Irradiation and 5-fluorouracil as Adjuvants in the Management of Invasive Bladder Carcinoma. A Cooperative Group Report after 4 Years

Vol. 104, July Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1970 by The Williams & Wilkins Co.

IRRADIATION AND 5-FLUOROURACIL AS ADJUVANTS IN THE MANAGEMENT OF INVASIVE BLADDER CARCINOlVIA. A COOPERATIVE GROUP REPORT AFTER 4 YEARS GEORGE R. PROUT, JR., NELSON H. SLACK

AND

IRWIN D. J. BROSS

From the Urological Service, The Massachusetts General Hospital, Boston, Massachusetts and the Roswell Parle Memorial Institute, Buffalo, New Yor/c

operative group under the aegis of the Clinical Studies Panel, an extramural committee of the Cancer Chemotherapy National Service Center. This group was developed during 1962 and its formation as well as some of its initial experiences is given elsewhere. 6 , 7 Based on reports concerning the administration of 5-fluorouracil (5-FU) as definitive treatment for advanced bladder carcinoma, 8- 10 the group included the use of this drug as a postoperative adjuvant modality. Provisions were also made for patients who had demonstrable muscle invasion and were to be treated definitively by transurethral resection to receive 5-FU postoperatively. Subsequently, the choice of transurethral resection as definitive therapy for invasive carcinoma was made so seldom by the participants that this portion of the study was discontinued after a year. In addition to the adjuvant program involving preoperative radiotherapy, an appropriate open operation and postoperative 5-FU, the group also decided to study 5-FU when used as definitive treatment in patients with advanced bladder carcinoma. The results of that study demonstrated the absolutely critical role of a placebo in a clinical trial. 11

Patients with invasive bladder carcinoma represent a serious problem that has not been resolved satisfactorily. Reports concerning the results of operation and radiotherapy for invasive bladder carcinoma vary for many reasons which include the physician's background and preference of treatment, patient selection, heterogeneity of the population with bladder carcinoma and heterogeneity of the neoplasms themselves. Therefore, comparison of results of treatment between series does not provide conclusions that are necessarily valid. The fact that surgical procedures and irradiation alone do produce survivors suggested that their combined use might result in an increase in the incidence of survival. Several investigators reported on their observations in this regard. 1- 5 While these studies are extremely important they have certain almost insurmountable defects, for example lack of random selection and lack of controls that tend to detract somewhat from the results. To obtain a more precise estimate of the results of adjuvant radiotherapy followed by an appropriate open operation we formed a coAccepted for publication June 25, 1969. Read at annual meeting of American Urological Association, San Francisco, California, May 11-15, 1969. This investigation was .supported by Public Health Service Research Grant number CA 06732 from the National Cancer Institute. 1 Whitmore, W. F., Jr.: Treatment of bladder tumors. Surg. Clin. N. Amer., 49: 349, 1969. 2 Galleher, E. P., Jr., Young, J. D., Jr., Mowad, J. J., Wizenberg, M. J. and Bloedorn, F. G.: A followup study of supervoltage irradiation followed by cystectomy for bladder cancer. J. Urol., 99: 59, 1968. 3 DeWeerd, J. H. and Colby, M. Y., Jr.: Bladder carcinoma. Combined radiotherapy; and surgical treatment. J. A. M.A., 199: 109, 1967. 4 Sagerman, R.H., Veenema, H.J., Guttmann, R., Dean, A. L., Jr. and Uson, A. C.: Preoperative irradiation for carcinoma of the bladder. Amer. J. Roentgen., 102: 577, 1968. 5 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.

6 Prout, G. R., Jr.: The development of a cooperative study and its preliminary observations on adjuvants (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., pp. 270284, 1967. 7 Prout, G. R., Jr.: In: Cancer Therapy by Integrated Radiation and Operation. Edited by B. Rush, Jr. and R.H. Greenlaw. Springfield, Illinois: Charles C Thomas, pp. 119-127, 1968. 8 Deren, T. L. and Wilson, W. L.: Use of a 5fluorouracil in the treatment of bladder carcinomas. J. Urol., 83: 390, 1960. 9 Field, J.B.: 5-Fluorouracil (NSC-19893) treatment of advanced cancer in ambulatory patients. Cancer Chemother. Rep., 33: 45, 1963. 10 Glenn, J. F., Hunt, L. D. and Lathem, J. E.: Chemotherapy of bladder carcinoma with 5-fluorouracil. Cancer Chemother. Rep., 27: 67, 1963. 11 Prout, G. R, Jr., Bross, I. D. J., Slack, N. H.

116

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA

TREA1T'1ENT PlJlN FOR ADJlNANT SlUDY

HISTOlJXJICAL EVIDENJ OF ffiSCI.E If'NASION r,

7'~

1-,~

~ O P E N SuRGERY~

~.

~c. FIG. 1.

TABLE 1. Dr. Rubin H. Flocks Dr. Clarence V. Hodges Dr. Wyland F. Leadbetter Dr. Dr. Dr. Dr.

Dr. Dr. Dr. Dr. Dr.

George R. Prout, Jr.* Juan Del Regato William L. Valk Marvin W. Woodruff

Protocol committee University of Iowa University of Oregon Massachusetts General Hospital Medical College of Virginia Penrose Cancer Hospital University of Kansas Roswell Park Memorial Institute Statistical Consultant, Roswell Park Memorial Institute Statistical Consultant, Roswell Park Memorial Institute

Committee of Radiotherapists E. Richard King Medical College of Virginia William S. Maxfield Johns Hopkins Hospital William T. Moss Northwestern University Juan Del Regato* Penrose Cancer Hospital Milford D. Schulz Massachusetts General Hospital UCLA Statistical Consultant, Roswell Park Memorial Institute

Committee chairman.

METHODS AND MATERIAL

Details of the protocol of our study which began December 13, 1964 are described in the appendix. Patient eligibility is dependent on 2 major considerations: 1) the patient is judged potentially curable and 2) there is histological evidence of muscle invasion. The patient is then randomized to receive or not to receive preoperative irradiation. In the former instance the irradiation must be from a supervoltage source and at least 4,500R must be delivered in 28 to 32 days. An open surgical procedure of the surgeon's 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.

117

choice must be carried out between 4 and 8 weeks after the last dose of irradiation. When irradiation is omitted, the appropriate open surgical procedure is done promptly. Postoperatively the patient is again randomized to receive 5-FU or a placebo beginning in 14 days (fig. 1). Followup periods are stipulated to insure recognition of toxicity related to treatment as well as recurrence of tumor. The final determinants are recurrence of tumor, death or 5-year survival. Figure 1 is a schematic representation of the plan of study. The protocol committees are listed in table 1 and the investigators and some of their associates responsible for the conduct of the study are listed in table 2. RESULTS

By December 1968, 325 patients had been admitted to the study (fig. 2). An analysis was made of the groups from an administrative standpoint (table 3). There are 170 eligible and 155 ineligible patients. The term ineligible is used to define patients who will not assist in evaluation of the entire therapeutic regimen. This is not to imply that many of these ineligibles cannot be used to answer questions relative to preoperative irradiation and other important considerations. The reasons for exclusion are detailed in table 4. Ejfect of irradiation on stage of neoplasm. The clinical and pathological stages in patients irradiated or not irradiated and who are eligible or ineligible are noted in tables 5 and 6. In tables 7 and 8 the eligible and ineligible patients are combined since there are actually no differences in these groups at this point in the treatment plan. For reasons that will be discussed, only those in the non-irradiated group are relevant with regard to clinical staging. It is evident that a low level of agreement between clinical and pathological stages exists in these patients. The effect of irradiation upon the tumor can be best discerned by comparing the incidence of tumor-free specimens in the 2 groups. Of the eligible irradiated patients 19 of 56 (34 per cent) had no tumor in their specimens while 8 of 75 (10 per cent) of the non-irradiated patients had no tumor in their specimens. Similar figures are derived for the ineligible patients and for the combined groups of eligible and ineligible patients, irradiation was associated with a tumorfree specimen in 33 per cent of 88 patients while in the non-irradiated group 9 per cent of 110

118

PROUT, SLACK AND BROSS TABLE 2 Urologist Dr. William A. Milner* Dr. Marcus L. Shoo be Dr. William H. Boyce Dr. Clair E. Cox Dr. James F. Glenn Dr. Saul Boyarsky Dr. Joseph Malin Dr. Rubin H. Flocks Dr. David Culp Dr. Mark Immergut Dr. William Valk Dr. F. Price Cossman Dr. George R. Prout, Jr. Dr. R. Carl Bunts Dr. Ian M. Thompson Dr. Gilbert Ross Dr. Chester Winter Dr. Clarence V. Hodges Dr. Jerry D. Giesy Dr. Harry C. Miller Dr. Marvin W. Woodruff* Dr. Gerald Hardner Dr. Joseph J. Kaufman Dr. Lester Persky Dr. Stephen A. Mahoney Dr. David Albert

Radiotherapist

Institution

Dr. Donald H. Baster

Albany Medical College

Dr. Damon D. Blake

Bowman Gray School of Medicine

Dr. Patrick J. Cavanaugh

Duke University

Dr. Howard B. Latourette

University of Iowa

Dr. Galen M. Tice

University of Kansas

Dr. Seymour H. Levitt

Medical College of Virginia

Dr. Gus R. Ridings

University of Missouri

Dr. Thomas Pomeroy Dr. Clifford V. Allen

Ohio State University University of Oregon

Dr. Philip Rubin Dr. John H. Webster

University of Rochester Roswell Park Memorial Institute

Dr. Justin J. Stein Dr. M. Western Reynolds

UCLA Western Reserve University

Consulting Pathologist Dr. Carlos Perez-Mesa

Ellis Fischel Cancer Hosptital

Dr. Robert K. Ausman Dr. Irwin D. J. Bross Dr. Nelson H. Slack

Statistical Center Director, Health Research, Inc. Chief, Dept. Biostatistics Senior Cancer Research Scientist

Roswell Park Memorial Inst. Roswell Park Memorial Inst. Roswell Park Memorial Inst.

Dr. G. Howard Gowent

Inst. Research Program, Special Pro-

National Cancer Institute

grams Branch

* Replaced by Doctor Woodruff, Dr. Gerald P. Murphy is now investigator at Roswell Park Memorial Institute.

t Dr. Laurence Foye, Chief, Clinical Investigation Branch, National Cancer Institute, has replaced Doctor Gowen.

patients had no tumor in their specimens. These differences are statistically significant (X2). To demonstrate these differences graphically the patients judged to be in a given clinical stage are shown in the actual pathological stage that was determined. The greatest effect seems to be exerted on the lesions that were judged to be in stages B2 or C though there is some effect on those in B 1 (fig. 3). Deaths, complications and the influence of irradiation. Deaths within 60 days of the operation or, if no procedure was done, within 60 days of admission to the study were noted (table 9). The cause of .death in each of the 26 patients was tabulated (table 10). In 6 of the 26 patients who died the cause was pulmonary emboli and in 9 cases metastatic cancer played a major role in producing death. The 20 patients who died postoperatively were separated according to whether they received preoperative irradiation (table 11). There were 10 patients in each group. Sixteen of

these patients had lethal postoperative complications and the patients are equally divided regarding irradiation. Thus, this adjuvant therapy had no role in increasing the death rate postoperatively. Most lethal complications occurred in patients treated with radical cystectomy but not out of proportion to the use of the operation in the group as a whole. Four of the most frequently encountered complications are shown in table 12 in which the cases are divided by operation and according to whether irradiation was given. The incidence of wound infection was higher in the irradiated patients reaching statistical significance (X 2) of the total group irradiated though not for cystectomy alone. Survival. An evaluation of therapeutic effectiveness in terms of survival cannot be made except on a sharply limited basis. Twelve months is the best dividing point since the highest proportion of deaths occurred within a year of the

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA

PATIENTS

THE,8.Jf!C PLAN

IN

ffiEc,

IRRADIATION

119

1968)

NoN-IRRADIATION

164

161

'n_ NOT RAD ATED

ll*

...

I IRRADIATED

NOT IRRADI

ED

142

7*

II

PI us two patients assigned

to but not irradiated who did have surgery.

101 ~JRGE?Y

223 30*

IV

**5

9 5-FU

9*

VI

28

PLACEBO

.51 5-FU

t?

VII

7 PLACEBO

. Fm. 2. Asterisk designates excluded patients with Roman numeral referring to therapy group columns m table 4 in which reasons for exclusion are listed. Double asterisk designates patients with forms in process. operation, a minimum of patients are withheld because of limited time on the study and followup loss for those on the study is minimal. Patients with less than 12 months in the study are withheld from the analysis. Data concerning recurrence are scanty and were not used in this report. The survival distribution for eligible patients separated by surgical treatment who were in the study for more than 1 year was noted (tables 13 and 14). The 12-month survival rates for all patients are shown in figure 4, A. In the irradiation series there is an apparent advantage for the placebo group (87 per cent) over the 5-FU group (61 per cent). The difference is not statistically significant as evidenced by the overlapping 95 per cent confidence limits. Further, from tables 13 and 14 it can be seen that 7 patients am loRt to followup in the placebo group. If, after recovery of the followup data, they are moved laterally (dead), no difference between the groups will exist. In the non-irradiation series the placebo and

5-FU groups appear similar to the irradiation 5-FU series because of the differential between the drug groups in the irradiation series. The combined survival rate for irradiated patients (71 per cent) shows some advantage over the combined rate for those not irradiated (62 per cent). Most patients who underwent partial cystectomy were in stage Br, a group that has enjoyed a relatively long survival (table 14). Therefore, the survival rates for patients undergoing cystectomy, total or radical, are shown in figure 4, B. The only bias demonstrated by including the partial cystectomy patients was to elevate the survival in the non-irradiated series by 7 to 9 per cent. When survival is related to the presence or absence of tumor in the surgical specimen, the results are seen in table 15. The group with no tumor that was not irradiated was specially selected since 6 of 7 patients were in clinical stage Br and the tumor was removed at the time of

120

PROUT, SLACK AND BROSS

the transurethral resection. Curiously, the irradiated group without tumor has survived less well than those with tumor. The patients in the former group, not made up largely of those with high stage tumors, have survived about as well TABLE

as the non-irradiated group with tumor present. It is tempting to speculate that the susceptible tumors were the more rapidly growing, more virulent neoplasms and, even though the local tumor was destroyed, metastases from these lesions produced death. This hypothesis and the other circumstances of this particular group of patients are being evaluated further.

3. Status of acljiwant study (December 1968) Option B

Entered Ineligible: No pathology form or followup data

Option A*

325 155

Total

T.rnLE 5. Comparison of clinical and pathological

334 157

staging in eligible, irracliatecl ancl non-irracliatecl patients Clinical Stage

148 No followup (No Q forms) available Delinquent (entered :2: 12 mos.) Entered < 12 mos. Followup available, but entered < 12 mos.

Pathological Stage

B1

21 15

Irradiated: Tumor absent 0 A B1

18

109 170

D,

Total

2 4

10 9

5

C D1

177

8 7

14 Total Non-irradiated: Tumor absent 0 A B1

156 No followup (No Q forms) available Delinquent (entered :2: 12 mos.) Entered < 12 mos. Follow up available, but entered < 12 mos.

25 4

22

21 13

C D1

118 118

20

12

56*

14 17 21 14

4 8 9

B2

Total Analyzable for 12-mo. surv.

D1

19

B2

Analyzable for 12-mo. surv. Eligible: No pathology form or followup data

C

B2

30

29

13

75t

* 6 additional patients had no pathological stage, additional patients had no pathological stage and/or clinical stage

t8

* Transurethral group. TABLE

4. Reasons for exclusion of 155 patients who hacl invasive blaclcler carcinoma Therapy Groups No Rx Irrad. Rand. to Only Irrad.

Protocol entry criteria Patient refused therapy Metastasis noted clinically, during radiotherapy or at operation Complication interrupted irradiation or prevented operation Complication prevented chemotherapy Complication interrupted chemotherapy Death before any therapy Death after irradiation and before operation Death after operation and before chemotherapy Death after chemotherapy Investigator withdrew patient Metastatic disease at entry Miscellaneous protocol violations Total

2 3

4 6

Irrad. & No Irrad., & Surg., Surg. All or Rx Rand. Surg., NoSurg., All or Drug Part Part of of to Irrad. No Drug Drug Chemo. Rx 5

4

5 g

8

Total

22

4

24

2 15

3D

7

10

4

12 2 11 6 14 155

4

1* 3* 11

4 4 3 37

29

30

2 33

6

* One patient in each group who was randomized into irradiation but never received it and was operated upon instead.

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA TABLE

G. Comparison of clinical and pathological staging in ineligible irradiated and non-irradiated patients

B,

Irradiated: Tumor absent 0

C

Total

10

13

2

4

2

3

4

10

15

32*

Tumor absent 0 A

Tumor absent 0 A B1

D1

C

12

2

5

13 13 11 17

35

35

10

17

15

88

33 per cent tumor-free specimens.

8. Comparison of clinical and pathological staging in non-irradiated eligible and ineligible patients

3

18

Di+i

29

4

Total

4 4

B2

13

B2 C

TABLE

B1

Total

Clinical Stage Pathological Stage Total

A

Total Non-irradiated:

7. Comparison of clinical and pathological staging in irradiated eligible and ineligible patients

TABLE

Clinical Stage

Pathological Stage

121

Clinical Stage Pathological Stage

B,

C

Total

35t

* Pathological stage not available in 6 cases; another patient excluded because muscle invasion was never proved. t Pathological stage not available in 3 cases; another patient excluded because muscle invasion was never proved.

Tumor absent O A Bi B2 C

10 2 11 9 4

D1 &D,

3 5 10 9 16

3 18

6

21 24 32

20

110

2

10

DISCUSSION

The experience of this group emphasizes the need for controlled, prospective studies in circumstances in which clinical problems fail to yield to conventional therapeutic approaches. While the data concerning the study are still preliminary, it seems quite likely that a decision concerning preoperative irradiation will be reached and, while in the process of generating data, the study has placed on a firm basis the fact that preoperative irradiation, when used as described, is not dangerous. Further, the necessary communication that must arise between different medical disciplines can only result in improved care for the patient. Multidisciplinary studies based on well-defined protocols such a,s ours also have beneficial effects on training programs because the house staff becomes deeply involved in the objective decisions that relate to patient evaluation and care. The house staff also comes to appreciate the difficulty with which truly accurate, reliable data are collected from clinical sources. One goal of this program was to determine if a group of urologists could work together effectively on a jointly agreed upon protocol. When the investigators joined to form the group, it seemed highly unlikely that they would be

40

46

9 per cent tumor-free specimens.

responsible for some of the defects that appear in table 4. Admission without muscle invasion, withdrawal by the investigator of patients because of dissatisfaction with the treatment assignment, previous irradiation, a second neoplasm; all these and many other circumstances have been encountered. The reasons for these occurrences are many and are probably related to the strongly motivated physician and his desire to contribute to the study as well as the particular circumstances that surround a given patient, Had the protocol been less rigid, greater numbers of patients might have been admitted. In fact, admission to the study might be closed now, but surely the population would be more heterogeneous and the results less well defined. It is likely that this study, as planned, will provide information concerning not only the modalities used but data about the neoplasm itself that have not been appreciated. Indeed, some unexpected growth characteristics of advanced bladder carcinoma have already been described. 11 Interpretation of the data requires clarification of one definition. A patient admitted to the

122

I ,.//

PROUT, SLACK AND BROSS CLINICAL STAGE B 1 IRRADIATED NON-IRRADIATED

CLINICAL STAGE B2

35 PATIENTS•--• 40 PATIENTS • - •

100

'"""'"'°

,s,,-irnrs •---•

NON IRRADIATED 46PATtENTS-•

I

CLINICAL STAGE C

~ ~

90

i-...

30

§ ~

20 I

,,// I

. .// I ./· 10

Absent

O

A

B1

10

·-----------

Absent

82

O

A

81

r

~

1 Absent

PATHOLOGICAL

PATHOLOGICAL STAGE

B1

B2

PATHOLOGICAL STAGE

FIG. 3. Graphic representation of percentage of patients in each pathological stage who were judged to be in clinical stages B 1 , B 2 and C. TABLE

9. Proportion of patients who cliecl within 60 clays of operation* or of entry into study if no operation was clone Types of Operation

No. patients No. patients dying Percentage

* Figure 2 shows

Partial

Total

33 2 6.1%

28 4 14.3%

Radical 124 11 8.9%

Cystostomy

Exp!. Celiotomy Diversion 21 3 14.3%

4

No Operation 91 6.6%

Total 304 26 8.6%

223 patients operated-213 are tabulated here because 10 patients have forms missing regarding procedure.

study and then dropped for any reason has been labeled "ineligible". Many of these patients received this identifying term shortly after admission but many others did not become ineligible until the surgical procedure revealed advanced disease or the patient experienced a postoperative complication that prevented him from being randomized into the 5-FU-placebo treatment cells. Thus, the patients included in certain analyses in this paper are ineligible only in a sense and are actually similar to their eligible counterparts. For instance, in judging the effect of irradiation on the tumors in tables 5 and 6 all patients went into the operating room as eligible. Therefore, both groups are of value in determining the effect of irradiation 011 the tumor. It is evident that irradiation produced a powerful effect on many tumors. About 67 per cent showed some response clinically that was characterized by a decrease in hydronephrosis, a decrease in the size of the tumor and/or a decrease in induration or palpability on bimanual examination. Agreement between the pathologists

in the cooperating centers and our referee pathologist, Dr. Carlos Perez-Mesa, has been almost perfect as to cell type, muscle invasion and absence of neoplasm. It is not clear why the material reported here and that reported by Whitmore1 should be at variance relative to the incidence of tumor-free surgical specimens. We have made extended efforts to check the validity of the tumor-free specimens from the inception of the ;;tudy and have observed a steady rate of about 30 per cent, a great difference from the 11 per cent he reports. Of course, differences in patients, pathologists and, most likely, in the outline of the experimental procedure all play a role in producing the discrepancy. The data relative to the effect of irradiation on the tumor might be misinterpreted. If one accepts the evidence in tables 5 to 8 that clinical staging is not particularly accurate when patients have muscle invasion, then it is true that one cannot determine absolutely the real effect of irradiation by examination of the surgical specimen. Only rough approximations can be made

123

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA

10. Cause of death, type of operation and therapy for patients who died within 2 months of operation or of entry into study if no operation was clone

TABLE

11. Postoperative cause of death in 20 patients separated according to whether they received irradiation

TABLE

Kon-Irradiated

Irradiated

Type of TherOper- apyt ation*

7 8

4 6

7

2 3

4

Causes of Death

J,fetastatic Ca., coronary occlusion Metastatic Ca., cardiac failure 1fetastatic Ca., uremia, pyelonephritis Metastatic Ca. GI hemorrhage lVIetastatic Ca. Cardiac arrest CV collapse, metastatic Ca. Ivietastatic Ca., atherosclerosis, pyelonephritis Pulmonary embolus Pulmonary embolus, pulmonary edema & congestion Pulmonary embolus, pneumonia Respiratory arrest, septicemia, uremia Peritonitis, pneumonia, atherosclerosis Cardiac arrest CVA, pulmonary embolus Cardiac arrest, peritonitis Pulmonary embolus Drug toxicity, pyelonephritis, cerebral edema Subacute bacterial endocarditis, splenic infarcttion, pulmonary emphysema Shock, peritonitis, pulmonary edema & congestion Cardiac failure Peritonitis Pulmonary embolus Metastatic Ca., hepatic failure !vietastatic Ca.

* I-partial, 2-total, 3-radical, 5-exploratory celiotomy. t 3-irra.diation, 5FU; 4-irradiation, placebo; 5-nonirradiation, 5FU; 6-non-irradiation, placebo; 7-random. to irradiation; 8-random. to non-irradiation.

and even these must be modified by the obvious therapeutic effect that the diagnostic transurethral resection sometimes has on the pathological stage. Further, a comparison of the survival of groups irradiated or not, according to pathological stages, may not be appropriate because the irradiation will likely have decreased the pathological stage in some patients and this effect cannot be taken into aceount. Thus, it becomes evident that clinical staging is not an academic exercise that can be omitted or estimated casually if 2 different forms of treatment are to be judged. In addition, careful evaluation of other aids is clearly in order. 12 • 13 With regard to survival, it is evident from the 12 Lang, E. K.: Triple cystogram and selective arteriography. J. A. M.A., 207: 342, 1969. 13 Vecnema, R. J., Fingerhut, B. and Girgis, A. S.: Histochemistry: a possible guide to therapy of bladder lumors. J. Urol., 90: 736, 1963.

Cardiac arrest Metastatic Ca., pyeloncphritis Peritonitis Pulmonary embolus (2) Drug toxicity, pyelonephritis Bacterial endocarditis Shock, peritonitis Cardiac failure :Metastatic Ca., hepatic failure 10 patients

CV collapse, metastatic Ca. Respiratory arrest Cardiac arrest CVA, pulmonary embolus Cardiac arrest, peritonitis Pulmonary embolus (3) Peritonitis Metastatic Ca.

10 patients

distribution of eligible patients in the according to treatment that the death rate is high postoperatively for the first 12 to 18 months (tables 13 and 14). Survival then seems to become relatively long. While the study has not progressed long enough to follow most of these patients to the time of their death, a number are alive after 2 or 3 years. The over-all survival experience is demonstrated by the life table for all eligible patients entered 12 or more months (fig. 5). The survival probability curve falls off rapidly for the first 18 months with little better than a 50 per cent chance from the outset of surviving longer. The curve then levels off, reflecting a much lower rate of death, such that there is a 40 per cent chance of surviving 3 or more years. Finally, the lack of any demonstrable influence of 5-FU on survival in addition to the difficulties and hazards it poses in administration has caused the investigators to drop the drug from the study. This is not to imply that 5-FU may not be effective when used in a fashion other than that described in the protocol.1 4 SUMMARY

The current status of a cooperative group evaluating the effect of preoperative Irradiation and postoperative 5-FU on patients with invasive bladder carcinoma is described. Within a 4-year period 325 patients have been admitted to the study. Of these 325 patients 170 are considered eligible and 155 are ineligible. Preoperative irradiation (4,500R in 28 to 32 14 Stein, J. J. and Kaufman, J. J.: The treatment of carcinoma of the bladder with special reference to the use of preoperative radiation therapy com-bined with5-fluorouracil. Amer. J. Roentgen., 102: 519, 1968.

124

PROUT, SLACK AND BROSS TABLE

12. Four most frequently encountered complications according to

whether irradiation was used Type of Operation

Ileus

Patients

Irradiated

85* 13 72 100* 20 80

Partial cyst.

Cystectomy Non-irradiated Partial cyst. Cystectomy

Wound Infection

Persistent Sinus

No.

%

%

No.

Dehiscence

No.

%

No.

%

15

21

2 12

15 17

4 22

3lt 31

1 5

8 7

17

21

8

5 10

16

20

11

14

* Not included in this analysis are 10 patients without forms indicating type of operation and those receiving cystostomy (3), celiotomy alone (21) and urinary diversion ·(4) since their complication rate was insignificant. t Significantly different proportions between irradiated and non-irradiated patients. TABLE

13. Distribution of month of cleath or last followup for 98 eligible patients receiving a cystectomy Irradiated 5-FU Alive

Dead 0-2 3-5 6-8 9-11 12-14 15-17 18-20 21-23 24-26 27-29 30--32 33-35 36-38 39-40

Non-Irradiated Placebo

Dead

5-FU Alive

3 3

Dead

1 3 2

3 1 2

Dead

Alive

2 6 4

2

3 2

2

Totals

13

TABLE

11

16

11

13

11

20

14. Distribution of month of death or last followup for 20 eligible patients receiving a partial cystectomy Irradiated

Months After Operation

5-FU Dead

Non-Irradiated Placebo

Alive

Dead

Placebo

5-FU Alive

Dead

12 13 16 21 23 27-30 32-35 41

Totals

Placebo Alive

Alive

Dead

Alive

2

2

days) was associated with absence of tumor in the surgical specimen in a third of the patients in contrast to 9 per cent in the non-irradiated patients.

2

3

3

Most deaths occurred within 18 months of operation. Life table survival probabilities for all eligible patients entered 12 months or longer were .66 and .55 at 18 months. A tumor-free

125

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA 10

100

80

60

20

26 )-FU

15 PLAC.

27

36

63

5-FU

PLAC.

COMB.

41

COMB.

NO, PATIENTS

23

13

36

5-FU

PLAC,

COMB.

22

29

5-FU PLAC.

5I

NO.PATIENTS

C0~'8.

NON-IRRADIATION

IRRADIATION

IRRADIATION

NON-IRRADIATION

FIG. 4. A, survival rate at 12 months with 95 per cent confidence intervals for all eligible patients in study for 12 months or more. B, survival rate at 12 months with 95 per cent confidence intervals for eligible patients in study for 12 months or more who had total or radical cystectomy.

specimen was no assurance that an increase in survival might be anticipated. In fact, these patients have survived less well for reasons that are not yet clear. Patients who had a partial cystectomy had a good prognosis, indicating a distinct degree of selection and, possibly, difference in tumor potential. Operative mortality rates were not influenced by either preoperative irradiation or 5-FU while the only significant increase in non-lethal complications was in wound infection when irradiation was used. Since 5-FU has shown no advantage in survival when used in the manner described its use has been discontinued. APPENDIX

Protocol for cooperative study to evaluate therapeutic effectiveness of chemotherapy and radiotherapy as adjuvants to an operatioll in treatment of primary carcinoma of the bladder. 15. Survival rates at 12 months for eligible patients with no residual tumor and with tumor at operation

TABLE

Irradiated No Tumor Survived ~ 12 mos. Total entered ~ 12 mos. minus followup loss Percentage survival rate at 12 mos.

Tumor

Non-Irradiated No Tumor

Tumor

12

22 29

7 7

31 56

58

76

100

57

1.0. Introduction. This protocol describes the conduct of a cooperative study to determine the therapeutic effectiveness of chemotherapy and preoperative radiotherapy as adjuvants to the surgical treatment of primary invasive bladder cancer. 2.0. Conduct of the study. A diagram depicts the program of study which is to be developed (see figure 1). 2.1. Conditions for patient eligibility: a. Patients who have bladder tumor in any of the following stages (Jewett-Marshall) : Stage Bi-superficial muscle mvas10n Stage B2-deep muscle invasion Stage C-tumor involving perivesical fat Stage D 1-metastases to pelvic lymph nodes or adjacent organs Staging of the disease is to be determined by bimanual examination, surgical exploration,* or other generally accepted techniques. b. Tissue suitable for grading of differentiation (I3roders' I-IV exclusive of papilloma) must be available. c. A patient previously treated in the study may be re-entered if recurrence of tumor is discovered and the patient qualifies in all other

* This was never used for clinical staging cited in the text (G. R. P., Jr.).

126

PROUT, SLACK AND BROSS 100

80

60

40

20

12

18

24

30

36

42

MONTHS AFTER SURGERY

Fm. 5. Life table of survival for all eligible patients in study entered 12 months or more ways. The new treatment option must be one other than used initially and a new study number must be assigned. Patients who have undergone previous therapy for bladder cancer not within the confines of this program may be admitted by meeting all of the requirements. 2.2. Conditions for patient ineligibility: a. Patients who are considered poor risks for an operation, radiotherapy, chemotherapy or who are 1) confined to bed or 2) require institutional care or equivalent attention because of advanced bladder cancer or any other disease. b. Patients with a white blood count less than 4,000 per cu. mm. or a platelet count less than 100,000 per cu. mm. taken on or within 7 days before the intended day of entry. c. Patients with a previous or concomitant malignancy other than bladder cancer or basal or squamous cell carcinoma of the skin. d. Patients who are pregnant. e. Patients with tumors of the bladder other than primary carcinoma. f. Patients who have had pelvic irradiation or cancer chemotherapy

within 2 months preceding the date they are scheduled to enter the study. g. Patients who are staff members or the relatives of staff members. 2.3. Selection of patients: Within the conditions of paragraphs 2.1 and 2.2 all patients for whom there is histological proof of primary carcinoma of the bladder with muscle invasion will be admissible to the study. Eligible study patients will be divided into 2 therapy groups: 1) patients who have been treated definitively in the immediate past by transurethral resection as the procedure of choice and 2) patients who are best treated by an open operative procedure in the judgment of the principal investigator. 2.4. Pre-therapy studies: History and physical examination information will be recorded on form U-1 for all patients. Required studies include 1) endoscopic evaluation, 2) excretory urogram, 3) cystogram, 4) blood urea nitrogen or non-protein nitrogen, 5) urinalysis, 6) white blood count, 7) hemoglobin measurement or hematocrit, 8) platelet count, 9) alkaline phosphatase and 10) chest x-ray. A principal investigator may elect to perform 1) urine cytology and 2) total serum protein and albumin-globulin ratio. If he does so, he will be

127

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA

expected to submit information on each for all patients under his care. Studies to be performed immediately before chemotherapy for patients who have received preoperative radiotherapy include: 1) hemoglobin 2) white blood count, 3) platelet count. 2.5. Standard operative procedure: According to the tenets of the surgeon, every effort should be made to complete the most suitable curative operation in each patient. A copy of the customary dictated operative report will be forwarded to the Statistical Unit. 2.5.1. Trarisurethral resection: These patients will be assigned randomly after resection into one of two adjuvant treatment groups: 1) 5-fluorouracil or 2) placebo. 2.5.2. Open operation: After the existence of muscle invasion has been established by endoscopic diagnostic resection, these patients will be assigned randomly 1) to receive preoperative adjuvant radiotherapy or 2) to proceed to operative procedure without radiotherapy. For patients who are given radiotherapy, an evaluation of its effect will be reported at the time of operation on form U-3. All patients will undergo an operation in accordance with paragraph 2.5, following which each will be assigned randomly to one of two adjuvant chemotherapy groups: 1) 5-fluorouracil and 2) placebo. 2.6. Pathology findings: One staff pathologist at each institution should supervise all tissue examinations, both gross and microscopic. Information will be recorded on form U-5 which will be attached to a copy of the customary dictated pathology report and forwarded to the Statistical Unit. Slides demonstrating the primary tumor and 0

6

0

surgery

8

9

15

15

15

15

15

14

15

16

17

18

15

15

15

15

15

10

11

12

7.5 19

20 7.5

13

as many involved sites as possible will be sent to the Statistical Unit for review by the consulting pathologist of the Bladder Adjuvant Study. 3.0. Patient assignment procedure. The random allocation of patients in the various treatment groups will be accomplished by direct prepaid telephone communication with the Statistical Unit as soon as the diagnosis of invasive bladder cancer has been established, the tumor is staged tentatively and the patient is deemed eligible. The following information concerning the patient will be given to the Statistical Unit: a) name, b) hospital number, c) age, d) height, e) weight, f) stage of tumor, g) operative procedure. The Statistical Unit will assign a study number and will notify 1) if the patient is to receive radiotherapy (for appropriate study groups) or 2) if chemotherapy is to be given, the number of the drug vials to be used. For the group of subjects who are given preoperative radiotherapy, a second phone call will be made to the Statistical Unit in the 48-hour period preceding definitive surgery to receive the chemotherapy treatment assignments as previously described. Immediately following the initial phone entry of any patient, form U-1 will be sent to the Statistical Unit. This form must reach the Statistical Unit within 96 hours of phone entry to permit the preparation of reports for transmis,;ion to official supervisory agencies of the federal government. 4.0. Method of adjuvant treatment procedures. 4.1. 5-Fluorouracil (double-blind): Patients receiving 5-fluorouracil as a surgical adjuvant will be treated with 15 mg. per kg. per day for 5 consecutive days beginning on the fifth day following transurethral resection or the fourteenth day following open operation after which 6 doses of 7.5 mg. per kg. per day will be given on alternate days. A diagrammatic representation of the treatment plan is given below. 14

7.5 21

22 7.5

15

16

7.5 23

24 7.5

17

18

26 7.5

20

7.5

7.5 25

19

27

28 7.5

21 7.5

29

30 7.5

Postop. Days mg./kg. Postop. Days mg./kg.

128

PROUT, SLACK AND BROSS

The dosage will be calculated on the basis of the actual or ideal weight of the patient, whichever is less, at a time immediately before the operation. The ideal weight is to be determined by consulting the chart provided in this protocol document as appendix 2. No patient will receive more than 1 gm. per individual dose, regardless of weight. The complete dose schedule will be administered in all cases excepting those in which toxicity appears before completion. Toxicity includes: a) stomatitis, b) lip ulceration, c) diarrhea, d) white blood count less than 3,000 per cu. mm., e) platelet count less than 100,000 per cu. mm. The white blood count and/or platelet count should be repeated before chemotherapy is suspended to reduce the influence of laboratory variation. 4.1.1. Method of 5-fluorouracil administratration: An intravenous infusion of 250 to 500 ml. 5 per cent dextrose in water or normal saline is begun and adjusted at a flow rate to produce an infusion of no less than 2 hours. The dose of 5-fluorouracil is placed in the whole volume of the infusion solution which is agitated to assure mixing. Patients are to receive drug from only the vials having the number assigned by the Statistical Unit.No substitution is to be made. In the event of breakage or other difficulty, the Statistical Unit will be contacted for further instructions. 4.2. Preoperative radiotherapy: 4.2.1. Quality and source of radiation: It is required that a roentgen or gamma beam of radiation be used externally. Equipment must be 1) at least 1 :.vIEV or 2) cobalt-60 or 3) a linear accelerator. Radiations are to be to a half value layer of no less than 9 mm. copper. 4.2.2. Techniques: The goal of this prnject will be to irradiate the region of the bladder and the potential sites of metastatic involvement within the true pelvis. Rotational techniques with any of the noted sources will be permissible. A minimum distance of 50 cm. from the source of the skin will be required for cobalt-60 sources.

The actual size and shape of fields and the direction of approach will be at the discretion of the radiotherapist. However, an antero-posterior roentgenogram will be made, marking the limits of entry ports, preferably using a contrast medium in the bladder for its localization. 4.2.3. Dosimetry: The dose will be calculated at 2 points: 1) in the center of the irradiated volume at the midline in the mid-antero-posterior plane of the pelvis and 2) on each side 5 cm. lateral to the other point. The dose to be administered at the midline point will be an average of no less than 1,000R per week with a minimum total dose of 4,500R delivered in 28 to 32 days. With rotational therapy the dose is to be measured in the center of the axis of rotation. 4.2.4. Post-radiotherapy interval: An operation will be performed not before 30 nor after 60 days following the completion of radiotherapy. 4.2.5. Evaluation of preoperative radiotherapy: At the time of open operation the surgeon will make comparative judgments regarding the condition and size of the tumor before radiotherapy and at operation in accordance with the information required on form U-3. 4.2.6. Code break: Code break information will be provided upon telephone request of the principal responsible investigator to the Statistical Unit. The reason for the code break request will be recorded in the patient's chart at the Statistical Unit. Every effort is to be made to maintain the integrity of the study by avoiding such requests except under most unusual circumstances. 5.0. Followup studies. 5.1. Early post-chemotherapy period: This period will be the 30 days subsequent to the administration of the last dose of chemotherapy. During this time all complications and toxic manifestations will be recorded on form U-4. The following studies will be performed twice weekly during the period

IRRADIATION AND 5-FU FOR INVASIVE BLADDER CARCINOMA

chemotherapy is given and in the early post-chemotherapy period as just defined: 1) hemoglobin, 2) white blood count, 3) platelet count. Treatment and early post-chemotherapy information will be recorded on form U-4. 5.2. Quarterly followup: All patients will be examined every 3 months for the length of the study. The detection of tumor recurrence will be one of the primary goals of this examination which will include at least the following evaluations: a) hemoglobin, b) white blood count, c) platelet count, d) alkaline phosphatase, e) chest x-ray, f) skeletal survey at 6-month intervals, g) IVP at 3 and 9-month followup visits; yearly thereafter. In addition for patients who have not undergone cystectomy, cystoscopy will be performed quarterly for the first 2 postoperative years, semiannually for the next 2 years and annually thereafter. Areas of possible recurrence are to be investigated by appropriate means. Biopsy verification of recurrence will be established whenever possible. Sus-

129

pected or proved recurrence will be reported on form Q. Regular protocol followup of all entered patients will continue until a proved recurrence has been reported to the Statistical Unit or the principal investigator receives written notification that this obligation is abrogated. 5.3. Additional therapy: Patients participating in the Bladder Adjuvant Study will be given no anti-tumor therapy other than described in this protocol until removed from the study by the appearance of a tumor recurrence, after which the physician may use any therapeutic modality. 5.4. Postmortem examination: Autopsy protocols should be secured whenever possible and submitted to the Statistical Unit. 6.0. Administrative responsibilities. 6.1. Statistical and logistical services: The Chemotherapy Statistical Unit at the Roswell Park Memorial Institute, Buffalo, New York, will provide these services, supported in part by a service contract with an agency of the federal government.