Somatostatin Analogs for HRPCa
Somatostatin analogs such as octreotide (e.g., Sandostatin) and lanreotide (e.g.,
Somatuline,) might have some activity against HRPCa, but generally as
single agents they have proven ineffective. When combined with
dexamethasone or an estrogen, however, they do have activity and
therefore might be useful during chemotherapy breaks or as a treatment
option to delay the start of chemotherapy. The
following report summarizes the various studies using somatostatin
analogs primarily in combination with dexamethasone or estrogens.
Definitions and Drug Names
IGF-1 - Insulin-like Growth Factor 1. IGF-1 plays a role in
inhibiting PCa cell death (apoptosis) caused by anti-cancer treatments.
Provides a "protective" effect to the cancer cells. There is
increased local bioavailability in the microenvironment of bone
metastases of IGF-1. Somatostatin analogs suppress IGF-1 production from
liver tissue.10
Somatostatin - this is a naturally occurring hormone produced in
many parts of the body. it signals the pituitary to reduce the
production of GH. As such it is known as a growth hormone
inhibitor (growth hormone and IGF-1.). Chemical messengers such as
gastrin are also reduced by somatostatin.
Sandostatin®(octreotide
acetate) - A short acting, synthetic version of somatostatin.
Sandostatin® LAR®
Depot, Novartis Pharma AG (octreotide acetate) - a long acting, synthetic version of
somatostatin. Formulated as a suspension in microspheres, it
dissolves slowly over 28 days allowing monthly injections (intragluteal).
lanreotide SR (Somatuline®,
Ipsen Biotech)
ethinyloestradiol (Lynoral) - a synthetic oral estrogen
(cardiovascular risk)
dexamethasone
- A glucocorticoid that minimizes the production of osteoblast-derived
growth factors such as IGF-1 (and transforming growth factor - β1).
CR Complete
Response
PR Partial
Response
SD Stable
Disease
PD Progressive
Disease
Clinical
Trials and Studies - Somatostatin analog only.
Maulard C et al
(1995)1 discussed a phase I-II clinical trial with 30
patients using a slow-release version of lanreotide. They suggested the
activity of lanreotide might be due to a reduction in the levels of
growth factors such as insulin growth factor 1 (IGF1). Each patient
received 30mg intramuscularly every week. Mean duration of
treatment was 12 weeks (range 2-60 weeks). PSA response rate (at
least a 50% decrease) was 20% and another 16% had a stabilized PSA.
Additionally, 40% had an improved performance status and 35% had reduced
bone pain. The response duration ranged from 16-60 weeks.
The authors indicated only minor toxicity -- a transient grade I
digestive side effect in a few patients. Thus monotherapy seems to have
only a minimal clinical response.
Clinical
Trials and Studies - Somatostatin analog and dexamethasone.
Koutsilieris M, et al (1999)2, described an "antisurvival
factor therapy" and had 4 patients (considered just to be a case
report). The therapy was aimed at reducing osteoblast-derived IGFs
(insulin-like growth factor). The 4 patients were hormone refractory
and were treated with 4mg dexamethasone every day, 30mg
lanreotide (somatostatin analog) intramuscularly every 14 days
along with triptorelin (3.75mg, I.M. every 28 days). All 4
patients had a response -- one had his PSA "normalized" (4 or less),
two had PSA responses of more than a 50% decrease in PSA and one had
stabilization of PSA (decline less than 50%).
Koutsilieris M, et al (2004)3
further examined this combination in 38 patients. The
therapy consisted of oral
dexamethasone (4 mg daily for the 1st month of treatment, tapered down to
1 mg daily by the 4th month after which 1mg daily was continued as a
maintenance dose and 20 mg octreotide i.m. injections every 28 days.
Patients also continued on LHRH-A. Some key results are in
the following table.
|
Koutsilieris et al (3) Summary of Results |
| |
Partial Response
≥ 50% decline in PSA |
Stable Disease
< 50% decline in PSA |
Progressive Disease |
| Objective Clinical Response |
23 (60.5%) |
9 (21.1%) |
7 (18.4%) |
| Time to Best Clinical Response |
Median of 3 months (2-6 mos.) |
- |
| Progression-free survival |
10 months |
7 months |
2 months |
This combination treatment reduced IGF-1 levels from an average of
181.6 ng/ml to 93.9 at PSA nadir. IGF-1 levels also stayed low at
disease progression. It should be noted that both octreotide and
dexamethasone reduce IGF-1 levels.
Interestingly, 3 patients improved in pain and performance status, but
had increases in PSA (less than 15% above baseline values) and then had
declines of > 50% with continued improvement in pain and performance
scores after 3 months. The median overall survival of patients in
this study was 14 months. Of note when considering this as a between
chemotherapy treatment (chemo holiday) -- 17 patients (44.7%) had
previously received chemotherapy (emcyt + etoposide or mitoxantrone +
prednisone.) Additionally, when viewed as a treatment to prevent a PSA
rise when off chemotherapy, there were 32 of the 38 patients who fell into
this category.
Also important was the toxicity of this treatment --
| Symptom |
Result |
Time |
No. and % |
| transient hyperglycemia |
max fasting blood glucose was ≤160 ng/dl |
only during 1st 2 months of treatment |
10 (26.8%) |
| mild facial Cushingoid features |
|
- |
12 (31.58%) |
| mild to moderate proximal muscle weakness |
subsided following protocol's tapering down of
dexamethasone |
- |
5 (13.16%) |
| mild epigastric-intestinal discomfort (cramps) |
controlled with oral antacids and / or supplements of
pancreatic enzymes |
- |
6 (15.8%) |
Dimopoulos MA, et al(2004)4
compared LHRH-A (triptorelin 3.75 mg intramuscularly every 28 days),
somatostatin analog (lanreotide 30 mg intramuscularly every 14 days) and
dexamethasone (4 mg tapered to 1 mg) with chemotherapy. The
chemotherapy group received estramustine 140 mg three times daily and etoposide
100 mg orally for 21 days -- an all oral chemotherapy. There
40 patients -- group 1 received the chemotherapy and from this group 20
patients' data was analyzed. Group 2 was the somatostatin analog
group and 18 of these patients' data was analyzed.
|
Dimopoulos MA, et al(2004)4
Results Summary
(b)
|
| |
Group 1 - Chemotherapy |
Group 2 - Somatostatin analog |
| PSA Response (at least a 50% decrease) |
45% (a) |
44% (a) |
| Bone Metastases |
|
|
| CR |
0 |
0 |
| PR |
12% |
13% |
| SD |
47% |
31% |
| PD |
41% |
56% |
| Measurable Disease |
|
|
| CR |
0 |
0 |
| PR |
29% |
30% |
| SD |
29% |
20% |
| PD |
42% |
50% |
| Changes in performance status and pain score |
not significantly different |
not significantly different |
|
Hematologic toxicity
Neutropenia/Anemia/Thrombocytopenia |
60/80/40% |
0/22/0% |
| Mild diabetes |
0 |
22% of patients |
| Overall survival |
18.8 months (a) |
18 months (a) |
| Time to Progression (overall) |
6 months |
4 months |
| Time to progression in PSA responder subgroup |
8 months (a) |
7.7 months (a) |
| Diarrhea |
20% |
6% |
| Fluid Retention |
40% |
33% |
(a) the difference between groups 1 and 2 were not
statistically different. (b) no data was given on IGF-1
levels. The median time for a PSA response
was 7 weeks in the chemotherapy group and 9 weeks in the combination
therapy group. This means that some patience must be exercised when
doing this therapy -- i.e., not quit it too soon. The somatostatin
analog combination looks very good compared to this particular
chemotherapy. Whether this would be true when compared to, say, say, taxotere and
prednisone cannot be said, but it does look like a good alternative
"second line" hormonal therapy. Clinical
Trials and Studies - Somatostatin analogs and Estrogen.
Di Silverio F and Sciarra A (2003)5 used ethinylestradiol
(1mg orally every day) and 73.9 mg lanreotide acetate intramuscularly
every 4weeks. LH-RH analogue was discontinued in this study. The
ethinylestradiol serving to suppress testosterone. There were 10
patients in the study. The PSA response rate (RR) (at least a 50%
decrease in PSA) was 90% (range 50.2% to 94.4%). Bone pain was improved
in all patients with a median duration of 17.5 months and performance
status was also improved in all patients with a median duration of 18
months. The median progression free survival was 18.5 months. There was also a statistically significant decrease in
serum Chromogranin A (CgA) while under treatment and it did not increase
at relapse. The median maximal decrease was 38.4% (range 28.6 to 64.9%). CgA
was not increased at relapse. This small study looks good, but
further work is needed to get some statistical data.
A review article
by Sciarra A et al (J. Urol. 2004)6 has also looked at the
combination of estrogens and somatostatin analogs. Their result
indicated negative experiences with somatostatin analogs used as
monotherapy as opposed to the positive result with combination
therapy.5 They also note that the combination therapy
targets the microenvironment of the cancer cells, this microenvironment
possibly conferring protection from apoptosis for them. In (5)
they had studied only 10 patients. However, in the present paper
they indicate that as of January 2004 they have data on 20 patients
using the lanreotide/ ethinylestradiol combination therapy. They
had 19 of 20 patients (95%) experience a PSA response of at least a 50%
decrease. These patients also experienced improvement in their European
Cooperative Oncology Group (ECOG) performance status scores and lessened
bone pain. CgA was also lowered as seen in the earlier cohort of
patients.
What is called a
case report (really an anecdotal report, but documented) was published
by Cerulli C. et al (Urology 2004.)7 This was one
patient was put on estramustine and lanreotide. The patient had failed
androgen deprivation (leuprorelin acetate 11.25mg every 12 weeks plus
bicalutamide 50mg daily.) These two drugs were discontinued for 2
months and PSA continued to rise (it is very unusual to stop the
leuprorelin acetate in addition to stopping the antiandrogen
bicalutamide.) The amount of oral estramustine (emcyt) taken was 420mg/day and the lanreotide acetate was
73.9mg i.m. every 4 weeks. The patients PSA dropped from 21.30ng/mL to
.10 and his chromogranin A level was down to 12ng/mL from 816 (after 33
months of follow-up). There was no clinical disease progression.
Nowhere to the authors mention what this patient's testosterone level
was. Stopping the Lupron may have resulted in testosterone
increase and the rise in PSA and the improvement seen might have been
due to the antiandrogen withdrawal response that was masked by the
rising testosterone level.
Cerulli C. et al
mention that the somatostatin analog was aimed at inhibiting the
protective antiapoptotic effect of the neuroendocrine system on prostate
cancer and the estramustine provided a "new" castration mechanism as
well as some direct cytotoxic effect on the prostate cancer. It would be
nice to see a large clinical trial to examine this combination more
thoroughly.
| Summary of
Di Silverio F and Sciarra A (2003)5 , Sciarra A et al (J. Urol. 2004)6 and
Cerulli C. et al (Urology 2004.)7 - Somatostatin
analogs and Estrogens |
| Reference |
# of patients |
PSA RR (>50% drop) |
Median Progression free
survival(months) |
| (5) Di Silverio et al |
10 |
90% |
18.5 months |
| (6) Sciarra et al |
20 |
95% |
- |
| (7) Cerulli et al |
1 (case report) |
PSA 21.3 reduced to .10, CgA decreased |
> 33 months |
A Possible
Caution
A cautionary
note -- in a paper by Logothetis CJ et al8 (1994), 22
patients received octreotide 100mg s.c., every 8 hrs over 6 weeks.
They found that Octreotide stimulates prostatic tumor growth and may
sensitize tumor cells to subsequent chemotherapy (5 of 6 patients who
were put on salvage chemotherapy had objective tumor regressions).
This is not a very promising result as far as it goes and there does not
seem to be any followup study of this.
Side
Effects/Interactions
For more
information on side effects and drug interactions, see the prescribing
information or the PDR. Links for this are listed below.
Discussion
Based on the above papers, it would seem that either adding
dexamethasone or estrogen to a somatostatin analog would prove
beneficial to hormone refractory prostate cancer patients.
The combination of somatostatin analogs and an estrogen carries some
risk of blood clots -- especially if an oral form is used (e.g.,
estramustine, ethinylestradiol) and thus some form of anticoagulation
is warranted, although it seems, seldom used.
There are no
reports on the use of transdermal estrogen patches as the source of
estrogen. Certainly as used by A. Sciarra et al without an LHRH
analog, the estrogens plus somatostatin analog combination has an
advantage. The other advantage of the estrogen combination vs
the dexamethasone combination is the median progression free survival
was 18.5 months with estrogen use and only 7 months for the
dexamethasone combination.
The questions arises as to what dose is appropriate for sandostatin
LAR plus an estrogen for maximal suppression of IGF-1? Little has
been done in this area. As near as this author can find, there
is no phase I dose escalation study of Sandostatin LAR in prostate
cancer, although there is data from studies with acromegaly. The above studies with estrogen used lanreotide at a 4
weekly dose of 73.9mg. A paper by P. Chanson et al9
indicated a dose of 20mg(22.4 mg actual) octreotide (1x/4 weeks) was
more effective than 60mg lanreotide (30mg 2x/4 weeks) in the patients
studied. One can extrapolate from the 73.9mg dose (perhaps a big
assumption) of lanreotide used in the above studies and get about 28mg
for the equivalent dose of octreotide - the next closest dose being
30mg. Octreotide (sandostatin LAR) comes in 10mg, 20mg, 30mg
formulations.
Koutsilieris M, et al (2004) 3
used 20mg octreotide (sandostatin LAR) and dexamethasone and got
substantial reduction in IGF-1, but the dexamethasone played a part in
this reduction. Davies PH et al, 10 used doses of
sandostatin LAR from 20-40mg for up to 3 years. After 1 year
they saw decreases of IGF-1 from 155pg/mL to 103pg/mL. One could
increase the dose of sandostatin and measure IGF-1 levels, but that
would require more than one injection at a time and quite possibly,
based on Davies paper, 30mg would be quite sufficient.
The usual prescription guidelines indicate that patients are started
on short acting Sandostatin injected subcutaneously at low dose for up
to two weeks before switching to the LAR formulation. Any patients
considering this therapy should work out an appropriate schedule of
starting it with their oncologist. RXList.com indicates, "The
most common adverse events are gastrointestinal, which usually begin
within the first few days of administration and usually subside within
2 to 8 weeks. In clinical trials, <3% of patients discontinued
Sandostatin® Injection because of G.I. symptoms."
The Novartis website has guidelines located at
Information on lanreotide SR is at
Note: The author is not a medical doctor and cannot render medical
advice. As a prostate cancer patient, this was written in an attempt to
understand these treatments and how it affects me. I make no claims that
this review is definitive, complete or authoritative and I request any
contributions to, or clarification of the subject which might contribute to
the issue or inquiry. In conjunction with a medical team, every cancer
patient must make their own decisions regarding treatment options. Your own
medical team's directions should be carefully followed.
References
1. Maulard C, Richaud P, Droz JP, et al: Phase I-II study of the
somatostatin analogue lanreotide in hormone-refractory prostate cancer.
Cancer Chemother Pharmacol 36:259-62, 1995.
2 . Koutsilieris M, Tzanela M, Dimopoulos T: Novel concept
of antisurvival factor (ASF) therapy produces an objective clinical
response in four patients with hormone-refractory prostate cancer: case
report. Prostate 38:313-6, 1999.3.
Koutsilieris M,
Mitsiades CS,
Bogdanos J,
Dimopoulos T,
Karamanolakis D,
Milathianakis C,
Tsintavis A., Combination of
somatostatin analog, dexamethasone, and standard androgen ablation
therapy in stage D3 prostate cancer patients with bone metastases, Clin
Cancer Res. 2004 Jul 1;10(13):4398-405.
4.
Dimopoulos MA,
Kiamouris C,
Gika D,
Deliveliotis C,
Giannopoulos A,
Zervas A,
Alamanis C,
Constantinidis C,
Koutsilieris M., Combination of LHRH
analog with somatostatin analog and dexamethasone versus chemotherapy in
hormone-refractory prostate cancer: a randomized phase II study,
Urology. 2004 Jan;63(1):120-5.
5. Di Silverio F, Sciarra A: Combination therapy of
ethinylestradiol and somatostatin analogue reintroduces objective
clinical responses and decreases chromogranin a in patients with
androgen ablation refractory prostate cancer. J Urol 170:1812-6, 2003.
6. Sciarra A,
Bosman C, Monti G, Gentile V, Gomez AM, Ciccariello M, Pastore A,
Salvatori G, Fattore F, Di Silverio F., Somatostatin analogues and
estrogens in the treatment of androgen ablation refractory prostate
adenocarcinoma, J Urol. 2004 Nov;172(5 Pt 1):1775-83.
7. Cerulli C, Sciarra A, Salvatori G, Di Silverio F.,
Long-term response to combination therapy with estramustine and
somatostatin analogue in a patient with androgen ablation-refractory
prostate cancer, Urology. 2004 Dec;64(6):1231.
8. Smith TL, SMS 201-995 in the treatment
of refractory prostatic carcinoma, Anticancer Res. 1994
Nov-Dec;14(6B):2731-4.
9. P. Chanson, et al, Comparison of octreotide acetate
LAR and lanreotide SR in patients with acromegaly, Clinical
Endocrinology, Volume 53 Issue 5 Page 577 - November 2000.
10. Davies PH, Stewart SE, Lancranjan L, Sheppard MC,
Stewart PM., Long-term therapy with long-acting octreotide (Sandostatin-LAR)
for the management of acromegaly, Clin Endocrinol (Oxf). 1998
Mar;48(3):311-6.
A recent review
article by A. Sciarra et al is worthwhile reading. See
Alessandro Sciarra*, Gianna Mariotti, Anna Maria Autran Gomez, Franco Di
Silverio, Role of somatostatin analogues in the treatment of
androgen ablation-refractory prostate, Cancer Therapy Vol 3, 159-166,
2005
(Last updated 4/21/06 by H. Hansen)
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