Commentary on Abstract #2391

Thalidomide (Thalomid) is a derivative of glutamic acid that was introduced as a nonbarbiturate hypnotic in 1956 by a West German company. It was used widely as an over-the-counter sedative and antiemetic drug in countries other than the United States. Because of its presumed safety and antinausea effect, it was given to pregnant women suffering from morning sickness and to influenza patients experiencing nausea. Subsequently, over 12,000 malformed babies were born as the result of fetal exposure to thalidomide early in pregnancy. When its teratogenic effects-notably flipperlike limbs-became known, thalidomide was withdrawn from the market in 1961. In the mid-1960s, after it was given as a sedative to a small number of leprosy patients in Israel afflicted with erythema nodosum leprosum, it was noted that the patients’ symptoms rapidly and markedly improved.

Worldwide use over the past 30 years has confirmed thalidomide as the preferred treatment for moderate to severe erythema nodosum leprosum in men. From the 1960s to 1998, the drug was only available for compassionate use, or on an investigational basis for the treatment of erythema nodosum leprosum. Its immunomodulatory activity provided the rationale for continuing research in numerous disorders believed to have an autoimmune or inflammatory basis. Its teratogenic effects, particularly phocomelia (severe infant limb defects), seem to be related to the inhibition of blood vessel formation. It was this information that prompted researchers to examine thalidomide’s antitumor activity by inhibiting blood vessel formation in growing tumors.

FDA Experience With Thalidomide

Hirschfeld et al (abstract #2391) described the U.S. Food and Drug Administration (FDA) experience with thalidomide for advanced malignancies. Data were compiled from 480 patients who received thalidomide on a compassionate basis through the FDA’s single-patient investigational new drug (IND) program. Thalidomide was administered to patients with a wide spectrum of cancers at various doses ranging from 50 to 2,400 mg/d. More than half of the patients received either 200 or 400 mg/d. Thirteen percent of the patients received thalidomide for 1 year or longer. The most common malignancies were breast, glioblastoma multiforme, prostate, melanoma, colon, pancreas, and renal cell. Responses were reported in 36 patients. Of the responders, 10 were documented to have received other anticancer agents.

Thalidomide was generally well tolerated with no apparent severe toxicities. The toxicity profile is similar to those reported previously, including somnolence, constipation, rash, fatigue, mental status changes, and, less commonly, shortness of breath, dry mouth, and peripheral neuropathy (J Am Acad Dermatol 20:1060-1063, 1989; Blood 86:3604-3609, 1995; Clin Pharmacol Ther 6:292-297, 1965; Clin Pharmacol Ther 6:298-302, 1965; Br J Dermatol 108:461-466, 1983). In addition, thalidomide did not seem to enhance the toxicity of other anticancer agents when it was used as combination therapy.

This report indicates that thalidomide has little activity as a single agent in this heterogeneous population of patients with advanced malignancies. These results do not preclude the antitumor activity of thalidomide in other settings, such as in patients with micrometastases or less advanced disease. Moreover, they do not preclude the synergistic activity of thalidomide in combination with other classically active agents, such as chemotherapy, hormone therapy, or biologic therapy. Further studies that include patients with less tumor burden and/or in combination with other agents are warranted.