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FAQ - Frequently Asked Questions About
HRPCa
Questions Answered below
Q1: Should I remain on hormone blockade now that I am hormone refractory?
Q2. I've had an orchiectomy so my testes don't produce
testosterone. My PSA is rising and my doctor has suggested that I get an
injection of Lupron (or Zoladex). Why?
Q3. What is PSADT and how is it used?
Q4. I'm on Lupron or Zoladex and my testosterone level is still above the
castrate level of 20ng/dl(.69 nmol/L). What can
I do to lower my testosterone level?
Q5. What is the definition of a castrate level of testosterone and
is there a clinically significant level?
Q6. I just started taxotere (mg/m2, every x weeks or y days) and my PSA has continued to rise. Is this a concern?
Q7. I'm HRPC. What kind of survival might I expect?
Q8. I've been told to take an antiandrogen (Casodex)
before starting Lupron to prevent flare in my testosterone level. Is
this really necessary?
Q1: Should I remain on hormone blockade now that I am hormone refractory?
A1: The question as to whether or not to continue with Lupron or Zoladex or other testosterone suppressing drug when on HDK, PC
Spes, DES, chemotherapy or whatever else is frequently asked. There are about 7
statements or papers/trials that on this that mostly point to staying on the LHRH
agonists. As is so often the case in
prostate cancer - it can be a very individual thing. So here they are:
1. Strum responded on P2P to a questioner with the
following --- it basically says that if you are on HDK that you should also
be on Lupron. Strum writes: “I would prefer to combine an AAW with the use
of a drug that has both androgen dependent and androgen independent killing
effects (HH - this is HDK). I would use Lupron or Zoladex in that setting as
well to prevent long-term stimulation of the pituitary and possible
over-ride via LH hyperproduction. What this means is that Ketoconazole or
Nizoral alone in time will result in increasing levels of LH that can
override the testicular suppression of Keto. I use a more aggressive
approach in an attempt to totally control the disease rather than treat and
be happy with a 4-6 month response. I want long term responses. I would also
be considering the use of chemotherapy if I felt that the above measures
were not eradicating the disease.” For a reference, see: English HF, Santner
SJ, Levine HB, Santen RJ, Inhibition of testosterone production with
ketoconazole alone and in combination with a gonadotropin releasing hormone
analogue in the rat, Cancer Res. 1986 Jan;46(1):38-42.
Abstract
2. This study concluded in a
retrospective trial (for chemo use, 1994) that continued androgen
suppression was not a significant factor in patient survival: Hussain M,
Wolf M. et al, “Effects of continued androgen-deprivation therapy and other
prognostic factors on response and survival in phase II chemotherapy trials
for hrpc: A SW Oncology group Report. J. Clin Onco 1994;12:1868-1875.
3. This study concluded, in a
retrospective review by the Eastern Cooperative Oncology Group, that there
was a modest survival advantage for patients with continued testicular
androgen suppression: Taylor, CD, Elson, P and Trump DL, “Importance of
continued testicular suppression in hormone-refractory prostate cancer,” J.
Clin. Oncol., 11: 2167, 1993.
4. A paper that demonstrated
that there was residual hormone activity, even in HRPC men is: Fowler, et
al. J. Urol 126:372-375, 1981. This paper’s proof was that exposure to
exogenous testosterone results in disease flare which reverses when
testosterone is discontinued. Thus, HRPC men, probably treated with
orchiectomy, were given testosterone externally, which led to increasing
extent of their disease.
5. Prostate cancer cells have LHRH
receptors. Human prostate cancer cells, even those known to be resistant to
androgen withdrawal (hrpc) possess LHRH receptors. When Lupron binds to
these LHRH receptors, the growth of the cancer cells slows or stops
altogether. See Halmos, G et al, “High Incidence of receptors for LHRH and
LHRH receptor Gene Expression in Human Prostate Cancers, J. Urology, 163,
623-629, February 2000 and the references contained therein. This is an
area being studies - there is a targeted cytotoxic LHRH analog AN-207 (used
in animal tumor models) “might” be possibly effective clinically (in
suppressing tumors).
6. Kamradt and Pienta, say that in a
non-protocol setting, it is the patients choice, but that if you are on one
of their trials (Univ. of Mich.) for hrpc patients you must maintain
testicular androgen suppression.
7. Eur Urol 1997;31(1):7-10 The
importance of continued endocrine treatment during chemotherapy of
hormone-refractory prostate cancer. Chao D, Harland SJ Department of
Oncology, UCL Medical School, Middlesex Hospital, London, UK. This paper
reports 3 cases where continued androgen deprivation was required to
maintain the response to chemotherapy. The 3 patients initially responded to
chemotherapy and then relapsed as demonstrated by rising PSA levels. They
then restarted hormone therapy which had been stopped(under the assumption
that it was now not needed) and their response to the chemotherapy thus
continued. The authors concluded by saying that in hormone-relapsed disease,
a significant proportion of the prostate cancer is still responsive to
androgen deprivation.
8. Stephen Strum, M.D., in a recent P2P post
responded this way:
Patient: We have been told to discontinue
Casodex/Zolodex now that my husband is on chemotherapy because they consider
him hormone refractory.
<Stephen Strum, MD> Bad idea. This leaves the Androgen
sensitive PC untreated and it will likely progress.
9. Reported patient results. Several men have reported stopping
hormone blockade while on chemotherapy and subsequently saw their PSA rise.
This was reversed by restarting HB. If you do stop, it is essential to
monitor your testosterone level also.
Q2. I've had an orchiectomy so my testes don't produce
testosterone. My PSA is rising and my doctor has suggested that I get an
injection of Lupron (or Zoladex). Why?
A2. See item 5 under Q1. This can lead
to a decrease in your PSA. If it doesn't, stopping the Lupron or Zoladex
would be appropriate. A recent paper on this is: Damyanov C, Tzingilev
B, Tabakov V. Treatment of an orchiectomized patient with hormone-refractory
prostate cancer with LH-RH agonists, Eur Urol. 2001 Oct;40(4):474-6;
discussion on page 477 in which a patient had a remission lasting at least 14
months.
Q3. What is PSADT and how is it used?
A3. PSADT = PSA Doubling Time. The time can be in days, months or
years. Often, hrpca men will see PSADT in 30 days or less. That
generally signals a treatment failure and provides an indication of the
urgency to change treatments. By plotting PSA vs time on semi-log
paper with PSA on the y-axis and time on the x-axis, you should see a
straight line indicating the characteristic exponential change in PSA (2, 4,
8, 16, 32, 64, etc). Think of this change as each cancer cell dividing in
two and then all the new cells dividing in two and this continuing on and
on. The slope of this line is the PSADT. If your PSA is bouncing
around, you cannot calculate a meaningful PSADT. An example plot of PSA
vs time is in chapter 6 of the booklet.
The formula for calculating PSADT is:PSADT = ln 2 X T/(ln
PSA2 - ln PSA1)
where:
T = time elapsed between test
results (in days preferably)
PSA2 = value of the latest PSA
test
PSA1 = value of the initial PSA
test
ln 2 = 0.693
This formula is valid for two data points and assumes that growth is a
straight line between the two points.
The MSKCC website has a PSADT calculator within their treatment decision
nomogram page. Go to
http://www.mskcc.org/mskcc/html/10088.cfm
and click on the Prostate Ca Nomogram. At the bottom of the pop up window
there is a PSADT tab. Results are in months and years. For example, .8
months = 24 days.
Q4. I'm on Lupron or Zoladex and my testosterone level is still above the
castrate level of 20ng/dl(.69 nmol/L). What can
I do to lower my testosterone level?
A4. The every 16 week injection of these drugs can sometimes be
depleted, so if you are measuring your testosterone level toward the end of
the 16 weeks, it might be elevated due to that reason. Go to a shorter
interval injection -- 12 weeks or less. Another possibility
is higher than expected adrenal androgen levels resulting in high normal
DHEA-S or androstenedione levels. These are metabolized to testosterone
within the PC cells and any prostate tissue.
You might also check that LH < 1. This would indicate that the Lupron or
Zoladex is doing all it can which may then implicate one of the above
causes.
Yet another possibility is the following which was posted to the p2p forum
by Dr. Stephen Strum: "Another possibility that I have
seen is poor absorption of Lupron or Zoladex that is associated with a soft
tissue reaction to the injection with a "mass" or "knot" felt at the site of
injection. These "knots" feel like hematomas but they are really
manifestations of some type of allergic reaction to something in the Lupron
or Zoladex. Such patients have a lack of drop in testosterone due to the
LHRH injection just not working."
Stephen Strum, MD has an educational article written on
understanding the endocrine
system located at the PCRI website. Read it for a more thorough explanation
than that given above.
Lastly, Oefelein MG et al in J. Urol 2000 Sep;164(3 Pt 1):726-9, wrote about
the need for monitoring serum testosterone levels during LHRH therapy. They
tested the 3-month depot LH-RH agonist and monitored total serum
testosterone and PSA every 28 days. The following table lists their results
for the number of men not achieving the stated castrate levels of
testosterone.
| Castrate Criteria |
N, % |
| ≤ 50 ng/dL |
2 men of 38, 5% |
|
≤ 20 ng/dL |
5 men of 38, 13% |
Another interesting result from this paper is that one of their patients had
a nadir testosterone of 70ng/dL using LH-RH agonist, then had an orchiectomy
and then his testosterone decreased to 10ng/dL.
Note on units: Outside of the United States (Canada, United Kingdom,
Europe etc, the testosterone units are nmol/L and a castrate
level of testosterone would be .69nmol/L (20ng/dl). A conversion factor of 28.8
can be used to go from one set of units to the other.
Q5. What is the definition of a castrate level of testosterone and
is there a clinically significant castration level?
A5. Oncologists disagree on what a castrate level of
testosterone should be -- some say <20ng/dL, others <50ng/dL.
One way of looking at it is -- what is the level of testosterone in men who
have had orchiectomies? In the paper by Oefelein MG et al (1), they
evaluated the testosterone level in 35 men who were surgically castrated (orchiectomy)
and found
the
median testosterone value to be 15 ng/dL (0.5 nmol/L; 95% confidence
interval 12 to 17 ng/dL). They therefore concluded that the castrate
level should be defined as less than 20 ng/dL (.7 nmol/L).
In another paper, Oefelein MG et al(2),
he reported that 38 men on 3 month depot LH-RH agonist therapy (Lupron or
Zoladex -- chemical castration) and found that 2(5%) failed to get below 50
ng/dL and 5 (13%) failed to get below 20ng/dL. One patient whose
lowest T was 70ng/dL and after an orchiectomy, T dropped to 10ng/dL.
Assuming that your testosterone will drop to 'castrate' levels just because
you are on Lupron - type drugs doesn't guarantee that that is what will
happen.
The question of clinical significance was only
recently answered by Morote J, et al (3). Patients (n=73) were
medically castrated and non-metastatic; 28 patients also received
bicalutamide. The "usual" cutoff points of 50 and 20 ng/dl were
examined. Testosterone levels were < 20ng/dl in 43.6%; between 20 and
50ng/dl in 31.5% and > 50 in the other 24.7%(18 patients). They found
that 32 ng/dl was the lowest level to have a significant impact on survival
free of androgen independent progression(AIP.) Median survival free of AIP
was 88 mos. for testosterone > 32ng/dl and 137 mos. for those below 32ng/dl.
(1) Oefelein MG, Feng
A, Scolieri MJ, Ricchiutti D, Resnick MI., Reassessment of the definition of
castrate levels of testosterone: implications for clinical decision making,
Urology. 2000 Dec 20;56(6):1021-4.
(2)
Oefelein MG, Cornum
R., Failure to achieve castrate levels of testosterone during luteinizing
hormone releasing hormone agonist therapy: the case for monitoring serum
testosterone and a treatment decision algorithm, J Urol. 2000 Sep;164(3 Pt
1):726-9.
(3) Morote J, Orsola A, Planas J, Trilla E, Raventós CX, Cecchini L, Catalán
R, Redefining Clinically Significant Castration Levels in Patients With
Prostate Cancer Receiving Continuous Androgen Deprivation Therapy, J Urol.
2007 Aug 13; [Epub ahead of print].
To compare the testosterone levels with the
different units, refer to the following table.
| "Castrate Criteria" (USA Units) |
Non-USA Castrate Values |
Comments |
|
≤50 ng/dl |
≤ 1.74 nmol/L |
"old criteria" often used as the level for clinical trials. |
|
≤ 32 ng/dl |
≤ 1.11 nmol/L |
See reference (3), clinically significant level. |
|
≤ 20 ng/dl |
≤ .69 nmol/L |
level of patients after
orchiectomie |
Note: The youthful testosterone level
ranges from 500-1200ng/dL.
Q6.
I just started taxotere (mg/m2, every x weeks or y days) and my PSA has continued to rise. Is this a concern?
A6. It isn't clear just how common this phenomenon is, but it does
happen. The first paper to mention this is the phase II, high dose pulsed
calcitriol and taxotere paper of Beer et al.
(1) Tomasz M. Beer, Kristine M. Eilers, Mark Garzotto, Merrill J. Egorin,
Bruce A. Lowe, W. David Henner, Weekly High-Dose Calcitriol and Docetaxel in
Metastatic Androgen-Independent Prostate Cancer; Journal of Clinical
Oncology, Vol 21, Issue 1 (January), 2003: 123-128.
In this paper, the authors give the following data for a continued PSA
rise (and subsequent decline) (note: this is .5mcg/kg day before taxotere;
taxotere 36mg/m2, 6 of 8 weeks): "Of the 30 PSA responders (37 total patients),
five had a transient initial rise in the PSA (median, 8.3%; range, 1% to
29%) before their PSA reduction." Additionally, "Of the 7 patients who did
not have a confirmed PSA response, five had stable disease for 3.7 to 8.7
months)." All patients in this study were chemotherapy naïve.
(2) Olbert PJ, et al, Clinical Significance of a prostate-specific antigen
flare phenomenon in patients with hormone-refractory prostate cancer
receiving docetaxel, Anticancer Drugs. 2006 Sep;17(8):993-996.
Olbert et al treated 44 patients with taxotere based regimens. They define
flare as an initial rising PSA while on taxotere which then drops to values
below baseline. The flare phenomena was observed in 8(18%) of the 44
patients. The patients who did not experience a flare and who
responded to treatment numbered 24(54.5%) and there were 12(27.3%)
non-responders. The flare group and the responder group had similar median
survival and these groups had significantly better survival than the
non-responder group(19 mos, 18 mos and 7 mos.) Toxicity was similar in all 3
groups. Their conclusion was "...the flare phenomenon does not indicate
therapeutic failure and should not lead to early withdrawal from therapy in
the absence of clinical signs of progression."
5. D. Sahi, C. H. Ohlmann, I. Cordia, U. Engelmann, A. Heidenreich, PSA
flare-up in patients with hormone-refractory prostate cancer (HRPCA)
receiving docetaxel-based chemotherapy: Incidence and differentiation from
progressive disease, Journal of Clinical Oncology, 2006 ASCO Annual Meeting
Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 14523.
Sahi et al, found that 13% of their patients saw a temporary "flare" and the
median PSA increase compared to baseline was 81% (range 25-239) and the
median following PSA decrease was 110.5%. PSA doubling times did not
distinguish between flare-up and progression.
5. Nelius T, Klatte T, de
Riese W, Filleur S., Impact of PSA flare-up in patients with
hormone-refractory prostate cancer undergoing chemotherapy, Int Urol
Nephrol. 2008;40(1):97-104. Epub 2007 Jun 30.
There were 74 patients who received taxotere and emcyt at Texas Tech. Median
survival in the flare-up group (8 patients) was 20 months and this did not
differ from the response group. The flare-up group's maximum PSA elevation
from baseline was between 3.4% and 28.3% between 3 and 6 weeks, followed by
a decline in PSA ≥ 50% in 7 of the 8 patients. Thus patients on a docetaxel
plus emcyt should continued a minimum of 6 weeks before removing them from
this treatment. The authors stated, "co-medication with dexamethasone/prednisolone
and/or estramustine itself can induce an initial PSA flare-up via androgen
receptor mutations."
6. Armstrong AJ, J. Clinical
Oncology 2007;25(Suppl):Abstract 5009. Here, a rise occurred in PSA in up to
23% of the patients before the PSA declined. This led the PCWG2 (Prostate
Cancer Clinical Trials Working Group 2, Scher H et al, J. Clin. Oncology
2008, 26;1148-1159.) to recommend that patients remain on treatment for at
least 12 weeks before deciding the effect of therapy.
7. A related part of this
question is when to stop chemotherapy? CN Sternberg indicated in her talk at
the ESMO Stockholm 2008 talk that the optimal duration of chemotherapy is
not known. The 2 phase III trials of taxotere chose arbitrary stopping
points: Tax 327 30 weeks; SWOG 9916 12 cycles. She also noted that there is
little information on drug holidays as opposed to therapy until progression
with only limited phase II data available on intermittent therapy. See Beer TM, Cancer 2008 Jan
15;112(2):326-30. and Calabro F and Sternberg CN, Eur Urol 2007
Jan;51(1):17-26.
Note: this flare-up phenomena has
also been seen with Liposomal doxorubicin (SD Fossa et al 2002, A
Heidenreich et al 2004.)
Q7. I'm HRPC. What kind of survival might I expect?
A7. A page has been written addressing this question. See
Survival.
Q8. I've been told to take an antiandrogen (Casodex)
before starting Lupron to prevent flare in my testosterone level. Is
this really necessary?
A8. This was answered in a recent paper by WK Oh et al. The reference
is Oh WK, Landrum MB, Lamont EB, McNeil BJ, Keating NL, Does Oral
Antiandrogen Use Before Leuteinizing Hormone-releasing Hormone Therapy in
Patients With Metastatic Prostate Cancer Prevent Clinical Consequences of a
Testosterone Flare?, Urology. 2009 Dec 3. [Epub ahead of print].
They assessed newly diagnosed metastatic prostate cancer patients (1566) of
whom 1245 (79.5%) received oral antiandrogens before initiating LHRH agonist
treatment. They found that complication rates did not differ by receipt of
oral antiandrogens. They assessed spinal cord compression, radiation
therapy, fractures, bladder outlet obstruction, and narcotic prescriptions
for pain within 30 days of starting LHRH therapy. Complication rates did not
differ by receipt of oral antiandrogens (all P >/= .17). Spinal cord
compression and pathologic fractures were extremely rare whether
antiandrogens were used or not. Their conclusion was "Antiandrogen therapy
before LHRH agonists in metastatic prostate cancer was not associated with
differences in fractures, spinal cord compression, bladder outlet
obstruction, or narcotic prescriptions." They had a final comment
that, "Rates of spinal cord compression or fracture were < 1% in the first
30 days after beginning LHRH agonist therapy regardless of antiandrogen
use."
Author: Howard Hansen; Updated 18 January 2010.
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