Read below to get some idea of the
dosing schedule and its impact on skeletal related events (SREs). The bottom line, there is potential for decreased
efficacy for longer dosing intervals. I have also not addressed the
duration of therapy question. One thing to remember is how men with bone
metastases vs men without bone mets might respond to therapy (without
mets, you are basically trying to prevent osteoporosis from developing).
Roughly 80-90% of patients with
advanced prostate cancer will develop bone mets and may experience
skeletal complications such as pathologic fractures. Pathologic
fractures are associated with decreased survival in patients with PCa
and may result in extended recovery or permanent impairment. SREs are
associated with a reduction in quality of life.
Markers of bone collagen breakdown, such as N-telopeptide, as well as
markers of osteoblast function, such as bone specific alkaline
phosphatase, appear to be of use in assessing and managing patients with
malignancies that metastasize to bone.
Zometa Dosing Schedule
Definitions
NTx - N-telopeptide (Cross-linked
N-telopeptide of Type I Collagen), a marker of bone collagen breakdown.
BAP - Bone Specific Alkaline
Phosphatase - A marker of osteoblast function.
Zometa - zolendronic acid, a potent
amino-bisphosphonate.
What is the FDA approved dose
and schedule for Zometa?
ANS. This was established by
several phase III trials showing that every 3 week Zometa, 4 mg,
diffused over at least 15 minutes delayed the onset of skeletal related
events(SRE) (spinal cord compression, radiation to the bone, surgery,
new chemotherapy) when compared to a placebo.) (1) The approval is for
men with HRPC stage disease with at least one bone metastasis. All other
uses would be considered "off label" which the doctor is free to
prescribe. Reference (1a) was not a randomized study, but was also every
3 weeks for a year dosing and found reduced NTx and BAP levels, BMD
increased, median time to SREs had not been reached and 11.9%
experienced an SRE. See also
http://www.hrpca.org/bisphosphonates.htm
What about other dosing schedules?
ANS. Other schedules are possible.
However, they have not directly shown that they delay the onset of SREs.
For example, every 3 months and once a year.
What were the every 3 month
studies?
MR Smith, MD et al (2) found that every
3 month dosing increased bone mineral density in the hip and spine in
men starting androgen deprivation therapy who had non-metastatic
prostate cancer. This was basically an osteoporosis study.
RS Israeli et al, (3), in patients
in their 1st year of androgen deprivation therapy and had locally
advanced disease, concluded that zoledronic acid (4 mg intravenously
every 3 months) was safe and effective in preventing bone loss and
reducing bone turnover in patients with prostate cancer when initiated
during the first year of androgen deprivation therapy; patients with low
baseline BMD experienced the greatest benefit. They found reduced NTx
levels and reduced bone specific alkaline phosphatase in the Zometa arm.
This was basically an osteoprosis study.
CW Ryan et al (4), with patients
who were hormone-sensitive, with and without bone metastases looked at
markers of bone turnover. This was an every 3 month dosing schedule and
they received 4 treatments altogether. They were on androgen deprivation
therapy for < 12 months when started on Zometa.
How about just once a year, is
that possible?
ANS. This was studied in
post-menopausal women in an osteoporosis study to increase BMD. In men,
MD Michaelson, et al (5) studied 40 patients, randomized Zometa vs
placebo; Zometa once / year, for a year total (e.g., they got one dose
of Zometa only on day 1 of the study). The men were nonmetastatic and
hormone sensitive (i.e., receiving Lupron or other GnRH agonist). BMD
went up and NTx went down in the Zometa group. Basically, the day 1 dose
lasted 12 months.
How about using Aredia (pamidronate)?
ANS. ONJ does occur with
pamidronate, but maybe at a lower frequency than with Zometa. MR Smith
et al (6) studied pamidronate for prevention of osteoporosis in
non-metastatic men with hormone sensitive disease who were on Lupron or
similar GnRH agonists. They found it prevented bone loss in these men. A
Lipton, et al (7) also looked at SREs using Pamidronate versus a placebo
(236 men) and found that pamidronate was no more effective than a
placebo in reducing bone pain or SREs over a 6 month period.
Do NTx and BAP (bone alkaline
phosphatase) predict for skeletal complications since we do have data on
that from the every 3 month and every 12 month studies?
ANS. MR Smith discusses this(8).
While it would take a large prospective clinical trial to provide a
definitive answer about the safety and efficacy of alternative doses and
schedules of zometa, Brown, et al (9) used data from patients with bone
metastases from PCa and other solid tumors who were on the placebo arm
of two Phase III trials of Zometa. They found that elevated levels of
urinary NTx are associated with shorter time to skeletal-related events,
skeletal disease progression and death. How about those on the Zometa
arm? This was looked at by RE Coleman, et al (10) using the Zometa arm
of 3 phase III trials for patients with bone metastases and they found
that higher levels of urinary NTx during treatment also was associated
with shorter time to skeletal-related events, disease progression and
death. Some NTx values from these references follow. Baseline urinary
NTx elevated (>60 nmol/mmol creatinine) in about 80% of patients in the
phase III trials. On Zometa, urinary NTx elevated in about 80% of the
breast or prostate cancer patients and in 10% of these patients, it was
"markedly elevated (>100 nmol/mmol creatinine.)
Mathew R. Smith(8) summarizes this
by saying that "...(1) elevated NTx is associated with adverse clinical
outcomes, and (2) urinary NTx is persistently elevated in a substantial
subset of patients during bisphosphonate treatment suggest that lower
doses and/or a less frequent schedule in unselected patients is likely
to decrease efficacy." He continues, "The substantial interpatient
variations in baseline markers of osteoclast activity and the response
to bisphosphonate treatment raise the question of whether individualized
bisphosphonate therapy represents an effective strategy to improve
safety, cost and convenience."
Are There Other Studies Using
NTx (N-telopeptide)?
See references (12)-(15). These are not specific to
prostate cancer, but provide more background information. It appears
that NTx may be the best marker available. Reference (15) also covers
Dpd and Alk Phos. LM Demers et al (15) say, "Biochemical markers of bone resorption and bone formation are
abnormally raised in the blood and urine of patients with metastatic
bone disease."
Furthermore, Demers et al showed that NTx and BAP appear
to be of use in assessing and managing patients with malignancies that
metastasize to the bone. There was a significant correlation with both
the presence of bone mets and the extent of skeletal involvement. Thus
NTx and BAP can be used to guide decision making regarding the treatment
of metastatic bone disease and to determine the effectiveness of
therapy.
How would one "individualize"
bisphosphonate treatment? Any information on survival and anti-tumor
activity?
ANS. One possible scenario would be
based on NTx levels at baseline and after initiating bisphosphonate
treatments. Those with elevated NTx might best be treated with standard
Zometa dosing intervals. Smith's observations do not provide any
specific guidance on this. The paper by Fred Saad (11) indicating that
the standard treatment schedule can provide quality of life benefits and
a trend toward increased survival argue for maintaining the shorter
dosing intervals, at least until further data becomes available. You can
read the text of Saad et al,
abstract 283 on-line. "Zoledronic acid
demonstrated preclinical evidence of antitumor activity in multiple
prostate cancer cell lines and animal models." They further conclude
that "recent exploratory
analyses and preclinical studies suggest that zoledronic acid can
provide quality-of-life and clinical benefits to patients with prostate
cancer. Zoledronic acid is the only bisphosphonate that has demonstrated
a trend toward prolonged survival compared with placebo in patients with
bone metastases from prostate cancer."
The Duration of Therapy
How long should one remain on
Bisphosphonate Therapy?
ANS. See reference (16). F.
Saad et al analyzed the data from the phase III trials for HRPC patients
with bone mets. 4mg vs a placebo, every 3 weeks for up to 24 months (422
pts). Their results included:
-
Zometa significantly decreased
the proportion of pts who experienced >1 SRE vs Placebo in HRPC (38%
vs 49%; p = 0.028; Saad F, et al. J Natl Cancer Inst.
2004;96:879-882)
-
Zometa significantly delayed
the median time to first SRE vs placebo by >5 months in pts with
HRPC (p = 0.009).
-
Zometa also significantly
reduced the risk of developing an SRE by 36% in HRPC vs placebo.
-
There was a trend towards an
~2.5-mo increase in survival for Zometa-treated HRPC pts (p = 0.103)
vs placebo. Zometa had an overall safety profile comparable with
that reported for other intravenous bisphosphonates.
So there is good data out to 24
months. There is probably data available for an even longer time, but if
one considers the time on Zometa vs benefit, you might choose to do
every 3 or 4 weeks for 2 years and then increase the interval (e.g., to
3 months).
An earlier study and abstract from
ASCO 2004 (17), concluded "This exploratory analysis suggests that
long-term treatment with Zol provides significant and ongoing clinical
benefit in patients with bone metastases from advanced prostate cancer.
Considering that patients who have an SRE are also at higher risk for a
subsequent SRE, this analysis suggests
that patients should continue on bisphosphonate therapy even after they
have
an SRE.
References
1. Fred Saad, Donald M. Gleason,
Robin Murray, Simon Tchekmedyian, Peter Venner, Louis Lacombe, Joseph L.
Chin, Jeferson J. Vinholes, J. Allen Goas, Bee Chen, "A Randomized,
Placebo-Controlled Trial of Zoledronic Acid in Patients With
Hormone-Refractory Metastatic Prostate Carcinoma," Journal of the
National Cancer Institute, Vol. 94, No. 19, 1458-1468, October 2, 2002.
1a. Polascik TJ, Given RW, Metzger
C, Julian SR, Vestal JC, Karlin GS, Barkley CS, Bilhartz DL, McWhorter
LT, Lacerna LV, Open-label trial evaluating the safety and efficacy of
zoledronic acid in preventing bone loss in patients with
hormone-sensitive prostate cancer and bone metastases, Urology. 2005
Nov;66(5):1054-9.
2. Smith MR, Eastham J, Gleason DM,
Shasha D, Tchekmedyian S, Zinner N., Randomized controlled trial of
zoledronic acid to prevent bone loss in men receiving androgen
deprivation therapy for nonmetastatic prostate cancer, J Urol. 2003 Jun;169(6):2008-12.
(3) Israeli RS, Rosenberg SJ,
Saltzstein DR, Gottesman JE, Goldstein HR, Hull GW, Tran DN, Warsi GM,
Lacerna LV, The effect of zoledronic acid on bone mineral density in
patients undergoing androgen deprivation therapy, Clin Genitourin
Cancer. 2007 Mar;5(4):271-7.
(4) Ryan CW, Huo D, Bylow K, Demers
LM, Stadler WM, Henderson TO, Vogelzang NJ, Suppression of bone density
loss and bone turnover in patients with hormone-sensitive prostate
cancer and receiving zoledronic acid, BJU Int. 2007 Jul;100(1):70-5.
(5) Michaelson MD, Kaufman DS, Lee
H, McGovern FJ, Kantoff PW, Fallon MA, Finkelstein JS, Smith MR.
Randomized controlled trial of
annual zoledronic acid to prevent gonadotropin-releasing hormone
agonist-induced bone loss in men with prostate cancer, J Clin Oncol.
2007 Mar 20;25(9):1038-42.
(6) Smith MR, McGovern FJ, Zietman
AL, Fallon MA, Hayden DL, Schoenfeld DA, Kantoff PW, Finkelstein JS, Pamidronate to prevent bone loss
during androgen-deprivation therapy for prostate cancer, N Engl J Med.
2001 Sep 27;345(13):948-55.
(7) Lipton A, Small E, Saad F,
Gleason D, Gordon D, Smith M, Rosen L, Kowalski MO, Reitsma D, Seaman
J., The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal
complications in both osteolytic and osteoblastic lesions: a comparison
to pamidronate," Cancer Invest 2002;20 Suppl 2:45-54.
(8) MR Smith, Commentary:
Bisphosphonates for Metastatic Bone Disease -- Too Much of Good Thing?,
BoneKEy-Osteovision, 2006 September;3(9):24-27.
(9) Brown JE, Cook RJ, Major P,
Lipton A, Saad F, Smith M, Lee KA, Zheng M, Hei YJ, Coleman RE., Bone
turnover markers as predictors of skeletal complications in prostate
cancer, lung cancer, and other solid tumors, J Natl Cancer Inst. 2005
Jan 5;97(1):59-69.
(10) Coleman RE, Major P, Lipton A,
Brown JE, Lee KA, Smith M, Saad F, Zheng M, Hei YJ, Seaman J, Cook R.,
Predictive value of bone resorption and formation markers in cancer
patients with bone metastases receiving the bisphosphonate zoledronic
acid, J Clin Oncol. 2005 Aug 1;23(22):4925-35. Epub 2005 Jun 27. Comment in: J Clin Oncol. 2005 Aug
1;23(22):4821-2.
(11) F. Saad, Benefits of
zoledronic acid in the treatment of prostate cancer: survival and
antitumor effects. Meeting: 2007 Prostate Cancer Symposium, Abstract No:
283.
(12)
Costa L, Demers LM, Gouveia-Oliveira A, Schaller J,
Costa EB, de Moura MC, Lipton A.,
Prospective evaluation of the peptide-bound collagen type I
cross-links N-telopeptide and C-telopeptide in predicting bone
metastases status,
J Clin Oncol. 2002 Feb 1;20(3):850-6.
(13)
Coleman RE, Major P, Lipton A, Brown JE, Lee KA, Smith M, Saad F,
Zheng M, Hei YJ, Seaman J, Cook R.,
Predictive value of bone resorption and formation markers in cancer
patients with bone metastases receiving the bisphosphonate zoledronic
acid,
J Clin Oncol. 2005 Aug 1;23(22):4925-35. Epub 2005 Jun 27. L Comment
in: J Clin Oncol. 2005 Aug 1;23(22):4821-2.
(14)
Brown JE, Cook RJ,
Major P, Lipton A, Saad F, Smith M, Lee KA, Zheng M, Hei YJ, Coleman RE. Bone turnover markers as predictors of skeletal complications in
prostate cancer, lung cancer, and other solid tumors,
J Natl Cancer Inst. 2005 Jan 5;97(1):59-69.
(15)
Laurence M. Demers, Luis Costa, Allan Lipton,
Biochemical markers and skeletal metastases Cancer, Volume 88, Issue S12, 2000. Pages 2919-2926.
(16) F. Saad, P. F. Mulders, A.
Lipton, K. Miller, The long-term benefits of zoledronic acid for
patients with genitourinary cancers. 2008 Genitourinary Cancers
Symposium (ASCO), abstract 378.
(17) F. Saad, D. M. Gleason, R.
Murray, N. S. S. Tchekmedyian, P. Venner, L. Lacombe, J. Chin, J. J.
Vinholes, M. Zheng, Y.-J. H, Continuing benefit of zoledronic acid for
the prevention of skeletal complications in men with advanced prostate
cancer.
Abstract No: 4575, ASCO.
