Based on a keynote address given by Marie Overgaard, md, at the
1998 American Society for Therapeutic Radiology and Oncology (ASTRO)
meeting. Dr. Overgaard is consulting oncologist, Aarhus University
Hospital, Denmark, as well as chair of the radiotherapy committee of
the Danish Breast Cancer Cooperative Group.
Radiotherapy is currently used as an adjuvant after mastectomy in
high-risk patients, after breast-conserving surgery in patients with
locally advanced disease or locoregional recurrences, and in
palliation. Dr. Overgaard focused her remarks on the most
controversial indication; namely, adjuvant locoregional irradiation
in early breast cancer, which, in principle, includes radiotherapy
after both mastectomy and breast-conserving surgery. The aim of
radiotherapy in early breast cancer is to improve both locoregional
control and overall survival.
Early Breast Cancer Trialists Meta-Analysis
The impact of radiotherapy on survival was evaluated in a
meta-analysis by the Early Breast Cancer Trialists
Collaborative Group published in the New England Journal of Medicine
in 1995. The results of studies comparing surgery alone vs the same
surgery plus radiotherapy indicated no benefit of irradiation at 10
years in terms of sur-vival for either node-negative or node-positive
patients. So why should we bother about this topic when the
gold standard in evidence-based medicinethe
meta-analysishas established that this issue is dead? Dr.
A second look at the overview analysis, however, reveals that,
although there was no difference in overall survival, there were
several important differences in the two treatment groups. First, the
addition of radiotherapy significantly reduced locoregional
recurrences, with a risk ratio of 0.33. Second, the analysis of
cause-specific deaths showed a small, but significant, reduction in
breast cancer deaths in irradiated patients, with a risk ratio of
0.94. This was counterbalanced by an excess of nonbreast cancer
deaths, mainly of cardiovascular disease, with a risk ratio of 1.24.
Thus, there is a clear general beneficial effect of radiotherapy on
local control. However, the potential beneficial effect of
radiotherapy on survival needs to be clarified further, Dr. Overgaard
said. A number of potential problems in the studies included in the
meta-analysis need to be kept in mind. These include the definition
of end points and aims of the trials, selection of patients according
to prognostic factors, quality of radiotherapy, and interaction with
other therapies, such as surgery and adjuvant endocrine therapy and chemotherapy.
Danish Breast Cancer Group Trials
In the first protocols initiated in 1977, the Danish Breast Cancer
Group (DBCG) evaluated the effect of adjuvant systemic therapy in
high-risk patients. At that time, all high-risk patients received
postoperative radiotherapy in addition to total mastectomy and
partial axillary dissection. As in many similar trials, the DBCG
found a positive effect of adjuvant systemic therapy on survival.
The theory that breast cancer seems to be a systemic disease, as
described by Bernard Fischer in 1980, implies that changes in
locoregional treatment are unlikely to affect survival. In light of
this, the DBCG decided to evaluate the role of postoperative
irradiation in high-risk patients who were also receiving adjuvant
systemic therapy. Dr. Overgaard focused her discussion on those protocols.
The aim of the DBCG 82B and 82C protocols, she noted, was to evaluate
postmastectomy irradiation in patients who were also given adjuvant
systemic therapy. Between 1982 and 1989, more than 3,000 patients
were enrolled in the two studies. The studies asked: (1) whether
postoperative radiotherapy is necessary in high-risk breast cancer
patients who also receive adjuvant systemic therapy; and (2) more
generally, whether optimal locoregional tumor control influences
survival in high-risk breast cancer patients who are also receiving
adjuvant systemic therapy. The 82B trial was published in 1997 in the New
England Journal of Medicine; the 82C trial has just been
accepted for publication.
According to the design of DBCG 82B and 82C, premenopausal patients
were randomized, after surgery, to receive either adjuvant systemic
chemotherapy with CMF (cyclophosphamide, methotrexate, and
fluorouracil) plus radiotherapy or CMF alone. Postmenopausal patients
were randomized to tamoxifen (Nolvadex) plus radiotherapy or
tamoxifen alone. Only high-risk patients were included (ie, those
with primary tumor size larger than 5 cm and/or positive nodes and/or
tumor invasion into skin or deep fascia on pathology).
All of the patients were initially treated with total mastectomy,
including clearing of level 1 axillary nodes and part of level 2
nodes. Patients randomized to radiotherapy received irradiation to
the chest wall and regional lymph nodes, including the internal
mammary chain, to a median absorbed dose of 48 to 50 Gy in 22 to 25
fractions over 5 weeks. The systemic treatment consisted of eight to
nine cycles of intravenous CMF every 4 weeks in premenopausal
patients, and 1 year of tamoxifen (30 mg/d) in postmenopausal
patients. Radiotherapy and CMF were given sequentially, with one
cycle of CMF before 5 weeks of radiotherapy; after 1 week, CMF was
continued every 4 weeks.
The 82B and 82C trials indicated that postmastectomy irradiation
combined with adjuvant systemic therapy in high-risk patients causes
a major reduction in locoregional recurrences and significantly
improves disease-free survival, as well as overall survival. These
effects of radiation therapy on survival are of the same magnitude as
those seen after adjuvant systemic therapy.
Other Trials of Radiation Plus Systemic Therapy
The Danish studies are not the only trials that have shown the
benefit of postoperative radiotherapy plus adjuvant systemic therapy,
Dr. Overgaard pointed out. For example, results of the British
Columbia trial, published by Joseph Ragaz et al in the New England
Journal of Medicine in October 1997, were similar to those of the
Danish trials. The British Columbia trial included high-risk
premenopausal patients treated with mastectomy and adjuvant CMF with
and without radiotherapy.
A number of other published studies evaluating the effect of
radiotherapy in high-risk breast cancer patients treated with
adjuvant systemic therapy (with or without radiotherapy) were also
included in the Early Breast Cancer Trialists meta-analyses
from 1995. Most of these studies are too small to show significant
effects on survival. However, the pattern of local recurrence in
irradiated vs nonirradiated patients is very similar in all of the
studies: a three to sixfold reduction in local recurrences.
From a review of the available studies evaluating the effect of
radiotherapy in the presence of adjuvant systemic therapy, Dr.
Overgaard concluded that postoperative radiotherapy in addition to
adjuvant systemic therapy causes a major reduction in locoregional
recurrences in this high-risk group, as well as a significant
reduction in breast cancer mortality, which is of clinically relevant magnitude.
Thus far, adjuvant systemic treatment does not sufficiently prevent
local recurrences, and such residual, inadequately treated
locoregional disease can lead to secondary dissemination and thereby
impair survival. Therefore, according to Dr. Overgaard, effective
locoregional treatment is necessary to cure patients with breast cancer.
This concept is in agreement with Samuel Hellmanns spectrum
theory (1994) that breast cancer is a heterogeneous disease. The
spectrum ranges from a disease that remains localized throughout its
course to a disease that is systemic when first detected. Thus,
there could be situations where metastasis would develop as a
consequence of residual, inadequately treated locoregional disease,
which is what we have seen, said Dr. Overgaard.
According to Dr. Overgaard, the most important message of the Danish
trials is that locoregional tumor control has an impact on survival.
The current challenge is to find the right balance of treatment
modalities that provides optimal local control.
Morbidity of Radiation Therapy
There are many delicate, critical structures around and behind the
breast, and radiation produces important adverse effects in these
structures. Some of these effects cause only minor symptomsfor
example, telangectasia of the skin and lung fibrosis limited to the
apex of the lungwhereas other complications, such as arm edema,
impairment of shoulder movement, and brachial plexopathy, can cause
serious disability. Ischemic heart disease, another complication of
radiation therapy, can even be life-threatening.
Morbidity from radiotherapy is influenced by interactions with
chemotherapy and surgery, Dr. Overgaard pointed out. It is also dose-
and fractionation-related, as well as volume- and target-related.
In the DBCG 77 trial, patients received concurrent CMF and
radiotherapy and were then randomized to receive further CMF or no
CMF to study the effect of simultaneous radiotherapy and CMF on late
skin fibrosis. For the same total radiation dose, simultaneous CMF
and radiotherapy resulted in increased late skin damage. To avoid
this problem, patients were given sequential chemotherapy and
radiotherapy in the present trial.
Data from the 1977 trial, in which hyperfractionation was used in
some radiotherapy departments while others used conventional
schedules, also show an interaction of radiation therapy with
surgery, Dr. Overgaard said. The frequency of arm edema increased
with the number of nodes removed. In addition, hyperfractionation, or
two large fractions weekly instead of five standard fractions weekly,
greatly increased the risk of arm edema, and, therefore, conventional
fractionation schedules were used in the 82 trials. The most
important end point, cardiac morbidity, has been evaluated in the 82B
and 82C trials, presented at the European Society for Therapeutic
Radiology and Oncology (ESTRO) meeting in Edinburgh (1998). No
evidence of increased long-term cardiac morbidity or mortality was
found in irradiated patients, compared with nonirradiated patients.
The Early Breast Cancer Trialists overview concluded that
some of the local therapies for breast cancer had substantially
different effects on the rates of local recurrence, such as the
reduced recurrence with the addition of radiotherapy to surgery, but
that there was no definite difference in overall survival at 10
years, Dr. Overgaard commented. This seems to disagree
with the general conclusion of the meta-analysis and the studies I
have just presented. Where lies the truth?
In Dr. Overgaards view, a general survival benefit from
radiotherapy would not be expected to emerge in an overview of such
heterogeneous trials. The survival benefit occurs in only a
proportion of those who benefit with regard to local
controlnamely, patients who do not yet have disseminated
disease. In the vast majority of patients, radiotherapy will only
confer a benefit with regard to local control; therefore, it is
important to select the relevant group if the objective of
radiotherapy is to improve survival. A clinical relevant benefit in
survival can be demonstrated in subgroups, including patients with
high-risk prognostic features, such as those who have positive lymph
nodes and those who also receive adjuvant systemic therapy to
overcome disseminated disease.
Although there is evidence of increased long-term cardiac morbidity
with radiotherapy, this apparently can be avoided by the use of a
proper treatment plan and radiation technique, as shown in the Danish trials.
Optimal locoregional tumor control has an impact on survival in early
breast cancer; there is also clear evidence that residual,
inadequately treated locoregional disease can result in subsequent
dissemination. In addition, adjuvant radiotherapy is an important
part of the multidisciplinary treatment of breast cancer. Thus, the
indications for radiotherapy are to improve locoregional control in
patients who have a high risk of developing locoregional recurrence
after surgery, and to improve survival in patients who have a high
risk of residual tumor after surgery and do not yet have disseminated
disease, or in whom adjuvant systemic therapy can control
The effort to find an optimal balance among the treatment
modalities must be continued, Dr. Overgaard concluded.
There are many problems to solve yetfor example, defining
the optimal extent of the target of radiotherapy and the optimal
timing with respect to systemic treatment. The challenge is to strive
for progress in both tumor control and reduced morbidity.