NCCN Updates its Treatment Guidelines for Breast Cancer

HOLLYWOOD, Florida—The 2002 National Comprehensive Cancer Network (NCCN) breast cancer treatment guidelines include a number of important updates regarding the use of aromatase inhibitors, leuteinizing hormone-releasing hormone (LHRH) agonists, and sentinel lymph node biopsy. Robert W. Carlson, MD, chair of the NCCN Breast Cancer Panel, presented the guidelines at the Seventh Annual NCCN Conference.

Based on results of the large, randomized Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, the panel elected to add a footnote to the guidelines for systemic adjuvant therapy of hormone-receptor-positive postmenopausal women with node-negative stage I-IIB disease (larger than 1 cm).

The footnote states that the selective aromatase inhibitor anastrozole (Arimidex) is an option to tamoxifen (Nolvadex) in this setting, pending further long-term evidence of anastrozole’s efficacy and safety.

ATAC showed a 17% reduction in risk of recurrence with the use of anastrozole (22% reduction in hormone-sensitive patients). The footnote states that "at the current time, anastrozole can be considered an option to tamoxifen after discussion of available data between physician and patient. These data do not address whether women currently on tamoxifen should be changed to anastrozole. Anastrozole is not appropriate for premenopausal women."

"The reason that we have left the two drugs as equivalent," said Dr. Carlson, professor of medicine and medical informatics, Stanford University, "is that we have 25 years of experience with tamoxifen. The aromatase inhibitors have been licensed since 1995 (anastrozole) and 1996 (letrozole [Femara]), so we don’t have long-term data on toxicities."

In the ATAC trial, anastrozole was also superior in reducing the incidence of contralateral breast cancers, with a 58% reduction. "This is a relatively remarkable result," Dr. Carlson said, "and it will be really important if it holds up, because we already know from the Breast Cancer Prevention Trial that tamoxifen reduces the risk of contralateral breast cancer by 50%. If we’re now seeing an additional 58% reduction, that’s an enormous risk reduction that could potentially be moved into the breast cancer prevention setting."

The new guidelines also upgraded the use of anastrozole and letrozole as equal to tamoxifen as first-line therapy for postmenopausal women with hormone-responsive recurrent breast cancer and no prior hormonal therapy. Dr. Carlson referred to two randomized trials of anastrozole vs tamoxifen in this setting that included more than 1,000 patients (J Clin Oncol 18:3748, 3758, 2000). The studies showed equivalence or superiority to tamoxifen in time to progression.

He cited a similar trial of letrozole in over 900 postmenopausal women with locally advanced or stage IV breast cancer (J Clin Oncol 19:2596, 2001). Patients were ER or PR positive or unknown; they were randomized to letrozole or tamoxifen with a crossover design at the time of progression.

Medium time to progression was increased about 50% with letrozole, compared with tamoxifen. Objective responses were also increased by about 50% favoring letrozole, he said.

As a result, he said, the guidelines now state that anastrozole, letrozole, or an antiestrogen are all appropriate first-line options in the treatment of invasive metastatic breast cancer in postmenopausal women who are ER positive, or have bony or soft tissue metastases only or asymptomatic visceral disease, and have received no prior antiestrogen or have been off antiestrogen therapy for more than a year.

LHRH Agonists

A meta-analysis based on four randomized trials of LHRH agonists in premenopausal women with metastatic breast cancer resulted in yet another change to the guidelines. The meta-analysis showed about a 22% reduction in hazard ratios for women treated with an LHRH agonist plus tamoxifen vs an LHRH agonist alone (J Clin Oncol 19:343, 2001).

The guidelines now state that an antiestrogen, such as tamoxifen, plus or minus an LHRH agonist is appropriate first-line therapy for premenopausal women with ER-positive disease, or bony or soft tissue metastasis only or asymptomatic visceral disease, and who have received no prior antiestrogen therapy or have been off antiestrogen therapy for more than 1 year.

For 2002, the NCCN breast cancer panel upgraded sentinel lymph node biopsy from a footnote to an option equal to axillary lymph node dissection in appropriate patients when performed by experienced sentinel lymph node biopsy teams. This decision was based more on extent of use than evidence, Dr. Carlson commented.

"Despite the absence of high level evidence and because of practice patterns across the United States, we are forced to make a recommendation," he said. "Based upon the available evidence, which is not high level evidence, it looks like sentinel lymph node biopsy is probably as accurate and as therapeutic as formal axillary dissection, and no one doubts that it has lower morbidity."

Dr. Carlson added that the committee strongly supports the performance and completion of multiple randomized clinical trials of sentinel lymph node biopsy, and possibly a meta-analysis, to prove if the "optimism surrounding sentinel node biopsy is deserved."