January 28, 2009 — Thalidomide may have use in the treatment of men who have biochemical recurrence of prostate cancer or a rise in their prostate-specific antigen (PSA) count after definitive therapy, according to a new randomized study from the National Cancer Institute.
In this population, the use of thalidomide was associated with an increase in PSA progression-free survival after intermittent androgen-deprivation therapy (ADT).
The median time to a new PSA increase was 17.1 months for thalidomide (vs 6.6 months for placebo) in the second phase of the study's crossover design. The effect occurred despite the fact that thalidomide, which has been shown to have antiangiogenic activity, had no effect on testosterone, note the study authors, led by William D. Figg, PharmD, head of the Molecular Pharmacology Section of the Center for Cancer Research at the National Cancer Institute, in Bethesda, Maryland, in a study published online January 23 in the Journal of Urology.
However, the study's use of ADT in men with "biochemical recurrence" was critically questioned in an accompanying editorial comment.
"PSA relapse after definitive therapy is common and is often associated with an excellent prognosis," writes Tomasz M. Beer, MD, associate professor of medicine in the Division of Hematology and Medical Oncology at the Oregon Health and Science University Cancer Institute, in Portland. "Hormonal therapy has not been shown to improve overall survival or delay clinically meaningful events in this setting."
But the researchers point out that intermittent ADT is "increasingly being used in patients with biochemical recurrence," and there might be "a role for instituting early treatment," they suggest.
In outlining their rationale for the study, the authors further explain that there is some research that suggests that ADT is better sooner rather than later. "The increasing use of ADT is based on studies suggesting clinical benefit in patients with early-stage prostate cancer treated earlier with ADT compared to those receiving it later in the disease course."
Dr. Figg and colleagues also note that the efficacy of antiangiogenic agents, such as thalidomide, is likely to be the greatest early on, when the disease burden is minimal.
Thalidomide was previously shown to be effective in combination with chemotherapy in patients with metastatic prostate cancer (Clin Cancer Res. 2001;7:1888; J Clin Oncol. 2004;22:2532) and, thus, was a candidate for treatment in earlier-stage disease, they suggest.
Study Details
All patients in the study had androgen-dependent adenocarcinoma of the prostate and 2 consecutively increasing PSA counts after local definitive therapy with radical prostatectomy, radiation therapy, or cryosurgery.
In phase A of the analysis, 147 patients were initially administered gonadotropin-releasing hormone agonists (GnRH-A) for 6 months, and subsequently received thalidomide or placebo. GnRH-A generally consisted of leuprolide (22.5 mg for 3 months) or goserelin (10.8 mg for 3 months).
For patients in phase A, the median time to PSA progression for those taking thalidomide was 15 months, compared with 9.6 months for those taking placebo (P = .21).
Once patients had PSA progression, defined by an increasing PSA greater than 5 ng/mL or reaching a minimum of 1 ng/mL, they were retreated with a GnRH-A for another 6 months, and then crossed over to the opposite treatment. This was phase B, which was completed by 88 patients.
The median time to PSA progression during phase B for the thalidomide group was 17.1 months, and for the placebo group was 6.6 months (P = .0002).
Thalidomide had no grade 3 or 4 toxicities that occurred in more than 5% of patients. Grade 2 hot flashes occurred in nearly half of the men in both the thalidomide and placebo groups, likely because of the ADT. The second most common side effect was grade 2 constipation, occurring in 41% of thalidomide-treated men and in 16% of placebo-treated men. Fatigue was also a common problem, occurring in 18.5% of thalidomide-treated men and in 10.6% of placebo-treated men.
Larger studies with longer follow-ups are needed to determine the usefulness of thalidomide in this setting, note the study authors.
Hormonal Therapy's Potential
Despite his criticisms, Dr. Beer praised the researchers for the novel approach to treatment in the study. "The authors should be congratulated for testing a novel antiangiogenic strategy in combination with androgen-deprivation therapy, rather than the more conventional approach of testing innovative approaches with chemotherapy," he writes in the editorial comment.
Dr. Beer also endorsed the idea of attempting to improve ADT. "Enhancement of hormonal therapy has great potential to improve outcomes in early- and late-stage prostate cancer," he writes. The potential is greater than that of chemotherapy, he notes, which has a much lower median time to progression (about 6 months) than hormonal therapy, with its median time to progression ranging from 16 to 48 months.
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