Summary Background Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of ...adjuvant bisphosphonate treatment in breast cancer. Methods We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal combining natural and artificial or not), and bisphosphonate class (aminobisphosphonate eg, zoledronic acid, ibandronate, pamidronate or other ie, clodronate). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). Findings We received data on 18 766 women (18 206 97% in trials of 2–5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87–1·01; 2p=0·08), distant recurrence (0·92, 0·85–0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83–0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73–0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78–0·94; 2p=0·002), distant recurrence (0·82, 0·74–0·92; 2p=0·0003), bone recurrence (0·72, 0·60–0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73–0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75–0·97; 2p=0·02). Interpretation Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. Funding Cancer Research UK, Medical Research Council.
Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant ...interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial.
PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT.
Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group body mass index (BMI) ≥30 had improved BCRFS compared with nonobese ones (BMI <30) hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30–0.89, P = 0.02. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26–0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60–1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups.
Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies.
NCT00798070.
A meta-analysis of trials of ESA use in patients with breast cancer receiving chemotherapy was conducted. Nine studies were analyzed (ESAn = 2346; controln = 2367). The overall stratified ...random-effects odds ratio (95% CI) was 1.17 (0.99–1.39) for death and 1.01 (0.87–1.16) for disease progression-related end points. Odds ratios remain consistent with prior data after including recent results.
New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin &agr;, epoetin &bgr;, darbepoetin &agr;, biosimilars).
A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control.
Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups OR, 1.20; 95% confidence interval (CI) 1.03–1.40. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94–1.34). In seven studies reporting progression-related end points (N = 4197; ESAn = 2088; controln = 2109), the OR was 1.01 (95% CI 0.87–1.16) for ESA compared with control.
After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.
This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a ...first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer.
Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2–18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS).
From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules.
Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.
•Multicenter double-blind phase II MADONNA trial evaluated antitumor activity and toxicity of docetaxel and sorafenib or matching placebo as a 1st line treatment in metastatic/locally advanced HER-2 negative breast cancer.•Increased hematological and skin toxicity led to slow patient accrual and early trail termination.•The trial failed to demonstrate improved PFS under addition of sorafenib to taxane-based chemotherapy in metastatic breast cancer.
Investigation of high-dose chemotherapy (HD-CT) compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and ≥10 axillary lymph nodes. From ...November 1993 to September 2000, 307 patients were randomized to receive after four cycles of epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2) i.v. (every 21 days) and either HD-CT of cyclophosphamide (1500 mg/m2), thiotepa (150 mg/m2) and mitoxantrone (10 mg/m2) i.v. for four consecutive days followed by stem cell transplantation or a SD-CT of three cycles CMF (cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, 5-fluorouracil 600 mg/m2, i.v. on day 1 and 8, respectively, every 28 days). After a median follow-up of 6.1 years, 166 events with respect to event-free survival (EFS) (SD-CT: 91, HD-CT: 75) have been observed. The hazard ratio of HD-CT versus SD-CT is estimated as 0.80 95% confidence interval (0.59, 1.08), P = 0.15. The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients and in patients with tumor grade 3 as compared with patients with tumor grade 1/2. With a follow-up of 6 years, there was a trend in favor of HD-CT with respect to EFS not being significant. A proper meta-analysis needs to be undertaken for an evaluation of subgroups of patients who might benefit from HD-CT.
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