December 16, 2010 (San Antonio, Texas) — Are 6 cycles of adjuvant chemotherapy for breast cancer better than 4?
This was one of the basic questions asked in Cancer and Leukemia Group B (CALGB) 40101, a phase 3 clinical trial of 3173 women with "good-risk" breast cancer that began in 2002.
"Many studies have looked at 4 vs 4 cycles or 6 vs 6 cycles of different regimens," said lead author Lawrence Shulman, MD, from Dana-Farber Cancer Institute in Boston, Massachusetts. However, this CALGB trial is the first time that 4 and 6 cycles have been compared, he told
Medscape Medical News.
The study's results, which were presented here at the 33rd Annual San Antonio Breast Cancer Symposium, were anticipated by 2 prominent breast cancer medical oncologists.
"It's a question many clinicians wonder about. We assume 4 cycles is enough," said Peter Ravdin, MD, PhD, before the start of the symposium in an interview with
Medscape Medical News. He is codirector of the annual meeting and is from the University of Texas Health Science Center at San Antonio.
"Does the duration of therapy matter?" asked Kathy Miller, MD, about the trial. She commented on the trial in her
Miller on Oncology videoblog before the annual breast cancer meeting. She is from Indiana University Simon Cancer Center in Indianapolis.
The answer is now in: "Six is no better than 4 for the general population in the study [or for the] subgroups," said Dr. Shulman.
That is to say, in women with good-risk invasive breast cancer (0 to 3 positive lymph nodes), relapse-free survival at 4 years was 91.6% for those randomized to 6 cycles and 91.8% for those randomized to 4 cycles (hazard ratio, 1.10; (95% confidence interval, 0.87 - 1.39;
P = .42). Relapse-free survival was the primary end point of the study.
At a median follow-up of 4.6 years (range, 2.5 to 8.0), the number of relapse-free survival events is 288 (138 with 4 cycles and 150 with 6 cycles). The average age of the women was 52 years.
Overall survival was a secondary end point, and both durations of therapy were, again, roughly equivalent in terms of percentage (in the mid-90s).
Which Drugs? What's the Design?
In one section of the study, the investigators randomized patients to either 4 or 6 cycles of the combination of doxorubicin (
Adriamycin) plus cyclophosphamide — which "has been the backbone of many adjuvant breast cancer regimens," said Dr. Shulman.
In the other section of study, the investigators randomized patients to either 4 or 6 cycles of the taxane paclitaxel (
Taxol).
The approach is known as a 2×2 factorial design and suited the investigators purposes.
At the beginning of his presentation, Dr. Shulman spoke about the study's agents and design.
Taxane-containing regimens have been compared with the workhorse combination of doxorubicin plus cyclophosphamide, and have shown favorable results but increased toxicity, he said. However, studies of locally advanced disease have "raised the possibility of equivalence of a single-agent taxane to [combination doxorubicin plus cyclophosphamide]-based regimens, avoiding the anthracycline and potentially reducing short- and long-term toxicity," said Dr. Shulman. The "ideal duration" of adjuvant therapy is not known, he added.
The study examined the ideal duration of doxorubicin plus cyclophosphamide and paclitaxel, and compared the combination with single-agent paclitaxel.
Dr. Shulman did not disclose the results from the showdown between the combination and paclitaxel because the data are not yet mature.
However, the investigators are comfortable in their assessment that 4 and 6 cycles have equivalent outcomes when patients receive either doxorubicin plus cyclophosphamide or paclitaxel.
"We can feel very comfortable giving women in this good-risk group 4 cycles," said Dr. Shulman.
The investigators of the multicenter trial also looked at subgroups of women. There was no comparison of women with positive and negative lymph nodes because 94% of patients were node negative.
But 64% of participants were estrogen-receptor positive and 20% were HER2 positive. Still, there was no statistically significant difference between the 4- and 6-cycle subgroups for either relapse-free or overall survival, reported Dr. Shulman.
Adverse Events Worse With 6 Cycles
The treatment schedule in the trial was changed twice; ultimately, chemotherapy was delivered every 2 weeks for both doxorubicin plus cyclophosphamide (60 and 600 mg/m2, respectively) and paclitaxel (175 mg/m2), and each was given for 4 or 6 cycles.
Serious adverse events were worse in the 6-cycle groups than in the 4-cycle groups. "Not surprisingly, 6 cycles of therapy is more toxic than 4," Dr. Shulman said.
In the combination groups, grade 3/4 neutropenia was most notable. It was higher in the 6-cycle group than in the 4-cycle group (34% vs 26%).
In the paclitaxel groups, grade 3/4 neuropathy was most notable. It was higher in the 6-cycle group than in the 4-cycle group (13% vs 6%).
The authors have disclosed no relevant financial relationships.
33rd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S6-3. Presented December 11, 2010.