Lung Cancer / Mesothelioma
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Loading ...We’re recognizing more and more that lung cancer in never-smokers (LCINS) is a distinct disease, with different patterns of who gets it, how the cancer behaves, and it responds to treatments. But this recognition is still a work in progress, coming from a background in which the party line has been that NSCLC is treated the same regardless of the histologic type (squamous, adenocarcinoma, large cell, or other), smoking history, or other factors. In fact, it’s fair to say that it’s still appropriate to treat never-smoking patients with the same approach that I described in other posts about NSCLC patients in general. But I do think of never-smokers a little differently because of its apparently distinct biology, and this does modify my practice recommendations.
To me, the guiding point, based on what we know right now, is that never-smokers have a high likelihood of receiving a significant benefit from oral EGFR tyrosine kinase Inhibitors (TKIs) like tarceva and iressa (see prior post). While the LCINS population isn’t as likely to have a significant response to EGFR TKIs as a population defined by the presence of an EGFR gene mutation (around 30-50% for never-smokers vs. 60-80% for EGFR mutation-positive patients) , they are a readily identifiable group of patients who consistently have a higher magnitude of benefit with EGFR inhibitors than we’re used to seeing with chemo. But there are absolutely other factors, since some studies corroborate my own clinical observations treating the LCINS population really demonstrates that Asian never-smoking women are clearly more likely to respond than some other groups, such as Caucasian never-smoking men.
Several clinical studies have shown that LCINS patients are a subset that receives the greatest clinical benefit in positive EGFR TKI trials, and they’re a group that benefits even when the overall trial is negative. They experienced a doubling of survival with tarceva as a single agent, and they were the group that showed a similar benefit when tarceva was added to carbo/taxol as first-line chemo. A clinical trial is currently being done in current or remote former light smokers that is testing tarceva vs. carbo/taxol/tarceva, so that will help us understand whether tarceva should be added to chemo (summary here). I haven’t favored that approach because several studies have suggested a detrimental effect of giving standard chemo and an EGFR TKI concurrently, but I hope and expect we’ll have a real answer in the next year or two.
In the meantime, what do I do? First, I do think that it’s completely reasonable to use the same strategy for never-smoking NSCLC patient that you would recommend for a current or former smoker. We have evidence that EGFR TKIs are unusually effective in the LCINS population, but we have almost no information about how never-smokers do with standard chemo. The TRIBUTE trial of carbo/taxol with or without tarceva showed that never-smokers receiving placebo had a very ordinary median survival of about 10 months (abstract here), but there have been a few suggestions in other trials that never-smokers may do a bit better. Overall, though, we don’t have enough information to say much about how standard chemo agents perform in never-smokers, except to say that thus far there hasn’t been any signal that they consistently have a high probability of a major benefit, in contrast with the EGFR TKIs.
So I offer the same standard therapy I’d give to a current or former smoker, but I also talk about potentially starting with an EGFR TKI, on or off of a trial. As a non-standard approach, my preference would be to do this under the auspices of a clinical trial, such as the SWOG trial that I’m leading that pairs tarceva and avastin for never-smokers (link here). This option isn’t for everyone, either because they are found to have brain metastases or another reason to be ineligible for avastin, or because they aren’t inclined to accept the risk even if they are technically eligible. In those cases, I think it’s definitely appropriate to consider tarceva as a single agent, off protocol, as a first line therapy. There’s no other treatment we know about for which we can say that LCINS patients have such a high probability of success, not only in terms of both likelihood of a major response, and (more importantly, I’d say) also duration of response/non-progression that can extend into years.
For patients who receive standard first line therapy, I just want to ensure that every LCINS patient receives an opportunity to see how well they might do with tarceva (the EGFR TKI commercially available in the US, and the only one proven to improve survival vs. placebo thus far), preferably as early as feasible. We see that likelihood of benefit with any cancer treatment, whether targeted therapy or standard chemo, is lower in patients with a poor performance status, so I don’t want to wait until these patient s become debilitated before offering them an EGFR TKI.
Beyond that, I have a series of trials for LCINS patients (see prior post). I believe that because they tend to have a genetically simpler cancer (without the accumulation of dozens of tobacco-induced mutations over many years), LCINS patients have a greater likelihood of having a profound response to other agents if the treatment effectively targets the Achilles’ Heel of the tumor.
Finally, there is some overlap between never-smokers and patients with bronchioloalveolar carcinoma (BAC), about 1/3 of whom never-smoked. Without enough evidence to say anything definitive, my sense is that smoking status is the more dominant factor than BAC histology, but further studies will tell us more. The special case of BAC, when it applies, is that it can be a very indolent cancer, and I think that situation merits special consideration, which I’ll cover separately.
Posted in: Chemotherapy, Clinical variables in EGFR therapy, Core Concepts, Epidermal growth factor receptor (EGFR)-based therapies, First-line treatment, Lung Cancer, Never-Smokers with Lung Cancer, Never-smokers with lung cancer, Non-Small Cell Lung Cancer (NSCLC), Special Populations in Lung Cancer, Stage IV/Advanced/Metastatic NSCLC, Targeted therapies, Treatment, What I Really Do
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Does (or will) Erbitux fit into this mix at all? Is there any evidence to suggest that lifelong nonsmokers do better (or worse) with it? And is there anything to suggest that Erbitux is less effective after Tarceva?
Similarly, is there anything to suggest that sorafenib is less effective after either Avastin or Tarceva?
Thanks!–Neil
neilb
Neil,
We don’t have much information on this, but my read is that erbitux is different from the EGFR TKIs in many respects. The FLEX trial didn’t show an expecially long progression-free survival for Asian patients, among whom more than half were never-smokers, and yet the survival among Asians was far better than for Caucasians. This strongly suggests that erbitux isn’t associated with the same “wow” response in never-smokers, but also that patients receiving EGFR TKIs after erbitux can still benefit greatly (in fact, the median survival for Asian patients was about 17 months in chemo/erbitux arm, and 20 months for chemo alone, I think because 73% of the chemo alone Asian patients received EGFR TKIs after first line, but only 50% of the chemo/erbitux patients did).
There is also a small amount of prior data that the EGFR mutations aren’t very well correlated with outcomes on erbitux, unlike the EGFR TKIs.
As far as I know, there’s almost no information out there about sorafenib results as a function of prior treatment. There were certainly some patients on the early trials who had received at least an EGFR TKI, but I don’t know of any data to suggest that prior recipients of an EGFR TKI or avastin are more or less likely to benefit from later sorafenib. I’m suspicious that prior avastin recipients may gain less from subsequent anti-angiogenic therapy like sorafenib, but I know of any real evidence to speak to that issue.
-Dr. West
thanks!
neilb
Dr. West,
I have recently found your site and have several questions I hope you can answer. My sister, age 52, African American, was always healthy (until now) and has never smoked. She was admitted to the hospital in early August with a cough and shortness of breath. The docs first thought was phenomonia, then infectious diseases were considered before a biiopsy showed undifferentiated squamous cell cancer in her lungs. CT of her lungs shows small, cloudy nodules dispersed across both lungs (sounds alot like BAC). I suppose, due to the type of tumor and the CT scan, 2 pathologists have suggested that the lung is not the primary site. She has had CT scans of everything. No signs of cancer in other parts of the body. 2nd opinion lung Onc took one look at CT scans and said it looked like BAC and asked for the 2nd pathology review. That review indicates the same thing: undiff. squamous cell - liklly from another source.
They immediately started her on Carboplatin/taxol (standard for treating squamous cell) with the plan to do 3 treatments before retesting. She begins 2nd treatement today. Here are my questions:
1) what can be done to confirm the primary source or get further “differntiation”?
2) Isnt knowledge of the primary source critical in defining a 1st line and follow-on treatment plan?
3) how do we develop a follow-on plan, do research etc. without this information?
4) can BAC be a possiblitiy with this diagnosis? how would we confirm this?
5) does any of the new, targeted therapies like Tarceva make any sense in this case?
6) with these small, dispersed, cloudy nodules, what is the best way to determine chemo success?
I would greatly appreciate your thoughts!
Thanks
Holdenon1
Holdenon1,
I’m very sorry to hear about your sister. It does sound like the docs there are doing all the right things and asking the right questions. After a second opinion on the pathology (which I was thinking of before I read further, that this had already happened), I think you’d generally treat this like a metastatic cancer of unknown primary (MCUP), which represents about 2-4% of cancers. In addition to the scans, I might consider having an ENT specialist do a good evaluation looking for a possible source in the head/neck area, since head/neck squamous cancers may be hard to detect but can spread to the lungs. It’s also possible that it’s just a very odd cancer that actually did start in the lungs. But it’s true that the BAC picture should be an adenocarcinoma, and that the clear majority of lung cancers in never-smokers are adeno, not squamous. Still, it’s possible that this cancer just didn’t read the textbook and is an odd bird.
There is a company called Rosetta Genomics that I believe is now coming out with a molecular test in which they believe they can identify the primary site for a metastatic carcinoma of unknown primary. I described this company in a post here:
http://cancergrace.org/lung/2008/07/22/rosetta-genomics-squamous-nsclc/
I described in a recent post that I am more influenced by the behavior of the cancer than how it appears under the microscope, but BAC shouldn’t be squamous, so I would approach such a case as a metastatic carcinoma of unknown primary or an advanced NSCLC. Frankly, that treatment is pretty much the same no matter what you’d call it: most typically a platinum-based doublet like carbo/taxol, possibly a different doublet, but no great reason to advocate one over another, I’d say. And with the pathology findings, many or most oncologists would not favor adding avastin, or using tarceva very early. As I’ve mentioned in a recent post about BAC, treating with chemo is quite appropriate, so it’s not that tarceva is clearly the first treatment, and that would be especially so if that pathology doesn’t support the BAC diagnosis. Beyond first line, I’d again consider the treatments for NSCLC, which also may be commonly used in other cancers — such as gemcitabine or navelbine. But I don’t have another suggestion of more research to do. You often have to just do the best you can with what you’ve got.
In terms of measuring response, sometimes you can see the dimensions shrinking, and sometimes you can see the density/opacity breaking up. Sometimes following how a patient feels can help. But we don’t have a great answer on how to measure BAC response.
I’m sorry I can’t give you more definitive answers, but the reason there are so many open questions after many other thoughtful doctors have already been involved is that your sisters is a remarkably complex case that may well not have any definitive answers, from anyone.
-Dr. West
Dr. West,
What you treat patient differently for diffused soft tissue type of lung cancer vs. solid tumor? Thanks.
Melissa
melissa
Melissa,
I’m not sure I completely understand your question, but I don’t treat differently based on the pattern of spread, except to say that if something called BAC has spread to brain, bones, liver, etc, rather than confined to lungs only, I think of it as standard invasive adenocarcinoma and not BAC. Also, if it’s called adenocarcinoma by biopsy but has fluffy, slowly progressing infiltrates in the lung and no cancer elsewhere, I think of it and would be inclined to treat it as BAC. So behavior counts more than histology to me. But I don’t treat differently if the cancer spread to the liver vs. the bones, for instance.
If that didn’t get to your question, please try to clarify and I’ll give it another go.
-Dr. West
Over three years ago, I tried Iressa (Gifitinib) and got no response. Is there any reason to try Tarceva, these being similar TKI-EGFR type of drugs? What about newer EGFR drugs? Thank you.
There has been greater interest in trying one EGFR inhibitor after another for people who have enjoyed a very good, prolonged response and then became resistant, and responses to tarceva after iressa are uncommon to rare, but they do occur. I am less familiar with responses to iressa after tarceva, and I consider iressa to be the less effective agent at standard doses.
I think there’s more reason to consider tarceva after iressa, since only the former has been shown to improve survival over a placebo. However, I really think it depends on how someone did on iressa. I think we need to make a distinction between response and clinical benefit, because many people can have no significant tumor shrinkage but still live longer because the iressa or tarceva prolongs the time interval before a person progresses. If a person showed stable disease but didn’t “respond” (and there are oncologists who have been looking for a miracle response and then took a patient off these agents if the cancer didn’t improve dramatically), I would consider there to be good reason to try another EGFR inhibitor, especially tarceva after the less consistently beneficial iressa. On the other hand, if a person demonstrated clear progression within a few months on an EGFR inhibitor, I wouldn’t be particularly optimistic about the results with a different EGFR inhibitor.
This is really no different from my thoughts about chemo agents. The patients who respond well, or at least progress less rapidly, on a first chemo regimen are also the ones most likely to benefit from a second and third line of chemotherapy.
As for newer EGFR drugs, I’d follow the same general principle that I’d be more inclined to recommend a clinical trial with a new EGFR inhibitor for someone who showed some benefit to EGFR inhibitor therapy previously than for someone who blew through a prior EGFR inhibitor with rapid progression. Several of these have had some “buzz” that they’re new and improved, but the proof will be in the outcomes with real patients, not the findings in a lab-based model with cultured cancer cells, which is often the source of the provocative comments about how impressive the next EGFR inhibitor is going to be. However, a few have shown responses in prior recipients of EGFR inhibitors and therefore have met that threshold, so perhaps we’ll see a real next generation EGFR inhibitor add some benefit beyond the iressa and tarceva we’ve been using.
-Dr. West
Hello, Dr. West,
I am writing from China. My mother is diagnosed with squamous cell lung cancer stageIIIB (T4N3M0). The primary site is in her left lung, with mediastinal and neck lymph nodes involvement. She is a non-smoker, but the cancer may have something to do with the polutions. Right now she is on her second round of chemo (Cisplatin/Navelbine). Should I talk to her doctor about adding Tarceva to her treatment? I also read somewhere that radiation combined with chemo may provide better overall outcome in some cases, does that apply here?
Thanks a lot for any input you may be able to provide.
yucca from China.
yuccaz
Yucca,
My first question would be whether it’s really absolutely true that the cancer originated in the lung. Although some lung cancers in never-smokers are squamous, I expect the clear majority to be adenocarcinomas, especially in an Asian population. Head and neck cancers are squamous tumors, and although we often see those in people with a significant history of tobacco and alcohol use, we also see them in people who aren’t drinkers or smokers.
If a lung cancer, I don’t think I’d apply a special “never-smoker” approach for a squamous cancer. I would still be inclined to try tarceva, which I would also do in a prior or even current smoker with a squamous cancer, but it wouldn’t vault to the top of my list. And I have never had any enthusiasm for treating patients with chemo and an EGFR oral inhibitor concurrently. See prior post below:
As for adding radiation, I would do that for a locally advanced NSCLC, which the staging of T4N3 NSCLC implies, but neck nodes are often actually spread through the blood stream and are truly metastatic. So I think it makes sense to discuss whether radiation added to chemo is something to consider, but it’s hard for me to get a good handle on whether this is really an appropriate option to pursue.
-Dr. West
Dr. West,
Thank you so much for you quick response.
We were quite puzzled by the lung cancer diagnosis as well in the begining. CT scan of her head, nose, bones, and the oral cavity all came back clean. And the CT scan of chest showed one dark area in anterior basal segment of left lower lobe, and it also suggested pericardial effusion. The biopsy of a neck lymph node suggested sqaumous cell cancer. She does not have any lung related symptom at all. But the doctor seems to be quite certain that it is lung cancer. What is your opinion based on this information?
Thanks a lot!
yuccaz
It sounds like they thought about the same things I did and looked very hard for an alternate explanation, so my impression is that they did a very thorough work-up and came to the best interpretation of an unusual situation.
DR. WEST
MY 40 YEAR OLD NEVER SMOKED SON WAS DIAGNOSED WITH STAGE FOUR ADENOCARCINOMA IN MARCH 2008–HE HAD SIX SESSIONS OF CARBOPLATIN TAXOL AND AVASTIN- LAST ONE JULY 16- LAST PET SCAN JULY 8 SHOWED NO PROGRESSION- HIS HEALTH SEEMS GOOD - HE WORKS OUT EVERY DAY -SINCE LAST CHEMO HE HAS NEEN GIVER AVASTIN AND ZOMETA EVERY THREE WEEKS-DUE FOR ANOTHER PET SCAN NEXT WEEK–I HAVE BEEN TOLD BY PEOPLE AT A MAJOR CANCER CENTER THAT AVASTIN DOES NOT WORK BY ITSELF AND THAT HE SHOULD GET TARCEVA-HE DOEN NOT HAVE THAT MUTATION FOR TARCEVA BUT HIS KRAS IS NORMAL-IN ONE OF YOUR POSTS YOU SAID THAT YOU KEEP PEOPLE ON AVASTIN ALONE-FOR HOW LONG-THANK YOU — LEE
leemessenger
leemessenger,
It’s true that we don’t typically start patients on avastin alone without either chemo or tarceva, but the large study that led to the approval of avastin gave it exactly the way he’s gotten it — 6 cycles of chemo, then avastin alone until progression (zometa would commonly be added along with that if there are bone mets). It’s certainly reasonable to add another agent, either chemo or tarceva to the avastin, but there is no evidence that doing this is better than continuing with avastin alone (or avastin/zometa). Having been involved with many expert panel discussions of how to manage such cases, I would say that the clear majority of lung cancer experts would be inclined to continue with the avastin without adding tarceva or a new chemo, BUT tarceva is also often especially helpful in never-smokers, so many people, myself included, would be tempted to add it pretty early. The “by the book” answer is really the avastin (+/- zometa) alone.
There is a trial being done by Genentech (makers of avastin, also sell tarceva) that is looking at this exact question, where all patients get maintenance avastin and half get immediate tarceva added, while the other half receive a placebo pill instead. That trial isn’t completed, so right now we just don’t know if adding tarceva (or a new chemo) to maintenance avastin improves clinical outcomes. The placebo part isn’t an unethical thing to do, because the “standard arm” of our current known best treatment is still avastin alone.
-Dr. West
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