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Complications following radiation therapy in carcinoma of the cervix and their treatment
Complications
following radiation therapy
in carcinoma of the cervix and their treatment Joseph
Price Oration
H.
KOTTMEIER,
L.
Stockholm,
Primum
et non
M.D.
Sweden
nocere.
tained in the years 1936 to 1947 and the incidence of complications was rather small. As a result of studies on the dosage distribution from the radium applied, an attempt w 1s made in January, 1949, to individualize radiation in carcinoma of the cervix and to irradiate every potential area of spread within the pelvis.12~ 20, 23 It soon became evident that the primary results were improved but the incidence of complications, especially in the bladder, sigmoid, and rectum, increased. Despite the last-mentioned fact, we have continued this individualized plan of radiation therapy. The planning of irradiation therapy must be based on two fundamental concepts: ( 1) the tumor control dose, and (2) the tolerance of healthy tissues to radiation. It is important to keep the time dose--volume dose relationship in mind. The same dose of irradiation will be much better tolerated when given to a small area of tissue than to a large area. Thus, it is possible to increase the total roentgens delivered throughout the extent of the disease if the radiation is carefully planned.
T rr 1s .4 r M in treating a malignant tumor is to cure the patient or to relieve her of severe symptoms without causing irreparable damage to normal tissue. A prolonged extensive radical operation or an intensive exhausting course of radiotherapy for carcinoma of the cervix may make the patient far more uncomfortable than the tumor has done. It is imperative, therefore, to control one’s enthusiasm in the treatment of a cancer that is not suitable for radical operation and does not respond well to irradiation. Complications may occur as sequelae of therapy and the frequency of these complications is increased by irradiation of advanced tumors. For many years gynecologists in Scandinavia have conceded that radiotherapy is the treatment of choice for primary cancer of the cervix. The commonly used method is the intracavitary application of radium supplemented by x-ray directed to the parametrium and regional lymph nodes. The Stockholm method5> w 321 33 was developed on the basis of extensive clinical experience. A 5 year cure rate of 42 per cent was mainFrom
the
Plans
Radiumhemmet.
of radiation
administration
Measurements performed on patients and phantomsZO, 23 have indicated that intrauterine radium is of utmost importance for the paracervical tissue, while in a growth
Presented at the Seventy-fourth Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 5-7, 1963.
854
Volume Number
RR 7
Radiation
with paravaginal extension vaginal radium gives better results. On the other hand, the maximum rectal dose at the level of the posterior fornix, which is the area of the injuries ordinarily seen in the rectum, depended on an amount of about 65 per cent of the intravaginal radium, provided the corpus was not sharply retroflexed. As a consequence of these various findings the dosage from the intrauterine radium was considerably increased in cases of endocervical tumors and of carcinomas with extension to the paracervical tissue. This change in technique, however, increased the incidence of complications in the uterus, urinary bladder, and intestines. Pyometra due to necrosis of the myometrium may be partly due to the belief we held for years that a fractionated irradiation with high intensity has some clinical and biological advantages over a protracted low intensity plan of radiation. We have not observed necrosis in the uterine wall since the distance from the radium applied to the tissue was increased from 4 to 7.5 mm. Experience has proved that a careful dilatation of the uterine canal may be performed without increasing the risk of dissemination of cancer cells in cases of paracervical extension. The prequisite for such an operation is the precise location of the external OS. Palpation, not inspection, will often reveal its position. Provided the OS is not easily located the application of radium should be postponed for a few weeks. Manipulations with instruments will increase the risk of local infection which, in turn, may affect unfavorably the prognosis and increase the risk of injury. Antibiotics have little value in the prevention of infections. Dosage measurements in the bladder and rectum and their clinical significance. The injuries that. occurred as sequelae of the change in technique were seen in the bladder, the lower sigmoid, and the rectum. In view of this fact and that of the improved primary cure rate, it was logical to try to correlate clinical observations and physical data. The elaborate three dimensional technique introduced by Lederman and Lamer-
therapy
complications
in cervical
cancer
855
Table I. Bladder injuries correlated with dosage in gamma roentgens measured in the bladder
.Gamma 2,000 3,000 4,000 5,000 6,000
r
0 to 1,999 to 2,999 to 3,999 to 4,999 to 5,999 and over
No. of patients
Grade 1 injuries (%)
54 102 93 5,7
11.1 15.6 11.8 22.8
40 16
17.5 6.2
Grade 2 and 3 in juries (%) 3.7 3.9 6.4 10.5 2.5 31.2
tonZ5 Nolan and Quimby,*g~ 3o Lewis and coworkers,26 and others yield accurate data for the individual patient but this method is time consuming and can, therefore, not be applied in practice. Roentgenograms were taken in all cases to check the position of the radium. The information was inadequate to calculate the dosage in the rectum and sigmoid. It was decided, therefore, to perform actual measurements in the bladder and rectum for each application. A 0.3 C.C. Sievert ionization chamber was applied in the end of a curved probe which was introduced first into the bladder and then into the rectum. Five hundred consecutive cases of carcinoma of the cervix treated from July, 1953, to September, 1954, were selected in an attempt to correlate rectalbladder reactions with dosage distribution. The results from this investigation have been reported by Gray and Kottmeier.14 The measurements in the bladder (Table I), and rectum yield information as to the correctness of the application of radium. Whenever the readings do not correspond to the expected figure or are excessive the intrauterine tandems or vaginal applicators are taken out and reinserted. Because of the steep gradient of dosage rates in intracavitary radium therapy, bladder and rectal doses should not be taken as absolute values. From the measurements carried out, however, and from a clinical point of view we feel justified in concluding that the measured tolerance dose from the in-
856
April 1, 1964 Am. J. Obst. & Gynec.
Kottmeier
Table II. Carcinoma of the cervix examined with a view to treatment from 1949 to 1957* State
/ No. of cases /
I
611
IIA
965
IIB III IV
964
% 17.4 27.8
1929
No treatment
710 234 25
Total
cases.
3.509
‘Only
symptomatic
radiation
54.9
27.8 20.3 6.7 0.7 was applied
in 220
cases.
serted radium amounts to 4,000 to 4,200 r in the rectum and to a slightly higher amount in the bladder provided regard is paid to the average dose over an area of 3 cm. These figures are by no means absolute levels for the radiation tolerance but clinical experience over several years has shown that they serve as a good basis for planning. In cases of advanced carcinoma the dosage mentioned may be exceeded. The figures do not apply to any other radiation technique or different calculation of dosages. Every institution should find the figures corresponding to the technique applied. We will not treat a carcinoma of the cervix without having the chance to record directly the dose along the posterior wall of the bladder and the anterior wall of the rectum. The use of this method has been accompanied by a considerable reduction in the number of radiation injuries. Material Primary radiotherapy has been given to 3,484 cases of invasive carcinoma of the cervix from 1949 to 1957. Table II presents the cases divided into the four stages.l Cases allotted to Stage II have been subdivided into Stage IIA and IIB with regard to the parametrial extension of the growth. Several institutions tend to allot cases of Stage IIB to Stage III. Treatment The majority of patients have received intracavitary radium and conventional roentgen therapy to the parametrium and area of
regional lymph nodes. The Radiumhemmet had no facilities for supervoltage radiation prior to 1958. Palliative irradiation has been given in 220 cases. They are included in the table. In cases receiving a full course of irradiation, a total dose of 3,200 to 3,500 r was delivered to the lateral pelvic wall from the radium and x-ray over a period of 10 to 12 weeks. A 5 year recovery rate of 54.2 per cent has been attained. In addition, about 2 per cent of the patients are living with cancer at 5 years. The respective cure rates are: Stage I, 87.3 per cent; Stage IIA, 68.1 per cent; IIB, 48.1 per cent; III, 30.6 per cent; and Stage IV, 7.3 per cent. One hundred and fifteen patients are known to have died from intercurrent disease. A primary healing after radiotherapy was not achieved in 717 cases (20.6 per cent). Sometimes it is difficult to establish whether complications such as fistulas, are caused by the growth in its terminal stage or by the therapy applied. The purpose of this presentation is to discuss the reactions and injuries that have occurred in cases of cervical carcinoma treated by irradiation in 1949 to 1957 and the management especially of urinary and intestinal complications (Table III, Fig. 1). Previously, means for the prevention of radiation injuries have been elucidated. Injuries have been more common in the series of cases presented than generally are observed at the Radiumhemmet.‘*, I5 This fact is related partly to the various experimental techniques used from 1949 to 1953. Primary
mortality
The primary mortality rate is low for radical hysterectomy, but it is also low for radiation therapy. Five patients (0.2 per cent) in Stages II, III, or IV have died during or immediately following treatment, 1 of them from sepsis and peritonitis, 1 from a heart attack, and 3 from uremia. Prevention
of infection
Extremely important is the prevention of infection (Table IV). Radium should never be applied simultaneously in the uterus and
Volume Number
88 7
Radiation
therapy
following
therapy
Mild cystitis and, sometimes, moderate diarrhea, scarcely necessitating any medication may follow directly the application of
Table III. Results in cases of carcinoma from 1949 through 1957
of the cervix
Symptom
Stage
I
*Absolute
cure
for
1,888
3,509
of cases treated
I
611
IIA IIB
965 964 I
III IV
710 234 TV
Clinically No.
neuer
cured
I
%
87.3 68.1 48.1 30.6 7.3
14 40 38 19 4
3 42 190 303 179
0.5 4.4 19.7 42.7 76.5
54.2
115
717
20.6
53.8*
rate.
No.
I through
857
at the Radiumhemmet
%
533 657 464 217 17
3,484 25
treat-
Table IV. Causes of death 1949 through 1957
Stage
I
cancer
at 5
free
No.
611 965 964 710 234
I through IV. Not accepted ment Total
treated
years
No. of cases
I IIA IIB III IV
in cervical
radium and are frequently seen also in the course of the external irradiation. These symptoms cannot be counted as complications as it is evident that a cancer that is not localized only to the cervix cannot be treated without producing some irritation of the bowels and bladder. However, treatment should be interrupted for some days if the patient feels uncomfortable from the diarrhea. Similar symptoms from the urinary tract or intestine will occur in all patients in whom reirradiation has been administered to recurrent disease on the pelvic wall in order to alleviate symptoms. This was also true of the 338 cases in which operative intervention was carried out because of a radioincurable tumor in 154 cases or recurrent disease in 184 cases.?l In the last 15 years electrosurgery, so-called unipolar fulguration
the vagina in cases with offensive discharge or other sign of infection. A pelveoperitonitis or sepsis will follow therapy and influence the prognosis unfavorably. The careful management of the individual case has decreased the incidence of pelvic infection following irradiation from 10 to 1.5 per cent. In a case of acute or chronic salpingitis it is imperative to remove the adnexa and postpone irradiation to 1 week or more after laparotomy. A 5 year cure rate of 65.7 per cent has been attained in 47 cases complicated by salpingitis treated in this manner, while the corresponding cure rate is only 14.4 per cent in 118 similar cases treated conservatively. Symptoms
complications
3,484
1929
in patients
Primary Sepsis\
by primary
Uremia\
Heart
1 2 1 6 (0.2%)
;$}
78
irradiation
Injuries
;}
6
19 4 115
in the years
Dead of carcinoma
Intercurrent disease
deaths
1 1
treated
Operation
,;]
No.
12
2 (3.3%)
6 (0.2%)
17 (0.5%)
f}
1 %
707
ifj
469 212
66:l 90.6
1,449
41.6
858
April
Kottmeier
.Anr. J. (ht.
I IA IB
2
54 0
I I
I 2
I 3
1 4
1 5 KARS
Fig. 1. .4pparent recovery rate in 3,484 cases of cancer of the cervix treated at the Radiumhemmet 1949 through 1957. (Table v j , has been the most common operative procedure at the Radiumhemmet. Radical hysterectomy has been performed in 53, and some kind of exenteration procedure in 7 cases. Electrosurgery has been carried out especially on patients in whom a radical hysterectomy is a questionable procedure; 277 such cases are included in this series. Fistulas immediately following operation are more frequently seen in cases in which a full course of irradiation has been administered previously. Such complications occurred in 12 out of 53 cases treated by radical hysterectomy and in 72 out of 277 cases in which an electrosurgical procedure has been carried out. Reirradiation or an operative procedure evidently makes the tissue more vulnerable and, consequently, contributes to late radiation damage (Table V) . late
complications
Late complications from radiation occur especially in the bladder, lower sigmoid, and An analysis will be given of the rectum. complications seen in 3,484 cases treated. Rectal complications. The usual time for rectal damage to occur is 6 to 18 months following initial radiation and is most fre-
1, 1964 & Gyner.
yuently seen after 6 to Y months (Figs. 2 and 3). The symptoms are bleeding, tenesmus or pain, and sometimes, constipation. On examination, the earliest lesion may show nothing by palpation but exhibit hyperemia on inspection. Later on there is an irregularity of the mucosa which becomes thickened and edematous. If the damage progresses in the mucosa an ulcer or even a fistula may occur. The lesion is usually localized in the anterior wall immediately behind the cervix. In cases in which the dose from the intrauterine radium has been considerably increased, the damage may appear higher up in the rectum or even in the lower sigmoid. The lesion in the rectal wall is classified as “intrinsic” while an “extrinsic” damage will signify a damage to the connective tissue or blood supply. *O*31 Such a fibrosis may lead to stenosis of the intestine. Bladder complications. Late radiation reactions in the bladder occur later than does the damage to the rectum (Figs. 2 and 3). Such injuries are seen sometimes several years following irradiation and we have
qocorance ytal number
m per cent of of cases treated
-r--l ---
6.0,
i-
,c: 0
i
i
3
Qriw?s
Fig. 2. Year of appearance of injury after radiation therapy in 3,484 cases treated at the Radiumhemmet from 1949 through 1957.
Volume Number
88 7
Radiation
observed such damage appear for the first time after 28 yearsl’T **I 34 The time that elapsed between the radiation and the onset of the symptoms is shorter in cases that have had large doses. The initial symptoms are frequent urination and, sometimes, hematuria and dysuria. Cystoscopy shows a slight hyperemic elevation with some telangiectatic vessels and bullous edema on the posterior wall right above the interureteric ridge. A sharply limited ulcer covered with grayish slough may appear in this area. In more severe cases necrosis may occur which,
Table V. Results in 717 radioincurable treated
by operation
therapy
complications
in cervical
cases and 230 cases of local recurrence
after radiation
Radioincurable cases Radical hysterectomy
Stage
No.
I IIA II3 III
1 a 10 4
IIA IIB
1 5
of
cases
at Fistulas
(No.1
1 2
(No.)
:
12
2 0
2 0
3
23 Exenteration
5
5 (21.7%)
3 6
Electrosurgery
I IIA IIB III IV
7 41 53 20 4
Local recurrences Radical hysterectomy
I IIA IIB
6
I II
Electrosurgery
I IIA IIB III IV
11 9 10
2
38
(31.2%)
43
(27.9%)
7 2 4
1 3
1 1
30
(24.0%)
2 3 2 13
(43.3%)
7 (23.3%)
1 1 2
Total cases operated upon Total cases symptom free after 5 years
14 6 1
(21.5%)
30 Exenteration
3 ia 13 3 1
1 5
125 154
Total cases operated upon Total cases symptom free after 5 years
2
24 53 60 13 2
14 25 20 7 0 152 184
859
if it deepens, will form a fistula. Sometimes, parts of a necrosis will be transformed into a stiff structure resembling a coral reef. The differential diagnosis between a radiation injury and a carcinomatous invasion of the bladder may occasionally be difficult. Repeated cystoscopic examinations facilitate the correct diagnosis. Biopsy should be avoided as it adds to the risk of fistula formation. Bladder complications were less frequent than rectal complications. If we consider every case with symptoms from the bladder or the rectum as damage of radiation, blad-
Symptom free 5 years Operation
cancer
a 13 16 4 1 66
(43.4%)
79
(42.9%)
(80%)
42
(27%)
860
Kottmeier
0
i
2
Fig. 3. Total cases of bladder and rectal injury observed after radiation therapy among 3,484 cases of carcinoma of the cervix treated at the Radiumhemmet from 1949 through 1957.
der complications have occurred in 279 cases, 8.0 per cent, and rectal, in 424, 12.1 per cent. In these figures, however, have not been included either the 61 vesicovaginal or 27 rectovaginal fistulas appearing immediately following operation or the complications in the terminal stage of the disease in 1,449 patients who have died from the cancer (41.6 per cent of the 3,484 patients treated). Rectovaginal fistulas have been diagnosed in 95 and vesicovaginal fistulas in 119 of these terminal cases, Types of rectal reactions and injuries. A subdivision of these 424 cases into four grades is desirable (Table VII). Grade 1 is represented by reactions with mild or no subjective symptoms and minimal objective changes in the mucosa. In 339 cases Grade 1 reactions have been observed. Jacox and Kligermanls correctly point out that these reactions cannot be considered as injuries. Thus there remain 85 cases with rectal injuries (2.4 per cent, Table VII). These arc divided into three further grades. Grade 2 is accompanied by frequent painful stools and the passage of mucus and blood for many months, even 2 years. On examination, areas of necrosis, ulcers, or moderate
stenosis are seen. Thirty-five of our cases were allotted to Grade 2. Grade 3 comprises the cases of rectal stenosis severe enough to require a colostomy. Sixteen of our cases belong to this category. Grade 4, finally, is the radiation fistulas. Thirty-four radiation fistulas have occurred. A survey of the 85 cases is given in Table VII. In 60 of the 85 cases the damage could be attributed to initial radiation. In 25 cases operative intervention or reirradiation of recurrences may have contributed to the injuries. Forty-three of the 85 patients are living free from cancer at 5 years. Three patients have died from intercurrent disease and 34, from cancer. In 6 cases the injuries themselves have been fatal. Two patients with Stage IIB carcinomas and Grade 3 injuries died as a result of the stenosis of the sigmoid, one from ileus, 3f/, years following initial therapy, and one immediately following a resection of the sigmoid performed 4 months after irradiation. In 4 other patients with Stage II carcinomas who all had received intensive doses, a fistula in the anterior wall of the rectum or sigmoid perforated into the peritoneal cavity. The fatal complications in these 4 cases occurred 11 months, 15 months, 2vz years, and 3f/z years, respectively, after initial therapy. Although only 6 out of 3,484 patients treated for carcinoma of the cervix by primary radiation have died from injuries due to therapy we should take into consideration the possibility of fatal complications when we are subjecting patients to higher and higher dosages. Similar complications have been reported by Brack: Everett and Dickson,4 Cosbie,6 Frick and associates lo, I1 and Fletcher and associates.“, ’ There is no doubt that many times it is rather difficult to determine the factors that account for injury in the rectum. In our experience the damage is due to high doses directly to the rectum and its mucosa. Factors, such as old age, syphilis, local infection, and surgical intervention may also be of importance. In Table VIII we have collected the factors that may explain the injuries occurring in the rectum.
Volume Number
88 7
Radiation
The treatment of Grade 1 and 2 reactions should be conservative. Mild laxatives given regularly prevent constipation. Rectal instillations of warm chamomile tea three times a day and local application of 25 to 75 mg. of hydrocortisone in a water-soluble base alleviate symptoms. Colostomy is indicated for stenosis (Grade 3) and fistula formation (Grade 4). The operation should be performed on the transverse colon as soon as troublesome symptoms appear. The fatal complications mentioned might have been avoided provided a colostomy had been done in due time. It is a mistake to carry out a primary resection of the intestinal stenosis. Such a procedure is not indicated until the injury has healed. Degrees of urinary bladder reactions and injuries Minimal objective changes with mild subjective symptoms (Grade 1) have been observed in 229 patients out of 279. These should be considered as late reactions and not as real injuries. In the majority of these cases the symptoms have disappeared after some weeks. In 50 cases, however, a bladder injury has been diagnosed (Table IX). In 31 instances a fistula occurred (Grade 3). In 19 cases a more or less extensive necrosis was found on cystoscopy or the patient suffered from pain or hemorrhage which required repeated blood transfusion and even hospitalization (Grade 2). The same comments are valid for the bladder injuries as for the rectal ones (Table VIII). High radiation doses and urinary infection will predispose to the occurrence of a bladder injury. Reirradiation of suspicious pelvic recurrences or operative intervention may have contributed to the fistula formation in 7 and in 4, respectively, of the 31 cases. Thirty-nine of the 50 patients with bladder radiation injuries are living with no evidence of cancer at 5 years. Two patients have died from nephrosclerosis, or pyelonephritis, and the fistula formation may have contributed to the fatal disease in these 2 cases. The treatment of mild reactions and of
therapy
complications
in cervical
cancer
861
of onset of symptoms to the bladder and rectum
from
Table VI. Time injuries
Time
Within 6 months 6 to 12 months 1 to 1% year 1 yL2to 2 years 2 to 3 years 3 to 4 years After 4 years Total
Urinary bladder
Rectum
1 3 6 9 13 12 6 50
8 41 19 5 8 2 2 85
Grade 2 injuries to the bladder is symptomatic. The patient should avoid heavy smoking. Especially important is the prevention of infection and the correct application of selected antibiotics in sufficient doses. Rest, repeated blood transfusions, and cauterization of the bleeding point through a cystoscope have been an aid in the treatment. Cauterization was applied in 2 cases. The method of dealing with the vesical fistula is a difficult problem. The destructive action of radiation on all tissues of the region produces a chronic condition in which the common surgical procedures used for repair of traumatic or obstetrical fistulas are unsuccessful. Repair procedures for vesicovaginal fistulas The fistulas considered for repair in the series of 3,484 cases of cervical carcinomas amounted to 88 (Table X) . Twenty-seven fistulas were the result of radiation injuries. Eight fistulas developed immediately or a few weeks following radical hysterectomy. This operation had been performed in 23 cases of radioincurable carcinoma and in 30 cases of recurrent carcinoma. Six patients died as a result of the operation ( 11.3 per cent). Eighteen patients are living free from evidence of cancer at 5 years (34 per cent). In 53 cases, finally, the fistula occurred following electrosurgery. This type of operation was described in Meig&* book, Surgical Treatment of Carcinoma of the Cerviz2’ In the last fifteen years this operation has been
862
Apil
Kottmeier
performed on many patients with advanced lesions in whom, otherwise, exenteration would have been the treatment of choice. Electrosurgery as a more or less extensive fulguration was carried out in 125 cases of radioincurable carcinoma and in 152 of recurrent carcinoma in the present series. The primary mortality from hemorrhage or infection amounted to 2.2 per cent. Ninetyfour of the 277 patients are living with no
Table VII. the cervix, -.
1, 1964
Am. J. Obst. & Gynec.
Incidence of radiation injuries treated from 1949 through 1957
evidence of cancer at 5 years (33.9 per cent). The 61 patients with surgically induced vesicovaginal fistulas had all received intensive radiation initially (Table Vj . The choice of operative procedure for the repair of vesicovaginal fist& is dependent on several circumstances. No patient should be operated upon if there is still evidence of carcinoma or the necrotic irradiated tissue has not sloughed off. A
to the rectum
in cases of carcinoma
of ---__
Primary Grade
radiation in 2 injuries
Primary Grade
radiation 3 injuries
in
Primary Grade
radiation 4 injuries
in
Stage I IIA IIB III IV -~ Total
611 965 964 710 234
4 6 10 7
1
1
5
1 2 4 4
1
35
Explanations
of the injuries
Grade
Unknown Infection and radiation Overdosage primarily Reirradiation Operation Most likely cancer Total
3 3
2
to the bladder
bladder 1 Grade
3
Grade
2
(
Grade
3
8 2 9
3 6 9 7 4 2
11 1 14 6 2 1
2 8 4 1 1
19
31
35
16
Stage I IIA IIB III IV Total
___.-
3.484
radiation in Grade 2 in juries 2 8 7 2
1.0 2.1 3.0 9.9 0.9
85
2.4
Rectum
Primary Grade
Primary Cases
__.-~~
6 20 29 28 2
and the rectum
Table IX. Incidence of injuries to the urinary bladder in the radiation of 3,484 cases of carcinoma of the cervix from 1949 through 1957
treated (No.) 611 965 964 710 234
3 4
..~34
16
llrinary Explanation
1 8 8 4 ___- 1
1 1 1 I
.~.__
3.484
Table VIII.
1
__ Alone
4 4 8 4
radiation 3 injuries
And operation
Grade
4 --
Total
5 6 10 5
26 17 50 22 12 7
il 34
.--__
treatment
in .4nd further radiation
1 2 1
/
1 4 L’
Total No.
%
7 13 21 9
1.1 1.3 2.2 1.3 ___-
19
31
50
1.4
Volume Number
88 7
Radiation
conservative operation should not be undertaken until the condition of the patient is good, the infection is under control, and the entire urinary tract has been investigated. Estimation of renal function is of importance. Intravenous pyelography and cystoscopy should be performed. Bastiaanse,2 Mandicas,27 and IngelmanSundberg16g I7 deserve the credit for having developed modern techniques in the repair of postradiation fistulas. Ingelman-Sundberg has acquired great experience in this field and has developed a method which has yielded good results. The first step of his operation is a scrupulous dissection of the fistula and the surrounding tissue. The dissection is performed vaginally under local anesthesia from a transverse incision below the external urethral orifice. With the position of the ureters identified the remnants of the vaginal wall are dissected free from the margins of the fistula. The dissection is continued until the bladder base is free from the cervix. The vaginal wall is mobilized so far laterally that the pubococcygeus muscles can be inspected. It is important to leave a good blood supply. The margins of the fistula are trimmed, and then approximated in the simplest way with a few stitches of chromic catgut leaving the mucous membrane of the bladder intact. It is not necessary to close the bladder tight. The bladder ligaments are sutured in the midline under the bladder base, if this can be done without tension. The next important step in this operation is to bring well-nourished tissue to the site of the fistula. Ingelman-Sundberg has tried different techniques to get a suitable flap. In cases heavily treated by irradiation the preference is given to the gracilis muscle. An incision is made through the skin and subcutaneous tissue from the inner epicondyle to a point on the descending ramus of the OS pubis about 2 cm. below the inferior border of the symphysis. After the muscle is carefully dissected without interruption of the chief blood and nerve supply, the muscle is drawn through the obturator foramen to the space between the bladder and vaginal wall. This part of the operation requires
therapy
complications
in cervical
cancer
863
great experience. The preparation of the canal is dependent on the anatomical conditions, and various techniques are used. The canal must have a width of two fingerbreadths in order not to constrict the blood supply of the muscle. The muscle is brought to the site of the fistula. The tendon is fixed against the opposite pelvic wall. The muscle is interposed between the bladder and the vaginal wall without tension and should cover the fistula as completely as possible. The vaginal wall is replaced and sutured with a few stitches. A very loose packing of gauze powdered with any suitable antiseptic is applied in order to abolish dead spaces between the vaginal wall, the graft, and the bladder. A good suction drainage of the bladder, preferably through a suprapubic cystotomy is necessary. The patient should stay in bed for at least 2 weeks. If the drainage is good and the tissue is well vascularized, the granulation from the tissue may be satisfactory to heal the fistula completely. Sometimes, a residual fistula remains after 4 or more weeks. A new transplantation procedure may be done in a similar manner. The pubococcygeus muscle, the rectus, the adductor longus, or the gracilis on the other side can be used. In postradiation cases, the operation as a rule has to be repeated one or two times. The operation described has been performed by Ingelman-Sundberg in many cases with satisfactory results. It has been carried out in 16 of the 88 vesicovaginal fistulas reviewed in this paper. The primary result was satisfactory in all cases. Two patients have died, one from pyelonephritis 2 years following operation. Conservative plastic operation is not indicated if renal function is unsatisfactory or bilateral hydronephrosis is present. Earlier a transplantation of the ureters to the colon, a Coffey operation, was tried in several cases. The results were unsatisfactory. A similar procedure was carried out in one of the cases in the series presented. So far the result is satisfactory. This comment is also valid for 7 cases in which a ureteroileal urinary diversion was made.
864
Kottmeier
Table X. Types of repair procedures of the cervix in the years 1949 through _.-.~ ___--
NO.
Vesicovaginal fistulas Injuries by radiation, etc. From electrosurgery Surgery
tDied *Two
Plastic surgery
?7 53 8
____.
Nephrec-
’ Ureteral implant in bladder or
tomy
COlOIZ
6* 3 1
~-~
j lleal bladder
!
Resettion of 1 intestine
No
operatiue I repair
10
1
6
14
1
1
38 6
1 1t
24 3
29 from
1
2
3 (J
23 3
1 4
3
2
17
nephritis.
A spontaneous healing of the fistula occurred in 4 cases. At present no operative intervention has been carried out in 58 of the 88 fistula formations. Six of the remaining 14 patients with postradiation fistula and the majority with postoperative fistulas have died of cancer. Injuries
in cases of carcinoma
31
complications after 1 week. patients died later
Spontaneous healing
injuries
27
Rectovaginal fistulas Injuries by irradiation, etc. From electrosurgery Surgery Ureteral
for irradiation 195 7 ---~-
to the ureters
In recent years special interest has been devoted to the ureter since it has been demonstrated that hydronephrosis or a nonfunctioning kidney due to carcinomatous obstruction of the ureter has a poor influence on prognosis. Intravenous pyelography was performed in 1,502 of the 3,484 cases prior to therapy. Hydronephrosis or a nonfunctioning kidney was revealed in 268 cases (17.8 per cent). Attention must be given to this hazard in the planning of therapy. A 5 year cure rate of 32.8 per cent was reached in the cases of hydronephrosis while it was 55.6 per cent in those with negative roentgenograms. Unfortunately, it has not been possible to carry out regular x-ray examinations in the follow-up of patients treated for carcinoma of the cervix. Pyelography, however, has been done in 57 of those 88 patients who are living symptom free at 5 years, in spite of positive roentgenograms prior to therapy.
Hydronephrosis remained in 16 cases while the renal function was quite normal in 41. The occurrence of hydronephrosis in a case previously treated by irradiation has been considered as a sign of recurrent tumor. There is no doubt that this observation is often correct. But it is evident that such a complication also may occur as a sequela of radiation fibrosis. Kirchhof-Y found no cancer in 18 out of 68 patients with fatal hydronephrosis and pyelonephritis. In 29 of the 3,484 cervical cancers hydronephrosis was observed which was evidently the result of parametrial fibrosis or scar tissue. Seven of these patients had coincidental vesicovaginal fistulas. Operative intervention certainly explained the hydronephrosis in 9 instances while in the remaining 20 it is likely that the radiation played an important role. In 6 of the cases, radioactive colloidal gold has been injected into the parametrial tissue transvaginally. From experimental and clinical studies we consider it justifiable to conclude that the application of colloidal gold into the parametrium does not improve the cure rate but increases the risk of fibrosis with secondary damage of ureters. Treatment of ureteral obstruction should be individualized (Table X) . In cases of
Volunle Number
88 7
Radiation
uncomplicated hydronephrosis the patient should be kept under careful observation. A nephrectomy was performed in 4 cases, a resection and reimplantation of the ureters in 3. The differential diagnosis between carcinomatous infiltration and fibrosis of parametrial tissue is extremely important in cases of anuria. Nephrostomy is not indicated in cases of cancer but should be carried out if the ureteral obstruction is due to scar tissue. This was the situation in 2 cases; one of these patients at present is living symptom free with an ilealbladder, performed because of vesicovaginal fistula which appeared following electrosurgery for an extensive recurrence. Puncture biopsy has proved to be of value in the differential diagnosis. Eighteen of the 29 patients suffering from postradiation or postsurgical hydronephrosis are living and in good health. Injuries
to the small
bowel
In addition to the various complications and injuries described appearing following irradiation in 1949 to 1957, I have to mention that obstruction of a small intestinal loop, requiring resection of the involved area, occurred in 3 patients who at present are free from disease. In another case in which a large intraperitoneal metastasis was treated locally by radium to stop hemorrhage from it, necrosis of an intestinal loop occurred. A unilateral fracture of the neck of the hip has been reported in 6 cases. In every case this was the result of an accident. No spontaneous fracture has occurred.
therapy
complications
in cervical
cancer
865
intercourse. In our experience, however, extensive adhesions occur only in cases of carcinoma that have invaded a large part of the vaginal wall. Young patients with localized carcinomas in the cervix and upper vagina as a rule have no trouble worth mentioning from intercourse. Supervoltage
irradiation
In my presentation I have tried to elucidate the problem we meet in radiation therapy of cancer of the cervix. From the beginning I called attention to the fact that all cases had received primary irradiation by intracavitary application of radium and conventional x-ray therapy. In the last four years the Radiumhemmet has acquired facilities for cobalt therapy. We have treated a selected number of advanced cases with cobalt in addition to the intracavitary radium. Although good results have been achieved in some cases it is, as yet, not possible to present any final results. But it is evident that different factors than have previously been mentioned should be considered in the administration of supervoltage irradiation. From the beginning cobalt therapy was given through one anterior, one posterior, and, sometimes, two lateral portals with a dose of 4,000 to 5,000 r3 over a period of 5 to 7 weeks. Serious complications, i.e., small bowel necrosis, have been reported by Fletcher and associates, Frick and co-workers, and others. The administration of external irradiation with increased dosages requires planning with a physicist in each case. Summary
Radium
reactions
in the vaginal
wall
Vault necrosis is frequently difficult to distinguish from recurrent cancer. It was observed in 26 cases, as a rule within 1 year after therapy. The necrosis may be cleaned up by local application of vitamins and antiseptics. One patient later died from metastases to the pelvic wall. In regard to the vault necrosis I call attention to the occurrence of adhesions in the vagina, which may involve most of the vagina and interfere with
A description has been given in detail of 3,484 cases of cervical carcinoma treated by intracavitary radium and orthovoltage x-ray therapy at the Radiumhemmet during the years 1949 through 1957. A 5 year relative apparent recovery rate of 54.2 per cent has been attained. The improvement in results has been achieved by individualization of radium therapy. This, however, has been accompanied by an increase in injuries.
866
.4ptil
Kottmeier
Rectal injuries have occurred in 2.4 per cent, bladder injuries in 1.4 per cent, and ureteral obstruction in about 1 per cent of the cases. Six patients with rectal injuries died from
Am. J. (ht.
I, 1964
& Gyurr.
complications of a stenosis or perforation of the intestine. Two patients with vrsicovaginal fistulas later developed pyelonephritis which explained the death and to which the bladder injury may partly have contributed.
REFERENCES
1.
Annual Report on the Results of Treatment in Carcinoma of the Uterus, Stockholm, 1960, vol. XII. 2. Bastiaanse, M. van Bouwdijk, and Sindram, I. S.: Virginia Med. 87: 547, 1960. 3. Becker, J., and Schubert, G.: Die Supervolttherapie, Stuttgart, 1961, Georg Thieme Verlag. 4. Brack, C. B., Everett, H. C., and Dickson, R.: Obst. & Gynec. 7: 196, 1956. J. A.: Gynecologic Cancer, ed. 3, 5. Corscaden, Baltimore, 1962, Williams & Wilkins Co. 6. Cosbie, W. G.: J. Obst. & Gynaec. Brit. Emp. 66: 843, 1959. 7. Fletcher, G. H.: Am. J. Roentgenol. 64: 95, 1950. G. H., Brown, T. C., and Rutledge, 8. Fletcher, F. N.: Am. J. Roentgenol. 79: 421, 1958. 9. Fletcher, G. H., Stowall, M., and Sampiere, V.: Radiotherapy of Cancers of the Cervix Uteri, Chicago, 1962, University of Texas, M. 0. Anderson Hospital and Tumor Institute. 10. Frick, H. C., II, Corscaden, J. A., Jacox, H. W.. and Tavlor. H. C., Jr.: Sure. Gynec. Sr 0b;t. 107: 4i7, ‘1958. I _ 11. Frick, H. C., II, Taylor, H. C., Jr., Guttman, R. J., Jacox, H. W., and McKelway, W. P.: Surg. Gynec. & Obst. 111: 493, 1960. Am. J. Roentgenol. 73: 35, 1955. 12. Garcia, M.: 13. Gray, M. J., Gusberg, S. B., and Guttmann, R.: Am. J. Roentgenol. 76: 629, 1958. M. J., and Kottmeier, H. L.: AM. J. 14. Gray, OBST. & GYNEC. 74: 1294, 1957; 82: 74, 1961. 15. Ingelman-Sundberg, A.: Acta radiol. Suppl. 64, 1947. A.: Arch. GynHk. 183: 16. Ingelman-Sundberg, 498, 1952. A.: Pathogenesis and 17. Ingelman-Sundberg, Operative Treatment of Urinary Fistulae in Irradiated Tissue, in Yorssef, A. F., editor: Gynecological Urology, Springfield, 1961, Charles C Thomas, Publisher. 18. Jacox, H. W., and Kligerman, M. M.: Year Book Radiol. 1958-1959, p. 328. 19. Kirchhoff, H.: Geburtsh. u. Frauenh. 20: 34, 1960.
20.
21. 22.
23. 24.
25. 26.
27. 28.
29.
30. 31.
32.
33.
34.
Kottmeier, H. L.: Carcinoma of the Female Genitalia, Abraham Flexner Lecture, Baltimore, 1953, Williams & Wilkins Co. Kottmeier, H. L.: Arch. Gynlk. 183: 494, 1952. Kottmeier, H. L.: The treatment by Fulguration of Recurrent Cancer of the Cervix Following Radiation, in Meigs, J. V., editor: Surgical Treatment of Cancer of the Cervix, New York, 1954, Grune & Stratton, Inc. Kottmeier, H. L.: AM. J. OBST. & GYNEC. 76: 243, 1958. Kottmeier, H. L.: The Urinary System in Cases of Uterine Carcinoma Treated by Irradiation, in Youssef, A. F., editor: Gynecological Urology, Springfield, 1961, Charles C Thomas, Publisher. Lederman, M., and Lamerton, L. F.: Brit. J. Radiol. 21: 11, 1948. Lewis, G. C., Jr., Chamberlain, R. H., Hale, J., and Payne, F. L.: Am. J. Roentgenol. 72: 975, 1954. Mandicas, A.: GynCc. et obst. 49: 72, 1950. Meigs, J. V., editor: Surgical Treatment of Cancer of the Cervix, New York, 1954, Grune & Stratton, Inc. Nolan. T. F.: Radiation Treatment of Carcinoma ‘of’ the Uterine Cervix, in Pack, G. T., and Ariel, J. M., editors: Treatment of Cancer and Allied Diseases, New York, 1962, Harper & Brothers. vol. VI. Nolan, J. F., and Quimby, E. H.: Radiology 40: 391, 1943. Paterson, R.: The Treatment of Malignant Disease by Radium and X-rays> London, 1948, Edward Arnold & Co. Schulz. M.. and Graham. 1. B.: Radiotherap; in’ Treatment of’ cancer of the Uterine Cervix, in Meigs, J. V., and Sturgis, S. H., editors: Progress in Gynecology, New York, 1957, Grune & Stratton, Inc., vol. III, p. 565. Sherman, A. J.: Cancer of the Female Reproductive Organs, St. Louis, 1963, The C. V. Mosby Company. Youssef, A. F.: Gynecological Urology, Springfield, 1961, Charles C Thomas, Publisher.
following radiation therapy
in carcinoma of the cervix and their treatment Joseph
Price Oration
H.
KOTTMEIER,
L.
Stockholm,
Primum
et non
M.D.
Sweden
nocere.
tained in the years 1936 to 1947 and the incidence of complications was rather small. As a result of studies on the dosage distribution from the radium applied, an attempt w 1s made in January, 1949, to individualize radiation in carcinoma of the cervix and to irradiate every potential area of spread within the pelvis.12~ 20, 23 It soon became evident that the primary results were improved but the incidence of complications, especially in the bladder, sigmoid, and rectum, increased. Despite the last-mentioned fact, we have continued this individualized plan of radiation therapy. The planning of irradiation therapy must be based on two fundamental concepts: ( 1) the tumor control dose, and (2) the tolerance of healthy tissues to radiation. It is important to keep the time dose--volume dose relationship in mind. The same dose of irradiation will be much better tolerated when given to a small area of tissue than to a large area. Thus, it is possible to increase the total roentgens delivered throughout the extent of the disease if the radiation is carefully planned.
T rr 1s .4 r M in treating a malignant tumor is to cure the patient or to relieve her of severe symptoms without causing irreparable damage to normal tissue. A prolonged extensive radical operation or an intensive exhausting course of radiotherapy for carcinoma of the cervix may make the patient far more uncomfortable than the tumor has done. It is imperative, therefore, to control one’s enthusiasm in the treatment of a cancer that is not suitable for radical operation and does not respond well to irradiation. Complications may occur as sequelae of therapy and the frequency of these complications is increased by irradiation of advanced tumors. For many years gynecologists in Scandinavia have conceded that radiotherapy is the treatment of choice for primary cancer of the cervix. The commonly used method is the intracavitary application of radium supplemented by x-ray directed to the parametrium and regional lymph nodes. The Stockholm method5> w 321 33 was developed on the basis of extensive clinical experience. A 5 year cure rate of 42 per cent was mainFrom
the
Plans
Radiumhemmet.
of radiation
administration
Measurements performed on patients and phantomsZO, 23 have indicated that intrauterine radium is of utmost importance for the paracervical tissue, while in a growth
Presented at the Seventy-fourth Annual Meeting of the American Association of Obstetricians and Gynecologists, Hot Springs, Virginia, Sept. 5-7, 1963.
854
Volume Number
RR 7
Radiation
with paravaginal extension vaginal radium gives better results. On the other hand, the maximum rectal dose at the level of the posterior fornix, which is the area of the injuries ordinarily seen in the rectum, depended on an amount of about 65 per cent of the intravaginal radium, provided the corpus was not sharply retroflexed. As a consequence of these various findings the dosage from the intrauterine radium was considerably increased in cases of endocervical tumors and of carcinomas with extension to the paracervical tissue. This change in technique, however, increased the incidence of complications in the uterus, urinary bladder, and intestines. Pyometra due to necrosis of the myometrium may be partly due to the belief we held for years that a fractionated irradiation with high intensity has some clinical and biological advantages over a protracted low intensity plan of radiation. We have not observed necrosis in the uterine wall since the distance from the radium applied to the tissue was increased from 4 to 7.5 mm. Experience has proved that a careful dilatation of the uterine canal may be performed without increasing the risk of dissemination of cancer cells in cases of paracervical extension. The prequisite for such an operation is the precise location of the external OS. Palpation, not inspection, will often reveal its position. Provided the OS is not easily located the application of radium should be postponed for a few weeks. Manipulations with instruments will increase the risk of local infection which, in turn, may affect unfavorably the prognosis and increase the risk of injury. Antibiotics have little value in the prevention of infections. Dosage measurements in the bladder and rectum and their clinical significance. The injuries that. occurred as sequelae of the change in technique were seen in the bladder, the lower sigmoid, and the rectum. In view of this fact and that of the improved primary cure rate, it was logical to try to correlate clinical observations and physical data. The elaborate three dimensional technique introduced by Lederman and Lamer-
therapy
complications
in cervical
cancer
855
Table I. Bladder injuries correlated with dosage in gamma roentgens measured in the bladder
.Gamma 2,000 3,000 4,000 5,000 6,000
r
0 to 1,999 to 2,999 to 3,999 to 4,999 to 5,999 and over
No. of patients
Grade 1 injuries (%)
54 102 93 5,7
11.1 15.6 11.8 22.8
40 16
17.5 6.2
Grade 2 and 3 in juries (%) 3.7 3.9 6.4 10.5 2.5 31.2
tonZ5 Nolan and Quimby,*g~ 3o Lewis and coworkers,26 and others yield accurate data for the individual patient but this method is time consuming and can, therefore, not be applied in practice. Roentgenograms were taken in all cases to check the position of the radium. The information was inadequate to calculate the dosage in the rectum and sigmoid. It was decided, therefore, to perform actual measurements in the bladder and rectum for each application. A 0.3 C.C. Sievert ionization chamber was applied in the end of a curved probe which was introduced first into the bladder and then into the rectum. Five hundred consecutive cases of carcinoma of the cervix treated from July, 1953, to September, 1954, were selected in an attempt to correlate rectalbladder reactions with dosage distribution. The results from this investigation have been reported by Gray and Kottmeier.14 The measurements in the bladder (Table I), and rectum yield information as to the correctness of the application of radium. Whenever the readings do not correspond to the expected figure or are excessive the intrauterine tandems or vaginal applicators are taken out and reinserted. Because of the steep gradient of dosage rates in intracavitary radium therapy, bladder and rectal doses should not be taken as absolute values. From the measurements carried out, however, and from a clinical point of view we feel justified in concluding that the measured tolerance dose from the in-
856
April 1, 1964 Am. J. Obst. & Gynec.
Kottmeier
Table II. Carcinoma of the cervix examined with a view to treatment from 1949 to 1957* State
/ No. of cases /
I
611
IIA
965
IIB III IV
964
% 17.4 27.8
1929
No treatment
710 234 25
Total
cases.
3.509
‘Only
symptomatic
radiation
54.9
27.8 20.3 6.7 0.7 was applied
in 220
cases.
serted radium amounts to 4,000 to 4,200 r in the rectum and to a slightly higher amount in the bladder provided regard is paid to the average dose over an area of 3 cm. These figures are by no means absolute levels for the radiation tolerance but clinical experience over several years has shown that they serve as a good basis for planning. In cases of advanced carcinoma the dosage mentioned may be exceeded. The figures do not apply to any other radiation technique or different calculation of dosages. Every institution should find the figures corresponding to the technique applied. We will not treat a carcinoma of the cervix without having the chance to record directly the dose along the posterior wall of the bladder and the anterior wall of the rectum. The use of this method has been accompanied by a considerable reduction in the number of radiation injuries. Material Primary radiotherapy has been given to 3,484 cases of invasive carcinoma of the cervix from 1949 to 1957. Table II presents the cases divided into the four stages.l Cases allotted to Stage II have been subdivided into Stage IIA and IIB with regard to the parametrial extension of the growth. Several institutions tend to allot cases of Stage IIB to Stage III. Treatment The majority of patients have received intracavitary radium and conventional roentgen therapy to the parametrium and area of
regional lymph nodes. The Radiumhemmet had no facilities for supervoltage radiation prior to 1958. Palliative irradiation has been given in 220 cases. They are included in the table. In cases receiving a full course of irradiation, a total dose of 3,200 to 3,500 r was delivered to the lateral pelvic wall from the radium and x-ray over a period of 10 to 12 weeks. A 5 year recovery rate of 54.2 per cent has been attained. In addition, about 2 per cent of the patients are living with cancer at 5 years. The respective cure rates are: Stage I, 87.3 per cent; Stage IIA, 68.1 per cent; IIB, 48.1 per cent; III, 30.6 per cent; and Stage IV, 7.3 per cent. One hundred and fifteen patients are known to have died from intercurrent disease. A primary healing after radiotherapy was not achieved in 717 cases (20.6 per cent). Sometimes it is difficult to establish whether complications such as fistulas, are caused by the growth in its terminal stage or by the therapy applied. The purpose of this presentation is to discuss the reactions and injuries that have occurred in cases of cervical carcinoma treated by irradiation in 1949 to 1957 and the management especially of urinary and intestinal complications (Table III, Fig. 1). Previously, means for the prevention of radiation injuries have been elucidated. Injuries have been more common in the series of cases presented than generally are observed at the Radiumhemmet.‘*, I5 This fact is related partly to the various experimental techniques used from 1949 to 1953. Primary
mortality
The primary mortality rate is low for radical hysterectomy, but it is also low for radiation therapy. Five patients (0.2 per cent) in Stages II, III, or IV have died during or immediately following treatment, 1 of them from sepsis and peritonitis, 1 from a heart attack, and 3 from uremia. Prevention
of infection
Extremely important is the prevention of infection (Table IV). Radium should never be applied simultaneously in the uterus and
Volume Number
88 7
Radiation
therapy
following
therapy
Mild cystitis and, sometimes, moderate diarrhea, scarcely necessitating any medication may follow directly the application of
Table III. Results in cases of carcinoma from 1949 through 1957
of the cervix
Symptom
Stage
I
*Absolute
cure
for
1,888
3,509
of cases treated
I
611
IIA IIB
965 964 I
III IV
710 234 TV
Clinically No.
neuer
cured
I
%
87.3 68.1 48.1 30.6 7.3
14 40 38 19 4
3 42 190 303 179
0.5 4.4 19.7 42.7 76.5
54.2
115
717
20.6
53.8*
rate.
No.
I through
857
at the Radiumhemmet
%
533 657 464 217 17
3,484 25
treat-
Table IV. Causes of death 1949 through 1957
Stage
I
cancer
at 5
free
No.
611 965 964 710 234
I through IV. Not accepted ment Total
treated
years
No. of cases
I IIA IIB III IV
in cervical
radium and are frequently seen also in the course of the external irradiation. These symptoms cannot be counted as complications as it is evident that a cancer that is not localized only to the cervix cannot be treated without producing some irritation of the bowels and bladder. However, treatment should be interrupted for some days if the patient feels uncomfortable from the diarrhea. Similar symptoms from the urinary tract or intestine will occur in all patients in whom reirradiation has been administered to recurrent disease on the pelvic wall in order to alleviate symptoms. This was also true of the 338 cases in which operative intervention was carried out because of a radioincurable tumor in 154 cases or recurrent disease in 184 cases.?l In the last 15 years electrosurgery, so-called unipolar fulguration
the vagina in cases with offensive discharge or other sign of infection. A pelveoperitonitis or sepsis will follow therapy and influence the prognosis unfavorably. The careful management of the individual case has decreased the incidence of pelvic infection following irradiation from 10 to 1.5 per cent. In a case of acute or chronic salpingitis it is imperative to remove the adnexa and postpone irradiation to 1 week or more after laparotomy. A 5 year cure rate of 65.7 per cent has been attained in 47 cases complicated by salpingitis treated in this manner, while the corresponding cure rate is only 14.4 per cent in 118 similar cases treated conservatively. Symptoms
complications
3,484
1929
in patients
Primary Sepsis\
by primary
Uremia\
Heart
1 2 1 6 (0.2%)
;$}
78
irradiation
Injuries
;}
6
19 4 115
in the years
Dead of carcinoma
Intercurrent disease
deaths
1 1
treated
Operation
,;]
No.
12
2 (3.3%)
6 (0.2%)
17 (0.5%)
f}
1 %
707
ifj
469 212
66:l 90.6
1,449
41.6
858
April
Kottmeier
.Anr. J. (ht.
I IA IB
2
54 0
I I
I 2
I 3
1 4
1 5 KARS
Fig. 1. .4pparent recovery rate in 3,484 cases of cancer of the cervix treated at the Radiumhemmet 1949 through 1957. (Table v j , has been the most common operative procedure at the Radiumhemmet. Radical hysterectomy has been performed in 53, and some kind of exenteration procedure in 7 cases. Electrosurgery has been carried out especially on patients in whom a radical hysterectomy is a questionable procedure; 277 such cases are included in this series. Fistulas immediately following operation are more frequently seen in cases in which a full course of irradiation has been administered previously. Such complications occurred in 12 out of 53 cases treated by radical hysterectomy and in 72 out of 277 cases in which an electrosurgical procedure has been carried out. Reirradiation or an operative procedure evidently makes the tissue more vulnerable and, consequently, contributes to late radiation damage (Table V) . late
complications
Late complications from radiation occur especially in the bladder, lower sigmoid, and An analysis will be given of the rectum. complications seen in 3,484 cases treated. Rectal complications. The usual time for rectal damage to occur is 6 to 18 months following initial radiation and is most fre-
1, 1964 & Gyner.
yuently seen after 6 to Y months (Figs. 2 and 3). The symptoms are bleeding, tenesmus or pain, and sometimes, constipation. On examination, the earliest lesion may show nothing by palpation but exhibit hyperemia on inspection. Later on there is an irregularity of the mucosa which becomes thickened and edematous. If the damage progresses in the mucosa an ulcer or even a fistula may occur. The lesion is usually localized in the anterior wall immediately behind the cervix. In cases in which the dose from the intrauterine radium has been considerably increased, the damage may appear higher up in the rectum or even in the lower sigmoid. The lesion in the rectal wall is classified as “intrinsic” while an “extrinsic” damage will signify a damage to the connective tissue or blood supply. *O*31 Such a fibrosis may lead to stenosis of the intestine. Bladder complications. Late radiation reactions in the bladder occur later than does the damage to the rectum (Figs. 2 and 3). Such injuries are seen sometimes several years following irradiation and we have
qocorance ytal number
m per cent of of cases treated
-r--l ---
6.0,
i-
,c: 0
i
i
3
Qriw?s
Fig. 2. Year of appearance of injury after radiation therapy in 3,484 cases treated at the Radiumhemmet from 1949 through 1957.
Volume Number
88 7
Radiation
observed such damage appear for the first time after 28 yearsl’T **I 34 The time that elapsed between the radiation and the onset of the symptoms is shorter in cases that have had large doses. The initial symptoms are frequent urination and, sometimes, hematuria and dysuria. Cystoscopy shows a slight hyperemic elevation with some telangiectatic vessels and bullous edema on the posterior wall right above the interureteric ridge. A sharply limited ulcer covered with grayish slough may appear in this area. In more severe cases necrosis may occur which,
Table V. Results in 717 radioincurable treated
by operation
therapy
complications
in cervical
cases and 230 cases of local recurrence
after radiation
Radioincurable cases Radical hysterectomy
Stage
No.
I IIA II3 III
1 a 10 4
IIA IIB
1 5
of
cases
at Fistulas
(No.1
1 2
(No.)
:
12
2 0
2 0
3
23 Exenteration
5
5 (21.7%)
3 6
Electrosurgery
I IIA IIB III IV
7 41 53 20 4
Local recurrences Radical hysterectomy
I IIA IIB
6
I II
Electrosurgery
I IIA IIB III IV
11 9 10
2
38
(31.2%)
43
(27.9%)
7 2 4
1 3
1 1
30
(24.0%)
2 3 2 13
(43.3%)
7 (23.3%)
1 1 2
Total cases operated upon Total cases symptom free after 5 years
14 6 1
(21.5%)
30 Exenteration
3 ia 13 3 1
1 5
125 154
Total cases operated upon Total cases symptom free after 5 years
2
24 53 60 13 2
14 25 20 7 0 152 184
859
if it deepens, will form a fistula. Sometimes, parts of a necrosis will be transformed into a stiff structure resembling a coral reef. The differential diagnosis between a radiation injury and a carcinomatous invasion of the bladder may occasionally be difficult. Repeated cystoscopic examinations facilitate the correct diagnosis. Biopsy should be avoided as it adds to the risk of fistula formation. Bladder complications were less frequent than rectal complications. If we consider every case with symptoms from the bladder or the rectum as damage of radiation, blad-
Symptom free 5 years Operation
cancer
a 13 16 4 1 66
(43.4%)
79
(42.9%)
(80%)
42
(27%)
860
Kottmeier
0
i
2
Fig. 3. Total cases of bladder and rectal injury observed after radiation therapy among 3,484 cases of carcinoma of the cervix treated at the Radiumhemmet from 1949 through 1957.
der complications have occurred in 279 cases, 8.0 per cent, and rectal, in 424, 12.1 per cent. In these figures, however, have not been included either the 61 vesicovaginal or 27 rectovaginal fistulas appearing immediately following operation or the complications in the terminal stage of the disease in 1,449 patients who have died from the cancer (41.6 per cent of the 3,484 patients treated). Rectovaginal fistulas have been diagnosed in 95 and vesicovaginal fistulas in 119 of these terminal cases, Types of rectal reactions and injuries. A subdivision of these 424 cases into four grades is desirable (Table VII). Grade 1 is represented by reactions with mild or no subjective symptoms and minimal objective changes in the mucosa. In 339 cases Grade 1 reactions have been observed. Jacox and Kligermanls correctly point out that these reactions cannot be considered as injuries. Thus there remain 85 cases with rectal injuries (2.4 per cent, Table VII). These arc divided into three further grades. Grade 2 is accompanied by frequent painful stools and the passage of mucus and blood for many months, even 2 years. On examination, areas of necrosis, ulcers, or moderate
stenosis are seen. Thirty-five of our cases were allotted to Grade 2. Grade 3 comprises the cases of rectal stenosis severe enough to require a colostomy. Sixteen of our cases belong to this category. Grade 4, finally, is the radiation fistulas. Thirty-four radiation fistulas have occurred. A survey of the 85 cases is given in Table VII. In 60 of the 85 cases the damage could be attributed to initial radiation. In 25 cases operative intervention or reirradiation of recurrences may have contributed to the injuries. Forty-three of the 85 patients are living free from cancer at 5 years. Three patients have died from intercurrent disease and 34, from cancer. In 6 cases the injuries themselves have been fatal. Two patients with Stage IIB carcinomas and Grade 3 injuries died as a result of the stenosis of the sigmoid, one from ileus, 3f/, years following initial therapy, and one immediately following a resection of the sigmoid performed 4 months after irradiation. In 4 other patients with Stage II carcinomas who all had received intensive doses, a fistula in the anterior wall of the rectum or sigmoid perforated into the peritoneal cavity. The fatal complications in these 4 cases occurred 11 months, 15 months, 2vz years, and 3f/z years, respectively, after initial therapy. Although only 6 out of 3,484 patients treated for carcinoma of the cervix by primary radiation have died from injuries due to therapy we should take into consideration the possibility of fatal complications when we are subjecting patients to higher and higher dosages. Similar complications have been reported by Brack: Everett and Dickson,4 Cosbie,6 Frick and associates lo, I1 and Fletcher and associates.“, ’ There is no doubt that many times it is rather difficult to determine the factors that account for injury in the rectum. In our experience the damage is due to high doses directly to the rectum and its mucosa. Factors, such as old age, syphilis, local infection, and surgical intervention may also be of importance. In Table VIII we have collected the factors that may explain the injuries occurring in the rectum.
Volume Number
88 7
Radiation
The treatment of Grade 1 and 2 reactions should be conservative. Mild laxatives given regularly prevent constipation. Rectal instillations of warm chamomile tea three times a day and local application of 25 to 75 mg. of hydrocortisone in a water-soluble base alleviate symptoms. Colostomy is indicated for stenosis (Grade 3) and fistula formation (Grade 4). The operation should be performed on the transverse colon as soon as troublesome symptoms appear. The fatal complications mentioned might have been avoided provided a colostomy had been done in due time. It is a mistake to carry out a primary resection of the intestinal stenosis. Such a procedure is not indicated until the injury has healed. Degrees of urinary bladder reactions and injuries Minimal objective changes with mild subjective symptoms (Grade 1) have been observed in 229 patients out of 279. These should be considered as late reactions and not as real injuries. In the majority of these cases the symptoms have disappeared after some weeks. In 50 cases, however, a bladder injury has been diagnosed (Table IX). In 31 instances a fistula occurred (Grade 3). In 19 cases a more or less extensive necrosis was found on cystoscopy or the patient suffered from pain or hemorrhage which required repeated blood transfusion and even hospitalization (Grade 2). The same comments are valid for the bladder injuries as for the rectal ones (Table VIII). High radiation doses and urinary infection will predispose to the occurrence of a bladder injury. Reirradiation of suspicious pelvic recurrences or operative intervention may have contributed to the fistula formation in 7 and in 4, respectively, of the 31 cases. Thirty-nine of the 50 patients with bladder radiation injuries are living with no evidence of cancer at 5 years. Two patients have died from nephrosclerosis, or pyelonephritis, and the fistula formation may have contributed to the fatal disease in these 2 cases. The treatment of mild reactions and of
therapy
complications
in cervical
cancer
861
of onset of symptoms to the bladder and rectum
from
Table VI. Time injuries
Time
Within 6 months 6 to 12 months 1 to 1% year 1 yL2to 2 years 2 to 3 years 3 to 4 years After 4 years Total
Urinary bladder
Rectum
1 3 6 9 13 12 6 50
8 41 19 5 8 2 2 85
Grade 2 injuries to the bladder is symptomatic. The patient should avoid heavy smoking. Especially important is the prevention of infection and the correct application of selected antibiotics in sufficient doses. Rest, repeated blood transfusions, and cauterization of the bleeding point through a cystoscope have been an aid in the treatment. Cauterization was applied in 2 cases. The method of dealing with the vesical fistula is a difficult problem. The destructive action of radiation on all tissues of the region produces a chronic condition in which the common surgical procedures used for repair of traumatic or obstetrical fistulas are unsuccessful. Repair procedures for vesicovaginal fistulas The fistulas considered for repair in the series of 3,484 cases of cervical carcinomas amounted to 88 (Table X) . Twenty-seven fistulas were the result of radiation injuries. Eight fistulas developed immediately or a few weeks following radical hysterectomy. This operation had been performed in 23 cases of radioincurable carcinoma and in 30 cases of recurrent carcinoma. Six patients died as a result of the operation ( 11.3 per cent). Eighteen patients are living free from evidence of cancer at 5 years (34 per cent). In 53 cases, finally, the fistula occurred following electrosurgery. This type of operation was described in Meig&* book, Surgical Treatment of Carcinoma of the Cerviz2’ In the last fifteen years this operation has been
862
Apil
Kottmeier
performed on many patients with advanced lesions in whom, otherwise, exenteration would have been the treatment of choice. Electrosurgery as a more or less extensive fulguration was carried out in 125 cases of radioincurable carcinoma and in 152 of recurrent carcinoma in the present series. The primary mortality from hemorrhage or infection amounted to 2.2 per cent. Ninetyfour of the 277 patients are living with no
Table VII. the cervix, -.
1, 1964
Am. J. Obst. & Gynec.
Incidence of radiation injuries treated from 1949 through 1957
evidence of cancer at 5 years (33.9 per cent). The 61 patients with surgically induced vesicovaginal fistulas had all received intensive radiation initially (Table Vj . The choice of operative procedure for the repair of vesicovaginal fist& is dependent on several circumstances. No patient should be operated upon if there is still evidence of carcinoma or the necrotic irradiated tissue has not sloughed off. A
to the rectum
in cases of carcinoma
of ---__
Primary Grade
radiation in 2 injuries
Primary Grade
radiation 3 injuries
in
Primary Grade
radiation 4 injuries
in
Stage I IIA IIB III IV -~ Total
611 965 964 710 234
4 6 10 7
1
1
5
1 2 4 4
1
35
Explanations
of the injuries
Grade
Unknown Infection and radiation Overdosage primarily Reirradiation Operation Most likely cancer Total
3 3
2
to the bladder
bladder 1 Grade
3
Grade
2
(
Grade
3
8 2 9
3 6 9 7 4 2
11 1 14 6 2 1
2 8 4 1 1
19
31
35
16
Stage I IIA IIB III IV Total
___.-
3.484
radiation in Grade 2 in juries 2 8 7 2
1.0 2.1 3.0 9.9 0.9
85
2.4
Rectum
Primary Grade
Primary Cases
__.-~~
6 20 29 28 2
and the rectum
Table IX. Incidence of injuries to the urinary bladder in the radiation of 3,484 cases of carcinoma of the cervix from 1949 through 1957
treated (No.) 611 965 964 710 234
3 4
..~34
16
llrinary Explanation
1 8 8 4 ___- 1
1 1 1 I
.~.__
3.484
Table VIII.
1
__ Alone
4 4 8 4
radiation 3 injuries
And operation
Grade
4 --
Total
5 6 10 5
26 17 50 22 12 7
il 34
.--__
treatment
in .4nd further radiation
1 2 1
/
1 4 L’
Total No.
%
7 13 21 9
1.1 1.3 2.2 1.3 ___-
19
31
50
1.4
Volume Number
88 7
Radiation
conservative operation should not be undertaken until the condition of the patient is good, the infection is under control, and the entire urinary tract has been investigated. Estimation of renal function is of importance. Intravenous pyelography and cystoscopy should be performed. Bastiaanse,2 Mandicas,27 and IngelmanSundberg16g I7 deserve the credit for having developed modern techniques in the repair of postradiation fistulas. Ingelman-Sundberg has acquired great experience in this field and has developed a method which has yielded good results. The first step of his operation is a scrupulous dissection of the fistula and the surrounding tissue. The dissection is performed vaginally under local anesthesia from a transverse incision below the external urethral orifice. With the position of the ureters identified the remnants of the vaginal wall are dissected free from the margins of the fistula. The dissection is continued until the bladder base is free from the cervix. The vaginal wall is mobilized so far laterally that the pubococcygeus muscles can be inspected. It is important to leave a good blood supply. The margins of the fistula are trimmed, and then approximated in the simplest way with a few stitches of chromic catgut leaving the mucous membrane of the bladder intact. It is not necessary to close the bladder tight. The bladder ligaments are sutured in the midline under the bladder base, if this can be done without tension. The next important step in this operation is to bring well-nourished tissue to the site of the fistula. Ingelman-Sundberg has tried different techniques to get a suitable flap. In cases heavily treated by irradiation the preference is given to the gracilis muscle. An incision is made through the skin and subcutaneous tissue from the inner epicondyle to a point on the descending ramus of the OS pubis about 2 cm. below the inferior border of the symphysis. After the muscle is carefully dissected without interruption of the chief blood and nerve supply, the muscle is drawn through the obturator foramen to the space between the bladder and vaginal wall. This part of the operation requires
therapy
complications
in cervical
cancer
863
great experience. The preparation of the canal is dependent on the anatomical conditions, and various techniques are used. The canal must have a width of two fingerbreadths in order not to constrict the blood supply of the muscle. The muscle is brought to the site of the fistula. The tendon is fixed against the opposite pelvic wall. The muscle is interposed between the bladder and the vaginal wall without tension and should cover the fistula as completely as possible. The vaginal wall is replaced and sutured with a few stitches. A very loose packing of gauze powdered with any suitable antiseptic is applied in order to abolish dead spaces between the vaginal wall, the graft, and the bladder. A good suction drainage of the bladder, preferably through a suprapubic cystotomy is necessary. The patient should stay in bed for at least 2 weeks. If the drainage is good and the tissue is well vascularized, the granulation from the tissue may be satisfactory to heal the fistula completely. Sometimes, a residual fistula remains after 4 or more weeks. A new transplantation procedure may be done in a similar manner. The pubococcygeus muscle, the rectus, the adductor longus, or the gracilis on the other side can be used. In postradiation cases, the operation as a rule has to be repeated one or two times. The operation described has been performed by Ingelman-Sundberg in many cases with satisfactory results. It has been carried out in 16 of the 88 vesicovaginal fistulas reviewed in this paper. The primary result was satisfactory in all cases. Two patients have died, one from pyelonephritis 2 years following operation. Conservative plastic operation is not indicated if renal function is unsatisfactory or bilateral hydronephrosis is present. Earlier a transplantation of the ureters to the colon, a Coffey operation, was tried in several cases. The results were unsatisfactory. A similar procedure was carried out in one of the cases in the series presented. So far the result is satisfactory. This comment is also valid for 7 cases in which a ureteroileal urinary diversion was made.
864
Kottmeier
Table X. Types of repair procedures of the cervix in the years 1949 through _.-.~ ___--
NO.
Vesicovaginal fistulas Injuries by radiation, etc. From electrosurgery Surgery
tDied *Two
Plastic surgery
?7 53 8
____.
Nephrec-
’ Ureteral implant in bladder or
tomy
COlOIZ
6* 3 1
~-~
j lleal bladder
!
Resettion of 1 intestine
No
operatiue I repair
10
1
6
14
1
1
38 6
1 1t
24 3
29 from
1
2
3 (J
23 3
1 4
3
2
17
nephritis.
A spontaneous healing of the fistula occurred in 4 cases. At present no operative intervention has been carried out in 58 of the 88 fistula formations. Six of the remaining 14 patients with postradiation fistula and the majority with postoperative fistulas have died of cancer. Injuries
in cases of carcinoma
31
complications after 1 week. patients died later
Spontaneous healing
injuries
27
Rectovaginal fistulas Injuries by irradiation, etc. From electrosurgery Surgery Ureteral
for irradiation 195 7 ---~-
to the ureters
In recent years special interest has been devoted to the ureter since it has been demonstrated that hydronephrosis or a nonfunctioning kidney due to carcinomatous obstruction of the ureter has a poor influence on prognosis. Intravenous pyelography was performed in 1,502 of the 3,484 cases prior to therapy. Hydronephrosis or a nonfunctioning kidney was revealed in 268 cases (17.8 per cent). Attention must be given to this hazard in the planning of therapy. A 5 year cure rate of 32.8 per cent was reached in the cases of hydronephrosis while it was 55.6 per cent in those with negative roentgenograms. Unfortunately, it has not been possible to carry out regular x-ray examinations in the follow-up of patients treated for carcinoma of the cervix. Pyelography, however, has been done in 57 of those 88 patients who are living symptom free at 5 years, in spite of positive roentgenograms prior to therapy.
Hydronephrosis remained in 16 cases while the renal function was quite normal in 41. The occurrence of hydronephrosis in a case previously treated by irradiation has been considered as a sign of recurrent tumor. There is no doubt that this observation is often correct. But it is evident that such a complication also may occur as a sequela of radiation fibrosis. Kirchhof-Y found no cancer in 18 out of 68 patients with fatal hydronephrosis and pyelonephritis. In 29 of the 3,484 cervical cancers hydronephrosis was observed which was evidently the result of parametrial fibrosis or scar tissue. Seven of these patients had coincidental vesicovaginal fistulas. Operative intervention certainly explained the hydronephrosis in 9 instances while in the remaining 20 it is likely that the radiation played an important role. In 6 of the cases, radioactive colloidal gold has been injected into the parametrial tissue transvaginally. From experimental and clinical studies we consider it justifiable to conclude that the application of colloidal gold into the parametrium does not improve the cure rate but increases the risk of fibrosis with secondary damage of ureters. Treatment of ureteral obstruction should be individualized (Table X) . In cases of
Volunle Number
88 7
Radiation
uncomplicated hydronephrosis the patient should be kept under careful observation. A nephrectomy was performed in 4 cases, a resection and reimplantation of the ureters in 3. The differential diagnosis between carcinomatous infiltration and fibrosis of parametrial tissue is extremely important in cases of anuria. Nephrostomy is not indicated in cases of cancer but should be carried out if the ureteral obstruction is due to scar tissue. This was the situation in 2 cases; one of these patients at present is living symptom free with an ilealbladder, performed because of vesicovaginal fistula which appeared following electrosurgery for an extensive recurrence. Puncture biopsy has proved to be of value in the differential diagnosis. Eighteen of the 29 patients suffering from postradiation or postsurgical hydronephrosis are living and in good health. Injuries
to the small
bowel
In addition to the various complications and injuries described appearing following irradiation in 1949 to 1957, I have to mention that obstruction of a small intestinal loop, requiring resection of the involved area, occurred in 3 patients who at present are free from disease. In another case in which a large intraperitoneal metastasis was treated locally by radium to stop hemorrhage from it, necrosis of an intestinal loop occurred. A unilateral fracture of the neck of the hip has been reported in 6 cases. In every case this was the result of an accident. No spontaneous fracture has occurred.
therapy
complications
in cervical
cancer
865
intercourse. In our experience, however, extensive adhesions occur only in cases of carcinoma that have invaded a large part of the vaginal wall. Young patients with localized carcinomas in the cervix and upper vagina as a rule have no trouble worth mentioning from intercourse. Supervoltage
irradiation
In my presentation I have tried to elucidate the problem we meet in radiation therapy of cancer of the cervix. From the beginning I called attention to the fact that all cases had received primary irradiation by intracavitary application of radium and conventional x-ray therapy. In the last four years the Radiumhemmet has acquired facilities for cobalt therapy. We have treated a selected number of advanced cases with cobalt in addition to the intracavitary radium. Although good results have been achieved in some cases it is, as yet, not possible to present any final results. But it is evident that different factors than have previously been mentioned should be considered in the administration of supervoltage irradiation. From the beginning cobalt therapy was given through one anterior, one posterior, and, sometimes, two lateral portals with a dose of 4,000 to 5,000 r3 over a period of 5 to 7 weeks. Serious complications, i.e., small bowel necrosis, have been reported by Fletcher and associates, Frick and co-workers, and others. The administration of external irradiation with increased dosages requires planning with a physicist in each case. Summary
Radium
reactions
in the vaginal
wall
Vault necrosis is frequently difficult to distinguish from recurrent cancer. It was observed in 26 cases, as a rule within 1 year after therapy. The necrosis may be cleaned up by local application of vitamins and antiseptics. One patient later died from metastases to the pelvic wall. In regard to the vault necrosis I call attention to the occurrence of adhesions in the vagina, which may involve most of the vagina and interfere with
A description has been given in detail of 3,484 cases of cervical carcinoma treated by intracavitary radium and orthovoltage x-ray therapy at the Radiumhemmet during the years 1949 through 1957. A 5 year relative apparent recovery rate of 54.2 per cent has been attained. The improvement in results has been achieved by individualization of radium therapy. This, however, has been accompanied by an increase in injuries.
866
.4ptil
Kottmeier
Rectal injuries have occurred in 2.4 per cent, bladder injuries in 1.4 per cent, and ureteral obstruction in about 1 per cent of the cases. Six patients with rectal injuries died from
Am. J. (ht.
I, 1964
& Gyurr.
complications of a stenosis or perforation of the intestine. Two patients with vrsicovaginal fistulas later developed pyelonephritis which explained the death and to which the bladder injury may partly have contributed.
REFERENCES
1.
Annual Report on the Results of Treatment in Carcinoma of the Uterus, Stockholm, 1960, vol. XII. 2. Bastiaanse, M. van Bouwdijk, and Sindram, I. S.: Virginia Med. 87: 547, 1960. 3. Becker, J., and Schubert, G.: Die Supervolttherapie, Stuttgart, 1961, Georg Thieme Verlag. 4. Brack, C. B., Everett, H. C., and Dickson, R.: Obst. & Gynec. 7: 196, 1956. J. A.: Gynecologic Cancer, ed. 3, 5. Corscaden, Baltimore, 1962, Williams & Wilkins Co. 6. Cosbie, W. G.: J. Obst. & Gynaec. Brit. Emp. 66: 843, 1959. 7. Fletcher, G. H.: Am. J. Roentgenol. 64: 95, 1950. G. H., Brown, T. C., and Rutledge, 8. Fletcher, F. N.: Am. J. Roentgenol. 79: 421, 1958. 9. Fletcher, G. H., Stowall, M., and Sampiere, V.: Radiotherapy of Cancers of the Cervix Uteri, Chicago, 1962, University of Texas, M. 0. Anderson Hospital and Tumor Institute. 10. Frick, H. C., II, Corscaden, J. A., Jacox, H. W.. and Tavlor. H. C., Jr.: Sure. Gynec. Sr 0b;t. 107: 4i7, ‘1958. I _ 11. Frick, H. C., II, Taylor, H. C., Jr., Guttman, R. J., Jacox, H. W., and McKelway, W. P.: Surg. Gynec. & Obst. 111: 493, 1960. Am. J. Roentgenol. 73: 35, 1955. 12. Garcia, M.: 13. Gray, M. J., Gusberg, S. B., and Guttmann, R.: Am. J. Roentgenol. 76: 629, 1958. M. J., and Kottmeier, H. L.: AM. J. 14. Gray, OBST. & GYNEC. 74: 1294, 1957; 82: 74, 1961. 15. Ingelman-Sundberg, A.: Acta radiol. Suppl. 64, 1947. A.: Arch. GynHk. 183: 16. Ingelman-Sundberg, 498, 1952. A.: Pathogenesis and 17. Ingelman-Sundberg, Operative Treatment of Urinary Fistulae in Irradiated Tissue, in Yorssef, A. F., editor: Gynecological Urology, Springfield, 1961, Charles C Thomas, Publisher. 18. Jacox, H. W., and Kligerman, M. M.: Year Book Radiol. 1958-1959, p. 328. 19. Kirchhoff, H.: Geburtsh. u. Frauenh. 20: 34, 1960.
20.
21. 22.
23. 24.
25. 26.
27. 28.
29.
30. 31.
32.
33.
34.
Kottmeier, H. L.: Carcinoma of the Female Genitalia, Abraham Flexner Lecture, Baltimore, 1953, Williams & Wilkins Co. Kottmeier, H. L.: Arch. Gynlk. 183: 494, 1952. Kottmeier, H. L.: The treatment by Fulguration of Recurrent Cancer of the Cervix Following Radiation, in Meigs, J. V., editor: Surgical Treatment of Cancer of the Cervix, New York, 1954, Grune & Stratton, Inc. Kottmeier, H. L.: AM. J. OBST. & GYNEC. 76: 243, 1958. Kottmeier, H. L.: The Urinary System in Cases of Uterine Carcinoma Treated by Irradiation, in Youssef, A. F., editor: Gynecological Urology, Springfield, 1961, Charles C Thomas, Publisher. Lederman, M., and Lamerton, L. F.: Brit. J. Radiol. 21: 11, 1948. Lewis, G. C., Jr., Chamberlain, R. H., Hale, J., and Payne, F. L.: Am. J. Roentgenol. 72: 975, 1954. Mandicas, A.: GynCc. et obst. 49: 72, 1950. Meigs, J. V., editor: Surgical Treatment of Cancer of the Cervix, New York, 1954, Grune & Stratton, Inc. Nolan. T. F.: Radiation Treatment of Carcinoma ‘of’ the Uterine Cervix, in Pack, G. T., and Ariel, J. M., editors: Treatment of Cancer and Allied Diseases, New York, 1962, Harper & Brothers. vol. VI. Nolan, J. F., and Quimby, E. H.: Radiology 40: 391, 1943. Paterson, R.: The Treatment of Malignant Disease by Radium and X-rays> London, 1948, Edward Arnold & Co. Schulz. M.. and Graham. 1. B.: Radiotherap; in’ Treatment of’ cancer of the Uterine Cervix, in Meigs, J. V., and Sturgis, S. H., editors: Progress in Gynecology, New York, 1957, Grune & Stratton, Inc., vol. III, p. 565. Sherman, A. J.: Cancer of the Female Reproductive Organs, St. Louis, 1963, The C. V. Mosby Company. Youssef, A. F.: Gynecological Urology, Springfield, 1961, Charles C Thomas, Publisher.