The Role of Adjuvant Chemotherapy Following Cystectomy for Invasive Bladder Cancer: A Prospective Comparative Trial

0022-534 7/91/1453-0459$03.00/0 Vol. 145, 459-467, March 1991 Printed in U.S.A.

THE ,]OURNP_L OF UROI..,OGY

Copyright(¢_; 1991 by AMERICAN UROLOGICid~ AssoCIA~'lON,

Original Articles THE ROLE OF ADJUVANT CHEMOTHERAPY FOLLOWING CYSTECTOMY FOR INVASIVE BLADDER CANCER: A PROSPECTIVE COMPARATIVE TRIAL DONALD G. SKINNER, JOHN R. DANIELS, CHRISTY A. RUSSELL, GARY LIESKOVSKY, STUART D. BOYD, PETER NICHOLS, WILLIAM KERN, JOANNE SAKAMOTO, MARK KRAILO AND SUSAN GROSHEN From the Departments of Urology, Medicine, Pathology and Preventive Medicine, University of Southern California School of Medicine, Kenneth Norris, Jr. Cancer Hospital and Hospital of the Good Samaritan, Los Angeles, California

ABSTRACT

We assigned 91 patients with deeply invasive, pathological stage P3, P4 or N+ and Mo transitional cell carcinoma of the bladder (with or without squamous or glandular differentiation) to adjuvant chemotherapy or to observation after radical cystectomy and pelvic lymph node dissection. For most patients chemotherapy was planned as 4 courses at 28-day intervals of 100 mg./M. 2 cisplatin, 60 mg./M. 2 doxorubicin and 600 mg./M. 2 cyclophosphamide. A significant delay was shown in the time to progression (p = 0.0010) with 70% of the patients assigned to chemotherapy free of disease at 3 years compared to 46% in the observation group. Median survival time for patients in the chemotherapy group was 4.3 years compared to 2.4 years in the observation group (p = 0.0062). In addition to treatment groups, important prognostic factors included age, gender and lymph node status. The number of involved lymph nodes was the single most important variable. We recommend adjuvant chemotherapy for patients with invasive transitional cell carcinoma after definitive surgical resection. KEY WORDS: bladder; carcinoma, transitional cell; drug therapy, combination

Approximately 50% of the patients with high grade bladder cancer and deep muscle invasion will die of disseminated disease within 2 years of presentation. 1 Failure is presumed due to occult systemic spread since following contemporary surgery the pelvis is the first site of recurrence in less than 10% of the patients with relapse. 1 •2 Adjuvant chemotherapy has been used in the perioperative management of bladder cancer in an attempt to improve survival after definitive regional management.3 Although encouraging trends have been seen, no randomized trials have been reported. Chemotherapy after recurrence will often result in temporary responses, representing a possibly limited survival advantage but not cure. 4- 7 We report the results of a prospective treatment comparison of a planned 4-month course of adjuvant chemotherapy versus observation following radical cystectomy with pelvic lymph node dissection in patients with pathological stage P3, P4 or N+ and Mo transitional cell carcinoma of the bladder. The study was designed to evaluate treatment associated effects upon time to progression and survival. MATERIALS AND METHODS

Between July 1980 and December 1988, 498 patients underwent exploratory laparotomy with the intent of performing bilateral pelvic iliac lymph node dissection with en bloc radical cystectomy and urinary diversion by 1 of the authors (D. G. S., G. L. or S. D. B.) as the primary management of invasive bladder cancer. 2 Preoperative evaluation included an electrocardiogram, chest x-ray, serum creatinine, alkaline phosphatase, serum glutamic oxaloacetic transaminase and lactic dehydrogenase. Patients with an elevated alkaline phosphatase Accepted for publication July 24, 1990. 459

underwent a 99 mtechnetium bone scan. Most patients also were evaluated with abdominal and pelvic computerized tomography (CT). Clinical criteria for cystectomy included histological evidence of muscle invasion or prostatic stromal invasion, high grade Tl tumors associated with carcinoma in situ, carcinoma in situ refractory to intravesical chemotherapy or immunotherapy, or recurrent multifocal disease following initial efforts at conservative therapy .1 None of these patients had received prior pelvic irradiation or systemic chemotherapy. All cystectomy W. specimens were processed by a standard technique (P. K.) with histological features and pathological staging established according to the tumors, nodes and metastases system.s-10 Of the 498 patients 36 had extension to the lymph nodes above the aortic bifurcation or intra-abdominal metastatic disease and 16 (3.2%) died as a direct result of the operation. Of the remaining 446 patients 229 had pathological stage P3, P4 or N+ and Mo disease and 160 were considered eligible for study based on the following criteria: surgically confirmed invasive carcinoma of the bladder, stage P3, P4 or N+ and Mo, no involved lymph nodes above the aortic bifurcation, age 9 to 75 years and signed informed consent. Ineligibility factors included prior noncutaneous malignancy within 10 years, prior chemotherapy or pelvic irradiation, bilirubin greater than 1.5 mg./dl., serum glutamic oxaloacetic transaminase more than 2 times normal, elevated alkaline phosphatase, white blood count less than 3,500 or platelet count less than 150,000, serum creatinine greater than 1.0 mg./dl./M. 2 at the time of enrollment, Karnofsky performance status less than 50, and medical, social or psychological factors that would make the patient a poor risk for completion of chemotherapy.

460

SKINNER AND ASSOCIATES

A total of 69 patients were ineligible for the study because of age (38 patients), prior malignancy (19) and medical factors, usually cardiac (12). Before they were discharged from the hospital after cystectomy the 160 patients were invited to participate in this trial in which therapy was to begin 6 weeks postoperatively. Of these patients 59 declined to participate (4 requested chemotherapy and 55 did not want chemotherapy), and 101 signed the informed consent and were enrolled and assigned to chemotherapy or to observation. Of the 101 patients 10 presented with a diagnosis of pure squamous cell carcinoma or adenocarcinoma, and they are not considered in this report. We report on the 91 patients with confirmed pure transitional cell carcinoma or transitional cell carcinoma associated with squamous or glandular differentiation with or without carcinoma in situ. The study design is outlined in figure 1. The protocol was reviewed and approved by the Institutional Review Board of the Los Angeles County/University of Southern California Medical Center. Treatment group assignment and follow up. Treatment assignment was made using a scheme designed to minimize differences between the chemotherapy and control group by stratifying according to gender, P stage, nodal stage and histology. 11 This procedure was performed independently of the study investigators by a member of the Clinical Investigations Support Office at the USC Norris Cancer Center. The treatment assignment was not known to either the investigators or to the patient until after the patient was enrolled in the study. This method of assignment effectively achieves a balanced random allocation of patients. All cases were accrued between July 1980 and December 1988, and followup information for this analysis was completed to May 1989. At the completion of active therapy patients were followed at 4-month intervals for the first year, at 6-month intervals for the following 3 years and at yearly intervals thereafter. Followup consisted of a chest x-ray, excretory urogram, biochemical liver profile and physical examination. Additional studies, including CT, magnetic resonance imaging (MRI) or bone scans, were obtained in symptomatic patients or those with abnormal laboratory values. Chemotherapy. Chemotherapy was begun 6 weeks after cystectomy. Drug treatment was delivered in 4 courses at 28-day intervals and consisted of 100 mg./M. 2 cisplatin, 60 mg./M. 2 doxorubicin and 600 mg./M. 2 cyclophosphamide (PAC). Patients were hospitalized for chemotherapy administration and generally received 1 to 2 I. normal saline for 2 hours before drug infusion. Cisplatin was delivered in 300 ml. 3% sodium chloride for 2 hours. Intravenous antiemetic therapy usually consisted of 10 mg. decadron, 100 mg. metaclopramide and 50 mg. benadryl, the latter 2 drugs repeated as necessary. During the initial study period (July 1980 to April 1983, 17 SCHEMA Carcinoma of Bladder Muscle Invasion Mo

P3, P4, N+

Cystectomy Pelvic Node Disection

_ . - - Randomize Chemotherapy 4 Cycles CISCA

-----·

Observation

University of Southern California

FIG. 1. Between July 1980 and December 1988, 91 patients with transitional cell carcinoma of bladder were enrolled and assigned either to adjuvant chemotherapy or to observation. Assignment was based on minimization program that considered gender, P stage, nodal status and histology.

patients) chemotherapy was modified on an individual basis using the human tumor cloning assay, 12 and 100 mg./M. 2 cisplatin were administered to 16 of the 17 patients. Of these 16 patients PAC chemotherapy was administered to 5, cisplatin, doxorubicin and an individualized drug to 4, cisplatin, cyclophosphamide and an individualized drug to 4, and cisplatin and an individualized drug to 3. Other drugs administered in combination included fluorouracil (3 patients), vinblastine (4) and bleomycin (3). One patient not receiving cisplatin was treated with methotrexate, actinomycin D, mitomycin and dimethyltriazeno imidazole carboxamine. From May 1983 all patients receiving chemotherapy were administered PAC. Statistical methods. The 2 outcome measures of primary interest were survival and the time to progression. Survival was defined as the number of days from the date of the cystectomy until death of any cause or was considered censored at the last followup. The time to progression was calculated as the number of days from cystectomy to documentation of progression of the disease; patients whose last followup occurred before progression were considered censored at that time. Four patients who died before progression were considered censored at that time for the computation of time to progression. In 1 of these patients who was in the observation group new primary cancer developed in the brain before progression and he died subsequently; for this patient time to progression was considered censored at the date of death. For 1 patient assigned to chemotherapy no information was available 23 days after cystectomy except that the date of death of unknown cause occurred at 2.3 years; in this case time to progression was censored at 23 days. One patient, who was assigned to chemotherapy but who never received treatment, died of a myocardial infarction at 1.9 years. Another patient who received 3 cycles of PAC died of a myocardial infarction 4.3 years after cystectomy. We examined 11 on-study patient characteristics for their effect on outcome and their impact on the association between treatment and outcome. The variables included age (64 years old or younger, 65 years old or older), time to cystectomy from original diagnosis (2.0 months or less, 2.1 to 12.0 months, 12.0 months or greater), gender, year of cystectomy (1980 to 1984, 1985 to 1988), number of positive nodes (0, 1, 2 or more), tumor grade (2, 3, 4), pathological stage (1 and 2, 3A, 3B, 4), histology (pure transitional, transitional variant), prior segmental resections (no, yes), number of prior transurethral resections of the bladder (Oto 3, 4 or more) and type of diversion (Kock, other). Kaplan-Meier product-limit estimates of the survival and time to recurrence were plotted. 13 •14 Standard errors for the probability of surviving or not recurring were based on Greenwood's formula. 14 The modified Wilcoxon test for censored data was used (stratified and unstratified) to test for statistical significance. 15 The Wilcoxon rather than the logrank test was chosen for its greater sensitivity to early differences in survival and time to recurrence. All p values reported are 2-sided. In all analyses the patients are classified according to the initial treatment assignment. The initial accrual goal was to enter 75 patients on each arm. Although not originally designed as a multistage trial, interim analyses were performed after 50 to 75 patients had been entered and followed for a minimum of 6 months. At the second interim analysis (75 patients) the chemotherapy arm demonstrated a benefit in terms of the recurrence-free interval that just achieved statistical significance at the 1-sided 0.05 level. At that time a decision was made to continue patient accrual for 2 more years. RESULTS

The characteristics of the 91 patients are presented in table 1. Of the patients 76% were men and 36% had lymph node involvement. There was a similar distribution of gender, P and N stage, age and prior surgical experience.

461

ADJUVANT CHEMOTHERAPY FOLLOWING CYSTECTOMY FOR INVASIVE BLADDER CANCER TABLE

l. Characteristics of patients with transitional cell carcinoma

at study entry No. Pts. (%)

All Pts. Total No. pts. Age (yrs.): Median Range 22-64 65+ Gender:

Observation

91

M F Yr. cystectomy: 1980-1984 1985-1988 Mos. to cystectomy: 0-2 2.1-12 12.1+ No. excised nodes: Median Range No. pos. nodes: 0 1 2+ Tumor grade: 2 3 4 Missing Pathological stage: 1 or 2 3A 3B 4 Histology: Pure transitional Variant Prior bladder resections: No Yes No. prior bladder resections: 0-3 4+ Diversion: Kock Other

Chemotherapy

47

44

62 22-75 52 39

62 30-73 26 (55) 21 (45)

61 22-75 26 (59) 18 (41)

69 22

35 (74) 12 (26)

34 (77) 10 (23)

42 49

22 (47) 25 (53)

20 (45) 24 (55)

36 29 26

18 (38) 15 (32) 14 (30)

18 (41) 14 (32) 12 (27)

32 4-96

32 4-78

34 5-96

58 17 16

31 (66) 10 (21) 6 (13)

27 (61) 7 (16) 10 (23)

6

45 39 1

4 (9) 23 (50) 19 (41) 1

2 (5) 22 (50) 20 (45) 0

8 17 44 22

5 7 24 11

3 10 20 11

72 19

36 (70) 11 (30)

36 (82) 8 (18)

79 12

38 (81) 9 (19)

41 (93) 3 (7)

83 8

43 (91) 4 (9)

40 (91) 4 (9)

58 33

31 (66) 16 (34)

27 (61) 17 (39)

(11) (15) (51) (23)

(7) (23) (45) (25)

Of the 44 patients randomized to chemotherapy 11 subsequently elected not to be treated and 33 received 1 or more courses of chemotherapy, including 6 cycles to 1 patient (3%), 4 cycles to 20 (61 %), 3 cycles to 2 (6%), 2 cycles to 6 (18%) and 1 cycle to 4 (12%). Cisplatin was administered to 32 of these 33 patients and 25 received either doxorubicin or cyclophosphamide. Patients declining chemotherapy after randomization were more likely to have negative lymph nodes but they were otherwise indistinguishable on the basis of weight loss, albumin, hemoglobin or creatinine. For all patients receiving chemotherapy the cisplatin dose averaged 85% of plan and the dose rate averaged 81 % of plan with 18 patients receiving 80% of plan or better. For patients receiving 4 cycles the cisplatin dose averaged 83% of plan and dose intensity 79% of plan. TABLE 2.

Wt. No. Cycles

No. Pts.

0 1 2 3 4+

11 4 6

The biological impact of treatment was assessed by sequential measures of weight, albumin, hemoglobin and creatinine in the patients who received chemotherapy (table 2). Values were calculated as percentage of preoperative baseline, and obtained at each chemotherapy administration and at 2-month followup. Postoperatively there was an average 9% weight loss that was not recovered until after chemotherapy was discontinued. Chemotherapy was associated with a steady decline in serum albumin that was not seen in those patients who did not receive chemotherapy. Hemoglobin changes were negligible in most patients. There was an average 10% increase in serum creatinine. No changes in alkaline phosphatase, serum glutamic oxaloacetic transaminase or lactic dehydrogenase were noted. There were 10 hospitalizations for complications of chemotherapy in 108 treatment courses: 4 patients were hospitalized once and 3 patients twice. The cause of hospitalization was neutropenia and fever in 5 instances, dehydration in 1, and dehydration, neutropenia and fever in 4. The average hospital stay was 5.2 days (range 2 to 9). There were no drug toxicity deaths and no significant long-term sequelae. Prognostic factor analysis and effect of treatment. Of the 91 patients 52 were alive at the last followup before the analysis termination date (May 1989), 35 died of disseminated disease, 3 died of other causes and 1 died of an undocumented cause. Median duration of followup was 32 months with all but 6 patients followed beyond 1 year. Figure 2 shows Kaplan-Meier plots comparing time to progression and survival for the 44 patients assigned to chemotherapy and the 4 7 patients assigned to observation. At 3 years the probability of disease recurrence for the chemotherapy group was 0.30 (standard error= 0.08) compared to 0.54 (standard error = 0.08) for the observation group (p = 0.011, unstratified Wilcoxon test). The probability of dying of bladder cancer within 3 years was 0.29 (standard error = 0.08) and 0.50 (standard error = 0.08) for the chemotherapy and observation groups, respectively. The probability of dying of any cause within 3 years was 0.34 (standard error = 0.08) for the chemotherapy group compared to 0.50 (standard error = 0.08) for the observation group (p = 0.099, unstratified Wilcoxon). Of the on-study.characteristics for which patients were prospectively stratified nodal status (no involved lymph nodes, 1 involved lymph node, or 2 or more involved lymph nodes) was strongly predictive of time to progression (p = 0.0005) and survival (p = 0.0001). Figures 3 and 4, and table 3 present the effect of chemotherapy within the 3 groups of patients as determined by nodal status. The benefit for chemotherapy was significant for time to recurrence (p = 0.0010 stratified Wilcoxon test) and for survival (p = 0.0062 stratified Wilcoxon test) after stratifying for the 3 lymph node subgroups. The chemotherapy benefit was seen in all 3 nodal groups. For lymph node negative and 1 lymph node positive cases protection from recurrence and the survival advantage are most clearly seen during the first 3 years. By 5 years the effect of chemotherapy is less evident. For patients with 2 or more positive lymph nodes relapse was rapid. Adjuvant therapy increased the median time to recurrence by 14 months but by 2 years there appeared to be no residual advantage of chemotherapy either

Effects of chemotherapy Albumin

Creatinine

Hemoglobin

Initiation of Chemotherapy

6-Mo. Followup

Initiation of Chemotherapy

6-Mo. Followup

Initiation of Chemotherapy

6-Mo. Followup

Initiation of Chemotherapy

6-Mo. Followup

92 (5) 90 (2)

96 (5) 71 (47) 84 (6)

97 (26) 96 (9)

104 (20) 97 (29) 79 (8)

128 (51) 89 (35)

109 (29) 108 (38) 101 (10)

108 (17) 111 (3)

90 (17) 93 (7) 84 (8)

91 (5)

98 (5)

96 (11)

86 (15)

99 (25)

110 (37)

98 (11)

100 (10)

2

21

Values are given as percentage of baseline (standard deviation). Weight, albumin, creatinine and hemoglobin change are calculated as percentage of baseline at initiation of chemotherapy and at 6-month followup.

462

SKINNER AND ASSOCIATES

A

B

EFFECT OF CHEMOTHERAPY ON SURVIVAL -

OBSERVATION (47)

-

EFFECT OF CHEMOTHERAPY ON TIME TO RECURRENCE - OBSERVATION (47)

CHEMOTHERAPY (44)

- CHEMOTHERAPY (44)

p R

1

0

p R 0 0.8 B A 8 0.6

B A O.B B I

L I 0.6 T

I L I T 0.4

y

s

0.4

y

u

R V 0.2 I V

A L

P3,P4,0R N+

N 0.2 E D

P3,P4,0RN+

p = 0.099 (Unstratified Wilcoxon)

p = 0,011 (Unstratified Wilcoxon)

O+------+---+----,---+---f-----+---+---+--------< 0

YEARS AFfER CYSTECTOMY

YEARS AFTER CYSTECTOMY

FIG. 2. Effect of chemotherapy on survival (A) and on time to progression (B) for 91 patients with pure transitional cell carcinoma or transitional cell carcinoma with either squamous or glandular differentiation, with or without carcinoma in situ. Tick marks on these curves represent patients who were still alive (A) or who had no recurrence (B) at last followup. NED, no evidence of disease. (A) LYMl'H NODE NEGATIVE p R 0 B

0BStRVArI0N(31l

(A) LYMPH NODE NEGATIVE

--CHEMOTHERAPY(27)

···-~·-·i

:>t+t· ·h

4,-~---H+

0.8

:.. -++···

A B I 0.6 L I 0.4 T

I

'--+---+--+----~

i

I

l--j

y 0.2 N E D

OBSLI!VATION (3T)

5

YEARS AFTER CYSTECTOMY

•·• CIIEMOTIIERAPY (27)

.............................

A 0.2 L I V E

0 0

-

p R 0 B A 0.8 B I L 0.6 I T 0.4 y

~

,,

.................. ..... ................

~

4

YEARS AFTER CYSTECTOMY

(B) ONE POSITIVE LYMPH NODE -

OBSERVATION (10)

(B) ONE POSITIVE LYMPH NODE

- CHEMOTHERAPY (7)

0

B 0.8

:...... ·+-·······-······-··--· ·····t·l- ·····-··-----+·------i

A

B

I 0.6 L I 0.4 T y 0.2 N E D

-

p R 0 B A 0.8 B I L 0.6 I T 0.4 y

p R

OHSERV ATION (IO)

-

CHEMOTHERAPY (7)

A 0.2 L I 0 V E

3

YEARS AFTER CYSTECTOMY

YEARS AFTER CYSTECTOMY

(C) 2+ POSITIVE LYMPH NODES -

OBSERVATION (6)

(C) 2+ POSITIVE LYMPH NODES

- CHEMOTHERAPY (IO) -

p

OBSERVATION(6)

- CHEMOTHERAPY (10)

R 0 B A 0.8 B I L 0.6

I T

y

0.4

A 0.2 E D

9

YEARS AFTER CYSTECTOMY

I V

E YEARS AFTER CYSTECTOMY

FIG. 3. Comparison of effect of chemotherapy on time to recurrence of patients with no positive lymph nodes (A), 1 positive lymph node (B) and 2 or more positive lymph nodes (C).

FIG. 4. Comparison of effect of chemotherapy on survival of patients with no positive lymph nodes (A), 1 positive lymph node (B) and 2 or more positive lymph nodes (C).

463

ADJ.UVA.NT CHE?vI0TF1ERA:~.=,,y FOLLDV1II\JG C\.'STECTOlV!Y FOR IN-~IASIVE BLADDER CA.l\JCER TABLE 3.

Summary of the effect of chemotherapy according to number of involved lymph nodes Time to Recurrence

Group of Pts.

Treatment Arm

All pts.

Observation Chemotherapy Observation No involved nodes Chemotherapy Observation 1 involved node Chemotherapy Observation 2+ involved nodes Chemotherapy Stratified p value = 0.0010

Median* Time to Progression (yrs.)

Total No. Pts.

No. Pts. Given Therapy

Wilcoxon P Value

47 44 31 27 10 7 6 10

26 16 13

0.011

Total No. Pts.

No. Deaths

Wilcoxon P Value

Median* Survival (yrs.)

47 44 31 27

22 17

0.099

11

0.14

2.41 4.25 6.82 8.41+ 1.42 7.59+ 0.58 1.42

0.043

6

8 1 5 9

0.017 0.17

1.92 6.58 7.33+ 6.58 1.00 7.59+ 0.33 1.50

Probability (SE)t of Not Recurring Within Yrs. 2 0.49 0.74 0.61 0.91 0.22 0.83 0.33 0.22

(0.08) (0.07) (0.09) (0.06) (0.14) (0.15) (0.19) (0.14)

3 0.46 0.70 0.57 0.85 0.22 0.83 0.33 0.22

(0.08) (0.08) (0.10) (0.08) (0.14) (0.15) (0.19) (0.14)

5 0.34 0.51 0.50 0.73 0.00 0.83 0.17 0.00

(0.09) (0.11) (0.10) (0.13) (0.15) (0.15)

Survival

Group of Pts.

Treatment Arm

Probability (SE)t of Not Dying Within Yrs. 2

All pts.

Observation Chemotherapy No involved nodes Observation Chemotherapy Observation 1 involved node Chemotherapy 2+ involved nodes Observation Chemotherapy Stratified p value = 0.0062

10

7 6 10

6 7 2 4 9

0.027 0.23

0.65 0.79 0.79 0.91 0.44 1.00 0.33 0.33

(0.07) (0.07) (0.08) (0.06) (0.17) (0.19) (0.16)

3 0.50 0.66 0.58 0.91 0.33 0.67 0.33 0.11

(0.08) (0.08) (0.11) (0.06) (0.16) (0.19) (0.19) (0.11)

5 0.44 0.39 0.58 0.52 0.00 0.67 0.33 0.00

(0.09) (0.11) (0.11) (0.16) (0.19) (0.19)

* Median times taken from Kaplan-Meier calculations. For numbers ending in+ the median has not been reached. Value given is the longest followup time.

t Probabilities are based on the

Kaplan-Meier calculations and standard errors (SE) are based on Greenwood's formula.

in terms of recurrence or of survival. In a retrospective analysis 2 other on-study patient characteristics, age and gender, were associated with outcome. Men 65 years old and older tended to do well whether or not they received chemotherapy. Within this subgroup of 29 men 7 had recurrence (4 of 15 in the observation arm and 3 of 14 in the chemotherapy arm) and 5 died. The probability of disease not recurring within 3 years was 0.93 (standard error = 0.05) and the probability of surviving 3 years was 0.88 (standard error = 0.06). The statistical significance of the benefit of chemotherapy persisted after stratifying by the 12 subgroups formed by cross-classifying patients according to nodal status, age and gender. (For recurrence the p value increased from 0.0010 to 0.0023 and for survival it decreased from 0.0062 to 0.0050.) DISCUSSION

To our knowledge this report represents the first comparative prospective trial designed to assess the potential benefits of adjuvant chemotherapy following cystectomy. We have shown a significant increase in the time to progression and in survival for patients with pure transitional cell carcinoma or transitional cell carcinoma associated with squamous or glandular differentiation, with or without carcinoma in situ, treated by cisplatin combination chemotherapy. The dominant prognostic factor for patients with invasive transitional cell carcinoma of the bladder is the extent of regional lymph node involvement at the time of cystectomy. Adjuvant chemotherapy benefited patients regardless of lymph node status. For patients with no or 1 positive lymph node this benefit appeared to be longer lasting than for patients with more extensive nodal involvement. Initial survival advantage does not necessarily imply a higher rate of cure. To answer the question of whether these initial survival advantages of adjuvant chemotherapy will translate into a higher proportion of cured patients will require a longer period of observation in this study and independent confirmation. Over-all, the median time to progression was increased by 4.7 years in the chemotherapy group (table 3). Patients with 2 or more nodes benefited least in absolute terms with median progression-free survival

extended to 1.2 years and survival to 0.8 years but even in this group the benefit of chemotherapy appeared to justify a 4month commitment. Of the 101 patients initially recruited to this study 5 were diagnosed with adenocarcinoma and 5 with pure squamous cell carcinoma. Of these 10 patients 5 were assigned to chemotherapy and 5 were assigned to observation. In 5 patients (3 in the chemotherapy arm and 2 in the observation arm) disease recurred and 6 have died. This apparent ineffectiveness of chemotherapy for nontransitional histological types is consistent with observations of others with experience in the management of bladder cancer. 4 ·5 In this trial the outcome for men 65 years old or older was good. Within the limitations imposed by small numbers we cannot draw conclusions regarding the benefit of chemotherapy in these patients. The excellent prognosis of this subgroup has not been our experience in the past. This study was performed at a single institution using a standardized technique for pelvic node dissection with en bloc cystectomy, and chemotherapy was administered only after surgical staging. That the study could be successfully concluded with a limited number of patients probably reflects the analysis advantage of precise surgical staging, the reduced variability of the outcome of studies conducted within a single institution and a relatively large treatment effect. Chemotherapy compliance was a significant problem. Of 44 patients assigned to chemotherapy only 33 received some treatment and only 21 completed the planned 4-month course. Patients terminating treatment early generally commented that the uncertain benefit was not worth the significant toxicity. It is hoped that with the demonstration of benefit reported here patient motivation and compliance will be improved. Refinements in surgery have reduced the incidence of pelvic recurrence without adjuvant radiation therapy to less than 10% .1 •2 Nonetheless, the majority of patients with pathological stage P3, P4 or N+ disease will die of disseminated disease following surgery alone. Since it now appears that patients benefit from adjuvant chemotherapy, the challenge is to improve the efficacy and patient acceptance of the treatment

464

SKINNER AND ASSOCIATES

program. Most approved cytotoxic chemotherapeutic agents have demonstrable activity against bladder cancer but responses tend to be short-lived with death of disease usually within 3 to 6 months after recurrence. 16 The cisplatin, doxorubicin and cyclophosphamide (PAC/ CISCA) combination used in this study had the highest reported response rates at the time the study was developed in 1980. 17 More recently the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) has been used for patients with advanced bladder cancer. In a randomized prospective trial comparing CISCA to M-V AC chemotherapy in patients with metastatic bladder cancer Logothetis et al reported a higher combined response rate for the group receiving M-VAC. 18 However, another study comparing cisplatin and methotrexate with cisplatin alone showed only a slight benefit of 2 drugs 19 and it has prompted the question of whether the compromise of cisplatin dose often involved in drug combination programs may not undermine the potential benefit of the most active component. 20 In addition, 3 other clinical trials have failed to show a significant benefit in terms of survival for patients treated with multidrug combinations compared to cisplatin alone. 21 - 23 At our university the successor study will compare an intense dose or alternate cisplatin combination chemotherapy regimen with the established M-VAC combination program.

13.

14. 15. 16.

17. 18.

19.

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20.

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EDITORIAL COMMENTS This article raises important questions about the treatment of invasive bladder cancer. The biological rationale for early chemotherapy for patients at high risk of recurrence after radical cystectomy is well known. A trial is presented in which patients with muscle invasive bladder cancer were randomized to cystectomy alone or to treatment with a variety of chemotherapeutic agents. Chemotherapy was determined for a number of years by a clonogenic assay to predict tumor sensitivity; during other periods patients were empirically treated with a combination of cisplatin, doxorubicin and cyclophosphamide. When this heterogeneous group of chemotherapeutic agents was compared to no treatment, there was an advantage in time of progression and overall survival for the chemotherapeutically treated patients. The statistical methods and analyses supporting this observation are sound. The question that now must be addressed is whether, based on this study, all patients who undergo cystectomy for invasive bladder cancer should be treated with postoperative chemotherapy routinely. My answer at this point is no. This study is provocative but it is flawed. Flawed, not in ways that are to be taken as criticism of the investigators, but simply this report represents the difficulties of clinical trials performed over long periods, as well as the major problem of treatment with a variety of chemotherapies. What this study does provide is a compelling reason to enter patients on ongoing and proposed randomized trials testing the role of chemotherapy in invasive bladder cancer. These trials should be designed with a control arm of no chemotherapy treatment. If patients are routinely treated with chemotherapy, based on this 1 trial, we may never clarify with certainty whether patients should be treated, and if treated, with what regimens and schedule.