For personal use only. Reproduce with permission from The Lancet Publishing Group. ARTICLES Summary Background Prostate carcinoma is linked to osteoblastic metastasis. We therefore investigated the value of bone- targeted consolidation therapy in selected patients with advanced androgen-independent carcinoma of the prostate. Methods 103 patients received induction chemotherapy, consisting of ketoconazole and doxorubicin alternating with estramustine and vinblastine. After two or three cycles of induction chemotherapy, we randomly assigned 72 patients who were clinically stable or responders to receive doxorubicin with or without strontium-89 (Sr-89) every week for 6 weeks. Findings Overall 62 of the 103 (60%, 95% CI 50–70) patients had a 50% or greater reduction in serum prostate- specific antigen concentration that was maintained for at least 8 weeks, and 43 (42%, 32–52) had an 80% or greater reduction. 49 (52%) patients with bone pain at registration had complete resolution of pain. After follow-up of 67 patients until death, the estimated median survival for all 103 patients was 17·5 months (range 0·5–37·7). For the 36 patients randomly assigned to receive Sr-89 and doxorubicin, the median survival time was 27·7 months (4·9–37·7), and for the 36 who received doxorubicin alone it was 16·8 months (4·4–34·2) (p=0·0014). The hazard ratio was 2·76 (95% CI 1·44–5·29). Interpretation Bone-targeted consolidation therapy consisting of one dose of Sr-89 plus doxorubicin once a week for 6 weeks, when given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival. Lancet 2001; 357: 336–41 See Commentary page ??? Introduction Results of clinical and laboratory studies lend support to the importance of bone metastasis in prostate cancer. Bone is the most common site of androgen-independent progression 1 and the only site of metastasis in most patients. 2 Specific interactions with the bone microenvironment have been implicated in the progression of prostate cancer. 3,4 Complications from skeletal metastases dominate the clinical picture of advanced prostate cancer. There is a direct relation between extent of osseous involvement and patients’ survival. 5,6 Individuals with progressive bony metastases and androgen-independent prostate cancer have a median survival of 9 months or less. 7–9 Because bone metastasis has an important role in the progression of prostate cancer, development of bone- targeted therapy will benefit patients. Organ-directed strategies have been tested in other types of tumours, such as colon carcinoma and osteogenic sarcoma, in which liver and lung, respectively, are the preferred sites of metastasis. 10,11 Several studies have suggested that organ-directed therapy in both these tumour types provides clinical benefit, even if there is metastasis. 10,11 With the introduction of bone-specific agents, 9,12–14 the value of bone-targeted therapy in prostate cancer can be tested. Previously, we tried to improve on existing bone- targeted therapy by combining a bone-homing radioisotope, strontium-89 (Sr-89), with doxorubicin. 15 The results of that study suggested that the treatment was feasible. In this study, we used the combination of Sr-89 and doxorubicin as a consolidation regimen for selected patients who were deemed to be threatened principally by osseous progression and who improved on induction chemotherapy. We reasoned that these patients would be the most likely to benefit from bone- targeted therapy. We designed the study to establish whether a bone- targeted strategy would be beneficial in the treatment of advanced androgen-independent carcinoma of the prostate. Patients treated with induction chemotherapy only have not been studied in this context. We therefore anticipated difficulties in the interpretation of a single- arm trial. 16 Our primary objective was to estimate the time to progression associated with the two consolidation strategies. Although the randomised design was not powered for any formal hypothesis testing, the study provided an opportunity to assess the clinical outcomes of the two arms. Most importantly, it allowed the generation of hypotheses and data for the design and conduct of a subsequent phase III trial. Methods Patients We enrolled patients with progressive androgen- independent carcinoma of the prostate affecting bone. We defined progressive disease by the presence of worsening cancer-related symptoms, or increasing 336 THE LANCET • Vol 357 • February 3, 2001 Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial Shi-Ming Tu, Randall E Millikan, Bayabel Mengistu, Ebrahim S Delpassand, Robert J Amato, Lance C Pagliaro, Danai Daliani, Christos N Papandreou, Terry L Smith, Jeri Kim, Donald A Podoloff, Christopher J Logothetis Departments of Genitourinary Medical Oncology (S Tu MD, R E Millikan PhD, B Mengistu BSc, R J Amato DO, L C Pagliaro MD, D Daliani MD, C N Papandreou MD, J Kim MD, C J Logothetis MD); Nuclear Medicine (E S Delpassand MD, D A Podoloff MD); and Biostatistics (T L Smith MSc), University of Texas, M D Anderson Cancer Center, Houston, Texas TX 77030, USA Correspondence to: Dr Shi-Ming Tu (e-mail: stu@notes.mdacc.tmc.edu)