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.

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Most of what I write about here highlights the evidence supporting treatments, and that’s certainly how we strive to practice oncology. But the reality is that patients and doctors often find themselves in the middle of settings where we don’t have any answers and need to rely on judgment, or we think we can potentially do better by defying conventional wisdom. Doctors lie all along the spectrum of being “data-driven” on one end and being a “cowboy” on the other end. The general perception is that many academics are more evidence-based, but I’m not sure that’s true: experts defy the guidelines all the time and say that the key is knowing when to follow and when to deviate from them.

One of the typical places in which we find ourselves at odds with a lack of evidence is in treating patients beyond about third line treatment. We have trials that show the evidence of a limited number of our treatments for NSCLC out to third line, and second line for SCLC. Most patients run out of energy and/or interest in treatment by about that time, but some patients have slow-growing and/or particularly responsive cancers and come back after multiple lines of treatment feeling well enough to come back to the clinic and ask, “what next?” Many people participating here are beyond the point where we have evidence that further treatment is beneficial. How do we manage these situations?

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   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. 

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   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).  

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   The treatment of relapsed SCLC isn’t especially controversial, because this is an area where there aren’t enough breakthroughs.  In someone fit enough to perform their own activities of daily living and getting out of the house, the main question is how long it has been since they completed their first line treatment.  Although some oncologists use a threshold of 6 months and others 12 months, most oncologists are inclined to recommend returning to the initial chemo regimen (most commonly cisplatin or carboplatin with etoposide), and I do the same, with a 6 month progression-free interval as my trigger.  That’s definitely a minority of patients, and for the rest I usually recommend topotecan, if we decide to pursue additional chemotherapy.  Irinotecan is another reasonable option, although without a proven second line benefit, but it certainly has activity in SCLC.   One of the limitations of topotecan until recently has been that it’s been available only as an IV formulation, and the standard and well studied way of giving it has been for 5 days in a row every three weeks.  That’s a real pain, frankly, and the new and recently FDA-approved oral tablets that have also been shown to have the same activity will make it a far more convenient therapy for everyone.    

    Additional alternatives, either instead of or after topotecan, include the aforementioned irinotecan, as well as gemcitabine, the taxanes, as well as navelbine (although not alimta, as this agent has been shown to be very dependent on histology and quite underwhelming against SCLC, as described in a prior post).   Among options that I might particularly consider as off the beaten path but particularly intriguing for unusually fit patients with relapsed SCLC is a combination of carboplatin/irinotecan given every three weeks, based on a clinical trial in which I participated (abstract here, manuscript submitted for publication.  But this wouldn’t be considered a standard approach.

   There’s also little question that clinical trials are especially appealing for relapsed SCLC, where we all hope to do better and develop newer treatments.  Amrubucin has certainly generated a good deal of deserved enthusiasm (as described in a prior post), as well as some hope for picoplatin (see prior post).  

   That said, many of my patients with relapsed SCLC have had a marginal/poor performance status, or a disinclination to pursue aggressive anticancer therapy  for relapsed SCLC when the benefits are more subtle than we’d want them to be.  A significant proportion have elected to focus on maximizing their comfort and foregoing more treatment, a reasonable decision that I’ve also been happy to support.

   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.  

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   The setting of unresectable, stage IIIA or IIIB NSCLC (without a malignant pleural effusion) is currently one for which what we feel is best for the patient isn’t necessarily something for which we have good evidence.  For fit patients, there is a strong consensus that giving concurrent chemo with radiation provides a modestly but consistently higher cure rate than giving chemo and radiation sequentially.   But that concurrent chemoradiation plan lasts for only 6-8 weeks, but whether there’s more we should be doing, or what we should do, is entirely unclear.

    As described in a prior post, several studies in the last decade have shown that about two cycles or 6-8 weeks of weekly chemotherapy along with about 60-66 Gray of radiation over 6-8 weeks is associated with the best survival results we’ve seen in unresectable, locally advanced NSCLC (somewhere in the 20% range long-term, and a median of about 16-18 months).  There are two main approaches in North America for the chemotherapy.  Some use the SWOG approach that showed very promising early results (prior post here), giving cisplatin and etoposide.  The other very common alternative that is widely used in a community setting is weekly carboplatin/taxol.   Until very recently had relatively little published experience to support it, but in the last few years now has been included in a few trials that demonstrate survival in the same ballpark as what we routinely see with cisplatin-based chemo: examples include RTOG trials such as described in a prior post and another abstract.

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   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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   I go to many meetings in which cases are presented and medical oncologists provide their repsonses about how they’d be inclined to treat a patient.  Although we bemoan the lack of much progress in managing small cell lung cancer, one of the effects of that is that there is pretty strong uniformity in how we manage it, since the standards are quite well established.

   Although several years ago there was a small Japanese trial that showed a significant survival benefit for the combination of cisplatin/irinotecan compared with cisplatin/etoposide, which led to growing use of irinotecan instead of etoposide outside of the US as well, North American trials over the last few years have not shown a similar benefit (summarized in prior post here).  This difference in outcomes by geography is likely real and related to relevant genetic differences in how Japanese and Caucasian patients process and respond to irinotecan vs. etoposide.  The North American studies have shown that the different regimens are comparable in activity, but that irintecan is associated with significant diarrhea, while etoposide is associated with more significant drops in blood counts.

   These days, the vast majority of US-based oncologists give a platinum with etoposide, fairly split between cisplatin and carboplatin.  My preference has generally been to use carboplatin in a setting in which we can’t cure the cancer, and for which there is a little evidence that they produce comparable results (see prior post).   In fact, historically most of the studies of ED-SCLC have used cisplatin/etoposide as the standard treatment, but one recent trial used carboplatin/etoposide and produced results every bit as good as what we see with cisplatin (see prior post).  This corroborated the more limited avidence that carboplatin was a less challenging but very comparable alternative to cisplatin.

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    To begin with, my overall impression is that the preponderance of evidence on adjuvant (post-operative) chemotherapy supports that it can reduce the recurrence risk and improve the survival at five years, which I’d presume to be pretty close to the “cure rate”.   The benefit isn’t uniformly distributed for all patients: higher risk patients, as defined by stage and other additional factors like number of lymph nodes involved and the grade of the cancer, also matter.  Our current standards converge on recommendations favoring post-operative chemo for stage II patients and the minority of patients who have “surprise” N2 nodal disease not detected before surgery and are therefore stage IIIA and without evidence of residual disease.  These patients derive a clinically significant benefit from chemo that more than offsets the small but real risk of serious side effects.

   I consider it important to remember that 0.5 - 1% of patients on most of the clinical trials of adjuvant chemotherapy died from the treatment, and the trial population is non-representative of the broader “real world” population that is sicker and older than the patients who went on these trials, on average.  And the most recent updates of one large adjuvant trial (prior post here) raises the specter that the risk from chemo may be not be captured completely in the first five years and that the outcomes may be more disappointing with follow-up beyond five years.  Overall, I consider this to be far more of a concern for the patients I would already consider to be marginal for adjuvant chemo — stage IB, or those who are already pretty frail and may be more harmed than helped by chemo.  The emerging story is telling me that it’s not just that adjuvant chemo either helps or it doesn’t help.  While it may help some, there could be detrimental effects, so it’s worth being judicious in deciding whether to pursue it: more is not necessarily better. 

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