Current Status of Thalidomide in the Treatment of Cancer
Current Status of Thalidomide in the Treatment of Cancer
Dr. Rajkumar has written an excellent overview of the current status of thalidomide (Thalomid) in the treatment of cancer. There is a constant demand for novel therapeutic strategies as alternative or complementary options to the existing armamentarium of chemotherapeutic agents for various malignant disorders.
Angiogenesis has been studied extensively as a mechanism of tumor growth and metastasis, and many agents that may suppress angiogenesis are being evaluated. Among them are matrix metalloprotease (MMP) inhibitors, vascular endothelial growth-factor (VEGF) receptor inhibitors, anti-VEGF antibodies, anti-integrin antibodies, endogenous protein inhibitors, and vascular targeting agents. Thalidomide is an antiangiogenic agent with an unknown mechanism of action, and it does not fall into any of these categories. The most popularly held theories of thalidomide’s mechanism of action are that it is either antiangiogenic, immunomodulatory, or suppresses cytokines (tumor necrosis factor [TNF]-alpha, interferon-gamma, or interleukin-2). Thalidomide may also suppress VEGF or basic fibroblast growth factor (both of which stimulate angiogenesis), or it may act by inhibiting TNF-alpha. Suppression of TNF-alpha is important in inducing a response in patients with Crohn’s disease and may also be a mechanism of antitumor activity.
Short History of the Use of Thalidomide
Thalidomide was sold as an over-the-counter sedative in the 1950s. It then became popular as an antinausea agent for pregnant women. In the 1960s, due to its teratogenic effect, further sales were banned, and thalidomide became an "orphan drug." Just as the drug was being abandoned, initial clinical trials in various neoplasms were underway. The enthusiasm for clinical trials soon evaporated due to a lack of tumor responses and the teratogenicity observed in pregnant women. These trials were not focused on a specific type of malignancy and, therefore, could not assess response rates. Moreover, they did not consider the safety of the drug in patients with advanced malignancies who are either infertile or unlikely to be procreative because of associated morbidities or psychological and emotional status.
With interest in thalidomide abating in the mid-1960s, no further clinical trials of the drug were undertaken. However, its effect in erythema nodosum leprosum was recognized in the 1960s, leading to US Food and Drug Administration approval of its use. Subsequently, in the 1980s, its activity in graft-vs-host disease was observed. Renewed interest in the use of thalidomide was sparked by the recent enthusiasm for antiangiogenic therapy and the initial observation of activity in patients with refractory myeloma.
Recent work by various investigators has shown that tumors do not grow beyond 1 to 2 mm in size in the absence of angiogenesis. The first clinical trial to demonstrate the efficacy of antiangiogenic agents in the antineoplastic setting was a trial of thalidomide in multiple myeloma. Clinical trials in other hematologic malignancies, such as acute myeloid leukemia and myelodysplastic syndrome, are currently underway. The theory of angiogenesis was applied to other diseases, and it was soon discovered that microvessel density is associated with poor prognosis in a variety of solid tumors.[3-5]
The efficacy of thalidomide in the treatment of solid tumors, however, is uniformly disappointing, with only anecdotal complete responses reported in the literature. The response of solid tumors appears to be superior with a combination of chemotherapy and thalidomide rather than either agent alone. Thalidomide has been administered either with or without carboplatin (Paraplatin) in patients with recurrent high-grade gliomas and has produced reasonable response rates.[6,7] Patients with metastatic colon cancer who are refractory to prior fluorouracil (5-FU) therapy have demonstrated superior responses to the combination of thalidomide and irinotecan (Camptosar) vs irinotecan alone (historical data). The responses may also reflect greater tolerance to irinotecan due to this agent’s suppression of gastrointestinal toxicities.
The correct dose of thalidomide for patients with malignant disorders is unknown. When administered as a single agent, the initial dose is usually 200 mg/d, with escalations to a maximum dose of 1,200 mg/d. When used in combination with chemotherapy, the maximum dose is around 300 to 400 mg/d. Whether antitumor activity is initiated at a particular dose is also unknown.
Health-care professionals and patients who are likely to use thalidomide should take heed: The enthusiasm for trying a new drug in patients with no other option may override one’s awareness of the potential toxicitiesespecially teratogenicityof the drug. Thalidomide should be used cautiously.
Although thalidomide has been reborn in the field of oncology, its future as an antineoplastic agent is still undecided. Its exact mechanism of action needs to be understood. The minimum dose required to treat patients is also still undetermined. Thalidomide analogs, which do not have the same toxicities but retain the antiangiogenic and immunomodulatory properties, need to be developed. Whether this drug will have a future role in the therapeutic armamentarium of oncology will only be known once randomized trials demonstrate its efficacy in various malignant disorders.
1. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994.
2. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-1571, 1999.
3. Takahashi Y, Tucker SL, Kitadai Y, et al: Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer. Arch Surg 132:541-546, 1997.
4. Kitadai Y, Haruma K, Tokutomi T, et al: Significance of vessel count and vascular endothelial growth factor in human esophageal carcinomas. Clin Cancer Res 4(9):2195-2200, 1998.
5. Leon SP, Folkerth RD, Black PM: Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 77:362-372, 1997.
6. Glass J, Gruber ML, Nirenberg A: Phase I/II study of carboplatin and thalidomide in recurrent glioblastoma multiforme (abstract 551). Proc Am Soc Clin Oncol 18:144a, 1999.
7. Fine HA, Figg WD, Jaeckle K, et al: Phase II trial of antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 18(4):708-715, 2000.
8. Govindarajan R, Heaton K, Broadwater R, et al: Effect of thalidomide on gastrointestinal toxicity of irinotecan. Lancet 356:566-567, 2000.