Thalidomide in Trials for Treatment of Prostate and Other Cancers
Positive Use for a Tragic Drug
November 19, 1999 New York /PSA Rising/ -- Thalidomide has been shown to
prevent the development of new blood vessels, a process known as angiogenesis.
A tumor cannot grow beyond the size of a pinhead without forming new blood
vessels to supply its nutritional needs. By blocking the development of new blood
vessels, researchers aim to cut off the tumor's supply of oxygen and
nutrients, indirectly stopping its growth and spread to other parts of the body.
Earlier this month at the annual meeting of the Chemotherapy Foundation in New York, Dr. William Figg reported on his trial of thalidomide for prostate cancer. The trial was a randomized Phase II study of the effectiveness of thalidomide for patients whose prostate cancer had come back after hormonal therapy. In these patients the cancer had spread to their bones. All the patients had stopped benefiting from combined androgen blockade and also had used up any benefit from withdrawal of the blockade drugs. Patients stayed on Lupron or Zoladex.
Dr. Figg said that he and his team decided to try thalidomide because prostate cancer is "highly dependent on new blood vessels" in order to grow and metastasize. The drug has a definite effect on the disease. "Thalidomide upregulates PSA," he said. He added that in his experience there is "no correlation between benefit and Gleason score."
The patients in this NCI study were randomized into two arms according to dose. Fifty patients (7 with D1 disease, 23 with D2) got a relatively low fixed dose of 200 mg/day. A smaller group of 14 patients started at 200 mg/day and took increasing doses by steps to a maximum of 1200 mg/day. PSA's were measured monthly. The patient took bone scan and computerized tomography (CT) every two months to measure the effect of the drug on tumors.
The researchers tested the patients' blood for proteins (VEGF, bFGF) that are known to activate endothelial cell growth and movement, because endothelial cells are the source of new blood vessels and have a remarkable ability to divide and migrate.
Fifty-eight percent of patients on low-dose got some decline of PSA and 68% at high dose. Eighteen percent at low dose had a more than 50% drop. Four patients got more than 50% drop maintained for more than 150 days (153, 191+, 191+, and 384 days, respectively). "No patient had a partial response on CT scan, but 2 patients had one or more lesions improve by bone scan and less pain/narcotics," Dr. Figg said.
Most patients had little if any benefit measurable by scans. The median time on study was around two months at low or high dose. The first scans were taken at two months. Half of the patients quit before going more than two months, either it didn't do anything for them or they could not tolerate the side-effects.
The main limiting side-effect of thalidomide in adult patients is neuropathy - tingling and numbness of the hands and feet on account of nerve-damage. These patients (if they stayed on study) had nerve conduction tests every 3 months.
Sleepiness, lethargy and sedation are common side-effects (thalidomide started out as a sedative). More than half of patients experience this. To minimize the impact, they took the drug at night. Constipation was quite serious for about 15% of patients, but treatable. Some patients experienced edema, headache, or dizziness.
Other centers testing Thalidomide include:
- New York University Medical Center, where Michael L. Gruber and Jon Glass have tried Thalidomide
plus carboplatin for Glioblastoma
Marsden/ Medical Oncology, University College, London, UK, where Tim Eisen has run
Thalidomide as continuous low-dose single agent for solid tumors. No prostate cancer patients enrolled. Good results in renal cancer.
Dr. Tim Eisen at Royal Marsden says that in the UK they won't (yet) allow testing of the high doses used in the USA. Thalidomide, he says, has multiple effects. According to Eisen, all antiagiogenic therapy seems most effective given daily or intermittently over along period. Therefore, for Thalidomide low dose appears to be essential. But then time to response may be quite long. Peripheral neuropathy is the main problem. His team required electrophysiological studies before and during treatment.
"We therefore chose to give a continuous (i.e. daily) low dose of 100 mg in this group of patients many of whom had previously received neurotoxic chemotherapy." In 66 patients median age 48 range 33-62, with advanced measurable cancer (ovarian, renal, melanoma, breast, lung -- no prostate), the dose given was 100 mg nightly till progression or toxicity. This regime was "well tolerated" for at least 11 (eleven) months even in patients who had previous neurotoxic therapy. But still 2 patients during 11 months developed grade 2 peri-neuropathy "which resolved when treatment was interrupted." Lethargy at this low dose was quite mild.
Eisen said palliative benefits may be immediate but "tumor shrinkage quite slow."
Related Stories External links will open in a new window
Thalidomide: From Dangerous Sedative to Anti-Cancer Drug (PSA Rising. November 1999)
Anti-Neuropathy Drug in Clinical Trials - effective against cisplatin and taxane drugs (PSA Rising, April 2000)
Thalidomide: Potential Benefits and Risk. An Open Public Scientific Workshop
Sponsored by the National Institutes of Health and the Food and Drug Administration,
September 9-10, 1997, Bethesda, MD.
Thalidomide Neuropathy National Institutes of Health (NIH) Thalidomide Meeting 9/9/97
Trust: Peripheral Nerve, a Closer Look
Supporting people affected by the neurological condition - PERIPHERAL NEUROPATHY
NCI's Division of Clinical
Sciences Will Test Thalidomide
in Patients with Advanced
Colon Cancer August 6, 1999
Thalidomide Information, FDA Center for Drug Evaluation and Research, July 16 1998
EntreMed page on Antiangiogenesis drugs including thalidomide
Thalidomide promotes metastasis of prostate adenocarcinoma cells (PA III) in L-W rats
Pollard M, Cancer Lett 1996 Mar 19;101(1):21-4
For links to some online cancer databases and journals see PCa Research page