NEW YORKLong banished from the pharmacopoeia because of its teratogenic effects, thalidomide(Drug information on 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. Barlogie said.
To test this, a multicenter phase III randomized study (SWOG-S9922) of dexamethasone(Drug information on dexamethasone), cyclophosphamide(Drug information on cyclophosphamide), etoposide(Drug information on etoposide), cisplatin(Drug information on 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(Drug information on daunorubicin) (100 mg/m2/d for 3 days) and cytarabine(Drug information on 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 colorectal cancer.
Rangaswamy Govindarajan, MD, of the University of Arkansas, described a study of 15 patients with metastatic colorectal cancer. All had progressed after fluorouracil(Drug information on fluorouracil) treatment. They received a median of three cycles of irinotecan(Drug information on 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(Drug information on melphalan) (Alkeran) and prednisone(Drug information on prednisone); vincristine, doxorubicin(Drug information on doxorubicin) (Adriamycin), and dexamethasone (VAD); chlorambucil(Drug information on 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 one of 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.