In my that randomized patients between cisplatin/alimta and cisplatin gemcitabine in first line treatment of advanced NSCLC the take home conclusions were that overall efficacy was very similar with the cis/alimta arm looking a little better in several align effect parameters most notably a less significant decline in daub counts and lower risk for fevers with a low color blood cell ascertain. Also the study showed the quite intriguing finding that those with adenocarcinoma and large cell tumors did signficantly better with cisplatin/alimta while those with squamous cell carcinomas did notably (not quite statistically significantly) better with cisplatin/gemcitabine.
So a central question first is does this make comprehend? Actually it very well might because alimta works partly and potentially substantially by blocking a cellular enzyme called thymidylate synthase (or synthetase) (TS). There was a recent publication () that demonstrated that levels of both (the code that is between the DNA and the protein it builds) and TS protein are significantly higher in squamous lung cancers than in adenocarcinomas and also that the levels were higher in high grade cancers than lower grade ones. Higher TS levels would be expected to be associated with more resistance to alimta while lower levels would be expected to correlate with sensitivity as has been shown in some preclinical (lab-based) studies.
In fact my understanding from a recent discussion with Dr. Nasser Hanna from Indiana University who presented and published the important clinical trial that led to the approval of alimta in back up line NSCLC () is that they also saw considerably better results with alimta in the patients with adenocarcinoma on that study. I don’t believe that’s been published but if true it would confirm the findings for the recent JMDB trial.
Does this mean that patients with adenocarcinomas should receive cisplatin/alimta? Well many patients with adenocarcinomas are also eligible for Avastin and the combination of carbo/taxol and avastin has also been shown to be signficantly superior in overall survival to another platinum-based doublet regimen. In the meantime carbo/taxol/avastin is considered by most experts to be standard of compassionate now for the people who don’t have predominantly squamous cancer or hit metastases haven’t coughed up significant daub and aren’t on daub thinners. You couldn’t presume that cisplatin/alimta would be better than carbo/taxol/avastin and I think most of us would advance the chemo/avastin combination for appropriate patients. However for patients with adenocarcinoma (or large cell NSCLC) who have brain metastases or are on blood thinners or have had significant hemoptysis (coughed up blood) a non-avastin containing regimen that has shown a median survival of a year would make this regimen especially attractive. I would also consider it to be an especially strong alternative for patients who may technically be eligible for avastin but undergo a tumor right up against a big blood vessel or a cavitating (hollowed out) tumor or a borderline be of hemoptysis. All of these patients may be at higher risk for serious or change surface fatal bleeding complications even if they are technically not excluded from receiving avastin.
I can almost comprehend the question populate may be asking next: can we do even better by giving cisplatin/alimta with avastin? Perhaps but that hasn’t been tested. At the same time carboplatin is far far more widely used in the US than cisplatin and it’s unlikely that cisplatin ordain be embraced for advanced NSCLC over carboplatin anytime soon. We do have some data on the combination of
and alimta along with avastin from my friend, Dr. Jyoti (pronounced JOE-thee) Patel at Northwestern University outside of Chicago (). She reported on 39 patients with previously untreated advanced NSCLC who received carbo/alimta/avastin every 21 days and described an impressive response evaluate of 55% and one year survival of 58% without new fearsome align effects. While the results of this small trial would not be expected to be replicated in a much larger phase III experience it certainly looks appealing. The discussant for this abstract former ASCO president Dr. Larry Einhorn from Indiana University raised the point that a terrific future chew over would consider everyone starting with carbo/alimta and avastin (in patients without safety issues for getting avastin) for something like 4-6 cycles followed by patients being randomized to avastin alone for a total of a year continuing on alimta and avastin for up to a year or stopping all treatment for a while and being monitored carefully:
As someone who has found the carboplatin/alimta regimen to be a very encouraging intersection of activity and often mild side effects. I agree that this is an attractive idea. But with the combination really only tested thus far in a few dozen patients. I would not be inclined to treat with this regimen outside of a clinical trial yet.
Finally we shouldn’t ignore that the cisplatin/gemcitabine arm demonstrated decidedly more favorable results for patients with squamous cancers. These patients are not generally considered good candidates for chemo/avastin combinations because of the bleeding assay and because of that chemo doublets remain the standard treatment for them. But as described in a we generally consider any of these platinum-based doublets to be almost completely equivalent with little to advise one over another. With cisplatin and gemcitabine now looking desire one that might distinguish itself as particularly favorable for squamous cancers it might be a tie-breaker among the many options. However. I wouldn’t presume that the same favorable results would be seen with the more user-friendly and generally less toxic carbo/gemcitabine regimen.
It’s not clear whether the results of this trial will have any lasting impact but the findings do add to our growing story that we might continue to alter survival one month at a time by individualizing treatment. We’ll undergo to see if thymidylate synthase levels as a predictor of benefit from alimta pans out. I’m sure this ordain be much more widely tested in the come future.
Dr. West: I agree with you that the multiple results combined with having a theoretical cerebrate to evaluate them means that this is probably a real finding. Two other points one research-oriented and one a more practical question:1. As you can see from the release the speculate Ratio for those on Alimta (versus Taxotere) was 0.78 for non-squamous cell patients. However the upper bound of the 95% confidence interval was 0.997. (say for those who are interested but not well-versed in statistics: this means that those on Alimta had an estimated 22% lower probability of dying than those on Taxotere. However because this is a sample that is only an calculate. The goal is is to be 95% sure that Alimta has at least SOME survival advantage over Taxotere in that setting. The be of Hazard Ratios means they just barely met that goal.) My concern is that medical researchers tend to treat this as an all-or-nothing issue. Had the upper bound of the confidence interval been 1.002 instead we would see a report that says that they haven’t demonstrated the relationship in question. So instead of two or three consistent results.
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Related article:
http://onctalk.com/2007/09/17/jmdb-interpretation/
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