NEW YORKLong banished from the pharmacopoeia because
of its teratogenic effects, thalidomide (Thalomid) has recently reemerged as a
potentially promising chemotherapeutic agent in a variety of cancers. Four
presentations at the Chemotherapy Foundation Symposium XVIII looked at its use
as a single agent and in combination therapy.
Bart Barlogie, MD, director, Arkansas Cancer Research Center,
Little Rock, reported on a phase II study of thalidomide as a single agent in
169 heavily pretreated patients with refractory multiple myeloma. Three
quarters had a previous autotransplant, and 53% had more than one
autotransplant. More than one third had chromosome 13 deletion, the most
adverse prognostic feature of the disease.
Thalidomide was given in escalating doses of 200 mg to 800 mg.
The majority of patients tolerated a dose of 400 mg. Dose-related toxicities
included constipation, weakness, somnolence, and tingling or numbness. The
median follow up is 22 months.
A 25% paraprotein reduction (PPR) was seen in 37% of patients;
30% had PPR of 50% or more, and 14% achieved a complete or near-complete
response. PPR was accompanied by a marked reduction or clearing of bone marrow
plasmacytosis and improved or recovered hemoglobin levels. Overall survival at
18 months was 55%.
"We saw a rapid recovery from anemia associated with
normalization of bone marrow and undetectable tumor lesions on MRI, conistent
with a true tumoricidal effect," Dr. Barlogie said.
It is not entirely understood how thalidomide works, Dr.
Barlogie said. It is thought to have antiangiogenic action and may have a
direct effect as well on the
c-myc gene, which is overexpressed in most multiple myeloma patients.
Because thalidomide has very little myelosuppressive toxicity,
it is an ideal agent for use in combination with cytotoxic chemotherapy, Dr.
To test this, a multicenter phase III randomized study
(SWOG-S9922) of dexamethasone, cyclophosphamide, etoposide, cisplatin
(Platinol), and G-CSF (Neupogen), with or without thalidomide, has been
initiated to compare the overall and progression-free survival and remission
rates in patients with refractory multiple myeloma. A total of 320 patients
will be accrued over 4 years.
Acute Myelogenous Leukemia
The antiangiogenic properties of thalidomide have been tried as
a means of combating the elevated vascular endo-thelial growth factor (VEGF)
plasma levels seen in patients with acute myelogenous leukemia (AML).
"Elevated VEGF levels correlate with shorter survival and disease-free
survival in patients with AML," said Jorge Cortes, MD, of M.D. Anderson
Cancer Center. Dr. Cortes described a trial of liposomal daunorubicin (100 mg/m2/d for 3 days) and cytarabine
(ara-C) 1 g/m2/d for 4 days, with or without thalidomide (400 to 600 mg daily).
Patients achieving a complete remission within 50 days of
starting therapy (early complete remission) continued for 3 months; 44% of
patients did so.
Although pretreatment VEGF levels were lower in patients who
showed an early complete remission, no difference in early complete remission
was seen between the two arms. The effect of thalidomide on duration of
response requires further follow-up.
Dr. Cortes speculated about the reasons thalidomide did not
appear to be effective: Any effect of VEGF could be mediated through mechanisms
other than angiogenesis; the degree of VEGF reduction was insufficient; a more
prolonged effect is required; the agents used negate the effect of thalidomide;
or thalidomide is inactive in AML.
Dr. Cortes said that the significance of VEGF in the prognosis
of AML warrants further study of inhibitors of VEGF and angiogenesis.
Thalidomide appears to have a protective effect on the
gastrointestinal toxicity of irinotecan (Camptosar) used in the treatment of
Rangaswamy Govindarajan, MD, of the University of Arkansas,
described a study of 15 patients with metastatic colorectal cancer. All had
progressed after fluorouracil treatment. They received a median of three cycles
of irinotecan (300 to 350 mg/m2) every 21 days and thalidomide 400 mg daily.
"There was a remarkable absence of GI toxicities,"
Dr. Govindarajan said. In view of that, as well as the enhanced response rates
observed in a pilot study, further evaluation of this combination therapy is
warranted, he said.
Spurred by the work of Dr. Barlogie and colleagues, researchers
at Cedars-Sinai Medical Center and Jonsson Comprehensive Cancer Center, Los
Angeles, studied the use of thalidomide in a small number of patients with
amyloidosis associated with plasma cell dyscrasias.
James R. Berenson, MD, director, Multiple Myeloma and Bone
Metastasis Program, described his experience with six patients. All had renal
involvement and two also had malignancies (multiple myeloma and Waldenstrom’s
macroglobulinemia). Previous treatment included steroids alone; melphalan
(Alkeran) and prednisone; vincristine, doxorubicin (Adriamycin), and
dexamethasone (VAD); chlorambucil; and peripheral blood stem cell transplant.
Thalidomide was given in 100 mg escalating doses daily, with
the maximum tolerated dose ranging from 100 to 400 mg. Four patients also
received oral steroids, prednisone, or dexamethasone. Patients were treated
from 3 to 7 months.
Improvement was seen across a range of symptoms: Macroglossia
and joint symptoms improved markedly; peripheral edema and proteinuria
decreased; serum albumin and creatinine levels improved. Diarrhea resolved in
three patients with GI symptoms, and quality of life improved in four.
Two patients who were treated with thalidomide alone died, but
the remaining four continue to do well on thalidomide and steroids. These
preliminary observations suggest that "oral thalidomide, especially in
combination with steroids, is an effective treatment in primary
amyloidosis," Dr. Berenson said.