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2000
NIH Consensus Development Conference on Adjuvant Therapy for
Breast Cancer
Overview:
Postmastectomy Radiotherapy
Jack
Cuzick, Ph.D.
The first
issue in cancer treatment to be addressed by a randomized
trial was the role of radiotherapy in breast cancer. Although
that trial took place in 1948, the question of whether radiotherapy
is an appropriate treatment for breast cancer remains controversial.
There is little doubt that radiotherapy is effective in improving
local control of the disease. The rate of local recurrence
with radiotherapy is reduced to about one-third of the rate
when surgery alone is used, although this absolute reduction
is very much dependent on the extent of the surgery and the
nodal status of the patient (see table 1). The relative reduction
in local recurrence is substantial in all trials and appears
to be unaffected by patient age, nodal status, dose, axillary
or internal mammary chain irradiation, adjuvant chemotherapy
or tamoxifen, or time of trial commencement. Slightly better
results are seen in larger trials and also in trials employing
smaller doses of radiotherapy per fraction.
What is
less clear is the effect of radiotherapy on patient survival.
This question has been examined in five large studies since
1987. In the first, Cuzick and colleagues observed an increase
in late mortality (Cuzick, Stewart, Peto, et al., 1987). A
subsequent study (Cuzick, Stewart, Rutqvist, et al., 1994)
found that this increase was due to cardiovascular mortality,
but it also suggested that there might be a late reduction
in breast cancer deaths. Two subsequent and much larger overviews
have confirmed and extended these observations (EBCTCG, 1995;
EBCTCG, 2000). The most recent study of radiotherapy involved
the examination of the deaths of more than 10,000 women out
of a total of about 20,000 women in 40 randomized trials worldwide.
No clear effect of radiotherapy on total mortality was found,
but the study found highly significant differences in breast
cancer deaths and non-breast-cancer deaths (see figures 1
and 2). After 20 years of followup, breast cancer deaths were
reduced by 4.8 percent, but non-breast- cancer deaths were
elevated by 4.3 percent. Both of these changes were highly
significant (p< 0.001). The change in non-breast-cancer deaths
emerged later than the change in breast cancer deaths, the
differences being 1.0 percent for breast cancer mortality
and 3.0 percent for non-breast-cancer mortality at 10 years.
Most of the excess non-breast-cancer deaths were due to vascular
disease, which increased by 30 percent. There were no significant
subgroup effects on the relative death rates from breast cancer
and from non-breast-cancer causes. However, an increased absolute
death rate was seen in the radiotherapy arm for older and
for node-negative women, due to the lower ratio of breast
cancer deaths to other kinds of death in those two groups.
More recent trials have reported larger overall mortality
benefits from radiotherapy, but the followup from these trials
is shorter, so uncertainty remains about the long-term mortality
effects, especially for non-breast-cancer deaths.
Table
1. Effects of radiotherapy allocation on 10-year probability
of local recurrence, by type of surgery and nodal status*
 Isolated
local recurrence (%)
|
| |
Radiotherapy
|
Control
|
Absolute
difference (SE)
|
|
Mastectomy
alone
|
11.3
15.5
|
28.6
44.9
|
17.3 (1.5)
29.4 (4.0)
|
 Node-negative
Node-positive |
Mastectomy
with axillary sampling
|
7.2
6.3
|
23.1
37.7
|
15.9 (2.8)
31.4 (1.9)
|
Node-negative
Node-positive |
Mastectomy
with axillary clearance
|
2.7
9.0
|
9.2
24.4
|
6.5 (1.3)
15.4 (1.4)
|
Node-negative
Node-positive |
Breast
conservation with axillary clearance
|
7.8
16.1
|
25.0
35.4
|
17.3 (1.7)
19.4 (3.4)
|
Node-negative
Node-positive |
Subtotals
|
7.9
9.3
|
23.2
32.0
|
15.3 (0.9)
22.7 (1.0)
|
All
Node-negative
All Node-positive |
| Total |
8.8
|
27.2
|
18.5
(0.7)
|
* 37
trials with data on local recurrence. All logrank tests for
local recurrence yield 2p<0.00001. From EBCTCG (2000)
Chief
among these uncertainties is whether the newer kinds of radiotherapy,
which allow for more accurate delivery of the dose, can achieve
reduction in breast cancer mortality without increasing cardiovascular
mortality. It will also be important to try to separate out
the effects of radiation of the breast/chest wall versus radiation
of lymph nodes. These questions are particularly relevant
for women with small tumors or ductal carcinoma in situ (DCIS)
who receive lumpectomy and radiotherapy, since their survival
rate is very good and deleterious late effects would be most
damaging.
It is
clear that radiotherapy is of net benefit to patients who
are at high risk of local recurrence and is inappropriate
for others where the risk is low. Much uncertainty still exists
about where to draw the dividing line between these groups
and the extent to which improved techniques have shifted this
boundary.
Preliminary
data from the next overview (to be published in September
2000) will be available before the consensus development conference
and should cast additional light on these uncertainties.
References
Cuzick
J, Stewart H, Peto R, Baum M, Fisher B, Host H, et al. Overview
of randomized trials of postoperative adjuvant radiotherapy
in breast cancer. Cancer Treat Rep 1987;71:15-29.
Cuzick
J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C,
et al. Cause-specific mortality in long-term survivors of
breast cancer who participated in trials of radiotherapy.
J Clin Oncol 1994;12:447-53.
Early
Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects
of radiotherapy and surgery in early breast cancer: an overview
of the randomized trials. N Engl J Med 1995;333:1444-55.
Early
Breast Cancer Trialists' Collaborative Group (EBCTCG). Favourable
and unfavourable effects on long-term survival of radiotherapy
for early breast cancer: an overview of the randomised trials.
Lancet 2000;355:1757-70.
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