Int J Clin Oncol (2003) 8:168–173 DOI 10.1007/s10147-003-0323-y

© The Japan Society of Clinical Oncology 2003

ORIGINAL ARTICLE Takehiko Okamura · Hidetoshi Akita · Keiichi Tozawa Noriyasu Kawai · Daisuke Nagata · Kenjiro Kohri

Bacillus Calmette–Guerin-refractory superficial bladder cancers: focus on pretreatment episodes

Received: August 22, 2002 / Accepted: March 31, 2003

Abstract Background. Reasons for development of bacillus Calmette–Guerin(BCG)-refractory superficial bladder cancers are unknown. In the present study, a series of cases was therefore analyzed, focusing on the influence of treatment before BCG application. Patients and methods. A total of 96 patients with superficial bladder cancers received six weekly intravesical instillations of BCG followed in some cases by a further six applications at monthly intervals. If tumors recurred, a further course of treatment in association with surgery or some other therapy was chosen, depending on the patient and the tumor condition. Results. Thirty-three cases (34.4%) demonstrated tumor recurrence within 24 to 146 months, including 9 with progression. Pretreatments had been performed in 19 of these cases (57.6%) whereas they had been conducted for only 10 (15.9%) of the BCG-effective cases. Of the total 96 patients, 29 received pretreatment with open surgery, systemic chemotherapy, intravesical instillation or oral administration of anticancer drugs, or immunotherapy. Sixty-six percent of these proved BCG refractory, in contrast to only 20.9% in the no-pretreatment group. Furthermore, 7 of the 9 patients demonstrating progression had undergone pretreatment. Conclusions. The data suggest that intravesical instillation of BCG is more effective when no prior treatment has been attempted, and that best results may be achieved if BCG is chosen as the initial therapy for superficial bladder cancer. When pretreatment has been performed and pT1 lesions recur, however, immediate total cystectomy should be advised.

T. Okamura (*) · H. Akita The Urology Division, Meijo Hospital, 1-3-1 San-nomaru, Naka-ku, Nagoya 460-0001, Japan Tel. ⫹81-52-201-5311; Fax ⫹81-52-201-5318 e-mail: [email protected] K. Tozawa · N. Kawai · D. Nagata · K. Kohri The Department of Nephro-Urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Key words Superficial bladder cancer · Intravesical instillation · BCG refractory · Pretreatment

Introduction Intravesical instillation therapy with bacillus Calmette– Guerin (BCG) is now widely used for prevention and treatment of superficial bladder cancers because posttreatment recurrence and multifocal development are very common with surgery alone. BCG is now also used for therapy of carcinoma in situ (CIS) as well as for preventing superficial bladder cancer recurrence after transurethral resection (TUR-Bt).1–5 It is in fact now being employed in cases without any prior surgery,6 and BCG therapy has indeed become the gold standard for both therapeutic and prophylactic control in urology departments. However, adverse effects of BCG are relatively frequent, including severe toxicity and general or focal infection with the bacterium itself,7–8 and not all urologists are of the opinion that BCG should be the first choice in the treatment of superficial bladder cancers. Therefore, many other approaches may be chosen depending on the conditions or attending doctor. After TUR-Bt, intravesical instillation of anticancer drugs is used in many cases, but a high risk of recurrence is reported with this approach, especially less than 2 years after the treatment.9 With grade 3 cases, systemic chemotherapy or even open surgery may be selected. In combination, irradiation and oral administration of anticancer drugs may also be applied, but results are not satisfactory in many cases. As our previous report documented that BCG intravesical instillation therapy is very effective as the first choice for treatment,10 the question of whether prior application of other therapeutic modalities may exert an adverse influence warrants attention. The present study was conducted to test this possibility, evaluating a large series of patients given intravesical BCG prophylactically after surgery, focusing on the effects of any pretreatment episodes.

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Patients and methods From March 1989 until September 2001, 96 patients were treated in Meijo Hospital and Nagoya City University Graduate School of Medical Sciences with intravesical instillations of BCG (Tokyo 172 strain, purchased from Nihon BCG, Tokyo, Japan) after TUR-Bt for superficial bladder tumors. Informed consent was received in all cases. The patient’s ages ranged from 33 to 84 years (average, 65.4), and the male : female ratio was 84 : 12 (7 : 1). All patients had a history of either multifocal or recurrent stage Ta to T1 papillary transitional cell carcinoma (TCC) (Ta : T1 ⫽ 33 : 63) without any other concurrent malignancies or active tuberculosis infection. Patients with concomitant CIS or bladder cancer with muscle invasion (more than stage pT2) were excluded. Of the total, 29 cases had been pretreated with open surgery (10 cases), systemic chemotherapy (11 cases), intravesical instillation of anticancer drugs (8 cases), oral administration of anticancer drugs (7 cases), or immunotherapy (5 cases), including combinations of these (Table 1). Systemic chemotherapy was generally only chosen for treatment of grade 3 lesions, although this was at the discretion of the responsible physician. Open surgery was performed for tumors of the upper urinary tract and for large solitary lesions. Details for treatments are given in Table 1. All the patients received a BCG instillation of 80 mg (40 mg for those aged 80 or older) suspended in 40 ml physiological saline (or, after March 1990, in distilled water due to the possibility of promoting effects of saline as found in our animal experiments11) once a week for 6 weeks, and then at 1-month intervals for up to another six times or no further treatment. The dose was selected on the basis of results of extensive studies by Akaza et al.12–13 In some cases treatment was terminated before the course of six instillations could be performed, but all patients received at least three. The patients were asked to refrain, if possible, from urination within 2 h of the instillation and were monitored for bladder irritation, temperature change, and other clinical symptoms. A tuberculin reaction, blood examinations, chest X-rays, cystoscopy, and urinary cytology were done in all cases conducted before and after six instillations and also at other times when considered appropriate. Follow-up was on a regular weekly basis and if tumors recurred, a further course of treatment in association with surgery or a different modality was chosen depending on the patient and the tumor conditions. Further recurrence

was again followed by surgery and a further course of treatment, for up to a total of four times in tolerant cases. The minimum follow-up period was 24 months, with a maximum of 146 months, after the BCG treatment. Surgically resected material was routinely fixed in 10% buffered formalin and embedded in paraffin for sectioning and histopathological assessment of hematoxylin and eosin-stained sections. Tumor grading and staging were performed with reference to the third edition of the General Rules for Clinical and Pathological Studies on Bladder Cancer of the Japanese Urological Association and the Japanese Society of Pathology. Multivariate statistical analysis was performed, using the Cox proportional hazard model, to analyze the synchronous influence of the various parameters. In addition, cumulative (nonrecurrence, without progression) rates were estimated using the Kaplan–Meier method, and the significance of differences between curves was tested by the log–rank test (SAS software). Monovariate statistical analyses were accomplished using Student’s t test and Mann–Whitney analysis with the statistical software package Stat View Version 5.0. (see the figures for the test applied). A value of P ⬍ 0.05 was considered as statistically significant.

Results Recurrence occurred in 33 of the total of 96 patients (37.5%), including 9 cases demonstrating progression (Fig. 1). These latter were characterized by increase in grade or stage during or subsequent to the treatment. Four exhibited focal intravesical recurrence, 2 undergoing total cystectomy (both were without pretreatment) and the other 2 receiving intravesical anticancer drugs (in 1, focal recurrence was followed by total cystectomy; in the other, focal invasion occurred, then death from cancer). There were 3 upper urinary tract recurrences, all of which underwent nephroureterectomy. One subsequently suffered intravesical focal recurrence, and a second course of BCG was performed, followed by total cystectomy because of a contracted bladder. In the second case, further recurrence was found in the opposite renal pelvis, and hemodialysis was conducted after a second open surgery for nephroureterectomy. The third case continues to be followed with oral administration of an anticancer drug. The

Table 1. Details of pretreatment episodes No. of patients

Types of pretreatments

Details of treatments

Interval to BCG therapy (months)

10 11 8 7 5

Open surgery Systemic chemotherapy Intravesical instillation of anticancer drugs Oral administration of anticancer drugs Immunotherapy

Nephroureterectomy (8), partial cystectomy (2) M-VAC (8), MEC (2), CDDP ⫹ ADM (1) ADM (3), epirubisine (2), MMC ⫹ CA (2) Tegafur (3), UFT (3), carmofur (1) Ubenimex (5)

4–312 (64.7 ⫾ 102.2) 2–32 (10.3 ⫾ 10.4) 1–75 (17.0 ⫾ 24.9) 1–17 (6.6 ⫾ 7.1) 1–9 (2.8 ⫾ 3.5)

BCG, bacillus Calmette-Guerin; M-VAC, methotrexate, vinblastine, adriamycine; CDDP, combination therapy; MEC, methotrexate, etoposide, CDDP, combination therapy; ADM, adriamycine; MMC, mitomycin C; CA, cytarabine; UFT, uracil and tegafur combination drug

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remaining 2 cases developed local invasion and distant metastases after the BCG treatment, and both patients rapidly deteriorated and died. Summaries of details for all these 9 cases are shown in Table 2 and Fig. 2. The remaining 24 recurrent cases were BCG resistant, with tumor recurrence but without tumor progression. All could be finally controlled with BCG and other anticancer drugs, without cancer-related death. Of the total 33 recurrent cases, 19 had undergone pretreatment before the BCG (57.6%). In contrast, only 10 of the total of 63 cases without

Fig. 1. Details for the total 96 cases:

recurrence had been pretreated (15.9%). A significant overall difference between the no-pretreatment and pretreated groups was found with regard to outcome (P ⬍ 0.0001, Mann–Whitney analysis) (Fig. 3). Monovariant statistical analyses were performed with reference to age, gender, stage, grade, and other parameters, but none of these parameters proved significant (data not shown). Recurrence-free survival and progression-free survival were compared for patients of the no-pretreatment and pretreated groups using the Cox proportional hazard model (Tables 3, 4), only pretreatment being significant for both recurrence and efficacy. In addition, Kaplan–Meier curves demonstrated significant differences for both (Figs. 4, 5), the prognosis being better without pretreatment. Kaplan– Meier curves generated for groups with pTa and pT1 lesions demonstrated a significant difference for the time to recurrence (Fig. 6).

, pretreated;
, untreated

Fig. 2. Details for the nine progression cases. rec., recurrence; UT, urinary tract; Meta, metastasis; Total, total cystectomy; Ives ACD, intravesical instillation of anticancer drug; PO ACD, per oral anticancer drug; HD, hemodialysis; BCG, bacillus Calmette–Guerin; Contracted, contracted bladder

Fig. 3. Comparison of no-pretreatment (left) and pretreated (right) groups. , no recurrence; , no progression; , progression; *, Mann–Whitney

Table 2. Details for the nine progression cases Age

Sex

Grad

Stagea

No. of tumors

Rec. time

Pretreatment

Combination therapy

Interval to recurrence (months)

Prognosis (months)

72 69 62 59 64 73 76 69 82

M M M M M M M F F

3 2 3 2 2 2 3 2 2

pT1 pT1 pT1 pT1 pT1 pT1 pT1 pT1 pT1

3 8 3 3 1 9 3 2 3

0 0 0 3 2 0 2 1 1

(⫺) (⫺) IVes ACD PO ACD, Chemo Open surg Chemo IVes ACD Open surg, Chemo Open surg, PO ACD

(⫺) (⫺) PO ACD IVes ACD IVes ACD Immuno PO ACD, IVes ACD Immuno, PO ACD PO ACD

7 9 4 19 32 72 6 9 2

Alive (Total C) (58) Alive (Total C) (34) Alive (Total C) (125) Alive (Open surg) (48) Alive (Open surg) (36) Alive (Open surg) (89) Tumor death (27) Tumor death (12) Tumor death (8)

M, male; F, female; Total C, total cystectomy; Rec., recurrence; IVes ACD, intravesical instillation of an anticancer drug; PO ACD, per oral anticancer drug; Chemo, systemic chemotherapy; Immuno, immunotherapy; Open surg, nephroureterectomy, etc. a Stage was decided on the basis of the third edition of the General Rules for Clinical and Pathological Studies on Bladder Cancer of the Japanese Urological Association and the Japanese Society of Pathology

171 Table 3. Statistical analysis of recurrence (Cox proportional hazard model) Factors

Division

Monovariate analysis

Multivariate analysis

Frequency distribution

Age Gender Grade Stage Number of tumors Primary/ recurrent Pretreatment

⬍65 ⭌65 Male Female G1 G2 G3 pTa pT1 1 ⭌2 Primary Recurrent No Yes

Nonrecurrent

Recurrent

38 49 77 10 25 48 14 33 54 27 60 43 44 65 22

3 6 7 2 0 6 3 0 9 1 8 4 5 2 7

Preadjustment risk ratio

Confidence interval

P value

Postadjustment risk ratio

Confidence interval

P value

1.56

0.390–6.238

0.5300

1.91

0.455–7.980

0.3775

2.16 – – – – –

0.449–10.402 – – – – –

0.3369 – – – – –

2.32 – – – – –

0.428–12.536 – – – – –

0.3300 – – – – –

3.51

0.438–28.045

0.2370

2.16

0.254–18.289

0.4816

1.24

0.333–4.623

0.7485

0.40

0.091–1.760

0.2252

8.45

1.754–40.732

0.0078**

12.27

2.215–67.932

0.0041**

** P ⬍ 0.01

Table 4. Statistical analysis of efficacy (Cox proportional hazard model) Factors

Division

Monovariate analysis Frequency distribution

Age Gender Grade Stage Number of tumors Primary/recurrent Pretreatment

⬍65 ⭌65 Male Female G1 G2 G3 pTa pT1 1 ⭌2 Primary Recurrent No Yes

Effect

No effect

29 34 57 6 20 33 10 28 35 22 41 34 29 53 10

12 21 27 6 5 21 7 5 28 6 27 13 20 14 19

Multivariate analysis

Preadjustment risk ratio

Confidence interval

P value

Postadjustment risk ratio

Confidence interval

P value

1.50

0.737–3.050

0.2639

1.57

0.735–3.332

0.2456

1.82

0.751–4.420

0.1845

1.28

0.484–3.375

0.6206

2.26 2.33

0.848–5.998 0.736–7.371

0.1030 0.1504

1.44 1.36

0.472–4.394 0.339–5.481

0.5221 0.6631

3.19

1.232–8.267

0.0169*

2.22

0.764–6.469

0.1427

2.35

0.966–5.697

0.0595

1.87

0.745–4.681

0.1831

1.57

0.780–3.175

0.2050

1.13

0.437–2.897

0.8063

3.62

1.811–7.235

0.0003**

2.75

1.180–6.385

0.0191*

* P ⬍ 0.05; ** P ⬍ 0.01

Discussion Although the present study was retrospective, and there are many kinds of possible biases between the BCG first-choice group and second-line group, the results obtained provide evidence that BCG should be selected as the first therapeutic agent for superficial bladder cancers. Although the anticancer mechanisms of BCG are not totally understood, they are generally considered to involve immunological reactions.14–18 Clinically, superficial bladder cancer is highly sensitive to BCG,19–22 and it is generally well established that stimulation of the immune system exerts only beneficial effects on tumor development. In contrast, anticancer drugs may sometimes act as tumor-promoting agents, both in animal experiments23 and in human cases,24 at least partly as a

result of immunological damage. Similar to open surgery, injury brings about local and general suppression of the immune system.25,26 The literature contains many reports of prophylactic effects of anticancer drugs on superficial bladder cancers,27–29 but long-term follow-up suggests that efficacy does not persist for many years.9 The prophylactic effects of BCG, on the other hand, are reported to extend over very long periods,19–21 including, in one report, a follow-up of greater than 10 years.30 Several trials of therapy with BCG in combination with anticancer drugs have been conducted, but the results have generally been controversial.31–33 As mentioned, the prophylactic effects of anticancer drugs are effective in the early period,9 and therefore a number of authors have proposed that early administration of mitomycin C should be combined with subsequent BCG

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Fig. 4. Recurrence-free survival curves for the no-pretreatment (solid line) and pretreated (dashed line) groups (P ⫽ 0.0014, log-rank test)

Fig. 6. Progression-free survival curves for the pTa (solid line) and pT1 (dashed line) groups (P ⫽ 0.0110, log-rank test)

our present results suggest the response to recurrence should be immediate total cystectomy, rather than BCG.

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Fig. 5. Progression-free survival curves for the no-pretreatment (solid line) and pretreated (dashed line) groups (P ⫽ 0.0001, log-rank test)

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