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.

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   As I’ve described previously (prior post here), the available evidence is pretty definitive that the vast majority of platinum-based doublets are remarkably similar in their overall activity.  There is a little evidence that cisplatin in a little bit more active (see prior post for details), but most oncologists feel that it’s clearly more challenging in terms of side effects, so carboplatin doublets are far more commonly used, including by me.   I’ve historically favored the doublet of carbo/gemcitabine for many patients, because the main side effects are decreases in blood counts with usually very little hair loss, nausea/vomiting, and many other unpleasant side effects.  I generally favor regimens that have mostly “paper toxicities” that you tell the patient about, compared with ones that the patient experiences and tells you about.  But I’ve used several different carbo-based doublet regimens. 

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   That said, let’s start on how I think about a patient presenting with new advanced NSCLC, which is the stage at which about half of the patients with NSCLC are diagnosed, and a higher proportion of my lung cancer patients (because many of the patients with early stage NSCLC, especially stage I, may not need or be feasible candidates for chemo).   

   Performance status is the first indicator.  There’s certainly some correlation with age, but most experts agree that the overall activity level of the patient counts far more than chronologic age.  A 77 year old man who walks his dogs 2 miles per days is a much stronger candidate for aggressive treatment than a 57 year old with severe emphysema who rarely leaves the house because she becomes short of breath making the bed or walking around.   Treating poorer risk patients is a separate issue, so we’ll concentrate on healthier patients who are able to manage their own activities of daily living (ADLs) without assistance and get out and about.  

   Within the healthier population with advanced NSCLC, the question I ask is whether they are a candidate for avastin (bevacizumab), which has been shown to improve survival for a limited subset of patients who don’t have brain metastases, squamous NSCLC, active heart disease,  require full dose blood thinners,  or have a history of coughing up blood (prior post here).  Since that initial approval of avastin for lung cancer, increasing evidence has emerged suggesting that it’s probably pretty safe to give avastin to patients with treated brain metastases (prior post here), and also for patients on blood thinners (prior post here), but right now the FDA approval doesn’t include these groups, and serious or even fatal bleeding  episodes can occur even in well-selected patients receiving the treatment, Avastin added to carbo/taxol, just as it was given in the large trial that led to its approval.  If a bleeding complication occurs in someone treated as Avastin was approved, it’s a terrible thing, but it’s known to happen.  But if, God forbid, a patient on blood thinners bleeds, or someone with a treated brain metastasis has a hemorrhage in their brain, there’s no way to prove it didn’t happen because you treated someone outside of the FDA guidelines.   And some people feel that even if you have a careful discussion with a patient with brain metastases or on blood thinners, and even if you document the risks well, a family member can still come back months after a patient’s unfortunate death and sue their doctor.  I happen to be one of those people, so I use avastin by the book.  And for the sake of completeness, I wouldn’t consider trying it in someone who has coughed up any significant amount of blood (more than slight flecks or streaking), nor someone with squamous NSCLC, since both groups continue to look like they have an unacceptable risk of bleeding complications.

  So if patients are eligible and are inclined to pursue it, I recommend carbo/taxol /avastin for up to six cycles, then maintenance avastin.  I don’t have a real problem with other platinum-based doublets combined with avastin, but no other regimen has shown a survival benefit, and cisplatin/gemctibine has failed to show a survival benefit in the AVAiL trial (prior post here).  This trial also showed that a lower dose looked comparable to the higher dose (but neither was better than placebo).  Putting it all together, I think it’s reasonable to give a lower dose, but I still favor the higher dose that was used in the ECOG trial, the only one that showed a survival benefit, particularly since the side effect profile wasn’t appreciably better with the lower dose. 

   Another point is that the failure of the AVAiL trial to show a survival benefit suggests to me that avastin’s benefit isn’t astounding: I would have hoped to see it significantly improve overall survival with  the cisplatin/gemcitabine regimen  if it were that remarkable (most oncologists have considered the regimen attached to avastin to be pretty much interchangeable, since we presumed that the effect of avastin would be the same for all of these doublets).  One large trial was positive, and another was negative, and I’m not sure that we’d consider it a standard of care if the negative trial had been reported first.  But as it was, US-based oncologists were already conditioned to accept avastin as part of our initial plan, and the AVAiL trial leaves enough unanswered questions that I don’t think it was enough to reverse our practice of giving it.  But it didn’t increase my confidence about how much the avastin was adding.  So I don’t think it’s a crucial mandate that every eligible patient receive avastin.  And it’s something I think about in a patient who is perhaps borderline for eligibility, maybe because of treated stable brain mets or anticoagulation or has had some mild hemoptysis (coughing up blood).  While there is growing experience suggesting that we can be more comfortable giving avastin to patients who may have previously been excluded or are just questionable for it, is it clearly beneficial enough to accept the risk if it didn’t show a benefit in both of the large trials that studied it?

   The other issue is that an analysis of patient age on the ECOG trial showed that elderly patients (defined as 70 and older) didn’t receive the same degree of survival benefit and experienced a significantly higher rate of many side effects compared with younger patients (prior post here).  The trial wasn’t designed to test this, and this remains a debatable point, but I definitely discuss this issue with older patients, and although I wouldn’t hesitate to recommend the triplet to a fit 72 year old, I’d think hard about how to guide a 78 year old.

   That’s more than enough for now.  I would estimate that only about 40% of my patients are eligible for avastin, so another post will cover how I approach healthier patients who aren’t candidates for avastin for one reason or another.

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It’s important to highlight that the discrepancy between the expected outcome based on a pathology report and the clinical picture in front of you can cut both ways.  In some cases, you may have a biopsy of a lung nodule that shows no cancer, but if it’s growing and continues to grow, that’s not very reassuring, and you’d suspect that the biopsy missed the diagnostic part of the tumor that would confirm viable cancer.  In other settings, a biopsy of a lung nodule might diagnose cancer, leading down a path toward the typical management with surgery, etc., but if you happened to have old films that showed that the nodule was actually minimally changed over 3 years or more, it might be reason to take a step back and wonder whether you haven’t already been furnished with some valuable information that might lead you to individualize and change your treatment plan.

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   Recently I saw a patient who had undergone surgery for stage II Non-Small Cell Lung Cancer and was receiving chemotherapy with another cancer doctor. He came to me for a second opinion. Among the questions he had was what tests should he get after completing all his treatment. (more…)

This was a rather complex study, presented by Dr. Dan Karp from MD Anderson in preliminary form last year (abstract here), in which patients with previously untreated advanced NSCLC were randomized two to one to receive either carbo/taxol alone or the same chemo combination with this IGF-1R antibody at either of two doses, IV every three weeks.  After randomizing 150 patients and seeing especially encouraging results in patients with squamous cancers, they then enrolled a few additional patients with squamous cancers to all receive chemo with the higher dose of the IGF-1R antibody.

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The original trial enrolled just under 1000 patients with stage I adenocarcinomas (a remarkably common presentation in Japan, where they really do see a fundamentally different lung cancer biology than we see in North America and Europe, at least).  This focus on patients with adeno NSCLC is based on earlier work that indicated this drug worked preferentially in adenocarcinoma tumors, and randomized patients with stage I tumors to observation or up to two years of daily oral chemotherapy after surgery (abstract here).    As shown in the curves below, there was a modest but significant survival benefit, and nearly all of that benefit was seen in patients with larger, higher risk T2 cancers, rather than the smaller T1 cancers with the lowest risk for recurrence and death:

Interestingly, this is really the most conclusive survival benefit we’ve ever seen for stage I NSCLC, and in the curve for the overall trial population (left curve), the separation of the curves that signifies a survival benefit from treatment doesn’t occur until four years out.   Unfortunately, this is with a drug not available in the US and was a benefit seen only in patients with stage IB adeno NSCLC: we haven’t been able to do another study with UFT to confirm this, but it’s currently a standard treatment in Japan.

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    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:

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