The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial

doi:10.1016/S0959-8049(99)00133-1

European Journal of Cancer

Volume 35, Issue 9, September 1999, Pages 1320-1325

https://doi.org/10.1016/S0959-8049(99)00133-1 Get rights and content

Abstract

The lymph nodes of the internal mammary chain represent a primary station draining the lymph from the breast and their removal or their irradiation has been considered an important step in breast cancer treatment. From January 1964 to January 1968, 737 patients with breast cancer were randomised at the National Cancer Institute in Milan to undergo either Halsted mastectomy or extended mastectomy with internal mammary node dissection. Patients with non-disseminated carcinoma classified as T1, T2, T3, N0, N1 were eligible for the study. No patients received postoperative radiotherapy or systemic therapy. After 30 years of follow-up, the overall survival curves and the specific survival curves do not show any difference between the patients of the two groups. Among the 558 patients who died in the 30 year interval period, 395 (71%) died from breast carcinoma (201 in the Halsted group and 194 in the extended mastectomy group) and 163 from other causes. This study shows that the removal of internal mammary nodes does not improve the survival of patients treated for breast carcinoma. This finding supports the theory that treatment of regional nodes does not influence the survival of cancer patients. The prognostic value of internal mammary node status is, however, high and a biopsy on a selected lymph node should be considered for staging purposes.

Introduction

Since the first attempts to treat breast cancer surgically a century ago, dissection of axillary nodes was always included in the surgical procedure 1, 2 whilst for many decades the internal mammary lymph nodes were ignored. It was only in the 1950s that the removal of internal mammary nodes interested a few surgeons becoming a not uncommon treatment in some centres with results that seemed to improve survival compared with the classic Halsted mastectomy [3]. To evaluate correctly the possible role of the dissection of the internal mammary nodes, an international randomised trial was started in 1963 and the preliminary results, published in 1976, showed no survival advantages in removing the internal mammary nodes [4]. The data obtained from the patients randomised at the Milan Cancer Institute were separately published in 1981 [5]. The issue of treatment of internal mammary nodes has, however, remained a matter of controversy especially with regard to the indication for radiotherapy and we consider it useful to report the long-term results of the Milan randomised trial conducted in the years 1964–1968 which compared patients treated by ‘Halsted mastectomy' with patients treated by the same operation plus removal of the internal mammary nodes.

Section snippets

Patients and methods

From January 1964 to January 1968, 737 patients with breast cancer were randomised to undergo either conventional Halsted mastectomy or extended radical mastectomy (i.e. with internal mammary nodes dissection); 716 were considered evaluable. As previously reported, this series was part of an international cooperative trial whose results were published in 1976. Patients with non-disseminated breast cancer classified as T₁, T₂, T_3a, N₀, or N₁ were eligible for the study.

The classical Halsted

Statistical methods

Main patient and tumour characteristics were described separately for the Halsted and extended radical mastectomy trial options by means of contingency tables.

The primary outcome considered was death from any cause. However, the long follow-up duration for many patients implied the occurrence of a sizeable number of deaths unrelated to breast cancer. Therefore, we also restricted the analysis to breast cancer-specific death, as ascertained during follow-up or by search for death certificates,

Results

Involvement of internal mammary nodes was recorded in approximately 20.5% (70/342) of the women who underwent extended mastectomy.

Patient observation time varied from 4–398 (median: 126) months. Table 2 reports the number of first neoplastic events and deaths observed during follow-up. The cause of death was breast cancer for 395 (71%) of the 558 women who died.

Discussion

The present analysis shows no difference in overall and specific survival in patients treated with Halsted radical mastectomy and in patients treated with the same operation plus dissection of internal mammary nodes. The type of operation employed in this trial was a radical one with complete dissection of the internal mammary node chain from the first to the fourth intercostal space, leaving no doubt about the fact that removing or not removing these nodes does not affect the prognosis.

The

References (24)

W.S Halsted
The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889 to January, 1894
Johns Hopkins Hosp. Bull.
(1895)
D.H Patey et al.
The prognosis of carcinoma of the breast in relation to the type of operation performed
Br. J. Cancer
(1948)
J.A Urban et al.
Significance of internal mammary lymph node metastases in breast cancer
Am. J. Roentgenol. Radium. Ther. Nucl. Med.
(1971)
J Lacour et al.
Radical mastectomy versus radical mastectomy plus internal mammary dissectionfive-year results of an international cooperative study
Cancer
(1976)
U Veronesi et al.
Inefficacy of internal mammary nodes dissection in breast cancer surgery
Cancer
(1981)
E.L Kaplan et al.
Non parametric estimation from incomplete observations
J. Am. Stat. Assoc.
(1958)
D.R Cox
Regression models and life tables
J. Royal Stat. Soc., series B
(1972)
S Durrleman et al.
Flexible regression models with cubic splines
Stat. Med.
(1989)
D.J Spiegelhalter et al.
Bayesian approaches to randomized trials
J. R Statist. Soc. A
(1994)
Harrell FE. Predicting Outcomes: Applied Survival Analysis and Logistic Regression. Uva Bookstore c/o Janice Johnson,...

U Veronesi et al.

Risk of internal mammary lymph-node metastases and its relevance on prognosis of breast cancer patients

Ann. Surg.

(1983)

U Veronesi et al.

Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes

Ann. Surg.

(1985)

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Original PaperThe dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial

Abstract

Introduction

Section snippets

Patients and methods

Statistical methods

Results

Discussion

The results of operations for the cure of cancer of the breast performed at the Johns Hopkins Hospital from June, 1889 to January, 1894

Johns Hopkins Hosp. Bull.

The prognosis of carcinoma of the breast in relation to the type of operation performed

Br. J. Cancer

Significance of internal mammary lymph node metastases in breast cancer

Am. J. Roentgenol. Radium. Ther. Nucl. Med.

Radical mastectomy versus radical mastectomy plus internal mammary dissectionfive-year results of an international cooperative study

Cancer

Inefficacy of internal mammary nodes dissection in breast cancer surgery

Cancer

Non parametric estimation from incomplete observations

J. Am. Stat. Assoc.

Regression models and life tables

J. Royal Stat. Soc., series B

Flexible regression models with cubic splines

Stat. Med.

Bayesian approaches to randomized trials

J. R Statist. Soc. A

Risk of internal mammary lymph-node metastases and its relevance on prognosis of breast cancer patients

Ann. Surg.

Prognosis of breast cancer patients after mastectomy and dissection of internal mammary nodes

Ann. Surg.

Original Paper
The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial