"... a velocity of PSA decline >11 ng/mL per month (HR 2.124 ...), and a time to PSA nadir ≤9 months (HR 0.276 ...) were significantly associated with an increased risk of progression to CRPC."
(They also found mets & a high nadir to be risk factors.)
Why would a faster fall of PSA to nadir, which most would consider a good response to ADT, accelerate CRPC?
Medicine (Baltimore). 2017 Sep;96(36):e7823. doi: 10.1097/MD.0000000000007823.
Rapidly decreasing level of prostate-specific antigen during initial androgen deprivation therapy is a risk factor for early progression to castration-resistant prostate cancer: A retrospective study.
Ji G1, Song G, Huang C, He S, Zhou L.
Author information
1
Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center of China, Beijing, China.
Abstract
To build a practical model for predicting the progression to castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT).In all, 185 patients with prostate cancer who had received ADT as the primary therapy at our institution, from 2003 to 2014, were retrospectively enrolled. The following clinical variables were included in the analysis: age, clinical tumor, node, metastasis stage, Gleason score, risk groups of prostate cancer, prostate-specific antigen (PSA) at the initiation of ADT, PSA nadir after ADT, velocity of PSA decline, and the time to PSA nadir. Cox proportional-hazards regression models were calculated to estimate effects of these variables on the time of progression to CRPC.On univariate and multivariate analyses, the presence of distant metastasis before ADT (hazard ratio [HR] 6.030, 95% confidence interval (CI) 3.229-11.263, P = .001), higher PSA nadir (HR 1.185, 95% CI 1.080-1.301, P = .001), a velocity of PSA decline >11 ng/mL per month (HR 2.124, 95% CI 1.195-3.750, P = .001), and a time to PSA nadir ≤9 months (HR 0.276, 95% CI 0.162-0.469, P = .004) were significantly associated with an increased risk of progression to CRPC.Patients with a rapidly decreasing PSA level in the initial phase of ADT are more likely to progress to CRPC. Our findings provide a practical approach to screen patients during ADT for early identification of those likely to progress to CRPC, allowing treatment to be modified to improve outcomes.
PMID: 28885333 DOI: 10.1097/MD.0000000000007823
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pjoshea13
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No doubt this is a disappointing truth. The anticipated action of ADT itself turning to a counterproductive process with misleading results. So in practice what can we really do? Face the inevitable approach of CRPC and move on to the next level of treatment or give up the ADT treatment when the PSA drop is too quick as indicated in this study? Looks like a Hobson's choice!
"A possible explanation for this finding (that a rapid decline in PSA is equated to a poorer outcome) is that rapidly growing tumours are preferentially ablated, but these tumours will regrow equally quickly if not completely destroyed"
My PSA was low at diagnosis (2.7) before I received ADT treatment (eligard). Does that mean that I am in the clear? Gleason 8 with a low PSA and a very palpable tumor was explained as being ominous. Not sure what to think now.
Based on the research, initial PSA is not as important, prognostically, as time to nadir and nadir. A nadir under 1 is encouraging. Some prostate cancers produce little PSA so initial number can be deceiving. Again, just my observation from reading the literature.
I hesitate to write here on my own experiences, largely because I do not want to dishearten anyone. I mostly just lurk nowadays. However, this area of the research resonates with me and I believe these indicators are decent at prediction of aggressiveness. At least it is true in Kevin's case and other men I know. Cancer is unpredictable at best and if it all made sense, we would have better treatments and outcome measures.
What do you think of the following protocol to prevent the development of castrate resistant PCa. When the PSA reaches .5 start Xtandi for 3 months then stop and stay off Xtandi until the PSA reaches .5 and then start Xtandi again. The idea being to keep the cancer cells from developing resistance by alternately providing the PCa with access to Testosterone then blocking access to Testosterone. I ran this by my Onco who stated he was not opposed to this treatment, but could not recommend it, because it was outside the normal protocol, and that I probably could not get the insurance to pay for the Xtandi with being castrate resistant. He also stated that if I wanted to pay $9500 a month out of pocket to go for it. During your research have you found a way to obtain Xtandi for a reasonable out of pocket while still being hormone sensitive. I know some would say just do Lupron for 3 months then get a shot of testosterone..this is less natural and I am aware of a few guys who made their PCa way more aggressive with T shots.
When Kevin was diagnosed with metastatic Pca in April, 2015 I scoured research for months based on his presentation. Initial PSA of 2740, time to nadir less than 6 months, nadir of 12 and this was during Lupron and Docetaxel. GleAson never determined due to widespread bone mets but ONC thought 10. Based on his progression, I felt prognosis was poor. He died 21 months later at the age of 45.
He was thrilled his PSA declined so quickly but I was fearful. I also think aggressive treAtment can accelerate growth of neuroendocrine cells. A catch 22. After he did provenge and started Jevtana he quickly progressed with bone marrow and liver invasion. This is all just my opinion and what I observed in my loved one.
Thanks for your observation & the link. The phenomenon is new to me & probably many others.
Makes no sense to me that the rapid PSA drop was due to cell death. Surviving cells may well have been aggressive, but why would they be more lethal just because many lesser cells died?
If the PSA drop was not accompanied by cell death (or timely death), however, that might possibly accelerate resistance in some of those cells. For instance, if HIF1alpha was induced, cells would be very aggressive. HIF generally appears when tumors outgrow their blood supplies, but HIF can appear even when cells are receiving normal supplies of oxygen.
Kevin's case is such a sad one. Thanks for staying involved.
I think your observation that aggressive treatment can accelerate the growth of neuroendocrine cells is right on and is the reason I will not get Provenge and Chemo...a Doc at the Mayo Clinic also told me they had seen this acceleration in a number of patients..thought Provenge and Chemo negatively affected the immune system.
Gus
It took 15 months for me to reach my nadir. 850 to 0.07.
Great post, I had heard about the time to nadir and how low a nadir was achieved related to overall prognosis.
I had an 840 PSA with GL7(4+3) in 01/15. Started ADT(Lupron/Casodex) and 15 Taxotere chemos thru 2015. I hit what I though was my nadir of 0.2 in 08/16 - so about 16 months. I ticked up to 0.3 for 8 monthly tests, 0.4 for 2 more and then 0.5 for the next 2. I went Vegan for a month and got down to 0.4. Added seafood the next month.
I also added Modified Citrus pectin, Ursolic acid, resveratrol, astaxanthin to the Metformin, Lipitor, Vit D, red Yeast Rice, Saw Palmetto, pomegranate, and Milk Thistle that I was already taking. Still fasting from 9pm to 1pm the next day - sipping on curry/black pepper, garlic veggie broth. I fasted 2 days before each chemo also.
PSA got down to 0.1! Individual results may vary as the ads state, but I'm hopeful as we all are. Oh, I stopped ADT after 30 months so I wouldn't encourage castrate resistance - I know that ADT withdrawal may be associated with a drop in PSA
My husband recently found out that his prostate cancer has returned. He had radiation in 1999. His PSA doubled and the doctor had him start Lupron. We did not get much more information other than his gleason score was 9. They used the cells that the doctor took out when he reamed out the urinary track scar tissue from the radiation for the biopsy last spring. I do not know what nadir is. or what you mean when talking about mets. Can someone explain this to me?
The nadir is the lowest point that the PSA reaches post therapy. The longer it takes and the lower it goes the better.
Longer Time To Nadir (>9 months) identified patients with prolonged Overall Survival in both lower and higher PSA nadir groups. PSA nadir <0.2 ng ml(-1) and prolonged TTN (>9 months) following PADT might be the most important early predictors for longer survival in prostate cancer patients with bone metastasis.
I'm sure you'll understand nadir from Randy's message, & probably mets, but just in case, mets are metastases. Those are plural. One met is a metastasis.
The previous explanations given were good. Metastasis is a tumor, a collection of PCa cells is a tumor. Have your husband discuss with your doctor taking Zytiga with Lupron, longer survival. With other treatments your husband's goal is to go on for more then an additional 10 years.
i always felt the longer it took to drop was added time to survival. The important thing is that lt keeps dropping an hopfully it never nadirs. both psa and T. before you go intermittent. Rocco
I would take the results of this study with a statistical grain of salt. There were 185 men under study, but PSAs at the initiation of ADT ranged from 1.4 to 3187.0. There were 37.3% with distant mets. There were 81.1% considered high risk from the beginning. And, the retrospective numbers were derived from records ranging from 2003 to 2014. In sub-categories of type/risk the times to CRPC also varied considerably.
More discussion details and tables are at this link.
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