- Email: [email protected]
Preoperative Irradiation as an Adjuvant in the Surgical management of Invasive Bladder Carcinoma
Vol. 105, Feb. Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1971 by The Williams & Wilkins Co.
PREOPERATIVE IRRADIATION AS AN ADJUVANT IN THE SURGICAL l\1ANAGE:.\1ENT OF INVASIVE BLADDER CARCINO:\IA GEORGE R. PROUT, JR., NELSON H. SLACK
AND
IRWIN D. J. BROSS
From the Urological Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts and Roswell Park Memorial Institute, Buffalo, New York
This progress report of the Urological Cancer Research Group (table 1) describes certain observations pertinent to the question of advising preoperative irradiation as an adjuvant in the surgical management of patients with invasive bladder carcinoma. Previous reports include details on the group's formation and some of its experiences, including an analysis of the effectiveness of 5-FU as definitive therapy in the treatment of advanced bladder carcinoma. 1 - 4 The data herein reported are drawn from evaluations made in December 1969, 5 years after the group first began admitting patients. METHODS AND MATERIALS
Criteria for the selection of patients and the therapeutic modalities used have been described. 4 Patients who have histological evidence of bladder carcinoma, who are judged potentially curable and who are candidates for an open surgical procedure are randomized by telephone call to Roswell Park Memorial Institute to receive or not to receive preoperative irradiation. When the patient is to receive irradiation, 4,500R is given Accepted for publication March 12, 1970. This investigation was supported by Public Health Service Research Grant No. CA 11787 (formerly CA 06732) and Nos. CA 10377 and CA 10378, National Cancer Institute. 1 Prout, G. R., Jr.: The development of a cooperative study and its preliminary observations on adjnvants (5-FU and irradiation) in the surgical treatment of bladder carcinoma. In: InterAmerican Conference on Toxicology and Occupational Medicine. Bladder Cancer; A Symposium. Edited by K. F. Lampe. Birmingham, Alabama: Aesculapius Publishing Co., p. 270, 1967. 2 Prout, G. R., Jr.: Adjuvants in the surgical treatment of bladder carcinoma. In: Cancer Therapy by Integrated Radiation and Operation. Edited by B. Rush, Jr. and R. H. Greenlaw. Springfield, Illinois: Charles C Thomas Co., 1968. 3 Prout, G. R., Jr., Bross, I. D. J., Slack, N. H. and Ausman, R. K.: Carcinoma of the bladder, 5-fluorouracil and the critical role of a placebo. A cooperative group report. I. Cancer, 22: 926, 1968. 4 Prout, G. R., Jr., Slack, No H. and Bross, I. D. J.: Irradiation and 5-fluorouracil as adjuvants in the management of invasive bladder carcinoma. A cooperative group report after 4 years. J. Urol., 104: 116, 1970. 223
TABLE
Urologist Dr. Marvin W. Woodruff
Dr. William H. Boyce
1
Radiotherapist
Dr. Donald H. Baster Dr. Damon D.
Blake
Dr. Clair E. Cox Dr. Joseph J. Kaufman
Dr. Justin J. Stein
Dr. Lester Persky Dr. David Albert
Dr..John Storaasil
Dr. Alfred DeFalco Dr. James F. Glenn Dr. Joseph Malin Dr. Rubin H. Flocks Dr. David Culp Dr. Mark Immergut Dr. William Valk Dr. George R. Prout, Jr. Dr. Ian M. Thompson Dr. Gilbert Ross Dr. Chester Winter Dr. Clarence V. Hodges Dr. Jerry D. Giesy Dr. Harry C. Miller Dr. Gerald P. l\Iurphy Dr. Gerald Hardner Dr. M. J. Vernon Smith Dr. R. Carl Bunts Dr. F. Price Cassman
Dr. Eo Salzman Dr. Patrick .L Cavanaugh
Institution Albany Medical College Bmv1nan Gray School of Medicine
University of California at Los Angeles Case v.rr estern Reserve e niversity Denver General Hospital Duke University
Dr. Howard B. Latourette
University of Iowa
Dr. Galen ~I. ri:ice Dr. Milford Schulz Dr. Gus R. Ridings
L niversity of Kansas Massachusetts General Hospital University of Missouri
Dr. Thomas Pomeroy Dr. Clifford V. Allen
Ohio State University Uniyersity of Oregon
Dr. Philip Rubin
U nb.rersity of Rochester Roswell Park lHernorial Institute
Dr. John H. Webster
Dr. Seymour H. Levitt
Medical College of Virginia
Dr. 1\.fax Boon
University of VVisconsin
between zero and 28 to 32 days and the dose is calculated at 2 points: 1) in the center of the irraoo diated volume at the midline in the mid anteroposterior plane of the pelvis and 2) on each side 5 cm. lateral to the other point. The dose administered at the midline point is an average of no less
PROUT, SLACK AND BROSS
224
than 1,000R per week. With rotational therapy the dose is measured in the center of the axis of rotation. Between 4 and 8 weeks following the last dose of irradiation an appropriate open surgical procedure (cystectomy 80 per cent of the time) is performed. Comprehensive initial evaluation, postirradiation, preoperative, quarterly followup and pathology forms are required for eligibility. For about 3 years patients were randomized 14 days postoperatively to receive 5-FU or a placebo on a double-blind basis. No effect of this drug was discernible and so its use was discontinued. When it is pertinent in the analyses these patients are always identified. RESULTS
Table 2 is a brief description of the status of the study. Patients termed not eligible are critically analyzed in table 3, where it is evident that adTABLE
2. Status of study as of December 31, 1969 Patients
Category Entered Not eligible Excluded No followup Protocol deviates (PDV) No followup Eligible No followup Followup available, but entered <12 mos. Available for survival analysis
TABLE
427 185 93
10 92 242 56 25 161
vanced disease not detected at entry, protocol violations and patient rejection of therapy were the leading causes of ineligibility. All of these ineligible patients must be considered in interpreting results to insure that a biased patient population does not lead to erroneous conclusions or conclusions that would have little meaning for the population of patients with invasive bladder carcinoma that is usually encountered. Figure 1 demonstrates the distribution of patients in the study as accurately as could be determined. Patients with delinquent forms and those admitted recently make this chart slightly imprecise. The encircled numbers represent noneligible patients in table 3 and the Roman numeral subscripts refer to the column headings in table 3. Tables 4 to 6 deal with an analysis of the effect of irradiation on the tumors treated. The investigators understaged tumors (eligible and ineligible patients) as follows: clinical stage B 1-46 per cent, B2-53 per cent and C-30 per cent. Overstaging also occurred but in lesser degrees. From the data in these tables it is evident that the procedure used to establish the existence of muscle invasion was effective in eradicating tumor, at least as detected by the usual pathological techniques, 7 per cent of the time. The use of preoperative irradiation improved this to an average of 34 per cent. This difference is statistically significant.
3. Reasons for ineligibility according to therapy received Therapy Groupst
Reason for Ineligibility•
Protocol entry criteria Patient refused therapy Metastasis noted clinically during radiotherapy or at operation Complication interrupted rad.; prevented operation Complication prevented chemotherapy Complication interrupted chemotherapy Death before any therapy Death after radiation and before operation Death after operation and before chemotherapy Death after chemotherapy Investigator withdrew patient Metastatic disease at entry Miscellaneous Total
Total
I
II
III
IV
V
VI
VII
3
3 12
3 7 7
2 5 12
6 5 18
4
4
8
3
4
9
9
25 33 48 9 11
2 6 5 5 2
2 13§
3 47
4 5 27
2 1
2+ 5+ 39
3 42
1 10
1 7
12 2 12 7 15 185
* Patients with 1 of the first 2 or the last 3 reasons are referred as "excluded" and those with one of the remaining reasons are referred as "protocol deviates" (PDV). t Therapy groups are: I-no therapy, randomized for irradiation; II-irradiation only; III-no therapy, randomized for non-irradiation; IV-received irradiation and operation but no drug; V-operation but no drug; VI-received irradiation, operation and all or part of drug regimen and VII-operation and all or part of drug regimen. t One patient received no irradiation. § In figure 1, group I includes the 2 patients footnoted in group IV,
225
PREOPERATIVE IRRADIATION FOR BLADDER CARCINOMA 427
IRRADIATION
NON· IRRADIATION 208
219
Not lrrndleited
@
23
I
IRRADIA ED
NOT IRRADIATED
No Surgery
No Surgery
@
15
II
111
131
*2 pts. nut irrad. but had surgery
I------_,,., 133
SURGERY
166
299
® IV
8
(12. V
~
31 5-FU
@
VI
J 4t, PL/lCERCJ
34 5-FU
CD
V 11
75
PLACEBO
Fm. l. Patients in study as of December 31, 1969. Circled numbers designate excluded patients. Roman numerals refer to therapy group columns in table 3 in which reasons for exclusion are listed. Uncircled numbers designate eligible patients. Asterisk indicates 2 patients included in group I because they were not irradiated; however, they underwent operation, re-entered diagram and are removed again in group IV.
Table 7 contains data on 156 patients who are divided according to the surgical treatment used and 4 frequently encountered complications. The term complete cystectomy includes the simple and radical cystectomies. ·while wound infection occurred more frequently in the preoperatively irradiated cystectomy group the difference in incidence was not significant until all kinds of operations associated with preoperative irradiation were included; with this information the difference becomes statistically significant. Table 8 lists patients admitted to the study who died within 60 days postoperatively or, if not operated upon, within 60 days of entry into the study. Comparison of patients who were irradiated preoperatively or not and who then had a cystectomy, revealed 10 patients in the former group and 8 patients in the latter group. Further, there was no predilection for a certain type of complication to occur in either group. The leading causes of death were metastatic carcinoma and pulmonary embolism.
Table 9 shows the survival status of eligible patients at risk 12 months or more. Followup has improved since the last report 4 but remains a problem. No therapeutic group demonstrates any advantage in this analysis. There is a 95 per cent confidence limit for these groups, proving this lack of advantage (fig. 2). Figure 3 is a curve developed from a life table that indicates the survival of the eligible patients in a different manner. The greatest mortality is experienced by 18 months preoperatively. Figure 4 separates survival according to whether the patient was irradiated preoperatively. While the non-irradiated, tumor-free groups had an initial. advantage, this has been lost in subsequent months. Clearly, lack of detectable tumor in the surgical specimen is not a positive predictive sign. DISCUSSION
DeWeerd and Colby indicated that it seemed impossible to follow a statistically-oriented plan involving rigid time periods and dose schedules of
226
PROUT, SLACK AND BROSS
4. Compari.~on of rliniral verM,.~ pathological staging in eligible irradiated and non-irradiated patients
TABLt:
Clinical Stage
Pathological Stage
Irradiation: Tumor absent
B1
Bt
12
12
0 A
2
81
III
Bt
7
C Di Total Non-irradiation: Tumor absent 0
C
III
4
2
2
5
31
30
2 3
[J) 15
[I)
5
8
[llJ
1 3
3 5
11
11D
9
2
40
I 19
35
16 10 8 78
I
2
8
B,
Total
11
[I]
A
D1 D,
30 3
5
Clinical Stage Pathological Stage
D2
6
6 1 1
81 C
Total D,
6. Comparsion of clinical and pathological staging in eligible and non-eligible irradiated and non-irradiated patients
TABLE
18 25 26 20 1 100
1
ID 6
Irradiation: Tumor absent G A
B, B, C D, D, Total ~on-irradiation: Tumor absent 0 A
B, B, C D,
5. Comparison of clinical and pathological staging in non-eligible* irradiated and non-irradiated patients
Pathological Stage
Irradiation: Tumor absent 0
A
81 8,
_ _ _Clinical _ _ _Stage _ _ _ _ _ Total"
B,
Total Non-irradiation: Tumor absent
D1
6 1 2
IIl
D, 11
2 2 3 7
2
3
III
2 I 16
5
2
19
I 6
C
D1 D,
C
4
2
(Il
10 3
42
3 1
3
2 3 4
81 8,
III
2
7
C
2
D1 D,
4
8 2
17
22
0
A
Total
2
m 3
4 7 19 2
7
2
48
• Only those PDV and excluded patients undergoing operation and having a pathological staging are included.
irradiation followed by an operation for patients with invasive bladder carcinoma. 5 This is true, at least in part, and is attested to by the number of ineligible patients in our program. Yet, the ques6 DeWeerd, J. H. and Colby, M. Y., Jr.: Bladder carcinoma. Combined radiotherapy and surgical treatment. J.A.M.A., 199: 109, 1967.
B,
C
18
16
7
D,
4
III 10
7
2
!Im
3
D,
Total
41 2 5 14 23 14 18 3 120
4
III
10
2
47
49
21
6
3
10
3 7
5
4 4
4 2
Im 10 5 9
D, Total
TABLE
B,
52
1
m 3
4
Ii§) 14 17 2 62
1 3
Im
1
7
[[I
26
8
25 29 33 39 3 148
tion of the effectiveness of preoperative irradiation seemed important to resolve if only because the modality has been used extensively in this role. Clearly, any advantage that might be added to a therapeutic regimen for the patient with invasive bladder carcinoma deserves thorough investigation. For this reason, investigators have persisted. In the analysis of the control population whose surgical specimens did or did not contain persistent tumor, there is clear-cut evidence that understaging is common. This inability to stage accurately is one of the most serious problems the clinical investigator faces because, if he cannot stage accurately, then he cannot assess correctly the effect that any non-surgical modality or combination of such modalities has on a given tumor by examining the pathological stage. At least 67 per cent of the irradiated patients had some decrease in the clinical stage of their tumors after irradiation and it is almost certain that some of the patients whose tumors were not eradicated nevertheless did have a reduction in pathological stage. Therefore, a comparison of survival in various pathological stages between patients irradiated and those not irradiated preoperatively becomes an illogical exercise. Transurethrally resected tissue should be carefully reviewed by the urologist and the pathologist jointly so that better, more accurate assessment will be accom-
227
PREOPERATIVE IRRADIATION FOR BLADDER CARCINOMA
TABLE
7. The incidence of 4 frequent complications according to type of operation for irradiated and non-irradiated patients*
Type of Operation
Irradiated: Partial cystectomy Complete cystectomy Cystostomy Exploratory celiotorny Urinary di version Total Non-irradiated: Partial cystectomy Complete cystectomy Cystostomy Exploratory celiotomy Urinary diversion Total
lieus Pts. Entered Postop. No.(%)
Persistent Sinus 'Wound Infection Wound Dehiscence No.(%) No. (%) No.(%)
17 96 1 11 I 126
1 (6) 19(20)
2 (12)
20(16)
17(13)
25 111
l (4) 23 (21)
14 (15)
5 (29t) 30(31)
1(9)
1 (6)
7(7) I (9)
35 (28t)
9(7)
11 (10)
21 (19)
l (4) 12 lll)
I (7 J
1 (7)
1(7)
l (33) 26 (17)
13 (8)
l (33) 23 (15)
1 (4)
2
15 3 156
2 (13) 1 (33) 16(10)
"" Includes patients classed as eligible or ineligible. t Significantly different proportions in the irradiation and non-irradiation series.
plished and the need for other diagnostic tools in clinical staging will be indicated. The experience of investigators has demonstrated that in the hands of radiotherapists working in this project the amount of irradiation given in the exact fashion described, followed by an open surgical procedure in the exact time sequence described is not associated with any increase in lethal complications nor any non-lethal ones aside from wound infections. Thus, the adjuvant use of irradiation seems entirely justifiable from the risk standpoint. However, as our experience has broadened, other influences of irradiation have become evident. For instance, there have been 60 patients who were randomized for irradiation who did not undergo an operation as opposed to 27 non-irradiated patients who did not undergo an operation. More patients refused therapy in the series randomized to irradiation than in the alternate group and more of those who refused did so with respect to the surgical part of the program, not the irradiation portion. Further, there were 9 patients with complications following irradiation who did not have an operation and 6 more patients who died after irradiation. Five other patients were excluded because of protocol violations while there were none in the nonirradiated group (table 3). From this survey it is evident that the inclusion of irradiation works subtle differences into the data. Further, the exclusion from the total program of certain patients suggests the possibility that bias may enter into the analyses since a "different" group of patients may finish the irradiation-operation program as
opposed to the patient treated with alone. This "different" group might be produced by the elimination of poor risks either as a result of the investigator's decision or progression of the disease. Thus, only a select group may finish the combined program to the apparent detriment of the control group. As time passes it seems that this and other phenomena will become better defined. With regard to survival, most considerations are best limited to 24 months, though there are several patients alive 3 and 4 years post-treatment. Though not shown in the tables or figures, the minority group of segmental resections patients), comprised largely of stage B 1 has survived. Eighty-eight per cent were alive at 12 months and nearly all of these have survived 18 months. These are included in the total survival analyses, thus producing some bias in that group. They and other special portions of the population will be considered specially in future publications. Life table plots of the separate treatment groups demonstrate, at best, only minor trends of little significance. The 95 per cent confidence limits for these separate groups are shown in figure 2 where it is evident that thus far no regimen has any advantage. Survival figures of the total group show a rapid loss up to 15 to 18 months with little more than a 50 per cent chance of survival at this time limit (fig. 3). The curve then levels off so that there is a 30 to 40 per cent chance of surviving more than 3 years. The shape of the curve suggests that there are at least 2
228
PROUT, SLACK AND BROSS
8. Causes of death, type of operation and therapy for patients dying within 2 months postoperatively or from entry if no operation
TABLE
Mo. Type of TherDied 0tyi~!apyt
0
7 7 4 6
0
3
0 0
0
0 0 0 0 0 0
3
3 3
3
3
0 0
7 5 8 8 8 8 8 7
1
2
7 7 8 8 8 7
2 2 3
8 3 3
3
3
3
4
3 3 3 3 5 5 5
4 7 6 8 7 5 8
9. Distribution of month of death or last followup for 161 eligible patients at risk 12 months or more
TABLE
Mos. Postop. Causes of Death
Metastatic carcinoma, coronary occlusion Myocardial infarction Cardiac arrest Cardiovascular collapse, metastatic carcinoma Metastatic carcinoma, atherosclerosis, pyelonephritis Metastatic carcinoma, cardiac failure, septicemia Peritonitie, pneumonia, atherosclerosis Respiratory arrest, septicemia, uremia Cardiac arrest, peritonitis Pulmonary embolus Cerebrovascular accident, pulmonary embolus Cardiac arrest Pulmonary embolus Metastatic carcinoma, uremia, pyelonephritis Pneumonia Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma GI hemorrhage Pulmonary embolus, pulmonary edema and congestion Pulmonary embolus, pneumonia Pulmonary embolus Drug toxicity, pyelonephritis, cerebral edema Subacute bacterial endocarditis, splenic infarct, pulmonary emphysema Shock, peritonitis, pulmonary edema and congestion Cardiac failure, metastatic carcinoma Metastatic carcinoma, septicemia, uremia Peritonitis Metastatic carcinoma Metastatic carcinoma, hepatic failure Metastatic carcinoma Metastatic carcinoma
* Type of operation codes: !-partial cystectomy, 2-total cystectomy, 3-radical cystectomy, 4-cystostomy, 5-exploratory celiotomy, 6-urinary diversion. t Therapy codes: 3-irradiation 5-FU, 4-irradiation placebo, 5-non-irradiation 5-FU, 6-non-irradiation placebo, 7-irradiation, 8-non-irradiation.
populations that are admitted to the study and complete the therapeutic plan. One of these has metastases already but they cannot be detected by the usual diagnostic studies and a surgical procedure also fails in this regard. The patients ultimately have distant and/or local disease and die within the first year or so. The second group is comprised of those patients living longer whose survival curve is now nearly flat. Many of them
0-1 2-3 4-5 6-7 8-9 10-11 12-13 14-15 16-17 18-19 20-21 22-23 24-25 26-27 28-29 30-31 32-33 34-35 36-37 38-39 40-41 42-43 44-45 46-47 48-49 50-51 52-53 Total
Irradiated 5-FU Placebo Dead Alive Dead Alive
2 2 3 3
3 2 1 1
2 2 2
4 1 2 3 2
Non-Irradiated Placebo 5-FU Dead Alive Dead Alive
1 4 2 2 3
2 4 2 3 6 5 4 1
1 3
5 2 2
3
2 1
2 2 2 2
2
4
2
2 2
3
20
11
13
25
18
16
31
27
may also have metastatic disease but it has been slower in manifesting itself. Adequate numbers of patients and further followup should clarify this issue. One other matter bears on the question of undetected metastatic disease. One might expect local pelvic recurrence to be a commonly encountered phenomenon in patients who are not cured. Further, if irradiation were effective in preventing local recurrences then the control group might suffer from these in excessive numbers. While the data are incomplete because the investigators either did not or could not record the first and subsequent sites of recurrence, there is information available on 88 patients relative to this important matter. From table 10 it can be seen that distant metastases as the first evidence of failure occurred with surprising frequency. The terminology used in tabulation is not exact and much of the data are derived from clinical impressions but, from the early death rate and the wide distribution of metastases, it seems reasonable to propose that 1) many of the metastases
PREOPERATIVE IRRADIA'I'ION FOR BLADDER CARCINOMA
229
100
BO
I II
..,.... 60 <
".., ""
:,.
~
::,
40
VJ
20
30 5-FU
33 Placebo
Combined
IRRADIATION
53
5-FU
NO. PATIENTS
Placebo
Combined
NON-IRRADIATION
Frn. 2. Survival rate at 12 months with 95 per cent confidence intervals for all eligible patients entered 12 months or more. 100
80
60
40
20
12
MONTHS
AFTER
18
30
36
.,
48
51
SURGERY
Frn. 3. Probability of survival for all eligible patients with followup
were present when the regimen was started; 2) local recurrences were not the rule; 3) preoperative irradiation may play a role in altering the incidence of pulmonary metastases but there is little to suggest that its use influences the incidence of metastases to sites like bowel, uterus, and, possibly, the perineum, the peritoneal vaginal remnant where direct implantation may be the mode of delivery and 4) preoperative irra-
diation demonstrated no advantage in preventing either recurrence or new tumors from arising in the bladders of patients treated by segmental resection. CONCLUSIONS
The 5-year status of a cooperative program designed to determine the effectiveness of pre-operative irradiation when used as an adjuvant
PROUT, SLACK AND BROSS
230
INITIAL
lOQ~~••••••••••••••\
8-
~'\
--"-~~M~~MOR
~: ; IRRADIATED
NO TUMOR TUMOR
7~
•....................\
'
\
~
NON-IRRADIATED
-~---==;-···
',
',,,___ , ___
\
\ ... \..\
\
~::;.--,, ., _____ ._··-··....···· ,,.___ .,··························· ,____________ _
1'2
i's
1'e
21
24
2'7
36
3§
36
3§
42
4'5
4'8
s'i
MONTHS AFTER SURGERY
Fm. 4. Probability of survival for irradiated or non-irradiated patients entered 12 months or more with tumor absent or present at operation. TABLE
10. Site of recurrence* for irradiated and
non-irradiated patients Site Scar Peritoneal cavity Ribs Spine Pelvis Lungs Iliac nodes Liver Rectum Bladder Shoulder Head Abdominal fluid Perineum Femur Pleural cavity Supraclavicular nodes Small bowel Colon Kidney Uterus Ureters Vagina Totalt
NonIrradiated Irradiated 3 9
2
2 4
4
2 3
10 2 3 4 6
35
52
* One recurrence per patient is recorded here. Nine patients had more than 1 recorded in which case the first is tabulated. t One cardiovascular recurrence in the pericardium is not tabulated. There were 11 irradiated and 14 non-irradiated patients who had recurrence but the site is unknown. Recurrence was noted at death but no autopsy was performed.
in the surgical management of invasive bladder carcinoma is described. Of 427 patients entered, 242 are currently eligible and 185 are ineligible.
The ineligible category includes 93 patients who were excluded from the study and 92 we called protocol deviates because, while they did not finish the study, they proceeded far enough to provide data that will help in answering certain questions such as the effects of preoperative irradiation on bladder carcinoma. Preoperative irradiation when given as described was effective in destroying the bladder tumors in about a third of the surgical specimens. When irradiation was not used, the diagnostic procedure removed the tumor 7 per cent of the time. Of the non-lethal complications the only statistically significant increase was found in wound infections. Lethal complications occurred without respect to treatment group. Estimates of clinical staging demonstrated no close correlation with the true stage. This defect makes accurate evaluation of the effect of preoperative irradiation difficult. A life-table curve for all eligible patients demonstrates rapid survival loss in the first 15 to 18 months postoperatively. Relatively few deaths occurred after 18 months and a number of patients are alive in their third, fourth and fifth years. Life tables for patients irradiated or not anrl with or without tumor in the surgical specimen suggested some initial advantage in survival for those whose tumors were eradicated by preoperative irradiation. Patients with tumor eradicated
PREOPERATIVE IRRADIATION FOR BLADDER CARCINOMA
by the diagnostic procedure (non-irradiated, no tumor) had a good prognosis with 100 per cent survival at 12 months, but experienced rapid loss thereafter to a survival probability similar to that of the other groups (approximately .40) at 30 months. Ninety-five per cent confidence limits for the different forms of therapy show overlap, support-
231
ing the conclusion that no regimen is better than another. Metastases found in patients who were treated according to the protocol requirements were widespread, showed no predilection for local recurrence and occurred without regard to whether the patient had received preoperative irradiation.
THE JOURNAL OF UROLOGY
Copyright © 1971 by The Williams & Wilkins Co.
PREOPERATIVE IRRADIATION AS AN ADJUVANT IN THE SURGICAL l\1ANAGE:.\1ENT OF INVASIVE BLADDER CARCINO:\IA GEORGE R. PROUT, JR., NELSON H. SLACK
AND
IRWIN D. J. BROSS
From the Urological Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts and Roswell Park Memorial Institute, Buffalo, New York
This progress report of the Urological Cancer Research Group (table 1) describes certain observations pertinent to the question of advising preoperative irradiation as an adjuvant in the surgical management of patients with invasive bladder carcinoma. Previous reports include details on the group's formation and some of its experiences, including an analysis of the effectiveness of 5-FU as definitive therapy in the treatment of advanced bladder carcinoma. 1 - 4 The data herein reported are drawn from evaluations made in December 1969, 5 years after the group first began admitting patients. METHODS AND MATERIALS
Criteria for the selection of patients and the therapeutic modalities used have been described. 4 Patients who have histological evidence of bladder carcinoma, who are judged potentially curable and who are candidates for an open surgical procedure are randomized by telephone call to Roswell Park Memorial Institute to receive or not to receive preoperative irradiation. When the patient is to receive irradiation, 4,500R is given Accepted for publication March 12, 1970. This investigation was supported by Public Health Service Research Grant No. CA 11787 (formerly CA 06732) and Nos. CA 10377 and CA 10378, National Cancer Institute. 1 Prout, G. R., Jr.: The development of a cooperative study and its preliminary observations on adjnvants (5-FU and irradiation) in the surgical treatment of bladder carcinoma. In: InterAmerican Conference on Toxicology and Occupational Medicine. Bladder Cancer; A Symposium. Edited by K. F. Lampe. Birmingham, Alabama: Aesculapius Publishing Co., p. 270, 1967. 2 Prout, G. R., Jr.: Adjuvants in the surgical treatment of bladder carcinoma. In: Cancer Therapy by Integrated Radiation and Operation. Edited by B. Rush, Jr. and R. H. Greenlaw. Springfield, Illinois: Charles C Thomas Co., 1968. 3 Prout, G. R., Jr., Bross, I. D. J., Slack, N. H. and Ausman, R. K.: Carcinoma of the bladder, 5-fluorouracil and the critical role of a placebo. A cooperative group report. I. Cancer, 22: 926, 1968. 4 Prout, G. R., Jr., Slack, No H. and Bross, I. D. J.: Irradiation and 5-fluorouracil as adjuvants in the management of invasive bladder carcinoma. A cooperative group report after 4 years. J. Urol., 104: 116, 1970. 223
TABLE
Urologist Dr. Marvin W. Woodruff
Dr. William H. Boyce
1
Radiotherapist
Dr. Donald H. Baster Dr. Damon D.
Blake
Dr. Clair E. Cox Dr. Joseph J. Kaufman
Dr. Justin J. Stein
Dr. Lester Persky Dr. David Albert
Dr..John Storaasil
Dr. Alfred DeFalco Dr. James F. Glenn Dr. Joseph Malin Dr. Rubin H. Flocks Dr. David Culp Dr. Mark Immergut Dr. William Valk Dr. George R. Prout, Jr. Dr. Ian M. Thompson Dr. Gilbert Ross Dr. Chester Winter Dr. Clarence V. Hodges Dr. Jerry D. Giesy Dr. Harry C. Miller Dr. Gerald P. l\Iurphy Dr. Gerald Hardner Dr. M. J. Vernon Smith Dr. R. Carl Bunts Dr. F. Price Cassman
Dr. Eo Salzman Dr. Patrick .L Cavanaugh
Institution Albany Medical College Bmv1nan Gray School of Medicine
University of California at Los Angeles Case v.rr estern Reserve e niversity Denver General Hospital Duke University
Dr. Howard B. Latourette
University of Iowa
Dr. Galen ~I. ri:ice Dr. Milford Schulz Dr. Gus R. Ridings
L niversity of Kansas Massachusetts General Hospital University of Missouri
Dr. Thomas Pomeroy Dr. Clifford V. Allen
Ohio State University Uniyersity of Oregon
Dr. Philip Rubin
U nb.rersity of Rochester Roswell Park lHernorial Institute
Dr. John H. Webster
Dr. Seymour H. Levitt
Medical College of Virginia
Dr. 1\.fax Boon
University of VVisconsin
between zero and 28 to 32 days and the dose is calculated at 2 points: 1) in the center of the irraoo diated volume at the midline in the mid anteroposterior plane of the pelvis and 2) on each side 5 cm. lateral to the other point. The dose administered at the midline point is an average of no less
PROUT, SLACK AND BROSS
224
than 1,000R per week. With rotational therapy the dose is measured in the center of the axis of rotation. Between 4 and 8 weeks following the last dose of irradiation an appropriate open surgical procedure (cystectomy 80 per cent of the time) is performed. Comprehensive initial evaluation, postirradiation, preoperative, quarterly followup and pathology forms are required for eligibility. For about 3 years patients were randomized 14 days postoperatively to receive 5-FU or a placebo on a double-blind basis. No effect of this drug was discernible and so its use was discontinued. When it is pertinent in the analyses these patients are always identified. RESULTS
Table 2 is a brief description of the status of the study. Patients termed not eligible are critically analyzed in table 3, where it is evident that adTABLE
2. Status of study as of December 31, 1969 Patients
Category Entered Not eligible Excluded No followup Protocol deviates (PDV) No followup Eligible No followup Followup available, but entered <12 mos. Available for survival analysis
TABLE
427 185 93
10 92 242 56 25 161
vanced disease not detected at entry, protocol violations and patient rejection of therapy were the leading causes of ineligibility. All of these ineligible patients must be considered in interpreting results to insure that a biased patient population does not lead to erroneous conclusions or conclusions that would have little meaning for the population of patients with invasive bladder carcinoma that is usually encountered. Figure 1 demonstrates the distribution of patients in the study as accurately as could be determined. Patients with delinquent forms and those admitted recently make this chart slightly imprecise. The encircled numbers represent noneligible patients in table 3 and the Roman numeral subscripts refer to the column headings in table 3. Tables 4 to 6 deal with an analysis of the effect of irradiation on the tumors treated. The investigators understaged tumors (eligible and ineligible patients) as follows: clinical stage B 1-46 per cent, B2-53 per cent and C-30 per cent. Overstaging also occurred but in lesser degrees. From the data in these tables it is evident that the procedure used to establish the existence of muscle invasion was effective in eradicating tumor, at least as detected by the usual pathological techniques, 7 per cent of the time. The use of preoperative irradiation improved this to an average of 34 per cent. This difference is statistically significant.
3. Reasons for ineligibility according to therapy received Therapy Groupst
Reason for Ineligibility•
Protocol entry criteria Patient refused therapy Metastasis noted clinically during radiotherapy or at operation Complication interrupted rad.; prevented operation Complication prevented chemotherapy Complication interrupted chemotherapy Death before any therapy Death after radiation and before operation Death after operation and before chemotherapy Death after chemotherapy Investigator withdrew patient Metastatic disease at entry Miscellaneous Total
Total
I
II
III
IV
V
VI
VII
3
3 12
3 7 7
2 5 12
6 5 18
4
4
8
3
4
9
9
25 33 48 9 11
2 6 5 5 2
2 13§
3 47
4 5 27
2 1
2+ 5+ 39
3 42
1 10
1 7
12 2 12 7 15 185
* Patients with 1 of the first 2 or the last 3 reasons are referred as "excluded" and those with one of the remaining reasons are referred as "protocol deviates" (PDV). t Therapy groups are: I-no therapy, randomized for irradiation; II-irradiation only; III-no therapy, randomized for non-irradiation; IV-received irradiation and operation but no drug; V-operation but no drug; VI-received irradiation, operation and all or part of drug regimen and VII-operation and all or part of drug regimen. t One patient received no irradiation. § In figure 1, group I includes the 2 patients footnoted in group IV,
225
PREOPERATIVE IRRADIATION FOR BLADDER CARCINOMA 427
IRRADIATION
NON· IRRADIATION 208
219
Not lrrndleited
@
23
I
IRRADIA ED
NOT IRRADIATED
No Surgery
No Surgery
@
15
II
111
131
*2 pts. nut irrad. but had surgery
I------_,,., 133
SURGERY
166
299
® IV
8
(12. V
~
31 5-FU
@
VI
J 4t, PL/lCERCJ
34 5-FU
CD
V 11
75
PLACEBO
Fm. l. Patients in study as of December 31, 1969. Circled numbers designate excluded patients. Roman numerals refer to therapy group columns in table 3 in which reasons for exclusion are listed. Uncircled numbers designate eligible patients. Asterisk indicates 2 patients included in group I because they were not irradiated; however, they underwent operation, re-entered diagram and are removed again in group IV.
Table 7 contains data on 156 patients who are divided according to the surgical treatment used and 4 frequently encountered complications. The term complete cystectomy includes the simple and radical cystectomies. ·while wound infection occurred more frequently in the preoperatively irradiated cystectomy group the difference in incidence was not significant until all kinds of operations associated with preoperative irradiation were included; with this information the difference becomes statistically significant. Table 8 lists patients admitted to the study who died within 60 days postoperatively or, if not operated upon, within 60 days of entry into the study. Comparison of patients who were irradiated preoperatively or not and who then had a cystectomy, revealed 10 patients in the former group and 8 patients in the latter group. Further, there was no predilection for a certain type of complication to occur in either group. The leading causes of death were metastatic carcinoma and pulmonary embolism.
Table 9 shows the survival status of eligible patients at risk 12 months or more. Followup has improved since the last report 4 but remains a problem. No therapeutic group demonstrates any advantage in this analysis. There is a 95 per cent confidence limit for these groups, proving this lack of advantage (fig. 2). Figure 3 is a curve developed from a life table that indicates the survival of the eligible patients in a different manner. The greatest mortality is experienced by 18 months preoperatively. Figure 4 separates survival according to whether the patient was irradiated preoperatively. While the non-irradiated, tumor-free groups had an initial. advantage, this has been lost in subsequent months. Clearly, lack of detectable tumor in the surgical specimen is not a positive predictive sign. DISCUSSION
DeWeerd and Colby indicated that it seemed impossible to follow a statistically-oriented plan involving rigid time periods and dose schedules of
226
PROUT, SLACK AND BROSS
4. Compari.~on of rliniral verM,.~ pathological staging in eligible irradiated and non-irradiated patients
TABLt:
Clinical Stage
Pathological Stage
Irradiation: Tumor absent
B1
Bt
12
12
0 A
2
81
III
Bt
7
C Di Total Non-irradiation: Tumor absent 0
C
III
4
2
2
5
31
30
2 3
[J) 15
[I)
5
8
[llJ
1 3
3 5
11
11D
9
2
40
I 19
35
16 10 8 78
I
2
8
B,
Total
11
[I]
A
D1 D,
30 3
5
Clinical Stage Pathological Stage
D2
6
6 1 1
81 C
Total D,
6. Comparsion of clinical and pathological staging in eligible and non-eligible irradiated and non-irradiated patients
TABLE
18 25 26 20 1 100
1
ID 6
Irradiation: Tumor absent G A
B, B, C D, D, Total ~on-irradiation: Tumor absent 0 A
B, B, C D,
5. Comparison of clinical and pathological staging in non-eligible* irradiated and non-irradiated patients
Pathological Stage
Irradiation: Tumor absent 0
A
81 8,
_ _ _Clinical _ _ _Stage _ _ _ _ _ Total"
B,
Total Non-irradiation: Tumor absent
D1
6 1 2
IIl
D, 11
2 2 3 7
2
3
III
2 I 16
5
2
19
I 6
C
D1 D,
C
4
2
(Il
10 3
42
3 1
3
2 3 4
81 8,
III
2
7
C
2
D1 D,
4
8 2
17
22
0
A
Total
2
m 3
4 7 19 2
7
2
48
• Only those PDV and excluded patients undergoing operation and having a pathological staging are included.
irradiation followed by an operation for patients with invasive bladder carcinoma. 5 This is true, at least in part, and is attested to by the number of ineligible patients in our program. Yet, the ques6 DeWeerd, J. H. and Colby, M. Y., Jr.: Bladder carcinoma. Combined radiotherapy and surgical treatment. J.A.M.A., 199: 109, 1967.
B,
C
18
16
7
D,
4
III 10
7
2
!Im
3
D,
Total
41 2 5 14 23 14 18 3 120
4
III
10
2
47
49
21
6
3
10
3 7
5
4 4
4 2
Im 10 5 9
D, Total
TABLE
B,
52
1
m 3
4
Ii§) 14 17 2 62
1 3
Im
1
7
[[I
26
8
25 29 33 39 3 148
tion of the effectiveness of preoperative irradiation seemed important to resolve if only because the modality has been used extensively in this role. Clearly, any advantage that might be added to a therapeutic regimen for the patient with invasive bladder carcinoma deserves thorough investigation. For this reason, investigators have persisted. In the analysis of the control population whose surgical specimens did or did not contain persistent tumor, there is clear-cut evidence that understaging is common. This inability to stage accurately is one of the most serious problems the clinical investigator faces because, if he cannot stage accurately, then he cannot assess correctly the effect that any non-surgical modality or combination of such modalities has on a given tumor by examining the pathological stage. At least 67 per cent of the irradiated patients had some decrease in the clinical stage of their tumors after irradiation and it is almost certain that some of the patients whose tumors were not eradicated nevertheless did have a reduction in pathological stage. Therefore, a comparison of survival in various pathological stages between patients irradiated and those not irradiated preoperatively becomes an illogical exercise. Transurethrally resected tissue should be carefully reviewed by the urologist and the pathologist jointly so that better, more accurate assessment will be accom-
227
PREOPERATIVE IRRADIATION FOR BLADDER CARCINOMA
TABLE
7. The incidence of 4 frequent complications according to type of operation for irradiated and non-irradiated patients*
Type of Operation
Irradiated: Partial cystectomy Complete cystectomy Cystostomy Exploratory celiotorny Urinary di version Total Non-irradiated: Partial cystectomy Complete cystectomy Cystostomy Exploratory celiotomy Urinary diversion Total
lieus Pts. Entered Postop. No.(%)
Persistent Sinus 'Wound Infection Wound Dehiscence No.(%) No. (%) No.(%)
17 96 1 11 I 126
1 (6) 19(20)
2 (12)
20(16)
17(13)
25 111
l (4) 23 (21)
14 (15)
5 (29t) 30(31)
1(9)
1 (6)
7(7) I (9)
35 (28t)
9(7)
11 (10)
21 (19)
l (4) 12 lll)
I (7 J
1 (7)
1(7)
l (33) 26 (17)
13 (8)
l (33) 23 (15)
1 (4)
2
15 3 156
2 (13) 1 (33) 16(10)
"" Includes patients classed as eligible or ineligible. t Significantly different proportions in the irradiation and non-irradiation series.
plished and the need for other diagnostic tools in clinical staging will be indicated. The experience of investigators has demonstrated that in the hands of radiotherapists working in this project the amount of irradiation given in the exact fashion described, followed by an open surgical procedure in the exact time sequence described is not associated with any increase in lethal complications nor any non-lethal ones aside from wound infections. Thus, the adjuvant use of irradiation seems entirely justifiable from the risk standpoint. However, as our experience has broadened, other influences of irradiation have become evident. For instance, there have been 60 patients who were randomized for irradiation who did not undergo an operation as opposed to 27 non-irradiated patients who did not undergo an operation. More patients refused therapy in the series randomized to irradiation than in the alternate group and more of those who refused did so with respect to the surgical part of the program, not the irradiation portion. Further, there were 9 patients with complications following irradiation who did not have an operation and 6 more patients who died after irradiation. Five other patients were excluded because of protocol violations while there were none in the nonirradiated group (table 3). From this survey it is evident that the inclusion of irradiation works subtle differences into the data. Further, the exclusion from the total program of certain patients suggests the possibility that bias may enter into the analyses since a "different" group of patients may finish the irradiation-operation program as
opposed to the patient treated with alone. This "different" group might be produced by the elimination of poor risks either as a result of the investigator's decision or progression of the disease. Thus, only a select group may finish the combined program to the apparent detriment of the control group. As time passes it seems that this and other phenomena will become better defined. With regard to survival, most considerations are best limited to 24 months, though there are several patients alive 3 and 4 years post-treatment. Though not shown in the tables or figures, the minority group of segmental resections patients), comprised largely of stage B 1 has survived. Eighty-eight per cent were alive at 12 months and nearly all of these have survived 18 months. These are included in the total survival analyses, thus producing some bias in that group. They and other special portions of the population will be considered specially in future publications. Life table plots of the separate treatment groups demonstrate, at best, only minor trends of little significance. The 95 per cent confidence limits for these separate groups are shown in figure 2 where it is evident that thus far no regimen has any advantage. Survival figures of the total group show a rapid loss up to 15 to 18 months with little more than a 50 per cent chance of survival at this time limit (fig. 3). The curve then levels off so that there is a 30 to 40 per cent chance of surviving more than 3 years. The shape of the curve suggests that there are at least 2
228
PROUT, SLACK AND BROSS
8. Causes of death, type of operation and therapy for patients dying within 2 months postoperatively or from entry if no operation
TABLE
Mo. Type of TherDied 0tyi~!apyt
0
7 7 4 6
0
3
0 0
0
0 0 0 0 0 0
3
3 3
3
3
0 0
7 5 8 8 8 8 8 7
1
2
7 7 8 8 8 7
2 2 3
8 3 3
3
3
3
4
3 3 3 3 5 5 5
4 7 6 8 7 5 8
9. Distribution of month of death or last followup for 161 eligible patients at risk 12 months or more
TABLE
Mos. Postop. Causes of Death
Metastatic carcinoma, coronary occlusion Myocardial infarction Cardiac arrest Cardiovascular collapse, metastatic carcinoma Metastatic carcinoma, atherosclerosis, pyelonephritis Metastatic carcinoma, cardiac failure, septicemia Peritonitie, pneumonia, atherosclerosis Respiratory arrest, septicemia, uremia Cardiac arrest, peritonitis Pulmonary embolus Cerebrovascular accident, pulmonary embolus Cardiac arrest Pulmonary embolus Metastatic carcinoma, uremia, pyelonephritis Pneumonia Metastatic carcinoma Metastatic carcinoma Metastatic carcinoma GI hemorrhage Pulmonary embolus, pulmonary edema and congestion Pulmonary embolus, pneumonia Pulmonary embolus Drug toxicity, pyelonephritis, cerebral edema Subacute bacterial endocarditis, splenic infarct, pulmonary emphysema Shock, peritonitis, pulmonary edema and congestion Cardiac failure, metastatic carcinoma Metastatic carcinoma, septicemia, uremia Peritonitis Metastatic carcinoma Metastatic carcinoma, hepatic failure Metastatic carcinoma Metastatic carcinoma
* Type of operation codes: !-partial cystectomy, 2-total cystectomy, 3-radical cystectomy, 4-cystostomy, 5-exploratory celiotomy, 6-urinary diversion. t Therapy codes: 3-irradiation 5-FU, 4-irradiation placebo, 5-non-irradiation 5-FU, 6-non-irradiation placebo, 7-irradiation, 8-non-irradiation.
populations that are admitted to the study and complete the therapeutic plan. One of these has metastases already but they cannot be detected by the usual diagnostic studies and a surgical procedure also fails in this regard. The patients ultimately have distant and/or local disease and die within the first year or so. The second group is comprised of those patients living longer whose survival curve is now nearly flat. Many of them
0-1 2-3 4-5 6-7 8-9 10-11 12-13 14-15 16-17 18-19 20-21 22-23 24-25 26-27 28-29 30-31 32-33 34-35 36-37 38-39 40-41 42-43 44-45 46-47 48-49 50-51 52-53 Total
Irradiated 5-FU Placebo Dead Alive Dead Alive
2 2 3 3
3 2 1 1
2 2 2
4 1 2 3 2
Non-Irradiated Placebo 5-FU Dead Alive Dead Alive
1 4 2 2 3
2 4 2 3 6 5 4 1
1 3
5 2 2
3
2 1
2 2 2 2
2
4
2
2 2
3
20
11
13
25
18
16
31
27
may also have metastatic disease but it has been slower in manifesting itself. Adequate numbers of patients and further followup should clarify this issue. One other matter bears on the question of undetected metastatic disease. One might expect local pelvic recurrence to be a commonly encountered phenomenon in patients who are not cured. Further, if irradiation were effective in preventing local recurrences then the control group might suffer from these in excessive numbers. While the data are incomplete because the investigators either did not or could not record the first and subsequent sites of recurrence, there is information available on 88 patients relative to this important matter. From table 10 it can be seen that distant metastases as the first evidence of failure occurred with surprising frequency. The terminology used in tabulation is not exact and much of the data are derived from clinical impressions but, from the early death rate and the wide distribution of metastases, it seems reasonable to propose that 1) many of the metastases
PREOPERATIVE IRRADIA'I'ION FOR BLADDER CARCINOMA
229
100
BO
I II
..,.... 60 <
".., ""
:,.
~
::,
40
VJ
20
30 5-FU
33 Placebo
Combined
IRRADIATION
53
5-FU
NO. PATIENTS
Placebo
Combined
NON-IRRADIATION
Frn. 2. Survival rate at 12 months with 95 per cent confidence intervals for all eligible patients entered 12 months or more. 100
80
60
40
20
12
MONTHS
AFTER
18
30
36
.,
48
51
SURGERY
Frn. 3. Probability of survival for all eligible patients with followup
were present when the regimen was started; 2) local recurrences were not the rule; 3) preoperative irradiation may play a role in altering the incidence of pulmonary metastases but there is little to suggest that its use influences the incidence of metastases to sites like bowel, uterus, and, possibly, the perineum, the peritoneal vaginal remnant where direct implantation may be the mode of delivery and 4) preoperative irra-
diation demonstrated no advantage in preventing either recurrence or new tumors from arising in the bladders of patients treated by segmental resection. CONCLUSIONS
The 5-year status of a cooperative program designed to determine the effectiveness of pre-operative irradiation when used as an adjuvant
PROUT, SLACK AND BROSS
230
INITIAL
lOQ~~••••••••••••••\
8-
~'\
--"-~~M~~MOR
~: ; IRRADIATED
NO TUMOR TUMOR
7~
•....................\
'
\
~
NON-IRRADIATED
-~---==;-···
',
',,,___ , ___
\
\ ... \..\
\
~::;.--,, ., _____ ._··-··....···· ,,.___ .,··························· ,____________ _
1'2
i's
1'e
21
24
2'7
36
3§
36
3§
42
4'5
4'8
s'i
MONTHS AFTER SURGERY
Fm. 4. Probability of survival for irradiated or non-irradiated patients entered 12 months or more with tumor absent or present at operation. TABLE
10. Site of recurrence* for irradiated and
non-irradiated patients Site Scar Peritoneal cavity Ribs Spine Pelvis Lungs Iliac nodes Liver Rectum Bladder Shoulder Head Abdominal fluid Perineum Femur Pleural cavity Supraclavicular nodes Small bowel Colon Kidney Uterus Ureters Vagina Totalt
NonIrradiated Irradiated 3 9
2
2 4
4
2 3
10 2 3 4 6
35
52
* One recurrence per patient is recorded here. Nine patients had more than 1 recorded in which case the first is tabulated. t One cardiovascular recurrence in the pericardium is not tabulated. There were 11 irradiated and 14 non-irradiated patients who had recurrence but the site is unknown. Recurrence was noted at death but no autopsy was performed.
in the surgical management of invasive bladder carcinoma is described. Of 427 patients entered, 242 are currently eligible and 185 are ineligible.
The ineligible category includes 93 patients who were excluded from the study and 92 we called protocol deviates because, while they did not finish the study, they proceeded far enough to provide data that will help in answering certain questions such as the effects of preoperative irradiation on bladder carcinoma. Preoperative irradiation when given as described was effective in destroying the bladder tumors in about a third of the surgical specimens. When irradiation was not used, the diagnostic procedure removed the tumor 7 per cent of the time. Of the non-lethal complications the only statistically significant increase was found in wound infections. Lethal complications occurred without respect to treatment group. Estimates of clinical staging demonstrated no close correlation with the true stage. This defect makes accurate evaluation of the effect of preoperative irradiation difficult. A life-table curve for all eligible patients demonstrates rapid survival loss in the first 15 to 18 months postoperatively. Relatively few deaths occurred after 18 months and a number of patients are alive in their third, fourth and fifth years. Life tables for patients irradiated or not anrl with or without tumor in the surgical specimen suggested some initial advantage in survival for those whose tumors were eradicated by preoperative irradiation. Patients with tumor eradicated
PREOPERATIVE IRRADIATION FOR BLADDER CARCINOMA
by the diagnostic procedure (non-irradiated, no tumor) had a good prognosis with 100 per cent survival at 12 months, but experienced rapid loss thereafter to a survival probability similar to that of the other groups (approximately .40) at 30 months. Ninety-five per cent confidence limits for the different forms of therapy show overlap, support-
231
ing the conclusion that no regimen is better than another. Metastases found in patients who were treated according to the protocol requirements were widespread, showed no predilection for local recurrence and occurred without regard to whether the patient had received preoperative irradiation.