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Mounting Evidence for Postmastectomy Locoregional Radiation Therapy

Mounting Evidence for Postmastectomy Locoregional Radiation Therapy

ABSTRACT: Postmastectomy locoregional radiation therapy markedly reduces the risk of locoregional recurrence. Several randomized trials, including two recently updated studies with 10- to 15-year follow-up, demonstrate an improvement in overall survival with radiation therapy. This improvement is seen in patients with one to three positive axillary lymph nodes, as well those with four positive nodes. Therefore, postmastectomy radiation therapy should be considered in all patients with node-positive breast cancer. Computed tomography (CT)–based treatment planning is recommended to minimize the cardiopulmonary morbidity of radiation therapy. [ONCOLOGY 13(8):1123-1135, 1999]

Introduction

Breast cancer is the most commonly diagnosed
malignancy in women in the United States, accounting for an estimated
176,000 new cases in 1999. Most women present without evidence of
distant metastases, and, thus, selection of optimal locoregional
treatment is important.

Numerous randomized clinical trials involving several thousand women
have demonstrated that breast-conserving therapy with wide excision
of the primary tumor and breast irradiation provides long-term
survival rates equivalent to those achievable with mastectomy.[1,2]
The National Cancer Institute 1995 consensus statement endorsed
breast-conserving therapy as appropriate and preferable treatment in
most patients with early-stage breast cancer.[3] Nevertheless, most
US women with early breast cancer continue to undergo a mastectomy,
apparently due to a combination of patient and physician preferences,
as well as logistical and access issues.[4]

Among patients who have a mastectomy, the role of postoperative
locoregional radiation therapy to the chest wall and draining
lymphatics has been very controversial. While numerous studies
demonstrate that locoregional radiation improves locoregional
control, the data regarding its effects on overall survival are
conflicting. Some trials suggest an improvement in overall
survival,[5-14] while others do not.[2,15-19]

Some of the conflicting results stem from the fact that certain
radiation therapy techniques can increase the risk of cardiac
disease.[16,18-22] Thus, some of the radiation-induced reduction in
death from breast cancer is negated by an increase in
radiation-induced cardiac deaths.[16,22]

Two trials recently updated in The New England Journal of Medicine
reported improvements in overall survival with locoregional radiation
therapy and have renewed enthusiasm for this approach.[8,11] This
article reviews the rationale for locoregional radiation therapy and
discusses the results of these two trials, as well their implications
for our understanding and treatment of breast cancer.

Rationale for Locoregional Radiation

Locoregional Control

Mastectomy and axillary dissection (usually levels 1 and 2) does not
remove all locoregional disease in all patients. The probability of
the surgeon not removing all microscopic cancer may be gauged
approximately by the rate of locoregional relapse following
mastectomy and is strongly related to the degree of axillary nodal
involvement.[8,11,23-28] Recurrences in the chest wall or regional
nodal sites (axillary apex, supraclavicular nodes, and, less
frequently, internal mammary nodes) occur in approximately 5% to 10%
of women with negative axillary nodes but increase steeply with the
degree of nodal involvement (Figure 1).
The data in Figure 1 are compiled
from multiple studies published over several decades that used
different methods to segregate patients and calculate the
locoregional relapse rate. Despite these limitations, an increasing
risk of locoregional recurrence is consistently related to the degree
of axillary involvement.

Figure 2 illustrates the results
from several randomized clinical trials that documented the
locoregional failure rates without (x-axis) and with (y-axis)
locoregional radiation therapy.[5,8,11,12,29-33] These data are
fairly well approximated by the line y = 1/3 x, suggesting that the
addition of radiation therapy reduces the locoregional relapse rate
by approximately 67%.

Since the absolute risk of locoregional relapse is highest in
patients with multiple positive nodes (Figure
1
), it has often been recommended that patients receive
locoregional radiation therapy to reduce locoregional recurrence if
they have four or more positive axillary nodes.[2,25] This may be a
logical approach with respect to locoregional recurrence but not with
respect to survival.[34]

Survival

If patients have residual regional disease after mastectomy,
locoregional radiation therapy can increase the cure rate only if no
subclinical distant metastases are present (or if present, if they
can be sterilized by systemic chemotherapy). The conventional wisdom
of the last few decades has been that breast cancer is a systemic
disease, that involvement of regional nodes is a sign of distant
spread, and, hence, that treatment of locoregional sites will not
affect survival.

These assumptions clearly are not borne out by the data.
Node-positive breast cancer is not always a systemic disease. A
significant fraction of patients are cured with local therapy alone,
without systemic therapy. As summarized in
Figure 3
, 30-year data from Memorial Sloan-Kettering Cancer
Center show that a fraction of patients with small or large cancers
and with negative or multiply-positive axillary lymph nodes can be
cured without systemic therapy.[35]

Similar data from Milan are shown in Figure
4
. Disease-free and overall survival rates at 10 years are ~ 20%
to 50% in patients with involved axillary and/or internal mammary
lymph nodes, without systemic therapy.[36]

Much of the focus of breast cancer research over the last few decades
has been on systemic therapy, leading to a general belief that local
treatment is relatively unimportant. This assertion was supported by
several studies in early-stage breast cancer showing that lumpectomy
plus breast irradiation resulted in a much improved breast control
rate than did lumpectomy alone, without marked differences in
survival.[1-3,37] Thus, large differences in breast recurrence rates
were not readily translated into differences in survival.

However, a recent meta-analysis comparing breast-conserving therapy
(lumpectomy plus radiation) with mastectomy suggested that breast
conservation (in many respects a more aggressive local therapy than
mastectomy) provided a superior survival rate, particularly in
node-positive patients.[38] The data suggest that breast cancer is
not always a systemic disease, even when regional nodes are involved,
and that more aggressive local therapy may improve survival.

Recent Trials

Danish Breast Cancer Cooperative Group Trial

Overgaard et al recently published the 10-year update of a trial of
1,473 premenopausal women randomized, following mastectomy, to
receive CMF (cyclophosphamide, methotrexate, and fluorouracil) with
or without locoregional radiation therapy.[8] All enrolled patients
had either positive axillary nodes (90%) and/or a ³
T3 tumor (15%).

The 10-year actuarial survival rate was 54% in the irradiated
patients vs 45% in those treated with mastectomy plus CMF alone (P =
.001; Figure 5). The magnitude of
the survival benefit was 12% in patients with T3, N0 disease, 8% in
those with one to three positive axillary nodes, and 12% in those
with four or more positive nodes (Table 1).

The irradiation technique included tangential treatment of the
ipsilateral chest wall and internal mammary nodes, as well as a
separate supraclavicular and axillary field. The radiation dose was
50 Gy in 5 weeks. The extent of the axillary surgery done in this
study was less than is typically performed in the United States, with
a median number of recovered nodes of seven.

British Columbia Trial

Ragaz et al reported 15-year results of 318 premenopausal women
randomized to receive CMF with or without locoregional radiation.[11]
The 15-year actuarial survival rate was 54% in the irradiated
patients vs 46% in those treated with mastectomy plus CMF (P = .07; Figure
6
). Only patients with positive nodes were included in this
study. (Unlike the Danish trial, the British Columbia trial excluded
patients with T3, N0 disease.)

Precise data on subsets of patients were not provided. However, the
authors noted that the magnitude of the relative benefit was similar
in the different subgroups. Subgroup analysis relating to the end
point of metastasis-free survival is shown in
Table 1
; the magnitude of benefit was the same in patients with
one to three positive axillary nodes as in those with four or more
positive nodes.

The extent of axillary dissection done in this study (median of 11
nodes recovered) was comparable to that performed in the United
States. The radiation technique was similar to that used in the study
conducted by Overgaard et al, although the fractionation scheme was
somewhat unusual (37.5 Gy in 3 to 4 weeks).

While the recent presentation of these two studies in The New
England Journal of Medicine
has renewed enthusiasm for
postmastectomy radiation, this really is not totally new information.
Early results from the study of

Overgaard et al were published in 1990 in The International
Journal of Radiation Oncology Biology and Physics
,[7] and the
study of Ragaz et al was presented twice at American Society of
Clinical Oncology annual meetings in 1993 and 1996.[9,10]

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