More on Megesterol for Prevention and Treatment of Cancer-Associated Cachexia

ABSTRACT & COMMENTARY

Synopsis: In this report of a clinical trial at a single institution in the Netherlands, treatment with MPA was associated with increased food intake, higher resting energy expenditure, and weight gain. The added weight was accounted for by an increase in fat mass without a significant gain in fat-free mass. MPA was well tolerated and may prove to be a useful adjunct in the treatment of patients with cachexia associated with advanced malignancy

Source: Simons JP, et al. Cancer 1998;82:553-560.

There remains controversy on the efficacy of medroxyprogesterone acetate (MPA) for the treatment of cancer-associated cachexia. Simons and colleagues report results from a carefully designed and executed and well-monitored study. In this double-blind clinical trial, 54 patients with non-hormone-sensitive cancer (predominantly lung primaries) and weight loss were randomly assigned to receive either MPA (500 mg) or placebo twice daily for 12 weeks. Food intake was measured by dietary history, body composition by deuterium-labeled water redistribution, and resting energy expenditure by indirect calorimetry. This three-month trial showed significant differences between the arms. The group taking MPA had increased food intake, a transient increase in resting energy expenditure, and an increase in fat mass (but no significant enhancement of fat-free mass). The increase in fat mass (between group difference) was 2.5 kg at 12 weeks (P = 0.0009). Fat-free mass was also slightly increased in the MPA group, but this was mostly comprised of edema; lean body mass excluding edema was not significantly influenced by the treatment. Resting energy expenditure increased significantly in the MPA-treated patients. Although several of the enrolled patients were not evaluable for a number of reasons, it appears that the MPA was well tolerated, producing even fewer side effects than placebo treatment.

COMMENTARY

The treatment of cancer-associated cachexia has been met with frustration. One reason for this is that typically, loss of body weight is an indicator of both progressive and aggressive disease. In fact, weight loss has become a biological marker of disease and it is likely that without effective treatment aimed directly at the tumor, any substantive alteration in body composition (positive or negative) would change the natural history of the disease. However, other factors (e.g., depression) may contribute to weight loss, and, to the extent that energy reserves are important in host defense, an effort to enhance nutrition and reduce weight loss may be of clinical value. Also, there are the questions of quality of life, self-image, and mood, which were not addressed in this study, but which might offer additional rationale for such approaches.

Another factor accounting for the frustration in the treatment of cancer-associated cachexia is the lack of a demonstrably effective agent. Several, such as glucocorticoids, cyproheptadine, and hydrazine have been proposed, but none have been proven effective in appropriately controlled prospective randomized clinical trials. However, the synthetic progestins (MPA and megesterol acetate) have met with some success in that they have been shown to improve appetite and produce weight gain independent of tumor response in patients with breast cancer,1,2 with similar but less well-documented results in patients with other malignancies.3,4 In these trials, it appeared that appetite was stimulated, but it was not clear whether this or the associated fluid retention accounted for weight gain.

The current trial from a single institution in the Netherlands attempts to address this question. Enrolled patients had malignancies considered to be hormone insensitive, and, for the duration of the trial (12 weeks), they received no other anti-tumor therapy. Of the 54 enrolled patients, only 33 were ultimately evaluable. Drop-outs occurred almost equally in the two treatment groups, with the most common causes being death or physical deterioration (7 patients), side effects (4 patients, all in the placebo group), or protocol violations (3 patients). Despite the attrition, there were sufficient evaluable patients to observe significant responses, particularly in body composition. At 12 weeks, the MPA patients had a mean gain in fat mass of 1 kg whereas the placebo-treated group had a mean loss of 1.5 kg. This is likely to relate to the observed increased food intake in the MPA group (as recorded by personal food diaries). Four of the MPA-treated patients had developed edema, and, when this was accounted for, there was no significant gain in fat-free mass. No patients experienced tumor regressions.

The findings are of value because they document a definite weight gain attributed to increased food intake and an associated gain in fat mass. Whether this is beneficial in treatment response or survival remains to be determined, but it is likely that it will have some influence on self image and quality of life for patients with advanced malignancy.

References

1. Loprinzi CL, et al. J Natl Cancer Instit 1990;82:1127.

2. Tchekmeydian NS, et al. Cancer 1992;69:1268.

3. Rowland KM, et al. J Clin Oncol 1996;14:135.

4. Simons JP, et al. J Clin Oncol 1996;14:1077.