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How Much Does Time Since Quitting and Amount Smoked Matter for LC Risk?
Though the topic of never-smokers with lung cancer is a particular focus of my interest and research, and there has been a greater focus on this topic in the last few years, most lung cancer is still related to smoking. However, we have clearly reached a point where the majority of people diagnosed with lung cancer are not current smokers at the time of their diagnosis, and about 60% have quit at some point. Many of these patients, and their families and friends, express surprise that they developed lung cancer, especially if someone had quit 20 or 30 years prior. How much does the risk for developing lung cancer decline over time, and does the amount smoked before quitting make a difference?
The short answer is that, as you would probably expect, smoking more “pack-years” (the product of average number of packs of cigarettes smoked per day X number of years smoking) is associated with a higher risk than smoking fewer, and that the risk of lung cancer declines over time but doesn’t get to the level of a never-smoker (which we know isn’t zero risk of lung cancer either). To illustrate, here are the “case-control” results that compare the smoking histories of 521 patients with lung cancer to over 76 thousand people without lung cancer in western Washington state (abstract here):
(click to enlarge)
The table highlights the following conclusions:
1) Over 60% of lung cancer is diagnosed in former smokers.
2) The lung cancer population appears to be skewed toward current smokers and ex-smokers as over-represented vs. people without LC, and more who quite within the last decade
3) The number of pack-years is greater in patients who developed lung cancer, both among current and former smokers.
US Smoking Patterns over Time
In Seattle, we just had an evening program for lung cancer awareness that included issues in lung cancer largely focused on rectifying the disparity in lung cancer funding and awareness compared with other cancers, but also on tobacco control and screening. One of the talks was by a pulmonologist colleague from the University of Washington, Dr. Jason Chien, who highlighted several notable points on smoking patterns and how they are related to risk of lung cancer.
The first point is that while we talk a lot about never-smokers with lung cancer, tobacco is still by far the most important risk factor contributing to lung cancer. Here’s a list of other variables, which pale in their impact compared to tobacco (“relative risk” means the multiplier compared to someone without a risk factor, so a relative risk of 2 means that a person with that exposure has twice the risk of somoene without it):
Tragically, unlike most or perhaps all other deadly diseases in the world, lung cancer has a major industry promoting the exposure to this deadly risk factor:
The Evolving Story of Maintenance (?) Therapy for Advanced NSCLC
At the recent Chicago lung cancer meeting, the idea of maintenance therapy emerged as a hot topic that is experiencing ongoing changes in our treatment approaches over time. The controversies about this topic begin with the very terminology. Here are four proposed names for the same basic idea:
1) maintenance therapy, which implies that one of the initial treatments is being continued on a longitudinal basis
2) consolidation therapy, which suggests that a new treatment is being used to induce an additional response in patients responding to first line therapy
3) sequential therapy, which indicates a prospectively planned transition from first line to the next treatment from the very beginning
4) early second line therapy, which emphasizes that this is basically just focusing on the timing of when to move to your second line treatment
At the Chicago meeting, the results from the previously described trial of immediate vs. delayed second line taxotere (docetaxel) (prior post here) was presented again, as was the trial of alimta (pemetrexed) vs. placebo as “maintenance” therapy (prior post here). Both trials initiated this randomization only in patients who had shown no progression after four cycles of first line therapy and weren’t receiving any other maintenance therapy like avastin (bevacizumab) or erbitux (cetuximab) — in this case, using maintenance in the arguably more correct form, since this would usually be continuing these after first line treatment with chemo and one of these agents.
There was also some discussion of the SATURN trial of tarceva (erlotinib) vs. placebo after four cycles of first line chemo. As described in a prior post, this trial was positive for its primary endpoint of progression-free survival, and we don’t know yet about any differences in overall survival. So now we have three trials that all support an early transition from first line to the next treatment, with each of the three best studied agents for second line treatment of advanced NSCLC.
Selection Bias, Eligibility Criteria, and Interpreting Trial Results (or, a little cynicism can be a good thing)
My kids are right in the middle of that time when they watch SpongeBob and see commercials for toys, cereals, and music, nearly every one is puncuated at the end with, “Daddy, can we get that? I want that.” There comes a time in everyone’s life, hopefully early on, when we learn that we won’t actually find eternal bliss with every advertised item. Juicy Fruit gum loses its flavor in about 10 seconds, Pepsi doesn’t actually make you hip, and the urinating feature of the Betsy Wetsy doll actually loses its appeal (though anyone who changes real diapers probably don’t see the appeal of paying for this feature). Learning that advertising makes things seem better than they really are is a truism we all need to learn.
The harsh reality is that many press releases and newsroom puff pieces about supposed cancer breakthroughs are pretty akin to TV commercials. Some represent true, meaningful benefits, but there are a few valuable rules that can help us determine which ones are more sizzle than steak. Many of these stories are planted to manipulate people, specifically to generate buzz, to lead doctors to change their prescribing habits or to get patients to ask for a particular treatment. Here are two key caveats worth bearing in mind to help discriminate fool’s gold from the real deal:
Three Major Trials With Zactima (Vandetanib) Reported
As a general rule, companies don’t sit on great news with their drugs. Without any insider knowledge, this was my concern about why we hadn’t heard anything about the results of three major lung cancer trials with the agent Zactima (vandetanib), which I had written a post about 8 months ago (see prior post about these trials with Zactima, an oral agent that inhibits both VEGF, a major mediator of angiogenesis, and the EGFR pathway). The recent lung cancer meeting in Chicago would have been the opportunity to present the results, but that meeting passed, and then some rather tepid results (here) were just reported less than a week after the meeting ended. Go figure…
To review, zactima has activity in NSCLC, as reviewed in my first post on the agent. The four large trials that were launched include the following comparisons in previously treated patients with advanced NSCLC:
1) second line treatment with taxotere (docetaxel) alone vs. docetaxel/zactima, a large phase III trial (ZODIAC)
2) second line treatment with alimta (pemetrexed) alone vs. alimta/zactima, a large phase II randomized trial ZEAL)
3) second or third line treatment with zactima vs. tarceva (erlotinib), a large phase III trial (ZEST)
4) zactima vs. placebo in previously treated patients, a large phase III trial (ZEPHYR)
Debate Over the Value of Progression-Free Survival Affects Clinical Decisions Now
Continuing on the introduction to the concept from a recent prior post, the issue of whether it’s important to see an improvement in progression-free survival (PFS) if there is no improvement in overall survival (OS) after additional therapy is going to be a central issue in lung cancer management, relevant in several key issues in coming years. This is actually a fortunate development, because it’s a by-product of there being enough valuable treatments to give sequentially that we’re questioning whether the order matters at the end of all of the treatments a patient will ultimately receive. The breast cancer community has been grappling with this issue for years, since there are a wide range of effective treatments for advanced breast cancer. Though two drug combinations have a higher response rate and PFS, that doesn’t translate to a higher OS when breast cancer patients typically receive more than four lines of treatment over time, so a typical approach is with sequential single agents rather than an urgent need to treat with the most aggressive therapy first. They also typically start with hormone therapies, which are often somewhat less active in terms of response rates and PFS but have an advantage of being associated with fewer side effects compared to standard chemotherapy.
Ten years ago it was actively debated whether there was a value in treating metastatic lung cancer, given how marginally effective and more challenging the treatments were. The concept of second line therapy really only took off around 2000-2001, when taxotere (docetaxel) was shown to improve survival, again modestly, and a challenging treatment as well. It’s really only been in the last five years, with the addition of alimta (pemetrexed) and the EGFR inhibitors iressa (gefitinib) and then tarceva (erlotinib) were introduced as additional options with activity in previously treated patients, and a side effect profile that patients and oncologists could more readily accept, that further lines of therapy became standard and anticipated. While 6-7 years ago there were almost no trials of new drugs being tested as second line treatments (alone or added to taxotere, for instance), there are now dozens of large trials of new agents being tested as second line, third line, even some fourth line options.
So we now need to struggle with the optimal order of the growing number of tools available. Is it better to use them combined early, or as single agents sequentially? And does the order matter? This issue is now at the center of our current debates.
Never-Smokers Needed for Study of Molecular Risk Factors for Lung Cancer
Actually, it’s some background information and your blood that’s needed.
Memorial Sloan-Kettering is running an important trial that is trying to determine some of the molecular factors that lead some never-smokers to develop lung cancer while other never-smokers don’t. The trial is just a one-time collection of information in a questionnaire, I believe about medical history and environmental exposures, and submission of two vials of blood. There is no cost to participants, with all packaging and mail expenses pre-paid, and the registration and additional information is online here.
Early Report: SATURN Trial of Maintenance Tarceva Positive for Improvement in Progression-Free Survival
Well, it happened again that the first word came from the financial community (report here), as we learned today that a large trial testing the value of maintenance tarceva (erlotinib), the oral EGFR inhibitor, provides a significant improvement in progression-free survival (PFS). In the following slide, I show the design for two similar trials that test the value of tarceva after four cycles of first line treatment of advanced NSCLC.
The first, called the ATLAS trial, is for avastin-eligible patients who would typically receive avastin alone as maintenance therapy after initial chemo/avastin. It randomizes patients to maintenance avastin/tarceva vs. avastin alone. We don’t have results from that trial yet. The results we have are from the SATURN trial, which asks a similar question but without the avastin: is there a significant delay in progression if patients who haven’t progressed after four cycles of platinum-based standard chemotherapy (and no avastin) receive tarceva as a maintenance therapy, compared with an oral placebo?
EGFR Mutations in the Second Line Setting
I just recently wrote a post (here) that describes how I became convinced that under certain circumstances there could be a genuine value in determining whether a particular lung cancer patient has a tumor with an EGFR activating mutation. While these have seemed to predict that these patients are quite likely to respond with dramatic tumor shrinkage, correct about 70% of the time, I had previously been impressed by how correlated EGFR mutation results were with some other clinical factors, such as being Asian and especially a history of never-smoking. But recent results that I described in my last post convince me that
1) mutations trump clinical factors
2) patients who receive EGFR inhibitors as first line therapy but don’t carry an EGFR mutation don’t seem to do as well as those who received chemo.
I also said that this doesn’t mean that patients without mutations don’t benefit from an oral EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) in the second or third line setting (the evidence is far stronger with tarceva, though, showing a survival benefit vs. placebo that hasn’t been shown with iressa). Member sunnyside then asked about the evidence with regard to EGFR mutations and second/third line treatment. Here’s what we know.
Is it Time for EGFR Mutation Testing? Confessions of a Newly Convinced, Former Clinical Selector
Those who have followed my writings over time will know that I haven’t been inclined to adopt a reflexive strategy of ordering molecular testing without good evidence that having this information will improve outcomes. Testing tumors for EGFR mutations is advocated by a vocal minority of lung cancer experts in Boston and New York City, but this hasn’t been advocated by the broader lung cancer community yet, or adopted as routine clinical practice. Although I’ve felt that we’ll have enough evidence to support broad use of molecular variables to individualize treatment for lung cancer patients in the next few years, I haven’t felt that they have a role yet, but I’ve now seen some results that I believe are enough for me to change that conclusion.
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