According to a randomized study run and reported by William D.Figg, PharmD, head of the Molecular Pharmacology Section of the Centerfor Cancer Research at the National Cancer Institute, in Bethesda, MD. And published online January 23, 2009 in the Journal of Urology (Vol. 181, pp.1104-13), Thalidomide may be effective for the treatment of men who have experienced a biochemical recurrence of prostate cancer (a rise in their PSA) after receiving another primary treatment.

Thalidomide inhibits the growth of new blood vessels (angiogenesis) and works as a potent anti-inflammatory. In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities as a consequence of thalidomide use by their pregnant mothers. Because of these startling deformities, Thalidomide almost became a lost drug. Today, researchers have started investigating Thalidomide for treating symptoms of prostate cancer, glioblastoma, lymphoma, arachnoiditis, Behçet’s disease, and Crohn’s disease. In a small clinical trial, Australian researchers found thalidomide sparked a doubling of the number of T cells in patients, allowing the patients’ own immune system to attack cancer cells.

In this study of prostate cancer survivors, the use of thalidomide was associated with an increase in PSA progression-free survival, the gold standard for success. The median time to a new PSA increase was 17.1 months for those men receiving thalidomide vs. 6.6 months for men receiving a placebo. What was more interesting was that this effect occurred despite the fact that thalidomide has no effect on testosterone levels. Since it does not make a man castrate the myriad negative side effects which are associated with traditional hormone therapy can be avoided.

In an accompanying editorial comment by Tomasz M. Beer, M.D., Associate Professor of Medicine in the Division of Hematology and Medical Oncology at the Oregon Health and Science University Cancer Institute, the current practice of using hormone therapy (ADT) to fight a biochemical recurrence was called into question. Dr. Beer said that, “PSA relapse after definitive therapy is common and is often associated with an excellent prognosis…..hormonal therapy has not been shown to improve overall survival or delay clinically meaningful events in this setting.”

Despite this claim, ADT is increasingly being used in men with biochemical recurrence and many researchers believe that there is good reason for instituting early ADT treatment. They state that there is research that suggests ADT is more effective when it is started earlier 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.

Similarly, 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 against metastatic prostate cancer (Clinical Cancer Research Vol. 7, p. 1888, 2001 and the Journal of Clinical Oncology 2004; Vol. 22, pp. 2532, 2004).

All men in Dr. Figg’s study were diagnosed with androgen dependent adenocarcinoma of the prostate and experienced two consecutively increasing PSA counts after local definitive therapy with radical prostatectomy, radiation therapy, or cryosurgery.

In phase A of the study’s analysis, 147 men were given gonadotropin- releasing hormone agonists (GnRH-A) for 6 months, and subsequently received thalidomide or placebo. GnRH-A generally consisted of leuprolide (22.5 mg every 3 months) or goserelin (10.8 mg every 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 = 0.21). Once men had a 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 = 0.0002).

Less than 5% of men in the study experienced grade 3 or 4 toxicities from the administration of the Thalidomide. Grade 2 hot flashes occurred in nearly half of the men in both the thalidomide and placebo groups, likely because of the ADT, not the thalidomide. The second most common side effect was grade 2 constipation, occurring in 41% of drug treated men and in 16% of placebo- treated men. Fatigue was also common; occurring in 19% of thalidomide treated men and in 11% of placebo treated men.

In conclusion, larger studies with longer follow-ups are needed to determine the usefulness of thalidomide in this setting.

Medscape, 28 January 2009

Joel T Nowak, MA, MSW