US Pharm.2008;33(7)(Oncology
suppl):3-13.
ABSTRACT:
Thalidomide, a drug once thought to have no clinical benefit due to its
significant toxicity, has now become a potential agent for the treatment of
hematologic malignancies and some solid tumors. Thalidomide in combination
with dexamethasone is approved for use in multiple myeloma. Current study data
show promising results for hepatocellular carcinoma, prostate, neuroendocrine,
and ovarian cancers, but larger studies are needed to fully define the role of
thalidomide in these cancers.
The serendipitous discovery of
novel uses for medications is not a new phenomenon. Drugs such as minoxidil
and finasteride for hair growth, nitroglycerin for vasodilation, and warfarin
for blood thinning effects all have their own unique development story.
Thalidomide, a drug once thought to have no clinical benefit due to its
significant toxicity, is approved for use in multiple myeloma and has now
become a potential agent for the treatment of various cancers. This article
aims to educate pharmacists about the history, mechanism of action,
indications, toxicities, and special dispensing requirements for thalidomide.
History of Thalidomide
Thalidomide was
first introduced in Germany in 1957 as an OTC sedative. It was also marketed
in 46 countries for the treatment of morning sickness in pregnant patients.1
Over the next few years, case reports of severe birth defects started to
appear. The most significant adverse events were amelia (lack of a limb) and
phocomelia (seal limb) in children whose mothers had taken thalidomide during
pregnancy. Other reported adverse events included deformities of the heart,
kidney, and eyes; absent or abnormal ears; cleft lip or palate; spinal cord
defects; and disorders of the gastrointestinal tract.1 It is
estimated that 8,000 to 12,000 infants were affected worldwide.2
The United States was not as widely affected as other countries due to delayed
approval of the drug by the FDA over concerns of peripheral neuropathy. During
the delayed approval process, evidence of the severe teratogenicity became
apparent and the product was removed from the worldwide market in 1962.1,2
In 1965, Sheskin et al
reported symptom resolution of erythema nodosum leprosum (ENL), an
inflammatory complication of leprosy, in a patient who was treated with
thalidomide for his insomnia.3 This eventually led the FDA to
approve thalidomide for the use of ENL in 1998.1 Due to its various
postulated mechanisms of action, thalidomide was soon being investigated for
use in a variety of cancers.
Pharmacology
The mechanism of
action of thalidomide has not been fully elucidated. However, it is known that
thalidomide possesses immunomodulatory, anti-inflammatory, and antiangiogenic
properties. The immunologic effects are caused by a suppression of excessive
tumor necrosis factor-alpha production and a down-regulation of selected cell
surface adhesion molecules that are involved in white blood cell migration.
Other anti-inflammatory properties come from suppression of macrophage
involvement in prostaglandin synthesis, and modulation of interleukin-10 and
interleukin-12 production by monocytes and lymphocytes. Thalidomide has also
been shown to increase the number of circulating natural killer cells, level
of interferon gamma, and level of interleukin-2.4 The
anti-angiogenic properties of thalidomide are thought to be caused by
inhibition of vascular endothelial growth factor and basic fibroblast growth
factor.5 The combination of these effects are thought to be
responsible for the anticancer activity of thalidomide.
Approved Uses in Cancer
Thalidomide in
combination with dexamethasone is currently FDA approved for use in patients
with newly diagnosed multiple myeloma. It is important to note that this
indication is based on response rates in clinical trials. To date, no increase
in survival has been shown in clinical trials.4 The use of
thalidomide for multiple myeloma was first reported by Singhal et al in 1999
in patients with relapsed/refractory multiple myeloma.6 Subsequent
single-agent studies showed response rates of 15% to 48%.7
Additional studies showed that thalidomide doses of up to 400 mg daily plus
pulse-dose dexamethasone (20 mg/m2 for 4 days beginning on days 1,
9, and 17, repeated for 3 cycles) increased the response rate by approximately
20% in relapsed/refractory patients.7,8
Clinical trials in previously
untreated patients have also shown good response rates with the combination of
thalidomide and dexamethasone. The ECOG E1A00 and MM003 trials showed
statistically significant partial response rates (63% and 69%, respectively),
a complete response of 4% (ECOG E1A00), and at least a very good partial
remission (almost complete disappearance of the tumor but still a suspicion
that some tumor remains) of 43.8% (MM003) when compared to high-dose dexa
methasone alone.9,10 These two studies also showed a longer
progression-free survival period with the combination of thalidomide and
dexamethasone compared to high-dose dexamethasone.9,10
The role of thalidomide in
asymptomatic patients is not clear and so far no overall survival benefit has
been demonstrated. Current guidelines suggest that thalidomide should not be
used in asymptomatic patients until a survival benefit is clearly demonstrated.11
Thalidomide is the adjunct
therapy of choice to add to the standard of care of melphalan plus prednisone
in elderly patients. A clear increase in overall survival in previously
untreated elderly patients was seen in a study by Facon et al when
melphalan/prednisone plus thalidomide was compared to melphalan/prednisone
alone or with reduced-intensity stem cell transplantation using melphalan.12
Of the 447 patients recruited, 196 received melphalan/prednisone (0.25 mg/kg
melphalan + 2 mg/kg prednisone given orally for 4 days in each of 12 six-week
cycles), 125 received melphalan/prednisone/thalidomide (0.25 mg/kg melphalan +
2 mg/kg prednisone given orally for 4 days in each of 12 six-week cycles, plus
thalidomide 400 mg/day), and 126 received reduced-intensity stem cell
transplantation using melphalan 100 mg/m2.
Currently, there are over 15
clinical trials investigating thalidomide as treatment or part of a treatment
regimen for both newly diagnosed and refractory/relapsed patients with
multiple myeloma.13 Results of these trials will help determine the
role of thalidomide in all stages of multiple myeloma.
Investigational Uses in Cancer
After a benefit in
multiple myeloma was seen with thalidomide, researchers began investigating
the drug for activity in other cancers. The results so far have been mixed and
no new FDA-approved indications have been developed. Clinical trials in breast
cancer, renal cell carcinoma, and small cell lung cancer have not shown a
benefit.14-17 However, trials in prostate cancer, hepatocellular
carcinoma, some neuroendocrine cancers, and ovarian cancer have demonstrated
positive results.18-24
Prostate Cancer:
For patients who have progressed to androgen independent or hormone refractory
prostate cancer, the addition of thalidomide to docetaxel may provide benefit.
Several studies comparing docetaxel alone to docetaxel plus thalidomide have
been published. One study showed a 53% response rate for the combination
therapy compared to a 37% response rate for docetaxel alone, and median
progression free survival for the combination arm was 5.9 months (survival of
25.9 months) compared to progression free survival of 3.7 months (survival
14.7 months) in the docetaxel only arm.18 Another docetaxel plus
thalidomide study showed 18 month survival in 69.3% of patients compared to
47.2% of patients treated with docetaxel alone (P <.05).19
These findings led Dahut et al to conclude that combination therapy with
docetaxel and thalidomide represents a promising new area of treatment for
metastatic androgen independent prostate cancer, but additional studies are
needed to define thalidomideexact role.18
Hepatocellular Carcinoma:
Several phase II studies with single-agent thalidomide have been published in
recent years. These studies were undertaken after anecdotal evidence suggested
that patients who were refractory to or ineligible for traditional
chemotherapy might have a good response with thalidomide.20,21
Phase II trials by Patt et al and Lin et al showed only a modest response rate
of 5% to 7%, which suggests that, as a single agent, the use of thalidomide
mostly offers disease stabilization in patients with hepatocellular carcinoma.20,22
The authors added that the combination of thalidomide with other
antiangiogenesis medications or chemotherapy agents could prove to be
beneficial in this patient population, and further studies are warranted.20
In a study by Hsu et al, patients who had a high tumor vascularity index,
identified by power Doppler ultrasound, had the best response to thalidomide.23
Therefore, using this diagnostic procedure may identify the best candidates to
receive thalidomide therapy.
Neuroendocrine Cancers:
Neuroendocrine cancers represent a family of malignancies that are often
characterized by hormonal excess. To date, systemic therapies have not been
very effective at destroying these tumors. However, the use of temozolomide, a
cytotoxic alkylating agent, has shown benefit in these types of tumors.24
Because of its antiangiogenic properties, thalidomide is a good theoretical
choice to add to temozolomide therapy. Kulke et al administered temozolomide
(150 mg/m2 for 7 days, every other week) plus thalidomide (50-400
mg daily) to 29 neuroendocrine cancer patients. An overall radiologic response
rate (defined according to Response Evaluation Criteria in Solid Tumors
guidelines) of 25%, a biochemical response rate (decrease in chromogranin A by
50% or more from baseline) of 40%, and a two-year survival rate of 70% were
noted in these patients. The authors suggested that this combination may
provide good benefit to this patient population, but further studies are
needed to define the exact role of temozolomide and thalidomide.24
Ovarian Cancer: A
recent study by Downs et al comparing topotecan to topotecan plus thalidomide
in recurrent ovarian cancer patients showed promising results for the
combination arm.25 The overall response rate was 21% for topotecan
and 47% for topotecan plus thalidomide. The progression free survival time was
four months for topotecan and six months for thalidomide. Both the response
rates (P = .03) and progression free survival times (P = .02)
were statistically significant. The median overall survival was 14.8 months
for topotecan and 18.8 months for topotecan plus thalidomide, although this
was not statistically significant (P = .67). The study authors
concluded that further phase III trials in women with recurrent ovarian cancer
should be conducted.25
Adverse Events
The most common
side effects seen in clinical trials were sedation, rash, dizziness,
constipation, tremor, and headache.26 While thalidomide carries a
black box warning and a pregnancy category X for its well-known
teratogenicity, two other significant toxicities have also emerged: peripheral
neuropathy and venous thromboembolism (VTE). Peripheral neuropathy associated
with thalidomide use is a well-known and feared adverse event, which commonly
leads to drug discontinuation. The most common complaint is paresthesias with
tingling sensation and slight loss of tactile and pain response at limb
extremities. It is reported to variable degrees (14% to 70% of cases) in
clinical trials, and previous use of neurotoxic agents may increase the risk.27
In general, VTE is a major
complication of cancer, occurring in 4% to 20% of patients, and certain
medications have been found to increase this risk.28
Thalidomide-associated VTE is a common toxicity associated with treatment. One
study reported VTE in 22.5% of thalidomide/dexamethasone-treated patients with
multiple myeloma.28 It
is estimated that patients on thalidomide are 2.6 times more likely to develop
VTE, and patients on combination therapy with thalidomide and dexamethasone
are eight times more likely to develop VTE.28 This increased risk
has led the American Society of Clinical Oncology to recommend that myeloma
patients treated with thalidomide and chemotherapy or dexa methasone receive
either low-molecular weight heparins or warfarin (to an international
normalized ratio of ~1.5) as prophylaxis against VTE.29
S.T.E.P.S Program
Due to the
teratogenic effects of thalidomide, the FDA and Celgene, the manufacturer of
thalidomide (Thalomid), created the System for Thalidomide Education and
Prescribing Safety (S.T.E.P.S.) program.30 The S.T.E.P.S. program
is a restricted distribution program that involves the patient, physician, and
pharmacist. Both the physician and the pharmacy must register with the
S.T.E.P.S. program before medication can be dispensed. Pharmacist
responsibilities are listed in Table 1. Additional information about
the S.T.E.P.S. program can be found at: www.thalomid.com/steps_program.aspx.
Patient responsibilities
include signing all consent forms and adhering to the S.T.E.P.S. program. For
female patients of childbearing age, two forms of birth control are mandated
throughout the treatment course. While not part of the specific S.T.E.P.S.
program, men are advised to wear condoms while being treated with thalidomide.30
A recent study revealed that
0.7% of patients received a prescription in violation of a black box warning,
which further increases the importance of programs like S.T.E.P.S.31
This program has been extremely successful in preventing the tragic birth
defects seen in the 1950s and 1960s. To date, of the 145,000 patients who have
been enrolled in the S.T.E.P.S. program, only three pregnancies have been
reported.30
The Pharmacist's Role
As the treatment of
certain cancers transition to oral therapies, the role of the pharmacist
becomes increasingly important. Being up to date on the appropriate use,
adverse effects, and special dispensing requirements is essential for
pharmacists to help manage these patients appropriately. By participating in
programs like S.T.E.P.S., pharmacists are taking a more active role in patient
care. As has been seen with the S.T.E.P.S. program, when patients,
pharmacists, and physicians work together, tragic events like those seen in
the 1950s and 1960s are avoided.
Conclusion
Thalidomide in
combination with dexamethasone is now accepted as a treatment of choice for
both treated and untreated patients with multiple myeloma. While initial
clinical experience in hepatocellular carcinoma, prostate, neuroendocrine, and
ovarian cancers is promising, the exact role of thalidomide in these cancers
is still being determined. Currently, there are over 15 clinical trials
evaluating thalidomide's benefit in cancer. Once these studies are published,
clinicians will have a better understanding of the exact role thalidomide will
play as an antineoplastic agent.
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