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Defining the Role of Post-Mastectomy Radiotherapy: The New Evidence

Defining the Role of Post-Mastectomy Radiotherapy: The New Evidence

ABSTRACT: In an early meta-analysis of the post-mastectomy radiotherapy trials, the use of obsolete radiotherapy techniques resulted in increased cardiac mortality. With maturation of these data and inclusion of more recent trials, however, a survival advantage is now emerging. This, in concert with the improvement in disease-free and overall survival evident in the larger studies of post-mastectomy radiotherapy with adjuvant chemotherapy, generates a new enthusiasm in support of post-mastectomy radiotherapy. The lessons we have learned from the earlier trials emphasize the importance of precise radiation planning and delivery so that long-term morbidity can be minimized and survival improved by the reduction in breast cancer deaths. [ONCOLOGY 10(7):991-1002, 1996]

Introduction

The current role of post-mastectomy radiotherapy as an adjuvant
treatment in stage II breast cancer has been challenged. Although
adjuvant radiation was once an established therapy in the management
of breast cancer, the routine use of systemic therapy in patients
at significant risk for distant (and local) dissemination has
caused some to question the need for locoregional radiotherapy.
Several issues must be considered when weighing the relative merits
of adjuvant locoregional radiotherapy:

  • Can systemic therapy improve locoregional control comparable
    to that achieved with radiotherapy, such that the addition of
    post-mastectomy radiotherapy offers no further benefit?
  • ·Are there subgroups of women at high risk for locoregional
    failure who would particularly benefit from the use of post-mastectomy
    radiotherapy?
  • ·If post-mastectomy radiotherapy improves locoregional
    control in the presence of chemotherapy, could this have an impact
    on overall survival?

To begin to understand the importance of post-mastectomy radiotherapy
in the current management of breast cancer, it is necessary to
first look at the role this modality has played prior to the use
of systemic treatment. Also, when formulating current recommendations
for the use of post-mastectomy radiotherapy, it is important to
extrapolate the lessons learned from the early trials.

Failure Patterns Following Mastectomy Alone

Analyses of locoregional failure have shown the chest wall to
be the most common site of failur [1-3]. Halverson et al reported
the chest wall to be the site of isolated locoregional recurrence
in 60% of patients with a locoregional failure, with an additional
10% of patients having the chest wall as a component of failure,
so that the chest wall was involved in 70% of the locoregional
failures [1].

The mastectomy scar is at greatest risk for recurrence [4]. Donegan
et al reported the scar or grafted area to be the most frequent
site of chest wall involvement, accounting for 42% of such recurrences
[4]. In most series, the supraclavicular/infraclavicular nodes
are the second most common site of locoregional failure, with
involvement as a single site in 10% to 20% patients.

Clinical recurrences occur less frequently in the internal mammary
nodes or in the axilla. From 5% to 10% of patients present with
an isolated failure at each site in an adequately dissected axilla
[5].

Predictors of Locoregional Failure Following Mastectomy Alone

Additional analyses have identified various factors that are predictive
of increased locoregional failure.

Positive Axillary Nodes--The finding of positive axillary
nodes has been shown consistently to be the major predictor of
chest wall failure [4,6,7]. Haagensen reported in one of the earliest
series, factors that predicted a local recurrence following mastectomy
[6]. Of 935 patients with either stage I or II disease treated
with radical mastectomy and followed for at least 10 years, axillary
node involvement was closely related to the risk of chest wall
recurrence, with recurrence rates up to 42% in patients with four
or more nodes positive.

Donegan et al performed a similar analysis of locally recurrent
breast cancer following radical mastectomy [4]. Among the 704
women studied, only 6.5% of patients with histologically uninvolved
axillary nodes had a local recurrence at 5 years, as compared
with 26% of women with pathologically involved nodes. The percentage
of local recurrence was directly correlated with the absolute
number of positive nodes: Involvement of 1 to 3 nodes was associated
with a 10% to 15% recurrence rate at 5 years; this rate increased
to 25% to 38% with 4 to 7 positive nodes and to 43% or higher
with 8 or more positive nodes.

In a trial from Stockholm, in which women were randomized to post-mastectomy
radiotherapy, histologic lymph node status was an independent
predictor of local recurrence. The relative risk for local failure
was three times greater among women with positive nodes than among
those with negative nodes [7].

Other factors have also been associated with increased
locoregional failure following mastectomy in the absence of systemic
therapy. The size of the primary lesion has been correlated with
local recurrence in some series [4,8-10]. Donegan and colleagues
found a direct association between tumor diameter and local recurrence,
with 0% of patients with tumors less than 1.0 cm having a local
failure, increasing to 16% for tumors 3.0 to 3.9 cm, 27% for lesions
5.0 to 5.9 cm, and greater than 30% for tumors exceeding 6.0 cm
[4]. This study did not correct for the presence of positive axillary
nodes, however, in determining this association.

In series reported by Rosenman et al [8] and Valagussa et al [9],
tumor size was strongly correlated with locoregional recurrence
in node-positive patients. Pathologic factors found in the Cancer
Research Campaign Trial to independently predict for increased
locoregional recurrence included the size of the primary lesion
[10].

Distance of the tumor to the pectoralis fascia may also affect
local failure. In one series examining local recurrence as a function
of the distance to the deep resection margin, seven of eight patients
with local recurrence had a margin of 0.5 cm or less [11].

Other factors that may also have an impact on chest wall recurrence
include lymphatic invasion and tumor grade [10,12].

Importance of Locoregional Control

Quality of life can be severely compromised by a locoregional
failure following mastectomy. Subsequent rates of locoregional
control with radiotherapy following a recurrence have been disappointing.
Reported control rates have ranged between 25% and 76%, depending
on tumor bulk and resectability, with an average control rate
of 50% [1-3,5]. Thus, even with optimal radiotherapy, 50% of patients
experiencing a locoregional failure will die with uncontrolled
locoregional disease. This argues strongly in favor of the delivery
of prophylactic radiotherapy following mastectomy for maximal
local control. In recent series in which radiotherapy has been
delivered to high-risk patients in conjunction with chemotherapy,
isolated locoregional recurrences have been reduced to 5% to 10%
[13].

It has also been suggested that increased locoregional control
influences survival. In every surgical series of stage I or II
breast cancer to date, locoregional therapy as sole therapy has
been curative in a majority of node- negative patients and a minority
of node-positive women [4,6,9]. Therefore, a finite percentage
of early-stage breast cancers are confined locoregionally and
are cured by definitive locoregional treatment. Conversely, a
minority of node-negative women and a majority of node-positive
women whose disease is locally controlled develop sites of distant
dissemination.

Sequential National Surgical Adjuvant Breast Project (NSABP) studies
comparing locoregional therapies have shown little correlation
between local control and overall survival [14,15]. Based on these
results, Fisher et al hypothesized that breast cancer is a systemic
disease at presentation, and that local control has little to
no impact on survival. An alternative hypothesis proposed by Hellman
suggests that breast cancer is a heterogeneous disease in which
subsets of women present with systemic disease, whereas others
have disease restricted to locoregional sites at diagnosis [16].
In the latter group, locoregional control would surely influence
outcome. Therefore, for reasons including both quality of life
and, potentially, overall survival, the maintenance of locoregional
control is an important goal.

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