the role of cytokines practice is not yet well defined [70, 71]. Some pre- (interleukin 1, interleukin 6, interferon gamma liminary differences are worthy of being defined: and tumour necrosis factor alpha) in the patho- – The activity of a treatment defines if the treat- genesis of cachexia, some other mechanisms might ment could act play a pathogenetic role together with or instead of – The efficacy of a treatment defines how much a the cytokine cascade, favouring a low activity of an treatment should act ‘anti-cytokines’ approach, or a mechanism of – The effectiveness of a treatment defines if the ‘escape’ in some patients [1, 68]. However, the pos- treatment actually acts in clinical practice [72,73]. sible variables occurring in the ‘cytokine-mediat- On the one hand, activity, efficacy and effec- ed’ anorexia-cachexia syndrome probably repre- tiveness are strictly related to each other; on the sent one of the main reasons supporting a target other hand, they are very different from a method- approach. An improvement in clinical results ological point of view: might be achievable by selecting patients using – The activity of a treatment is defined by phase biological predictive factors of response, when we II trials are able to detect biological markers in daily clini- – The efficacy of a treatment is defined by phase cal practice [31–39, 42–44]. III trials – The effectiveness of a treatment is defined by phase IV trials. Outcomes of a Palliative Treatment of Cancer Moreover, the main outcomes and the surrogate Cachexia outcomes of a medical approach should be defined in clinical research, and the relationship between Although a ‘target approach’ to cancer cachexia is main and surrogate outcomes represents an open still too far off to be validated definitively, the question not yet fully answered [74–79]. Indeed, assessment of the outcome of a treatment repre- there are no definitive data distinguishing main and sents an interesting field of investigation in clini- surrogate end-points in quality-of-life assessment, cal practice. The definition of an outcome in pal- and the relationship between symptom control and liative medicine may be considered a general prob- quality of life in an outcome analysis is still unclear. lem, but cancer cachexia represents one of the Symptom assessment surely represents the core of most paradigmatic examples in this field of clini- the validated instruments for quality-of-life assess- cal research. Some years ago, the consensus data of ment, but it cannot represent by itself a validated the Outcomes Working Group of the American instrument for quality-of-life assessment. It follows Society of Clinical Oncology (ASCO) distinguished that symptom assessment can be an index of activi- the outcomes of a treatment into patient outcomes ty of a treatment, or a surrogate end-point of quali- (survival and quality of life) and cancer outcomes ty of life, but quality of life must be considered (response rate), and gave higher priority to patient either the main outcome of a treatment in palliative outcomes [69]. Although the guidelines of the care, or the main index of efficacy of the treatment working group did not strictly concern palliative [74]. If we assume that symptom assessment repre- care, they can be translated into the palliative care sents an index of activity, and quality of life an dimension, as similar documents have never been index of efficacy of a treatment, we can re-analyse produced for palliative care. It follows that quality the clinical trials investigating corticosteroids or of life should be identified as the main patient out- progestagens in cancer anorexia-cachexia, revisiting come, and quality-of-life assessment should repre- the results from an outcome point of view. 656 Davide Tassinari, Marco Maltoni

Clinical Evidence of Activity,Efficacy and doubts about the need for an evidence-based pallia- Safety of a Palliative Treatment with tive medicine. Consequently, we shall review the Corticosteroids or Progestagens in Cancer outcomes of the palliative treatment with corticos- Anorexia-Cachexia Syndrome teroids or progestagens against cancer cachexia from an evidence-based point of view [82, 83]. Much biological evidence supports the activity of corticosteroids and progestagens in the treatment of cancer anorexia-cachexia through the inhibition Activity,Efficacy and Safety of Corticosteroids in of the cytokine cascade, which concurs with the Palliative Treatment of Cancer Cachexia clinical manifestations of the syndrome [42–44]. Although many data support the use of corticos- However, although the role of progestagens and cor- teroids in palliative care, their use is only support- ticosteroids as pathogenetic treatments of cancer ed in part by evidence-based rules [84]. The two cachexia is well defined, it may be interesting to main reasons for this limit are: review the clinical role of the two categories of – The use of corticosteroids goes back to a ‘pre- drugs using an ‘evidence-based’ approach, and evidence-based’ era in medicine, and, like some focusing on the outcomes of the two treatments. other old approaches, it could be assigned to a The first step is the definition of the levels of evi- kind of ‘traditional knowledge’ in medicine dence and the grading of the recommendations, as – The ‘experience-based’ evidence of their use in identified by the main groups of research in clinical clinical practice (methodologically the oppo- oncology [80, 81]. Table 1 shows the levels of evi- site of the ‘evidence-based’ approach) is so high dence and the grading of the recommendations that it would be hard for their use not to be used by the Italian Association of Medical Oncology considered as the ‘standard procedure’ in ‘evi- (AIOM), the European Society of Medical Oncology dence-based’ confirmatory randomised trials. (ESMO) and ASCO. Although an evidence-based Many interesting randomised clinical trials approach can be applied only in part to the particu- support the use of corticosteroids in the treatment lar dimension of palliative care, there are few of cancer cachexia [85–89]. Although the pivotal

Table 1.Levels of evidence and grading of recommendations

Grading of recommendations Level of evidence Type of evidence

A I Evidence is obtained from meta-analysis of multiple, well-designed, controlled studies. Randomised trials with low false-positive and low false-negative errors (high power)

B II Evidence is obtained from at least one well-designed experimental study. Randomised trials with high false- positive and/or negative errors (low power)

III Evidence is obtained from well-designed, quasi experimental studies such as non-randomised, controlled single-group, pre-post, cohort, time or matched case- control series

C IV Evidence is from well-designed, non-experimental studies such as comparative and correlational descrip- tive and case studies

D V Evidence is from case reports and clinical examples 10.11 Progestagens and Corticosteroids in the Management of Cancer Cachexia 657 trial of Moertel et al. dates back to 1974 [85], and other important trials were published in the 1980s [86–89], some considerations can be made II II II approaching the results from an outcome point of (Table 1) (Table view. All trials showed that corticosteroids (dexamethasone or prednisolone, or methylprednisolone) induce a temporary benefit against different cachexia-related symptoms, improving the appetite, food intake, sensation of well-being, and performance status. Conversely, no trial demonstrated an improvement in body weight. Moreover, Main outcomesMain of Level evidence Improve appetite Improve appetite Improve the trials of Robustelli della Cuna and Popiela [88, appetite Improve Improve food intake Improve Improve pain control Improve 89] approached the dimension of quality-of-life quality ofImprove life quality ofImprove life I I assessment during the treatment, and tried to go performance status Improve beyond symptom assessment in the outcome assessment in palliative care. Besides these interesting results detailed in Table 2, there is much evidence that corticosteroids can act against some

other symptoms, that are related to, but not consti- 61 40 116 403 173 tutive of, cancer cachexia, such as asthenia, or nausea and vomiting [90–93]. It follows that corticosteroids are very useful in some different condi- tions of clinical practice, when cachexia coexists with other syndromes such as asthenia, nausea 125 mg four times daily 125 mg four and vomiting, or dyspnoea. Such a versatility of d corticosteroids is only partially known from a COD COD PCCT PCCT PCCT PCCT PCCT pathophysiological point of view. As concerns can- Trial designTrial of Number patients cer cachexia, corticosteroids may be supposed to act by inhibiting the immune response and d d ne cytokine cascade, and acting on the central nerv- c 16 mg twice daily; c a

ous system. However, other characteristics can b partially counterbalance the data of activity. The above-mentioned trials and some others reported that the activity against cachexia-related symptoms is limited to a few weeks, and the relevant Molecule side-effects (peptic ulcer, cataract, opportunistic design cross-over Oral prednisolone Oral dexamethasone

infections, glucose intolerance, myopathy) can times5 mg three daily; Oral methylprednisolone b COD,

often make it difficult to use corticosteroids in methylprednisolone Parenteral clinical practice. It follows that corticosteroids can surely be considered an active and probably effica- cious approach against cancer cachexia, but short- ness of action and side-effects suggest their use is limited to patients with advanced disease and expected short duration of survival [8, 94]. Finally, type, dosage and route of administration remain 0.75–1.5 mg four times daily;0.75–1.5 mg four ill defined, and low dosages (less than 1 mg/kg of a prednisone equivalent) seem recommendable in clinical trialsRandomised of cachexia in cancer corticosteroids daily clinical practice [8]. Table 2. Table References et al.Popiela [89] Bruera et al. [87] Dosages: Moertel et al. [85] Willox et al.Willox [86] Robustelli della Cuna et al. della Cuna Robustelli [88] methylprednisolo Parenteral PCCT, clinical trial; placebo-controlled 658 Davide Tassinari, Marco Maltoni

Activity,Efficacy and Safety of Progestagens in used in the trials were not validated for the ter- Palliative Treatment of Cancer Cachexia minal phase of neoplastic disease) – Duration of the treatment and follow-up too The use of progestagens in the palliative treatment short to evaluate the impact of the treatment of cancer cachexia has been largely investigated in on overall quality of life the past few years, and to date they represent the – Secondary relevance of cancer cachexia in the treatment of choice [1–6, 8, 9, 94]. However, despite status of terminal or pre-terminal patients. the large amount of data about activity, efficacy Another issue can help in understanding the and safety of medroxyprogesterone acetate or reasons for such a discrepancy in the outcomes of megestrol acetate [95–111], and the supposed the palliative approach with progestagens to can- down-regulation of the cytokine cascade as their cer cachexia. Quality of life is probably the main main mechanism of action [42–44], some consid- end-point of a therapeutic approach in palliative erations can be made. Unlike what has been care. Moreover, it represents a multidimensional observed about the clinical evidence of efficacy of aspect of the patient’s life, and health-related qual- corticosteroids in cancer cachexia, many ran- ity of life is what we usually try to assess in clinical domised trials support the efficacy of progesta- research [114]. Symptom improvement is one of gens, and two meta-analyses have been published the main domains in the health-related improve- in recent years, demonstrating their palliative role ment in quality of life, but it does not represent the [95, 96]. Nevertheless, two issues are to be high- quality of life by itself. Likewise, symptom assess- lighted in the evaluation of the evidence of efficacy ment plays an important role in quality-of-life of progestagens in cancer cachexia: assessment, but it cannot be considered the quali- – Evidence suggests that progestagens can down- ty-of-life assessment by itself. It follows that symp- regulate the cytokine cascade, but there are no tom assessment can be considered an index of data supporting the role of cytokine dosage as activity of a treatment against a clinical syndrome, a predictive factor of response while health-related quality of life is the main – There is much evidence that progestagens can index of efficacy. Likewise, symptom assessment improve appetite and weight gain in patients can be assumed as a surrogate outcome of quality with cancer cachexia, but the evidence is not of life, that should be assessed within,but not enough to relate such an improvement to an instead of, quality-of-life assessment [74]. In any improvement of quality of life. case, to date progestagens represent the treatment In our systematic review of the literature, we of choice of cancer cachexia, and they can be con- selected 15 randomised clinical trials published sidered one of the most active options, but the before June 1999. All trials assessed the effect of dosage of the treatment still remains undefined. In progestagens on body weight, and all trials but two an interesting (even though questionable) trial, evaluated appetite improvement as an end-point of Loprinzi et al. tried to investigate the problem of the treatment. Although weight gain or appetite the most active dosage of megestrol acetate in can- improvement were evaluated differently in the dif- cer cachexia, comparing four doses in 342 patients ferent trials (the differences consisted in the time [106]. The patients were randomised to receive or the method of assessment), a significant role of oral megestrol acetate at doses of 160, 480, 800 and progestagens was observed in both (Table 3). 1280 mg/day and were evaluated monthly for Quality of life was assessed in nine trials [97–105], response. The trial demonstrated a positive but a positive role of high doses of progestagens dose–response effect on appetite stimulation, but was observed in just two [101, 102] (Table 4). We no significant effect on weight gain (only a trend tried to understand the reasons for the lack of cor- in favour of high doses was shown), without any relation between weight gain or appetite improve- difference in the occurrence of side-effects. In par- ment and quality of life, and identified three possi- ticular, an improvement was observed up to 800 ble factors: mg/day, while no further improvement was – Insufficient sensitivity of the instruments used observed for higher doses. Despite these interest- for quality-of-life assessment (the instruments 10.11 Progestagens and Corticosteroids in the Management of Cancer Cachexia 659

Table 3. Randomised clinical trials of progestagens in cancer cachexia

Author Number of patients Arms Outcomes Level of evidence (Table 1)

Bruera et al. [97] 84 MA 480 mg vs placebo Weight gain II Improve appetite

De Conno et al. [98] 42 MA 160 mg vs placebo Weight gain II Improve appetite

Simons et al. [99] 206 MPA 1000 mg vs placebo Weight gain I Improve appetite

Vedell et al. [100] 150 MA 160 mg vs MA 480 mg vs placebo Weight gain I Improve appetite

Beller et al. [101] 240 MA 160 mg vs MA 480mg vs placebo Weight gain I Improve appetite Improve quality of life

Kornek et al. [102] 31 MPA 500 mg vs placebo Weight gain II Improve appetite Improve quality of life

Rowland et al. [103] 243 MA 800 mg vs placebo Weight gain I

Tchekmedyian et al. [104] 89 MA 1600 mg vs placebo Weight gain II Improve appetite

Westman et al. [105] 255 MA 320 mg vs placebo Weight gain I Improve appetite

Feliu et al. [107] 150 MA 240 mg vs placebo Weight gain I Improve appetite

Schmoll et al. [108] 91 MA 480 mg vs MA 960 mg vs placebo Weight gain II Improve appetite

Downer et al. [109] 60 MPA 300 mg vs placebo Weight gain II Improve appetite

Loprinzi et al. [110] 133 MA 800 mg vs placebo Weight gain I Improve appetite

Neri et al. [111] 279 MPA 1000 mg vs placebo Weight gain I

Bruera et al. [112] 40 MA 480 mg vs placebo Weight gain II Improve appetite

Jatoi et al. [113] 469 MA 800 mg vs DBN 5 mg vs Weight gain I MA 800 mg + DBN 5 mg Improve appetite Improve quality of life

MA, megestrol acetate; MPA, medroxyprogesterone acetate; DBN, dronabinol 660 Davide Tassinari, Marco Maltoni

Table 4.Randomised clinical trials with quality of life as end-point

Author Number Arms Quality-of-life Results of patients assessment

Bruera et al. [97] 84 MA 480 mg Functional living No differences in quality- vs placebo index – cancer of-life assessment

De Conno et al. [98] 42 MA 160 mg Therapy impact No differences in quality- vs placebo questionnaire of-life assessment

Simons et al. [99] 206 MPA 1000 mg EORTC-QLQ-C30 No differences in quality- vs placebo questionnaire of-life assessment

Vedell et al. [100] 150 MA 160 mg vs Seven linear analogue No differences in MA 480 mg vs placebo self-assessment scales quality-of-life assessment

Beller et al. [101] 240 MA 160 mg vs Six linear analogue Improvement in overall MA 480 mg vs placebo self-assessment scales quality of life of patients treated with MA

Kornek et al. [102] 31 MPA 500 mg Functional living Improvement in overall vs placebo index – cancer quality of life of patients treated with MPA

Rowland et al. [103] 243 MA 800 mg Visual analogue quality- No differences in quality- vs placebo of-life scale of-life assessment

Tchekmedyian 89 MA 1600 mg 29-item, patient-rated No differences in quality- et al. [104] vs placebo linear analogue scale of-life assessment

Westman et al. [105] 255 MA 320 mg vs placebo EORTC-QLQ-C30 No differences in quality- of-life assessment

Jatoi et al. [113] 469 MA 800 mg vs DBN FACT-cachexia Improvement in quality- 5 mg vs MA 800 mg + DBN 5 mg of-life assessment for MA or MA + DBN

MA, megestrol acetate; MPA, medroxyprogesterone acetate; DBN, dronabinol

ing and methodologically correct results, on the significant) difference in the outcomes in the basis of pharmacoeconomic considerations the four arms, though questionable, is reasonable. authors suggested starting with lower doses of It follows that it might be acceptable from a megestrol acetate, reserving higher doses to resist- clinical point of view to start with lower doses ant patients. Some consideration can be made in of megestrol acetate (160 mg/day), reserving this regard: higher doses for resistant patients – There is a positive correlation between out- – The use of a cost-minimisation analysis (that come and dosage (at least up to 800 mg/day), needs comparable outcomes to be applied and this methodologically correct result could among the different hypotheses) is quite incor- be applied to clinical practice. Moreover, the rect and unfit for this kind of application. lack of a dose-related incidence of side-effects The trial of Loprinzi et al. correctly approaches reinforces the conclusions of the trial for a clin- the problem of the proper dose of megestrol ical application acetate, and suggests a correct instrument to guide – The considerations of the authors regarding a clinicians in daily clinical practice. Conversely, the clinically non-significant (although statistically final considerations may be considered correct 10.11 Progestagens and Corticosteroids in the Management of Cancer Cachexia 661 from a clinical and biological point of view, but (fluoxymesterone) in a trial involving 496 patients incorrect from a pharmacoeconomic point of view, with cancer cachexia, randomly assigned to these because of the improper use of a pharmacoeco- three treatment options [115]. The results are nomic analysis in a setting that does not require interesting: such considerations. - Fluoxymesterone induced a significantly lower Finally, all data in the literature indicate that appetite enhancement and did not have a high doses of progestagens are usually safe, and favourable toxic profile serious side-effects are not frequent in clinical - Megestrol acetate and dexamethasone induced practice [8, 9, 95–112]. Both medroxyprogesterone similar appetite enhancement and similar acetate and megestrol acetate increase the risk of changes in non-fluid weight status, with a non- thromboembolic events, peripheral oedema, significant trend favouring megestrol acetate breakthrough bleeding, hyperglycaemia, hyperten- for both parameters sion and Cushing’s syndrome, but patients taking - Dexamethasone had more corticosteroid-type high doses of progestagens have to stop the treat- toxicity and a higher rate of drug discontinua- ment sporadically because of the occurrence of tion than megestrol acetate, because of toxicity serious side-effects [8]. and/or patient refusal - Megestrol acetate had a higher rate of deep venous thrombosis than dexamethasone. Corticosteroids or High Doses of Progestagens:The Best To understand better when and why to choose Choice in Clinical Practice? corticosteroids or progestagens in clinical prac- In the previous paragraphs we have reviewed the tice, the data of Loprinzi merit integration with evidence supporting the use of corticosteroids or those reported by De Conno et al. in a randomised, progestagens in the treatment of cancer anorexia- placebo-controlled trial comparing the clinical cachexia, supplying either the evidence of activity response of megestrol acetate and placebo in 42 and efficacy (if any), or the limits of their use in patients evaluated at 7 and 14 days after beginning clinical practice. The next step is the evidence- the treatment [98]. Appetite improvement started based analysis of the reasons for selecting one significantly earlier in patients treated with mege- approach rather than another in clinical practice. strol acetate than in those receiving placebo. It fol- Most reviews suggest some assumptions that are lows that both these trials may modify, at least in worthy of critical analysis: part, the current clinical habit reported by qualita- – The effect of corticosteroids against cachexia- tive review literature: related symptoms is generally fast but short, – Both progestagens and corticosteroids can act usually limited to a few weeks. Moreover, the against cachexia-related symptoms in the early serious side-effects frequently occurring in and late phases of the disease chronic treatments limit their indication to – The actual clinical advantage of progestagens is patients with advanced disease and short the lower occurrence of serious side-effects expected survival [8, 9] and the lower rate of discontinuation of the – The relative latency of action and the higher treatment activity and safety of progestagens in compari- – Although the cost of corticosteroids is lower son with corticosteroids make them the treat- than that of progestagens, a correct analysis of ment of choice for patients with an expected cost minimisation (assuming an equal effect survival greater than 3–4 weeks. This assump- between dexamethasone and megestrol acetate, tion is supported by either clinical or pharma- as reported by Loprinzi et al. [115]), which coeconomic considerations, as corticosteroids includes either the pharmaceutical costs or cost less than progestagens [8, 9, 94]. those for the treatment of side-effects, seems to Loprinzi et al. analysed the different profile of favour progestagens as the treatment of choice corticosteroids (dexamethasone), progestagens in cancer cachexia. (megestrol acetate) and anabolic corticosteroids On the basis of these observations, progestagens 662 Davide Tassinari, Marco Maltoni

should be considered as first-choice treatment in cachexia, although a lot of evidence supports a cancer cachexia, whereas the use of corticosteroids high activity of both of them (and particularly of should be limited to patients with short life progestagens). Many efforts must be made to expectancy, because of their worse safety profile. define better the outcomes of the palliative treatments, and the recovery of quality of life as the main outcome in palliative care, as well as the Conclusions inclusion of symptom improvement in a compre- hensive quality-of-life assessment, will be the chal- Cancer anorexia-cachexia syndrome represents a lenge of the next years. To date, corticosteroids, relevant problem in the treatment of patients with and mostly progestagens, are the most active advanced neoplastic disease. In the past few years, options in the treatment of cancer cachexia, and many authors have investigated the mechanisms they have to be considered the standard options underlying the clinical manifestations of the syn- for the next clinical trials. Two possible scenarios drome and its relevance in terms of quality of life. may be suggested for the dimension of future clin- Much evidence supports the role of corticosteroids ical trials: and progestagens in the treatment of the syn- – A ‘biological’ characterisation of the patients drome, and there are guidelines that address the based on the identification of predictive mark- choice in daily clinical practice. Nevertheless, some ers of response. The outcomes might be dimensions remain undefined and merit further improved by selecting the patients to be treated investigations. A crucial, open question is the defi- on the basis of the predictive value of response nition of the treatment in clinical practice. to a particular treatment Although the identification of primary and surro- – A review of clinical outcomes in palliative care, gate outcomes in palliative care is not limited to focusing on ‘health-related’ quality of life as cancer cachexia, it is important to observe that a well as on symptom improvement, as a better palliative treatment against cachexia, even though approach to patients and their relatives in the able to improve cachexia-related symptoms, prob- latter stages of the patient’s life. ably does not improve patient quality of life. At present, clinical evidence of activity sup- Likewise, our ‘evidence-based’ knowledge is often ports the use of progestagens as the standard based on surrogate end-points of clinical efficacy. option in the treatment of cancer cachexia, and These limits do not allow us to state that corticos- starting from such an evidence base we should teroids or progestagens are effective therapeutic continue to improve our knowledge on the out- options in the palliative approach to cancer come research in cancer cachexia.

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