Member Sandra recently asked the question that several other people have asked in one form or another: how do we choose among the treatment options for second line therapy in NSCLC. I’ve covered in several posts and a huge number of responses in the Q&A Forum the leading options we generally consider for second line therapy for NSCLC. I’ve consistently stated that there are three agents that are most commonly used — taxotere, alimta, and tarceva — because they’ve all been pretty well studied, and they’re all approved by the US FDA for this setting based on the evidence available. Moreover, they also have what appears to be very comparable activity: taxotere and alimta have been compared head to head and shown to have remarkably similar efficacy (post here), and while we don’t have data yet for direct comparisons of tarceva vs. one of these chemo options, we do have data from the large INTEREST trial (post here) that showed that iressa, which the preponderance of evidence would say is the slightly weaker EGFR inhibitor vs. tarceva, had the same efficacy as taxotere in a huge worldwide trial.
So we’ve got these three leading options (and it’s also reasonable consider others, even if they aren’t as well studied), and how do we choose among them? My first question is whether I’m inclined to recommend chemo or an EGFR inhibitor as second line therapy. And the two leading factors I’d consider are prior response to chemo in first line, and smoking status. To me, they both count pretty similarly. The main principles are that if someone responded well to chemo in first line, they’re more likely to respond well to second line chemo. On the other hand, someone who progressed after the first two cycles is not someone I’d be especially optimistic about for a better response to second line chemo. So the better the first line outcome with chemo, the more inclined I’d be to recommend more chemo; conversely, the more disappointing the outcome, the more inclined I’d be to recommend EGFR inhibitor therapy with tarceva, although in this case I’m selecting it as the “not more chemo” choice more than because it’s an EGFR inhibitor. I’d consider it more of a wild card, and a wild card is good when you’re expecting a bad outcome with what you’ve already got (for instance, more chemo), but it’s less appealing if you’re expecting a good outcome with what you’re holding.
The second big factor is smoking status. We’ve spoken mostly about never-smokers, and as I’ve mentioned all over the website, never-smokers appear to have a distinct biology (post here) and are consistently more likely to do well with EGFR inhibitors like tarceva (post here). So in my mind, never-smokers should receive tarceva early: many experts consider it to be an appropriate first line treatment (I’d consider myself in that camp), but if not used first line, I’d almost always advocate to use it second line. And I wouldn’t wait for someone to have major progression on first line chemo. If a never-smoker’s scans looked convincingly worse, even if the difference didn’t technically meet criteria for progressive disease, I’d almost certainly move them to tarceva ASAP. But the important point is that while that’s a neat answer for the 10-15% of lung cancer patients who never smoked, what about the other 85-90%? And the point is that it isn’t ALL or NOTHING, ever-smoker or never-smoker. People who smoked relatively little (say, less than an average of a pack per day for 10 or 15 years) and who quit smoking 20 or 30 years before diagnosis often have the molecular and treatment characteristics of the never-smoker population (as described in one of the referenced posts above, on different response to treatment in never-smokers). Some of our current trials on smoking status also include remote, light smokers in addition to never-smokers. We don’t know if they will do as well as never-smokers, but in the real world, the less a person has smoked and the longer they’ve been off of tobacco, the more likely I think it is that they’ll get an impressive benefit from tarceva. However, I don’t want to completely overstate this association. There are never-smokers who don’t benefit, and there are smokers who do well with tarceva as well. Smoking status is just a useful predictive tool, not a guarantee.
So putting this together, I’d definitely advocate chemo for someone who responds well to first line chemo and has a significant smoking history. And I’d strongly favor tarceva second line for someone who either has a minimal/remote smoking history or progressed quickly through chemo. What is someone is a remote and/or light prior smoker AND responded pretty well to chemo? Either choice is very reasonable, so I talk with the patient about whether they’d prefer IV chemo or an oral targeted therapy, discuss the different side effect profiles, and then make a decision or flip a coin (kidding — hasn’t happened yet). And most of the time, whichever we didn’t do second line is going to remain a feasible third line option, so it’s more choosing the order of treatment than which treatment they’ll get. We don’t need to burn bridges, unless a person declines too quickly to tolerate more therapy.
In terms of which chemo, either is very appropriate, but I and many other oncologists have come to clearly favor alimta. If patients haven’t lost their hair, most would prefer not to lose it (which occurs far more commonly on taxotere). Alimta was approved by the US FDA based on its modestly more favorable toxicity profile overall vs. taxotere, and although the differences weren’t striking, my clinical experience, and that of many of my oncology colleagues, is that the toxicity of alimta is appreciably less than taxotere, overall. Of course, there are patients who have a hard time with it, just as with any cancer medication.
In patients who are strong enough for long enough, it’s possible to give first line therapy and then all three of these agents at some point, and sometimes more. But beyond these general principles, I largely individualize my treatment plans with patients, as most oncologists do.
I’d be interested in learning how Dr Laskin approaches second line therapy. She may have a similar approach, or she may have a different perspective, working in a system that, from my vantage point, has more rigid guidelines in place. There’s plenty of lattitude for differing views, but at the present time, this is how I approach my patients after they have completed first line therapy.
posted by Dr. West @ 6:05 pm link to this post
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February 11th, 2008 at 9:05 pm
sdixon,
My comments on the current standards of care for second line chemo are in the subject archives, so you should be able to see my general recommendations. I can’t tell someone the best course for them — this site can’t replace the input from a person’s doctor. I can tell you that while I share your concern about going from one taxane to another in a move from first to second line, there isn’t any evidence I’m aare of that shows that prior recipients of taxol are less likely to respond to taxotere than taxol-naive patients. In fact, response rates for prior taxol recipients appears to be just as good. However, with a history of progression on another taxane, it’s an even greater concern, but I don’t think there’s enough information on that question to give a real answer.
Gemcitabine/alimta combination is feasible and appears generally safe, but it’s not standard to use combinations of chemotherapy in previously treated patients. The overall data show a bit of an improvement in response rate, fa more problems with side effects, and no significant improvement in survival compared with single agent chemo in this setting.
-Dr. West
February 8th, 2008 at 11:52 pm
My 71 yr old non-smoking mother diagnosed 6/07 Stage IIIB NSCLC squamous cell. Inoperable, began concurrent radiation and 6 rounds of Carboplatin-taxol based chemotherapy. Chemo did not work since it has now spread to her bones and liver. Radiation shrunk the primary lung tumor somewhat. Six wks of Tarceva more disease progression. Options are now Mayo study of Doxetaxol w/Obatoclax mesylate (targeting BCR Protein for cell destruction) or Alimta w/gemzar. What is best course? She appears healthy and strong! What are the odds another Taxol based chemo will work 3 months later when it didn’t work the first time. She is running out of time…please advise!!!
February 7th, 2008 at 10:34 am
Thanks, Dr. West. I now feel as if I am pretty well prepared to deal with any future need to look at second line treatments for my husband.
I am always reminded in readng your responses and posts that this whole business is actually many shades of grey, and involves some subjectivity and critical reasoning on a case by case basis.
My husband is a pretty passive patient and counts on me to do my homework. I take the job seriously, so try to stay ahead of developments by arming myself with information. I appreciate your helping me with it.
Mary
February 6th, 2008 at 9:49 pm
There’s no rules on avastin in patients who had a brain metastasis that was surgically removed. We generally consider patients to be ineligible for avastin with evidence of primarily squamous histology, but we’d generally consider it OK to give to someone with NSCLC that isn’t/can’t be defined any further by subtype. And while there’s no hard rules on cavitation, some people do consider it a factor suggestive of increased risk of bleeding, although that could reflect the fact that cavitation is more commonly seen with squamous lung tumors.
And that smoking history sounds fairly light and remote to me.
-Dr. West
February 6th, 2008 at 1:33 pm
Well, he’s caucasian, male (obviously), and probably what you would class as a remote smoker - maybe a pack a day from age 18 to age 31, quitting 21 years ago. His tumor histology is squamous cell, moderately differentiated. Both his lung tumor and his brain tumor were noted as being quite ulcerated/necrotic. Is Avastin generally not going to be in the line up under those conditions? Thanks very much
February 5th, 2008 at 10:12 pm
Fair enough, but there’s also the factor of smoking status that can be useful.
And with the clarification you provide, I’d be a little more skeptical about chemo.
-Dr. West
February 5th, 2008 at 9:24 am
Thanks for your response, Dr. West. When the met originated is kind of hard to determine. He had a clean brain MRI 10/06, chemo November ‘06 - January ‘07, and a 3 cm brain met found around 4/1/07 (about 8 weeks after chemo ended.) I guess I have always assumed that in order for the brain tumor to be 3cm and extremely symptomatic 4/1, it was probably growing during the chemo period. This could be an erroneous assumption, but it led me to think maybe standard chemo did not do it’s job. I just want us to be in the best possible position if the need for 2nd line treatment arises to make the best choice…but really, we don’t even have any evidence to indicate that a targeted therapy would work, either. I think I’ll just stop looking ahead, and hope the need never arises to select a treatment. Thanks again.
February 4th, 2008 at 9:33 pm
Mary,
The key is whether this developed while he was on chemo or whether this was really there all along. It’s not uncommon to not really look at the brain until there’s a problem, in which case you could wonder whether the brain met was there but not noticed until after chemo.
The simple error is that yes, new brain metastases are progression. But if you ask about how that falls into the rules for selecting chemo vs. tarceva, my answer is that there are no such rules. This analysis is just how I approach patients in the second line setting. Several other very thoughtful experts, including Dr. Laskin, have a very similar approach, but not everyone does. So there’s no real algorithm here, just some principles we find helpful in prioritizing the options. And partcularly in “borderline” cases, even the experts often disagree about their rankings of the next treatment to try.
-Dr. West
February 4th, 2008 at 10:24 am
Dr. West, I’m not sure how I posed a simple question (above)in such a convoluted way. Here is the actual question, hopefully made clearer: my husband is currently NED. However, I guess it is possible that the day may come when we may need to look at further treatment.
He developed a brain met immediately after finishing chemo last year. Would you consider that to be a poor response to chemo? I wasn’t sure if brain mets are looked at the same way as other progression.
If that does constitute progression, then I would guess that a targeted therapy would make more sense as a second line than standard chemo would, should a second line ever be needed.
I just wasn’t sure if a brain met is considered a chemo “failure”, since there is a lot of concept out there that maybe standard chemo does not effectively treat the brain.
Mary