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Treating Bronchioloalveolar Carcinoma by Not Over-Treating It: What the Experts Really Do (and Don’t Do)
I’m completing a chapter in a key lung cancer textbook on managing multi-focal bronchioloalveolar carcinoma, a clinical entity that is in the process of being re-labeled lepidic predominant adenocarcinoma (LPA) (lepidic meaning scale-like, which is the classic way that the cells are defined as spreading when looked at under a microscope). I suspect that it will continue to be called multifocal or advanced BAC for a long time (after all, the formal staging of small cell lung cancer goes from stages 1 to 4, but nobody ever uses that, classifying it as just limited or extensive stage).
When asked to write this chapter, I faced the challenge of there being very little actual hard data on managing multifocal BAC. Though many experts have a very similar approach, this is actually based on expertise, good judgment, and clinical experience more than data we can point to, and I don’t think this approach has ever been articulated in a scientific paper or book chapter, so I’m hoping this will be a valuable addition to the literature.
As I reviewed the papers out there, what struck me most are two things:
1) There is incredible variability in the appearance and clinical behavior of what is called advanced BAC in the clinical world — some of it is aggressive and imminently threatening, and much of it is very slow growing and among the least threatening cases ever labeled as lung cancer.
2) People with a very slow growth rate are likely to do very, very well no matter what treatments they get, as much despite as because of those treatments. In many cases, interventions are pursued on patients who are destined to do very well, and then when their short term survival is good, the people who did that intervention write a paper saying how their approach is feasible and attractive because the patients did well — not recognizing, or at least glossing over the idea, that they were going to do very well anyway.
I would say that in no other area of lung cancer care is it more important to distinguish between what can be done and what should be done. And the real experts know when to not intervene.
So here is the algorithm I developed, which isn’t beautiful, but you can see that it focuses on seeing what is actually changing rather than treating reflexively based on a label on a pathology report or single a scan finding. Essentially, it says to try to avoid intervening at all unless or until you see clinically significant change (which I would consider as something that is readily apparent as progression on scans done 6 months apart or less), and then if you see progression, clarify whether it’s limited to one lesion or progressing more diffusely in multiple areas.
How does the diagnosis of BAC shape systemic therapy considerations today?
It’s not uncommon for a question here to be about the a pathologist’s terminology on a report that equivocates about whether a lesion is bronchioloalveolar carcinoma (BAC) or another form of adenocarcinoma, perhaps “well-differentiated adenocarcinoma”, especially if it has a radiographic appearance of a hazy infiltrate or many small ground glass opacities. Meanwhile, there’s a new classification of lung cancer subtypes that obliterates the term BAC, instead favoring a definition of adenocarcinoma in situ, classifying small non-invasive lesions previously called BAC as a pre-malignant condition. How have the changes over the past few years changed how we should approach BAC?
I would have to say that the new reassignment of BAC as adenocarcinoma in situ hasn’t taken the lung cancer world by storm and that I still think of the clinical entity as BAC. For the preceding decade, the definition the pathologist’s used technically excluded a lesion with even 1% or 5% of the lesion being invasive as being called BAC, even if it acted for all the world like BAC. Clinicians learned not to be too hung up on a pathologist’s technical definitions and tended to define BAC more functionally/operationally. General oncologists and expert lung cancer specialists alike managed BAC based on the overall picture of how it behaved if it looked like a BAC pattern.
Basics of Bronchioloalveolar Carcinoma (BAC)
Bronchioloalveolar carcinoma, or BAC, is a unique subtype of non-small cell lung cancer (NSCLC) that has unique features in terms of the demographics of who gets it, how it appears on scans, how it often behaves, and potentially in how it responds to treatment. It is a subset of lung cancer for which most of what we know emerged in the last 10 years, with our understanding of this entity, and even the definition of BAC, still evolving.
What is BAC?
BAC was first identified and defined as a separate subtype of lung cancer by Dr. Averill Liebow in 1960. At that time, he highlighted it as a form of well differentiated adenocarcinoma of the lung that appeared to not be able to invade the surrounding lung scaffolding and spread within the lung(s), presumably aerogenously and/or through lymphatic channels.
(click on image to enlarge)
Round Table Discussion with Experts: Indolent BAC in an Elderly Man
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
Podcast: Play in new window | Download (46.2MB) | Embed
Interview with Dr. Matthew Horton, Pathologist, Part 2: Neuroendocrine Lung Tumors & Bronchioloalveolar Carcinoma
This is a continuation of my discussion with Dr. Matthew Horton, a pathologist with a special training and a great expertise in lung pathology who works here in Seattle at a company called CellNetix.
This portion of our discussion covers the spectrum of neuroendocrine lung tumors, ranging from carcinoids to small cell lung cancer and large cell neuroendocrine carcinomas; we then turn to a discussion of bronchioloalveolar carcinoma (BAC), including everything from a little history to a look forward at a new interpretation of BAC. Below you’ll find the audio and video versions of our discussion (the video with a few images of what we’re talking about), and the associated transcript and figures.
Dr-horton-pt-2-neuroendo-lung-tumors-and-bac-audio-podcast
Dr-horton-pt-2-neuroendo-lung-tumors-and-bac-transcript
Podcast: Play in new window | Download (40.2MB) | Embed
An Uplifting Case: Tarceva after Iressa Led to a Great Response
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.
BAC No More?
The most expert lung cancer pathologists in the world are planning a revision of the classification of lung adenocarcinomas that is expected to be approved and implemented next year, and it’s going to make some big changes. Specifically, it’s planning to eliminate the diagnosis of bronchioloalveolar carcinoma (BAC), reflecting our evolving understanding of this disease.
BAC with lesions less than 2 cm is now being designated as a pre-cancerous adenocarcinoma in situ (AIS), which essentially means it’s a pre-invasive condition with a favorable prognosis. In fact, the available literature, largely from Japan but also including evidence from other parts of the world, shows a 100% 5-year survival for a <2 cm AIS, which is far more commonly the non-mucinous BAC sybtype. The size limit is significant, however, because larger lesions are felt far more likely to have at least some area of invasive disease.
The invasive portion of what is now in the spectrum of BAC with focal invasion to adenocarcinoma with BAC features has a major impact on prognosis. In fact, the size of that invasive component is what drives prognosis, not the invasive part:
The Invasive Component in AdenoBAC Drives Prognosis
So a largely pre-invasive (adenocarcinoma in situ) lesion with a small area of invasiveness will now be designated as minimally invasive adenocarcinoma, and it also has a 100% cancer-specific survival at 5 years.
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.
[display_podcast]
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:
What I Really Do: BAC and Slowly Progressing Cancers
In the last few years BAC has become increasingly studied and recognized as a distinct clinical subtype of lung cancer. The classic BAC syndrome is characterized by progression limited to the lungs, and its growth can be quite variable. The definition of BAC based on pathology has been applied pretty variably: although it should really be a non-invasive cancer that shouldn’t be able to spread outside of the lungs because it can’t invade into the bloodstream, most clinical trials now permit a combination of invasive adenocarcinoma with BAC features. Probably largely because of that, some of what is called BAC looks and acts and responds just like standard lung adenocarcinoma. At the same time, we are still learning a lot about even the pure form of BAC, such as the finding that the two major subtypes of BAC, mucinous and non-mucinous, may be fundamentally different.
BAC has historically been perceived as unresponsive to chemo, or less than other forms of lung cancer at least. That may be so, but in truth many experts believe that this really may be a misperception because the BAC syndrome includes a diffuse infiltrate of multiple lesions rather than a discrete mass that can be measured readily. At the same time, BAC is actually uncommon enough that that it hasn’t really been broken out from larger trials of NSCLC in general. The real interest in studying BAC has only developed in the last 5-10 years, and in that time BAC patients have been much more likely to have been studied in trials of EGFR inhibitors than chemo. In these trials, the EGFR TKIs have demonstrated response rates in the range of 15-25%, along a fairly encouraging survival. A minority of patients do remarkably well, with prolonged responses and survival (reviewed in prior post). And it looks like the impressive results with EGFR inhibitors are largely if not exclusively seen in patients with the non-mucinous BAC subtype (see prior post).
Actions Speak Louder than Words: When Pathology and the Clinical Picture Don’t Fit
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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