NEWS

Near-Final Word on Adjuvant Chemotherapy for Breast Cancer Is Good News

Brian Vastag

The largest-ever compilation of trial data on early breast cancer has confirmed that adjuvant chemotherapy reduces death rates up to 15 years after disease onset. The meta-analysis also provides strong evidence in favor of tamoxifen treatment for women with hormone-responsive tumors.

The report, published earlier this summer in The Lancet by the European Breast Cancer Trialists' Collaborative Group (EBCTCG), shows that adjuvant chemotherapy provides "a very definitive alteration in the course of breast cancer. It's not just a temporary boost," said Gabriel Hortobagyi, M.D., president-elect of the American Society of Clinical Oncology and chair of the department of breast medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston.



View larger version (139K):
[in this window]
[in a new window]
 
Gabriel Hortobagyi

 
Clinicians began regularly using adjuvant chemotherapy for breast cancer in the early 1980s. But early clinical trials were too small to resolve debate about the effectiveness of the individual treatments. "We were just arguing about ghosts because we didn't have the data," Hortobagyi said.

To help resolve the issue, Sir Richard Peto, professor of medical statistics and epidemiology at Oxford University, organized the EBCTCG in 1985. This latest report from the group covers data from 145,000 women enrolled in 194 clinical trials and shows that chemotherapy provides increasingly larger reductions in death rates at 15 years versus 5 years post-treatment.

Author Sarah Darby, Ph.D., a statistician at the Clinical Trial Service Unit at the University of Oxford, and colleagues credit this effect for saving thousands of lives. "Although newer treatments are arriving, the long-term benefits from these older treatments are probably the main reason why [breast cancer] mortality rates are steadily falling in the U.S. and Europe," said Darby.

In a commentary that accompanied the meta-analysis, Karen Gelmon, M.D., of the British Columbia Cancer Agency, Vancouver, concluded that the data "suggest that adjuvant systemic therapies do cure a proportion of women with early-stage breast cancer." She adds that the findings are "reassuring" after three decades of debate regarding the efficacy of chemotherapy for early breast cancer. In 2001, a National Institutes of Health consensus panel recommended chemotherapy after surgery for most women with early-stage breast cancer.

In the report, the Oxford group examines first-generation chemotherapy regimens, including cyclophosphamide, methotrexate, and fluorouracil (CMF), as well as second-generation regimens, including fluorouracil, doxorubicin, and cyclophosphamide (FAC).

Gelmon noted that first-generation regimens have largely fallen out of favor. And in fact, the meta-analysis confirms that second-generation regimens do in fact outperform the earlier treatments. Women younger than 50 who underwent FAC-type chemotherapy enjoyed the largest benefits. At 15 years post-treatment, 32% of such women had died from breast cancer, compared with 42% of control subjects. But the benefit for women aged 50–69 years was less substantial. At 15 years, 47% who had received FAC or FEC had died of breast cancer, compared with 50% of control subjects. (The authors note that there were too few participants aged 70 and older to perform a separate mortality analysis.)

Hortobagyi cited two factors in the age discrepancy. First, chemotherapy tends to do a better job of treating estrogen receptor–negative tumors than estrogen receptor–positive tumors, and premenopausal women have proportionately more of the receptor-negative type. "The mix is different, so the benefit is more prominent for younger women."

Second, for premenopausal women who do have estrogen receptor–positive tumors, "chemotherapy essentially has a dual effect. It functions as chemotherapy in fighting the cancer directly, and it also functions as hormonal therapy by suppressing the ovaries."

And it turns out that the benefits of hormone therapy itself are substantial. The meta-analysis shows that in women of all ages with estrogen receptor–positive tumors, 5 years of tamoxifen therapy yields a 31% relative reduction in the risk of death. One or 2 years of tamoxifen confers a 15% relative reduction in risk of death. The benefits are synergistic when chemotherapy is added.

Gelmon suggested that the data will finally put to rest lingering questions about the effectiveness of hormonal therapy for breast cancer—a debate that has run almost as long as the one regarding adjuvant chemotherapy.

Although the meta-analysis supports the effectiveness of older chemotherapy regimens, the authors noted that the drugs they analyzed are falling out of favor as newer drugs with fewer side effects, such as Herceptin (trastuzumab) and modern aromatase inhibitors, filter into clinics. Clinical trials with these third-generation treatments have generated positive results, but the meta-analysis included only data through 2000, so these newer regimens were not included.

Despite seeing the delay as "enormously unfortunate," though, Hortobagyi culls a larger message from the report. "We can apply the lessons of well-designed and appropriately sized clinical trials, coupled with high-quality diagnostic tests, to other types of cancer—colorectal and lung in particular. Our colleagues who deal with these cancers are learning from us, and the acceleration of translation of knowledge to the clinic is going to help save thousands of lives. Those are the important lessons from this kind of meta-analysis—and they are every bit as important as the other conclusions."



             
Copyright © 2005 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement