Elsevier

Clinical Nutrition

Volume 31, Issue 2, April 2012, Pages 176-182
Clinical Nutrition

Original article
Randomized phase III clinical trial of a combined treatment with carnitine + celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome

https://doi.org/10.1016/j.clnu.2011.10.005Get rights and content

Summary

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 + 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 + Celecoxib 300 mg/day or arm 2, l-carnitine 4 g/day + celecoxib 300 mg/day + 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 + 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.

Introduction

Cachexia has been recognized for a long time as an adverse effect of cancer. It occurs in 50–80% 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 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)-α play central roles in the pathophysiology of 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-α.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, l-carnitine (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

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 + 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).

Section snippets

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 + celecoxib (arm 1) vs carnitine + celecoxib + 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

Patients

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 46–82. Patients were randomly assigned to arm 1: l-carnitine + celecoxib (n = 31) or arm 2: l-carnitine + celecoxib + MA (n = 29). All patients were referred to the Department of Medical Oncology, University of Cagliari. The patients enrolled in each arm were comparable at

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 of patients enrolled, is that recently published by us11: the results are very promising but its

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

Acknowledgments

We thank Ms. Anna Rita Succa for her technical assistance in editing the article.

References (50)

  • V.E. Baracos et al.

    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)
  • M.J. Tisdale

    Mechanisms of cancer cachexia

    Physiol Rev

    (2009)
  • J.M. Argiles et al.

    The role of cytokines in cancer cachexia

    Curr Opin Support Palliat Care

    (2009)
  • G. Mantovani et al.

    Managing cancer-related anorexia/cachexia

    Drugs

    (2001)
  • J.M. Argiles et al.

    Optimal management of cancer anorexia-cachexia syndrome

    Cancer Manag Res

    (2010)
  • E. Del Fabbro

    More is better: a multimodality approach to cancer cachexia

    Oncologist

    (2010)
  • A. Jatoi 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)
  • A. Jatoi et al.

    Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study

    J Clin Oncol

    (2002)
  • G. Mantovani et al.

    Cancer-related anorexia/cachexia syndrome and oxidative stress: an innovative approach beyond current treatment

    Cancer Epidemiol Biomarkers Prev

    (2004)
  • G. Mantovani 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)
  • G. Mantovani et al.

    Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia

    Oncologist

    (2010)
  • J.P. Simons et al.

    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)
  • E.G. Berenstein et al.

    Megestrol acetate for the treatment of anorexia-cachexia syndrome

    Cochrane Database Syst Rev

    (2005)
  • M. Mourtzakis et al.

    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)
  • ATS statement: guidelines for the six-minute walk test

    Am J Respir Crit Care Med

    (2002)
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