Conservation of bladder function in patients with invasive bladder cancer treated by definitive irradiation and selective cystectomy

Inr. I Rodration Onmlogy Yol Phys Vo! Prtntcd ,n the U.S.A All rtghts resewed

7. pp.

03M)-3016/81/050569-05502.aO/0 Copyright 0 1981 Per&mm

569-573

Press Lid

??Original Contribution CONSERVATION OF BLADDER FUNCTION IN PATIENTS WITH INVASIVE BLADDER CANCER TREATED BY DEFINITIVE IRRADIATION AND SELECTIVE CYSTECTOMY GEORGE J.

MARK

B. GOODMAN, FRCP(C), FRCR,’ T. GREGORY ELWOOD, M.D.,’ FRCP(C) AND JOHN BALFOUR,

HISLOP,

M.D.,’

M.D., FRCS(C)3

Four hundred seventy patients with invasive bladder cancer treated by definitive irradiation (5000 rad or more) and selective cystectomy were followed to assess their survival status and bladder function status. (90 % were followed for at least 10 years or to death.) The survival rates for these patients were similar to those obtained in studies of preoperative irradiation with compulsory cystectomy: 5 and 10 year survival rates were 38 and 22% respectively. Sixty-five to 70% of these survivors lived with healthy, functioning bladders to at least 10 years after treatment. Seventy-five patients had a selective cystectomy, usually for recurrent disease, with an operative mortality rate of 11%. Pre-irradiation catheterization, used to control bladder distension and to reduce the possibility of geographic miss in irradiating the tumour, had no effect on the control of local disease or on the long-term survival of patients. Therefore, definitive irradiation with selective cystectomy warrants serious consideration in treating patients with invasive bladder cancer, especially considering the quality of life and the high proportion of patients who retain functioning bladders. Bladder conservation, Bladder cancer. Definitive irradiation,

Selective cystectomy,

Irradiation

METHODS

INTRODUCTION

AND

failures. MATERIALS

A recent review of the long-term survival of 883 patients treated at the A. Maxwell Evans Clinic in Vancouver, British Columbia showed that high dosage irradiation, with selective cystectomy for persistent or recurrent tumor, is an effective means of treating invasive bladder cancer while conserving functioning bladders.’ This paper examines the issues of irradiation failure and conservation of functioning bladders in patients with clinically staged B and C bladder cancer treated by cobalt irradiation of 5000 rad or more with selective cystectomy. Irradiation failure may result from errors in technique as well as from radioresistance of the tumor. One source of technical error relates to distension of the bladder during the course of irradiation treatment, which could result in missing the tumor site. One study found that 16 out of 37 patients were at risk of missing the tumor with beam-directed cobalt because of bladder distension.’ This paper examines this issue also by assessing the impact of pre-irradiation catheterization with continuous drainage during treatment on survival and local recurrence.

Between 1959 and 1972, 470 patients with invasive bladder cancer were registered at the A. Maxwell Evans Clinic and received cobalt irradiation at dosages of 5000 rad or more. Doses were usually given in 15 equal daily fractions over three weeks, using three or more fields IO x 8 cm2 or smaller. All patients had clinically staged B and C bladder cancer and no prior history of malignancy. For each patient, the clinical stage was agreed by authors 1 and 3 after review or repetition of the cystoscopic findings, palpation under anesthesia, radiography and tumor biopsy. These patients were in general older males in good general condition (Table 1). A study was done to identify irradiation failures and to determine the status of all 470 patients in terms of survival and of bladder function. This follow-up involved reviewing their medical records to September 1979 or death. The assessment of bladder status when last seen was usually based on clinical examination; however, if there was a cystoscopy report, then this took precedence. Four hundred and twenty-one (90%) were followed for at least 10 years or to death. The length of follow-up for the

‘Director, A. Maxwell Evans Clinic, 2656 Heather Street, Vancouver, British Columbia, V5Z 333. *Division of Epidemiology, Cancer Control Agency of British Columbia, # 700-686 West Broadway, Vancouver, British Columbia V5Z 1G I. ‘Emeritus Professor, Division of Urology, University of British Columbia, Vancouver, British Columbia. V6T I W5.

Dr. Hislop was supported by National Health Fellowship 6605-1622-47 from the National Health Research & Development Program. Reprint requests to: Dr. G. B. Goodman. Accepted for publication I6 February I98 I.

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Radiation Oncology 0 Biology ??Physics

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May 1981, Vohme7, Number 5

Table 1. Characteristics of the 470 study patients Distribution

Characteristics Age sex (male:female) General condition Good Fair Poor Unknown Tumor clinical stage’

mean 65.8 years range 34-84 years 4.9:1 5% 88 10 1 2 77 23

: Tumor grade’ I 2 3 4 Unknown

3 28 45 22 2

remainder ranged from 55 to 119 months with a median follow-up of 95 months. Survival rates were determined from the start of irradiation treatment by the product-limit method3 for all patients: for patients retaining their bladders, for patients receiving pre-irradiation catheterization with continuous drainage during treatment and for patients receiving no such catheterization. (Pre-irradiation catheterization was not introduced until October 1962; thereafter, it was done for all patients.) These survival rates consider death from all causes. Since patients could die from causes other than bladder cancer, survival rates were then adjusted by age-specific and sex-specific general population death rates to derive the relative survival rate, which is an estimate of survival based only on deaths from bladder cancer.’ In addition, the relative proportions of survivors with and without bladders were determined for all patients alive at 1, 3, 5 and 10 years after starting irradiation treatment.

.....

Fig. 1. Survival rates for 470 patients with invasive bladder carcinoma treated by definitive cobalt irradiation with selective cystectomy.

tent or recurrent disease. There were 235 reported deaths because of bladder cancer and 13 reported deaths because of complications of treatment. Eight of these 13 deaths were attributed to complications of cystectomy, an operative mortality rate of 11% (7 of the 8.died within two months after surgery and 1 died four months after surgery from septicemia attributed to the numerous transfusions required for surgery). Over 90% of the study patients were followed for at least 10 years or to death. On examining- their disease status when last seen alive or at death, 253 (54%) patients were reported to have local and/or metastatic disease: 133 (28%) had local recurrent or persistent disease only, 52 (11%) had metastatic disease only, and 68 ( 14%) had both recurrent and metastatic disease. The bladder status of surviving patients was assessed at various periods of time after irradiation treatment. There was little change in the proportion of survivors with healthy, functioning bladders over the 10 years of follow-up, ranging from 65 to 70% of all survivors (Fig. 3). Although the proportion of survivors with cystectoAll

p&ients:

M

Uncatheterized O---O Catheterized

RESULTS Survival Of the 470 patients with clinical Stage B and C bladder cancer, 38% survived 5 years and 22% survived 10 years (Fig. 1). The percentage of patients alive and with a functioning bladder were 32% at 5 years and 17% at 10 years. These survival rates were based on deaths from all causes. In estimating the survival based only on deaths from bladder cancer, the relative survival rates for all patients regardless of bladder status rose to 46% at 5 years and 34% at 10 years. Relative survival was also calculated for those receiving and for those not receiving pre-irradiation catheterization; no differences in survival were found (Fig. 2).

All pationts with functioning bladders:

c-o o-o

0

I

Uncathetorized Cathotrised

I

I

I

I

I

2

4

6

8

10

Years After Starting Treatment

Irradiation failures In the period under review, 75 patients had a cystectomy following definitive irradiation, mainly for pcrsis-

Fig. 2. Relative survival rates for all patients and for all patients with functioning bladders by pre-irradiation catheterization status.

Conserving bladders while treating bladder cancer 0 G. B. GOODMAN

er al.

20 r 0

Functioning and healthy bfadder

m

Functioning bladder but with recurrent or persistent disease

m

Functioning bladder but contracted

571 (62)

Cystectomy for recurrent or persistent disease Cystectomy for contracted bladder Cystectomy for other reasons

(

Number of survivors at given year

) Number of survivors at given year

0

Ol-

5 1 10 3 Years After Starting Treatment

1

Fig. 3. Distribution of bladder status in survivors at various periods after treatment.

mies remained low, it increased steadily from 7% at one year after treatment to 19% at ten years after treatment (Fig. 4). By ten years after treatment, 68% of the survivors still had healthy, functioning bladders, 7% had diseased bladders, 3% had contracted bladders, 3% had both diseased and contracted bladders and 19% no longer had bladders. Pre-irradiation catheterization had little effect on the control of local disease: 43% of the catheterized patients and 40% of the uncatheterized patients had recurrent or persistent disease when last seen alive or at death. So it is not surprising that there were no significant differences in the bladder status of survivors receiving catheterization and those not receiving catheterization (Table 2). However, metastatic disease was significantly more frequent in the catheterized patients (28% as compared to 16% p < 0.025). The length of follow-up did not differ much between catheterized patients and uncatheterized patients, especially up to 5 years after irradiation: 100% of the uncatheterized patients and over 99% of the Table 2. Comparison

3

5

10

Years After Starting Treatment

Fig. 4. Distribution of reasons various periods after treatment.

for cystectomy

in survivors

catheterized patients were followed for at least 5 years or to death. DXSCUSION Two major concerns in treating patients with invasive bladder cancer are curing the disease and conserving a functioning bladder. Considering first the issue of survival, similar 5 year survival rates have been found for patients with clinically staged B and C tumors treated by preoperative irradiation with compulsory cystectomy and for those treated by definitive irradiation with salvage cystectomy (Table 3). However, for such a comparison of survival rates to be meaningful, one must first ensure that the groups are comparable. Table 3 gives survival by tumor stage only and does not consider other important prognostic factors, such as age, genera1 condition or tumor grade. Two randomized controlled trials have addressed these problems. In Wallace and Bloom’s study of 189 patients,” the overall 5 year survival rates were 33% for

of bladder status in catheterized survivors and in uncatheterized and 5 years after starting treatment Percentage I Year

survivors at 1.3

of survivors at 3 Years

5 Years

Number Survivors with functioning Healthy Recurrence Contracture Disease status unknown Survivors after cystectomy Recurrence Contracture Other

bladders

90 71 15, s* 1 10 4 4

*Some survivors had both recurrence of disease and contracte’d UC = uncatheterized survivors; C = catheterized survivors.

at

94 71 16* 7* 3 6 4 0 2 bladders,

84 62 . II* 18* 0 16 9 0 6

88 67 13* 8* 3 12 9

83 60 14: 17* 0 17 14 0 3

1 2

and hence were counted

twice.

85 70 6* 8* 3 15 11 2

Radiation Oncology *

572

Table 3. Comparison

Report

Biology 0 Physics

Treatment

(rad) with compulsory cystectomy 4000 + cystectomy 32006600 + cystectomy 4500-5000 + cystectomy Miller” 5000 + cystectomy Whitmore et 01.‘~~” 2000 + cystectomy 4000 + cystectomy 6000 + cystectomy Definitive irradiation (rad) with salvage cystectomy (Including only patients receiving salvage cystectomy) Wallace and Bloom” 6000 + cystectomy Galleher et ~1.~ 6000 + cystectomy (Including all patients receiving definitive irradiation r Wallace and Bloom” 6000 + cystectomy Miller” 7000 + cystectomy Caldwell et al.* 6000-7000 k cystectomy

study

I, Volume 7. Number 5

of 5 year survival rates from various studies assessing the treatment

Preoperative irradiation Wallace and Bloom” Galleher et 01.~

Current

May 198

5000 f cystectomy

Clinical Stage

BK

B,C A&S B,C BS

B,C B,C

of patients with invasive bladder cancer

Number of patients

5 year survival

Recurrence rate (local)

(%)

(%)

71

33b 33 36 28 42 41 38

-c -

52b 38

-

23b 21 4ob 32b ‘lb 38b

45

21 26 72 14 86 90

18 BJ I4 BS salvage cystectomy) 85 BK 182 BS 34 B, 81 B2 49 C 470 B,C

16 20 26 -

42

Salvage cystectomy”

N/Ad

Operative mortality (%)

N/A

8 12 8 3 9 11 16

100% 100%

11 0

N/A N/A N/A N/A

Nl A

21% 6% 5% 10%

II 12 II

“Proportion of all patients receiving salvage cystectomy for residual or recurrent disease. bSurvival rates derived by the actuarial or product-limit methods.’ Where possible, the 5 year survival rates are reported for patients with clinical Stages B and C bladder cancer only. The rates for local recurrence, salvage cystectomy and operative mortality are derived from the available information on all patients receivina the stated treatment. and hence mav not be restricted to clinical Stages B and C. c = nit available; d = N/A = not applicable.

preoperative irradiation (4000 rad in four weeks) with radical cystectomy and 23% for definitive irradiation (6000 rad in six weeks) with salvage cystectomy for irradiation failure, a difference which was not statistically significant (p - 0.08). The better survival rates for preoperative irradiation with radical cystectomy were restricted to patients under age 65 years; for those over age 65 the survival rates were virtually the same for both treatment methods. Wallace and Bloom concluded that the treatment of choice was preoperative irradiation with radical cystectomy for patients under age 65. and definitive irradiation with salvage cystectomy for patients over age 65. In a randomized prospective clinical trial of 68 patients reported by Miller,” the 5 year survival rates for the two treatment methods were significantly different: 46% for preoperative irradiation (5000 rad in five weeks) with radical cystectomy and 22% for definitive irradiation (7000 rad in seven weeks) with salvage cystectomy for irradiation failure. However, we could not look at differences in survival by age in Miller’s study because this information was lacking. The effect of age on treatment outcome needs further investigation considering the age distribution of patients with invasive bladder cancer. In the current study, there were approximately equal numbers of patients under age 65 and over age 65. The other issue of major concern in treating patients with invasive bladder cancer is the possibility for conserving a functioning bladder. A substantial proportion (2030%) of bladders removed routinely after irradiation

have shown no residual disease.@‘.“‘-‘* In the current study, a high proportion (65-70s) of survivors was able to live with a healthy, functioning bladder to at least IO years after treatment. Seventy-five (16%) patients had a selective cystectomy with an operative mortality rate (11%) comparable to rates found for preoperative irradiation with cystectomy. Other studies have likewise found comparable mortality and morbidity rates for salvage cystectomy and preoperative irradiation with compulsory cystectomy.” Selective cystectomies were most frequently required for persistent or recurrent disease. One source of failure in local disease control is geographic miss in irradiating the tumor. Since an earlier study found that 16 of 37 patients treated by irradiation for bladder cancer had distended bladders beyond the field of irradiation,’ it was proposed that this source of irradiation failure could be eliminated by catheterization before irradiation and continuous drainage during treatment. In the current study, pre-irradiation catheterization with continuous drainage was found to have no effect on the long-term survival of patients or their bladders. There was no significant difference in recurrence rates between those catheterized and those not catheterized. The reason for the apparent increased frequency of metastases in patients receiving catheterization is not clear. This may simply reflect differences in disease reporting practices over time or, possibly, this may be a chance finding. In any case, it is not likely to reflect a true difference

Conserving bladders while treating bladder cancer 0 G. B. GOODMAN er of.

lecause survival, which is largely dependent on the develbpment of metastases, was virtually identical for those :atheterized and fdr those not catheterized. Considering the impact of cystectomy on the patients’ quality of life, the high proportion of disease-free bladlers removed routinely after irradiation, and the controfersy regarding which treatment has better survival. lefitiitive irradiation with selectivexystectomy warrants

serious consideration

573

of patients with trials of definitive irradiation with selective cystectomy and preoperative irradiation with compulsory cystectomy are needed that consider patients under age 65 and over age 65 separately. in evaluating the outcome of such a trial, the patient’s quality of life should be considered in addition to length of survival. invasive

bladder

in the treatment

cancer.

Further

controlled

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3.

Coldman, A.J., Elwood, J.M.: Examining Can. Med. Assoc. J. 121: 1065-1071, 1979.

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4. Cummings, K.B., Shipley, W.U., Einstein, A.B., Cutler S.J.: Current concepts in the management of patients with deeply invasive bladder carcinoma. Semin. Oncol. 6: 220228, 1979. _5

Deweerd, J.H., Colby, M.Y. Jr.: Bladder carcinoma treated by irradiation and surgery: interval report. J. Urol. 109: 409-413,1973.

6. Galleher,

E.P. Jr., Young, J.D. Jr., Campbell, E.W. Jr., Wizenberg. M.J., Jacobs, M.A., Millstein, D.I.: Pre-cystectomy radiation for carcinoma of the bladder: 17-year experience. J. Urof. 118: 179-183. 1977.

7. Goodman, G.B.. Balfour, J.: Carcinoma Cobalt therapy. J. Ural. 92: 30-36, 1964.

of the bladder:

8. Goodman, G.B., Balfour. J.: Local recurrence of bladder cancer after supervoltage irradiation. J. Can. Assoc. Radiol. 15: 92-98, 1964.

9. Goodman, G.B., Balfour, J., Hislop, T.G., Elwood, J.M.: Carcinoma bladder-20 year results and experience with irradiation and selective cystectomy. Progress in Cancer Research and Therapy (in press). IO. Miller, L.S.: Bladder cancer-Superiority of preoperative irradiation and cystectomy in clinical stage B2 and C. Cancer 39: 973-980, 1977. I I. Wallace, D.M., Bloom, H.J.G.: The management of deeply infiltrating (T3) bladder carcinoma: Controlled trial of radical radiotherapy versus preoperative radiotherapy and radical cystectomy (first report). Br. J. Ural. 48: 587-594, 1976. 12. Whitmore, W.F. Jr., Batata, M.A., Choneim, M.A., Grabstald, H., Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Ural. 118: 184-187, 1977. 13. Whitmore, W.F. Jr., Batata, M.A., Hilaris, B.S., Reddy, G.N., Unal, A., Ghoneim, M.A., Grabstald, H., Chu, F.: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer. Cancer 40: 1077-1086. 1977. 14. Wizenberg, M.J.: Invasive bladder cancer-definitive irradiation and salvage cystectomy. Semin. Oncol. 6: 229-235,

1979.