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Dr. Jared Weiss is an Associate Professor of Clinical Research for Hematology/Oncology at the University of North Carolina School of Medicine in Chapel Hill, NC. He completed fellowship in Hematology and Oncology at the University of Pennsylvania and residency in Internal Medicine at Beth Israel Deaconess Medical Center in Boston, MA. He received his Doctor of Medicine at Yale University School of Medicine in New Haven, CT and his B.S. in neuroscience at Brown University, in Providence, RI.

Stage IV Lung Cancer in the Elderly Part 2: There are real differences between older and younger patients
Jared Weiss, MD

Almost two months ago, I wrote about stage IV NSCLC in the elderly. There, I reviewed existing data and focused on the published results of the French study (IFCT-050, aka Quoix study) that showed that elderly patients, just like younger patients, do better with platinum-doublet regimens in the first line than with one drug. That article focused on the fit elderly, and I promised a follow-up article on the less fit elderly. Well, here we are.

That original article noted that lung cancer is predominantly a disease of the elderly, with median age of presentation 71 years. What is unique about the elderly? Most obviously, they have lived longer. With longer life comes more time for any genetic predispositions to manifest themselves. Further, just like any machine, the body takes on wear and tear with aging. Eighty-five percent of lung cancer patients smoked at some point in their lives. On GRACE, we don’t judge patients for either smoking or not smoking, but we do address the real biologic differences between smokers and non-smokers and how this influences optimal care. Mostly, this has focused on specific mutations that are more or less common based on smoking status. However, in the context of the elderly, another factor comes into play, a smoking-age interaction: more years of life, on average, means more years of smoking and more total cigarettes. Since cigarettes harm the body, older smokers will tend to be less healthy than older nonsmokers.

With more medical problems come more drugs


On average, older patients have more medical problems than younger ones and therefore also more pills. Drugs can interact. Regardless of lung cancer, this can be a problem. Drug interactions can make drug levels too high or too low of one or both of the drugs, leading to side effects or lack of efficacy. This problem is particularly prominent in lung cancer patients as compared to other cancers. Why? The combined influence of older age at diagnosis (remember, our median age of diagnosis is 71) and the smoking factor means that our patients will tend to have more medical problems and therefor will take more medicines at the time of their diagnosis, as compared to patients with other cancers. I cannot write a comprehensive list of drug interactions, but I do want to highlight two drugs that are commonly used in lung cancer patients that have many drug interactions: Coumadin (warfarin, a blood thinner) and tarceva (erlotinib). How can the lung cancer patient best deal with drug interactions? When available, a good pharmacist can be extremely helpful. In my clinic, I have the unique blessing of a full-time thoracic-oncology-specialized pharmacist to review all of my patients’ medications. While most patients don’t have a thoracic-oncology-pharmacist, every patient does have a pharmacist and review of medications is part of his or her job. Further, many of the new electronic systems check for drug interactions and doctors are getting increasingly savvy to the problem themselves. Finally, I recommend that the drug list be regularly reviewed with consideration of stopping medicines that aren’t helpful.

Let’s move on to talk about some of the specific problems of the elderly that are particularly relevant to the care of the elderly patient with lung cancer.

With aging comes weaker bones

osteoporosis2In doctor language, the condition of weaker bones is called, “osteoporosis.” The frequency of osteoporosis increases with age, particularly with menopause, and it’s important because the risk of fracture increases with it. Smoking also independently increases the risk of fractures regardless of lung cancer or age.

Fractures are a big problem in lung cancer patients because lung cancer can spread to the bone. There is something that can be done about this. There are two drugs that can strengthen bones in patients with cancer that has spread there— zoledronic acid (zometa) and denosumab (xgeva), and we’ve written a lot about both on GRACE before. There are even hints that these drugs may improve cancer outcomes.

The older kidney


Kidney function declines slowly across a person’s lifetime. By the time a patient reaches the average age of diagnosis of metastatic lung cancer (71), just over half will still have kidney functional considered within the normal range. Many cancer drugs are cleared by the kidney and some can damage the kidneys. The most problematic drug in common use for lung cancer is cisplatin, which bears a high risk of kidney damage and is mostly cleared by the kidneys. In the US, most oncologists use carboplatin for stage IV patients anyway because it has fewer side effects. Carboplatin is particularly favored for patients with impaired kidney function. First, it is MUCH less toxic to the kidneys. Also, the formula by which carboplatin is dosed (called the AUC method) accounts for kidney function, making the drug much easier to use in people with abnormal kidney function. Alimta (pemetrexed) is mostly cleared by the kidneys; at more severe levels of kidney problems, the clearance of alimta becomes unpredictable and so the manufacturer recommends against its use at a certain level of kidney dysfunction. Gemzar (gemcitabine) is also mostly renally cleared and sometimes requires dose-reduction in people with poor kidney function. Taxol (paclitaxel), docetaxel and vinorelbine are easier to use with renal dysfunction because the kidneys clear less of the drug. We've talked before on GRACE about the big problem of blood clots in lung cancer, and I voiced a preference for the use of lovenox over Coumadin. One exception is in patients with impaired renal function since the kidneys clear lovenox.

The older brain


My sister is a nephrologist (kidney doc), and I used to tease her that the kidney is the wussiest organ in the body. While it’s true that the kidneys will (at least temporarily) shut down at small provocation, the brain is much the same. Insults such as fevers, brain mets, increased pressure or really any change to its local environment can cause brain failure. What do I mean by brain failure? In response to too much stress, such as a new environment (the hospital), fevers, infections (most commonly urinary infections, but also pneumonia and other infections), the older brain can become confused and lose orientation to time and place. Doctors call this delirium, and it can be a serious problem . Younger brains often recover rapidly from insults—children can take pretty significant bangs to the head and be up and going minutes later. However, the older brain can sometimes take a long time to start working normally.

The Heart, the liver and the blood: Less of a problem in the elderly than commonly believed


Cardiac (heart) function, liver function and blood counts can indeed decline with aging. These problems are sometimes raised as reasons to not aggressively treat the elderly with stage IV lung cancer. If any of these organs have a severe problem that might lead to death before lung cancer, then it makes sense to reconsider therapy on an individualized basis. However, in general, I believe that concerns for problems with each of these three organs are sometimes given too much weight in arguing against full, appropriate therapy.

Chemo can stress the heart. In particular, chemo can lead to anemia and folks who have had heart attacks or even angina don’t tolerate anemia well; this risk can be lowered with careful checks of blood counts and administration of blood transfusions as needed. Most of the drugs used for lung cancer do not commonly cause heart problems directly. The most famous chemotherapy drugs for causing heart problems are the anthracyclines, such as doxorubicin (adriamycin). This drug is sometimes used in thymoma regimens and is the “A” in “CAV” sometimes used for SCLC. Some lung cancer drugs do require a lot of fluid—in patients with heart failure (CHF) this can be made safer through the use of diuretics (water pills), such as lasix (furosemide).

Age related changes in liver size and blood flow have a surprisingly small effect on chemo tolerance in the elderly. Taxol, docetaxel and vinorelbine do need dose-adjustment for liver problems and in severe cases of liver failure, gemcitabine should be avoided.

Doctors commonly assume that blood counts will be much worse in older patients on chemo than in younger patients. While limited trial data suggest this, an objective look at the literature on chemo tolerance in the elderly argues otherwise. Perhaps more importantly, blood counts can easily be checked and followed—complete blood counts (CBCs) require a small amount of blood to check and only several minutes to run (on a machine called a Coulter Counter).

Final thoughts
In the first post, I talked about the fit elderly patient with a core take-home point that fit elderly patients should be treated similarly to fit younger patients. In this post, I have focused on common ailments that affect elderly lung cancer patients and how it can affect their treatment. From this approach, it might seem that there are only two groups of elderly patients: the fit, and the less fit and that doctors are very good at recognizing the difference between these two groups. It might also seem that all fit patients tolerate therapy well. Since neither of these points is true, I think that further commentary is needed. This subject matter may be worthy of a future post of its own, but I’d like to be sure to get across a few key points immediately.

Not all elderly patients who seem fit at presentation tolerate therapy well. Doctors and family may declare, “she’s 80 going on 50,” and sometimes this perspective is maintained as the patient tolerates therapy even better than many younger patients. But other seemingly fit patient older patients show their age and frailty in ways that they hadn’t before treatment. These patients were vulnerable, but that vulnerability was not obvious at presentation.

One of the most powerful tools to define the strengths and vulnerabilities of the elder patient is geriatric assessment. It’s remarkably effectively and remarkably low-tech. There are different kinds of geriatric assessment, but the general idea is to systematically ask about functional status, other medical problems, psychological status, social support, nutritional status, cognitive function and medications. Some of these assessments are very comprehensive, but there are also fast ones that can identify most problems. These assessments can often demonstrates vulnerabilities that more casual examination does not, allowing for interventions or for changes in therapeutic choices.

New lines of research also seek to evaluate biologic markers of frailty. I’m particularly excited about a marker called p16INK4a. p16INK4a levels increase nearly tenfold over sixty years of life. The gene is a tumor suppressor that correlates with both chronologic age and physiologic age. What do I mean by "physiologic age?" The marker increases with inactivity and tobacco use. Further, it increases with chemo. Maybe one day, p16INK4a or another blood test could better define which older patients will tolerate chemo well and benefit with increased duration of life and quality of life and which ones will be more harmed than helped.

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