Cabergoline Reduces Efficacy of Radiotherapy in Cushing’s Disease, Small Study Suggests

Cushing’s disease patients who are treated with cabergoline while undergoing conventional fractionated radiotherapy have a higher risk of disease recurrence after initial remission, a small study has found.

The study, “Cabergoline may act as a radioprotective agent in Cushing’s disease,” was published in Clinical Endocrinology.

Radiation therapy can be an effective method of controlling Cushing’s disease — a condition caused by a tumor in the pituitary gland — particularly when the tumor cannot be removed surgically or when surgery fails to remove the whole tumor.

Conventional fractionated radiotherapy, or CRT, is a form of radiation therapy in which lower doses of radiation are given over a longer period.

The current medical literature suggests that CRT is effective at achieving remission in about three-quarters of Cushing’s disease patients, and to date, there has not been any documented case of recurrence following such a remission.

However, the researchers behind the new study found this to be inconsistent with their experience in the clinic, where they found disease recurrence after CRT in a few of their Cushing’s disease patients.

Thus, the researchers analyzed their data for Cushing’s patients treated with CRT to better understand the treatment’s long-term outcomes.

The analysis included data for 42 patients (12 males and 30 females) who were followed for at least one year after radiation therapy. They were 24 years old on average. Two patients received CRT as the first line of treatment; the remainder had surgery first.

In total, 29 (69%) achieved clinical remission, which occurred a median of one and a half years after CRT. Of these, six (20.7%) later experienced recurrence, a median of 74 months after initial remission. Using statistical models, the researchers looked for clinical factors that were predictors of remission.

They found that most clinical features, including age, sex, disease severity, and tumor characteristics, were not associated with recurrence, but one clinical feature was: the use of cabergoline around the same time as CRT, referred to as peri-CRT cabergoline use. In fact, peri-CRT cabergoline use was found in all six people who experienced a recurrence.

Cabergoline is a medication that works on the pituitary gland to decrease the secretion of adrenocorticotropic hormone, the hormone that ultimately drives excess production of cortisol, which is the defining feature of Cushing’s syndrome.

Importantly, peri-CRT cabergoline use was not significantly associated with whether an individual would go into remission in the first place but was associated with whether they would experience recurrence after an initial period of remission. Additionally, this association was independent of follow-up time and the use of another medication, ketoconazole (which was the only other medication analyzed).

Based on this finding, the researchers speculated that peri-CRT cabergoline use might offer pituitary tumors protection against radiotherapy.

Specifically, they pointed to the fact that radiation is most effective in killing cells that are actively dividing — which is why it is used against cancer cells that divide rapidly and uncontrollably. The researchers noted that previously published data suggests that dopamine agonists (the class of drugs to which cabergoline belongs) may stop pituitary cancer cells from dividing, which may in turn limit the efficacy of CRT.

At this point, such a “radioprotective” (protective against radiotherapy) effect is largely speculative, since the current study showed only an association, not a cause-and-effect relationship. The small sample size and the fact that treatment was provided on a case-by-case basis do not allow more robust conclusions to be drawn as would a clinical trial with a larger sample size and stricter protocols.

“Use of cabergoline in the peri-CRT period did not affect initial remission after CRT but was associated with increased recurrence after initial remission,” the researchers stated. “Hence, we caution against the peri-CRT use of cabergoline in [Cushing’s disease] patients. However, further studies with larger number of patients and longer follow-up as well as basic in-vitro studies to elucidate radioprotective effects of cabergoline are needed.”