Bone-targeted Therapy Research Articles

Predictors for Skeletal-Related Events in Patients with Advanced Multiple Myeloma.

Most patients with advanced multiple myeloma (MM) develop bone lesions during their disease course. Myeloma bone disease can result in potentially debilitating and life threatening skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, the need for palliative radiotherapy (RT) or surgery to bone, and hypercalcemia of malignancy. Bone-targeted therapies that prevent or delay SRE onset may maintain quality of life (QOL) and functional independence in patients with advanced MM. Yet, the risk factors for SREs in this patient population are not fully understood. Exploratory analyses were conducted to identify potential SRE risk factors in patients with bone lesions from MM who received either zoledronic acid or pamidronate every 3 to 4 weeks for up to 24 months in a large, randomized trial. Patients with complete baseline demographics, disease characteristics, and markers of bone metabolism information available were included (n=282). Dichotomous variables included sex, race (white/other), narcotic analgesics (yes/no), Eastern Cooperative Oncology Group performance status (active/impaired), prior SRE (yes/no), and values with a defined upper limit of normal (creatinine, lymphocyte %, hemoglobin, serum glutamic oxaloacetic transaminase, albumin, lactate dehydrogenase [LDH], and calcium). Continuous variables included age, weight, cancer duration, Functional Assessment of Cancer Therapy-General score, Brief Pain Inventory (BPI) score, and bone markers (eg, urinary N-telopeptide of type I collagen [NTX], deoxypyridinoline [DPD]). Paraprotein type was also included. Univariate and multivariate analyses to determine relative risks (RR) for reduced time to first SRE associated with baseline variables using Cox regression models were developed, and those that were not significant at the 5% level were removed by backward elimination to generate a reduced model. In the reduced multivariate model, lower weight (RR=0.94 per 5-kg increase; P=.021), higher BPI scores (RR=1.16 per 1-unit increase; P < .001), race other than white (RR=0.60; P=.028), need for narcotic analgesics (RR=1.61; P=.017), and high levels of NTX (RR=1.68 per 100-nmol/mmol creatinine increase; P=.005) significantly correlated with reduced time to first SRE. Pathologic fracture and RT to bone were the most common SREs; in multivariate models, lower weight and higher BPI scores were associated with increased RRs of both fractures and RT to bone. Race and DPD levels were also significant covariates for fractures, whereas high levels of LDH correlated significantly with need for RT. Because bone resorption marker levels were significant covariates, the correlation between baseline NTX and time to first SRE was assessed. High baseline NTX (≥ 50 nmol/mmol creatinine) was associated with increased risk of shorter time to first SRE: by a significant 67% in the zoledronic acid group (n=210; P=.015) and by a 57% trend in the pamidronate group (n=108; P=.114). Taken together, lower weight and pain parameters (eg, BPI or narcotic analgesics) correlated consistently with skeletal morbidity risks in patients with advanced MM. Treatments that facilitate the restoration of bone homeostasis, as evidenced by bone marker normalization, may reduce the risk of SREs, thus maintaining QOL in this patient population.

Bone metastases in prostate cancer: a targeted approach

New therapies are needed for hormone refractory prostate cancer. Promising new treatments specifically target metastatic disease in the bone, the predominant site of spread in prostate cancer. Recent advances in the understanding of the biology of the tumor-bone microenvironment are leading to the development of new bone-targeted therapies. In this article, we review current and developing clinical strategies designed to control prostate-cancer bone metastases. Newly developed biologic therapies that target prostate-cancer bone metastases have shown promising results in animal models and clinical trials. Additionally, currently established drugs such as bisphosphonates and bone-seeking radiopharmaceuticals are being applied in novel ways in an effort to improve patient care. Therapies targeting bone in advanced prostate cancer have demonstrated improvements in morbidity, and more recently, in overall survival. The continuing development and use of these targeted therapies have the potential to alter the course of this currently fatal disease.

Clinical benefit of bone-targeted radiometabolic therapy with 153Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer

Bone metastases are responsible for most of the morbidity associated with hormone-refractory prostate cancer (HRPC). 153Sm-ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) has been approved for palliation of painful skeletal metastases. We retrospectively investigated the possible synergistic effect on survival of 153Sm-EDTMP (given to HRPC patients for bone pain palliation) and chemotherapy. Forty-five HRPC patients were evaluated, with a median age of 71 years. The number of metastatic bone sites was <or=10 in 25 patients and >10 in 20 patients. Median serum PSA was 224 ng/ml. Bone pain was mild in 6 patients, moderate in 16, severe in 22 and intolerable in 1. Fifteen patients were only treated with 153Sm-EDTMP (group A), while 30 patients also received chemotherapy (estramustine phosphate or mitoxantrone plus prednisone) at variable times: between 3 and 5 months after 153Sm-EDTMP (14 patients, group B) or within 1 month after 153Sm-EDTMP (16 patients, group C). Haematological toxicities observed after either regimen were in general mild, consistent with common observations after either 153Sm-EDTMP or chemotherapy, and without any additive adverse effects in the patients receiving both 153Sm-EDTMP and chemotherapy. Bone pain palliation to some degree was induced by 153Sm-EDTMP in 32/45 patients (71.1%), the proportion of patients with a favourable clinical response being significantly higher in group C than in group A (87.5% vs 53.3%, p = 0.0388). Also in terms of biochemical response (serum PSA levels), patients of group C performed significantly better than patients of group A (p = 0.0235). Overall median survival from the time of administration of 153Sm-EDTMP was 15 months in the total cohort of 45 patients, and was significantly longer in group C than in either group B (30 months vs 11 months, p = 0.023) or group A (30 months vs 10 months, p = 0.008). The results of this study confirm that 153Sm-EDTMP is effective in terms of pain relief and PSA response, with minimal toxicity. When it was administered in combination with chemotherapy, prolonged survival indicated actual clinical benefit, while there were no additive toxicities. These results provide the rationale for future prospective evaluation of combined therapeutic strategies.

Future Treatment of Bone Metastases

All bone surfaces are periodically remodeled by the coupled and balanced action of osteoclasts and osteoblasts, of which the activities are regulated by a variety of cytokines and growth factors. Patients with cancer metastatic to the skeleton often develop osteolytic bone lesions, in which the actions of osteoclasts and osteoblasts remain coupled, but become imbalanced in sites adjacent to the tumor. The result is net bone loss. Many cancers secrete osteoclast-stimulating cytokines, which increase bone resorption by osteoclasts. In turn, factors released from the bone matrix during osteolysis can stimulate tumor growth. In this so-called "vicious cycle," there are multiple sites that are targets for new bone-directed therapies. A variety of new agents for the treatment and prevention of osteolytic bone metastasis are currently being developed. These include new agents that inhibit osteoclast differentiation, bone adhesion, and osteoclast function. These new strategies have evolved from a better understanding of the interaction between tumor cells and cells in the bone marrow microenvironment. There is great promise that these new bone-targeted therapies can decrease the frequent skeletal-related events that greatly diminish quality of life of patients with bone metastases.

2238: A Phase I Trial of Samarium-153-Lexidronam With Hormonal Therapy and Radiation Therapy for High-Risk, Clinically Non-Metastatic Prostate Cancer

The majority of men dying of prostate cancer have bone as the only site of metastasis. Because of this predictable pattern of progression, the development and clinical evaluation of bone-targeted therapy will benefit patients.

The changing pattern of management for hormone-refractory, metastatic prostate cancer

Prostate cancer responds initially to hormonal manipulation by androgen withdrawal and peripheral androgen blockade. The inevitable progression to a hormone-refractory state is accompanied by an exacerbation of local symptoms and metastatic spread, principally to the bones, which has a considerable impact on quality of life and survival. Treatment of hormone-refractory prostate cancer is palliative, and surgery and radiotherapy are used for the relief of lower urinary tract symptoms and localized painful bony metastases. Systemic treatments are not widely accepted in this setting, but clinical trials have demonstrated the potential for bone targeting agents such as strontium-89 and the bisphosphonates to palliate painful bone metastases and to delay progression in certain settings. Chemotherapy with mitozantrone in combination with steroids has previously been shown to have palliative benefits and to delay progression. The additional costs incurred by the use of chemotherapy or bone-targeting therapies may be offset by gains in overall care with fewer in-patient admissions compared with steroid monotherapy. Recent clinical trials have demonstrated that docetaxel significantly improves patient quality of life, and importantly, increases survival. Future studies investigating the timing of chemotherapy, combinations with existing treatments or other novel therapies are underway.

Markers of bone metabolism in prostate cancer

Although bone metastases from prostate cancer are described as osteoblastic, markers of both osteoblastic and osteoclastic activity are strikingly elevated in men with metastatic prostate cancer. Elevated markers of osteoblastic and osteoclastic activity are associated with adverse clinical outcomes in men with prostate cancer--outcomes including shorter time to skeletal complications, disease progression, and death. Bone marker measurement appears to be a promising method for monitoring the efficacy of bone-targeted therapy. Additional studies are needed to assess the potential role of bone markers in identifying men at highest risk for development of bone metastases.

Bone-targeted therapy in advanced androgen-independent prostate carcinoma: A feasibility study

4793 Background: Bone metastasis is a major complication for prostate carcinoma patients, and some times the first indication of progressive disease and worsening prognosis. Various bone target rad...

Bone-targeted therapy consisting of zoledronate, thalidomide, and gamma interferon in renal cell carcinoma: a phase II study

4769 Purpose: Evaluate the efficacy and safety of a bone-targeted regimen consisting of zoledronate, thalidomide, and gamma IFN in patients with renal cell carcinoma and bone metastases. Patients and Methods: Fifteen patients were enrolled on the study between 11/14/02 and 11/7/03. Impending pathological fractures or spinal cord compressions were controlled by surgery or radiation therapy prior to study. Zoledronate (4 mg) was given intravenously once every 4 weeks. Thalidomide (300 mg) was taken orally once every day. Gamma IFN (100 mcg) was given subcutaneously once every week. Patients were evaluated for the presence of calcification in osteolytic metastases, time to skeletal-related events, and levels of bone formation and resorption markers (i.e., bone-specific alkaline phosphatase, urine N-telopeptide and deoxypyridinoline). Results: Twelve patients had previously received surgery, radiation, or embolization for their bone metastases. Eleven patients had multiple (more than three) sites of bone involvement. Nine patients also had non-osseous metastases in the lungs, liver, lymph node, pancreas, and/or adrenal gland. The median time to progression was 8.3 weeks (range, 2.1–48 weeks). The median time to skeletal-related event was 13.7 weeks (range, 3.1 - 46.4 weeks). Two patients discontinued treatment because of adverse drug reactions (deep venous thrombosis or myocardial infarction). Two patients had pain improvement and developed calcification in the osseous metastases. They also had increased bone formation marker or decreased bone resorption marker. Conclusions: A bone-targeted regimen combining zoledronate, thalidomide, and gamma IFN is well tolerated and may provide clinical benefit for selected patients with renal cell carcinoma and bone metastases. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Merck, Pfizer Celgene, Eli Lilly, Novartis

272 Bone-targeted therapy for androgen-independent prostate cancer (AIPCa)

272 Bone-targeted therapy for androgen-independent prostate cancer (AIPCa)

Bone-targeted therapy for AIPCa

4729 Background: Prostate carcinoma is linked to osteoblastic metastasis. We investigated the value of bone-targeted therapy in selected pts with AIPCa. Eligibility included progressive AIPCa affecting bone, presence of worsening cancer-related symptoms, increasing prostate-specific antigen (PSA) values on 2 occasions at least 2 weeks apart, castrate serum testosterone concentrations of < 50 ug/L, disease progression after antiandrogen withdrawal, life expectancy > 3 three months, Zubrod performance status of ≤ 2, and normal organ/marrow function. Methods: Each pt received strontium-89 at 4 mCi on week 1, day 1. Each course of chemotherapy lasted for 8 weeks. Pts were treated in weeks 1, 3, and 5 with doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on the 1st first day of every week) in combination with ketaconazole (400 mg orally 3 times a day daily for 7 days). In weeks 2, 4, and 6, treatment consisted of paclitaxel (100 mg/m2 intravenously on the first day of every week) in combination with estramustine (280 mg orally 3 times a day for 7 days). After completion of 2 courses of chemotherapy, patients with stable or responding disease completed 2 further courses. Pts were then placed on maintenance ketaconazole until their disease progressed. Results: 19 pts have enrolled. 13 pt have completed strontium-89 and 4 courses of chemotherapy. 6 pts are too early for evaluation. Based on a reduction in PSA concentrations of at least 50% from baseline maintained for at least 8 weeks, 9 pts responded to treatment. 1 pt had at least an 80% reduction in PSA concentrations. All pts with symptomatic bone pain reported that the pain improved during treatment. Toxic effects were assessed and included: 3 pts who developed deep venous thrombosis. 8 pts had grade 4 neutropenia. Severe thrombocytopenia grade ≥ 3 occurred in 6 pts.Other common side effects were; edema, fatigue, pain flare, nausea, vomiting, raised transaminases, and skin reaction. Conclusions: Bone-targeted therapy consisting of one dose of strontium-89 plus alternating chemotherapy demonstrated promising activity in pts with AIPCa with an acceptable tolerability. This program continues to enroll pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amersham

Bone-targeted therapy for AIPCa

4729 Background: Prostate carcinoma is linked to osteoblastic metastasis. We investigated the value of bone-targeted therapy in selected pts with AIPCa. Eligibility included progressive AIPCa affecting bone, presence of worsening cancer-related symptoms, increasing prostate-specific antigen (PSA) values on 2 occasions at least 2 weeks apart, castrate serum testosterone concentrations of < 50 ug/L, disease progression after antiandrogen withdrawal, life expectancy > 3 three months, Zubrod performance status of ≤ 2, and normal organ/marrow function. Methods: Each pt received strontium-89 at 4 mCi on week 1, day 1. Each course of chemotherapy lasted for 8 weeks. Pts were treated in weeks 1, 3, and 5 with doxorubicin (20 mg/m2 as a 24-hour intravenous infusion on the 1st first day of every week) in combination with ketaconazole (400 mg orally 3 times a day daily for 7 days). In weeks 2, 4, and 6, treatment consisted of paclitaxel (100 mg/m2 intravenously on the first day of every week) in combination with estramustine (280 mg orally 3 times a day for 7 days). After completion of 2 courses of chemotherapy, patients with stable or responding disease completed 2 further courses. Pts were then placed on maintenance ketaconazole until their disease progressed. Results: 19 pts have enrolled. 13 pt have completed strontium-89 and 4 courses of chemotherapy. 6 pts are too early for evaluation. Based on a reduction in PSA concentrations of at least 50% from baseline maintained for at least 8 weeks, 9 pts responded to treatment. 1 pt had at least an 80% reduction in PSA concentrations. All pts with symptomatic bone pain reported that the pain improved during treatment. Toxic effects were assessed and included: 3 pts who developed deep venous thrombosis. 8 pts had grade 4 neutropenia. Severe thrombocytopenia grade ≥ 3 occurred in 6 pts.Other common side effects were; edema, fatigue, pain flare, nausea, vomiting, raised transaminases, and skin reaction. Conclusions: Bone-targeted therapy consisting of one dose of strontium-89 plus alternating chemotherapy demonstrated promising activity in pts with AIPCa with an acceptable tolerability. This program continues to enroll pts. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amersham

Metastatic bone disease: future directions.

Bone cancer is common and difficult to treat. Current bone-targeted therapies include radiation and bisphosphonates. Both treatments can provide pain relief, but neither has been shown to prolong survival. Because bisphosphonates are osteoclast-targeted therapies, they do not exhibit significant tumor-killing properties in humans. Often, patients with asymptomatic skeletal metastases are treated with observation. New treatments are needed for patients known to have bone metastases and those who are at high risk for having bone metastases develop. Enzyme prodrug gene therapy treatment strategies currently are being explored for their potential benefit in designing novel therapies for bone cancer.

Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial

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. 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. 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). 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.

Clinical and pathologic aspects of spontaneous canine prostate carcinoma: A retrospective analysis of 76 cases

BACKGROUND Pet dogs and men share a vulnerability for the development of prostate carcinoma. The purpose of this study was to further characterize the clinical and pathologic features of spontaneous canine prostate carcinoma. METHODS A multiinstitutional, retrospective study was conducted using 76 dogs with prostate carcinoma that underwent postmortem evaluation. For each case, clinical and pathologic data were tabulated and hematoxylin/eosin-stained tissue sections from the primary tumor and metastatic lesions were evaluated. Prostatic carcinomas were subclassified based upon the presence of glandular, urothelial, squamoid, or sarcomatoid differentiation. We focused our analysis on dogs that differed with respect to morphologic features of the primary tumor, lifetime duration of testicular hormone exposure, and presence of skeletal metastases. RESULTS The vast majority of canine prostate carcinomas affected elderly sexually intact dogs or dogs that underwent surgical castration after sexual maturity. Adenocarcinoma was the most frequent histologic type, although more than half of canine prostate carcinomas exhibited intratumoral heterogeneity. In many cases, primary tumors showed mixed morphology, characterized by two or more types of differentiation. Duration of testicular hormone exposure was significantly different between dogs with adenocarcinoma and dogs with mixed morphology tumor, but did not appear to influence the frequency or pattern of metastases. Overall, gross metastases were present in 80% of dogs with prostate carcinoma. Skeletal metastases were present in 22% of cases, and the predominantly axial skeletal distribution of these lesions was similar to that reported in men with prostate carcinoma. Young dogs were at highest risk for development of skeletal metastases. CONCLUSIONS This study provides a more complete characterization of spontaneous prostate carcinoma of dogs in terms of morphologic heterogeneity, skeletal metastases, and the influence of testicular hormones. Prostate carcinoma in pet dogs provides an immunocompetent, autochthonous tumor system that mimics certain aspects of human prostate cancer. This spontaneous model may contribute to our understanding of the factors that regulate carcinogenesis within the aged prostate, and to the development of chemoprevention strategies or bone-targeted therapies. Prostate 45:173–183, 2000. © 2000 Wiley-Liss, Inc.

Clinical and pathologic aspects of spontaneous canine prostate carcinoma: a retrospective analysis of 76 cases.

Pet dogs and men share a vulnerability for the development of prostate carcinoma. The purpose of this study was to further characterize the clinical and pathologic features of spontaneous canine prostate carcinoma. A multiinstitutional, retrospective study was conducted using 76 dogs with prostate carcinoma that underwent postmortem evaluation. For each case, clinical and pathologic data were tabulated and hematoxylin/eosin-stained tissue sections from the primary tumor and metastatic lesions were evaluated. Prostatic carcinomas were subclassified based upon the presence of glandular, urothelial, squamoid, or sarcomatoid differentiation. We focused our analysis on dogs that differed with respect to morphologic features of the primary tumor, lifetime duration of testicular hormone exposure, and presence of skeletal metastases. The vast majority of canine prostate carcinomas affected elderly sexually intact dogs or dogs that underwent surgical castration after sexual maturity. Adenocarcinoma was the most frequent histologic type, although more than half of canine prostate carcinomas exhibited intratumoral heterogeneity. In many cases, primary tumors showed mixed morphology, characterized by two or more types of differentiation. Duration of testicular hormone exposure was significantly different between dogs with adenocarcinoma and dogs with mixed morphology tumor, but did not appear to influence the frequency or pattern of metastases. Overall, gross metastases were present in 80% of dogs with prostate carcinoma. Skeletal metastases were present in 22% of cases, and the predominantly axial skeletal distribution of these lesions was similar to that reported in men with prostate carcinoma. Young dogs were at highest risk for development of skeletal metastases. This study provides a more complete characterization of spontaneous prostate carcinoma of dogs in terms of morphologic heterogeneity, skeletal metastases, and the influence of testicular hormones. Prostate carcinoma in pet dogs provides an immunocompetent, autochthonous tumor system that mimics certain aspects of human prostate cancer. This spontaneous model may contribute to our understanding of the factors that regulate carcinogenesis within the aged prostate, and to the development of chemoprevention strategies or bone-targeted therapies.