SEOUL, South Korea --- Thalidomide (Thalomid) apparently can be appended to the long list of failed new strategies for small-cell lung cancer, researchers said here..
SEOUL, South Korea, Sept. 6 -- Thalidomide (Thalomid) apparently can be appended to the long list of failed new strategies for small-cell lung cancer, researchers said here.
Despite promising results in early phase and smaller studies, the drug failed a large randomized controlled trial to impact SCLC survival (P=0.24) or disease progression (P=0.45) when given with chemotherapy and as maintenance therapy.
Furthermore, the addition of thalidomide significantly increased thrombotic events by 7% compared with placebo (P=0.005), Siow-Ming Lee, Ph.D., of University College London in London, and colleagues reported at the International Association for the Study of Lung Cancer meeting.
"I think we all believe the greatest impact in improving survival will come from targeted therapies, although the course to date has been very challenging," commented Karen Kelly, M.D., of the University of Kansas Medical Center in Kansas City, who was the discussant for the study.
Decreasing incidence of SCLC has been "countered by an increase in frustration over the fact that we have not been able to have any major advances in systemic therapy since the '80s," she said.
"Twenty-five years of evaluating various chemotherapy cocktails have failed to produce a survival benefit over platinum and etoposide," she added.
Dr. Lee's group had previous shown in a phase II study that a low-dose thalidomide regimen with chemotherapy and as maintenance therapy was well tolerated. A subsequent phase III study by another group showed the combination increased survival by three months over placebo.
So Dr. Lee and colleagues planned a large phase III study in previously untreated SCLC patients.
It included 724 patients at 79 British centers randomized to receive up to six three-week courses of etoposide and carboplatin (Paraplatin) with placebo or 100 mg of thalidomide. This was followed by up to two years of maintenance therapy with placebo or thalidomide (100, 150, or 200 mg).
All patients, men and women, were required to use contraception because of thalidomide's teratogenic effect and could not have a history of any thromboembolic event.
A preliminary analysis after a median follow-up of two years in all patients, 611 patients had died.
Median survival was no different in the two groups (10.2 versus 10.5 months, hazard ratio 1.10, P=0.24). Likewise, one-year survival was 37.8% versus 41.4% and two-year survival was 12.9% versus 13.3%.
"We have to consider that there could be some antagonistic action," Dr. Kelly said.
Progression-free survival showed a similar pattern with no advantage to thalidomide over placebo (median 7.8 versus 7.9 months, HR 1.06, P=0.45). Nor did any sub-group have clear evidence of benefit, Dr. Lee said.
Nevertheless, the thalidomide combination was well tolerated, he said. Hematological and non-hematological toxicity and other grade 3-4 adverse events were similar between groups, except thrombotic events (18% versus 11%, P=0.005) and constipation (6% versus 1%) were more common with thalidomide.
The reason thalidomide failed is not clear, Dr. Kelly said, though she suggested the dose may have played a role.
Despite the results of this trial and lack of progress in treatment of the disease, the frustration is tempered by hope that the irinotecan-cisplatin combination will improve on the standard etoposide-cisplatin regimen in a Southwestern Oncology Group trial soon to be reported, she concluded.