**5.6 Megace**

Megestrol acetate (Megace) stimulates appetite, increases feeding behavior, alone-reduces lean body mass-but in combination with testosterone therapy and resistance exercise training, increases lean body mass in underweight elderly men [29]. This combination of Megace, testosterone, and resistance training may be beneficial in cancer patients. Megace alone decreased muscle mass but when combined with testosterone AND exercise resulted in a substantial increase in muscle mass in 12 weeks of training and administration [29]. It was hypothesized by the authors that Megace binds to the androgen receptor and blocks the action of testosterone. However, when combined with resistance exercise and testosterone replacement (100 mg/week) resulted in substantial muscle growth (hypertrophy). Therefore, resistance exercise, in some way acts, permissively to allows underweight elderly men to maintain muscle mass when testosterone is low and in the face of testosterone replacement to increase muscle mass. Likely, this is through the androgen receptor.

### **5.7 Testosterone and anabolic steroids**

Testosterone and anabolic steroids are anabolic to skeletal muscle [30]. Bhasin et al. [30] illustrated the fact that testosterone is anabolic to skeletal muscle in stepwise fashion with increasing dosage. The correlation between log testosterone and lean body mass (a surrogate for muscle mass) was 0.73, a very strong correlation. Urban et al. [6] reported that the mechanism of action of testosterone, with regard to, skeletal muscle anabolism in elderly individuals with low testosterone (testosterone < 480 ng/dL), was an increase in muscle protein synthesis which appear by elevated muscle IGF-1 concentrations and to be mediated by an elevation of IGF-1 in skeletal muscle. Cancer patients in general are hypogonadal (testosterone concentrations less than 300 ng/dL; Burney et al. [31]). Therefore, the administration of testosterone or its much less androgenic (secondary side effects) analogue anabolic steroids would appear to be a logical step in the treatment of cancer cachexia which may at least partly be due to low testosterone concentrations. The only caveat is that cancers that are hormone sensitive may not be a good candidate for testosterone or anabolic steroid therapy due to possible proliferation of the tumor. Nandrolone decanoate, an intramuscular injectable anabolic steroid and oxandrolone, an oral anabolic steroid are very low in secondary side effects because of their low androgenic to anabolic ratio. They have been used in other disease populations such as HIV [7] for oxandrolone and nandrolone decanoate [8]. Thus, the utility of these drugs along with testosterone in cancer would appear unquestionable. Clinical trials using these anabolic agents in an off label fashion in multiple types of cancer is warranted.

### **5.8 Monoclonal antibodies**

A logical step in decreasing the cachexia associated with cancer would be neutralizing circulating IL-6 and TNF-α with monoclonal antibodies.

There are many monoclonal antibodies to TNF-α FDA approved for other uses. To the best of my knowledge, there are one or a few monoclonal antibodies to IL-6 for different indications than cancer. Clearly, as discussed in a recent letter to the editor [5], this would be a very important application of monoclonal antibody technology.
