Σάββατο, 25 Μαρτίου 2017

ADJUVANT BIPHOSPHONATE USE IN BREAST CANCER PATIENTS

The use of two bisphosphonates as adjuvant therapy should be considered for all postmenopausal women with early breast cancer who are deemed to be candidates for adjuvant therapy, according to a new joint clinical practice guideline from Cancer Care Ontario and the American Society of Clinical Oncology (ASCO).
The guideline's recommendations are based on a literature review showing that the bone-modifying agents zoledronic acid (Zometa, Novartis) and clodronate (Bonefos, Bayer) reduced bone recurrence and improved survival in postmenopausal patients with nonmetastatic breast cancer, say members of the expert panel, chaired by Sukhbinder Dhesy-Thind, MD, associate professor at McMaster University in Hamilton, Ontario, Canada.
These findings were seen in patients who had naturally occurring menopause and those with menopause induced by ovarian suppression or ablation, the authors point out. Most (83%) patients in these clinical trials were also receiving systemic adjuvant chemotherapy.
"It is recommended that, if available, zoledronic acid (4 mg intravenously [over 15 minutes or longer] every 6 months [for 3 to 5 years]) or clodronate (1,600 mg/d orally [for 2 to 3 years]) be considered as adjuvant therapy for postmenopausal patients with breast cancer who are deemed candidates for adjuvant systemic therapy," the experts say in an report published onlineMarch 6 in the Journal of Clinical Oncology.
The use of adjuvant bisphosphonates may modestly reduce the risk of breast cancer-related outcomes," Catherine Van Poznak, MD, one of four ASCO representatives on the panel, confirmed in an email. Dr Van Poznak, who is associate professor at the University of Michigan in Ann Arbor, added that more research needs to be done. 
The confidence in the existing data is challenged by the limited hypothesis testing and the lack of a proven mechanism explaining the differential effects based on menopausal status (including ovarian suppression)," Dr Van Poznak told Medscape Medical News. "Data are needed to identify which women are most likely to benefit from an adjuvant bone-modifying agent, as well as data defining means to select the drug, dose, dosing interval, and duration of therapy."
In addition, clinicians in the United States and Canada may face obstacles to acting on these recommendations, including regulatory approval, cost, and availability, the guideline authors acknowledge.
Approval for bisphosponate drug, dose, and schedule "varies internationally," Dr Van Poznak said, adding that, "The specific bisphosphonate regimens acknowledged in the guideline reflect the data available for the systematic review." 
In the United States, zoledronic acid is approved for treatment of low bone mass and metastatic disease, but clodronate is not available. In Canada, zoledronic acid is approved for adjuvant treatment of breast cancer in postmenopausal women and clodronate is approved for the management of hypercalcemia of malignancy and for treatment of bone metastases.
"It is recognized that in many health care settings, bone-modifying agents such as bisphosphonates may currently be available, approved, and/or funded in specific doses and schedules only for the indications of improving bone mass and for treatment of bone metastases," the guideline authors say. "As such, users of this guideline should consider available resources and access — as well as any other barriers within their local health care settings — to using the treatments recommended in this guideline for adjuvant breast cancer."
For clinicians to use these bone-modifying agents as adjuvant therapy, "drug formularies and governing bodies may need to revise approved dose and scheduling parameters for these relevant medications before clinicians may be able to use them," they point out.
For now, the guideline will inform clinicians considering the use of an adjuvant bisphosphonate and allow them to have a detailed discussion with patients when the time comes. When bisphosphonate therapy is being considered, a patient's risk for osteonecrosis of the jaw and renal impairment would need to be assessed, and any potential dental or oral health problems should be managed by a dental practitioner before any treatment begins, the guideline authors note.
"The final decision of whether or not to administer bisphosphonates should be made during consultation between the patient and oncologist, taking into account patient and disease characteristics, including risk of recurrence, and weighing the potential benefits and risks," they advise.
A "key portion" of the evidence for these recommendations comes from the Early Breast Cancer Trialists' Collaborative Group meta-analysis of individual-patient data; an analysis of these data published in The Lancet in 2015 concluded that adjuvant bisphosphonates save lives in postmenopausal women. The analysis also found that patients at higher risk for recurrence appeared to benefit most from these bone-modifying agents.
Data on the use of bisphosphonates other than zoledronic acid and clodronate were very limited, the guideline authors note. "There is a need for more information comparing different agents and schedules, and it is recommended such trials be conducted to establish the utility and optimal administration of other bisphosphonates for adjuvant therapy," they say.
There was also insufficient evidence to make a recommendation for patients receiving systemic adjuvant therapy for completely resected local recurrence. Similarly, a recommendation couldn't be made for the adjuvant use of the human monoclonal antibody denosumab (Prolia, Amgen) — despite "promising" results in reducing fractures — because long-term survival data were lacking. "Further results of the ABCSG-18 and D-CARE trials may provide stronger evidence for adjuvant denosumab use," Dr Dhesy-Thind and colleagues say.
Despite "clear evidence" for the use of bisphosphonates in the treatment of metastatic cancer to the bone, as well as in patients at high risk for fragility fractures, these applications "go beyond the scope of the guidelines," the authors point out. However, when bone-modifying agents are given for bone health as well as adjuvant therapy, this could "influence the specific bisphosphonate selected," they say.
Many bone-modifying agents have clearly labeled indications for the prevention and treatment of osteoporosis, Dr Van Poznak pointed out, calling bone health "an important survivorship issue to be taken into account in conjunction with anticancer systemic therapies." Still, bone-modifying agents used to prevent and treat osteoporosis have not been sufficiently prospectively studied for anticancer outcomes, she emphasized. "If a bone-modifying agent is to be used in the adjuvant setting, the goals of its use should be very clearly outlined," she told Medscape Medical News.
Dr Van Poznak also noted that use of therapeutic bone-modifying agents in the nonmetastatic setting will be discussed at the forthcoming ASCO annual meeting, to be held June 2 to 6 in Chicago.
Dr Dhesy-Thind has disclosed no relevant financial relationships. Dr Van Poznak discloses financial relationships with Bayer (institutional) and UpToDate. Several other panel members disclose relationships with Amgen (institutional), Novartis, Johnson & Johnson, Pfizer, Genomic Health, Genentech, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, and MOTUS. 
J Clin Oncol. Published online March 6, 2017.Full text

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