ADT & " cycling of the coagulation cascade"

[pjoshea13]

The SWOG 9346 [A9346] trial sought to compare subsequent "health events" in men receiving Goserelin (Zoladex) + Bicalutamide (Casodex) continuously (ADT) versus intermittently (IADT).

"... induction therapy ... for 7 months. If the PSA level declined to <4.0 ng/mL, patients were randomized to either continuous or intermittent ADT."

They identified a subgroup (636) of men who had no other insurance than Medicare, & somehow obtained Medicare claim information.

It might not surprise some that 24% of the ADT arm suffered "ischemic and thrombotic events" during the 10 year follow-up, but it will stun many that 33% of the IADT arm had similar events. IADT is supposed to improve quality of life over ADT - not compromise it.

The study was published in January [1]

The latest Urology Times issue contains more info & a possible explanation [2]:

Cycling of coag. cascade may increase risk.

“One might ask, why would ischemic-thrombotic events be lower for patients on continuous ADT? We know there is an increased risk of diabetes and certain cardiovascular diseases with any exposure to ADT. Consulting with my hematology colleagues, they pointed out that the cycling of the coagulation cascade may increase risk, as it does for women on hormone replacement therapy or on birth control pills. The risk is highest in the first 6 months, after initiation of ADT. So, it may increase with each initiation of treatment,” Dr. Hershman said."

In other words, the transition to ADT creates a spike in clotting risk, & IADT has multiple transitions - therefore more cumulative risk.

{The 5-year experience of ischemic and thrombotic events was 14% for ADT, but 25% for IADT. For ischemic events alone: 5-years = 4% & 9%; 10-years = 7% & 12% - for ADT & IADT, respectively.}

The take-home message that professionals are coming away with is that IADT is unsafe. My feeling is that more should be done to control coagulation.

My GP told me that there are no prophylactic drugs to reduce clotting risk. Warfarin is prescribed only after an event - assuming one survives the event. Two such events & one becomes a warfarin lifer. Under these circumstances, warfarin is considered to be the lesser of two evils - it is a dangerous drug & people die because of it.

I have posted about the need to monitor coagulation factors, & the possibility of controlling them via nattokinase & anti-inflammatories. This study is a wake-up call. The percentages are too high, & continuous ADT is not the answer. In the absence of risk-reduction drugs, one must take control.

-Patrick

[1] oncology.jamanetwork.com/ar...

[2] urologytimes.modernmedicine...

[WinnipesaukeeBob]

The naturopathic approach to lessening and breaking up blood clots is nattokinase, 100mg per day. It also breaks up mucus in the lungs to help antibiotics fight lung infections, and to lessen inflamation.

I have used nattokinase for fifteen years with no noticeable side effects. My heart function and blood pressure have been excellent through four years of ADT and several bouts of radiation.

[pjoshea13 in reply to WinnipesaukeeBob]

I find that I need a higher dose. I believe that one should monitor D-dimer. LabCorp has a ref. range of zero to 0.49 ug FEU/mL, but the lowest number they report is "<0.20". I would be concerned if my number was higher. It might mean that I should increase the dose to keep ahead of clotting activity.

I also monitor fibrinogen - the precursor to fibrin, which forms the clot. LabCorp range is 193-507 mg/dL. (507 is way too high IMO.) My last reading was 184, so I eased up on the dose.

I have known men on the standard bottle dose run into clotting issues. Given the way that cancer interferes with coagulation factors, it would be unreasonable to expect the normal dose to be sufficient for PCa cases.

Here's a study from June on the effect of a single dose (2,000 FU NK) on healthy youg men [1]:

"Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/261...

[luee]

hi Patrick,

the 24% for ADT and the 30% for IADT are certainly alarming for ischemic and thrombotic heart events for those 2 groups of men.

i wonder what is that percentage for men in the general population, who are cancer free but still suffer the heart events.

michael

[pjoshea13 in reply to luee]

Hi Michael,

Yes, certainly, such events would not be rare in a PCa-free Medicare-eligible population during a 10-year follow-up. The men would be at least 75 by the end of the study.

However, it is generally accepted that men with PCa have a greater risk of such events, even if not on ADT, & that ADT increases the risk.

In a Swedish-UK study from Oct. [1]:

"TED {thromboembolic disease} risk was assessed for 42,263 PCa men on ADT compared to a matched, PCa-free cohort of 190,930 men."

"GnRH agonist users {+67%} and surgically castrated men {+61%} were at increased TED risk versus the comparison cohort"

"Men on AA {anti-androgen} monotherapy were at decreased risk" - half the risk. Why?

"TED risk was highest among those who switched from AA to GnRH agonists, {pulmonary embolism risk factor = 2.55}. This increased from 2.52 ... in year one, to 4.05 ... in year two."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/264...

[BigRich]

"Men on AA {anti-androgen} monotherapy were at decreased risk" - half the risk. Why?

Based on my prior readings, I have believed that for fifteen years, but I still don,t know why!