Dose-dense doxorubicin and cyclophosphamide followed by weekly paclitaxel with trastuzumab and lapatinib in HER2/neu-overexpressed/amplified breast cancer is not feasible because of excessive diarrhea

Abstract

Purpose: Dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab (PT) is feasible. Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer. We conducted a pilot study of dose-dense AC followed by PT plus lapatinib (PTL) followed by trastuzumab plus lapatinib (TL).

Patients and methods: Patients with stages I to III, HER2-positive breast cancer and left ventricular ejection fraction (LVEF) of > or = 50% were enrolled. Treatment consisted of AC (60 mg/m(2) and 600 mg/m(2)) for 4 cycles every 2 weeks (with pegfilgrastim 6 mg on day 2) followed by paclitaxel (80 mg/m(2)) for 12 doses weekly plus trastuzumab and lapatinib. Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel) and lapatinib (1,000 mg daily) were given for 1 year. The primary end points were feasibility defined as > or = 80% patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of < or = 4%.

Results: From March 2007 to April 2008, we enrolled 95 patients. Median age was 46 years (range, 28 to 73 years). At a median follow-up of 22 months, 92 were evaluable. Of the 92 patients, 41 patients (45%) withdrew for PTL-specific toxicities. Overall, 40 (43%) of 92 patients had lapatinib dose reductions, and 27 (29%) of 92 patients had grade 3 diarrhea. Three patients (3%) had congestive heart failure; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL.

Conclusion: Dose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction, mostly caused by unacceptable grade 3 diarrhea. Lapatinib (1,000 mg/d) was not feasible combined with weekly PT.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram. AC, doxorubicin plus cyclophosphamide; dd, dose-dense; PTL, paclitaxel plus trastuzumab plus lapatinib; CHF, congestive heart failure; LVEF, left ventricular ejection fraction; QTc, corrected QT interval; TL, trastuzumab plus lapatinib.

Fig 2.

Treatment schema: Complete blood count every 2 weeks during doxorubicin plus cyclophosphamide (AC) followed by paclitaxel plus trastuzumab plus lapatinib (PTL) and every 3 to 6 weeks during trastuzumab plus lapatinib (TL); liver function test every 2 to 4 weeks during AC followed by PTL and every 3 to 6 weeks during TL; magnesium and potassium levels every 3 to 6 weeks during PTL followed by TL; troponin I and C-reactive protein biomarkers every 2 weeks during AC followed by PTL and at months 6, 9, and 18; ECG and multigated acquisition scan (MUGA) at baseline and at months (mo) 2, 6, 9, and 18.

Fig 3.

Left ventricular ejection fraction (LVEF) results. AC, doxorubicin plus cyclophosphamide; PTL, paclitaxel plus trastuzumab plus lapatinib; TL, trastuzumab plus lapatinib.