Neoadjuvant Carboplatin Increases pCR Rates in TNBC

Photo Courtesy © SABCS/Todd Buchanan 2013

William M. Sikov, MD

Study investigators reported at the 2013 San Antonio Breast Cancer Symposium that the addition of carboplatin to standard neoadjuvant chemotherapy increased pathologic complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). This finding was based on data from the multicenter CALGB/Alliance 40603 study. Efficacy data for bevacizumab, in the same study, were less impressive and showed increased toxicity.

“Clearly, pCRs were increased with either bevacizumab or carboplatin, but the side effects were more concerning in the bevacizumab arms,” said William M. Sikov, MD, of Brown University, Providence, Rhode Island.

Anthracycline- and taxane-based neoadjuvant chemotherapy results in a pCR in about one third of patients with TNBC, and pCRs are associated with improved recurrence-free and overall survival. In advanced triple-negative disease, platinum analogues are active, and the addition of bevacizumab increases response rates and time to progression.

Based on this, the phase II CALGB 40603 study aimed to determine if the addition of either carboplatin, bevacizumab, or both to standard neoadjuvant chemotherapy significantly increased pCR rates in 454 patients with stage II/III TNBC.

Up to Two Thirds of Patients Achieve pCR  

Patients with stage II/III TNBC were randomized in a 2x2 schema to receive weekly paclitaxel for 12 courses plus dose-dense anthracycline/cyclophosphamide alone, or with bevacizumab every 2 weeks for 9 cycles, carboplatin AUC 6 every 3 weeks for 4 cycles or the combination. The primary endpoint was pCR in the breast, and a secondary endpoint was pCR in the breast and axilla. The study was not powered to detect a difference in recurrence-free survival or overall survival.Investigators evaluated the effect of carboplatin on all patients receiving it (alone or in combination) and the same for bevacizumab.

“The addition of carboplatin to standard neoadjuvant chemotherapy significantly increased the pCR in the breast and also in the breast plus axilla,” Sikov reported.

Pathologic complete response rates in the breast were 60% for patients receiving carboplatin and 46% in patients who did not receive carboplatin, an increase of 76% (P= .0018). Defined by no disease in the breast or axilla, pCR rates increased to 54% and 41%, respectively, a 71% increase (P= .0029), according to Sikov.

The addition of bevacizumab was also associated with an improvement in pCR in the breast only (not the axilla), producing pCRs in 59% of patients receiving the drug and 48% of patients not taking bevacizumab, a 58% increase (P= 0.0089). Pathologic complete response rates for both breast and axilla were 52% and 44%, respectively, a 36% nonsignificant increase (P= .0570).

When carboplatin and bevacizumab were used in combination against the chemotherapy backbone, the highest pCR rate was achieved, 67%, but thePvalue for the carboplatin/bevacizumab interaction was .52, indicating a lack of a synergistic effect.

Grade 3 and higher neutropenia was more common with carboplatin, as was thrombocytopenia, but grade 3 and higher hypertension and postsurgical complications were more common with bevacizumab.  

“Post-surgical complications were increased with bevacizumab (9% vs 5% without bevacizumab), even though bevacizumab was stopped at least 6 weeks prior to surgery,” he noted.

Bevacizumab was discontinued in 23% of assigned patients and in 6% to 13% for other agents.

Should Carboplatin Be Routinely Added?

“Bevacizumab did increase pCRs, but at the cost of significant toxicities, and I don’t think it should be routinely added,” Sikov maintained.“We now have two randomized studies [GeparSixto] showing increases in pCR rates with the addition of carboplatin to chemotherapy [in triple-negative disease],” Sikov said. “Neither study was powered for recurrence-free survival or overall survival,” he added, but he added that the assumption is that achievement of pCR could well impact these outcomes.

He said that while bevacizumab also increases pCR rates, “in all studies, there were increases in toxicity, including febrile neutropenia, hypertension, bleeding, clotting, and other things.”

“Should carboplatin be routinely added? With the caveat that we don’t have long-term results, and we don’t know if increasing pCR results in a significant improvement in recurrence-free or overall survival,” Sikov asked. “In the neoadjuvant setting, my answer to that question would be ‘yes.’”

Lajos Pusztai, MD, DPhil, of Yale University, New Haven, Connecticut, the formal discussant of the paper, noted that several randomized trials have not established the benefit of carboplatin as neoadjuvant therapy in patients with triple-negative disease. “This provides a valuable new treatment option for patients with high-risk triple-negative disease,” he said. “The impact on survival may be modest, but real, I believe. Patient-level benefits, other than survival, exist that can be derived from more effective neoadjuvant chemotherapies.”

Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). The 2013 San Antonio Breast Cancer Symposium, December 10—14, 2013.Abstract S5-01.

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