cachexia syndrome

Clinical Nutrition 31 (2012) 176e182

Contents lists available at SciVerse ScienceDirect

Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu

Original article

Randomized phase III clinical trial of a combined treatment with carnitine þ celecoxib  megestrol acetate for patients with cancer-related anorexia/cachexia syndrome Clelia Madeddu a, Mariele Dessì a, Filomena Panzone a, Roberto Serpe a, Giorgia Antoni a, Maria Chiara Cau a, Lorenza Montaldo b, Quirico Mela b, Marco Mura c, Giorgio Astara a, Francesca Maria Tanca a, Antonio Macciò a, Giovanni Mantovani a, * a

Department of Medical Oncology, University of Cagliari, Cagliari, Italy Department of Internal Medicine and Rheumatology, “Azienda-Ospedaliero Universitaria di Cagliari”, Monserrato, Cagliari, Italy c Department of Radiology, University of Cagliari, Cagliari, Italy b

a r t i c l e i n f o

s u m m a r y

Article history: Received 19 July 2011 Accepted 11 October 2011

Background & aims: A phase III, randomized non-inferiority study was carried out to compare a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine þ celecoxib  megestrol acetate for the treatment of cancer-related anorexia/cachexia syndrome (CACS): the primary endpoints were increase of lean body mass (LBM) and improvement of total daily physical activity. Secondary endpoint was: increase of physical performance tested by grip strength and 6-min walk test. Methods: Sixty eligible patients were randomly assigned to: arm 1, L-carnitine 4 g/day þ Celecoxib 300 mg/day or arm 2, L-carnitine 4 g/day þ celecoxib 300 mg/day þ megestrol acetate 320 mg/day, all orally. All patients received as basic treatment polyphenols 300 mg/day, lipoic acid 300 mg/day, carbocysteine 2.7 g/day, Vitamin E, A, C. Treatment duration was 4 months. Planned sample size was 60 patients. Results: The results did not show a significant difference between treatment arms in both primary and secondary endpoints. Analysis of changes from baseline showed that LBM (by dual-energy X-ray absorptiometry and by L3 computed tomography) increased significantly in both arms as well as physical performance assessed by 6MWT. Toxicity was quite negligible and comparable between arms. Conclusions: The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination þ megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment. Ó 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Cancer-related anorexia cachexia Carnitine Celecoxib Megestrol acetate Lean body mass Physical activity

1. Introduction Cachexia has been recognized for a long time as an adverse effect of cancer. It occurs in 50e80% of cancer patients and is associated with reduced physical function reduced tolerance to anticancer therapy and reduced survival.1 Recently, an international consensus statement has defined cancer cachexia as “a multifactorial syndrome defined by an on-going loss of skeletal muscle mass (with or without loss of fat * Corresponding author. Cattedra di Oncologia Medica, Università di Cagliari, Azienda Ospedaliero-Universitaria di Cagliari, S.S. 554, Km 4,500, 09042 Monserrato (CA), Italy. Tel./fax: þ39 070 5109 6253. E-mail address: [email protected] (G. Mantovani).

mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current body weight and height (body mass index [BMI] <20 kg/ m2) or skeletal muscle mass (sarcopenia)”.1 Its pathophysiology is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism.2 Proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a play central roles in the pathophysiology of

0261-5614/$ e see front matter Ó 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. doi:10.1016/j.clnu.2011.10.005

C. Madeddu et al. / Clinical Nutrition 31 (2012) 176e182

cancer-anorexia cachexia syndrome (CACS).3 There is evidence that “chronic inflammation”, low-grade, tumor-induced activation of the host immune system, which shares several characteristics with the “acute-phase response,” is involved in CACS.4 Although the understanding of cachexia has greatly improved over the past decade, cachexia is still rarely recognized, assessed and actively managed. To date, despite several efforts in basic and clinical research, CACS treatment still represents an important unmet need in clinical practice. A plethora of treatments have been proposed for the cachectic syndrome, but, unfortunately, not a single one is completely satisfactory.5 Past efforts to treat cancer cachexia with nutritional or medical interventions probably failed because they were directed at appetite stimulation alone, usually with a single therapeutic agent. Even two-agent combinations have been largely proven to be ineffective6: randomized clinical trials of dual medical therapy using megestrol with either fish oil or dronabinol showed no gain in weight or appetite compared with megestrol alone.7,8 A more effective approach is likely to be a simultaneous, combined, multi-targeted approach addressing the different mechanisms contributing to CACS. On the basis of this rationale, we carried out an open phase II study which demonstrated the efficacy and safety of an integrated oral treatment based on pharmaco-nutritional support, antioxidants, and drugs in 39 advanced cancer patients with CACS: 22 out of 39 patients were considered responders and achieved a significant improvement of the key endpoint variables lean body mass (LBM), fatigue, appetite, quality of life (QL), IL-6, and TNF-a.9,10 These results prompted us to carry out a phase III randomized study11 to establish the most effective and safest treatment able to improve the identified “key” variables (primary endpoints) of CACS, i.e., increase in LBM, decrease of resting energy expenditure (REE), improvement of fatigue. Three hundred thirty-two eligible patients with CACS were randomized to one of five treatment arms: arm 1, medroxyprogesterone (500 mg/day) or megestrol acetate (320 mg/day); arm 2, oral supplementation with eicosapentaenoic acid; arm 3, Lcarnitine (4 g/day); arm 4, thalidomide (200 mg/day); and arm 5, a combination of the above. Treatment duration was 4 months. Analysis of variance showed a significant difference between treatment arms: the post-hoc analysis showed the superiority of arm 5 over the others for all primary endpoints (LBM, REE and fatigue). Toxicity was quite negligible, and was comparable between arms.11 1.1. Aim of the study Based on these results and with the aim to simplify the treatment approach and obtain a better patient compliance, in November 2009 we started a phase III, randomized non-inferiority study comparing a two-drug combination carnitine þ celecoxib  megestrol acetate for the treatment of CACS: the primary endpoints were increase of LBM, and, as a special point of interest, the improvement of total daily physical activity. The secondary endpoint was the increase of physical performance tested by grip strength and 6-min walk test (6MWT). Additionally, we assessed at baseline and after treatment the following parameters: REE, fatigue, Eastern Cooperative Oncology Group Performance Status (ECOG PS) and Glasgow Prognostic Score (GPS), serum levels of proinflammatory cytokines, appetite and global QL (as measured by the EORTC-QLQ-C30).

177

(arm 1) vs carnitine þ celecoxib þ megestrol acetate (arm 2) for the treatment of CACS. The protocol was approved by the institutional ethics committee. Written informed consent was obtained from all patients. The trial was carried out in accordance with Good Clinical Practices and the Helsinki Declaration. The ethical review was carried out by the institutional ethics committee who ascertained that the study was being conducted in strict compliance with the approved protocol. 2.1.1. Eligibility criteria Patients (aged 18e85 years) with histologically confirmed advanced stage tumor at any site, loss of at least 5% of ideal or preillness body weight in the previous 6 months (associated with abnormal values of proinflammatory cytokines and/or C-reactive protein) and a life expectancy  4 months, were eligible. Patients could be receiving concomitant antineoplastic chemotherapy or hormone therapy in the palliative medicine setting or supportive care only. Opioids were allowed for the treatment of cancer pain. 2.1.2. Exclusion criteria Women of child-bearing age and patients with a mechanical obstruction to feeding, medical treatments inducing significant changes in patient metabolism or body weight (corticosteroids for prevention of chemotherapy-induced emesis were allowed, if indicated), and a history of thromboembolism, cardiac disease, such as congestive heart failure (class III or IV according to the New York Heart Association Functional class) or left ventricular ejection fraction 35%, uncontrolled hypertension (systolic pressure >140 mmHg and diastolic pressure >90 mmHg), previous myocardial infarction, unstable angina, uncontrolled arrhythmia, positive history for cerebrovascular events, inflammatory bowel diseases, gastrointestinal ulcers were excluded. 2.1.3. Intervention There was no dietary restriction to patients food intake nor dietary supplementation. Basic treatment: polyphenols (300 mg/ day) were supplemented with 2 tablets (Nova-QÒ; Pharma Gam, Cagliari, Italy), lipoic acid (300 mg/day, present in Nova-Q tablets), carbocysteine (FluifortÒ; Dompe’, Milan, Italy) (2.7 g/day), vitamin E (400 mg/day), vitamin A (30,000 IU/day), and vitamin C (500 mg/ day), all orally, was administered to all enrolled patients. It should be taken into account that a similar quantity of polyphenols is contained in a normal diet. Patients were then randomized 1:1 by random number table by and independent biostatician to: (1) L-carnitine (CarniteneÒ; SigmaTau, Rome, Italy) (4 g/day) þ Celecoxib (CelebrexÒ; Pfizer, Rome Italy) (arm 1) or (2) L-carnitine (CarniteneÒ; SigmaTau, Rome, Italy) (4 g/day) þ Celecoxib (CelebrexÒ; Pfizer, Rome Italy) þ megestrol acetate (MA) (320 mg/day) (arm 2). The planned treatment duration was 4 months. A placebo arm was not included for the following reasons: (1) it could not be considered ethical, as there is one treatment currently approved in Europe for the treatment of CACS, i.e. progestagens; (2) the results of two of our previous studies showing progestagens efficacy10,11; (3) the efficacy of progestagens vs placebo was observed in randomized clinical trials.12,13 2.2. Efficacy endpoints

2. Patients and methods 2.1. Study design The study was a phase III, randomized non-inferiority trial comparing the efficacy and safety of a two-drug combination (including nutraceuticals, i.e. antioxidants) with carnitine þ celecoxib

The primary efficacy endpoints were: an increase of LBM, an improvement of total daily physical activity. LBM was assessed by 3 methods: (1) conventional bioelectrical impedance analysis (Bioelectric Impedance Analyser 101, Akern Spa, Firenze, Italy)9; (2) dual-energy X-ray absorptiometry (DEXA) using a Hologic Delphi W scanner (Hologic Inc., Bedford, MA); and

178

C. Madeddu et al. / Clinical Nutrition 31 (2012) 176e182

(3) regional computed tomography (CT) at L3, currently considered the highest precision technique, able to provide more details on fatfree mass and specific muscle mass compared to DEXA or BIA.14 Total daily physical activity and the associated energy expenditure was carried out with an appropriate electronic device (SenseWear PRO2 Armband, SensorMedics Italia, Milan, Italy) which is able to identify the specific type of physical activity (e.g., walking, running, lying down) in such a way as to attribute to it a “functional quality”,15 and assess total energy expenditure (TEE), i.e., the sum of REE plus the energy spent in physical activity (active energy expenditure [AEE]).

treatment) was assessed using a paired Student’s t-test or Wilcoxon signed-rank test when appropriate. The analysis was performed on an intent-to treat basis. P values are reported including Bonferroni’s corrections for multiple comparisons. All analyses were carried out with two-sided tests using a 5% type 1 error rate. SPSS version 15.0 (SPSS Inc., Chicago, IL) was used. Results were considered significant for p < 0.05.

2.2.1. Secondary endpoint Secondary endpoint was the assessment of physical performance by grip strength through a Jamar Hydraulic Hand Dynamometer (Sammons Preston, Bolingbrook, IL) and 6-min walk test. For the grip strength assessment, the dominant hand was determined and then three consecutive hand grip tests were performed with the dominant hand followed by three consecutive hand grip strength tests in the other hand: the mean of the 3 values of the dominant hand was reported. The 6-min walk test was performed in a standardized fashion for each patient according to previously published guidelines.16 Briefly, the distance walked on a straight, flat surface in 6 min at a self-determined pace was measured. Patients were encouraged to walk as far as possible within the 6min test and were instructed to stop during the test if pain, dyspnea, or other symptoms developed; no encouragement was given during the test. The walked distance (i.e., the 6MWT) was recorded in meters. Additionally, fatigue, REE, body weight, appetite by visual analog scale and serum levels of IL-6 and TNF-a by enzyme-linked immunosorbent assays (Immunotech, Marseille, France), plasma levels of C-reactive protein (CRP) by nephelometry, QL by the EORTC-QLQ-C30 and GPS were also assessed. As for clinical outcome variables objective clinical response, progression-free survival (PFS), and overall survival (OS) have been reported. The endpoints were assessed before treatment and at 4, 8, and 16 weeks after treatment start.

From October 2009 to November 2010 approximately 80 patients were screened for the study: 60 of them met all the eligibility criteria and were thus selected for inclusion in the trial. The mean age was 65.2  8.7 years, range 46e82. Patients were randomly assigned to arm 1: L-carnitine þ celecoxib (n ¼ 31) or arm 2: L-carnitine þ celecoxib þ MA (n ¼ 29). All patients were referred to the Department of Medical Oncology, University of Cagliari. The patients enrolled in each arm were comparable at baseline on the basis of the most common stratification factors (Table 1). Four

2.2.2. Safety endpoints Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0).17 2.3. Statistical analysis Results from our previous clinical trial11 were used to determine the sample size, based on a two-sided t-test to detect noninferiority of LBM and total daily physical activity changes from baseline between the 2 treatment arms. On the basis of our previous clinical investigations, it was anticipated that arm 1 would have a 2.1 kg mean increase in LBM and that the expected standard deviation (SD) would be 1.5 kg. Using these calculations, and considering an a-type error of 0.05 and a b-type error of 0.20 (power 80%), a sample size of 30 patients per arm was needed to detect a mean LBM change 2.0 kg (assuming a SD of 1.0 kg) in each treatment arm. Differences between groups at baseline were analyzed by the c2 test for categoric variables and by Student’s ttest (or Wilcoxon rank sum test when appropriate) for continuous variables. The primary objective was to compare the two arms as for changes in the primary endpoints before and after treatment (16 weeks versus baseline) by carrying out the t-test for changes. Moreover, the benefit obtained as for primary and secondary endpoints in each arm (difference between baseline and after

3. Results 3.1. Patients

Table 1 Patient clinical characteristics. Arm 1 No. (%) Patients enrolled 31 Patients evaluable 29 (93.5) Male 17 (58.6) Female 12 (41.4) Age (years) 62.6  8.1 Weight (kg) 54.6  12.6 Height (cm) 162.8  9.8 BMI <18.5 9 (31) 18.5e25 16 (55.2) >25 4 (13.8) Weight loss <5 1 (3.4) 5e10% 15 (51.7) >10% 13 (44.9) Tumor site Head and neck 7 (24.1) Lung 6 (20.8) Colorectal 4 (13.8) Stomach 4 (13.8) Ovary 4 (13.8) Pancreas 3 (10.3) Esophagus 1 (3.4) Biliary ducts 0 Liver 0 Stage of disease IIIB 1 (3.4) IV 28 (96.6) ECOG PS 0 2 (6.9) 1 7 (24.1) 2 17 (58.7) 3 3 (10.3) Glasgow Prognostic Score 0 3 (10.3) 1: albumin<32 g/l 3 (10.3) 1: CRP >10 mg/l 10 (34.5) 2 13 (44.9) Concomitant palliative chemotherapy Yes 22 (76) No 7 (24)

Arm 2 No. (%)

pa

29 27 16 11 66.3  10.7 54.7  10.8 163.5  6.98

n.s.

n.s. n.s. n.s.

8 (29.6) 16 (59.3) 3 (11.1)

n.s.

2 (7.4) 14 (51.9) 11 (40.7)

n.s.

6 6 3 3 3 3 1 1 1

(22.1) (22.1) (11.1) (11.1) (11.1) (11.1) (3.8) (3.8) (3.8)

n.s.

2 (7.4) 25 (92.6)

n.s.

2 (7.4) 8 (29.6) 15 (55.6) 2 (7.4)

n.s.

4 (14.8) 3 (11.1) 9 (33.3) 11 (40.7)

n.s.

21 (78) 6 (22)

n.s.

n.s. Not significant. Abbreviations: BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status; CRP, C-reactive protein. a chi square.

C. Madeddu et al. / Clinical Nutrition 31 (2012) 176e182

patients (2 in arm 1 and 2 in arm 2) dropped out for early death due to progressive disease: therefore, 56 patients were evaluable (Fig. 1).

179

arm 2 (p ¼ 0.052). Appetite improved significantly in both arms. Results are reported in Table 2. 3.4. Clinical outcome variables

3.2. Primary efficacy endpoints Primary Efficacy Endpoints were assessed by the physician in charge monthly during periodical clinical visits. According to our primary objective, that is, a comparison between arms, the t-test for changes did not show significant difference between the two arms as for LBM and total daily physical activity. The analysis of changes from baseline showed that LBM, as assessed by DEXA, significantly increased both in arm 1 and in arm 2 (p ¼ 0.026 and p ¼ 0.036, respectively). The L3-CT analysis showed an improvement in the estimated LBM (kg) both in arm 1 and in arm 2 (p ¼ 0.048 and p ¼ 0.001, respectively). LBM as assessed by BIA did not change significantly in either arm. Indeed, BIA evaluation of LBM, which is an indirect assessment of fat-free mass, is currently considered an obsolete method in comparison to the most innovative and precise techniques such as DEXA (which measures directly the LBM expressed as kg) and CT scan. The changes of total daily physical activity between arms were not significant. The analysis of total daily physical activity did not show significant changes from baseline in either arm (only a trend for an improvement of AEE (kcal/day) was observed in both arms). Results are reported in Table 2. 3.3. Secondary efficacy endpoint The comparison between arms did not show significant differences. The assessment of physical performance by 6MWT test showed an improvement in both arms (p ¼ 0.015 and p ¼ 0.038, respectively), whilst grip strength by dynamometer did not change significantly in either arm (Table 2). As for the additional variables assessed, we observed that REE (p ¼ 0.041 and 0.048, respectively), fatigue (p ¼ 0.036, p ¼ 0.025, respectively), ECOG PS (p ¼ 0.009 and p ¼ 0.030, respectively) and GPS score (p ¼ 0.003 and p ¼ 0.015respectively) decreased significantly in both arms. Body weight did not change significantly in arm 1 (p ¼ 0.455), whilst it showed a trend toward an increase in

The objective clinical response was assessed according to the RECIST criteria18 by the physician in charge before and at the end of the treatment. It showed progressive disease (PD) in 50% of patients and did not change during treatment in either arm and was not different between the 2 arms. This suggests that the different antineoplastic treatments administered did not have different impact on the clinical outcome, nor was there interaction between the intervention arms. Likewise, the median PFS and median OS were not significantly different between arms. In detail, PD was observed in 48% of patients in arm 1 and 48.1% of patients in arm 2, stable diseases (SD) in 41% of patients in arm 1 and 43% of patients in arm 2, partial response (PR) in 11% of patients in arm 1 and 8.9% of patients in arm 2. Median PFS was 5.1  2.1 (range 2e12þ) months in arm 1 and 6.4  3.2 (range 3e14þ) months in arm 2. Median OS was 8  4.2 (range 4e24þ) months in arm 1 and 7.2  3.4 (range 3e14þ) months in arm 2. 3.5. Safety Specific treatment-related toxicity was quite negligible and comparable between treatment arms (Table 3). The very moderate side effects occasionally induced by the study treatment were very easily distinguishable from the well-known side effects of chemotherapy. Only two patients with grade 3 diarrhea were reported (1 in each arm), which led to the withdrawal of carnitine for 2 weeks. Overall, patient compliance was very good. 4. Discussion Clinical management of cancer cachexia is currently both limited and complex19 and therefore, to date, there is no a standard clinical approach for its treatment. Although several studies have been carried out none have achieved sufficiently satisfactory results to be proposed as standard treatment for CACS. Undoubtedly, one of the most interesting and certainly one with the largest sample size

Fig. 1. CONSORT Diagram. Abbreviations: PD, Progressive disease.

180

C. Madeddu et al. / Clinical Nutrition 31 (2012) 176e182

Table 2 Primary and secondary endpoints before and after treatment. Parameter

Arm 1

Arm 2

Baseline Primary endpoints LBM (kg) BIA DEXA L3-TC Physical activity Steps (count) TEE (kcal/day) AEE (kcal/day) AEE (min/day) METs (mean/day) Secondary endpoints Grip Strength (Kg) 6MW (meters) REE (Kcal/day) Fatigue (MFSI-SF score) Body weight (kg) Appetite (score) IL-6 (pg/ml) TNF alpha (pg/ml) CRP (mg/l) ECOG PS GPS Score EORTC-QLQ-C30

After treatment

39.8  8.3 38.6  9.5 31.9  12.6

pa

40.9  8.7 41.0  9.2 32.4  10.9

0.316 0.026 0.048

Comparison between arms

Baseline

pa

pb

44.6  5.9 43.8  6.4 41.8  8.5

0.676 0.036 0.041

0.407 0.333 0.656

After treatment

41.0  57.5 41.3  7.5 40.5  6

2739 1525 198 52 1.2

    

2595 455 184 66 0.2

3129 1538 227 72 1.3

    

2256 309 199 61 0.3

0.677 0.582 0.079 0.090 0.242

1803 1339 125 40 1.2

    

1209 498 118 32 0.3

3131 1847 306 78 1.3

    

2958 423 281 63 0.3

0.061 0.092 0.082 0.083 0.215

0.086 0.264 0.064 0.107 0.670

26.1 429 1334.6 27.3 54.6 6.2 24.7 27 29 1.8 1.2 60.6

           

8.9 55.8 279.9 19.1 12.6 2.3 28.2 4.96 37.3 0.5 0.7 16.3

29.9 474 1245 19.9 55.4 7.6 20.6 26.4 21.2 1.4 0.8 61.9

           

7.8 78.5 429 16.6 11.8 2.8 17.8 5.2 19.7 0.7 0.6 16.6

0.140 0.015 0.041 0.036 0.455 0.046 0.543 0.829 0.291 0.009 0.003 0.333

27.5 411 1440.6 22.3 54.7 5.9 22.4 27.6 21.8 1.7 1.1 63.9

           

8.2 86.6 139.8 21.8 10.8 1.8 26.8 9.4 28.1 0.6 0.7 16.2

29.2 464 1321 13.5 57.2 7.3 19.4 26.5 10.3 1.4 0.6 70.5

           

9.1 96.5 213 11.8 11.8 2.3 29.2 6.7 11.6 0.8 0.6 16.2

0.380 0.038 0.048 0.025 0.053 0.016 0.781 0.475 0.239 0.030 0.015 0.258

0.338 0.626 0.448 0.981 0.342 0.250 0.877 0.548 0.840 0.796 0.698 0.514

Abbreviations: LBM, lean body mass; BIA, bioimpedance analysis; DEXA, dual-energy X-ray absorptiometry; REE, resting energy expenditure; L3-CT, computed tomography at 3rd lumbar vertebra; IL, Interleukin; TNF, tumor necrosis factor; CRP, C-reactive Protein; ECOG PS, Eastern Cooperative Oncology Group performance status; GPS, Glasgow prognostic score; 6MW, 6-min walk test; EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30; MFSI-SF, Multidimensional Fatigue Symptom Inventory-Short Form. Bold types refers to statistically significant differences. a Student’s t-test for paired data. b t-test for change between arms.

of patients enrolled, is that recently published by us11: the results are very promising but its translation into clinical practice may be somewhat cumbersome due to the treatment complexity. Therefore, the aim of the present study was to attempt to design a clinical trial which should be at the same time easy to administer, effective and safe. Thus, we selected among the drugs tested in our previously published papers those which had been shown to be the most active components both as single-agent and in a combined approach.11 Firstly, we included L-carnitine. Indeed, a previous paper published by us showed that the L-carnitine administration (6 g/day for 30 days) was effective in improving fatigue and increasing LBM and appetite in 12 weight-losing advanced cancer patients.20 L-Carnitine is a cofactor required for transforming the free longchain fatty acids into acyl-carnitine and for their subsequent transport into the mitochondrial matrix to produce acetylcoenzyme A through the b-oxidation pathway. The relationship between coenzyme A and carnitine is pivotal for cell energy metabolism: coenzyme A is required for beta-oxidation, metabolism of several amino acids, pyruvate dehydrogenase synthesis, and Table 3 Toxicity assessed as the worst toxicity per patient. Arm 1

Diarrhea Epigastralgia Thromboembolism/Deep vein thrombosis

pa

Arm 2

Grade 1/2

Grade 3/4

Grade 1/2

Grade 3/4

0 1 0

1 0 0

0 1 0

1 0 0

Abbreviation: n.s., not significant. Bold types refers to statistically significant differences. a c2 test.

n.s. n.s. n.s.

thus for triggering the tricarboxylic acid cycle.21 Results from a recent experimental study in cachectic mice suggested that Lcarnitine ameliorates cancer cachexia by regulating serum TNFa and IL-6 levels as well as modulating the expression and activity of Carnitine Palmitoil Transferase in the liver.22 Recently, it has been shown that L-carnitine plays a central role in skeletal muscle fuel metabolism by reducing muscle carbohydrate use during lowintensity exercise and leading to a better matching of glycolytic pyruvate dehydrogenase complex and mitochondrial flux, thereby reducing muscle anaerobic energy generation during highintensity exercise.23 Moreover, there is evidence that L-carnitine is able to reduce oxidative stress and chronic inflammation, which are involved in the pathogenesis of cancer cachexia and its metabolic alterations.24 Some findings both in animal models25 and in humans26,27 demonstrated that administration of L-carnitine attenuates the inflammatory process in pathological conditions, reducing the circulating levels of proinflammatory cytokines and acute phase proteins. However, there are not yet data on cancer cachexia. Collectively, these metabolic effects resulted in a reduced patient perception of effort and fatigue.23 As a second drug to be combined with L-carnitine we selected a COX-2 inhibitor such as celecoxib: it was selected for its antiinflammatory and anti-catabolic properties and also because some recent clinical trials have showed its efficacy in cancer cachexia both as single agent28 and in combination.29 Moreover, in a recently published phase II non randomized study we demonstrated that celecoxib (300 mg/day for 4 months) was able to significantly increase LBM and decrease TNF-a as well as improve muscle strength, quality of life, performance status, and GPS without significant (grade 3e4) toxicities.30 In the present study, the anti-inflammatory activity of celecoxib may account for the decrease of GPS, an inflammation-based prognostic score, in both

C. Madeddu et al. / Clinical Nutrition 31 (2012) 176e182

arms. However, proinflammatory cytokines did not change significantly, probably for their high inter-patient variability in the small sample size of the present study. The treatment approach also included as basic treatment key antioxidant agents shown to be effective in our previous studies31e33: they can counteract CACS-associated oxidative stress involved in promoting hypothalamic anorectic pathways and upregulating protein degradation in cachexia inducing experimental tumors.34 Therefore, our combination treatment included both an anticatabolic agent, i.e., the anti-inflammatory agent celecoxib, directed toward both fat and muscle catabolism, and an anabolic agent, i.e., L-carnitine, able to improve muscle energy metabolism and synthesis of macromolecules such as contractile proteins.35 Indeed, long-term (24 weeks) intravenously administration of Lcarnitine (2 g/day) to uremic patients undergoing hemodialysis leads to an increase of about 7% in the diameter of type I and type IIa fibers, as well as to a reduction in atrophic fibers, thus suggesting a specific effect of L-carnitine on type I and IIa fibers, which are characterized by predominant oxidative metabolism and therefore require carnitine for fatty oxidation to produce energy. Considering the pathophysiology of cachexia, this could be an ideal therapeutic combination approach to reverse the abnormal metabolism of CACS.36 We have compared to this two-drug combination (arm 1) with the same combination þ MA. The rationale was: MA is currently the only approved drug for CACS in Europe and, moreover, it is supported by the largest literature in the field. The anticachectic mechanism of MA has not been as yet fully understood and may be partly attributed to glucocorticoid activity and its ability to downregulate the synthesis and release of proinflammatory cytokines37 and increase food intake by neuropeptide Y release.38 Several randomized studies in mixed groups of weight-losing cancer patients have suggested that MA improves appetite and stabilizes weight to an extent greater than placebo.39 However, the weight gain observed with progestagens is mainly made up of water and fat mass,12 having virtually no influence on LBM and functional activity.40 Recently, a Cochrane Database systematic review13 concluded that MA improves appetite and weight gain in cancer patients, whereas no conclusion about QL could be drawn. Moreover, progestagens have also relevant adverse effects such as thromboembolism, transient adrenal insufficiency, edema, and central nervous system effects (confusion, headache, dizziness, and sleep disturbances) which may limit the routine use of MA for the treatment of CACS.41 Therefore, the overall beneficial advantage vs the safety profile of MA for the treatment of CACS is still to be assessed. In the present trial we have not included eicosapentaenoic acid (EPA) since several studies failed to demonstrate its efficacy, especially as single treatment, and showed some difficulties in achieving patient compliance.42,43 However, very recently some clinical trials,44e46 not yet published when the present trial was started, have shown a somewhat positive effect of EPA for the treatment of weight-losing advanced cancer patients. Thalidomide was also not included, despite its moderate efficacy in improving some secondary endpoints as a single agent in our previous study11: the reasons were its relative scarce manageability, difficulty to acquire and often a poor compliance by patients for disturbing adverse effects (such as somnolence, peripheral neuropathy). Moreover, thalidomide administration requires a safety surveillance system because of its teratogenic potential for newborns. The results of the present study showed that both treatment arms were able to improve the primary endpoints LBM and total physical activity and the secondary endpoint physical performance (grip strength and 6MWT) and were substantially equivalent as for efficacy. Both treatment arms also obtained a significant improvement of

181

fatigue, a distressing symptom for cancer patients notoriously resistant to pharmacotherapy.47 Moreover, both arms showed to be safe. In conclusion, the results of the present study showed that the two-drug combined approach was not inferior to the arm containing MA. The lack of superiority of the arm containing MA may be an important finding taking into account our aim to develop an easy to administer, ambulatorial oral treatment with safe, low cost drugs which will be easy to translate into the current clinical practice. Additionally, it should be highlighted that the analysis of body composition showed that the arm including MA obtained an increase of water (data not shown): therefore, as already known, MA seems to induce an increase of body weight due mainly to increase of water. An urgent need for research in cancer cachexia is to define common diagnostic and outcome criteria in order to improve the robustness of conclusion of clinical trials and allow their translation into clinical practice. An important consideration regarding our study is that it shares as selected primary endpoints the same identified key features of cancer cachexia as defined by the recent international consensus.1 Moreover, it is worthy of note that the results of our study are validated by the use of the most renowned and innovative technique currently available (L3-CT) for the assessment of LBM. Indeed, the use of CT scan imaging for the evaluation of muscularity provides a high methodological standard and is an important development in our ability to diagnose, classify and evaluate the treatment of CACS.48 Furthermore, it is worth noting that we included as primary endpoint the “non-exercise free-living physical activity” and as secondary endpoint the assessment of physical performance capacity (by grip strength and 6MWT). These outcome measures for cachexia studies offer a patient-centered endpoint concerned with functional status, psychosocial well-being, independence and represents an additional significant tool for the evaluation of efficacy of medical anticachectic interventions.49,50 The results of the present study showed a non-inferiority of arm 1 (two-drug combination) vs arm 2 (two-drug combination þ megestrol acetate). Therefore, this simple, feasible, effective, safe, low cost with favorable cost-benefit profile, two-drug approach could be suggested in the clinical practice to implement CACS treatment. Conflict of interest The authors have no conflicts of interest to declare. Statement of authorship Each author has participated sufficiently, intellectually or practically, in the work to take public responsibility for the content of the article, including the conception, design, and conduction of the experiment and for data interpretation (authorship). CM and GM conceived, designed, coordinated the study, drafted the manuscript and revised it critically. CM also performed data collection and statistical analysis. FP, GA, FMT, MD and AM participated in the design and coordination of the study, carried out the studies, and helped to draft the manuscript. GA, RS, MCC, LM, QM and MM helped to carry out the studies. All authors read and approved the final manuscript. Acknowledgments We thank Ms. Anna Rita Succa for her technical assistance in editing the article. Appendix. Supplementary material Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.clnu.2011.10.005.

182

C. Madeddu et al. / Clinical Nutrition 31 (2012) 176e182

References 1. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011;12:489e95. 2. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009;89:381e410. 3. Argiles JM, Busquets S, Toledo M, Lopez-Soriano FJ. The role of cytokines in cancer cachexia. Curr Opin Support Palliat Care 2009;3:263e8. 4. Mantovani G, Maccio A, Massa E, Madeddu C. Managing cancer-related anorexia/cachexia. Drugs 2001;61:499e514. 5. Argiles JM, Olivan M, Busquets S, Lopez-Soriano FJ. Optimal management of cancer anorexia-cachexia syndrome. Cancer Manag Res 2010;2:27e38. 6. Del Fabbro E. More is better: a multimodality approach to cancer cachexia. Oncologist 2010;15:119e21. 7. Jatoi A, Rowland K, Loprinzi CL, Sloan JA, Dakhil SR, MacDonald N, et al. An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort. J Clin Oncol 2004;22:2469e76. 8. Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, et al. Dronabinol versus megestrol acetate versus combination therapy for cancerassociated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 2002;20:567e73. 9. Mantovani G, Madeddu C, Maccio A, Gramignano G, Lusso MR, Massa E, et al. Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment. Cancer Epidemiol Biomarkers Prev 2004;13:1651e9. 10. Mantovani G, Maccio A, Madeddu C, Gramignano G, Lusso MR, Serpe R, et al. A phase II study with antioxidants, both in the diet and supplemented, pharmaconutritional support, progestagen, and anti-cyclooxygenase-2 showing efficacy and safety in patients with cancer-related anorexia/cachexia and oxidative stress. Cancer Epidemiol Biomarkers Prev 2006;15:1030e4. 11. Mantovani G, Maccio A, Madeddu C, Serpe R, Massa E, Dessi M, et al. Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia. Oncologist 2010;15:200e11. 12. Simons JP, Schols AM, Hoefnagels JM, Westerterp KR, ten Velde GP, Wouters EF. Effects of medroxyprogesterone acetate on food intake, body composition, and resting energy expenditure in patients with advanced, nonhormone-sensitive cancer: a randomized, placebo-controlled trial. Cancer 1998;82:553e60. 13. Berenstein EG, Ortiz Z. Megestrol acetate for the treatment of anorexiacachexia syndrome. Cochrane Database Syst Rev 2005:CD004310. 14. Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab 2008;33:997e1006. 15. Dahele M, Skipworth RJ, Wall L, Voss A, Preston T, Fearon KC. Objective physical activity and self-reported quality of life in patients receiving palliative chemotherapy. J Pain Symptom Manage 2007;33:676e85. 16. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111e7. 17. National Cancer Institute e Cancer therapy evaluation program: common terminology criteria for adverse events v4.0 (CTCAE). Available at: http://ctep.cancer. gov/2009; May 28, 2009. 18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228e47. 19. Fearon KC. Cancer cachexia: developing multimodal therapy for a multidimensional problem. Eur J Cancer 2008;44:1124e32. 20. Gramignano G, Lusso MR, Madeddu C, Massa E, Serpe R, Deiana L, et al. Efficacy of l-carnitine administration on fatigue, nutritional status, oxidative stress, and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition 2006;22:136e45. 21. Stephens FB, Constantin-Teodosiu D, Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 2007;581:431e44. 22. Liu S, Wu HJ, Zhang ZQ, Chen Q, Liu B, Wu JP, et al. L-carnitine ameliorates cancer cachexia in mice by regulating the expression and activity of carnitine palmityl transferase. Cancer Biol Ther 2011:12. 23. Wall BT, Stephens FB, Constantin-Teodosiu D, Marimuthu K, Macdonald IA, Greenhaff PL. Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans: the dual role of muscle carnitine in exercise metabolism. J Physiol 2011;589:963e73. 24. Silverio R, Laviano A, Rossi Fanelli F, Seelaender M. L-carnitine and cancer cachexia: clinical and experimental aspects. J Cachex Sarcopenia Muscle 2011;2:37e44. 25. Miguel-Carrasco JL, Mate A, Monserrat MT, Arias JL, Aramburu O, Vazquez CM. The role of inflammatory markers in the cardioprotective effect of L-carnitine in L-NAME-induced hypertension. Am J Hypertens 2008;21:1231e7. 26. De Simone C, Tzantzoglou S, Famularo G, Moretti S, Paoletti F, Vullo V, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1e12.

27. Savica V, Santoro D, Mazzaglia G, Ciolino F, Monardo P, Calvani M, et al. Lcarnitine infusions may suppress serum C-reactive protein and improve nutritional status in maintenance hemodialysis patients. J Ren Nutr 2005;15:225e30. 28. Lai V, George J, Richey L, Kim HJ, Cannon T, Shores C, et al. Results of a pilot study of the effects of celecoxib on cancer cachexia in patients with cancer of the head, neck, and gastrointestinal tract. Head Neck 2008;30:67e74. 29. Cerchietti LC, Navigante AH, Peluffo GD, Diament MJ, Stillitani I, Klein SA, et al. Effects of celecoxib, medroxyprogesterone, and dietary intervention on systemic syndromes in patients with advanced lung adenocarcinoma: a pilot study. J Pain Symptom Manage 2004;27:85e95. 30. Mantovani G, Maccio A, Madeddu C, Serpe R, Antoni G, Massa E, et al. Phase II nonrandomized study of the efficacy and safety of COX-2 inhibitor celecoxib on patients with cancer cachexia. J Mol Med 2010;88:85e92. 31. Mantovani G, Maccio A, Madeddu C, Mura L, Gramignano G, Lusso MR, et al. Antioxidant agents are effective in inducing lymphocyte progression through cell cycle in advanced cancer patients: assessment of the most important laboratory indexes of cachexia and oxidative stress. J Mol Med 2003;81:664e73. 32. Mantovani G, Maccio A, Madeddu C, Mura L, Gramignano G, Lusso MR, et al. Quantitative evaluation of oxidative stress, chronic inflammatory indices and leptin in cancer patients: correlation with stage and performance status. Int J Cancer 2002;98:84e91. 33. Mantovani G, Maccio A, Madeddu C, Mura L, Gramignano G, Lusso MR, et al. The impact of different antioxidant agents alone or in combination on reactive oxygen species, antioxidant enzymes and cytokines in a series of advanced cancer patients at different sites: correlation with disease progression. Free Radic Res 2003;37:213e23. 34. Laviano A, Meguid MM, Preziosa I, Rossi Fanelli F. Oxidative stress and wasting in cancer. Curr Opin Clin Nutr Metab Care 2007;10:449e56. 35. Giovenali P, Fenocchio D, Montanari G, Cancellotti C, D’Iddio S, Buoncristiani U, et al. Selective trophic effect of L-carnitine in type I and IIa skeletal muscle fibers. Kidney Int 1994;46:1616e9. 36. Burckart K, Beca S, Urban RJ, Sheffield-Moore M. Pathogenesis of muscle wasting in cancer cachexia: targeted anabolic and anticatabolic therapies. Curr Opin Clin Nutr Metab Care 2010;13:410e6. 37. Mantovani G, Maccio A, Esu S, Lai P, Santona MC, Massa E, et al. Medroxyprogesterone acetate reduces the in vitro production of cytokines and serotonin involved in anorexia/cachexia and emesis by peripheral blood mononuclear cells of cancer patients. Eur J Cancer 1997;33:602e7. 38. McCarthy HD, Crowder RE, Dryden S, Williams G. Megestrol acetate stimulates food and water intake in the rat: effects on regional hypothalamic neuropeptide Y concentrations. Eur J Pharmacol 1994;265:99e102. 39. Madeddu C, Maccio A, Panzone F, Tanca FM, Mantovani G. Medroxyprogesterone acetate in the management of cancer cachexia. Expert Opin Pharmacother 2009;10:1359e66. 40. Inui A. Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin 2002;52:72e91. 41. Kumar NB, Kazi A, Smith T, Crocker T, Yu D, Reich RR, et al. Cancer cachexia: traditional therapies and novel molecular mechanism-based approaches to treatment. Curr Treat Options Oncol 2010;11:107e17. 42. Fearon KC, Von Meyenfeldt MF, Moses AG, Van Geenen R, Roy A, Gouma DJ, et al. Effect of a protein and energy dense N-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 2003;52:1479e86. 43. Dewey A, Baughan C, Dean T, Higgins B, Johnson I. Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev 2007:CD004597. 44. Weed HG, Ferguson ML, Gaff RL, Hustead DS, Nelson JL, Voss AC. Lean body mass gain in patients with head and neck squamous cell cancer treated perioperatively with a protein- and energy-dense nutritional supplement containing eicosapentaenoic acid. Head Neck 2010;33:1027e33. 45. van der Meij BS, Langius JA, Smit EF, Spreeuwenberg MD, von Blomberg BM, Heijboer AC, et al. Oral nutritional supplements containing (n-3) polyunsaturated fatty acids affect the nutritional status of patients with stage III non-small cell lung cancer during multimodality treatment. J Nutr 2010;140:1774e80. 46. Ryan AM, Reynolds JV, Healy L, Byrne M, Moore J, Brannelly N, et al. Enteral nutrition enriched with eicosapentaenoic acid (EPA) preserves lean body mass following esophageal cancer surgery: results of a double-blinded randomized controlled trial. Ann Surg 2009;249:355e63. 47. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P. A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst 2008;100:1155e66. 48. Baracos VE, Reiman T, Mourtzakis M, Gioulbasanis I, Antoun S. Body composition in patients with non-small cell lung cancer: a contemporary view of cancer cachexia with the use of computed tomography image analysis. Am J Clin Nutr 2010;91:1133Se7S. 49. Maddocks M, Byrne A, Johnson CD, Wilson RH, Fearon KC, Wilcock A. Physical activity level as an outcome measure for use in cancer cachexia trials: a feasibility study. Support Care Cancer 2010;18:1539e44. 50. Mantovani G, Madeddu C, Serpe R. Improvement of physical activity as an alternative objective variable to measure treatment effects of anticachexia therapy in cancer patients. Curr Opin Support Palliat Care 2010;4:259e65.