Preop Chemotherapy May Have Advantages in Primary Breast Cancer

ASCO--A brief, intensive preoperative chemotherapeutic regimen failedto improve breast cancer survival over conventional adjuvant chemotherapyin a 1,500-patient randomized trial, Dr. Eleftherios Mamounas said forthe National Surgical Adjuvant Breast Project (NSABP). However, preoperativetreatment often resulted in complete clinical remission prior to surgery.

Moreover, Dr. Mamounas said, the initial response to preoperative chemotherapycorrelated with disease-free survival, suggesting that preoperative treatmentmay provide useful prognostic information to guide follow-up therapy.

The NSABP investigators compared the efficacy of short-term intensivepreoperative chemotherapy with doxorubicin (60 mg/m²) and cyclophosphamide(600 mg/m²) given every three weeks for four cycles versus the sameregimen after surgery. Women age 50 or older also received tamoxifen (Nolvadex).

About half the patients in each treatment arm were age 49 or youngerat enrollment, and a quarter were ages 50 to 59. Roughly three fourthsof the patients were node negative, and 25% to 30% had tumors smaller than2 cm; 13% had tumors larger than 5 cm.

"The primary purpose of the study was to determine if preoperativechemotherapy, as opposed to postoperative chemotherapy, will be more effectivein terms of disease-free survival and overall survival in patients whohave operable breast cancer," Dr. Mamounas said.

Secondary aims related to clinical and pathological responses to preoperativechemotherapy and to the ability of preoperative therapy to downstage axillarynodes and increase lumpectomy rates. The investigators also wanted to seewhether tumor response to preopera-tive chemotherapy correlated with disease-freeor overall survival.

At a mean follow-up of six years, patients in each treatment arm hada 67% disease-free survival rate and 80% overall survival rate, Dr. Mamounassaid.

Nodal Downstaging

Preoperative chemotherapy did result in nodal downstaging, as 60% ofpatients had negative nodes at surgery versus 42% of patients who had conventionaladjuvant chemotherapy. Preoperative therapy also was associated with ahigher rate of lumpectomy, 68% versus 60%.

Notably, 249 patients given preopera-tive chemotherapy had completeclinical remissions prior to surgery. In 63 of these patients, no evidenceof tumor could be found on histologic examination of specimens. Another26 patients had only ductal carcinoma in situ (DCIS).

Evaluation of disease-free survival by initial response to preoperativechemotherapy revealed a correlation. Disease-free survival exceeded 80%in the 89 patients who had complete remissions or residual DCIS, but wasabout 70% or less in patients who had responses other than complete responseor DCIS after preoper-ative chemotherapy. A similar pattern emerged foroverall survival. The two treatment arms did not differ with respect tosite of first recurrence.

"In patients with operable breast cancer, preoperative chemotherapyis safe and results in high rates of clinical tumor response and increasedrates of breast preservation," Dr. Mamounas said. "When comparedto postoperative chemotherapy, preoperative treatment results in equivalentdisease-free survival, distant disease-free survival, and overall survival."

On the basis of these results, he continued, "preoperative chemotherapymay be considered an alternative to standard adjuvant chemotherapy in patientswho are candidates for chemotherapy."

Dr. Mamounas said that the results have led NSABP investigators to launchanother clinical trial to explore the effects of preoperative chemotherapy.The trial will randomize patients to the doxorubicin-cyclophosphamide combination,followed by surgery or followed by preoperative or postoperative administrationof docetaxel (Taxotere).

"Preoperative chemotherapy results in equivalent overall and disease-freesurvival, and provides additional information that can be useful to guidefurther systemic and local intervention," he said. "We plan topursue this finding in the upcoming trial."

The purpose of the new trial, he said, is to see whether the additionof a taxane will prolong disease-free survival and overall survival, andincrease clinical and pathological response rates, rates of axillary nodedownstaging, and breast preservation.