Interest in thalidomide (Thalomid) has intensified in recent years as
research has identified and elucidated its immunomodulatory,
anti-inflammatory, and antiangiogenic properties. In this supplement,
we present a selection of abstracts about thalidomide from the 36th
Annual Meeting of the American Society of Clinical Oncology. The
abstracts are categorized by subject into solid tumors, hematologic
malignancies, and supportive care. To place these data into
perspective, we have invited Drs. Wen-Jen Hwu, of Memorial
Sloan-Kettering Cancer Center, James R. Berenson, of Cedars-Sinai
Medical Center and UCLA School of Medicine, and Eduardo Bruera, of
The University of Texas M. D. Anderson Cancer Center, to comment on
these important abstracts.
Thalidomide, also known as alpha-(N-phthalimido)glutarimide, consists
of a two-ringed structure with an asymmetric carbon in the
glutarimide ring. Thalidomide exists as an equal mixture of S-(-) and
R-(+) enantiomers that interconvert rapidly under physiologic
conditions. Thalidomide is sparingly soluble in water and ethanol,
which to date has prevented the availability of an intravenous formulation.
Mechanism of Action
Clinical investigations of thalidomide have been conducted in
patients with diverse diseases. Even though over the past several
years its antiangiogenic properties have been hypothesized to be the
major cause of its antitumor activity, thalidomides
immunomodulatory properties appear to be diverse, and the probable
factor in its success as an antitumor agent as compared to other pure
Thalidomide reduces phagocytosis by polymorphonuclear leukocytes.
This may explain its action in inflammatory processes that involve
predominantly mononuclear cell accumulation, such as chronic
cutaneous lupus erythematosus. Thalidomide inhibits monocyte
phagocytosis without any sign of cytotoxicity in monocytes or
polymorphonuclear cells. Thalidomide inefficiently, but
selectively, inhibits the production of tumor necrosis
factoralpha (TNF-alpha) in human monocytes in a dose-dependent
fashion, with no effect on total protein synthesis or the production
of other cytokines.[3,4] The process of inhibition is not a complete
one.[4,5] Thalidomide also reduces the half-life of TNF-alpha mRNA
from approximately 30 to 17 minutes.
Thalidomides ability to inhibit TNF-alpha production may depend
on the stimulus or the cellular source of production. In addition,
there are difficulties in measuring TNF-alpha levels in patients for
several reasons: the normal circulating level of the cytokine has not
been defined, its release in response to systemic inflammation is
often phasic, and its half-life is short.[6,7]
To complicate matters, there are two active forms of TNF-alphaa
membrane-bound protein and a circulating homotrimer, with only the
latter typically being a measurable component.[6,7] Measurements of
TNF-alpha levels may detect receptor-bound circulating homotrimer,
which may not be active. Thus, serum levels may not accurately
reflect TNF-alpha activity.
The ability of thalidomide to inhibit TNF-alpha production in vitro
has not always been reproducible in vivo. Indeed, in two studies,
increases in serum TNF-alpha levels were seen with thalidomide
treatment.[8,9] This discordance might be the case in solid tumor
malignancies, and does not appear to have an impact on response. (See
Dr. Wen-Jen Hwus commentary on thalidomide in solid tumors.)
TNF-alpha plays a critical role in the pathogenesis of plasma-cell
dyscrasia such as in multiple myeloma. This molecule might play a
central role in the pathogenesis of plasma-cellrelated
amyloidosis. More importantly, a large number of amyloid patients
have congestive heart failure, where the TNF-alpha levels appear to
be a central cytokine. Our group has shown that the TNF receptor
etanercept (Enbrel) has activity in managing the disease, and
certainly a drug such as thalidomide might also result in a
significant response in this group of patients with poor prognosis.
Multiple myeloma and other hematologic malignancies are targets to be
investigated for therapeutic benefit. In myeloma, cytokines that are
secreted into the microenvironment of the marrowsuch as
interleukin-6, interleukin-1-beta, interleukin-10, and
TNF-alphamodulate the growth and survival of myeloma cells;
thalidomide may alter the secretion and biologic activity of such
cytokines. DAmato and colleagues first demonstrated
thalidomides antiangiogenic activity, which has been postulated
to have clinical therapeutic applications in solid tumors and other
diseases. This aspect of the action of thalidomide is detailed in
Dr. Berensons commentary on thalidomide in hematologic
malignancies. More recently, experiments have shown that a
combination of thalidomide and sulindaca nonsteroidal
anti-inflammatory drug with antiangiogenic activityinhibited
angiogenesis to a greater degree than either agent alone. This
observation should be carefully studied, and considered for
application in a disease such as colon cancer or its predisposing conditions.
Another important aspect of thalidomides proposed mechanism of
action is its influence on T cells. In healthy volunteers,
thalidomide decreases the ratio of circulating helper T cells to
suppressor T cells, because of a reduction in helper T cells and an
apparent increase in suppressor T cells. Its effect may be
mediated at the level of cytokine regulation. A potent and specific
effect on cytokine production relating to helper T cells has been
shown. In peripheral blood mononuclear cell cultures, thalidomide
enhances the production of interleukin-4 and -5 and inhibits
interferon gamma production. Thalidomide is a potent costimulator
T cells in vitro. The drugs effects are synergistic with
stimulation by means of the T-cell receptor complex, thereby
increasing interleukin-2mediated cell proliferation and
interferon gamma production. Costimulation is more pronounced in CD8
lymphocytes than in CD4 lymphocytes. Based on these findings, the
combination of thalidomide and other cytokines is currently being
investigated, especially in malignancies that have shown some
response to interferons and interleukins.
Another mechanism that may be important in the management of
malignancies is related to thalidomides ability to cause
oxidative damage to DNA mediated by free radicals, which probably has
a role in the teratogenicity of thalidomide. Thalidomide, by
modulating the profile of adhesion molecules, may influence the
growth and survival of tumor cells. The adhesion of malignant
plasma cells to bone marrow stromal cells triggers the secretion of
cytokines, augmenting the growth and survival of myeloma cells and
inducing drug resistance in them.[10,19]
Dosage and Toxicity
As my colleagues have emphasized, there does not appear to be an
identified dose or schedule that should be followed when using
thalidomide. Several studies are focusing on defining this important aspect.
Toxicity related to thalidomide use is a critical issue that more
often than not results in premature discontinuation of an effective
therapy. From our experience, and that of others, it does appear that
the drug is not well tolerated when used in patients with poor
performance status, or when the dose is escalated in a rapid fashion.
Careful patient evaluation and education results in continuing
therapy in over 98% of the patients at the Cleveland Clinic. The most
common adverse effects are dose-dependent somnolence and
dizziness.[1,20] To minimize these complications, we administer
thalidomide as a once-daily dose in the evening, initiated at low
doses (50100 mg/d). The dose is escalated at 50100 mg/wk
to the maximum dose specified according to the disease or the
Relative to the dizziness, which appears to be related to the
hypotensive effect of the drug, special care should be taken to
ensure the patients fluid intake is increased. Patients should
also be advised to sit upright for a few minutes before standing from
a recumbent position. This is particularly important in diseases such
as multiple myeloma, where dehydration and low hemoglobin due to
different factors are common events. Tolerance to thalidomides
sedative properties usually develops over time.
Constipation is a common side effect experienced by 3% to 30% of
patients. Narcotics, decreased mobility, and electrolyte imbalances
worsen constipation. In our experience, initiating all patients on
two Senokot-S a day, to be titrated up to eight tablets according to
their symptoms, has eliminated this side effect. Chronic thalidomide
therapy can produce peripheral neuropathy. The neuropathy results
from axonal degeneration without demyelination in the sensory fibers
of the lower and occasionally upper extremities. Risk of peripheral
neuropathy appears to rise with patient age and cumulative dose of
thalidomide, resulting in an incidence of approximately 25% in
nonlepromatous patients on chronic thalidomide therapy.
We have shown that 35% to 40% of patients with plasma-cell dyscrasia
have a functional vitamin B12 and folate deficiency. Detecting
and treating this deficiency generally results in the drug being
better tolerated. Thalidomide-induced erythematous macular rash,
usually involving the trunk and back, has been reported. This rash is
not likely to be pruritic; it usually occurs within 2 to 13 days
after initiation and reverses after discontinuation, with or without
the use of antihistamines. Severe, life-threatening epidermal
damage has been reported.[1,21] Our policy is to observe the patients
carefully, and discontinue the drug only if the rash worsens.
Thalidomide is a complex immunomodulatory agent whose role in
oncology practice is as yet not fully clear. Studies to define the
dose, schedule, and role in combination with other cytokines and
chemotherapy are underway.
1. Thalomid capsules (thalidomide) prescription product insert.
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inhibits tumor necrosis factor-a production by stimulated human
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inhibits Th1 cytokine production in mitogen- and antigen-stimulated
human peripheral blood mononuclear cell cultures. Clin Exp Immunol
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primary human T lymphocytes, preferentially inducing proliferation,
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17. Parman T, Wiley MJ, Wells PG: Free radical-mediated oxidative DNA
damage in the mechanism of thalidomide teratogenicity. Nat Med
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19. Damiano JS, Cress AE, Hazelhurst LA, et al: Cell adhesion
mediated drug resistance (CAM-DR): Role of integrins and resistance
to apoptosis in human myeloma cell lines. Blood 93:1658-1667, 1999.
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21. Celgene. Request for Medical Information. Thalomid and cancer.
Document #702. Revised February 1999.
22. Beckmann MJ, Hussein MA, Lichtin A, et al: Low serum vitamin B12
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functional cobalamin deficiency (abstract 97). Am J Clin Pathol