Huge Trial Casts Doubt on Bisphosphonates for Breast Cancer

M. Alexander Otto, MMS, PA

June 29, 2021

Five years of treatment with bisphosphonates after chemotherapy for high-risk early breast cancer is too much, say researchers reporting new results from a phase 3 trial with almost 3000 women.

Current guidelines call for 3 to 5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.

However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival ― regardless of menopausal status ― between the 1540 women who received intravenous zoledronate over a 5- year period and 1447 women who received such therapy over a 2-year period.

What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.

Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm, in Ulm, Germany, and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, "treatment with zoledronate for 5 years should not be considered in patients with early breast cancer."

The study was published online on June 24 in JAMA Oncology.

An accompanying editorial went even further, stating not only that "shorter duration of treatment is sufficient" but also that the whole idea of bisphosphonates for breast cancer is in doubt.

With "the modest outcomes of bisphosphonates compared with no bone targeted therapy in historical trials" and the low rates of recurrence with modern treatment ― less than 10% in the trial ― "what, if any, is the benefit from adjuvant bisphosphonates? It's time to reevaluate the guidelines," say the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto, Toronto, Canada.

"We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer," they write.

Risk for Necrosis With 5 Years of Zoledronate

The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.

The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.

The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.

At a mean of 5 years' follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.

There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up, vs 7.2% in the 2-year group.

Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate ― including 7.6% with grade 3/4 events ― vs just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.

In the 5-year group, 8.3% of partients experienced bone pain and 5.1% experienced arthralgia, vs 3.7% and 3.1%, respectively, in the 2-year arm.

Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only three in the 2-year arm.

Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in five in the 2-year group.

The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Friedl has received payments from Novartis.

JAMA Oncol. Published online June 24, 2021. Abstract, Editorial

M. Alexander Otto is a physician assistant with a master's degree in medical science, and an award-winning medical journalist who has worked for several major news outlets before joining Medscape. Email: aotto@mdedge.com.

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