2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer

Recent NSABP Adjuvant Studies in Primary (Stage One) Breast Cancer

Bernard Fisher, M.D.

Data on the effects of adjuvant chemotherapy and endocrine therapy on breast cancer obtained from randomized trials conducted during the 1970s and early 1980s were evaluated at a consensus development conference convened by the National Institutes of Health (NIH) in 1985. The conference concluded that there was inadequate information to recommend therapy other than surgery for women with negative nodes (Consensus Conference, 1985).

By 1990, however, findings from trials conducted by the National Surgical Adjuvant Breast Project (NSABP) and by other investigators warranted a new conference to reconsider the treatment of early-stage breast cancer. Participants at the 1990 meeting concluded that "the rate of local and distant recurrence following local therapy for node-negative breast cancer is decreased by both adjuvant combination of cytotoxic chemotherapy and by adjuvant tamoxifen" (NIH Consensus Conference, 1991). The conference also concluded that patients with tumors equal to or less than 1 cm now had an excellent prognosis and did not require adjuvant therapy outside of clinical trials. The participants noted, however, that studies so far were not large enough, nor followup long enough, to estimate accurately the interactions between menopausal status or steroid receptor positivity and adjuvant therapy in node-negative patients. They also noted that there were too few patients with estrogen receptor (ER)-negative tumors to permit evaluating the benefit of treatment with tamoxifen, that the followup period had been too short to obtain meaningful data on the mortality of women with breast cancer, and that no information was available to aid in determining the effects of combination chemotherapy plus tamoxifen in node-negative breast cancer patients. In the years since the 1990 conference, information on these issues has been obtained from six NSABP trials involving a total of 11,620 node-negative patients with primary breast cancer.

Findings for Adjuvant Chemotherapy

In the NSABP B-13 trial, women with breast cancer were randomized to receive either surgery and no chemotherapy or surgery followed by 12 courses (1 year) of methotrexate (M) and sequentially administered fluorouracil (F), (M¨F), followed by leucovorin (Fisher, Dignam, Mamounas, et al., 1992). Findings through more than 12 years of followup demonstrated that improvements in disease-free survival (DFS) and overall survival as a result of that form of chemotherapy, first reported after 5 years, had persisted (p=0.004 and 0.039, respectively). A second trial, B-19, was conducted to determine if the alkylating agent cyclophosphamide (C) contributed an additional benefit when administered along with methotrexate and fluourouracil (CMF). Over a 6-month period, patients received either six courses of M¨F or six courses of CMF. Through an 8-year followup period, CMF produced greater DFS and overall survival advantages (p=0.0004 and p=0.039, respectively).

The NSABP subsequently initiated a B-23 study because of contradictory information about the propriety of using tamoxifen with chemotherapy, and because of uncertainty about the relative worth of doxorubicin (Adriamycin, A), cyclophosphamide, and CMF for treatment of breast cancer (Fisher, Anderson, Tan-Chiu, et al., in press). Women with breast cancer (n=2,008) were randomized to receive either CMF plus placebo, or CMF plus tamoxifen, or doxorubicin and cyclophosphamide plus placebo, or doxorubicin and cyclophosphamide plus tamoxifen. Six cycles of CMF were given over 6 months; four cycles of AC were administered over a period of 63 days. No significant differences in the rates of relapse-free survival (RFS), event-free survival (EFS), or overall survival were observed among the four groups through 5 years of followup, either for all patients (p=0.9, 0.8, and 0.8, respectively) or for those £49 or o50 years of age. The study also demonstrated that CMF was more effective than M¨F for women with ER-negative tumors. There were, however, no significant differences in outcome between women who received 6 months of CMF and those treated with 2 months of AC. No significant advantage over that achieved from chemotherapy alone was found when tamoxifen was given with either regimen.

Findings on Tamoxifen

NSABP B-14 was initiated in 1982 to determine the effectiveness of tamoxifen in breast cancer patients with negative nodes (Fisher, Dignam, Bryant, et al., 1996; Fisher, Dignam, Bryant, et al., in press). In 1989, a report on 5 years of followup on more than 2,800 randomized patients found a significant advantage from treatment with tamoxifen. The DFS and overall survival rates persisted for more than 12 years (p=0.000005 and 0.0013, respectively). The therapy was also associated with a significant reduction in contralateral and ipsilateral breast cancer, but no additional benefit was observed from administration of tamoxifen beyond 5 years. These benefits were obtained with a relatively low incidence of side effects.

NSABP B-20, a study that involved more than 2,300 women, was aimed at testing the hypothesis that the addition of either M¨F or CMF to tamoxifen would result in a greater benefit than that which could be achieved with tamoxifen alone (Fisher, Dignam, Wolmark, et al., 1997). After 8 years, there continue to be significant disease-free survival and overall survival advantages from the use of tamoxifen plus chemotherapy (44 percent versus 77 percent, p=0.002, for DFS; and 92 percent versus 88 percent, p=0.018, for survival). The B-20 study found no subgroup of women with breast cancer who did not benefit from administration of CMF with tamoxifen.

Findings on Patients with Tumors Less Than or Equal to 1 Cm and 1.1 to 2 Cm In an attempt to resolve uncertainty about prognosis and treatment for patients with negative nodes and either ER-negative or ER-positive tumors of £1 cm, data from women in five NSABP randomized trials were analyzed collectively (Fisher, Dignam, Tan-Chiu, et al., in press). The 8-year rates of recurrence-free survival (RFS) for women with ER-negative tumors of £1 cm treated with surgery alone or with surgery plus chemotherapy were 81 percent and 90 percent, respectively (p=0.06). Survival was similar in both groups (93 percent and 91 percent, respectively; p=0.65). The RFS rates for women with tumors between 1.1 and 2.0 cm were 77 percent for surgery and 81 percent for surgery plus chemotherapy (p=0.11). Overall survival was 77 percent and 84 percent, respectively (p=0.01).

The 8-year RFS rate for women with ER-positive tumors treated with surgery alone was 86 percent, compared with 93 percent after tamoxifen (p=0.01). When both tamoxifen and chemotherapy were given, the RFS was 95 percent (p=0.07). The survival rates among women in these three treatment groups were 90 percent, 92 percent (p=0.41), and 97 percent (p=0.01), respectively. The RFS rate for women with tumors of 1.2 to 2.0 cm treated with surgery alone was 75 percent, and with tamoxifen 88 percent (p <0.001). The RFS rate was greater after chemotherapy and tamoxifen (91 percent) than after tamoxifen administration alone (p=0.003). Overall survival was 83 percent after surgery, 88 percent after tamoxifen was given (p=0.001), and 93 percent after both tamoxifen and chemotherapy (p=0.002).

Conclusion:

The prognosis for women with ER-negative or ER-positive tumors of £1 cm and negative nodes was somewhat better than the prognosis for women with tumors between 1.1 and 2.0 cm. The prognosis was not sufficiently favorable, however, to dismiss systemic therapy as a possible option for certain women with tumors of £1 cm. A cutoff point in the array of tumor sizes below 10 mm that would justify systemic therapy remains to be established.

Radiation and/or Tamoxifen after Lumpectomy for Tumors of £ 1 Cm

The first results obtained from NSABP B-06 raised the question of whether there are cohorts of women for whom radiation therapy might be replaced with tamoxifen. NSABP B-21 was conducted to address that issue. Women (n=1,009) were randomized to either tamoxifen alone, radiation plus placebo, or radiation plus tamoxifen. Recently reported results demonstrated a rate (1,000 patients per year) of local recurrence of 23.3 for women who received tamoxifen, 11.7 for those who received radiation plus placebo, and 3.4 for those who received radiation plus tamoxifen (Wolmark, Dignam, Margolese, et al., 2000).

Conclusion:

Radiation and tamoxifen administered in combination prevent local recurrence to a greater extent than does radiation alone. Tamoxifen alone is inferior to radiation in preventing recurrence.

Comment

Although almost all of the NSABP studies have demonstrated a benefit from therapy, they have all engendered controversy with regard to their clinical application. As the prognosis for both treated and untreated cohorts of breast cancer patients becomes better, therapeutic decision-making becomes more difficult. The question arises as to whether some proportion of women in a cohort can be justifiably "written off" because it has been decided that the group's prognosis is sufficiently good to negate treatment of any of them despite evidence that some of them might benefit from a therapy of demonstrated efficacy. Many women with breast cancer die each year because they have received either inadequate treatment or no treatment at all. Many others die despite having received "effective" treatment. Under these complex circumstances, it would be inappropriate to deny any woman the opportunity to receive therapy from which she might benefit.

References

Consensus conference. (No authors listed.) Adjuvant chemotherapy for breast cancer. JAMA 1985;254:3461-3.

Fisher B, Anderson S, Tan-Chiu E, et al. Tamoxifen and chemotherapy for axillary-node negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol (in press).

Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529-42.

Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen for node-negative breast cancer: updated findings. J Natl Cancer Inst (in press).

Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, et al. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 1996;14:1982-92.

Fisher B, Dignam J, Tan-Chiu E, et al. Prognosis and treatment of patients with breast tumors of £1 cm and negative axillary nodes. J Natl Cancer Inst (in press).

Fisher B, Dignam J, Wolmark N, De Cillis A, Emir B, Wickerham DL, et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997;89:1673-82.

NIH consensus conference. (No authors listed.) Treatment of early-stage breast cancer. JAMA 1991;265:391-5.

Wolmark N, Dignam J, Margolese R, et al. The role of radiotherapy and tamoxifen in the management of node-negative invasive breast cancer £1.0 cm treated with lumpectomy: preliminary results of NSABP protocol B-21. [abstract]. Proc Am Soc Clin Oncol 2000;19,271.

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