Comparable results seen with substitution of paclitaxel for cyclophosphamide in high-risk breast cancer

Treatment with doxorubicin/paclitaxel may be option for certain patients with high-risk breast cancer.

In patients with high-risk breast cancer, treatment with doxorubicin plus paclitaxel followed by weekly paclitaxel was an equally effective and potential treatment option to doxorubicin plus cyclophosphamide followed by paclitaxel.

In a phase 3, multicenter trial, researchers, led by David Loesch, MD, from US Oncology Research, compared DFS between these two treatment groups in women with operable, stage I to stage III adenocarcinoma of the breast.

They assigned patients to treatment Arm 1, consisting of doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 3 weeks for four cycles followed by paclitaxel 175 mg/m² every 3 weeks for four cycles (n=915), or to Arm 2, consisting of doxorubicin 50 mg/m² plus paclitaxel 200 mg/m² every 3 weeks for four cycles followed by paclitaxel 80 mg/m² weekly for 12 weeks (n=915).

Median follow-up was 63.4 months for Arm 1 and 64 months for Arm 2. The researchers hypothesized that cardiotoxicity would be minimized in treatment Arm 2.

“By incorporating newer, more effective drugs and by optimizing the dose and schedule of administration, improved outcomes are possible,” they wrote.

The results were published in The Journal of Clinical Oncology.

Outcomes similar between treatments

Median DFS and OS were not reached with either treatment. Three-year survival rates were 93% for Arm 1 vs. 86% for Arm 2; 5-year survival rates were 94% for Arm 1 vs. 89% for Arm 2.

Currently, 811 patients in Arm 1 and 829 patients in Arm 2 are alive, according to the researchers. Six-year DFS was 81.7% (95% CI, 72%-88.3%) in Arm 1 vs. 87% (95% CI, 81.3%-91.1%) in Arm 2.

Reasons for discontinuation of study treatment included disease relapse/recurrence for 6.9% of patients in Arm 1 and 5.1% of patients in Arm 2; toxicity for 12.6% of Arm 1 and 20% of Arm 2; and patients request/withdraw consent for 8.9% of Arm 1 and 7.9% of Arm 2.

There were 104 deaths in Arm 1 vs. 88 in Arm 2. Relapse/recurrence was the cause of death for 79.8% of Arm 1 patients and 76.7% of Arm 2 patients.

Hematologic toxicity was the most common treatment-related adverse event and included neutropenia and leukopenia, followed by nonhematologic events, including neuropathy, myalgia, nausea, fatigue, arthralgia and vomiting.

In an unplanned subgroup analysis, ER-negative/PR-negative (P=.06) and triple-negative (P=.07) subgroups favored the treatment in Arm 2. OS ranged as long as to 79.2 months in Arm 1 compared with 85 months in Arm 2 (P=.08) and DFS was similar between Arm 1 (79.2 months) and Arm 2 (84.3 months; P=.35).

A dose-dense paclitaxel regimen is as efficacious as doxorubicin plus cyclophosphamide followed by paclitaxel, according to the researchers.

Trial criticism

In an accompanying editorial, however, Angelo DiLeo, MD, PhD, head of Sandro Pitigliani Medical Oncology Unit, and Catherine Oakman, MD, department of oncology at the Hospital of Prato, Italy, disagreed that the findings of this study may guide practice.

The authors cited several areas of concern within the trial, including trial design. In addition, having two variables in the experimental Arm prevented assessment of the contribution of each variable, they explained.

“It is impossible to ascertain whether any differences in Arm 2 are attributable to cyclophosphamide omission or altered paclitaxel schedule,” they wrote.

The authors also expressed that patient selection was problematic, as eligibility was defined by tumor risk factors rather than tumor biology, and that the trial lacked a centralized biomarker evaluation.

“We must address the discordance between heterogeneous disease biology and homogeneous treatment recommendations from clinical trials; we must be more ambitious, beginning with sound biologic hypotheses and moving to targeted trial design and patient selection,” they wrote.

For more information:

• DiLeo A. J Clin Oncol. 2010;doi:10.1200/JCO.2009.24.1000.
• Loesch D. J Clin Oncol. 2010;doi:10.1200/JCO.2009.24.1000.