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Improved Clinical Definition of Bladder Carcinoma by Preoperative External Radiotherapy
Vol. 109, March Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1973 by The Williams & Wilkins Co.
IMPROVED CLINICAL DEFINITION OF BLADDER CARCINOMA BY PREOPERATIVE EXTERNAL RADIOTHERAPY RALPH J. VEENEMA, RUTH GUTTMANN, AURELIO C. USON, JOHN SENYSZYN NICHOLAS A. ROMAS
AND
From the Departments of Urology and Radiotherapy, Columbia University, College of Physicians and Surgeons, New York, New York
Since 1960 a basic part of our program of combined radiotherapy and operation includes interval cystoscopy, biopsy and re-evaluation of the bladder neoplasm 2 weeks after 3,000 to 4,000 rads supervoltage radiotherapy. Our experience with 109 patients from 1960 through 1965 was evaluated and reported previously. 1 This 5-year experience led to a modification of the program in 1966. COMBINED THERAPY PROGRAM, 1960 TO 1965 There were 109 patients seen between 1960 and 1965. Preoperative supervoltage radiotherapy of 3,000 to 4,000 rads within 3 to 4 weeks in 15 to 20 fractions was well tolerated. The endoscopic examination 2 to 4 weeks after completion of the preoperative radiotherapy could be done with clarity and an open operation encountered minimal edema or adverse radiotherapy tissue reaction. Combined preoperative radiotherapy (3,000 to 4,000 rads) and cystectomy did not improve the poor outlook for 36 patients with stages C and D tumor and did not make operable any patients previously considered inoperable. All 25 patients with stage D disease died of carcinoma in 6 to 18 months and 10 of 11 patients with stage C tumors died of carcinoma; the remaining patient was lost to followup at 3 ½ years. A conservative operation, that is partial cystectomy or endoscopic excision, following preoperative radiotherapy for 10 patients with stage B bladder tumors was inadequate treatment. Recurrence in the bladder was common and 7 of these patients died of carcinoma; 1 died of other causes at 2 years and 2 are living at 8 years. Of 21 total cystectomies after external radiotherapy in patients with stage B tumor only 6 patients are living 6 to 9 years. Three of the 21 patients died postoperatively, 10 died of carcinoma in 1 to 4 years and 2 died of other causes at 6 months and 2 years (survival 28.5 per cent, 6 to 9 years). After preoperative radiotherapy, a false sense of security was obtained in 10 patients who had negative biopsies and in 5 with biopsies indicating only a focus of intra-epithelial carcinoma. Eleven of the 15 patients died (8 of carcinoma, 2 postoperatively and 1 of carcinoma of the cecum). Accepted for publication June 6, 1972. 1 Veenema, R. J., Guttmann, R., Uson, A. C., Sagerman, R. H., Dean, A. L., Jr. and Ciardullo, L.: Combined radiotherapy, surgery and chemotherapy in carcinoma of the bladder. Cancer, 20: 1879, 1967.
Four patients are living 5 to 8 years postoperatively (3 had total cystectomies and 1 had partial cystectomy). In instances in which negative biopsies were obtained at interval cystoscopy it became obvious that, to achieve real benefit, treatment must be increased to a full dose of radiotherapy or a more definitive operation must be performed. Additional postoperative radiotherapy in 14 patients contributed to increased morbidity after an open operation in 6 of 8 patients and did not seem to improve results. Given early after an endoscopic operation on stages A and B tumors. the treatment was well tolerated and appeared to be beneficial in 4 of 6 patients. In 26 patients who had large, bulky stage A tumors, preoperative radiotherapy seemed to be distinctly valuable in reducing tumor size and clarifying the extent of the pathology. It thus appeared to aid in the selection of the surgical approach to the tumors and more definitive biopsies could be obtained. After preoperative radiotherapy reduced the size of the tumor, the bladders of 14 patients who had stage A tumors were preserved by doing partial cystectomy or endoscopic excision. In this group of 14 patients the 3-year .survival rate is 78.6 per cent and the 7-year survival is 43 per cent (6 patients are well 6 to 10 years, 2 are lost to followup but were living at 3 ½ years, 2 died of other causes 3 and 4 years later, 3 died of carcinoma in 3, 5 and 11 years and there was 1 postoperative death). Twelve patients had total cystectomy after the preoperative external radiotherapy for large stage A tumors. In this group there is a 67 per cent 6year plus survival rate (8 patients are well 6 to 10 years, 1 died without carcinoma. 1 died of carcinoma and there were 2 postoperative deaths). COMBINED THERAPY PROGRAM,
1966
TO
1970
Based on our 1960 to 1965 experience and still hoping to develop a program that would improve survival rates while preserving bladder function whenever possible, we emphasize various aspects in our combined therapy program from 1966 through 1970 in 57 patients. Progression to a total minimum tumor dose of 6,000 rads in 9 to 10 weeks in a split course was done in all patients with invasive stages B and C tumors and large stage A tumors in whom the interval evaluation showed a favorable response to radiotherapy. Thus, a full course of radiotherapy could be obtained and its effects evaluated before 397
398
VEENEMA AND ASSOCIATES
an open operation was done on tumors which appeared highly radiosensitive at the interval cystoscopy. The fractional course of radiotherapy was given promptly to avoid undue delay between courses and thus complicate the dose calculations. Postoperative radiotherapy was also given to reach a total minimum tumor dose of 6,000 rads in a similar split course after endoscopic excision of a tumor which proved on final pathology to be at least stage B, if cystectomy was refused or was medically contraindicated. When the bladder was preserved by doing partial cystectomy or endoscopic resection in stage A tumors, the preoperative radiotherapy was supplemented by postoperative thio-tepa instillations in an effort to reduce recurrences within the bladder. Total cystectomy was advised when the interval cystoscopy showed persistent invasive tumors. Partial cystectomy was used selectively only for dome lesions in which excellent resection margins were available. Stage O tumors continued to be managed endoscopically and with thio-tepa instillations for multiple small superficial tumors. 2 STAGING BLADDER TUMORS
We use the Jewett classification for staging bladder tumors, which can also be readily converted to the international (UICC) system (table 1). 3 In addition to the usual endoscopic biopsies, bimanual examinations and x-ray techniques for staging, special studies by triple contrast cystograms, 4 in vitro radioautograms for deoxyribonucleic and ribonucleic acid synthesis 5 • 6 and electron microscopy of tissue sections 7 were also done on many tissue sections. The relationship of these studies to staging has been previously reported; they were done mainly for research purposes in an effort to better define the tumor. These studies continue. In this paper the references to changes in the bladder tumors after preoperative radiotherapy indicate the gross changes noted at the 2 Veenema, R J., Dean, A. L., Jr., Uson, A. C., Roberts, M. and Longo, F.: Thiotepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. Urol., 101: 711, 1969. 'Jewett, H.J. and Strong, G. H.: Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J. Urol., 55: 366, 1946. 'Taylor, D. A., Macken, K. L., Veenema, R J. and Bachman, A. L.: A preliminary report of a new method for the staging of bladder carcinoma using a triple contrast technique. Brit. J. Radiol., 38: 667, 1965. 'Veenema, R. J., Fingerhut, B. and Lattimer, J. K: Experimental studies on the biological potential of bladder tumors. J. Urol., 93: 202, 1965. •Fingerhut, B., Veenema, R. J., Graff, S. and Butler, M. P.: Observations on RNA in prostate and bladder neoplasms. J. Urol., 101: 608, 1969. 7 Tannenbaum, M., Veenema, R. J. and Lattimer, J. K.: More accurate staging of bladder cancers through electron microscopy. J. Urol., 103: 432, 1970.
interval cystoscopy and on conventional light microscopy tissue sections. The number of patients who underwent combined therapy during this 5-year period is smaller than the 1960 to 1965 group since no known stage D 1 tumors were included and patients known to be poor surgical risks were given 6,000 rads external radiotherapy tumor dose in 6 weeks without undergoing interval re-evaluation. Also, no patient was started in the study who did not understand and agree to the need to progress to full treatment. This was considered essential since in the 1960 to 1965 series of 109 patients, 16 refused interval evaluation and further treatment. All 16 patients died of bladder carcinoma in 1 to 4 years. RESULTS
A total of 57 patients was treated in the combined program from 1966 through 1970. The evaluation of results was based on the tissue sections which showed the most advanced stage of the disease (tables 2 and 3). All 57 patients were considered candidates for total cystectomy at the initial evaluation. This choice was based on the findings of invasive neoplasm or a large bladder tumor which was difficult to stage and often presented as a chaotic bladder. After preoperative radiotherapy the tumors were changed sufficiently at the interval evaluation to permit an attempt to preserve the bladder in 19 patients. In 14 patients there was reduced histological staging of the tumors at the interval cystoscopy. The results in the 38 patients who underwent total cystectomy are noted in table 4. There was an 18 per cent mortality rate but it is too early for the statistic to be meaningful. After January 1965 total cystectomy did not include pelvic lymphadenectomy. There seemed to be increased adherence of tissue to the pelvic vessels and often thickening of the posterior peritoneum after the preoperative radiation. We discontinued pelvic lymphadenectomy since we anticipated that this combined with the external radiotherapy might increase morbidity and since we were not convinced that the procedure added appreciably to any reported survival statistics. Partial cystectomy was done in 6 cases when the preoperative radiotherapy clarified the pathology sufficiently to suggest that adequately clear margins were present for partial excision (table 5). Postoperative radiotherapy was not given to these 6 patients since in 5 the surgical margins were clear and a total cystectomy was done in 1 patient in whom the neoplasm was at the surgical margin. Endoscopic excision of residual tumor was done in 5 patients after preoperative radiotherapy reduced the size of the neoplasm sufficiently to permit transurethral excision (table 6). Two of these patients received postoperative radiotherapy (for stage B tumor in 1 patient and suspected stage B tumor in the other).
399
DEFINITION OF BLADDER CARCINOMA BY PREOPERATIVE EXTERNAL RADIOTHERAPY TABLE
Description
Living and Well
Carcinoma in situ Tumor with infiltration into subepithelial tissue Tumor with infiltration into superficial muscle Tumor with infiltration into deep muscle Tumor with infiltration into adjacent organs
Stage 0 Stage A
Tls Tl
Stage B,
T2
Stage B,, C
T3
Stage D
T4
Stage D 1
N + (regional)
Stage D,
M+ (distant)
TABLE
4. Preoperative radiotherapy and total cystectomy in 38 patients (1966-1970)
1
TABLE
International Union Against Cancer Classification
Jewett and Strong Classification
Tumor with lymph node invasion below bifurcation of iliac arteries Tumor with lymph node invasion in periaortic region
Living without Ca Living with Ca Dead of Ca Dead of other causes Postop. deaths Lost to followup
T, (A)
23 2 18
7
T, (Bl
8 0 3 0
0 1 3
4
T,(A) T,(BJ T,(BJ T,(C) T,(D)
7* 8 9
8 2
T, (D)
,........Ts-...... (C) (BJ 6 0
2 0
0
1
0 2 5 0
0
0
4
Dead Ca
3-5
1-3 Yrs.
Yrs.
Postop.
0 0 3 0 0
4 4
3
Bt 6
0
* 1 lost to followup.
t 1 died at 2 years of other causes. TABLE
5. Preoperative radiotherapy and partial cystectomy in 6 patients (1966-1970) No. Pts.
Results
T,(A)
1970) Total Pts.
Stage
Stage
2. Tumor classification in 57 patients (1966-
No. Pts.
Ca in margins; total cystectomy, living and well-2 yrs. 2 mos. Dead Ca-4 yrs. 3 mos. Living and well-2 yrs.
T,(B,)
Dead M. I. and Int. Obst.-!½ yrs. Dead Ca-8 mos.; 4 ½yrs,
T,(BJ T,(C)
TABLE
6. Preoperative radiotherapy and transurethral
resection (1966-1970)
2 0
Without postoperative external radiotherapy: TABLE
Stage T, (A), 3 pts.: 1 died, 4 yrs.-other causes 1 living and well, 3 yrs. 1 living and well, 9 mos. With postoperative external radiotherapy: Stage T, (A)-1 living and well, 1 yr. Stage T, (B)-1 living and well, 4 yrs.
3. Results of combined therapy in 57 patients
(1966-1970) Living Without Ca
UICC
Jewett
No. Pts.
1-3 Yrs.
T, T,
A
B,
T--B,
'-c
T,
D
13 13 13 10 8
5 3 2 None
3-5 Yrs. 2 3 0
* Three patients died of other causes (2, 4 and 5 years).
t One patient died of other
%
53.8' 61.5 46.1 20t 0
--·---
TABLE
7. Radiotherapy completed to 6,000 rads after
interval cystoscopy (1966-1970)* Living and Well
Stage
No. Pts.
Yrs.
causes (2 years).
In 10 patients radiotherapy was increased to 6,000 rads minimum total tumor dose in 9 to 10 weeks (split course) after the interval evaluation and following a preoperative dose of 3,000 to 4,000 rads (table 7). In 7 of these 10 patients radiosensitivity appeared to have been correctly predicted. Two of these 7 patients were poor surgical risks and, although there was no response to the 3 and 4-week course of 3,000 and 4,000 rads, the decision was made to proceed to a total of 6,000 rads. No further tumor response was obtained from the additional radiotherapy. In 3 of the 10 patients the decision to proceed to fulldose radiotherapy, based on a significant response to preliminary radiotherapy (3,000 to 3,500 rads), proved to be incorrect. In 2 of these 3 cases interval cystoscopy was negative and in 1 patient there was reduced size and staging of the tumor. All 3 had neoplasm present after 6,000 rads in 9 to 10 weeks (split course) and underwent subsequent total cystectomy. The elapsed time between completion of the
1-3
T,(A) T,(B,) T,(B,)
4
* Elapsed time:
1 0 0
Dead ~---
3-5 Yrs. 0
Ca 0 0
Other 1 (4 yrs.) 0 1 (6 mos.)
Failure and Total Cystectomy
2
success-33 days, failures-27 days.
preliminary radiotherapy and the start toward full-dose radiotherapy was always of concern and our efforts were directed toward minimal delay. It has been noteworthy that the elapsed interval was 33 days in the patients who thus far appear successfully treated and 27 days in those who were failures. Complications from radiotherapy and operations were noted (table 8). The experience in the 1966 to 1970 group of 57 patients is similar to that previously reported in the 1960 to 1965 senes. DISCUSSION
The aim of interval cystoscopy and re-evaluation of patients after 3,000 to 4,000 rads in 3 to 4 weeks of preoperative external radiotherapy was
VEENEMA AND ASSOCIATES
400 TABLE
8. Complications and postoperative deaths (1966-1970)
TABLE
9. Results of attempt to save the bladder in 29 patients (1960-1965)
Complications from surgery
Obstructed ureters at anastomosis
Stage
2
No. Pts.
Urinary infection Leakage at ureteral anastomosis
A B C
Pulmonary embolus Transient intestinal obstruction Suprapubic sinus drainage
Complications from radiotherapy TABLE
Leukopenia
Rectal hleeding Dermatitis Proctitis Cystitis
1
(2,800R, 3,600R) (1,200R) (2,000R)
3
4
14 10 5
Hepatitis Wound dehis. and anast. leakage Respiratory acidosis
an attempt to assess radiosensitivity and to preserve the bladder whenever possible. Since a retained bladder carries with it the known risk of recurrent tumors, the most definitive solution to the problem of bladder neoplasms is total cystectomy. However, this procedure is not the easiest solution for patients to accept; it carries with it significant morbidity and mortality and may be over-treatment for some patients. We believe preoperative radiotherapy of 3,000 to 4,000 rads has given improved clinical definition of bladder tumors and has helped us to make decisions when to attempt to preserve a bladder. During the 10-year period 166 patients who were candidates for total cystectomy received preoperative external radiotherapy. Since 16 patients refused further evaluation after radiotherapy, documented changes can only be reported in 150 cases. Of the 150 patients re-evaluated at interval examination, 65 had distinct improvement in the neoplasm after the preoperative radiotherapy. In 43 of these 65 patients an attempt was made to preserve the bladder (24 patients 1960 to 1965; 19 patients 1966 to 1970). As previously noted, we were in error by not proceeding promptly to definitive (partial cystectomy or transurethral resection) surgical excision or to full-dose radiotherapy when a good response to preliminary radiotherapy was observed in the 29 patients in the 1960 to 1965 series. Nevertheless, 12 patients (41.4 per cent) can be considered successful and their followup time significant (table 9). In the 1966 to 1970 group of 57 patients, an attempt to preserve the bladder was made in 19 cases. Eight of these patients (42 per cent) are considered successful and are able to be followed (table 10). Only 3 of the 19 patients have died of bladder carcinoma and 4 have died of other causes at 6 months to 4 years after treatment. Total cystectomy was done in 5 cases after failure
Lost to Followup
6 2 0
2 (3'!, yrs.) 0 1 (3 yrs.)
Living and
Stage
Ca 3 7
3
Other Causes
2 1 1
Postop.
1 0 0
10. Results of attempt to save bladder in 19 patients (1966-1970) No. Pts.
Postoperative deaths Pulmonary embolus Congestive heart failure Cardiac arrest
Dead
Living and Well 6+ Yrs.
A
8
B C
9
2
Dead
Well 1-3 Yrs.
3-5 Yrs.
Ca
2 3
Other Causes
Failure and Total Cystectomy
2 2
of the attempt to save the bladder by partial cystectomy in 1 patient and full-dose external radiotherapy (6,000 rads split course) in 4 patients. It is noteworthy that there are 4 patients with stage B bladder neoplasms in this group of 19 patients who are now well (1 at 3 years and 3 at 5 years) without recurrence. The 1 patient at 3 years had preoperative external radiotherapy and partial cystectomy and the 3 at 5 years had preoperative external radiotherapy and transurethral excision followed by postoperative external radiotherapy. The improvement in the stage B group is encouraging and suggests a benefit from the completion to full-dose external radiotherapy or to a definitive -operation after the preoperative external radiotherapy. There appears to be merit in an interval cystoscopy and re-evaluation of a patient with bladder neoplasm after preoperative radiotherapy. In selected patients it may be possible to save the bladder. Further refined tools are needed to determine the response of a bladder neoplasm to preoperative radiotherapy. Also, improved methods are needed to monitor or assess progress of patients during followup after complete therapy, to minimize the chance of missing the optimum time to proceed with total cystectomy if recurrence develops. The hazard of retaining such bladders with their potential for recurrent tumors may be reduced in the future as we learn more about the urinary carcinogens, enzymes involved and agents which can render these substances inactive. Perhaps additional bladders could have been saved if we routinely added postoperative radiotherapy whenever endoscopic excision of a stage A tumor was done. With the added information obtained from electron microscopy we now know that about half of the tumors that are diagnosed as stage A by light microscopy are by electron microscopy more deeply infiltrating. 7 In documented stage C tumors, an interval reevaluation after preoperative external radio-
DEFINITION OF BLADDER CARCINOMA BY PREOPERATIVE EXTERNAL RADIOTHERAPY
therapy may give some indication of radiosensitivity and, thus, have some value in deciding whether to proceed to full-dose external radiotherapy in a patient whose surgical risk is marginal or to proceed to total cystectomy. SUMMARY
The results of treatment for bladder carcinoma were reviewed in 2 groups of patients treated between 1960 and 1965, and 1966 and 1970. Therapy consisted of preoperative supervoltage radiotherapy (3,000 to 4,000 rads minimum tumor dose within a 3 to 4-week period) and then re-evaluation before proceeding to additional treatment. We attempted to assess radiosensitivity and to preserve the bladder whenever it seemed to be possible. During the 10-year period 166 patients who were candidates for total cystectomy received preoperative external radiotherapy. Sixteen patients refused the interval examination and re-
401
fused additional treatment. All 16 patients died of bladder carcinoma in 1 to 4 years. Of the 150 patients re-evaluated 2 to 4 weeks after completing the preoperative external radiotherapy, 65 showed distinct gross or microscopic improvement in the neoplasm. In 48 of these 65 patients an attempt was made to preserve the bladder. This attempt has thus far been successful in 8 of 29 patients (27.5 per cent) who are well and have been followed for more than 6 years, plus 4 patients who died of other causes (total 12 of 29 or 41.4 per cent). Nineteen patients have had followup for only 1 to 5 years and in 8 of 19 patients (42 per cent) plus 4 patients who have died of other causes (12 of 19, or 63 per cent) the attempt to preserve the bladder has been successful. Although preoperative external radiotherapy can improve the gross and microscopic appearance of bladder tumors at the interval examination, the need to proceed to either full-dose radiotherapy or to a definitive operation is emphasized.
THE JOURNAL OF UROLOGY
Copyright © 1973 by The Williams & Wilkins Co.
IMPROVED CLINICAL DEFINITION OF BLADDER CARCINOMA BY PREOPERATIVE EXTERNAL RADIOTHERAPY RALPH J. VEENEMA, RUTH GUTTMANN, AURELIO C. USON, JOHN SENYSZYN NICHOLAS A. ROMAS
AND
From the Departments of Urology and Radiotherapy, Columbia University, College of Physicians and Surgeons, New York, New York
Since 1960 a basic part of our program of combined radiotherapy and operation includes interval cystoscopy, biopsy and re-evaluation of the bladder neoplasm 2 weeks after 3,000 to 4,000 rads supervoltage radiotherapy. Our experience with 109 patients from 1960 through 1965 was evaluated and reported previously. 1 This 5-year experience led to a modification of the program in 1966. COMBINED THERAPY PROGRAM, 1960 TO 1965 There were 109 patients seen between 1960 and 1965. Preoperative supervoltage radiotherapy of 3,000 to 4,000 rads within 3 to 4 weeks in 15 to 20 fractions was well tolerated. The endoscopic examination 2 to 4 weeks after completion of the preoperative radiotherapy could be done with clarity and an open operation encountered minimal edema or adverse radiotherapy tissue reaction. Combined preoperative radiotherapy (3,000 to 4,000 rads) and cystectomy did not improve the poor outlook for 36 patients with stages C and D tumor and did not make operable any patients previously considered inoperable. All 25 patients with stage D disease died of carcinoma in 6 to 18 months and 10 of 11 patients with stage C tumors died of carcinoma; the remaining patient was lost to followup at 3 ½ years. A conservative operation, that is partial cystectomy or endoscopic excision, following preoperative radiotherapy for 10 patients with stage B bladder tumors was inadequate treatment. Recurrence in the bladder was common and 7 of these patients died of carcinoma; 1 died of other causes at 2 years and 2 are living at 8 years. Of 21 total cystectomies after external radiotherapy in patients with stage B tumor only 6 patients are living 6 to 9 years. Three of the 21 patients died postoperatively, 10 died of carcinoma in 1 to 4 years and 2 died of other causes at 6 months and 2 years (survival 28.5 per cent, 6 to 9 years). After preoperative radiotherapy, a false sense of security was obtained in 10 patients who had negative biopsies and in 5 with biopsies indicating only a focus of intra-epithelial carcinoma. Eleven of the 15 patients died (8 of carcinoma, 2 postoperatively and 1 of carcinoma of the cecum). Accepted for publication June 6, 1972. 1 Veenema, R. J., Guttmann, R., Uson, A. C., Sagerman, R. H., Dean, A. L., Jr. and Ciardullo, L.: Combined radiotherapy, surgery and chemotherapy in carcinoma of the bladder. Cancer, 20: 1879, 1967.
Four patients are living 5 to 8 years postoperatively (3 had total cystectomies and 1 had partial cystectomy). In instances in which negative biopsies were obtained at interval cystoscopy it became obvious that, to achieve real benefit, treatment must be increased to a full dose of radiotherapy or a more definitive operation must be performed. Additional postoperative radiotherapy in 14 patients contributed to increased morbidity after an open operation in 6 of 8 patients and did not seem to improve results. Given early after an endoscopic operation on stages A and B tumors. the treatment was well tolerated and appeared to be beneficial in 4 of 6 patients. In 26 patients who had large, bulky stage A tumors, preoperative radiotherapy seemed to be distinctly valuable in reducing tumor size and clarifying the extent of the pathology. It thus appeared to aid in the selection of the surgical approach to the tumors and more definitive biopsies could be obtained. After preoperative radiotherapy reduced the size of the tumor, the bladders of 14 patients who had stage A tumors were preserved by doing partial cystectomy or endoscopic excision. In this group of 14 patients the 3-year .survival rate is 78.6 per cent and the 7-year survival is 43 per cent (6 patients are well 6 to 10 years, 2 are lost to followup but were living at 3 ½ years, 2 died of other causes 3 and 4 years later, 3 died of carcinoma in 3, 5 and 11 years and there was 1 postoperative death). Twelve patients had total cystectomy after the preoperative external radiotherapy for large stage A tumors. In this group there is a 67 per cent 6year plus survival rate (8 patients are well 6 to 10 years, 1 died without carcinoma. 1 died of carcinoma and there were 2 postoperative deaths). COMBINED THERAPY PROGRAM,
1966
TO
1970
Based on our 1960 to 1965 experience and still hoping to develop a program that would improve survival rates while preserving bladder function whenever possible, we emphasize various aspects in our combined therapy program from 1966 through 1970 in 57 patients. Progression to a total minimum tumor dose of 6,000 rads in 9 to 10 weeks in a split course was done in all patients with invasive stages B and C tumors and large stage A tumors in whom the interval evaluation showed a favorable response to radiotherapy. Thus, a full course of radiotherapy could be obtained and its effects evaluated before 397
398
VEENEMA AND ASSOCIATES
an open operation was done on tumors which appeared highly radiosensitive at the interval cystoscopy. The fractional course of radiotherapy was given promptly to avoid undue delay between courses and thus complicate the dose calculations. Postoperative radiotherapy was also given to reach a total minimum tumor dose of 6,000 rads in a similar split course after endoscopic excision of a tumor which proved on final pathology to be at least stage B, if cystectomy was refused or was medically contraindicated. When the bladder was preserved by doing partial cystectomy or endoscopic resection in stage A tumors, the preoperative radiotherapy was supplemented by postoperative thio-tepa instillations in an effort to reduce recurrences within the bladder. Total cystectomy was advised when the interval cystoscopy showed persistent invasive tumors. Partial cystectomy was used selectively only for dome lesions in which excellent resection margins were available. Stage O tumors continued to be managed endoscopically and with thio-tepa instillations for multiple small superficial tumors. 2 STAGING BLADDER TUMORS
We use the Jewett classification for staging bladder tumors, which can also be readily converted to the international (UICC) system (table 1). 3 In addition to the usual endoscopic biopsies, bimanual examinations and x-ray techniques for staging, special studies by triple contrast cystograms, 4 in vitro radioautograms for deoxyribonucleic and ribonucleic acid synthesis 5 • 6 and electron microscopy of tissue sections 7 were also done on many tissue sections. The relationship of these studies to staging has been previously reported; they were done mainly for research purposes in an effort to better define the tumor. These studies continue. In this paper the references to changes in the bladder tumors after preoperative radiotherapy indicate the gross changes noted at the 2 Veenema, R J., Dean, A. L., Jr., Uson, A. C., Roberts, M. and Longo, F.: Thiotepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. Urol., 101: 711, 1969. 'Jewett, H.J. and Strong, G. H.: Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J. Urol., 55: 366, 1946. 'Taylor, D. A., Macken, K. L., Veenema, R J. and Bachman, A. L.: A preliminary report of a new method for the staging of bladder carcinoma using a triple contrast technique. Brit. J. Radiol., 38: 667, 1965. 'Veenema, R. J., Fingerhut, B. and Lattimer, J. K: Experimental studies on the biological potential of bladder tumors. J. Urol., 93: 202, 1965. •Fingerhut, B., Veenema, R. J., Graff, S. and Butler, M. P.: Observations on RNA in prostate and bladder neoplasms. J. Urol., 101: 608, 1969. 7 Tannenbaum, M., Veenema, R. J. and Lattimer, J. K.: More accurate staging of bladder cancers through electron microscopy. J. Urol., 103: 432, 1970.
interval cystoscopy and on conventional light microscopy tissue sections. The number of patients who underwent combined therapy during this 5-year period is smaller than the 1960 to 1965 group since no known stage D 1 tumors were included and patients known to be poor surgical risks were given 6,000 rads external radiotherapy tumor dose in 6 weeks without undergoing interval re-evaluation. Also, no patient was started in the study who did not understand and agree to the need to progress to full treatment. This was considered essential since in the 1960 to 1965 series of 109 patients, 16 refused interval evaluation and further treatment. All 16 patients died of bladder carcinoma in 1 to 4 years. RESULTS
A total of 57 patients was treated in the combined program from 1966 through 1970. The evaluation of results was based on the tissue sections which showed the most advanced stage of the disease (tables 2 and 3). All 57 patients were considered candidates for total cystectomy at the initial evaluation. This choice was based on the findings of invasive neoplasm or a large bladder tumor which was difficult to stage and often presented as a chaotic bladder. After preoperative radiotherapy the tumors were changed sufficiently at the interval evaluation to permit an attempt to preserve the bladder in 19 patients. In 14 patients there was reduced histological staging of the tumors at the interval cystoscopy. The results in the 38 patients who underwent total cystectomy are noted in table 4. There was an 18 per cent mortality rate but it is too early for the statistic to be meaningful. After January 1965 total cystectomy did not include pelvic lymphadenectomy. There seemed to be increased adherence of tissue to the pelvic vessels and often thickening of the posterior peritoneum after the preoperative radiation. We discontinued pelvic lymphadenectomy since we anticipated that this combined with the external radiotherapy might increase morbidity and since we were not convinced that the procedure added appreciably to any reported survival statistics. Partial cystectomy was done in 6 cases when the preoperative radiotherapy clarified the pathology sufficiently to suggest that adequately clear margins were present for partial excision (table 5). Postoperative radiotherapy was not given to these 6 patients since in 5 the surgical margins were clear and a total cystectomy was done in 1 patient in whom the neoplasm was at the surgical margin. Endoscopic excision of residual tumor was done in 5 patients after preoperative radiotherapy reduced the size of the neoplasm sufficiently to permit transurethral excision (table 6). Two of these patients received postoperative radiotherapy (for stage B tumor in 1 patient and suspected stage B tumor in the other).
399
DEFINITION OF BLADDER CARCINOMA BY PREOPERATIVE EXTERNAL RADIOTHERAPY TABLE
Description
Living and Well
Carcinoma in situ Tumor with infiltration into subepithelial tissue Tumor with infiltration into superficial muscle Tumor with infiltration into deep muscle Tumor with infiltration into adjacent organs
Stage 0 Stage A
Tls Tl
Stage B,
T2
Stage B,, C
T3
Stage D
T4
Stage D 1
N + (regional)
Stage D,
M+ (distant)
TABLE
4. Preoperative radiotherapy and total cystectomy in 38 patients (1966-1970)
1
TABLE
International Union Against Cancer Classification
Jewett and Strong Classification
Tumor with lymph node invasion below bifurcation of iliac arteries Tumor with lymph node invasion in periaortic region
Living without Ca Living with Ca Dead of Ca Dead of other causes Postop. deaths Lost to followup
T, (A)
23 2 18
7
T, (Bl
8 0 3 0
0 1 3
4
T,(A) T,(BJ T,(BJ T,(C) T,(D)
7* 8 9
8 2
T, (D)
,........Ts-...... (C) (BJ 6 0
2 0
0
1
0 2 5 0
0
0
4
Dead Ca
3-5
1-3 Yrs.
Yrs.
Postop.
0 0 3 0 0
4 4
3
Bt 6
0
* 1 lost to followup.
t 1 died at 2 years of other causes. TABLE
5. Preoperative radiotherapy and partial cystectomy in 6 patients (1966-1970) No. Pts.
Results
T,(A)
1970) Total Pts.
Stage
Stage
2. Tumor classification in 57 patients (1966-
No. Pts.
Ca in margins; total cystectomy, living and well-2 yrs. 2 mos. Dead Ca-4 yrs. 3 mos. Living and well-2 yrs.
T,(B,)
Dead M. I. and Int. Obst.-!½ yrs. Dead Ca-8 mos.; 4 ½yrs,
T,(BJ T,(C)
TABLE
6. Preoperative radiotherapy and transurethral
resection (1966-1970)
2 0
Without postoperative external radiotherapy: TABLE
Stage T, (A), 3 pts.: 1 died, 4 yrs.-other causes 1 living and well, 3 yrs. 1 living and well, 9 mos. With postoperative external radiotherapy: Stage T, (A)-1 living and well, 1 yr. Stage T, (B)-1 living and well, 4 yrs.
3. Results of combined therapy in 57 patients
(1966-1970) Living Without Ca
UICC
Jewett
No. Pts.
1-3 Yrs.
T, T,
A
B,
T--B,
'-c
T,
D
13 13 13 10 8
5 3 2 None
3-5 Yrs. 2 3 0
* Three patients died of other causes (2, 4 and 5 years).
t One patient died of other
%
53.8' 61.5 46.1 20t 0
--·---
TABLE
7. Radiotherapy completed to 6,000 rads after
interval cystoscopy (1966-1970)* Living and Well
Stage
No. Pts.
Yrs.
causes (2 years).
In 10 patients radiotherapy was increased to 6,000 rads minimum total tumor dose in 9 to 10 weeks (split course) after the interval evaluation and following a preoperative dose of 3,000 to 4,000 rads (table 7). In 7 of these 10 patients radiosensitivity appeared to have been correctly predicted. Two of these 7 patients were poor surgical risks and, although there was no response to the 3 and 4-week course of 3,000 and 4,000 rads, the decision was made to proceed to a total of 6,000 rads. No further tumor response was obtained from the additional radiotherapy. In 3 of the 10 patients the decision to proceed to fulldose radiotherapy, based on a significant response to preliminary radiotherapy (3,000 to 3,500 rads), proved to be incorrect. In 2 of these 3 cases interval cystoscopy was negative and in 1 patient there was reduced size and staging of the tumor. All 3 had neoplasm present after 6,000 rads in 9 to 10 weeks (split course) and underwent subsequent total cystectomy. The elapsed time between completion of the
1-3
T,(A) T,(B,) T,(B,)
4
* Elapsed time:
1 0 0
Dead ~---
3-5 Yrs. 0
Ca 0 0
Other 1 (4 yrs.) 0 1 (6 mos.)
Failure and Total Cystectomy
2
success-33 days, failures-27 days.
preliminary radiotherapy and the start toward full-dose radiotherapy was always of concern and our efforts were directed toward minimal delay. It has been noteworthy that the elapsed interval was 33 days in the patients who thus far appear successfully treated and 27 days in those who were failures. Complications from radiotherapy and operations were noted (table 8). The experience in the 1966 to 1970 group of 57 patients is similar to that previously reported in the 1960 to 1965 senes. DISCUSSION
The aim of interval cystoscopy and re-evaluation of patients after 3,000 to 4,000 rads in 3 to 4 weeks of preoperative external radiotherapy was
VEENEMA AND ASSOCIATES
400 TABLE
8. Complications and postoperative deaths (1966-1970)
TABLE
9. Results of attempt to save the bladder in 29 patients (1960-1965)
Complications from surgery
Obstructed ureters at anastomosis
Stage
2
No. Pts.
Urinary infection Leakage at ureteral anastomosis
A B C
Pulmonary embolus Transient intestinal obstruction Suprapubic sinus drainage
Complications from radiotherapy TABLE
Leukopenia
Rectal hleeding Dermatitis Proctitis Cystitis
1
(2,800R, 3,600R) (1,200R) (2,000R)
3
4
14 10 5
Hepatitis Wound dehis. and anast. leakage Respiratory acidosis
an attempt to assess radiosensitivity and to preserve the bladder whenever possible. Since a retained bladder carries with it the known risk of recurrent tumors, the most definitive solution to the problem of bladder neoplasms is total cystectomy. However, this procedure is not the easiest solution for patients to accept; it carries with it significant morbidity and mortality and may be over-treatment for some patients. We believe preoperative radiotherapy of 3,000 to 4,000 rads has given improved clinical definition of bladder tumors and has helped us to make decisions when to attempt to preserve a bladder. During the 10-year period 166 patients who were candidates for total cystectomy received preoperative external radiotherapy. Since 16 patients refused further evaluation after radiotherapy, documented changes can only be reported in 150 cases. Of the 150 patients re-evaluated at interval examination, 65 had distinct improvement in the neoplasm after the preoperative radiotherapy. In 43 of these 65 patients an attempt was made to preserve the bladder (24 patients 1960 to 1965; 19 patients 1966 to 1970). As previously noted, we were in error by not proceeding promptly to definitive (partial cystectomy or transurethral resection) surgical excision or to full-dose radiotherapy when a good response to preliminary radiotherapy was observed in the 29 patients in the 1960 to 1965 series. Nevertheless, 12 patients (41.4 per cent) can be considered successful and their followup time significant (table 9). In the 1966 to 1970 group of 57 patients, an attempt to preserve the bladder was made in 19 cases. Eight of these patients (42 per cent) are considered successful and are able to be followed (table 10). Only 3 of the 19 patients have died of bladder carcinoma and 4 have died of other causes at 6 months to 4 years after treatment. Total cystectomy was done in 5 cases after failure
Lost to Followup
6 2 0
2 (3'!, yrs.) 0 1 (3 yrs.)
Living and
Stage
Ca 3 7
3
Other Causes
2 1 1
Postop.
1 0 0
10. Results of attempt to save bladder in 19 patients (1966-1970) No. Pts.
Postoperative deaths Pulmonary embolus Congestive heart failure Cardiac arrest
Dead
Living and Well 6+ Yrs.
A
8
B C
9
2
Dead
Well 1-3 Yrs.
3-5 Yrs.
Ca
2 3
Other Causes
Failure and Total Cystectomy
2 2
of the attempt to save the bladder by partial cystectomy in 1 patient and full-dose external radiotherapy (6,000 rads split course) in 4 patients. It is noteworthy that there are 4 patients with stage B bladder neoplasms in this group of 19 patients who are now well (1 at 3 years and 3 at 5 years) without recurrence. The 1 patient at 3 years had preoperative external radiotherapy and partial cystectomy and the 3 at 5 years had preoperative external radiotherapy and transurethral excision followed by postoperative external radiotherapy. The improvement in the stage B group is encouraging and suggests a benefit from the completion to full-dose external radiotherapy or to a definitive -operation after the preoperative external radiotherapy. There appears to be merit in an interval cystoscopy and re-evaluation of a patient with bladder neoplasm after preoperative radiotherapy. In selected patients it may be possible to save the bladder. Further refined tools are needed to determine the response of a bladder neoplasm to preoperative radiotherapy. Also, improved methods are needed to monitor or assess progress of patients during followup after complete therapy, to minimize the chance of missing the optimum time to proceed with total cystectomy if recurrence develops. The hazard of retaining such bladders with their potential for recurrent tumors may be reduced in the future as we learn more about the urinary carcinogens, enzymes involved and agents which can render these substances inactive. Perhaps additional bladders could have been saved if we routinely added postoperative radiotherapy whenever endoscopic excision of a stage A tumor was done. With the added information obtained from electron microscopy we now know that about half of the tumors that are diagnosed as stage A by light microscopy are by electron microscopy more deeply infiltrating. 7 In documented stage C tumors, an interval reevaluation after preoperative external radio-
DEFINITION OF BLADDER CARCINOMA BY PREOPERATIVE EXTERNAL RADIOTHERAPY
therapy may give some indication of radiosensitivity and, thus, have some value in deciding whether to proceed to full-dose external radiotherapy in a patient whose surgical risk is marginal or to proceed to total cystectomy. SUMMARY
The results of treatment for bladder carcinoma were reviewed in 2 groups of patients treated between 1960 and 1965, and 1966 and 1970. Therapy consisted of preoperative supervoltage radiotherapy (3,000 to 4,000 rads minimum tumor dose within a 3 to 4-week period) and then re-evaluation before proceeding to additional treatment. We attempted to assess radiosensitivity and to preserve the bladder whenever it seemed to be possible. During the 10-year period 166 patients who were candidates for total cystectomy received preoperative external radiotherapy. Sixteen patients refused the interval examination and re-
401
fused additional treatment. All 16 patients died of bladder carcinoma in 1 to 4 years. Of the 150 patients re-evaluated 2 to 4 weeks after completing the preoperative external radiotherapy, 65 showed distinct gross or microscopic improvement in the neoplasm. In 48 of these 65 patients an attempt was made to preserve the bladder. This attempt has thus far been successful in 8 of 29 patients (27.5 per cent) who are well and have been followed for more than 6 years, plus 4 patients who died of other causes (total 12 of 29 or 41.4 per cent). Nineteen patients have had followup for only 1 to 5 years and in 8 of 19 patients (42 per cent) plus 4 patients who have died of other causes (12 of 19, or 63 per cent) the attempt to preserve the bladder has been successful. Although preoperative external radiotherapy can improve the gross and microscopic appearance of bladder tumors at the interval examination, the need to proceed to either full-dose radiotherapy or to a definitive operation is emphasized.