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
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
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
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
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
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,