Trastuzumab therapy in women with metastatic HER2-positive breast cancer is associated with significant gains in progression-free and overall survival but at the expense of cardiac toxicities such as heart failure and reduced left ventricular ejection fraction, according to a Cochrane Review.
The review of seven randomized, controlled trials involving 1,497 HER2-positive patients treated with trastuzumab, alone or in combination with other therapies, found the drug extended the time to death between 5 and 8 months and extended time to disease progression by 2-12 months, as reported June 11 in Cochrane Database of Systematic Reviews.
Treatment with trastuzumab led to a statistically significant improvement in overall survival (hazard ratio, 0.82; 95% CI 0.71-0.94; P = .004), and in progression-free survival (HR, 0.61; 95% CI 0.54-0.70; P less than .00001), compared with the control groups.
Trastuzumab was significantly more effective at improving overall survival when used as a first-line treatment (HR, 0.79; 95% CI 0.67-0.94; P = .006) and failed to achieve statistical significance when used after disease progression.
Coadministration with taxanes such as paclitaxel also led to a statistically significant improvement in overall survival (HR, 0.80; 95% CI 0.65-0.99; P = .04) and in progression-free survival (HR, 0.53; 95% CI 0.42-0.68).
"The meta-analysis showed a significant improvement in overall survival and progression-free survival for trastuzumab-containing regimens, which is possibly greater when considering patients treated as first-line compared to its use beyond progression, or patients receiving taxane-based regimens," wrote Ms. Sara Balduzzi, a statistician with the Italian Cochrane Centre, and her colleagues.
The review was prompted by concerns about the risks vs. benefits of trastuzumab (Cochrane Database Syst. Rev. 2014 June 11 [doi:10.1002/14651858.CD006242.pub2]).
"The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system," the authors wrote.
The incidence of a severe cardiac event was 4.7% in the trastuzumab group, compared with 1.1% in the control group, reflecting a more than threefold increase in risk (relative risk, 3.49; 90% CI 1.88-6.47; P = .0009).
Coadministration with an anthracycline increased the risk of a severe cardiac event fivefold, compared with treatment with anthracycline alone (RR, 5.43; 90% CI 2.28-12.94; P = .001).
In five trials, there were also 28 cases (5.9%) of left ventricular ejection fraction (LVEF) decline in the 478 women treated with trastuzumab, compared with 9 cases out of 460 (2%) in the control group (RR, 2.65; 90% CI 1.48-4.74; P = .006).
One study reported information on brain metastases; There were 42 cases (17.9%) out of 235 in the trastuzumab-containing group and 21/234 (9.0%) in the control group (RR, 1.99; 95% CI 1.32-3.01). Another study, which allowed the accrual of patients with known brain metastases, reported that 9 (6.2%) out of the 146 patients treated with trastuzumab experienced central nervous system progression, whereas 15 patients (10.3) out of the 145 treated with lapatinib alone experienced progression while on the study (RR, 0.60; 90% CI 0.31-1.16), the authors reported.
Researchers also observed a nonsignificant increase in the risk of neutropenic fever among women treated with trastuzumab.
Overall, there were 752 women in the trastuzumab-containing arm and 745 controls.
One author declared speaking engagements, consultancies, and an institutional grant from the pharmaceutical industry. There were no other conflicts of interest declared.