That's the title of a piece in today's NY Times [1].
It must be a dozen years since someone told me that the men who have better survival are those with good albumin levels. Those with <4.0 don't do well.
Since diagnosis, I use a lot of polyphenols, which inhibit NFkB. NFkB is chronically activated in PCa & triggers the production of the inflammatory metabolites of arachidonic acid. My albumin rose from 3.9 at diagnosis, to 4.5.
Maybe 5 years ago, I read about the modified Glasgow score. It's a childishly simple algorithm, using C-reactive protein & albumin to spot hospital patients likely to have serious problems after a procedure. It's very effective.
Turns out that subclinical inflammation is a killer. Even 5-year survival in healthy individuals is lowered by subclinical inflammation.
A 2001 study: "Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering." [2] had me wondering how much survival benefit depended on control of inflammation, rather than cholesterol control. After all, as the Times article mentions: "About half of people who have heart attacks have normal cholesterol levels ..."
"The drug that was studied, canakinumab, is already marketed under the brand name Ilaris, but was approved to treat a type of juvenile rheumatoid arthritis and other rare disorders, not heart disease. It costs about $200,000 a year and is made by Novartis, which paid for the new study."
Canakinumab, "a drug that fights inflammation, can reduce the risk of heart attacks and strokes, and possibly lung cancer, in people who have already had one heart attack and are at high risk for another, a new study finds."
Well, I'm not going to get excited about a $2000,000 anti-inflammatory.
"Unlike statins, it has no effect on cholesterol. Instead, it reduces inflammation — the response by the immune system to injury or infection — which researchers have long suspected of playing a role in cardiovascular disease and cancer."
Unfortunately, it "suppresses part of the immune system".
From an editorial in the NEJM [3]:
"For more than 20 years, our understanding of the biology of atherosclerosis has incorporated the so-called inflammatory hypothesis. Inflammatory cells and signals drive the healing response to vascular injury, allowing the initiation and growth of atherosclerotic plaque. Inflammatory reactions probably increase plaque instability, possibly resulting in plaque rupture, fissuring, or erosion and setting up the substrate for the thrombotic response that causes myocardial damage or infarction. Yet, no strictly antiinflammatory drugs are used to treat patients with coronary artery disease. Effective cardiovascular drugs with antiinflammatory effects, such as aspirin and statins, predominantly exert therapeutic benefits by means of mechanisms other than inflammation. Intriguing results from JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) showed that, among patients with an elevated level of high-sensitivity C-reactive protein, a nonspecific inflammatory marker, a statin resulted in a lower risk of cardiovascular events than placebo.3 However, because the level of low-density lipoprotein (LDL) cholesterol was also lowered from baseline in statin-treated patients, it was impossible to conclude that altering the inflammatory state was responsible for the clinical benefit."
"Canakinumab {is} a human monoclonal antibody against interleukin-1β ... The inhibition of interleukin-1β lessens inflammation by down-regulating a variety of markers involved in autoimmunity. Canakinumab has been or is being evaluated in several conditions in which autoimmunity and inflammation play key mechanistic roles."
"As compared with placebo, canakinumab reduced the high-sensitivity C-reactive protein level from baseline in a dose-dependent fashion by 3 months and sustained it throughout the dosing period, with no reduction in the LDL cholesterol level."
"the modest overall effect was completely driven by a lower incidence of myocardial infarction"
"The investigators noted an intriguingly lower risk of cancer mortality with canakinumab than with placebo"
However, there were "significantly more deaths from infection".
The study in NEJM is: "Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease" [4].
Back to the Times:
"“This is the first evidence we have that if you inhibit this inflammatory process without changing cholesterol at all, you’re getting a risk reduction,” said Dr. Paul M. Ridker, the first author of the study and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston." {Doh!}
The Lancet published the cancer findings [5]:
"Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 ...)"
"Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality."
However, "Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group."
Dr. Charles M. Rudin, the chief of thoracic oncology at Memorial Sloan Kettering Cancer Center in New York [1]:
"... the finding is pretty impressive, and the biology makes sense,” Dr. Rudin said. “We know inflammation is a driver of lung cancer progression.”"
This isn't really about canakinumab, or inhibition of interleukin-1β (which seems like a bad idea), but about the concept of tackling inflammation to improve survival.
When I have posted on inflammation in the past, I have though that maybe the message wouldn't get through. Would a man with extensive mets believe that lowering inflammation could buy a lot more time? It could be a lot more time than Taxotere, IMO.
Lung cancer is much faster than PCa & kills ~70%. Deaths were reduced by 77% in the study period. Maybe the cancer was merely slowed? But that's the point - inflammation speeds up proliferation.
See:
"Inflammation. [1] Neutrophil-to-Lymphocyte Ratio [NLR]"
"Inflammation. [2] Albumin & C-Reactive Protein [CRP]"
"Inflammation. [3] SedRate, Fibrinogen, IL-6, TNFalpha."
"Inflammation. [4] How to Change the Numbers"
-Patrick
[1] nytimes.com/2017/08/27/scie...
[2] ncbi.nlm.nih.gov/pubmed/111...
[3] nejm.org/doi/full/10.1056/N...
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