VOL.
116,
No.
i
EXPERIENCE
WITH TWICE-A-DAY FRACTIONATION CLINICAL RADIOTHERAPY*
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IN
By
LEONARD
ELEANOR
J. SHUKOVSKY, D.
M.D.,t
MONTAGUE,
M.D.,
and
HOUSTON,
GILBERT H. FLETCHER, H. RODNEY WITHERS,
M.D.4 M.D.II
TEXAS
ABSTRACT:
Theoretical reasons have led to the treatment of 24 patients with advanced, rapidly growing squamous cell carcinomas of the head and neck, and 17 patients with inflammatory carcinoma of the breast with twice-a-day fractionation. After initial reduction in dose in both series, acute reactions and sequelae are similar to those in conventionally treated patients. The relative control rates are better than would be expected from conventional irradiation.
E
VERY so often one observes continued growth of a tumor mass during a course of external irradiation. This observation is made not uncommonly in patients with squamous cell carcinomas of the upper respiratory and digestive tracts, usually growing neck lymph nodes.5 As a rule, these patients have a short history of disease, indicating that one is dealing with a fastgrowing cancer, either at the primary site or in the neck lymph nodes, or both. Initially, in some head and neck cancers, growth was arrested by adding per week two booster doses, each of 250 rads, through a small field within the treatment fields, thus giving the growing tumor mass a total weekly dose of I ,500 rads (2oo X 5
eight weeks followed ( Baclesse technique) tive
a
Presented
This National
t
at
the
Fifty-seventh
Anntal
Meeting
the University ofTexas System Cancer investigation was supported in part by Cancer Institute.
Assistant
Professor
of Radiotherapy. Radiotherapy.
Present
of the
Center, Public
Section
of Experimental
noninflammatory
AND
METHOD
From April, 1972, through August, 1974, patients have been treated with twice-aday fractionation at the M. D. Anderson Hospital. The patients selected form two groups: (I) head and neck squamous cell carcinomas; and (2) inflammatory breast cancers. All treatments have been given with #{176}#{176}Co. Portal arrangements for both head and neck and breast patients have been planned according to the techniques outlined in Fletcher’s Textbook of Radiotherapy.4 Almost all patients have had every field irradiated at each session.
AND
American
Joseph’s
Radiotherapy.
I
A
42
HYPERFRACTIONATION
Saint
tumors.
treatment
MATERIAL
Head, Department of § Professor of Radiotherapy.
II Chief,
the
scheme was designed to halve the over-all treatment time. Although both regimens use two treatments per day, the concepts underlying the two approaches arc quite different from one another.
The
basic
Radium
Society,
M. D. Anderson Hospital Health Service Research
AddreSs:
in
twiccaday
+250X2) for the two to four weeks. This technique can be used only if a small volume is involved, otherwise the mucosa would not tolerate continued treatment at this high weekly dose rate. Therefore, a twice-a-day hyperfractionation schedule was initiated with the purpose of increasing the irradiation effectiveness to rapidly growing tumors in the head and neck. For patients with inflammatory carcinoma of the breast, 6,ooo rads given in
From
as
by a booster dose are not nearly so effec-
55
Hospital,
and Grants
NECK
rationale lsla
Verde,
FOR
HEAD
CANCERS
in Puerto
the Rico,
treatment May
Tumor Institute, Houston, Texas. CA-o5o9, CA-o6294, and CA-o64
Tampa,
Florida.
-9,
of 1975. from
the
Shukovsky,
I
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RES
:
FRACTIONATION
CELL
CARCINOMA
PIRATORY
OF THE
AND
(Analysis
SQUAMOUS
DIGESTIVE
March,
TRACTS
5975) 5
Pyriform
2
4
sinus
Pharyngeal wall Oral tongue Floor of mouth Paranasal sinuses postoperative
this
group
the the
number over-all
of
the
2 I
I I
recurrence
ofpatients
was
of fractions treatment
rapidly
3
that,
doubling
four
weeks.
Moist
skin,
usually
close
tumor
cells
sur-
viving one dose of irradiation could redistribute themselves throughout the division cycle, moving from the resistant phases into the sensitive phases by the time of the next treatment; this is an extension of a basic concept advanced as early as 1914 by Schwarz.8 The over-all treatment time would remain six or seven weeks and therefore there would be no increased malignant cell repopulation. Preliminary clinical cxperiments indicated that if, instead of one fraction of 200 rads per day, two fractions arc used, about b-I 20 rads per fraction will produce the same degree of reaction on the oropharyngeal mucosa. This small amount of recovery of the mucosal epithehum
is in keeping
with
Withers
without increasing time, a proportion
dividing
by
and
the
clinical
skin
1976
JANUARY,
separated by eight hours (I 6 hours overnight), five days a week, 1,100-1,200 rads per week (I 10-I 20 rads tumor dose per fraction) were delivered. The total tumor dose, with one exception, has ranged from 6,ooo to 7,500 rads in five to six and onehalf weeks. The acute mucositis across the faucial arch was plotted weekly. The mucositis grading as seen in Figure i very closely matched the reaction seen with I,ooo rads per week with once-a-day fractionation.6 Three patients never developed more than a marked redness; in all others, a studded or confluent mucositis peaked in three to
UPPER
Base of tongue Nasopharynx Tonsillar area
Massive
Montague
I
TABLE TWICE-A-DAY
Fletcher,
cx-
periments of Dutreix et al.,3 which showed that in the range of daily doses used in conventional fractionation the recovery is not so high as predicted by the theory of sublethal damage. All but three of the 24 head and neck patients had either a T4 primary or N3 neck lymph nodes, or had a massive postoperative recurrence (Tables and II). In several of the patients, the disease was so advanced that no treatment would have been attempted had it not been for the hope associated with trying a different irradiation scheme. Wi th twice-a-day fractionation
desquamation to
the
of
junctional
the
area
of
the neck fields, occurred near the end of treatment in one-half of these patients. All reactions healed quickly after the completion of radiation therapy. There have been three cases of late complications, one marked fibrosis, one soft tissue necrosis with bone exposure, and a fatal hemorrhage secondary to necrosis and ulceration in the site of the tumor on the pharyngeal wall. Since these complications were seen early in the study when the total dose was 7,000 to 7,500 rads (Fig. 2), the dose to subsequent patients was reduced to 6,ooo to 7,000 rads. One patient who had a massive recurrence after a radical neck dissection received only ,ooo rads in 30 days because the treatment was interrupted due to carotid artery exposure. All but four patients in the present series
TABLE SQUAMOUS
CELL
RESPIRATORY
AND
(Analysis
T T1 T2 T3 T4 Also,
II
CARCINOMA
OF THE
DIGESTIVE
March,
UPPER
TRACTS
1975)
N0
N1
N2
-
-
-
-
-
-
N3
I -
-
-
I
2
-
-
2
4
I
m assive
8
2
-
recu rrence
post surgery
=3
No.
126,
VOL.
Twice-A-Day
I
Fractionation
I
57
Mucositis Mucositis
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Confluent Confluent Studded Studded Red
4-F
Red+ Red
+
+ Red+
1
0
3
2
4
5
6
7
8
0
Weeks
FIG. I. (1) Mucositis with once-a-day sitis with twice-a-day fractionation, Fletcher and MacComb : Radiation 1962, p. ii.)
fractionation 1,100-1,200
Therapy
( 29/31)
of
persistence
of
disease
or
recur-
rence appear by one year (Table III). The cumulative recurrence rate is least with the twice-a-day scheme, despite the fact that the disease in this group of patients was, on the main, more advanced than in the other two groups (Table III). The time-dose information has been plotted in Figure 2. Three of the five patients with recurrences have received 6,ooo rads
or
less.
A
line
has
been
patients.
lesion
Two
had
radiation
patients
a modified
neck
therapy.
In
both
squamous
advanced
CASE seen
in
I.
i
8
1974,
cell
carcinoma,
cm
in
diameter,
of
the base of the bilateral neck 6 cm, fixed
in the right subdigastric area. There was also a 3 cm right parotid lymph node (Fig. 3, zl and B). The staging of the lesion was TINIB. The patient
was
treated
with
tionation, all fields rads midline tumor in
favor
of
cervical to
the
chain
The
rads
right the
side.
spinal
primary
tumor
dose
final tumor
twice-a-day
frac-
at each session, per week, loaded
was treated of
the
covering
5,780
the
limit
60Co
treated dose
The
left
7 MeV
cord
dose.
fields
reduced
in five weeks
to 7X6
rads
7,000
I
electrons The
were
dose was
2
posterior
with lesion
I,150
at cm.
in 43 days.
8000
of
N3 neck
dissection
after
instances,
::::
the
old white female with a rapidly
was first enlarging
I
Confrol
0
Control
w:Ih
Comp!coOon
Recurrence
5000
A
30
34
38 Time
FIG.
cancers.
A 53 year
March,
rads in weeks. (B) Muco.. rads in -6 weeks. (Courtesy: of the Oral Cavity and Oropharynx,
5,500
the right tonsillar area involving tongue. There were multiple lymph nodes, the largest measuring
pathologist was unable to find evidence of any remaining malignant cells. Despite the high control rate of local and neck disease, only six patients are currently alive without evidence of disease. Distant metastases are common in these patients with
8
the
an
with
7
6
hand-drawn
above four of the five recurrences with inclusion of only one controlled lesion. Neck disease has been controlled in 24
5
4
Weeks
at I,ooo rads/week to rads/week to 6,ooo-7,5oo in the Management of Cancer
have been followed for more than one year. The cumulative recurrence rates in patients previously treated for advanced lesions at the M. D. Anderson Hospital with either a split-course or once-a-day irradiation at 850 rads per week are compared in Table III. In these advanced lesions, 9 percent
3
2
2. Time-dose
patients treated (one patient with analysis).
scattergram
with a T
42
46
50
(days)
for
23
head and neck
twice-a_day fractionation lesion is excluded from
the
I
8
Shukovsky,
Fletcher,
Montague
RECURRENCE
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OF THE
RATES
UPPER
T3
IN
No. Split
course
rads/3 wk.; 3 rads/4 wk. Total
4,000
time
10
wk.*
85o
rads
for
wk. then
5 days/wk.
wk.
Total
dose
rads
in 9-94
wk.*
Twice-a-day rads
a
Five
days-a-week
t
Three Nine
patients patients
Studded
oped
and
T2 disease, one without primary
then
the
(20
I
3C).
weeks
tumor.
one year
of
after
This
radiation
RA PID TREATMENT BREAST
In this
(45
percent)
(21
percent)
9
(40
percent)
(21
percent)
4
1974
one treated less than
mucositis
the
in the
of and
2
with yr.
devel-
and fourth weeks A moist desquamation
of
anterior
treatment skin healed
completion
of
radi-
patient
is alive
and
well
therapy. FOR
INFLAMMATORY
CANCER
in
order
to
produce
a
brisk
erythema foPowed by a dry desquamation. The technique, however, avoids total nudation of all of the skin included in tangential fields which would require cral weeks to heal. Severe skin atrophy telangiectasia
18
percent)
4
(I I percent)
The modified Baclesse technique used at the M. D. Anderson Hospital since 1954 with megavoltage delivers 6,ooo rads in 8 weeks, i.e., 750 rads per week, followed by a boost of 2,000 to 4,000 rads at I ,000 rads per week. Bolus is used for parts of the treatment
Mo.
(79
8
percent)
2
to
ation therapy. Two months after the completion of irradiation a modified right upper neck dissection was performed. The specimen contained no detectable
17
(75 percent)
4
to
1973
from T and recurrence
confluent
third
(Fig.
three
I I
24
1970
July July
over a 2.5 X7 cm area developed upper neck at the completion (Fig. 3D). Both the mucosa within
Mo.
12
(48 percent)
I9t
6,ooo-
CARCINOMA
6 Mo.
2
1968
CELL
TRACTS
I975)
to
20
Aug. Feb.
5976
treatment. with alive
during
treatment
8
SQUAMOUS
DIGESTIVE
5
23
I-Ia
T4
Residual
March 1965 July 1967
7,500-8,000
fractionation; rads/wk., in -6 wk.*
1,100-1,200 7,500
for rads
I,000-I,500
AND
March,
of Patients
3,000
wk. rest
AND
RESPIRATORY
(Analysis
J ANUARY,
III
TABLE CUMULATIVE
Withers
and
always
protracted
develop
technique,
dethe sevand
later. it is possible
5,000
rads/4
(Modified
wk. eliminated from : Fletcher.’)
from
analysis.
that the rapid growth of tumor cells in inflammatory carcinoma out-strips the regeneration that occurs in the skin, and that, therefore, protraction of the total treatment time in this group of patients might be expected to favor the tumor. The other tissues in the breast are essentially nonproliferative and are not spared by protraction. Therefore, it seemed reasonable to accelerate the treatment schedule to minimize the unfavorable differential between tumor growth and skin regeneration during treatment. This can be achieved by using two fractions per day instead of one, allowing sufficient time between fractions for complete repair of sublethal injury in the proliferating skin epithelium. This halved the over-all treatment time from eight to four weeks. The total dose had to be reduced to compensate for the difference in over-all treatment time.7 Each tangential field is treated at every session. A boost of 2,000 rads in two weeks to 3,000 rads in three weeks is to follow. Seventeen patients with inflammatory carcinoma
of
the
breast,
manifested
cally by erythema, peau d’orange, wheals or ridges, have been treated twice-a-day fractionation. The first
clini-
and with a seven
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VOL.
Twice-A-Day
126, No.
patients
received
in
weeks.
four
bolus weeks, moist
5,400
In
was used for both patients desquamation
the
Fractionation
I
rads
in 40
fractions
took
first
two
patients,
laying
delivery
patients
were
four fractions. At six developed a confluent over the breast which
r
.,s
no
several
bolus
a confluent
weeks
was
to
heal,
therefore
of the boost. treated used.
and
with One
the
other
The 5,400
patient
four
59
de-
next rads
five and
developed an almost
:
s
i
i-#{149}_
-
,
_,t
-
I
6o
Shukovsky,
7 Downloaded from www.ajronline.org by 180.218.219.74 on 11/12/15 from IP address 180.218.219.74. Copyright ARRS. For personal use only; all rights reserved
:
FRACTIONATION CARCINOMA
April
OF
THE
March
tion
pneumonitis.
I974
skin
over
1975) Survival
Breast
NED*
yr.
>I
The sequelae, nor even
CASE tory
(II/II)t
27
(3/Il)
(5/v)
43
89 (16/18)
33
developed most
has
there
a radia-
patients,
the
telangiectasia
is some
fibrosis
so far, bothersome.
have
and of
the
not
been
A 61 year
II.
in September,
percent
71
Total
breast. disabling
have breast
and
1976
JANUARY,
In
the
atrophy
Control in
100
Withers
over two years. Three patients
INFLAMMATORY
percent Withoutchemotherapy With chemotherapy
and
BREAST
I972-August
(Analysis
Montague
IV
TABLE
TWICE-A-DAY
Fletcher,
1973,
carcinoma
of
inflammatory
old white female was seen with a massive inflammathe left breast. The area of
component,
consisting
erythe.
of
(3/7)
ma, peau d’orange, and ridges, entire breast measuring 20X 12
411).
(6/18)
The
prior
patient
covered cm (Fig. chemotherapy
did not receive
the
to irradiation. a No
evidence
of disease.
t
Two patients area which was metastasis
The
had recurrent disease not treated twice-a-day
outside
the
irradiated
areas
in the and that
internal mammary one patient had
spread
into
the
a
breast
tangential
weeks
four
breast.
both
confluent has been tients to patients
moist reduced
desquamation. for the last rads
5,100
have
had
using
no
only
a
The eleven bolus.
brisk
dose paThese
erythcma
and the
dry desquamation. With this scheme, weekly rate was i ,300 rads instead of 750 rads as in the eight week treatment. The peripheral lymphatics were treated conventionally. Seven patients with massive disease received various types of multidrug chemotherapy to initiate regression. The most commonly used drugs were methotrexate, 5-fluorouracil, cytoxan, and adriamycin. In several of these patients, a dramatic regression and at times complete clinical disappearance of the disease was obtained. Local control in the breast has been achieved
in 89 percent
(i6
of
i8)
of the
pa-
used.
lar,
and
mation
4B),
patients tion
previously wi th
conventional
treated
at
obtained
this
in
institu-
fractionation.2
Six of the 18 patients are alive without disease for more than one year. Two of these patients have now been followed for
dose
each
session.
were
in
fractionation, No
mammary,
areas
with
a
a “squeeze
in two
weeks
bolus
supraclavicu-
treated
small
area
boost”
of2,ooo
of
fractions)
(20
twice-a-day
convention-
fractionation
moistness
rads was
to
given
the
(Fig.
tumor
dose
also
with
breast.
The patient is alive and well one and a half years after treatment. The chronic changes in the breast consist of skin atrophy and fibrosis (Fig. 4C). DISCUSSION HEAD
AND
Hyperfractionation vanced
head
mucosal appear
to
NECK
has and
neck
been
used
in ad-
carcinomas.
Acute
reactions and late complications be similar to those observed
conventional
conventional
rate
at
through
tumor
ally with #{176}#{176}Co to 5,000 rads in five weeks plus a boost to palpable axillary lymph nodes. After a two week rest to allow healing of a dry desqua-
with
control
60Co
rads
twice-a-day
internal
axillary
with
,ioo
treated The
ough
percent
treated to
with
fields
was
tients with or without adjuvant chemotherapy (Table Iv). All patients with local control survived for more than one year. There is no difference in the control rate in the patients who received or 5,100 rads. This control rate compares favorably a 62
was
fields
treatment,
assessment
although
of late
effects
in
a thoris hampered
by the poor survival of patients with late stage disease. Interestingly, acute skin reactions in the neck were more severe in the twice-a-day hypcrfractionation nomenon
the mucosa cycle
not
faucial
sensitization
regimen
once-a-day observed
pillar.
than
in
irradiation, in
the
the
a phemucosa
of
This may reflect more in the skin than in the oral as a result of differences in the cell redistribution. The skin reactions
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VOL.
126,
healed tumor greater cells in The
No.
Twice-A-Day
i
in a few weeks. The improved local control rate may also reflect a effect of redistribution of malignant the cell cycle. control rates with twice-a-day frac-
tionation
have
with
conventional
that
the
been
increased
over
fractionation,
therapeutic
Three-times-a-day
ratio
those
indicating
was
fractionation
been
used by B#{224}ckstr#{246}m et al.’ in 17 head and neck patients with seemingly good results. Comparison with the present series is not feasible since the daily dose rate was 300 rads
were tients
and,
furthermore,
operated in
their
on. series,
Of
most
of the
four
inoperable
two
were
patients alive
RAPID
pa-
TREATMENT
OF
THE
BREAST
The skin reactions in the breast were accentuated and required the tion
bolus
of
from have
6,000
been
fractionation
improved. has
161
Fractionation
as well to
as reduction
5,100
rads.
increased treatment.
tage to this twice-per-day the shortening by four treatment time.
patients elimina-
of the
dose
The control rates over conventional An added advanfractionation is weeks of over-all
Gilbert H. Fletcher, M.D. Department of Radiotherapy The University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute Houston, Texas 77025
and
well for over one year. Although our results are preliminary, they warrant the use of this scheme in patients with earlier disease and in whom distant metastases would not curtail the follow-up.
REFERENCES
A., JAKOBSON, P. A., LITTBRAND, B., and WERSALL, J. Fractionation scheme with low individual doses in irradiation of carcinoma of mouth. -Icta radio!. (Therapy), 1973, 12,
I.
BCKSTR#{246}M,
2.
BARKER,
401-406.
J. L.,
NELSON,
A.
J., and
MONTAGUE,
I
Shukovsky,
62
E.
D. Inflammatory Publication pending.
Downloaded from www.ajronline.org by 180.218.219.74 on 11/12/15 from IP address 180.218.219.74. Copyright ARRS. For personal use only; all rights reserved
3.
Cellular application
4.
FLETCHER, Second
breast.
WAMBERSIE, A., recovery in human to dose fraction
and BOUNIK, C. skin reactions: number over-all in radiotherapy. Europ. 7.
relationships
Cancer,
of
9, 159-167.
1973,
G.
H.
edition.
Textbook of & Febiger,
Lea
Radiotherapy. Philadelphia,
FLETCHER, human
7. Radiol.,
and
G. H. Clinical
dose-response curves of epithelial tumours. Brit.
malignant
‘973,
46,
1-12.
Withers G. H.,
1976
JANUAXY,
W. S. Radiaof Cancer of the Oral Cavity and Oropharynx. Charles C Thomas, Publisher, Springfield, Ill., 1962, p. 51. 7. FLETCHER, G. H., BARKLEY, H. T., JR., and 6.
FLETCHER,
Therapy
in
and
MACCOMB,
the Management
L. J.
SHUKOVSKY,
Present
status
of
time
factor
in clinical radiotherapy. Part II: nominal standard dose. 7. de radiol., d’Ifecfro/. ci de med. nuc!Caire., 1974, 55, 745-75 I.
G.
8. SCHWARZ,
1973.
5.
Montague
tion
J.,
DUTREIX,
time
carcinoma
Fletcher,
durch
Heilung
tiefliegender
Karzinome
kontgenbestrahlung von der K#{246}rperoberfl#{228}che aus. M#{252}nchen. med. Wchnschr., 1914,
6i,
1733.
116,
No.
i
EXPERIENCE
WITH TWICE-A-DAY FRACTIONATION CLINICAL RADIOTHERAPY*
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IN
By
LEONARD
ELEANOR
J. SHUKOVSKY, D.
M.D.,t
MONTAGUE,
M.D.,
and
HOUSTON,
GILBERT H. FLETCHER, H. RODNEY WITHERS,
M.D.4 M.D.II
TEXAS
ABSTRACT:
Theoretical reasons have led to the treatment of 24 patients with advanced, rapidly growing squamous cell carcinomas of the head and neck, and 17 patients with inflammatory carcinoma of the breast with twice-a-day fractionation. After initial reduction in dose in both series, acute reactions and sequelae are similar to those in conventionally treated patients. The relative control rates are better than would be expected from conventional irradiation.
E
VERY so often one observes continued growth of a tumor mass during a course of external irradiation. This observation is made not uncommonly in patients with squamous cell carcinomas of the upper respiratory and digestive tracts, usually growing neck lymph nodes.5 As a rule, these patients have a short history of disease, indicating that one is dealing with a fastgrowing cancer, either at the primary site or in the neck lymph nodes, or both. Initially, in some head and neck cancers, growth was arrested by adding per week two booster doses, each of 250 rads, through a small field within the treatment fields, thus giving the growing tumor mass a total weekly dose of I ,500 rads (2oo X 5
eight weeks followed ( Baclesse technique) tive
a
Presented
This National
t
at
the
Fifty-seventh
Anntal
Meeting
the University ofTexas System Cancer investigation was supported in part by Cancer Institute.
Assistant
Professor
of Radiotherapy. Radiotherapy.
Present
of the
Center, Public
Section
of Experimental
noninflammatory
AND
METHOD
From April, 1972, through August, 1974, patients have been treated with twice-aday fractionation at the M. D. Anderson Hospital. The patients selected form two groups: (I) head and neck squamous cell carcinomas; and (2) inflammatory breast cancers. All treatments have been given with #{176}#{176}Co. Portal arrangements for both head and neck and breast patients have been planned according to the techniques outlined in Fletcher’s Textbook of Radiotherapy.4 Almost all patients have had every field irradiated at each session.
AND
American
Joseph’s
Radiotherapy.
I
A
42
HYPERFRACTIONATION
Saint
tumors.
treatment
MATERIAL
Head, Department of § Professor of Radiotherapy.
II Chief,
the
scheme was designed to halve the over-all treatment time. Although both regimens use two treatments per day, the concepts underlying the two approaches arc quite different from one another.
The
basic
Radium
Society,
M. D. Anderson Hospital Health Service Research
AddreSs:
in
twiccaday
+250X2) for the two to four weeks. This technique can be used only if a small volume is involved, otherwise the mucosa would not tolerate continued treatment at this high weekly dose rate. Therefore, a twice-a-day hyperfractionation schedule was initiated with the purpose of increasing the irradiation effectiveness to rapidly growing tumors in the head and neck. For patients with inflammatory carcinoma of the breast, 6,ooo rads given in
From
as
by a booster dose are not nearly so effec-
55
Hospital,
and Grants
NECK
rationale lsla
Verde,
FOR
HEAD
CANCERS
in Puerto
the Rico,
treatment May
Tumor Institute, Houston, Texas. CA-o5o9, CA-o6294, and CA-o64
Tampa,
Florida.
-9,
of 1975. from
the
Shukovsky,
I
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RES
:
FRACTIONATION
CELL
CARCINOMA
PIRATORY
OF THE
AND
(Analysis
SQUAMOUS
DIGESTIVE
March,
TRACTS
5975) 5
Pyriform
2
4
sinus
Pharyngeal wall Oral tongue Floor of mouth Paranasal sinuses postoperative
this
group
the the
number over-all
of
the
2 I
I I
recurrence
ofpatients
was
of fractions treatment
rapidly
3
that,
doubling
four
weeks.
Moist
skin,
usually
close
tumor
cells
sur-
viving one dose of irradiation could redistribute themselves throughout the division cycle, moving from the resistant phases into the sensitive phases by the time of the next treatment; this is an extension of a basic concept advanced as early as 1914 by Schwarz.8 The over-all treatment time would remain six or seven weeks and therefore there would be no increased malignant cell repopulation. Preliminary clinical cxperiments indicated that if, instead of one fraction of 200 rads per day, two fractions arc used, about b-I 20 rads per fraction will produce the same degree of reaction on the oropharyngeal mucosa. This small amount of recovery of the mucosal epithehum
is in keeping
with
Withers
without increasing time, a proportion
dividing
by
and
the
clinical
skin
1976
JANUARY,
separated by eight hours (I 6 hours overnight), five days a week, 1,100-1,200 rads per week (I 10-I 20 rads tumor dose per fraction) were delivered. The total tumor dose, with one exception, has ranged from 6,ooo to 7,500 rads in five to six and onehalf weeks. The acute mucositis across the faucial arch was plotted weekly. The mucositis grading as seen in Figure i very closely matched the reaction seen with I,ooo rads per week with once-a-day fractionation.6 Three patients never developed more than a marked redness; in all others, a studded or confluent mucositis peaked in three to
UPPER
Base of tongue Nasopharynx Tonsillar area
Massive
Montague
I
TABLE TWICE-A-DAY
Fletcher,
cx-
periments of Dutreix et al.,3 which showed that in the range of daily doses used in conventional fractionation the recovery is not so high as predicted by the theory of sublethal damage. All but three of the 24 head and neck patients had either a T4 primary or N3 neck lymph nodes, or had a massive postoperative recurrence (Tables and II). In several of the patients, the disease was so advanced that no treatment would have been attempted had it not been for the hope associated with trying a different irradiation scheme. Wi th twice-a-day fractionation
desquamation to
the
of
junctional
the
area
of
the neck fields, occurred near the end of treatment in one-half of these patients. All reactions healed quickly after the completion of radiation therapy. There have been three cases of late complications, one marked fibrosis, one soft tissue necrosis with bone exposure, and a fatal hemorrhage secondary to necrosis and ulceration in the site of the tumor on the pharyngeal wall. Since these complications were seen early in the study when the total dose was 7,000 to 7,500 rads (Fig. 2), the dose to subsequent patients was reduced to 6,ooo to 7,000 rads. One patient who had a massive recurrence after a radical neck dissection received only ,ooo rads in 30 days because the treatment was interrupted due to carotid artery exposure. All but four patients in the present series
TABLE SQUAMOUS
CELL
RESPIRATORY
AND
(Analysis
T T1 T2 T3 T4 Also,
II
CARCINOMA
OF THE
DIGESTIVE
March,
UPPER
TRACTS
1975)
N0
N1
N2
-
-
-
-
-
-
N3
I -
-
-
I
2
-
-
2
4
I
m assive
8
2
-
recu rrence
post surgery
=3
No.
126,
VOL.
Twice-A-Day
I
Fractionation
I
57
Mucositis Mucositis
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Confluent Confluent Studded Studded Red
4-F
Red+ Red
+
+ Red+
1
0
3
2
4
5
6
7
8
0
Weeks
FIG. I. (1) Mucositis with once-a-day sitis with twice-a-day fractionation, Fletcher and MacComb : Radiation 1962, p. ii.)
fractionation 1,100-1,200
Therapy
( 29/31)
of
persistence
of
disease
or
recur-
rence appear by one year (Table III). The cumulative recurrence rate is least with the twice-a-day scheme, despite the fact that the disease in this group of patients was, on the main, more advanced than in the other two groups (Table III). The time-dose information has been plotted in Figure 2. Three of the five patients with recurrences have received 6,ooo rads
or
less.
A
line
has
been
patients.
lesion
Two
had
radiation
patients
a modified
neck
therapy.
In
both
squamous
advanced
CASE seen
in
I.
i
8
1974,
cell
carcinoma,
cm
in
diameter,
of
the base of the bilateral neck 6 cm, fixed
in the right subdigastric area. There was also a 3 cm right parotid lymph node (Fig. 3, zl and B). The staging of the lesion was TINIB. The patient
was
treated
with
tionation, all fields rads midline tumor in
favor
of
cervical to
the
chain
The
rads
right the
side.
spinal
primary
tumor
dose
final tumor
twice-a-day
frac-
at each session, per week, loaded
was treated of
the
covering
5,780
the
limit
60Co
treated dose
The
left
7 MeV
cord
dose.
fields
reduced
in five weeks
to 7X6
rads
7,000
I
electrons The
were
dose was
2
posterior
with lesion
I,150
at cm.
in 43 days.
8000
of
N3 neck
dissection
after
instances,
::::
the
old white female with a rapidly
was first enlarging
I
Confrol
0
Control
w:Ih
Comp!coOon
Recurrence
5000
A
30
34
38 Time
FIG.
cancers.
A 53 year
March,
rads in weeks. (B) Muco.. rads in -6 weeks. (Courtesy: of the Oral Cavity and Oropharynx,
5,500
the right tonsillar area involving tongue. There were multiple lymph nodes, the largest measuring
pathologist was unable to find evidence of any remaining malignant cells. Despite the high control rate of local and neck disease, only six patients are currently alive without evidence of disease. Distant metastases are common in these patients with
8
the
an
with
7
6
hand-drawn
above four of the five recurrences with inclusion of only one controlled lesion. Neck disease has been controlled in 24
5
4
Weeks
at I,ooo rads/week to rads/week to 6,ooo-7,5oo in the Management of Cancer
have been followed for more than one year. The cumulative recurrence rates in patients previously treated for advanced lesions at the M. D. Anderson Hospital with either a split-course or once-a-day irradiation at 850 rads per week are compared in Table III. In these advanced lesions, 9 percent
3
2
2. Time-dose
patients treated (one patient with analysis).
scattergram
with a T
42
46
50
(days)
for
23
head and neck
twice-a_day fractionation lesion is excluded from
the
I
8
Shukovsky,
Fletcher,
Montague
RECURRENCE
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OF THE
RATES
UPPER
T3
IN
No. Split
course
rads/3 wk.; 3 rads/4 wk. Total
4,000
time
10
wk.*
85o
rads
for
wk. then
5 days/wk.
wk.
Total
dose
rads
in 9-94
wk.*
Twice-a-day rads
a
Five
days-a-week
t
Three Nine
patients patients
Studded
oped
and
T2 disease, one without primary
then
the
(20
I
3C).
weeks
tumor.
one year
of
after
This
radiation
RA PID TREATMENT BREAST
In this
(45
percent)
(21
percent)
9
(40
percent)
(21
percent)
4
1974
one treated less than
mucositis
the
in the
of and
2
with yr.
devel-
and fourth weeks A moist desquamation
of
anterior
treatment skin healed
completion
of
radi-
patient
is alive
and
well
therapy. FOR
INFLAMMATORY
CANCER
in
order
to
produce
a
brisk
erythema foPowed by a dry desquamation. The technique, however, avoids total nudation of all of the skin included in tangential fields which would require cral weeks to heal. Severe skin atrophy telangiectasia
18
percent)
4
(I I percent)
The modified Baclesse technique used at the M. D. Anderson Hospital since 1954 with megavoltage delivers 6,ooo rads in 8 weeks, i.e., 750 rads per week, followed by a boost of 2,000 to 4,000 rads at I ,000 rads per week. Bolus is used for parts of the treatment
Mo.
(79
8
percent)
2
to
ation therapy. Two months after the completion of irradiation a modified right upper neck dissection was performed. The specimen contained no detectable
17
(75 percent)
4
to
1973
from T and recurrence
confluent
third
(Fig.
three
I I
24
1970
July July
over a 2.5 X7 cm area developed upper neck at the completion (Fig. 3D). Both the mucosa within
Mo.
12
(48 percent)
I9t
6,ooo-
CARCINOMA
6 Mo.
2
1968
CELL
TRACTS
I975)
to
20
Aug. Feb.
5976
treatment. with alive
during
treatment
8
SQUAMOUS
DIGESTIVE
5
23
I-Ia
T4
Residual
March 1965 July 1967
7,500-8,000
fractionation; rads/wk., in -6 wk.*
1,100-1,200 7,500
for rads
I,000-I,500
AND
March,
of Patients
3,000
wk. rest
AND
RESPIRATORY
(Analysis
J ANUARY,
III
TABLE CUMULATIVE
Withers
and
always
protracted
develop
technique,
dethe sevand
later. it is possible
5,000
rads/4
(Modified
wk. eliminated from : Fletcher.’)
from
analysis.
that the rapid growth of tumor cells in inflammatory carcinoma out-strips the regeneration that occurs in the skin, and that, therefore, protraction of the total treatment time in this group of patients might be expected to favor the tumor. The other tissues in the breast are essentially nonproliferative and are not spared by protraction. Therefore, it seemed reasonable to accelerate the treatment schedule to minimize the unfavorable differential between tumor growth and skin regeneration during treatment. This can be achieved by using two fractions per day instead of one, allowing sufficient time between fractions for complete repair of sublethal injury in the proliferating skin epithelium. This halved the over-all treatment time from eight to four weeks. The total dose had to be reduced to compensate for the difference in over-all treatment time.7 Each tangential field is treated at every session. A boost of 2,000 rads in two weeks to 3,000 rads in three weeks is to follow. Seventeen patients with inflammatory carcinoma
of
the
breast,
manifested
cally by erythema, peau d’orange, wheals or ridges, have been treated twice-a-day fractionation. The first
clini-
and with a seven
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VOL.
Twice-A-Day
126, No.
patients
received
in
weeks.
four
bolus weeks, moist
5,400
In
was used for both patients desquamation
the
Fractionation
I
rads
in 40
fractions
took
first
two
patients,
laying
delivery
patients
were
four fractions. At six developed a confluent over the breast which
r
.,s
no
several
bolus
a confluent
weeks
was
to
heal,
therefore
of the boost. treated used.
and
with One
the
other
The 5,400
patient
four
59
de-
next rads
five and
developed an almost
:
s
i
i-#{149}_
-
,
_,t
-
I
6o
Shukovsky,
7 Downloaded from www.ajronline.org by 180.218.219.74 on 11/12/15 from IP address 180.218.219.74. Copyright ARRS. For personal use only; all rights reserved
:
FRACTIONATION CARCINOMA
April
OF
THE
March
tion
pneumonitis.
I974
skin
over
1975) Survival
Breast
NED*
yr.
>I
The sequelae, nor even
CASE tory
(II/II)t
27
(3/Il)
(5/v)
43
89 (16/18)
33
developed most
has
there
a radia-
patients,
the
telangiectasia
is some
fibrosis
so far, bothersome.
have
and of
the
not
been
A 61 year
II.
in September,
percent
71
Total
breast. disabling
have breast
and
1976
JANUARY,
In
the
atrophy
Control in
100
Withers
over two years. Three patients
INFLAMMATORY
percent Withoutchemotherapy With chemotherapy
and
BREAST
I972-August
(Analysis
Montague
IV
TABLE
TWICE-A-DAY
Fletcher,
1973,
carcinoma
of
inflammatory
old white female was seen with a massive inflammathe left breast. The area of
component,
consisting
erythe.
of
(3/7)
ma, peau d’orange, and ridges, entire breast measuring 20X 12
411).
(6/18)
The
prior
patient
covered cm (Fig. chemotherapy
did not receive
the
to irradiation. a No
evidence
of disease.
t
Two patients area which was metastasis
The
had recurrent disease not treated twice-a-day
outside
the
irradiated
areas
in the and that
internal mammary one patient had
spread
into
the
a
breast
tangential
weeks
four
breast.
both
confluent has been tients to patients
moist reduced
desquamation. for the last rads
5,100
have
had
using
no
only
a
The eleven bolus.
brisk
dose paThese
erythcma
and the
dry desquamation. With this scheme, weekly rate was i ,300 rads instead of 750 rads as in the eight week treatment. The peripheral lymphatics were treated conventionally. Seven patients with massive disease received various types of multidrug chemotherapy to initiate regression. The most commonly used drugs were methotrexate, 5-fluorouracil, cytoxan, and adriamycin. In several of these patients, a dramatic regression and at times complete clinical disappearance of the disease was obtained. Local control in the breast has been achieved
in 89 percent
(i6
of
i8)
of the
pa-
used.
lar,
and
mation
4B),
patients tion
previously wi th
conventional
treated
at
obtained
this
in
institu-
fractionation.2
Six of the 18 patients are alive without disease for more than one year. Two of these patients have now been followed for
dose
each
session.
were
in
fractionation, No
mammary,
areas
with
a
a “squeeze
in two
weeks
bolus
supraclavicu-
treated
small
area
boost”
of2,ooo
of
fractions)
(20
twice-a-day
convention-
fractionation
moistness
rads was
to
given
the
(Fig.
tumor
dose
also
with
breast.
The patient is alive and well one and a half years after treatment. The chronic changes in the breast consist of skin atrophy and fibrosis (Fig. 4C). DISCUSSION HEAD
AND
Hyperfractionation vanced
head
mucosal appear
to
NECK
has and
neck
been
used
in ad-
carcinomas.
Acute
reactions and late complications be similar to those observed
conventional
conventional
rate
at
through
tumor
ally with #{176}#{176}Co to 5,000 rads in five weeks plus a boost to palpable axillary lymph nodes. After a two week rest to allow healing of a dry desqua-
with
control
60Co
rads
twice-a-day
internal
axillary
with
,ioo
treated The
ough
percent
treated to
with
fields
was
tients with or without adjuvant chemotherapy (Table Iv). All patients with local control survived for more than one year. There is no difference in the control rate in the patients who received or 5,100 rads. This control rate compares favorably a 62
was
fields
treatment,
assessment
although
of late
effects
in
a thoris hampered
by the poor survival of patients with late stage disease. Interestingly, acute skin reactions in the neck were more severe in the twice-a-day hypcrfractionation nomenon
the mucosa cycle
not
faucial
sensitization
regimen
once-a-day observed
pillar.
than
in
irradiation, in
the
the
a phemucosa
of
This may reflect more in the skin than in the oral as a result of differences in the cell redistribution. The skin reactions
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VOL.
126,
healed tumor greater cells in The
No.
Twice-A-Day
i
in a few weeks. The improved local control rate may also reflect a effect of redistribution of malignant the cell cycle. control rates with twice-a-day frac-
tionation
have
with
conventional
that
the
been
increased
over
fractionation,
therapeutic
Three-times-a-day
ratio
those
indicating
was
fractionation
been
used by B#{224}ckstr#{246}m et al.’ in 17 head and neck patients with seemingly good results. Comparison with the present series is not feasible since the daily dose rate was 300 rads
were tients
and,
furthermore,
operated in
their
on. series,
Of
most
of the
four
inoperable
two
were
patients alive
RAPID
pa-
TREATMENT
OF
THE
BREAST
The skin reactions in the breast were accentuated and required the tion
bolus
of
from have
6,000
been
fractionation
improved. has
161
Fractionation
as well to
as reduction
5,100
rads.
increased treatment.
tage to this twice-per-day the shortening by four treatment time.
patients elimina-
of the
dose
The control rates over conventional An added advanfractionation is weeks of over-all
Gilbert H. Fletcher, M.D. Department of Radiotherapy The University of Texas System Cancer Center M. D. Anderson Hospital and Tumor Institute Houston, Texas 77025
and
well for over one year. Although our results are preliminary, they warrant the use of this scheme in patients with earlier disease and in whom distant metastases would not curtail the follow-up.
REFERENCES
A., JAKOBSON, P. A., LITTBRAND, B., and WERSALL, J. Fractionation scheme with low individual doses in irradiation of carcinoma of mouth. -Icta radio!. (Therapy), 1973, 12,
I.
BCKSTR#{246}M,
2.
BARKER,
401-406.
J. L.,
NELSON,
A.
J., and
MONTAGUE,
I
Shukovsky,
62
E.
D. Inflammatory Publication pending.
Downloaded from www.ajronline.org by 180.218.219.74 on 11/12/15 from IP address 180.218.219.74. Copyright ARRS. For personal use only; all rights reserved
3.
Cellular application
4.
FLETCHER, Second
breast.
WAMBERSIE, A., recovery in human to dose fraction
and BOUNIK, C. skin reactions: number over-all in radiotherapy. Europ. 7.
relationships
Cancer,
of
9, 159-167.
1973,
G.
H.
edition.
Textbook of & Febiger,
Lea
Radiotherapy. Philadelphia,
FLETCHER, human
7. Radiol.,
and
G. H. Clinical
dose-response curves of epithelial tumours. Brit.
malignant
‘973,
46,
1-12.
Withers G. H.,
1976
JANUAXY,
W. S. Radiaof Cancer of the Oral Cavity and Oropharynx. Charles C Thomas, Publisher, Springfield, Ill., 1962, p. 51. 7. FLETCHER, G. H., BARKLEY, H. T., JR., and 6.
FLETCHER,
Therapy
in
and
MACCOMB,
the Management
L. J.
SHUKOVSKY,
Present
status
of
time
factor
in clinical radiotherapy. Part II: nominal standard dose. 7. de radiol., d’Ifecfro/. ci de med. nuc!Caire., 1974, 55, 745-75 I.
G.
8. SCHWARZ,
1973.
5.
Montague
tion
J.,
DUTREIX,
time
carcinoma
Fletcher,
durch
Heilung
tiefliegender
Karzinome
kontgenbestrahlung von der K#{246}rperoberfl#{228}che aus. M#{252}nchen. med. Wchnschr., 1914,
6i,
1733.
