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Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases.

ABSTRACT: Bone metastases frequently occur in patients with advanced solid tumors, particularly breast and prostate cancers, and nearly all patients with multiple myeloma have some degree of skeletal involvement. The strides made in treating these primary tumors have extended median survival times and thereby increased patient risk for skeletal-related events (SREs), including pathologic fractures, spinal cord compression, need for palliative radiation therapy or surgery to bone, and hypercalcemia. Bisphosphonates, inhibitors of osteoclastic bone resorption that were first established as treatment of osteoporosis, have been shown to prevent and/or delay SREs related to malignancy. The results of a large, randomized phase 3 study comparing zoledronic acid and pamidronate in breast cancer or multiple myeloma patients with osteolytic lesions showed that the incidence of SREs, time to first SRE, and risk of developing a SRE were similar between treatment groups. However, in patients with solid tumors (excluding breast or prostate cancer) metastatic to the bone, only zoledronic acid has demonstrated clinical efficacy. Although bone turnover marker levels, such as N-telopeptide of type I collagen, have been shown to correlate with clinical response, additional studies are needed to validate their ability to predict response to bisphosphonate therapy.

SUBMITTER: Polascik TJ

PROVIDER: S-EPMC2769231 | biostudies-other | 2009 Sep

REPOSITORIES: biostudies-other

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Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases.

Polascik Thomas J TJ

Drug design, development and therapy 20090921

Bone metastases frequently occur in patients with advanced solid tumors, particularly breast and prostate cancers, and nearly all patients with multiple myeloma have some degree of skeletal involvement. The strides made in treating these primary tumors have extended median survival times and thereby increased patient risk for skeletal-related events (SREs), including pathologic fractures, spinal cord compression, need for palliative radiation therapy or surgery to bone, and hypercalcemia. Bispho ...[more]

PMID: 19920919

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Project description:Introduction In patients with metastatic disease involving weight-bearing bones, postoperative radiotherapy (PORT) is commonly administered following surgical stabilization of an impending or confirmed pathologic fracture to reduce the risk of a seeded local recurrence. The goal was to re-evaluate the beneficial effect of PORT in a modern cohort of patients and determine any potential clinical predictors of skeletal-related events (SREs) which were defined as a pathologic fracture or the necessity for radiation or surgery to the affected bone. Methods Consecutive patients undergoing surgical stabilization of metastatic disease to weight-bearing bones of the extremities between 2012 and 2019 were reviewed. Patient, disease, and treatment factors were abstracted. The cumulative incidence of SREs was determined using competing risks methodology; overall survival (OS) was estimated using the Kaplan-Meier method. Results A total of 82 patients were identified, 74% of whom had undergone intramedullary nail fixation and 26% internal fixation or replacement. The femur was the most commonly involved bone (94%). A majority (78%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1-2. Bone-strengthening agents were given to 38% and PORT to 54%. The median PORT dose was 30 Gy in 10 fractions and the median percent coverage of surgical hardware was 100% (range, 25-100). SREs occurred in 10 of 82 patients. There were no differences between no RT and RT groups for the two-year cumulative incidence of SREs (8.2% vs 11.5%, p=0.59) or two-year cumulative incidence of local failure (10.8% vs 4.6%, p=0.53). The only identified predictors of SREs were the use of bone-strengthening agents (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.05-1.06, p=0.06) and malnutrition (HR 3.69, 95% CI 0.91-14.93, p=0.07). For patients treated with PORT, a biologically effective dose or percent coverage of surgical hardware was not associated with SREs. Conclusion In this series, the addition of PORT following surgery for metastatic disease involving weight-bearing bones does not significantly affect the rate of SREs. The use of bone-strengthening agents appears protective, and malnourished patients appear particularly at high risk for future SRE.

Project description:Importance:Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective:To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants:Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n?=?1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions:Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n?=?911) vs every 12 weeks (n?=?911) for 2 years. Main Outcomes and Measures:The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results:Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of -0.3% [1-sided 95% CI, -4% to ?]; P?<?.001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Conclusions and Relevance:Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. Trial Registration:clinicaltrials.gov Identifier: NCT00869206.

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Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases.

Publications

Bisphosphonates in oncology: evidence for the prevention of skeletal events in patients with bone metastases.

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