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.

False Hope

This past week, the House passed its “Right to Try” bill, which would give dying patients easier access to experimental drugs. The Senate has already passed a version of this ill-conceived legislation and Trump is an enthusiastic supporter, viewing it as a means of defanging the FDA and of demonstrating his great compassion for the American people. The bill itself, if it is signed into law, will not affect very many people and most of them are not likely to be elderly. But it is the first step in a campaign to destroy drug regulation. That is an issue for all of us, and for older people, as the greatest per capita consumers of prescription medications, in particular.

A STAT article on the subject quotes Andrew McFadyen, executive director of a non-profit patient advocacy group: “I think this is the first step, for sure. Tear down as many regulations as possible, take away all oversight, and let it be the Wild West of medicine.” He continues that its Republican proponents “opened the door to Koch brothers and Goldwater to rip apart the FDA, and then other government bodies after that.”

It’s important to recognize three things: 1) the FDA plays an enormous role in patient safety. Tearing up the regulatory framework, as Trump and his ilk favor, would have devastating consequences for health and well-being; 2) the history of granting desperate patients access to experimental drugs is one of offering false hope and enormous suffering; 3) the track record of the experimental drugs that the current legislation would support is mediocre.

The FDA approval process keeps us safe. When the FDA was first created in 1906, all it required was that drug labels accurately report the contents of medication. No longer was it permissible to sell “tonics” such as “Pinkham’s Vegetable Compound” or “Mrs. Winslow’s Soothing Syrup” without divulging on the label that the former contained alcohol and the latter morphine. 

The idea that FDA approval required that a drug be demonstrably safe and effective came much later. This amendments to the law were finally passed in 1938--after 5 years of debate--after the sulfa disaster of 1937: a liquid form of the new antibiotic, sulfa, had become widely available and was marketed for use in children. Because there were no safety tests performed, nobody seemed to have noticed that it was made with ethylene glycol (the active ingredient of antifreeze), a toxic chemical that causes liver failure and death—and that killed over 100 children. 

The requirement that drug companies actually perform randomized controlled trials to determine the safety and efficacy of proposed new drugs had to await the thalidomide disaster of the early 1960. Only after pregnant women treated with sleeping pills gave birth to babies with severe congenital malformations was were the Kefauver-Harris amendments to the FDA passed in 1962.

The track record of experimental drugs is poor. While the proponents of the new legislation, conservative groups such as the Goldwater Institute (named after Barry Goldwater) focus on “free choice” as the rationale for making untested substances available to the public, the widespread assumption is that substances entering a “phase III” clinical trial are all but proven drugs—just a few more bureaucratic hurdles, and they will be FDA approved. In fact, a phase III trial is designed to determine whether a drug that has shown some evidence of efficacy in a smaller, earlier trial (one that was focused primarily on looking for side effects) is actually effective. Many drugs that reach the Phase III stage do not move on in the approval process because they are not found to work. For cancer drugs, only 40% move ahead.

One of the most dramatic examples of the unfortunate consequences of premature access to an experimental therapy is the case of bone marrow transplant for advanced breast cancer. In the 1990s, more than 30,000 American women received bone marrow transplants at the cost of millions of dollars, extremely unpleasant side effects (including death—treatment-related mortality was reportedly as high as 15%). Insurance companies found themselves pressured to pay for the therapy—until several randomized controlled trials definitively demonstrated that it was no better than conventional chemotherapy.

The sad reality is that dying patients are vulnerable to claims that a cure is lurking around the corner. More often than not, what they are being offered is an opportunity to spend their dwindling resources on a bottle of false hope, often suffering enormously in the process. This is what the “right to try” legislation offers. The House and Senate versions must be reconciled for “right to try” to become law. Tell your senator to halt the assault on the FDA and keep drugs safe and effective.

To Cover or Not to Cover

The day of decision is coming. The Centers for Medicare and Medicaid Services (CMS) will decide soon whether to go along with the recommendation of the independent review panel, MEDCAC, against coverage of lung cancer screening using low dose CT-scans, or to bow to political pressure  to cover the test (see my post on June 23, Politicians: Keep Out). A spate of recent commentaries in medical journals weigh in on the debate. Most seem to support coverage, although they add a few caveats. Two of these caveats are intriguing: using a registry to actually generate data about what happens to older patients who are screened with lung CT scans and mandating the use of a formal shared decision making process.

Writing in a recent issue of JAMA, Harold Sox, a distinguished physician with a long career promoting evidence-based medicine, recognizes the weaknesses of the available data, principally the National Lung Cancer Screening Trial (NLST). The NLST simply was not representative of the Medicare population because it included only a small number of patients over age 65 and only a very small number over 70. Moreover, the patients followed—who had a lower risk of death if they underwent the screening with CT scans compared to screening with regular xrays—in all likelihood did not have multiple other chronic conditions, the norm for Medicare patients. But Sox is clearly worried about depriving those older patients who might benefit from screening if Medicare categorically refuses to cover the test. He therefore veers towards recommending coverage, but with the proviso that a registry be maintained that tracks all patients who are screened to see what happens to them. In principle, this information could be used to modify the rules about coverage later on. Taking away coverage for something that was previously offered is certainly possible—coverage of bone marrow transplants for breast cancer was rescinded after it was found to be both tremendously toxic and no more beneficial than conventional, less risky treatment—but it happens rarely because of pressure from patient advocacy groups, regardless of the data.

A second opinion piece in the same issue of JAMA argues that CMS should provide coverage but should address MEDCAC’s concerns by mandating “shared decision-making.” Shared decision-making rests on patients’ understanding the risks and benefits of the various options and deciding, in concert with their physician, which approach is most consistent with their own values and preferences. Now I am a fan of shared decision-making. And I support the use of decision aids, as proposed by the authors of this article, which are formal tools that systematically describe the risks and benefits of the alternatives in clear, readily understandable language illustrated by simple graphics. But for shared decision making to make sense, we have to know the risks and benefits of the alternatives. The reason that patients should have a choice to make is that some patients may be willing to accept one risk (say losing their independence) in exchange for a particular benefit (say a small chance of extending their life) while other patients might not. In the case of CT-scanning for lung cancer, the problem is that we simply don’t know what the risks and benefits are in older patients in general and in older patients with multiple co-morbidities in particular. So it’s just not possible to design clear and accurate decision aids to help patients think about screening for lung cancer.

The real issue is whether and under what circumstances it is appropriate to extrapolate from situations where we do have data to situations where we don’t. Sometimes there are plenty of good reasons for making such a leap. It seems reasonable to provide a treatment to a mature 17-year-old, for example, even though he is technically a child, and even though studies of the treatment were done in patients over age 18. After all, physiologically and socially, the 17-year-old is almost identical to the 18-year-old. Sometimes what initially seems reasonable proves not to be: it turns out that the data on first generation left ventricular assist devices (a high tech device that is essentially a partial artificial heart) could not be extrapolated from men to women because the devices were often too big to fit into a woman’s chest. Sometimes, however, there is good reason to believe that data obtained from one group cannot be extrapolated to another. There is good a priori reason to believe that neither safety nor efficacy data will be the same in old, sick patients as in young, healthy patients. It is eminently plausible to believe that the 75 year old with heart disease and diabetes might run into problems when undergoing open chest surgery to remove a lung cancer. The only way to know is to do a study involving older patients: there aren't any good shortcuts. 

Agreeing to pay for the test would no doubt be politically expedient. It would not be a wise decision.

New Cancer Treatments: Hype or Hope?

If you are a man, you have a 1 in 6 chance of developing prostate cancer during your lifetime. The good news is that most men will die with prostate cancer, not of prostate cancer. The bad news is that some men will succumb to a virulent form of prostate cancer: even with surgery and/or radiation therapy, tens of thousands will develop metastatic disease. Initially, prostate cancer typically responds to hormonal therapy (the cancerous cells need male sex hormones to thrive so treatment that lowers the level of these hormones can hold the cancer at bay). But if it stops responding to hormonal treatment and new metastases develop, patients are in trouble. The cancer often travels to bones, causing pain and fractures. Sometimes it causes spinal cord compression, which can cause paralysis. According to the National Cancer Institute, about 32,000 men die of prostate cancer in the US every year.

When the Seattle-based biotech company Dendreon announced a radical new approach to the treatment of prostate cancer, the enthusiasm was palpable. As the company reports on its website, it is in the business of "transforming lives through the discovery, development, and commercialization of novel therapeutics." Its new strategy for prostate cancer is more like a vaccine than a drug and it involves a highly individualized approach rather than one-size-fits-all chemotherapy. Treatment entails drawing blood from a patient, removing the white blood cells, treating them in the laboratory to endow them with special anti-prostate cancer fighting properties, and then returning them to the patient. Three randomized controlled trials suggested that the new approach, called autologous cellular immunotherapy or sipuleucel-T (brand name Provenge) is effective with relatively modest side effects. The Food and Drug Administration approved sipuleucel-T in April, 2010. Now Medicare is trying to decide whether to pay for the therapy. Medicare has commissioned a "technology assessment" to evaluate the evidence that the treatment is effective; it has carefully reviewed all the available data, and it has assembled its advisory committee to make a recommendation. Much of the reason for all this scrutiny is cost: a full course of treatment (three infusions) is just under $100,000.

Since the FDA has found sipuleucel-T "safe and effective," isn't any restriction of usage by Medicare simply government interference in the practice of medicine? That's one way to spin Medicare's concern. It's certainly the view of the company that makes the sipuleucel-T system. But a sober assessment of the facts suggests the alleged benefits of immunotherapy may well be exaggerated: the system has only been shown to work in a small fraction of men with so-called castration-resistant metastatic prostate cancer; it does not prolong the length of time men go without progression of the disease; and its efficacy may depend on the use of conventional chemotherapy.

Which men stand to benefit from sipuleucel-T? To be eligible to participate in one of the 3 clinical trials of sipuleucel-T, men had to meet a whole slew of criteria. They had to have low testosterone levels (indicating their disease was progressive despite lowering of the male sex hormone), they had to be in generally good health (as indicated by independence in their daily activities), they couldn't be experiencing pain or taking narcotics for pain, and they couldn't have lung, liver, or brain metastases. In this carefully selected group, sipuleucel-T increased median survival by 4 months. We simply don't know whether the observed effectiveness of sipuleucel-T applies to men who do not meet these criteria.

What exactly does sipuleucel-T do? The first two clinical trials of sipuleucel-T concentrated on measuring the length of time before a patient's cancer progressed. The assumption was that even if the new treatment didn't cure prostate cancer-it didn't-it might extend quality of life, if not length of life, by offering patients a period in which they had no measurable tumor growth. Neither study found any such effect: the time until progression of the disease was in the range of 10-11 weeks with either sipuleucel-T or placebo. But surprisingly, median overall survival was 4 months longer with sipuleucel-T. A third study, undertaken after the first two and published in the New England Journal of Medicine, deliberately chose overall survival as the main outcome measure (presumably since using the time to progression hadn't shown that the $100,000 therapy offered an advantage). Consistent with its predecessors, this study also found survival was better with sipuleucel-T (25.8 months versus 21.7 months), although again, median time to progression was identical in both groups (14.6 weeks versus 14.4 weeks). Biologically, this result was puzzling: as an accompanying editorial commented, it is hard to understand how sipuleucel-T could prolong life without having any measurable effect on tumor growth.

Why do men with castration- refractory metastatic prostate cancer live longer with sipuleucel-T than with placebo? It's not clear. But one curious observation is that once the tumor progressed-which it did in 90% of people during the course of the study-physicians were free to treat patients with other anti-cancer regimens such as conventional chemotherapy, and more of the patients who had gotten sipuleucel-T opted for such treatment. It's possible that it was in fact the chemotherapy that contributed to the survival advantage in this group of otherwise healthy older men, although the mathematical models generated by the authors to adjust for differences in treatment after relapse dispute this interpretation.

It seems that the latest and greatest treatment for prostate cancer may not be so wonderful after all. And if it is approved by Medicare, it will almost certainly be used "off label," that is for other patients with castration-resistant prostate cancer, including those on narcotics for bone pain and with lung or liver metastases, patients who were excluded from the original studies. Physicians are legally allowed to use an approved treatment modality in any circumstance they think it might be effective. If Medicare approves immunotherapy without restrictions, the treatment is likely to be applied to thousands of men who are far older, sicker, and more impaired than the men in whom the treatment was tested. Whether these men will benefit at all is unknown-there are simply no studies that address that question. But if sipuleucel-T is of uncertain benefit in the healthiest men, it is even less likely to help those who have multiple other medical problems. Treating 1000 men with immunotherapy will cost Medicare $100 million. But what if it's 10,000 men? Do we really want to spend a billion dollars on a treatment that, at best, might extend life a few months and, at worst, will have no benefit at all but may cause fevers, chills, and tremors?

Politicians have finally recognized that we need to curb the rate of rise of expenditures in the Medicare program. The only sensible way to achieve this end is to require Medicare to function within a budget. And if we don't want to do this by simply limiting the amount of money that Medicare pays out to private insurance companies in the form of vouchers-an approach that will have no effect on the rate of rise of medical expenditures and will merely shift the cost from the federal government to the consumer-we will need to finally insist that Medicare make coverage decisions responsibly, taking cost into account. Medicare is constrained by law to cover treatments that are "reasonable and necessary." Surely it is not reasonable to approve a treatment that costs $100,000 unless it has clearly been shown to work. If the therapy is effective in some patients, its use should be restricted to the types of patients in whom it has proved useful. Finally, Medicare should be able to set the price it is willing to pay for such treatment based on its cost-effectiveness compared to alternative treatments. That's not government intrusion into the practice of medicine; it's common sense.