LISBON, Portugal — The benefits and risks of giving patients medical therapy after surgery to prevent regrowth of nonfunctioning pituitary adenomas (NFPAs) was the first of a series of debates at the European Congress of Endocrinology (ECE) 2017, with the final vote revealing a 50-50 split of opinion from the audience.
NFPAs are the second most common type of pituitary tumor. NFPA-affected patients experience a variety of symptoms caused by the pressure of the tumor on the surrounding tissue, including headaches and visual disturbances. Surgery is the treatment of choice; the debate centered on what to do next.
Radiation therapy can be effective in preventing tumor regrowth but is used sparingly due to unpleasant and serious side effects such as headaches, nausea, pituitary damage, and injury to the optic nerve. Therefore, 50% of patients experience tumor regrowth and require further surgery and radiotherapy.
A departure from this standard of care of radiation therapy or further surgery upon tumor regrowth is the use of the dopamine agonist cabergoline immediately after surgery. Data from a retrospective analysis published in 2016 suggest a significant benefit from this new approach (Eur J Endocrinol. 2017;175;63-72).
Don’t Know Which Tumors Will Grow Further: Treat Them All?
Speaking in favor of adding medical therapy was Yona Greenman, MD, from Tel Aviv-Sourasky Medical Center, Israel, who was the lead author of this 2016 study.
“This treatment is effective, and side effects are minimal. [Use of cabergoline] prevents the need for invasive interventions, which have far more serious side effects and complications than oral therapies,” she urged.
And although she conceded that in giving preventive treatment with cabergoline it was not yet possible to know which patients would go on to progress, she noted that the number needed to treat (NNT) for cabergoline to prevent the growth of one tumor is just 2.5 and to prevent additional surgery or radiation is 3.3.
By comparison, the NNT with statins to prevent one nonfatal myocardial infarction (MI) in an individual who has already had an MI is about 40.
Arguing against this approach was Stylianos Tsagarakis, MD, from Evangelismos Athens General Hospital, Greece, who presented the case for not treating residual tumors with medical therapy, preferring instead to use radiotherapy upon tumor regrowth.
“My main objection to medical therapy is that it is not possible to select which patients will experience recurrence,” he pointed out.
“If the tumor is aggressive then the patients should receive surgery and radiotherapy immediately, but if it is more indolent, the patient should be monitored for regrowth and given radiotherapy if necessary, because it is far more effective,” he added.
“The radiotherapy doses used in these cases [tumor regrowth] are low dose with minimal exposure risk to the patient,” he noted. And importantly, only 40% to 50% of patients experience recurrence.
“These tumors are slow growing and many will shrink on their own. If we have to treat 50% of patients for nothing then I’m reluctant to do this. If medical therapy is used widely after surgery then many patients would receive potentially unnecessary therapy over many years,” he explained.
Dopamine Agonist Postsurgery Reduces Tumor Size by 38%
Discussing the specific data from her 2016 study, Dr Greenman explained that the study included patients who had undergone surgery for NFPAs and had residual tumor detected on postoperative MRI.
One patient group received postoperative preventive drug therapy with cabergoline (n=55, preventive-treatment group); two other groups were included — patients who received drug therapy upon detection of tumor regrowth during follow-up (remedial-treatment group, n=24), and a control group that received no medication (n=60).
Tumor mass decreased in 38% of patients vs 0, remained stable in 49% vs 53%, or enlarged in 13% vs 47% in the preventive group and control groups, respectively; in the remedial-therapy group, shrinkage or stabilization was achieved in 58% of enlarging tumors (P < .0001).
More Studies Needed
Both Drs Tsagarakis and Greenman did agree that more studies are needed, ideally a randomized controlled trial (RCT), but funding is not forthcoming currently. “We also need a long follow-up to monitor outcomes with recurrence as an end point, which can take many years to occur,” Dr Tsagarakis highlighted.
Dr Greenman noted that common practice currently is not to treat, and patients are not given the option of medical therapy: “Doctors are still skeptical. It’s difficult to change practice that has been followed for years.”
Regarding side effects, Dr Tsagarakis noted that dopamine agonists have been used in Parkinson’s disease but at very high dose (3 mg/day), whereas in the treatment of NFPAs, the dose aimed for with cabergoline was 2 mg/week, which is substantially lower.
He pointed out that evidence showed that there is a risk of heart-valve disease with the use of cabergoline in Parkinson’s disease, but that there remains some uncertainty with respect to this when the drug is used at these lower doses in tumors.
Dr Greenman said “no valvular abnormalities have been associated with these [tumor] doses, despite the concern.”
She also noted that cabergoline was and continues to be the treatment of choice for prolactinomas, the most prevalent pituitary tumor, “and its safety record is robust based on decades of treatment in thousands of patients.”
In closing Dr Tsagarakis reiterated: “I don’t want to give therapy that is unnecessary for many of my patients….In the case of NFPA, this is radiotherapy — and new forms are safer in terms of side effects such as secondary tumors.”
Dr Greenman again summarized her key points. “This treatment [cabergoline] is effective and prevents the need for invasive interventions that have far more serious side effects and complications than oral therapies.
“I think [NFPA] patients should at least be given the option and have a choice in this, rather than sitting and waiting for the tumor to grow.”
At the start of the debate 56% of delegates were in favor of medical therapy and 44% against. After the debate the figures settled at 50-50 for both sides.
Dr Tsagarakis and Dr Greenman have declared no relevant financial relationships.
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European Congress of Endocrinology 2017. May 21, 2017; Lisbon, Portugal.
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