Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update

PURPOSE

To update recommendations of the American Society of Clinical Oncology (ASCO)-Ontario Health (Cancer Care Ontario [CCO]) adjuvant bone-modifying agents in breast cancer guideline.

METHODS

An Expert Panel conducted a systematic review to identify new, potentially practice-changing data.

RESULTS

Four articles met eligibility criteria and form the evidentiary basis for revision of the previous recommendations.

RECOMMENDATIONS

Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities. The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool provides estimates of the benefit of adjuvant bisphosphonate therapy and may aid in decision making. Factors influencing the decision to recommend adjuvant bisphosphonate use should include patients’ risk of recurrence, risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy. When an adjuvant bisphosphonate is used to prevent breast cancer recurrence, the therapeutic options recommended by the Panel include oral clodronate, oral ibandronate, and intravenous zoledronic acid. The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline; this is a consensus recommendation. The Panel does not recommend adjuvant denosumab to prevent breast cancer recurrence, because studies did not show a consistent reduction of breast cancer recurrence in any subset of those with early-stage breast cancer.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Focused Update

Guideline Question

What is the role of bisphosphonates and other bone-modifying agents in adjuvant therapy among patients with breast cancer?

Target Population

Postmenopausal (natural or induced) patients, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, with nonmetastatic breast cancer for whom a bone-modifying agent is being considered as an adjuvant systemic therapy to reduce the risk of breast cancer recurrence (ASCO’s breast cancer guideline for cisgender [or nontransgender] men recommends that men with early-stage breast cancer should not be treated with bone-modifying agents to prevent recurrence).

Target Audience

Oncology specialists, other health care providers (including primary care physicians, specialists, nurses, social workers, and any other relevant member of a comprehensive multidisciplinary cancer care team), caregivers, and patients.

Methods

An Expert Panel was convened to update clinical practice guideline recommendations on the basis of a systematic review of the medical literature.

Updated Recommendations

NOTE. The Panel acknowledges that access to adjuvant bone-modifying agents discussed herein is not universal because of limited reimbursement or availability.

Recommendation 1.1.

Adjuvant bisphosphonate therapy should be discussed with all postmenopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of hormone receptor status and human epidermal growth factor receptor 2 status, who are candidates to receive adjuvant systemic therapy. Adjuvant bisphosphonates, if used, are not substitutes for standard anticancer modalities.

The benefit of adjuvant bisphosphonate therapy will vary depending on the underlying risk of recurrence and is associated with a modest improvement in overall survival. The NHS PREDICT tool⁸ provides estimates of benefit of adjuvant bisphosphonate therapy and may aid in shared decision making.

Factors influencing the decision to recommend adjuvant bisphosphonate use that should be weighed in the discussion with patients include the patient’s risk of recurrence, the risk of side effects, financial toxicity, drug availability, patient preferences, comorbidities, and life expectancy (type: informal consensus; evidence quality: intermediate; strength of recommendation: moderate).

Recommendation 2.1.

The Panel supports starting bisphosphonate therapy early, consistent with the points outlined in the parent CCO-ASCO guideline. Many studies initiated bisphosphonate within 3 months of definitive surgery or within 2 months of completion of adjuvant chemotherapy; this is a consensus recommendation. The therapeutic options, listed alphabetically, with the strongest supporting data include:

• oral clodronate (1,600 mg daily for 2-3 years)
• oral ibandronate (50 mg daily for 3 years)
• zoledronic acid; dosing regimens as per the protocols of the clinical trials (including the option of dosing 4 mg once every 6 months for 3 years or dosing 4 mg once every 3 months for 2 years)

Patient preference should be factored into the choice of adjuvant bisphosphonate therapy. Access to adjuvant bisphosphonate therapy may currently limit choice of agent depending on jurisdiction (type: evidence-based, benefits outweigh harms; evidence quality: intermediate; strength of recommendation: moderate).

Recommendation 3.1.

The Panel does not recommend the use of adjuvant denosumab (type: evidence-based, benefits outweigh harms; evidence quality: intermediate; strength of recommendation: moderate).

Key evidence.

Two Phase III studies of adjuvant denosumab did not show a consistent reduction of breast cancer recurrence in any subset of patients with early-stage breast cancer. The larger study, D-CARE, did not show improvement in cancer outcomes with use of denosumab.