Does Locoregional Radiation Therapy Improve Survival in
Breast Cancer? A Meta-Analysis
By Timothy J. Whelan, Jim Julian, Jim Wright, Alejandro R. Jadad, and Mark L. Levine
Purpose: Recent randomized trials in women with
node-positive breast cancer who received systemic treatment report that locoregional radiation therapy improves
survival. Previous trials failed to detect a difference in survival that results from its use. A systematic review of randomized trials that examine the effectiveness of locoregional radiation therapy in patients treated by definitive
surgery and adjuvant systemic therapy was conducted.
Methods: Randomized trials published between
1967 and 1999 were identified through MEDLINE database, CancerLit database, and reference lists of relevant articles. Relevant data was abstracted. The results
of randomized trials were pooled using meta-analyses
to estimate the effect of treatment on any recurrence,
locoregional recurrence, and mortality.
Results: Eighteen trials that involved a total of 6,367
patients were identified. Most trials included both pre-
and postmenopausal women with node-positive breast
cancer treated with modified radical mastectomy. The
type of systemic therapy received, sites irradiated, techniques used, and doses of radiation delivered varied
between trials. Data on toxicity were infrequently reported. Radiation was shown to reduce the risk of any
recurrence (odds ratio, 0.69; 95% confidence interval
[CI], 0.58 to 0.83), local recurrence (odds ratio, 0.25;
95% CI, 0.19 to 0.34), and mortality (odds ratio, 0.83;
95% CI, 0.74 to 0.94).
Conclusion: Locoregional radiation after surgery in
patients treated with systemic therapy reduced mortality. Several questions remain on how these results
should be translated into current-day clinical practice.
J Clin Oncol 18:1220-1229. © 2000 by American
Society of Clinical Oncology.
URING THE LAST 50 years, the efficacy of postoperative locoregional radiation (to the chest wall or
breast and regional lymph nodes) in women who undergo
surgery for breast cancer has been examined in a number of
randomized clinical trials.1,2 Results demonstrate a reduction in breast cancer locoregional recurrence but no difference in overall survival. Many of these studies were of small
sample size. Hence, the role of postoperative locoregional
radiation has remained unclear, and as a result, there is
variation in its use in clinical practice.
The results of recent randomized trials demonstrate that,
after mastectomy, postoperative locoregional therapy improves survival in women with node-positive breast cancer
who also received adjuvant systemic therapy.3-5 The results
of these studies differ from those of previous studies and
support the hypothesis that when systemic therapy is given
to reduce the burden of micrometastatic disease, locoregional radiation may impact on overall survival. These
studies have stimulated much discussion concerning the use
of locoregional radiation therapy in routine clinical prac-
tice.6,7 There remain a number of unanswered questions
regarding the generalizability of these findings to patients
with node-negative disease and to those treated with breastconserving surgery. There is the concern that the use of
locoregional radiation in patients treated with more doseintensive or anthracycline-containing chemotherapy may be
less effective and will be associated with an increase in
cardiac toxicity8,9 and acute leukemia.10 The rate of significant arm lymphoedema that impacts on a patient’s quality
of life may also increase.11-13
We wanted to review all trials of locoregional radiation
therapy in women treated with systemic therapy to determine if the mortality effects observed in recently published
studies were consistent with those in other trials and to
assess the generalizability of these findings to current
practice. Previous meta-analyses have either not included
trials in which patients were treated with adjuvant systemic
therapy or have not focused on this group of studies.1,2 Our
specific objectives were to conduct a systematic review of
randomized trials that examined the effectiveness and toxicity of locoregional radiation therapy in patients with breast
cancer treated by definitive surgery and adjuvant systemic
therapy, to perform a meta-analysis of the results of these
trials, and to consider possible factors (patient- and treatment-related) that could influence the treatment effect.
D
From the Departments of Medicine, Clinical Epidemiology, and
Biostatistics, McMaster University, and Cancer Care Ontario, Hamilton Regional Cancer Centre, Hamilton, ON, Canada.
Submitted July 13, 1999; accepted November 29, 1999.
Address reprint requests to Timothy J. Whelan, Hamilton Regional
Cancer Centre, 699 Concession St, Hamilton, ON L8V 5C2, Canada;
email [email protected].
© 2000 by American Society of Clinical Oncology.
0732-183X/00/1806-1220
1220
METHODS
Study Identification
A structured search was conducted to identify randomized controlled
trials of locoregional radiation therapy after definitive surgery in
Journal of Clinical Oncology, Vol 18, No 6 (March), 2000: pp 1220-1229
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1221
LOCOREGIONAL RADIATION THERAPY
women with breast cancer treated with systemic therapy, which was
defined as adjuvant chemotherapy or hormonal therapy. A trial was
suitable for inclusion if it fulfilled the following criteria:
● was published in a peer-reviewed journal in any language;
● all patients were treated by definitive surgery, ie, either radical/
modified radical mastectomy or lumpectomy plus an axillary
dissection;
● patients in both treatment arms received the same systemic
therapy;
● allocation of locoregional radiation treatment was said to be
randomized;
● radiation therapy was delivered to the regional lymph nodes and
chest wall or breast; and
● median follow-up was 5 years or more.
Abstracts, as well as published papers, were acceptable. If the same
trial had been published more than once, the most recently published
data were used. Potentially eligible studies were identified by use of the
following strategy:
● A MEDLINE and CancerLit search was completed for the period
from 1966 to July 1999. Search terms included the following
combined subject headings: breast neoplasms, systemic treatment,
radiation therapy, randomization, and meta-analysis.
● The citation lists of all retrieved articles were examined to identify
other potentially relevant reports.
● In addition, we manually reviewed relevant journals published in
the first 6 months of 1999.
A citation identified by any of the search strategies was reviewed by
at least two of the investigators. The decision to select an article was
based on information available in the published report and was reached
by consensus. Three trials were considered inappropriate for inclusion
in our study: one trial that included patients with locally advanced
disease not treated by definitive surgery,14 one that compared monochemotherapy plus radiation with polychemotherapy alone,15 and one
that had less than 5 years of follow-up.16
Potentially eligible studies were randomly sorted into two groups,
and each group was assigned to an investigator for independent review
and data abstraction. After completing the review, each of the reviewers assessed the other reviewer’s studies. Any disagreement in abstracted data was resolved by referral to the hard copy of the article or
by review by another investigator.
We assumed that the randomization was adequately implemented
and that follow-up was complete in the studies that met our inclusion
criteria, unless otherwise stated in the published reports. The methodologic quality of the randomized controlled trials17 was considered by
the use of a validated instrument18 that independently assesses the
method of randomization, the use of double blinding (not applicable),
and the description of withdrawal and dropouts. Scores range from 0
(low quality) to 5 (high quality).
Data Collection and Statistical Analysis
The following information was gathered from each report: name of
the first author, year of publication, number of patients randomized to
locoregional radiation therapy or no locoregional radiation therapy,
stage of disease, type of surgery, type of systemic therapy, locoregional
sites irradiated, technique used, dose and fractionation schedule of
radiation, sequencing of chemotherapy and radiation therapy, median
follow-up, and the number of patients who experienced treatment
toxicity, whose disease recurred at any site, whose disease recurred
locally, and who died.
The analysis was performed on published data; no attempt was made
to obtain data on individual patients. The reported follow-up times for
any recurrence, locoregional recurrence, and death varied between
studies. The maximum published follow-up interval that was available
was used. Whenever possible, the raw number of events was used,
which was the case for the majority of the trials. In two trials, the
number of events was estimated from published survival curves. For
this approach, the follow-up time was restricted to a point at which
approximately 50% of the patients had been observed (median followup). The number of events was obtained by applying a set square to the
survival curve at the time of median follow-up, reading off the
percentage surviving, and multiplying by the total number of patients
randomized to the group to estimate the absolute number of survivors.
The validity of the abstracted data was assessed by repeated crosschecking. This approach is approximate but reasonably accurate in the
context of constant hazard and was considered sufficiently robust for
the purposes of this analysis.
In view of the limited description of toxicity in the reports, such data
were not summarized. To estimate the effect of treatment on any
recurrence, locoregional recurrence, and mortality, the results of
randomized trials were pooled using meta-analysis. The primary
analysis combined the study-specific odds ratios by use of precisionbased (or inverse variance) weights (alternatively called logit or
Woolf19 estimators) under the assumptions of both fixed and random
effects as described by Laird and Mosteller.20 In the fixed effect model,
the weighting of two of the largest studies3,5 was 50.4% of the total. In
the random effects model, the weighting for the two Danish studies was
37.8%. Results were similar, and those of the random effects model are
shown because they are the most conservative. The pooled treatment
effect is expressed as an odds ratio (⫾ 95% confidence interval [CI])
such that estimates more than 1.0 favor control and those less than 1.0
favor radiation therapy. All P values and 95% CIs were two-sided.
Assessments of homogeneity and overall association were undertaken
by use of ␹2 tests.
Exploratory Analysis of Factors That Influence the
Treatment Effect
An exploratory analysis was performed for patient and technical
factors that might influence the effect of treatment on mortality. The
consistency of the treatment effect (odds ratio) was compared between
studies grouped by the following variables: extent of disease (advanced, defined as stage III disease or ⬎ 50% of patients with ⬎ three
nodes positive, v early), degree of axillary dissection (extensive,
defined as an axillary evacuation, complete removal of contents, or a
minimum number of nodes [⬎ six] removed, v less extensive, defined
as ⱕ level II dissection with no minimum number of nodes specified),
anthracycline-based chemotherapy (yes v no), radiation technique
(mega- v orthovoltage), extent of radiation (all locoregional sites,
defined as chest wall or breast and supraclavicular, axillary, and
internal mammary nodes, v not), dose of radiation therapy (ⱖ 45 Gy
v ⬍ 45 Gy), timing of radiation therapy (⬎ 6 months since initiation of
systemic therapy v ⬍ 6 months), rate of locoregional failure in the
control arm (⬎ median v ⱕ median), and methodologic quality score of
study (ⱖ 2 v ⬍ 2).
A random effects regression model was applied to the data according
to the methods of Berkey et al.21 All factors were coded as 1 or 0, and
each was assessed individually and in the context of a multivariate
model that contained the other factors. The factors, degree of axillary
dissection, and rate of locoregional recurrence were not included in the
latter analysis because of the limited number of studies in which this
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1222
WHELAN ET AL
Table 1.
Trial (first author, year initiated)
22
RCTs of Locoregional Radiation Therapy: Patient Characteristics
No. of Patients
Stage
Surgery
Extent of AX Dissection
DeBoer, 1979
Foroglou,23 1979
Grohn,24 Klefstrom,25 1976
Tramprisch,26 1977
Blomqvist,27 1981
Hayat,28 1981
Amparo,29 Gervasio,30 1980
Cooper,31 Muss,32 1976
Schmoor,33 1984
Griem,34 1974
McArdle,35,36 1976
Ve´lez-Garcia,37–40 1976
Ahmann,41 Martinez,42 1973
50
71
79
88
99
112
112
159
199
218
219
239
241
NS
NS
III
NS
II
II
II
II
II
II & III
II
II & III
II & III
M
M
MRM
M
MRM
MRM
MRM
RM/MRM
MRM
MRM
MRM
RM/MRM
MRM
Olson,43 1982
Ragaz,4 1976
Arwidi,44 Ryden,45 Tennvall-Nittby,46 1978
312
318
768
III
II
I & II
MRM
MRM
MRM
NS
NS
AX fat removed
NS
AX evacuation
NS
NS
ⱖ 10 nodes removed
⬎ six nodes dissected
NS
Clearance of AX contents
Complete dissection ⱖ 10 nodes
Complete removal of AX
contents
⬎ eight nodes (median, 17)
Level II
Dissection to AX vein
II & III
II & III
TM ⫹ AD
TM ⫹ AD
Level I and part of II
Level I and part of II
Overgaard,5,47 1981
Overgaard,3 Mouridsen,48 1981
1,375
1,708
Chemotherapy
CMFP ⫾ BCG
Chemo-endocrine
VAC ⫾ levamisole
LMF
CAFt ⫹ tamoxifen
CMF
AC
CMF, L-PAM
CMF
CMF, MF, AC
CMF
CMF
CFP
CAFTH
CMF
Cyclophosphamide,
tamoxifen
Tamoxifen
CMF
Abbreviations: AC, doxorubicin, cyclophosphamide; AD, axillary dissection; AX, axillary; BCG, bacille Calmette-Guérin; CAFt, cyclophosphamide, doxorubicin,
ftorafur; CAFTH, cyclophosphamide, doxorubicin, fluorouracil, tamoxifen, fluoxymesterone; CFP, cyclophosphamide, fluorouracil, prednisone; CMF, cyclophosphamide, methotrexate, fluorouracil; CMFP, cyclophosphamide, methotrexate, fluorouracil, prednisone; LMF, Leukeran, methotrexate, fluorouracil; L-PAM,
melphalan; M, mastectomy, not otherwise specified; MF, methotrexate, fluorouracil; MRM, modified radical mastectomy; NS, not specified; RCT, randomized
controlled trial; RM, radical mastectomy; TM, total mastectomy; VAC, vincristine, doxorubicin, cyclophosphamide.
information was available. Only main effects (no interactions) were
considered. All testing was performed treating the ratio of the estimated
coefficient to its standard error as a t statistic, with degrees of freedom
equal to the number of studies minus the number of estimated
coefficients minus three. All P values and 95% CIs were two-sided.
RESULTS
Eighteen randomized trials that met our inclusion criteria
were identified and reviewed in detail (Tables 1 and 2).
Fifteen trials were published independently,3-5,24,25,27-48
and three trials were published only as part of a metaanalysis.22,23,26 The studies, which comprised a total of
6,367 patients, were initiated between 1973 and 1984. One
half of the trials (n ⫽ 9) involved fewer than 200 patients,
and only two trials involved more than 1,000 patients
(median, 209 patients; range, 50 to 1,708 patients). Median
follow-ups ranged from 7.5 to 14.5 years.
Patient Characteristics
Most trials included both pre- and postmenopausal
women. Two trials included only premenopausal patients,3,4
and one trial included only postmenopausal patients.5 The
majority of the trials limited eligibility to patients who were
node-positive. One trial was limited to patients with more
than four positive nodes,40 and two trials were limited to
patients with stage III disease.25,43 Several trials included
patients with node-negative breast cancer, stage III disease,
with either primary tumors greater than 5 cm or involvement of the skin or muscle.3,5,25,34,43 Only one trial included
patients with node-negative breast cancer with primary
tumors 2 to 5 cm.46
In the majority of trials, patients were treated with
modified radical mastectomies. No trials were identified that
treated patients with lumpectomies plus axillary dissections.
The extent of axillary dissection was reported in 12 trials. In
the majority of these trials, patients were treated with
extensive axillary dissections.25,27,32,33,36,40,42,43,46 In three
trials, patients were treated with less extensive dissections.3-5
Systemic Therapy
By definition, all trials included patients treated with
systemic therapy, and in three trials, different systemic
therapy was used for different strata.32,34,46 Cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy
was used in nine trials,3,4,22,28,32-34,36,40 an anthracyclinebased regimen in five trials,25,27,30,34,43 other polychemotherapy in three trials,26,34,42 and monochemotherapy in two
trials.32,46 Combined chemo-endocrine therapy was used in
three trials,23,27,43 and tamoxifen alone was used in two
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1223
LOCOREGIONAL RADIATION THERAPY
Table 2.
RCTs of Locoregional RT: Interventions
RT
Radiation Regimen
Trial (first author, year initiated)
22
Site
Dose
(Gy)
Fraction
Time
(weeks)
14
25-30
15-25
20
15
20-25
12
25
25
20
15
25
24
2.5
5-6
3-5
4
4
4-5
4
4-6
5
5
3
5
7.5
23
16
20
4.5
3-4
7
DeBoer, 1979
Foroglou,23 1979
Grohn,24 Klefstrom,25 1976
Tramprisch,26 1977
Blomqvist,27 1981
Hayat,28 1981
Amparo,29 Gervasio,30 1980
Cooper,31 Muss,32 1976
Schmoor,33 1984
Griem,34 1974
McArdle,35,36 1976
Ve´lez-Garcia,37-40 1976
Ahmann,41 Martinez,42 1973
CW, SC, AX
CW, SC, AX, IMN
CW, SC, AX, IMN
CW, SC, AX
CW, SC, AX, IMN
CW, SC, AX, IMN
CW, SC, AX, IMN
⫾ CW, SC, AX, IMN
CW, SC, AX, IMN
CW, SC, AX
CW, SC, AX, IMN
CW, SC, AX, IMN
⫾ CW, SC, AX, IMN
40
50-60
45-50
40
45
40-50
36-45
45-50
44-50
45
37.8
50
50
Olson,43 1982
Ragaz,4 1976
Arwidi,44 Ryden,45 Tennvall-Nittby,46
1978
Overgaard,5,47 1981
Overgaard,3 Mouridsen,48 1981
CW, SC, AX, IMN
CW, SC, AX, IMN
CW, SC, AX, IMN
46-50
35-37.5
38-48
CW, SC, AX, IMN
CW, SC, AX, IMN
48-50
48-50
22-25
22-25
5
5
Energy
Timing of RT
Megavoltage
Megavoltage/orthovoltage
Megavoltage
Megavoltage
Megavoltage
Megavoltage
Megavoltage/orthovoltage
Megavoltage
Megavoltage
Megavoltage
Orthovoltage
Megavoltage
Megavoltage/orthovoltage/
electrons
Megavoltage
Megavoltage
Megavoltage/orthovoltage/
electrons
Megavoltage/electrons
Megavoltage/electrons
NS
NS
Prechemo
NS
Sandwich, 2/3 cycles
Sandwich, 6/7 cycles
Prechemo
Prechemo
Sandwich, 2/3 cycles
Postchemo
Prechemo
Prechemo
Concurrent
Postchemo
Sandwich, 4/5 cycles
Concurrent
Concurrent
Sandwich, 1/2 cycles
Abbreviations: RT, radiation therapy; CW, chest wall; SC, supraclavicular lymph nodes; AX, axillary lymph nodes; IMN, internal mammary nodes; Prechemo,
before chemotherapy; Postchemo, after chemotherapy.
trials.5,46 Two trials used immunotherapy in addition to chemotherapy.22,25
Radiation Therapy
In the majority of trials, radiation was delivered to the
chest wall, supraclavicular, axilla, and internal mammary
nodal areas. In three trials, the internal mammary nodes
were not irradiated22,26,34; in two other trials, radiation to
the chest wall was optional, depending on the size of the
primary tumor32 or whether the tumor involved the skin.42
Field arrangements or techniques varied from trial to trial
and within trials. The chest wall was irradiated with two
tangent fields4,32-34,43 or with a single direct electron or
photon field.3,5,25,27,42,46 The supraclavicular and axillary
nodes were irradiated either with an anterior field with a
posterior patch3-5,25,27,34,42,43,46 or with an anterior field
alone.3,32-34,43,46 The internal mammary nodes were irradiated with a single anterior field4,25,43,46 or were included in
chest wall irradiation, either by the wide tangents32,37 or by
an electron field to the chest wall.3,5 An inverted L field (or
hockey stick) was used to treat the supraclavicular, axillary,
and internal mammary nodes in four trials.27,32,33,40 Techniques to avoid substantial cardiac irradiation by the use of
electrons alone3,5,46 or mixed electron photon beam33,43
were used in five trials. The technique was not described in
seven trials.22,23,26,28,30,36,40
Radiation was delivered primarily with megavoltage
linear accelerators. Orthovoltage was used either solely36 or
in combination with megavoltage machines23,30,42,46 in five
trials. The dose of radiation ranged from 35 to 60 Gy given
in 12 to 30 fractions. Radiation was delivered in 21⁄2 to 7
weeks. The most common fractionation schedule was 50 Gy
in 25 fractions over a 5-week period.3,5,23,25,28,32,33,40,42,43
Compliance with radiation therapy was reported in seven trials
and ranged from 68% to 100% (median, 96%).3-5,27,34,36,43
In two trials, fewer than 85% of the patients who were
randomized to radiation therapy received the intervention.34,43 The scheduling of radiation therapy and chemotherapy was described in 15 trials. Radiation was given
before chemotherapy in five trials,25,30,32,36,40 sandwiched
between cycles in five trials,3,4,27,28,33 concurrent with
systemic therapy in three trials,5,42,46 and after chemotherapy in two trials.34,43
Methodologic Quality of Studies
The methodologic quality scores along with the number
of trials that achieved them were as follows: 1 (seven trials),
2 (seven trials), and 3 (four trials). The four trials with a
score of 3 provided adequate description of the randomization procedure and the handling of withdrawals and dropouts. No trial involved blinded allocation to treatment, thus
higher scores were not obtained.
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1224
WHELAN ET AL
Fig 1. Meta-analysis of locoregional radiation therapy randomized trials: any recurrence.
Abbreviations: N, number; OR,
odds ratio; CI, confidence interval;
TAM, tamoxifen; CMF, cyclophosphamide, methotrexate, fluorouracil.
Toxicity
Data on toxicity of therapy were variably reported.
Information was available from eight trials.3-5,27,30,34,42,43
Acute toxicity was infrequently reported, occurring in the
trials as follows: severe skin toxicity, 2.7%43 and 5%42;
myelosuppression attributed to radiation therapy, 2%43 and
32%27; and radiation pneumonitis, 1%,4 15%,42 and 23%.27
Radiation esophagitis occurred in 17% of patients42 in one
trial. This last study had particularly high rates of acute and
long-term toxicity and was the only trial in which radiation
was given concurrently with chemotherapy.
With respect to late toxicity, no cases of brachial plexus
neuropathy were reported. Arm edema was reported in three
trials. The incidence ranged from 0% to 25% (median, 3%)
in nonirradiated patients and from 10% to 54% (median,
12%) in irradiated patients.4,42,43 Cardiac toxicity, primarily
congestive heart failure, was reported in six trials.4,27,30,34,42,43 In trials using CMF, no cardiac complications were reported in patients treated with chemotherapy
alone.4,42 One case of pericarditis was reported in a patient
treated with CMF and radiation therapy.42 In trials in which
patients were treated with anthracycline-containing chemotherapy,27,30,34,38 the incidence of congestive heart failure in
nonirradiated patients ranged from 0% to 19.2% (median,
2.6%). The incidence of cardiac failure in irradiated patients
ranged from 1.9% to 23.6% (median, 3.2%). In two other
studies,3,5 no increase in 12-year cumulative morbidity or
mortality from ischemic heart disease was observed in
irradiated patients.49 The incidence of secondary cancers
was reported in only two trials4,32; no increase was noted in
irradiated patients. One case of acute myelogenous leuke-
mia was reported in a patient treated with CMF and
radiotherapy.4
Recurrence and Mortality
Data for recurrence were available for 13 trials. Radiation
was shown to reduce the risk of any recurrence, with an
odds ratio of 0.69 (95% CI, 0.58 to 0.83; P ⫽ .00004) (Fig
1). This seemed to be largely a result of a reduction in local
regional recurrence, with an odds ratio of 0.25 (95% CI,
0.19 to 0.34; P ⬍ .000001) (Fig 2).
Data for mortality were available for all trials. Radiation
was shown to reduce mortality with an odds ratio of 0.83
(95% CI, 0.74 to 0.94; P ⫽ .004). The test for heterogeneity
was negative (P ⫽ .26) ( Fig 3). A positive treatment effect
was seen in six of nine trials that contained more than 200
patients. In two of the three trials with negative treatment
effects, compliance with radiation therapy was poor.
The meta-analysis was performed excluding the two large
Danish trials.3,5 The resulting odds ratio for mortality was
0.89 (95% CI, 0.76 to 1.05; P ⫽ .17). We compared these
two studies with the remaining studies in a regression
model; the difference between the study data sets was not
significant (P ⫽ .15).
Exploratory Analysis of Factors That Influenced the
Treatment Effect
On univariate analysis, only timing of radiation therapy
(ⱖ 6 months v ⬍ 6 months) was statistically significant
(Table 3). The odds ratio for mortality in the trials in which
radiation was administered within 6 months of starting
chemotherapy was 0.78, compared with 1.14 in trials in
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1225
LOCOREGIONAL RADIATION THERAPY
Fig 2. Meta-analysis of locoregional radiation therapy randomized trials: locoregional recurrence.
which radiation was delayed. On multivariate analysis,
timing of radiation continued to demonstrate an effect on
treatment (P ⫽ .03), and radiation technique (megavoltage
v orthovoltage therapy) was also shown to be predictive of
treatment effect (P ⫽ .05).
DISCUSSION
The role of locoregional radiation therapy after definitive
surgery in the management of breast cancer has been
evaluated extensively since 1949. The majority of early
trials focused on patients who did not receive adjuvant
systemic therapy. These studies showed that radiation decreases locoregional recurrence, but an effect on overall
survival has not been detected. Many of these trials were of
relatively small sample size. An update reported by Cuzick
et al1 of a meta-analysis of trials that were initiated before
the era of chemotherapy or hormonal therapy suggests that
locoregional radiation after mastectomy decreased deaths
caused by breast cancer but that this decrease was offset by
an increase in deaths caused by cardiac disease. The excess
risk for cardiac mortality seems to be greatest for trials that
used older radiation techniques in which a high dose was
delivered to the myocardium, eg, with the use of orthovoltage therapy to treat the chest wall50 or wide tangents to treat
the internal mammary nodes.51 The results of recently
published randomized trials of radiation therapy after mas-
Fig 3. Meta-analysis of locoregional radiation therapy randomized trials: mortality.
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Copyright © 2000 American Society of Clinical Oncology. All rights reserved.
1226
WHELAN ET AL
Table 3.
Effect of Radiation on Mortality: Influence of Patient or
Treatment Factors*
Factor
Extent of disease
Early
Advanced
AX dissection
Less Extensive
Extensive
Anthracycline use
No
Yes
Radiation technique
Megavoltage
Orthovoltage
Extent of radiation
All sites
Not all sites
Dose of radiation
ⱖ 45 Gy
⬍ 45 Gy
Timing of radiation
⬍ 6 months
ⱖ 6 months
Locoregional recurrence
⬎ 24%†
ⱕ 24%
Methodologic quality
ⱖ2
⬍2
No. of
Studies
Odds
Ratio
95% CI
P
(random effects)
10
5
0.79
0.93
0.70-0.90
0.70-1.22
.53
3
9
0.73
0.90
0.62-0.86
0.73-1.10
.12
13
5
0.79
1.00
0.70-0.89
0.73-1.38
.25
13
5
0.78
0.94
0.69-0.89
0.74-1.19
.40
13
5
0.79
1.05
0.70-0.89
0.77-1.45
.10
12
6
0.79
0.89
0.70-0.90
0.71-1.11
.65
12
3
0.78
1.14
0.69-0.89
0.80-1.62
.05
6
7
0.77
0.89
0.66-0.90
0.73-1.10
.60
11
7
0.80
0.92
0.71-0.91
0.65-1.29
.59
* Univariate analysis in random effects regression model.
† Median value.
tectomy in patients treated with systemic therapy demonstrate that radiation not only reduces the risk of locoregional
failure, but improves survival.3-5 These trials have stimulated much discussion about the role of locoregional radiation after surgery in present-day clinical practice.6,7 To gain
a better understanding of the use of this modality, we
performed a systematic review of all randomized trials of
locoregional radiation therapy after definitive surgery in
patients treated with systemic treatment.
The results of the meta-analysis are consistent with the
three recently published trials, ie, locoregional therapy not
only reduced local failure, but improved disease-free and
overall survival.3-5 Why are the results of our meta-analysis
different from those of previous randomized trials and
meta-analyses?52 First, this meta-analysis focused only on
patients who were treated with systemic therapy. The
meta-analysis by Cuzick et al1 did not include these trials.
The overview by the Early Breast Cancer Trialists’ Collaborative Group did not specifically focus on this group of
patients.2 We wanted to test another hypothesis that could
potentially explain why previous meta-analyses failed to
detect an impact of radiation therapy on mortality. This
hypothesis was that patients required adjuvant systemic
therapy to allow locoregional radiation to manifest its effect.
Systemic therapy, particularly chemotherapy, though effective in preventing distant metastases, is likely to be less
effective in preventing locoregional recurrence in which the
tumor burden is large. In patients who have distant failures
reduced with chemotherapy, the effect of radiation therapy
on preventing locoregional recurrence and resulting secondary systemic recurrence may be more evident. We performed a systematic review to determine which trials were
appropriate to include. Each trial was scrutinized to determine eligibility and to extract appropriate data. One trial14
included in the previous overview by the Early Breast
Cancer Trialists’ Collaborative Group was excluded in our
meta-analysis because it contained patients with locally
advanced disease not treated by definitive surgery. One
published trial25 that was not included in the overview was
included in our meta-analysis.
Second, a number of the trials in our meta-analysis had
longer follow-up than was available in trials from previous
published meta-analyses.2 Third, many trials included in our
meta-analysis used relatively modern radiotherapy techniques, which delivered a more uniform dose and avoided
excessive cardiac irradiation that could have resulted in
increased tumor-cell kill and decreased cardiac mortality.
The two Danish studies are noteworthy in this regard for
their use of a technique that substantially reduced cardiac
irradiation. The limited reports of long-term toxicity support
this association,49 but further follow-up will be necessary to
confirm this effect.
We recognize that two of the largest trials in the metaanalysis were positive. However, it is important in any
meta-analysis to include all studies. We used the random
effects model to weight all the trials that were included in
our analysis. This is conservative because it gives less
weight to larger trials than does the fixed effects model.3,5 In
addition, although there are limitations to such an approach,
we performed the meta-analysis excluding the two Danish
trials. The results, excluding these trials, were not inconsistent with the overall results.
Even though our results demonstrate an impact of locoregional radiation on survival, the issue is whether the results
are generalizable to current clinical practice. The reviewed
studies were initiated 15 to 25 years ago and, for the most
part, represent patients with node-positive breast cancer
treated with modified radical mastectomy, CMF chemotherapy, or tamoxifen who received radiation to the chest wall
and all nodal areas at risk either before or within several
months after starting systemic therapy. Breast cancer treatment has changed dramatically since the inception of these
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Copyright © 2000 American Society of Clinical Oncology. All rights reserved.
1227
LOCOREGIONAL RADIATION THERAPY
studies in terms of surgical management, systemic treatment, and radiation therapy. Presently, many women with
node-positive breast cancer are treated with lumpectomies
and level I and II axillary dissections. Most are also treated
with breast irradiation consistent with the goal of breastconserving therapy. It remains unclear what additional
benefit further locoregional radiation would have in this
situation. The technique for providing breast irradiation
often results in a substantial dose of radiation not only to the
chest wall, but to the dissected lower axilla and a proportion
of the internal mammary nodes. Systemic treatment has also
changed. Presently, many women are treated with more
effective anthracycline-based regimens followed by longterm hormonal therapy. Again, it remains unclear what
additional benefit in absolute terms locoregional radiation
would have in this context, and concern remains about the
potential for increased cardiac toxicity when radiation
therapy is delivered in addition to anthracycline-based
chemotherapy.9 Finally, the timing and extent of radiation
therapy has also changed. Radiation is now commonly
delivered after chemotherapy to avoid acute interactions
with chemotherapy, and the internal mammary nodes are
infrequently treated because of the low risk of recurrence
and to avoid excessive cardiac irradiation.
The results of the exploratory analyses showed that when
radiation is delivered with older techniques, such as the use
of orthovoltage, or is given 6 months after the initiation of
systemic therapy, it may be less effective. It is important
that these results are interpreted cautiously, because they
involve indirect nonrandomized comparisons between trials
and because the relatively small number of trials evaluated
leads to the risk of false-positive and false-negative conclusions. The use of orthovoltage is associated with increased
intrathoracic, including cardiac, irradiation53 and has been
associated previously with increased long-term cardiac
morbidity.50,54 Delay in radiation therapy has been associated with decreased locoregional control.55,56 Radiation
therapy was delivered after six months of systemic therapy
in only three trials, and it is unclear whether the effect on
treatment had more to do with poor compliance in these
studies or with a true biologic effect. Locoregional radiation
therapy also seemed to be less effective when all regional
sites were not irradiated and in patients treated with anthracycline-based chemotherapy, but these associations were
not statistically significant. These results raise many interesting questions about the incorporation of locoregional
radiation therapy in modern practice, in which anthracycline-based chemotherapy is commonly used and radiation
therapy is often given after completion of systemic therapy.
These associations need to be evaluated further in future
trials that assess the role of locoregional radiation therapy.
A potential limitation of our meta-analysis is that it was
based on trial-specific rather than patient-specific data.
These different types of meta-analyses have been referred to
as meta-analysis of the literature and meta-analysis of
individual patient data (MAP), respectively.57 A number of
concerns have been discussed in the literature regarding
meta-analyses that are based on trial-specific or aggregate
data.57,58 These include lack of incorporation of unpublished trials, inclusion of trials with relatively short followup, the use of estimated event rates obtained from published
reports, and analysis based on end-of-trial event rates
instead of on the measurement of the effect of treatment
over time. The systematic review in this study included both
published and unpublished trials that were published as part
of a previous meta-analysis. One trial with a relatively short
follow-up was excluded from the analysis, and in only two
of 18 trials were event rates estimated. The meta-analysis
performed on these studies was based on end-of-trial event
rates. Concern that such analyses that use odds ratios may
be less accurate than those that incorporate hazard ratios has
not always been substantiated. In a previous study of patients
with ovarian cancer, the results of these analyses were not
markedly different.57 The median follow-up of trials incorporated in our meta-analysis was more than 10 years. It is likely
that any treatment effect obtained from radiation given 10
years previously would be less at the time of follow-up.
However, a 10-year follow-up may not provide sufficient time
for any negative effect on mortality, such as cardiac toxicity, to
become evident.59 This represents a potential limitation of the
analysis, but the data support a benefit of locoregional radiation
for up to 10 years.
Through a systematic review, we had the opportunity to
extract data not found in previous meta-analyses regarding
the methodologic quality of studies, the influence of treatment factors (eg, timing of radiation) on outcome, and
toxicity.1,2 Another potential benefit of an analysis based on
published data is the inclusion of trials for which only
published data is available, as was the case for one particular study in our analysis.25 We believe a MAP would be an
important step in the assessment of locoregional radiation
therapy and may provide a better quantitative estimate of
the treatment effect. However, given the large number of
trials involved in our meta-analysis, it is unlikely that the
results of the meta-analysis would change qualitatively.
Individual patient data would also afford investigators more
power to consider potential predictive factors of the treatment effect. It is important to note, though, that a MAP may
not overcome the problems of lack of generalizability of
results caused by changes in practice over time.
The results of this meta-analysis support an evolution in
oncologists’ thinking concerning the biology of breast
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Copyright © 2000 American Society of Clinical Oncology. All rights reserved.
1228
WHELAN ET AL
cancer. One half century ago, the prevailing theory was that
breast cancer spread by stepwise local extension, which
resulted in more extensive surgery. By the 1970s and 1980s,
this view had been replaced by that of breast cancer as a
systemic disease. The recent thinking is that both hypotheses are valid.60 Our results support the notion that, in the
presence of adjuvant systemic therapy, local regional control is important and that reduction in locoregional recurrence may prevent secondary systemic spread from regional
sites and, thus, prolong survival. Since the inception of these
trials, many changes have occurred in the management of
breast cancer, and it remains unclear how locoregional radiation should be incorporated into current practice. Several
randomized trials that evaluate the integration of locoregional
radiation into the current management of breast cancer are in
progress or in the planning stages. On the basis of our review,
it is vital that these studies have sufficient power to detect
important clinical differences and to consider the potential
impact of treatment variables such as radiation technique and
timing of radiotherapy on mortality and toxicity. These studies
will help clarify the role of this treatment modality in the
current multidisciplinary management of breast cancer.
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Copyright © 2000 American Society of Clinical Oncology. All rights reserved.