Progress in Systemic Chemotherapy of Primary Breast Cancer

BETHESDA, Md—The aggregate benefit of adjuvant systemic chemotherapy is "greater than many would think," reflecting "real and substantial" progress, Gabriel N. Hortobagyi, MD, professor and chairman of Breast Medical Oncology, M.D. Anderson Cancer Center, said at the NIH Consensus Conference on Adjuvant Therapy for Breast Cancer.

Dr. Hortobagyi presented an overview of the progress made in systemic chemotherapy, especially with combinations of agents. He said that the 2000 meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group confirms and expands upon the 1995 meta-analysis, and shows a substantial advantage of chemotherapy over surgery alone, both for node-positive and node-negative breast cancer, in terms of reducing the risk of recurrence and death.

For trials involving tamoxifen (Nolvadex), the magnitude of the benefit in reducing the risk of recurrence is greater than the reduction in the odds of death.

He said that "aggregate data best reflect the state of the art." However, he reminded attendees that meta-analysis is the great "averager."

"With a meta-analysis, you don’t get the best results but the average results. These average results are important to the generation of hypotheses but they do not represent the best that chemotherapy has to offer," he pointed out.

Dr. Hortobagyi said the recent meta-analysis offers the following messages regarding adjuvant therapy:

Age is an important determinant of efficacy. Patients younger than 50 have a substantially greater reduction in the odds of recurrence or death than older patients. "How much of this is real and how much is related to the adequacy of treatment is unresolved," he added.

There is a correlation between the efficacy of adjuvant chemotherapy and estrogen-receptor (ER) status, with greater benefit seen in the ER-negative subgroup.

Regarding duration of chemotherapy, prolonged treatment beyond 6 months with the same regimen does not confer additional benefit above and beyond 4 to 6 months of treatment. It is believed that 6 months is probably as effective as 1 year of chemotherapy, but the minimum treatment duration is not as clearly defined, and less than 6 months of treatment may be less effective.

"With commonly employed single-therapy regimens, about 4 to 6 months of treatment will convey maximum benefit. If you use sequential regimens, you may need to prolong the duration to deliver enough of both regimens," he said.

Anthracyclines

The 1995 meta-analysis found that the addition of an anthracycline to adjuvant systemic chemotherapy reduces the odds of recurrence by about 12% and the odds of death by 11%. This "highly significant effect" was even more pronounced in the 2000 meta-analysis, which found a 16% reduction in recurrences and a 15.7% reduction in mortality, he reported.

In a large trial of almost 4,000 patients (SWOG S8897 or INT 102) that compared CMF (cyclophosphamide, methotrexate, fluorouracil) to CAF (cyclophosphamide, Adriamycin, fluorouracil) in node-negative breast cancer, a substantial absolute difference—3% to 4%—was seen in favor of the anthracycline-containing regimen in terms of the 5-year estimate of relapse. But smaller randomized trials have not always shown advantages; in fact, their results have been "all over the map," he noted.

"If you pool the data, you see a therapeutic advantage, a significant reduction in the odds of recurrence or death," he said. "But I have been concerned over the adoption of AC (Adriamycin/cyclophosphamide) as a standard without having compared it to the other two anthracycline combinations. Two-drug combinations using doxorubicin or epirubicin [Ellence] clearly show equivalence to CMF. But our goal is not equivalence to CMF—CMF is a regimen that could use improvement."

On the other hand, he said, looking at three- or four-drug regimens containing cyclophosphamide or fluorouracil, most of these show a significant improvement in outcomes, both relapse-free survival and overall survival. "This would suggest the three-drug combinations are superior to CMF whereas the two-drug combinations are equal to CMF," he said.

Dr. Hortobagyi said that he "tentatively concludes" that anthracycline-containing regimens are clearly more effective than regimens without anthracyclines, that they appear particularly useful in premenopausal patients, and that regimens that also contain 5-fluorouracil and cyclophosphamide are more effective than AC alone."

He added, however, that there is no evidence that AC is equivalent to FAC (fluorouracil, Adriamycin, cyclophosphamide), because these regimens have not been formally compared. Whether FAC is superior because of its third drug or the duration of therapy (usually 6 to 8 cycles) is unclear, he said.

In CALGB 9344, paclitaxel (Taxol) added to AC conferred a substantial benefit in reducing the risk of recurrence or death in node-positive patients. This finding essentially changed the standard of practice in the United States, but not in Europe, where oncologists remain cautious about adopting this practice, he said.

According to Dr. Hortobagyi, the reduction in risk of recurrence and death with chemotherapy is as follows:

Combination chemotherapy vs no combination chemotherapy reduces the annual odds of recurrence by 23% and the odds of death by 17%, highly significant benefits.

The addition of doxorubicin or epirubicin confers an additional 12% benefit.

The further addition of paclitaxel conveys an incremental benefit of 22% to 25%, highly significant (assuming the data will be confirmed).

Other Issues

Dr. Hortobagyi summarized a large body of literature on chemotherapy dose by stating that dose reductions below optimal maximally tolerated doses without growth factor support are "harmful."

The National Surgical Adjuvant Breast and Bowel Project (NSABP) trials have shown that two- to fourfold increases in cyclophosphamide doses do not improve outcome, and dose intensification studies for doxorubicin and epirubicin suggest a dose-response correlation that is "probably a threshold effect more than a linear correlation," he said.

In the higher dose ranges, with autologous stem cell support, five studies have not shown a statistically significant reduction in the odds of recurrence or death. However, a couple of trials, such as the CALGB trial reported by Peters have shown a small (though not significant) reduction in recurrences, which has not yet translated into a survival benefit. Currently, more than a dozen randomized controlled trials continue to study this issue.

For ER-positive tumors, the pairing of chemotherapy and tamoxifen provides improved results vs either method alone, both in older and younger women, Dr. Hortobagyi said.

"The overall benefit of systemic therapies is often underestimated," he said. To illustrate, he described the treatment benefit in an average 35-year-old women with a 3-cm infiltrating ductal carcinoma, five positive nodes, and negative estrogen receptors. He calculated her risk of recurrence at 54%. "Treatment with CMF will reduce this risk by 37%, resulting in a residual risk of 34%. Use of CAF would further reduce this risk to about 30%. And the addition of Taxol should bring her risk down to about 20%," he said.

Each component is modest, but the overall aggregate is substantial, Dr. Hortobagyi said. This patient’s maximum reduction in risk is from 54% to 20% (about a 63% reduction). If this patient were node-negative, with a lower baseline risk of recurrence, her risk reduction would still be about 57%, he said.

"But this benefit does not come without toxicity," he cautioned. "For high-risk patients, the therapeutic effect of both tamoxifen and chemotherapy is much greater than the risk of toxicity. For low-risk patients, the window narrows and the benefit-to-risk ratio is smaller."