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Coumadin/Warfarin and Lung Cancer Survival
Although in the last few years there has been a greater focus on low molecular weight heparins (LMWHs), which are injected, the oral anticoagulant (blood thinner) has been studied in this capacity and is certainly widely used in clinical practice for patients with blood clots due to its oral administration, which is desirable particularly if treatment may be indefinite. This agent interferes with several proteins involved with the body’s normal mechanism for blood clotting, which is good if you need to heal a wound, but it’s a delicate balance that is harmful if people develop clots more often than they’re needed, which is often the case with cancer. We know that cancer patients who develop a blood clot are at a higher risk of a recurrent blood clot than other people who don’t have cancer but have a blood clot.
Although heparin has been more extensively studied in this setting, there is some limited evidence that coumadin may have some direct inhibitory effects on tumor growth and metastatic spread (abstract here). Typically, the results in actual people are more complicated. In 1984, a large trial with 431 patients from the VA system with a wide range of cancer types (lung, head and neck, colon, and prostate cancer) were randomized to receive chemotherapy with either life-long coumadin or a placebo (abstract here). There were no significant differences in overall survival for the general cancer population, but among the 50 patients with SCLC, median survival was doubled (50 vs. 24 weeks, p = 0.03). Here are the survival curves for coumadin vs. placebo with NSCLC and SCLC:
(click to enlarge) Continue reading
Do Anticoagulants (Blood Thinners) Improve Survival in Cancer?
Blood clots are a common problem in cancer, including lung cancer, and several studies have shown that this contributes to diminished survival in cancer patients (abstract here):
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Once a blood clot has been detected, most typically a deep vein thrombosis (DVT) that is commonly detected in the leg, or a pulmonary embolus (PE) (clot in the lung), the standard treatment is blood thinners, usually starting with either “unfractionated” heparin, the older form that is given through an ongoing IV and requires frequent checks of the level of blood thinning and adjustment, or “low-molecular weight heparin” (LMWH), which includes just active pieces of the heparin protein, for which there are several brands that are given once or twice daily as a subcutaneous (under the skin) injection and have a more reliable level of blood thinning, so constant monitoring of the level of blood thinning is not required. Patients commonly transition to the oral blood thinner warfarin/coumadin after several days, largely due to the convenience of maintaining a prolonged blood thinning effect with an oral treatment instead of daily injections (and keeping an IV drip of unfractionated heparin going indefinitely, requiring constant checks of the blood, isn’t feasible). LMWH is also very expensive, while coumadin is quite inexpensive.
The American College of Cancer Physicians (ACCP) actually recommends that patients stay on subcutaneous LMWH (an agent known as dalteparin/Fragmin, based on some trial results we’ll review) for 3-6 months for the majority of cancer patients who develop a blood clot (ACCP reference here). While there isn’t an established optimal duration of keeping blood thinners going after a blood clot in a patient, it is generally felt that the underlying cancer continues to put a patient at greater risk for future blood clots, so blood thinners are often recommended to continue as long as a person has active cancer (so if someone has been treated and has no evidence of disease, it’s considered appropriate to discontinue blood thinners (anticoagulation). Continue reading
Cancer Trials Terminology: Study Design & Stats
Like most medical specialties, oncology is part art and part science. There’s plenty of room for individualizing treatment plans, but as a specialty we try be evidence-based. These are treatments that can be very helpful for patients, but also can have significant side effects, so we want to be guided by as much information as possible about the anticipated risks and benefits of treatment. I’ve been using the terminology of oncology trials throughout all of these discussions, so I wanted to take some time to discuss what the terms mean and how to interpret a survival curve. Whether here or from other sources, what you may read can have details that are not necessarily obvious. Here are some of the basics of oncology terminology.
First, trials can be retrospective, which means looking back at results of patients being treated a certain way, or prospective, which means that patients who have a similar cancer and stage are assigned a uniform treatment plan. Prospective trials are generally more informative, but retrospective reviews of information can provide good hints of whether certain patients respond well to a treatment, for instance, or whether others with a certain tumor histology develop a particular side effect.
As I mentioned in my discussion of drug development, phase III trials are randomized, which means that there is essentially an electronic coin flip between treatment A and treatment B. Usually in phase III trials we are testing a new approach vs. the prior standard treatment. Trials can be open-label, in which the doctor and patient know exactly what treatment is being given, single-blinded, in which the doctor/medical team know the treatment but the patient does not, or double-blinded, which is when neither medical team nor the patient know the treatment a patient is getting. Double-blinded trials generally include a placebo, an inactive IV or pill that appears indentical to the active medication. This is to clarify whether the differences between arm A and arm B are truly because of the drug or because of the placebo effect, which describes the range of effects people ascribe to a drug even when it has no active properties. This can be important for many reasons, because patients with progressing cancer may feel increasing pain or cough or fatigue that they ascribe to a new medication rather than to the underlying disease. By the same token, coming off of harsh chemotherapy can leave people feeling better, so a trial of a new treatment that starts after completing challenging treatment may leave people feeling better because of the new drug or just because they’re not doing the harder treatment anymore. Finally, there’s a potentially powerful psychosomatic effect from taking a drug that everyone believes is going to be the next great thing. A placebo helps determine what the active drug is really doing.
(click to enlarge) Continue reading
The Basics of Drug Development and Clinical Trials
We are all interested in having the promising new agents that we hear about in news stories emerge through clinical trials to become a proven, valuable anti-cancer agent in human patients that becomes commercially available. But that process takes a very significant amount of both money and time. One recent and rather famous book, The $800 Million Pill, described the drug development process and indicated that it cost several hundred million dollars to bring a new agent to market (hence the name). In addition, the common estimates are that about 1 in 1000 agents gets from drug discover to te marketplace, that it takes 10-15 to go through that process, and that about 1 in 5 agents that is tested in humans is ultimately approved for clinical use. So let’s review the highlights of the process, which is shown in a figure below:
(click to enlarge) You can see that there are many steps in the daunting process.
The figure, and a lot of the content of what I’m talking about, is covered at a very good website that is run by the Center for Drug Evaluation and Research, which is part of the US FDA. Continue reading
Metabolic Imaging: How PET Scans Are Changing Oncology
PET stands for positron emission tomography, and this generally uses a safe radioactive tracer molecule called 18F-fluoro-2-deoxy-D-glucose (FDG). Fortunately, that’s not on the quiz — you don’t need to know it. All that is worth knowing is that PET scans offer “metabolic imaging”, which detects differences in the metabolism of tissues. The most metabolically active tissues have the greatest needs for sugar from the bloodstream, and when the sugar is labelled, the scans detect these areas as “PET-avid”. The objective measurement is a number called a “standard uptake value”, or SUV, where higher numbers mean a higher metabolic rate. While metabolic activity can be increased with inflammation, infection, and normal body activities (organs like heart, brain, and bowel have uptake normally from regular ongoing activity — this is NOT a bad thing) the reason we all care is that PET scans tend to pick up cancer, because cancer cells generally have greater metabolic activity and are dividing faster than most normal tissue.
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Some slower growing cancers, such as bronchioloalveolar carcinomas(BAC), are much less consistently reported to appear on PET scans than other NSCLC tumors. And there is some evidence that higher SUV activity of lung tumors correlates with faster progression and worse prognosis. Continue reading
Molecular Signatures in Lung Cancer: A Growing Trend of Individualizing Treatment
Today we cannot predict the behavior of individal patient tumors and need to overtreat some patients and undertreat others. However, the science behind lung cancer has now moved a step forward by identifying a “molecular signature” of key genes that may predict patient survival. This week’s New England Journal of Medicine (NEJM) included a very provocative manuscript by a group in Taiwan that studied tumor tissue from a series of patients who had surgery for NSCLC and identified five key genes that could help them separate those with a good prognosis from those with a poor prognosis. Similar to a prior NEJM article from a research group at Duke that identified a large collection of genes that distinguished better prognosis and worse prognosis patients with early stage NSCLC, the article this week by Chen and colleagues out of Taiwan was designed to do a better job than just relying on our current staging system to predict clinical outcomes for patients with lung cancer.
Their technique was complex, and these results need to be reproduced widely before this approach becomes established and incorporated into clinical decision-making. But there were certainly robust differences between the two groups they identified by molecular signatures. The median survival was twice as long in the low-risk group as in the high risk group (40 months vs. 20 months), and there was a more than doubling in the median relapse-free survival (29 vs. 13 months for high- vs. low-risk, respectively).
I’ll review some of how they came to this point, but even trying to simplify this, it’s pretty scientifically complex. You may want to take some Tylenol in advance. Continue reading
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