We’ve always been tempted to see if we can add more to standard approaches to improve our outcomes. In SCLC, people have attempted to add taxol to cisplatin and etoposide as part of the PET regimen (platinum + etoposide + taxol). Although heavily tested, it clarified that triplet therapy with standard chemo for SCLC appears to be associated with no improvement in outcomes but with a very significant improvement in side effects, including risk of dying from treatment.
In the late 1990s, when taxol was still one of the newer drugs for lung cancer, several groups, including SWOG, CALGB, and a Greek lung cancer group ran small clinical trials that looked promising for a few dozen trials. However, the Greak Lung Cancer Cooperative Group reported results of a randomized trial that closed early, comparing cisplatin/etoposide to the triplet that added taxol, having included 133 patients with either LD-SCLC or ED-SCLC (paper here):
Despite giving G-CSF (white blood cell growth factor) support in order to reduce potential toxicity, the study showed that patients getting the triplet didn’t do any better and had far worse drops in blood counts and a significant increase in deaths due to treatment:
(neutropenia is low white cells, and thrombocytopenia is low platelets).
But this wasn’t a huge trial, and perhaps the PET triplet looked bad for this one study.
Unfortunately, it didn’t fare any better in a trial across North America (an Inter-group trial including the various cancer cooperative study groups)(abstract here). This was much larger and had the same basic design of standard doublet platinum-etoposide vs. PET triplet, and it included nearly 600 patients with ED-SCLC:
As with the Greek trial, the triplet was associated with essentially identical activity, but the rate of dying from treatment was more than doublet with the triplet (and the WBC growth factor protected people with the PET triplet from low WBCs but not low platelets).
These two studies have pretty much clarified that the PET triplet is dangerous and doesn’t add anything, and I suspect we’d find similar results with other triplets with standard chemo. As noted in a prior post, doublet chemo with a targeted agent like avastin is feasible, but it’s not clear that it really adds anything either. Platinum and etoposide may be the same regimen we’ve been using for more than a decade, but only because it has withstood the test of time and many challengers thus far.
posted by Dr. West @ 11:12 pm link to this post
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November 6th, 2007 at 8:14 am
Dr. West,
Have there been any triplet studies completed with P+E and irinotecan?
Also, I don’t think that we should generalize about triplet therapies just yet.
ICE: ifosfamide + carboplatin + etoposide is a triplet that has been studied and used with success.
Here is another more recent reported successful triplet that can be used safely:
http://ufscc.ufl.edu/Patient/cancernews.aspx?section=cancernews&id=40812
Jim
November 7th, 2007 at 3:06 pm
Jim,
Well, I agree that you make an excellent point about the combination of platinum-etoposide with ifosfamide: it did look in the 1990s like it improved survival compared with platinum/etoposide, but it has never taken off, largely because of concern about toxicities, particularly neurologic toxicity with ifosfamide, which can be completely unpredictable and severe, including seizures or coma (not common, but awful when it happens). It was also assocated with a median survival of just 9.1 months in the trial that was its shining moment, and we have seen very similar results with platinum-esoposide on other trials since then. It’s certainly a fair choice, and it’s not quite correct for me to say that triplet chemotherapy has been unsuccessful. It would be more accurate for me to say that the PET combination isn’t a winner and that no other triplet has taken the world by storm yet either.
I don’t know of any studies with the triplet of cisplatin (or carbo), etoposide, and irinotecan, but there could be one out there flying under my radar screen. I imagine it would be pretty challenging in terms of risk of side effects. There are serious and even fatal side effects with the two drug combinations done by the book, and I imagine that many chemo triplets would be associated with a real risk that fatalities from treatment could exceed 5%.
I am aware of combinations of doublet chemo with avastin and reported a separate post on that. I would consider the concept of doublet plus targeted therapy to be different enough situation that I wouldn’t lump them in the same basket with chemo triplets. As for chemo doublets plus avastin, I think the jury’s still out on that concept, and larger trials are in the works to test doublet chemo vs. doublet chemo + avastin.
-Dr. West