Iressa does not improve survival for patients with the most common form of lung cancer, The Lancet
Main Category: Lung CancerArticle Date: 02 Nov 2005 - 17:00 PDT
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A randomised trial in this week's issue of The Lancet has found that the lung cancer drug Iressa (gefitinib) is not associated with a significant improvement in survival for people with non-small cell lung cancer (NSCLC). However, the study did find some evidence of benefit among never-smokers and patients of Asian origin.
Lung cancer causes more than 1 million cancer related deaths each year worldwide; NSCLC accounts for 80% of all lung cancer. With current first-line chemotherapy regimens median survival is 7-10 months. However, for patients who have chemotherapy resistant disease, treatment options are limited and new therapies are needed. Iressa was approved in a number of countries for the treatment of NSCLC after two trials showed that the drug could improve tumour shrinkage in previously treated patients with advanced NSCLC.
Nick Thatcher (Christie Hospital, Manchester, UK) and colleagues recruited 1692 patients with chemotherapy resistant disease from 210 centres in 28 countries into the trial. 1129 patients were assigned to receive Iressa and 563 a placebo. The investigators found that survival did not differ significantly between the two groups. However, when the researchers looked at subgroups of the participants they found that the drug significantly improved the median survival by 4 months for patients of Asian origin and by 2.8 months for patients who had never smoked.
Professor Thatcher comments: "While the result is disappointing, in that gefitinib was not associated with a significant improvement in survival in a general population of NSCLC patients, there was an increase in survival in patients of Asian origin and in patients who never smoked. We now need to find pragmatic ways of identifying which patients are more likely to benefit with these new treatments." (Quote by e-mail; does not appear in paper)
In an accompanying comment Roy Herbst (Anderson Cancer Center, Texas, USA) states: "EGFR inhibitors, including gefitinib, certainly have a role in the management of selected patients with lung cancer but, it will now be important to conduct prospective studies to identify and validate the molecular markers which predict for their maximal effect" (Quote by e-mail; does not appear in published comment)
Joe Santangelo
j.santangelo@elsevier.com
Lancet
thelancet.com
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Iressa Does Help Those
posted by Gregory D. Pawelski on 27 May 2006 at 9:25 pmSeveral new "targeted" drugs have been introduced during the last few years. Most of them have been developed for use in solid tumors but some have also emerged for hematological maligancies. These new "targeted" drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.
Unfortunately, the introduction of these new drugs has not been accompanied by specific predictive tests allowing for a rational and economical use of the drugs. Given the technical and conceptual advantages of CCDRTs together with their performance and the modest efficacy of therapy prediction based on analysis of genome expression as published so far, there is reason for a renewal in the interest for CCDRTs for optimized use of medical treatment of malignant disease.
There was a recent study using an angiogenesis assay, describing correlations between cell culture assay results (cell death in response to Iressa exposure) and survival of 31 patients with non-small cell lung cancer who had received extensive prior chemotherapy. These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered the assay laboratory tests. There were striking correlations between test results and patient survival.
By inhibiting anti-apoptosis with Iressa (or even Tarceva), the cells undergo apoptosis and die. And it is detected at the whole cell level in the cell culture assays and reported out -- prospectively -- that this correlates strikingly with patient survival. Not only is it a very important predictive test, but it is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.
Over the past few years, gene expression profiling has been suggested as the best or only way of determining ex vivo drug sensitivity. However, the cliinical application of these DNA content assays have been shown to correlate only with response and not survival. And due to almost all patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of CCDRT. CCDRTs can actually integrate all the gene expression into one convenient test result.
In obtaining information from gene mutations (DNA content assays) and/or gene expression (RNA content) it must be realized that DNA structure is only important insofar as it predicts for RNA content, which is only important insofar as it predicts for protein content, which is only important insofar as it predicts for protein function, which is important only insofar as it predicts for cell response, which is only important insofar as it predicts for tumor response and function. In other words, it correlates only with response and not survival, in entirely retrospective (not prospective) studies.
What are the data supporting the use of testing DNA, RNA and Protein expression? Two retrospective studies from two Harvard-affiliated hospitals, showing response, but not survival advantages, with a grand total of twenty six correlations. And a subsequent study, presented in the July 14, 2005 issue of the New England Journal of Medicine from another laboratory that did not show correlations between gene mutations and patient survival (Volume 353:133-144 Number 2).
Not only is cellular profiling (Cell Function Analysis) a very important predictive test, but it is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.
Source: Human Tumor Assay Journal
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