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Old 12-08-2010, 02:00 PM   #1
Hopeful
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(BCIRG 007 Study): Two Highly Active Therapeutic Regimens

Breast Cancer Multicenter Phase III Randomized Trial Comparing Docetaxel and Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With HER2-Gene-Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens

J Clin Oncol. 2010 Nov 29;[Epub Ahead of Print], V Valero, J Forbes, MD Pegram, T Pienkowski, W Eiermann, G von Minckwitz, H Roche, M Martin, J Crown, JR Mackey, P Fumoleau, J Rolski, Z Mrsic-Krmpotic, A Jagiello-Gruszfeld, A Riva, M Buyse, H Taupin, G Sauter, MF Press, DJ Slamon

This multicenter, phase III randomized trial comparing trastuzumab plus docetaxel (TH) with trastuzumab, carboplatin, and docetaxel (TCH) in women with HER2+ metastatic breast cancer showed no significant difference in response rate, time to progression, or overall survival.


Evidence from a phase III study by Roberts et al suggests that combined paclitaxel, carboplatin, and trastuzumab are associated with improved response rate and time to progression (TTP), with a borderline significant improvement in overall survival (OS) when compared with paclitaxel plus trastuzumab in HER2+ metastatic breast cancer. Thus, Valero et al conducted a multicenter, phase III randomized clinical trial, the Breast Cancer International Research Group study 007 (BCIRG 007) to investigate whether addition of a platinum derivative to trastuzumab and docetaxel (TH) would produce similar benefits. The unblinded study enrolled 263 patients, aged 18 to 75 years, from 80 international centers. The patients had HER2+ metastatic breast cancer and had not received previous platinum-based therapy or trastuzumab for metastatic disease. Patients were stratified by center and prior neoadjuvant therapy and then randomized to treatment with eight 3-week cycles of TH or docetaxel, carboplatin, and trastuzumab (TCH). The TH regimen comprised trastuzumab 2 mg/kg via 30-minute infusion on days 1, 8, and 15 and docetaxel 100 mg/m2 on day 1. The TCH regimen consisted of the same trastuzumab schedule, docetaxel 75 mg/m2 on day 1, and carboplatin AUC 6 on day 1. The first trastuzumab infusion for each group was delivered as 4 mg/kg over 90 minutes. After eight cycles, trastuzumab was continued at 6 mg/kg once every 3 weeks until progression or unacceptable toxicity. The primary endpoint was TTP. Secondary endpoints were response rate, duration of response, and OS. Efficacy was assessed in the intent-to-treat population. Safety was assessed in all patients who received one dose of therapy.

Among the study cohort, 10% of patients were ≥ 65 years of age, 62% had visceral metastases, 46% had metastases to more than two organs, and 50% had prior adjuvant or neoadjuvant therapy, 10% of whom received a taxane. Median number of treatment cycles for each arm was eight. Median cumulative dose in the TH and TCH groups was 777 mg/m2 vs 596 mg/m2, respectively, for docetaxel and 90 mg/kg vs 88 mg/kg, respectively, for trastuzumab. Median cumulative dose for carboplatin in the TCH group was 264 mg/mL/min.

The most common toxicities associated with TH were fatigue (81.7%), sensory neuropathy (58.0%), stomatitis (57.3%), nausea (55.0%), nail changes (55.0%), diarrhea (51.1%), myalgia (48.1%), and rash (44.3%). For TCH, the most prevalent toxicities were fatigue (80.9%), nausea (76.3%), diarrhea (56.5%), stomatitis (51.1%), vomiting (50.4%), sensory neuropathy (45.8%), myalgia (34.4%), and nail changes (33.6%). Neutropenia was more common with TCH than with TH (87.8% vs 74.0%), but grade 3/4 neutropenia was similar for both (13.0% vs 12.2%). Neutropenic infections were more frequent for TH (16.8% vs 9.2%). Decline in left ventricular ejection fraction (LVEF) > 15% was reported in 5.5% vs 6.7% of patients, respectively. LVEF decline was comparable for TH and TCH (median 9.0 points for each). Three deaths were reported, including one in the TH group (from cardiac arrest) and two in the TCH group (one from neutropenic infection and one from sepsis).

Median TTP was statistically similar for TH and TCH (11.07 vs 10.35 months; hazard ratio [HR], 0.914; 95% CI, 0.694–1.203; log-rank P = .57), as was median OS (37.1 vs 37.4 months; HR, 1.015; 95% CI, 0.759–1.358; log-rank P = .99) and response rate (72% for both, log-rank P = .97). Median duration of response was not significantly different for TH vs TCH (10.74 vs 9.43 months). Treatment effect remained similar for the two groups after adjustment for potentially confounding variables; visceral metastases, number of organs involved, and prior adjuvant therapy were prognostic factors (risk ratio for TCH vs TH, 1.060; 95% CI, 0.803–1.399; P = .68).

Results of this multinational randomized phase III trial showed that addition of carboplatin to TH did not significantly improve TTP, OS, or response rate in the setting of HER2+ metastatic breast cancer, perhaps because the effect of carboplatin is negated by the 33% higher docetaxel dose in the TH vs the TCH regimen. These results are unsupported by those reported by the phase III study by Robert et al comparing trastuzumab, paclitaxel, and carboplatin with trastuzumab and paclitaxel. However, in the latter study, equivalent doses of chemotherapy were compared. Thus, both TH and TCH have acceptable safety profiles and are active regimens for HER2+ advanced breast cancer.

Hopeful
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Old 12-08-2010, 08:49 PM   #2
'lizbeth
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Re: (BCIRG 007 Study): Two Highly Active Therapeutic Regimens

I did the TH, but didn't tolerate the higher docetaxel well, had to reduce in 4 of the treatments.
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