GRACE :: Lung Cancer

lung cancer histology

Redefining Lung Cancer: Seeing the Patterns from Individual Colors

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This month’s Journal of Thoracic Oncology includes a landmark article, written by a multidisciplinary group of lung cancer experts that features several of the leading lung cancer pathologists in the world, that is attempting to do no less than present a new categorization of the pathology of lung cancer, focusing primarily on adenocarcinomas, but also touching on other lung cancer subgroups. Among the concepts included is a proposal that the term bronchioloalveolar carcinoma (BAC) be discontinued and recategorized based on whether patients have any invasive component to their lung cancer or not, and whether is is mucinous or non-mucinous. As significant as it is to redefine an entire disease of BAC, the concepts it introduces have implications that actually lead to a fundamentally different way of thinking about lung cancer, or at least NSCLC.

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Rising to the Challenge of Narrowed Patient Subgroups

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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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Lung Cancer FAQ: I’ve just been diagnosed with advanced NSCLC. What treatment should I be starting with??

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The initial or “first line” management of advanced NSCLC has evolved quite a bit over the past 10 years, in that time moving from a much more uniform approach of very similar treatment for just about everyone to a revised approach that is far more individualized. First, we assess key issues like the subtype of NSCLC, focusing largely on whether it is squamous cell or non-squamous NSCLC, because treatment tends to diverge very early based on this factor. Second, a patient’s performance status is another important issue, as patients who are frail often need a customized approach, because a more aggressive standard approach may be prohibitively difficult and even harmful. Third, a minority of patients (about 10% in North America and Europe, closer to 1/3 in Asia) will have a particular molecular marker, specifically a mutation in the epidermal growth factor receptor (EGFR), that is associated with a high probability of having a dramatic and long-lasting response to targeted therapy that inhibit the EGFR pathway. This particular activating mutation is most typically seen in never-smokers or people with a minimal, remote prior smoking history who also have an adenocarcinoma subtype of NSCLC.

Recommendations for first line therapy are most typically for a two drug chemotherapy combination, often with the drug Avastin (bevacizumab) — a targeted therapy that blocks the blood supply to the cancer — added for many patients who don’t have squamous NSCLC. However, for patients with an EGFR mutation identified before they have started treatment, several recent studies have demonstrated that the rate of significant tumor shrinkage and the time before the cancer progresses are significantly longer with an oral agent that works as an EGFR inhibitor, such as Iressa (gefitinib) or Tarceva (erlotinib). Consequently, one of these agents is increasingly recognized as a very appealing first line treatment approach.

Elderly patients are often treated the same as younger patients if they have minimal limitations in their activity level. In contrast, frail patients are sometimes recommended to receive single agent chemotherapy rather than a multi-agent combination that may be prohibitively difficult to tolerate. The available evidence suggests that elderly and frail patients who have an EGFR mutation also typically have a very significant response to EGFR inhibitor therapy.

Further information is available through the following links:

Podcast on introduction to first line chemotherapy for advanced NSCLC

Podcast on personalization of first line therapy

Reference library summary on selecting optimal first line treatment for advanced NSCLC

Using molecular markers to guide treatment: The IPASS trial

Alimta (pemetrexed) benefit is histology-specific

Treatment approaches for first line therapy in frail patients with advanced NSCLC

Podcast discussion of managing advanced NSCLC in the frail and/or elderly

Iressa (gefitinib) for frail patients with an EGFR mutation


Introduction to Small Cell Lung Cancer: Prevalence, Initial Symptoms, Work-Up, and Staging

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General Introduction to Small Cell Lung Cancer

Lung cancer consists of two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Approximately 85% percent of all lung cancer patients have NSCLC, and the remaining 15% have SCLC.

histology-breakdown-of-lung-cancer (click on image to enlarge)

In 2010, the American Cancer Society has estimated that approximately 222,000 new cases of lung cancer will be diagnosed, of which 35,000 will have SCLC. Even though both subtypes are lung cancers, they are considered as separate diseases in most ways, and the management of these two cancers is different. It is important to recognize that the treatments applicable for NSCLC, including many newer agents that have been approved and are the subject of increasing research and media attention, are not clearly relevant for patients with SCLC.

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Dr. Suresh Ramalingam on Personalizing First Line Therapy for Advanced NSCLC: Podcast Available

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I’m very pleased to offer the excellent podcast produced from the recent webinar by Dr. Suresh Ramalingam, a leader in the lung cancer field who heads the Thoracic Oncology Program at Emory University in Atlanta. He’s also a good friend I’ve known since our fellowship training days, and he was kind and generous enough to refuse the honorarium we offered for his participation, instead requesting that it be donated back and used for other GRACE programs. Instead, he was happy to do this entirely out of a commitment to the lung cancer community. This is part of a small series of programs supported by an educational grant from Eli Lilly, so we are now enabled to do an additional program because of his generosity.

His webinar provides a very brief historical overview of NSCLC in general and then advanced NSCLC in particular, including a historical perspective of the evolving standards of care first with chemotherapy alone, and then with the integration of targeted therapies. He describes how our approach now individualizes our treatment recommendations based on such issues as particular NSCLC histology, molecular factors, performance status, and sometimes age to offer what we hope will deliver the best combination of efficacy and safety for a patient.

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The Predicament of Poorly Differentiated NSCLC/NSCLC NOS

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A topic that came up in a recent expert round table case discussion was the issue of how to manage a patient with a lung cancer for which the pathology report says “NSCLC not otherwise specified (NOS)”, or “poorly differentiated NSCLC, NOS”. What does this actually mean, and what does it mean in terms of treatment options?

Tumors of pretty much all types are categorized by their tumor grade, how “differentiated” they are, which basically means, “how much do the cancer cells look like the cells they started out as?”. Different cells of the body start out as stem cells, which means that they’re not specialized to be any special kind of cell, like one that detects light in the back of the retina, lines the esophagus, or is optimized for lung function. Most cells of the body are differentiated, so that the appearance under a microscope shows that it’s a liver cell, part of the kidney filtering mechanism, heart muscle, etc.

Cancer cells, however, have mutations in them that make them grow and divide faster than other cells (that’s why they make a tumor that pushes other tissues aside), and they usually have several. As they grow and divide, they often make sloppy copies of their DNA that leads to more mutations. Cancers therefore are made of cells that may look a lot like the normal cells they originated from (well-differentiated), or they have lots of mutations that make the cells look so chaotic that they don’t look at all like the cells they started out as (poorly differentiated).

Today, oncologists want to know whether a non-small cell lung cancer (NSCLC) is an adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma, etc. But about 20% of the time on various studies, we get an answer back of “NSCLC not otherwise specified”. As explained by Dr. Matt Horton, expert lung cancer pathologist, a lung tumor may be classified as NSCLC NOS because of either of two reasons:

1) there isn’t enough tissue, because the biopsy material was very scant, or

2) the tumor is so poorly differentiated that even with all of the material in the world, a good pathologist couldn’t identify the underlying NSCLC histology

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Interview with Lung Cancer Pathologist Matthew Horton, Pt 1: Intro to NSCLC Subtypes

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I had the opportunity to sit down with Dr. Matthew Horton, a pathologist who works with my own group at Swedish Cancer Institute in Seattle, at a pathology company called CellNetix. He did subspecialty training in lung pathology and is a terrific resource for my colleagues and me, and now for a wider audience.

The first part of our discussion focused on the major subtypes (called histologies) of NSCLC, including adenocarcinomas, squamous cell carcinomas, large cell carcinomas, and the related large cell neuroendocrine carcinomas, along with a significant fraction of NSCLC tumors that can’t be classified despite our efforts. So check out the links below for 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-intro-to-lc-path-nsclc-subtypes-audio-podcast

dr-horton-intro-to-lc-path-nsclc-subtypes-transcript

dr-horton-intro-to-lc-path-nsclc-subtypes-figures

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Thalidomide Fails to Improve Survival in NSCLC

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In this week’s Journal of Clinical Oncology the final results of the phase III trial investigating chemotherapy with or without thalidomide in previously untreated NSCLC patients were published. Most people remember thalidomide for the horrifying birth defects (absence of arms and legs, etc) that resulted in the 1960s when pregnant women were given thalidomide for morning sickness. Since this debacle, thalidomide has been a highly controlled substance that has gotten a lot of understandably bad press, and this experience led to a number of necessary changes in the way the government investigates the safety of drugs before releasing them for widespread usage.

More recently thalidomide has become a standard treatment for multiple myeloma, a type of cancer of white blood cells. Much of the efficacy of thalidomide has been attributed to anti-angiogenic effects against vascular endothelial growth factor (VEGF) and fibroblast growth factor, both potentially important targets in lung cancer (we all know the story of Avastin (bevacizumab) in NSCLC, and anti-VEGF antibody). Thalidomide has shown some promise in preclinical models of NSCLC, and has also shown some indications of activity in small cell lung cancer (as Dr. West has covered in the past). It works well in multiple myeloma, but has some potentially worrisome side-effects even if you are not pregnant, principally increased risk of blood clots, constipation, and peripheral neuropathy.

In this most recent study, Dr. Lee and colleagues randomly assigned 722 patients in the United Kingdom with previously untreated NSCLC to either carboplatin and gemcitabine plus placebo or the same chemotherapy plus thalidomide, followed by up to 2 years of maintenance thalidomide (or placebo). The primary endpoint was overall survival. The thalidomide was started at 100mg daily, escalated to 150mg daily in the second month, and the maintenance dose was 200mg daily, a pretty standard dose.

The results were overall disappointing, essentially showing no hint of benefit from the addition of thalidomide in the overall group. The response rates were the same in the two groups (40% and 42% for thalidomide and control). The median overall survival of the thalidomide and control groups was 8.5 and 8.9 months.

PFS and Overall Survival Curves

PFS and Overall Survival Curves

In addition, the group decided to do a post-hoc (after the fact) subgroup analysis by tumor histology. We know that certain drugs, like pemetrexed, seem to have different effects on different types of NSCLC, so why not thalidomide? In fact, there did appear to be worse outcomes in the non-squamous patients treated with thalidomide, with only 8% of patients on thalidomide surviving at 2 years compared to 18% on placebo. In the squamous cell patients, however, it was just the opposite, with 20% of patients on thalidomide surviving 2 years compared to only 12% on placebo. It is hard to know how much weight to give this small but statistically significant difference. Continue reading


Why Avastin is a No-No for Patients with Squamous NSCLC: A Brief History

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At the time that OncTalk (the predecessor to GRACE) was just getting off the ground in the fall of 2006 (wow, three years have gone quickly!), Avastin (bevacizumab) was just getting FDA approval in the first line treatment of advanced NSCLC. The main focus was on the randomized trial that showed a survival benefit and led to its approval, and in the rush to generate summaries of the treatment highlights for various treatment settings in lung cancer, the story of Avastin skipped over its development in lung cancer. Many people may know that Avastin is given only in patients with non-squamous cancers, but it’s worth backtracking to understand why.

The first significant trial of Avastin in NSCLC was a randomized phase II trial done at Vanderbilt University and that enrolled about 100 patients with advanced NSCLC who received either chemotherapy with carbo/taxol (paclitaxel) alone every three weeks., or the same chemo with Avastin at either 7.5 or 15 mg/kg IV every three weeks. This trial was open to patients with any NSCLC histology. Importantly, patients who were enrolled on the chemo only arm as first line therapy were allowed to cross over to the Avastin alone (at the higher dose) after progression on carbo/taxol.

johnson-cbtaxbev-ph-ii-schema(Click on image to enlarge)

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Alimta and Lung Cancer Histology: Targeting Conventional Chemo Effectively

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I think one of the most important lead stories from ASCO 2008 got buried. Nobody’s really talking about it yet, but they should.

Amidst the results that led to an arguable role for erbitux and more compelling evidence to move second line chemo to bridge first and second line chemo together, we also received what I would consider to be very convincing clinical evidence that we can identify populations of lung cancer patients who are far more or less likely to benefit from alimta (pemetrexed), one of our most commonly used drugs in advanced NSCLC. Although alimta is considered a conventional chemo and not a targeted therapy, we’re getting increasing evidence of how to target our convention chemo (such as by using ERCC1 levels to predict sensitivity to cisplatin, as discussed in a prior post). The new data from the JMEN trial of maintnenance alimta vs. placebo provides what I’d consider to be downright convincing evidence that alimta is a quite effective treatment for patients with non-squamous NSCLC and also appears to be far less effective or even simply not effective for patients with squamous cell NSCLC.

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