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Endocrine Care |
Department of Experimental Physiology (M.K., C.M.), Medical School, University of Athens, Athens, 11527 Greece; Department of Urology (T.D.), Panagia Hospital, Foundation of Public Insurance, Thessaloniki, 55132 Greece; Institute of Brachytherapy and Urology (A.I., A.N.), Ygeia Health Center, Maroussi, Athens, 15123 Greece; Department of Urology (T.L.), Thriassion General Hospital, National System of Public Health, Athens, 19200 Greece
Address all correspondence and requests for reprints to: Michael Koutsilieris, M.D., Ph.D., Department of Experimental Physiology, Medical School, University of Athens, 75 Mikras Asias, Goudi 115 27, Athens, Greece. E-mail: mkouts{at}medscape.com
Abstract
We evaluated whether the combination of triptorelin, a LHRH analog (LHRH-A), with dexamethasone and lanreotide, a somatostatin analog, can produce objective clinical responses in metastatic androgen ablation-refractory prostate cancer (stage D3) patients who have relapsed, after combined androgen blockade (LHRH-A plus antiandrogen) and antiandrogen withdrawal.
Eleven stage D3 patients with diffuse bony metastases, who had progressed despite initial responses (lasting <12 months) to combined androgen blockade therapy and subsequently failed antiandrogen withdrawal, received oral dexamethasone (4 mg daily for the first month, tapered down to 2 mg after the first month and 1 mg after the second month, and continued on 1 mg thereafter) and lanreotide (30 mg im every 14 d) in combination with triptorelin (3.75 mg im every 28 d). Serum prostate-specific antigen, alkaline phosphatase, performance status, and bone pain were assessed monthly during therapy. Fasting blood glucose was measured biweekly, and serum IGF-I, T, and dehydroepiandrosterone sulfate levels were assessed at baseline, at response to the combination therapy, and at relapse from it.
Ten of 11 stage D3 patients [90.9% of patients; 95% confidence
interval (CI), 58.7–99.8%] had durable objective clinical responses
(including 
50% prostate-specific antigen decline in 8
patients, 72.7%; 95% CI, 39–94%). All patients reported significant
and durable improvement of bone pain (for a median duration of 13
months; 95% CI, 12–14 months; range, 6–22 months) and performance
status (median duration, 19 months; 95% CI, 13–25 months; range,
7–22 months) without major treatment-related side effects. The median
progression-free survival was 7 months (95% CI, 4–10 months; range,
3–17 months), and the median overall survival was 18 months (95% CI,
16–20 months; range, 7–22 months). Five of six total deaths occurred
secondary to disease progression. We observed a statistically
significant (P = 0.018) reduction in serum IGF-I
levels at response to the combination therapy (60% reduction of
baseline IGF-I levels). Dehydroepiandrosterone sulfate levels, although
already significantly suppressed at baseline, had an additional
significant reduction (P < 0.02) at response to
therapy. T levels remained suppressed within castration levels (<3
nmol/liter, at baseline and throughout therapy, including relapse).
The combination therapy of LHRH-A with dexamethasone plus somatostatin analog produces objective clinical responses and symptomatic improvement in androgen ablation (LHRH-A) refractory prostate cancer patients.
THE PROGRESSION TO androgen ablation-refractory stage (stage D3) of prostate cancer corresponds to cancer cell escape from androgen withdrawal-induced apoptosis (1, 2). Bone metastases of prostate cancer almost always represent the exclusive site of disease progression to stage D3 (3, 4, 5, 6) and are the stronghold of chemotherapy-resistant tumor growth (4, 5). In addition, the actual number of metastatic foci is associated with limited clinical response to androgen ablation therapy and poor overall survival (4, 5, 6). Of note, salvage chemotherapy cannot extend the median survival of approximately 10 months for stage D3 patients (3, 7, 8, 9).
We have documented that osteoblast-derived survival factors, such as IGF-I, can protect human prostate cancer cells from chemotherapy-induced apoptosis (10), suggesting that osteoblasts mediate, at least in part, acquired tumor resistance to anticancer therapies (10). In line with these data, disease progression to stage D3 occurs always in the IGF-I-rich milieu of osteoblastic metastases and rarely at the primary site (11, 12, 13) or other extraskeletal sites, e.g. the lung (5, 6, 14).
We have documented, both in vitro and in vivo, that glucocorticoids down-regulate the expression of osteoblast- derived survival factors, such as IGF-I and TGFß1, as well as the prostate cancer cell-derived urokinase-type plasminogen activator, which regulates IGF-I and TGFß1 bioavailability, locally, via the hydrolysis of IGF-binding proteins and the activation of latent TGFß1 (15, 16, 17, 18). Moreover, lanreotide, a long-acting somatostatin analog (SM-A), suppresses GH- dependent liver-derived circulating IGF-I (19). In addition, a combination therapy of dexamethasone and lanreotide with the LHRH analog (LHRH-A), triptorelin, provided encouraging initial responses (within 3 months) in four terminally ill patients with androgen ablation-refractory and chemotherapy-resistant prostate cancer (20). Herein, we report the durable objective responses and symptomatic improvement achieved in 10 of 11 terminally ill, stage D3 prostate cancer patients who have received this combination for a median follow-up of 18 months.
Patients and Methods
Patients and treatment
We prospectively evaluated 11 patients with androgen ablation
therapy-refractory (stage D3) prostate cancer who received combination
therapy consisting of the following: 1) oral dexamethasone, 4 mg daily
for the first month of treatment, tapered down to 2 mg after the first
month and 1 mg after the second month, and continued on 1 mg thereafter
for the entire follow-up period; 2) lanreotide (SM-A), 30 mg im every
14 d; and 3) triptorelin (LHRH-A), 3.75 mg im every 28 d. All
patients were treated on an outpatient basis, following the principles
outlined in the Declaration of Helsinki (21) and a
protocol reviewed and approved by the local ethics committee for human
subjects research. Concomitant presence of another advanced stage
malignancy or life expectancy of less than 3 months were criteria for
exclusion. No patients were excluded from this study on the basis of
cardiopulmonary, renal, gastrointestinal function, or diabetes. None of
the patients had a history of prostatectomy or radiation therapy. All
patients had diffuse skeletal metastases (>6 metastatic foci),
documented by radionuclide bone scan and computerized tomography scan.
These patients had no evidence of measurable soft tissue metastases,
except lymph nodes, as assessed by computerized tomography scan. Table 1
summarizes the baseline clinical
characteristics of our patients.
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). Criteria for
progression after previous therapies included rising PSA levels to more
than 50% of PSA nadir and a minimum PSA increase of 5 ng/ml each month
for 2 months (i.e. >10 ng/ml total increase of PSA) for
responders (or >25% of baseline PSA for nonresponders), and/or
detection of new metastatic foci on bone scan, and/or deterioration of
performance status with increasing bone pain. LHRH-A was administered
in all patients continuously, both before and during our combination
therapy. Secondary to the chronic LHRH-A administration, T levels in
all patients were within castrated levels (<3 nmol/liter) upon
enrollment and throughout the study.
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Patients were evaluated monthly with physical examination and measurements of T, PSA, and alkaline phosphatase (AP), complete blood counts, and liver function tests. Serum T, dehydroepiandrosterone sulfate (DHEA-S), and IGF-I levels were assessed at baseline, at response to therapy (at the time of PSA nadir), and after relapse from the combination therapy. T and DHEA-S levels were measured using commercially available RIA diagnostic kits (Testo-CT2 kit, Schering-Plough Corp. S.p.A. Milan, Italy for T measurements and a DHEA-S RIA kit from Immunotech, Miami, FL). IGF-I was quantified by ELISA kit (R&D Systems Europe, Abingdon, UK). Follow-up bone scans for detection of new metastatic foci were performed every 6 months. In view of the effects of SM-A on pancreatic function (19) and dexamethasone on blood glucose (20), all patients were instructed to appropriately modify their diet in regards to lipid and carbohydrate intake. Blood glucose levels were monitored biweekly during the first 3 months of antisurvival factor (ASF) therapy and monthly thereafter. For patient 3, with a known history of diabetes mellitus, the dosage of his oral antidiabetic drug was increased.
Evaluation of symptomatic improvement and quality of life were performed with the Eastern Cooperative Oncology Group (ECOG)-World Health Organization (WHO) performance status score (22) and a bone pain score that provides, on a 4-point scale, a composite expression of bone pain and analgesic requirements (0, lack of bone pain, without use of analgesics; 1, mild pain, defined as pain intensity reducing the physical activity, but responsive to mild analgesic consumption; 2, moderate pain requiring moderate consumption of analgesics; 3, severe to excruciating pain, refractory to extensive consumption of analgesics). Any reduction of ECOG or bone pain score lasting more than 1 month was considered a palliative response.
The following criteria were used to evaluate the response after at least two successive measurements, as previously described (22): complete response, indicated PSA normalization (<4 ng/ml); partial response, at least 50% decrease from baseline; stable response, less than 50% PSA decrease from baseline. Progression-free survival (PFS) was calculated from the start of combination therapy to disease progression or death from any cause, whichever occurred first. Disease progression was defined as PSA increase by 50% above the nadir or best PSA response or 25% above the baseline for nonresponders, at a minimum of 5 ng/ml (22), development of new bone lesions on bone scan, deterioration of performance status, or increased bone pain. We also evaluated an alternative expression of time to PSA progression, reported by Sartor et al. (23), based on the more conservative criterion of PSA rise by more than 10 ng/ml above the PSA nadir or the baseline levels of nonresponders. Overall survival was calculated from the start of therapy to death from any cause (or end of follow-up).
Statistical analysis
In this longitudinal clinical trial design, as defined by
Spilker (24), the objective and symptomatic responses of
each patient receiving the combination therapy (LHRH-A plus
dexamethasone plus SM-A) are compared in a pairwise fashion with his
baseline (e.g. refractoriness to LHRH-A alone, baseline
levels of PSA, AP and baseline bone pain, and performance status
scores), i.e. each patient’s baseline status serves as a
control for the assessment of his response to therapy, without the need
for a separate control group and for randomization of patients in a
treatment vs. a control group. Therefore, the
(nonparametric) Wilcoxon’s rank test for paired samples was used to
compare the baseline ECOG and bone pain scores with their respective
values during combination treatment. The rate of reintroduction of
responsiveness to LHRH-A, after the initiation of combination therapy,
was compared with the baseline refractoriness of patients to LHRH-A
using the McNemar’s paired 
2 test (with the
Yates correction). The nonparametric Friedman’s ANOVA (for multiple
relates samples) and the Wilcoxon’s rank test for paired samples were
used to assess potential changes in IGF-I, DHEA-S, and T
levels at baseline, at the time of PSA nadir, and at relapse from the
combination therapy. All aforementioned statistical tests are
nonparametric, and their use is appropriate for analyses involving a
small number of patients. Survival analysis was performed with the
Kaplan-Meier method.
Results
Initial objective and symptomatic responses
Within 6 months of combination therapy, 10 of 11 patients (90.9%;
95% CI, 58.7–99.8%) responded with a decline of PSA and AP levels,
corresponding to a statistically significant (in comparison to the
baseline refractoriness) rate of re-introduction of responsiveness to
LHRH-A and its combination with dexamethasone and lanreotide
(McNemar’s paired 2 test; P
< 0.01). Eight of 10 responders (or 8 of 11 patients in total, 72.7%;
95% CI, 39–94%) had PSA decline by more than 50% of baseline
levels. Of note, two patients had normalization of PSA (<4.0 ng/ml)
during the combination therapy, whereas no such responses were observed
during initial androgen ablation therapy. The PSA and AP responses
(Fig. 1) were accompanied by
concomitant statistically significant reduction in bone pain score
(P = 0.036), suggesting reduction of metastatic burden
in bones (Tables 3 and 4), as well
as significant improvement in the ECOG
performance status score (P = 0.036). During
combination therapy, six patients (54.6%; 95% CI, 23.4–83.3%)
experienced lack of bone pain without use of analgesics, for a median
duration of 7 months (95% CI, 2–12 months; range, 2–14 months). All
11 patients experienced improvement of bone pain for a median of 13
months (95% CI, 12–14 months; range, 6–22 months). Ten of 11
patients achieved normal performance status (ECOG score = 0) for a
median duration of 6 months (95% CI, 4–8 months; range, 1–17
months). All 11 patients achieved ECOG/WHO scores of less than 2 for a
median duration of 11 months (95% CI, 7–15 months; range, 6–22
months). All 11 patients had improvement of performance status, which
lasted for a median of 19 months (95% CI, 13–25 months; range, 7–22
months) (Table 5).
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PFS and overall survival
Nine of 10 responders to our combination therapy eventually
progressed after 7–16 months of follow-up (Table 6). The median PFS was 7 months, either
as calculated according to PSA Working Group criteria (22)
(95% CI, 4–10 months; range, 3–17 months), or using the more
conservative criteria of Sartor et al. (23)
(95% CI, 4–10 months; range, 1–17 months) (Table 6). One of 10
responders is still progression-free after 17 months of follow-up.
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). Five of them succumbed to disease progression,
manifested by rising PSA, AP, deterioration of bone pain (patients 2,
6, 7, and 8), and renal failure (patient 5), after 18 months (patient
2), 10 months (patient 5), 17 months (patient 7), and 16 months
(patient 8) of follow-up, respectively. Patient 6 died of
cancer-unrelated cause (pulmonary embolism following emergent surgery
for acute abdomen) while experiencing a partial response (PSA decline
>50%) after 7 months of follow-up (Table 6). Serum IGF-I levels, hormonal data, and side effect profile
Comparison of serum IGF-I levels at baseline, at maximal response
(PSA nadir), and at relapse from therapy revealed a significant change
of IGF-I levels during the course of the combination therapy
(P = 0.009; Friedman’s nonparametric ANOVA). Indeed,
the administration of this combination therapy was associated with
a significant decrease in the serum IGF-I levels at response as
compared with the baseline IGF-I levels [serum IGF-I levels
(mean ± SD), at baseline (at study
entry), 25.11 ± 6.63 nmol/liter; at maximal response (PSA
nadir), 10.13 ± 3.23 nmol/liter; P = 0.018;
Wilcoxon’s rank sum test] (Fig. 2A).
Interestingly, the patients’ serum IGF-I levels were not increased at
relapse (mean ± SD, 11.75 ± 3.55
nmol/liter) in comparison to the levels at maximal response (PSA
nadir) (P = 0.116; Wilcoxon’s rank sum test),
suggesting that serum IGF-I levels may be not involved at relapse from
this combination therapy (Fig. 2), although a clear answer to it would
have been better provided by measurements of IGF-I concentrations in
bone metastases.
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). During this
combination treatment, we observed a modest, yet statistically
significant change in serum DHEA-S levels
(P = 0.022, Friedman’s test) (Fig. 2C). Indeed, there
was a statistically significant (P = 0.028, Wilcoxon’s
rank sum test) reduction in serum DHEA-S levels at maximal
response (PSA nadir) (0.54 ± 0.09 µmol/liter) vs.
baseline serum DHEA-S levels (mean ±
SD, 1.35 ± 0.15 µmol/liter). However, at
relapse the DHEA-S levels (mean ±
SD, 0.55 ± 0.05 µmol/liter) did not
differ (P > 0.6) from the ones at response, suggesting
that the relapse from the combination therapy is unlikely to be
associated with changes in serum adrenal androgen concentrations. It
must also be emphasized that both at baseline and throughout the course
of combination therapy, the DHEA-S levels were well below
the age-adjusted lowest limit of normal range, resulting from the
long-term therapy with LHRH-A (Fig. 2).
The mean fasting blood glucose levels of our patients remained within
normal levels (3.58–6.33 mmol/liter) throughout the study (Fig. 2D),
although three patients (patients 1, 2, and 4) developed, during the
first 2 months of treatment, transient hyperglycemia with maximum
fasting blood glucose levels not exceeding 8.8 mmol/liter (160 ng/dl).
Furthermore, patients 1, 2, and 4 developed mild facial Cushingoid
features, whereas patients 3 and 4 reported mild proximal muscle
weakness. These side effects subsided after dexamethasone tapering. No
cardiovascular, renal, or liver-gastrointestinal complications were
reported, with the exception of mild epigastric discomfort (patients 3,
4, and 10), effectively controlled with antacid regimen.
Discussion
Metastatic prostate cancer patients that have relapsed from CAB (LHRH-A plus antiandrogen) and subsequently failed the antiandrogen withdrawal manipulation face an adverse prognosis without clearly established options for further treatment. This study was designed to address whether, in these patients refractory to LHRH-A, the combination of LHRH-A with SM-A plus dexamethasone can offer objective responses and/or symptomatic improvement. The design of this pilot trial involved a longitudinal methodology, as defined by Spilker (24), which is appropriate for study of even small cohorts of patients and allows for pair-wise comparisons of each patient’s objective (e.g. serum PSA, AP) or symptomatic (e.g. bone pain, performance status) responses to the combination therapy (i.e. LHRH-A with SM-A plus dexamethasone) vs. the patients’ baseline status (i.e. refractoriness to LHRH-A). In this longitudinal study of androgen ablation therapy-refractory prostate cancer patients, the combination of LHRH-A with SM-A plus dexamethasone produced objective clinical responses in 10 of 11 patients, as documented by the significant PSA declines, including PSA decline by more than 50% of baseline, in 8 patients. This magnitude of PSA response is generally associated with a significant survival advantage (25, 26, 27). It is unlikely that these objective responses are attributable to favorable baseline clinical characteristics of our patients, because all of them had diffuse bone metastases (more than six foci) and short clinical responses to CAB (<12 months), which both correspond to powerful adverse prognostic factors (4, 5, 6, 28) and had significantly compromised performance status (median baseline ECOG score = 3).
This novel approach has been preceded by previous uses of glucocorticoids or SM-A monotherapies in advanced prostate cancer. Glucocorticoid monotherapy has been attempted (29, 30, 31) as a palliative therapy in the setting of aminoglutethimide-induced medical adrenalectomy, and transient symptomatic improvements were recorded in some studies (30, 31, 32, 33), performed, though, before recognition of antiandrogen withdrawal as an active therapeutic maneuver. Subsequent trials, which controlled for antiandrogen withdrawal, all involved hormone refractory, yet chemotherapy-naïve patients (23, 34, 35). Combination therapy of mitoxantrone plus prednisone (10 mg daily) offered at least 50% PSA decline in 33% of stage D3 patients and less than 50% PSA decline in 29% (34), or in 36% of stage D3 patients (35) for a median survival of 10 months, as opposed to at least 50% PSA decline in 22% and less than 50% PSA decline in 12% of stage D3 patients for a median duration of response of 4 months in patients receiving prednisone (10 mg) monotherapy. Prednisone monotherapy (20 mg daily) led to at least 50% PSA decline in 34% of stage D3, yet chemotherapy-naïve, patients for a median PFS of 2 months and median overall survival of 12 months (23). Previous investigation using SM-A monotherapy mainly targeted SM-receptor-mediated antiproliferative or proapoptotic effect on prostate cancer cells (36, 37, 38, 39) or SM-receptor positive cancer cells using cytotoxic compounds linked to SM-A achieving minimal, if any, clinical responses in stage D3 patients (40, 41).
Direct comparison of the aforementioned clinical studies with our data may not be feasible. Interestingly, however, the combination therapy in our study achieved a very high rate of 50% or greater PSA decline (8 of 11, 73%; 95% CI, 39–89%), prolonged PSA responses, extended PFS (median PFS of 7 months), and overall survival (median of 18 months), which exceeds the 9–10 month median overall survival of stage D3 patients. Very importantly, this combination therapy led to marked and sustained improvement of bone pain and performance status, without any major side effects.
A potential mechanism for the efficacy of this combination regimen
involves the abrogation of the protective effect of IGF-I on prostate
cancer cells. This mechanism is indicated by a series of in
vitro and in vivo studies (10, 15, 16, 17, 18).
IGF-I serves as a major survival factor for prostate cancer cells; it
blocks the induction of apoptosis, is conferring to them an acquired,
nongenetically determined, form of resistance to proapoptotic
anticancer therapies when they reside in the bone microenviroment
(10), and may even synergize with genetically determined
forms of resistance in certain subclones of tumor cells
(42) to potentiate the survival of cancer cells.
Glucocorticoid monotherapy down-regulates osteoblast- derived IGF-I
but cannot effectively neutralize the incoming influx to the bone of
circulating GH-dependent liver-derived IGF-I (43, 44).
SM-A monotherapy suppresses GH-dependent liver-derived IGF-I but cannot
abrogate the osteoblast-derived IGFs and prostate cancer
cell-derived urokinase-type plasminogen activator-mediated hydrolysis
of IGF-binding proteins, which increases IGF-I bioavailability, locally
(15, 16, 17, 18, 20). Therefore, it is likely that the combination
of dexamethasone and SM-A acts as an anti-survival factor (ASF) therapy
that comprehensively blocks the action of IGF-I. The significant
reduction (
60% of baseline) of circulating IGF-I, documented in
this cohort of patients, as well as our previous preclinical data,
suggests that a reduction of the survival factor activity of IGF-I on
prostate cancer cells is a very likely mechanism accounting for at
least part of the encouraging responses that were observed. However,
additional studies will be required to fully elucidate the precise
in vivo mechanism of action for the combination of LHRH-A
with dexamethasone plus SM-A. Ongoing studies are addressing the
question whether a more pronounced reduction in IGF-I levels could
further prolong the responses to the combination therapy and whether
the degree of response to the combination therapy correlates with the
degree of IGF-I suppression. Particular emphasis is also placed on
complementing the studies on peripheral blood IGF-I with accurate and
reproducible quantification of the local IGF-I protein levels at the
sites of bone metastases, without imposing significant discomfort or
risk to the patients.
Additional studies are also under way to address whether the reduction
in DHEA-S levels conferred by the combination therapy
contributes to the objective and symptomatic responses of patients
enrolled in our study. At the initiation of the combination treatment,
the serum DHEA-S levels were significantly lower than the
age-adjusted lower limits of normal values (DHEA-S levels
at castration reflect the concentration/metabolism of adrenal
androgens). Interestingly, our combination therapy induced a further
significant reduction in DHEA-S levels. This is apparently
caused by dexamethasone, which suppresses adrenal androgen production.
Conceivably, the latter could contribute to the mechanism of action of
ASF therapy. However, it is unlikely to be the determining factor of
clinical response to ASF therapy because, before enrollment in this
study, all patients had progressed to stage D3 despite the use of
antiandrogens that block the activity of residual adrenal androgens.
This raises the possibility that residual adrenal androgens and
androgens locally produced by intracrine transformation of adrenal
androgen precursors
(DHEA/DHEA-S/
4-androstenedione)
have an attenuated contribution to the establishment of the hormone
refractory phenotype. It is therefore conceivable that the responses
achieved by this combination therapy cannot be fully accounted for by
the suppression of the residual DHEA-S levels. Instead, it
may be postulated that this suppression is mainly potentiating the
antitumor effect caused by the significant suppression of IGF-I. Such a
notion would also be consistent with data indicating a synergy of
residual adrenal androgens with IGF-I or other protein kinase signaling
pathways in stimulating transcription of androgen receptor-dependent
genes (e.g. antiapoptotic genes) (45). Such
synergistic effect by suppression of both IGF-I bioavailability and
residual androgens may account in part for responses previously
observed with combinations of adrenolytic agents (e.g.
ketoconazole) and glucocorticoids in advanced prostate cancer
(46). Ketoconazole alone (without glucocorticoids) was
initially reported to offer temporary remissions (47).
Presently, glucocorticoids are administered concomitantly with
ketoconazole to prevent the side effects produced by the adrenolytic
agent-induced adrenal failure. Because glucocorticoids can also
suppress the local IGF-I bioavailability at the bone
microenvironment, they may account, at least in part, for
responses achieved with glucocorticoid-containing ketoconazole
regimens.
Of note, glucocorticoids have been reported either to increase (48, 49) or not to change (50, 51) the PSA expression in human prostate cells, suggesting that the PSA decline during the combination therapy is not related merely to a dexamethasone-induced suppression of PSA expression, but that the decline of PSA during the responses to the combination therapy or, conversely, its rise at relapse from it, reliably reflects changes in tumor burden in general. The anti-inflammatory properties of dexamethasone per se cannot explain the clinical responses of our study, because bony metastases in prostate cancer are predominantly associated with deposition of woven bone tissue rather than the presence of inflammatory infiltrates (11). Moreover, the clinical responses observed in this study involved improvement of pain and performance status, concomitant to declines of PSA and AP. Conversely, at relapse, the increases of PSA and AP were associated with worsening bone pain and deterioration in performance status. Through its diverse pharmacological effects, dexamethasone may account for a significant part of the symptomatic improvement achieved by the combination therapy. However, this improvement appears to be temporally associated with the changes in objective response markers that reflect the tumor burden (PSA) or its effect on the bone (AP). Therefore, it is suggested that the main mechanism(s) of action of dexamethasone, in this combination treatment, very likely affect(s) those microenvironmental mechanisms regulating the growth and/or survival of the metastatic cells, rather than involving a nonspecific anti-inflammatory or analgesic effect.
It should be emphasized that any definitive conclusions regarding the usefulness of this combination therapy, in comparison to other proposed treatment strategies for stage D3 prostate cancer, can only be drawn in randomized controlled clinical trials. The results of our study indicate that such trials are warranted, because the combination of LHRH-A with dexamethasone plus SM-A had a favorable toxicity profile and offered objective and symptomatic responses in patients with limited treatment options, compromised performance status, severe bone pain, and refractoriness to conventional hormonal therapy strategies. This combination therapy may also illustrate a novel paradigm in cancer treatment in which therapies may target not only the cancer cell itself but also its microenvironment, which can confer protection to metastatic cancer cells from apoptosis. If this paradigm and, especially, the role of IGF-I as a major target of this combination are to be confirmed, it is conceivable that the conceptual framework of this approach may be applied to other IGF-I-responsive malignancies, e.g. breast (52, 53), liver, and ovarian cancer, or myeloma.
Acknowledgments
Footnotes
Present address for C.M.: Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115.
Abbreviations: AP, Alkaline phosphatase; ASF, antisurvival factor; CAB, combined androgen blockade; CI, confidence interval; DHEA-S, dehydroepiandrosterone sulfate; ECOG, Eastern Cooperative Oncology Group; LHRH-A, LHRH analog; PFS, progression-free survival; PSA, prostate-specific antigen; SM-A, somatostatin analog; WHO, World Health Organization.
Received August 16, 2000.
Accepted August 23, 2001.
References
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