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Current Status of Thalidomide in the Treatment of Cancer

Current Status of Thalidomide in the Treatment of Cancer

ABSTRACT: Tumor angiogenesis is a critical factor in the growth and metastasis of most malignant neoplasms. Thalidomide (Thalomid), banned from clinical use in the 1960s because of severe teratogenicity, has been shown to possess antiangiogenic properties. A recent clinical trial of antiangiogenic therapy with thalidomide demonstrated significant activity in a group of patients with relapsed refractory myeloma. Although its mechanism of action remains unclear, several trials have since confirmed that thalidomide is active in 25% to 35% of patients with relapsed myeloma. As a result, thalidomide has reemerged in clinical practice and is now actively being studied in the treatment of several cancers. Major toxicities associated with the use of thalidomide include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. This article summarizes the current status of thalidomide therapy in cancer. [ONCOLOGY 15(7):867-879, 2001]

Introduction

Thalidomide (Thalomid) has made
a big comeback into clinical
practice. It is actively being investigated for the treatment of a wide variety
of malignant and nonmalignant conditions in the United States and around the
world. Although the US Food and Drug Administration (FDA) has licensed
thalidomide only for use in erythema nodosum leprosum (a type of immune reaction
seen in leprosy), most prescriptions written today are for the treatment of
various cancers, particularly multiple myeloma. Over the last 2 to 3 years,
there has been a substantial increase in the number of studies of this agent for
the treatment of cancer, and the results are being reported ongoingly. This
article reviews the history, pharmacology, and current status of thalidomide in
the treatment of cancer. Other related uses, including its role in the treatment
of cancer cachexia, insomnia, and graft-vs-host disease, are beyond the scope of
this review and are not discussed.

Brief Historical Background

Thalidomide was first introduced into clinical practice as a
sedative. Beginning in the late 1950s, it was marketed in more than 40
countries. In the United States, the FDA was concerned about nerve damage and
did not approve thalidomide for clinical use. In countries in which it was
available, thalidomide became popular because of its association with good sleep
quality and an unusually low risk of fatal overdose (unlike other sedatives
marketed at the time).

Subsequently, thalidomide was found to be effective in the
treatment of pregnancy-related morning sickness. Unfortunately, many women took
thalidomide before its severe teratogenic potential was realized in 1961. As a
result, almost 10,000 children worldwide were born with birth defects. The fetal
malformations associated with thalidomide involved the extremities (phocomelia),
ears, eyes, and the gastrointestinal tract.[1,2] Thalidomide was withdrawn from
the market in 1962.

Pregnant women are vulnerable to its teratogenic effects between
days 27 and 40 of gestation. The mechanism of its teratogenicity is unclear, but
may be related to its antiangiogenic properties or inhibition of tumor necrosis
factor-alpha (TNF-alpha) production.[3] Free-radical-mediated oxidative
damage to DNA has also been postulated as a mechanism of its teratogenic
effects.[4] A single pill (50 mg) may be sufficient to cause the teratogenic
effects.

Despite its tragic past, thalidomide has reentered clinical
practice due to its immunomodulatory and antiangiogenic properties. It was
reported to be effective in the treatment of erythema nodosum leprosum in the
mid-1960s.[5] Over the past 10 years, studies of thalidomide have confirmed its
efficacy in the treatment of AIDS-related cachexia and aphthous ulcers. It has
also been effective in the treatment of aphthous ulcers in patients with Behçet’s
disease and in the treatment of chronic graft-vs-host disease. In 1998, the FDA
approved thalidomide for use in erythema nosodum leprosum, with substantial
precautions.

Early Clinical Trials of Thalidomide in Cancer

Thalidomide began to be studied as an anticancer agent within
months of the discovery that it caused teratogenicity. In 1962, only 4 months
after the initial reports of its severe teratogenicity, Rogerson questioned
whether a drug with such remarkable inhibitory powers on growing tissues can be
used as an anticancer agent.[6] Within a week, Woodyatt responded that he had
used thalidomide to treat a woman with a malignant mixed mesodermal tumor of the
uterus, and was waiting to see if it demonstrated any activity.[7]

Over the next few years, interest in studying the drug as an
anticancer agent persisted, and led to the initiation of at least two trials in
the early 1960s. The Eastern Cooperative Oncology Group (ECOG) administered
thalidomide to 21 patients with 14 types of advanced cancer, at doses ranging
from 600 to 2,000 mg/d.[8] Included in the ECOG study were two patients
with multiple myeloma. Although no tumor responses were noted, significant
subjective palliation of symptoms was seen in seven patients (33%). The
researchers also noted that there probably was a slowing of tumor growth in two
patients with rapidly progressive disease. They concluded that further study was
warranted.

Grabstad and Golbey reported on 71 patients who received
treatment with thalidomide for a variety of cancers.[9] Doses ranged from 300 to
2,000 mg/d. One patient with renal cell carcinoma achieved resolution of
pulmonary metastases. No other responses were seen. In addition to these two
published studies, there was at least one other investigation conducted in more
than 100 patients with advanced cancer, which failed to show any response to
thalidomide therapy.[8]

It is not clear whether the lack of response seen in these
trials was due to the advanced stage of the disease in the patients receiving
treatment or whether it was just a reflection of the inadequate imaging methods
used to measure response. In any case, following the completion of these initial
trials, interest in thalidomide as an anticancer agent diminished greatly.

Tumor Angiogenesis

Angiogenesis—the formation of new blood vessels—occurs
physiologically during embryonal growth, wound healing, and in the female
genital system during the menstrual cycle. Angiogenesis is critical for the
proliferation and metastases of most malignant neoplasms.[10] In the absence of
angiogenesis, tumors cannot grow beyond 1 to 2 mm in size.[10] Increased
angiogenesis is an adverse prognostic factor in several tumors, including
hematologic malignancies such as myeloma.[11-15]

Over the past few years, there has been a marked interest in
tumor angiogenesis, especially after the discovery of angiostatin and
endostatin, two potent antiangiogenic compounds.[16,17] Enthusiasm for studying
thalidomide as an anticancer agent has paralleled the increased interest in
tumor angiogenesis due to reports suggesting that the drug possessed potent
antiangiogenic properties.[18]

Thalidomide Therapy in
Multiple Myeloma

Single-Agent Therapy in
Relapsed Myeloma

Singhal and colleagues at the University of Arkansas conducted
the first trial investigating the activity of thalidomide in relapsed
myeloma.[19] Most patients in this study had failed stem cell transplantation.
Treatment consisted of oral doses of thalidomide at 200 mg/d initially for 2
weeks, then increased by 200 mg/d every 2 weeks, up to a maximum daily
dose of 800 mg/d, depending on toxicity. The overall response rate was 32%.
Median time to response was 1 month. Approximately 10% of patients achieved
³
 90% reduction in paraprotein levels. Paraprotein responses were
accompanied by improvements in anemia and other symptoms.

Among the 48 patients who underwent repeat bone marrow analysis
after thalidomide therapy, 81% had confirmation of paraprotein responses. The
best predictor of response was a plasma cell labeling index < 0.2. Median
duration of response had not been reached after 14.5 months of follow-up.
Considering that 90% of patients in this study had failed transplantation, these
results are impressive. An update to this study confirmed the activity
of thalidomide in 169 patients with relapsed myeloma.[20,21] Overall
survival at 18 months was 55%, and event-free survival was 30%.

We reported on 16 patients with relapsed myeloma treated at the
Mayo Clinic on a similar schedule of thalidomide.[22,23] Of these patients, 25%
had failed prior stem cell transplantation; 88% had received two or more
chemotherapy regimens prior to beginning thalidomide therapy, including 25% who
had failed four or more regimens. Four patients (25%) achieved a partial
response to therapy, thus confirming the initial results obtained at the
University of Arkansas. A larger Mayo Clinic phase II study of thalidomide in
relapsed myeloma reconfirmed these findings.[24]

Several other groups have also demonstrated the single-agent
activity of thalidomide in relapsed and refractory myeloma.[21, 23-34] Table 1
summarizes the results of the major trials of single-agent thalidomide in
relapsed myeloma.[21,23-34] Response rates ranged from 25% to 75%. Based on the
evidence thus far, thalidomide can clearly be recommended for the treatment of
relapsed myeloma, although the FDA has not yet approved it for this indication.

Combination Therapy in
Relapsed Myeloma

Ongoing studies are assessing the efficacy of thalidomide in
combination with other effective agents for myeloma (Table 2).[33,35,36] In one
investigation conducted by Weber and colleagues, 24 of 47 patients (52%) with
resistant myeloma responded to the combination of thalidomide and
dexamethasone.[35] Single-agent therapy with dexamethasone and thalidomide had
previously failed in many (46%) of these patients, suggesting a synergistic
effect with this combination.

Barlogie and colleagues have used thalidomide in a combination
chemotherapy regimen known as DT-PACE (dexamethasone, thalidomide, cisplatin
[Platinol], doxorubicin [Adriamycin], cyclophosphamide [Cytoxan, Neosar],
etoposide) for patients with aggressive myeloma and plasma cell leukemia.[37]
Responses were observed in four of five patients, including three who achieved a
complete response. Updated results reported for 43 patients indicate a 40%
response rate after two cycles of therapy, and no unfavorable effects on
subsequent stem cell harvest.[38]

Coleman and colleagues are studying the combination of
thalidomide, low-dose dexamethasone, and clarithromycin (Biaxin). Preliminary
results show significant activity.[36] More data are needed, however, and the
role of clarithromycin in the combination needs to be clarified. Kropff and
colleagues are evaluating a combination of hyperfractionated cyclophosphamide,
pulsed dexamethasone, and thalidomide.[39]

Previously Untreated Myeloma

Given the activity of thalidomide in relapsed myeloma, studies
are now evaluating the effect of this agent as first-line therapy in previously
untreated patients with myeloma (Table 1). Preliminary results from an ongoing
Mayo Clinic study showed that the combination of thalidomide and dexamethasone
is very active in this setting, with a response rate of 77%.[33] The initial
protocol called for escalation of the dose of thalidomide up to 800 mg/d.
However, among the first seven patients treated, two developed grade 3/4 skin
toxicity including one patient with toxic epidermal necrolysis.[40] The protocol
was then amended to stop dose escalation of thalidomide, and keep the dose
constant at 200 mg for the subsequent 19 patients studied.

Major grade 3/4 toxicities included the development of a rash in
three patients, and syncope, sedation, constipation, arrhythmia, and myalgia in
one patient each. This regimen may be an appropriate oral alternative to
infusional chemotherapy with VAD (vincristine, doxorubicin [Adriamycin],
dexamethasone) as initial treatment of myeloma in preparation for stem cell
transplantation. However, these results are preliminary and require further
confirmation.

ECOG is developing a randomized trial of thalidomide plus
dexamethasone vs dexamethasone alone in newly diagnosed symptomatic myeloma.
This study will help confirm the activity of combination therapy with
thalidomide plus dexamethasone in previously untreated myeloma and determine if
there is any significant excess toxicity associated with this regimen. An
ongoing randomized study at the University of Arkansas is investigating whether
the addition of thalidomide to a chemotherapy regimen has a role in the
management of newly diagnosed myeloma, and whether thalidomide has a role in
posttransplant maintenance.

Thalidomide is also being studied as a single agent in patients
with previously untreated asymptomatic myeloma. Initial reports show a response
rate of approximately 35%.[33,34] However, because the main goal of therapy in
patients with smoldering and indolent myeloma is to delay the need for
chemotherapy, more data on the durability of response are needed before this
strategy can be recommended for standard clinical practice. Moreover, the effect
of prolonged thalidomide therapy on stem cell harvest is unknown.

Summary of Thalidomide
Therapy in Myeloma

It is clear from the data discussed above that thalidomide is
effective in the treatment of relapsed and refractory myeloma. In patients who
are refractory to thalidomide, the addition of dexamethasone may induce a
response, even if patients have previously failed steroid therapy. Studies are
ongoing to define the role of thalidomide alone or in combination with other
chemotherapeutic agents or dexamethasone in previously untreated myeloma. In
light of toxicity concerns, previously untreated patients should receive
thalidomide therapy primarily in the context of carefully conducted clinical
trials. Further studies are needed to determine whether thalidomide has a role
in maintenance therapy following transplantation.

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