CANCER OF THE BREAST

The Role of Radiation Therapy After Mastectomy

LUTHERw. BRADY,MD,* GILBERT MD+ AND SEYMOUR H. LEVITT,
H. FLETCHER, MDt

Breast cancer represents the most common malignancy in women accounting

for at least 25% of all cancers in women. The survival pattern for five-year
periods since 1940 to 1969 show a similarity of death patterns indicating that
patients continue to die of their disease u p to 15 and 20 years after diagnosis.
Proper management of early stage disease remains an enigma despite repeated
clinical studies of alternative treatment techniques. With the advent of more
effective screening techniques, more patients are being shown to have dissemi-
nated disease at the time of initial diagnosis, clinically unsuspected. From these
data, major factors have emerged which allow for the prediction of the ultimate
survival of the patient with breast cancer. The successful treatment for breast
cancer must be measured not only by survival but by local and regional control
of the disease process. Local treatment, whether surgical, radiotherapeutic, or a
combination of both, only influences the disease process within the treated area
and can have no significant effect on occult distant metastases already present at
the time of the initial treatment. Local treatment can, however, control disease
on the chest wall and in the regional lymphatics of the breast. The role of
radiation therapy in the management of carcinoma of the breast varies widely
depending upon the extent and the rate of progression of the disease. Freedom
from local-regional tumor is of immeasurable benefit to patients whose quality
of life is thus profoundly improved. Continued evaluation of therapeutic mod-
alities available for the treatment of carcinoma of the breast has failed to answer
basic questions. Data are now available to support the need for postoperative
radiation therapy in selected groups of patients. Waiting until there is local or
regional recurrence of breast cancer only allows for associated dissemination of
the disease. The majority of patients presenting with chest wall recurrence also
have disseminated disease at the same time. It must be emphasized that selec-
tion in almost all series blurrs the results. Therefore, caution is mandatory in
their interpretation. The ultimate appropriate treatment program in light of
the data presently available may prove to be surgery, postoperative radiation
therapy, and long-term chemoprophylaxis.
Cancer 39:2868-2874, 1977.

T H E SUCCESSFUL T R E A m E N r FOR BREAST CAN-

cer must be measured, not only by survival,
but also by local and regional control of the
disease process. Local treatment, whether surgi-
cal, radiotherapeutic, or a combination of both,
only influences the disease process within the
treatment volume. It has no effect on occult
distant metastases already present at the time of
initial treatment. Freedom from local regional
tumor is of great benefit to patients whose qual-
ity of life is thus profoundly improved.
Careful documentation of anatomic lymph

Presented at the Conference on Breast Cancer: A Rcport
to the Profession. sponsored by the White House, the Na-
tional Cancer Institute and the American Cancer Society,
November 23-23, 1976, Washington, n.C .
From the *Hahnemann hledical College and Hospital,
Philadelphia. PA; the '[Jniversity of Texas System Cancer
C:entrr. h1.D. Anderson Hospital and l'umor Institute,
Houston TS; and 'University of Minnesota School of
hledicine. Minneapolis, h l N .
* Hylda Cohn/American Cancer Society Professor of
Clinical Oncology and Professor and Chairman, 'Depart-
mcnt of Radiation Therapy and Nuclear Medicine, The
2868
Hahnemann Medical College and Hospital, Philadelphia,
PA.
' Professor and Head, Department of Radiotherapy, The
University of Texas System Cancer Center, h1.D. Anderson
liospital and Tumor Institute, Houston, TX.
I Professor and Chairman, Department of Therapeutic
Radiology, University of Minnesota, School of Medicine,
Minneapolis, .MN.
Address for reprints: Luther W. Brady, M D , Department
of Radiation Therapy and Nuclear hledicine, Hahnemann
Medical College and Hospital, 230 N. Broad Street, Phila-
delphia, PA 19102
Accepted for publication iMarch 2, 1977.
No. 6 THERAPY
ROLEOF RADIATION AFTER MASTECTOMY Brady et al. 2869

\
Suprrclrviculrr nodes
d J , ~ l n t r r n r ~ jugular route
\ \ -,Sentinel-Dlep inferior

Central nodrs t rrnrpectorrl route

Interpectorrl nodes
Of Rottar
-
FIG. 1. Three major routes for
spreading of breast cancer

Retropectorrl ro
Int. mammary route

Ant. prepericrrdirl nodes

97 -'c

node drainage has evolved from study of the
evolution and spread of breast cancer. T h e de-
tailed study of lymphatic channels has identified
three major routes of spread: 1) directly into the
axilla; 2) via the interpectoral chain to the ax-
illary apex and supraclavicular nodes; and 3)
into the internal mammary chain. (Fig. 1).l 3
There is no more controversial subject in the
management of carcinoma of the breast than
the use of postoperative irradiation in conjunc-
tion with radical or modified radical mas-
tectomy. 5 ~ 7 ~ 1 2 ~ 1 s ~ 1 8 ~ 2 3 ~ 2Throughout
6~27~28
and the 1940s, there was an abundance of liter-
ature on the subject without conclusive evidence
that postoperative irradiation after radical mas-
tectomy increased survival rates. Until 1950, the
techniques employed treated the chest wall, the
dissected axilla, and, occasionally, the supracla-
vicular fossa. Low dosages were employed and
there was no attempt to irradiate the internal
mammary chain.
1. Control of Subclinical Disease with Irradiation in Breast Cancer within Five Years
TABLE
(Supraclavicular and Parasternal Areas)
T h e first randomized clinical trial of post-
operative irradiation in conjunction with radical
mastectomy was carried out in Manchester in
the mid 1 9 5 0 ~It. ~did
~ not show an increased
survival rate, but only a diminution in lo-
cal/regional failures. The program utilized 250
kV with the dose of 3250 R in three weeks at a
midpoint through parallel opposed portals to
the supraclavicular area and axilla. To the inter-
nal mammary chain field, 4250 R skin dose was
delivered in three weeks. Since then, there have
the 1930s been several randomized trials of irradiation
combined with radical mastectomy or simple
mastectomy with irradiation compared with ex-
tended radical or radical mastectomy. Other
trials of simple excision of the tumor with irra-
diation have been compared with radical mas-
tectomy. In all of these trials, including those
reported by M ~ W h i r t e r , 'Kaae,
~ the Guy's
Hospital Randomized Trial, the Cancer
Campaign Study,' the National Surgical Adju-

Axillary
recurrence Supraclavicular recurrence Parasternal nodule

Without irradiation Axilla +in the Surgical +

Axilla in Surgical Specimen''
20-2670 9% Central or Inner Quadrants
(25/ 264)

2%" Axilla + in the Surgical Specimen +

Axilla in Surgical S p e ~ i m e n ~ " ~ ~
With irradiation 11-13% 3500 rads/3 w k s l l ~ l a 0% Central or Inner Quadrants
1.5% 4500-5000 rads/ 5 wks" (0/204) 4500-SO00 rada/S wks
1.2% 5000-5500 rads/7 wks"
2870 CANCER
June Supplement 1977 Vol. 39

TABLE
2. Carcinoma of the Breast: Incidence of Local Recurrence in a Randomized Study

Site of
Treatment recurrence One year ( W ) Two years ( W ) Three years (%)

Surgery and radiotherapy Chest wall 1.4 3 4.6

Nodal 0.7 1 1.7
Both 1.9 (of 427) 3 (of303) 5.1 (of 175)

Surgery only Chest wall 4.8 9.6 12

Nodal 5.8 12 7.1
Both 9.2 (of 207) 17 (of 146) 17 (or84)

From: de Schryver, 1976.'

vant Breast Program,' etc., all indicate that
there was no improvement in the survival rates
in the combined treatment. However, in several
series a diminution in the incidence of lo-
cal/regional failures has been observed with the
combined treatment (Tables 1 and 2).
For the first time, in July 1976, a randomized
clinical trial of radical mastectomy alone or with
postoperative irradiation using a 'Cobalt tele-
therapy device has shown statistically significant
improved crude and disease-free survivals in the
postoperatively irradiated group of patients with
histologically positive axillary nodes. (Fig. 2)"9"
In the study by Host there is an increased sur-
vival rate when postoperative irradiation is given
with 'Cobalt teletherapy through direct portals
when compared with kilovoltage radiation ther-
apy (Fig. 3). In the two phases of the study, the
survival curves in the patients operated alone are
identical indicating that the clinical material
was the same in the two phases of the study.
(Fig. 4) Host concludes that the improved sur-
vival rates utilizing the 'Cobalt teletherapy in-
strumentation are due to an increased tumor
dose. Local and regional recurrences were fewer
in the irradiated group of patients with Stage I1
disease (Table 3).
Distant metastases were observed at the same
rate in Stage I patients in both treated groups.
(Table 4) I n the patients with Stage I1 disease,
however, distant metastases were seen in 28% of
the patients in the irradiated group compared
with 39% of the patients treated by surgery
alone. The latter difference is mainly due to an
earlier occurrence of metastases in Stage I1 pa-
tients who were treated by surgery alone. Thus,
only 11 patients in the 'Cobalt irradiated group
had distant metastases during the first two years
compared to 2 1 patients who had surgery alone.
A statistically significant higher cure rate with a
technique of irradiation of the peripheral lym-
phatics leads one to critically review all of the
previous clinical randomized trials of post-
operative irradiation in combination with radi-
cal mastectomy, modified radical mastectomy,
or simple mastectomy.

FIG. 2. Stage I1 mammary car-

cinoma 'Oco trial, axillary nodes
histologically positive.

0 2 4 6 0 2 4 6
Years after t r e a t m e n t Years after t r e a t m e n t
Survival F r e e o f disease
P= 0.05

From: Host, Herman, 1976

No. 6 THERAPY
ROLEOF RADIATION AFTER MASTECTOMY Brady et a/.
c
C
Q)
2 \\
2 \
60
- '
\t
0 2 4
Years a f t e r c o m b i n e d t r e a t m e n t
6 40
Internal mammary chain and chest wall
o---d
through tangential portals
2,500 Rads to 3,100 Rads
Supraclavicular area and axilla
through parallel opposed portals.
-
3,600-Rads front skin doses
1,800 Rads back}
lnfraclavicular and supraclavicular
areas and internal mammary chain
through direct portals.
5.000 Rads in 4 weeks
From: Host, Herman, 1976.
FIG. 3. Stage I1 mammary carcinoma-axillary
histologically positive.
Such a careful review has been carried out by
Fletcher" demonstrating that all of the pre-
viously reported clinical trials fail to show any
improved survival rate when radiation is used
postoperatively in conjunction with mas-
tectomy, since the crucial lymph nodes received
an uncertain radiation dosage because of lack of
proper anatomical coverage. Five thousand rads
in five weeks delivered through direct portals
with careful attention to the patterns of regional
dissemination eliminate the appearance of
supraclavicular and parasternal lymph node in-
volvement. (Table 5). With lower dosages or
lack of coverage by treatment, the control rate
drops drastically. (Table 6) The data derived
from the histologic examination of the specimen,
the location of the tumor in the breast, and the
status of the axillary lymph nodes must be in-
corporated into the determination of the appro-
priate treatment plan for the patient.
T h e indications for irradiation of the pe-
ripheral lymphatic areas alone have been formu-
2871
58%
I
0 2 4 6
Years after surgical treatment
From: Host, Herman, 1976.
FIG. 4. Survival curves for patients with surgery only.
lated by Tapley. (Table 7). A minimum tumor
dose of 5000 rads to the peripheral lymphatic
areas delivered in five weeks is adequate yielding
high local control rates without producing sig-
nificant fibrosis or other complications. Since
only the apex of the axilla is irradiated, the
incidence of arm edema is not increased beyond
nodes that produced by the radical mastectomy.
Chest wall recurrences will be more frequent
when positive axillary lymphadenopathy is
found, when the breast mass is large, or when
the tumor involves skin or underlying tissue by
attachment or edema. If a large number of ax-
illary lymph nodes are involved with tumor, the
local recurrence rate may reach 45%. Patients
with primary lesions 1 cm or less in diameter
rarely develop chest wall recurrences, although
when the lesion becomes 5 cm or more in diame-
ter more than 33% of the patients will develop
local recurrences. Therefore, this must be taken
into consideration in the choice of individuals
who would be postoperatively irradiated.
TABLE 3. Cancer of the Breast, Phase 2 Study:
Frequency of Homolateral Supraclavicular Lymph Node
Metastases
" 0 Controls
Stage I 3/171 (1.8%) 5/186 (2.7%)
Stage 11 3/95 (3.2%) 13/92 (14.1%)
From: Host, 197615
2872 CANCER
June Supplement 1977
TABLE 4. Cancer of the Breast, Phase 2 Study:
Frequency and Time from Primary Treatment to Appearance of First Distant Metastasis
Frequency
T O 21/171 (12%)
Stage I 19/186 (10%)
Controls
T O 27/95 (28%)
Stage I1
Controls 36/92 (39%)
From: Host, 1976.''
A treatment program to the chest wall should
be done either through parallel opposed tan-
gential fields using a photon beam in the mega-
voltage range or, if appropriate, electron beam
with appropriate energy selection predicted o n
the thickness of the chest wall. The calculated
tumor dose should be 5000 rads in five weeks
delivered by these techniques. It is more appro-
priate to irradiate the lymph nodes draining
the breast in separate fields from those used to
treat the chest wall. The indications for irradia-
tion of the peripheral lymphatic areas and the
chest wall are identified in Table 8."
Axillary recurrences are extremely rare follow-
ing radical axillary dissection for operable dis-
ease. Since postoperative irradiation of the en-
tire axilla causes a slight increase in arm edema,
the entire axilla is irradiated only when 1 ) very
few lymph nodes have been recovered suggesting
an incomplete axillary dissection; 2 ) where there
is preoperative description of a large axillary
lymph node greater than 3 cm in diameter with
or without fixation; and 3) where there is extra
nodal disease described in the pathology report.
Recent data from the Stockholm Breast Can-
cer Trial' indicate that the survival disease-free
rates are better with either preoperative or post-
operative radiation therapy. It is pointed out
that this increased survival is due to the eradica-
tion of disease locally and regionally. This is
TABLE 5. Effectiveness of Local Regional Irradiation in
Breast Cancer
Axilla pusitive in surgical specimen
No irradiation*' 4,500-5,000 rads/
Supraclavicular 5 wks to peripheral regression of tumors, they explored different
lymphatics"
20-26% 1.5%
Axilla positive in surgical specimen
central or inner quadrant ~ l
N~ irradiation= 4,500-5,000
Parasternal 5 wks to peripheral than cells with markers for B-lymphocytes.
lymphatics
(MDAH)
9% 0 90
(2 5/ 264) ~ 2 0 4 ) lymphocytes. Thus, three years after radio-
VOl. 39
Months following primary treatment
0-11 12-23 24-
3 9 9
2 6 11
2 9 16
8 13 15
demonstrated by the greater incidence of local
and regional failures in the non-irradiated pa-
tients. There was no significant difference in the
Stockholm Trial in distant metastases between
the two groups of patients treated. The fact that
distant metastases appear at the same time in
the irradiated and non-irradiated patients is an
important observation. Other reports have in-
dicated that distant metastases may appear
sooner in the irradiated group relating it to the
effects of radiation on the immune response.
These data are not borne out by the results of
the Radiumhemett Trial. 15,1'
Evidence has suggested that local radio-
therapy is immunosuppressive. l4 Recent data
also confirm the fact that age, nutrition, surgery,
chemotherapy, as well as many other events to
which the patient is subjected, are also immuno-
suppressive for varying periods of time. I n cer-
tain animal tumors, Crile' and Perez et ~ 1 . have
'~
suggested that far less immunosuppression re-
sults from radiation than from surgical removal
of the regional lymph nodes. The question,
therefore, of the influence of radiation on the
immune mechanism is, at best, unclear.
I n a recent report by Blomgren et a1.' a re-
evaluation of the studies concerning radiation
induced changes of the circulating lymphocyte
pool in breast cancer patients treated with ra-
diotherapy was carried out. They confirmed
that radiation therapy directed to different parts
of the body can induce severe peripheral
lymphopenia. Since experimental studies have
show that T-lymphocytes may be important for
lymphocytes subpopulations in the radiotherapy
treated patients with carcinoma of the breast.
I n coitrast to the results of Stjernswgrd et
. they repeatedly demonstrated that cells
~ ~ 9 ~ ~
with markers for T-lymphocytes decrease less
However, they emphasize that the regeneration
of B-lymphocytes is more rapid than that of T-
therapy given postoperatively in breast cancer,
No. 6 THERAPY
ROLEO F RADIATION AFTER MASTECTOMY Brady et al.
TABLE
6. Control of Subclinical Disease
in Function of Dose*
Adenocarcinoma of the breast
3,000-3,500 rads (89pts) =60-70%
4,000 rads (121 pts) =80%
5,000 rads (273) pts) >95%
From Fletcher, 1974.
* 1,000 rads/week-5 days a week.
there is still a T-lymphopenia. The conflicting
evidences of Stjernswtird et al. may be explained
by his use of incompletely purified lymphocyte
preparations when determining lymphocyte
subpopulations. Monocytes which are know to
increase in frequency after radiotherapy and
which were not removed by these investigators
have surface markers in common with B-
lymphocytes. Thus, the tests performed by
Stjernswiird et al. 28,30 might have falsely yielded
low frequency of T-lymphocytes.
I n contrast to the findings of Stjernswiird et
al.29*30 and in accordance with those of McCredie
et a1.,22 Blomgren el a1.’ did not observe any
significant depression of PHA response in vitro
following radiotherapy. The PPD reactivity, on
the other hand, is markedly depressed immedi-
ately after radiotherapy and returns to normal
levels about five months after treatment. Con-
trary to the statements of Stjernswiird, Blom-
gren et al. have not seen any difference in the
relative frequency of T-lymphocytes between ir-
radiated and non-irradiated breast cancer pa-
tients with metastases. The irradiated patients,
however, have lymphopenia and for this reason
their total T-lymphocyte counts are lower. The
number of patients examined until now has been
very limited due to the fact that most patients
with metastases are on drug treatment making
them unsuitable for lymphocyte studies. O n the
other hand, observations indicate a significant
correlation between PPD response in vitro and
the presence of metastases, the stimulability of
lymphocytes in the presence of PPD being
strongly depressed at the time of discovery of
distant metastases.
Therefore, there is no evidence that there are
diminished survival rates with postoperative ir-
radiation. 20*21 Stjernswiird’s data are invalid be-
cause he failed to use the recent survival rates of
the Edinburgh trial but also because he used the
crude survival rates and not the disease-free
rates from the Fisher trial.
Continued evaluation of therapeutic mod-
alities available for carcinoma of the breast is
only now beginning to give answers to basic
questions. There is absolutely no statistically
2873
TABLE 7. Cancer of the Breast: Indications for Irradiation
of Peripheral Lymphatic Areas Alone
Histology
of axillary Areas
Location of the lesion nodes irradiated
~ ~~~ ~~
Outer quadrants negative none
Small inner of central negative internal
quadrant lesions mammary
chain nodes
Outer, inner, or central few positive peripheral
quadrant lesions (< than 20%) lymphatics*
without grave signs
* Supraclavicular fossa, apex of axilla, internal mammary
node chain.
valid evidence that radiation therapy after de-
finitive surgery for breast cancer affects the sur-
vival in a deleterious way.20,21The data from
Host substantiate that claim. Postoperative irra-
diation in breast cancer diminishes the in-
cidence of local/regional failures, and Host’s
data show a n improved survival rate and higher
disease-free rates.
As with any experimental treatment program,
individual, uncontrolled, experimental regi-
mens, however well intentioned, should not be
undertaken foolishly. T h e value of the various
treatment techniques available in carcinoma of
the breast must be demonstrated without ques-
tion, recognizing the known, suspected, and po-
tential risk of the treatment involved.
It must be emphasized that selection blurs all
results. Therefore, caution is required in their
interpretation. The ultimate appropriate treat-
ment program in the light of the present avail-
able data may prove to be surgery, postoperative
radiation therapy, a n d long-term chem-
oprophylaxis.
Classical radical mastectomy or modified
radical mastectomy performed on patients with
clinically operable outer quadrant disease with a
histologically negative axillary dissection pro-
duces excellent results in terms of survival and
local/regional control of tumor. These patients
do not need postoperative radiation therapy. Pa-
tients with central or inner quadrant primary
tumors with or without histologically positive
axillary nodes as well as patients with outer
quadrant lesions with positive axillary nodes
TABLE
8 Indications for Irradiation of Peripheral
Lymphatic Areas and Chest Wall
20% or more positive axillary nodes
Breast mass < 5 cm
Fixation of tumor to pectoral fascia
Skin fixation, edema, or erythema
Multiple foci of invasive tumor
Vascular, perineural, or lymphatic invasion
2874 CANCER
June Supplement 1977
should receive postoperative radiation therapy.
The objectives in the use of radiation therapy
as an adjuvant to radical mastectomy or modi-
fied radical mastectomy are often poorly de-
fined. However, the utilization of postoperative
radiation therapy should be carried out in those
patients where identifiable factors influencing
the prognosis of the patient can be altered by the
administered treatment program. Under those
circumstances, the irradiated volumes and dos-
ages are absolutely critical to the ultimate out-
come.. Therefore, the volumes to be treated
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