PEARL I & PEARL II: Diamonds in the EBM Rough

Published - Written by John Staples

Can uterine fibroids be a big problem? They were for Mrs Mahadevamma. In 2005, she had a 66-pound fibroid removed by Dr Pushpanjali Malipatil and his team, earning both patient and surgeon a spot in the Guinness World Records.

Although the majority of fibroids are only a fraction of the size of the record-setting tumor, they can still result in menorrhagia, iron-deficiency anemia, pelvic discomfort, and impaired fertility. A number of treatment alternatives (see NEJM studies from Edwards et al. and Goodwin et al.) are available, but more effective and better-tolerated options are badly needed.

In this week’s NEJM, Dr. Jacques Donnez (Université Catholique de Louvain, Brussels, Belgium) and colleagues present two short-duration, double-blind, multi-center trials that examine the utility of ulipristal acetate (a progesterone receptor modulator) prior to planned surgery in pre-menopausal women with symptomatic uterine fibroids.

In the PEARL I trial, 237 women with fibroids, excessive uterine bleeding, and anemia were randomized to ulipristal 5mg daily, ulipristal 10mg daily, or placebo. At the end of the 13-week trial, uterine bleeding was controlled for about 92% of ulipristal-treated women compared to only 19% of the placebo-treated group (p<0.001 vs. either ulipristal group). The fibroid volume shrunk for the ulipristal groups (21% smaller in size for the 5mg group and 12% smaller for the 10mg group) to a greater extent than it did for the placebo group (3% larger in size; p<0.01 vs. either ulipristal group). From this, the authors conclude that ulipristal is more effective than placebo for the medical treatment of symptomatic fibroids.

Run in a clinical setting similar to that of PEARL I, the PEARL II trial provides evidence that daily oral ulipristal is non-inferior to monthly intramuscular leuprolide acetate for the medical treatment of symptomatic fibroids prior to planned uterine surgery. Notably, the ulipristal groups experienced significantly fewer hot flashes than the leuprolide acetate group, suggesting that ulipristal is the better-tolerated treatment.

In an editorial accompanying the PEARL I & II trial reports, Dr. Elizabeth Stewart (Mayo Clinic, Rochester, Minnesota) characterizes these studies as “an important step” toward effective medical therapy for fibroids. But challenges remain. In both trials, an unusual histological pattern of benign, “non-physiologic” endometrial change occurred in the majority of ulipristal-treated women. Although the changes resolved within six months of drug discontinuation, the potential long-term adverse effects of ulipristal on the endometrium are somewhat concerning. Dr. Stewart believes this is one reason longer-duration trials are necessary.

“Fibroids are incredibly common, and the symptoms they cause can be extremely troubling to patients,” says primary care provider and NEJM deputy editor Dr. Caren Solomon, “While more (and longer term) studies are needed to inform the appropriate role for ulipristal in fibroid therapy, the PEARL trials make an important contribution to the search for better medical treatments for uterine fibroids.”