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Correlating Inflammation with Risk of Lung Cancer
A new study from the National Institutes of Health is being published in the journal of Clinical Oncology and demonstrates that elevated levels of C-Reactive Protein (CRP), a biomarker of chronic inflammation, is associated with lung cancer. Specifically, the study matches serum from 592 patients with lung cancer to 670 control patients who participated in a large cancer screening study known as the Prostate, Lung, Colorectal, and Ovary (PLCO) Trial and did not prove to have lung cancer; it also compared the forms of common genetic variants of CRP known as single nucleotide polymorphisms (SNPs, and pronounced “snips”: see here for further discussion) of CRP from DNA material of 378 lung cancer patients to that of 447 controls.
Evolving Issues with ALK Rearrangements
I thought I’d just take a moment to talk about what I’m finding with regard to ALK rearrangements in patients with NSCLC (see here for review). I hope and expect that there will be more to learn at the ASCO conference in early June, either in the setting of official presentations on the subject or through informal discussions with my colleagues who are also involved with this work.
First, several patients are finding their way to me after getting their tumor tissue tested at a lab doing this work outside of an official trial capacity. I’ve had patients get their tumor tissue tested commercially through the Pathology Departments at the University of Colorado and Massachusetts General Hospital, and I understand that Genzyme is now offering this testing. I hear that other labs are rapidly working toward offering testing, so the barrier of testing only being available through the central lab and only offered through the oncology centers involved with the crizotinib trials is no longer as major a factor as it was. However, some new challenges have emerged:
1) While tumor tissue can be tested and found to be positive for an ALK rearrangement at an outside lab, this positive result doesn’t wave a patient into a crizotinib trial. Tissue still needs to be sent to the central lab run by Abbott in cooperation with Pfizer. This also means that some patients will run out of available tissue after sending their preliminary ALK test and may well need another biopsy to obtain tissue to send the official one to the central lab that counts. This even applies for tumor tissue tested at Mass General, even though they were the reference lab before the Abbott lab got going.
2) I’ve had my first patient who tested positive at an outside lab, then had tissue sent to the Abbott lab, to get a result of “negative for ALK mutation”. It’s unclear whether the outside lab was wrong, the central reference lab is wrong, or whether it’s an issue with there being heterogeneity of tumor tissue, with some samples showing an ALK rearrangement and others not showing this. We’ve seen humbling findings of heterogeneity for EGFR mutations in very limited studies, so it wouldn’t surprise me if different areas of cancer in the same person, or even different areas of the same tumor, could have different results in terms of detection of ALK rearrangements. Right now, Pfizer agreed to have more tissue sent for retesting, but it’s unsettling to think that it all hinges on results from one lab that can produce results different from other experienced labs.
Stage IIIA Non-Small Cell Lung Cancer (NSCLC): A Range of Multi-Disciplinary Approaches
Introduction to Locally Advanced NSCLC
About the only thing that lung cancer experts agree on in the management of stage IIIA NSCLC with N2 nodes involved is that this setting is the most controversial one in the field of lung cancer. First, it’s worth backing up to clarify what we mean when we talk about stage III, also referred to as locally advanced, NSCLC. As outlined in another summary chapter, staging is based on the 3 components of Tumor (the primary cancer from which everything originated), Nodal status (which lymph node areas has the cancer spread to), and Metastases (has it gone through the bloodstream to develop new lesions in more distant locations, most common the liver, adrenal glands, bones, other parts of the lungs, or the brain). Below are schematic drawings from a not quite current staging system after a new revision in 2010, but this is the staging upon which eligibility for our prior studies are based. Nodes on the same (ipsilateral, in medical jargon) side of the mid-chest (mediastinum, between the lungs), are called N2 nodes, which are considered more advanced than N1 nodes inside the same lung lobe as the main cancer. Nodes on the opposite side (contralateral) of the mediastinum, or above the collarbone/clavicle (supraclavicular nodes) are termed N3 nodes, which are associated with a higher stage and less favorable prognosis than N2 or N1 nodes. The other potential determinant of locally advanced NSCLC is a higher tumor stage: a tumor that involves chest wall or is close to the carina, which is the split of the main airway (trachea) into right and left main bronchi, can be resected but is complicated and designated T3. A tumor that involves classically unresectable structures (though potentially with exceptions, depending on circumstances and the surgeon) that are shown below are called T4. The division between N2 and N3, and between T3 and T4, separates stages IIIA and IIIB, as shown below:
(click on image to enlarge)
Q&A Session for Dr. Socinski’s Maintenance Therapy for NSCLC Webinar Available
Dr. Mark Socinski, international leader in the field of lung cancer, from the University of North Carolina at Chapel Hill, gave a terrific presentation on timing and selection of treatment after the first line setting for advanced NSCLC. In addition to the podcast of his presentation itself, here now is the question and answer session that followed it.
The Q&A portion includes slides with the questions as well as some slides that illustrate key points. Below, you’ll find the audio and video versions of the podcast, the figures, and also the transcript of the program.
socinski-qa-session-maintenance-therapy-audio-podcast
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socinski-qa-session-maintenance-therapy-transcript
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Chemotherapy Selection for 1st line Non-Small-Cell Lung Cancer (NSCLC) — The Importance of Getting it Right the First Time
Introduction: Why Chemotherapy?
Every cancer therapy has two purposes: to improve duration of life, and to improve quality of life. Every other measure of chemotherapy success, such as response rate or progression-free-survival, is a surrogate to these two true goals. I am using the broken record as my pseudo-apology for repeating this mantra repeatedly on GRACE, to my colleagues, and in my mind every time I make a treatment decision.
Chemotherapy is the most important treatment for achieving these two goals in stage IV disease. Stage IV means that the cancer has spread and is no longer curable. Incurable is not the same as untreatable. Cure means eliminating every last cancer cell. Treatment means providing real benefit, in the form of achieving these two goals.
Cancer cells are microscopic. The tip of a pen is the size of more than ten billion cells. So, if a single cell has spread to a site, say, the liver, you won’t be able to see that cell on a CT or even the most sophisticated PET/CT. So, once you see the cancer having spread to distant sites, it becomes systemic-in more sites than you can see; we call this “metastatic” or stage IV disease. To achieve our two key goals, you need to knock down the cancer everywhere-the places that you can see and those you can’t. Chemo gets almost everywhere in the body and is therefore the best and most important way to do this for most patients with metastatic disease.
The Glass Half Full for Later Treatment Options in Advanced NSCLC
It was nearly three years ago when the results of a randomized phase III trial of the chemotherapy agent Javlor (vinflunine) compared with standard second line Taxotere (and its proven survival benefit in previously treated advanced NSCLC), both drugs given IV every three weeks. I summarized the results of that trial shortly after the ASCO meeting in 2007, but to be honest, I didn’t even remember if I had done that. Javlor has barely been spoken of since then. The results showed completely equivalent efficacy and some greater GI side effects with Javlor, including constipation, abdominal pain, and nausea in the Javlor arm (though more hair loss with Taxotere). In contrast, Alimta (pemetrexed) had recently been shown to have equivalent efficacy but a modestly better side effect profile, at least in terms of blood counts dropping. Over time, Alimta became a leading second line option, while Javlor hasn’t been submitted for FDA approval and hasn’t generated much discussion as a treatment option thus far.
While I was among the many people who gave a collective yawn when the results were presented from the trial of Javlor vs. Taxotere, it’s now three years later (a much longer interval than what you’d see for more eagerly discussed findings), and the results are being published in the Journal of Clinical Oncology, still showing completely superimposable efficacy results.
(click on image to enlarge)
The results aren’t any better, but at this point I’m much more inclined to see the glass as half full than half empty, and I’d be eager to have this agent available for my patients. What’s changed over the past three years?
Maintenance Therapy in NSCLC Program by Dr. Mark Socinski, now available as Podcast
I’m very pleased to offer the podcast materials for the recent webinar by Dr. Mark Socinski, medical oncologist and leader of the excellent Thoracic Oncology Program at the University of North Carolina, in Chapel Hill. He’s been a long-time leader of the entire field of lung cancer for many years, and he’s among the best at synthesizing new information into a cogent perspective.
Here is the audio and video versions of the podcast, along with the figures and transcript that go with the program.
socinski-maintenance-therapy-webinar-audio-podcast
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socinski-maintenance-therapy-webinar-transcript
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An Introduction to Lung Cancer
The GRACE Lung Cancer Reference Library is made possible by an educational grant from Pfizer, who had no input in its contents.
What is cancer?
One of my patients once told me that she likened her cancer cells to misbehaving children and I think that this was a wise explanation. When a baby is born, it starts as a sperm fertilizing an egg, creating a single cell. That cell is pluripotent, meaning that it is capable of making all of the different kinds of cells that will ultimately be needed in the body. The cell will divide, then divide again, then divide again. In the process, the “daughter” cells become increasingly specialized. By birth, a baby has many different kinds of cells, each with very specialized functions and most of them have lost the ability to divide further or spread to other parts of the body. They are programmed to die in response to signals from other cells.
Each of these cells is a little factory, performing its specified functions. The tools that the cell uses to carry out these functions are called proteins. In order to make a protein, the cell starts with the DNA blueprint that is housed in a structure called the nucleus. The nucleus can be thought of us a little fortress-enclosed island containing stacks of blueprints in a big lake that is the cell. The DNA is transcribed (copied) into stuff called RNA, which travels out of the nucleus into the cytoplasm (which could be thought of like the water in the lake). In the lake, the RNA attaches to a structure called the ribosome (think of it as a small, floating protein factory) where it is translated into a protein.
ARQ 197: Novel c-MET inhibitor shows promise in early clinical trial results with Tarceva
Earlier this week, the Boston (Woburn, actually)-based company Arqule announced preliminary results from a trial of their investigational oral c-MET inhibitor ARQ 197 combined with the EGFR inhibitor Tarceva (erlotinib), which sent their stock soaring. Although I and other investigators dislike learning about potentially important cancer trial outcomes from the business news outlets, this was again following that pattern. Unlike some other press releases describing preliminary outcomes, however, this one truly does impress me. We’ll certainly need to learn a lot more, but I believe that this drug may represent a meaningful improvement, at least for a subset of patients with advanced NSCLC.
c-Met is a receptor tyrosine kinase implicated in tumor cell migration, invasiveness, and proliferation, and it is abnormal in many human cancers. Importantly, about 20% of patients with an epidermal growth factor receptor (EGFR) mutation who initially respond well to an oral EGFR inhibitor are found to have a c-MET mutation, and it is currently believed that this mutation contributes to “acquired resistance” to these agents when patients progress over time. The drug ARQ 197 inhibits c-Met and inhibitrs cancers in preclinical models, which is great, but the real test is how well a drug works in real patients, who are far more complex than test tube or animal models of cancer. The results highlighted in the press release strongly suggest what I would consider to be a potentially clinically meaningful benefit. So let’s dig deeper.
Surgery for Limited SCLC
Here’s the podcast from a webinar I did last month with Dr. Weiss on the subject of whether patients with very limited small cell lung cancer (SCLC) should perhaps undergo surgery as a first intervention. Historically, surgery isn’t considered as a typical treatment for patients with SCLC, even if it’s very early stage, but some results from retrospective experiences suggest that the patients who undergo surgery in this setting do very well. While that’s true, the central question is whether they do well because they receive surgery or because they had a very unusual SCLC that was able to be detected so early. This podcast covers the evidence and the lingering questions about this topic. Along the way, it also provides some discussion of the general characteristics of SCLC.
Here’s the audio and video versions of the podcast, along with the figures and transcript for the program.
west-surgery-for-limited-sclc-audio-podcast
west-surgery-for-limited-sclc-figures
west-surgery-for-limited-sclc-transcript
Podcast: Play in new window | Download (57.0MB) | Embed
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