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Clinical Trial
. 2021 Aug 1;7(8):1149-1157.
doi: 10.1001/jamaoncol.2021.1854.

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized Clinical Trial

Thomas W P Friedl  1 , Tanja Fehm  2 , Volkmar Müller  3 , Werner Lichtenegger  4 , Jens Blohmer  5 , Ralf Lorenz  6 , Helmut Forstbauer  7 , Visnja Fink  1 , Inga Bekes  1 , Jens Huober  1 , Julia Jückstock  8 , Andreas Schneeweiss  9 , Hans Tesch  10 , Sven Mahner  8 , Sara Y Brucker  11 , Georg Heinrich  12 , Lothar Häberle  13 , Peter A Fasching  13 , Matthias W Beckmann  13 , Robert E Coleman  14 , Wolfgang Janni  1 , Brigitte Rack  1
Affiliations
Clinical Trial

Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized Clinical Trial

Thomas W P Friedl et al. JAMA Oncol. .

Abstract

Importance: Bisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear.

Objective: 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.

Interventions: 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).

Results: 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 reduced.

Trial registration: ClinicalTrials.gov Identifier: NCT02181101.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Friedl reported receiving honoraria from Novartis outside the submitted work. Dr Fehm reported receiving personal fees from Novartis, Pfizer, MSD, AstraZeneca, Roche, Teva, and Onkowissen outside the submitted work. Dr Müller reported receiving speaker honoraria from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, and Seattle Genetics, and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Seattle Genetics, and Nektar; institutional research support from Novartis, Roche, Seagen, and Genentech; and travel grants from Roche, Pfizer, and Daiichi Sankyo outside the submitted work. Dr Blohmer reported receiving personal fees from Amgen, AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche, SonoScape, Sysmey, and ExactSciences, and grants from Myriad outside the submitted work. Dr Forstbauer reported receiving personal fees from Amgen, Celgene, and Roche outside the submitted work. Dr Huober reported receiving grants and personal fees from Novartis and Lilly; travel expense reimbursement from Roche; grants and personal fees from Celgene; travel expense reimbursement from Pfizer; personal fees from AstraZeneca, MSD, AbbVie, and Hexal; grants from Hexal; and travel expense reimbursement from Daiichi, Celgene, and Novartis outside the submitted work. Dr Mahner reported receiving personal fees from AbbVie; grants, as well as honoraria, and reimbursement for travel expenses from AstraZeneca; grants from Clovis; grants, honoraria, and reimbursement for travel expenses from Eisai; grants from GSK; grants, honoraria, and reimbursement for travel expenses from Medac; personal fees from MSD, Novartis, Olympus Europa, and Pfizer; grants, honoraria, and reimbursement for travel expenses from PharmaMar and Roche; personal fees from Sensor Kinesis; grants, honoraria, and reimbursement for travel expenses from Tesaro; and personal fees from Teva outside the submitted work. Dr Brucker reported receiving personal fees from Roche Pharma Honoraria AdBoard, Pfizer Honoraria AdBoard; and honoraria from AstraZeneca, MSD, Teva, and Storz outside the submitted work. Dr Fasching reported receiving personal fees from Novartis, AstraZeneca, Pfizer, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, Cepheid, Lilly, Pierre Fabre, Seagen, and Hexal; and grants from BioNTech during the conduct of the study. Dr Coleman reported receiving personal fees from Amgen, AstraZeneca, Scancell, ITM, Boehringer Ingelheim, and Elsevier outside the submitted work. Dr Janni reported receiving grants from Sanofi-Aventis during the conduct of the study. Dr Rack reported receiving grants from Novartis, Sanofi-Aventis, AstraZeneca, Chugai, and Lilly during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Patient Flow Diagram
DFS indicates disease-free survival; FEC-Doc, 3 cycles of combined fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel; FEC DocG indicates 3 cycles of combined fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel and gemcitabine.
Figure 2.
Figure 2.. Disease-Free Survival and Overall Survival According to Zoledronate Treatment Duration
A, Disease-free survival: 5-year zoledronate treatment, 129 events; 2-year zoledronate treatment, 121 events; P = .83, log-rank test. B, Overall survival: 5-year zoledronate treatment, 59 events; 2-year zoledronate treatment, 57 events; P = .71, log-rank test.
Figure 3.
Figure 3.. Results of Explorative Subgroup Analyses in Terms of the Comparison of Disease-Free Survival Between Patients With 5 or 2 Years of Zoledronate Treatment Duration
The diamonds indicate the hazard ratios (5 vs 2 years of zoledronate treatment), and diamond size is proportional to the number of patients per subgroup. The horizontal lines indicate the corresponding 95% CIs for the hazard ratios. The solid vertical line represents a hazard ratio of 1.0 (ie, no difference in survival between 5 and 2 years of zoledronate treatment). DFS indicates disease-free survival; FEC-Doc, 3 cycles of combined fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel; FEC DocG indicates 3 cycles of combined fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel and gemcitabine.
Figure 4.
Figure 4.. Bone-Recurrence–Free Survival According to Zoledronate Treatment Duration
Bone-recurrence–free survival includes any first distant recurrence involving bone metastases as event (with or without recurrences at other distant sites): 5-year zoledronate treatment, 25 events; 2-year zoledronate treatment, 28 events; P = .43, log-rank test.
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