Prostate Cancer: Confusion Reigns

In reading some of the recent reports on PCa decisions regarding “watchful waiting” and surgery, as well as the benefit of PSA, one seems to get confused. Let me examine just three recent papers:

1. The recent NEJM Scandinavia studies conclude[1]:

Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk. A large proportion of long-term survivors in the watchful-waiting group have not required any palliative treatment.

This is a clear statement of substantial efficacy. Survival is key and this Trial demonstrates it.

2. In a recent JAMA article the author’s state[2]:

Available evidence favors clinician discussion of the pros and cons of PSA screening with average-risk men aged 55 to 69 years. Only men who express a definite preference for screening should have PSA testing. Other strategies to mitigate the potential harms of screening include considering biennial screening, a higher PSA threshold for biopsy, and conservative therapy for men receiving a new diagnosis of prostate cancer….

They continue:

Before 2009, conflicting observational data and 2 small trials could not resolve this controversy.7- 9 Two large randomized trials published in 2009 that were expected to provide definitive conclusions yielded conflicting results. Therefore, the benefits and harms of prostate cancer screening continue to be debated….Recent interest in more patient-centered care emphasizes the importance of informing men about risks and benefits of PSA screening. However, recent clinical practice guidelines provided conflicting results..

The Trials referred to are the European and American Trials I have analyzed before on several occasions. Both, in my opinion and based upon my analysis, are flawed. The European Trial measured PSA much too infrequently thus leading to high mortality and both used a threshold of 4.0 with no attention to velocity, age, family history, or percent free. That is both Trials used a 1992 standards through a 2009 period. The standard had dramatically changed and it was never reflected in the Trial data.

3. In an earlier NEJM articles the authors conclude[3]:

During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death….Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points.

This was a Veteran’s Department study. As such one must consider, in my opinion, how they function as compared to a more conventional medical establishment. The statements above do appear conflicting. On the one hand mortality was 5.8% versus 8.4% in the two groups, favoring prostatectomy. However the conclusions state that there is no difference in mortality.

How does a physician and patient interpret this data? The U.S. Government conducted Trial in my opinion is problematic at best. The JAMA result is one where we have on the one hand and on the other. The Scandinavian study seems clear cut. Yet confusion still reigns.

This is why any study of comparative clinical effectiveness is of dubious merit. The data is not available and the Trials are oftentimes contradictory.

References

1.     Bill-Axelson, A., et al, Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer, NEJM, March 6, 2014.

2.     Hayes, J., M. Barry, Screening for Prostate Cancer With the Prostate-Specific Antigen Test, JAMA. 2014; 311(11):1143-1149.

3.     Wilt, T., et al, Radical Prostatectomy versus Observation for Localized Prostate Cancer, NEJM, July 25, 2012.

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[1] http://www.nejm.org/doi/full/10.1056/NEJMoa1311593

[2] http://jama.jamanetwork.com/article.aspx?articleid=1841972

[3] http://www.nejm.org/doi/full/10.1056/NEJMoa1113162

Genome Size

There is a piece in Nature which has some interest. It is the determination of the genome size of the pine tree, Loblolly. This is a pine which may make it as far north as where I am in New Jersey. It is a bit strange in that it grow branches only on the side where there is strong sunlight.

Nature states:

A species of pine tree native to the southeastern United States has a genome with 23 billion base pairs, more than 7 times the length of the human genome....Another team, made up of many of the same researchers and led by Jill Wegrzyn at the University of Connecticut in Storrs, characterized around 50,000 of the genes and estimated that 82% of the loblolly genome is made from repetitive elements. This work, the first pine genome assembled so far, provides a foundation to study the biology of conifers, the authors say.

As a question to pose: How would a plot of gene length versus lifetime of species appear? Namely would say a Ginkgo have lots or excess base pairs or what? Just a thought.

Yield Curve March 2014

 The above is a comparison of the Yield curves for the past few years. The current yield curve as of yesterday reflects a reasonable trend with no significant or drastic rise. The FED action seems to be moderate even though they are backing off.

The above demonstrates the two key measures and the spread. The spread has remained constant for a while which shows stable expectations. We again show this below:

It is a reasonable and stable spread. In a sense this may be a return to some slow normalcy.

Too Much Information

In a recent JAMA paper on whole genome sequencing the authors examine 12 patients in detail and the results were mixed. One patient had BRCA mutation which was beneficial. The others were a mixed bag.

As the authors conclude:  

In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

The problem is several fold. First there are many know genes with uncertain effects. Second there are many unknown genes with totally uncertain effects. Yes the genome has been mapped for over a decade but the unknow genes are "known" but their effects are uncertain. Third there are many epigenetic effects which are uncertain. Fourth many cancers are the result of subtle in lesion changes not reflective of a large scale sample.

The authors continue:  

As technical barriers to human DNA sequencing decrease and the cost of whole-genome sequencing (WGS) approaches $1000, WGS and protein-coding genome sequencing (whole-exome sequencing [WES]) are increasingly used in clinical medicine. Both WGS/WES can successfully aid clinical diagnosis, reveal the genetic basis of rare familial diseases, and explicate novel disease biology^. Regardless of context, even in apparently healthy individuals, WGS/WES are expected to uncover genetic findings of potential clinical importance. However, comprehensive clinical interpretation and reporting of clinically significant findings are seldom performed. As WGS/WES are applied more broadly, questions have been raised about the duty for discovery, interpretation, and reporting of clinical findings. Recently published recommendations define genetic variant types in a minimum list of inherited disease genes that are suggested to be subject to discovery, reporting, and clinical follow-up regardless of the primary indication for sequencing, patient preference, or patient age. Despite this, the technical sensitivity and reproducibility of clinical genetic findings using WGS and the clinical opportunities and costs associated with discovery and reporting of these and other clinical findings in WGS data remain undefined.

 The problems that can be seen is that many patients may demand the tests or physicians can see a way to "sell" the tests and the result will be an added load on the already burdened Health Care system to deal with what is at best conjecture. One wonders how this fits into the ACA?

Le Moyen Age

There is a wonderful piece in Nature this week on the work of Grosseteste. It discusses his work on Light and the Universe. The authors conclude that his efforts were hardly those of some monk in the Dark Ages. Indeed, I have argued that before, and even more so, there were efforts during the true Dark Ages from 600-1000 AD. But Grosseteste worked during the 13th Century, a truly remarkable time.

The authors state:

 De Luce (On Light), written in 1225 in Latin and dense with mathematical thinking, explores the nature of matter and the cosmos. Four centuries before Isaac Newton proposed gravity and seven centuries before the Big Bang theory, Grosseteste describes the birth of the Universe in an explosion and the crystallization of matter to form stars and planets in a set of nested spheres around Earth.

They conclude:

 Because projects such as ours can be of significant scientific and cultural value, scientific granting agencies should consider funding arts and sciences projects or partnering with arts and humanities councils to translate other early scientific works, for example. The eight-century journey from Grosseteste's cosmological ideas to our own offers a rich illustration of the slow evolution in our understanding, and of the delight to be found in reaching out into nature with our imagination.

However there were two stumbling blocks they faced. he first was  the lack of the mathematical tools. No calculus and they still stumbled even with Algebra. Second, was the lack of tools to measure, and even more so agreed upon measurements. Time was difficult, distance the same, and thus velocity problematic. Yet substantial insight and progress was made.

Incidentalomas

Incidentalomas are things a physician may find during the normal course of an exam, such as an imaging study, which may or may not be of any significance, but most likely may be followed up on. For example if a woman over 60 complains to her physician about a bloated feeling in the abdomen and then is sent for a CAT scan and the image of the ovaries is uncertain, then significant follow up is ordered even though it looks like an old cyst. She may just be eating the wrong thing but now we have a mass set of tests and specialists involved.

Now consider the same thing but apply it to a genetic testing. A patient is worried about breast cancer and BRCA gene is tested and appears to be abnormal. What next. Well we know the stats and the patient is so informed. But what if it is some other gene? Some gene where we do not really know that well, say a 5% or even 20% increase in risk. Then what. Make it even more complex. Assume we have all normal genes but that key genes are methylated in their promoter regions. Have we tests for that as well? The gene may be there but can never be expressed. Furthermore perhaps we must look at genes which are organ specific. The list goes on.

In the recent NEJM there is an excellent piece on this issue. They state:  

The problem with the genomic–radiologic analogy is more than a matter of semantics. The comparison may give nonexperts a false impression of our ability to efficiently interpret genetic or genomic findings and to understand how they might affect a person's health. It perpetuates a myth about the level of our current understanding of the genome and of individual genetic variants — the notion that we can interpret all the information from genomic sequencing as quickly and accurately as we can interpret an x-ray. This myth can affect the public, patients, research participants, and clinicians who lack training or experience in genetics or genomics. And the myth will become more problematic as genomic sequencing becomes faster, cheaper, and more widespread. Despite impressive ongoing efforts that will continue to yield great progress, we are not at the point where interpreting a genomic data set is similar to interpreting a radiologic study.

Indeed, genetic test results are useful in a small body of applications. Furthermore we often do not know what to do if we discover a more complex issue. Thus the true concern as to their current use.

One need look no farther than the multiplicity of tests for Ca. Which one really works. And WHY? Yet to be answered.

PCa Survival

In a recent NEJM paper the authors discuss the use of a prostatectomy versus watchful waiting in prostate cancer patients[1]. The authors note: 

A total of 447 of the 695 men enrolled in the study (64%) had died by the end of 2012. This total included 200 men in the radical-prostatectomy group and 247 men in the watchful-waiting group. The cumulative incidence of death at 18 years was 56.1% in the radical-prostatectomy group and 68.9% in the watchful-waiting group (a difference of 12.7 percentage points; 95% confidence interval [CI], 5.1 to 20.3), corresponding to a relative risk of death in the radical-prostatectomy group of 0.71 (95% CI, 0.59 to 0.86; P<0 .="">

The authors conclude:

A significant absolute reduction in the rate of death from any cause, the rate of death from prostate cancer, and the risk of metastases in the radical-prostatectomy group continued after up to 23.2 years of follow-up (median, 13.4 years), with no evidence that these benefits diminished over time. In analyses according to age and tumor risk, the effects were more pronounced in men younger than 65 years of age and in men with intermediate-risk tumors. However, among men older than 65 years of age who underwent radical prostatectomy, there was a significantly decreased risk of metastases and need for palliative treatment. We observed a substantial difference in the prevalence of disease burden between the study groups.

From SSI data we have the following Figure of percent surviving from 65 onwards[2]. Note that by 87 years of age only 33% of those alive at 65 are still living. This is for all causes.

Now the data from the study can be compared as follows:

1. Death from any cause in prostatectomy group was 56%

2. Death from any cause in the watchful waiting group was 69%

3. Death from any cause in the general population was at 66%.

4. Death from any cause in the combined groups was 68%.

The conclusion is quite interesting. Those having a prostatectomy actually lived longer no matter what than all others. Therefore, the USPTF’s concern of unwarranted prostatectomies is greatly in question. Now SEER data lists 2.6 million with PCa in the US[3]. Making a gross calculation we could state that the 13% difference would result in an excess 338,000 cumulative deaths if we adhere to watchful waiting. That is more than 100 times those lost in 9/11.

One must be concerned that data of this sort will be denied under CER methods so as to reduce costs in the ACA world. Again this is just an observation.

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[1] http://www.nejm.org/doi/full/10.1056/NEJMoa1311593

[2] http://www.ssa.gov/OACT/STATS/table4c6.html

[3] http://seer.cancer.gov/statfacts/html/prost.html

Input Less Output Equals Net Accumulation

A law of nature, if you burn 1800 Kcal per day and consume 2100 Kcal per day, then the excess of 300 Kcal over about 12 days will add one pound. Now today in the NY Times we have another excuse for obesity, antibiotics.

The author writes:

And yet, scientists still could not explain the mystery of antibiotics and weight gain. Nor did they try, really. According to Luis Caetano M. Antunes, a public health researcher at the Oswaldo Cruz Foundation in Brazil, the attitude was, “Who cares how it’s working?” Over the next few decades, while farms kept buying up antibiotics, the medical world largely lost interest in their fattening effects, and moved on. In the last decade, however, scrutiny of antibiotics has increased. Overuse of the drugs has led to the rise of antibiotic-resistant strains of bacteria — salmonella in factory farms and staph infections in hospitals. Researchers have also begun to suspect that it may shed light on the obesity epidemic.

 Now it is not only genes, advertising, it is also antibiotics. It may just as likely be global warming, climate change, or whatever the latest fad is. What it is, simply, is eating too many calories and expending too few. That law of nature has not changed. Perhaps the calories per pound of pork has increased, then eat less pork. 

All one has to do is go into any American restaurant. Large plates, immense portions of high calorie food and great numbers of obese people consuming the plates, one after another. Any one of the many chain restaurants serve massive platters of excess calories and the patrons consume the food with glee. There is no price, yet, for many of them, and their obesity. Yet as it continues to grow the costs will explode. 

There is no benefit to "discovering" new reasons why these people are fat. They eat too much. The whole business of blaming some exogenous factors when the fault lies within is a major failing of our society. For every 0.1 that a person is over a BMI of 25.0, there should be a tax of say $500. That ought to stem some of the tide. Sort of a new idea on income redistribution. Think about it.

Economists and Insight

There seems to be a sudden interest in the automation of the manufacturing processes as well as in many other parts of our economy. What is quite surprising is the sudden discovery of this process, especially by academics, and moreover especially by economists.

So much of classic microeconomics is predicated on the assumption of massive capital investments and long capital lives of such investment. In the past thirty years we have seen shortened lives of capital plant and in some cases the elimination of such means of production totally. Vertical integration has migrated to globalization, in the extreme.

Now in a recent piece by a Berkeley Economist on the left there appears to be a sudden discovery of automation[1]. The author states:

In their compelling new book The Second Machine Age, Erik Brynjolfsson and Andrew McAfee document the progress in artificial intelligence that is enabling computers to exceed what they were capable of only a few years ago. The leaps in machine intelligence, along with the connection of human beings around the world in a common digital network, will enable the development of new technologies, goods and services. The authors are optimistic about the “bounty” or economy-wide benefits of brilliant machines. But they warn that the distribution or “spread” of these benefits will be uneven. Their fears are justified. During the last three decades, even before breakthroughs in artificial intelligence, computers have been replacing and multiplying the physical labor of human beings. Improvements in computer and communications technologies have also enabled employers to offshore many routine tasks that machines cannot directly replace.

Now, as I have noted several times in this line of discussion, it was Norbert Wiener in the late 1940s who first called out the changes to our economy by the use of intelligent machines in his many writings on Cybernetics. In fact, as the father of what we know see as “automated everything”, he raised the concern as to what this would do to our economy. Thus almost seventy years ago we knew what was happening and it was not just artificial intelligence.

The above sudden insight to artificial intelligence has itself been slowly evolving for almost the same period initiated also by Wiener’s colleagues and co-workers. Wiener had in the 40s a keen insight into the obvious which was totally missed by all economists for decades, and they seem now to want the praise for discovering it some seventy years after it was first well-articulated.

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[1] http://www.project-syndicate.org/commentary/laura-tyson-considers-appropriate-policy-responses-to-the-next-wave-of-automation

CCE and the Road to Hell

In a recent law proposed in Congress the intent is to eliminate liability if the physician follows a standard method of care[1]. Thus there is a “Safe Harbor” established. The article states:

Physicians who are Medicare and Medicaid providers would be granted increased liability protection if they can demonstrate that they followed established clinical guidelines, according to a bill introduced in Congress this week. The Saving Lives, Saving Costs Act, introduced by Reps. Andy Barr (R-KY) and Ami Bera (D-CA), would create a "safe harbor" for physicians who follow best practice guidelines. Physicians also could request that state-level malpractice suits be moved to federal courts.

The concern is that the Safe Harbor is established by following a Comparative Clinical Effectiveness standard established by the Government. The article states:

"Rather than being directed by Washington, the guidelines will be developed by the physician community based on the best available scientific evidence," according to a joint statement by the legislators. "Guidelines should be developed through a transparent process by a knowledgeable, multidisciplinary panel of experts." A physician who is being sued could "argue that he or she adhered to the relevant practice guidelines, which would cause a suspension in the proceedings while an independent medical review panel investigates." If the panel determines that the physician conformed to the guidelines, or that failure to conform was neither the cause nor the proximate cause of the alleged injury, the case would be dismissed pending clear and convincing evidence that the medical review panel was in error, the statement said.

Now this has certain concerns. Specifically those relating to CCE Standards. The problem with them are:

1. They are not patient specific. They are patient general and the fact of the matter is patients are all different. Thus by following the “Standard” it may actually cause harm to the patient.

2. The development of a consensus for Standards is a timely process. It also is one that all too often reaches a least common denominator. It also, if one see the results of the ACA, may be driven by both non-physicians and worse, physicians having no expertise in the area of the “Standard”. One need look no further than the USPTF and the Prostate Cancer debate as well as the proposed standards emanating from PCORI, where “patients” get to opine on what is correct.

3. Standards when delivered often are reached after extensive developments may have occurred in the treatment and studies. Thus Standards reflect a substantial time lag in the process. The adherence to “old” practices again may result in poorer levels of care.

4. Standards are also now used to manage the physician. The physician, if in fear of a law suit, will be forced to adhere to the Standard and thus not use their own judgment and patient specific information.

5. Standards can be used to penalize the physician as well as set limits on care. It can in a way be a back door way of rationing health care. Standards developed by Government bodies of political appointees are clearly a mechanism under the current Administration to delimit care and reduce costs.

Thus this Bill, with possibly some good intentions, will reduce the level of health care. One must remember that the road to Hell is lined with such “good intentions”.

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[1] http://www.medscape.com/viewarticle/821588?nlid=50786_2701&src=wnl_edit_dail

Russia and Ukraine

First, for all of those who have never been East of the Hamptons, it is NOT The France, The Germany, The Poland, and not The Ukraine. It is Argentina and The Argentine. But not The Ukraine. It is The United States but not The Canada.

Now on to Russia and Ukraine. Having been in both spots, and not being a George Kennan, only having companies and business partners, Russia does not like instability on its borders. I recall once meeting with a banker from London and one of my "associates" in Moscow when we discussed building a fiber across Belarus. The banker asked what about the political instability in Belarus. My Russian associate slammed his fist down and said he will send in tanks. The banker was a bit concerned as how best to fit that assurance into his due diligence report. But in nutshell that is the Russian way.

I also recall a meeting I had with Deutsche Telecom in Moscow. It was an endless ride from my hotel to the outskirts. I went to the executive conference room and it had a beautiful view of some monument below. When the head of the office came in I was fooling enough to ask what the monument was. It was  German tank, it was as far as the Germans had gotten to Moscow. They DT office was allowed to get across the street but no closer. Russians have a long memory, whether it is Napoleon or Hitler. They want a buffer.

Thus an unstable Ukraine is a concern. It all depends on how one vies the current instability. Is it to get a better Ukraine or a Western organized coup. I do not suspect the latter but given recent releases from Snowdon one could guess from the past this could be their view. Thus Ukraine must remain a buffer.

So what should the West do? Good question. It depends on how far Putin will push. One could imagine that he wants to recover Haigia Sophia in Constantinople, I mean Istanbul. That could make him a Saint Vladimir in the eyes of many. It would also resolve the straits passage problem. It would also remind us of 1914.

Over 100,000 Visits!

Just noticed that we have had over 100,000 visitors over the past five years. Thanks for dropping by to the idiosyncratic web site, a collection of various insights and commentary.