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Postmastectomy Radiation: Then and Now

Postmastectomy Radiation: Then and Now

ABSTRACT: With the increased use of doxorubicin-based chemotherapy, chemoendocrine therapy, and high-dose chemotherapy with autologous bone marrow transplantation or peripheral blood progenitor-cell reinfusion, the role of postmastectomy radiation in the treatment of stages II-III breast cancer has been challenged. Despite these therapies, 20% to 30% of patients with four or more positive nodes, primary tumor size 5 cm , or more or pectoral fascia involvement will develop an isolated locoregional recurrence. Postmastectomy radiation decreases the incidence of locoregional recurrence to 10% or less in these high-risk patients, and modifications in technique can minimize long-term cardiac mortality. A recent meta-analysis has demonstrated a decrease in breast cancer mortality of approximately 10% with postmastectomy radiation, which is similar to the effect of adjuvant systemic therapy in axillary node-positive patients. Future studies are needed to further define the subset of patients who will benefit from postmastectomy radiation and to more precisely quantitate this benefit. [ONCOLOGY 11(2):213-237, 1997]

Introduction

The rationale for postmastectomy adjuvant radiation is the prevention
of recurrent disease in the chest wall and regional nodes following surgery.
Theoretically, clinically occult disease at the operative site or in regional
nodes could serve as a source for the development of distant metastases.
Therefore, eradication of this disease may have the potential for decreasing
the incidence of distant metastases and improving disease-free and overall
survival. Although the relationship between locoregional control and distant
metastases has generated considerable debate, there is increasing evidence
that all patients with breast cancer do not have systemic disease from
the inception,[1,2] and that there may be a causal relationship between
local control and distant metastases.[3,4]

Using a competing risk approach, Arriagada et al[4] recently analyzed
the results of the Stockholm trial, which randomized 960 women to premastectomy
or postmastectomy radiation vs observation. This analysis recognized the
competing risks for a first event, including locoregional failure, distant
metastases, contralateral breast cancer, non-breast cancer, second malignancy,
and death due to other causes. The addition of radiation significantly
decreased the 15-year cumulative incidence of local failure as a first
event (6% vs 26%; P less .0001) or any event (11% vs 36%; P less .0001).
Radiation did not significantly reduce the incidence of distant metastases
as a first site of failure (29% vs 23%; P = .48), but it did significantly
decrease the overall 15-year cumulative incidence of distant metastases
(37% vs 45%; P = .04). This benefit, however, was limited to the axillary
node-positive patients (54% cumulative incidence with radiation vs 72%
without; P = .01).

Following locoregional recurrence, 66% of the observation group developed
distant metastases, as compared with 82% of the radiation group. Therefore,
radiation decreased the total incidence of distant metastases by decreasing
the incidence of locoregional recurrence as the first site of failure and
the subsequent distant metastases associated with such a recurrence. The
authors estimated a 2% and 4% sur-vival benefit with postmastectomy radiation
at 10 years and 15 years, respectively, for axillary node-negative patients.
For axillary node-positive patients, the survival benefits were 6% at 10
years and 9% at 15 years.

An additional argument in support of postmastectomy radiation is the
prevention of the morbidity associated with uncontrolled locoregional disease.
Delaying radiation until the time of re-currence ultimately results in
long-term control in only 50% to 60% of patients.[5-11]

As a result of the increased use of doxorubicin-based chemotherapy,
che- moendocrine therapy, and high-dose chemotherapy supported by autologous
bone marrow transplantation or peripheral blood progenitor-cell reinfusion,
the role of postmastectomy radiation in the treatment of stages II-III
disease has been challenged. This article will survey the long history
of trials evaluating postmastectomy radiation--both the earlier studies
(then) and more recent trials (now)--to determine whether or not this challenge
is justified.

Then

Prospective Randomized Trials

Some of the earliest prospective randomized trials of breast cancer
treatment evaluated the role of postmastectomy radiation. These trials
can be divided into two groups: (1) those evaluating the role of radiation
following radical or modified radical mastectomy,[12-20] and (2) those
evaluating the role of radiation following simple mastectomy.[21-26] These
early trials have been criticized for the lack of a consistent randomization
process and inadequate stratification,[12-14] unequal patient distribution
among the treatment arms,[14] the use of confounding ad-juvant therapy,[14,19]
and inadequate radiation in terms of the total dose[12-14,19,27,28] used
and/or the regions treated.[12-14,19]

Despite these criticisms and variations in patient eligibility, the
results achieved were similar.[29] All but one of the trials[26] demonstrated
a decrease in the incidence of locoregional recurrence with radiation.
Moreover, radiation resulted in a decrease in the incidence of distant
metastases in five trials [15,16,19,21,22,26] and a significant improvement
in disease-free survival in four trials.[15,16,19,24,26] None of the trials
showed a significant overall survival benefit for radiation.

A combined analysis of the long-term results of the Oslo and Stockholm
trials found no significant overall or disease-free survival benefit of
radiation therapy in axillary node-negative patients. However, radiation
significantly improved the 10-year disease-free and distant disease-free
survival rates in axillary node-positive patients.

Meta-analyses

1987 Meta-analysis--A meta-analysis of the mortality results
from eight randomized trials evaluating postmastectomy radiation without
adjuvant chemotherapy was first published in 1987 by Cuzick et al.[30]
The analysis included results of the Manchester I, II and Regional trials,
the National Surgical Adjuvant Breast and Bowel Project (NSABP) B04 trial,
the Stockholm trial, the Oslo I and II trials, the Cancer Research Campaign
trial, the Edinburgh I trial, and an unpublished trial from Heidelberg
that compared radical mastectomy alone to radical mastectomy plus radiation.
In this analysis, radiation therapy afforded no survival benefit for the
first 10 years of follow-up. However, in patients who survived more than
10 years, radiation significantly increased mortality. Data were unavailable
on the specific causes of death.

Subsequent reports from the individual trials[19,20,31-33] indicated
that the increased mortality was related to cardiovascular disease. Patients
with left-sided tumors and those who received orthovoltage or cobalt-60
irradiation of the regional nodes were at greater risk for death due to
cardiovascular disease.

The publication of this meta-analysis coincided with the increased use
of doxorubicin-based chemotherapy regimens for axillary node-positive patients
and the initiation of clinical trials for adjuvant therapy in axillary
node-negative women. As a result, interest in and recommendations for postmastectomy
radiation diminished.

Update of 1987 Meta-analysis--In 1994, Cuzick et al[34] published
an update of the 1987 meta-analysis with specific causes of death for all
of the trials except NSABP B04. The previously reported significant increase
in mortality from all causes in the 10-year survivors was no longer evident.
An increase in cardiac deaths was observed in patients who received radiation,
but this was offset by a decrease in the number of breast cancer-related
deaths, especially in the more recent trials. After 10 years, no significant
differences in mortality were seen among patients who received radiation
following a simple mastectomy. After 15 years, cardiac-related causes of
death were increased in patients who received radiation following a radical
or modified radical mastectomy. The increased mortality was most apparent
in women who were 50 years or more of age and clinically node-negative.

Radiation technique was implicated in these results. Trials that employed
orthovoltage irradiation[20,31] or cobalt-60 irradiation of the internal
mammary nodes[19,33] demonstrated an increased incidence of cardiac deaths.
This meta-analysis suggests that with improvements in radiotherapy technique,
and hence, the avoidance of cardiac morbidity and mortality, postmastectomy
radiation may have the potential for significantly improving survival due
to a decrease in breast cancer-related deaths.

Second Meta-analysis--In 1995, the Early Breast Cancer Trialists'
Collaborative Group published a second meta-analysis of prospective randomized
trials of radiation and surgery for operable breast cancer.[66] This analysis
included 36 trials initiated before 1985, 32 of which evaluated the role
of postmastectomy radiation with or without chemotherapy. Data on cause
of death were available from 28 trials.

Overall mortality was not increased in the patients who received radiation.
Rates of 10-year survival were 63% in axillary node-negative patients who
received radiation vs 62.8% in those who did not. The corresponding numbers
were 47.7% and 46.3% for axillary node-positive patients. Radiation resulted
in a decrease in the number of breast cancer deaths but an increase in
the number of non-breast cancer deaths, which, for the first 2 decades
after treatment, was more evident in women 60 years or more of age. Radiation
reduced the rate of local recurrence by 67%. The authors were unable to
assess the relationship between improved local control and distant metastases
with the available data.

Therefore, two meta-analyses have demonstrated the ability of postmastectomy
radiation to decrease the risk of locoregional recurrence and breast cancer-related
deaths and emphasize the importance of minimizing long-term morbidity with
appropriate techniques.

Risk Factors for Locoregional Recurrence After Mastectomy and No
Systemic Therapy

In surgical series in which adjuvant systemic therapy has not been used,
the risk of a local (chest wall) or regional (axilla, supraclavicular,
or internal mammary node) recurrence following radical or modified radical
mastectomy has been related to primary tumor size and axillary nodal status.[14,35-47]
Patients with primary tumors 5 cm or more in diameter and those with four
or more positive axillary nodes have a 25% to 30% incidence (high risk)
of locoregional recurrence.[14,35-39,41,46] In contrast, patients with
primary tumors 2 cm or less or negative axillary nodes have a 5% to 10%
incidence (low risk) of locoregional recurrence. Patients who have primary
tumors 2 to less than 5 cm in diameter or one to three positive axillary
nodes have a 10% to 15% incidence (intermediate risk) of locoregional recurrence.[14,35,365,39,41,46]
Additional factors that correlate with an increased risk of locoregional
recurrence following mastectomy include young age ( 40 years or less),[35,48,49]
negative estrogen receptors,[50,51] high histologic grade,[44,52,53] and
pectoral fascia involvement.[35,54]

Data are limited regarding the correlation between mastectomy resection
margin status and the risk of a chest-wall recurrence. Axillary node-negative
patients with primary tumors 5 cm or less and a close margin ( 4 mm or
less) have a 6% incidence of locoregional recurrence.[40] Mentzer et al[55]
were unable to correlate the incidence of locoregional recurrence with
margin status in 100 women with stage II breast cancer. Unfortunately,
margin status was assessed grossly in 67% of these patients. None of the
four patients with a positive margin who did not receive radiation experienced
a locoregional recurrence. Locoregional recurrences developed in 3 of 25
patients with a margin 2 mm, or less 5 of 45 patients with a margin 5 mm,
or less and 1 of 33 patients with a margin more than 5 mm.

The most common site for a locoregional recurrence is the chest wall,
either as a single site or a component of multiple sites.[5,6,10,11,56]
Approximately 40% of the chest-wall recurrences involve the mastectomy
scar.[52,57] The second most common site is the supraclavicular region.[5,6,10,11,56]
Axillary recurrences are uncommon in the dissected axilla, especially when
10 or more axillary nodes are removed.[58] The presence of extracapsular
extension does not increase the risk of an axillary recurrence,[59-62]
provided that an adequate dissection has been performed. Internal mammary
node recurrences represent less than 10% of ll locoregional recurrences.[5,6,10,11,56]

The majority of locoregional recurrences postmastectomy occur within
5 years of surgery.[6,11,52,57,63,64] Incidence peaks in the second year.[52]
Montague[65] reported that 34% of locoregional recurrences following mastectomy
occurred after 5 years and 10%, after 10 years.

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