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Treatment for PSA-Negative (low PSA relative to tumor volume) Prostate Cancer

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Posted 7/19/2009 2:51 PM (GMT 0)
I'm trying to figure out what to do about my unusual PC case. Washington DC area urologist/oncologists admit they are "over their heads".

I was diagnosed 4 months ago when PSA rose to 2.3 ng from 1.3 ng over 15 months (free PSA was 26%). Biopsy showed 7/15 cores with cancer (5 cores contained 40% to 80%); all Gleason 3 + 3 =6 with perineural invasion in 4 cores. Pathologist said cell structure of tumor was moderately well differentiated.

Robotic radical surgery at NIH two months ago showed large tumor (30% of 44cc gland). Surgical pathology also showed Gleason 3 + 4 = 7, pT3a with focal extracapsular extension on left and perineural invasion. NED staining was negative. Negative margins (but close in one spot), seminal vesicles clear, 0/10 pelvic lymph nodes with no evidence of disease. Pre-operation MRI of pelvis did identify one marginally enlarged para-aortic, retroperitoneal lymph node; I plan to repeat pelvic MRI this week.

My 6 week PSA was ND (<0.04 ng/dL), but a PAP (prostatic acid phosphatase) blood test taken a few days later measured 0.8 U/L. (Pre-operative PAP = 1.4 U/L.) My urologist says PAP test results may be unreliable since lab does so few of them, but this finding is most frightening. It suggests that my cancer had spread beyond prostate, but it is not producing measurable quantities of PSA. I (probably foolishly) started taking Avodart immediately after my prostatectomy, and just stopped taking it about 10 days ago. NIH now says that adjuvant radiotherapy (30 days) is recommended. That won't help if there are distant mets.

I need some help! Does anybody know something about post-surgery PAP measures. It would seem that this measurement should be ND or close to zero after radical surgery if all the cancer was removed. Also, it seems clear that my cancer is the very rare PSA-negative variety with a very poor prognosis. Standard treatments have not been effective. Can anybody suggest a program or physician that can help me. NIH has been great, but they are treating me as if my disease is "garden variety" adenocarcinoma when a more aggressive approach is necessary.

This week, I have an appointment to see Dr. "Snuffy" Myers, but I want to explore all possibilities. Any information or suggestions?

Dan
Posted 7/19/2009 7:16 PM (GMT 0)

Whom did the original pathology, was he one of the few experts that exist, like:  Bostwick, Oppenheimer, Epstein, Grignon and just a few others?????

Did you know that there are 18 variant types of PCa....not many pathologists are all that good at telling which one you have(let alone the more precise gleasons scores, perinureal invasion etc.), it can make a huge difference if one has 'small cell' PCa verses the typical cases that are found.

In your case type of PCa, plodity testing(pathology stuff) would have been useful at the beginning to know before choosing a modality, even now you can have those slides reviewed??? Why bother?  There are some PCa types that do not even respond 'hardly' to hormone therapies and/or some other drugs. Not intended to scare the ever living out of you or anyone, but facts and knowledge on PCa is much better than hypothesis and basically good guesses which is doled out to patients way more that we are lead to know or believe. Always get second opinions on any major decision on any treatment, it could make your head spin to know what the real score is on medical treatments etc. Salvage therapies and primary treatments are sold to patients without the most complete data and information, that might have been possible to obtain and this is the factual truth ....and yes there is always grey areas and unknowns (period) with PCa. How frank and honestly are you being told on your own PCa situation, lookout for sugar coating and so called guarantees, etc.

There is no way we know what type of PCa or variant you could have and it could even be the most typical version. The same goes for your uro-doc, has no clue on any of that he just reads the report from whomever was the pathologist, it is assumed you had a great pathologist, atleast we hope. Knowing up front that expert patho-docs are out there, get it sent to them or as a second opinion unto them, $350-500+ is average cost and insurance may pay it anyway.  Cost is higher for plodity testing and other optional tests, pay for it.

John T can fill you in about possible scanning options and methods that are out there. It is a choice you might consider, otherwise you are looking at hormone and drug therapies and there are tons of possible scenarios, even if your uro says that there are 2 or 3  drugs to consider (that is b.s.), they may be 2 or 3 he likes selling as they are highly profittable. Anyway you would be firing a uro at this point and hiring an onco-doc and best likely if it were a PCa onco-doc, in most cases.

Best to you, I fired my uro-doc 5 yrs. ago, best thing I ever did. The onco-doc is exactly what I needed and has made a world of difference in quality of life, costs and outcomes and side effects and totally honesty and frankness which is priceless in our scenarios . (7 yrs.+ warrior with omnious original stats and in better shape now than I was under the uro-doc....go figure) Dx-2002 March/April

Posted 7/20/2009 1:04 AM (GMT 0)
Meyers is one of the best you can get. Also Stephen Strum in Asland Ore would be my 1st choice in this difficult case.
The Combidex MRI is the only MRI that can identify Lymphnode involvement. The other MRIs or CTs only identify enlarged lymphnodes. Meyrs is familiar with this test, ask him about it when you are there.
This is a tough case of PC and you need a good detective (oncologist) to figure out what's going on.
JohnT
Posted 7/20/2009 2:10 PM (GMT 0)
To: John T. and Zufus,

I greatly appreciate your information.  John T. has been helping me understand my disease for several months now.  One big question that I have not resolved yet has to do with post-op PAP.  It would seem that this measurement should be either zero or close to zero (nd) if all the cancer had been removed during my robotic prostatectomy.  Can anybody help clarify this situation.  Are there any more benign reasons that PAP would be elevated (0.8 u/L)?  I would like to be able to verify that I have metastatic disease ASAP if that is indeed the case.

I am exploring going to Netherlands for Combidex imaging of LNs. but I have not heard back yet since submitting my information to Dr. Barentsz.

 

I have been experiencing some unusual, mild pain and tenderness in the groin and lower abdomen area over the last several weeks (almost two months after surgery).  Of course, it is easy to be paranoid, but I  wonder if these sensations are indicative of disease progression or just recovery from surgery.

Dan

Posted 7/20/2009 8:18 PM (GMT 0)
Dan,

If you want to know about PAP then Stephen Strum is the guy to talk to. I would call him and get a phone consult.
JT
Posted 7/20/2009 10:50 PM (GMT 0)
Dan,
This isn't the first time I have heard of PSA negative recurrent prostate cancer, my best friends father just pulled that one out, and Gordy, a long time former member here, also had a recurrance without PSA rise. No PSA, but he is positive for PAP. it would seem a good move to have further tests done. Myers is a good step, but so it MD Anderson.

Let us know how the meeting with Dr. Myers goes...

Tony
Posted 7/21/2009 12:59 AM (GMT 0)
Dan,

don't know if this will help at all, but I did find and opinion about post prostatectomy PAP. Perhaps a repeat test would help. Apparently the specimen cannot set for more than 3 hours at room temp. Sometimes uros send this stuff out, so specimen handling could also be in question.

Neha Vapiwala MD, Senior Editor for Oncolink, responds:

Dear Colleague,
Thank you for your interest and question.

Acid phosphatases are a group of enzymes, which are proteins found in living organisms that are critical for various chemical reactions. In the 1930's, it was discovered that these acid phosphatases were found in high concentrations within the prostate gland. Furthermore, there were found to be responsive to androgen (male hormone) regulation. Although present in the highest concentrations in the prostate, acid phosphatases can also be found in various other tissues in the body as well as in various isoenzymatic forms. Different assays that can accurately measure acid phosphatase levels have been attempted in order to be more prostate cancer-specific. Thus, the measurement of prostatic acid phosphatase (PAP) was developed. Unfortunately, although the ability to detect very low levels of PAP exists, i.e. high sensitivity), the specificity of this test as a reliable marker of prostate cancer is still quite limited.

Other inherent problems with prostatic acid phosphatase measurements are:

PAP levels fluctuate greatly over the course of just 24 hours, whereas serum varies little over weeks to months (and sometimes years)
PAP is less stable than PSA, causing increased variability in the lab reading
False elevations of PAP after prostate manipulation are notable
Sensitivity of PAP is much less than PSA, causing more false negatives.
Based on the many documented inconsistencies with PAP, it has no significant role at present in the monitoring of patients after initial therapy. PSA is much better in that regard. Initial PAP readings maybe helpful in estimating risk of extracapsular extension: the higher the PAP, the higher the risk for having cancer outside the prostate at the time of presentation. However, this should not be the only screening test obtained since PSA has a much higher prognostic value when used in combination with digital rectal examination.
Posted 7/22/2009 12:31 PM (GMT 0)
What a wonderful source of useful information this site has been. I had spent a lot of time trying to identify technical information about PAP that you guys helped clarify. Thanks again! Today, I drive down to Earlysville, VA to meet with Dr. Myers. I hope this will be productive.

Personally, one of my biggest challenges revolves around how to quantify the risk associated with my very unusual PC (pre-op PSA = 2.3 ng, tumor involved 30% of gland-12cc). Alison Bertle in UK calls it PSA-negative disease. All available evidence suggests that low PSA/high tumor vol. may represent a rare phenotype with an especially poor prognosis. Birtle noted that tissue staining on her 33 subjects displayed a high rate of reactivity to PSMA, Androgen Receptor and PAP, but not much to PSA. I wonder if this means that PSMA, AR and PAP are better serum markers for PSA-negative disease.

My doctors have been more inclined to look at my individual risk measures to derive the prognosis (post-op PSA<0.04, Gleason 3 + 4, pT3a, focal ECE, no SV involvement, pelvic LN 0/10). These measures do put me at relatively high risk of recurrence, but they do no elevate me to the bleak prognosis that UK and Japanese studies (PSA/TTV N. Hayashi) describe.
My challenge has been trying to convince doctors that my situation is more serious than simply high risk where adjuvant IMRT is the next step. (I do want a Combidex scan, but the delay in treatment presents a problem.)

Thanks again for all the great information.

John T, it sounds like you are progressing well through treatment. Keep in touch.

Dan
Posted 7/22/2009 1:40 PM (GMT 0)
Here is an article about PAP. http://www.cancernetwork.com/display/article/10165/59708 It states (among other things): "After prostatectomy, PSA levels nearly always drop to undetectable levels in the absence of residual disease. PAP, on the other hand, commonly remains in the detectable range after prostatectomy, because of other tissue sources. As a result, PAP is not a sensitive marker for residual, subclinical disease."
Posted 7/22/2009 8:40 PM (GMT 0)
Read this.  PAP is meaning less, even if your PSA is rising....

Monitoring Disease Recurrence

PAP also is clearly inferior to PSA in identifying subclinical disease persistence after prostatectomy or radiation therapy.[10] After prostatectomy, PSA levels nearly always drop to undetectable levels in the absence of residual disease. PAP, on the other hand, commonly remains in the detectable range after prostatectomy, because of other tissue sources. As a result, PAP is not a sensitive marker for residual, subclinical disease.

Clinical recurrence is almost always preceded by a rising PSA. PAP, on the other hand, frequently remains in the normal range, even in the presence of clinically evident metastases. Oesterling and colleagues reported that 100% of patients with clinically evident recurrence had elevated PSA levels, while only 50% had an elevated PAP.[25] National Prostatic Cancer Project investigators reported that almost a quarter of patients with clinically evident metastatic disease had normal PAP.[17]

Here is the whole article.  One of the Dr. that wrote it Dx me.

http://www.cancernetwork.com/display/article/10165/59708

Posted 7/23/2009 5:47 PM (GMT 0)
Yesterday, I finally met with Dr. Myers in Earlysville, VA.  I am still trying to digest everything.   There are so many issues.  Essentially, Dr. Myers was the first physician to fully recognize how serious my low PSA, high tumor volume disease really is.  He emphasized that it must be treated very aggressively.  My next step is to get a Combidex scan ASAP before progressing to ADT and broad IMRT over the entire pelvis and lower back.  "Hot" lymph nodes (from Combidex) will be specifically targeted. 

Dr. Myers also noted that measurable PAP was not unusual after radical surgery.  To try to keep a lid on my disease until treatment can be started, I am now taking Avodart and a variety of supplements that Dr. Myer recommends.

I know this will be a very tough year for me, but there appears to be some hope for gaining control of this aggressive disease.

Again, I want to thank everyone for all the information.

Dan

Posted 7/23/2009 6:12 PM (GMT 0)
This is exactly why patients should get a 2nd opinion from a noted prostate oncologist. Most Urologists and radiologists, even though they specialize in prostate cancer, don't really understand the disease from a biological level.
Dan, have fun in Nijmegegen, it's a lovely city with a lot of great places to eat. Stay at the Mecure, it's right at the railway station and you can walk to town or catch a cab next door at the station. You will have plenty of free time as the combidex is only about an hour and you have to go for two days. Take the train from Schipol to Nijmegegen, it runs about every 30 min and is a 1 1/2 hour ride.
Spend an extra day or two and see Amstradam while you are there.
Good luck and keep us posted.

JT
Posted 7/23/2009 8:20 PM (GMT 0)
John T,
Thanks for the information on Nijmegegen. I certainly hope that I can get there sometime soon.
Dan
Posted 7/23/2009 9:21 PM (GMT 0)

O.K. I am confused.  What is NED staining?  Is this done everywhere as routine?  Are you concerned because of the tumor volume or the NED staining?  I was pre surgery 2.7 PSA, gland 36cc.  Post op was gleason 6 organ confined.  I had surgery at J.H. by Dr. Partin.  Epstein did my pathology.  They said tumor volume was "moderate." Partin said they don't give a percentage.  Histologic Type: Adenocarcinoma.  First PSA was <.1 undetectable.  I had a PAP pre surgery and it was .5 on a scale of 0 - 3.5 my Oncologist said that is practically non-existant. Reinhartdm, what alarmed you about your post surgery stats?

Thanks 


Posted 7/24/2009 1:54 AM (GMT 0)
Reply to ChrisR's question:
My biggest concern is the very low ratio of my PSA (2.3) to my tumor volume (11-12cc). Those rare patients with this particular characteristic most often have very aggressive disease, even when some of the indicators don't look so bad. In my case, prior to surgery, most doctors thought I was low risk because of my low PSA. After my surgery, the size of my tumor (30% of gland), the stage (pT3a), ECE, Gleason 3 + 4 = 7, all tell a very different story. In some cases, Neuroendocrine differentiation (NED) can provide a clue to the very low PSA relative to tumor volume. Your PAP was very low which is good (although PAP is quite variable). My 0.8 PAP was after my surgery when I no longer had a prostate. That is why I was concerned.

Dan
Posted 7/24/2009 11:00 AM (GMT 0)
I guess I have not seen anyone concerned about tumor volume like you before.  I have read studies from J.H. that says tumor volume makes no difference. I don't know.
Posted 7/24/2009 4:26 PM (GMT 0)
chris,

Tumor volume is extremely important, but most doctors don't know how to use it. A given Gleason tumor throws off a set amount of PSA per cc of tumor volume. Therefore if you know the gleason score and the PSA you can calculate the tumor volume; conversely if you know the gleason and the tumor volume you can calculate the psa. If these number don't correlate then there is something else going on, either the PC has spread and psa is being generated somewhere other than the tumor or the PC is a variant that needs to be identified.

In Dan's case the psa is lower than it should be therefore a variant is suspected. In my case the original Dx of a small G6 didn't corrolate with a psa of 40. My uro oncologist didn't understand this, only when I went to a prostate oncologist and he explained that my stats didn't make sense because my psa should have been 6 instead of 40. He found another much larger tumor that 12 biopsies and an MRIS had missed. This tumor could not be removed by surgery because of it's location. If I would have gone with the original DX I would now either be incontenant or have had a reoccurrance.

It is very important that all the numbers, psa, gleason, and tumor volume correlate so you know what you are dealing with. I think that a lot of patients are misdiagnosed and never realize it, hence the large number of reoccurrances and positive margins. This is why I always recommend getting a 2nd opinion from a prostate oncologist.

JohnT

Posted 7/24/2009 9:52 PM (GMT 0)
Thanks John. My PSA pre-surgery was 2.76. I had a gland size of 36cc. My pre-op and post-op gleason score was 6. Johns Hopkins described tumor volume as moderate. I had a 50 point biopsy before surgery and it found 6 cores less than 2%-5% each. I had small focus in each lobe. Do my stats suggest anything strange to you guys? Dr. Partin was my surgeon at John Hopkins and said it was a good outcome and he is not concerned for my future. I don't know what to think. I was bothered by the fact it was in 7 spots after the surgery, but J.H. was not and said it is typical...By the way my first PSA was 5 years ago and it was 2.4 at 38 years old.  So you see it did not move much in 5 years.

Post Edited (ChrisR) : 7/24/2009 3:55:22 PM (GMT-6)

Posted 7/25/2009 1:03 AM (GMT 0)
Chris,
Looks like the typical G6 multifocal PC. PSA looks reasonable given the small core size. The slow rise of your psa indicates that it was non agressive. I think your doctor is correct and you have nothing to worry about. Looks like you had a great outcome.
JohnT
Posted 7/29/2009 2:07 PM (GMT 0)
I have a real dilemma.   My robotic prostatectomy conducted at NIH two months ago revealed a very large tumor (30% involvement) with a low pre-op PSA (2.3 ng), Gleason of 3 + 4, pT3a with extracapsular extension, perineural invasion.  My first post-op PSA was non-detect (<0.4 ng), but I was already taking Avodart and my PSA was never a very sensitive indication of tumor burden, anyway.  Everybody agrees that adjuvant IMRT to the prostatic bed is warrented at this point.  The question: Will this treatment be sufficient?

I met with Dr. Charles "Snuffy" Myers last week and he was the first doctor to recognize the rare and especially problematic type of PC I suffer from (low PSA with large tumor).   Dr. Myers' prescribed a treatment regimen that is far more aggressive than NIH.  It starts with a Combidex MRI scan of lymph nodes, followed by triple-block hormone treatment, followed after three months with extensive IMTR to the entire pelvic area and lower back.  Focus radiation would be directed at any "hot" lymph nodes.  The triple hormone block would be extended for one year.

My challenge is that every local oncologist I have dealt with tells me that the extra aggressive combination of multiple hormone treatment and extensive radiation is associated with too much morbidity.  I trust Dr. Myers' diagnosis.  It is  exactly the same conclusion I independently arrived at (although all the local doctors have disagreed with me).

Have any of you gone through this multiple hormone/IMRT protocol?  What can you tell me about your experience?

Dan

Posted 7/29/2009 3:28 PM (GMT 0)
I had a reverse problem. My Radiation doc feels that I had high PSA for the amount of cancer found at RRP. With the PSA rising he wants to do a two months HT (one month Casodex + Lupron, then just Lupron) followed by IMRT to pelvic area (40 treatments). HT to continue for six months. I am in month 2 of HT and so far I don't feel very different. I have hot flushes and while I am able to achieve erection (with Viagra) I am unable to orgasm. I start IMRT on Aug 21.
Posted 7/29/2009 9:47 PM (GMT 0)
I would stick with what Myers recommends. He knows a lot more about this stuff than a radiation oncologist. He been through it so he knows what he is talking about.

JT
Posted 8/20/2009 3:27 AM (GMT 0)

Reinhartdm,

I am wondering how you are doing?  I found your post interesting in that my husband also went to NCI and we found them to be wonderful.  He had his first biopsy there and of course, all things changed once the results came back.  PSA was 3.28, 4 out of 14 cores positive - some up to 90% involved - Gleason 3+4.  Sent biospy to Dr. Epstein for 2nd opinion - came back 3+3.  Pre-surgical path again 3+4 at Northwestern in Chicago.  Had RRP with Dr. Catalona.  Post surgical path:  32 g. prostate, Gleason 3+4, adenocarcinoma arising within the right lobe and involving 10% to 20% of the submitted prostate.  Tumor focally perforates right capsule and focally extends to the inked surgical margin on the right side.  Extensive perineural invasion.  Right margin focal, positive.  Extraprostatic extension (in fat) focal (<2 microscopic foci).  Staging:  T3a.  All other areas reported clear.  Excised wider on right side but both nerve bundles spared.  100% continent upon removal of catheter--good news!  Starting the injections, so we'll see how that goes.  First PSA was 0.0 a few weeks ago, next one in 3-4 months.  If PSA rises above 0.1, then radiation is recommended.

I realize going forward that PSA is the leading indicator but I am still extremely worried about the situation.  We started watching the PSA when he was age 50 and it was 5.2, went to a urologist and it was 2.6, another urologist (UWH) 2.8, 3.2, 2.9, 3.2, then recommended to wait one year and it was 4.  We initiated going to NCI for the MRI guided biopsy, and the rest continues on.

I don't want to wake up and find we should have been more aggressive, so am exploring all options on what to do if the PSA starts to rise, or if we should even wait until then.  I am normally very optimistic but this diagnosis is a difficult hit, as you all know.  My dad passed away from PcA in January and my husband arrived at 4.0 a few weeks later.  Now to move forward and make the right decisions.

Any help is appreciated....

Many thanks to all!

 

Posted 10/26/2009 9:02 PM (GMT 0)
I have read in numerous places that often times the PAP does not decrease after prostate cancer treatment, because there are other tissue sources of PAP. I am curious what Dr. Snuffy Meyers had to say about the PAP, specifically.
Posted 10/27/2009 3:32 PM (GMT 0)
My low PSA (2.3 ng) and large tumor (30% of 44 g prostate) presents a most unusual situation.  The limited data on "PSA-negative" prostate cancer strongly suggests that it is usually a most aggresive phenotype.  My May 28 robotic prostatectomy at NIH disclosed a large tumor with perineural invasion and focal extracapsular extension.  My Gleason Score was upgraded to 3 + 4; Bostwick agreed with this score but added that there was 90% three and 10% four (some not-so-bad news).  I have been trying to get a DNA Ploidy analysis at Bostwick, but this has been delayed by a number of communication problems.  My ultimate goal is to try to understand the peculiarities of my disease.

I have been under the care of Dr. "Snuffy" Myers for the last four months.  He was the first doctor to recognize how aggressive my disease actual may be, and he has prescribed a most aggresive treatment strategy; ADT3 and then full pelvic IMRT at Datolli Cancer center.  (ADT3 will continue for one year.)  My Combidex MRI in Nijmegen by Dr. Barentsz identified two very suspicious pevic lymph nodes with 1.5 mm white structures.  Color doppler TRUS by Dr. Sorace at Datolli Center indicated some vascularization in the prostatic bed that could well be new growth of PC.  I've been on ADT for over two months now, and plan to start IMRT in about a month.  My testosterone measurement of two weeks ago was 13 ng, and I feel like it has continued to decline (tiredness, fogginess).

At this point, I don't know what additional tests I might get.  Dr. Myers and other doctors feel that PAP is not that valuable.  One problem is laboratory variation; very few PAPs are conducted, so there is serious question about each labs ability.  Also, PAP varies widely within an individual over the day.  Before my surgery my PAP was 1.4 ng/dL, and after surgery, it was .8 and later .95.  No one seems to know how to interpret these numbers.

I have also had CGA, CEA and NSE measured on different occasions, and sometimes these numbers have been elevated, but there are several different (and sometimes more benign) explanations for elevations.  I'll try to keep.

Dan

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