Japanese Journal of Clinical Oncology Advance Access originally published online on October 26, 2007
Japanese Journal of Clinical Oncology 2007 37(11):852-857; doi:10.1093/jjco/hym129
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© 2007 Foundation for Promotion of Cancer Research
Background Variables for the Patients with Invasive Bladder Cancer Suitable for Bladder-preserving Therapy
Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Ibaraki, Japan
For reprints and all correspondence: Hideyuki Akaza, Department of Urology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan. E-mail: akazah{at}md.tsukuba.ac.jp
Received February 22, 2007; accepted June 3, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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Objective: The present study was undertaken to identify the patients suitable for bladder preservation by analysis of our data.
Methods: The subjects of this study were all 72 patients with T2–3N0M0 bladder cancer who underwent bladder-preserving therapy in our institute. The therapy involved intra-arterial chemotherapy with MTX and CDDP and concomitant radiotherapy.
Results: Of the evaluable 70 cases, complete response (CR) was confirmed in 57 cases (81.4%). Among 56 bladder preserved cases, 47 (83.9%) preserved their functioning bladder, and 9 underwent salvage radical cystectomy at the following period. The median follow-up was 45.3 months. The 5-year cause-specific survival rate was 81% and the 5-year overall survival rate was 66%. On the basis of the results of univariate analysis, variables contributing to CR were selected. In T2, tumor size of 
3 cm was scored 0 and >3 cm was scored 1, whereas single tumor was scored 0 and multiple were scored 1. In T3, tumor size of 3 cm was scored 0 and >3 cm was scored 1, whereas G2 was scored 0 and G3 scored 1. The CR rates were 93.8, 92.6, and 62.9% for total scores of 0, 1, and 2, respectively (P = 0.003; score 0 or 1 versus 2). The overall survival rate was significantly higher in the former group (P = 0.003).
Conclusion: Bladder-preserving therapy can be acceptable for cases of single T2N0M0 tumor with a size of 3 cm and for T3N0M0 cases with a tumor size of 3 cm.
Key Words: invasive bladder cancer • bladder preservation • chemotherapy • radiotherapy
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INTRODUCTION |
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At present, radical cystectomy is performed as a standard treatment for invasive bladder cancer. However, when treated with neoadjuvant therapy, 10–20% of patients with invasive bladder cancer exhibited complete response (CR) (1,2). Furthermore, the possibility of achieving a higher CR rate with combined chemotherapy and radiotherapy has been reported. However, whether bladder-preserving therapy is acceptable for treatment of invasive bladder cancer when the quality of life (QOL) of individual patients is taken into account remains controversial (3,4). Results of bladder-preserving therapy for invasive bladder cancer have been reported from several facilities, and have revealed 5-year overall survival rates of 49–63% and 5-year bladder preservation rates of 38–43% (5–12).
Invasive bladder cancer involves diverse background factors such as the degree of histological grade, number of tumors, size, and T category. No previous study of bladder-preserving therapy has included an adequate analysis of individual background variables. The conditions under which this therapy has been applied have thus remained unclear.
At the Department of Urology of the Tsukuba University Hospital, a prospective study of bladder-preserving therapy has been carried out since 1990, involving all cases of metastasis-free invasive bladder cancer (T2–3N0M0). The results of bladder-preserving therapy obtained thus far at our facility are not inferior to those of radical cystectomy for T2–3 cases carried out in other facilities (5,13). In this study, we examined the results so far obtained in our study, to identify the background variables associated with cases in which bladder preservation was feasible.
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PATIENTS AND METHODS |
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The subjects of this study were 72 patients with bladder cancer (T2–3N0M0) who visited our department between 1990 and 2005 and who consented to bladder-preserving therapy after having been adequately informed by the physicians (Table 1). The median age of the subjects was 70 years (range: 37–89 years). There were 57 males and 15 females. T category was T2a in 28 cases, T2b in 11 cases, and T3b in 33 cases. The histological type of all cases was transitional cell carcinoma. The histological grade was G2 in 15 cases and G3 in 57 cases. Pre-selected cold cup biopsy, carried out in all cases, revealed coexistence of carcinoma in situ (CIS) in one case.
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The first step of treatment was as complete resection of tumor by TURBT as possible. The regimen for bladder-preserving therapy we used, as described elsewhere (5), included intra-arterial chemotherapy (three doses of MTX 30 mg/m2 and CDDP 50 mg/m2 at intervals of 3 weeks) and simultaneous radiotherapy (41.4 Gy, 23 fr) of the small pelvis. Intra-arterial chemotherapy employed the Seldinger method. That is, after embolization of the superior gluteal arteries bilaterally, the entire amount of the anti-cancer drugs planned for one dose was infused through both the right and left internal iliac arteries over a period of approximately 2 h.
Approximately 3 weeks later, a second TURBT and urinary cytology were performed to check residual tumor. If no residual tumor was detected, the site which appeared to be that of removal or disappearance of tumor was marked with a transurethrally inserted Ir needle and then subjected to additional proton beam irradiation [33.0 Gy (11 fr)] to preserve the urinary bladder. If the proton irradiation equipment was unavailable, for reasons such as machine maintenance, the tumor site was irradiated with X-rays. In such cases, to reduce the risk of complications resulting from differences in distribution of the radiation, the radiation dose was reduced to 20 Gy.
After bladder-preserving therapy, each patient was followed every 3 months by cystoscopy, urinary cytology, and chest X-ray and every 6 months by abdominal CT scans. Upon detection of recurrent bladder tumor, non-muscle invasive cancer was treated with TURBT and intravesical instillation therapy, though radical cystectomy was performed if necessary.
RISK STRATIFICATION
For stratification of the risk of bladder preservation, we selected factors representing the features of tumor, for which differences in the CR rate were noted in separate analyses of individual factors, on the basis of the results of univariate analysis of individual factors. After that, factors exhibiting little correlation were paired to explore pairs of factors that would increase the difference in the CR rate and aid identification of sub-groups with low CR rates. We used only two-factor pairs, given the numbers of subjects and categories involved in this study, since combining three or more factors for the T2 group and the T3 group might markedly reduce the number of sub-groups.
STATISTICAL ANALYSIS
CR rate was analysed by Fisher's exact test. The Kaplan–Meier method was employed for calculation of survival rates. These parameters were subjected to the log-rank test. Multivariate analysis of risk used a Cox proportional hazard model.
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RESULTS |
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Of the 72 patients enrolled in this study, 2 failed to complete the treatment because of comorbidity or withdrawal of consent by the patient. Excluding these 2 cases, the remaining 70 cases were examined. As evaluated by TUBRT after intra-arterial chemotherapy and radiotherapy, 57 of the 70 cases (81.4%) exhibited disappearance of tumor (CR). One of these 57 patients underwent radical cystectomy at his own request, and the urinary bladder was preserved in the remaining 56 cases. Of the 56 cases, 35 were treated with proton beam and 21 were treated with X-ray. Of the 13 patients found to have residual tumor, 9 underwent radical cystectomy and the remaining 4 cases received best supportive care (these 4 patients did not consent to undergo radical cystectomy).
During the median follow-up period of 49.7 months, 36 (64.3%) of the 56 patients with bladder preservation remained free of recurrence. Recurrence was noted in 20 cases, including 18 cases of recurrence in the bladder (non-muscle invasive cancer in 17 cases and invasive cancer in 1 case) and 3 cases of distant metastasis (1 with both recurrence of non-muscle invasive cancer and distant metastasis). The patients exhibiting recurrence of non-muscle invasive cancer underwent TURBT or radical cystectomy, and none of them died of cancer. As an end result, 47 (83.9%) of 56 cases preserved their functioning bladder. Nine cases underwent salvage radical cystectomy without specific complication related to bladder-preserving therapy. The urinary diversions performed by were ileal conduit in six cases, ureterocutaneostomy in two cases and Indiana pouch in one case.
For the 70 cases analysed (median follow-up period: 45.3 months), the 5-year cause-specific survival rate was 81% and the 5-year overall survival rate was 66%. For the 56 patients with bladder preservation (median follow-up period: 49.7 months), the 5-year cause-specific survival rate was 87% and the 5-year overall survival rate was 70%. As adverse reactions, temporary nausea and vomiting as well as symptoms of bladder irritation were noted in many cases, but all subsided after the end of treatment. Mild sciatic neuropathy was noted in 15 cases, and bladder atrophy was observed in 2 cases. These 2 cases with bladder atrophy were underwent radical cystectomy as a treatment for bladder cancer recurrence.
RESULTS OF RISK STRATIFICATION FOR BLADDER PRESERVATION
The factors analysed were age (<70 or not less than 70 years), sex (male or female), maximum tumor size (not >3 cm or more than 3 cm), number of tumors (single or multiple), and histological grade (G2 or G3). Univariate analysis of differences in the CR rate associated with each of these factors was carried out for the T2 and T3 groups (Table 2). As a result, it was considered appropriate to identify tumor size and number of tumors in the T2 group, and tumor size and histological grade in the T3 group as risk factors, respectively. Using a two-point scale, each of these factors was scored as follows: tumor size (3 cm or less: 0, >3 cm: 1), number (single: 0, multiple: 1), grade (G1-2: 0, G3: 1). The scores for all risk factors were totaled.
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Table 3 shows the relationships between total score of risk stratification and CR rate for the T2 and T3 groups. For the patients with total scores of 0 and 1, CR rates were 93.3% and 94.1% in the T2 group, and 100% and 90.0% in the T3 group, respectively. For the patients with total score of 2, the CR rate was 71.4% in the T2 group and 60.0% in the T3 group. The 13 T3 cases with tumor size 5 cm or more had a CR rate of 53.9%, and 6 of them underwent radical cystectomy. When CR rate was calculated for the entire study population (T2 group + T3 group), it was found to differ significantly between the patients with total score of 0 or 1 (93.0%) and those with total score of 2 (62.9%) (P = 0.003).
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We then examined the relationship between cause-specific survival and total score (Fig. 1A). Survival rate did not differ significantly between the patients with a total score 0 or 1 and those with a total score of 2, and a good survival curve was obtained for each group. On multivariate analysis (Table 4), the risk ratio of total score 2 against cause-specific survival was 2.06 (P = 0.343) for the entire study population (T2 group + T3 group). In the 14 cases in which bladder preservation was not possible (Table 1), prognosis was significantly poorer than for the cases in which bladder preservation was possible (P = 0.021).
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The prognosis in terms of overall survival (Fig. 1B) was significantly poorer for the patients with a total score of 2 (P = 0.021). On multivariate analysis (Table 4), the risk ratio of the patients with a total score 2 against overall survival was 1.94 (P = 0.170), and 1.65 (P = 0.096) for the patients in whom bladder preservation was not possible. Age was identified as the factor most closely determining overall survival, with a risk ratio of 5.51 (P < 0.001), although this finding could have been naturally expected. The prognosis of the 13 T3 cases with tumor size 5 cm or more was not particularly poor.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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In recent years, a number of reports have been published concerning bladder-preserving therapy for invasive bladder cancer (5–12). In the present study, the 5-year overall survival rate for all 70 patients was 66%. This result was similar to the data of patients treated with radical cystectomy. Nishiyama et al. (13) reported that the 5-year overall survival rate in T2 and T3 were 74.7 and 57.9%, respectively. Stein et al. (14) also reported that the 5-year overall survival rate in T2a, T2b, and T3 were 72, 58, and 38%, respectively. It would be of great benefit to patients if this type of therapy could maintain both QOL and bladder function (15,16).
However, adequate medical evidence for the validity of bladder-preserving therapy has not yet been obtained. Findings reported for this therapy include the following: (i) it is advisable to resect the tumor as completely as possible by TURBT before bladder-preserving therapy; (ii) higher efficacy can be expected if chemotherapy is combined with radiotherapy; (iii) preservation of the bladder is possible only in cases in which TUR biopsy after treatment reveals no residual tumor (17).
In terms of drug distribution in the tumor-affected area, intra-arterial infusion therapy is superior to intravenous therapy. Furthermore, since the area supplied by the artery for infusion of anti-cancer drugs in cases of bladder cancer includes no organ degrading or eliminating the anti-cancer drugs, it can be expected that drugs infused intra-arterially will be distributed in the organs beyond this area in concentrations comparable to those observed following intravenous infusion. Stewart et al. (18) compared plasma drug levels following intra-arterial infusion of cisplatin with intravenous infusion of the same drug, and found that infusion of the drug into arteries other than the hepatic artery (which supplies an area including organs involved in drug degradation and elimination) resulted in a plasma drug level comparable to that after intravenous infusion.
At present, significance of development of the technique of bladder-preserving therapy is in selecting the patients suitable for this therapy to improve preservation of the bladder with a high degree of safety, rather than preserving the bladder of all patients (19). According to previous reports, the outcome of this therapy is poor in cases of T4 tumor or multiple tumors (9), cases complicated by hydronephrosis (8), and certain other patients. However, many studies did not discuss whether bladder preservation could be actively performed, on the basis of clear-cut comparison of background variables.
Gospodarowicz (20) reported that patients for whom tumor stage is T2–3, tumor size is <5 cm, tumor is distant from the bladder apex, and diffuse CIS lesions are absent can be considered indicated for bladder preservation. At our facility, we make it a rule to perform pre-selected biopsy for all patients planned to receive bladder-preserving therapy. Complication by CIS was noted in only 1 of the 70 cases examined in the present study. The frequency of CIS among cases of non-muscle invasive bladder cancer is reported to be 25% (21) in the USA and 6% (22) in Japan. This difference appears to reflect the difference between Japan and the USA in frequency of CIS complicating invasive bladder cancer. In the present study, the recurrent tumor found in the preserved bladder was non-muscle invasive cancer in 17 of the 18 cases. This finding appears important as concerns the mechanism of carcinogenesis of bladder cancer. It seems likely that Japanese patients with invasive bladder cancer are more commonly indicated for bladder-preserving therapy than American patients.
Because our facility limited bladder-preserving therapy to T2–3N0M0 cases from the beginning of our use of this type of treatment, it was possible for us to identify prognostic factors in detail. We performed analyses to answer the following questions: (i) which patients with invasive bladder cancer should undergo bladder-preserving therapy? (ii) what percentage of the T2–3N0M0 patients indicated for radical cystectomy should receive bladder-preserving therapy?
We first developed scoring system to identify the probability of CR after TURBT for each patient. According to the complex of two factors such as larger size and multiplicity in T2 and larger size and Grade 3 in T3 are candidate for prediction factors. Patients had two factors simultaneously became low probability of CR. Therefore, we counted each factor as one point, then patients had point two are low probability of CR. Patients counted point zero or one were relatively high probability of CR. We used this system to identify the probability of CR after TURBT as the points counted two or not. We think this system is easy to identify and use for each patient. The residual tumor after TURBT is an important prognostic factor for local control and survival (23). The tumor size and the multiplicity may relate to the residual tumor after TURBT. These factors were then scored, and risk stratification was performed to predict efficacy and prognosis. When the T2 and T3 cases were combined, CR rates were 93.8 and 92.6% for the cases with total scores of 0 and 1, respectively, and 62.9% for the cases with a total sore of 2. Furthermore, the CR rate was only 53.9% for the T3 cases with tumor size 5 cm or more. These findings suggest that patients with invasive bladder cancer with a total score of 0 or 1 are suitable for bladder-preserving therapy, whereas a total score of 2 necessitates careful determination whether bladder-preserving therapy is indicated. In the analysis of survival, no significant difference was found in cause-specific survival rate between the patients with a total score of 0 or 1 and those with a total score of 2. Of the 10 patients with a total score of 2 and found to have residual tumor, 7 underwent radical cystectomy. It was thus shown that prognosis is not necessarily poor even for patients who fail to exhibit CR to bladder-preserving therapy, if these patients subsequently undergo radical cystectomy.
From 1982, Japanese Urological Association (JUA) set the registration system for bladder cancer patients. The main statistical data have been reported annually and in 2006, the data between 1998 and 2000 were published (22). We compared the data of our patients with those of the JUA registry. In 1997, 2724 registered patients with bladder cancer received treatment at the major hospitals belonging to the JUA (Table 5). Of these, 147 patients with T2N0M0 and 77 patients with T3N0M0 underwent radical cystectomy. The percentage of patients with a total score of 0 or 1 among these cases was 59.5% for the T2N0M0 group and 33.2% for the T3N0M0 group. These patients might be managed by bladder-preserving therapy.
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In recent years, development of molecular biological markers such as p53 and Ki-67 have advanced (24), and these markers will be utilized as prognostic factors in the near future. The results of the analyses we performed suggest that the range of patients indicated for bladder preservation will further expand following establishment of more detailed criteria for background variables and conditions such as number of tumors, tumor size, and histological grade, among others.
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CONCLUSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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We analysed background variables for selection of patients with invasive bladder cancer suitable for bladder-preserving therapy, and found that bladder-preserving therapy can be recommended for cases of single T2N0M0 tumor with a size of 3 cm or less (59.5%) and for T3N0M0 cases with a tumor size of 3 cm or less (33.2%), although T2N0M0 and T3N0M0 cases have been usually considered indicated for radical cystectomy.
Conflict of interest statement
None declared.
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References |
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