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The prognostic significance of ureteral obstruction in carcinoma of the bladder
Int. J. Radiolion
Oncology
Biol. Phys.. 1977. Vol. 2. PP. 169-l
100.
Pergamon Press.
Printed in the U.S.A
a Original Contribution
THE PROGNOSTIC SIGNIFICANCE OF URETERAL OBSTRUCTION IN CARCINOMA OF THE BLADDER RICHARD GREINER, Department
M.D., of Radiation
CONSTANTIN SKALERIC, M.D. Therapy,
UniversitHtsklinik
Inselspital,
and PIERRE VERAGUTH, M.D.?_ Bern, Switzerland
The prognostic significance of ureteral obstruction is discussed on the basis of 225 patients with a histologically proven carcinoma1 of the bladder, who where treated between January 1960 and March 1972. 148 patients had normal or only slightly disturbed urinary flow, 77 had an ureteral obstruction. In all patients the treatment involved the operation with varying techniques and the subsequent irradiation with doses of cu. 7000-7500 rad. The patients were subdivided according to the TNM-classification of the UICC in relation to the findings of urography and lymphography.” The patients of category T2 + 3 with ureteral obstruction have a significantly poorer survival rate, p = 0.01. In the category T3 the significance of difference is p = 0.05. In only 6% of the patients could an improvement of urinary flow after radiotherapy be ascertained. Patients with ureteral obstruction should be classified at least in category T3. If radical operative procedures are contraindicated, the radiotherapy should be confined to more palliative procedures. The ureter obstruction has the same importance as a criterion for a poor prognosis as the positive lymphography. Bladder cancer, [Jreteral obstruction,
Lymphography,
TNM classification,
INTRODUCTION
Radiotherapy.
METHODS
The general value of retrospective studies carried out to improve the results of treatment is, no doubt, rather small. With carcinoma of the bladder, too, it is the prospective, controlled and randomized studies that assess the indication and significance of methods of treatment and help reduce the failure rate because of new techniques. However, retrospective procedures lend themselves to answering special questions and to utilizing the experiences gained over the past years. It was our task to evaluate the evidence of ureteral obstruction in carcinoma of the bladder on the basis of the results of radiotherapy at our clinic. We wanted to investigate the prognostic: significance of ureteral obstruction and compare it with other malignant tumors in the minor pelvis where urinary flow disturbance is known as a poor prognostic symptom5,6V’0 and evaluated accordingly. We alsco wanted to answer the question of how often radiotherapy succeeds without preliminary operation in removing ureteral obstruction caused by carcinoma. We spoke of ureteral obstruction whenever clear radiological evidence of urinary flow disturbance prevailed which could be explained only in connection with the tumor.
AND
MATERIALS
Our study included 225 patients with histologically proven carcinoma of the bladder, who were given percutaneous irradiation with a total tumor dose of a minimum of 4500 rad over the period January 1960 to March 1972. Not included are 78 patients with the histological diagnosis of papillary tumor. In each case at least one urographic examination was performed prior to the beginning of treatment. In 134 of 225 patients (60%) the urography was normal, in 14 patients (6%) there was a minima1 disturbance in the urinary flow and 77 patients (34%) had unilateral or bilateral ureteral obstruction. Only this last group of patients has been considered in determining the prognostic significance of ureteral obstruction. Each patient was categorized according to the TNM classification of the UICC.13 Where there was any doubt, the patient was placed in the lower category. The follow-up was complete in all patients, but the cause of death could not be established in IO patients. The findings of urography and lymphography were compared in order to evaluate their prognostic significance. Since lymphocavo-urography (LCU) was performed only sporadically from 1960-65, we did not
tDirector.
Seydoux for their help in preparing this manuscript, Guelfo Poretti, M.Ph., chief-physicist of the department radiation therapy, for his help in statistical problems.
Acknowledgements-We would like to thank Miss Maria Campian, Miss Annemarie Weber and Mrs. Rosemarie 1095
Mr. of
IO96
Radiation
Oncology
0 Biology 0 Physics
November-December
take the findings
into consideration at that time. Since 1966, however, LCU has been part of the routine diagnostic program and was performed in 99 of 124 patients.
1977, Volume
2, No.
II
and No.
I2
groups. Therefore the patients with ureteral obstruction are not subdivided in these analyses and form one group including all degrees of obstruction. Table 1 shows the frequency of ureteral obstruction in the category T2, T3, T4. Table 2 shows the distribution of histological types.
Radiotherapy volt irradiation Patients were given high exclusively with a minimum dose of 4500 rad covering the entire tumor volume. In the majority of patients the total dose amounted to 7000-7500 rad, applied with a variety of field arrangements. In about 30% the split course technique was performed (duration of therapy 12-14 weeks). In the early 1960s the tumor dose per fraction was 200-250 rad, 6 times weekly, later on 170-200rad, 5 times weekly, i.e. about 40 fractions in 50-60 days. Fixed field sizes never exceeded 12 x 12 cm. In individual cases, the length of the rotating electron beam field was 14 cm. In approximately half the patients, treatment was combined with high energetic-X-rays (30-33 MeV) of the betatron and fast electrons up to 35 MeV. About 30% of the patients were given electron beam irradiation exclusively using the rotation-technique. 6oCoirradiation was used only occasionally.
Comparison of survival rates Tables 3(a) and (b) show the classification and survival rates of patients with carcinomata of the bladder with ureteral obstruction and with normal urography. The differences are evident. The survival time of patients in each tumor category with urinary flow disturbance is significantly less. Figure 1 demonstrates these differences graphically. The mortality rate of patients in category T2 and T3 with ureteral obstruction is the same as that of the patients in category T4 with normal urography within the first 2 years after radiotherapy. All the patients in category T4 with obstruction died within 16 months after therapy. Table 4 shows the comparison of the survival rates in relation to the findings of urography for those patients in the categories T2 + 3. The group T4 is not included, since these patients should only be treated palliatively.
RESULTS Cause of death The most common causes of death for patients with obstruction were the lack of response of the primary tumor to the irradiation and the development of metastases. On the other hand, for those patients
Ureteral obstruction was established in 77 of 225 patients. At first these patients had been divided into several subgroups according to the radiological degree of urinary flow disturbance, however, there were no prognostic differences between these sub-
Table 1. Frequency of ureteral obstruction. Classification of patients according to the TNM-system of UICC. Patients with slight flow disturbance without hydronephrosis are included in the group “no obstruction” T2
T3
Total
T4
Urography
No.
%
No.
%
No.
%
No.
%
Obstruction No obstruction Total
14 48 62
22.6 77.4 100
45 88 133
33.8 66.2 100
18 12 30
60 40 100
77 148 225
34.2 65.8 100
Table 2. Histological
Histology Transitional-cellcarcinoma Papillary Non-papillary Squamous epithelialcarcinoma Cytology or insufficient differentiation Total
type, frequency and percent distribution and without ureteral obstruction Frequency No. %
Obstruction No. %
in patients
with
No obstruction No. %
89 96
39.5 40.3
21 38
24 40
68 58
76 60
13
5.8
7
54
6
46
27 225
14.4 100
11 77
41 100
16 148
59 100
Ureteral obstruction
Table
3(a). Survivors in [the category ureteraL obstruction
1 yr Category T2 T3 T4 Total
Table
No.
No.
%
14 45 18 77
8 19 4 31
57 42 22 40
3(b). Survivors in the category ureteral obstruction
1 yl Category
No.
No.
%
T2 T3 T4 Total
48 88 12 148
41 56 5 102
85 64 42 69
tThese patients had an anterior tion of the cancer.
T2, T3, T4: with
Survivors 3 yr No. % 3 6 0 9
21 13 0 12
T2,
Survivors 3 yr No. % 25 25 4 54
in carcinoma
52 28 33 36
suprapubic
5 yr No.
%
2 2 0 4
14 4 0 5
T3,
T4: no
5 yr No.
%
20 20 3 43
42 23 25t 29
wall infiltra-
Table 4. Comparison of survival time of patients in the categories T2+ 3 with and without ureteral obstruction. Significance of difference p = 0.01
Urography
No.
Obstruction No obstruction
59 136
1 yr No. % 27 97
46 71
Survivors 3 yr No. % 9 50
15 37
5 yr No.
%
4 40
7 29
of the bladder
0 R.
GREINER
et al.
1097
with normal urography the most common causes of death were tumor recurrence and intercurrent deaths (Table 5). Nearly half of the patients with ureteral obstruction had primary tumors which failed to respond or responded only poorly to irradiation. The effect of irradiation on ureteral obstruction Control urographies were carried out in 51 of 78 patients with ureteral obstruction, but without urinary diversion before the beginning of radiotherapy. The one giving the most favorable result for radiotherapy as compared to the pre-irradiation situation was taken into consideration. Nevertheless the urography of only 3 patients out of 51 showed a significant improvement of urinary flow (Table 6). No connection could be ascertained between the values of BUN and creatinine and the existence and/or the degree of ureteral obstruction. Prognostic comparison between urographic and lymphographic findings In 57 of 148 patients without ureteral obstruction and in 32 of 77 patients with ureteral obstruction we compared the prognostic significance of disturbed or normal urinary flow in carcinoma of the bladder with lymphographic findings. The comparison was made only for patients in the category T2 and T3. The patients in each category were divided into 4 groups according to the results of lymphography and urography (Table 7). There was a clear difference in survival between the patients in category T2 and T3 with both normal urography and negative lymphography. But in case of ureteral obstruction or positive lymphography in both the categories the results were unsatisfying (Fig. 2). DISCUSSION
Time
after radiotherapy,
years
Fig. 1. Survival curves of patients in category T2, T3 and T4 in relationship to the findings in urography. (----), No ureteral obstruction; (.-), Ureteral obstruction.
None of the tumor classifications of bladder cancer considers ureteral obstruction to be of prognostic significance. Since the cause of urinary flow disturbance is not firmly established the commission of UICC has not taken ureteral obstruction into consideration in TNM staging;13,14 however, in case of carcinoma of the cervix this is regarded as a criterion.13 Hydronephrosis or non-functioning kidney caused by stenosis of the ureter, which has to be regarded as tumorous, calls for classification as T3 even if a lesser category is indicated according to the other parameters. In their most recent classification FIG0 (Intl Federation of Gynecologists and Obstetricians), too, considers a deterioration of prognosis in cases of ureteral obstructior?’ and assigns such patients even in the absence of other parameters, to Stage IIIB.6 The UICC commission possibly may hesitate to consider ureteral obstruction because of the lack of data. In carcinoma of the bladder hardly
Radiation
1098
Oncology
0 Biology 0 Physics
November-December
1977, Volume
Table 5. Cause of death in relationship to the findings in urography. the patients of the category T2 and T3
T2 Cause of death Total Tumor Metastases Recurrence Intercurrent Unknown
No.
32 10
Obstruction T3 T2+3 No. %
1 1
4 0
No.
Better No change Worse Total
3 24 24 51
2
4
II
and No.
12
Included are
No obstruction T3 T2+3 No. %
5
9
9
should be classified at least in category T3, as with ureteral obstruction in patients with carcinoma of the cervix, even if this is not justified according to other criteria. The patients in category T2 with ureteral obstruction have an even poorer prognosis than those
Table 6. Influence of radiotherapy on the primary ureteral obstruction without urinary diversion before the beginning of radiotherapy and frequency of uremia caused by the uncontrolled primary tumor at the time of death Influence of radiotherapy
5 1
T2
2, No.
Death with uremia No. % 0 3 12 15
0 12 50 30
any analyses for the significance of ureteral obstruction* are available. In case of cancer of the cervix, obstruction of a ureter normally indicates extensive growth, whereas in bladder cancer the location of the growth in the bladder is of importance. On the basis of our findings, ureteral obstruction is established as a criterion for a poor prognosis in patients with bladder cancer. In regard to the 5-year survival rates the significance of difference for patients in categories T2+ 3 is p = 0.01; for patients in category T3 it is p = 0.05. Since the ureteral obstruction has the same importance as a criterion for poor prognosis in the category T2, all the patients with ureteral obstruction Table
12 5% (3/24) II% (l/9)
/
4-e Time
after
radiotherapy.
Fig. 2. Survival curves of patients in category T2+3 in relationship to the findings of urography and lymphography. (----), No obstruction, neg. lymphography; (-.-.-), No obstruction, path. lymphography; (---), Obstruction, ), Obstruction, path. lymphogneg. lymphography; (--raphy.
7. Survival rate of patients in the category T2 and T3 in relationship to the findings in urography and lymphographyt Survivors No.
5 yr %
Category
Urography
Lymphography
No.
T2
Normal Normal Obstruction Obstruction
Negative Positive Negative Positive
22 1 6 2
10 0 1 0
45.5 0 17 0
T3
Normal Normal Obstruction Obstruction
Negative Positive Negative Positive
26 8 18 6
9 1 2 0
34.5 12.5 11 0
tPatients
from 1966 to 1972.
years
Ureteral obstruction in carcinoma of the bladder 0 R. GREINER
in category T3 without ureteral obstruction. In addition to those patients included in this study, we have treated 78 patients with the histological diagnosis of papillary tumor of the bladder without invasive growth. Nineteen of these patients had an ureteral obstruction, mostly an unilateral hydronephrosis. However, they also demonstrate the poor prognosis associated with ureteral obstruction: only 1 patient survived 5 years. The results of treatment in patients with ureteral obstruction are unsatisfactory, particularly if only biopsy was performed before the beginning of radiotherapy. In such patients too much has been expected of the radiotherapy. This is evident in the follow-up urographies: in only 3 of 51 patients could an improvement of urinary flow be ascertained, whereas in nearly half the patients urinary flow was shown to As is known from deteriorate despite irradiation. carcinoma of the cervix, tumorous ureteral obstruction shows little irradiation sensibility; normalization is reported in less than 10% of the cases.‘*? Irradiation as the sole therapeutic measure, however, hardly offers the chance of a cure to these patients, as is shown by our findings. Acknowledgement of these facts should be of prime influence for radiotherapists when setting their goals, since higher doses in these situations only increase the complication rate but not the rate of healing. Right from the beginning the symptom of ureteral obstruction demands thorough evaluation if not an entire change in the concept of treatment as such; this is especially true in patients where a combined operation-irradiation treatment is clinically not contraindicated. It might well be that ureteral obstruction as a criterion for a poor prognosis plays a less decisive role if the concept of therapy is other than that current in our institution. Following operation (biopsy, transurethral resection (TUR) suprapubic tumor resection, partial cystectomy, urinary diversion) our patients were given percutaneous irradiation with total doses of, in general, between 7000 and 7500rad. These so called conservative procedures are set against modern therapeutical protocols.‘“~4~7-9~“~‘5-‘7 Unfortunately, little is said about the symptom of ureteral obstruction in these reports. Hence, it cannot be ascertained whether ureteral obstrtrction does indeed play a less
patients
et al.
1099
decisive role as a symptom for a poor prognosis in modern therapeutic procedures. The report by Mahoney et al.’ mentioning a possible overestimation of primary ureteral obstruction as a criterion for operability does not, however, answer the question of prognostic significance. There may be a correlation T stage, the P stage according between the primary to regressionI and primary ureteral obstruction after pre-irradiation and operation. In addition, despite regression of the tumor with pre-irradiation the primary finding of ureteral obstruction may well result in a therapeutic failure. We feel that investigations to this effect may be useful. For, if curability of carcinoma of the bladder in the case of ureteral obstruction does indeed improve with pre-irradiation and cystectomy, it would be advisable to adopt this therapeutic procedure. If, on the other hand, even the modern techniques of treatment fail to improve poor prognosis of ureteral obstruction this means that principally the radiotherapeutical procedures should be confined to more palliative procedures. In the two most commonly used classifications (Jewett-Strong-Marshall-Whitmore,lh TNM of UICC13) lymphographic findings are taken into consideration as prognostic criteria which influence the choice of therapy. Therefore it seemed to be a rewarding task to compare the prognoses according to both the lymphographic and the urographic findings. Our studies have established that the prognosis deteriorates, with normal as well as pathological lymphography, in the presence of a ureteral obstruction; the ureteral obstruction has the same prognostic importance as a pathological lymphography. The coincidence of positive nodes in the lymphography and ureteral obstruction has led to death in each case within 18 months after the beginning of treatment in patients of the category T2 and T3. The UICC commission will set up a new TNM classification of bladder cancer after completion of this test period. We trust that in reporting our findings we can take a step towards convincing the commission that particular attention should be given to the bad prognostic significance of ureteral obstruction.
REFERENCES 1. Bloom, H.J-G., Wallace, D.M.: Tumors of the bladder. In Handbuch der Med. Radiologie, ed. by Zuppinger, A. Berlin, Springer-Verlag, 1971, Vol. 19, Part 3, pp. 430494. 2. Bowles, W.T., Silber, J.: Carcinoma of the bladder. A
?Patients with ureteral obstruction are often patients with contraindications for more radical
high risk operative
computer analysis of 516 patients. J. Ural. 107: 245-247, 1972. 3. Fish, J.C., Fayos, J.V.: Carcinoma of the urinary bladder. Radiology 118: 179-182, 1976. 4. Goffinet, D.R., Schneider, M.J., Glatstein, E.J., Ludwig,
procedures.
1100
5.
6.
7.
8. 9.
10.
11.
Radiation
Oncology
0 Biology
l
Physics
H., Ray, G.R., Dunnick, N.R., Bagshaw, M.A.: Bladder cancer: results of radiation therapy in 384 patients. Radiology 117: 149-153, 1975. Ilija, F.A., O’Leary, J.A., Frick, H.C.: Prognostic significance of ureteral obstruction in carcinoma of the cervix. Cancer 19: 689-690, 1%6. Kottmeier, H.L.: Presentation of therapeutic results in carcinoma of the female pelvis: experience of the annual report on the results of treatment in carcinoma of the uterus, vagina and ovary. Gynecol. Oncol. 4: 13-19, 1976. Mahoney, E.M., Weber, E.T., Harrison, J.H.: Postdiversion pre-cystectomy irradiation for carcinoma of the bladder. J. Ural. 114: 46-49, 1975. Mallo, N., Vecente, J.: Diagnostic and therapeutic patterns of bladder tumors. Europ. Ural. 1: 96-98, 1975. Morrison, R.: The results of treatment of cancer of the bladder. A clinical contribution to radiobiology. C/in. Radiol. 26: 67-75, 1975. Moss, W.T., Brand, W.N., Battifora, H.: The urinary bladder. In Radiation Oncology. Rationale, Technique, Results. Saint Louis. Mosby, 1973, 4th Edn, pp. 362377. Prout, G.R., Slack, N.H., Bross, J.D.D.: Preoperative
November-December
12.
13.
14.
15.
1977, Volume
2, No.
II
and No.
12
irradiation as an adjuvant in the surgical management of inversive bladder carcinoma. J. Ural. 105: 223-231, 1971. Slater, J.M., Fletcher, G.H.: Ureteral strictures after radiation therapy for carcinoma of the uterine cervix. Am. J. Roentgenol. 111: 269-272, 1971. UICC-International Union Against Cancer. TNMClassification of Malignant Tumor. Geneva, de Buren, 1974, 2nd Edn. Vogler, H., Rothkopf, M., Mebel, M.: Experiences based on the classification of bladder tumors according to the TNM-System. Europ. Ural. 1:93-95, 1975. Van der Werf-Messing, B.H.P.: Treatment of carcinoma of the bladder with radium. Clin. Radiol. 16:
16-26, 1965. 16. Van der Werf-Messing, bladder T,N,M, treated
B.H.P.: Carcinoma of the by pre-operative irradiation Third report of B.R.T.J. Can-
followed by cystectomy. cer 36: 718-722, 1975. 17. Whitmore, W.F., Grabstald, H., Mackency, R.A., Iswariah, J., Phillips, R.: Preoperative irradiation with cystectomy in the management of bladder cancer. Am. J. Roentgenol. 102: 570-576, 1%8.
Oncology
Biol. Phys.. 1977. Vol. 2. PP. 169-l
100.
Pergamon Press.
Printed in the U.S.A
a Original Contribution
THE PROGNOSTIC SIGNIFICANCE OF URETERAL OBSTRUCTION IN CARCINOMA OF THE BLADDER RICHARD GREINER, Department
M.D., of Radiation
CONSTANTIN SKALERIC, M.D. Therapy,
UniversitHtsklinik
Inselspital,
and PIERRE VERAGUTH, M.D.?_ Bern, Switzerland
The prognostic significance of ureteral obstruction is discussed on the basis of 225 patients with a histologically proven carcinoma1 of the bladder, who where treated between January 1960 and March 1972. 148 patients had normal or only slightly disturbed urinary flow, 77 had an ureteral obstruction. In all patients the treatment involved the operation with varying techniques and the subsequent irradiation with doses of cu. 7000-7500 rad. The patients were subdivided according to the TNM-classification of the UICC in relation to the findings of urography and lymphography.” The patients of category T2 + 3 with ureteral obstruction have a significantly poorer survival rate, p = 0.01. In the category T3 the significance of difference is p = 0.05. In only 6% of the patients could an improvement of urinary flow after radiotherapy be ascertained. Patients with ureteral obstruction should be classified at least in category T3. If radical operative procedures are contraindicated, the radiotherapy should be confined to more palliative procedures. The ureter obstruction has the same importance as a criterion for a poor prognosis as the positive lymphography. Bladder cancer, [Jreteral obstruction,
Lymphography,
TNM classification,
INTRODUCTION
Radiotherapy.
METHODS
The general value of retrospective studies carried out to improve the results of treatment is, no doubt, rather small. With carcinoma of the bladder, too, it is the prospective, controlled and randomized studies that assess the indication and significance of methods of treatment and help reduce the failure rate because of new techniques. However, retrospective procedures lend themselves to answering special questions and to utilizing the experiences gained over the past years. It was our task to evaluate the evidence of ureteral obstruction in carcinoma of the bladder on the basis of the results of radiotherapy at our clinic. We wanted to investigate the prognostic: significance of ureteral obstruction and compare it with other malignant tumors in the minor pelvis where urinary flow disturbance is known as a poor prognostic symptom5,6V’0 and evaluated accordingly. We alsco wanted to answer the question of how often radiotherapy succeeds without preliminary operation in removing ureteral obstruction caused by carcinoma. We spoke of ureteral obstruction whenever clear radiological evidence of urinary flow disturbance prevailed which could be explained only in connection with the tumor.
AND
MATERIALS
Our study included 225 patients with histologically proven carcinoma of the bladder, who were given percutaneous irradiation with a total tumor dose of a minimum of 4500 rad over the period January 1960 to March 1972. Not included are 78 patients with the histological diagnosis of papillary tumor. In each case at least one urographic examination was performed prior to the beginning of treatment. In 134 of 225 patients (60%) the urography was normal, in 14 patients (6%) there was a minima1 disturbance in the urinary flow and 77 patients (34%) had unilateral or bilateral ureteral obstruction. Only this last group of patients has been considered in determining the prognostic significance of ureteral obstruction. Each patient was categorized according to the TNM classification of the UICC.13 Where there was any doubt, the patient was placed in the lower category. The follow-up was complete in all patients, but the cause of death could not be established in IO patients. The findings of urography and lymphography were compared in order to evaluate their prognostic significance. Since lymphocavo-urography (LCU) was performed only sporadically from 1960-65, we did not
tDirector.
Seydoux for their help in preparing this manuscript, Guelfo Poretti, M.Ph., chief-physicist of the department radiation therapy, for his help in statistical problems.
Acknowledgements-We would like to thank Miss Maria Campian, Miss Annemarie Weber and Mrs. Rosemarie 1095
Mr. of
IO96
Radiation
Oncology
0 Biology 0 Physics
November-December
take the findings
into consideration at that time. Since 1966, however, LCU has been part of the routine diagnostic program and was performed in 99 of 124 patients.
1977, Volume
2, No.
II
and No.
I2
groups. Therefore the patients with ureteral obstruction are not subdivided in these analyses and form one group including all degrees of obstruction. Table 1 shows the frequency of ureteral obstruction in the category T2, T3, T4. Table 2 shows the distribution of histological types.
Radiotherapy volt irradiation Patients were given high exclusively with a minimum dose of 4500 rad covering the entire tumor volume. In the majority of patients the total dose amounted to 7000-7500 rad, applied with a variety of field arrangements. In about 30% the split course technique was performed (duration of therapy 12-14 weeks). In the early 1960s the tumor dose per fraction was 200-250 rad, 6 times weekly, later on 170-200rad, 5 times weekly, i.e. about 40 fractions in 50-60 days. Fixed field sizes never exceeded 12 x 12 cm. In individual cases, the length of the rotating electron beam field was 14 cm. In approximately half the patients, treatment was combined with high energetic-X-rays (30-33 MeV) of the betatron and fast electrons up to 35 MeV. About 30% of the patients were given electron beam irradiation exclusively using the rotation-technique. 6oCoirradiation was used only occasionally.
Comparison of survival rates Tables 3(a) and (b) show the classification and survival rates of patients with carcinomata of the bladder with ureteral obstruction and with normal urography. The differences are evident. The survival time of patients in each tumor category with urinary flow disturbance is significantly less. Figure 1 demonstrates these differences graphically. The mortality rate of patients in category T2 and T3 with ureteral obstruction is the same as that of the patients in category T4 with normal urography within the first 2 years after radiotherapy. All the patients in category T4 with obstruction died within 16 months after therapy. Table 4 shows the comparison of the survival rates in relation to the findings of urography for those patients in the categories T2 + 3. The group T4 is not included, since these patients should only be treated palliatively.
RESULTS Cause of death The most common causes of death for patients with obstruction were the lack of response of the primary tumor to the irradiation and the development of metastases. On the other hand, for those patients
Ureteral obstruction was established in 77 of 225 patients. At first these patients had been divided into several subgroups according to the radiological degree of urinary flow disturbance, however, there were no prognostic differences between these sub-
Table 1. Frequency of ureteral obstruction. Classification of patients according to the TNM-system of UICC. Patients with slight flow disturbance without hydronephrosis are included in the group “no obstruction” T2
T3
Total
T4
Urography
No.
%
No.
%
No.
%
No.
%
Obstruction No obstruction Total
14 48 62
22.6 77.4 100
45 88 133
33.8 66.2 100
18 12 30
60 40 100
77 148 225
34.2 65.8 100
Table 2. Histological
Histology Transitional-cellcarcinoma Papillary Non-papillary Squamous epithelialcarcinoma Cytology or insufficient differentiation Total
type, frequency and percent distribution and without ureteral obstruction Frequency No. %
Obstruction No. %
in patients
with
No obstruction No. %
89 96
39.5 40.3
21 38
24 40
68 58
76 60
13
5.8
7
54
6
46
27 225
14.4 100
11 77
41 100
16 148
59 100
Ureteral obstruction
Table
3(a). Survivors in [the category ureteraL obstruction
1 yr Category T2 T3 T4 Total
Table
No.
No.
%
14 45 18 77
8 19 4 31
57 42 22 40
3(b). Survivors in the category ureteral obstruction
1 yl Category
No.
No.
%
T2 T3 T4 Total
48 88 12 148
41 56 5 102
85 64 42 69
tThese patients had an anterior tion of the cancer.
T2, T3, T4: with
Survivors 3 yr No. % 3 6 0 9
21 13 0 12
T2,
Survivors 3 yr No. % 25 25 4 54
in carcinoma
52 28 33 36
suprapubic
5 yr No.
%
2 2 0 4
14 4 0 5
T3,
T4: no
5 yr No.
%
20 20 3 43
42 23 25t 29
wall infiltra-
Table 4. Comparison of survival time of patients in the categories T2+ 3 with and without ureteral obstruction. Significance of difference p = 0.01
Urography
No.
Obstruction No obstruction
59 136
1 yr No. % 27 97
46 71
Survivors 3 yr No. % 9 50
15 37
5 yr No.
%
4 40
7 29
of the bladder
0 R.
GREINER
et al.
1097
with normal urography the most common causes of death were tumor recurrence and intercurrent deaths (Table 5). Nearly half of the patients with ureteral obstruction had primary tumors which failed to respond or responded only poorly to irradiation. The effect of irradiation on ureteral obstruction Control urographies were carried out in 51 of 78 patients with ureteral obstruction, but without urinary diversion before the beginning of radiotherapy. The one giving the most favorable result for radiotherapy as compared to the pre-irradiation situation was taken into consideration. Nevertheless the urography of only 3 patients out of 51 showed a significant improvement of urinary flow (Table 6). No connection could be ascertained between the values of BUN and creatinine and the existence and/or the degree of ureteral obstruction. Prognostic comparison between urographic and lymphographic findings In 57 of 148 patients without ureteral obstruction and in 32 of 77 patients with ureteral obstruction we compared the prognostic significance of disturbed or normal urinary flow in carcinoma of the bladder with lymphographic findings. The comparison was made only for patients in the category T2 and T3. The patients in each category were divided into 4 groups according to the results of lymphography and urography (Table 7). There was a clear difference in survival between the patients in category T2 and T3 with both normal urography and negative lymphography. But in case of ureteral obstruction or positive lymphography in both the categories the results were unsatisfying (Fig. 2). DISCUSSION
Time
after radiotherapy,
years
Fig. 1. Survival curves of patients in category T2, T3 and T4 in relationship to the findings in urography. (----), No ureteral obstruction; (.-), Ureteral obstruction.
None of the tumor classifications of bladder cancer considers ureteral obstruction to be of prognostic significance. Since the cause of urinary flow disturbance is not firmly established the commission of UICC has not taken ureteral obstruction into consideration in TNM staging;13,14 however, in case of carcinoma of the cervix this is regarded as a criterion.13 Hydronephrosis or non-functioning kidney caused by stenosis of the ureter, which has to be regarded as tumorous, calls for classification as T3 even if a lesser category is indicated according to the other parameters. In their most recent classification FIG0 (Intl Federation of Gynecologists and Obstetricians), too, considers a deterioration of prognosis in cases of ureteral obstructior?’ and assigns such patients even in the absence of other parameters, to Stage IIIB.6 The UICC commission possibly may hesitate to consider ureteral obstruction because of the lack of data. In carcinoma of the bladder hardly
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Table 5. Cause of death in relationship to the findings in urography. the patients of the category T2 and T3
T2 Cause of death Total Tumor Metastases Recurrence Intercurrent Unknown
No.
32 10
Obstruction T3 T2+3 No. %
1 1
4 0
No.
Better No change Worse Total
3 24 24 51
2
4
II
and No.
12
Included are
No obstruction T3 T2+3 No. %
5
9
9
should be classified at least in category T3, as with ureteral obstruction in patients with carcinoma of the cervix, even if this is not justified according to other criteria. The patients in category T2 with ureteral obstruction have an even poorer prognosis than those
Table 6. Influence of radiotherapy on the primary ureteral obstruction without urinary diversion before the beginning of radiotherapy and frequency of uremia caused by the uncontrolled primary tumor at the time of death Influence of radiotherapy
5 1
T2
2, No.
Death with uremia No. % 0 3 12 15
0 12 50 30
any analyses for the significance of ureteral obstruction* are available. In case of cancer of the cervix, obstruction of a ureter normally indicates extensive growth, whereas in bladder cancer the location of the growth in the bladder is of importance. On the basis of our findings, ureteral obstruction is established as a criterion for a poor prognosis in patients with bladder cancer. In regard to the 5-year survival rates the significance of difference for patients in categories T2+ 3 is p = 0.01; for patients in category T3 it is p = 0.05. Since the ureteral obstruction has the same importance as a criterion for poor prognosis in the category T2, all the patients with ureteral obstruction Table
12 5% (3/24) II% (l/9)
/
4-e Time
after
radiotherapy.
Fig. 2. Survival curves of patients in category T2+3 in relationship to the findings of urography and lymphography. (----), No obstruction, neg. lymphography; (-.-.-), No obstruction, path. lymphography; (---), Obstruction, ), Obstruction, path. lymphogneg. lymphography; (--raphy.
7. Survival rate of patients in the category T2 and T3 in relationship to the findings in urography and lymphographyt Survivors No.
5 yr %
Category
Urography
Lymphography
No.
T2
Normal Normal Obstruction Obstruction
Negative Positive Negative Positive
22 1 6 2
10 0 1 0
45.5 0 17 0
T3
Normal Normal Obstruction Obstruction
Negative Positive Negative Positive
26 8 18 6
9 1 2 0
34.5 12.5 11 0
tPatients
from 1966 to 1972.
years
Ureteral obstruction in carcinoma of the bladder 0 R. GREINER
in category T3 without ureteral obstruction. In addition to those patients included in this study, we have treated 78 patients with the histological diagnosis of papillary tumor of the bladder without invasive growth. Nineteen of these patients had an ureteral obstruction, mostly an unilateral hydronephrosis. However, they also demonstrate the poor prognosis associated with ureteral obstruction: only 1 patient survived 5 years. The results of treatment in patients with ureteral obstruction are unsatisfactory, particularly if only biopsy was performed before the beginning of radiotherapy. In such patients too much has been expected of the radiotherapy. This is evident in the follow-up urographies: in only 3 of 51 patients could an improvement of urinary flow be ascertained, whereas in nearly half the patients urinary flow was shown to As is known from deteriorate despite irradiation. carcinoma of the cervix, tumorous ureteral obstruction shows little irradiation sensibility; normalization is reported in less than 10% of the cases.‘*? Irradiation as the sole therapeutic measure, however, hardly offers the chance of a cure to these patients, as is shown by our findings. Acknowledgement of these facts should be of prime influence for radiotherapists when setting their goals, since higher doses in these situations only increase the complication rate but not the rate of healing. Right from the beginning the symptom of ureteral obstruction demands thorough evaluation if not an entire change in the concept of treatment as such; this is especially true in patients where a combined operation-irradiation treatment is clinically not contraindicated. It might well be that ureteral obstruction as a criterion for a poor prognosis plays a less decisive role if the concept of therapy is other than that current in our institution. Following operation (biopsy, transurethral resection (TUR) suprapubic tumor resection, partial cystectomy, urinary diversion) our patients were given percutaneous irradiation with total doses of, in general, between 7000 and 7500rad. These so called conservative procedures are set against modern therapeutical protocols.‘“~4~7-9~“~‘5-‘7 Unfortunately, little is said about the symptom of ureteral obstruction in these reports. Hence, it cannot be ascertained whether ureteral obstrtrction does indeed play a less
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decisive role as a symptom for a poor prognosis in modern therapeutic procedures. The report by Mahoney et al.’ mentioning a possible overestimation of primary ureteral obstruction as a criterion for operability does not, however, answer the question of prognostic significance. There may be a correlation T stage, the P stage according between the primary to regressionI and primary ureteral obstruction after pre-irradiation and operation. In addition, despite regression of the tumor with pre-irradiation the primary finding of ureteral obstruction may well result in a therapeutic failure. We feel that investigations to this effect may be useful. For, if curability of carcinoma of the bladder in the case of ureteral obstruction does indeed improve with pre-irradiation and cystectomy, it would be advisable to adopt this therapeutic procedure. If, on the other hand, even the modern techniques of treatment fail to improve poor prognosis of ureteral obstruction this means that principally the radiotherapeutical procedures should be confined to more palliative procedures. In the two most commonly used classifications (Jewett-Strong-Marshall-Whitmore,lh TNM of UICC13) lymphographic findings are taken into consideration as prognostic criteria which influence the choice of therapy. Therefore it seemed to be a rewarding task to compare the prognoses according to both the lymphographic and the urographic findings. Our studies have established that the prognosis deteriorates, with normal as well as pathological lymphography, in the presence of a ureteral obstruction; the ureteral obstruction has the same prognostic importance as a pathological lymphography. The coincidence of positive nodes in the lymphography and ureteral obstruction has led to death in each case within 18 months after the beginning of treatment in patients of the category T2 and T3. The UICC commission will set up a new TNM classification of bladder cancer after completion of this test period. We trust that in reporting our findings we can take a step towards convincing the commission that particular attention should be given to the bad prognostic significance of ureteral obstruction.
REFERENCES 1. Bloom, H.J-G., Wallace, D.M.: Tumors of the bladder. In Handbuch der Med. Radiologie, ed. by Zuppinger, A. Berlin, Springer-Verlag, 1971, Vol. 19, Part 3, pp. 430494. 2. Bowles, W.T., Silber, J.: Carcinoma of the bladder. A
?Patients with ureteral obstruction are often patients with contraindications for more radical
high risk operative
computer analysis of 516 patients. J. Ural. 107: 245-247, 1972. 3. Fish, J.C., Fayos, J.V.: Carcinoma of the urinary bladder. Radiology 118: 179-182, 1976. 4. Goffinet, D.R., Schneider, M.J., Glatstein, E.J., Ludwig,
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H., Ray, G.R., Dunnick, N.R., Bagshaw, M.A.: Bladder cancer: results of radiation therapy in 384 patients. Radiology 117: 149-153, 1975. Ilija, F.A., O’Leary, J.A., Frick, H.C.: Prognostic significance of ureteral obstruction in carcinoma of the cervix. Cancer 19: 689-690, 1%6. Kottmeier, H.L.: Presentation of therapeutic results in carcinoma of the female pelvis: experience of the annual report on the results of treatment in carcinoma of the uterus, vagina and ovary. Gynecol. Oncol. 4: 13-19, 1976. Mahoney, E.M., Weber, E.T., Harrison, J.H.: Postdiversion pre-cystectomy irradiation for carcinoma of the bladder. J. Ural. 114: 46-49, 1975. Mallo, N., Vecente, J.: Diagnostic and therapeutic patterns of bladder tumors. Europ. Ural. 1: 96-98, 1975. Morrison, R.: The results of treatment of cancer of the bladder. A clinical contribution to radiobiology. C/in. Radiol. 26: 67-75, 1975. Moss, W.T., Brand, W.N., Battifora, H.: The urinary bladder. In Radiation Oncology. Rationale, Technique, Results. Saint Louis. Mosby, 1973, 4th Edn, pp. 362377. Prout, G.R., Slack, N.H., Bross, J.D.D.: Preoperative
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irradiation as an adjuvant in the surgical management of inversive bladder carcinoma. J. Ural. 105: 223-231, 1971. Slater, J.M., Fletcher, G.H.: Ureteral strictures after radiation therapy for carcinoma of the uterine cervix. Am. J. Roentgenol. 111: 269-272, 1971. UICC-International Union Against Cancer. TNMClassification of Malignant Tumor. Geneva, de Buren, 1974, 2nd Edn. Vogler, H., Rothkopf, M., Mebel, M.: Experiences based on the classification of bladder tumors according to the TNM-System. Europ. Ural. 1:93-95, 1975. Van der Werf-Messing, B.H.P.: Treatment of carcinoma of the bladder with radium. Clin. Radiol. 16:
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B.H.P.: Carcinoma of the by pre-operative irradiation Third report of B.R.T.J. Can-
followed by cystectomy. cer 36: 718-722, 1975. 17. Whitmore, W.F., Grabstald, H., Mackency, R.A., Iswariah, J., Phillips, R.: Preoperative irradiation with cystectomy in the management of bladder cancer. Am. J. Roentgenol. 102: 570-576, 1%8.