Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory and/or warning information has been released.
- March 22, 2016 – Opioid pain medicines : The U.S. Food and Drug Administration (FDA) is warning about several safety issues with the entire class of opioid pain medicines. These safety risks are potentially harmful interactions with numerous other medications, problems with the adrenal glands, and decreased sex hormone levels. They are requiring changes to the labels of all opioid drugs to warn about these risks.
Note from the National Guideline Clearinghouse (NGC) and the American Society of Clinical Oncology (ASCO): In planning the 2011 update, ASCO changed the scope of the guidelines to reflect changes in the field since the previous guideline. Reflecting the Update Committee's anticipation that data on new types of agents, including osteoclast inhibitors, may be available for future updates of this guideline, this guideline uses the term bone-modifying agents. The terminology in Recommendations 1, 2, 4, 6, and 7 has been changed from bisphosphonate to bone-modifying agent. The recommendations within the guideline focus on the drugs denosumab, zoledronic acid, and pamidronate because they are currently available in the United States.
Six of the recommendations are substantively the same as in the 2003 guidelines for bone-modifying agents for metastatic breast cancer. The current guideline has added a new recommendation regarding osteonecrosis of the jaw (ONJ), a condition recognized after the preparation of the 2003 guidelines. This guideline on metastatic breast cancer also reviews data on a new bone-modifying agent, denosumab. In contrast with the previous version, this guideline now focuses solely on patients with evidence of bone metastases. (See Table 1, "Summary of the 2011 Recommendations" in the original guideline document for more detailed information.)
Clinical Question 1
What are the indications for using bone-modifying agents to reduce the risk of skeletal-related events (SREs) in patients with metastatic breast cancer? When is the best time to initiate treatment with bone-modifying agents?
Recommendation 1. For patients with breast cancer who have evidence of bone metastases, denosumab 120 mg subcutaneously every 4 weeks, intravenous (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 computed tomography scan or magnetic resonance imaging 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, computed tomography scans, or magnetic resonance imaging is not recommended outside of a clinical trial. There is insufficient evidence relating to efficacy to support one bone-modifying agent over another.
Clinical Question 2
What is the role of bone-modifying agents in the presence of extraskeletal metastases without evidence of bone metastases?
Recommendation 2. 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.
Clinical Question 3A
What are the renal safety concerns of bone-modifying agent therapy?
Recommendation 3A. In patients with a calculated serum creatinine clearance of more than 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 renal function has been incompletely assessed. The packet insert of zoledronic acid provides guidance for dosing when baseline serum creatinine clearance is ≥30 and less than 60 mL/min. Infusion times less than 2 hours with pamidronate or less than 15 minutes with zoledronic acid should be avoided. The Panel recommends that serum creatinine be monitored before each dose of pamidronate or zoledronic acid, in accordance with U.S. Food and Drug Administration (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 less than 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 in patients on denosumab, pamidronate, or zoledronic acid.
Clinical Question 3B
What are the osteonecrosis of the jaw (ONJ) safety concerns of bone-modifying agent therapy?
Recommendation 3B. ONJ 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.
Clinical Question 4
What is the optimal duration of bone-modifying agent therapy for patients with metastatic breast cancer?
Recommendation 4. The Panel suggests that, once initiated, bone-modifying agents should be 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 stopping bone-modifying agents after one or more adverse SREs.
Clinical Question 5
What are the best intervals between dosing?
Recommendation 5. 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.
Clinical Question 6
What is the role of bone-modifying agents in control of pain secondary to bone metastases?
Recommendation 6. 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 agent therapy. This is required by good clinical practice. The standard of care for pain management includes the use of nonsteroidal anti-inflammatory agents, opioid and nonopioid analgesics, corticosteroids, adjuvant agents, interventional procedures, systemic radiopharmaceuticals, local radiation therapy, and surgery. 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.
Clinical Question 7
What is the role of biochemical markers of bone turnover to guide initiation of therapy in patients without a prior skeletal event, predict treatment response, guide adjustments to bone-modifying agent therapy, or independently predict future fractures?
Recommendation 7. The use of the biochemical markers to monitor bone-modifying agent use is not recommended for routine care.
Special Commentary on the Role of Vitamin D Deficiency and Bone-Modifying Agents
In the absence of definitive data, it is the Update Committee’s expert consensus that if there are no contraindications to calcium and vitamin D supplementation, then patients receiving bone-modifying agents should receive them at doses and schedules similar to those used in the clinical trials of the bone-modifying agents, both to support bone health and decrease the risk of bisphosphonate-induced hypocalcemia. U.S. health authorities generally recommend a minimum consumption of vitamin D of 200 U (5 µg) a day. For the prevention and treatment of osteoporosis in adults, vitamin D 800 U daily is often recommended.
Metastatic breast cancer with bone metastases
Assessment of Therapeutic Effectiveness
To update the recommendations on the role of bone-modifying agents* in the prevention and treatment of skeletal-related events (SREs) for patients with metastatic breast cancer with bone metastases
*Reflecting the Update Committee's anticipation that data on new types of agents, including osteoclast inhibitors, may be available for future updates of this guideline, this guideline uses the term bone-modifying agents.
Patients with breast cancer with evidence of bone metastases
- Bone-modifying agents approved for breast cancer metastatic to the bone:
- Zoledronic acid
- Close monitoring for hypocalcemia in patients with creatinine clearance <30 mL/min or on dialysis who may be treated with denosumab
- Dental examination and preventive dentistry before using bone-modifying agents (BMAs)
- Cancer bone pain management including standard of care and use of bone-modifying agents
Note: The use of the biochemical markers to monitor bone-modifying agent use was considered but not recommended for routine care.
- Skeletal-related events (SREs)
- Time to SRE
- Adverse events
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data
Literature Search Strategy
For this guideline, computerized literature searches of MEDLINE and the Cochrane Collaboration Library were conducted. Searches of the English-language literature from January 2003 to July 15, 2009, were conducted to address each of the original guideline questions; additional searches on biochemical markers of bone turnover (August 28, 2009) and on osteonecrosis of the jaw (ONJ) (March 16, 2010) were conducted. A supplemental search limited to randomized controlled trials (RCTs) on efficacy and case-control or cohort studies on adverse events was conducted on November 11, 2010. Search terms included the following: "breast neoplasms," "metastasis," "bone density conservation agents," "diphosphonates," and "biologic markers." Additional terms included generic and brand names of bone-modifying agents. Searches for efficacy outcomes were limited to published phase III RCTs, systematic reviews, and meta-analyses. For adverse events, the search was broadened to include observational studies because some adverse events of bone-modifying agents are rare. The Update Committee recognized these data as not as significant as data from comparative studies. For biomarker studies, reports were examined of prospective studies or retrospective analyses of prospectively collected samples with prospective aspects. The literature search terms are available in Data Supplement 4. A summary of the literature search results is provided in a QUORUM diagram in Data Supplement 5. Update Committee members provided additional references from personal files. (See the "Availability of Companion Documents" field for data supplements.)
Inclusion and Exclusion Criteria
Articles were selected for inclusion if they met the following criteria: participants had metastatic breast cancer and participants were randomly assigned to receive a bone-modifying agent or placebo or an alternative intervention. Outcome measures for efficacy and adverse event studies included at least one of the following: skeletal-related events (SREs) and time to SRE, adverse events, pain, and quality of life (see Definition of Terms in the original guideline document).
A total of 54 articles were included for data extraction
- 3 systematic reviews
- 14 randomized controlled trials (RCTs)
- 9 pooled/subset/secondary analyses of RCTs
- 26 cohort/case-control studies
- 1 other
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Relevant articles were selected and reviewed, and one reviewer extracted the data. For each article meeting the inclusion criteria, data were extracted on patient characteristics, study design and quality, intervention, and outcomes. The primary articles and the extracted data were available to the Update Committee and were discussed during the teleconferences.
Study Quality and Limitations of the Literature
The definition of skeletal-relating event (SRE) was not uniform across all studies; for example, some studies excluded hypercalcemia of malignancy (HCM). In addition, different efficacy end points were used in different trials. There is a low incidence of some adverse events.
The American Society of Clinical Oncology (ASCO) convened the Update Committee to lead the 2011 update. The Update Committee met, via three teleconferences, on February 1, February 22, and November 23, 2010, to consider the evidence for each of the 2011 recommendations. A writing group of the Update Committee and ASCO staff drafted the guideline. The guideline was circulated in draft form to the Update Committee.
The guideline developers reviewed published cost analyses.
Internal Peer Review
As per standard American Society of Clinical Oncology (ASCO) practice, the guideline was submitted to Journal of Clinical Oncology for peer review. The entire Update Committee, ASCO's Clinical Practice Guidelines Committee, and the ASCO Board of Directors reviewed and approved the final document.
The type of evidence supporting the recommendations is not specifically stated.
The recommendations are based on published randomized controlled trials, systematic reviews, and cohort/case-control studies. Refer to the "Literature review and analysis" sections of the original guideline document for specific evidence for each recommendation.
- Appropriate use of bone-modifying agents in metastatic breast cancer
- Intravenous (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 was associated with a modest pain control benefit in controlled trials.
- Pamidronate and zoledronic acid are associated with renal deterioration, particularly in patients with pre-existing renal impairment and in patients who receive multiple cycles of bisphosphonate therapy. The incidence of renal deterioration associated with pamidronate (90 mg) or zoledronic acid (4 mg) ranged between 6.2% and 12%. New dosing guidelines for patients with pre-existing renal impairment were added to the zoledronic acid package insert in January 2005. These guidelines recommend a lower initial zoledronic acid dose (ranging from 3.0 to 3.5 mg) depending on the estimated creatinine clearance. No similar dosing guideline exists for pamidronate. Pamidronate and zoledronic acid should be withheld from patients developing renal deterioration. Once serum creatinine returns to within 10% of baseline, therapy can be resumed.
- Denosumab has been associated with statistically significantly less renal deterioration than zoledronic acid. In a study of denosumab versus zoledronic acid, renal toxicity occurred more frequently with zoledronic acid than denosumab. The denosumab packet insert states that patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at a greater risk of severe hypocalcemia than patients with normal renal function. The Update Committee recommends monitoring of electrolytes and renal function on a regular basis during therapy with bone-modifying agents.
- Longer follow-up from the zoledronic acid versus pamidronate studies has not changed the 2003 guideline's conclusion that the safety of the two agents seems to be similar with respect to nonrenal adverse events. The new agent, denosumab, demonstrated similar rates of nausea and vomiting compared with bisphosphonates and lower rates of arthralgia and asthenia. Acute-phase reactions were reported with both bisphosphonates and denosumab, although at lower rates with the latter. No new reports of ocular adverse effects were identified within the parameters of this guideline's literature search.
- Osteonecrosis of the jaw (ONJ) has been seen in patients treated with denosumab. The population incidence/prevalence and the etiology of ONJ remain unknown. The FDA labeling of denosumab, pamidronate, and zoledronic acid advises that patients should maintain good oral hygiene and have preventive dental examinations before initiating therapy, as well as avoid invasive dental procedures whenever possible. If an invasive manipulation of the bone underlying the teeth is clinically indicated before starting bone-modifying agent therapy, initiation of bone-modifying agent therapy should be ideally delayed for 14 to 21 days to allow for wound healing, if the clinical situation permits. The incidence of ONJ specifically in women with breast cancer metastatic to the bone seems to range from approximately 2.5% to 8.8% in cohort studies.
The American Society of Clinical Oncology's (ASCO's) practice guidelines reflect expert consensus based on clinical evidence and literature available at the time they are written and are intended to assist physicians in clinical decision making and identify questions and settings for further research. Because of the rapid flow of scientific information in oncology, new evidence may have emerged since the time a guideline was submitted for publication. Guidelines are not continually updated and may not reflect the most recent evidence. Guidelines address only the topics specifically identified in the guideline and are not applicable to interventions, diseases, or stages of disease not specifically identified. Guidelines cannot account for individual variation among patients and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances and preferences. ASCO guidelines describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO guidelines or for any errors or omissions.
An implementation strategy was not provided.
Quick Reference Guides/Physician Guides
|Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, Bosserman LD, Geoghegan C, Hillner BE, Theriault RL, Zuckerman DS, Von Roenn JH. American Society of Clinical Oncology clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. Alexandria (VA): American Society of Clinical Oncology (ASCO); 2011. 17 p. [77 references]|
Not applicable: The guideline was not adapted from another source.
2000 Mar (revised 2011)
American Society of Clinical Oncology - Medical Specialty Society
American Society of Clinical Oncology (ASCO)
Panel Members: 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 Update Committee was assembled in accordance with American Society of Clinical Oncology (ASCO)'s Conflict of Interest Management Procedures for Clinical Practice Guidelines ("Procedures," summarized at www.asco.org/guidelinescoi ). Members of the Update Committee completed ASCO's disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the guideline. Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony. In accordance with the Procedures, the majority of the members of the Update Committee did not disclose any of these relationships.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership: None; Consultant or Advisory: Linda Bosserman, Amgen (C), Roche (C); Catherine Van Poznak, Amgen (C); Gary Yee, Amgen (C), Roche (C); Stock Ownership: None; Honoraria: Linda Bosserman, Abraxis BioScience, Amgen, Roche; Research Funding: Catherine Van Poznak, Amgen, Novartis; Expert Testimony: None; Other Remuneration: None
This is the current release of the guideline.
This guideline updates a previous version: Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003 Nov 1;21(21):4042-57.
Electronic copies: Available from the American Society of Clinical Oncology (ASCO) Web site .
Print copies: Available from Clinical Oncology, Cancer Policy and Clinical Affairs, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; E-mail: email@example.com .
The following are available:
- American Society of Clinical Oncology (ASCO) clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. Executive summary. 2011. 9 p. Electronic copies: Available in Portable Document Format (PDF) from the American Society of Clinical Oncology (ASCO) Web site.
- American Society of Clinical Oncology (ASCO) clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. Slide set. 2011. 29 p. Electronic copies: Available in Portable Document Format (PDF) and PowerPoint from the ASCO Web site.
- Metastatic breast cancer bone modifying agents guideline update. Data supplements. 2011. 17 p. Electronic copies: Available in Portable Document Format (PDF) from the ASCO Web site.
The following is available:
- What to Know: ASCO's guideline on bone-modifying drugs for breast cancer. Alexandria (VA): American Society of Clinical Oncology; 2011 Feb. Electronic copies: Available from the American Society of Clinical Oncology Web site .
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