19 research outputs found
314 COMBINATION OF SOMATOSTATIN ANALOG, DEXAMETHASONE, AND STANDARD ANDROGEN ABLATION THERAPY IN STAGE D3 PROSTATE CANCER PATIENTS WITH BONE METASTASES
Combination of somatostatin analog, dexamethasone, and standard androgen ablation therapy in stage D3 prostate cancer patients with bone metastases
Purpose: Androgen ablation-refractory prostate cancer patients (stage
D3) develop painful bone metastases and limited responsiveness to
conventional therapies, hence the lack of universally accepted “gold
standard” treatment for this poor prognosis clinical setting. We
tested the safety and efficacy in stage D3 patients of the combination
hormonal therapy, which combines administration of somatostatin analog
and dexamethasone with standard androgen ablation monotherapy
(luteinizing-hormone releasing-hormone analog or orchiectomy).
Experimental Design: Thirty eight patients with stage D3 prostate cancer
(mean age 71.8 +/- 5.9 years) continued receiving androgen ablation
therapy in combination with oral dexamethasone (4 mg daily for the 1st
month of treatment, tapered down to 1 mg daily by the 4th month, with 1
mg daily maintenance dose thereafter) and somatostatin analog (20 mg
octreotide i.m. injections every 28 days).
Results: Twenty-three of 38 patients (60.5%) receiving this combination
regimen had partial responses [PR, greater than or equal to50%
prostate-specific antigen (PSA) decline], 9 (21.1%) had stable disease,
and 7 (18.4%) had progressive disease. In 47.7% (18 of 38) of
patients, their serum PSA levels decreased with treatment but did not
return to their respective baselines until the end of follow-up (or
death from non-prostate cancer-related causes). The median
time-to-return to baseline PSA was 12 months (95% CI, 7-17 months),
median progression-free survival was 7 months (95% CI, 4.5-9.5 months),
median overall survival was 14 months (95% CI, 10.7-17.4 months), and
median prostate cancer-specific overall survival (defined as time from
onset of combination therapy until prostate cancer-related death) was
16.0 months (95% CI, 11.9-20.1 months). All patients reported
significant and durable improvement of bone pain and performance status
(for a median duration of 14 months; 95% CI, 9-19 months), without
major treatment-related side effects. We observed a statistically
significant (P < 0.01) reduction in serum insulin-like growth factor-1
levels at response to the combination therapy. T levels remained
suppressed within castration levels at baseline and throughout therapy,
including relapse.
Conclusion: The combination therapy of dexamethasone plus somatostatin
analog and standard androgen ablation manipulation produces objective
clinical responses and symptomatic improvement in androgen
ablation-refractory refractory prostate cancer patients
Molecular evidence-based use of bone resorption-targeted therapy in prostate cancer patients at high risk for bone involvement
Background: To improve median survival of patients with prostate cancer
that has metastasized to bone, we need to better understand the early
events of the metastatic process in skeleton and develop molecular tools
capable of detecting the early tumor cell dissemination into bones
(micrometastasis stage). However, the initial phase of tumor cell
dissemination into the bone marrow is promptly followed by the migration
of tumor cells into bone matrix, which is a crucial step that signals
the transformation of micrometastasis to macrometastasis stage and
clinically evident metastasis. The migration of cancer cells into bone
matrix requires the activation of local bone resorption. Such an event
contributes to tumor cell hiding/escaping from high immunologic
surveillance of bone marrow cells. Within bone matrix, tumor cells are
establishing plethoric cell-cell interactions with bone marrow-residing
cells, ensuring their survival and growth. Recently, RTPCR detections of
tumor marker transcripts, such as PSA and PSMA mRNA performed in RNA
extracts of peripheral blood nucleated cells and bone marrow biopsy,
have enabled the stratification of patients with clinically localized
prostate cancer being of high risk for extraprostatic disease and bone
involvement. Therefore, it is conceivable that bisphosphonate blockade
of bone resorption can inhibit the migration of tumor cells into bone
matrix during the early phase of disease dissemination into bone marrow
(micrometastasis stage). Consequently, assessment of the efficacy and
efficiency of bisphosphonates to arrest the evolution of bone lesions in
this particular clinical setting of patients with clinically localized
prostate cancer and positive molecular staging status (high risk for
bone involvement) is warranted
Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton
Bone is the most frequent site of metastases of prostate cancer and is
almost always the first and frequently the only site of metastases where
disease will progress to stage D3. In addition, the number of skeletal
metastatic foci is the most powerful independent prognostic factor of
limited response to hormone ablation therapy and poor survival of
patients with advanced prostate cancer. Furthermore, disease progression
frequently occurs in the osteoblastic metastases, even though androgen
ablation therapy still provides adequate and sustained control of
disease at the primary site. Notably, the management of metastatic
disease onto bones has traditionally relied on therapeutic modalities,
which almost exclusively aim at directly inducing cancer cell death.
However, accumulating pieces of evidence, from both the clinical and the
basic research front, point to major limitations of this conventional
approach. The in vivo response of malignant cells to anticancer
therapies is directly influenced by the local microenvironment in which
they metastasize. In particular, organ sites frequently. involved in
metastatic diseases, such as the bones, appear to confer to metastatic
cells protection from anticancer drug-induced apoptosis. This protection
is mediated by soluble growth factors and cytokines released by the
normal cellular constituents of the host tissue microenvironment. The
characterization of bone microenvironment-related survival factors has
led to the development of a novel hormone manipulation which can
re-introduce clinical responses in patients with stage D3 prostate
cancer
Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton.
Combination of dexamethasone and a somatostatin analogue in the treatment of advanced prostate cancer
The local microenvironment at the sites of cancer metastases protects tumour cells from anticancer drug-induced apoptosis via mechanisms, such as soluble growth factors and cytokines. The concept of antisurvival factor (ASF) therapy as a component of anticancer treatments aims at neutralising the protective effect conferred upon cancer cells by the survival factor(s) derived by the local microenvironment, in order to enhance the sensitivity and/or reverse the resistance of tumour cells to other anticancer therapeutic strategies. Herein, we review the translation of this concept from ex vivo studies to clinical applications in the setting of prostate cancer refractory to androgen ablation (stage D3). At this stage, which predominantly involves bone metastases, insulin-like growth factor 1 (IGF-1) production (either growth hormone (GH)-dependent or GH-independent) can protect tumour cells from apoptosis, despite the significant suppression of androgens. The application of the ASF therapeutic concept involves the combination of dexamethasone (which suppresses GH-independent IGF-1) and somatostatin analogue (which suppresses endocrine, GH-dependent IGF-1) with the pro-apoptotic effect of the testicular androgen suppression by sustained use of LHRH analogues. In stage D3, patients who had failed anti-androgen withdrawal, chemotherapy and also had several other adverse prognostic features, the ASF-based combination achieved durable objective responses and major symptomatic improvement, paving the way for future applications of this approach. The ASF-based combination therapy illustrates a novel paradigm in cancer treatment: anti-tumour treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumour microenvironment and neutralise the protection it confers on metastatic cancer cells. The favourable toxicity profile of this therapeutic approach calls for its testing in a randomised controlled setting in metastatic prostate cancer and, conceivably, in other IGF-1-responsive malignancies
648What is the optimal dose of botulinum toxin a dysport in neurogenic detrusor overactivity? A dose-effect study
Combination therapy using LHRH and somatostatin analogues plus dexamethasone in androgen ablation refractory prostate cancer patients with bone involvement: A bench to bedside approach
The development of resistance to anticancer therapies is a major hurdle in preventing long-lasting clinical responses to conventional therapies in hormone-refractory prostate cancer. Herein, the molecular evidence documenting that bone metastasis microenvironment survival factors (mainly the paracrine growth hormone-independent, urokinase-type plasminogen activator-mediated increase of IGF-1 and the endocrine production of growth hormone-dependent IGF-1, mainly liver-derived IGF-1 production) produce an epigenetic form of prostate cancer cells that are resistant to proapoptotic therapies is reviewed. Consequently, the authors present the conceptual framework of a novel antibone microenvironment survival factor, mainly an anti-IGF-1 hormonal manipulation for androgen ablation refractory prostate cancer (a combination of conventional androgen ablation therapy [luteinising hormone-releasing hormone agonist-A or orchiectomy]) with dexamethasone plus somatostatin analogue, which yielded durable objective responses and major improvement of bone pain and performance status in stage D3 prostate cancer patients. © 2006 Informa UK Ltd