Multiple randomized trials have compared local control and overall
survival in women treated with radical mastectomy, modified radical
mastectomy, or total mastectomy followed by either post-mastectomy
radiotherapy or observation [10,14,17-23]. As shown in Table 1,
these trials extend over a wide range of time, with the majority
conducted 20 to 30 years ago. Therefore, it is not surprising
that the techniques and equipment used to administer radiotherapy
in these trials are not comparable to those employed today. Many
of the earlier trials used orthovoltage machines with energies
inadequate to treat the entire depth of the target tissues at
risk. Some trials were designed to treat only the regional lymph
nodes and excluded the chest wall from the treatment volume. As
discussed above, the chest wall is the major site of locoregional
failure; therefore omission of the chest wall from the treatment
field would be expected to result in increased locoregional recurrence.
Other criticisms of these trials include the use of inadequate
total doses and large daily fraction sizes, and inappropriate
patient selection. As demonstrated in Table 1, the total doses
delivered often were below the dose adequate to control microscopic
disease, ie, 45 to 50 Gy . Fractionation schemes commonly
involved daily doses in excess of 2 Gy, which could increase chronic
morbidity, most notably, to the heart and lung. These trials typically
included patients at low risk for locoregional recurrence, which
would have reduced their statistical power to demonstrate an advantage
for post-mastectomy radiotherapy. Also, in many of the total mastectomy
trials, patients underwent only axillary node sampling, which
could have underestimated pathologic nodal involvement.
·Early Analyses of Trial Results--Despite these limitations
in the design and execution of the post-mastectomy trials, every
trial evaluating locoregional control still demonstrated a benefit
from the addition of radiotherapy; the magnitude of this benefit
ranged from 8% to 20%, depending on the length of follow-up. In
early analyses of the results, however, the favorable effect of
radiotherapy on locoregional control did not translate into a
significant overall survival advantage. In fact, a meta-analysis
of 10-year survivors from eight post-mastectomy radiotherapy trials
begun prior to 1975 demonstrated a decreased survival among women
who received adjuvant radiotherapy, compared to controls .
A subsequent report presented cause-specific mortality data for
all patients who died more than 10 years after entry into the
trials and provided updated follow-up on all women entered into
these studies . Only cardiac-related causes of death were
increased among patients who received radiotherapy. The increase
in cardiac deaths was attributed to radiotherapeutic techniques
no longer in use. The update demonstrated that this negative effect
on overall survival was almost balanced, however, by a reduction
in breast cancer deaths among irradiated patients entered into
the more recent trials. Specifically, women who received radiotherapy
in the Stockholm, Manchester Regional, Cancer Research Campaign,
and NSABP trials had a survival benefit relative to controls [10,14,20,21].
The updated analysis supported a causal relationship between maximal
local control achieved with adjuvant radiotherapy and improved
cancer-specific survival .
Early Breast Cancer Trialists' Overview--The Early Breast
Cancer Trialists' Collaborative Group recently published an overview
of the effects of radiotherapy and surgery in early-stage breast
cancer . Included in this analysis were results of 35 trials
randomizing a total of 17,273 women to either radiotherapy plus
surgery or surgery alone. As expected, radiotherapy produced a
highly significant reduction in the rate of isolated local recurrences.
In the 32 trials that reported site of recurrence, 6.7% of women
receiving radiotherapy developed an isolated local failure, as
compared with 19.6% of patients in the surgery-only groups (odds
Information was available from 28 trials on causes of death. Among
the women assigned to receive radiotherapy, 34.1% died of breast
cancer, as opposed to 36.9% of controls; this yielded an odds
ratio of .94 in favor of radiotherapy (P = .03). Although overall
mortality was 40.3% with radiotherapy vs 41.4% without it, this
difference did not achieve statistical significance due to non-breast
cancer deaths. However, the reduction in breast cancer-related
deaths among women treated with radiotherapy was, again, suggestive
of improved breast cancer-specific survival due to maximal local
Improved Survival vs Cardiac Mortality: The Stockholm Study--The
competing issues of improved survival secondary to radiotherapy
and the potential for cardiac mortality associated with radiotherapeutic
technique are perhaps best contrasted in the Stockholm study .
In this study, premenopausal and postmenopausal women either received
preoperative radiotherapy or postoperative radiotherapy or were
observed following modified radical mastectomy. For the earlier
patients enrolled in the study who received radiotherapy, the
chest wall was treated with electrons, and the breast and regional
nodes, including bilateral internal mammary nodes, were treated
with cobalt-60 therapy. In the latter half of the study, the contralateral
internal mammary nodes were omitted from the radiotherapy field.
As shown in Table 1, with a mean follow-up of 16 years, the rate
of locoregional recurrence as a first failure was only 4% in both
the preoperative and postoperative arms, as compared with 20%
among the controls (P less than .001). The reduction in locoregional
recurrences was observed in both node-negative and node-positive
women. The risk of distant failure was decreased in both the preoperative
and postoperative radiotherapy groups, with a significant benefit
in relapse-free survival following radiotherapy. This reduction
in distant metastases and subsequent reduction in breast cancer
deaths was restricted to the node-positive group.
Among patients treated with cobalt-60 to left-sided lesions and
regional nodes, a significant increase in ischemic heart disease
was seen compared to surgical controls. No such increase was seen
among patients who underwent cobalt-60 therapy of right-sided
cancers or those with left-sided cancers treated with electrons.
Therefore, omission of the heart from the radiation beam, in addition
to delivery of a therapeutic radiation dose, resulted in improved
survival secondary to post-mastectomy radiotherapy.
Reanalysis of the Stockholm Data-- Arriagada et al recently
reanalyzed the Stockholm data to determine the effect of local
recurrence on distant dissemination . The authors used a competing
risk model to estimate the occurrence of all events leading to
an overall event rate. This approach took into account all possible
occurrences, including local failure, distant failure, new primary
malignancies, contralateral breast cancers, and intercurrent deaths,
such that an event-free survival could be calculated.
Using 15-year cumulative incidence rates for all patients in the
study, the authors showed a fivefold decrease in the risk of local
recurrence with radiotherapy (P less than 10-4). In the analysis
of total events, radiotherapy also significantly reduced the rate
of distant metastases (P = .04). An analysis of patients with
pathologically negative nodes indicated that radiotherapy reduced
local failure 10-fold compared to unirradiated controls but had
no effect on the rate of distant recurrence. This contrasted with
the results in node-positive patients, in whom radiotherapy produced
a significant decrease not only in local recurrence but also in
In a Cox regression analysis of factors predictive of distant
dissemination, both tumor size and histologic node size were predictive
of distant metastases, with relative risks of 1.35 and 2.83, respectively.
A local recurrence was highly predictive of distant recurrence,
with a relative risk of 6.0. This analysis suggested that the
decrease in distant metastases was related to the prevention of
This finding, in addition to the results of the Cox analysis in
node-positive women, suggested that post-mastectomy radiotherapy
in patients with positive nodes may decrease the rate of distant
metastases by preventing local recurrences and avoiding secondary
dissemination. Thus, this analysis further supports the contribution
of locoregional control to improved survival.
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