Relative radiation sensitivities of human organ systems / 2

326 Pages·1990·34.928 MB·English

ADVISORY BOARD
K. I. ALTMAN P. C. HANAWALT
J. Z. BEER O. F. NYGAARD
B. A. BRIDGES S. OKADA
U. HAGEN C. STREFFER
Advances in
R A D I A T I ON B I O L O GY
Relative Radiation Sensitivities of Human Organ Systems, Part II
Edited by
JOHN T. ίΕπ KURT I. ALTMAN
DEPARTMENT OF RADIOLOGY DEPARTMENT OF RADIATION
AND RADIATION BIOLOGY BIOLOGY AND BIOPHYSICS
COLORADO STATE UNIVERSITY THE UNIVERSITY OF ROCHESTER
FORT COLLINS, COLORADO MEDICAL CENTER
ROCHESTER, NEW YORK
Associate Editors
Ursula K. Ehmann Ann B. Cox
DEPARTMENT OF PATHOLOGY RADIATION SCIENCES DIVISION
VETERANS ADMINISTRATION UNITED STATES AIR FORCE
MEDICAL CENTER SCHOOL OF AEROSPACE
PALO ALTO, CALIFORNIA MEDICINE
BROOKS AIR FORCE BASE, TEXAS
Volume 14
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Preface
The radiation sensitivity of an organ system, human or otherwise, can
be assessed on the basis of the severity and the rapidity with which the
effects of radiation become manifest. This second volume on "Relative
Radiation Sensitivities of Human Organ Systems" discusses organ sys­
tems not included in the previous volume (Advances in Radiation Biol
ogy, Volume 12). Once again, the response to radiation exposure is ap­
proached from the point of view of the radiation therapist whose aim it is
to halt the proliferation of neoplastic tissue by destroying it, while at the
same time preserving as much as possible of the unaffected normal tissue
in or near the radiation field.
Radiation biology has provided insight into some of the factors deter­
mining radiation sensitivity; data on the quantification of cell population
dynamics with respect to cell proliferation, cell killing, and cell death
have become crucial in designing radiation therapy schedules, especially
those which involve dose fractionation. The following chapters focus on
the radiation sensitivities of particular human organ systems and draw
from the large body of data which have accumulated in the years since
Wilhelm Roentgen discovered X-rays.
I am greatly indebted to Professor Yosh Maruyama for invaluable ad­
vice and many helpful discussions and comments. I am also indebted to
Babette S. Altman for her never-failing assistance in the stylistic editing
of this volume and to Professors Peter T. Rowley and Dean H. Lockwood
for reviewing sections of the manuscripts.
KURT I. ALTMAN
IX
Contents of Volume 12
Relative Radiosensitivities of the Thymus, Spleen, and
Lymphohemopoietic Systems
Yosh Maruyama and Jose M. Feola
Relative Radiosensitivities of the Small and Large Intestine
Aldo Becciolini
Relative Radiosensitivities of the Oral Cavity, Larynx, Pharynx, and
Esophagus
Joeila F. Utley
Relative Radiation Sensitivity of the Integumentary System: Dose
Response of the Epidermal, Microvascular, and Dermal Populations
John O. Archambeau
Relative Radiosensitivity of the Human Lung
Elizabeth L. Travis
Relative Radiosensitivity of Fetal Tissues
R. L. Brent, D. A. Beckman, and R. P. Jensh
Tolerance of the Central and Peripheral Nervous System to Therapeutic
Irradiation
Steven A. Leibel and Glenn E. Sheline
XI
Relative Radiosensitivity of the Urinary Bladder in
Cancer Therapy
JOHN A. STRYKER,* DAVID B. ROBINS,t AND
DONALD E. VELKLEYt
*DEPARTMENT OF RADIOLOGY, DIVISION OF RADIATION THERAPY
tDEPARTMENT OF ANATOMIC PATHOLOGY
THE M. S. HERSHEY MEDICAL CENTER
THE PENNSYLVANIA STATE UNIVERSITY
HERSHEY, PENNSYLVANIA 17033
I. Introduction
For many years injuries to the urinary bladder have been a significant
problem for many patients following radiotherapy for pelvic malignancy
(Dean, 1927; Schmitz, 1930). Bladder complications are seen most com­
monly following treatment for cancer of the cervix but they also develop
following treatment for prostate and bladder cancer. In spite of this
known clinical problem, with a few notable exceptions, radiobiologists
have shown little interest in the radiobiology of the bladder and most of
the publications in this field are clinical reviews. Nevertheless, some ex­
perimental work has been done and it is the purpose of this review to
survey the clinical and experimental literature in an attempt to find new
approaches toward the prevention of bladder complications in clinical ra­
diotherapy.
In modern series of patients treated for cervix carcinoma the inci­
dence of late radiation reactions in the bladder is reported. For example,
Kottmeier (1964) reported an incidence of 8% among 3484 cases treated
at the Radiumhemmet between 1949 and 1957. Alert et al. (1980) subse­
quently reported an incidence of radiation cystitis of 14% and vesicovagi-
nal fistula of 1.5% among 2248 cases treated between 1966 and 1972 at
three oncologic centers in Cuba.
1
Copyright © 1990 by Academic Press, Inc.
ADVANCES IN RADIATION BIOLOGY, VOL. 14 All rights of reproduction in any form reserved.
2 JOHN A. STRYKER ET AL.
In patients treated for prostate carcinoma with external-beam radio­
therapy (ERT) the incidence of bladder injuries was only 3.4% among 267
patients treated at the Mallinkrodt Institute of Radiology between 1967
and 1978 and reported by Pilepich et al. (1981). However, in a larger pro­
spective multiinstitutional study from the Radiation Therapy Oncology
Group (RTOG) involving 526 patients treated between 1976 and 1983, the
incidence of radiation cystitis was 11.4% and hematuria 5.7% (Pilepich
etal., 1987).
Analysis of bladder injuries in patients treated for bladder cancer is
more difficult because of the presence of the bladder carcinoma, which
may itself be associated with symptomatology; however, in one analysis
reported by Bloedorn et al. (1962) the incidence of severe cystitis was 7%
among 101 patients treated, and 3% had a contracted bladder. In another
series reported by Shiels et al. (1986), the incidence of late complications
was 12.5% among 88 patients treated between 1978 and 1982.
II. Clinical Syndromes in Radiation-Induced Bladder Injury
Acute radiation cystitis is the syndrome seen during the course of
treatment in many patients undergoing ERT (Maier, 1972). In the third
week of a fractionated course of treatment, dysuria and frequency of uri­
nation may develop. The symptoms mimic those seen with infection but
cultures of the urine fail to grow a significant number of organisms. Cys-
toscopic findings include blanching of the mucosa with submucosal pete-
chiae, hyperemia of the mucosa, and occasionally an intense red velvet
appearance (Watson et al., 1947; Goldberg et al., 1984).
In most cases the symptoms of acute radiation cystitis are mild and
resolve spontaneously. Occasionally the symptoms are more severe, ne­
cessitating interruption of treatment for 1 or 2 weeks. Pyridium, an orally
administered drug that is excreted in the urine to provide a topical analge­
sic effect, is often used during this time to provide symptomatic relief.
The most important clinical syndromes are those that develop months
or years after completion of treatment. Hematuria is the most common
presenting symptom of chronic radiation cystitis. The bleeding is usually
mild and self-limited, but occasionally frank hemorrhaging can develop,
necessitating transfusions. In severe cases, multiple episodes of hemor­
rhaging occur over many months. Cystoscopic findings during this time
include erythema with prominent tortuous blood vessels, bullous edema,
and bleeding ulceration. Alternatively, the mucosa may appear atrophic
and pale with fine, telangiectatic vessels.
Large mucosal ulcers at the base of the bladder can also be seen cysto-
scopically during the chronic period and these may be associated with
RADIOSENSITIVITY OF URINARY BLADDER 3
TABLE I
GRADES OF SEVERITY FOR BLADDER INJURIES IN 132 PATIENTS
TREATED FOR CERVIX CARCINOMA
Percentage
Grade Injury of cases
0 No bladder symptoms 92
1 Occasional episodes of hematuria 1
2 Frequent episodes of hematuria 2
3 Vesicovaginal fistula or other 5
injury requiring surgery
infection (Herger and Sauer, 1942). In women treated for cervix carci­
noma, the bladder ulceration can lead to vesicovaginal fistulas. Contrac­
tion of the bladder can also occur as a late effect, causing symptoms of
urinary frequency and nocturia and in severe cases urinary incontinence
(Farquharson et al., 1987).
Most authors grade the severity of late-occurring complications. For
example, in our series of patients treated for cervix carcinoma at the Her-
shey Medical Center the grading system shown in Table I was used
(Stryker et al., 1988). In our series of patients treated for prostate carci­
noma a similar grading system (see Table II) was used (Leonard and
Stryker, 1986). Since the bladder is irradiated in every patient with cer­
vix, prostate, or bladder carcinoma, a small number of grade 1 injuries
are inevitable and acceptable. Measures should be directed toward pre­
vention of grade 2 and 3 injuries.
TABLE II
GRADES OF SEVERITY FOR BLADDER INJURIES IN 96 PATIENTS
TREATED FOR PROSTATE CARCINOMA
Percentage
Grade Injury of cases
0 No bladder symptoms 83.5
1 One episode requiring medical 11.5
attention
2 Two or more episodes requiring 3
medical attention
3 Complication severe enough to 2
require surgery
4 JOHN A. STRYKER ET AL.
III. Pathology
Pathologic alterations in the bladder related to radiation injury can
broadly be divided into acute and chronic changes. Acute irradiation
changes in humans are less well documented than those in animals.
Hueper et al. (1942) studied the acute reaction in dogs that were sacri­
ficed 5 days to 10 months after receiving 1200 rad to the bladder in three
fractions over 3 days with orthovoltage X rays. The first changes noted
were in the lamina propria and included interstitial edema, capillary con­
gestion, and dilatation. Subsequently, some epithelial cells underwent
vacuolar degeneration and nuclear pyknosis. Following progressive epi­
thelial degeneration the damaged epithelium desquamated, leaving a sin­
gle layer of basal cells or an entirely denuded surface covered by a fibri-
nous exudate. In some cases, hyperplasia of the bladder epithelium with
cellular crowding and irregularity developed. In the lamina propria, vary­
ing degrees of edema, perivascular lymphocytic infiltration, and intersti­
tial hemorrhage were identified. In those cases in which ulceration en­
sued, reepithelialization was not identified before at least 5 weeks
postirradiation.
The acute changes seen in the bladders of rats after radiation exposure
are less pronounced than those seen in dogs. Antonakopoulos et al. (1982)
irradiated the bladders of rats with 20 Gy of orthovoltage X rays in a
single fraction and performed light and electron microscopy 1 week to 20
months postirradiation. At 1 week postirradiation the bladder epithelium
appeared grossly and histologically unremarkable; however, an increase
in the number of lysosomes in basal epithelial cells was noted on electron
microscopy. At one month, though grossly normal, the bladder epithe­
lium showed histologic evidence of focal basal cell necrosis and a sparse
intraepithelial infiltrate of macrophages. Only at 3 months postirradiation
were changes identified in both intermediate and basal epithelial cells.
Significant changes seen at that stage included focal intracellular edema
and ballooning. Electron microscopy showed some of these edematous
cells to contain very large lysosomes while others contained increased
amounts of smooth endoplasmic reticulum (SER).
Acute radiation injury to the human bladder was described as early as
1942 by Warren et al. (see Warren, 1942). The first changes noted were
primary erythema due to hyperemia occurring within 24 hr. Fajardo and
Berthrong (1978) describe a second wave of hyperemia, desquamation of
urothelial cells, and edema 3-6 weeks later. Shallow ulcers may appear
at this stage although they are usually first seen at a later stage. It is
important to note that radiation-induced epithelial irregularity may
closely mimic transitional carcinoma in situ, making it difficult to differ-
RADIOSENSITIVITY OF URINARY BLADDER 5
entiate one from the other. In such instances, Koss (1975) suggests a re­
peat biopsy 3 months later. If epithelial abnormality is still present, it is
more likely an indication of in situ radioresistant carcinoma than radia­
tion-induced abnormality.
The chronic pathologic alterations in the bladder after radiation ther­
apy are well described in humans (Gowing, 1960; Fajardo and Berthrong,
1978). Upon gross examination, the bladder is usually small, shrunken,
and contracted. The wall is thick and fibrotic. The mucosa is edematous
and erythematous, and telangiectasia of vessels is apparent. Superficial
or deep epithelial ulcerations may be present. The histologic changes seen
are many and varied. Squamous metaplasia is common (Fig. 1). There is
often focal or extensive mucosal ulceration, extending superficially into
the lamina propria or into or beyond the muscle layers. The crater base
is composed of dense fibrous connective tissue and the crater is usually
filled with a fibrinous exudate, sometimes mixed with polymorphonuclear
leukocytes. Alternatively, the nonulcerated transitional epithelium may
show variable degrees of hyperplasia with or without abnormality (Fig.
2). Changes seen within the stroma include variable degrees of edema,
chronic inflammation, and fibrosis. Fibroblasts are characteristically
large, plump, and hyperchromatic (Fig. 3). Blood vessels are usually
prominent. Endothelial cells are frequently enlarged and swollen. Ad­
vanced lesions may show intimal fibroplasia with relative luminal narrow­
ing, fibrosis of the media, and occasional complete hyalinization of the
wall.
Antonakopoulos et al. (1984) described ultrastuctural changes in bi­
opsy specimens from patients as long as to 22 years after completion of
a course of radiotherapy. Within all layers of the transitional epithelium,
increased numbers of lysosomes and autophagic vacuoles are seen in the
first few months postirradiation. Nuclei are pleomorphic and some are
pyknotic. About 40% of cases show microvilli on the luminal surfaces
of epithelial cells. There is also thickening of the basement membrane
separating urothelium from lamina propria. Irregular, bizarre, sometimes
multinucleated fibroblasts are identified within the stroma. Blood vessels
show swelling of endothelial cells, thickening of basement membranes,
and dilatation of SER. Capillaries may show total loss of the endothelial
lining. Bladder musculature may undergo extensive changes including
myofibrillar edema, accumulation of intracellular lysosomes, and irregu­
larity of fiber shape and size. Extensive fibrosis within the muscle coat
occurs with the passage of time.
The late-occurring pathologic alterations seen in the bladders of dogs
following irradiation are similar to those observed in humans. However,
in the rat study reported by Antonakopoulos et al. (1982) there was a