July 29, 2018

Treatment for Alzheimer's or False Alarm?

The most promising treatment of Alzheimer’s disease to date uses monoclonal antibodies to rid the brain of amyloid plaques. These plaques are widely thought to be crucial in the development of Alzheimer’s disease, the form of dementia that afflicts over 5 million Americans—and, unless we find a way to cure or prevent it, will afflict millions more in the coming years. Researchers hope that these drugs will prove to be “disease-modifying,” that they will disrupt the cascade of events that produces the symptoms of the disease. 

So far, the studies of monoclonal antibodies in this setting have been very disappointing: Bapinezumab: 3 failed trials. Solanezumab: 3 failed trials. Crenezumab: 1 failed trial. In the past year, three major pharmaceutical companies, Eli Lilly, AstraZeneca, and Merck, all stopped development of the monoclonal antibodies they were testing against Alzheimer’s disease. Another company, Pfizer, closed its neurodegenerative disease research section entirely. Now we learn that a Phase II trial of the as yet unnamed agent “BAN2401” actually “looks promising.” How promising?

Like its cousins, BAN2401 is a “humanized monoclonal antibody.” That means an antibody that was developed in mice and modified so it wouldn’t be rejected as alien by the human immune system. Now mice don’t normally get Alzheimer’s disease but certain strains have been genetically engineered so that they do. Using the genetically engineered mouse model, a monoclonal antibody was created that binds to amyloid. Today, this chemical is called BAN2401; when it enters the next stage of assessment, it will presumably acquire a name that ends in “zumab” to indicate it is just such a humanized monoclonal antibody. So, what do we know about this nameless entity?

We know that BAN2401 made it through a Phase I trial that tested its safety, tolerability, and pharmacokinetics in 80 people with mild to moderate dementia. We know it then entered Phase II of testing in people aged 50-90 with evidence of amyloid on their PET scans and either mild Alzheimer’s disease or mild cognitive impairment (a condition that is not dementia but often evolves into dementia). Five different dose regimens were administered intravenously and compared to placebo in terms of their effects on cognition and on brain amyloid deposits on PET scan. We know that when the preliminary results were announced last December, no cognitive benefit was reported. But now, after 18 months of study, the final results are in. They were presented at the Alzheimer’s Association International Conference in Chicago this past week.

What we don’t know is how this study will fare when subjected to peer review. We don’t know what the final paper will look like. But here’s what I can glean from the press release by Eisai, the company that collaborated with Biogen to develop and test the drug, and the reports by the news media:

--The amount of amyloid in the brain (as measured by PET scan) decreased with all the doses tested. The more drug, the greater the change. The findings were statistically significant. 

--There was no discernible effect on cognitive function except in the 161 people who were treated with the highest dose of BAN2401. In those 161 people, cognitive function deteriorated over time, just as it did in all the other groups, but it deteriorated less.

--Cognitive function was measured in a way that differs from the way it has been measured in other studies of treatments for Alzheimer’s disease. The researchers used a composite measure made up of several scales, each of which has been individually validated as a way to assess mental status, but only one of which is regularly used to report the outcome of clinical trials of Alzheimer’s drugs. 

--The patients tested included a mix of people with mild dementia and people with mild cognitive impairment (who don’t actually have dementia but aren’t entirely normal either) and the study had no way to determine whether the effectiveness of BAN2401 was any different in the two subgroups.

What does all this mean? The PET scan changes indicate that the monoclonal antibodies were successful in destroying amyloid deposits in the brain. That doesn’t prove that whatever effect the drug had was due to its amyloid-busting, but it’s suggestive. It also indicates that to the extent that the drug was a failure, it wasn’t a failure because it didn’t destroy amyloid. 

How should we interpret the cognitive changes? It’s hard to know, given that the researchers used a non-standard means of measuring clinical decline (a test they called ADCOMS). We cannot, for example, say that BAN2401 is better than one of the other monoclonal antibodies that was deemed a failure since nobody looked at the effect of the other drug on the “ADCOMS.” What we can say is that a 30 percent change in the rate of decline may be statistically significant but clinically, it’s a lot less impressive. Everyone  deteriorated, including those given the highest dose regimen; they just deteriorated a little less. How much of a difference actually occurred depends on the absolute decline: suppose the score went from 100 at baseline to 80 at the end of the study in the controls (I don’t know what the actual numbers are, so this is hypothetical). A 30 percent difference in the rate of decline means that the score in the treated group dropped from 100 to 86.  Is that clinically meaningful? Probably not.

So, no, BAN2401 is not likely to likely to dramatically change the course of Alzheimer’s disease. I hope the FDA does not allow the drug’s manufacturers catapult it into a clinical trial prematurely, before it goes through Phase 3 testing. But it has taught us a few valuable lessons. 

We now know that monoclonal antibodies can be designed that destroy amyloid plaques in the brain. We know that only the highest tolerated dose of the drug has any chance of being clinically useful. We should also realize the importance of studying patients with early dementia and those with MCI separately—it’s possible that using monoclonal antibodies once dementia has set in is too late, and I suppose that it’s also possible that using them before dementia has developed is too early. Finally, the study reminds us of the importance of a uniform methodology in conducting this kind of work. If the test that was previously regarded as the gold standard, the ADAS-Cog, is not the right test to use, then researchers need to agree on that and decide collectively what test to use instead. 

ABC News reported the drug as “giving patients hope” and showing “big promise.” Fortune magazine asserted that “world leaders want to end Alzheimer’s by 2025; a new drug breakthrough means we just might.” Investors are closer to the mark: Eisai’s stock price fell 10 percent after the data were reported.


July 23, 2018

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.

July 16, 2018

Us or Them?

Nearly 30 years have passed since Congress passed the Patient Self-Determination Act, enthroning advance care planning as an important part of care in the last phase of life. While the frequency with which patients designate someone to serve as their proxy in the event of incapacity has increased dramatically and the use of various planning instruments such as living wills and instructional directives has also risen, in most settings no more than one-third of patients with serious illness actually have conversations with their physicians about their preferences. 

Assuming that it’s a good idea for patients with serious illnesses to speak with their physicians about their goals of care, whose responsibility is it to raise the question? Does it make more sense to concentrate on educating physicians to communicate well about goals or to focus on empowering patients? 

Over the years, different initiatives have targeted one population or the other. The Robert Wood Johnson’s “Project on Death in America,” a multi-hundred-million-dollar project launched in 1994, focused to a large extent on prospective patients. The AMA’s program, “Education on Palliative and End-of-Life Care” (EPEC), also introduced in the 1990s, is targeted entirely to physicians (in fact, the “P” in the title used to refer to physicians: when first launched, the program was called “Educating Physicians on End-of-Life Care”.) More recently, a series of videos by Angelo Volandes of ACP Decisions aims to show patients and their families what various medical treatments entail, while the “Serious Illness Conversation Guide” from Susan Block, Atul Gawande and others at Ariadne Labs offers a checklist of questions to help physicians structure their discussions.

So, who needs more attention, the doctors or the patients? A new study in Health Affairs may offer some clues. I should point out at the outset that the Health Affairs article does not seek to weigh in on the question of whether to concentrate on physicians or on patients when designing interventions to promote advance care planning. The aim of the study, as indicated by its ponderous title, “Factors Contributing to Geographic Variation in End-of-Life Expenditures for Cancer Patients,” is to understand why some regions of the US spend so much more on care near the end of life than other reasons, with no discernible difference in outcomes. 

There are methodological problems with this study, as with all studies that start with death and work backwards—it is possible that although the people who died had similar outcomes (perhaps not surprising, as they all died), other people who weren’t considered in the study because they didn’t die were more likely to do well if more money was spent on them. Nonetheless, we have two groups of people with advanced lung or colorectal cancer on whom very different amounts of money were spent—in the lowest quintile, the average outlay was $10,131 and in the highest quintile, the average expenditure was $19,318). Was the decision to spend more coming from patient pressure or was it something that physicians were pushing for?

What the authors found was that in the high spending areas, physicians were less knowledgeable about treating dying patients (by their self-report), less comfortable providing care to patients near the end of life, and had less favorable attitudes toward hospice than their counterparts in the low spending areas. The high spending areas also tended to have more specialty physicians but fewer primary care physicians, as well as fewer hospices (per capita) than elsewhere. But—and here’s the key—patients’ beliefs about what they wanted were no different in high and low-spending areas.

All the statistically significant findings were in the domain of physicians, not patients:



Now, this finding does not directly translate into the question of who drives decision-making near the end of life in general and advance care planning discussions in particular. But it strongly suggests that physicians play an outsized role in shaping what happens to patients. Many patients don’t have pre-determined preferences; their values do not unambiguously determine what kind of medical treatment they should get. Or, if they do have some idea of what would be best for them, they are nonetheless strongly influenced by the views of their physicians. If “shared decision-making” is to work, both partners need to be informed and on board—and the physicians are particularly in need of some attention.

July 08, 2018

Where We Die

Honoring patient preferences, which is shorthand for providing an approach to medical treatment consistent with what patients say they want, has become a fundamental tenet of American medicine. And one preference that the vast majority of Americans share, according to multiple studies, is the wish to die at home. 

Whether dying at home is actually what patients want when they are faced with impending death, rather than an abstract preference expressed when they are healthy, is another matter—and I’ve previously argued that as hospital-based palliative care improves and home-based palliative care places an ever-growing burden on families, hospitals have become more attractive as a site for dying. But what patients tend to agree on is that they don’t want to suffer as they are dying.

To the extent that hospital care entails interventions such as ventilators or ICU treatment or chemotherapy, patients are reluctant to subject themselves to this type of care, especially if its likelihood of prolonging life is remote. To the extent that fewer hospital deaths and more home deaths is a marker for less suffering at the end of life, change in this direction is very desirable. A new study by Teno and colleagues shows we are continuing to make progress in this direction.

A few years ago, Teno et al performed a similar study comparing the experience of patients in 2000 to the comparable experience in 2009. What they found then was a marked decrease in the percentage of elderly Medicare fee- for-service decedents (health-policy-speak for people over age 65 with conventional Medicare who died) who expired in the hospital (32.6 percent vs 24.6 percent). Over the same period, however, they found ICU use increased among decedents in the last month of life (from 24.3 percent to 29.2 percent) as did the percentage of dying patients who underwent a transition of care (nursing home to hospital, for example) in the last 3 days of life (10.3 percent to 14.2 percent). The current study updates these findings by extending the period of analysis to 2015 and by adding data from older patients enrolled in Medicare Advantage programs, who now account for 30 percent of the Medicare population.

What they discovered today was that the proportion of hospital deaths among the fee-for-service group has continued to fall, going from 32.6 percent in 2000 to 24.6 percent in 2009 to 19.8 percent in 2015. ICU use in the last 30 days of life, which had risen between 2000 and 2009, remained stable at the 2009 level in 2015. Transitions to another site of care in the last 3 days of life, which had also risen between 2000 and 2009, went back down in 2015 to the same level as in 2000. And the chance of being enrolled in hospice at the time of death rose from 21.6 percent in 2000 to 50.4 percent in 2015. When the investigators looked at a sample of Medicare Advantage patients, they found these individuals had the same experience in 2015 as their fee-for-service counterparts.

What does all this mean? I suspect what it means is that when we know with a high degree of certainty that someone is going to die in the very near future, we tend to focus on comfort care. If physicians, patients, and families recognize that death is imminent, hospitalization is relatively unlikely, as is ICU care or transfers from home or nursing home to another site of care. However, physicians often cannot be so certain that death is likely to occur in the next few weeks or months. As long as the usual strategy is to pursue maximally aggressive care until death is virtually sure to occur in the immediate future, and then to abruptly transition to care focused exclusively on comfort, the picture we see today is likely to continue.

There is another approach. That approach involves opting for a goal that is neither comfort only nor life-prolongation at any cost. Instead, maximization of function is paramount; treatment aimed at prolonging life is also acceptable, provided it will not affect quality of life in a major way. So, too, is comfort a goal, but only to the extent that it does not conflict with maintaining function. For people who are frail, extremely old, or both this alternative strategy translates into fewer hospitalizations, fewer ICU stays, and fewer transitions of care in the final stage of life, whether that period is measured in weeks, months, or even years. 

Medical treatment does not have to be all or none; there is something in between. It’s quite possible that many people would opt for this type of care—if only they knew it existed.