Progression Of Bone Lesions Research Articles

772P - Abituzumab (Di17E6, Emd 525797) Treatment for Chemotherapy-Naive Patients with Asymptomatic or Mildly Symptomatic Metastatic Castration-Resistant Prostate Cancer (Mcrpc): Primary Outcomes of the Placebo-Controlled Phase 2 Study Perseus (Nct01360840)

ABSTRACT Aim: Abituzumab, a humanized monoclonal IgG2 antibody (Ab) targeting av integrins, suppressed tumor growth in preclinical models and was well tolerated in a phase 1 study in mCRPC patients (pts). This exploratory double-blind trial investigated abituzumab 750 or 1500 mg vs placebo added to standard of care in mCRPC pts. Methods: Eligible pts had radiologic disease progression (rPD) of bone lesions Results: Median PFS (ITT) was 3.3, 3.4 (HR = 0.89 [95% CI: 0.57, 1.39]), and 4.3 months (HR = 0.81 [95% CI: 0.52, 1.26]) with placebo, abituzumab 750, and 1500 mg, respectively. PD was reported in 72, 68, and 65% of pts, respectively, incl. bone lesion PD in 42% of the control arm and in 23% of each abituzumab arm. Less than 2 new bone lesions at weeks 12, 18, and 24, respectively, were reported in 7, 3, and 3% of pts receiving placebo; in 12, 12, and 7% of pts treated with abituzumab 750 mg; and in 12, 10, and 5% of pts receiving abituzumab 1500 mg. of 74 OR-evaluable pts with ST lesions at baseline (BL), 1 pt each receiving placebo or abituzumab 1500 mg achieved partial response. Abituzumab's previously reported safety profile was confirmed. Generation of Abs directed against abituzumab was low: binding Abs were detected post-BL in 3/45, 5/44, and 2/49 evaluable pts treated with placebo, abituzumab 750, and 1500 mg, respectively (highest post-BL level). Candidate BMs (eg, decorin) predictive of prolonged PFS (HR = 0.44 [95% CI: 0.24, 0.83]) with abituzumab were identified. Conclusions: Median PFS with abituzumab 1500 mg was modestly longer than with 750 mg or placebo. Compared with placebo, pts receiving abituzumab experienced bone lesion PD less frequently. Further analysis of clinical efficacy is needed. Disclosure: K. Miller: Consultant or advisory role for, and honoraria from Merck KGaA; M. Hussain: Research funding from Merck KGaA, Genentech, Pfizer, and Medivation for clinical trials (contract with University of Michigan); S. Le Moulec: Advisory board for Astellas, Bayer, and Sanofi; I. Rybicka, R. Bruns and J. Straub: Employee of Merck KGaA.

Serum Level Of Parathyroid Hormone Is Associated With Risk Factors and Clinical Outcomes In Multiple Myeloma

BackgroundParathyroid hormone (PTH) is synthesized and secreted by the chief cells of the parathyroid gland. PTH has a positive impact on hematopoietic stem cells by indirectly decreasing hematopoietic cell apoptosis, and is currently being investigated as a potential therapeutic to stimulate hematopoiesis and enhance bone marrow engraftment. According to previous study, it was hypothesized that elevated PTH may mediate the induction of multiple myeloma (MM) through the biologic effects of IL-6. However, there was no comprehensive study regarding clinicopathological implications of PTH in MM. This study investigated the pathological and clinical implications of serum PTH in MM patients and relationship with other risk factors of MM. Patients and MethodsA total of 115 patients who were newly diagnosed with MM were enrolled between 2006 and 2012. Serum PTH level was measured by automated 2-site chemiluminescent sandwich assay (Abbott Diagnostics). The medical parameters were reviewed for age, sex, PTH, plasma cell percentage in bone marrow, serum M protein, immunoglobulin level, free light chain (FLC) - kappa and lambda, FLC ratio, calcium, creatinine, hemoglobin, albumin, beta-2 microglobulin, lactate dehydrogenase (LDH), international staging system (ISS) stage, international myeloma working group (IMWG) response, chromosome abnormality, bone lesion, treatment outcome, and so on. The collected data was analyzed by PASW 18.0. We performed Spearman's correlation analysis, Mann Whitney U-test, Kruskall Wallis test, time dependent Cox regression analysis, survival analysis by Kaplan-Meier method, etc. ResultsSerum PTH level of 115 myeloma patients was 24.7±34.9 (ranged 0.0-284.1) pg/mL. Serum level of IgG, IgM, FLC-lambda, albumin, and LDH was in positive correlation with serum PTH. Age, plasma cell percentage, M protein, IgA, FLC-kappa, FLC ratio, calcium, creatinine, hemoglobin, and beta-2 microglobulin showed negative correlation with PTH. Among those above, IgM (rho=0.190, p=0.045) and calcium (rho=-0.220, p=0.043) revealed statistically significant correlation with serum PTH. Serum PTH level in MM patients was not significantly different according to the group of IMWG response (p=0.450) and ISS stage (p=0.414). Meanwhile, there was no significant difference of PTH according to chromosomal abnormality (p=0.353), bone lesion (p=0.207), and disease progression (p=0.322). Besides, only calcium level was meaningfully different (p=0.016) by the comparison of clinical parameters between MM patient's group with high PTH level and non-high PTH group (cut-off PTH level=68.3 pg/mL, Mann Whitney U-test). Relative to non-high PTH (<68.3 pg/mL) group, the hazard ratio was higher for group with high PTH level (≥68.3 pg/ml) ([HR] 3.037; p=0.524; 95% CI, 0.100∼92.586; Table 1). With regard to the prognostic implication of serum PTH value, the patient group with above 68.3 pg/mL showed moderate, inferior progression free survival (PFS) than non-high PTH group (median, 5 months vs. 13 months, p=0.056, Fig.1B). However, no overall survival (OS) differences were found between high PTH group and non-high PTH group (Fig. 1A). Interestingly, subgroup analysis showed that patients with high PTH level significantly had an inferior PFS than those with non-high PTH level. In detail, the subgroup were as follows; patients who reached the complete remission (CR) state (N=25) defined by IMWG response criteria at the end of follow up period (median, 3 months vs. 41 months, p=0.001, Fig.1C), patients (N=41) who belonged to ISS stage II (median, 1 months vs. 15 months, p=0.006, Fig.1D), patients (N=97) with no chromosome abnormality (median, 4 months vs. 15 months, p=0.034, Fig.1E), patients (N=28) who have undergone transplantation (median, 3 months vs. 18 months, p=0.009, Fig.1F). ConclusionThis study showed that blood PTH level in MM at diagnosis was associated with risk factors and clinical outcome in MM patients. Disclosures:No relevant conflicts of interest to declare.

Hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid on bone metastasis of lung cancer

Hyaluronan is known to have pivotal roles in the growth, migration and invasion of malignant tumors. Bone metastases are critical lesions greatly impairing the quality of patients with malignancies. We investigated whether hyaluronan synthesis inhibitor supplements the inhibitory effects of zoledronic acid, which is a conventional therapeutic agent for bone metastasis. We examined the effects of methylumbelliferone, an inhibitor of hyaluronan synthesis and/or ZA on the tumorigenicity of one murine lung carcinoma and two human (A549, SK-MES-1) lung cancer cell lines in vitro. The interaction between methylumbelliferone and zoledronic acid was analyzed using Calcucyn software. With a murine bone metastasis model of lung cancer in vivo, we investigated the inhibitory effects and interaction of the two drugs on the progression of metastatic bone lesions. Methylumbelliferone or zoledronic acid treatment individually suppressed proliferation, migration and invasion of 3 cell lines, and combination treatment showed synergistic effects. Although methylumbelliferone as a single agent did not enhance apoptotic activity, it showed additive effects on apoptotic activity to those of zoledronic acid. Co-localization of CD44 and ezrin, which might be a pathway of hyaluronan signaling, was abrogated by methylumbelliferone treatment. Combination therapy showed additive inhibitory effects on metastatic bone lesions in vivo, which paralleled the inhibition of hyaluronan accumulation by methylumbelliferone, and inhibition of osteoclastogenesis. Although the detailed mechanisms underlying the synergistic or additive inhibitory effects of these two drugs should be further analyzed, inhibition of hyaluronan synthesis by methylumbelliferone is a promising novel therapeutic candidate for bone metastasis of lung cancer in addition to zoledronic acid.

965TiP - A Phase II Study (PERSEUS) of Two Doses of EMD 525797 (DI17E6) in Patients (PTS) with Asymptomatic or Mildly Symptomatic Metastatic Castrate-Resistant Prostate Cancer (MCRPC)

ABSTRACT Purpose Expression and function of αv-integrins are deregulated in prostate cancer, and αv-integrins are thought to play an important role in prostate cancer metastasis. EMD 525797 (DI17E6) is a humanized monoclonal IgG2 antibody specifically directed against αv integrin receptors (αvs1, αvs3, αvs5, αvs6, and αvs8). It has been shown to target tumor cells, the tumor's environment (e.g. osteoclasts and osteoblasts), as well as angiogenic blood vessels. Previous studies with EMD 525797 have shown a favorable tolerability profile in healthy volunteers and in mCRPC pts. A phase II trial is investigating the anticancer activity of 2 dose levels of EMD 525797 in asymptomatic or mildly symptomatic mCRPC pts. Methods Adult pts with CRPC who show radiologic progression of bone lesions with/without soft tissue lesions within 28 days prior to randomization are eligible for inclusion. Exclusion criteria are: acute pathologic fracture, spinal cord compression, or hypercalcemia at screening; prior chemotherapy, biologic, or experimental therapy for mCRPC; or radiotherapy to bone lesions and/or orthopedic surgery for pathologic fractures. A total of 216 pts receiving standard of care (luteinizing hormone-releasing hormone [LHRH] antagonists) and bisphosphonate therapy will be randomized 1:1:1 to receive in a blinded manner placebo, 1500 mg or 750 mg EMD 525797 (all 1-h intravenous [IV] infusions) on day 1 of every 3-week cycle until radiographic disease progression (PD). At progression, therapy will be unblinded and pts in the placebo group who show asymptomatic or mildly symptomatic radiographic confirmed PD can receive open-label therapy with 1500 mg EMD 525797. The primary endpoint is composite progression-free survival, defined as the time (months) from randomization date to first documented sign of objective radiographic PD or death from any cause. Secondary endpoints include efficacy (e.g. overall survival and time to progression), safety, the pharmacokinetic profile of EMD 525797, and the exploration of a relationship between the number of circulating tumor cells and clinical outcomes. As of April 2012, 106 pts have entered the trial. Disclosure K. Miller: Membership on an advisory board for Merck KGaA, Darmstadt, Germany, G. Mordenti: Employee of Merck KGaA, Darmstadt, Germany, H. Lannert: Employee of Merck KGaA, Darmstadt, Germany. All other authors have declared no conflicts of interest.

Treatment patterns in men with castration-resistant prostate cancer receiving docetaxel.

e15165 Background: Docetaxel has been a standard of care for castration-resistant prostate cancer (CRPC) in the US since 2004 (TAX 327), yet little has been reported on its patterns of use in routine practice. To help understand these patterns, a retrospective study was conducted and is reported here. Methods: Medical records from 394 patients treated in the US were reviewed: 48 from oncology (N=344) and 8 from urology (N=50) practices. Inclusion criteria were: CRPC diagnosed between 2004 and 2010; received docetaxel; discontinued docetaxel due to rising PSA, progression of bone lesions, or progression of nodal or visceral metastases. Data were collected from physicians using an internet-based case report form. We evaluated patient demographics, characteristics of the docetaxel regimen and other treatments used until docetaxel discontinuation. Results: Patients had a mean [±SD] age of 66.5 [8.9] years, the majority (63%) were white, and geographic dispersion was similar to the US population. The majority of patients initiated docetaxel between 2008 and 2010. After CRPC diagnosis, 8% of patients initiated another cancer-directed therapy before starting docetaxel. Most (78.9%) patients initiated docetaxel with prednisone, while 18.5% initiated docetaxel alone and 2.6% initiated with other drugs. Half of patients initiated docetaxel within 1 month after CRPC diagnosis, while 25% started ≥6 months later. Other non-chemotherapy treatments used with docetaxel were hormonal therapy (22.8%), radiotherapy (17.3%), and surgery (4.1%). Most patients (75%) received ≥4 docetaxel cycles, half received ≥6 cycles, 25% received ≥8 cycles and 10% received ≥10 cycles. Increased tumor mass, with/without new bone lesions or rising PSA, was the most common reason for docetaxel discontinuation (74% of patients). Conclusions: Concordant with guidelines, docetaxel and prednisone was the preferred first-line chemotherapy regimen in CRPC patients. However, one quarter of patients did not initiate docetaxel until ≥6 months after CRPC diagnosis and total exposure varied considerably, with only 10% receiving ≥10 cycles. Future studies are needed to describe specific reasons for docetaxel delay and sub-maximal exposure in some CRPC patients.

Non-invasive MicroCT Imaging Characterization and In Vivo Targeting of BB2 Receptor Expression of a PC-3 Bone Metastasis Model

A devastating progression of human prostate cancer is the development of bone metastasis. Animal models of bone metastasis induced by inoculating human prostate cell lines into mice are well established. Here, we report the characterization of a mouse model of prostatic bone metastasis using non-invasive microCT and targeted microSPECT imaging of bone tumors using the bombesin receptor (BB2r)-avid radiolabeled peptide, (111)In-DOTA-8-Aoc-BBN[7–14]NH(2). Immunocompromised mice were inoculated with human prostate cancer cells by intracardiac injection. Metastatic lesion development was monitored by serially imaging mice weekly with microCT. Mice with CT imaging-confirmed bone lesions were administered (111)In-DOTA-8-Aoc-BBN[7–14]NH(2) for microSPECT imaging of BB2r expressing lesions. Metastatic bone lesions as small as 0.3 mm in diameter were detected by microCT image analysis as early as 21 days after tumor cell inoculation and had wide anatomical distribution. MicroSPECT imaging using (111)In-DOTA-8-Aoc-BBN[7–14]NH(2) successfully targeted BB2r expressing metastatic bone lesions of the tibia at day 29. MicroCT imaging can accurately and non-invasively follow the onset and progression of metastatic bone lesions in mouse models of prostate cancer. Micro-CT coupled with BB2r Micro-SPECT imaging affords the opportunity to obtain a combined receptor/anatomic map of metastatic bone lesion status in this mouse model.

Neovascular Niche for Human Myeloma Cells in Immunodeficient Mouse Bone

The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138+ myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin+ MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin− population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.

Pediatric Gaucher experience in South Marmara region of Turkey

The aim was to represent the clinical characteristics of six children with Gaucher disease and to describe the results of three years' enzyme replacement therapy. The data of six Gaucher patients treated with imiglucerase for more than three years were collected. Age, gender, anthropometric measurements, physical examination findings, ophthalmological evaluations, blood counts, liver function tests, liver and spleen sizes, and bone mineral density of the patients were recorded. Clinical presentations, progressions and therapeutic achievements were evaluated. At the time of diagnosis, all patients were clinically type 1 Gaucher disease. Bone lesions, thrombocytopenia and hepatosplenomegaly were found in all patients at diagnosis. After three years of therapy, normalization of blood cell counts, liver and spleen sizes, bone mineral density, and growth was achieved in all patients. Two patients developed neurological symptoms on enzyme replacement therapy, and the diagnosis in these patients was changed to Gaucher type 3. We observed progression of vertebral bone lesions in three patients despite treatment. The results of enzyme replacement therapy are satisfying, but the possibility of deterioration in clinical findings despite therapy should be kept in mind.

Brain‐derived neurotrophic factor is a potential osteoclast stimulating factor in multiple myeloma

Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. The mechanisms of enhanced bone resorption in patients with myeloma are not fully defined. We have previously identified the role of brain-derived neurotrophic factor (BDNF) in proliferation and migration of MM cells. In our study, we investigated whether BDNF was possibly involved in MM cell-induced osteolysis. We showed that BDNF was elevated in MM patients and the bone marrow plasma levels of BDNF positively correlated with extent of bone disease. In osteoclast formation assay, bone marrow plasma from patients with MM increased osteoclast formation and the effect was significantly blocked by neutralizing antibody to BDNF, suggesting a critical role for BDNF in osteoclast activation. Furthermore, the direct effects of recombinant BDNF on osteoclast formation and bone resorption support the potential role of BDNF in the MM bone disease. BDNF receptor TrkB was expressed by human osteoclast precursors and a Trk inhibitor K252a markedly inhibited osteoclast formation stimulated with BDNF, demonstrating that BDNF used TrkB for its effects on osteoclast. Finally, bone marrow plasma BDNF level positively correlated with macrophage inflammatory protein-1α and receptor activator of nuclear factor-κB ligand, two major osteoclast stimulatory factors in MM. These results support an important role for BDNF in the development of myeloma bone disease.

Brain-Derived Neurotrophic Factor Is a Potential Osteoclast Stimulatory Factor In Multiple Myeloma

AbstractAbstract 1917 Background and Objective:Multiple myeloma (MM) is characterized by accumulation of monoclonal plasma cells in the bone marrow and progression of lytic bone lesions. The mechanisms of enhanced bone resorption in patients with myeloma are not fully defined. We have previously identified the role of brain-derived neurotrophic factor (BDNF) in proliferation and migration of MM cells. In the present study, we investigated whether BDNF was present in marrow from patients with MM and possibly involved in MM cell-induced osteolysis. Methods and Results:Levels of bone marrow plasma BDNF was measured by ELISA in a cohort of individuals with MM and controls. The concentration of BDNF was found to be significantly elevated in patients with MM (879 ± 93) pg/ml when compared with bone marrow plasma derived from normal control subjects (186 ± 52) pg/ml (p < 0.001). Moreover, bone marrow plasma levels of BDNF positively correlated with plasma cell burden and extent of bone disease in MM patients. In osteoclast formation assay, bone marrow plasma from 31 of 37 patients with MM tested significantly stimulated the formation of osteoclast when compared to controls (61.8 ± 7 [mean ± SEM for the 31 patients] versus 25.2 ± 6 TRAP+ multinucleated cells/well [mean ± SEM for the 12 controls]; p < 0.01). The effect was significantly blocked by a neutralizing antibody to BDNF (p < 0.05), suggesting a critical role for BDNF in osteoclast activation. Furthermore, BDNF was found to dose-dependently increased the formation of multinucleated, TRAP+ osteoclast. The direct effects of recombinant BDNF on osteoclast formation and bone resorption support the potential role of BDNF in the MM bone disease. Using reverse-transcriptase polymerase chain reaction analysis and western blotting assay, we demonstrated that BDNF receptor TrkB was expressed by human osteoclast precursors and a Trk inhibitor K252a markedly inhibited osteoclast formation stimulated with BDNF. These data suggested that TrkB is the functional receptor mediating BDNF's effect on osteoclast formation. Finally, bone marrow plasma BDNF level positively correlated with macrophage inflammatory protein (MIP)-1α (r = 0.45, p < 0.005) and receptor activator of nuclear factor-κB ligand (RANKL) (r = 0.68, p < 0.0001), two major osteoclast stimulatory factors in MM. Conclusion:Taken together, our results demonstrate the ability of MM cells to secret BDNF correlates with the severity of osteoclastic bone resorption, and provide evidence that BDNF play a causal role in the development of MM bone lesions through TrkB receptor. Disclosures:No relevant conflicts of interest to declare.

Relationship of osteolytic biochemical indicators of bone metabolism with the therapeutic effect in breast cancer patients with bone metastases

The aim of this study was to access the relationship of osteolytic bone metabolic markers such as serum type I collagen carboxy-terminal telopeptide (sICTP), N-terminal cross-linked telopeptides of type I collagen (uNTx), urinary pyridinoline (uPyd) with the therapeutic effect in breast cancer patients with bone metastases. 120 patients with breast cancer were included in this study. The levels of sICTP, uNTx and uPYD were measured by ELISA assay. The differences were compared between patients with and without bone metastasis. The patients with bone metastasis were treated and followed up as clinically indicated. The levels of all above mentioned biomarkers in patients with bone metastasis were significantly higher than that in patients without bone metastasis (P < 0.01). A significant correlation was found between each two markers (r > 0.5, P < 0.01). The biomarkers were examined again in 45 patients with bone metastasis after treatment to evaluate the treatment response. The median follow-up was 10 months. Based on clinical evaluation criteria, 25 patients were responders and 20 were non-responders. For responders, after 3 months treatment, the levels of the three bone markers were significantly reduced (P = 0.025, P < 0.001, P < 0.001). But for non-responders, with progression of bone lesions, the levels of the three markers were significantly raised (P = 0.011, P = 0.002, P = 0.002). By means of multiple logistic regression with stepwise selection, the uPyd and uNTx activities were closely correlated with treatment response (OR = 17.0, P = 0.019; OR = 16.7, P = 0.015), however, the sICTP did not show any correlation with treatment response P = 0.841). The levels of sICTP, uNTx and uPyd may be used as indicators in assessment of the effect of antiresorptive treatment and evaluation of prognosis in breast cancer patient with bone metastases.

Efficacy of targeted therapy in patients with renal cell carcinoma with pre-existing or new bone metastases

This single-centre retrospective analysis of data from three randomised studies and two expanded-access studies compared the effect of interferon (IFN)-alfa, sunitinib, and sorafenib on the occurrence and progression of metastatic bone lesions in patients with renal cell carcinoma (RCC). The analysis included 292 patients: 107 received sunitinib 50 mg/day in 6-week cycles (Schedule 4/2), 147 received sorafenib 800 mg/day, and 38 received placebo or IFN-alfa 9 MU t.i.w. Pre-existing metastatic bone lesions were reported in 82 patients, of which 30 experienced progression. Twenty-three of 210 patients developed new bone lesions. Overall, sunitinib appeared slightly more effective than sorafenib or IFN-alfa at extending mean time to progression of pre-existing bone lesions (P = 0.057). Compared with sorafenib, sunitinib significantly decreased formation (P = 0.034) and prolonged time to occurrence of new bone lesions (P = 0.047). Further evaluation of the effect of these therapies on bone metastases in RCC is warranted.

Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer

Patients with breast carcinoma often develop bone metastases that carry a high risk of complications. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with metastatic bone disease following breast cancer. The primary efficacy end point of the study was the proportion of patients who developed skeletal-related events (SREs, defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in anti-neoplastic therapy and surgery to bone). Secondary end points included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. In 150 patients (148 [female symbol] / 2 [male symbol]) with breast carcinoma and bone metastases, treatment with intravenous ibandronate 6 mg over 15 min every 4 weeks for 24 months significantly reduced the proportion of patients who experienced an SRE compared with placebo (36% vs. 48%; P = 0.027). Time to first SRE was also delayed significantly (median 457 vs. 304 days; P = 0.007). Multiple event analysis showed that ibandronate reduced the risk of developing an SRE by 32% (hazard ratio = 0.69; 95% confidence interval 0.42-0.79; P = 0.003). In general, ibandronate was well tolerated with very rare grade 3 or 4 toxicity. In this study, ibandronate was shown to be significantly more effective than placebo as a treatment for metastatic bone disease from breast cancer using multiple end points.

A phase I study of zoledronic acid (ZA) and low-dose cyclophosphamide (CTX) in children with recurrent/refractory neuroblastoma (NB): A New Approaches to Neuroblastoma Therapy (NANT) study

10022 Background: ZA, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone metastases occur in 60% of children with advanced NB. A xenograft mouse model demonstrated ZA with low dose chemotherapy delayed progression of NB bone lesions prompting a phase I trial of ZA. Methods: Three dose levels of intravenous ZA (2, 3, or 4 mg/m2) administered every 28 days were evaluated with continuous daily oral CTX (25 mg/m2/day) in patients with recurrent/refractory NB and bone metastases. The primary objective was to determine a recommended dose of ZA for future trials. PKs with the first dose of ZA and serial serum IL-6 levels (stimulator of osteoclast activity) were evaluated. Results: 21 patients (14 male), median age 7.9 years (0.8–26.6 years), were enrolled at ZA dose levels 2 mg/m2 (n=4), 3 mg/m2 (n=3), and 4 mg/m2 (n=13). Seventy-five cycles were administered with median of 1 cycle per patient (range 1–18). Two DLT (Gr 3 hypophosphatemia) occurred at 4 mg/m2 ZA. Other Gr 3 or 4 toxicities included hypocalcemia (n = 2), elevated transaminases (n = 2), neutropenia (n = 2), anemia (n = 1), lymphopenia (n = 1), and hypokalemia (n = 1). A fracture related to osteosclerosis occurred after 18 cycles. There were no renal or dental complications. There was 1 complete response, 9 stable disease median 4.5 cycles (range 3–18), and 10 progressions (central review pending). At 4 mg/m2, mean serum IL-6 levels decreased from 3.9 pg/mL (95% CI: 2.8–5.2 pg/mL) (n = 11) to 2.9 pg/mL (95% CI: 1.8–4.4 pg/mL) after cycle 1 (n = 8). ZA PK were similar to adults. Conclusions: ZA with low dose CTX is well tolerated with evidence of clinical benefit in children with recurrent/refractory NB. The recommended ZA dose for future study is 4 mg/m2 every 28 days. No significant financial relationships to disclose.

The importance of combined hematologic and CT diagnosis for monitoring response in patients with multiple myeloma treated with Bortezomib based therapy

8597 Background: To assess the potential role of radiological monitoring (conventional CT) of lytic bone lesions for diagnosis of progressive (PD) or relapsing (R) multiple myeloma (MM) in comparison with laboratory-based diagnosis, soft-tissue based CT-diagnosis and combined hematologic-radiological diagnosis. Materials and Methods: Between 3/03 and 12/07, 201 patients with MM underwent nonenhanced whole-body low-dose multidetector-CT (WBLD-MDCT) survey parallel to hematological follow up (582 investigations). CT-scans were performed using a standardized low-dose protocol assessing number and size of lytic bone lesions (bone window setting, bW) similar to conventional X-ray diagnosis. In addition, number, size and density of medullary and extra-medullary lesions (soft-tissue window setting, s-tW) were analyzed. Progressive or relapsing myeloma was defined by progression of lytic bone lesions, medullary and extra-medullary tumor infiltration and/or of established basic hematologic parameters. Results: 210/582 investigations showed PD or R. 50/210 (24%) yielded the correct diagnosis by all three methods, 50/210 (24%) were diagnosed correctly by WBLD-MDCT (bW), 133/210 (63%) by laboratory-based testing and 195/210 (93%) by WBLD-MDCT (s-tW) as well as by the combination of the latter two. 8/26 assessments of R were biomarker negative. Only 1 of these examinations proved positive on WBLD-MDCT (bW) while the other 7 were correctly diagnosed by WBLD-MDCT (s-tW) due to progress of medullary infiltration and/or extra-medullary manifestation. Of the biomarker-negative assessments of PD (84/210), only 24 (24/84) showed progress of osteolysis on WBLD-MDCT (bW) while all were correctly assessed by WBLD-MDCT (s-tW). Discussion: This retrospective analysis indicates that monitoring of lytic bone lesions in patients with MM is inaccurate for assessment of progression or relapse of multiple myeloma. Due to the effects of specific chemotherapy and accompanying bisphosphonates therapy, progression of lytic bone lesions seems to occur much later in the course of the disease showing slower growth kinetics compared with medullary and extra-medullary myeloma manifestations. No significant financial relationships to disclose.

Zoledronic Acid and Survival in Patients with Metastatic Bone Disease from Lung Cancer and Elevated Markers of Osteoclast Activity

Bone metastases from non-small cell lung cancer (NSCLC) are associated with skeletal-related events (SREs) and elevated levels of N-telopeptide of type I collagen (NTX) in some patients. Zoledronic acid (ZOL) reduces SRE risk and NTX levels. To assess effects of baseline variables, including NTX levels (normal = NTX < 64 nmol/mmol creatinine; high = NTX > or = 64 nmol/mmol creatinine), on treatment effects in NSCLC patients, a retrospective analysis was performed in NSCLC patients with bone metastases (N = 382) treated with ZOL or placebo every 3 weeks in a 21-month randomized clinical trial in patients with NSCLC or other solid tumors. Cox proportional hazards models assessed relative risks (RRs) of SREs, bone lesion progression, and death. Multivariate models analyzed covariate effects on survival. For both placebo- and ZOL-treated patients, high baseline NTX correlated with increased SRE risk (p = 0.068 and 0.012, respectively). Although high versus normal baseline NTX correlated with more than twofold increased risks of bone lesion progression and death in the placebo group (p = 0.039 and 0.001, respectively), correlations were weaker in the ZOL group (RR = 1.38; p = 0.0186 and RR = 1.27; p = 0.142, respectively), suggesting an interaction effect of ZOL and baseline NTX. Among patients with high baseline NTX, ZOL significantly reduced the RR of death by 35% versus placebo (p = 0.024). Per multivariate analysis, ZOL treatment (p = 0.005), higher lymphocyte count (p = 0.011), performance status 0 to 1 (p = 0.012), and absence of narcotic use (p = 0.016) correlated with improved survival. This retrospective analysis revealed statistically significant correlations between ZOL and increased survival versus placebo in NSCLC patients and high baseline NTX levels.

維持透析中の進行性腎癌骨転移例に対しゾレドロン酸を投与した

Zoledronic acid is reported to significantly reduce skeletal morbidity and prolong time to bone lesion progression in patients with bone metastases from various malignant tumors including renal cell carcinoma. Due to renal uptake and elimination of zoledronic acid, however, it is difficult to control dose alignment in patients with kidney dysfunction. We reviewed significance of hemodialysis and monitoring of serum creatinine and calcium in patients with ESRD. (Cases) We experienced two cases of end-stage renal disease (ESRD) with bone metastases from advanced renal cell carcinoma. Zoledronic acid was given to both patients by 15 minutes intravenous infusion followed by hemodialysis 24 hours later. Systemic cytokine infusion and oral thalidomide were also given to both patients. Level of serum calcium reduced in one case two weeks later, and treated by calcium administration. No other adverse effects were noted for more than six months of combination therapy. Both cases maintained stable disease not only for bone metastases but also for the systemic condition without any organ failure. Even in patients under maintenance hemodialysis, zoledronic acid can be given with certain safety and efficacy by hemodialysis 24 hours after administration and intense monitoring of serum calcium level. We think this is the first report of zoledronic acid treatment to ESRD patients with bone metastases from malignant tumors.

Ibandronate is effective in preventing skeletal events in patients with bone metastases from colorectal cancer

Patients with metastatic colorectal carcinoma (CRC) often develop bone metastases with a high risk of complications. Ibandronate is a novel single-nitrogen bisphosphonate that has been shown to be effective for treating bone metastases from breast cancer. A randomized, placebo-controlled trial was conducted to evaluate the efficacy and safety of ibandronate in patients with bone metastases from CRC. The primary efficacy end point was the proportion of patients with skeletal-related events (defined as pathologic fracture, spinal cord compression, radiation therapy to bone, change in antineoplastic therapy or surgery to bone). Secondary end points included time to first skeletal event, skeletal morbidity rate (events/year) and time to progression of bone lesions. In 73 patients with CRC, treatment with intravenous ibandronate 6 mg administered via a 15-min infusion significantly reduced the proportion of patients with skeletal events (39% vs. 78% with placebo; P = 0.019) and prolonged the time to first event by at least 6 months (median >279 vs. 93 days with placebo; P = 0.009). Ibandronate also significantly reduced the skeletal morbidity rate (mean 2.36 vs. 3.14 with placebo; P = 0.018) and prolonged time to progression of bone lesions (214 days vs. 81 days with placebo; P = 0.018). Ibandronate was well tolerated with very rare grade 3 or 4 toxicity. Furthermore, the incidence of renal adverse events was comparable with placebo and there were no clinically relevant changes in serum creatinine. Ibandronate provided significant clinical benefits for patients with bone metastases secondary to CRC. These results indicate that ibandronate may be an effective treatment for patients with metastatic bone disease following CRC. Larger studies are required for further assessment.

Hypercalcemia and Osteolytic Bone Lesions in B-Cell Chronic Lymphocytic Leukemia: A Case Report

Hypercalcemia and osteolytic bone lesions are rare associations of chronic lymphocytic leukemia. Different pathogenetic mechanisms have been postulated. We report a case of chronic lymphocytic leukemia with hypercalcemia, osteolytic bone lesions, and pathologic fractures without the evidence of Richter's transformation. Hypercalcemia was present at diagnosis and resolved with chemotherapy but recurred with disease progression and development of osteolytic bone lesions. A review of the literature is presented.

Effect of zoledronic acid (Zol) compared with placebo on overall disease and bone lesion progression in patients (pts) with bone metastases from certain solid tumors: Stratification by baseline characteristics

18541 Background: Zol has been shown to significantly reduce the risk of skeletal complications compared with placebo in pts with bone metastases from a wide range of solid tumors including a delay of bone lesion progression in pts with renal cancer. To assess whether Zol may reduce the risk of overall disease or bone lesion progression in pts with solid tumors other than breast, non-small cell lung, and prostate cancers, we conducted a retrospective analysis of pts enrolled in a large, randomized, controlled trial. Methods: Pts treated with Zol or placebo were retrospectively stratified by baseline characteristics, including Brief Pain Inventory (BPI) composite pain score, time from initial cancer diagnosis to development of bone metastases, and duration of cancer. The relative risk (RR) of disease progression during 25 months on study was analyzed using the Cox proportional hazards model (stratified log rank). Results: Median baseline BPI pain score was 2.75, median time with cancer was 15 months, and median time to development of bone metastases was 8.5 months. In pts with a baseline BPI score ≥ 2.75 (n = 236), Zol treatment significantly reduced the RR of disease progression by 34% (hazard ratio [HR] = 0.657; P = .014) and the RR of bone lesion progression by 32% (HR = 0.680; P = .028) compared with placebo. Additionally, in pts with cancer duration &lt;15 months (n = 193), Zol treatment reduced the RR of disease progression by 45% (HR = 0.547; P = .002) and the RR of bone lesion progression by 40% (HR = 0.605; P = .016) compared with placebo. Similarly, among pts who developed bone metastases &lt; 8.5 months from initial diagnosis of cancer (n = 193), Zol treatment significantly reduced the RR of disease progression by 39% and the RR of bone lesion progression by 48% compared with placebo (HR = 0.611; P = .009 and HR = 0.519; P = .004, respectively). Conclusions: This exploratory analysis suggests that Zol has potential antitumor effects that may reduce the risk of overall disease and bone lesion progression in pts who have higher pain scores and shorter time to development of bone metastases. Prospective studies are needed to confirm this result. [Table: see text]