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Major urologic complications following radium and x-ray therapy for carcinoma of the cervix
Major urologic complications
following radium
and x-ray therapy for carcinoma of the cervix ROBERT
M.
CUSHING,
HAROLD
M.
M.
LEONARD New
York,
M. New
M.D.
TOVELL, LIEGNER,
M.D M.D.
York
A long-term study of the major urologic complications following radium and x-ray therapy in 369 cases of carcinoma of the cervix, treated between 1939 and 1955, has been made. The radiation technique employed during this period was a short-term intensiue radiation exposure method. The mean time of onset of the major urologic complications following treatment was similar whether due to cancer or to radiation, being 12.1 and 12.3 months, respectively. Seventeen (4.6 per cent) were noted to haue major urologic complications on admission due to cancer. An additional 17 patients developed major urologic complications due to cancer after treatment. The mean survival time of the latter series was 17.4 months, with 10 patients surviving less than one year. Only 10 (2.7 per cent) patients deueloped major urologic complications due to radiation therapy. Of this small group, 7 lived for a mean survival time of 4.5 years, while the 3 remaining were still aliue at 10, 17, and 25 years, respectively.
RETROSPECTIVE study has THIS been undertaken to determine the immediate and late major urologic complications associated with radium and x-ray therapy in the treatment of carcinoma of the uterine cervix. Specifically, the purpose was to determine which patients had developed complications that could be attributed to radium therapy and which patients had developed complications that could be attributed to extension of disease involving the urinary tract. The urologic complications encountered that were classified as major were as follows: marked hydronephrosis, pyonephrosis, pyelonephritis, poorly functioning or nonfunctioning kidneys, hydroureter, ureteral stricture with obstruction, ulceration of the bladder, and vesicovaginal fistula. Urinary complications classified as minor (hyperemia,
trigonitis, cystitis, but not subjected Materials
and
or urethritis) were noted to analysis in this review. methods
A total of 443 patients were admitted to the Woman’s Hospital, New York City between the years 1939 and 1955 inclusive with the diagnosis of cervical carcinoma. Of these, 74 patients were either not treated or were treated surgically and have been excluded from this study. The remaining 369 patients received radium and x-ray therapy as the primary treatment for their malignancy and form the basis of this study. Of the 369 patients, 1.55 (42 per cent) survived 5 years or more. Two hundred and two patients (54.7 per cent) failed to survive 5 years and 12 (3.3 per cent) were lost to follow-up. When symptoms warranted, the urinary tract was investigated both before and after treatment to determine the presence and extent of complications in this area. Complications were attributed to radiation only after biopsy material or autopsy ex-
From the Department of Obstetrics and Gynecology, Woman’s Hospital, St. Luke’s Hospital Center, and the Radiation Therapy Service, St. Luke’s Hospital Center.
750
Urologic
aminations failed to reveal residual cancer. Clinical examination and ultimate survival time were also employed in evaluating the etiology of complications. Method of radiation. The irradiation methods employed during the 17 year period considered in this paper have been reported by others.lD, s The radium technique was based on the principle of a high-intensity dose rate, delivering a high dose in a short period of time. The radium application consisted of a 100 mg. capsule in the cervical canal and the distribution of 6 high-intensity platinum-iridium needles, each containing 12.5 mg. of radium, around the circumference of the portio vaginalis of the cervix. The duration of the radium application ranged between 24 and 36 hours, resulting in 400 r per hour to point A. The radiation secluelae in the urinary tract have been attributed to radium therapy rather than to external x-ray therapy, since the latter was directed only to the parametria. X-ray was delivered from a 200 kv. unit and calculated to give 2,000 to 2,400 r air dose exposure through each of four ports in a 24 to 42 day pc:riod. The midline structures were shielded. In addition, x-ray therapy was sometimes given through lateral or split direct perineal ports. Occasionally, transvaginal cone therapy was used, delivering 75 r (air dose) per treatment until 5,000 r (air dose) was delivered. Parametrial tissue doses of 2,400 to 3,000 r were achieved with multiple portals, including perineal fields. Of the 369 patients treated, 239 had cystoscopy and intravenous pyelograms performed when indicated. The remaining 130 patients did not have cystoscopy, since the absence of urologic symptoms throughout the management of their disease, as well as the follow-up period, did not warrant a urologic investigation. The extent of disease in all patients was staged according to the International Classification. Results
Of the 369 patients treated, 286 had evidence of urologic complications prior
no to
complications
after
cervical
irradiation
751
Table I. Urologic treatment --___-
complications in thP of cancer of the cervix I_ -- ---. -____ ! -7.-.---.- / gyi$i;; /’ Before treatment
Complications
No.
286 66 17 369
None
Minor Major Total _____----.*Due:
j
complicYr-
After
treatment ‘j&
j No.
1 %
’
tions >TLi--
67.0 20.8 11.9 I 00
77.5 248 17.9 77 4.6” 44 100 ___-.-~ 369
11 .!.9 .- “7 _._ y.3 --. .~311 _..._ 1’1.2 _
to canwr.
Table II. Etiology
of major
urologic
complications
treatment
j Total pn/ tie+ zrith major cornljlications
No.
j No.
After Before treatment 1-7;
Due to cancer Due to radiation ___I____ Total
17
17
1 %
-1.6
17
4.6
34
4.6
10 2.7 10 7.3 4-t 27 ___-----~-..-_.
j
5%
!).:! 2.7 11.9 _ -.__
treatment. Of these 286 patients, 248 remained free of urologic complications following treatment and thereafter as long as they remained under observation, namely: until death or through 1964 (Table I), Minor urinary tract disturbances were encountered in 66 patients prior to treatment and in 77 patients following treatment. The 11 additional patients in this group experienced symptoms attributable to a transient radiation cystitis. Major urologic complications beforc treatment caused by the cervical cancel- were diagnosed in 17 patients at the time of admission to the hospital. In the majority of these patients, the urinary tract complications persisted following treatment. An additional 27 patients developed one or more llrologic complications following treatment. Of these 27 patients, 17 developed urinary complications that were due to persistent or recurrent malignant disease alone. Only IO patients
752
Cushing,
Tovell,
and
Liegner
Table III. Number of patients with and without urologic complications before treatment grouped according to stage of disease and degree of complication
Sn;fff*eof 1:: I!$:; iNij$1??’ I II III IV Total
104 160 21 1
80.6 79.2 72.4 11.1
24 34 6 2
18.6 16.8 20.7 22.2
1 8 2 6
0.7 3.9 6.9 66.7
129 202 29 9
286
77.5
66
17.9
17
4.6
369
Table IV. Number of patients with and without urologic complications after treatment, grouped according to stage of disease and degree of complications Stage of disease I II III IV Total *Includes existing prior
developed complications that could be solely attributed to radium therapy (Table II). The number of patients grouped according to their degree of urinary tract involvement and the extent of their primary disease encountered before treatment and after treatment is shown in Tables III and IV, respectively. As might be expected, before treatment fewer complications were encountered in the patients with less advanced lesions. Of the 331 patients with Stage I and Stage II cancer, 9 (or 2.7 per cent) had major urologic complications, while of the 38 patients with Stage III and Stage IV cancer, 8 (or 21 per cent) had a major complication (Table III). Following treatment, a further increase in the incidence of major complications was encountered in both the group of patients with less advanced disease and the group of patients with more advanced disease. Of the 331 patients with Stage I and Stage II cancer, 32 (or 9.7 per cent) had a major complication, and of the 38 patients with Stage III and Stage IV cancer, 12 (or 31.5 per cent) had a major complication (Table IV). The percentage of major complications according to the stage of disease and encountered during the follow-up period, as shown in Table IV, expresses the well-known and insidious problem frequently encountered in following patients irradiated for cancer of the uterine cervix. In the 44 patients shown in the group with major urologic
cations __________ No. j % 90 142 15 1
70.0 70.3 51.7 11.1
248
67.2
17 patients to treatment.
cations No. / % 31 24.0 36 17.8 8 27.6 2 22.2 77 with
20.9 major
cations No.
/ %
Total No.
8 6.0 24 11.9 6 20.7 6 66.7
129 202 29 9
44 11.9*
369-
urologic
complications
complications, 17 ( or 38.6 per cent) had a previously diagnosed major urinary tract complication before therapy was initiated, which could be assumed to be due to continuing or extending disease. In the remaining 27 (or 61.4 per cent) of this group, the major complication encountered at follow-up could have been attributed to either the disease alone or to the treatment alone or, which is less likely, to a combination of both these factors. The basic cause of such problems can only be resolved by appropriate biopsies or the passage of time.
Major urologic complications before treatment. There were 17 patients whose major urologic complications existed prior to therapy. Ten of these patients had 2 or more sites in the urinary tract severely involved. There were 5 patients with both renal and ureteral complications. Of the 6 patients with cancer invading the bladder, 3 had vesicovaginal fistulas associated with disturbances of the ureter or kidney or both.
Major urologic complications after treatment due to cancer. There were 17 patients whose major urologic complications were encountered after therapy. These complications were attributed to continuing disease. In this group, 5 patients developed vesicovaginal fistulas. Fourteen patients were originally classified as having a Stage I or Stage II lesion and 3 patients were classified as
Volume Number
101 6
having a Stage III lesion. There Stage IV lesions in this group.
Urologic
were
no
Major urologic complications due to treatment. There were 10 patients whose major urinary complications were attributed to radium therapy alone. One patient had a Stage III lesion and the remaining 9 patients had earlier lesions. Vesicovaginal fistulas developed in 6 patients at 7, 13, 14, 16, 25, and 27 months, respectively, and 5 of these were successfully repaired. In the sixth patient a bilateral ureteral-sigmoid anastomosis was done at 9 months after the vesicovaginal fistula appeared. She died one month later of general peritonitis. Of the remaining 4 patients, 2 developed extensive ulcerations of the bladder with advanced renal infection in one and 2 patients developed complications resulting from ureteral obstruction.
Time of onset of urologic complications and survival time of patient. The time of onset of the major urologic complications due to cancer and occurring after treatment and that due to radium was approximately the same, being 12.1 and 12.3 months, respectively. The survival time in each of these two groups of patients is quite different, as would be expected.ll The 17 patients whose complications were due to continuing disease survived for a mean time of 17.4 months. On the other hand, 3 of the 10 patients whose complications were considered to be due to the radium were alive and well at 10, 17, and 25 years, respectively, following treatment, and the remaining 7 patients lived for a mean survival time of 4.5 years. In contrast, the group of 17 patients with major urinary complications due to cancer encountered before treatment survived only for a mean period of 11.3 months following treatment. Comment The tolerance of the urinary bladder to irradiation may be better understood by observing bladder reactions following radiation treatments for carcinoma of this organ. Only a mild early mucosal reaction will be produced by doses of 3,000 r delivered to
complications
after
cervical
irradiation
753
the bladder in 4 weeks by external radiation.“l It has been shown that the bladder will tolerate local radium implants up to 8,000 r.16 With radon seed implants, a minimum dose of 7,000 gamma P has been used with few complications. Friedman and LewiP have delivered 6,000 to 10,OOP gamma r from a central source of radium contained in a special Foley-type catheter. by two insertions 5 to 12 days apart. In 50 patients, 10 developed severe acute reactions, 7 developed late reactions, 17 developed onlv mild reactions, and 16 showed no reactions at all. Liegner and TayloP treated 42 p:gtients with bladder cancer by means of it supervoltage cobalt-60 unit and delivered a calculated tumor dose of about 6,000 I’. There were no bladder complications In two thirds of the patients treated. It is t:\,ident even with maximum radiation directcbd to the bladder itself and where complications might be expected to follow that a large pcsrcentage of patients escape serious reactions. In the present series, the range of radiation exposure as previously described was u~cd in each of the 10 patients that subsequently developed urologic complications that w:‘re attributed to the radiation. The minim*lm exposure was 3,600 mg. hours of radium in 2 patients in this group. It is emphasized that the technique employed during this period was a short-time intensive radialion exposure method, even more intensive than that used in Stockholm during the same period. Radiation therapists today segard these radium exposures as large biologic tissue doses considering the short-time close involved. Despite this intensive espcsure technique, with no fractionation, there were only 10 patients who suffered major woio~ic damage. Both clinical and postmortem studies,‘. “. ‘7 E-‘~. “. “’ have shown that untreated patients with carcinoma of the cervix commonly die of uremia resulting from occlusion oI’ the ureters. According to Beach’ 60 to 80 per cent and to Valkz7 70 to 90 per rent die from this cause. In our own clinic, SacMt’” ” studied 688 patients treated far carcinoma
754
Cushing,
Tovell,
and
Liegner
of the cervix and reported a 4.9 per cent urologic complication rate following radiation therapy. He concluded that most of the urologic complications were caused by the disease itself. In our series of 369 patients, one third of the patients with major urologic tract damage on admission had invasion of the bladder with cancer. Half of these, or 3 of the 6 patients so afflicted, had accompanying vesicovaginal fistulas associated with ureteral or renal complications or both. In patients with such advanced disease, radiation therapy had only a limited value, as most of them died within a few months. Only 5 survived beyond one year. Patients with cervical cancer who develop major urologic complications due to continuing disease after treatment survive only slightly longer than do treated patients who had major urologic complications due to cancer existing prior to treatment. In those patients with urologic complications not associated with any identifiable residual disease and, therefore, presumably secondary to the treatment alone, the cancer was usually cured. Moreover, in these cases the damage may resolve spontaneously or, if persistent, may be managed later by appropriate measures. Vesicovaginal fistulas and ureteral obstructions comprised almost all of the major urologic complications that occurred due to radiation. There were 6 cases of vesicovaginal fistula, 1.6 per cent of all patients receiving irradiation. This incidence compares favorably with the incidence of 1.4 per cent reported by Burns, Everett, and Brack3 and by Kottmeier.15 In addition, there were 6 cases of ureteral obstruction, 1.6 per cent of the total number of patients included in this study, The action of radium which produces a proliferation of connective tissue
REFERENCES
1. Beach, E. W.: J. Urol. 68: 178, 1952. 2. Behney, C. A.: AM. J. OBST. & GYNEC. 26: 608, 1933. 3. Burns, B. C., Everett, H. S., and Brack, C. B.: AM. J. OBST. & GYNEC. 80: 997, 1960.
with subsequent contraction is responsible* for the obstruction in only a few cases? due to the proximity of the ureters to the lateral walls of the cervix as they traverse the basts of the broad ligaments. Invasion of the cancer into the same area is, however, the usual cause. Based upon the results of this study, we conclude that the lower urologic tract is largely resistant to the effects of radiation, even though it receives a high dose during irradiation of the cervix with the high-intensity exposure radium technique. This is substantiated by the fact that in only 10 of 369 cases treated (2.7 per cent) could major urologic complications be attributed to radium therapy despite significant exposure and high dose rate to point A (400 r per hour*), It is seen that the major urologic complications manifest themselves about one year after radiation therapy, and that 37 per cent of the total patients were proved to be free of cancer. It would seem that since 12 months following treatment is the critical period, the patient ought to have thorough investigation at this time. Intravenous pyelograms and biopsies in strategic areas should be taken; and one may even take a second look intra-abdominally in the presence of induration. The induration may very well be only fibrosis of the tissues. A nonfunctioning kidney of longstanding may have a return of function after resolution of the edema and fibrosis surrounding the ureter, and a vesicovaginal fistula may be repaired in the absence of cancer. Energetic care and follow-up will bring surprisingly good results.
“Calculated by orthogonal reconstruction implant described in text: 960 r to 14,400 to 36 hours.
4. 5. 6. 7.
of actual radium to point A in 24
Dean, Archie L.: J. A. M. A. 89: 1121, 1927. Dean, Archie L.: J. Urol. 29: 559, 1933. Drexler, L. S., and Howes, W. E.: AM. J. OBST. & GYNEC. 28: 197, 1934. Everett, H. S.: AM. J. OBST. & GYNEC. 38: 889, 1939.
complications
8. 9. 10. II. 1’. 13. 14.
15. 16.
17. 18.
Everett, H. S., Brack, C. B., and Farber, G. J.: AM. J. OBST. & GYNEC. 58: 908, 1949. Ewing, James: Neoplastic Diseases, Philadelphia, 1922, W. B. Saunders Company. Farrar. L. K. P.: AM. ”1. OBST. & GYNEC. 10: 205, 1925. Friedman, M., and Lewis, L. G.: Am. J. Roentgenol. 79: 6, 1958. Graves, R. C., Kickham, C. J. E., and Nathanson, I. T.: T. Ural. 36: 618. 1936. Howes, Wm. E., and Straus, H.: Am. J. Roentgenol. 41: 63, 1939. Jaffe, H. L., Meigs, J. V., Graves, R. C., and Kickham. C. J. E.: Surg. Gynec. & Obst. 70: 178, 1940. Kottmeier, H. L.: AM. J. OBST. & GYNEC. 88: 854, 1964. Lenz, M., Cahill, G. F., Melicow, M. M., and Donlan, C. P.: Am. J. Roentgenol. 58: 486, 1947. Leucutia. T.: Am. J. Roentgenol. 53: 180, 194s. Liegner, L., and Taylor, J. A.: J. Urol. 87: 373, 1962.
19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
after cervical
Long, OBST. Martin, gem;.
irradiation
755
J. P., and Montgomery, J. B.: ANL. J. & GYNEC. 59: 552, 1950. C., and Rogers, F. T.: Am. J. Rorlrt15: 336, 1926. W. T.: Therapeutic Radiology, St. Louis, 1959, The C. V. Mosby Company. Randall, L. M., and Buie, L. A.: AM. J. OBST. & GYNEC. 45: 503, 1943. Rhamy, R. K., and Stander, R. W.: .\m J. Roenteenol. 87: 41. 1962. Schmiyz. Henry: ‘Am. J. Roentgenol. 24: 47, 1930. Sackett, N.: New York State J. Med. 35: 22, 1935. Sackett. N.: Virginia M. Monthly, Jlrne. 1937. 47: 686, 1942. Valk, Wm. L.: J. Ural. Ward, G. G.. and Farrar, L. K. P.: J. A. M. A. 91: 296, 1928. Davies, J.: Woman’s Hosp. Bull. 1: 34, 1959. 130 East 65th Street Nut3 York, New York
10021
following radium
and x-ray therapy for carcinoma of the cervix ROBERT
M.
CUSHING,
HAROLD
M.
M.
LEONARD New
York,
M. New
M.D.
TOVELL, LIEGNER,
M.D M.D.
York
A long-term study of the major urologic complications following radium and x-ray therapy in 369 cases of carcinoma of the cervix, treated between 1939 and 1955, has been made. The radiation technique employed during this period was a short-term intensiue radiation exposure method. The mean time of onset of the major urologic complications following treatment was similar whether due to cancer or to radiation, being 12.1 and 12.3 months, respectively. Seventeen (4.6 per cent) were noted to haue major urologic complications on admission due to cancer. An additional 17 patients developed major urologic complications due to cancer after treatment. The mean survival time of the latter series was 17.4 months, with 10 patients surviving less than one year. Only 10 (2.7 per cent) patients deueloped major urologic complications due to radiation therapy. Of this small group, 7 lived for a mean survival time of 4.5 years, while the 3 remaining were still aliue at 10, 17, and 25 years, respectively.
RETROSPECTIVE study has THIS been undertaken to determine the immediate and late major urologic complications associated with radium and x-ray therapy in the treatment of carcinoma of the uterine cervix. Specifically, the purpose was to determine which patients had developed complications that could be attributed to radium therapy and which patients had developed complications that could be attributed to extension of disease involving the urinary tract. The urologic complications encountered that were classified as major were as follows: marked hydronephrosis, pyonephrosis, pyelonephritis, poorly functioning or nonfunctioning kidneys, hydroureter, ureteral stricture with obstruction, ulceration of the bladder, and vesicovaginal fistula. Urinary complications classified as minor (hyperemia,
trigonitis, cystitis, but not subjected Materials
and
or urethritis) were noted to analysis in this review. methods
A total of 443 patients were admitted to the Woman’s Hospital, New York City between the years 1939 and 1955 inclusive with the diagnosis of cervical carcinoma. Of these, 74 patients were either not treated or were treated surgically and have been excluded from this study. The remaining 369 patients received radium and x-ray therapy as the primary treatment for their malignancy and form the basis of this study. Of the 369 patients, 1.55 (42 per cent) survived 5 years or more. Two hundred and two patients (54.7 per cent) failed to survive 5 years and 12 (3.3 per cent) were lost to follow-up. When symptoms warranted, the urinary tract was investigated both before and after treatment to determine the presence and extent of complications in this area. Complications were attributed to radiation only after biopsy material or autopsy ex-
From the Department of Obstetrics and Gynecology, Woman’s Hospital, St. Luke’s Hospital Center, and the Radiation Therapy Service, St. Luke’s Hospital Center.
750
Urologic
aminations failed to reveal residual cancer. Clinical examination and ultimate survival time were also employed in evaluating the etiology of complications. Method of radiation. The irradiation methods employed during the 17 year period considered in this paper have been reported by others.lD, s The radium technique was based on the principle of a high-intensity dose rate, delivering a high dose in a short period of time. The radium application consisted of a 100 mg. capsule in the cervical canal and the distribution of 6 high-intensity platinum-iridium needles, each containing 12.5 mg. of radium, around the circumference of the portio vaginalis of the cervix. The duration of the radium application ranged between 24 and 36 hours, resulting in 400 r per hour to point A. The radiation secluelae in the urinary tract have been attributed to radium therapy rather than to external x-ray therapy, since the latter was directed only to the parametria. X-ray was delivered from a 200 kv. unit and calculated to give 2,000 to 2,400 r air dose exposure through each of four ports in a 24 to 42 day pc:riod. The midline structures were shielded. In addition, x-ray therapy was sometimes given through lateral or split direct perineal ports. Occasionally, transvaginal cone therapy was used, delivering 75 r (air dose) per treatment until 5,000 r (air dose) was delivered. Parametrial tissue doses of 2,400 to 3,000 r were achieved with multiple portals, including perineal fields. Of the 369 patients treated, 239 had cystoscopy and intravenous pyelograms performed when indicated. The remaining 130 patients did not have cystoscopy, since the absence of urologic symptoms throughout the management of their disease, as well as the follow-up period, did not warrant a urologic investigation. The extent of disease in all patients was staged according to the International Classification. Results
Of the 369 patients treated, 286 had evidence of urologic complications prior
no to
complications
after
cervical
irradiation
751
Table I. Urologic treatment --___-
complications in thP of cancer of the cervix I_ -- ---. -____ ! -7.-.---.- / gyi$i;; /’ Before treatment
Complications
No.
286 66 17 369
None
Minor Major Total _____----.*Due:
j
complicYr-
After
treatment ‘j&
j No.
1 %
’
tions >TLi--
67.0 20.8 11.9 I 00
77.5 248 17.9 77 4.6” 44 100 ___-.-~ 369
11 .!.9 .- “7 _._ y.3 --. .~311 _..._ 1’1.2 _
to canwr.
Table II. Etiology
of major
urologic
complications
treatment
j Total pn/ tie+ zrith major cornljlications
No.
j No.
After Before treatment 1-7;
Due to cancer Due to radiation ___I____ Total
17
17
1 %
-1.6
17
4.6
34
4.6
10 2.7 10 7.3 4-t 27 ___-----~-..-_.
j
5%
!).:! 2.7 11.9 _ -.__
treatment. Of these 286 patients, 248 remained free of urologic complications following treatment and thereafter as long as they remained under observation, namely: until death or through 1964 (Table I), Minor urinary tract disturbances were encountered in 66 patients prior to treatment and in 77 patients following treatment. The 11 additional patients in this group experienced symptoms attributable to a transient radiation cystitis. Major urologic complications beforc treatment caused by the cervical cancel- were diagnosed in 17 patients at the time of admission to the hospital. In the majority of these patients, the urinary tract complications persisted following treatment. An additional 27 patients developed one or more llrologic complications following treatment. Of these 27 patients, 17 developed urinary complications that were due to persistent or recurrent malignant disease alone. Only IO patients
752
Cushing,
Tovell,
and
Liegner
Table III. Number of patients with and without urologic complications before treatment grouped according to stage of disease and degree of complication
Sn;fff*eof 1:: I!$:; iNij$1??’ I II III IV Total
104 160 21 1
80.6 79.2 72.4 11.1
24 34 6 2
18.6 16.8 20.7 22.2
1 8 2 6
0.7 3.9 6.9 66.7
129 202 29 9
286
77.5
66
17.9
17
4.6
369
Table IV. Number of patients with and without urologic complications after treatment, grouped according to stage of disease and degree of complications Stage of disease I II III IV Total *Includes existing prior
developed complications that could be solely attributed to radium therapy (Table II). The number of patients grouped according to their degree of urinary tract involvement and the extent of their primary disease encountered before treatment and after treatment is shown in Tables III and IV, respectively. As might be expected, before treatment fewer complications were encountered in the patients with less advanced lesions. Of the 331 patients with Stage I and Stage II cancer, 9 (or 2.7 per cent) had major urologic complications, while of the 38 patients with Stage III and Stage IV cancer, 8 (or 21 per cent) had a major complication (Table III). Following treatment, a further increase in the incidence of major complications was encountered in both the group of patients with less advanced disease and the group of patients with more advanced disease. Of the 331 patients with Stage I and Stage II cancer, 32 (or 9.7 per cent) had a major complication, and of the 38 patients with Stage III and Stage IV cancer, 12 (or 31.5 per cent) had a major complication (Table IV). The percentage of major complications according to the stage of disease and encountered during the follow-up period, as shown in Table IV, expresses the well-known and insidious problem frequently encountered in following patients irradiated for cancer of the uterine cervix. In the 44 patients shown in the group with major urologic
cations __________ No. j % 90 142 15 1
70.0 70.3 51.7 11.1
248
67.2
17 patients to treatment.
cations No. / % 31 24.0 36 17.8 8 27.6 2 22.2 77 with
20.9 major
cations No.
/ %
Total No.
8 6.0 24 11.9 6 20.7 6 66.7
129 202 29 9
44 11.9*
369-
urologic
complications
complications, 17 ( or 38.6 per cent) had a previously diagnosed major urinary tract complication before therapy was initiated, which could be assumed to be due to continuing or extending disease. In the remaining 27 (or 61.4 per cent) of this group, the major complication encountered at follow-up could have been attributed to either the disease alone or to the treatment alone or, which is less likely, to a combination of both these factors. The basic cause of such problems can only be resolved by appropriate biopsies or the passage of time.
Major urologic complications before treatment. There were 17 patients whose major urologic complications existed prior to therapy. Ten of these patients had 2 or more sites in the urinary tract severely involved. There were 5 patients with both renal and ureteral complications. Of the 6 patients with cancer invading the bladder, 3 had vesicovaginal fistulas associated with disturbances of the ureter or kidney or both.
Major urologic complications after treatment due to cancer. There were 17 patients whose major urologic complications were encountered after therapy. These complications were attributed to continuing disease. In this group, 5 patients developed vesicovaginal fistulas. Fourteen patients were originally classified as having a Stage I or Stage II lesion and 3 patients were classified as
Volume Number
101 6
having a Stage III lesion. There Stage IV lesions in this group.
Urologic
were
no
Major urologic complications due to treatment. There were 10 patients whose major urinary complications were attributed to radium therapy alone. One patient had a Stage III lesion and the remaining 9 patients had earlier lesions. Vesicovaginal fistulas developed in 6 patients at 7, 13, 14, 16, 25, and 27 months, respectively, and 5 of these were successfully repaired. In the sixth patient a bilateral ureteral-sigmoid anastomosis was done at 9 months after the vesicovaginal fistula appeared. She died one month later of general peritonitis. Of the remaining 4 patients, 2 developed extensive ulcerations of the bladder with advanced renal infection in one and 2 patients developed complications resulting from ureteral obstruction.
Time of onset of urologic complications and survival time of patient. The time of onset of the major urologic complications due to cancer and occurring after treatment and that due to radium was approximately the same, being 12.1 and 12.3 months, respectively. The survival time in each of these two groups of patients is quite different, as would be expected.ll The 17 patients whose complications were due to continuing disease survived for a mean time of 17.4 months. On the other hand, 3 of the 10 patients whose complications were considered to be due to the radium were alive and well at 10, 17, and 25 years, respectively, following treatment, and the remaining 7 patients lived for a mean survival time of 4.5 years. In contrast, the group of 17 patients with major urinary complications due to cancer encountered before treatment survived only for a mean period of 11.3 months following treatment. Comment The tolerance of the urinary bladder to irradiation may be better understood by observing bladder reactions following radiation treatments for carcinoma of this organ. Only a mild early mucosal reaction will be produced by doses of 3,000 r delivered to
complications
after
cervical
irradiation
753
the bladder in 4 weeks by external radiation.“l It has been shown that the bladder will tolerate local radium implants up to 8,000 r.16 With radon seed implants, a minimum dose of 7,000 gamma P has been used with few complications. Friedman and LewiP have delivered 6,000 to 10,OOP gamma r from a central source of radium contained in a special Foley-type catheter. by two insertions 5 to 12 days apart. In 50 patients, 10 developed severe acute reactions, 7 developed late reactions, 17 developed onlv mild reactions, and 16 showed no reactions at all. Liegner and TayloP treated 42 p:gtients with bladder cancer by means of it supervoltage cobalt-60 unit and delivered a calculated tumor dose of about 6,000 I’. There were no bladder complications In two thirds of the patients treated. It is t:\,ident even with maximum radiation directcbd to the bladder itself and where complications might be expected to follow that a large pcsrcentage of patients escape serious reactions. In the present series, the range of radiation exposure as previously described was u~cd in each of the 10 patients that subsequently developed urologic complications that w:‘re attributed to the radiation. The minim*lm exposure was 3,600 mg. hours of radium in 2 patients in this group. It is emphasized that the technique employed during this period was a short-time intensive radialion exposure method, even more intensive than that used in Stockholm during the same period. Radiation therapists today segard these radium exposures as large biologic tissue doses considering the short-time close involved. Despite this intensive espcsure technique, with no fractionation, there were only 10 patients who suffered major woio~ic damage. Both clinical and postmortem studies,‘. “. ‘7 E-‘~. “. “’ have shown that untreated patients with carcinoma of the cervix commonly die of uremia resulting from occlusion oI’ the ureters. According to Beach’ 60 to 80 per cent and to Valkz7 70 to 90 per rent die from this cause. In our own clinic, SacMt’” ” studied 688 patients treated far carcinoma
754
Cushing,
Tovell,
and
Liegner
of the cervix and reported a 4.9 per cent urologic complication rate following radiation therapy. He concluded that most of the urologic complications were caused by the disease itself. In our series of 369 patients, one third of the patients with major urologic tract damage on admission had invasion of the bladder with cancer. Half of these, or 3 of the 6 patients so afflicted, had accompanying vesicovaginal fistulas associated with ureteral or renal complications or both. In patients with such advanced disease, radiation therapy had only a limited value, as most of them died within a few months. Only 5 survived beyond one year. Patients with cervical cancer who develop major urologic complications due to continuing disease after treatment survive only slightly longer than do treated patients who had major urologic complications due to cancer existing prior to treatment. In those patients with urologic complications not associated with any identifiable residual disease and, therefore, presumably secondary to the treatment alone, the cancer was usually cured. Moreover, in these cases the damage may resolve spontaneously or, if persistent, may be managed later by appropriate measures. Vesicovaginal fistulas and ureteral obstructions comprised almost all of the major urologic complications that occurred due to radiation. There were 6 cases of vesicovaginal fistula, 1.6 per cent of all patients receiving irradiation. This incidence compares favorably with the incidence of 1.4 per cent reported by Burns, Everett, and Brack3 and by Kottmeier.15 In addition, there were 6 cases of ureteral obstruction, 1.6 per cent of the total number of patients included in this study, The action of radium which produces a proliferation of connective tissue
REFERENCES
1. Beach, E. W.: J. Urol. 68: 178, 1952. 2. Behney, C. A.: AM. J. OBST. & GYNEC. 26: 608, 1933. 3. Burns, B. C., Everett, H. S., and Brack, C. B.: AM. J. OBST. & GYNEC. 80: 997, 1960.
with subsequent contraction is responsible* for the obstruction in only a few cases? due to the proximity of the ureters to the lateral walls of the cervix as they traverse the basts of the broad ligaments. Invasion of the cancer into the same area is, however, the usual cause. Based upon the results of this study, we conclude that the lower urologic tract is largely resistant to the effects of radiation, even though it receives a high dose during irradiation of the cervix with the high-intensity exposure radium technique. This is substantiated by the fact that in only 10 of 369 cases treated (2.7 per cent) could major urologic complications be attributed to radium therapy despite significant exposure and high dose rate to point A (400 r per hour*), It is seen that the major urologic complications manifest themselves about one year after radiation therapy, and that 37 per cent of the total patients were proved to be free of cancer. It would seem that since 12 months following treatment is the critical period, the patient ought to have thorough investigation at this time. Intravenous pyelograms and biopsies in strategic areas should be taken; and one may even take a second look intra-abdominally in the presence of induration. The induration may very well be only fibrosis of the tissues. A nonfunctioning kidney of longstanding may have a return of function after resolution of the edema and fibrosis surrounding the ureter, and a vesicovaginal fistula may be repaired in the absence of cancer. Energetic care and follow-up will bring surprisingly good results.
“Calculated by orthogonal reconstruction implant described in text: 960 r to 14,400 to 36 hours.
4. 5. 6. 7.
of actual radium to point A in 24
Dean, Archie L.: J. A. M. A. 89: 1121, 1927. Dean, Archie L.: J. Urol. 29: 559, 1933. Drexler, L. S., and Howes, W. E.: AM. J. OBST. & GYNEC. 28: 197, 1934. Everett, H. S.: AM. J. OBST. & GYNEC. 38: 889, 1939.
complications
8. 9. 10. II. 1’. 13. 14.
15. 16.
17. 18.
Everett, H. S., Brack, C. B., and Farber, G. J.: AM. J. OBST. & GYNEC. 58: 908, 1949. Ewing, James: Neoplastic Diseases, Philadelphia, 1922, W. B. Saunders Company. Farrar. L. K. P.: AM. ”1. OBST. & GYNEC. 10: 205, 1925. Friedman, M., and Lewis, L. G.: Am. J. Roentgenol. 79: 6, 1958. Graves, R. C., Kickham, C. J. E., and Nathanson, I. T.: T. Ural. 36: 618. 1936. Howes, Wm. E., and Straus, H.: Am. J. Roentgenol. 41: 63, 1939. Jaffe, H. L., Meigs, J. V., Graves, R. C., and Kickham. C. J. E.: Surg. Gynec. & Obst. 70: 178, 1940. Kottmeier, H. L.: AM. J. OBST. & GYNEC. 88: 854, 1964. Lenz, M., Cahill, G. F., Melicow, M. M., and Donlan, C. P.: Am. J. Roentgenol. 58: 486, 1947. Leucutia. T.: Am. J. Roentgenol. 53: 180, 194s. Liegner, L., and Taylor, J. A.: J. Urol. 87: 373, 1962.
19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.
after cervical
Long, OBST. Martin, gem;.
irradiation
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J. P., and Montgomery, J. B.: ANL. J. & GYNEC. 59: 552, 1950. C., and Rogers, F. T.: Am. J. Rorlrt15: 336, 1926. W. T.: Therapeutic Radiology, St. Louis, 1959, The C. V. Mosby Company. Randall, L. M., and Buie, L. A.: AM. J. OBST. & GYNEC. 45: 503, 1943. Rhamy, R. K., and Stander, R. W.: .\m J. Roenteenol. 87: 41. 1962. Schmiyz. Henry: ‘Am. J. Roentgenol. 24: 47, 1930. Sackett, N.: New York State J. Med. 35: 22, 1935. Sackett. N.: Virginia M. Monthly, Jlrne. 1937. 47: 686, 1942. Valk, Wm. L.: J. Ural. Ward, G. G.. and Farrar, L. K. P.: J. A. M. A. 91: 296, 1928. Davies, J.: Woman’s Hosp. Bull. 1: 34, 1959. 130 East 65th Street Nut3 York, New York
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