© 2007 THE AUTHORS 60 JOURNAL COMPILATION © 2007 BJU INTERNATIONAL | 100, SUPPLEMENT 2, 60–62 Supp Article ANTI-SURVIVAL FACTOR AND ANDROGEN ABLATION-REFRACTORY PROSTATE CANCER KOUTSILIERIS et al. Combination of somatostatin analogues and dexamethasone (antisurvival-factor concept) with luteinizing hormone-releasing hormone in androgen ablation-refractory prostate cancer with bone metastasis Michael Koutsilieris, Theodore Dimopoulos*, Constantine Milathianakis†, John Bogdanos, Dimitrios Karamanolakis, Nicholas Pissimissis, Antonis Halapas, Peter Lembessis, Andreas Papaioannou‡ and Antigone Sourla¶ Department of Experimental Physiology, Medical School, National & Kapodistrian University of Athens, Goudi-Athens, *Urology Clinic, Panagia General Hospital, Thessaloniki, †Urology Clinic, ‘Metaxa’ Anticancer Hospital, Piraeus, ‡Urology Clinic, Argos General Hospital, Argos, and ¶Endo/OncoResearch Laboratories, Diagnostic Medical Center, Athens, Greece cross-talk with growth factor signalling pathways [5]. Therefore, the presence of appropriate survival factor (SF) stimuli, such as those from IGF-I in bone, can compensate the prostate cancer cells for the lack of androgen support during AAT. It is conceivable that chemotherapy-induced apoptosis is abrogated by the same SF pathways that confer resistance to hormonal therapy in the first place [4–6]. This possibility has led to the concept that inhibition of SF activity in the bone metastasis microenvironment might be clinically important. Thus we review hormonal manipulation suppressing SFs in the bone metastasis microenvironment (anti-SF [ASF] therapy) in prostate cancer refractory to AAT and resistant to chemotherapy. At our institution the novel concept of ASF manipulation was tested in combination with AAT in terminally ill patients with prostate cancer who: (i) had progressed to the stage independent of AAT and were receiving combined androgen blockade (LHRH analogue plus flutamide); (ii) had no response to antiandrogen withdrawal manipulation; and (iii) had no response to salvage chemotherapy [6]. The concept of ASF therapy was designed to test whether a regimen of somatostatin analogue (SM-A) and dexamethasone would reintroduce objective clinical responses in patients with stage D3 and who had disease progression while receiving AAT. The ASF therapy included oral dexamethasone (4 mg daily during the first month of treatment, tapered to 3, 2 and 1 mg daily during the second, third and fourth months, respectively, with 1 mg daily maintenance dose thereafter during the entire follow-up period) plus SM-A (Somatuline Autogel®, Ipsen, Slough, UK: lanreotide, 120 mg i.m. every 28 days; or Sandostatin-LAR®, Novartis Int. Basel, Switzerland: octreotide, 30 mg i.m. every 28 days) in combination with hormone ablation therapy (orchidectomy or LHRH agonist: triptorelin, 3.75 mg i.m. every 28 days, or leuprolide, 3.75 mg i.m. every 28 days, or respective 3-month depot injections). The ASF therapy was initially tested in patients who had prostate cancer refractory to AAT (Table 1) [7]. In all, 44 patients were prospectively evaluated for enrolment in a phase II investigator-driven clinical trial, and 38 of them provided informed consent to receive ASF therapy. The ASF therapy produced objective clinical responses (disease stabilization or partial responses) in > 80% of these patients (including 60% of patients whose PSA level decreased by half or more); the median progression-free survival was 7 months, the median overall survival 14 months and the median prostate cancer-specific overall survival 16 months. These objective clinical responses were accompanied by a favourable side-effect profile, which included only slight increases of serum glucose and mild proximal muscle weakness, that were mostly related to oral dexamethasone administration. Notably only three of 19 patients who had octreotide scintigraphy (which detects somatostatin receptor-2) at study entry had a positive scan that was consistent with sites of increased uptake detected by 99m Tc bone scintigraphy. Moreover, only one of these patients had an objective clinical response to ASF therapy. Notably, 13 of 16 patients with negative octreotide scintigraphs showed objective INTRODUCTION Androgen ablation therapy (AAT), the first-line therapy for prostate cancer with bone involvement, initially offers an objective clinical response. However, the development of refractoriness to AAT (stage D3) signals a poor median survival for such patients. The best clinical response at this stage was reported for the regimen of docetaxel plus prednisone, which was recently shown to be better than that for mitoxantrone plus prednisone (overall survival 18 vs 16 months, respectively) [1]. The development of bone metastasis involves specific host-tissue recognition of circulating prostate cancer cells. This recognition is followed by tumour cell migration to and invasion of the bone matrix and, finally, by the establishment of local cell–cell interactions with cells residing in the bone matrix, thus leading to osteoblastic metastasis [2,3]. However, the predominantly bone-specific nature of the refractoriness to AAT implies that specifically local environmental cues, and not only genetic factors related to clonal evolution of the tumour, might be responsible for rescuing prostate cancer cells from apoptosis induced by androgen deprivation [4,5]. It might be that host tissues such as bone that are rich in IGF-I, TGF- β 1, interleukin-6, parathyroid-related peptide and/or endothelin-1 are sanctuaries for prostate cancer cells, and this possibility might also account for the change by prostate cancer cells from an androgen-dependent to an androgen-independent phenotype while they still have active androgen receptors (ARs) [5,6]. It appears that a baseline level of AR activation can potentially be reinforced by