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
treatment volume. It has no effect on occult
distant metastases already present at the time of
initial treatment. Freedom from local regional
disease process. Local treatment, whether surgi- tumor is of great benefit to patients whose qual-
cal, radiotherapeutic, or a combination of both, ity of life is thus profoundly improved.
only influences the disease process within the Careful documentation of anatomic lymph

Presented at the Conference on Breast Cancer: A Rcport Hahnemann Medical College and Hospital, Philadelphia,
to the Profession. sponsored by the White House, the Na- PA.
tional Cancer Institute and the American Cancer Society, ' Professor and Head, Department of Radiotherapy, The
November 23-23, 1976, Washington, n.C . University of Texas System Cancer Center, h1.D. Anderson
From the *Hahnemann hledical College and Hospital, liospital and Tumor Institute, Houston, TX.
I Professor and Chairman, Department of Therapeutic
Philadelphia. PA; the '[Jniversity of Texas System Cancer
C:entrr. h1.D. Anderson Hospital and l'umor Institute, Radiology, University of Minnesota, School of Medicine,
Minneapolis, .MN.
Houston TS; and 'University of Minnesota School of Address for reprints: Luther W. Brady, M D , Department
hledicine. Minneapolis, h l N . of Radiation Therapy and Nuclear hledicine, Hahnemann
* Hylda Cohn/American Cancer Society Professor of Medical College and Hospital, 230 N. Broad Street, Phila-
Clinical Oncology and Professor and Chairman, 'Depart- delphia, PA 19102
mcnt of Radiation Therapy and Nuclear Medicine, The Accepted for publication iMarch 2, 1977.
2868
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 T h e first randomized clinical trial of post-
evolution and spread of breast cancer. T h e de- operative irradiation in conjunction with radical
tailed study of lymphatic channels has identified mastectomy was carried out in Manchester in
three major routes of spread: 1) directly into the the mid 1 9 5 0 ~It. ~did
~ not show an increased
axilla; 2) via the interpectoral chain to the ax- survival rate, but only a diminution in lo-
illary apex and supraclavicular nodes; and 3) cal/regional failures. The program utilized 250
into the internal mammary chain. (Fig. 1).l 3 kV with the dose of 3250 R in three weeks at a
There is no more controversial subject in the midpoint through parallel opposed portals to
management of carcinoma of the breast than the supraclavicular area and axilla. To the inter-
the use of postoperative irradiation in conjunc- nal mammary chain field, 4250 R skin dose was
tion with radical or modified radical mas- delivered in three weeks. Since then, there have
tectomy. 5 ~ 7 ~ 1 2 ~ 1 s ~ 1 8 ~ 2 3 ~ 2Throughout
6~27~28 the 1930s been several randomized trials of irradiation
and the 1940s, there was an abundance of liter- combined with radical mastectomy or simple
ature on the subject without conclusive evidence mastectomy with irradiation compared with ex-
that postoperative irradiation after radical mas- tended radical or radical mastectomy. Other
tectomy increased survival rates. Until 1950, the trials of simple excision of the tumor with irra-
techniques employed treated the chest wall, the diation have been compared with radical mas-
dissected axilla, and, occasionally, the supracla- tectomy. In all of these trials, including those
vicular fossa. Low dosages were employed and reported by M ~ W h i r t e r , 'Kaae,
~ the Guy's
there was no attempt to irradiate the internal Hospital Randomized Trial, the Cancer
mammary chain. Campaign Study,' the National Surgical Adju-
1. Control of Subclinical Disease with Irradiation in Breast Cancer within Five Years
TABLE
(Supraclavicular and Parasternal Areas)

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 strumentation are due to an increased tumor
there was no improvement in the survival rates dose. Local and regional recurrences were fewer
in the combined treatment. However, in several in the irradiated group of patients with Stage I1
series a diminution in the incidence of lo- disease (Table 3).
cal/regional failures has been observed with the Distant metastases were observed at the same
combined treatment (Tables 1 and 2). rate in Stage I patients in both treated groups.
For the first time, in July 1976, a randomized (Table 4) I n the patients with Stage I1 disease,
clinical trial of radical mastectomy alone or with however, distant metastases were seen in 28% of
postoperative irradiation using a 'Cobalt tele- the patients in the irradiated group compared
therapy device has shown statistically significant with 39% of the patients treated by surgery
improved crude and disease-free survivals in the alone. The latter difference is mainly due to an
postoperatively irradiated group of patients with earlier occurrence of metastases in Stage I1 pa-
histologically positive axillary nodes. (Fig. 2)"9" tients who were treated by surgery alone. Thus,
In the study by Host there is an increased sur- only 11 patients in the 'Cobalt irradiated group
vival rate when postoperative irradiation is given had distant metastases during the first two years
with 'Cobalt teletherapy through direct portals compared to 2 1 patients who had surgery alone.
when compared with kilovoltage radiation ther- A statistically significant higher cure rate with a
apy (Fig. 3). In the two phases of the study, the technique of irradiation of the peripheral lym-
survival curves in the patients operated alone are phatics leads one to critically review all of the
identical indicating that the clinical material previous clinical randomized trials of post-
was the same in the two phases of the study. operative irradiation in combination with radi-
(Fig. 4) Host concludes that the improved sur- cal mastectomy, modified radical mastectomy,
vival rates utilizing the 'Cobalt teletherapy in- 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/. 2871

c
C
Q)

2 \\

2 \
60
- '
\t 58%

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 I
Internal mammary chain and chest wall 0 2 4 6
o---d
through tangential portals Years after surgical treatment
2,500 Rads to 3,100 Rads
Supraclavicular area and axilla From: Host, Herman, 1976.
through parallel opposed portals. FIG. 4. Survival curves for patients with surgery only.

-
3,600-Rads front skin doses
1,800 Rads back}
lated by Tapley. (Table 7). A minimum tumor
dose of 5000 rads to the peripheral lymphatic
lnfraclavicular and supraclavicular
areas and internal mammary chain areas delivered in five weeks is adequate yielding
through direct portals. high local control rates without producing sig-
5.000 Rads in 4 weeks nificant fibrosis or other complications. Since
only the apex of the axilla is irradiated, the
From: Host, Herman, 1976.
incidence of arm edema is not increased beyond
FIG. 3. Stage I1 mammary carcinoma-axillary nodes that produced by the radical mastectomy.
histologically positive.
Chest wall recurrences will be more frequent
when positive axillary lymphadenopathy is
Such a careful review has been carried out by found, when the breast mass is large, or when
Fletcher" demonstrating that all of the pre- the tumor involves skin or underlying tissue by
viously reported clinical trials fail to show any attachment or edema. If a large number of ax-
improved survival rate when radiation is used illary lymph nodes are involved with tumor, the
postoperatively in conjunction with mas- local recurrence rate may reach 45%. Patients
tectomy, since the crucial lymph nodes received with primary lesions 1 cm or less in diameter
an uncertain radiation dosage because of lack of rarely develop chest wall recurrences, although
proper anatomical coverage. Five thousand rads when the lesion becomes 5 cm or more in diame-
in five weeks delivered through direct portals ter more than 33% of the patients will develop
with careful attention to the patterns of regional local recurrences. Therefore, this must be taken
dissemination eliminate the appearance of into consideration in the choice of individuals
supraclavicular and parasternal lymph node in- who would be postoperatively irradiated.
volvement. (Table 5). With lower dosages or
lack of coverage by treatment, the control rate
TABLE 3. Cancer of the Breast, Phase 2 Study:
drops drastically. (Table 6) The data derived Frequency of Homolateral Supraclavicular Lymph Node
from the histologic examination of the specimen, Metastases
the location of the tumor in the breast, and the
status of the axillary lymph nodes must be in- " 0 Controls
corporated into the determination of the appro-
Stage I 3/171 (1.8%) 5/186 (2.7%)
priate treatment plan for the patient. Stage 11 3/95 (3.2%) 13/92 (14.1%)
T h e indications for irradiation of the pe-
ripheral lymphatic areas alone have been formu- From: Host, 197615
2872 CANCER
June Supplement 1977 VOl. 39

TABLE 4. Cancer of the Breast, Phase 2 Study:

Frequency and Time from Primary Treatment to Appearance of First Distant Metastasis

Months following primary treatment

Frequency 0-11 12-23 24-

T O 21/171 (12%) 3 9 9
Stage I 19/186 (10%) 2 6 11
Controls

T O 27/95 (28%) 2 9 16
Stage I1
Controls 36/92 (39%) 8 13 15

From: Host, 1976.''

A treatment program to the chest wall should demonstrated by the greater incidence of local
be done either through parallel opposed tan- and regional failures in the non-irradiated pa-
gential fields using a photon beam in the mega- tients. There was no significant difference in the
voltage range or, if appropriate, electron beam Stockholm Trial in distant metastases between
with appropriate energy selection predicted o n the two groups of patients treated. The fact that
the thickness of the chest wall. The calculated distant metastases appear at the same time in
tumor dose should be 5000 rads in five weeks the irradiated and non-irradiated patients is an
delivered by these techniques. It is more appro- important observation. Other reports have in-
priate to irradiate the lymph nodes draining dicated that distant metastases may appear
the breast in separate fields from those used to sooner in the irradiated group relating it to the
treat the chest wall. The indications for irradia- effects of radiation on the immune response.
tion of the peripheral lymphatic areas and the These data are not borne out by the results of
chest wall are identified in Table 8." the Radiumhemett Trial. 15,1'
Axillary recurrences are extremely rare follow- Evidence has suggested that local radio-
ing radical axillary dissection for operable dis- therapy is immunosuppressive. l4 Recent data
ease. Since postoperative irradiation of the en- also confirm the fact that age, nutrition, surgery,
tire axilla causes a slight increase in arm edema, chemotherapy, as well as many other events to
the entire axilla is irradiated only when 1 ) very which the patient is subjected, are also immuno-
few lymph nodes have been recovered suggesting suppressive for varying periods of time. I n cer-
an incomplete axillary dissection; 2 ) where there tain animal tumors, Crile' and Perez et ~ 1 . have
'~
is preoperative description of a large axillary suggested that far less immunosuppression re-
lymph node greater than 3 cm in diameter with sults from radiation than from surgical removal
or without fixation; and 3) where there is extra of the regional lymph nodes. The question,
nodal disease described in the pathology report. therefore, of the influence of radiation on the
Recent data from the Stockholm Breast Can- immune mechanism is, at best, unclear.
cer Trial' indicate that the survival disease-free I n a recent report by Blomgren et a1.' a re-
rates are better with either preoperative or post- evaluation of the studies concerning radiation
operative radiation therapy. It is pointed out induced changes of the circulating lymphocyte
that this increased survival is due to the eradica- pool in breast cancer patients treated with ra-
tion of disease locally and regionally. This is diotherapy was carried out. They confirmed
TABLE 5. Effectiveness of Local Regional Irradiation in
that radiation therapy directed to different parts
Breast Cancer of the body can induce severe peripheral
lymphopenia. Since experimental studies have
Axilla pusitive in surgical specimen
No irradiation*' 4,500-5,000 rads/
show that T-lymphocytes may be important for
Supraclavicular 5 wks to peripheral regression of tumors, they explored different
lymphatics" lymphocytes subpopulations in the radiotherapy
20-26% 1.5% treated patients with carcinoma of the breast.
I n coitrast to the results of Stjernswgrd et
Axilla positive in surgical specimen
central or inner quadrant ~ l . they repeatedly demonstrated that cells
~ ~ 9 ~ ~

N~ irradiation= 4,500-5,000 with markers for T-lymphocytes decrease less

Parasternal 5 wks to peripheral than cells with markers for B-lymphocytes.
lymphatics However, they emphasize that the regeneration
(MDAH)
9% 0 90
of B-lymphocytes is more rapid than that of T-
(2 5/ 264) ~ 2 0 4 ) lymphocytes. Thus, three years after radio-
therapy given postoperatively in breast cancer,
No. 6 THERAPY
ROLEO F RADIATION AFTER MASTECTOMY Brady et al. 2873
TABLE
6. Control of Subclinical Disease TABLE 7. Cancer of the Breast: Indications for Irradiation
in Function of Dose* of Peripheral Lymphatic Areas Alone

Adenocarcinoma of the breast Histology

of axillary Areas
3,000-3,500 rads (89pts) =60-70% Location of the lesion nodes irradiated
4,000 rads (121 pts) =80% ~ ~~~ ~~

5,000 rads (273) pts) >95% Outer quadrants negative none

Small inner of central negative internal
From Fletcher, 1974. quadrant lesions mammary
* 1,000 rads/week-5 days a week. chain nodes
Outer, inner, or central few positive peripheral
quadrant lesions (< than 20%) lymphatics*
there is still a T-lymphopenia. The conflicting without grave signs
evidences of Stjernswtird et al. may be explained
by his use of incompletely purified lymphocyte * Supraclavicular fossa, apex of axilla, internal mammary
preparations when determining lymphocyte node chain.
subpopulations. Monocytes which are know to valid evidence that radiation therapy after de-
increase in frequency after radiotherapy and finitive surgery for breast cancer affects the sur-
which were not removed by these investigators vival in a deleterious way.20,21The data from
have surface markers in common with B- Host substantiate that claim. Postoperative irra-
lymphocytes. Thus, the tests performed by diation in breast cancer diminishes the in-
Stjernswiird et al. 28,30 might have falsely yielded cidence of local/regional failures, and Host’s
low frequency of T-lymphocytes. data show a n improved survival rate and higher
I n contrast to the findings of Stjernswiird et disease-free rates.
al.29*30 and in accordance with those of McCredie As with any experimental treatment program,
et a1.,22 Blomgren el a1.’ did not observe any individual, uncontrolled, experimental regi-
significant depression of PHA response in vitro mens, however well intentioned, should not be
following radiotherapy. The PPD reactivity, on undertaken foolishly. T h e value of the various
the other hand, is markedly depressed immedi- treatment techniques available in carcinoma of
ately after radiotherapy and returns to normal the breast must be demonstrated without ques-
levels about five months after treatment. Con- tion, recognizing the known, suspected, and po-
trary to the statements of Stjernswiird, Blom- tential risk of the treatment involved.
gren et al. have not seen any difference in the It must be emphasized that selection blurs all
relative frequency of T-lymphocytes between ir- results. Therefore, caution is required in their
radiated and non-irradiated breast cancer pa- interpretation. The ultimate appropriate treat-
tients with metastases. The irradiated patients, ment program in the light of the present avail-
however, have lymphopenia and for this reason able data may prove to be surgery, postoperative
their total T-lymphocyte counts are lower. The radiation therapy, a n d long-term chem-
number of patients examined until now has been oprophylaxis.
very limited due to the fact that most patients Classical radical mastectomy or modified
with metastases are on drug treatment making radical mastectomy performed on patients with
them unsuitable for lymphocyte studies. O n the clinically operable outer quadrant disease with a
other hand, observations indicate a significant histologically negative axillary dissection pro-
correlation between PPD response in vitro and duces excellent results in terms of survival and
the presence of metastases, the stimulability of local/regional control of tumor. These patients
lymphocytes in the presence of PPD being do not need postoperative radiation therapy. Pa-
strongly depressed at the time of discovery of tients with central or inner quadrant primary
distant metastases. tumors with or without histologically positive
Therefore, there is no evidence that there are axillary nodes as well as patients with outer
diminished survival rates with postoperative ir- quadrant lesions with positive axillary nodes
radiation. 20*21 Stjernswiird’s data are invalid be-
cause he failed to use the recent survival rates of TABLE
8 Indications for Irradiation of Peripheral
Lymphatic Areas and Chest Wall
the Edinburgh trial but also because he used the
crude survival rates and not the disease-free 20% or more positive axillary nodes
rates from the Fisher trial. Breast mass < 5 cm
Continued evaluation of therapeutic mod- Fixation of tumor to pectoral fascia
Skin fixation, edema, or erythema
alities available for carcinoma of the breast is Multiple foci of invasive tumor
only now beginning to give answers to basic Vascular, perineural, or lymphatic invasion
questions. There is absolutely no statistically
2874 CANCER
June Supplement 1977 Val. 39

should receive postoperative radiation therapy. should be compatible with the patterns of dis-
The objectives in the use of radiation therapy semination of the disease locally and regionally
as an adjuvant to radical mastectomy or modi- and the dosage employed adequate to insure the
fied radical mastectomy are often poorly de- maximum potential for local control. It is ob-
fined. However, the utilization of postoperative vious that postoperative radiation therapy in se-
radiation therapy should be carried out in those lected cases does great good and does not do
patients where identifiable factors influencing harm. Successful treatment must be evaluated,
the prognosis of the patient can be altered by the not only in terms of survival, but by the local
administered treatment program. Under those and regional control of the disease process. With
circumstances, the irradiated volumes and dos- this in mind, freedom from such local and re-
ages are absolutely critical to the ultimate out- gional disease greatly improves the quality of life
come.. Therefore, the volumes to be treated for the patient.
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