Japanese Journal of Clinical Oncology

INTRODUCTION

Breast cancer patients with metastasis-positive lymph nodes show a poorer prognosis than those with metastasis-negative lymph nodes (1). Even today, histopathological lymph node status is the most useful indicator of prognosis. The outcome of treatment for breast cancer without lymph node metastasis has reached a plateau. However, it is unclear whether the prognosis of breast cancer with lymph node metastasis has improved recently, because a variety of confounding factors may affect patient survival. The purpose of this study was to examine whether and to what extent the outcome of treatment for lymph-node positive patients actually improved between the periods 1965-75 and 1976-86 at a single institute.

PATIENTS AND METHODS

The subjects of this study were 1595 patients with breast cancer positive for lymph node metastasis, who were treated by mastectomy with or without adjuvant chemoendocrine therapy at the National Cancer Center Hospital between 1965 and 1986. Stage IV patients were also included to avoid the influence of stage migration. The mastectomy procedures included the modified and radical modes. Dissected lymph nodes (LN) were axillary LN alone in modified cases and axillary LN with or without parasternal and/or supraclavicular LN in radical cases. We classified these patients into four groups stratified by the time of initial surgery (1965-75/1976-86) and menopausal status (premenopause/postmenopause): Group I (1965-75/premenopause; 34l cases), Group II (1976-86/premenopause; 541 cases), Group III (1965-75/postmenopause; 269 cases), Group IV (1976-86/postmenopause; 444 cases). We compared Group I (GI) with Group II (GII) and also Group III (GIII) with Group IV (GIV) with regard to background factors and prognosis. All the patients were followed up for at least l0 years. A few patients were lost to follow-up; no case (0%) in GI, 18 cases (3.3%) in GII, three cases (1.1%) in GIII and 10 cases (2.2%) in GIV. With regard to the background factors, complete data were not available for every patient either because the data themselves were missing or appropriate tests had not been performed. All the data including pathological and clinical data were retrieved from the medical charts of the patients. Disease-free and overall survival curves were computed by the Kaplan-Meier method and differences between the curves were analyzed using the log rank test. Differences in background factors between the groups were tested for significance by the Student's t-test or chi-squared test. Relative risks and 95% confidence intervals(CI) for mortality of the patients were calculated for each postoperative adjuvant therapy.

RESULTS

With respect to clinicopathological background factors, there was no significant difference between GI and GII and between the GIII and GIV except for the use of postoperative adjuvant chemotherapy, endocrinetherapy and radiotherapy and changes in operation modes (Table 50 and 2). Significant changes between the periods 1965-75 and 1976-86 were more frequent use of modified radical mastectomy and postoperative adjuvant chemotherapy and/or endocrinetherapy and less frequent use of postoperative radiotherapy in both pre- and postmenopausal patients. Regimens of chemotherapy and/or endocrinetherapy of each group are shown in Table 3. The use of multiple-agent adjuvant chemotherapy, which was mostly CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or ACMF (adriamycin, cyclophosphamide, methotrexate, 5-fluorouracil) therapy, was more common in 1976-86 than in 1965-75, irrespective of menopausal status (p < 0.01). However, with regard to tumor size, there was a significant difference between GIII and GIV. For premenopausal patients, the 5- and 10-year disease-free survival rates in GI and GII improved significantly by 20.0 and 19.3%, respectively (Fig.1; p < 0.01). In GI and GII, the 5- and 10-year overall survival rates also improved significantly by 11.9 and 15.6%, respectively (Fig.2; p < 0.01). For postmenopausal patients, the 5- and 10-year disease-free survival rates in GIII and GIV improved significantly by 19.2 and 16.4%, respectively (Fig.3; p < 0.01). In GIII and GIV, the 5- and 10-year overall survival rates also improved significantly by 16.1 and 15.7%, respectively (Fig.4; p < 0.01). Therefore, there was a significant improvement in the prognosis of breast cancer patients with positive lymph nodes between the earlier period (GI and GIII; 1965-75) and the later period (GII and GIV; 1976-86), regardless of menopausal status. As shown in Table 4, adjuvant chemotherapy could contribute to the improved prognosis of node-positive patients. However, the effects of postoperative adjuvant endocrinetherapy or radiotherapy were not favorable.

Table 3. Chemoendocrine therapy regimens used as adjuvant therapies of breast cancer

	No. of patients (%)
	Group II	Group II	Group III	Group IV
Type of treatment
Multiagents	32 (33%)	286 (56%)*	26 (33%)	209 (56%)*
Single agent	65 (67%)	224 (44%)	52 (67%)	184 (46%)*
Drugs
Cyclophosphamide	12	454	16	354
Fluoropyrimidines	32	217	31	159
Mitomycin C	30	8	22	66
Methotrexate	0	155	1	118
Adriamycin	0	96	0	89
Vindesine	0	17	0	11
Tamoxifen	0	45	0	49
Others	33	61	24	43

*p < 0.01.

Table 4. Relative risks and 95% confidence intervals for mortality of node-positive breast cancer patients treated in 1965-86 stratified by postoperative adjuvant therapies

Variable	Relative risk	95% CI	p
Premenopausal
Chemotherapy (Yes/No)	0.50	0.37-0.67	p < 0.01
Endocrinetherapy (Yes/No)	2.18	1.19-2.18	p = 0.02
Radiotherapy (Yes/No)	4.05	2.99-4.05	p < 0.01
Postmenopausal
Chemotherapy (Yes/No)	0.49	0.35-0.69	p < 0.01
Endocrinetherapy (Yes/No)	0.85	0.47-2.53	NS
Radiotherapy (Yes/No)	3.79	2.57-5.60	p < 0.01

DISCUSSION

Figure 1. Disease-free survival curves for node-positive premenopausal patients stratified by the time of initial diagnosis.

Figure 2. Overall survival curves for node-positive premenopausal patients stratified by the time of initial diagnosis.

Figure 3. Disease-free survival curves for node-positive postmenopausal patients stratified by the time of initial diagnosis.

Our study confirmed that the patients with node-positive breast cancer treated at our hospital showed an improvement in both disease-free and overall survival between the periods 1965-75 and 1976-86. We believe that there is a trend toward an increase in the likelihood of cure in node-positive breast cancer patients (2,3). Changes in the patterns of surgery did not adversely affect the patients' survival (3). These data suggest that changing patterns of operation mode or postoperative radiotherapy provides no survival benefit in breast cancer patients, as many authors have reported previously (4,5). Recently, several authors have indicated that postoperative radiotherapy significantly reduces local recurrence and improves long-term survival (6,7). However, the results have been criticized with regard to the quality of surgery (8). It is likely that the effect of postmastectomy radiation can be limited to high-risk patients for local recurrence (9). Many clinical trials have suggested a causal link between adjuvant chemotherapy and/or endocrinetherapy and the improved survival of breast cancer patients (1). Our data also suggested that more frequent use of postoperative adjuvant chemotherapy, particularly multiple agent chemotherapies, could contribute to the improved survival of node-positive patients. However, the results for postoperative radiotherapy or endocrinetherapy were misleading. These confusing results were mainly attributed to the fact that the present study was not a prospective study or a case-control study, but a retrospective observational study. In addition, the postmenopausal patients in our study had smaller tumors in the later (1976-86) than in the earlier (1965-75) period. The reason for the improved survival of postmenopausal patients may depend on the tumor size. Earlier detection by mammography or other diagnostic imaging procedures may have contributed to the improved survival of patients (10). Furthermore, the prognosis of postmenopausal patients tended to be influenced by many other factors, which were not directly linked with breast cancer. These factors cannot be adjusted even by multivariate analysis. Additionally, there is a further possibility that the biological behavior of breast cancers may have changed to a less aggressive type owing to changes in lifestyle and environmental factors. It was reported that changes in lifestyle, such as excess intake of fat and calories, might be related to the increased incidence of breast cancer in Japan (11). However, up to now, there has been no clear evidence for the association between the biological behavior of breast cancer and environmental factors.

Figure 4. Overall survival curves for node-positive postmenopausal patients stratified by the time of initial diagnosis.

In conclusion, 10-year disease-free and overall survival rates of premenopausal breast cancer patients have improved by approximately 15-20% in our hospital between the periods 1965-75 and 1976-86. Although we are unable to suggest a direct reason for this improvement in prognosis, we think that combination chemotherapy greatly increases the likelihood of survival in node-positive patients.

References

1. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic or immunetherapy. 133 randomized trials involving 31 000 recurrences and 21 000 deaths among 75 000 women. Parts 1 and 2. Lancet 1992;339:1-15, 71-85.

2. Edwards MJ, Gamel JW, Feuer EJ. Improvement in the prognosis of breast cancer from 1965 to 1984. J Clin Oncol 1998;16:1030-5. MEDLINE Abstract

3. Cody HS III, Edward HL, Carols T, Jerome AU. Have changing treatment patterns affected outcome for operable breast cancer? Ann Surg 1991;213:297-307.

4. Lacour J, Le M, Hill C, Kramar A, Contesso G, Sarrazin D. Is it useful to remove internal mammary nodes in operable breast cancer? Eur J Surg Oncol 1987;13:309-14. MEDLINE Abstract

5. Meier P, Ferguson DJ, Karrison T. A controlled trial of extended radical versus radical mastectomy: ten-year results. Cancer 1989;63:188-95.

6. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-55.

7. Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956-62. MEDLINE Abstract

8. Tamer ME, Homel P, Braverman AS. Radiotherapy and chemotherapy in high-risk breast cancer. N Engl J Med 1998;338:329-33.

9. Early Breast Cancer Trialists' Collaborative Group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. N Engl J Med 1995;333:1444-55.

10. Morimoto T, Sasa M. Current status of screening for breast cancer and tasks for introduction of mammographic screening in Japan. Breast Cancer 1998;5:227-34.

11. Tominaga S, Kuroishi T. Epidemiology of breast cancer in Japan. Breast Cancer 1995;2:1-7.

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Received July 8, 1998; accepted September 9, 1998
For reprints and all correspondence: Takashi Fukutomi, Department of Surgical Oncology, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan. E-mail: tfukutom{at}gan2.ncc.go.jp

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