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BACKGROUND: Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting. METHODS: Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence. RESULTS: At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P = .3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P = .6283) were similar at month 61. CONCLUSIONS: Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated. Cancer 2012. © 2011 American Cancer Society.

Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid-induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level < 3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3-4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.

Purpose: Zoledronic acid (ZOL) given every 3 to 4 weeks can reduce skeletal-related events (SRE) in patients with bone lesions from multiple myeloma. This study evaluated efficacy and safety of less-frequent ZOL dosing based on bone turnover markers in patients with 1 to 2 years of prior bisphosphonate therapy. Experimental Design: Patients received ZOL (4 mg) every 4 or 12 weeks based on urinary N-telopeptide of type 1 collagen (uNTX) levels (every 4 weeks if uNTX ≥50 nmol/mmol creatinine, every 12 weeks if uNTX < 50). Results: Of 121 patients enrolled (mean age, 63.8 years; median follow-up, 21 months), 4 patients started ZOL every 4 weeks and 117 received ZOL every 12 weeks based on uNTX at study entry. All 4 patients who initiated ZOL every 4 weeks switched to every 12 weeks due to decreased uNTX. Thirty-eight of 117 patients who initiated ZOL every 12 weeks switched to ZOL every 4 weeks due to disease progression (n = 20), increased uNTX (n = 14), and SREs (n = 4). Overall SRE incidence was low; 7 (5.8%) and 5 (4.9%) patients experienced an SRE during years 1 and 2, respectively. Mean (SD) SRE rate at year 2 was 0.01 (0.03) per person-year. The 2-year incidence rate for osteonecrosis of jaw was 3.3%. Four deaths were reported, none related to ZOL. Conclusions: Less frequent ZOL dosing (every 12 weeks over 2 years) maintains a low SRE rate and can be safely administered for up to 4 years. Clin Cancer Res; 22(6); 1378–84. ©2015 AACR. See related commentary by Fonseca and Jain, p. 1301

This study was designed to evaluate the efficacy and safety of combined zoledronic acid and docetaxel/carboplatin in patients with non-small cell lung cancer (NSCLC) as preclinical studies showed synergistic antitumoral activity with bisphosphonates and docetaxel. Patients with inoperable stage IIIB or stage IV NSCLC were randomized 2:1 to receive docetaxel 75 mg/m 2 and carboplatin area under the concentration time curve 6 with (Arm A) or without (Arm B) zoledronic acid 4 mg every 3 weeks for 6 cycles. Patients responding in Arm A were rerandomized to receive monthly zoledronic acid (maximum: 12 months [Arm A1] or no zoledronic acid [Arm A2]). Patients responding in Arm B entered Arm B1 for follow-up evaluation only. The primary endpoint was the proportion of patients without disease progression; secondary endpoints were time to disease progression (TTP), TTP in bone, best overall response rate, 1-year overall survival (OS) time, and safety; study not powered to detect endpoint differences. Of 150 patients, 98 were randomized to Arm A and 52 to Arm B. In the treatment phase, results were similar between groups in the proportion of patients without disease progression (40.9% vs 38.8%; P = .8096) and median TTP (132 d vs 132 d; P = .9622). One-year OS times and best overall response rates were 266 d vs 206 d ( P = .4855) and 64.1% vs 72% ( P = .3423), respectively; the study was not powered to detect differences. In the follow-up phase, TTP and OS time were similar. Adding zoledronic acid to docetaxel/carboplatin in advanced stage NSCLC patients was well tolerated, but provided little to no effect on disease progression endpoints.

Abstract 5122 Background: Standard monthly infusions of 4 mg zoledronic acid (ZOL) have been proven effective at reducing the risk of skeletal complications in patients with multiple myeloma (MM). It is hypothesized that patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. The Z-MARK study evaluates whether patients who have been treated with IV bisphosphonates (BP) for 1–2 years can safely be treated long-term with less frequent dosing of ZOL based on bone turnover markers. Materials and Methods: MM patients (N=121) who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received ≥4 prior doses, with baseline calculated creatinine clearance (CrCl) of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL q4 or q12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol Cr - infusion q4 weeks, uNTX Results: As of the May 9, 2011 data cut-off date, 31.3% (9.6% due to AEs, 14.5% withdrew consent, and 7.2% due to other reasons) in A and 36.8% (15.8% due to AEs, 10.5% withdrew consent, and 10.5% due to other reasons) in B discontinued early. The mean age was 63.8 years, with approximately 1:1 male/female ratio. The baseline mean (SD) for uNTX and calculated CrCl was 21.3 (11.8) nmol/mmol Cr and 84.8 (34.7) mL/min, respectively. Based on the International Staging System, 79.5% of the patients were stage I or II and 14.5% were stage III at enrollment in A. The same in B were 71.1% and 21.1%. The median time from initial MM diagnosis to enrollment was 18.4 months in both groups. In A, 67.5% had ≥1 osteolytic lesions and of these 37.5% had >6; in B, 73.7% had ≥1 and of these 42.9% had >6. In A, 83.1% had received ZOL only, 13.3% had received PAM only; in B, 92.1% had received ZOL only and 2.6% had received PAM only prior to enrollment. The median duration of prior BP therapy was 13.8 in A and 14.8 months in B. In A, 73.5% had ≥1 SREs at enrollment; in B the same was 76.3%. Four patients started study ZOL treatment on the q4-weeks dosing schedule and 117 patients started on the q12-weeks schedule (based on uNTX values at study entry). Thirty four of 117 patients assigned to q12-week dosing were switched to q4 weeks (14 due to increased uNTX, 4 due to SREs, and 16 due to disease progression). In study Year 1, no patient in A had any SRE while 7 patients in B had SREs (3 pathologic fractures, 3 spinal cord compressions, 4 radiations to bone, 1 surgery to bone, 1 hypercalcemia of malignancy). Only 5.8% of patients had any SRE in the first year. In A, 90.4% of patients had any adverse event (AE) while it was 100% in B. The most common AEs were upper respiratory tract infection (23.1%), fatigue (23.1%), cough (19%), diarrhea (19%), pneumonia (18.2%), pyrexia (18.2%), arthralgia (16.5%) and nausea (15.7%). The percentage of patients with any serious AE was 26.5 in A and 57.9 in B. Overall, 14.9% (12.0% in A, 21.1% in B) of patients had an AE leading to ZOL discontinuation. At Week 48, the median % change in uNTX was −11.1 in A and 12.5 in B. For serum Cr, no change in the median was observed in either group at Week 48. One death was reported on study (not suspected to be related to ZOL). There were 3 reports of osteonecrosis of the jaw (ONJ) in A, suspected to be related to ZOL, and no report of ONJ in B; the median time on ZOL was 17.0 months for A and 17.3 months for B. Discussion: These Z-MARK PA results show that bone marker directed dosing is feasible in patients who had 1–2 years of prior IV BP therapy. The low number of SREs observed within 1 year of study follow up is possibly due to the persistent protective effects from IV BP treatment prior to study entry and on study. Additional follow up is needed to determine the potential predictive value and the long-term benefits of bone marker directed dosing of ZOL in MM patients following standard IV BP treatment. Disclosures: Raje: Acetylon: Research Funding; Astra Zeneca: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Zoledronic acid: Studying alternate dosing schedule in multiple myeloma(bone marker directed dosing). Vescio:Novartis Pharmaceuticals Corporation: Speakers Bureau. Tran:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis: Employment, Equity Ownership. Argonza-Aviles:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anderson:Novartis Pharmaceuticals Corporation: Consultancy.

Abstract 2971 Background: Standard monthly infusions of 4 mg zoledronic acid (ZOL) have been proven effective at reducing the risk of skeletal complications in patients with multiple myeloma (MM). It is hypothesized that patients with normal bone metabolism may not require as intense a treatment schedule as patients with accelerated bone resorption. The Z-MARK study evaluates whether patients who have been treated with IV bisphosphonates (BP) for 1–2 years can safely be treated long-term with less frequent dosing of ZOL based on bone turnover markers. Materials and Method: One hundred twenty one patients with MM who had started standard monthly IV BP (ZOL or pamidronate, PAM) 1–2 years prior to enrollment and received at least 4 prior doses, with baseline calculated creatinine clearance of ≥30 mL/min, were enrolled. Patients received 4mg IV ZOL every 4 or 12 weeks based on their most recent urine NTX (uNTX) measurement (uNTX≥50 nmol/mmol creatinine - infusion q4 weeks, uNTX Results: The mean age of the IA patients was 65.5 years, with approximately 1:1 male/female ratio. The baseline mean (SD) for uNTX and calculated creatinine clearance was 21.3 (12.3) and 82.4 (35.2), respectively. Based on the International Staging System (ISS), 75% of the patients were stage I or II and 20% were at stage III at enrollment. The median time from initial MM diagnosis to enrollment was 17.7 months. Seventy three percent of the patients had one or more osteolytic lesions, 37% of the total had more than six. Eighty three percent of the patients had received ZOL only, 12% had received PAM only, and 5% had received both ZOL and PAM prior to study enrollment. The median duration of prior BP therapy was 14.1 months. Sixty eight percent of the patients had 1 or more SREs at enrollment. Seventy six percent of the patients received fewer than 8 ZOL infusions (either as q4 or q12 weeks) on study. Two patients started study ZOL treatment on the q4-week dosing schedule and 58 patients started on the q12-week schedule (based on uNTX values at study entry). Forty five of 60 patients stayed on the initial treatment schedule based on their uNTX. Thirteen patients assigned to q12-week dosing switched to q4 weeks, out of which 10 stayed on q4-week dosing, and 2 patients initially on q4-week dosing switched to q12-week schedule. Two patients, both on the q12-week schedule, had SREs on study (1 with spinal cord compression and 1 with 4 instances of radiations to bone). Ninety five percent of patients had any adverse event (AE) and 32% had any serious AE. The most common AEs were upper respiratory tract infection (25%), fatigue (18%), back pain (15%), musculoskeletal pain (15%), pyrexia (15%), cough (15%) and diarrhea (15%). Thirteen percent of patients had an AE leading to discontinuation of the study drug. In both uNTX and serum creatinine, no change in the medians was observed at Week 48. There was one death on study (not suspected to be related to ZOL) and no report of osteonecrosis of the jaw (ONJ). Discussion: These interim results of the Z-MARK study show that bone marker directed dosing is feasible and safe in preventing skeletal complications associated with MM in patients who had 1–2 years of prior IV BP therapy. The low number of SREs observed is possibly due to the short follow-up period and persistent protective effects from IV BP treatment. Additional follow up is needed to determine the potential predictive value and the long-term benefits of bone marker directed dosing of ZOL in MM patients following standard IV BP treatment. Disclosures: Raje: Novartis Pharmaceuticals Corporation: Consultancy, Investigator; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Acetylon: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Zoledronic acid: Studying alternate dosing schedule in multiple myeloma (bone marker directed dosing). Vescio:Novartis Pharmaceuticals Corporation: Investigator, Speakers Bureau. Montgomery:Novartis Pharmaceuticals Corporation: Investigator. Parameswaran:Novartis Pharmaceuticals Corporation: Investigator. Tran:Novartis Pharmaceuticals Corporation: Employment. Warsi:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Argonza-Aviles:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Anderson:Novartis Pharmaceuticals Corporation: Consultancy, Investigator.

Background: Aromatase inhibitor (AI) therapy effectively increases disease-free survival in postmenopausal women (PMW) with ER+ and/or PR+ breast cancer (BCa). However, the use of AIs results in nearly complete ablation of estrogen production which can lead to accelerated bone loss and increased fracture risk. The Z-FAST study evaluated the efficacy and safety of zoledronic acid (ZOL) in preventing AI associated bone loss in PMW with early breast cancer (EBC) who received adjuvant letrozole (LET).Material and Methods: 602 PMW with stage I-IIIa ER+ and/or PR+ BCa starting LET (2.5 mg qd x 5 yrs) were randomized (1:1) to upfront ZOL (4 mg IV q 6 mos) vs delayed ZOL. The delayed arm (D) received ZOL when either the post-baseline T-score decreased to -1), and no U pts as compared to 4.9%(4) D pts became severely osteopenic (T Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4083.

Background:Non-steroidal aromatase inhibitors (AIs) are standard of care in the adjuvant treatment of postmenopausal women with hormone receptor positive (HR+) early stage breast cancer. Side effects such as arthralgia and/or myalgia (A/M) occur in 20 -35% of women on AI therapy with onset as early as 1-2 months from AI initiation. As many as 20% of patients may discontinue therapy due to A/M. Switching to another AI could improve the A/M and allow patients to remain on AI therapy. This study evaluated if patients (pts) who discontinued anastrozole (Ana) due to grade 2-3 A/M would be able to continue AI therapy if switched to Let. We measured whether switching to Let resulted in a lower proportion of grade >2 A/M symptoms and less discontinuation among women who previously discontinued Ana therapy due to A/M.Methods: Pts were eligible for treatment with Let (2.5mg/day for 6 months) if they were postmenopausal, HR+, had early stage breast cancer including LCIS and DCIS, and experienced grade 2-3 A/M on Ana resulting in discontinuation. Pts taking analgesics for any reason were excluded. A/M symptoms and self reported quality of life (QoL) outcomes were assessed by Basic Pain Inventory (BPI), Visual Analog Scale (VAS) and Health Assessment Questionnaires (HAQ) at baseline, during Let therapy and upon study completion. Pts tolerating Let therapy at 6 months had the option of continuing Let for their prescribed course of 5 years.Results: The study enrolled 261 pts of which 2 pts were ineligible. The median age of pts was 61, and 235 (90%) were Caucasian, 14 (5.4%) were Black, 3 (1.2 %) were Asian and 9 (3.4%) were other. At baseline, 107 (41.0%) and 70 (26.8%) had grade 2 or higher A/M respectively. At study completion, fewer patients suffered from grade ≥ 2 A/M, 61 (23.6%) and 46 (17.8%) respectively. Changes in QOL assessments showed a statistically significant improvement (p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 805.

Abstract #2067 Background: Changes in biochemical markers of bone turnover are expected to be predictors of long-term changes in bone mineral density (BMD). We studied the potential of bone-specific alkaline phosphatase (BSAP) and serum N-telopeptide (sNTX) at 6 and 12 months (mo) in predicting BMD of the lumber spine (LS) and total hip (TH) at 48 mo in Z-FAST study. Methods: Postmenopausal women with ER+ and/or PR+ early stage breast cancer were randomized 1:1 into Up-front (U) or Delayed (D) arms (N=301 in each). Patients (pts) in U received zoledronic acid (ZOL) 4 mg IV q6 mo starting at baseline; pts in D started ZOL q6 mo when their LS or TH T-score fell below -2. All pts started Letrozole 2.5 mg/day for 5 years. Levels of BSAP and sNTX were assessed at screening and every 6 mo on a subset of pts. LS and TH BMD were assessed by dual-energy x-ray absorptiometry (DEXA) at screening, 6 mo and every 12 mo thereafter for all available pts. This is an exploratory analysis to investigate the correlation between short-term % changes from baseline in BSAP and sNTX and long-term % changes from baseline in BMD. Pearson correlations and Receiver Operating Characteristics (ROC) analysis were performed. We report the results based on 48 mo data. Results: The Pearson correlations between % change in BSAP at 6 mo and LS BMD at 48 mo were -0.13 [(N=38, not significant (NS)] and -0.17 (N=39, NS) in arms U and D respectively. The correlations between % change in BSAP at 12 mo and LS BMD at 48 mo were -0.15 (N=39, NS) in U and -0.43 (N=38, p=0.0077) in D. Very similar correlations were obtained for % change in sNTX at 6, 12 mo and LS BMD at 48 mo in D, but in U the correlations were smaller and positive. The correlations between % change of both markers at 6, 12 mo and TH BMD at 48 mo were all NS at 0.05. ROC analysis showed that at best performance (maximum of sensitivity plus specificity), for any increase in sNTX at 12 mo, the sensitivity (SE), specificity (SP), positive predictive value (PPV) and negative predictive value (NPV) to predict LS BMD loss at 48 mo was 74%, 77%, 85% and 63% in D. For BSAP change of 3%, the four ROC parameters were 71%, 71%, 81% and 59% respectively. For prediction of TH BMD loss, the SE, SP and NPV were lower for both markers with higher PPV. In U, the SE, SP and PPV were all much lower with very high NPV for both markers and BMD loss. Conclusion: Interim results of Z-FAST data show that short-term changes in BSAP and sNTX have the potential for predicting long-term bone loss. The weaker correlations in U also suggest that zoledronic acid may have a direct preventive effect on bone loss independent of changes in the markers. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2067.