2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer

Who Should Not Receive Chemotherapy?
U.S. Databases and Trials

Monica Morrow, M.D.

Breast cancer patients in whom chemotherapy could be avoided include (1) those with an extremely favorable prognosis who are unlikely to experience any meaningful prolongation of survival from a treatment that is potentially both toxic and costly, (2) those in whom clear evidence of benefit from chemotherapy is lacking, and (3) patients in whom the toxicity of chemotherapy outweighs the benefits.

Favorable Prognosis Groups

Subsets of node-negative breast cancer patients with a favorable prognosis have usually been defined on the basis of tumor size or histologic subtype. Several large studies indicate that patients with tumors less than or equal to 1 cm in size have survival rates in excess of 90 percent. In the Breast Cancer Detection Demonstration Project (BCDDP), stage I cancers had an 8-year survival of 90 percent, and for those less than 1 cm in size, survival was 95 percent (Seidman, Gelb, Silverberg, et al., 1987). These figures are similar to data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute from the same time period, where 8-year survival for stage I carcinoma (n=5,479) was 92 percent (Carter, Allen, Henson, 1989). In the BCDDP group of tumors less than 1 cm in size, survival was 96 percent for screen-detected tumors and 94 percent for interval cancers. In both BCDDP and SEER, survival rates greater than 90 percent were reported for women both under and over age 50. In a subsequent SEER report, 5-year survival was 99.2 percent for 269 tumors less than 0.5 cm and 98.3 percent for the 791 tumors between 0.5 and 0.9 cm in size (Henson, Ries, Freedman, et al., 1991). In NSABP B-21, a study of invasive carcinomas less than or equal to 1 cm with negative axillary nodes, 5-year survival was 97 percent for the 1,009 patients under study, regardless of treatment (radiotherapy, radiotherapy plus tamoxifen, tamoxifen). A subset of patients with node-negative tumors less than 1 cm with a poor prognosis has not been identified. The National Cancer Data Base (NCDB) reported a 5-year survival of 98.4 percent for 22,288 patients with tumors less than 1 cm diagnosed between 1985 and 1991. For the subset of patients with tumor grade, survival ranged from 98.6 percent for grade 1 tumors to 96.0 percent for grade 3 tumors.

The addition of histologic grade and histologic tumor type to size allows expansion of the pool of favorable patients who will receive minimal benefit from chemotherapy. A SEER report combining stage and grade found a 95 percent 5-year survival for grade 1, stage I patients versus 83 percent for grade 3, stage I patients. Rosen, Groshen, Kinne, et al. (1993) observed that 20- year disease-free survival for patients with breast cancer of special histologic types (tubular, mucinous, papillary, medullary, adenocystic) up to 3 cm in diameter was 87 percent. Although the favorable prognosis for medullary carcinoma is not confirmed in all reports, a literature review of 300 node-negative tubular cancers of all sizes (the majority with long-term followup) identified only four relapses (1.3 percent). Failure to recognize the prognostic value of grade and histologic type assumes particular importance as the use of screening mammography continues to increase. There is a clear relationship between small tumor size and low histologic grade, and favorable subtypes such as tubular carcinoma are identified more frequently in screened populations, putting an increasing number of women with breast cancer at risk for overtreatment

Lack of Clear Evidence of Benefit/Toxicity

The NSABP B-20 trial compared the use of tamoxifen alone to tamoxifen plus chemotherapy in estrogen receptor (ER)-positive breast cancer (Fisher, Dignam, Wolmark, et al., 1997). After 5 years, a 4 percent to 5 percent improvement in disease-free survival was seen with the addition of chemotherapy, and subset analysis failed to identify a subset of patients who did not benefit from the addition of chemotherapy. However, a detailed analysis of prognosis for the 4,000 node-negative, ER-positive patients who participated in NSABP B-14 found marked heterogeneity in the ER-positive patient population (Bryant, Fisher, Gunduz, et al., 1998). For the most favorable subset of patients (1 cm tumor, ER-positive, low S-phase), 10-year disease-free survival was 85 percent. For this group of patients, the addition of chemotherapy with a 30 percent reduction in events would result in an absolute disease-free survival benefit of only 3 percent to 4 percent at 5 years. For patients age 60 to 70, an increased hazard of death was noted compared to those in their 50s. However, after correction for second primary cancers and deaths due to other causes, the rate of treatment failure was constant for women over age 50. In the age 60 to 70 group, the absolute benefit of chemotherapy should be assessed in the context of the patient's overall health status and risk of death from other causes.

For patients age 70 and older with ER-negative cancers, evidence of a survival benefit from adjuvant chemotherapy is less clear. The Oxford overview showed no improvement in relapse-free or overall survival after chemotherapy in this group, but only 600 women over age 70 were available for analysis. Diab, Elledge, Clark (1999) examined the outcome of 401 patients age 75 and older who received no adjuvant therapy. Five-year overall survival for the node-negative patients was 70 percent, compared to 69 percent for the general population matched for age and sex. Desch and colleagues used a Markov model to estimate the benefit of chemotherapy in ER-negative patients with stage I breast cancer (Desch, Hillner, Smith, et al., 1993). The gain in life expectancy for a 75-year-old was 2.9 months, which fell to 1.8 months after adjustment for quality of life. For the entire group of women age 60 to 80, the average survival benefit never exceeded the duration of chemotherapy.

Based on the preceding information, chemotherapy does not appear to be warranted in (1) any subset of women with node-negative breast cancers less than 1 cm in size; (2) women with node-negative, special histologic subtypes of cancer up to 3 cm in size; (3) grade 1, stage I breast cancers; (4) ER-positive, node-negative patients in favorable prognostic groups; and (5) node-negative, ER-negative patients over age 70.

References

Bryant J, Fisher B, Gunduz N, Costantino JP, Emir B. S-phase fraction combined with other patient and tumor characteristics for the prognosis of node-negative, estrogen-receptor-positive breast cancer. Breast Cancer Res Treat 1998;51:239-53.

Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status and survival in 24,740 breast cancer cases. Cancer 1989;63:181-7.

Desch CE, Hillner BE, Smith TJ, Retchin SM. Should the elderly receive chemotherapy for node-negative breast cancer? A cost-effectiveness analysis examining total and active life-expectancy outcomes. J Clin Oncol 1993;11:777-82.

Diab SG, Elledge RM, Clark GM. Favorable biological characteristics and clinical outcome in elderly patients with invasive ductal carcinoma (IDC) of the breast. [abstract]. Proc Am Soc Clin Oncol 1999;18:70a.

Fisher B, Dignam J, Wolmark N, DeCillis 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.

Henson DE, Ries L, Freedman LS, Carriaga M. Relationship between outcome, stage of disease, and histologic grade for 22,616 cases of breast cancer. The basis for a prognostic index. Cancer 1991;68:2142-9.

Rosen PP, Groshen S, Kinne DW, Norton L. Factors influencing prognosis in node-negative breast carcinoma: analysis of 767 T1N0M0/T2N0M0 patients with long-term follow-up. J Clin Oncol 1993;11:2090-100.

Seidman H, Gelb SK, Silverberg E, La Verda N, Lubera JA. Survival experience in the Breast Cancer Detection Demonstration Project. CA Cancer J Clin 1987;37:258-90.

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