Thalidomide in the treatment of cancer cachexia: A randomised placebo controlled trial

Mailpoint 813, Level E, South Block, Southampton General Hospital, Southampton SO16 6YD, UK.
Gut (Impact Factor: 14.66). 05/2005; 54(4):540-5. DOI: 10.1136/gut.2004.047563
Source: PubMed


Proinflammatory cytokines, especially tumour necrosis factor alpha (TNF-alpha), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-alpha synthesis, may represent a novel and rational approach to the treatment of cancer cachexia.
To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer.
Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double blind, randomised controlled trial. The primary outcome was change in weight and nutritional status.
Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients (eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had gained on average 0.37 kg in weight and 1.0 cm(3) in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference -2.59 kg (95% confidence interval (CI) -4.3 to -0.8); p = 0.005) and 4.46 cm(3) (absolute difference -5.6 cm(3) (95% CI -8.9 to -2.2); p = 0.002) in the placebo group. At eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm(3) in AMA compared with a loss of 3.62 kg (absolute difference -3.57 kg (95% CI -6.8 to -0.3); p = 0.034) and 8.4 cm(3) (absolute difference -7.9 cm(3) (95% CI -14.0 to -1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001).
Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer.

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    • "Therefore, thalidomide is a novel and rational treatment approach for CACS. In a randomized, placebo-controlled trial, thalidomide was found to be well tolerated and effective in slowing weight loss and improving arm muscle mass and physical function in 33 patients with advanced pancreatic cancer and CACS.36 Recently, a meta-analysis was performed to assess whether thalidomide is an effective treatment for CACS,37 and the authors concluded that there is inadequate evidence to recommend the use of this drug in clinical practice. "
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    ABSTRACT: Cancer-related anorexia and cachexia syndrome (CACS) is a complex multifactorial condition, with loss of lean body mass, chronic inflammation, severe metabolic derangements, reduced food intake, reduced physical activity, and poor quality of life as key symptoms. Cachexia recognizes different phases or stages, moving from precachexia through overt cachexia to advanced or refractory cachexia. The purpose of this review is to describe currently effective approaches for the treatment of cachexia, moving forward to drugs and treatments already shown to be effective but needing further clinical trials to confirm their efficacy. We then introduce novel promising investigational drugs and approaches which, based on a strong rationale from the most recent data on the molecular targets/pathways driving the pathophysiology of cachexia, need to be tested either in currently ongoing or appropriate future clinical trials to confirm their clinical potential. Although different drugs and treatments have been tested, we can speculate that a single therapy may not be completely successful. Indeed, considering the complex clinical picture and the multifactorial pathogenesis of CACS, we believe that its clinical management requires a multidisciplinary and multitargeted approach. In our opinion, appropriate treatment for cachexia should target the following conditions: inflammatory status, oxidative stress, nutritional disorders, muscle catabolism, immunosuppression, quality of life, and above all, fatigue. A comprehensive list of the most interesting and effective multitargeted treatments is reported and discussed, with the aim of suggesting the most promising with regard to clinical outcome. A critical issue is that of testing therapies at the earliest stages of cachexia, possibly at the precachexia stage, with the aim of preventing or delaying the development of overt cachexia and thereby obtaining the best possible clinical outcome for patients.
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    • "Several treatment interventions aiming to reverse or restrict the progression of cachexia, include the use of pharmacological interventions with anticachectic agents and the targeting of inflammatory cytokines thought to mediate cachexia, mainly TNF-α [62, 63]; however, results remain equivocal. Anti-TNF treatment in patients with chronic inflammatory diseases experiencing cachexia reported no increase in muscle mass despite improvements in inflammatory markers, disease activity and physical function [64, 65]. "
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    ABSTRACT: Cancer cachexia is a debilitating consequence of disease progression, characterised by the significant weight loss through the catabolism of both skeletal muscle and adipose tissue, leading to a reduced mobility and muscle function, fatigue, impaired quality of life and ultimately death occurring with 25-30 % total body weight loss. Degradation of proteins and decreased protein synthesis contributes to catabolism of skeletal muscle, while the loss of adipose tissue results mainly from enhanced lipolysis. These mechanisms appear to be at least, in part, mediated by systemic inflammation. Exercise, by virtue of its anti-inflammatory effect, is shown to be effective at counteracting the muscle catabolism by increasing protein synthesis and reducing protein degradation, thus successfully improving muscle strength, physical function and quality of life in patients with non-cancer-related cachexia. Therefore, by implementing appropriate exercise interventions upon diagnosis and at various stages of treatment, it may be possible to reverse protein degradation, while increasing protein synthesis and lean body mass, thus counteracting the wasting seen in cachexia.
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    • "À quatre semaines les patients sous thalidomide (200 mg/j) gagnaient 0,37 kg et 1 cm 3 de masse musculaire brachiale contre une perte de 2,21 kg (différence de −2,59 kg (95 % IC −4,3 à −0,8) ; p = 0,005) et 4,46 cm 3 (différence de −5,6 cm 3 (95 % IC −8,9 à −2,2) ; p = 0,002) dans le groupe placebo. À 8 semaines, les patients du groupe thalidomide avaient perdu 0,06 kg contre une perte de 3,62 kg (différence de −3,57 kg (95 % IC −6,8 à −0,3) ; p = 0,034) dans le groupe placebo [38]. La thalidomide n'avait pas d'effet sur l'appétit et ne peut donc être considéré comme un orexigène. "

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