Four cycles of adjuvant chemotherapy are sufficient for most breast cancer patients, according to results of a Phase III trial of 3,173 women reported at the CTCR-AACR San Antonio Breast Cancer Symposium.
“We found that six cycles is not superior to four cycles of therapy for patients with primary breast cancer and zero to three positive axillary nodes,” said Lawrence N. Shulman, MD, Chief Medical Officer of Dana-Farber Cancer Institute, in his presentation of the results of the Cancer and Leukemia Group B (CALGB) 40101 trial.
The patients in the study were an average of 52 years old; 64% had estrogen--receptor-positive tumors, and 20% were HER2-positive.
Using a 2×2 factorial design, the researchers randomized patients to have either four or six cycles of doxorubicin plus cyclophosphamide (AC), or to four or six cycles of the taxane paclitaxel.
Doxorubicin plus cyclophosphamide “has been the backbone of many adjuvant breast cancer regimens worldwide for the past three decades,” Dr. Shulman said.
“Over the past decade or decade and-a-half, taxane-containing regimens have been compared with AC, showing favorable results but increased toxicity.
“More recently, studies in locally advanced disease raised the possibility of equivalence of single-agent taxane to AC-based regimens, avoiding the anthracycline and potentially reducing short and long-term toxicity. The ideal duration of adjuvant therapy for good-risk breast cancer patients is unknown.”
The CALGB 40101 trial had two primary goals:
To determine the equivalence of paclitaxel to AC in terms of relapse-free survival rates.
To determine if longer therapy (six cycles) is superior to shorter therapy (four cycles), regardless of agent, regarding relapse-free survival events.
While the study was powered for 567 relapse-free survival events, the Data Safety Monitoring Board (DSMB) released data for six versus four cycles of therapy in September 2010, when there were only 288 events.
At a median follow-up period of 4.6 years, there were 150 relapse-free survival events among patients in the six-cycle arm and 138 events in the four-cycle arm.
The four-year relapse-free survival rate, the primary endpoint, was 91.6% for patients randomized to six cycles and 91.8% for those randomized to four cycles of chemotherapy.
“Although there are only 288 relapse-free survival events at this point, based on the present data, our statistician friends tell us that the Bayesian predictive probability of concluding superiority of six cycles with the 567 events originally planned for is very small—only 0.001,” Dr. Shulman said.
“That's probably why the DSMB released the data,” he said.
The four-year overall survival rates, a s-econdary endpoint, were 95.3% in the six-cycle arm and 96.4% in the four--cycle arm, against a difference that was not significant.
Subgroup analyses based on ER status and HER2 status also showed no statistically significant difference between the four and six-cycle arms for either relapse-free or overall survival rates.
More Side Effects with Six Cycles
While dosages were changed twice, the final regimen involved doxorubicin plus cyclophosphamide (60 and 600 mg/m2, respectively) or paclitaxel (175 mg/m2), delivered every two weeks, for four or six cycles.
“Not surprisingly, six cycles of therapy is more toxic than four,” Dr. Shulman said.
Among patients in the AC arm, 34% of patients given six cycles developed Grade 3/4 neutropenia, compared with 26% in the four-cycle arm.
In the paclitaxel groups, the major toxicity was Grade 3/4 neuropathy, which affected 13% of patients given six cycles and 6% given four cycles.
Data regarding whether paclitaxel is equivalent to AC are not yet mature, he said.
Had Been Eagerly Awaited
The results of the study, the first to compare four versus six cycles of adjuvant chemotherapy, have been eagerly awaited, attendees said.
“We have assumed four cycles is sufficient,” said Peter Ravdin, MD, PhD, Co-Director of the symposium and Director of the Breast Health Clinic at the Cancer Therapy & Research Center of The University of Texas Health Science Center at San Antonio.
Now, he said, there are hard data to back up the assumption.