悪液質に対する運動と薬物療法

今日は、5th Cachexia Conferenceの抄録集の中から、Exercise, anticatabolic strategies and the treatment of cachexiaの抄録を紹介します。

Exercise, anticatabolic strategies and the treatment of cachexia
Giovanni Mantovani, Clelia Madeddu, Antonio Macciò
Department of Medical Oncology, University of Cagliari, Italy

悪液質ではないがんのリハにおける運動療法（積極的な有酸素運動とレジスタンストレーニング）の有効性はかなり検証されてきています。がんのリハはリハ領域でもトピックといえます。

ただ、悪液質のがん患者に対して、どの程度の運動療法を行うのがよいのかのエビデンスはまだ不明です。この抄録では、廃用を予防し身体活動を推奨する程度の運動は、多領域からの悪液質に対する包括的治療として記載されています。今後の研究課題ですが、現時点では維持的なリハは行うべきと考えています。

CRPがいくつ以下なら積極的リハ可能、いくつ以上なら維持的リハのみ可能という単純な基準があれば一番わかりやすいのですが、そのような基準も今のところはありません。ただ、プレアルブミンに関しては16以上なら積極的リハ可能、5以下なら維持的リハのみ可能とはいえると思います。

あと薬物療法として、メドロキシプロゲステロン、EPA（エイコサペンタエン酸）、L-カルニチン、サリドマイド（日本では奇形児の問題が大きかったので、現在は多発性骨髄腫でしか使えませんね）およびこれら4種類すべての5群間でがん悪液質への効果があるかをみたランダム化比較試験では、4種類すべて投与した群で除脂肪体重が有意に増加し疲労が改善し、大きな副作用は認めなかったようです。

日本でそのまま臨床応用できる研究結果では全くありませんが、悪液質に対しては原疾患に対する治療とともに、食事療法、運動療法、薬物療法の併用が必要なことは確かだと思います。NSTでもここまで踏み込んだ提案をすることが望ましいと考えています。

Physical activity, and even more so, exercise tolerance are greatly reduced (by approximately 40%) in cancer cachexia due to wasting of lean body mass and fatigue. On the other hand, as physical activity is also an important component of the physical and social domains of quality of life (QL), any restoration of physical activity levels and exercise training may translate into an improvement in QL for cachectic cancer patients [1].
Physical activity and exercise should require a normal muscle mass, and an adequate level of QL and motivation, both lacking in cachectic patients. The cachectic status itself and the related lack of physical activity, in turn, may worsen cachexia thus triggering a vicious circle. Therefore, it is crucial to act on both components, i.e. lean body mass and patient motivation. As for the increase of lean body mass a central role is played by anticatabolic strategies which should have as a target:
- the reduction of the production/release of the proinflammatory cytokines
- the inhibition of the muscle protein catabolism by inhibiting the ubiquitin/proteasome pathway(bortezomib and EPA)
- an increase on muscle protein synthesis (steroid androgen receptor modulators – SARMs -, oxandrolone)
- the increase of energy intake, by ghrelin and ghrelin mimetics

As regards the patient motivation, physical activity itself and exercise, such as programs of resistance training and aerobic exercise, may have an important role and may contribute, in turn, to an increase of lean
body mass [2]. When devising a therapeutic program for cancer cachexia, the emphasis should be placed on multimodal therapies that tackle all issues simultaneously. These interventions should combine highprotein nutritional supplements, the downregulation of proinflammatory cytokines and chronic inflammation by anti-inflammatory agents and routine mobilisation programs to prevent deconditioning and encourage physical activity. In this context, we have carried out a phase III randomised clinical trial in cachectic cancer patients to establish which was the most effective and safest treatment to improve lean body mass and fatigue as primary end-point, and as secondary endpoint, among others, the increase of physical activity level measured by a portable electronic device. Three hundred and thirty-two assessable patients with cancer cachexia were randomly assigned to one of five arms of treatment: 1 - medroxyprogesterone 500 mg/d or megestrol acetate 320 mg/d; 2 - oral supplementation with EPA; 3 - L-carnitine 4 g/d; 4 - thalidomide 200 mg/d; 5 - a combination of the above agents. Treatment duration was 4 months. Analysis of changes from baseline showed that LBM significantly increased in the combination regimen (arm 5).
Fatigue improved significantly in arm 5. Total daily physical activity showed that total energy , and active energy, expenditure increased significantly in arm 5. Toxicity was substantially negligible and comparable
between treatment arms [3].

The results of our trial, showing the efficacy of a combined treatment approach, seem to confirm the basic assumption that the treatment of cancer cachexia, a multifactorial syndrome, is more likely to yield success
with a multitargeted approach which may have the potential to reverse the predominant features of cachexia, i.e. progressive loss of muscle mass and function and improve the associated symptoms that affect QL.

References:
1. K.C.H. Fearon. Cancer cachexia: Developing multimodal therapy for a multidimensional problem.
Eur J Cancer 2008; 44: 1124-1132
2. Lee W Jones, Neil D Eves, Mark Haykowsky, Stephen J Freedland, John R Mackey. Exercise intolerance in cancer and the role of exercise therapy to reverse dysfunction.
Lancet Oncol 2009; 10: 598–605
3. Mantovani G, Maccio’ A, Madeddu C, Serpe R, Massa E, Dessì M, Panzone F, Contu P. Randomised phase III clinical trial of 5 different arms of treatment on 332 patients with cancer cachexia.
The Oncologist, submitted for publication, July 2009