Bisphosphonate treatment in patients with early breast cancer has
become part of care, but the optimal treatment duration is still
To compare 2 vs 5 years of zoledronate treatment following adjuvant
chemotherapy in patients with early breast cancer.
Design, Setting, and Participants
The SUCCESS A phase 3 multicenter randomized open-label clinical
trial with a 2 × 2 factorial design enrolled
3754 patients from September 21, 2005, to March 12, 2007 (last
patient out, May 7, 2014). Final data analysis was conducted from
September 2019 to October 2020. In 250 German study centers,
patients were eligible for participation in the SUCCESS A trial if
they had either node-positive or high-risk node-negative (defined as
at least 1 of the following: tumor size ≥ pT2,
histologic grade 3, negative hormone receptor status, or age ≤35
years) primary invasive breast cancer.
Patients were first randomized to adjuvant chemotherapy with 3
cycles of fluorouracil, epirubicin, and cyclophosphamide followed by
3 cycles of docetaxel with or without gemcitabine (not presented in
this report). After chemotherapy, patients underwent a second
randomization of 5 years of zoledronate treatment (4 mg
intravenously every 3 months for 2 years, followed by 4 mg
intravenously every 6 months for 3 years) vs 2 years of zoledronate
treatment (4 mg intravenously every 3 months for 2 years).
Main Outcomes and Measures
The primary end point of the study was disease-free survival;
secondary end points were overall survival, distant disease-free
survival, and the incidence of skeletal-related adverse events.
Survival times were measured from 2 years after the start of
zoledronate treatment (landmark analysis).
Overall, data on 2987 patients were available for analysis; median
age was 53 (range, 21-86) years. Disease-free survival, overall
survival, and distant disease-free survival did not differ
significantly between the 2 treatment arms (5 vs 2 years) as shown
by adjusted multivariable Cox proportional hazards regression models
(disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25;
P = .81; overall survival: HR, 0.98; 95% CI,
0.67-1.42; P = .90; distant disease-free survival: HR,
0.87; 95% CI, 0.65-1.18; P = .38). Adverse events were
observed more often in the 5-year (46.2%) vs 2-year (27.2%)
zoledronate treatment arm, which was particularly true for the
skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%)
and arthralgia (5 years, 5.1% vs 2 years, 3.1%).
Conclusions and Relevance
The results of this phase 3 randomized clinical trial indicate that
extending the zoledronate treatment beyond 2 years does not improve
the prognosis of high-risk patients with early breast cancer
receiving chemotherapy, suggesting that the currently recommended
bisphosphonate treatment duration of 3 to 5 years could be
ClinicalTrials.gov Identifier: NCT02181101.
Friedl T W P, Fehm T, Müller V, Lichtenegger W, Blohmer J, Lorenz
R, Forstbauer H, Fink V, Bekes I, Huober J, Jückstock J,
Schneeweiss A, Tesch H, Mahner S, Brucker S Y, Heinrich G, Häberle
L, Fasching P A, Beckmann M W, Coleman R E, Janni W, Rack B.
Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs
2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized
Clinical Trial. JAMA Oncol 2021; 7:1149-1157.