SEQUENTIAL CHEMOTHERAPY MORE EFFECTIVE IN BREAST CANCER

June 3, 2010 — The sequential administration of chemotherapy was more effective than concurrent administration in women with operable node-positive breast cancer. The sequential ACT regimen — doxorubicin (Adriamycin) and cyclophosphamide followed by docetaxel (Taxotere) — had a greater impact on disease-free survival than a doxorubicin/docetaxel combination or concurrent ACT.

According to a study published in the June 3 issue of the New England Journal of Medicine, the sequential administration of ACT provided a significant 17% reduction in mortality, compared with doxorubicin/docetaxel treatment (P = .03). It also showed a nonsignificant 14% reduction in mortality compared with concurrent ACT (P = .09).

Disease-free survival was also better with sequential ACT than with the 2 other therapeutic regimens, and the authors note that their results suggest that a shorter course of treatment is not as effective as a longer one.

However, in an accompanying editorial, Matthew Ellis, BChir, PhD, professor of medicine at Washington University School of Medicine in St. Louis, Missouri, points out that the conclusion that a longer duration of treatment is better "should not be considered a general principle, but rather a product of the unbalanced design of the study."

The study, the National Surgical Adjuvant Breast and Bowel Project B-30 trial, was developed to identify a short-course, taxane-based chemotherapy regimen for patients with node-positive breast cancer. Some of the results were presented in 2008 at the San Antonio Breast Cancer Symposium, and were reported by Medscape Oncology at that time.

Longer Regiment Not Necessarily Superior

The study compared 3 regimens in patients with operable early-stage node-positive disease: 4 cycles of doxorubicin, cyclophosphamide, and docetaxel (concurrent ACT); a similar 12-week regimen with just doxorubicin and docetaxel; and a 24-week regimen in which docetaxel was administered separately from the doxorubicin/cyclophosphamide combination (sequential ACT).

The primary goals of the study were to assess whether concurrent ACT is more effective than sequential ACT, and if a doxorubicin/docetaxel regimen is as effective as concurrent ACT.

It is only in the context of this trial that longer regimens are better, explained Dr. Ellis; there have been other trials where shorter regimens were more effective, such as the CALGB 9741 trial.

CALGB 9741 supported the principle of dose density; the shorter regimens offer the same drug dose but in a more condensed period of time. That was not the case in this trial, he told Medscape Oncology.

As Dr. Ellis notes in his editorial, "it is hard to escape the conclusion that the inferior results associated with the 12-week regimens in this trial were mainly due to the significant dose reductions required to make the doxorubicin–docetaxel and concurrent-ACT regimens feasible."

"You simply can't force 3 drugs together and expect to give them at the regular dose," he said. "Giving myelosuppressive drugs at the same time almost always increases the side effects, and you have to lower the doses."

To accurately compare regimens of different lengths, the same drugs need to be given at the same dose, Dr. Ellis said. "This trial was not designed to establish any kind of principle."

He also wonders why the drugs were given concurrently in the first place. "This was never made clear, and there is no evidence that there is any sort of synergy between them," Dr. Ellis explained. "We shouldn't put drugs together just to do it. If you put together a combination, then there has to be rationale behind it."

Ovarian Suppression or Toxicity

Another result from the study is that patients who developed amenorrhea that lasted at least 6 months had better overall survival. This was the case across all treatment groups, independent of estrogen-receptor (ER) status. It had been thought that the value of ovarian suppression was restricted to ER-positive disease, and the study authors write that this is one of the "most intriguing findings of this trial."

Although ovarian ablation has been associated with an improved outcome in premenopausal women, Dr. Ellis pointed out that "direct ovarian suppression with a drug or surgery is not the same thing as ovarian toxicity from chemotherapy."

"It could be that the women who are going into menopause are experiencing more toxicity, and that is why they are getting the dose effect," he said. "They are metabolizing the drug more slowly, and therefore getting a higher dose and an enhanced clinical effect."

Dr. Ellis notes that ovarian suppression could also alter the clinical course of ER-negative disease, which might account for the benefit seen in both ER-positive and ER-negative patients. "Ovarian surgery appears to reduce the risk of breast cancer among carriers of the breast-cancer susceptibility gene BRCA1, in whom ER-negative and HER2-negative disease is the predominant presentation," he writes. It might be that ovarian suppression alters tumor progression in ER-negative disease indirectly, possibly through the tumor microenvironment.

Study Details

In this study, Sandra M. Swain, MD, from Washington Hospital Center in the District of Columbia, and colleagues randomized 5351 patients with operable, node-positive, early-stage breast cancer to 1 of the 3 trial groups.

At a median follow-up of 73 months, the authors observed that overall survival was better with sequential ACT (8-year overall survival, 83%), than with doxorubicin/docetaxel (overall survival, 79%; hazard ratio [HR] for death, 0.83; P = .03) and concurrent ACT (overall survival, 79%; HR, 0.86; P = .09).

Disease-free survival was also better with sequential ACT (8-year disease-free survival, 74%) than with doxorubicin/docetaxel (69%; HR for recurrence, a second malignant condition, or death, 0.80; P = .001) and concurrent ACT (69%; HR, 0.83; P = .01).

Doxorubicin/docetaxel showed noninferiority to concurrent ACT for overall survival (HR, 0.96; 95% confidence interval, 0.82 - 1.14).

As far as toxicity, patients receiving sequential ACT had a higher incidence of grade 3 or 4 adverse events (65%) than 45% of patients receiving doxorubicin/docetaxel and 48% of patients receiving concurrent ACT. Sequential ACT was also associated with significant increases in stomatitis, febrile neutropenia, and infection, compared with the other therapies, and arthralgia, fatigue, and vomiting were reported less frequently with doxorubicin/docetaxel.

There were 5 treatment-related deaths with sequential ACT (<1%), 7 with doxorubicin/docetaxel (<1%), and 12 with concurrent ACT (<1%).

The study was funded by Public Health Service grants from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by Sanofi-Aventis. The study authors report a number of financial relationships, as detailed in the paper. Dr. Ellis reports consulting for Bristol-Myers Squibb, Sanofi-Aventis, Novartis, Pfizer, AstraZeneca, Abraxis, and GlaxoSmithKline.

N Engl J Med. 2010;362:2053-2065.