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 This is an original JCO publication from 2011. Please visit the JCO website to access the full article.


Role of Bone-Modifying Agents in Metastatic Breast Cancer


 

 Authors

Catherine H. Van Poznak, Sarah Temin, Gary C. Yee, Nora A. Janjan, William E. Barlow, J. Sybil Biermann, Linda D. Bosserman, Cindy Geoghegan, Bruce E. Hillner, Richard L. Theriault, Dan S. Zuckerman and Jamie H. Von Roenn

 

THE BOTTOM LINE

 

 

 

Intervention

  • Bone-modifying agents (BMAs), including bisphosphonates

 

Target Audience

  • Medical Oncologists, Radiation Oncologists, Surgical Oncologists, Palliative Care Providers

 

Key Recommendations

  • BMAs are recommended for patients with metastatic breast cancer with evidence of bone destruction.
  • Denosumab 120 mg subcutaneously every 4 weeks; intravenous (IV) pamidronate 90 mg over no less than 2 hours every 3 to 4 weeks; or IV zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks
  • One BMA is not recommended over another.
  • In patients with creatinine clearance 60 mL/min, no change in dosage, infusion time, or interval is required; monitor creatinine
  • level with each intravenous bisphosphonate dose.
  • In patients with creatinine clearance 30 mL/min or on dialysis who may be treated with denosumab, close monitoring for hypocalcemia is recommended.
  • All patients should have a dental examination and preventive dentistry before using a BMA.
  • At onset of cancer bone pain, provide standard of care for pain management and start BMAs.
  • Use of biochemical markers to monitor BMA use is not recommended for routine care.

 

Methods

  • Systematic review of medical literature and analysis of the medical literature by the Update Committee of an Expert Panel

 

Additional Information

  • The recommendations, clinical questions, and a brief summary of the literature and discussion are in this Executive Summary

 

 

SUMMARY OF RECOMMENDATIONS

 

 

Recommendation Category2003 Recommendations2011 RecommendationsChange
Recommendation 1: Indications and time of initiationFor breast cancer patients who have evidence of bone destruction on plain radiographs, IV pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. Starting bisphosphonates in women with an abnormal bone scan and an abnormal CT or MRI scan showing bone destruction, but normal plain radiographs, is considered reasonable by Panel consensus based on the findings in women with lytic or mixed lytic/blastic changes on plain radiographs. There is insufficient evidence relating to efficacy to support one bisphosphonate over the other. For each of the guidelines, clinical judgment should also take into consideration the patient's general performance status and overall prognosis.For patients with breast cancer who have evidence of bonemetastases, denosumab 120 mg subcutaneously every 4 weeks,IV pamidronate 90 mg delivered over no less than 2 hours, or zoledronic acid 4 mg over no less than 15 minutes every 3 to 4 weeks is recommended. Starting bone-modifying agents in women with an abnormal bone scan and an abnormal CT scan or MRI showing bone destruction, but normal plain radiographs, is considered reasonable by Panel consensus based on the findings in women with lytic or mixed lytic/blastic changes on plain radiographs. Starting bone-modifying agents in women with only an abnormal bone scan but without evidence of bone destruction on radiographs, CT scans, or MRI is not recommended outside of a clinical trial. There is insufficient evidence relating to efficacy to support one bone-modifying agent over another.Addition of new bone-modifying agent. Term changed from bisphosphonates to bone-modifying agents.
Recommendation 2: Role of bone-modifying agents in the presence of extraskeletal metastasesStarting bisphosphonates in women without evidence of bone metastases even in the presence of other extraskeletal metastases is not recommended. This clinical situation has not been studied using IV bisphosphonates and should be the focus of new clinical trials. Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction on radiographs, CT scans, or MRI is not recommended.Starting bone-modifying agents in women without evidence of bone metastases even in the presence of other extraskeletal metastases is not recommended. This clinical situation has been inadequately studied using IV bisphosphonates or other bone-modifying agents and should be the focus of new clinical trials.(Unchanged in substance from 2003) Term changed from bisphosphonates to bone-modifying agents.
Recommendation 3A: Renal safety concernsIn patients with pre-existing renal disease and a serum creatinine < 3.0 mg/dL (265μmol/L), no change in dosage, infusion time, or interval of pamidronate or zoledronic acid is required. Use of these bisphosphonates among patients with worse function has been minimally assessed. Infusion times < 2 hours with pamidronate or < 15 minutes with zoledronic acid should be avoided. The Panel recommends that serum creatinine should be monitored prior to each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly but there is no evidence upon which to base a recommendation for time intervals. In contrast to multiple myeloma patients, there currently are no data to support routine assessments for albuminuria in patients with breast cancer.In patients with a calculated serum creatinine clearance > 60 mL/min, no change in dosage, infusion time, or interval of pamidronate or zoledronic acid administration is required. Use of bone-modifying agents among patients with reduced renalfunction has been incompletely assessed. The packet insert of zoledronic acid provides guidance for dosing when baseline serum creatinine clearance is≥ 30 and < 60 mL/min. Infusion times < 2 hours with pamidronate or < 15 minutes with zoledronic acid should be avoided. The Panel recommends that serum creatinine should be monitored prior to each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling. Serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly. The risk of hypocalcemia with denosumab dosed at 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance < 30 mL/min or receiving dialysis. Monitor for hypocalcemia in patients with impaired creatinine clearance. There is no evidence to guide the interval for monitoring serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin with denosumab, pamidronate, or zoledronic acid.Addition regarding denosumab. A change in serum creatinine clearance threshold. Last sentence of 2003 recommendation taken out. Term changed from bisphosphonates to bone-modifying agents.
Recommendation 3B: ONJN/AONJ is an uncommon but potentially serious condition associated with the use of bone-modifying agents. The Update Committee concurs with the revised FDA label for zoledronic acid and pamidronate and the FDA label for denosumab and recommends that all patients with cancer receive a dental examination and necessary preventive dentistry prior to initiating therapy with inhibitors of osteoclast function unless there are mitigating factors that preclude the dental assessment. These recommendations should be observed whenever possible. While receiving inhibitors of osteoclast function, patients should maintain optimal oral hygiene and, if possible, avoid invasive dental procedures that involve manipulation of the jaw bone or periosteum. Although most cases of ONJ have occurred in patients treated with IV bisphosphonates and bone-modifying agents who underwent an invasive dental procedure, cases have occurred spontaneously and have been reported in patients treated with other bone-modifying agents, including oral bisphosphonates and direct osteoclast inhibitors.New recommendation
Recommendation 4: Optimal durationThe Panel suggests that once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient's general performance status. The Panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events.The Panel suggests that once initiated, bone-modifying agentsbe continued until evidence of substantial decline in a patient's general performance status. The Panel stresses that clinical judgment must guide what constitutes a substantial decline. There is no evidence addressing the consequences of stoppingbone-modifying agents after one or more adverse skeletal-related events.(Unchanged in substance from 2003) Term changed from bisphosphonates to bone-modifying agents.
Recommendation 5: Optimal intervals between dosingFor breast cancer patients who have evidence of bone destruction on plain radiographs, IV pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence relating to efficacy to support one bisphosphonate over the other. For each of the guidelines, clinical judgment should also take into consideration the patient's general performance status and overall prognosis.For patients with breast cancer who have evidence of bone destruction on plain radiographs, denosumab 120 mg subcutaneously every 4 weeks,IV pamidronate 90 mg delivered over 2 hours, or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended.Addition of new bone-modifying agent. The second-to-last sentence of 2003 recommendation is in Recommendation 1 of 2011 recommendations. The last sentence from 2003 recommendation applies to all recommendations.
Recommendation 6: Role of bone-modifying agents in pain controlThe Panel recommends that the current standards of care for cancer pain management must be applied throughoutbisphosphonate therapy and are required by good clinical practice. These standards of care for pain management include analgesics, corticosteroids, interventional procedures, nonsteroidal anti-inflammatory agents, systemic radiopharmaceuticals, and local radiation therapy. Among other therapeutic options, IV pamidronate or zoledronic acid may be of benefit among women with pain caused by bone metastases to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, because it wasassociated with a modest pain control benefit in controlled trials.The Panel recommends that the current standards of care for cancer bone pain management be applied at the onset of pain, in concert with the initiation of bone-modifying agenttherapy. This is required by good clinical practice. The standard of care for pain management includes the use ofnonsteroidal anti-inflammatory agents, opioid and nonopioidanalgesics, corticosteroids, adjuvant agents,interventional procedures, systemic radiopharmaceuticals, local radiation therapy, andsurgery.Bone-modifying agents are an adjunctive therapy for cancer-related bone pain control and are not recommended as first-line treatment for cancer-related pain.IV pamidronate or zoledronic acid may be of benefit for patients with pain caused by bone metastases and contribute to pain relief when used concurrently with analgesic therapy, systemic chemotherapy, radiation therapy,and/or hormonal therapy.Bone-modifying agents have been associated with a modest pain control benefit in controlled trials.Change in timing of pain management. Term changed from bisphosphonates to bone-modifying agents.
Recommendation 7: The role of biochemical markersThe use of the biochemical markers to monitor bisphosphonate use is not suggested for routine care.The use of the biochemical markers to monitor bone-modifying agent use is not recommended for routine care.(Unchanged in substance from 2003) Term changed from bisphosphonates to bone-modifying agents.
  • NOTE. For each of the recommendations, clinical judgment should also take into consideration the patient's general performance status, patient preferences, and overall prognosis. Italicized text indicates minor changes. Bolded text indicates substantive changes.

  • Abbreviations: IV, intravenous; CT, computed tomography; MRI, magnetic resonance imaging; FDA, US Food and Drug Administration; N/A, not applicable; ONJ, osteonecrosis of the jaw.

 

    

 

 

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