Japanese Journal of Clinical Oncology Advance Access originally published online on April 7, 2009
Japanese Journal of Clinical Oncology 2009 39(6):381-386; doi:10.1093/jjco/hyp023
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© The Author (2009). Published by Oxford University Press. All rights reserved
Bladder Preservation Therapy Conducted by Intra-arterial Chemotherapy and Radiotherapy for Muscle Invasive Bladder Cancer
1 Department of Urology, National Hospital Organization Shikoku Cancer Center
2 Department of Radiation Oncology, National Hospital Organization Shikoku Cancer Center, Japan
For reprints and all correspondence: Katsuyoshi Hashine, Department of Urology, National Hospital Organization Shikoku Cancer Center, 160 Minamiumemoto, Matsuyama 791-0280, Japan. E-mail: khashine{at}shikoku-cc.go.jp
Received January 15, 2009; accepted February 24, 2009
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Abstract |
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Objective: A previous paper reported favorable results of intra-arterial chemotherapy in combination with radiotherapy for muscle-invasive bladder cancer. The current study will update those results.
Methods: Between January 1992 and December 2006, 94 patients with confirmed muscle invasion were treated with intra-arterial chemotherapy and concurrent radiotherapy after an initial complete transurethral resection. Intra-arterial chemotherapy consisted of cisplatin (Days 1–3) and pirarubicin (Days 8–10), and radiation was administered with the chemotherapy (2 Gy/session) with a total dosage of 44 Gy. The median age was 67.0 years. There were 60 patients in T2, 19 patients in T3 and 15 patients in T4. The median follow-up period was 72.9 months in the survivors.
Results: Among these patients, 84 patients (89.4%) obtained a complete response (CR) and 10 patients did not achieve a CR. Between the CR and non-CR patients, the clinical stage and the existence of hydronephrosis were significantly different. The cause-specific survival rates at 5 and 10 years were 76.2% and 67.5%, respectively. The overall survival rates at 5 and 10 years were 66.6% and 47.4%, respectively. A Cox proportional hazard model showed that only the cause-specific survival rate was associated with a CR after treatment. The bladder preservation rates were 89.7% at 5 years and 87.6% at 10 years. Myelosuppression was the major adverse event but it was manageable. Non-hematological sever adverse events were rare.
Conclusions: Bladder preservation therapy shows good survival and good bladder preservation rates. Clinical stage T2 and the absence of hydronephrosis are favorable factors.
Key Words: bladder preservation therapy • chemotherapy • radiotherapy • invasive bladder cancer
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INTRODUCTION |
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A radical cystectomy has been considered to be the gold standard treatment for muscle-invasive bladder cancer. Shariat et al. (1) reported that the recurrence-free and bladder cancer-specific survival following a radical cystectomy was 58% and 66% after 5 years, respectively. Many investigators report similar results (2–5). However, a radical cystectomy requires urinary diversion. Therefore, a cystectomy reduces the quality of life (QOL) for the patient. The surgical technique of urinary diversion has been improved and the decrease in QOL score has been reduced in patients treated by a cystectomy. The use of a neobladder is a superior method, but it has some problems such as night-time incontinence so it is inferior to the patients' own bladder. Therefore, bladder preservation therapy (BPT) is under investigation as an alternative to a radical cystectomy.
BPT was introduced in our institute at the beginning of the 1980s and had been performed for patients who want to preserve their own bladder. When this treatment was introduced, doxorubicin (ADM) was used for intra-arterial chemotherapy (6). This regimen yielded good results, but in the 1990s, cisplatin (CDDP)-based regimen was adopted (7). The procedure for BPT includes a complete transurethral resection of bladder tumor (TUR-BT) with intra-arterial chemotherapy combined with radiotherapy and the preliminary results have been reported (7). CDDP and pirarubicin (THP) were selected for intra-arterial chemotherapy. THP is the anti-tumor drug classified as an anthracycline. This drug has little heart toxicity in comparison with ADM and the effect is equivalent. Therefore, it is often used like ADM in Japan. Each drug was delivered three times to improve the efficacy. Those results were good and few severe adverse events were observed (7). This therapeutic regimen has continued until now and this present study provides an update of the results.
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PATIENTS AND METHODS |
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The primary indication for BPT is a good performance status [Karnofsky performance status (KPS) >70%], adequate hematologic, renal and hepatic functions and the absence of metastasis. There was no consideration of the clinical T stage and histological type. All patients were informed that the standard treatment is a radical cystectomy and that the efficacy of BPT is currently under investigation. After receiving this information, the patients chose their treatment, cystectomy or BPT. BPT was performed for patients who wanted to preserve their own bladder. Between January 1992 and December 2006, 138 patients had confirmed muscle invasion of bladder carcinoma without metastasis (T2-4N0M0). The TNM classification was staged according to the American Joint Committee on Cancer staging system (6th 2002). Among them, 113 patients were eligible for BPT. Of these patients, 94 patients elected to undergo BPT. On the other hand, a radical cystectomy was performed for 17 patients. Systemic chemotherapy plus radiation was performed on one patient because intra-arterial chemotherapy was impossible due to arteriosclerosis. One other patient refused any treatment and took palliative treatment only. Twenty-five patients were not eligible for BPT because of other advanced cancer or poor conditions. Among them, 17 patients were treated by radiation with or without low-dose CDDP and 8 patients treated by palliation only.
The treatment regimen for BPT has been described previously (7). First, all the visible tumor is removed and muscle layer is resected as deeply as possible, until usually extra-vesical fat layer is visible. After a complete TUR-BT, intra-arterial chemotherapy consisting of CDDP, administered at 25 mg/m2 for Days 1–3, and THP, administered at 15 mg/m2 for Days 8–10. CDDP was reduced to 20 mg/m2 in patients over 75 years old. Radiation (2 Gy/session) was administered with the chemotherapy to the whole pelvis using the two-field technique. Three patients were administered carboplatin instead of CDDP due to mild renal dysfunction during treatment and two patients were administered methotrexate (MTX) or epirubicin instead of THP. Prior to chemotherapy, a port (P-U CELSITE PORT ‘TORAY’, Japan) was placed in the femoral subcutaneous tissue <5 cm from the inguinal lesion and a catheter (ANTHRON P-U CATHETER, ‘TORAY’, Japan) was placed in the abdominal aorta >2 cm from the bifurcation and connected. CDDP and THP were infused through the port for 10 min and the bilateral femoral arteries were pressed as forcefully as possible during the infusion. These treatments were administered three times every 4 weeks and then radiotherapy was continued to a total dosage of 44 Gy. In the early phase of this protocol, radiotherapy was administered up to a dose of 60 Gy. However, because of severe adverse events, such as contracted bladder, we then reduced the dose to 44 Gy.
One month after treatment, a TUR-BT was performed for a histological examination. A complete response (CR) is defined as no residual cancer in TUR specimens and negative cytology after treatment, and non-CR was defined as viable cancer in TUR specimens or positive cytology. If patient did not achieve a CR, a radical cystectomy was recommended. Patients with CR were kept under careful observation. The observation schedule included computed tomography and cystoscopy every 3 months for 2 years and every 6 months after 3 years and cytology was observed every 3 months. Written informed consent was obtained from all patients before the initiation of treatment.
All adverse events were graded using the version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events. Recurrence was divided into superficial recurrence and invasive recurrence. Superficial recurrence was Ta/T1/Tis and invasive recurrence was confirmed in regard to muscle invasion. Progression was defined as invasive recurrence and the presence of metastasis. Progression-free survival, cause-specific survival and overall survival were calculated by the Kaplan–Meier method. A logistic regression analysis was used to analyze the factors associated with CR and a Cox regression analysis was used for the factors associated with survival. The patients' characteristics between CR and non-CR were compared using the independent sample t-test for continuous parameters and the 
2 test for categorical parameters. A P value of <0.05 was considered to be statistically significant. All statistical analyses were conducted using the SPSS 16.0J statistical software package (SPSS, Tokyo, Japan).
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RESULTS |
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Patients' characteristics are listed in Table 1. The median age was 67 years. All patients showed good performance status (KPS > 70%). Hydronephrosis was observed in 18 patients. There were 60 patients in T2, 19 patients in T3 and 15 patients in T4. Seventy-nine patients included only urotherial carcinoma; on the other hand, 15 patients included an adenocarcinoma or squamous cell carcinoma with or without urotherial carcinoma (only one patient was pure adenocarcinoma). The median dosage of radiotherapy was 44 Gy (36–60 Gy). As of June 2008, 56 patients were still alive and the median follow-up period was 72.9 months in these survivors.
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Among these patients, 84 patients (89.4%) achieved a CR. Among these CR patients, 18 patients experienced recurrences, 3 patients in the superficial bladder cancer and 15 patients in the progression. In the progression patients, 4 patients had recurrence in the bladder and 11 patients experienced metastasis. Among the progression patients, four patients underwent a radical cystectomy and others received chemotherapy. One patient required a radical cystectomy for a contracted bladder during the follow-up period, but this patient developed pelvic cancer. Including this patient, carcinoma in the upper urinary tract was found in two patients who underwent a radical nephroureterectomy. Ten patients did not achieve a CR. Among them, three patients underwent a radical cystectomy. The other patients refused to undergo a radical cystectomy, three of these were treated with additional chemotherapy and patients remained under observation (Fig. 1). Between the CR and non-CR patients, the clinical stage and the existence of hydronephrosis were significantly different and primary or recurrent tumors tended to be significant. No other factors were significantly associated with a CR (Table 1).
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The progression-free survival rates at 5 and 10 years were 73.5% and 70.3%, respectively. The cause-specific survival rates at 5 and 10 years were 76.2% and 67.5%, respectively. The overall survival rates at 5 and 10 years were 66.6% and 47.4%, respectively (Fig. 2). Using a Cox proportional hazard model, only the cause-specific and overall survival rates were associated with a CR after treatment. Other factors, such as the clinical stage, tumor size and the existence of hydronephrosis, were not significant. On the other hand, the factors that predicted CR were the clinical stage and the existence of hydronephrosis (Table 2). The cause-specific survival curves according to the clinical stage and the existence of hydronephrosis are shown in Fig. 3. The bladder preservation rate was 89.7% at 5 years and 87.6% at 10 years.
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Myelosuppression was the major adverse event in this series of BPT. Grade 3/4 neutropenia occurred in 77.7%, but febrile neutropenia occurred in 13.9%. Anemia and thrombocytopenia with grade 3/4 occurred in 35.1% and 36.2%, respectively. Among them, 16% of the cases required blood or platelet transfusion. Non-hematological adverse events with Grade 1/2 were common, but with Grade 3/4 were rare. Fatigue with Grade 3/4 occurred in 9.6%. No patients had severe gastrointestinal toxicity and only four patients (4.3%) had Grade 3 diarrhea (Table 3). Ten patients had infections. Among them, six patients were infected in their port site and three patients developed sepsis. Five patients removed their port and four patients exchange the port, one patient was cured by antibiotics and one patient had already completed the original treatment schedule before infection. Pyelonephritis, meningitis and herpes zoster occurred in other two, one and one patient, respectively. Ureteral stenosis occurred in five patients and among them two patients required stenting.
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Non-hematological severe adverse events were observed in six patients. A contracted bladder was observed in three patients, and among them, two patients required a radical cystectomy and revealed no residual cancer. One patient with a contracted bladder was observed with no surgical treatment and he died of other causes (ileus). Macrohematuria and/or rectal bleeding were observed in three patients who required a blood transfusion. These six patients with severe adverse events were treated during the early phase in the protocol. Up to now, no severe adverse events have been observed and no patient has died of any adverse events.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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A radical cystectomy is a standard treatment for muscle-invasive bladder cancer (1–5). However, a radical cystectomy requires urinary diversion and the QOL of the patients declines. Because of the decrease in QOL, BPT has been investigated and modified for selective patients. The problems of BPT in comparison with a radical cystectomy concern the CR rate and bladder preservation rate after treatment and the indications for BPT. In RTOG 85-12, patients with invasive bladder cancer were treated by a combination of CDDP and radiation (8). This study reported that the CR rate was 66%, the 5-year survival rate of BPT was 52% and the bladder preservation rate was 52%. Other investigators report similar results (8–11). Recently, multimodality therapy is able to achieve bladder preservation for selective patients with invasive bladder cancer (12–14).
However, there have so far been few studies describing BPT with a radical cystectomy and there is no evidence of which treatment is better. Stein reported the outcomes of 1054 radical cystectomies (2). In their report, the recurrence-free and overall survival rates for all 1054 patients at 5 years were 68% and 60%, respectively, and it was 66% and 43%, respectively, at 10 years. However, among these patients, 421 patients had pT1 disease or less. When the results of BPT are compared with radical cystectomies, the problem is that BPT is assessed by the clinical stage and radical cystectomy is assessed by the pathological stage. In the current study, there were no patients with under-staging among the T2 patients because muscle invasion was confirmed in TUR specimens. In contrast, over-staging may be included in the T3/T4 but the rate of over-staging is less frequent because of the recent progress in image diagnosis. Stein reported that the 10-year recurrence-free and overall survival rates were 66% and 43% in all patients (2). On the other hand, the current results revealed that the 10-year cause-specific survival and overall survival rates were 67.5% and 47.4% in all cases. From this result, the current results are equal to those with a radical cystectomy.
Moreover, in this study, the result was better than previous results with BPT. Generally, CR rate for BPT has been reported to range from 60% to 70%, whereas the 5-year cause-specific survival is approximately 50% and bladder preservation rate is 38–66% (8–14); however, the current results exceeded the findings of previous reports regarding all measurements. After BPT, if a radical cystectomy is required, the BPT itself is not meaningful. In this study, the bladder preservation rate was 87.6% at 10 years after treatment. Moreover, the preserved bladder had good function and their QOL was age appropriate (15).
One of the reasons for the good results in survival and bladder preservation rate is the drug delivery system, using intra-arterial chemotherapy. Intra-arterial infusion therapy is superior to intravenous therapy in terms of drug distribution in the tumor-affected area. Stewart et al. (16) comparing plasma drug levels following intra-arterial infusion of CDDP with intravenous infusion of the same drug found that intra-arterial infusion resulted in enhanced exposure in comparison to intravenous infusion. For this reason, intra-arterial chemotherapy is suitable for BPT. Miyanaga et al. (17) reported similar results with intra-arterial chemotherapy. This indicates that intra-arterial chemotherapy for BPT might improve the survival and bladder preservation rate. However, there is no optimal treatment schedule and the development of a regimen for BPT is necessary in the future. However, intra-arterial chemotherapy is apparently suitable for BPT because of the high CR rate.
Finally, although many patients achieved CR, some patients did not. Therefore, the indication for BPT is the most important problem. In the multivariate analysis, it was clear that absence of hydronephrosis and the clinical stage were significantly associated with a CR. No other factors were associated with CR, including tumor size and primary/recurrence tumor. Patients without hydronephrosis and with T2 show better survival than those with hydronephrosis and/or T3/T4. Patients without hydronephrosis and clinical stage T2 have a good indication for BPT. Miyanaga et al. (17) reported that tumor size, tumor number and grade were used and BPT can be acceptable for cases of single T2 tumor with a size of <3 cm and for T3 cases with a tumor size <3 cm. In this study, BPT can be acceptable for cases of T2 tumor without hydronephrosis.
Hematological adverse events of Grade 3/4 were usually observed, especially neutropenia. However, febrile neutropenia was observed in 13.9% and it was manageable. These adverse events were observed at either the same frequency or less in comparison with M-VAC (MTX, vinblastine, ADM plus CDDP) therapy or GC (gemcitabine plus CDDP) therapy, which are the standard chemotherapy protocols for urotherial carcinoma (18,19). In non-hematological events, the adverse events were low in comparison with M-VAC and GC therapies (18,19). In this therapy, infection of the port was very important. If the port is removed, the treatment cannot been administered. It is important to protect the port site from infection.
There were some limitations in this study. First, this study was not a randomized study and had a small sample size. Therefore, these results cannot be compared directly with radical cystectomies. Moreover, it is thought that there were various selection biases in this study. However, the data quality is comparatively high because this treatment was performed for consecutive patients with muscle-invasive bladder cancer and did not select intentionally. Therefore, the selection bias was minimal. Although there are some limitations in this study, BPT yielded good results. If the treatment schedule and indication for BPT are established, BPT may become the optional treatment in association with a radical cystectomy. Therefore, a randomized control trial is required for BPT.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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