• Breast Cancer Disease Site Group. Warr D, Johnston M. Use of bisphosphonates in women with breast cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Apr [online update]. 34 p. (Practice guideline report; no. 1-11). [68 references]

Breast cancer

Assessment of Therapeutic Effectiveness
Prevention
Treatment

Internal Medicine
Oncology
Radiation Oncology

Physicians

To make recommendations regarding the use of bisphosphonates in patients with breast cancer:

• To reduce pain, reduce the likelihood of skeletal events other than hypercalcemia, improve quality of life, or improve survival in women with bone metastases due to breast cancer
• To reduce the likelihood of bone metastases or improve survival in women with breast cancer that is locally advanced or metastatic to sites other than bone
• To reduce the risk of bone metastases or to improve survival in women with early stage breast cancer

Women with breast cancer

Bisphosphonates (clodronate, pamidronate, ibandronate, or zoledronate)

• Bone pain
• Skeletal events other than hypercalcemia
• Quality of life
• Adverse effects
• Development of bone metastases
• Survival

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

The literature search found three evidence-based practice guidelines, two systematic reviews, twenty-eight randomized trials, one full report, and the results of a study, presented in two abstracts at the 2003 San Antonio Breast Cancer Symposium (SABCS), which pooled data from three randomized trials.

Expert Consensus (Committee)

Not applicable

Meta-Analysis of Randomized Controlled Trials
Review of Published Meta-Analyses
Systematic Review
Systematic Review with Evidence Tables

Because a well-conducted published meta-analysis was available, the Breast Cancer Disease Site Group (DSG) did not conduct their own pooled analysis. The DSG did, however, conduct supplementary sensitivity analyses to make the meta-analysis more directly relevant to the guideline questions listed in the original guideline document and to assess the impact of recently published evidence. For both the published meta-analyses and the sensitivity analyses by the DSG, the overall effect of bisphosphonates versus control was determined by pooling data using the Review Manager software (RevMan 4.1) provided by the Cochrane Collaboration (Metaview© Update Software). Results are expressed as relative risks (also known as risk ratios) with 95% confidence intervals (CI). A relative risk (RR) >1.0 indicates that patients in the bisphosphonate group had a higher probability of experiencing an event compared with those in the control group; conversely, a relative risk <1.0 favours bisphosphonate over control. The published meta-analysis presented pooled results based on the fixed-effects model but noted that "random-effects models were also examined." In order to facilitate direct comparisons with the results of the published meta-analysis, the DSG used the fixed-effects model for sensitivity analyses.

In the published meta-analysis, mortality data were pooled across a set of trials in patients with advanced breast cancer. In the first sensitivity analysis, the DSG restricted this analysis to patients with bone metastases. The second sensitivity analysis was restricted to patients without evidence of bone metastases. In the third sensitivity analysis, mortality data from a trial of adjuvant bisphosphonates that was published after completion of the published meta-analysis was added. In all cases, the numbers of patients dying during the trial and the numbers randomized were used for the meta-analysis.

Expert Consensus

In 2002, the Breast Cancer Disease Site Group (DSG) reviewed the updated and rewritten guideline report, which incorporated new evidence on the long-term use of oral clodronate and on adjuvant bisphosphonates, as well as data from two trials comparing zoledronate to pamidronate. The scope of the revised guideline was similar to the original but the single guideline question "Should bisphosphonates be used in patients with bone metastases from breast cancer?" was expanded to three: one related to patients with bone metastases, one to patients with advanced disease but no bone metastases, and one to the adjuvant use of bisphosphonates. The DSG suggested that the questions be further modified to include the outcomes of interest in each of these three settings. They also identified a need for more discussion on gastrointestinal toxicity and any new evidence presented at the 2002 American Society of Clinical Oncology (ASCO) meeting.

The DSG noted that it is uncertain whether bisphosphonate therapy can prevent skeletal complications in patients with a short life expectancy (less than 4 to 6 months), because the largest studies excluded these patients. Although the median time to first skeletal event was shorter than six months in the pamidronate studies that provide the best available evidence, the data do not show a difference emerging between pamidronate and control until approximately six months after study entry. The data suggest that the use of bisphosphonates to prevent skeletal events will require a considerable duration of administration. In contrast, pain relief can occur within days when bisphosphonates are used as an adjunct for pain control. Ultimately, the decision about whether or not it is appropriate to offer therapy when survival may be short rests with the treating physician.

DSG members discussed the use of clodronate in patients who have difficulty tolerating oral medications because of existing nausea, vomiting, or esophagitis. The DSG strongly advocated that such patients should be spared a trial of oral clodronate before being offered intravenous pamidronate. Two DSG members suggested extending this recommendation to patients without nausea or vomiting, but in whom there is a high likelihood of gastrointestinal upset related to any medication, as well as patients who are likely to develop nausea, vomiting, or esophagitis from planned radiotherapy or emetogenic medication. Other DSG members felt that predicting which patients may develop these problems would be difficult and that they could be managed by a brief interruption of oral clodronate or by switching to intravenous pamidronate at the next cycle of chemotherapy.

The DSG agreed that the revised guideline should include four new recommendations, in addition to those made in 1998:

1. Patients with a short expected survival (i.e., less than 6 months) who have well controlled bone pain may be an exception to the recommendation for bisphosphonates in women with bone metastases from breast cancer.
2. Patients with bone metastases from breast cancer who have difficulty tolerating oral medications (e.g., those with nausea/vomiting or esophagitis) should be offered intravenous pamidronate, without a trial of oral clodronate.
3. Intravenous zoledronate is an alternative to pamidronate when a shorter infusion time (15 minutes) is important.
4. Bisphosphonates are not recommended to prevent bone metastases in women with locally advanced breast cancer or non-skeletal metastases.

The DSG considered extending their recommendations to men with breast cancer. No randomized trials have assessed the efficacy of bisphosphonates in men with breast cancer, but men have participated in randomized trials of bisphosphonates for multiple myeloma. Since there is no evidence to suggest that the benefit in multiple myeloma is gender specific, it is reasonable to recommend the use of bisphosphonates in men with breast cancer that is metastatic to bone. The DSG also noted that there was no evidence for continuing or switching bisphosphonates after a skeletal event. Qualifying statements were added to the recommendations to address these two issues.

Not applicable

Published cost analyses were reviewed.

External Peer Review
Internal Peer Review

Practitioner feedback was obtained through a mailed survey of 127 practitioners in Ontario (88 Medical Oncologists and 39 Radiation Oncologists). The survey consisted of 21 questions about the quality of the practice-guideline-in-progress (PGIP) report and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Breast Cancer Disease Site Group (DSG) reviewed the results of the survey.

Final approval of the guideline report was obtained from the Practice Guidelines Coordinating Committee (PGCC).

• Women with breast cancer who have bone metastases should be offered treatment with oral clodronate, intravenous pamidronate, or intravenous zoledronate.
  • An exception may be patients with a short expected survival (i.e., less than six months), who have well-controlled bone pain.
  • Patients who have difficulty tolerating oral medications (e.g., those with nausea/vomiting or esophagitis) should be offered intravenous pamidronate or zoledronate.
  • Intravenous zoledronate may be preferable to pamidronate when a shorter infusion time (15 minutes versus two hours, respectively) is important.
  • Intravenous clodronate has not been examined for its ability to reduce morbidity from bone metastases with long-term use. When clodronate is used for this purpose, the oral route is recommended.
• In patients with bone metastases and pain, treatment with pamidronate, zoledronate, or clodronate may be a useful adjunct to conventional measures for pain control.
• Bisphosphonates are not recommended to prevent bone metastases or improve survival in women with locally advanced breast cancer or non-skeletal metastases.
• Current evidence is insufficient to support the use of bisphosphonates as adjuvant therapy to either prevent skeletal events or improve survival in women with early-stage breast cancer.

None provided

The recommendations are supported by evidence-based practice guidelines, meta-analyses, and randomized controlled trials.

Appropriate use of bisphosphonates in patients with breast cancer to improve patient outcomes (e.g., pain relief, symptom control, survival, disease progression)

• One randomized placebo-controlled trial detected an increased rate of gastrointestinal complaints with oral clodronate. Local reactions at the injection site were more common with pamidronate than with placebo, no-treatment control, or zoledronate. Uveitis is a rare but documented complication of treatment with pamidronate, requiring urgent referral to an ophthalmologist.
• The standard doses of the bisphosphonates reviewed here are oral clodronate 1.6 g/day, intravenous pamidronate 90 mg every 3–4 weeks, and intravenous zoledronate 4 mg every 3–4 weeks. Randomized trials that compared different doses detected no significant differences in pain scores among doses, but observed that 3.2 g of clodronate was associated with hypocalcemia and that pain was reduced more quickly with 90 mg of pamidronate compared to lower doses.

• There is no evidence from clinical trials that address the optimal duration of bisphosphonate use.
• There are no data on the efficacy of bisphosphonates in men with breast cancer, but men have participated in randomized trials of bisphosphonates for multiple myeloma. Since there is no evidence to suggest that the benefit detected in multiple myeloma trials is gender specific, it is reasonable to recommend the use of bisphosphonates in men with breast cancer that is metastatic to bone.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgement in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Breast Cancer Disease Site Group. Warr D, Johnston M. Use of bisphosphonates in women with breast cancer [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Apr [online update]. 34 p. (Practice guideline report; no. 1-11). [68 references]

Not applicable: The guideline was not adapted from another source.

1998 Nov 9 (revised 2004 Apr)

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Practice Guidelines Initiative (PGI) is the main project of the Program in Evidence-based Care (PEBC), a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Breast Cancer Disease Site Group

Members of the Breast Cancer Disease Site Group disclosed potential conflict of interest information.

None available

This summary was completed by ECRI on August 19, 1999. The information was verified by the guideline developer as of September 17, 1999. This summary was updated by ECRI on April 12, 2002, July 21, 2003, and September 24, 2004. The updated information was verified by the guideline developer on October 20, 2004. This summary was updated by ECRI on May 20, 2005, following the U.S. Food and Drug Administration advisory on Aredia (pamidronate disodium) and Zometa (zoledronic acid).