Clinical Investigation
Influence of Lymphatic Invasion on Locoregional Recurrence Following Mastectomy: Indication for Postmastectomy Radiotherapy for Breast Cancer Patients With One to Three Positive Nodes

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Purpose

The indication for postmastectomy radiotherapy (PMRT) in breast cancer patients with one to three positive lymph nodes has been in discussion. The purpose of this study was to identify patient groups for whom PMRT may be indicated, focusing on varied locoregional recurrence rates depending on lymphatic invasion (ly) status.

Methods and Materials

Retrospective analysis of 1,994 node-positive patients who had undergone mastectomy without postoperative radiotherapy between January 1990 and December 2000 at our hospital was performed. Patient groups for whom PMRT should be indicated were assessed using statistical tests based on the relationship between locoregional recurrence rate and ly status.

Results

Multivariate analysis showed that the ly status affected the locoregional recurrence rate to as great a degree as the number of positive lymph nodes (p < 0.001). Especially for patients with one to three positive nodes, extensive ly was a more significant factor than stage T3 in the TNM staging system for locoregional recurrence (p < 0.001 vs. p = 0.295).

Conclusion

Among postmastectomy patients with one to three positive lymph nodes, patients with extensive ly seem to require local therapy regimens similar to those used for patients with four or more positive nodes and also seem to require consideration of the use of PMRT.

Introduction

In many cases in the 1960s, postmastectomy radiotherapy (PMRT) was delivered mainly to regional lymph nodes, not the chest wall (1). This procedure reduced locoregional recurrence rates (LRR) but did not contribute to improvement of survival rates of patients. It gradually came to be shown thereafter that addition of chest wall irradiation resulted in better treatment outcomes including survival rates.

In and after 1997, large-scale clinical trials began to reveal the fact that in primary breast cancer patients with positive lymph nodes, PMRT, as provided in current clinical practice, not only reduced locoregional recurrences but also improved overall survival 2, 3, 4, 5, 6, 7, 8. Recently issued clinical practice guidelines, including those of the American Society of Clinical Oncology (9), the National Comprehensive Cancer Network (10), and the Japanese Breast Cancer Society, recommend PMRT for cases of primary breast cancer with four or more positive axillary lymph nodes. Then, questions arise as to whether PMRT is needed for such cases with one to three positive nodes, and if it is, for what patient subgroups. Those questions remain unanswered 11, 12, 13, 14.

In the present study, we focused on lymphatic invasion (ly), which is regarded as an independent prognostic factor in cases of negative lymph nodes (15). The term ly reflects migration of intralymphatic tumor cells into regional lymph nodes; we considered the possibility of lymphatic obstruction being caused by tumor cells in cases of extensively.

Depending on ly status, LRR for patients with one to three positive nodes may be comparable to those of patients with four or more positive nodes. On the other hand, depending on ly status, LRR may be low even in the presence of four or more positive nodes. Following the hypothesis that PMRT targets and eradicates or decreases residual tumor cells in regional lymphatics, it is deemed critical to consider the indication for PMRT based on LRR.

The purpose of the present study was, focusing on the ly factor, to identify postmastectomy patient subgroups with one to three positive lymph nodes for whom PMRT might be indicated.

Section snippets

Methods and Materials

Retrospective analysis of 1,994 patients with histologically tumor-positive lymph nodes, including micrometastases but not isolated tumor cells, who had undergone mastectomy without postoperative radiotherapy between January 1990 and December 2000 at our hospital was performed; at that time, PMRT was performed on a limited basis to high-risk patients with 10 or more positive nodes because it was thought that the LRR of postmastectomy patients was low. Clinical data including age, T stage,

Results

The median follow-up period for the 1,994 patients was 112 months, with locoregional recurrence in 306 (15.3%) patients. Larger tumor size, more extensive ly, and greater number of positive lymph nodes were associated with higher LRRs, with LRR surpassing 30% in patients with ly++ or 10 or more positive nodes. Univariate analysis revealed that T stage, ly status, and number of positive nodes were particularly strong risk factors (p < 0.001) (Table 1). Although significant difference was

Discussion

The utility of PMRT has been established, including evidence of the Danish clinical trial in 1997 (2) and meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group in 2005 (7). In the United States and Europe, the value of PMRT is a time-proven treatment. In Japan, postoperative irradiation tended to remain uncommon for some time, in response to very low LRRs reported in the US 12, 18. In the 1990s at our hospital, PMRT was not a standard therapy; therefore, we had a number of

Conclusions

Postmastectomy patients with one to three positive lymph nodes showed a particularly high LRR in the presence of extensive ly. This subgroup seems to require local therapy regimens similar to those for patients with four or more positive nodes and should be considered for the indication of PMRT. In postmastectomy patients with one to three positive lymph nodes, because the risk of locoregional recurrence is low even if it is T3, not ly++, PMRT could be considered negatively.

Acknowledgment

The authors thank Drs. Yoshinori. Ito, S. Takahashi, N. Tokudome, R. Yoshida, A. Kuwayama, N. Uehiro, K. Masumura, K. Inoue, Yuko Ito, R. Hashimoto, I. Fukada, Y. Chihara, M. Higa, Y. Fukami, H. Shima, H. Sai, A. Okada, R. Yonekura, and R. Gokan from the Breast Oncology Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research for their valuable comments and support.

References (20)

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