WHAT IS EVIDENCE?

From Aristarchus of Samos’ 3^rd century BC geocentric concepts to Copernicus and Galileo to Johannes Kepler’s heliocentrism, science is always in a state of exploration and flux. Whether it is in the Newtonian mechanics of force and gravity to the Quantum mechanics of ethereal entanglements, humans have dared to go further, taking the road less travelled. Today’s scientific world, bowing at the altar of evidence seems forcing itself into an exile of the ossified “what is.” Yet evidence is fluid and ever-changing. Today’s evidence is tomorrow’s discard.

What if we could harness the miseries of cancer by turning on and off genes? Well that has been done. What if we could shut down pathways from the surface of the cancer cell to its innards; the nucleus, and stop it from dividing? Done that too. What if we could suppress the oncogenes that trigger the cancer cell growth? Done that as well. What if we could grow a battalion of tumor suppressor genes within the cell to prevent its doubling and dividing? Well we seem to be there now. And what if we could shut down the cargo proteins from transporting material in and out of the cells to allow them to bloat and die? We might be there as well. You see, don't you, that science progresses on the shoulders of giants in a drip, drip fashion; one idea igniting another thought and then another and then empiricism begins...if one would allow it, that is. (BTW: I have NO Conflict of interest with the Karyopharm Therapeutics). 

A drug called Selinexor (KPT-330) made by Karyopharm Therapeutics seems to fit the bill. It has been used in Multiple Myeloma with significant results in previously heavy-treated patients with Multiple Myeloma and found a 20% Response Rate. That may not appear significant unless one thinks about the previous heavy therapeutic exposure. (STORM Trial Data). Additionally Selinexor has been used in Diffuse Large B-Cell Lymphoma and initial reports are seeing benefits there as well. “To date, Selinexor has been administered to more than 1800 patients across company-sponsored and investigator-sponsored clinical trials. Evidence of single-agent anti-cancer activity has been observed in many patients and Selinexor has been sufficiently well-tolerated to allow several of these patients to remain on therapy for prolonged periods. Over 20 patients have remained on study for over 12 months, with the longest patients on study for over 24 months” (1). In the solid tumor world there are reports of Selinexor having some impact in Sarcomas. (2).

Another mode of action being utilized by the same pharmaceutical agency is to inhibit the cargo protein transit. Two products, PAK4 and NAMPT “causing co-inhibition by catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide, or NAD. NAD is a universal energy- and signal-carrying molecule involved in mitochondrial function, energy metabolism, calcium homeostasis, anti-oxidation, and paradoxically generation of oxidative stress, gene expression, immunological functions, aging, and cell death. leads to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis.”

So harnessing the tumor suppressor elements and blocking the cargo movement shuts down the process of cell division. In biz terms it would be like a block in the supply chain of materials, inventory drops, revenue diminishes and sustainability is questioned.

This brings me back to the premise of using “evidence” as a hard and fast rule in treating patients. Science is continuously evolving due to exploration and discovery. The limits are only those of the limits of thought. Maria Sklodowska better known as Marie Curie who founded the science of Radioactivity, twice a Nobel winner continued to work in refining the knowledge till her last breath. Evidence to her was a snapshot in time of what we know at the moment. The "why" always tinkered with her thought process and pushed her into her intellectual grist mill. So today's well versed bureaucrats constantly serving the "public's best interests" seem to forget what made today's progress and achievements. Limiting progress under the guise of guidelines and templates to achieve uniformity thus limits the art and stifles the science of science and medicine.

The two examples above are how progress flows, never in a straight line but through tortuous paths hitting pay-dirt sometime and sometime just dirt. The idea to illustrate such principles of thought needs historical background and a future unseen but imagined foreground. To limit our knowledge within the pages of books is akin to imprisonment of the soul of discovery. Our thoughts and ideas need to skim the surface of information and thus enter the depth of newer spheres. Perhaps we should consider the innovator, discoverer in all of us physicians and continue to explore venues unseen, unheard and unknown rather than punch time clocks, check boxes and fill our eyes with the glow of the flickering computer screens.

1.     https://myelomaresearchnews.com/2016/05/17/for-ines-karyopharms-selinexor-first-in-human-phase-1-clinical-trial-data-published-in-journal-of-clinical-oncology/

2.     http://www.cancernetwork.com/sarcoma/selinexor-shows-promise-phase-i-sarcoma-trial

TO TREAT or NOT TO TREAT

That is the question...

An argument ensues and the voices get louder. The points of view are bandied about and the loudest voice has the sway. Today the voice with the most promoted resonance is one that deems that “Less is More” and is couched in the premise that doing more, causes “harm.” Harm is defined as potential risks related to interventional therapy, be it surgery, radiation therapy or drug therapy. Citing examples of prostatic infections from biopsies in establishing diagnosis of prostate cancer to emotional stress and in some cases establishing PTSD as a causation of diagnostic and treatment intervention.

What is even more striking is that physicians not wanting to standout against the zeitgeist and be ridiculed are following the piper in lockstep and agreeing with the “Rationing “ concept of healthcare(1).

Allow me to dissect this new frame of reference.

Let us start with a malignancy such as Ductal Carcinoma in Situ (DCIS). Some ivory wall experts believe that DCIS is not even a malignancy. They harp at the 98% survival rate at 10 years for such a diagnosis. But clearly there is more than meets the non-discerning eye.

The difference between the DCIS and invasive cancer is the breach of the basement membrane (a membrane that keeps the contents of the duct within the duct). So a breach indicates that the cancer cell has transmigrated to the tissues outside the duct. But here is a path less travelled in their minds. 

A duct is a convoluted path of continuity (seen in these radiology duct images), not a straight line as represented on the cartoon above and pathology slides are cut in a linear razor sharp format, so the duct can from the pathologist point of view present with multiple views in the specimens but not all. 

Hence where a breach might have happened might not be represented in the pathologist’s slide at all. And no two are the same

Arrows point to cancer outside the duct

On the other hand, sitting out the DCIS for months in a “Less is More” policy the cancer cells continue to, as is their wont, acquire more DNA mutation and ultimately seek the outside the duct environment to flourish. As this article suggests that radiation therapy benefits patients with DCIS versus Observation, further negates the argument of “sitting on one’s hands” (2).

Look no further than  the Prostate Cancer scenario, where a “low risk” defined prostate cancer relegated to the “observation deck or watchful waiting” policy has led to an increased risk of more aggressive prostate cancer diagnoses. Again one shouldn’t be mystified as the experts are and try to rationalize in pretzel fashion the reasoning behind that transgression (4).

Clearly in the legal circles, “delay in diagnosis” is a big money maker for the plaintiffs and their legal eagles. The lawyers dressed up in pin-striped suits and charming ties make pitches to the jury by using terms like “negligence and such” to get a better pay day. And most such large verdicts are clearly in their favor and against the physicians. And yet the ivory walled tower consultants seem uninterested in that aspect of the disproportionately weighted coin (3). For individual cases of such “malpractice” are the domain of the doctor and their insurer not the matters for the policy experts.

What to do?

Clearly, the answer lies in the physician’s personal judgment. Unfortunately the drumbeat in the medical literature by the experts, who use statistical graphics of “waterfalls” and “forest plots” constantly hammering the ear drums holds a sway to some physicians (Nowadays, it appears the majority 53.1%). Bombarded by the constant level of rhetoric from the “Choosing Wisely” crowd and the “Less is More” cost container segment of the experts the mistruths seem to be gaining ground and impacting patient care (1).

Isn't it ironic that causation is definitely implied through correlation in most of the “studies.” Isn't it further sad that the belief in such idiocy continues to gain ground and the vast conspiratorial impact of the probability function of p-value through tortuous mathematical indiscretion has become the mainstay of medical science. Using the p-value one can create any scenario to befit any belief , thought or nuance. There are legions of “P-Hackers” among us (6, 7)!

Pushing the needle further a study suggests that metastatic renal cell cancer should be placed on the observation deck also since many survive longer than anticipated (5). Assuming that DNA mutations are a function of biology and thus can happen anytime as Immune surveillance can be overwhelmed anytime, the logic in this “study” escapes, especially when there are newer therapies available for care of these patients. The thought comes to mind that it is all about costs at this point and time. The administrators and Managers point the finger of fault while they collect handsome bonuses. The average hospital cost devoted to administrative serves was 24.3% in 2015 (8). And that my friends is in the Billions.

The irony of it all in costs and purported care

So what do we do? If you still believe in the coffee enemas, then all hope is lost. Barring that, a self imposed moratorium in instant belief of the “studies” should be the way to go. The ability to understand, the ability to reason, the ability to weigh the consequences and the ability to define the world according to those fundamental principles of reality and not some hogwash pseudo-science.

If we only had a bulletproof mechanism to establish the indolent versus the aggressive, things could be different. But we don’t. Even Genome Assays are a point in time and do not presage further change in the genetic structure. So we remain in the dark and in so doing we stretch the limits of our understanding into policy mistakes that harm our patients in the end.

REFERENCES:

1. http://link.springer.com/article/10.1007/s11606-016-3756-5

2. http://jco.ascopubs.org/content/early/2015/01/20/JCO.2014.57.9029.abstract

3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114209/

4. http://www.northwestern.edu/newscenter/stories/2016/07/metastatic-prostate-cancer-cases-skyrocket.html

5. http://www.ncbi.nlm.nih.gov/pubmed/24752340

6. https://freakonometrics.hypotheses.org/19817

7. http://fivethirtyeight.com/features/science-isnt-broken/#part1

8. http://www.nejm.org/doi/full/10.1056/NEJMsa022033#t=article

CANCER MEDICINE COSTS

Some of the successes have not and may never be shared with patients if the current policies remain in effect. Or to put it in the current metaphorical terms; the spoils of the battles won in the war against cancer may never reach the most vulnerable patients with cancer.

There is a drumbeat of the rising cost of medical care, so much so that experts are twisting their already convoluted selves into pretzels to prove that the cost of care is directly correlated to the over diagnosis, over harm, over use and over reach in caring for the patients by their physicians. One wonders at the wisdom of that. But what is true, reveals itself easily. 

In every article written, an element of cost seems to take center stage. In fact most articles in medicine are not complete unless a paragraph on cost is couched to win over the publication mantle. Most of the blame is hurled at the doorstep of the treating physicians. Thus the rise of mantras such as “Choosing Wisely” and “Less is More.”

Digging through the morass of expense, a few easy to locate, issues are self-evident:
Administrative Costs: CMS alone projects them to be at $361 Billion in 2014 and these are conservative estimates at best. 

Hospital Costs especially the “facility fees” that make cost of care to the patients treble if not quadruple. 

Overuse of Diagnostics estimated by Peter Orzag to run in the $700 Billion range and that includes Defensive medicine, Newer technology use, and excess use for profit.
Pharmaceutical costs…this is the subject we discuss below.

If one were to use $1 as the total cost of healthcare in the United States, estimates suggest the following (based on the CMS Data Dump of 2012-2013:
$0.36 are for hospital costs
$0.15 Administrative costs
$0.26 for Pharmaceutical Costs
$0.07 for Physician care
$0.16 other, including fraud and abuse

The Pharmaceutical costs have been inching or rather “yarding” upwards at a scale not seen before.

A recent research letter termed, “The Rising Price of Cancer Drugs—
A New Old Problem?” in the JAMA Oncology authored by Vinay Prasad, MD, MPH is a fascinating read on the explosive increase in cancer medicines. The first salvo that brought the issue to the public consciousness is when Turing Pharmaceutical company raised the price of pyrimethamine overnight by 5000%.This was followed shortly after by the price increase of the oft used in pediatric/adult allergic response, Epipen by 600%. In fact, Eighty-six cancer drugs reported average sales price in both January 2010 and January 2015. “ The following 11 drugs underwent price increases of 100% or more: carmustine, oral methotrexate, cyclophosphamide injection, oral cyclophosphamide, mitomycin, oral busulfan, leucovorin, vinblastine, oral etoposide, pegaspargase, and oral melphalan." The Authors in the article further state; “For in- stance, although our investigation finds that the price of oral cyclophosphamide increased 300% after adjusting for inflation, absolute Medicare Part B spending on this drug increased from 1 million to 90 million dollars.”

What is most disconcerting is that older drugs have increased dramatically in price even when inflation adjustments are taken into account. This does not bode well for the average citizen who will find with their rising premiums, deductibles and Copays that medical care for their cancer is out of their reach, either by insurer denial or by the cost of the drug itself.

The ills in the recent rise of the pharmaceutical costs can be deciphered fairly easily, if one were to wear a neutral, non partisan hat. How does the Pharmaceutical company advance the costs to such astronomical levels? However one must keep in mind that innovation does come at a price, as long as it is not beyond the reach of the average individual and not dependent on a third party to the exclusion of reasonableness.

Answer: Easy

If there is a policy in the government, which has been strongly bandied about by lobbyists that there be a Non-Compete clause and that free market principles of supply demand and negotiations are not to be considered, then raising prices to any level are borne off the rising premiums for all and the burden on tax payers who cover expenses for Medicare and Medicaid.

Speaking of newer drug costs per year, such as the Biologics; Some are given below:
Perjeta - $126,000 / year
Keytruda - $150,000 / year
Opdivo - $158,000 / year
Ibrance - $142,440 / year

These newer biologics aim for individualized therapy based on available molecular diagnostic criteria (these have their own inherent costs). So the advances in medicine are restricted to most patients given the exorbitant costs of diagnosis and the drug treatment. The costs of the drugs are in most cases arbitrary and capricious. If one remembers the “Provenge” debacle that led to the bankruptcy of the parent company Dendreon because they marketed “Provenge" for Prostate Cancer at $104,000. The problem; drug seemed to give an average of 4 months increase in the Progression Free Survival. Perjeta, however gives us a progressive increase in survival over the 3 year period noted in the CLEOPATRA trial (encircled). ( http://cancerres.aacrjournals.org/content/72/24_Supplement/P5-18-26.short )

Perjeta on the other hand shows an increasing Survival rate (CLEOPATRA Trial) with time as shown below:

With Ibrance for instance, “The median PFS by blinded independent central review was 30.5 months versus 19.3 months, respectively. The objective response rate was 42 percent with the combination versus 35 percent in the control group,” in the PALOMA-2 Trial.

The most encouraging drug remains Keytruda with a 3- year 40% survival rate at present in Malignant Melanoma.

To solve the problem, one has to look at the mechanics that increase it’s complexity. A simpler Free Market in drug pricing where patient needs are aligned with the profits of the company. The so called “Social Responsibility” mantra bandied about by the C suite only satisfies their conscience of “doing good.” The government is not without blame either in allowing this form of wealth recapture from ordinary citizens. The positive regression line points to un-affordability...

Newer drug costs are mostly blamed on the $1.2 - $2 Billion needed to do Research and Development. These are overly inflated numbers by the pharmaceutical companies. The attempt here is to justify the high price point. 

Some blame also lies at the feet of the FDA where ties to the pharmaceutical industry make choices in their self interests to raise or lower the bar for approvals and designations. Dr. Saurabh Jha (@RogueRad) writes eloquently about the revolving door of the FDA and the Pharmaceutical Industry citing Dr. Vinay Prasad (@vinayprasad82) in a recent article, Money and virtue: An odd tension in health care; “In public choice economics there’s a phenomenon known as “regulatory capture.” Briefly, regulators sculpt regulations which benefit certain industries, and industry influences regulators, by promising a lucrative career, to create regulations which give them an advantage. Remember, regulations are a barrier to entry — successful capitalists love regulations, aspiring capitalists hate regulations.” And so it is in the deeper dungeons where policy and people meet, the clink of champagne glasses occurs.

In all, the system is badly broken. if the falcon cannot hear the falconer anymore, the center cannot hold and chaos is about to reign.

SMOKING & CANCER

The unflinching bastion of self destruction, smoking, remains the killer of killers. 7000 chemicals and 70 of those cancer provoking, makes smoking a scourge on humanity.  The information about smoking is well distributed to the general populace but common, stale news is no news in this hyped, always new information gathering world. Yet in face of all that information smokers still continue to live in the, “its all about the present and the past is who cares,” world. They live the mantra of “be in the present” and damn themselves to a continuity of misery for the future.

Statistics:

480,000 Americans succumb to cigarette and tobacco related products each year. That in itself is a travesty until you find out alcohol, car accidents, HIV, guns and illicit drugs combined do not wreck similar havoc on humanity. And to be sure smokers live shorter and unhealthier lives than non-smokers. And you can take that to the bank!

Chemicals associated with burnt tobacco:
Acetone – found in nail polish remover
Acetic Acid – an ingredient in hair dye
Ammonia – a common household cleaner
Arsenic – used in rat poison
Benzene – found in rubber cement
Butane – used in lighter fluid
Cadmium – active component in battery acid
Carbon Monoxide – released in car exhaust fumes
Formaldehyde – embalming fluid
Hexamine – found in barbecue lighter fluid
Lead – used in batteries
Naphthalene – an ingredient in mothballs
Methanol – a main component in rocket fuel
Nicotine – used as insecticide
Tar – material for paving roads
Toluene - used to manufacture paint

As most articles proclaim correctly, “smoking not only causes cancer. It can damage nearly every organ in the body, including the lungs, heart, blood vessels, reproductive organs, mouth, skin, eyes, and bones.”

This means each year smoking causes about 1 out of 5 deaths in the US. 30% of all cancers deaths are tobacco related, must give us pause. This complex tapestry of probabilities from smoking gets rolled up into a single tube conveying bad or worse news. The scale and damage caused by smoking is the single biggest healthcare problem wielded on humanity. In a multibillion dollar industry, the expenses in dealing with this disaster are close proxies for the truth.

Smoking and Cancer:

So, lung cancer is not he only cancer to materialize from a cigarette smoke. Many others fit the bill and include:

Mouth Cancer
Larynx Cancer
Pharynx Cancer
Esophagus Cancer
Kidney Cancer
Cervix Cancer
Bladder Cancer
Pancreas Cancer
Liver Cancer
Stomach Cancer
Colon/rectum Cancer
Myeloid leukemia

With so many cancers linked to cigarette smoke one wonders why and how? A recent article seems to suggest some possibilities in answering just such a question.

A study in Circgenetics; Epigenetic Signatures of Cigarette Smoking caught my eye. The Authors claimed that the epigenetic “footprint” of cigarette smoking became a carrier on the DNA for 30 years or longer. Now let us dissect that issue just a bit. If the “footprint” of the damaging effects on cigarette smoking resides as a methylating influence on the DNA, such influence can be furthered in its impact through other superimposed “nurturing” influences as well over time? In other words “piling on” of genetic influence can be the mitigating etiology of cancers found several years after cessation of cigarette smoking. Or putting it another way, say a person was exposed to a chemical but nothing really happened for a long time and then he/she started smoking, the “piling on” of such epigenetic burden on the DNA may influence mutation of a gene at a critical point to elicit unmitigated cell growth. Another example being Asbestos; a silicate material can slowly damage the lung by causing scarring of the lung lining resulting in Mesothelioma. Now add cigarette smoking to the burden and a higher rate of lung cancer occurs in these unfortunate individuals. The referenced study below describes at least ONE influence on at least 7000 genes. It makes it easier to understand from this, the far-reaching health impact and the various diseases that emanate from the act of smoking; the wide array from cancer to cardiovascular disease such as heart attacks and strokes, from emphysema, to miscarriages and low birth-weight infants and from osteoporosis of the bones to early deaths. The composite of this giant and dark tapestry unfolds a story like no other in the untimely frost that silences a voice.

For those needing to see more scientific methodological proof behind the study:

“To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<0 .0000001.="" font="">

Conclusions—Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
https://www.ncbi.nlm.nih.gov/pubmed/27651444

Oh and speaking about costs, that everyone nowadays is screaming about in healthcare, the CDC states, “Smoking-related illness in the United States costs more than $300 billion each year, including: Nearly $170 billion for direct medical care for adults. More than $156 billion in lost productivity, including $5.6 billion in lost productivity due to secondhand smoke exposure.” Reducing cost of the healthcare burden by 1/3rd on both the private and public sector would be easy if we educated strongly and stopped nurturing victimhood of addiction.

A word to the wise: Please don’t smoke!

REFERENCES:

American Cancer Society. Cancer Prevention & Early Detection Facts & Figures 2015-2016. Atlanta, Ga: American Cancer Society; 2015.

American Heart Association. Smoking & Cardiovascular Disease (Heart Disease). February 17, 2014. Accessed at www.heart.org/HEARTORG/GettingHealthy/QuitSmoking/QuittingResources/Smoking-Cardiovascular-Disease_UCM_305187_Article.jsp#.VjuXViu8SxY on November 5, 2015.

American Lung Association. How Serious is COPD. Accessed at www.lung.org/lung-health-and-diseases/lung-disease-lookup/copd/learn-about-copd/how-serious-is-copd.html on November 5, 2015.

TO WATCH OR TREAT?

That is again the question.

You might have heard this, or not. It was big news and yet it was not. After years of slaying the beast of PSA screening that was conjured up as over treatment and harm, the swallows once again came back to their nests.

If one looks at it objectively and without bias, one finds a disdain for early intervention. But why if it saves lives. And now we have a formal basis to declare that PSA screening followed by surgical intervention saves lives. 

Had they taken the Tyrol regional (Western Austria) study to heart, a place where free healthcare is the norm and everyone gets a PSA screening followed by definitive treatment, the conclusions drawn were: “In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer.”

Now comes data from the latest ProtecT Trial study that accrued 82,429 men aged between 50 to 69 years. 2,664 (3.2 percent) had clinically localized prostate cancer. 1643 were randomized. Cancer specific deaths included 8 in the “watchful waiting” group, 5 in the Surgical intervention arm and 4 in the Radiation therapy arm. Progression of disease was noted as follows:

112 patients in the “watchful waiting” group (or 22.9 events per 1,000 person-years). 46 in the surgery group. 46 in the Radiation group.“All cause mortality” deaths from any cause were equal in all three groups: 59 in the active monitoring group. 55 in the surgery group. 55 in the EBRT group. (The difference in the rates of all-cause mortality was not statistically significant (P = 0.87).

An interesting data from the trial revealed that:

27 men would have needed immediate initial surgery as opposed to initial active monitoring to avoid 1 case of metastatic disease

9 men would have needed immediate initial treatment (with surgery or EBRT) as opposed to active monitoring to avoid 1 case of clinical progression.

The question raised is of consequence to the lives of the many. Was the “watchful waiting” a science driven enterprise of empiricism or a pseudoscientific undertaking of tortured probabilities to prove that “Less is more” resource utility? A question that should haunt the experts at some level.

The Editorial on New England Journal of Medicine by Anthony D’Amico, MD PhD caught my attention. Now that the cat is out of the bag, even now there are statements that trouble the mind; for instance…”Therefore, if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment,3 monitoring should be considered only if he has life-shortening coexisting disease such that his life expectancy is less than the 10-year median follow-up of the current study.” This sentence lends itself to further scrutiny, “if a man wishes to avoid metastatic prostate cancer and the side effects of its treatment, monitoring should be considered…” What does the author/doctor who wrote this think? The patient’s response as, “No sir I do not wish to avoid the dastardly effects of the malignancy and the necessitated treatment of the said metastatic disease?”

A sort of cover is also used here implying the following, “However, the increasing use of surveillance is already of potential concern, considering that men enrolled in PIVOT had a shorter life expectancy owing to coexisting disease than men of similar age entered into the Surveillance, Epidemiology, and End Results database.” In other words using PSA screening in these patients with co-morbidities lends itself to a potential bias in favor for the surgical side. True we need to use the modalities of treatments judiciously and with care to represent in the best interests of the patient.

In the end, however, the author goes on to say, “First, men assigned to active monitoring were significantly more likely to have metastatic disease than those assigned to treatment (P=0.004 for the overall comparison), with an incidence that was more than twice as high (6.3 per 1000 person-years vs. 2.4 to 3.0 per 1000 person-years). There was also a trend toward decreased death from prostate cancer among men assigned to surgery (hazard ratio, 0.63; 95% confidence interval [CI], 0.21 to 1.93) or radiation and androgen-deprivation therapy (hazard ratio, 0.51; 95% CI, 0.15 to 1.69) versus active monitoring.” 

Reasonable people make reasonable assumptions and thus reasoned judgment is called into play. The PSA screening tool is a worthwhile endeavor especially when conjugated with surgical intervention, as the Tyrol data from 2008 shows  and the current ProtecT Trial seems to suggest. Screening and early intervention improves people’s lives. Although Disease specific mortality is lowered the all cause mortality is not. A consideration here might be the age and co-morbid states of the population under study? You might argue about “All cause mortality” and “disease specific mortality” here but anyway you look at it the answer just stares back at you, defiantly.

So is PSA Screening a good thing? Answer: Yes.
Is Definitive surgical intervention in Early Prostate Cancer vs. "watchful waiting" a good thing? Answer: Yes.
Both answers appear accurate to date, unless you have extricated yourself from the predicate of being mortal. In that case, you might assign yourself the throne of a consultant expert and beam down guidelines to the plebeians.

REFERENCES:

1. Treatment or Monitoring for Early Prostate Cancer. Anthony V. D’Amico, M.D., Ph.D
http://www.nejm.org/doi/full/10.1056/NEJMe1610395#t=article

2. http://www.forbes.com/forbes/welcome/?/sites/benjamindavies/2016/09/14/prostate-cancer-screening-trial-shows-psa-screening-works-sort-of/&toURL=http://www.forbes.com/sites/benjamindavies/2016/09/14/prostate-cancer-screening-trial-shows-psa-screening-works-sort-of/&refURL=https://www.google.com/&referrer=https://www.google.com/

3. Bartsch, G et al. Tyrol Prostate Cancer Demonstration Project: early detection, treatment, outcome, incidence and mortality. BJU Int. 2008 Apr;101(7):809-16 http://www.ncbi.nlm.nih.gov/pubmed/18321314