Contemporary Cystectomy with Pelvic Node Dissection Compared to Preoperative Radiation Therapy Plus Cystectomy in Management of Invasive Bladder Cancer

[;022-534'7 /84/:3l6-:0S9$0Z.0C/O THE JOURNAL OF -U?tOLOGY

Copyright© 1984 by The Vli;.liams & "V\nliiins Co,

CONTEivIPORARY CYSTECTOMY PELVIC DISSECTION COMPARED TO PREOPERATIVE RADIATION THERAPY PLUS CYSTECTOMY IN MANAGEMENT INVASIVE BLADDER CANCER DONALD G. SKINNER*

AND

GARY LIESKOVSKY

From the Department of Surgery/Division of Urology, University of Southern California School of Medicine, Los Angeles, California

ABSTRACT

Between August 1971 and August 1982, 197 consecutive patients underwent single stage radical cystectomy with pelvic lymph node dissection and urinary diversion as definitive management of high grade, invasive bladder cancer. In 100 patients 1,600 rad of radiation therapy were given for 4 days preoperatively and 97 patients underwent an operation only. Although not constituting a prospective randomized study, an analysis of these 2 groups of patients managed during an 11-year period by the same surgical team, using identical surgical technique, provides useful information that questions the benefit of preoperative radiation therapy in the management of high grade, invasive bladder cancer. Other factors, such as improved surgical technique with meticulous pelvic node dissection as well as better preoperative and postoperative care, may be responsible for survival results of contemporary surgery only that equal those reported following combination therapy protocols using preoperative radiation therapy. Contemporary surgery with or without preoperative radiation therapy yielded a 5-year survival rate free of tumor of 75 per cent for patients with pathologic stages P2 and P3A disease, 44 per cent with P3.A and P3B disease, and 36 per cent with P4 disease and positive pelvic nodes. The value of radiation therapy before radical cystectomy for invasive bladder cancer remains uncertain. 1- 5 Most studies that support the use of preoperative radiation compared modern data on survival following combination therapy to smvival figures for operation only performed ?::20 years ago when the mortality and morbidity of the operation were high, and patient selection was different. 6- 11 The only prospective randomized study was conducted the National Surgical Adjuvant Bladder Project in which patients with clinical stage T2 or greater (N-) disease were randomized to a surgery only g:rnup or to a group treated by standard fractionation radiation (4,500 rad) followed an operation 4 to 6 weeks later. However, this study failed to demonstrate a significant advantage to the combination therapy group. 12 • 13 Nevertheless, many investigators continue to expound the value of some type of radiation therapy before cystectomy to cystectomy alone. with 197 consecutive patients We report our ""''"'"'",., a standard single treated during an 11-year n1eticulous pelvic iliac lymph node dissection with en radical cystectomy and ileal conduit urinary diversion. Of these patients 100 received a high short course of radiation therapy rad for 4 followed immediate and 97 1n1<1P·rw,,nt. an nn~,-,,,r,ron only. Although not <>rnns:t.1-r.11,-i-.rn a randmnized prospective the number of patients undergoing contemporary surgery performed by the same surgical team during a relatively short period provides useful information concerning efficacy of high dose, short course preoperative radiation therapy. MATERIALS AND METHODS

Between August 1971 and August 1982, 202 consecutive patients without clinical evidence of disseminated disease underwent exploration with the intent to perform a single stage radical cystectomy and urinary diversion in an attempt to cure invasive bladder cancer. Preoperative screening for metastatic Accepted for publication February 10, 1984. *Requests for reprints: Division of Urology, Suite 5900, University of Southern California Medical Center, 2025 Zonal Ave., Los Angeles, California 90033.

disease, in addition to a careful physical examination, includ6d a chest x-ray, serum alkaline phosphatase and biochemical liver profile. Bone and liver scans were not obtained routinely unless the alkaline phosphatase or other liver function studies were abnormal, hepatomegaly was present or the patient had symptoms suggestive of metastases, There were 5 cases that were unresectable, based on the findings of unexpected malignant retroperitoneal fibrosis, extensive nodal disease above the aortic bifurcation or liver metastases. These patients were excluded from the study. Patients who had been treated initially by definitive radiation therapy and became candidates for salvage cystectorn.y through local failure were excluded from the study, as were patients who received different courses of planned preoperative radiation elsewhere before being referred for cystectomy. In 100 patients a course of high dose radiation therapy (1,600 rad) was delivered for 4 followed immediately Of these !-'"'""'""'" 97 were treated between 1971 and uecernb,'Jr 4 After that study have been reported on in 1978 µa,,u,.,.1c:> underwent without ~n,Ana·cc,~n,n radiation in an effort to determine ;:;:c:;e11::::!,;::: of contemporary surgery and to look ai; ;,v,,cm,at benefits of adjuvant chemotherapy. Ninety-seven "'"'"'"·'"" are available for all but 2 being treated since 1978. All operations were done a standard surgical"--"""'"-'"lymph node dissection was in which a meticulous pelvic performed en bloc with a radical cystectomy. The details of this operative procedure have been recorded on film. 14 •15 Before 1980 patients were managed at the UCLA Hospital and since January 1980 at the USC Hospital of the Good Samaritan in Los Angeles. Surgical specimens were processed routinely and evaluated by a staff pathologist, who reported grade and stage according to tumor, nodes and metastasis guidelines. All patients were followed until recurrence or beyond 5 years, or at least through March 1983. Once recurrence was established patients were considered treatment failures and survival curves free of tumor were created actuarially according to the method of Kaplan and Meier. 16 The average age of patients undergoing surgery only was 62

1069

1070

SKINNER AND LIESKOVSKY

years and the male-to-female ratio was 2.7:1. The average age of patients undergoing combination preoperative radiation and surgery was 59 years, and the male-to-female ratio was 4.8:1. Indications for cystectomy included any muscle-invading cancer not deemed suitable for segmental resection regardless of grade, any high grade tumor associated with carcinoma in situ, rapidly recurring multifocal high grade tumors or carcinoma in situ only with irritative bladder symptoms unresponsive to intravesical chemotherapy. All patients had poorly differentiated tumors except 7 who had rapidly recurring multifocal grade II lesions, including 4 in the irradiated group and 3 in the surgery only group. There were 6 patients with primarily squamous differentiation, including 2 in the radiation group and 4 in the surgery only group. From 1976 through 1977 all patients with pathologic stages P3B, P4 and/or N+ disease were offered adjuvant prophylactic chemotherapy consisting of 1 gm./m. 2 cyclophosphamide per month for 6 months beginning 4 to 6 weeks postoperatively. Ten patients were treated (8 with N+ disease) and 17 were followed expectantly (12 with N+ disease). All had received preoperative radiation therapy. From 1978 through June 1980 all patients with P3B, P4 and/ or N + disease were offered adjuvant chemotherapy consisting of 100 mg./m. 2 cisplatinum a month for 4 months beginning 6 to 8 weeks postoperatively. Five patients (3 with N+ disease) were treated and 4 patients with N + disease were followed expectantly. In addition, 1 patient with extensive nodal disease (22 of 42 positive nodes) was treated more aggressively with combination chemotherapy, consisting of 100 mg./m. 2 cisplatinum and 650 mg./m. 2 cyclophosphamide each month for 4 months. None of these patients received preoperative radiation therapy. Beginning in July 1980 a prospective study was initiated in which patients with pathologic stages P3B, P4 and/or N+ disease were randomized into 2 groups. Group 1 included 18 patients who received combination chemotherapy with cisplatinum and cyclophosphamide or 100 mg./m. 2 cisplatinum plus at least 2 other agents that were identified by the in vitro clonogenic assay as individually tumor-sensitive drugs each month for 4 months. Group 2 included 14 patients who were randomized to expectant followup. Of the patients with pathologic stage P2 or greater disease 64 per cent had symptoms or the diagnosis of bladder cancer established <4 months after cystectomy.

Postoperative morbidity of single stage bilateral pelvic iliac lymph node dissection with en bloc radical cystectomy and urinary diversion indicating the effect of the complication on postoperative hospital stay 1,600 Rad+ Cystectomy

Cystectomy Only

Complication No. Pts. None Wound infection/dehiscence Prolonged ileus/partial small bowel obstruction Sepsis ± urine leak

82 6

7 1

Loop infarction, occlusion, femoral to femoral bypass Vascular, clot to toe Rectal fistula Pyelonephritis/colic Cardiac/ arrhythmia Thrombophlebitis/pulmonary embo!ism U reteroileal obstruction (N tube) Acute cholecystitis Brachia! palsy (temporary) Stoma relocation Enteroloop fistula Totals

1 1

Av. Postop. Days 12.0 25.5 29.1

100

Av. Postop. Days

83 1 4

Operative mortality

11.2 14 28.2

1

Operative mortality 22

2

11.5

1 0

18

l

9 21 50 22.3

2

31

32

0 1 1

No. Pts.

28 28 1 1 97

27.7

Note the slight increase in the incidence of wound infection and prolonged ileus or partial small bowel obstruction in patients receiving preoperative radiation compared to surgery alone. It should be emphasized that 165 of the 197 patients suffered no complication, with an average postoperative hospital stay of <12 days.

INV ASl\l'E BlADDIER CANCER Contemporary Surgery 11s. 1600 R • Surgery 8/71-8/82 H)()

80

0--0...... (23)(23) 'ti, {22)-..

33 Pts r-:1 = Surgery Only 25 Pts o--o .: 1600 R + Surgery

(14)

\,

( ) :: + Pts

(19)\,

(16}......

% Alive 60

,;~,<~?r,-o--o~cs>

without Disease

Alive and at Risk

(10)(7) (7} <4)

so%

(13) (13>' .. o-E--0--0--0-~o.. (12) (1 2) ( 11 )"""'0--0--0-=0 43%

40

(9) (8) (7) (5)

20

RESULTS

Among the 197 patients 3 died during the postoperative period, for an over-ali operative mortality rate of 1.5 per cent. Of the 3 deaths 2 occurred in the surgery only group. There were 18 early postoperative complications in the group receiving preoperative radiation therapy, resulting in 1 death, for an over-all complication rate of 18 per cent. The average postoperative stay without complications was 12.0 days and with complications not associated with death it was 27.7 days. There were 14 early postoperative complications in the group undergoing surgery only, resulting in 2 deaths and a complication rate of 14 per cent. The average postoperative hospital stay without complication was 11.2 days and with complications not associated with death it was 22.3 days. The complications and their influence on hospital stay are listed in the table. Note the increased incidence of wound infection and prolonged ileus or partial small bowel obstruction in the preoperative radiation therapy group compared to the surgery only group. Through March 1983 there have been 32 tumor recurrences in the 100 patients receiving preoperative radiation therapy and 19 tumor recurrences in the group undergoing surgery only. This difference is thought to reflect the mean followup between the 2 groups and an analysis of failure sites reveals a similar distribution between the 2 groups. Pelvic, wound or urethral recurrence signifying failure to control the local tumor devel-

0

6

12

111

24

30

36

42

48

54

60

MonU,s Following Cystectomy

FIG. 1. Survival free of tumor calculated actuarially according to method of Kaplan and Meier comparing 33 patients with pathologic stages P3A and P3B disease who underwent surgery only to 25 patients with similar pathologic stage who received 1,600 rad radiation for 4 days preoperatively.

oped in 9 patients receiving preoperative radiation therapy and in 7 patients undergoing surgery only, for an over-all local failure rate of 8 per cent. Of these 16 patients with pelvic recurrence 12 had tumor involvement of the perivesical fat or positive pelvic nodes. When the 2 groups are broken down according to pathologic stage there is no difference in survival free of tumor. Because the followup is shorter in the surgery only group, actuarial survival curves have been created only in those pathologic stages when tumor recurrence is expected early. Figures 1 and 2 show the actuarial survival free of tumor of 58 patients with pathologic stages P3A and P3B disease, and of 59 patients with positive pelvic nodes or invasion of the stroma of the prostate, respectively. Figure 3 shows the over-all actuarial survival free of tumor for the entire group of 197 patients according to pathologic stage.

BLAD])ER. CAi~CER

radiation and radical cystectorn_y shovv proven1-ent 1n local co:n"trol as vvell as ~ to series in which 30 years ago.4- 12 In their illl

% Aliv® 60

~:::•::: 40

26 Pts l ~ ~"' Surgery Only

~(s~\::;},,o

r

l ~

33 Pts O=~O

:a

1600 R + S:_ffgery

(26)\

Pis Alive &nd at Risk

,:~~-,'° 'rn)';;~>C:i~',o--o,

,.,,,,.,,.,,..,, 7

(10}

(9)

_L--J__J_,__~~~-~~~~-~~~~~~. :!4 30 36 4:< ~B 5,1

60

(1,)

(11)(10)

20

0

associates w,n~r.,e~o,rl a 37 per cent for receiving 4,000 rad n.,,.~''"""''°' compared to a 17 per cent 59 survival for w,c,v-••y surgery in the surgery group was 40 per cent compared to a 12 recurrence in patients receiving preoperative

44%

( 131 { 13 )(~~}"'o-~o=-o-=o-~o-~0--0-o-0==0-~ 35% (11)

Months troi;~'Jwi~g Cyste(l';ftomw

FIG. 2. Survival free of tumor calculated method of Kaplan and NJ:eier comparing 26 patients P4 disease and N+ dissection who underwent with similar pathologic stage who received 4 days preoperatively.

Exp~r~~r,ee .8/f 1 =S/S.2 HY! ;;:,tg

U>,.,UOLNV•-'<

=

P1 + P1s

6? Pts

0••• 0 = P,2 + P3p,

50 Pts

ii--=-ti 00

64%

44% 36%

Op ti.fort 3/197

=

1.5%

ComplicaUons 32/197

{)=

=

16%

Pts Alive and at Risk

·~-~~.__j_____J

46

so

FIG. 3. Survival free of turner calculated actuarially ,,,",e,,~,,·rl,nrr of 197 consecutive radicai 11ode dissection \Vith µaow,,0s;,~

report on combination therapy there have been a number of published reports from various centers throughout the world, indicating that protocols using preoperative radiation rn<>r<>nu and radical cystectomy significantly improved survival compared to contemporary definitive radiation therapy or to historical surgery only series:- 12 , 18· 19 In the late 1960s the National Surgical Adjuvant Bladder Project Group initiated a prospective randomized study to determine the effects of preoperative radiation therapy cornto surgery only. 13 Of the 475 patients entered in the study approximately half completed the prescribed therapies, 100 receiving radiation and surgery, and 129 receiving surgery 12 Although 5-year survival figures show a slight edge to radiation .,.,,,,·,anu there was no significant difference. 12 Furwhen one considers that patients randomized to combination who subsequently never undenvent surgery were deleted from the study and analysis, and that a greater percentage of with solid tumors and invasive disease v1ere randorr1ized to to discern any advantage to the It seems more plausible that contemporary other than radiation are responsible for the significantly improved survival Currently reported. r11H'\W"1P•rl n,.A,'\niOTCotn,TA and postoperative surgical care, and surgical technique reduced the mortality and of the nn,,or;at,nn Current operative mortality rates range from 1 to 5 per cent AA·=~-~,,.A~ to the 12 to 22 per rates r"'~"·",-""' historically. Also, current C.VrnJf'HS.O,S"JH rates of 14 to 20 per cent are 0UiUCH,m.,uuMsvc,,u, a meticulous dissection facilitates n<>vt,~,.,.,., of the curative in up to 35 per cent of the nodes. 20 In our these factors the last 11 years and an indicates no benefit to a 1 «•cu,,c,va therapy in ruay contribute also to better inasmuch as the lower of the .A.-A~~b--US,S-S,.,A'UH

To cletern1ine 'Arhether biased the results of this

deemed poor without clinical evidence of u,,,,,,,w,rn.accu

;vvv,,,u,vu

on and included. 2 oth,2r centers have w,,-, .... ,. .,-,,,, similar data ouv,,,,rn," survival rates among with invasive bladder cancer contemporary smgery without radiation. 2 •3 In ~~~"'"'-~"' and associates have shovn1 that the decade in which nn·rrn,~1- with a clinical stage of bladder cancer underwent surgery was more to the chance of survival free of tumor than whether radiation Perhaps the area in which preoperative radiation therapy may benefit patients the most is in reducing the incidence of pelvic recurrence as the first site of tumor failure. YT\f e observed no difference in the rate of pelvic failure (9 per cent among those receiving preoperative radiation therapy and 7 per cent among those undergoing surgery only). Our pelvic recurrence rate is similar to that reported by Montie and associates 2 among their surgery only patients and similar to that repmted by rma.•,,rcr,

24 v1ho recei·ved of data revealed that at 12 monthc, ,_,0,c,.•,rn,0 r,ec,enrin,11 faired better in terms of survival free 18 was no treated and expectant a of to nonradiated patients no difference regardless of whether they received chemotherapy. The issue of adjuvant chemotherapy will be the subject of another report. 17 DISCUSSION

The concept of preoperative radiation therapy in an effort to reduce pelvic recurrence and lessen the possibility of tumor dissemination at the time of surgery 1s appealing, and the published results of the combination of varying dosages of

0

1072

SKINNER AND LIESKOVSKY

Whitmore and associates6 •7 in patients receiving 2,000 rad for 5 days preoperatively or 4,000 rad standard fractionation during 4 to 6 weeks followed by a rest period before surgery. A low pelvic recurrence rate in patients not receiving preoperative radiation therapy is dependent upon a meticulous surgical technique without surgical bladder injury or tumor spill. van der Werf-Messing has shown that when tumor spill occurs preoperative radiation therapy can reduce significantly the incidence of wound implantation. 21 It may be argued that in lieu of the low morbidity of high dose, short course preoperative radiation therapy its use might protect the patient from less than optimal surgery. If the operation results in any tumor spill or is not meticulous in terms of the node dissection, then the results may not be as good as when radiation therapy is used. It seems questionable that this is a valid argument to promote routine use of radiation. In conclusion, our study demonstrates that contemporary surgery using meticulous pelvic lymph node dissection and en bloc radical cystectomy yields actuarial 5-year survival rates free of tumor of 75 per cent for patients with superficial disease (Pl + PlS), 64 per cent when a cystectomy specimen demonstrates varying depths of muscle infiltration (P2 and P3A), 44 per cent when the tumor penetrates deeply into muscle or involves the perivesical fat (P3A-P3B) and 36 per cent for positive pelvic nodes (N +) or direct invasion of the stroma of the prostate (P4). These results are as good as any reported to date using any combination of radiation therapy before surgery and are significantly better than those reported historically. We have been unable to demonstrate any benefit to the use of preoperative radiation therapy in our hands and, by the same token, have observed no significant disadvantage to its use. Despite improved survival, between 50 and 65 per cent of the patients with tumor penetration of the perivesical fat or with metastases to the pelvic lymph nodes have widespread metastatic disease within 30 months (90 per cent within 24 months). This implies the need for development of adjuvant systemic therapy protocols, as well as methods for early detection of patients with invasive disease. In this regard, it should be emphasized that two-thirds of our patients with pathologic stage P2 or greater disease had symptoms or the diagnosis of bladder cancer established <4 months from the time of surgery.

5. 6.

7.

8. 9.

10. 11. 12. 13. 14. 15.

16. 17. 18.

REFERENCES

19. 1. Radwin, H. M.: Radiotherapy and bladder cancer: a critical review. J. Urol., 124: 43, 1980. 2. Montie, J.E., Straffon, R. A. and Stewart, B. H.: Radical cystectomy without radiation therapy for carcinoma of the bladder. J. Urol., 131: 477, 1984. 3. Mathur, V. K., Krahn, H. P. and Ramsey, E.W.: Total cystectomy for bladder cancer. J. Urol., 125: 784, 1981. 4. Skinner, D. G., Tift, J. P. and Kaufman, J. J.: High dose, short

20. 21.

course preoperative radiation therapy and immediate single stage radical cystectomy with pelvic node dissection in the management of bladder cancer. J. Urol., 127: 671, 1982. Skinner, D. G.: Current perspective in the management of highgrade invasive bladder cancer. Cancer, 45: 1866, 1980. Whitmore, W. F., Jr., Batata, M.A., Ghoneim, M.A., Grabstald, H. and Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. Whitmore, W. F., Jr., Batata, M. A., Hilaris, B. S., Reddy, G. N., Unal, A., Ghoneim, M. A., Grabstald, H. A. and Chu, F.: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer. Cancer, 40: 1077, 1977. Whitmore, W. F., Jr.: Integrated irradiation and cystectomy for bladder cancer. In: Carcinoma of the Bladder. Edited by J. G. Connolly. New York: Raven Press, p. 235, 1981. Whitmore, W. F., Jr., Grabstald, H. A., Mac~enzie, A. R., Ishwariah, G. and Phillips, R.: Preoperative irradiation and cystectomy in the management of bladder cancer. Amer. J. Roentgen., 102: 570, 1968. Chan, R. C. and Johnson, D. E.: Integrated therapy for invasive bladder carcinoma: experience with 108 patients. Urology, 12: 549, 1978. Reid, E. C., Oliver, J. A. and Fishman, I. J.: Preoperative irradiation and cystectomy in 135 cases of bladder cancer. Urology, 8: 247, 1976. Slack, N. H., Bross, I. D. J. and Prout, G. R., Jr.: Five-year followup results of a collaborative study of therapies for carcinoma of the bladder. J. Surg. Oncol., 9: 393, 1977. Prout, G. R., Jr., Slack, N. H. and Bross, I. D. J.: Preoperative irradiation as an adjuvant in the surgical management of invasive bladder carcinoma. J. Urol., 105: 223, 1971. Skinner, D. G.: Technique of radical cystectomy. Urol. Clin. N. Amer., 8: 353, 1981. Skinner, D. G. and Lieskovsky, G.: Motion picture: technique of anterior exenteration. Presented at annual meeting of American Urological Association, Las Vegas, Nevada, April 17-21, 1983 and at annual meeting of American College of Surgeons, Film Library of American College of Surgeons. Kaplan, E. L. and Meier, P.: Nonparametric estimation from incomplete observations. J. Amer. Stat. Ass., 53: 457, 1958. Skinner, D. G., Daniels, J. R. and Lieskovsky, G.: Adjuvant chemotherapy following cystectomy for deeply invasive bladder cancer: current status. Urology, in press. Miller, L. S. and Johnson, D. E.: Megavoltage irradiation for bladder cancer: alone, postoperative, or preoperative? In: Seventh National Cancer Conference Proceedings. Philadelphia: J. B. Lippincott Co., p. 771, 1973. Wallace, D. M. and Bloom, H.J. G.: The management of deeply infiltrating (T3) bladder carcinoma: controlled trial of radical radiotherapy versus preoperative radiotherapy and radical cystectomy. Brit. J. Urol., 48: 587, 1976. Skinner, D. G.: Management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. J. Urol., 128: 34, 1982. van der Werf-Messing, B.: Carcinoma of the bladder treated by suprapubic radium implants. Eur. J. Cancer, 5: 277, 1969.