The Right Way to Treat Cancer

Kudos to Judith Graham of Kaiser Health News for yet again identifying a new development that has the potential to enormously affect the medical care of older people. Her article, “Geriatric Assessments Could Fine Tune Cancer Care for Older Adults,” pointed me to the American Society of Clinical Oncology's (ASCO) new guidelines for the management of patients over age 65 with cancer. The headline (and I know that journalists don’t generally write the headlines for their articles) is the only part of the article that’s misleading: the changes suggested would not merely “fine tune” oncologic care for older people, they would radically transform it.

Here’s the situation: 70 percent of cancer patients are over age 65 and that number will rise in the next 20 years. Looked at differently, the risk of developing cancer at some point if you are a man over age 70 is one in three, and the risk for women is one in four. Despite the predominance of older cancer patients, most clinical trials of chemotherapy drugs include few if any older people: they have too many other problems to meet the eligibility criteria for participating in the study. But those same people, with all their other medical problems and functional impairments, are regularly given chemotherapy, based on the results of studies that didn’t involve anyone like them. That’s a problem. 

What we do know is that 50 percent of older patients with advanced cancer experience severe toxicity from chemotherapy in the first three months of treatment. We also know that the Institute of Medicine’s recent study, “Delivering High Quality Cancer Care," found that the current delivery system is “ill-equipped to address the needs of older patients.” Oncologists agree with this assessment, stating that “the care of older adults with cancer needs to be improved” and putting the responsibility on themselves. Specifically, only one quarter or less of oncologists felt confident in their ability to recognize dementia, identify a fall risk, or assess functional status. And we know from a recent study that patients shift their priorities from sheer survival to quality of life as functional status declines. In light of these observations, what does ASCO recommend?

The new guideline, “Practical Assessment and Management of Vulnerability in Older Patients Receiving Chemotherapy,” makes a series of evidence-based suggestions. From the perspective of patients and their families, what’s important to know is that oncologists who are contemplating administering chemotherapy to people over age 65 should provide a geriatric assessment to identify problems they might not otherwise recognize. Specifically, they should take simple steps to look for falls, to determine how well patients can function day to day, to identify all other medical diagnoses besides the cancer that might impact treatment, to screen for depression, to evaluate cognition and nutrition, and to assess the social support system. Because the guideline is meant to be practical, it suggests specific tools that oncologists can use to achieve these ends. The guideline also advocates determining the approximate life expectancy, both the cancer life expectancy and the non-cancer life expectancy. 

What is the point of all this? How might it help older patients with cancer? The main objective is to avoid both over-treatment and under-treatment, where “too much” and “too little” must be assessed in light of the best available data about what treatment could achieve and knowledge of the patient’s preferences. How the oncologist presents the options should reflect the facts about what the consequences of treatment are likely to be. How much misery a person is willing to endure might well be affected by how much he or she has to gain in the best-case scenario and how much there is to lose in the worst-case, given the nature of the cancer and the patient’s other medical conditions. In short, the information from a geriatric assessment should guide the process of shared decision-making involving the physician, the patient, and the patient’s family, leading to an “integrated, individualized plan of care.”

But there’s another potential outcome, one that perhaps paradoxically undermines the accuracy of the predictive tools on which the recommendations rely. There is the possibility that performing a geriatric assessment will lead to implementing the recommendations of that assessment with resultant improved capacity to withstand the rigors of chemotherapy. The authors of the guideline recognize this possibility. They say, “While there are not yet completed RCTs [randomized controlled trials] that demonstrate that GA-guided care, or ‘GA with management,’ definitely improves outcomes of older patients with cancer, this care model has been shown to improve outcomes in older noncancer populations.”  Randomized controlled trials are reportedly ongoing to evaluate the ability of “GA-guided care” to actually improve outcomes in older cancer patients—not merely to modify their willingness to undergo chemotherapy in the first place, but also their longevity and quality of life if they do accept chemotherapy.

The first step is for patients and caregivers to request and oncologists to perform geriatric assessment. The second step is to act on the findings of the assessment. That doesn’t just mean using the information to guide decision-making about cancer treatment; it means, first and foremost, making some changes that will optimize the patient’s overall condition. These changes might include physical therapy, modification of the non-cancer medical regimen, or providing more social support. 

It might be necessary to delay instituting chemotherapy, and delay talking about whether to start chemo until certain basic interventions have taken place. 

One analogy that may be helpful is rehab. When a patient and family are struggling to decide if it’s going to be possible to return home after a debilitating hospitalization, it’s often helpful to begin with a stay at a rehab facility. The goal is to optimize the patient’s condition before making important decisions about where to live. A second analogy is depression. Depression may color a patient’s decisions about preferences for care. In general, whenever feasible, it’s desirable to treat depression before accepting a patient’s views about, say, limiting care for some other medical condition, as representing his or her true wishes. 

So, by all means, let’s do geriatric assessments on older patients with cancer. How, exactly, that will shape care remains to be determined.

Food for Thought

The global anti-aging industry is valued at over $195 billion and will grow to $275 billion by 2020. But the assessment of the effectiveness of its products made by three leading scientists in 2002 has not changed. And what they said is that “no currently marketed intervention—none—has yet been proved to slow, stop, or reverse human aging, and some can be downright dangerous.” They then go on to say that "the public is bombarded by hype and lies." Or, as one of the triumvirate put it in a recent NY Times article, "as soon as the scientists publish any glimmer of hope, the hucksters jump in and start selling."  

In light of this reality, my internal alarms started going off when I saw the headline in last week’s NY Times, “My Dinner with Longevity Expert Dan Buettner (No Kale Required).” Granted, the article was in the “Fashion and Style” section of the Times, not the health section and not the science section. Now don't get me wrong: diet and exercise do matter: eating well and remaining active decrease the chance of developing disease and disability. Not only that, but modifying what you eat in the hope that it will promote longevity is far more benign than purchasing expensive supplements or herbal remedies that have no proven efficacy and are quite possibly harmful. But still—is Dan Buettner really a “guru of the golden years” who has spent “the last 10 year unlocking the mysteries of longevity?” He traveled to five of the places on the globe with the longest lived people: Icaria, Sardinia, Okinawa, the Nicoya Seaside of Costa Rica, and Loma Linda, California and wrote up his interviews. He was not funded by the NIH as the report would have us believe: he was funded by National Geographic to report on peoples who were being studied by teams of scientists funded by NIH. He did write a cover story for National Geographic in 2005 about the people he met on his travels and how they lived, particularly how they ate. And he converted his article into a book, The Blue Zone Solution, published by National Geographic Press this past spring.

            National Geographic ran a cover story about diet and longevity once before. The magazine reported in 1973 on Dr. Alexander Leaf’s travels to the Caucasus where he studied people who ostensibly were 120 years old. It would turn out that these human marvels were actually only in their nineties, at best. In fact, according to Dr. Tom Perls, head of the New England Centenarian Study, 98% of claims of age over 115 are false, as are 65% of claims to be 110. 

            I’m not sure why the NY Times ran this story. But I was sufficiently intrigued to look into what we do know about diet and longevity.

         For starters, it’s important to distinguish between people who live a long time and people who live a very long time. What is pretty clear is that the variability in life span for people in the first category can be explained by a mixture of environmental and genetic factors. We can’t control who our parents were, but we can control, to some extent, our environment. So what we eat is one of the things that does matter, at least as far as increasing our chances of making it into our eighties is concerned. Exceptional longevity—centenarians and “super-centenarians” (people over age 110) are a different story. For this group, it’s all about genetics. 

            But can we say much more than what was concluded from the Whitehall study, a longitudinal study of aging in Canada that found the 4 behaviors that increased the chances of being in good health after age 60 are regular physical activity, eating fruits and vegetables daily, drinking alcohol in moderation, and not smoking? What do we learn by looking at  the dietary habits of people in Buettner’s “blue zones” of above average longevity?  

          For several decades, geriatrician Bradley Willcox and his twin brother, anthropologist Craig Willcox, have been leaders of the Okinawan Centenarian Study. They have identified a variety of factors which, together, seem to account for the long lives of Okinawans. It’s not just about diet. It’s also about living in a culture that values group activities and fosters a strong sense of community. It’s about living in a slower paced, low pressure world where people get around by bicycle. But yes, it’s also about diet. And while each of the longevity hot spots of the world has its own culinary specialties, they all have much in common. They all feature a high intake of unrefined carbohydrates and a moderate intake of protein, mainly from fish and legumes. Their foods have a low glycemic load, include a goodly number of anti-oxidants, and are low in saturated fats.

         How much of a role diet plays in the 30-50% of longevity that is due to environmental factors is unclear. Also unclear is whether diet interacts with social factors to make a difference. It’s conceivable that what you eat matters, but it matters a good deal more if you also live in an all-embracing community. At least as interesting as the Sardinians and the Costa Ricans are the Seventh Day Adventists of Loma Linda (whom, to be fair, Buettner visited as well). The people of Loma Linda are physically active and tend to be vegetarians. They are also very involved in their community and deeply committed to their religious faith. So maybe, just maybe, it’s not only what we eat that determines how long we live. Just some food for thought.

No Quick Fix for Mortality

Quercetin hit the airwaves this week, when the media reported that scientists have found "a new class of drugs that dramatically increases healthy lifespan.” Not to be confused with Coenzyme Q10, another naturally occurring compounded touted as an antioxidant that delays aging, Quercetin is a “natural compound” sold in health food stores as an anti-inflammatory agent. But now it is has been dubbed a “senolytic,” a drug that slows aging by alleviating symptoms of frailty, improving cardiac function, and extending a healthy lifespan. Sounds great. But before you rush to buy some, lets look at the evidence.

The article on which this promising claim is based is a highly technical paper in the journal Aging Cell entitled, “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” The authors argue that aging is due in large part to cellular senescence, which in turn means the process by which cells lose the capacity to grow. These senescent cells secrete all kinds of chemicals that are hypothesized to produce decline and death. But not all the cells in an organism become senescent at once. In fact, only 15% of the cells of very old primates are “senescent.” The idea is to kill off these senescent cells, thus preventing them from making those disease-making chemicals. 

It turns out that a variety of drugs, all belonging to this new class of “senolytics,” selectively kill senescent cells. And indeed, when a combination of two drugs, a known cancer drug and the compound Quercetin, were given to old mice, they lived longer and had lower rates of “age-related symptoms and pathology” compared to old mice that didn’t get the cocktail. The two drugs worked especially well together, but each drug alone was effective. So where’s the rub? Why not rush out and buy some Quercetin, which is available now and without a prescription?

It’s not that Quercetin might be harmful. The FDA has studied the compound and determined that it has no significant toxicity because it is destroyed in the intestinal tract--before it can even get into the bloodstream. So while the drug might in principle do something if given intravenously, taking the currently available formulation won’t. Parenthetically, you certainly don’t want to buy some Dasatinib either, the other drug used in the study. Dasatinib is a “targeted chemotherapy” drug, used to treat the relatively rare blood cancer, Chronic Myelogenous Leukemia (CML), when the preferred drug, Gleevec, stops working. It costs roughly $10,000 for a thirty-day supply. It is approved only for use in blood cancers, though in principle it could be prescribed off- label for other non-proven indications.

Another reason for holding off on your Quercetin purchase is that its effectiveness has been demonstrated only in rodents. Using mice to explore the genetic underpinnings of mortality has a venerable history: the gerontologist David Sinclair, for example, has been using a mouse model to study Sirtuin genes, genes that appear to protect against aging. He has discovered "sirtuin-activating compounds," small molecules that decrease frailty--in mice. These frail mice exhibit muscle weakness, they get heart disease, and they die earlier than their non-frail counterparts. But whether frail mice are truly analogous to humans, in whom frailty entails heightened vulnerability to stressors, and in whom frailty translates into an increased risk of falls, delirium, and disability, is another matter.

The main reason for skepticism about the latest claims about an immortality pill goes back to the article written by Olshansky, Hayflick and Carnes in 2002 and republished by Scientific American in 2008 that debunks all claims to have discovered the fountain of youth. These scientists take seriously the desire to promote healthy aging. They see the virtue in postponing the aging process altogether rather than tackling the diseases of old age one at a time: if aging is a zero-sum game, then curing cancer, for instance, would simply mean that more people will die of Alzheimer’s disease. But they are horrified by the amount of money desperate people spend on anti-aging products that are no more likely to be beneficial and just as apt to be harmful as many of the quack nostrums of the nineteenth century.

Today, a number of companies are peddling “anti-aging” drugs. Elysium, cofounded by Lenny Guarante of MIT (David Sinclair’s mentor), makes “Basis,” a mixture of nicotinamide and pterostilbene (an anti-oxidant), which it sells on line. Even Novartis, a major drug manufacturer, is trying to get into the anti-aging market with rapamycin, as Bloomberg News reported with enthusiasm.

None of these drugs has been proven to work. Some may be harmful. All are costly. It's not necessary to discuss  the ethical concerns about trying to lengthen the human lifespan to have an opinion about Quercetin. It's an interesting chemical for scientists to study in the laboratory, but it's not ready for prime time.

More or Less

True or false?

1) Medications have led to improved health (T)

2) Medications are helpful for many chronic conditions (T)

3) Most older patients have several chronic diseases (T)

4) Most older patients take many medications (T)

5) More pills mean better health (F)

Sometimes, less is more. For patients with advanced dementia, most of whom are in their eighties and many of whom have other chronic conditions such as high blood pressure or high cholesterol, it just doesn’t make any sense to take all the drugs that are usually prescribed for them. In a recent article in JAMA Internal Medicine, researchers looked at a large sample of nursing home patients to determine the proportion taking medications “of questionable benefit.” What they found was that over half of nursing home residents with advanced dementia were taking at least one such drug.

We could get distracted by methodological concerns: after all, the classification used by the researchers was based on the consensus of experts, who in turn relied on whatever data were available, which was virtually never high quality, randomized clinical trials. Moreover, these experts assumed that for patients with advanced dementia, a “palliative orientation to care,” is appropriate, though this is not necessarily what the patients’ surrogate prefer. But the point, as the authors of the current paper argue, is that commonly used medications such as lipid lowering drugs and chemotherapy are at the very least “of questionable benefit.” In fact, as suggested by the editorial accompanying the article, the overuse of medications in advanced dementia is just the tip of the iceberg. Medications of questionable benefit are commonplace in frail elders and older people with moderate dementia, not just in those whose dementia is so advanced that death is imminent.

Greg Sachs, Chief of Geriatrics at Indiana University, proposed a framework for thinking about whether a medication is useful in an older person. He suggested beginning with life expectancy. Older people who are in excellent health and can expect to live for another 5 or 10 years are very different from those who are in the last year of life since some medicines work by immediately ameliorating symptoms and other medicines will only provide benefit after they’ve been taken for years. This leads to the next question: what is the lag time before a medication achieves the desired effect? (Pain medicines, for example, are effective within hours or at most days; some antidepressants work within days, others take weeks to kick in; medicines to control cholesterol are generally intended to prevent heart disease years in the future.) Finally, what are the patient’s goals? Is the patient interested in a longer life, no matter what price he has to pay, in which case he might want to take a medication with a small chance of working and a high risk of side effects (such as certain chemotherapy drugs)? Or is he interested in maximizing quality of life, in which case he might want a medication that makes him feel better regardless of the consequences for his length of life (choosing, for example, pain medication over chemotherapy for cancer).

Deciding whether or not a particular medication makes sense for a given older individual is not always easy. But it’s crucial to realize that more is sometimes less. More medications mean more opportunities for dangerous interactions among drugs. The greater the number of medicines, the greater the risk of an adverse drug reaction. Optimal drug regimens are generally determined by studying younger patients who have only one thing wrong with them—the disease to be treated with that medication. Extrapolating to older people, whose bodies handle drugs differently from their younger counterparts, who have multiple illnesses, and who may have a limited life expectancy, is perilous. Prescribing many medications for the elderly can be an excellent way to treat their diseases—but it might be a trick.

The Coming Cataclysm

Some time in the next 6 years the world will experience an unprecedented cataclysm. Not a tsunami or an epidemic or a large scale war, although those are possible, too. This seismic shift will go undetected by the majority of the world’s population and yet it will change our lives. Between 2015 and 2020, for the first time in world history, the population of people over 65 will be greater than the population of children under 4.

It’s all nicely laid out in a report issued a few months ago that didn’t get very much attention. I didn’t notice it at all. It was the US Census Bureau’s Report “65+ in the United States” and it consists of nothing but statistics. Most of the observations and the predictions are nothing new: the population of older people has grown (it reached 40.3 million in 2010); the median age is increasing (up from 22.9 in 1900 to 37.2 in 2010); life expectancy has shot up (going from 47.3 at birth in 1900 to 78.7 at birth in 2010 and going from 11.9 years at age 65 in 1900 to 19.2 years in 2010); more women than men make it to old age (in the over 90 set, there are only 38 men for every 100 women); the population is becoming more diverse: 84.8% of the population self-identify as white in 2010 compared to 86.9% in 2000).

But buried amid the welter of interesting but not novel data about the US are some striking statistics about the entire world. First and foremost is the unprecedented demographic shift that will take place between 2015 and 2020: the total number of people over age 65 will exceed the number who are 4 or younger. This is because both fertility and mortality rates have been falling. As a result, people over 60 went from 8% to 11% of the population between 1950 and 2011, but by 2050 they will make up 22% of the world's population--2 billion people. Looked at a little differently, the global population is projected to increase by a factor of 3.7 between 1950 and 2050, but during that same century, people who are 60+ will go up by a factor of 10 and people who are 80+ by a factor of 26. 

Today, the countries with the highest proportion of people over 60 are Japan (31%), Italy (27%), and Germany (26%) with 7 other European countries not far behind. But the countries that are aging most rapidly include 4 in the Middle East (UAE, Iran, and Oman) and 4 in Asia (Singapore, Korea, Viet Nam, and China).

Accompanying the shifting age distribution will be an ever more dramatic dependency ratio: the number of people over 65 for every 100 people aged 20-64. This means that fewer and fewer young people will have to sustain more and more old people. And it will be in the low and middle income countries that all this transformation will be occurring most rapidly.

The reason all this matters is that it will put an enormous strain—economic, medical, and social—on everyone, but especially on the poorest countries in the world. It will affect demand—for goods (more walkers than tricycles) and for labor (more personal care attendants than elementary school teachers). The net effect may be as destabilizing as nuclear weapons. As a position paper published by the State Department and the National Institute on Aging put it, global aging represents a “triumph of medical, social, and economic advances over disease”—but it also represents an enormous and most governments have not even begun to plan for the long term.

So we have one more thing to worry about, along with climate change and religious fundamentalism and infectious diseases. What can we do about it? We do not need to accept the doomsday scenario of massive workforce shortages, asset market meltdowns, economic growth slowdowns, financial collapse of pension and healthcare systems, and mass loneliness and insecurity. But we do need to take steps now.

There are lots of interventions that can make a difference. 

One is to raise the normal legal retirement age. Another is to use international migration. A third is to reform health care systems, incorporating new models of long term care. A fourth is to encourage businesses to employ older workers, enabling them to work part time and facilitating their continuing productivity through environmental modifications that address mobility, vision, hearing, and other deficits. Economists, sociologists, demographers, historians and physicians at places including the World Bank and the Stanford University Center on Longevity have come up with a menu of strategies.

It’s up to all of us to pressure both the private and public sectors to act. Contact your senators and representatives. Write letters to the editor to major newspapers. The time to act is now.