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The Variability of Bronchioloalveolar Carcinoma (BAC): Non-Mucinous and Mucinous BAC
One of the themes that we’ve covered in some of the posts introducing the clinical entity of BAC is the variability in its natural history. In fact, much of what we’ve been learning about BAC has been in the last several years, and we’re still learning more about it all the time. One of the things we’ve struggled with is the range of outcomes, that some patients can experience rapid deterioration and no response at all to EGFR inhibitors, while other patients can have a remarkably slow progression, and they sometimes will have an astounding regression of disease from EGFR inhibitors. It sometimes seems as if there are at least a couple of diseases being labelled as BAC. In fact, that’s the case, and it’s been part of the confusion in why some people don’t fit a simplified view of what is supposed to happen in BAC. So let’s talk about mucinous and non-mucinous BAC.
Non-mucinous BAC is the largest group, accounting for about 40-60% of the patients, while perhaps 30-40% have mucinous BAC, and about 10-15% fall in between and are classified as mixed or indeterminate. In truth, this is pretty high-level classification that is not always (or even often) mentioned in pathology reports of BAC, and I would consider it relatively unreliable if read from a small amount of tissue and/or read by a pathologist without much expertise in lung cancer. In truth, even expert pathologists differ in how they interpret BAC diagnoses. Here’s a slide of BAC and adeno subtypes under the microscope:
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Mucinous BAC is the subtype that is associated with a cough productive of thick sputum, and it tends to appear more localized and pneumonia-like on CT scans than non-mucinous BAC, which appears most commonly as a buckshot appearance of lots of tiny, diffuse nodules:
EGFR Inhibitors in Women and Men
Throughout their development over the past years, the EGFR tyrosine kinase inhibitors Iressa (gefitinib) and Tarceva (erlotinib) have been identified as seeming to be particularly helpful in women compared with men. Only Tarceva is commercially available in the US, but Iressa is widely used in other parts of the world, including Asia, where it continues to be avidly used and studied. Both of these drugs have a consistently higher response rate in women, which has led to some different use patterns in women and men. In fact, some US oncologists relegating Tarceva now just to women, despite the fact that it was shown to have a survival benefit in the general population (of women and men). So what’s the fuss about EGFR-based therapies and women?
The differences in response rate were noted in the first reasonably large trials of EGFR inhibitors, which gave Iressa at varying doses to patients predominantly outside of the US (including significant numbers of patients from Asia) in one trial (IDEAL-1 abstract here), and another predominantly from within the US (IDEAL-2 abstract here). In an analysis of multiple variables in these trials, women had a higher response rate in both; the IDEAL-1 trial reported that women were 2.65 times as likely to respond to Iressa as men were, while the IDEAL-2 trial reported that women had a response rate of 19%, compared with 3% for the men on that trial (an approximately 6-fold difference!! Eighteen of their 22 responses on the trial were in women, even though women accounted for less than half of the patients). As described in a prior post, the larger Iressa trial known as ISEL (abstract here), with nearly 1700 previously treated patients randomized 2 to 1 to receive Iressa or placebo, showed no overall survival benefit; women on this trial had a nearly three-fold higher response rate of 14.7%, compared with just 5.1% for men. In the study of Iressa in patients with advanced bronchioloalveolar carcinoma (BAC) that I led (abstract here), women had a median survival more than twice that of men (19 vs. 8 months), and the response rate was nearly twice as high in women as in men, although this was not statistically significant (20% vs 11%):
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Better Results from Chemo in Women than in Men
While we are still working on figuring out the mechanisms underlying differences in the lung cancers of women vs. men, the efficacy and survival paint a consistent picture that women with lung cancer live longer than men regardless of the lung cancer subtype, stage, or treatment used (summary here). Large studies have reported that women have an approximately 15-20% improvement in survival, controlling for other variables, when compared to men. Women appear to have a superior survival in surgical trials (abstract here) and also trials with chemo and radiation (abstract here). Although there are some trials in which significant differences are not seen, we don’t see trials in which do better than women with lung cancer.
Turning to sex differences in response to chemo, you can see from a few trials that women typically have a median survival that is 1-2, and in some studies 3-4 months, better than their male counterparts:
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Sex Differences in Lung Cancer Risk and Outcome
We have rarely divided cancers along the lines of sex, except for the obvious ones like breast, prostate, testicular, ovarian, etc., but there is growing evidence to begin to consider patient sex in the field of lung cancer. (As a semantic point for the delicate souls out there who will wonder why I use the word “sex” throughout this post (but notice my restraint in not putting it in bold), it isn’t an attempt to broaden interest by turning OncTalk into an adults only website: the term gender applies to whether a person identifies themselves as male or female as a sociological variable, but patient sex is the biological, genetic and non-transferable assignment). We’ll start to explore some of what we’re learning, and I understand that some very intriguing information on sex-based differences will be presented at the American Society for Clinical Oncology Annual Conference in early June. I’ll give you those updates when they’re publicly available.
First, there’s the issue of the changing patterns of lung cancer. A review of a large database of cancer patients (free full article here) revealed that younger patients with lung cancer (<50) are more likely to be women, and that women disproportionately develop adenocarcinomas and small cell lung cancer, with a relative dearth of squamous cell carcinomas. This suggests that there are differences in the risk factors that can lead to lung cancer in men vs. women. In addition, I’ve described in a previous post some work by Dr. Heather Wakelee at Stanford that shows a disproportionate number of women who are life-long never-smokers in multiple case series. Continue reading
Smokers and Tarceva: Is More Better?
As I’ve described in a prior post, one of the most consistent findings in the work with the EGFR inhibitors Iressa (gefitinib) and Tarceva (erlotinib) is that never-smokers are far more likely to demonstrate a response and survival benefit than patients who do smoke or did smoke. Here, for instance, is the set of survival curves separated by smoking status for the large randomized trial of tarceva vs. placebo in previously treated patients with advanced NSCLC (abstract here):
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We really haven’t explored why that as, and that’s partly because there is a lot we don’t know. We do know that never-smokers are far more likely to have mutations than current or ex-smokers with lung cancer, but it’s really not all or nothing. The likelihood of having an EGFR mutation is higher in ex-smokers than in current smokers, and it’s also a gradually higher likelihood with a longer period since patients quit smoking, and with less overall tobacco exposure in terms of pack-years, the product of the number of packs smoked per day (PPD) x the number of years smoked, so 2 PPD x 20 years would be a 40 pack-year history. You can see that between never-smokers and major smokers are a population of patients who fall in between in terms of their smoke exposure and likelihood of having an EGFR mutation (abstract here):
But it’s probably not all about EGFR mutations, which are still only seen in a minority of patients with lung cancer, somewhere in the 5-15% range in the US (more in Asia). It’s quite possible that one of the more important issues may be the metabolism and different pharmacokinetics (the way a drug is processed by the body, specifically the changing levels in the blood over time) between smokers and non-smokers, which may mean that what is an optimally effective dose in a smoker may be higher than the optimal dose in a non-smoker. Continue reading
Chemo or Chemoradiation as Optimal Induction Therapy for Resectable Stage III NSCLC
One of the more common approaches to treating stage IIIA NSCLC with N2 lymph nodes (mediastinal, or mid-chest, on the same side as the primary tumor) is chemotherapy or chemoradiation before surgery. For those who recommend induction therapy (treatment before planned resection), there is a pretty even split between those who recommend chemotherapy alone and those who recommend chemo with concurrent radiation. So how do knowledgeable people come to different conclusions, and who is right?
Pursuing at least chemotherapy before surgery, rather than just surgery alone, for stage IIIA N2 NSCLC, has been pretty well established for more than a decade. In 1994, two small trials were reported that had randomized patients to either surgery alone or chemotherapy before surgery. One study, conducted by Rafael Rosell and the Spanish Lung Cancer Group (abstract here), stopping after a preliminary analysis with the first 60 patients showed a dramatic benefit in favor of the recipients of chemotherapy. While limited because of the small size, a second trial done in the US by Jack Roth and colleagues from MD Anderson Cancer Center (abstract here) also randomized patients to up front surgery or chemo followed by surgery, and this study also was stopped after 60 patients were enrolled after 60 patients were enrolled because of very significant benefits in favor of the patients who received chemo before surgery. This trial was published just months after the Spanish trial, and alhough there were issues with some of the specifics of the trials, and they only enrolled 120 patients between them, the benefits were so striking that it made pre-operative therapy with chemotherapy a standard approach. The results of these trials are summarized in the following slide/figure:
Pre-operative Chemotherapy for Early Stage NSCLC?
Over the last several years, chemotherapy after surgery has become the standard strategy for improving survival compared to surgery alone, at least for stage II and IIIA patients who don’t have mediastinal (N2) lymph nodes involved, and it’s often used also for patients with stage IB NSCLC (no lymph nodes, but a larger tumor or tumor involvement with the pleural lining around the lung). However, another approach that has been studied, albeit less so than adjuvant (post-operative) chemotherapy is neoadjuvant (pre-operative, also known as induction) chemotherapy. This strategy has several potential advantages over administering chemo after surgery. First, when we’re trying to improve survival with chemo by treating potential micrometastases, neoadjuvant chemotherapy has the potential to start treating these micrometastases at the earliest possible time. In addition, chemotherapy before surgery can allow us to assess how responsive the cancer is to treatment, in a way that post-operative chemo cannot. We can see how much the tumor shrank on repeat CT scans (+/- PET scans), and we can look at changes in the tumor itself after it has been removed at surgery. Perhaps more importantly, there is the potential that in patients who have a tumor that may require a more extensive surgery such as a bilobectomy (lwo right-sided lobes) or pneumonectomy (full lung resected), it may be possible to shrink the tumor enough before surgery to do a lobectomy (in fact, people still debate whether you should do the surgery that was needed before the induction therapy, or whether you can do surgery and just remove the area that it shrunk to. This is really a question of whether there are residual “islands” of viable tumor outside of the newly shrunken borders of a tumor after treatment). It is also possible to identify a small minority of patinets who progress immediately, despite treatment, which happens perhaps 5-10% of the time. In those patients who develop progression with metastases before getting to surgery, you could consider them as having lost the chance for cure with surgery, but we really think these are the patients who would have shown progression immediately after surgery if they had gone straight to the operating room, so they have probably been spared a surgery that would not have helped them.
But the leading reason that we would consider pre-operative chemotherapy to be potentially more helpful than post-operative chemo is that we think you can get it in more reliably. One of the biggest problems with adjuvant chemo is that patients are just recovering from a MAJOR surgery, and many have recently lost a bunch of weight, they’re in pain, they’re constipated because of their pain meds, or any of many other problems people can have after major surgery. They may not be able to get through a challenging plan for 3-4 cycles of chemo, since chemo isn’t exactly a cake walk even for people who didn’t just have major surgery. The trials of adjuvant chemo, which only included the patients motivated and fit enough after surgery to consider chemo (which definitely isn’t every patient), have consistently shown that only about two thirds can get through the majority of planned treatment:
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