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minimally invasive adenocarcinoma


Optimal Systemic Therapy for Bronchioloalveolar Carcinoma (BAC)

GRACE Cancer Video Library - Lung



Bronchioloalveolar carcinoma (BAC) is an unusual subtype of lung cancer; medical oncologist Dr. Jack West reviews the evidence on the best systemic therapy to treat advanced, multifocal BAC.

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One of the unusual subtypes of lung cancer is known as bronchioloalveolar carcinoma, or BAC. That is a subgroup of adenocarcinoma, and many clinicians treat is as a special case. Because of that, it’s fair to ask the question of, “what is the best whole body, or systemic, therapy for that setting?” There are some clinicians who will tell patients that standard chemotherapy does not work and shouldn’t be tried at all. There are some people who feel that oral EGFR inhibitors, drugs like Iressa (gefitinib), or Tarceva (erlotinib), or Gilotrif (afatinib), might be the treatment of choice. But those are all oversimplifications based on prior information, and we now know better. In fact, as is often the case, we need to individualize for the particular patient, and their cancer.

The first main question to ask is whether it’s necessary to treat at all. Some patients will have an advanced or metastatic, cancer, but it is not growing at a pace that is really a threat, and for patients who don’t have symptoms, and who might have very slow-growing cancer, there shouldn’t be any rush to start treatment right away, just because they have what is technically called stage 4 cancer. There are patients who can go very long periods of times with no symptoms and feel well for months, or even years.

But, if patients demonstrate clinically significant progression of their disease, and especially if they have symptoms, it’s appropriate to think about what the best whole body, systemic therapy is. 


The trial that really changed our prospective on how to approach these patients was called IPASS. This was an Asian study of over 1,200 patients, from Asia, who had a never-smoking history, and an adenocarcinoma. And this group of Asian never-smokers with an adenocarcinoma are the kinds of patients who we have long recognized as being especially likely to respond well to oral EGFR inhibitors. Because of that, this trial directly tested Iressa to standard chemotherapy in a large number of patients who were enriched to likely respond well. However, it did not require that patients have an EGFR mutation, because the story about EGFR mutations was still being developed, and we didn’t know how important that really was — really not until this trial.

The study looked for a significant difference in progression-free survival — the time before the cancers began growing again, after an initial response or stable disease. When we look at the results for progression-free survival in the bottom left part of this slide, you can see that it’s an unusual pattern — it crisscrosses – it’s kind of like a figure eight, and when we see that, it suggests that there’s actually two different populations within the broad group here. The study was designed to look for EGFR mutations in patients where there was tissue available, and they looked at over 400 patients who did have tissue available, and found that 60% of the patients did have an EGFR mutation, which of course means that 40% did not, even though they were Asian never-smokers with an adenocarcinoma, and a group that we might reflexively want to give these oral therapies to. 

But, as you can see from the curves shown in the middle and the right side of the bottom portion of the slide, you got completely different results if patients did have an EGFR mutation, versus if they did not. If you did have an EGFR mutation, you did remarkably better getting the oral EGFR inhibitor. On the other hand, if you do not have an EGFR mutation, you did far, far better by getting standard chemotherapy, and we also see this when we look at the response rates. 


In fact, when you look at the patients with an EGFR mutation, Iressa was associated with a response rate of 71%; if you didn’t have that mutation, your response rate to Iressa was 1%. You were far better served by getting chemotherapy if you don’t have an EGFR mutation — you had a response rate of about 23-24%, which is, of course, much better than that 1% with Iressa.

So, this really changed our thinking about the field — we used to, perhaps, think that we could clinically separate patients and say, if you’re Asian, never-smoker, if you have an adenocarcinoma, we can just start by giving you an EGFR inhibitor, and expect that we were serving you well. In fact, this showed that if you guessed wrong, you could really do a disservice to the patient. That the patients who don’t have an EGFR mutation should get standard chemotherapy as their first-line treatment, and the same applies to advanced BAC — in patients who don’t have an EGFR mutation, they should go on to get standard chemotherapy, unless they have another driver mutation that we would standardly look for, such as an ALK rearrangement, or possibly a ROS1 rearrangement.

So this is how we now treat advanced BAC — it is individualized based on the molecular characteristics of their cancer. You look for a driver mutation, and if you find one for which we have an oral therapy that tends to work very well, that is your first-line treatment of choice. If you don’t find one of those driver mutations, your first-line treatment of choice is standard chemotherapy based, potentially adding the drug Avastin or bevacizumab, which is an anti-angiogenic agent.


Surgery Options for Smaller, Slow-Growing Lung Cancers

GRACE Cancer Video Library - Lung



Dr. Eric Vallieres, thoracic surgeon, discusses the potential to do smaller lung surgeries on patients with a lung cancer that poses a minimal risk of recurrence.


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The standard of care in 2015 for an early stage lung cancer is surgery, and that surgery had been established in the early ‘90s as being a lobectomy. The way that was done back then is that we took tumors that were less than 3 cm in size, we went to the operating room,

GCVL_LU-D03 Figures 1a ML.001

made sure all the lymph nodes were okay, flipped a coin — half of the patients got a lobectomy, and the other half got less than lobectomy, and that could have been either a wedge resection, or a segmentectomy.

GCVL_LU-D03 Figures 1a ML.002

When they analyzed the results of that study, and the first author on that was Ginsberg, they noticed that patients who had had a lobectomy did better: they lived cancer-free longer, they had less recurrence, it was a better operation. So, back in the early ‘90s, that study established lobectomy as a standard of care.

Now, that was 20 years ago, and 20 years ago we were treating tumors that were larger than what we are seeing today, because today people are getting CAT scans — either screening CAT scans, or for-other-reason CAT scans, and we’re picking up on a lot of little, little tumors that we never knew existed before because the x-rays were not good enough. As a result of that, we are now seeing tumors that are 1 cm in size, 8 mm, 12 mm, that we rarely, if ever, saw before. The Ginsberg trial — most of those tumors were over 2 cm in size, so the question is, do we really need to do a lobectomy for those little tumors that we’re now picking up today? Those 8 mm tumors, 9 mm tumors, first question; the second question is, we’re also seeing a different type of cancer today that we never saw when I was in training — I never knew these things existed, and they were so-called, for a while, bronchioloalveolar carcinomas, and now the term is more early, well-differentiated adenocarcinomas,

GCVL_LU-D03 Figures 1a ML.003

either in situ or minimally invasive, or invasive, adenocarcinoma — it’s a field that’s evolving. But these tumors are small, not very aggressive, don’t metastasize, and there is certainly a fair amount of evidence, mainly out of Japan, to show that you do not need to do a lobectomy for these particularly not very aggressive, early adenocarcinomas that have not invaded. 

As a result of that, those new tumors, and the fact that we’re seeing smaller tumors in general, has brought back the concept that maybe we don’t need to do a lobectomy for all of the lung cancers that we’re seeing today. And in fact, there is a study in North America right now that is ongoing, looking at the role of lobectomy, or less, in tumors of 2 cm or less in size; that study is accruing, it’s been accruing for many years, but it’s getting there. In Japan, they’ve already closed a thousand patient study addressing the same question — we don’t have the results yet. So, it’s the same design as the Ginsberg trial, 20 years later, just with smaller tumors to see whether or not we need to do a lobectomy.

GCVL_LU-D03 Figures 1a ML.004

The one thing we have to understand though, is that not every 10 mm tumor has the same biology, and there are 10 mm (or 1 cm) tumors that can be fairly aggressive. That’s particularly true when the tumor is a solid tumor, not just one of those, what we call in radiological terms, a ground-glass opacity, which tend to be more of a not very aggressive type of tumor, and we have to be careful that we cannot — I don’t think, personally, not having seen the results of those two trials, but I don’t think that we can just across the board say every tumor under 1 cm should be treated or can be treated with less than a lobectomy, and I think we have to realize that there are some of those tumors where more of a bigger operation may still be warranted.

But, there are a lot of these less aggressive types of tumors, those adenocarcinoma in  situ (or AIS), or minimally invasive adenocarcinoma where the focus of invasion that is only 5 mm or less in size, where you can do a very small operation, a wedge, and you get away with it. Similarly, if you elect to treat these patients with focal radiation therapy, you probably will do very well — these tumors don’t metastasize, and you can limit your field of radiation for those tumors, just as we can limit our field of surgery, and you’ll probably do very, very well for these particularly biologically favorable tumors, which are new.


Myths and Misconceptions About Bronchioloalveolar Carcinoma (BAC)

GRACE Cancer Video Library - Lung

GCVL_LU-AA02_Myths and Misconceptions About Bronchioloalveolar Carcinoma (BAC)

Unfortunately, there is as much misinformation as good information about the unusual subtype of lung cancer known as bronchioloalveolar carcinoma (BAC) or adenocarcinoma in situ. Dr. Jack West reviews the top 5 myths.

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One of the unusual subtypes of lung cancer is known as bronchioloalveolar carcinoma of the lung, or BAC. This is a rare type of cancer, about 2, 3, 4%, but it has its own lore about it and with that comes some misinformation and myths about managing BAC that I sometimes see causing some bad treatment decisions. I wanted to discuss some of those, as someone who has focused on BAC as a major concept in my own research over the last several years.

The first myth to address is that it is always slow growing or sometimes it may always be considered fast growing. In fact, there’s a lot of variability in how BAC behaves. Sometimes it can be the slowest growing cancer you will ever see; even when it does grow, it might grow by a millimeter or two as a single nodule every year or two.

On the other hand, it is not always an indolent or slow-growing process and you can sometimes see it lead to increasing symptoms over a course of just weeks. So, each case needs to be individually assessed and you need to see how a patient is feeling over time, how their imaging is changing over time, and treat each case individually based on what you observe.

Another myth that we sometimes see is that BAC does not respond to standard chemotherapy. One of the challenges is that BAC tends to appear on scans not as a discreet measurable spot, some solid lesion in the lungs that you can readily measure the size of as it grows or shrinks, but rather as a hazy area that might be one spot; it might be multiple nodules that are all hazy, or it might be a diffused cloudy area. But that haziness is not readily measurable — it’s kind of like trying to measure how cloudy it is one day to the next if it’s just kind of diffusely gray outside.

The problem is that measuring tumor shrinkage is how we historically graded how chemotherapy works, and if you can’t measure it shrinking, we’ve sometimes just categorically said ”treatment doesn’t work.“ However, when you look carefully at some studies that have given the same treatment to patients whether they have BAC or another form of lung cancer, particularly an adenocarcinoma, which BAC is a subtype of, you really tend to see that it responds comparably to other forms of lung cancer to the same chemotherapy. So it is really a bit of misinformation that chemotherapy does not work for BAC.

Another myth that has emerged is that EGFR inhibitors such as Iressa (gefitinib) or Tarceva (erlotinib) are the treatment of choice for BAC. Now, this myth emerged because many of the patients who have responded extremely well to these oral EGFR inhibitors have BAC, and because of that it’s been presumed that it is the treatment of choice. In fact, what we’ve seen is that patients who have an EGFR mutation are the very ones who will most likely benefit from EGFR inhibitors, and many patients with BAC will have one of these EGFR mutations, but certainly not all, and if patients don’t have one of these mutations they tend not to do that well with these agents. So, an EGFR inhibitor is not necessarily the treatment of choice.

Another issue that comes up is that if surgery could be done, it should be done. That might even apply if patents have three of four different spots. What we sometimes see is that patients may want to have surgery because you want to get it out, and many surgeons are inclined to oblige if they feel they can safely do that surgery — but it’s not always a good idea. If there is one spot of cancer, taking it out is almost always a great idea as long as a patient can tolerate it. On the other hand, if there are 3 or 4 or 6 spots, even if it’s possible to get them all out, it’s not likely that that’s all the cancer that is or will ever be. When you see multiple spots that usually means that, in addition, there are other spots likely to emerge over time just like if you take out a bunch of dandelions from your lawn, if your lawn has multiple dandelions, you can’t pull them out and expect that’s the end of that and you’ll never see them again. In addition to the visible disease, there’s invisible disease. There are little seeds, and there’s likely to be additional cancers that pop up, and at some point many patients miss the lung that got removed for the surgery when there are new BAC lesions a few years later.

And the fifth myth that I’d like to address is the idea that treatment should be started immediately or promptly. Now, I mentioned that the pace of BAC is quite variable: sometimes it’s extremely slow, sometimes it’s quite aggressive. In patients who have a very slow process, they can do very well and often have no symptoms for years on end. There are even patients who might never be affected and have their life limited by the cancer, even if it’s growing. If it’s growing by a few millimeters at a time it does not necessarily need treatment and patients might do well for 5 or 10 years or more.

So, there’s no clear incentive to starting a treatment like chemotherapy or even a pill-based therapy like an EGFR inhibitor, that has side effects associated with it and that works typically for a limited amount of time, if this is a problem that you’re going to be managing over a very chronic basis. You just don’t want to exhaust your treatments long before they are needed. So one strong idea is if a patient has a minimal amount of cancer that’s growing slowly and they don’t have symptoms, it makes good sense to think about holding off on treatment until there’s a clear need to intervene.


Bronchioloalveolar Carcinoma (BAC): What is It?

GRACE Cancer Video Library - Lung

GCVL_LU-AA01_Bronchioloalveolar Carcinoma (BAC): What is It?

Bronchioloalveolar carcinoma (BAC), also known as adenocarcinoma in situ, is an unusual subtype of lung cancer with its own appearance under a microscope and on imaging. Dr. Jack West introduces some of the basics of the unique features of BAC.

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One of the unusual sub-types of lung cancer is called bronchioloalveolar carcinoma, or BAC. In fact, it’s a pretty controversial type of cancer, with its own behavior and its own prognosis. It also goes by a few potentially different names. The older name for it is BAC, bronchioloalveolar carcinoma, but some pathologists use a new terminology and call it adenocarcinoma in situ. We’ll talk more about what that means, but the behavior tends to be quite unusual.

GCVL_LU-AA01 - BAC intro slide 1b

When you look at it under a microscope, it has its own appearance that does not invade or make solid tumors that go into the lung tissue. Instead, it has what’s called a lepidic pattern. Lepidic means scale-like, and so it really causes just a thin lining that overlies the thin air sacks for the lungs, but that interferes with the ability of the lungs to exchange air. Because of that, it causes shortness of breath and a cough in many people, at least if there is a significant size to the area involved.

GCVL_LU-AA01 - BAC intro slide 2b

BAC can be quite variable. It can be just a very tiny little nodule, it can be multiple spots throughout the lungs, or it can be very large areas of confluent involvement in one or more lungs. And of course, the more of the lung that’s involved, the more severe a patient’s symptoms tend to be.

It has a unique appearance because it tends not to grow invading into tissues and then jumping into the blood and spreading elsewhere — it’s really limited to the lungs only. We will often see a pattern of diffused haziness within the lungs on a chest x-ray or a CAT scan and sometimes you’ll see a spattering of lots of nodules within the lungs as its own pattern.

One of the newer terms for it is adenocarcinoma in situ, and this implies a pre-malignant condition. By that, it means that it is not actually a life-threatening cancer, and this speaks to the often very favorable prognosis of these lesions, at least when they’re smaller and a solitary spot in the lungs. In those cases, when they’re taken out, they have a nearly 100% survival at 5 years. However, the survival is more variable when patients have multiple nodules or when they have larger areas involved.

In addition, the term adenocarcinoma in situ really applies to a non-mucinous cancer, and there are other adenocarcinomas that make mucin, a product of what becomes phlegm or mucus, that patients will sometimes cough up. If patients have cancer that does make this mucin, it tends not to have as favorable a prognosis.

We’ll talk more about how multi-focal BAC is managed in a separate video.

Dr West

How Long A Period of Follow-Up is Long Enough to Be Confident a Ground Glass Opacity Won’t Grow?


GGO over timeAn interesting article from Japan was published out in the Journal of Thoracic Oncology that asks how long a duration of follow-up imaging of a ground-glass opacity (GGO) is really needed to be confident it’s going to remain stable and not grow.   It’s very common to see small lung nodules that are ambiguous in their significance, for which follow-up scans are typically recommended rather than diving into a biopsy, and non-solid, hazy GGOs are another form of lung lesion that might possibly represent a lung cancer but are also the way a little inflammation or small infection would appear.   Even when they turn out to be something technically called cancer based on its appearance under the microscope, it’s often a non-invasive adenocarcinoma (sometimes termed bronchioloalveolar carcinoma, or BAC, but shifting in terminology to adenocarcinoma in situ, or AIS) or minimally invasive adenocarcinoma (MIA), in which the invasive component is less than 5 mm in diameter.  Even when they grow, it can be at an extremely slow pace.

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