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New Podcast on the ABCs of BAC
Here’s a video slide presentation that provides a basic introduction to bronchioloalveolar carcinoma (BAC), including the demographics, natural history, imaging appearance, and patterns of response that make it a unique subpopulation within lung cancer. The audio only version is below the video.
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In addition, we’ve got the final slides in pdf form, so people can follow along with the audio or just study them at your own pace, along with the transcript from the presentation:
The Subtleties of Progressive Disease: Why Some Oncologists Continue EGFR Inhibitors (or Other Agents) after Progression
One of the basic concepts of oncology is that you treat patients with different drugs once they’ve shown progression on a treatment, rather than continue that a patient has presumably become resistant to. However, there are some exceptions to this: many or most women with breast cancer continue the antibody herceptin (trastuzumab) even after progression, adding it to one chemo and then the next, and the same is often done with avastin in colon cancer and sometimes lung cancer as well. In the past few years, there has been interest in whether the patients who respond well to an EGFR inhibitor like tarceva (erlotinib) or iressa (gefitinib) should continue on it for a while or even forever after showing the first evidence of progression on an EGFR inhibitor.
It may help for us all to take a step back and remember that the goal of improving survival and slowing the progression of a tumor may occur not only if the cancer is shrinking or even if it’s holding steady. If the cancer might potentially be growing quickly, even slowing the progression may translate to an improvement in how a patient does. In the lab, basic scientists examine the growth of a cancer in lab animals and consider it beneficial if the cancer progression is slower over time when a new treatment is added, compared with a placebo or some alternative approach. But in the grading system oncologists use, we don’t discriminate between slow progression and faster progression — it’s just considered a disappointment and time to move on.
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The point is that imperfect brakes is better than no brakes. In fact, in some settings of especially effective treatments for other cancers, some investigators noticed that patients who were progressing slowly on a previously very effective treatment showed a rapid rebound progression when they stopped the treatment (as if they jumped from the blue line to the yellow line in the figure above). So a few years ago, the folks at Memorial Sloan Kettering Cancer Center (MSKCC)studied a small number of patients with either EGFR mutations or a prolonged response to EGFR inhibitors who were showing some progression (abstract here). They did CT scans and PET scans right before and right after patients took a planned three week break from their EGFR inhibitors, and they also assessed how these patients were feeling. After restarting their EGFR inhibitors and repeating scans and checking patient symptoms, they added another novel agent called everolimus, an mTor inhibitor (see prior post for discussion of the novel agent approach of mTor inhibitors alone and combined with EGFR inhibitors). For the more visually oriented, this is the overall design of the complicated trial:
A New Look at Maintenance Treatment after First-Line Chemotherapy in NSCLC
With the recent publication of the Eli Lilly-sponsored phase III trial of immediate versus delayed Taxotere (docetaxel) after the completion of first-line chemotherapy in patients with advanced NSCLC (abstract of paper by Fidias and colleagues here), I think the time has come to critically evaluate this as a potentially practice-changing concept. Call it whatever you want: maintenance therapy, sequential treatment, or early/immediate second-line therapy, but whatever you do, don’t call it a fluke. The idea behind maintenance is simple: after finishing your initial 4-6 cycles of platinum-doublet chemotherapy, you move immediately on to more treatment rather than stopping and waiting for the cancer to progress. In the last year and half, we have seen four major phase III trials test some version of maintenance treatment with chemo or Tarceva, and all have generally supported a benefit. The Fidias paper is the first of these to be published, so let’s take a closer look at the design:
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In this trial, 566 previously untreated patients with metastatic NSCLC were all initially treated with carboplatin and gemcitabine. Those that finished four cycles without progression were randomly assigned to either receive Taxotere immediately and continue it for a maximum of 6 cycles, or to be followed and receive Taxotere once their cancer started to progress. The trial was designed to be large enough to see a 4 month improvement in overall survival (OS), which in retrospect seems ridiculously ambitious. To give you a comparison, the ECOG 4599 trial, which led to the approval of Avastin in lung cancer, only showed a 2 month improvement in OS.
In any case, the trial did not quite make the 4 month improvement, missing it by a little over a month (OS 12.3 months for immediate Taxotere versus 9.7 months for delayed; p=0.085), but it did have an impressive improvement in progression-free survival (PFS; 5.7 versus 2.7 months; p=0.0001), which is a measure of patients still alive without progressive cancer. Essentially what this means is that patients who started immediately on Taxotere delayed the progression of their cancer by 3 months compared to those who waited, and lived an average of almost 3 months longer. This is a pretty clinically significant improvement, although there are some important things to point out about this trial. First, only 309 patients (out of the original 566) made it to the randomization, so these were already the patients who were doing very well after first-line chemo. Second, 37% of the patients (58 of 156) who were designated to receive the delayed Taxotere never got it (as opposed to only 8 patients in the immediate arm), about half of them because their cancer progressed so much that they were unable to get more treatment. So it is unclear if the benefit of immediate Taxotere was truly better effect, or just the results of most of the patients in the immediate Taxotere group actually getting the chemo.
Angiogenesis in First Line Advanced NSCLC: Focus on Avastin (Bevacizumab)
Video presentation describing the concept behind angiogenesis and the evidence on the anti-angiogenic agent avastin (bevacizumab) in NSCLC.
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Or access via web link here.
Slide/figure images from the video presentation are available as a pdf here: Angiogenesis FL Adv NSCLC Vodcast images
Transcript is here: Angiogenesis FL Adv NSCLC Vodcast Transcript
Podcast: Play in new window | Download (33.0MB) | Embed
What I Really Do: Potentially Resectable Stage IIIA NSCLC
I’ve covered stage IIIA NSCLC in several prior posts, mentioning that it’s a clinical setting that is among the most controversial, but I don’t think I’ve really described my real world approach. To review, the controversy is that for stage IIIA NSCLC with mediastinal lymph node involvement on the same side as the tumor (N2 nodes), some people would recommend surgery as a main treatment strategy, and others would recommend chemo and radiation without surgery. The trials that have directly compared a surgical to a non-surgical approach have shown no significant survival benefit for either approach. However, one key study demonstrated that patients who underwent surgery had a lower risk of a recurrence of lung cancer, but this was largely offset by a higher risk of treatment complications and even death related to the more aggressive treatment of chemo and radiation followed by surgery (see prior post).
There is also the question for people who are planned to undergo surgery of whether they should start with surgery or receive “induction”/neo-adjuvant therapy beforehand. And if they receive induction therapy, should it be with chemo alone or chemo and radiation together? The typical standard is that for patients who have mediastinal node involvement identified before planned surgery, we usually give chemo with or without radiation as well before surgery. You could make the argument that it’s just as good to give it afterward, but stage III NSCLC is a setting in which the risk of recurrence with surgery alone is very high, and I’d feel far more optimistic about getting in chemo +/- radiation as well as surgery by starting with induction therapy and following with surgery, rather than starting with surgery and hoping to get additional therapy post-operatively. Too many patients can’t or won’t take more treatment after a big lung surgery to really expect that you can deliver it in the adjuvant (post-operative) setting.
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.
What I Really Do: EGFR Inhibitor Rashes
Though EGFR inhibitors like tarceva can produce some terrific and long-lasting results in many patients, they aren’t toxicity-free. The “targeted therapies” we use just have a very different side effect profile from standard chemo, and the EGFR inhibitors are well known to have skin-related side effects as the leading problem, with loose stools/diarrhea as a less nearly ubiquitous second place issue. In fact, it’s become increasingly well accepted that it’s desirable for patients receiving drugs like tarceva (erlotinib), iressa (gefitinib), or erbitux (cetuximab) to have some degree of a rash: in the studies that have looked at this issue, patients who have no rash don’t have as good a survival and almost never show a significant response, with a frequently seen association of a “severity of rash-dependent” association in which patients with more problematic rashes tending to do the best (see prior post).
This might lead some people to presume that it’s helpful to increase the dose beyond the standard amount, but there’s no evidence that this is the case. A previous trial that escalated dose beyond the standard for patients who didn’t have a rash actually showed disappointing results (see prior post), and my interpretation is that someone’s ability to benefit from EGFR inhibitors is “more nature than nurture”. By this I mean that the people who are going to get a major rash are just very sensitive to the effects, good and bad, of these agents, and the people who don’t generate a skin response can’t be forced into a rash any more than you could transform that male ex-smoker with squamous cancer into a female never-smoking Asian patient with an adenocarcinoma. It’s just not going to happen.
The other implication of this work is that you don’t need to suffer from a terrible rash to be the beneficiary of an EGFR inhibitor: you just need to be a person who could have a terrible rash. Since many of the patients who are most sensitive to rash and other side effects of these drugs could be so bothered by these problems that they stop them and are disinclined to ever try them again, but may be the biggest beneficiaries, I think it’s far more important to get people on a dose that they can tolerate long term. The biggest breakthrough with this class of drugs is that there are some people who can take them and show no progression for a year or even many years, but you can’t do that if every day is endless misery because of the side effects.
What I Really Do: Transition from First to Second Line NSCLC
The general approach to NSCLC is in transition right now, as the line between first and second line therapy are becoming increasingly blurred. A few years ago, the clear standard was that we usually stop first line chemo after four to six cycles, then follow a patient clinically and radiographically until they show evidence of progression, at which time we’d start second line treatment. But now, a growing proportion of our standard treatment protocols include a maintenance phase of ongoing treatment with a targeted therapy after 4-6 cycles, usually of platinum-based chemo with that same targeted therapy. So while we don’t have established proof of the value of maintenance therapy, it’s most common to continue avastin (bevacizumab) as a single agent after 4-6 cycles with platinum-based doublet chemo. While erbitux (cetuximab) is less clearly established and less commonly used, the trial that demonstrated a survival benefit also included a maintenance phase. Erbitux, however, is a more practically challenging situation than with avastin because erbitux is a weekly treatment, not especially convenient for ongoing maintenance therapy.
At the same time that we have first line treatment extending out beyond 4-6 treatments until progression, there are studies moving second line treatment earlier, so that there is a seamless transition to starting right after first line treatment ends, usually after 4 cycles. An initial study with taxotere (docetaxel) IV every three weeks after 4 cycles of carboplatin/gemcitabine that tested immediate vs. delayed second line therapy (starting at the time of progression) showed a highly positive difference in progression-free survival favoring immediate second line taxotere, and a strong trend toward superior overall survival (see prior post for details). While that trial raised the attention of many oncologists to this question, it didn’t lead to a sea change in how we manage patients. Most of the other experts I spoke with agreed that we’d like to see another trial show a similar result, which is what we got this year with a trial of alimta (pemetrexed) vs. placebo IV every three weeks after four cycles of any of several platinum-based doublets. As highlighted in a prior post, this study showed results that I would consider remarkably similar to the taxotere trial, again with a highly significant improvement in progression-free survival and a nearly statistically significant improvement in overall survival (p = 0.06) that was nearly three months in absolute terms. The key shortcoming of the trial was that only half of the patients randomized to placebo went on to receive any second line therapy, since there are many parts of Europe that don’t consider it a clear standard of care, and that’s where the study was primarily completed. Even with that important caveat, I would consider the results to be so compelling that it merits a change in my practice. What’s more, the results with alimta were limited to the patients with non-squamous NSCLC, who actually had a 5 (!) month improvement in overall survival, while the squamous patients actually had a detriment in their survival on the alimta arm (hence the change in the FDA label that removes the approval of alimta for patients with squamous NSCLC).
What I Really Do: Mild or “Subclinical” Progression
One of the topics that frequently occurs in the clinic, and that patients often ask about, is the situation in which there is some suggestion of slight progression. This can take the form of many different situations: a rising tumor marker (see prior post), a slight increase in the uptake on PET (see prior post), perhaps an increase in cough or pain between CT scans, or perhaps just a scant amount of disease progression on the CT that isn’t enough to lead to a definite transition to some alternative. This isn’t an area where there are any good studies, so we are left with our best judgment and no substantial information to inform us.
What I Really Do: Frail and/or Elderly Patients with Advanced NSCLC
I doubt there is a group of lung cancer patients more common but less well studied than the substantial subset of frail and/or very elderly patients with advanced NSCLC. While “elderly” patients, usually defined as age 70, have been evaluated as a subset of the population in larger studies and even been the subject of specific studies just for the elderly, most of this work has shown that fit elderly patients do as well as younger patients getting the same aggressive treatment. What we have relatively little information about is how frailer patients, regardless of age but certainly more likely to be in their mid-70s or older, should be treated.
The available evidence shows that either a carboplatin doublet (I don’t advocate for cisplatin here) or single-agent chemo are feasible and associated with our best results. Among doublets, carbo/taxol (paclitaxel) looks favorable, and I’ve also felt very comfortable with carbo/gemcitabine, a combination that is usually associated with very little in the way of perceived side effects other than fatigue, and most of the adverse side effects are so called “paper toxicity” of low blood counts that the doctor needs to tell a patient about, not the other way around. However, older patients tend to have more of a problem with maintaining adequate blood counts without needing treatment delays, injections of white blood cell stimulators like neulasta (pegfilgrastim) or neupogen (filgrastim), or transfusions of red blood cells). Still, with minimal hair loss and nausea, and no requirement for steroids (which can be a problem in patients with diabetes because it increases blood sugar levels), carbo/gem is an option I’ve commonly turned to. And now with more extensive study, carbo/alimta (pemetrexed) is emerging as a convenient, quite well-tolerated doublet, but one I’d only consider for patients with non-squamous cancers, since converging evidence strongly indicates that alimta is simply not effective against squamous NSCLC (see prior post). I haven’t yet had occasion to use a carbo/alimta doublet in a marginal performance status patient, but if alimta is approved with a platinum as a first line agent by the FDA soon, it will become a leading consideration for my non-squamous patients.
The decision about whether to recommend a single agent or a doublet is really a hard one, for which I use a combination of a read on the general health of a patient and also their concern about side effects. Since either approach is completely reasonable, I lean more toward a single drug if a patient is kind of wobbly, expresses concern about whether treatment for advanced NSCLC is “worth” the side effects, etc. – and despite the findings that fit elderly can do well with treatments commonly used in 60 year-olds, I’m still more likely to recommend a single agent approach for a patient of about 78 or older. But it’s always got to be individualized. I’m actually giving a 76 year-old man cisplatin/navelbine as adjuvant therapy (a setting in which I am particularly wary about causing excess harm) because he appears to be healthier than many 62 year olds, and it’s a curative therapy setting where cisplatin may make a difference. If he were receiving treatment for metastatic disease, I wouldn’t even hesitate to give him a doublet, even projecting his age forward by a few years. But I’ve also recently struggled with the “carbo doublet vs. single agent” question in an aggressively minded, pretty well-appearing 79 year old man, then elected to give single agent therapy and was very glad I did when he had a remarkably hard time, and I turned him from a fit 79 into a frail 79 in a hurry (thankfully, just temporarily).
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