Lung Cancer / Mesothelioma
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Loading ...While there have been new agents introduced and rapidly changing standards in advanced NSCLC, another 40% of patients with NSCLC have locally advanced (stage III) NSCLC, many of whom with disease that is not resectable but is potentially curable with agressive chemo and radiation. Last year’s ASCO meeting included results that strongly suggested that consolidation taxotere after 6-7 weeks of concurrent chemo and radiation may not add a benefit, and in an important trial by the Hoosier Oncology Group (affectionately known as the HOG), the best treatment was with just two cycles of cisplatin/etoposide chemotherapy along with radiation (as detailed in a prior post).
Many oncologists, myself included, have been reluctant to accept that just two cycles of chemo and seven weeks radiation are really enough to treat stage IIIB disease, which is clearly more of a threat than stage II NSCLC, for instance, and for which we standardly give four cycles of platinum-based chemo. Most US-based oncologists give either two cycles of cisplatin/etoposide with concurrent chest radiation, or weekly low-dose carboplatin/taxol for about 7 weeks while a patient is getting radiation, and it’s a bit unsettling to think that either there aren’t potential improvements to be made by adding new agents, either to replace some of our older standards or to add along with the chemo/radiation concurrently or as a different consolidation therapy. Cisplatin/etoposide/RT has been used now for both limited SCLC and locally advanced NSCLC for 20 years, so we’re all impatient to see new agents take their place and define some new standards.
A couple of interesting trials that integrated some of these newer agents were presented at ASCO this year. The first was done by the Radiation Therapy Oncology Group (RTOG) and presented by my friend George Blumenschein from MD Anderson Cancer Center in Houston (abstract here). This study was built on the alternative standard approach (to cisplatin/etoposide) of low-dose weekly carbo/taxol concurrent with radiation, which is sometimes preceded or followed by “full dose” chemotherapy to treat micrometastatic disease in other parts of the body more effectively, because we believe that the low dose weekly carbo/taxol primarily helps make the radiation work better but doesn’t have much of an anticancer effect on other cells in the body. So this study, known as RTOG 0324, tested the activity and feasiblity of adding weekly erbitux, the targeted therapy and monoclonal antibody against EGFR with some evidence for activity in metastatic NSCLC (prior post here), along with concurrent carbo/taxol/radiation and then along with an additional two cycles of full dose carbo/taxol after the radiation portion was completed. The trial enrolled 84 patients with unresectable locally advanced NSCLC, with a design and highlights as shown here:
This relatively small test was primarily a test of feasibility of giving this regimen and testing whether it merits further development in larger trials. The investigators noted that the median survival of 22.7 months was the best that the RTOG has seen in this setting, although it’s not particularly different from the HOG results with just cisplatin/etoposide/radiation, and no fancy new targeted therapy added. The side effects we always see with concurrent chemo and radiation, primarily esophagitis (inflammation of the esophagus) and pneumonitis (inflammation of the lungs) were well within the typical range for the regimens we use routinely, although the group did report 5 patient deaths attributed to the treatment, from a variety of causes. While concerning, this 6% death rate from treatment is right in the same range that SWOG and HOG have seen with aggressive treatment, reminding us that our treatments for locally advanced NSCLC can be so challenging that they can be a competing survival threat along with the cancer itself. Based on the encouraging results overall, the RTOG is adding erbitux to their current question of testing higher vs. lower dose radation. Here’s what they’re trying to make their new trial look like:
So this trial should give us information about whether we should raise the dose of radiation and whether we should add erbitux to the mix.
Next we’ll cover a trial that introduces alimta into the stage III NSCLC setting, along with erbitux.
Posted in: Chemotherapy, Epidermal growth factor receptor (EGFR)-based therapies, Non-Small Cell Lung Cancer (NSCLC), Radiation therapy, Stage III/Locally Advanced NSCLC, Targeted therapies, Treatment, Unresectable locally advanced NSCLC
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Dr. West
I’ve seen many articles comparing Cetuximab to Avastin in the NSCLC setting. Clearly in the headline numbers Avastin looks somewhat better when comparing similar patients. (advanced non-squamous, non-small cell lung cancer) I belive Avastin had an hr= 0.80 and Erbitux was at hr=0.83
The one difference I don’t hear is how the ps=2 patients could have effected Erbitux’s results. Would these patients have effected the Flex results?
Thanks
jbogd1
First, I would consider the difference between a hazard ratio of 0.80 and 0.83 to be pretty meaningless, especially considering that these trials were done on different continents with different treatment practices, and the FLEX trial with erbitux allowed patients with a performance status of 2 (more marginal). Don’t forget that a European trial with avastin (AVAstin in Lung cancer, or AVAiL, trial) has been reported as negative for survival (just a press release, no details yet), so if you factor that in, the combined hazard ratio for avastin will likely be higher than 0.83. And for readers not well acquainted with hazard ratios, lower numbers are better, and a number below 1.00 means that there’s a benefit to the new treatment, and a number over 1.00 means that there’s a harmful effect of a new treatment. So I don’t think you can meaningfully surmise that one targeted therapy is clearly superior to another. In the US, people will likely stick with avastin for avastin-eligible patients, but I think that is primarily because the US-based trial was clearly positive, and that carries more weight in the US, and also because it’s become a standard over 2-3 years. It takes more compelling evidence to make a new standard than to dethrone an established one, and avastin is the incumbent here.
But in terms of interpreting what the inclusion of marginal PS patients may have done, we can’t say. Including performance status 2 (PS2) patients will be associated with lower overall survival numbers, but we just can’t predict whether they’d be likely to get more, less, or the same benefit with the targeted therapy as more fit patients. It primarily means that you can’t compare the raw numbers of median survival, for instance, between the two studies, because the populations were different. The ECOG 4599 US-based trial of carbo/taxol with or without avastin was definitely among the most cherry-picked patient populations in a large trial, so you’d expect them to do better regardless of the novel treatment (and the control group did do unusually well for a trial in advanced NSCLC, in fact).
-Dr. West
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