Lung Cancer / Mesothelioma
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Loading ...Someone recently asked a question about a recommendation she had received about being treated with a first-line combination of gemzar (gemcitabine) and navelbine (vinorelbine), because we have focused so much on doublets of either cisplatin or carboplatin with a newer drug like taxol (paclitaxel), taxotere (docetaxel), gemzar, navelbine, or most recently possibly alimta (pemetrexed). Why don’t we pair the partners of the platinums and perhaps do even better?
In the early 2000s, that was a timely question, as we wondered whether the platinum drugs might be more of a “legacy” component of the combinations we used — perhaps these newer drugs could combine to form their own doublets like taxol/gemzar, taxotere/gemzar, and gemzar/navelbine. One early trial completed in Greece (abstract here) randomized previously untreated advanced NSCLC patients to receive either taxotere/cisplatin or taxotere/gemzar. It looked at response rates as the primary objective, showed remarkably similar results overall, and a significantly higher response rate with taxotere/cis for patients with non-adenocarcinoma tumors and taxotere/gem for patients with an adenocarcinoma:
For years after that, we really didn’t hear much about histology until very recent work highlighted that there may be substantial differences in the activity of certain chemo drugs for different NSCLC histologies (example post here). Various other studies showed the comparability of non-platinum doublets to platinum doublets, such as this one (abstract here):
You can see that the three arms all performed remarkably similarly, with completely overlapping survival curves. So one of the hopes for non-platinum doublets, that they would be superior to platinum doublets, hasn’t panned out, but they’re yet another alternative. A meta-analysis (abstract here) that compared multiple trials of platinum vs. non-platinum doublets showed a more favorable survival with platinum doublets, actually, but that included many very old regimens, and there were no significant differences when only newer doublets with the agents described above (so called, “third generation agents”) were used.
The other consideration is that non-platinum doublets may have fewer side effects. Overall, they did have fewer platinum-related side effects, such as kidney damage, nausea/vomiting, and hearing loss, but on balance, the side effects with non-platinum doublets were different (and depended on the doublet being considered), but not clearly less.
With nothing to clearly recommend them over platinum-based doublets except perhaps for patients who needed to specifically avoid platinum-based side effects, they have remained yet another fine option but haven’t displaced platinum-based doublets. But that may change if we move to a time of individualizing treatment, specifically if we can predict that some patients won’t benefit from platinum-based agents. I’ve written about potentially useful marker proteins like ERCC1 (see prior post), which at high levels appears to be associated with resistance to platinum. Some recent studies that have assigned particular treatment regimens based on ERCC1 and other molecular factors have given non-platinum doublets to many of the patients (as described in prior post). Though still preliminary, if this type of promising work becomes validated in larger studies, we could see a resurgence of these non-platinum doublets 5 years after they were pushed aside as just a lateral move, perhaps the ideal choice for well-selected patients.
Posted in: Chemotherapy, First-line treatment, Lung Cancer, Non-Small Cell Lung Cancer (NSCLC), Stage IV/Advanced/Metastatic NSCLC, Treatment
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Nobody followed up on “platinum-based doublets appear more effective versus non-adenocarcinomas, while non-platinum-based doublets appear more effective against adenocarcinomas.” (my summary of those results). Wow. I think the Greek results are stunningly strong (and both sides of the equation are statistically significant). Certainly, they should have been worthy of follow-up. Is there more to the story?–Neil
neilb
They raised the eyebrows of a lot of people at the time, but it didn’t quite catch on. I had to dust off that old slide because I used to show it in 2002 and 2003, but it’s been a fading concept for the past 5 years as nothing further came out of it. A few points:
1) While response rate was higher, survival wasn’t different at all on that trial
2) There were other platinum vs. non-platinum trials, and this observation wasn’t consistently seen (although not consistently checked either)
3) Related to the infrequency of checking, it has taken years for the lung cancer community to move away from the years of results that suggested that the histologic subtype didn’t matter. I think there are still many buried results in our studies, but you can’t see the results unless you go and look
4) Reliability of assigning histology is just not great, especially as fine needle aspirations of nodules, which yield just a few cells, became prevalent as a diagnostic test, at least in the US. You need a little more tissue and vigilant, dedicated pathologists to make a good diagnosis of (sub)histology like squamous or adeno, and even the experts sometimes just can’t say anything defitive.
We’re getting there now, but the world had to catch up.
-Dr. West
Dr. West: Thanks. That clears some things up. Of course, the lack of reliability would be more likely to lead to false negative results rather than false positives.
Practically, as someone who progressed on first-line carboplatin, taxotere, and Velcade, the study you cite makes me think that a non-platinum-based doublet should at least be on the table the next time my oncologist and I have to make a treatment decision (and he’s a Greek national and may actually know some of the researchers).–Neil
neilb
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