Thalidomide: the teratogenic drug that found a role in cancer treatment

Though once associated with tragedy, thalidomide now has promise as a treatment for patients with hematologic malignancies.

Nearly 50 years ago, an increasing number of babies worldwide were born with deformities and missing limbs. The babies had fallen victim to the teratogenic effects of thalidomide, a drug commonly taken at the time by pregnant women to avoid morning sickness.

A 1962 photo of a baby born with an extra appendage connected to the foot caused by the pregnant mother taking the drug thalidomide. Source: NCI

The thalidomide nightmare helped to broaden the FDA’s authority when it changed the way in which drugs are developed, tested and regulated within the United States. Although the drug is still commonly associated with horrific images of malformed babies, thalidomide has come full circle medically and now plays an important role in the treatment of multiple myeloma.

From drug approval to drug removal

In Germany in 1956, Chemie Gruenenthal GmbH, a small inexperienced pharmaceutical company, first introduced thalidomide (Contergan) as a non-barbiturate sedative-hypnotic. The drug, which was available without a prescription, was widely used in Germany and in 1960 sales reached 14.6 tons. Proven in animal models to be less toxic than its counterparts, thalidomide became widely popular throughout Europe and Canada. The drug was used to treat irritability, weak concentration, stage fright, anxiety, depression and hypothyroidism and was later used to treat morning sickness related to pregnancy.

At the time, the FDA did not approve thalidomide due to reported adverse effects associated with long-term use of the drug, including tingling of the hands and feet. New drug applications did not have to prove efficacy, but only safety. Frances Kelsey, MD, PhD, an FDA medical officer, continued to reject the drug’s applications for lack of proof that the drug was safe for humans, particularly for embryos. By this time, however, hundreds of doctors in the United States had received the drug for use in clinical trials. In 1961, early reports on safety were emerging from other countries, and it appeared that the FDA had made a wise decision.

In November 1961, a German pediatric geneticist at The University of Hamburg, Widulind Lenz, MD, discovered an association between thalidomide and an increase in the number of cases of phocomelia, a congenital malformation where hands and feet are attached to shortened arms and legs. Once Lenz notified the manufacturer of his findings, the drug was removed from the market.

One month later, in a letter written to The Lancet, William G. McBridge, MD, a gynecologist and obstetrician from Australia, documented similar associations between the drug and the birth of children with missing digits, limbs and phocomelia. In 1962, a report by Lenz confirmed the association and estimated that the number of cases of thalidomide embryopathy was about 4,400.

In response to the tragedy created by thalidomide, the United States Congress enacted legislation in 1962 to employ the rigorous testing that is required today before any drugs receive approval.

Adverse effects

Teratogenicity is the most severe and well-known adverse effect associated with thalidomide. Babies born with malformations such as amelia, phocomelia, bone hypoplasia and absence of bones resulted from the thalidomide tragedy. Abnormalities of the external ear, eye and neural tube, along with internal organ defects, congenital heart deformity and spina bifida are also documented harms.

Though the mechanism of teratogenic activity is not known, according to experts, the intact phthalimide or phthalimidine group may be responsible.

Treatment with thalidomide is also associated with neuropathy. Though peripheral neuropathy is usually reversible after drug discontinuation, cases of irreversible sensory loss have been documented.

Constipation and sedation are the most common adverse effects, which are assumed to relate to dose. More recently, however, when used in combination with conventional chemotherapy among patients with multiple myeloma and prostate cancer, thalidomide has been associated with a higher incidence of deep vein thrombosis.

Thalidomide comes full circle

In the mid-1960s, thalidomide was shown to be effective in the treatment of erythema nodosum leprosum, and in 1998 the FDA approved thalidomide (Thalomid, Celgene) for this indication. More importantly, however, is the role of thalidomide in the treatment of myeloma.

In a trial of 84 patients with multiple myeloma, 90% of whom relapsed after autologous stem cell transplantation, treatment with thalidomide was associated with an overall response rate of 32%. Additional trials demonstrated an overall response rate between 25% and 45% with responses lasting between nine and 12 months; after two years, 10% of patients were free of progression.

In 2006, the FDA approved thalidomide, in combination with dexamethasone, for use in patients with newly diagnosed multiple myeloma.

Though the reason for thalidomide’s activity in hematologic malignancies is unknown, some experts hypothesize that the therapeutic effect observed in myeloma is a result of the drug’s immunomodulatory properties.

Additional indications for thalidomide are continually being studied. Due to its effect on tumor necrosis factor-alpha, thalidomide is said to be effective in patients with inflammatory conditions such as arthritis and Crohn’s disease. Thalidomide is also used off-label for treating HIV-related mouth and throat ulcers and is thought to be effective in Kaposi’s sarcoma, weight loss and body-wasting associated with HIV.

Whether thalidomide is effective in additional cancers is an ongoing question. Preliminary results of thalidomide in combination with other drugs may be a promising treatment option for patients with numerous cancers, including renal cell, brain tumors, melanoma and myelofibrosis. Even if it proves not to be effective, thalidomide’s role in medical history and the evolution of drug regulation in the United States, is undeniably important. – by Stacey L. Adams

For more information:

• Annas GJ. Am J Public Health. 1999;89:98-101.
• Botting J. Drug News Perspect. 2002;15:604-611.
• Burkholz H. Giving thalidomide a second chance. Food and Drug Administration website. www.fda.gov/fdac/features/1997/697_thal.html.
• Franks ME. Lancet. 2004;363:1802-1811.
• Hussein MA. Expert Rev Anticancer Ther. 2005;5:25-31.
• Quick Reference: Fact Sheets. Thalidomide. March of Dimes website. www.marchofdimes.com/professionals/14332_1172.asp#head1. Updated August, 2008. Accessed Feb. 27, 2009.
• Silverman WA. Pediatrics. 2002;110:404-406.
• Thalidomide: Research advances in cancer and other conditions. Mayo Clinic website. www.mayoclinic.com/health/thalidomide/HQ01507. Updated Dec. 20, 2008. Accessed Feb. 27, 2009.
• von Moos R. Swiss Med Wkly. 2003;133:77-87.