A very recent issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, featured a very good review article by the surgical group at NYU about increasing interest in the concept of whether sublobar resection may be comparably effective as a lobectomy for some patients with early stage NSCLC; this article was also accompanied by a thoughtful editorial by expert thoracic surgeon Frank Detterbeck at Yale.  (A review of the different types of lung cancer surgery is available through my prior post, and also a great podcast with thoracic surgeon Dr. Eric Vallières).

   The excellent review article starts with the background that the general premise that thoracic surgery has been dominated by the results of a pivotal randomized study published in 1995 by the now-defunct Lung Cancer Study Group that showed that sub-lobectomy in early stage NSCLC patients was associated with a higher risk for loco-regional recurrence, a lower survival at 5 years out, and no significant improvement in lung function compared with lobectomy.  However, we can be thankful that there have been many advances in management of lung cancer over the past 15-20 years since the trial was actually conducted.  First, squamous cell carcinoma was the dominant histologic subtype of NSCLC at that time, whereas now there is more adenocarcinoma and bronchioloalveolar carcinoma than we used to see.  Second, it’s now possible to do many lung surgeries with video-assisted thoracoscopic surgery (VATS) that make it possible to do a safer and less rigorous surgery (either lobectomy or sub-lobectomy).   Third, with CT scans getting so much better over time, we’re now regularly detecting many more tiny nodules than ever before.  The lung cancers detected based on symptoms in 1991 are different from the asymptomatic lung cancers that may well be detected increasingly by CT screening in 2011.  Do we really want to remove 1/5 of the lung capacity for an 8 mm nodule?  Because we’re using data from much larger and different cancers when we decide to do that.

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Only a few years ago, oncologists saw lung cancer as divisible into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with very little relevance to any division beyond that point.  We knew that patients with NSCLC could be categorized into having adenocarcinoma (including the subset of that larger group, bronchioloalveolar carcinoma (BAC), squamous, large cell and large cell neuroendocrine carcinoma, and into those with and without a significant smoking history, and other demographic variables, but they weren’t a primary focus when we didn’t perceive that these differences had clinical significance in our treatment recommendations.  And at that time, most people received remarkably similar treatments, with first line trials in advanced NSCLC incredibly commonly designed as carbo/Taxol (paclitaxel) +/- new drug, and second line trials of Taxotere (docetaxel) +/- new drug, or a direct comparison to placebo in previously treated patients.

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In one of my earliest posts about bronchioloalveolar carcinoma (BAC) (in the dark ages, pre-Twitter), I wrote on the subject of managing small BAC-type lesions, which tend to appear as small hazy areas called “ground glass opacities” (GGOs) and suggested that some of these cancers may be so indolent that they don’t need to be treated, even if they have the word “carcinoma” in the diagnosis.

(a representative GGO identified by arrow)

Now there is a proposal to change BAC to “adenocarcinoma in situ“, a pre-cancerous condition, reflecting the idea that these lesions have such a favorable prognosis that they shouldn’t necessarily be put in the same category as invasive lung cancers (pure BAC is a non-invasive lesion that shouldn’t be able to get into the bloodstream and spread outside of the lungs).  And now, there’s a new article out of Japan that describes the experience of patients with BAC and multiple GGOs, some of which were resected and some not very accessible and some just watched.  It turned out that just watching seemed to be a pretty good strategy.

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This is the first part of a case presentation I did with two great colleagues: Dr. Anne Tsao, who is a medical oncologist and lung cancer expert at MD Anderson Cancer Center in Houston, and Dr. Alex Farivar, who is a terrific thoracic surgeon at my own institution, Swedish Cancer Institute in Seattle.

This case is an elderly gentleman who has a very indolent but growing lung lesion.  His story brings up questions of how concerned to be in following a nodule in a patient of advanced age and with competing medical issues, whether surgery that is less than a lobectomy might be considered, as well as the systemic therapy options for bronchioloalveolar carcinoma.

Here are the audio and video versions of the podcast, along with the transcript and figures.

expert-round-table-tsao-and-farivar-pt-1-bac-audio-podcast

expert-round-table-tsao-and-farivar-pt-1-bac-figures

expert-round-table-tsao-and-farivar-pt-1-bac-transcript

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   I just wanted to tell people about a remarkable patient I just saw who is delighted to have had a remarkable response to Tarceva a few years after responding to Iressa.  She made my day.

   In truth, her case was remarkably long before this.  She was diagnosed with bronchioloalveolar carcinoma (BAC) all the way back in 1995 (I was finishing med school, no kids — life was simpler then).  She had undergone a left lower lobectomy for localized disease initially, but her cancer recurred in late 1998, confirmed on a bronchoscopy, and she began experiencing a cough then.  She was initially treated with chemo and responded well for several years, with some changes in her chemo but generally doing well before being started on Iressa. 

   She recalls that within days of starting Iressa, her recurring cough improved dramatically, and she did well on it for over 5 years before her scans progressed and her cough worsened.   She ultimately discontinued it back in May of this year, starting Alimta then.  And though we might have hoped and expected that she’d show another great response, she actually continued to progress on that, with a worse scan and cough after two cycles.  So this shows us that her cancer doesn’t quite respond to everything.

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   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:

ABCs of BAC Slide Set

ABCs of BAC Transcript

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   In my last post I outlined the typical clinical scenario for pneumonic bronchioloalveolar carcinoma (BAC), which is typically the mucinous subtype of this unusual disease.  In fact, we are still actively learning a great deal about BAC, enough for the lung cancer experts to begin to develop a more sophisticated view that the mucinous and non-mucinous subtypes have different behaviors and respond differently to treatments.  Here is a case that illustrates a situation that I would consider to be typical for the mucinous, pneumonic form of BAC.

    Ella A. was 74 year-old woman with a very long smoking history of about 50 years, who quit last month in the face of worsening pulmonary and other symptoms.  Specifically, she experienced an initial dry cough that became productive of sputum over a six-month period, during which time she also developed increasing shortness of breath and a 20-pound weight loss for a woman who was pretty slender beforehand.  This led her to her primary care physician, which showed extensive “consolidation”, shadows in both lungs and particularly extensive on the left.  These findings were confirmed on a CT.

 (Click to enlarge)

As you might suspect, this led to a referral to a pulmonologist for a brochoscopic biopsy.  The pulmonolgist needed to start her on oxygen before he could do a thorough bronchoscopy.  The biopsy revealed well differentiated BAC, but the pathologist (an expert in lung pathology) didn’t have enough material to specify whether it was mucinous or non-mucinous.

   Frankly, at the time when I first met her, in December of 2006, there were only the early inklings that this could be relevant.  We don’t have much more information since then, except for the anecdotal experiences of myself and a few others who treatment many patients with BAC, which have corroborated the early impression that the well described effectiveness of oral EGFR inhibitors like iressa (gefitinib) and tarceva (erlotinib) in BAC appeared to be limited to the non-mucinous subtype.

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   One of the issues with BAC is that I’ve referred to it as potentially very indolent, but as we’ve learned more about BAC, it’s become clear that there is a great degree of heterogeneity in BAC cases.  We’re learning that the cases that are more often slowly progressing and sometimes exceptionally responsive to EGFR inhibitors like tarceva and iressa are far more likely to be non-mucinous BAC.  These typically have the appearance of innumerable small nodules throughout the lungs.  There is a form that is the opposite: with sweeping areas of consolidation (also known as opacity) throughout entire areas of lung, typically mucinous, and essentially never responsive to EGFR inhibitors based on what we know right now.  This form is called pneumonic BAC, and it is typically very aggressive and unfortunately seems to be resistant to most of our treatments. 

   It’s called pneumonic BAC because it looks for all the world like pneumonia on an x-ray or CT, and I suspect that just about every patient who is ultimately diagnosed with pneumonic BAC is treated for at least weeks and often months with antibiotics.  The classic example is that it involves much or sometimes all of a lobe of the lung:

Because it’s mucinous BAC, these patients often describe coughing up large amounts of frothy sputum.

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Warning: this symptom can be a little gross, so the delicate flowers out there should skip this post.

One of the more unusual but quite vexxing symptoms we sometimes see in lung cancer is called bronchorrhea, which is the copious production of watery sputum, specifically at least 100 ml per day. The setting in which it’s most frequently seen is in bronchioloalveolar carcinoma (BAC), and we typically think of it as being a manifestation of the mucinous subtype. In its worst form, patients can drain vast amounts of phegm each day, typically worst in the morning. Patients have told me that they lean their head down off the bed to drain a half a liter or more at a time before starting their day. Though rare, there have been frequently cited cases that have been life-threatening because of severe electrolyte imbalances that develop from losing so much fluid and salt (case report here). Interestingly, there’s a sheep virus that appears clinically remarkably similar to BAC (though there hasn’t been a human form of the virus ever isolated, despite searching), and I’ve seen video footage of researchers demonstrating bronchorrhea by lifting the hind legs of the sheep into the air, putting a beaker under its nose, and letting the watery mucus drain out for several minutes. Sorry, I told you this post has some indelicate moments. I don’t think that video’s on YouTube yet.

Unfortunately, bronchorrhea is a very difficult symptom to treat effectively. Among the things that have been tried and were written up as possibly successful in individual cases have been steroids (abstract here), inhaled indomethicin (a non-steroidal anti-inflammatory drug)(abstract here and here), a drug called octreotide (reference here), radiation therapy to the most “consolidated” area of lung (reference here), and most recently EGFR tyrosine kinase inhibitors like iressa (full text here, another abstract here, and there are several other reports out there).

The ideal situation is to treat the underlying cancer effectively, rather than just the symptom.   In that sense, the EGFR inhibitors are pretty unique in being the best treatment if a particular person’s BAC happens to respond.  Based on the fairly large phase II studies that have been done with iressa and tarceva in BAC, the response rate with this class of drugs is in the 15-25% range (see prior post for review).  So for the patients who respond to an EGFR agent, it’s a potentially dramatically helpful treatment for a long time.  For the majority of patients who don’t respond to one of these agents, the others are things that can be tried, but most of what’s been reported is a single case of a treatment that worked, not a trend of multiple cases.  In truth, it’s probably never going to possible to run a study and enroll 20 patients to get a particular treatment, because bronchorrhea is an uncommon symptom of an uncommon disease.  But these are a few things that people may try, and I’d be very interested if there are people out there who have had success with any of these approaches.  Another one I’d be inclined to try, although I’ve never seen mention of it being done before, is inhaled lasix, the effective diuretic, which is an approach I’ve heard of hospice folks using to treat secretions.

In the meantime, bronchorrhea is often unpleasant, sometimes scary, and potentially life-threatening complication that nobody sees enough to become an expert at managing.

   I’ve been involved in a wide range of discussions, both here and in my own clinical, about the fairly common situation of how to approach a situation in which the story on paper and what you see actually happening are incompatible.  For instance, last week I and several of my colleagues participated in a journal club (a group discussion of a new and/or controversial journal article or two), in which the topic was the potential utility of doing surgery for unusually early small cell lung cancer tumors.  We’ve also had several recent questions about patients in whom the diagnosis of bronchioloalveolar carcinoma (BAC) is being considered, and it’s not clear whether to treat this sometimes very indolent cancer as a full-fledged NSCLC, a non-entity that might sometimes be ignored, or as a separate category worthy of being managed differently from the standard approaches for other NSCLC subtypes.

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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