Friday, 8 February 2019

Adding lifestyle changes to medication can deliver a knockout punch

Does screening for prostate cancer with the prostate-specific antigen (PSA) test save lives? A new study suggests that it does, but at the risk of exposing men with slow-growing tumors that may not be life-threatening to treatments they may not really need.

Published in Annals of Internal Medicine, the study reconciles conflicting results from the two largest clinical trials yet looking into whether PSA screening reduces prostate cancer death rates. One of them, the Prostate, Lung, Colorectal and Ovarian (PLCO) clinical trial divided 76,693 American men between the ages of 55 and 74 into two groups. Half the men got a PSA test every year for six years, while the other half — the control group — got their usual medical care, which may or may not have included screening. Results published in 2012 showed that more men from the screening group were diagnosed with prostate cancer after 13 years of follow-up. But prostate cancer death rates in the screening and the control groups were the same, indicating that PSA screening hadn’t saved any lives.

The other clinical trial, called the European Randomized Study of Screening for Prostate Cancer (ERSPC), enrolled 182,160 men, aged 50 to 74, from various European countries. Half of those men were offered PSA screening once every four years; the remaining men in the control group got usual medical care, which might have included screening. Results also published in 2012 showed that after about 11 years of follow-up, 299 men from the screening group had died of prostate cancer, compared to 462 men from the control group. Those data suggested that screening lowers the relative risk of prostate cancer death by 21%.

Researchers have been grappling with these conflicting results ever since, especially because the PLCO trial had a significant shortcoming. As was not the case in the ERSPC trial, large numbers of men in the PLCO control group had at one time or another been given a PSA test. The PLCO researchers should have been comparing prostate cancer death rates among men who had been screened or not screened for the disease. But the PLCO screening and control groups weren’t dissimilar enough in this respect that researchers could detect survival differences between them reliably.
A new approach

To address that problem, the research team combined and then reanalyzed data from both studies using different statistical methods that could limit the contaminating impact of PSA screening on the PLCO controls. And after this statistical adjustment, the researchers discovered that the final results from both trials were comparable: depending on the specific statistical analysis used, PSA screening was associated with a 25% to 32% lower relative risk of dying from prostate cancer.

Researchers have long agreed that the lifesaving benefits from PSA screening are small. The new study doesn’t change that overall perception, though it “does provide more evidence that screening can be beneficial,” said lead author Alex Tsodikov, a professor of biostatistics at the University of Michigan School of Public Health in Ann Arbor.

Still, the benefit should be interpreted in the proper context. Men in the United States have a roughly 3% risk of dying from prostate cancer over their lifetimes.

If PSA screening drops that risk by roughly a third, then the lifetime odds of dying from prostate cancer fall from 3% to just over 2%. Put another way, the new analysis shows that more than 1,000 men would have to be screened with a PSA test — and more than 35 treated — to prevent a single prostate cancer death.

In an accompanying editorial, Andrew Vickers, a biostatistician at the Memorial Sloan Kettering Cancer Center in New York, acknowledged that PSA screening “does good by saving lives, but also causes harms in terms of overdiagnosis and overtreatment.” Therefore, PSA screening should be deployed strategically to maximize benefits.

For instance, screening should be abandoned in men over the age of 70 who aren’t likely to benefit from it, and biopsies should be limited to men who screen positive and are also at high risk for aggressive, life-threatening prostate cancer according to new and emerging types of biomarkers, Vickers proposed. With these and other approaches, he claimed, overdiagnosis might be reduced by up to 70%.

Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of, cautioned that the lifesaving benefits of PSA screening remain uncertain, given underlying differences in how the PLCO and ERSPC studies were conducted.

Though statistical reanalysis can provide some additional clarity, “the new study does little to advance our understanding of the benefits versus harms from screening,” he said. “What we need, and what many investigators are working on, are ways to assign appropriate treatments based on a prostate tumor’s genetic makeup. Only then, in the context of prospective controlled studies, will we be able to place the utility of PSA-based screening in the proper context,” Dr. Garnick said. Osteoarthritis is the form of joint disease that’s often called “wear-and-tear” or “age-related,” although it’s more complicated than that. While it tends to affect older adults, it is not a matter of “wearing out” your joints the way tires on your car wear out over time. Your genes, your weight, and other factors contribute to the development of osteoarthritis. Since genes don’t change quickly across populations, the rise in prevalence of osteoarthritis in recent generations suggests an environmental factor, such as activity, diet, or weight.

Osteoarthritis of the knee will affect at least half of people in their lifetime, and is the main reason more than 700,000 people need knee replacements each year in the US.
The obesity-arthritis connection

To explain the rise in the prevalence of osteoarthritis in recent decades, most experts proposed that it was due to people living longer and the “epidemic of obesity,” since excess weight is a known risk factor for osteoarthritis. Studies have shown not only that the risk of joint disease rises with weight, but also that even modest weight loss can lessen joint symptoms and in some cases allow a person to avoid surgery.

But a remarkable new study suggests there is more to the story.
Challenging a common assumption

Researchers publishing in the Proceedings of the National Academy of Sciences examined skeletons from people who had died and donated their bodies to research. Information regarding presence of knee osteoarthritis, age at death, body mass index (BMI), cause of death, and other data were compared for more than 1,500 people who died between 1905 and 1940 (the “early industrial group”) and more than 800 people who died between 1976 and 2015 (the “post-industrial group”).

A third group of skeletons obtained from archeological sites were also assessed for osteoarthritis of the knee. They came from prehistoric hunter-gatherers living hundreds to thousands of years ago, and early farmers living between 900 and 300 BP. BMI could not be determined for these individuals, but gender could be determined and age was estimated based on features of their skeletons.

The findings were intriguing:

    The prehistoric skeletons and early 1900s cadavers had similar rates of knee osteoarthritis: 6% for the former and 8% for the latter.
    With a prevalence of 16%, the more recent skeletons had at least double the rate of knee osteoarthritis as those living in centuries past.
    Even after accounting for age, BMI, and other relevant information, those in the post-industrial group had more than twice the rate of knee osteoarthritis as those in the early industrial group.

Limitations of this study include BMI estimates at the time of death that might not reflect body weight during most of the person’s life, a study population (bodies donated for medical research or from archeological digs) that might not be representative of the population at large, and lack of accurate information regarding diet, activity, and other important factors. Even so, the findings shake some long-held assumptions and make the rise in osteoarthritis in recent years more mysterious than before.
So what?

These findings call into question assumptions about the reasons osteoarthritis is becoming more common. And they suggest that slowing or reversing the dramatic increase in obesity in recent years may not have as much of an impact on knee osteoarthritis as we’d thought. Finally, if longevity and excess weight do not account for the rising rates of knee osteoarthritis, what does? The list of possibilities is long, and as suggested by the authors of this study includes:

As is so often the case in medical research, this new study raises more questions than it answers. We’ll need a better understanding of why and how osteoarthritis develops before we can prevent it or improve its treatment. There are already many dedicated researchers exploring these important questions.
For most of us, whether to screen for cancer is a no-brainer. Who wouldn’t want a simple test to prevent cancer or identify it at an earlier, more treatable stage? However, as with many things, the screening decision is more complex than it may appear. For example, the test may not be particularly “simple,” such as undergoing screening colonoscopy. For prostate cancer, even after 30-plus years of using a screening blood test called the prostate specific antigen, or PSA, it still isn’t clear how well it prevents prostate cancer deaths. This has led to conflicting and changing recommendations about whether to screen or not. Earlier this year, I commented on revised recommendations from the US Preventive Services Task Force (USPSTF) — a group that advises primary care physician such as myself about a wide range of topics including cancer screening.
A new look at old studies

The PSA test was used for many years without any clear evidence for or against it, and without the USPSTF providing a specific recommendation. This changed in 2009 after the publication of two large trials, one from the US and the other from Europe. Unfortunately, they showed conflicting results — no benefit in the US trial versus a small benefit in the European one. This led the USPSTF to recommend against PSA screening based on the negative results from the US trial, as well as evidence of potential harms of PSA testing from overdiagnosis and treatment of small, benign-appearing cancers unlikely to spread or lead to death. Earlier this year, the USPSTF proposed changing its recommendations to say that health care providers should now discuss the pros and cons of the test with eligible male patients to help them decide whether to have the test or not, using a process called shared decision making.

If all this wasn’t confusing enough, a new study recently re-examined these two (now old) trials and concluded that they really aren’t as different as we thought. The authors of the new study did new analyses showing that PSA testing decreased prostate cancer deaths similarly in these trials. So, what’s going on, and will the USPSTF again change its recommendation?

In brief, the new study used original data from these two trials and computer modeling to control for important differences. These differences included lower rates of prostate cancer overall and more control patients getting a PSA test done (who shouldn’t have) in the US trial. The European trial performed PSA screening less frequently but called the test result abnormal at a lower value than the US trial. After accounting for all these differences, the new study reported that men in both trials who underwent screening as recommended had lower rates of death due to prostate cancer.
What now?

Though this new study may explain why these two trial results differed, I don’t expect the USPSTF will change its recommendation. Personally, I have long favored shared decision making with my patients, and think the USPSTF finally got it right. Why? First, despite all the fancy modeling in this study, it sought to examine the benefit of the PSA test under ideal circumstances, rather than what actually took place. Moreover, the benefit of PSA testing seems large in relative terms (20-30%), but is small in absolute terms. I’d have to screen over 1,000 men with the PSA test to prevent one prostate cancer death. Moreover, decades of using the test have also uncovered real harms — many men are being diagnosed and treated for prostate cancers that otherwise never would have been detected or caused harm. Finally, prostate cancer therapies for those with serious disease needing treatment have improved a great deal since these trials were done, lowering the value of earlier detection.

I support calls to move on from the overly simplistic debate of PSA test: yes or no. Rather, it is time to figure out how to better inform all eligible men about the benefits and harms of PSA testing. For those who elect to have the test, we need to do a better job figuring out who needs treatment when prostate cancer is found, and how to make sure we avoid harming those without such disease — harm that can be both psychologic in terms of worry and physical in terms of side effects from treatment.

Plenty of research supports the common-sense notion that a healthy lifestyle can prevent or treat many diseases. A diet high in fruits, veggies, whole grains, and plant protein and low in processed carbs, added sugars, saturated fats; regular physical activity; and emotional well-being are the potent treatments that can prevent the need for or even replace many prescription medications.

Yet lifestyle interventions are still not “mainstreamed” into primary care.
The power of lifestyle changes for diabetes

Here is yet another study supporting intensive lifestyle intervention, this time for diabetes. The study authors seem to downplay their findings, which, frankly, baffled me. I’m happy to enthusiastically report that this study strongly confirms what I’ve often observed over the past 15 years in medicine: the way we live and what we put in our mouths can be way more powerful than many of the pills we’re prescribed.

Basically, the study authors recruited 98 people with type 2 (adult-onset) diabetes who were all pretty similar. They had had diabetes for less than 10 years and their blood sugars were not completely out of control (HbA1c* less than 9%); they were not on insulin; they all had a body mass index between 25 and 40 (that is, they were overweight).

They divided people into two groups for a year. Both groups stayed on their regular medications. The standard care group (34 people) received basic counseling and education in type 2 diabetes, including lifestyle advice by a nurse at the start of the study and again every three months.

The other group (64 people) also received a pretty intensive lifestyle intervention:

    five to six exercise sessions per week, consisting of 30 to 60 minutes of supervised aerobic activity, along with two to three sessions of weight training
    an individualized nutrition plan with dietary counseling, including calorie restriction for the first four months
    a smart watch/step counter and encouragement to be physically active in their leisure time (with a goal of at least 10,000 steps per day).

The lifestyle group did have slightly better overall blood sugar control after a year, but the real kicker was this: 73% of the lifestyle participants were able to decrease the dosage of their diabetes medications, compared to only 26% of the standard care group. And, over half of the lifestyle participants could safely discontinue their medications! As a matter of fact, 44% of the standard care group had to have their medications increased during the study, compared to only 11% in the lifestyle group.

*HbA1C is the abbreviation for hemoglobin A1c, the product formed by the attachment of glucose (blood sugar) to hemoglobin (a protein in red blood cells). A test for HbA1c is a useful measure of blood sugar control over time. An HbA1C level between 4% and 5.6% means that blood sugar has been in a good range over the past few months.
Other improvements in measure of health

In addition, the lifestyle group enjoyed significant improvements in pretty much all their measurements: weight (13.2 lbs. lost, compared to 4.4 lbs.), BMI (31 to 29, compared to 32.5 to 32), and abdominal fat (2 lbs. lost, as compared to 0.2 lbs.), with a gain in lean body mass (i.e. muscle). Over a third of the lifestyle group lost over 10% of their body weight, compared with 3% of the standard care group. And the lifestyle folks also experienced a significant improvement in their physical fitness, as measured by a fancy machine measuring oxygen uptake by the body during intense exercise.

The study authors seemed to emphasize that lifestyle improved blood sugar only modestly better than standard care at 12 months. What was incredibly striking, though, was the trend in the blood sugars over the entire year. At six months, the lifestyle group’s HbA1c levels decreased very significantly, from 6.6% to 6.2%, while the standard care group’s HbA1c increased from 6.7% to 6.9%. At 12 months, both groups drifted closer to where they had started, with the lifestyle group still a bit better than the standard care group at 6.3% as compared to 6.6%.
Why is this?

There are two possible reasons. One was that the lifestyle group had fully supervised exercise and dietary counseling sessions (including calorie restriction) for only the first four months, and after that, supervision was progressively decreased, and as a result people were less likely to stick with the program. In fact, the article shows that participation in the exercise and dietary counseling sessions dropped off over the year.

Another factor is that the participants’ diabetes medication was being adjusted throughout the study for health and safety reasons. If the HbA1c dropped below 6.5%, then their medication was decreased, and if it stayed that low or went lower, the medication was discontinued. Likewise, if the HbA1c went above 7.5%, then the medication was increased. The lifestyle group did have more episodes of low blood sugar than the standard care side, and while that can be dangerous, it also signals that the lifestyle participants needed less medication as time went on. Many studies over several years have shown the relative safety of the flu vaccine in pregnancy. Although studies involving women in the first trimester of pregnancy are limited, those studies that did include women vaccinated in the first trimester of pregnancy did not show an association with miscarriage.

In a recent study, the data suggest an association between getting a flu shot and having a miscarriage within 28 days of the vaccine, especially in those women who were also vaccinated against the H1N1 strain in the prior year.

These results are surprising. One potential explanation is the specific inflammatory response triggered by the H1N1 vaccine, with a repeat vaccination causing an even more significant response to occur. As noted by the authors of a commentary published with the original article, “One important takeaway message from this study is that seasonal vaccine formulations are not all the same.”

Expert panels including the American Congress of Obstetricians and Gynecologists have not changed their opinion based on these study results, noting that the study included only a small number of women, and those results are not outweighed by the significant amount of existing data supporting flu vaccine safety. The current guidelines that the flu vaccine is strongly recommended in pregnancy, and is safe to be given in any trimester, remain unchanged.

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