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Thalidomide Prolongs Survival in Patients With Extended-Disease Small-Cell Lung Cancer Who Respond to Chemotherapy: Presented at WCLC

By Chris Berrie

BARCELONA, SPAIN -- July 8, 2005 -- The antiangiogenic agent thalidomide as a single agent following response to etoposide/cisplatin/cyclophosphamide/epidoxorubicin (PCDE) provides a prolonged survival for patients with extended-disease small-cell lung cancer (ED-SCLC), according to research presented here July 6^th at the 11^th World Conference on Lung Cancer (WCLC).

"Thalidomide mainly acts through an antiangiogenic effect that consists of the repression of key angiogenic genes and down-regulation of [vascular endothelial growth factor] and [fibroblast growth factor beta] secretion," said Jean-Louis Pujol, MD, PhD, study chairman and professor, thoracic oncology unit, Montpellier Academic Hospital, Montpellier, France.

This randomized, double-blind, placebo-controlled, prospective phase 3 trial was designed to determine whether single-agent thalidomide can prolong survival of patients with ED-SCLC following their response to PCDE chemotherapy

For eligibility to the study, patients had to have histologically or cytologically proven SCLC with extensive disease (according to the Veterans Administration Lung Study Group criteria). In particular, women needed to be over 50 years old and in postmenopausal status, and all patients had to have adequate bone marrow, renal, cardiac, and hepatic functions, with no symptomatic brain metastases.

The researchers treated 119 patients with 2 courses of PCDE administered in 6 cycles, 4 weeks apart -- etoposide 100 mg/m² on days 1 to 3; cisplatin 100 mg/m² on day 2; cyclophosphamide400 mg/m² on days 1 to 3; 40 mg/m² 4'-epidoxorubicin on day 1. G-CSF primary prophylaxis was also recommended.

Patients who recovered from PCDE toxicity and achieved a response were given 4 additional cycles of PCDE plus either 400 mg daily of thalidomide or placebo for a maximum of 2 years. Thalidomide dose reductions were allowed, depending on whether specific adverse effects became apparent.

Tumor assessment after the first 2 PCDE cycles demonstrated 11 complete recoveries and 86 partial recoveries, giving an overall response rate of 81.4%.

With 5 patients showing poor recovery to the initial PCDE cycling, the remaining 92 were randomized to thalidomide or placebo group.

The characteristics of the 2 treatment arms were well balanced, except for the higher metastatic liver involvement in the thalidomide arm (61.2% vs 41.9%). Equal proportions of patients in each group received the 6 planned cycles of PCDE (75.5% vs 74.4%).

The reasons for withdrawal differed between the 2 groups, with toxicity as the main reason in 32.7% versus 19.1%, and disease progression in 42.9% versus 60.4%.

The response rates after cycle 4 showed a significantly higher overall response rate with thalidomide than placebo (81.6% vs 62.8% for placebo; P =.05).

With a minimum follow-up of 1 year after randomization, better median survival was seen in the thalidomide group (11.7 vs 8.7 months), with 1-year survival rates of 49.0% versus 30.2%.

In the Cox model of overall survival following randomization, patients in the thalidomide group had the longest survival, with a hazards ratio of 0.46 (95% confidence interval, 0.24-0.93; P =.03). The only other significant value was performance status.

Hematological toxicities arising in the thalidomide versus placebo cycles showed no significant toxicity differences between the 2 groups. However, serious (grade 2 or greater) sensory neuropathy and constipation were both higher in the thalidomide arm (32.6% and 24.5%, vs 11.7% and 7.0%).

Dr. Pujol said that while thalidomide prolongs survival in patients with ED-SCLC who respond to chemotherapy, "The poor tolerability profile of this compound precludes its prolonged application and jeopardizes any long-lasting effects."

However, he stressed that the mode of action of thalidomide as an antiangiogenic agent indicates that this process should now be investigated in more detail as a potential therapeutic approach for patients with ED-SCLC.


[Study title: A Prospective, Randomised Phase 3, Double-Blind, Placebo-Controlled Study of Thalidomide in Extended-Disease (ED) Small-Cell Lung Cancer Patients After Response to Chemotherapy. Abstract O-159]

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