Mechanism of Action of High Dose Progestins in CACS

Our early experience (first half of the 1980s) has clearly demonstrated that the use of 'high' doses (i.e. more than 500 mg daily intramuscularly, IM or orally, PO) of medroxyprogesterone acetate (MPA) in the treatment of advanced breast cancer patients can increase body weight in about 50% of treated patients [3]. It was associated with a better appetite and performance status and seemed to be unrelated to a direct antineoplastic effect (Fig. 1, top). Therefore, we assumed that high-dose MPA had an anabolic effect, similar to that observed with testosterone derivatives [1, 2]. Nevertheless, some questions concerning the body weight

Fig. 1. High-dose (> 500 mg/day) medroxyprogesterone acetate in cancer patients. Top Subjective remission in breast cancer patients. Bottom Improvement in appetite/body weight in hormone-sensitive tumours (HST) or non-hormone-sensitive tumours (NHST). (Modified from [3,4])

increase arose from these observations:

1. Is it related to or independent from the anti-tumour effect of MPA?

2. Is it based on a 'true' anabolic effect or a steroidal effect?

3. To what extent is it due to fluid and electrolyte retention?

The first question has been answered in a trial on a group of 65 patients with non-hormone-sensitive tumours, undergoing treatment with 2000 mg/day of MPA (Fig. 1, bottom): appetite (anorexia) improved in 62% of patients, while body weight increased significantly (more than 0.5 kg) in 63% [4].

In order to try to demonstrate a 'true' anabolic effect, a group of 10 patients with advanced nonhormone-sensitive cancer was submitted to treatment with high-dose MPA (> 500 mg/day, PO or IM) for 30 days. Before and after treatment, anthropometric parameters (body weight, skin-fold plicometry, muscular strength) and metabolic parameters (protein, calories and nitrogen intake, measured by dietary survey; urinary nitrogen excretion measured by Kieldahl's method, and nitrogen balance) were registered. While anthropometric parameters showed no significant increase, except for muscular strength (24.4 kg before, 29.1 kg after, p < 0.02), we clearly demonstrated [5] a significant improvement in the nitrogen balance, protein and caloric intake (Fig. 2). Finally, in another group of 10 advanced cancer patients, no detectable effect on water and salt metabolism was demonstrated [6] by the evaluation of the exchangeable sodium pool with the 22Na method.

A possible explanation of the 'true' anti-cachectic effect of this drug was found by some authors [7, 8] who studied the influence of MPA administration on the various pro-cachectic cytokines, showing a down-regulatory effect on the synthesis and release of interleukin (IL)-1, IL-2, IL-6, tumour necrosis factor-a (TNF-a) and serotonin.

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