Figure 1. Rationale for our
combination therapy with somatostatin analogue and estrogen
Cancer Therapy Vol 3, 159-166, 2005
Role of somatostatin analogues in the treatment of androgen
ablation-refractory prostate adenocarcinoma
Alessandro Sciarra*, Gianna
Mariotti, Anna Maria Autran Gomez, Franco Di Silverio
Department of Urology, University
La Sapienza, Rome, Italy
__________________________________________________________________________________
*Correspondence: Dr. Sciarra Alessandro, Department of Urology, University La Sapienza, Via
Nomentana 233, 00161 Rome, Italy; Tel./Fax +39 6 44 6959 ; e-mail:
sciarrajr@hotmail.com
Key words: prostate
neoplasms, somatostatina analogues, neuroendocrine
Abbreviations:
antisurvival, (ASF); chromogranin A, (CgA); combined androgen blockade, (CAB);
computerized tomography scan, (CT); Growth Hormone, (GH); insuline-like growth
factor, (IGF); neuroendocrine, (NE); progression –free survival, (PFS);
prostate specific antigen, (PSA); somatostatin receptors, (SSTR);
Summary
The
progression to androgen ablation-refractory stage (D3) of prostate cancer
corresponds to cancer cell escape from androgen withdrawal-induced apoptosis.
Of note, salvage chemotherapy cannot extend the median survival of
approximately 10 months for stage D3 patients. Novel therapeutic strategies
that target the molecular basis of androgen resistance are therefore required.
We reviewed the literature on the use of somatostatin analogues in the
treatment of D3 prostate adenocarcinoma and we analysed the rationale and
clinical results of our combination therapy using lanreotide and
ethinylestradiol. Negative experiences have been reported on the use of
somatostatin analogues in monotherapy. On the other hand, interesting results
have been obtained as combination therapy and the median progression free
survival reported in our experience using lanreotide acetate plus
ethinylestradiol, clearly surpassed the 10 months survival historically
described for stage D3 patients. The use of somatostatin analogues in
combination therapy for the treatment of D3 prostate cancer, sustains the novel
concept in cancer treatment in which therapies may target not only cancer cell
itself but, in combination, also its microenvironment, which can confer
protection from apoptosis.
The progression to androgen
ablation-refractory stage (D3) of prostate cancer corresponds to cancer cell
escape from androgen withdrawal-induced apoptosis (Landstrom et
al, 1994).
Of note, salvage chemotherapy can extend the median survival of approximately
10 months for stage D3 patients (Koutsilieris et al, 1990; Hudes et al, 1992). Novel therapeutic
strategies that target the molecular basis of androgen resistance are therefore
required.
We previously proposed a combination
therapy of ethinylestradiol and somatostatin analogue to reintroduce objective
clinical responses in metastatic androgen ablation-refractory prostate cancer
patients (Di Silverio and Sciarra, 2003).
The purpose of this article is to
review the literature on the use of somatostatin analogues in the treatment of
prostate adenocarcinoma and to analyse the rationale and clinical results of
our combination therapy.
II. Somatostatin analogues in monotherapy
Native somatostatin
is characterised as an inhibitory peptide with exocrine, endocrine and
autocrine activity (Newman et al, 1987). The general inhibitory function of somatostatin
is wide ranging and affects a number of organ systems.The effect of
somatostatin on various organ systems are thought to be mediated via specific
somatostatin receptors (SSTR). To date, five different subtypes (SSTR 1-5) have
been identified and cloned in human tissue (Hejna et al, 2002). While all
five subtypes display a similar affinity to somatostatin, there are major
differences in binding of currently available somatostatin analogues (Pollak
and Schally, 1998) to various SSTR subtypes. Investigations concerning the
exact intracellular mechanisms effected by different SSTRs with regards to
cellular proliferation and induction of apoptosis are ongoing. Recently, SSTR
subtype expression has been characterized in various neoplastic tissues (Reubi et al, 2001). There
appears to be a predominance of only one or two SSTR subtypes in most tumors
investigated. There is a clear predominance of SSTR 1 expression in prostate
cancers, which may also express SSTR 5. The highly SSTR 2 affine octapeptide
somatostatin analogues such as octreotide remains the drugs of choice for
application in a majority of pure neuroendocrine tumors, since such tumors most
often express predominantly SSTR 2 (Pollak and Schally, 1998). However, other
somatostatin derivates, such as lanreotide, which have a good affinity of SSTR
5 in addition to that for SSTR 2, may advantageously identify SSTR 5 expressing
tumors, such as prostate adenocarcinoma.
Somatostatin
analogues, however, seem to interact at tissue level, also through a receptor
binding independent mechanism (Hejna et al, 2002).
Long-acting
somatostatin analogues have been developed, specifically designed for antitumor
activity. Schally, (1988) synthesised > 300 analogues using solid-phase
methods resulted in octapeptide Òsuper analoguesÓ, which are more potent and
have longer durations of action than either native somatostatin and octreotide.
Several clinical
trials have demonstrated impressive efficacy of somatostatin analogues in a
variety of hypersecretory disorders resistant to standard therapy (Hejna et al, 2002). They have
also proved useful for the management of symptoms caused by neuroendocrine diseases.
The primary effect of somatostatin analogues is not a direct cytotoxic effect
of neuroendocrine cells but the inhibition of the release of various peptides
hormones secreted by neuroendocrine cells (Hejna et al, 2002). The
observation that somatostatin analogues inhibit the release of various
neuroendocrine products has stimulated interest in its use as an
antiproliferative and proapoptotic agent. Antiproliferative and proapoptotic
actions of somatostatin analogues have been demonstrated in various tumor
models including breast, prostate, colon, pancreatic (Murphy et al, 1987; Schally,
1988; Smith and Solomon, 1988).
Moreover,
somatostatin analogues have a wide therapeutic index and are apparently free of
major side effects (Schally, 1988). Most of the reported side-effects are
gastrointestinal in nature and include minor nausea, diarrhoea, constipation.
Clinical trials and
experiences on the use of somatostatin analogues as monotherapy for the
treatment of prostate cancer, reported negative results (Table 1) (Carteni et al, 1990; Dupont et al, 1990; Logothetis et al, 1994; Verhelst et al, 1994; Figg et al, 1995; Maulard et al, 1995; Vainas et al, 1997; Koutsilieris et al, 2001; Di Silverio
and Sciarra, 2003). Octreotide was used to treat patients with advanced
hormonal-refractory prostate cancer in a study by Logothetis et al, (1994).
Table
1.
Hormone-refractory prostate cancer: clinical experiences with somatostatin
analogues
|
Treatment |
Dosage
|
Number cases
|
Results
|
Reference
|
|
Octreotide |
100mg tds s.c. |
7 |
Pain reduction |
Carteni et al, 1990 |
|
Octreotide |
600-1350mg/day s.c. |
10 |
Disease progression after 21 days |
Dupont et al, 1990 |
|
Octreotide |
400-1000mg/day s.c. |
5 |
Temporary halt in PSA rising |
Verhelst (28) |
|
Octreotide |
100mg qds s.c. |
22 |
Stimulation of prostate tumor growth |
Logothetis et al, 1994 |
|
Lanreotide |
30mg once a week i.m. |
30 |
20% partial response (PSA decrease) 40% improvement performance status |
Maulard et al, 1995 |
|
Lanreotide |
4-24 mg/day s.c. |
25 |
No modifications |
Figg et al, 1995 |
|
Octreotide |
Not clarified |
14 |
Symptom-free responses |
Vainas et al, 1997 |
|
Lanreotide plus dexamethasone |
30 mg/14 days i.m. + 4 mg/day os |
11 |
90% objective (PSA decrease) and symptomatic
response Progression-free survival =7 months |
Koutsilieris et al, 2001 |
|
Lanreotide acetate plus ethinylestradiol |
73.9 mg i.m. every 4 weeks + 1 mg/day os |
10 |
90% objective (PSA decrease) and symptomatic
response Progression-free survival = 18.5 months |
Di Silverio and Sciarra, 2003 |
The dose of
octreotide applied to 24 cases was 0.1 mg s.c. every 8 h for 6 weeks. No
patients had objective evidence of tumor regression and in 10 cases serum
prostate acid phospatase level rose at an accelerated rate after 1-2 months of
treatment. However, 6 patients underwent salvage chemotherapy after octreotide
therapy and 5 of whom achieved objective tumor regression. The authors
therefore concluded that octreotide monotherapy might stimulate prostatic tumor
growth but may also sensitise tumor cells to subsequent chemotherapy.
A total of 30
patients with hormone-refractory prostate cancer were treated with a
slow-release formulation of lanreotide (30 mg i.m. once a week) by Maulard et
al, (1995). Toxicity related to the treatment was minor, performance status and
bone pain improved in 40% and 35% of patient respectively, but a PSA decrease
by at least 50% was reported only in 20% of cases.
III. Somatostatin analogues in combination therapy: it exist a rationale
The mechanism of
action of somatostatin analogues may suggest the use of these drugs not in
monotherapy but in combination therapy for tumors such as prostate cancer. Also
in breast cancer favourable results have been obtained by the use of
somatostatin analogues in combination therapy. Twenty-two post-menopausal
patients with metastatic breast cancer were randomised to receive either
40mg/day of tamoxifen or a combination consiting of 40 mg tamoxifen plus 0.2 mg
of octreotide tds s.c. (Bontenbal et al, 1998). An objective response
was found in 36% of the patients treated with tamoxifen alone and in 55% of
patients treated with the combination therapy.
The management of
metastatic neoplasias has traditionally relied on therapeutic modalities, which
almost exclusively aim at directly inducing cancer cell death. However, the in
vivo response of malignant cells to anticancer therapies is directly influenced
by the local microenvironment in which they reside (or metastasise)
(Koutsilieris et al, 2002).Microenvironment factors may attenuate the antitumor activity of
several cytotoxic agents on neopalstic cells.In particular, organ sites
frequently involved in metastatic advanced diseases, appear to confer to
neoplastic cells protection from anticancer drug-induced apoptosis. This
protection may be mediated by several mechanisms including growth factors
cytokines released by the normal cellular constituents of the host-tissue
microenvironment (Koutsilieris et al, 2000). Therefore additional emphasis should be placed
on the design of novel treatments that can neutralise the protection that the
microenvironment offers to tumors cells. An example of the role of the
microenvironment in protecting tumor cells from anticancer therapies is within
the setting of hormone- refractory prostate cancer. For years, it has been a
widely accepted notion that resistance to hormonal therapy is an outcome
exclusively determined at the genetic level and involving mutations that
neutralise pro-apoptotic intracellular pathways and/or activates anti-apoptotic
ones (Koutsilieris et al, 2002). It is now well documented that this resistance can also be
conferred by epigenetic mechanisms (Sciarra et al, 2003a). These mechanisms
result from the interaction of the tumor cells with the local microenvironment,
either at local or metastatic sites. Major mediators of this interaction are
neuropeptides secreted by neuroendocrine (NE) cells in prostate tissue and
insuline-like growth factor (IGF) –1. The locally bioavailability of
these peptides and growth factors on prostate cancer cells, activates
anti-apoptotic mechanisms more than proliferative direct effects. These
represent real survival pathways involved in prostate cancer progression and
androgen-deprivation therapy resistancy. The development of survival
factor-mediated resistance to anticancer therapies is a major hurdle preventing
long-lasting clinical responses to conventional or investigational therapies
(Koutsilieris et al, 2002). This realisation has led to the novel concept of antisurvival
(ASF) therapy for prostate cancer as a component of anticancer treatments and
to the concept of a combination therapy for hormone-refractory disease.This
approach is novel as instead of attempting to directly induce cancer cell
apoptosis, it aims at neutralising the protective effect conferred upon cancer
cells by the survival factors. This neutralisation alone may not induce
apoptosis, but it can enhance the sensitivity or reverse the resistance of
tumors cells to other anticancer strategies with direct cytotoxic effects
(Reyes-Moreno et al, 1998; Koutsilieris et al, 2000, 2002).
On these basis,
Koutisileris et al, (2001) firstly proposed a combination therapy with
dexamethasone and long acting somatostatin analogue in stage D3 prostate cancer
patients, i.e. patients with metastatic prostate cancer who had become
refractory to combined androgen blockade. In this setting, Growth Hormone (GH)
– independent and GH-dependent production of IGF-1 has been implicated in
the development of a epigenetic form of cancer cells resistance to
pro-apoptotic therapies. Among its diverse pharmacological effects,
dexamethasone acts to downregulate the GH-independent production of IGF-1,
whereas somatostatin analogue suppresses the level of GH-dependent IGF-1. This
paradigm of an ASF therapy, which was practically an anti-IGF-1 therapy,
yielded objective responses and major improvement of bone pain and performance
status in D3 cases. The treatment schedule includes administration of oral
dexamethasone plus long acting somatostatin analogue (lanreotide or octreotide
in i.m. injections) in combination with androgen ablation therapy.In the initial
cohort of patients receiving the combination therapy the median overall
survival clearly surpassed 12 months and also their post-relapse performance
status and bone pain were still significantly improved compared to their
baseline status, even months after relapse.
The stimulating
feature of this ASF approach is that its combination with LHRH-analogues can
reintroduce clinical responsiveness to LHRH analogues.
IV. Somatostatin analogues in combination with estrogens
We previously
analysed (Di Silverio and Sciarra, 2003) for the first time in the literature,
whether, in patients with stage D3 prostate cancer, the combination of
ethinylestradiol and lanreotide can offer objective responses and/or
symptomatic improvements.
We followed the
study design used by Koutsilieris et al, (2001). As Koutsilieris et al, (2001)
we evaluated patients with metastatic androgen ablation-refractory prostate
cancer. However, differently to Koutsilieris et al, we discontinued the LHRH
analogue and we started a combination therapy with ethinylestradiol and
lanreotide acetate.
The rationale for
our combination therapy is: 1- to inhibit the protective (antiapoptotic) effect
of NE system on prostate adenocarcinoma cells (somatostatin analogue); 2- to
use a new mechanism to induce castration (estrogen); 3- to add a direct
cytotoxic effect on prostate cells (estrogen) (Figure 1). Some studies have shown that the number of NE tumor
cells (25-25) and chromogranin A (CgA) serum levels increase during hormonal
therapy (Abrahamsson, 1996; Angelsen et al, 1997;
Monti et al,
2000;
Sciarra et
al, 2003a,
b) for prostate adenocarcinoma. As previously underlined, at the cellular
level, refractoriness to androgen ablation therapy occurs principally because
prostate cancer cells can be rescued from androgen ablation-induced apoptosis.
It has been shown that Bcl2 proto-oncogen, which is an antiapoptotic factor, is
preferentially expressed in foci of prostate adenocarcinoma cells in the
vicinity of NE differentiation (Segal and Cohen, 1994; Jongsma et al, 2000). In hormone-
refractory (D3) prostate cancer, NE cells may protect prostate adenocarcinoma
cells from anticancer therapies through the neutralization of pro-apoptotic
intracellular pathways.
The rationale for
somatostatin-analogue therapy in D3 prostate tumor is not to directly induce
cancer cell apoptosis but to neutralize the protective effect conferred upon
cancer cells by the survival factors derived by NE prostate cells.
The
antigonadotropic effect of estrogens has been exploited therapeutically. Both
experimental and clinical evidence suggest that estrogen therapy may be
superior to castration in terms of efficacy for the treatment of advanced
prostate cancer (Robinson et al, 1995; Chang et al, 1996; Rosenbaum et al, 2000; Smith et al, 2000). Moreover,
analysing prostatectomy specimens of untreated and treated (CAB) prostate
cancer patients, Kruithof-Dekker et al, (1996) showed that androgen deprivation
leads to an upregulation of estrogen receptor expression in prostate cancer
tissue. It has been supposed that the beneficial effect of estrogens is based
not only on reduction of the androgen concentration but also on a simultaneous
direct cytotoxic effect (Hudes et al, 1992) on prostate cancer cells. All these data support
our rationale: to discontinue LHRH-analogue and to substitute it with estrogen
therapy. An important question is whether responses achieved in our study most
likely constitute an indirect evidence of a potential survival benefit offered
by the combination therapy rather than a response to lanreotide only or
ethinylestradiol only.
As previously
showed, in advanced hormonal-refractory prostate cancer, negative experiences
have been reported on the use of somatostatin analogues in monotherapy (Carteni
et al, 1990; Dupont et al, 1990; Logothetis et al, 1994; Verhelst et al, 1994; Figg et al, 1995; Maulard et al, 1995; Vainas et al, 1997). On the other
hand, the median progression free survival reported in our study clearly
surpassed the 10 months survival historically described for stage D3 patients,
even when estrogen therapy or salvage chemotherapy is administered (Hudes et al, 1992; Chang et al, 1996).
However, additional
studies will be required to fully elucidate the precise in vivo mechanism of
action for the combination of estrogens with somatostatin analogues.
As for the study of
Koutsilieris et al, (2001) the design of our pilot trial involved a
longitudinal methodology, as defined by Spilker (1991), which is appropriate
for study of even small cohorts of patients. In our first experience (Di
Silverio and Sciarra, 2003), we prospectively evaluated 10 consecutive patients
with stage D3 disease, who received a combination therapy
Figure 1. Rationale for our
combination therapy with somatostatin analogue and estrogen
consisting of the following:
1)oral ethinylestradiol (1mg daily); 2) lanreotide (lanreotide acetate 73.9 mg
in every 4 weeks). None of these cases had a history of severe cardiovascular
diseases, neither a history of other disorders or therapies or conditions known
to interfere with CgA levels. All patients had diffuse skeletal metastases
(> 3 metastatic foci) documented by radionuclide bone scan and computerized
tomography scan (CT). All patients had previously experienced objective
clinical responses to combined androgen blockade (CAB) using triptorelin plus
antiandrogen (flutamide, bicalutamide) documented by prostate specific antigen
(PSA) decline by more than 50% of baseline, which had lasted for less than 24
months. Upon progression, all patients were withdrawan from antiandrogens for
at least 6 weeks (no patients responded). Therefore, all patients discontinued
CAB and received the combination therapy ethinylestration plus lanreotide (Figure 2). In this first experience,
90% (95%CI =55.5-99.8%) of cases had objective (complete= PSA < 4 ng/ml, or
partial= at least 50% PSA decrease from baseline) clinical response to the
combination therapy, corresponding to a statistically significant (in
comparison to the baseline refractoriness) rate of re-introduction of
responsiveness to the combination with lanreotide and ethinylestradiol
(McNemarÕs paired c2 test; p<0.01).
In responders, median time to PSA nadir was 5 months (range 3-12 months; 95% CI
4-8 months). In all cases, the PSA responses were accompanied by concomitant
statistically significant reduction in bone pain score (p=<0.0001), as well
as significant improvement in the ECOG performance status score (p<0.0001).
The symptomatic improvement of pain and performance status appeared to be
temporally associated with the changes in objective response markers and it is
suggested that the main mechanism of action of this combination therapy affects
those mechanisms regulating the growth and/or survival of the metastatic cells,
rather than involving a non-specific anti-inflammatory or analgesic effect (Koutsilieris et al, 2001). The rates
and the time to achieve the symptomatic and objective responses that we
described, are comparable to those reported in the study of Koutsilieris et al,
(2001). However, with our combination therapy we obtained a longer duration of
objective responses. In particular, median duration of bone pain response, ECOG
response and progression –free survival (PFS) was 17.5 (95% CI 12-19), 18
(95% CI 12-19) and 18.5 (95% CI 14-21) months respectively in our study and 13
(95% CI 12-14), 19 (95% CI 13-25) and 7 (95% CI 3-10) months in the study of
Koutsilieris et al, (2001) We analysed modifications in serum CgA levels during
the combination therapy. Comparison of serum CgA levels at baseline, during
follow-up, at maximal response and at relapse from therapy revealed a
significant change of CgA levels during the course of the combination therapy
(P<0.0001; FriedmanÕs nonparametric ANOVA). We observed a significant
decrease in serum CgA levels during the administration of the combination
therapy (median value of maximal CgA decline = 38.4% of baseline levels; 95%CI
33.2-50.3% range 28.6%-64.9%), as compared with the baseline CgA levels.
In our patients,
time to CgA nadir was lower than time to PSA nadir; therefore it seems that CgA
response preceded PSA response. Our baseline levels of CgA were similar to
those reported in other experiences on metastatic prostate cancer cases
(Jongsma et
al, 2000;
Sciarra et
al, 2003b).
The significant reduction of circulating CgA, documented in this cohort of
patients suggests that a reduction of NE activity on prostate cancer cells may
be a mechanism accounting for at least part of the encouraging responses that
were observed. Interestingly, the patientsÕserum CgA levels were not
significantly increased
Figure 2. Study design for our
trial (4) on lanreotide acetate and ethinylestradiol combination therapy in D3
prostate cancer cases.
at relapse suggesting that NE
activity may be not involved at relapse from this combination therapy. The
modifications in CgA levels reported in our study are lower if compared with
those observed in pathologically confirmed NE tumors such as small cell
carcinoma of the lung. However, we must remember that NE differentiation of
prostate adenocarcinoma consists of the presence of NE cells with a focal
distribution in the common prostatic adenocarcinoma (Jongsma et al, 2000; Sciarra et al, 2003b). A limit of
our analysis may be the determination of only serum expression of CgA. However,
none of our cases presented a history of other disorders known to interfere
with CgA levels. Some authors reported a significant correlation between serum
and tissue expression of CgA in prostate cancer (Jongsma et al, 2000; Sciarra et al, 2003b). Moreover,
in 8 cases we had the opportunity to analyse CgA expression at prostate tissue
level by immunohistochemistry. Prostate tissue specimens were obtained by
transrectal ultrasound-guided prostate biopsy and formalin fixed and paraffin
embedded prostate specimens were sectioned to 5mm thick prior to the analysis. Diffuse immunohistochemical staining for
CgA was found in biopsies obtained in D3 cases at baseline from our therapy. On
the contrary a limited and focal staining for CgA was showed in cases with
objective clinical response to our combination therapy.
No major treatment
related side effects were reported during the combination therapy. In
particular no serious cardiovascular renal, or liver-gastrointestinal events
were found during the follow-up, with the exception of transient mild
epigastric discomfort, effectively controlled with antacid regimen. None of our
10 cases discontinued the treatment due to side effects related to the
combination therapy. All cases developed gynecomastia and mild breast pain. It
is true that none of our cases had a history of severe cardiovascular diseases
at baseline, but the dose (1 mg) of ethinylestradiol and the duration of
follow-up (no longer than 24 months) may also contribute for differences with
other experiences on estrogen therapy (Robinson et al, 1995; Rosenbaum et al, 2000; Smith et al, 2000).
At January 2004, 20
D3 cases have been included in our analysis and submitted to the combination
therapy with ethinylestradiol and lanreotide (Sciarra et al, 2004). Criteria for inclusion and study protocol were similar to those
previously described (Di Silverio and Sciarra, 2003).
Results continue to
be encouraging and supporting the rational for our combination therapy.In
particular, at January 2004 19 out of the 20 cases (95%) showed objective
(complete = 5 cases (25%) or partial = 14 cases (70%)) clinical response to the
combination therapy demonstrated by at least 50% PSA decrease from baseline. In
only one case the biochemical response was accompanied by a reduction in the
number of bone metastases at bone scan. Two out of the 20 patients (10%) died,
both of prostate cancer (at 10 and 16 months respectively) and 6 cases (30%)
developed clinical progression (rising PSA levels to more than 50% of PSA
nadir) (mean of 7.8 months, median of 7 months, range 4-12 months) during the
follow-up. All other 14 patients (70%) are still alive without disease
progression after a median of 16.5 months (mean of 13.9 months, range 4-24
months) of follow-up during the combination therapy (Sciarra et al, 2004).
V. Conclusions
It should be
emphasized that any conclusion regarding the usefulness of this combination
therapy, in comparison to other proposed treatment strategies for stage D3
prostate cancer, can only be drawn in randomised controlled clinical trials.
The results of our study indicate that such randomised trials are warranted,
because the combination of ethinylestradiol and lanreotide had a favourable
toxicity profile, offered objective and symptomatic responses in patients with
limited treatment options and refractoriness to conventional hormonal therapy
strategies and in particular, offered a median overall survival that was
superior to the 10 -month median survival for hormone-refractory patients.
This combination
therapy also sustains the novel concept in cancer treatment in which therapies
may target not only cancer cell itself but, in combination, also its
microenvironment, which can confer protection from apoptosis.
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