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Post-Diversion Pre-Cystectomy Irradiation for Carcinoma of the Bladder
Vol. 114, July
THE JOURNAL OF UROLOGY
Copyri~ht © 1975 by The Williams & Wilkins Co.
Printed in U.S.A.
POST-DIVERSION PRE-CYSTECTOMY IRRADIATION FOR CARCINOMA OF THE BLADDER E. M . MAHONEY, E. T. WEBER
AND
J. H. HARRISON
From the Department of Surgery, Division of Urologic Surgery and the Department of Radiation Therapy, Harvard Medical School, the Peter Bent Brigham Hospital and the Carney Hospital, Boston, Massachusetts
ABSTRACT
In 47 patients treated sequentially with urinary diversion and laparotomy staging, irradiation therapy and total cystectomy for invasive carcinoma of the bladder, the mortality rate was 2 per cent and the complication rate was 20 per cent. The survival rate was most favorable in patients in whom the pathologic specimen revealed no tumor after irradiation. The lower mortality and morbidity rates are attributed to staging of surgical procedures and the challenge remains to increase the number of patients in whom carcinoma of the bladder is converted by irradiation therapy to a lower stage or no tumor. The life-threatening course of invasive carcinoma of the bladder and our concern for the generally unsatisfactory results of surgical treatment alone stimulated adoption of a prospective protocol, combining irradiation therapy and operation. Despite variation in sequence and method previous reports have demonstrated that t he combination of these modalities enhan ces the effectiveness of treatment. 1·• The natural division of con structive and extirpative surgery by separate operations and advances in the technique of irradiation therapy have reduced mortality and morbidity. 5 · 7 Since 1964, 47 consecutive patients for whom cystectomy had been recommended were treated by post-diversion pre-cystectomy irradiation (table 1) . METHOD
This protocol provided for ilea! conduit urinary diversion with staging by laparotomy, a 4 or 5-week course of irradiation 2 weeks later and total cystectomy, some with pelvic lymph node dissections and all with total prostatoseminal vesiculectomy, 6 weeks after irradiation. Individual patient re sponse and hospital course necessitated variation in x -ray dosage, interval and specific operation. In general, patients with grades 1 to 4, recurrent, multiple or sessile, low stage tumors and those with deep neoplasms without metastases were accepted for this series. Five patients who had stage D 1 tumor, because of a single tumor bearing regional lymph node, demonstrated at initial staging and diverting operation, were accepted for sequential t herapy. The average age of t he 47 patients was 64 years, with a median of 64. In 36 patients treatment Accepted for publication October 11, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19- 23, 1974. 4fi
consisted of staging diversion, irradiation t herapy and total cystectomy. One patient was treated with laparotomy and transurethral resection of the tumor because the staging operation had revealed distant tumor containing lymph nodes . Urinary diversion and irradiation therapy only were done in 6 patients, and diversion and second-stage cystec tomy without irradiation were done in 4. Patients who did not undergo cystectomy did not do so either because of the findings established at t he staging operation or the patient's general condition or wishes, which contraindicated further surgery. This group received irradiation therapy. The 4 patients who underwent diversion and cystectomy but omitted irradiation did so on the advice of t he radiotherapist or for p ersonal reasons . Although all tumors were classified by grades, using Broder's index, our primary concern was in staging. The Marshall 8 modification of the system described by Jewett and Strong was used. 9 As advocated by Whitmore and associates in analyzing a small number of cases, the tumor stage was grouped into superficial (0 , A and B, tumors), deep (B2 and C tumors) and metastatic (D, and D 2 tumors) . 6 The primary diagnostic procedures to determine the stage of the neoplasm were excretory urography (IVP), metastatic x-ray series, pulmonary tomogram,.liver scan and cystoscopic examination with observation of the lesion for size, location in t he bladder and contour, whether pedunculated or sessile . Transurethral biopsy was performed with special care not to perforate the bladder wall, and thereby iatrogenically advance the stage of t he cancer. Fractionated cystography was used routinely. Contrast cystography, pelvic angiography and lymphangiography were performed rarely. Staging by exploration at the initial operation proved valuable. Lymph node bearing areas were
POST-DIVERSION PRE-CYSTECTOMY IRRADIATION FOR CARCINOMA OF BLADDER TABLE
1. Sequential mana{?ement: urinary diversion ,
x-ray therapy, cystectomy No. Pts. Staging exploration Diversion and x-ray therapy Diversion and cystectomy Diversion, x-ray therapy and cystectomy Total
1 6 4
36 47
examined and suspicious nodes were biopsied. Involvement and extent of the bladder tumor were noted and, when feasible, the margins were outlined by silver clips. Whenever possible the radiotherapist was in attendance at cystoscopic examination and laparotomy. In this series no unsuspected organ involvement was unveiled . Of the 47 staging laparotomies and/or simultaneous urinary diverting procedures, 4 patients were found to have otherwise unsuspected tumor-bearing lymp h , nodes. Urinary diversion was accomplished in 1 patient by ureterosigmoidostomy and in 45 patients by ureteroileal cutaneous anastomoses. The finding of pericaval lymph node involvement at the renal level precluded diversion in 1 patient. Pelvic radiation doses varied from 4,000 to 6,000 rads. By approximating the number of rads to the nearest 1,000, 21 patients received 4,000 rads, 10 received 5,000 rads and 11 received 6,000 rads. Since July 1968 all patients in this megavoltage series were treated on the 4 mv. or the 8 mv. linear accelerator with doses calculated at mid pelvic depth. Most of these patients received 4,000 to 5,000 rads in 20 to 25, 200-rad mid pelvic doses. Usually anterior and posterior opposing portals were used, although an occasional patient was treated by 360 degrees rotation. The treatment volume included bladder, prostate and seminal vesicles, together with the pelvic lymph nodes to the level of the aortic bifurcation. If the decision to treat with definitive radiation alone was made each patient was individually studied and planned for 3-field therapy or rotational treatment with a more confined treatment volume. This procedure ,f has allowed us to deliver 6,000-rad doses within 6 weeks with improved tumor effect and normal tissue sparing. During the last 2 years all such patients have been planned on a treatment simulator using contrast in the bladder and rectum to more accurately define the pelvic structures. After 6 to 8 weeks a radical cystectomy was . ·> performed with or without lymph node dissection pending clinical judgment at the time of operation. The procedure included en bloc removal of the bladder, prostate, seminal vesicles, enveloping fascia, fat and peritoneum. In the female patient the entire urethra and bladder were removed and in some patients the uterus, ovaries, fallopian tubes and anterior vaginal wall, depending on the extent and location of the tumor.
47
RES ULTS AND DISCUSSION
The mortality rate in this series was 2 per cent and involved 1 patient who died after urinary tract diversion of antecedent and persistent cicatricial tracheal stenosis and postoperative peritonitis . The low mortality rate has been attributed to the staging of the operative procedures. A single stage operation with or without irradiation carried a considerably higher mortality (table 2). 1 · 2 · 4 · 6 · 10 · 16 Similar observations have been made by Laskowski and associates.• Of the 87 operations in this series there were 18 postoperative complications. This complication rate of 20 per cent compared favorably to complication rates in the literature of 66 per cent following 1-stage radical cystectomy. 7 The postoperative complications were pelvic abscess in 2 patients, cardiorespiratory failure in 2, hematuria in 2, myocardial infarct in 1, atelectasis in 1, wound infection or dehiscence in 3 and unilateral hydronephrosis in 2. One death has been described. Stomal stenosis developed in 1 patient requiring reoperation. Complications requiring reoperation and which were attributed to irradiation included 1 dissolution of the ileo-ileal anastomosis, 1 perforation of the sigmoid colon and 1 cutaneous vaginal fistula. These appeared to be related to the interval between cystectomy and irradiation therapy, rather than the amount of rads delivered. The complications mentioned preceded the techniques which were adopted in July 1968. The patient in whom a sigmoid fistula developed had had a stage C lesion and died of local recurrence 2 years after initiation of sequential therapy. Another patient in whom a cutaneous vaginal fistula developed is still alive at 6 years, having had a stage B 2 lesion clinically and no tumor by pathological examination. She had received 6,000 rads and is free of disease at this time. Those patients in whom the interval between irradiation therapy and cystectomy was 6 to 8 weeks were noted to have a minimal number of complications which could be attributed to preoperative irradiation. However, mild side effects including proctitis, diarrhea, frequency, hematuria and skin reaction have occurred. Of importance is the fact that the urinary diversion is done prior to irradiation and, therefore, carries none of the possible complications that might be attributed to preoperative irradiation. Tertiary operation was performed for solitary metastases in 3 patients ( table 3) . One patient had cerebral symptoms 4 months after completion of treatment. A solitary metastatic lesion was demonTABLE
2. Relative mortality rates (%)
Reference 7 authors 4 authors 1. 2 • 4 • Current series 10- 16
6
1-stage cystectomy X-ray and 1-stage cystectomy Sequentia l management: diversion, x-ray, cystectomy
15 9
2
48
MAHONEY , WEBER AND HARRISON TABLE
3. Tertiary operation for solitary metastasis Operation
Cerebellum Urethra Urethra
Excision TUR of urethra X-ray and ure threctomy
Total Survival 1 yr. 8 mos. 4 yrs. 7 yrs.
After Third Operation 1 yr. 6mos. 4 yrs.
strated in the cerebellum, excised successfully, and the patient lived 1 year thereafter. Another patient had a tumor in the remaining urethra 3 years after treatment of the bladder neoplasm. The urethral lesion was irradiated and total urethrectomy was performed subsequently. He lived 4 years thereafter, totaling a survival of 7 years, and died of an unrelated cause. The IVP remains an important adjunct to the staging of tumors of the bladder. The pre -diversion IVPs are compared to the stage of the lesion in the cystectomy specimen following irradiation. Normal upper urinary tracts were demonstrated preoperatively by IVP in 2 of 8 patients with stage D disease and 5 of 13 patients with stages B 2 and C neoplasms. Abnormal upper urinary tracts by IVP were present conversely in 7 of 19 patients with stage 0, A or B 1 and 2 of 5 patients with no tumor in the operative specimen. The IVP would appear to have been misleading in downgrading and upgrading the stages of the tumor. Reliance on the findings of the upper tract is an adjunct to clinical staging but does not determine definitive therapy. The duration of survival of the 27 patients who have died during the 10-year period of observation in this study has been correlated with the stage of the tumor at the time of examination of the pathological specimen. Two patients with no tumor lived an average of 6 years, 4 patients with stage 0 , A or B 1 tumors lived 3 years, 13 patients with stage B 2 or C tumors lived 1 year and 8 patients with stage D tumors lived 2 years . The average duration of survival of these 27 deceased patients was 2.5 years. One might assume that irradiation therapy has reduced the stage of the tumor, obviously , in the no tumor group, but even in B 2 and C stages. This might indicate that some tumors in these 13 patients had even been in the D stage clinically . The pathologic stage appears to correlate well with the prognosis. Of the 27 deaths 15 patients died of recurrent disease. The pathological stage in these 15 patients was B 2 or C in 9 patients, D in 5 patients and no tumor in 1 patient. Four patients died of distant metastases and 11 of recurrent neoplasm in the pelvis . Fourteen of these 15 patients had been demonstrated by operation and pathologic speci men to have had stage B 2 , C or D neoplasm. The series of 20 patients surviving is too small to allow one to come to any conclusions. Three patients with no tumor are presently alive for an average of 5 years, 15 patients with stage 0, A or B 1 tumors are alive an average of 3 years and 2 pa-
tients with stage D tumors are alive an average of 1 year. All except 1 patient with stage D disease were clinically cured of cancer. The reduction in stage by irradiation therapy is impressive. Of the 18 patients with no tumor or stage 0 , A or B 1 tumor by pathologic examination, 10 had been by clinical evaluation stage 0 , A or B 1 and 8 stage B 2 or C tumors. Of the 8 clinical stage B 2 or C tumors 2 were converted to pathologically no tumor and 6 from clinical stage B 2 or C to pathologic stage 0 , A or B 1 • Accepting an error in clinical staging, 8 the reduction in stage for 8 of 20 living patien ts must be attributed to the effects of irradiation. The duration of survival of the entire series of 47 patients is difficult to interpret at this time because of small numbers in each category and because there are 20 patients alive with 19 free of clinically detectable disease (table 4) . The 14 patients who after irradiation still had deeply invasive tumors (B 2 or C) have all died, with an average and a mean survival of 1 year. However, 12 of these 14 patients had stage C disease and only 2 had stage B2 tumors . The over-all survival was an average of 2.5 years with a median of 2.5 years . Five patients with clinical and histologic carci noma of the bladder were demonstrated aft er irradiation therapy to have no tumor in the bladder specimen by gross and histologic examination (table 5) . Three of these patients had been judged to have superficial stage tumor and 2 deep stage neoplasm . One patient did have a small question aTABLE 4.
Survival rates for pathological stage No. P ts.
Survival
Total
Alive
Dead
Average Median (yrs.) (yrs.)
No tumor 0,A,B, B,,C D
5 18 14 10
3 14 1 2
2 4 13 8
5 3 1 1.5
6 2
Tota ls
47
20
27
2.5
2.5
3 patients lost to followup. TABLE
5. Survival in pathologic stage , no tumor remaining (sequential management)
Clinical Grade Stage
Pathology No tumor
X Radiation (rads)
Surviva! (yrs.)
5,900
6
Alive- free of disease
4,400
3
Alive-free of disease
Status
4
B,
3
B,
3
B,
Single focus micro
4,000
5
Alive- free of disease
2
B,
No tumor
5,095
6
Died of cancer
4
B,
No tumor
5,480
6
Died-no tumor at postmortem ex amination
POST-DIVERSION PRE-CYSTECTOMY IRRADIATION FOR CARCINOMA OF BLADDER
:j -
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·~
I
ble focus of carcinoma. Another patient lived 6 years and died of an unrelated illness. There was no tumor found at the postmortem examination. A third patient who lived 6 years died of locally recurrent disease. The remaining 3 patients are alive, well rehabilitated and free of disease at 3, 5 and 6 years following sequential treatment. The potential for irradiation to convert invasive carcinoma of the bladder to no tumor would appear to correlate well with an improved prognosis. The average patient in this small group received more than the average number of rads in the series . The data suggest that when irradiation succeeds in completely destroying the neoplasm in a larger number of patients sequential therapy may be expected to yield an improved survival rate. CONCLUSION
Post-diversion pre -cystectomy irradiation re duces mortality and morbidity by 1) eliminating any irradiation engendered damage to tissues prior to ilea! conduit construction, 2) sparing the occa sional patient a radical cystectomy by information obtained at surgical staging and 3) performing diversion and extirpative surgery at separate operations. The reduction in mortality and morbidity and the satisfactory rehabilitation allow and make advisable sequential therapy as treatment of choice at an earlier point in the growth and development of this cancer. Combination of 2 effective modalities in this manner, irradiation therapy and surgery, appears to be beneficial in the treatment of invasive carcinoma of the bladder. The operation for diversion is one dedicated to the preservation of renal function. The operation of cystectomy and lymphadenectomy is for removal of malignant disease. The diversion and extirpative procedures are biologically and philosophi cally different, and are best performed separately. It would seem that the innovation of irradiation therapy after diversion and before cystectomy is a valuable addition to the treatment of this cancer. REFERENCES
1. Prout, G. R., Jr., Slack, N. H. and Bross, I. D. J.:
Preoperative irradiation as an adjunct in the
49
surgical management of invasive bladder carcinoma. J. Urol., 105: 223, 1971. 2. DeWeerd, J. H. and Colby, M. Y., Jr.: Bladder carcinoma treated by irradiation and surgery : interval report. J. Urol., 109: 409, 1973. 3. Werf-Messing, B., van der: Carcinoma of the bladder treated by preoperative irradiation followed by cystectomy. Eur. J. Cancer, 7: 467, 1971. 4. Laskowski, T. Z., Scott, R., Jr. and Hudgins, P. T.: Combined therapy: radiation and surgery in the treatment of bladder cancer. J. Urol., 99: 733 , 1968. 5. Reid, E. C., Mount, B. M. and Sullivan, N.: Preoper-
ative irradiation and radical cystectomy for bladder cancer . Urology, 1: 42, 1973. 6. Whitmore, W. F., Jr. , Grabstald, H., MacKenzie, A. R., Iswariah, J. and Philips, R.: Preoperative irradiation with cystectomy in the management of bladder cancer. Amer. J. Roentgen., 102: 570, 1968.
7. Grimes, J. H., Hart, J . M., Glenn, J. F. and Anderson, E. E.: Staged approach to invasive vesical malignancy. J. Urol., 108: 872, 1972. 8. Marshall, V. F.: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J. Urol., 68: 714 , 1952. 9. Jewett, H. J. and Strong, G. H.: Infiltrating carcinoma of the bladder: relation to depth of penetration of the bladder wall to incidence of local extension and metastases. J. Urol., 55: 366, 1946. 10. Whitmore, W. F., Jr. and Marshall, V. F.: Radical total cystectomy for cancer of the bladder: 230 consecutive cases five years later. J. Urol., 87: 853, 1962. 11. Parkhurst, E. C. and Leadbetter, W. F.: A report on 93 ilea! loop urinary diversions. J. Urol., 83: 398, 1960. 12. Cordonnier, J . J.: Cystectomy for carcinoma of the bladder. J. Urol. , 99: 172, 1968. 13. Glantz, G. M.: Cystectomy and urinary diversion. J. Urol., 96 : 714, 1966. 14. Burnham, J. P. and Farrer, J.: A group experience
with uretero-ileal-cutaneous anastomosis for urinary divers ion: results and complications of the isolated ilea! conduit (Bricker procedure) in 96 patients. J. Urol., 83: 622, 1960. 15. Brown, H. M. and Elliot, J. S.: Bladder cancer: an evaluation of diagnosis and treatment of 93 patients. J. Urol., 102: 63, 1969. 16. Stone, J. H. and Hodges, C. V.: Radical cystectomy for invasive bladder cancer. J. Urol., 96: 207 , 1966.
, j
l J
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THE JOURNAL OF UROLOGY
Copyri~ht © 1975 by The Williams & Wilkins Co.
Printed in U.S.A.
POST-DIVERSION PRE-CYSTECTOMY IRRADIATION FOR CARCINOMA OF THE BLADDER E. M . MAHONEY, E. T. WEBER
AND
J. H. HARRISON
From the Department of Surgery, Division of Urologic Surgery and the Department of Radiation Therapy, Harvard Medical School, the Peter Bent Brigham Hospital and the Carney Hospital, Boston, Massachusetts
ABSTRACT
In 47 patients treated sequentially with urinary diversion and laparotomy staging, irradiation therapy and total cystectomy for invasive carcinoma of the bladder, the mortality rate was 2 per cent and the complication rate was 20 per cent. The survival rate was most favorable in patients in whom the pathologic specimen revealed no tumor after irradiation. The lower mortality and morbidity rates are attributed to staging of surgical procedures and the challenge remains to increase the number of patients in whom carcinoma of the bladder is converted by irradiation therapy to a lower stage or no tumor. The life-threatening course of invasive carcinoma of the bladder and our concern for the generally unsatisfactory results of surgical treatment alone stimulated adoption of a prospective protocol, combining irradiation therapy and operation. Despite variation in sequence and method previous reports have demonstrated that t he combination of these modalities enhan ces the effectiveness of treatment. 1·• The natural division of con structive and extirpative surgery by separate operations and advances in the technique of irradiation therapy have reduced mortality and morbidity. 5 · 7 Since 1964, 47 consecutive patients for whom cystectomy had been recommended were treated by post-diversion pre-cystectomy irradiation (table 1) . METHOD
This protocol provided for ilea! conduit urinary diversion with staging by laparotomy, a 4 or 5-week course of irradiation 2 weeks later and total cystectomy, some with pelvic lymph node dissections and all with total prostatoseminal vesiculectomy, 6 weeks after irradiation. Individual patient re sponse and hospital course necessitated variation in x -ray dosage, interval and specific operation. In general, patients with grades 1 to 4, recurrent, multiple or sessile, low stage tumors and those with deep neoplasms without metastases were accepted for this series. Five patients who had stage D 1 tumor, because of a single tumor bearing regional lymph node, demonstrated at initial staging and diverting operation, were accepted for sequential t herapy. The average age of t he 47 patients was 64 years, with a median of 64. In 36 patients treatment Accepted for publication October 11, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19- 23, 1974. 4fi
consisted of staging diversion, irradiation t herapy and total cystectomy. One patient was treated with laparotomy and transurethral resection of the tumor because the staging operation had revealed distant tumor containing lymph nodes . Urinary diversion and irradiation therapy only were done in 6 patients, and diversion and second-stage cystec tomy without irradiation were done in 4. Patients who did not undergo cystectomy did not do so either because of the findings established at t he staging operation or the patient's general condition or wishes, which contraindicated further surgery. This group received irradiation therapy. The 4 patients who underwent diversion and cystectomy but omitted irradiation did so on the advice of t he radiotherapist or for p ersonal reasons . Although all tumors were classified by grades, using Broder's index, our primary concern was in staging. The Marshall 8 modification of the system described by Jewett and Strong was used. 9 As advocated by Whitmore and associates in analyzing a small number of cases, the tumor stage was grouped into superficial (0 , A and B, tumors), deep (B2 and C tumors) and metastatic (D, and D 2 tumors) . 6 The primary diagnostic procedures to determine the stage of the neoplasm were excretory urography (IVP), metastatic x-ray series, pulmonary tomogram,.liver scan and cystoscopic examination with observation of the lesion for size, location in t he bladder and contour, whether pedunculated or sessile . Transurethral biopsy was performed with special care not to perforate the bladder wall, and thereby iatrogenically advance the stage of t he cancer. Fractionated cystography was used routinely. Contrast cystography, pelvic angiography and lymphangiography were performed rarely. Staging by exploration at the initial operation proved valuable. Lymph node bearing areas were
POST-DIVERSION PRE-CYSTECTOMY IRRADIATION FOR CARCINOMA OF BLADDER TABLE
1. Sequential mana{?ement: urinary diversion ,
x-ray therapy, cystectomy No. Pts. Staging exploration Diversion and x-ray therapy Diversion and cystectomy Diversion, x-ray therapy and cystectomy Total
1 6 4
36 47
examined and suspicious nodes were biopsied. Involvement and extent of the bladder tumor were noted and, when feasible, the margins were outlined by silver clips. Whenever possible the radiotherapist was in attendance at cystoscopic examination and laparotomy. In this series no unsuspected organ involvement was unveiled . Of the 47 staging laparotomies and/or simultaneous urinary diverting procedures, 4 patients were found to have otherwise unsuspected tumor-bearing lymp h , nodes. Urinary diversion was accomplished in 1 patient by ureterosigmoidostomy and in 45 patients by ureteroileal cutaneous anastomoses. The finding of pericaval lymph node involvement at the renal level precluded diversion in 1 patient. Pelvic radiation doses varied from 4,000 to 6,000 rads. By approximating the number of rads to the nearest 1,000, 21 patients received 4,000 rads, 10 received 5,000 rads and 11 received 6,000 rads. Since July 1968 all patients in this megavoltage series were treated on the 4 mv. or the 8 mv. linear accelerator with doses calculated at mid pelvic depth. Most of these patients received 4,000 to 5,000 rads in 20 to 25, 200-rad mid pelvic doses. Usually anterior and posterior opposing portals were used, although an occasional patient was treated by 360 degrees rotation. The treatment volume included bladder, prostate and seminal vesicles, together with the pelvic lymph nodes to the level of the aortic bifurcation. If the decision to treat with definitive radiation alone was made each patient was individually studied and planned for 3-field therapy or rotational treatment with a more confined treatment volume. This procedure ,f has allowed us to deliver 6,000-rad doses within 6 weeks with improved tumor effect and normal tissue sparing. During the last 2 years all such patients have been planned on a treatment simulator using contrast in the bladder and rectum to more accurately define the pelvic structures. After 6 to 8 weeks a radical cystectomy was . ·> performed with or without lymph node dissection pending clinical judgment at the time of operation. The procedure included en bloc removal of the bladder, prostate, seminal vesicles, enveloping fascia, fat and peritoneum. In the female patient the entire urethra and bladder were removed and in some patients the uterus, ovaries, fallopian tubes and anterior vaginal wall, depending on the extent and location of the tumor.
47
RES ULTS AND DISCUSSION
The mortality rate in this series was 2 per cent and involved 1 patient who died after urinary tract diversion of antecedent and persistent cicatricial tracheal stenosis and postoperative peritonitis . The low mortality rate has been attributed to the staging of the operative procedures. A single stage operation with or without irradiation carried a considerably higher mortality (table 2). 1 · 2 · 4 · 6 · 10 · 16 Similar observations have been made by Laskowski and associates.• Of the 87 operations in this series there were 18 postoperative complications. This complication rate of 20 per cent compared favorably to complication rates in the literature of 66 per cent following 1-stage radical cystectomy. 7 The postoperative complications were pelvic abscess in 2 patients, cardiorespiratory failure in 2, hematuria in 2, myocardial infarct in 1, atelectasis in 1, wound infection or dehiscence in 3 and unilateral hydronephrosis in 2. One death has been described. Stomal stenosis developed in 1 patient requiring reoperation. Complications requiring reoperation and which were attributed to irradiation included 1 dissolution of the ileo-ileal anastomosis, 1 perforation of the sigmoid colon and 1 cutaneous vaginal fistula. These appeared to be related to the interval between cystectomy and irradiation therapy, rather than the amount of rads delivered. The complications mentioned preceded the techniques which were adopted in July 1968. The patient in whom a sigmoid fistula developed had had a stage C lesion and died of local recurrence 2 years after initiation of sequential therapy. Another patient in whom a cutaneous vaginal fistula developed is still alive at 6 years, having had a stage B 2 lesion clinically and no tumor by pathological examination. She had received 6,000 rads and is free of disease at this time. Those patients in whom the interval between irradiation therapy and cystectomy was 6 to 8 weeks were noted to have a minimal number of complications which could be attributed to preoperative irradiation. However, mild side effects including proctitis, diarrhea, frequency, hematuria and skin reaction have occurred. Of importance is the fact that the urinary diversion is done prior to irradiation and, therefore, carries none of the possible complications that might be attributed to preoperative irradiation. Tertiary operation was performed for solitary metastases in 3 patients ( table 3) . One patient had cerebral symptoms 4 months after completion of treatment. A solitary metastatic lesion was demonTABLE
2. Relative mortality rates (%)
Reference 7 authors 4 authors 1. 2 • 4 • Current series 10- 16
6
1-stage cystectomy X-ray and 1-stage cystectomy Sequentia l management: diversion, x-ray, cystectomy
15 9
2
48
MAHONEY , WEBER AND HARRISON TABLE
3. Tertiary operation for solitary metastasis Operation
Cerebellum Urethra Urethra
Excision TUR of urethra X-ray and ure threctomy
Total Survival 1 yr. 8 mos. 4 yrs. 7 yrs.
After Third Operation 1 yr. 6mos. 4 yrs.
strated in the cerebellum, excised successfully, and the patient lived 1 year thereafter. Another patient had a tumor in the remaining urethra 3 years after treatment of the bladder neoplasm. The urethral lesion was irradiated and total urethrectomy was performed subsequently. He lived 4 years thereafter, totaling a survival of 7 years, and died of an unrelated cause. The IVP remains an important adjunct to the staging of tumors of the bladder. The pre -diversion IVPs are compared to the stage of the lesion in the cystectomy specimen following irradiation. Normal upper urinary tracts were demonstrated preoperatively by IVP in 2 of 8 patients with stage D disease and 5 of 13 patients with stages B 2 and C neoplasms. Abnormal upper urinary tracts by IVP were present conversely in 7 of 19 patients with stage 0, A or B 1 and 2 of 5 patients with no tumor in the operative specimen. The IVP would appear to have been misleading in downgrading and upgrading the stages of the tumor. Reliance on the findings of the upper tract is an adjunct to clinical staging but does not determine definitive therapy. The duration of survival of the 27 patients who have died during the 10-year period of observation in this study has been correlated with the stage of the tumor at the time of examination of the pathological specimen. Two patients with no tumor lived an average of 6 years, 4 patients with stage 0 , A or B 1 tumors lived 3 years, 13 patients with stage B 2 or C tumors lived 1 year and 8 patients with stage D tumors lived 2 years . The average duration of survival of these 27 deceased patients was 2.5 years. One might assume that irradiation therapy has reduced the stage of the tumor, obviously , in the no tumor group, but even in B 2 and C stages. This might indicate that some tumors in these 13 patients had even been in the D stage clinically . The pathologic stage appears to correlate well with the prognosis. Of the 27 deaths 15 patients died of recurrent disease. The pathological stage in these 15 patients was B 2 or C in 9 patients, D in 5 patients and no tumor in 1 patient. Four patients died of distant metastases and 11 of recurrent neoplasm in the pelvis . Fourteen of these 15 patients had been demonstrated by operation and pathologic speci men to have had stage B 2 , C or D neoplasm. The series of 20 patients surviving is too small to allow one to come to any conclusions. Three patients with no tumor are presently alive for an average of 5 years, 15 patients with stage 0, A or B 1 tumors are alive an average of 3 years and 2 pa-
tients with stage D tumors are alive an average of 1 year. All except 1 patient with stage D disease were clinically cured of cancer. The reduction in stage by irradiation therapy is impressive. Of the 18 patients with no tumor or stage 0 , A or B 1 tumor by pathologic examination, 10 had been by clinical evaluation stage 0 , A or B 1 and 8 stage B 2 or C tumors. Of the 8 clinical stage B 2 or C tumors 2 were converted to pathologically no tumor and 6 from clinical stage B 2 or C to pathologic stage 0 , A or B 1 • Accepting an error in clinical staging, 8 the reduction in stage for 8 of 20 living patien ts must be attributed to the effects of irradiation. The duration of survival of the entire series of 47 patients is difficult to interpret at this time because of small numbers in each category and because there are 20 patients alive with 19 free of clinically detectable disease (table 4) . The 14 patients who after irradiation still had deeply invasive tumors (B 2 or C) have all died, with an average and a mean survival of 1 year. However, 12 of these 14 patients had stage C disease and only 2 had stage B2 tumors . The over-all survival was an average of 2.5 years with a median of 2.5 years . Five patients with clinical and histologic carci noma of the bladder were demonstrated aft er irradiation therapy to have no tumor in the bladder specimen by gross and histologic examination (table 5) . Three of these patients had been judged to have superficial stage tumor and 2 deep stage neoplasm . One patient did have a small question aTABLE 4.
Survival rates for pathological stage No. P ts.
Survival
Total
Alive
Dead
Average Median (yrs.) (yrs.)
No tumor 0,A,B, B,,C D
5 18 14 10
3 14 1 2
2 4 13 8
5 3 1 1.5
6 2
Tota ls
47
20
27
2.5
2.5
3 patients lost to followup. TABLE
5. Survival in pathologic stage , no tumor remaining (sequential management)
Clinical Grade Stage
Pathology No tumor
X Radiation (rads)
Surviva! (yrs.)
5,900
6
Alive- free of disease
4,400
3
Alive-free of disease
Status
4
B,
3
B,
3
B,
Single focus micro
4,000
5
Alive- free of disease
2
B,
No tumor
5,095
6
Died of cancer
4
B,
No tumor
5,480
6
Died-no tumor at postmortem ex amination
POST-DIVERSION PRE-CYSTECTOMY IRRADIATION FOR CARCINOMA OF BLADDER
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I
·~
I
ble focus of carcinoma. Another patient lived 6 years and died of an unrelated illness. There was no tumor found at the postmortem examination. A third patient who lived 6 years died of locally recurrent disease. The remaining 3 patients are alive, well rehabilitated and free of disease at 3, 5 and 6 years following sequential treatment. The potential for irradiation to convert invasive carcinoma of the bladder to no tumor would appear to correlate well with an improved prognosis. The average patient in this small group received more than the average number of rads in the series . The data suggest that when irradiation succeeds in completely destroying the neoplasm in a larger number of patients sequential therapy may be expected to yield an improved survival rate. CONCLUSION
Post-diversion pre -cystectomy irradiation re duces mortality and morbidity by 1) eliminating any irradiation engendered damage to tissues prior to ilea! conduit construction, 2) sparing the occa sional patient a radical cystectomy by information obtained at surgical staging and 3) performing diversion and extirpative surgery at separate operations. The reduction in mortality and morbidity and the satisfactory rehabilitation allow and make advisable sequential therapy as treatment of choice at an earlier point in the growth and development of this cancer. Combination of 2 effective modalities in this manner, irradiation therapy and surgery, appears to be beneficial in the treatment of invasive carcinoma of the bladder. The operation for diversion is one dedicated to the preservation of renal function. The operation of cystectomy and lymphadenectomy is for removal of malignant disease. The diversion and extirpative procedures are biologically and philosophi cally different, and are best performed separately. It would seem that the innovation of irradiation therapy after diversion and before cystectomy is a valuable addition to the treatment of this cancer. REFERENCES
1. Prout, G. R., Jr., Slack, N. H. and Bross, I. D. J.:
Preoperative irradiation as an adjunct in the
49
surgical management of invasive bladder carcinoma. J. Urol., 105: 223, 1971. 2. DeWeerd, J. H. and Colby, M. Y., Jr.: Bladder carcinoma treated by irradiation and surgery : interval report. J. Urol., 109: 409, 1973. 3. Werf-Messing, B., van der: Carcinoma of the bladder treated by preoperative irradiation followed by cystectomy. Eur. J. Cancer, 7: 467, 1971. 4. Laskowski, T. Z., Scott, R., Jr. and Hudgins, P. T.: Combined therapy: radiation and surgery in the treatment of bladder cancer. J. Urol., 99: 733 , 1968. 5. Reid, E. C., Mount, B. M. and Sullivan, N.: Preoper-
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7. Grimes, J. H., Hart, J . M., Glenn, J. F. and Anderson, E. E.: Staged approach to invasive vesical malignancy. J. Urol., 108: 872, 1972. 8. Marshall, V. F.: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J. Urol., 68: 714 , 1952. 9. Jewett, H. J. and Strong, G. H.: Infiltrating carcinoma of the bladder: relation to depth of penetration of the bladder wall to incidence of local extension and metastases. J. Urol., 55: 366, 1946. 10. Whitmore, W. F., Jr. and Marshall, V. F.: Radical total cystectomy for cancer of the bladder: 230 consecutive cases five years later. J. Urol., 87: 853, 1962. 11. Parkhurst, E. C. and Leadbetter, W. F.: A report on 93 ilea! loop urinary diversions. J. Urol., 83: 398, 1960. 12. Cordonnier, J . J.: Cystectomy for carcinoma of the bladder. J. Urol. , 99: 172, 1968. 13. Glantz, G. M.: Cystectomy and urinary diversion. J. Urol., 96 : 714, 1966. 14. Burnham, J. P. and Farrer, J.: A group experience
with uretero-ileal-cutaneous anastomosis for urinary divers ion: results and complications of the isolated ilea! conduit (Bricker procedure) in 96 patients. J. Urol., 83: 622, 1960. 15. Brown, H. M. and Elliot, J. S.: Bladder cancer: an evaluation of diagnosis and treatment of 93 patients. J. Urol., 102: 63, 1969. 16. Stone, J. H. and Hodges, C. V.: Radical cystectomy for invasive bladder cancer. J. Urol., 96: 207 , 1966.
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