ADJUVANT CHEMOTHERAPY IN THE NODE-NEGATIVE BREAST CANCER PATIENT - 11/09/11
Resumen |
Adjuvant therapy in women with axillary node metastases from breast cancer is beneficial, but the role of adjuvant therapy in women with node-negative breast cancer is controversial. By definition, all clinically apparent disease can be removed surgically in patients with early breast cancer. Although the majority of patients with early breast cancer are cured with surgical therapy alone, about 30% of node-negative patients eventually die of their disease.21 Node-negative patients, with their smaller tumor burden, might be expected to benefit more from adjuvant systemic therapy to prevent recurrent disease. After surgery, various types of “systemic adjuvant” therapy may be administered, including polychemotherapy and hormonal therapy. The two most widely tested therapies are those that involve tamoxifen, an antiestrogen drug that may be taken daily for years, and a combination of cytotoxic drugs. But is it necessary to treat 100% of the node-negative patients in order to benefit the 30% of women at risk of recurrence and death? Ideal management would identify and eliminate those patients who would not benefit from adjuvant systemic therapy because of a favorable prognosis or because of resistance to therapy.
Many adjuvant chemotherapy trials have included small numbers of node-negative as well as node-positive patients. In general, it is necessary to study a much larger cohort and to obtain longer follow-up of node-negative patients than node-positive patients because these patients have a lower relapse rate and longer time to relapse than a population of node-positive patients. Many studies around the world have been designed and performed in order to determine whether or not polychemotherapy or hormonal therapy can prolong disease-free survival in patients following surgical therapy for breast cancer. Several key questions have been asked in these trials:
1 | Which patients with breast cancer will benefit from adjuvant therapy? |
2 | What are the benefits of adjuvant therapy following surgery for patients with breast cancer? |
3 | What criteria can be used to identify the patients with breast cancer who will not benefit from adjuvant therapy? |
Whereas most node-positive patients eventually die of metastasis, 70% of node-negative women are cured after local treatment alone. Although the nodal status has an effect on the natural history of breast cancer, the evidence is clear that nodal status has little effect on the proportional risk reduction of recurrence or survival produced by adjuvant therapy (tamoxifen/chemotherapy) given after surgical treatment. The benefits of systemic therapy are relative reduction in recurrence and death across all stages of disease. For example, if 60% of node-positive patients die of metastasis at 10 years, then 60% could possibly benefit from adjuvant therapy. If 70% of node-negative women are cured 10 years after local treatment and have no potential to benefit from adjuvant therapy, 30% of axillary node–negative patients may benefit from adjuvant therapy. If one assumes a sample size of 100 patients in each group and that adjuvant chemotherapy results in a 33% proportional reduction of mortality for both groups, the number of additional node-positive patients who are alive 10 years later is 20, compared with 3 in the node-negative group. The 10-year survival for the node-positive patients increases from 40% to 60%, and the 10-year survival for the node-negative patients increases from 90% to 93%. Although the absolute number of patients cured is greater for the node-positive group, the relative decrease in annual risk of death is the same for both groups. The annual death rate or hazard rate for each year of follow-up can be calculated for both of these groups, and the ratio of the hazard function for the treated and untreated control patients can be taken as an estimate of the survival benefit derived from therapy.
The benefits of adjuvant therapy following the surgical treatment of node-positive breast cancer have been confirmed in numerous studies. After a median follow-up of 20 years, Bonadonna et al 4 confirmed significantly better rates of relapse-free survival and total survival in premenopausal patients with at least one positive axillary lymph node following treatment with cytotoxic adjuvant therapy with cyclophosphamide, methotrexate, and fluorouracil. The patients randomly received either CMF for 12 cycles or no further treatment. No adjuvant endocrine therapy or postoperative irradiation was administered. Overall, the benefit was a 34% reduction in the relative risk of relapse and a 26% reduction in the relative risk of death. Chemotherapy with CMF, as given in this study, did not improve outcome significantly in postmenopausal women. The authors believe that this difference in effectiveness was probably due to the low dose of chemotherapy that many postmenopausal women received. Cancer and Leukemia Group B 26 showed that both premenopausal and postmenopausal women given regimens involving high or moderate doses of cyclophosphamide, doxorubicin, and fluorouracil had significantly better disease-free and overall survival than those given low-dose regimens.
Tamoxifen was first used as treatment for metastatic breast cancer in 1971.6 There have been numerous studies examining the effects of tamoxifen in the adjuvant setting, especially in postmenopausal women. The earliest study began in 1975 in Copenhagen.18 The NATO (Nolvadex Adjuvant Trial Organisation) 3 study is one of the largest and most mature studies, demonstrating significant improvement not only in the disease-free survival but also in overall survival. The study included node-positive premenopausal women and both node-positive and node-negative postmenopausal women. A large proportion (60%) of the women were node negative. The Scottish Trial of Adjuvant Tamoxifen 25 of 1312 women confirmed that systemic treatment with tamoxifen for 5 years significantly increased relapse-free survival and total survival in premenopausal and postmenopausal, node-positive, estrogen receptor–positive breast cancer patients. When the node-negative group was broken out separately, there were too few events to achieve statistical significance.
Adjuvant therapy with cytotoxic therapy improves disease-free survival and overall survival in women with axillary node–positive breast cancer, and tamoxifen improves disease-free survival and overall survival in studies that include node-negative and node-positive patients. Is there a benefit from adjuvant therapy for women with axillary node–negative breast cancer? The natural history of node-negative and node-positive patients with breast cancer differs. The natural history of node-negative breast cancer involves both a lower likelihood of disease recurrence than in node-positive patients and a longer time until treatment failure does occur. But the survival of women with stage I disease is not optimal. Survival has been estimated to be approximately 85% for 5 years and 75% for 10 years. Nissen-Meyer et al 16 performed one of the early randomized breast cancer adjuvant therapy trials in 1965. Cyclophosphamide was given intravenously for 6 consecutive days beginning on the day of mastectomy to 507 patients who had undergone mastectomy, while 519 randomized control subjects underwent surgery alone. Most patients received chest-wall radiation therapy. At 20 years, the relapse-free survival was 52% in the treatment group and 39.5% in the control group. The crude survival was only marginally different. The benefit extended to both premenopausal and postmenopausal patients and was independent of axillary node status. A randomized adjuvant breast cancer trial (OSAKO) was initiated in 1974 in eastern Switzerland, when virtually no additional prognostic factors other than axillary nodal status were available. Patients received LMF (Leukeran [chlorambucil], methotrexate, and fluorouracil) followed by bacille Calmette-Guérin (BCG). This protocol with oral chemotherapy plus BCG immunotherapy was the first study to demonstrate a significant increase in survival in node-negative breast cancer patients, 22, 23 but it was largely ignored. Overall survival was 61% for the control group and 79% for the treated group. This study did not significantly change the adjuvant management of node-negative breast cancer. Possible explanations for the apparent disregard of the OSAKO study may be the inclusion of immunotherapy in the treatment arm. In addition, many may have thought that OSAKO referred to a study of Japanese women (rather than eastern Swiss) and did not relate the results of the study to “western” breast cancer. The adjuvant trial of CMF in node-negative women by Bonadonna and colleagues from Milan showed dramatic benefit and focused attention on the adjuvant therapy of these patients. The benefits of adjuvant cytotoxic therapy for patients with axillary node–negative breast cancer have also been confirmed by Intergroup, the National Surgical Adjuvant Breast and Colon Project (NSABP), and the International Breast Cancer Study Group (IBCSG).9, 11, 13 Notably, in the Intergroup study, the disease-free survival of the treated or high-risk group exceeded the disease-free survival not only of the matched untreated control group but also of the “too favorable to be treated” group. Postoperative women with breast cancer but without histopathologic evidence of metastases to the axillary lymph nodes or clinical metastases were studied. A group of 655 “good-risk” patients who were estrogen receptor–positive (ER+) with primary tumors less than 3 cm were registered for observation. The 5-year disease-free survival among patients with ER+ tumors greater than 3 cm who had received chemotherapy was 86%, compared with 78% in the registered good risk patients. Based on these studies, cytotoxic therapy does appear to provide a distinct benefit to selected women with axillary node–negative breast cancer. The role of tamoxifen in axillary node–negative, estrogen receptor–positive breast cancer has proven beneficial in combined studies of node-positive and node-negative breast cancer. The NSABP B-14 trial randomized 2644 premenopausal and postmenopausal women who were node negative and ER+ to either tamoxifen or placebo for 5 years. There was a significant difference in disease-free survival and overall survival for the tamoxifen-treated group. Tamoxifen was shown to decrease rates of ipsilateral and contralateral breast recurrence, as well as rates of distant recurrence.8
Node-negative breast cancer patients do benefit from adjuvant therapy with tamoxifen and cytotoxic therapy in randomized trials. Although these data prompted the National Cancer Institute's clinical alert of May 18, 1988, there was skepticism about such a significant change in the adjuvant therapy of node-negative breast cancer. Were there numerous unpublished negative studies that could correct a publication bias? Was the benefit exaggerated for the node-negative patients who received adjuvant therapy? Some of these issues led the Early Breast Cancer Trialist Group (EBCTG) to analyze all data regarding systemic therapy of axillary node–negative breast cancer.
In a worldwide collaboration, the EBCTG reviewed information on mortality and recurrence for women in any published or unpublished randomized trial that began before 1985 with any aspect of systemic adjuvant therapy for early breast cancer. This worldwide collaboration between the EBCTG provides the largest amount of properly randomized evidence ever brought together for the review of the effects of any form of cancer therapy on long-term outcome. Data could be verified on 75,000 women. Approximately 30,000 women participated in tamoxifen trials, 3,000 women in an ovarian ablation trial, 11,000 in polychemotherapy trials, 15,000 in other chemotherapy comparisons, and 6,000 in immunotherapy trials. There were highly significant reductions in the annual rates of both recurrence and of death in most women treated with tamoxifen or polychemotherapy. The effect with tamoxifen was greater in women older than 50 and with polychemotherapy younger than 50. Ovarian ablation produced a relative reduction in risk of the same order of magnitude as polychemotherapy in women younger than 50 but had no benefit in those older than 50. Immunotherapy produced no net effect. (Tamoxifen also reduced the risk of development of contralateral breast cancer by 39%.) For tamoxifen and for polychemotherapy, recurrence is reduced chiefly during years 0 to 4, but the decrease in mortality is highly significant both during and after years 0 to 4. Cumulative differences in survival produced by these two treatments (median 2 years tamoxifen, 1 year polychemotherapy) are larger at 10 and 5 years. We have little information beyond 10 years (except for ovarian ablation). Both direct and indirect randomized comparisons show long-term polychemotherapy (12 months) to be no better than shorter (6 months) regimens. They do show polychemotherapy to be significantly better than single-agent chemotherapy. Indirect randomized comparison shows that long-term tamoxifen (2 years or even 5 years) is significantly more effective than shorter tamoxifen regimens (1 year). The benefit of adjuvant therapy varies with age and estrogen receptor status in the data reviewed by the EBCTG. In patients less than 50 years (premenopausal), polychemotherapy caused a 25% relative rate reduction, oophorectomy 25%, and tamoxifen 12%. In patients over 50 years (postmenopausal), polychemotherapy caused 12% relative rate reduction, oophorectomy none, and tamoxifen 25%. In some of the individual trials that were included in the review, relative reductions were as high as 35% or as low as 5% to 10%.
These results presented by the EBCTG 7 represent the largest amount of randomized evidence ever brought together for review of the effects of any forms of cancer therapy on long-term outcome. They effectively assess the significant effects of polychemotherapy and endocrine therapy on 10-year outcome. For recurrence, the evidence is clear that nodal status has little effect on the proportional risk reduction produced by tamoxifen or by polychemotherapy; both of which are highly significant, even for node-negative patients. The personal risk reduction appears to be true for mortality as well (Figure 1, Figure 2, Figure 3). Evidence that tamoxifen, like Premarin, can increase the risk of endometrial cancer has raised concerns about its use and evaluation of patients receiving tamoxifen. The benefits of adjuvant tamoxifen for patients with node-negative breast cancer so far outweigh the increase in endometrial cancer that no case can be made for its omission. For women receiving tamoxifen, no suggestion of benefit has been shown for any monitoring beyond annual routine gynecologic examination with evaluation of uterine size. Patients are instructed to report any vaginal bleeding at once. Because the absolute and relative risks of recurrence and death can be modified by the addition of adjuvant systemic therapy to the surgical treatment of axillary node–negative breast cancer, it is imperative to identify those patients with node-negative breast cancer who are at greatest risk for early recurrence, with the most potential to benefit from adjuvant treatment. Once axillary nodal status has been eliminated as the primary prognostic factor, secondary prognostic factors become essential to identify those patients at greatest risk for recurrence.
Several of the published studies for adjuvant therapy and early breast cancer have demonstrated a decreased recurrence and improved survival in response to chemotherapy for stage I patients with estrogen receptor–negative tumor and a similar response from tamoxifen for those patients with receptor-positive tumors. In addition to these two patterns of response, more sensitive indicators are necessary in order to identify those patients with stage I disease with a high risk for relapse. This need has prompted a surfeit of prognostic factor studies. Unfortunately, a considerable portion of the data regarding prognostic factors is derived from relatively small retrospective studies, and many factors have not been tested in rigorous multivariate analysis. Yet, despite the limited data on the predictive value of secondary prognostic factors, treatment decisions based on these data must be made on thousands of axillary node–negative breast cancer patients each month. The need to analyze and utilize these data for decision-making prompted the National Institutes of Health Consensus Development Conference to ask how prognostic factors should be used in the management of axillary node–negative breast cancer. Secondary prognostic factors include tumor size, histologic grading and subtype, ER and PR expression, oncogene expression, DNA, and S-phase measurement.
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Vol 76 - N° 2
P. 327-341 - avril 1996 Regresar al número
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- CONTROVERSY IN BREAST RECONSTRUCTION
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