THALIDOMIDE FOR THE TREATMENT OF BIOCHEMICALLY RECURRENT PROSTATE CANCER (PSA Recurrence)

According to a randomized study from the National Cancer Institute 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 and failing another primary treatment.  This study was 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.

In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with significant deformities as a consequence of thalidomide use by their pregnant mothers.  Because of these startling deformities doctors stopped perscribing it, Thalidomide almost became a lost drug.

Today, researchers have rediscovered Thalidomide and started investigating it for treating symptoms of prostate cancer, glioblastoma, lymphoma, arachnoiditis, Behçet’s disease, and Crohn’s disease.  In a small 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.  Additionally,  Thalidomide inhibits the growth of new blood vessels (angiogenesis) which are required by tumors to grow as well as working as a potent anti-inflammatory.

In this population of prostate cancer survivors, men with biochemical recurrences, the use of thalidomide has been shown to be  associated with an increase in PSA progression-free survival.  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, had no effect on testosterone levels, thus not causing the myriad negative side effects which are associated with the removal of testosterone (ADT).

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 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 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.

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. The drug 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 the study were diagnosed with androgendependent adenocarcinoma of the prostate and had two consecutively increasing PSA counts after local definitive therapy with radical prostatectomy, radiation therapy, or cryosurgery.

In phase A of the 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).

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, 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.

So, why isn’t Thalidomide in more common usage today?  Why do we rarely hear about it from our doctors?  Yes,  larger studies with longer follow-ups are needed to confirm the usefulness of thalidomide in this setting, but then again there is some serious questions about the ability of traditional ADT to extend life.

Maybe economics are involved in this?  The drug manufacturers  can not make the level of profits from a generic drug like Thalidome that can be made from one of their drugs under a patent.

Medscape, 28 January 2009

Joel T Nowak, MA, MSW

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