© 2004 Foundation for Promotion of Cancer Research
Treatment of Invasive Bladder Cancer: Lessons from the Past and Perspective for the Future
Department of Urology, Sapporo Medical University School of Medicine, Sapporo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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Radical cystectomy with lymphadenectomy is the gold standard for treatment of invasive bladder cancer. However, the treatment alone does not always provide a satisfactory result for the disease extending outside the bladder. In this review we discuss several clinical issues in the diagnosis and treatment of this invasive disease. Although the quality of diagnostic imaging modalities has improved, they are still not sensitive enough for the staging of the disease, especially for early invasive disease. In addition, lack of serum markers hinders appropriate monitoring of patients with the disease. Regarding the surgical aspect of lymphadenectomy, the area of its dissection, the standard number of nodes retrieved and the method of pathological examination should be established so that the clinical benefits of surgery can be more clearly defined. Neoadjuvant chemotherapy for invasive disease is promising for improvement of survival of patients. A chemotherapy regimen as effective as, but less toxic than, MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has been reported and several phase III clinical trials have been launched to determine the benefits of adjuvant or neoadjuvant chemotherapy with newly developed agents. However, we still lack a chemotherapy regimen more effective than MVAC, which is the most crucial issue in the treatment of this invasive disease. An alternative option for such disease may be bladder preservation with transurethral resection of tumor followed by chemoradiotherapy. However, patients who are indicated for this treatment may be limited to those with early invasive disease having certain favorable clinical and pathological features.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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Bladder cancer is the second most common genitourinary cancer. In Japan, 12 000 patients are newly diagnosed as having this disease and 5000 patients die of it per year (1). It is usually divided into superficial and invasive diseases. The former is defined as that confined to the mucosal or submucosal layer of the bladder. In the latter, cancer cells invade the muscle layer or extend beyond it. The superficial disease found in two-thirds of patients with bladder cancer is basically managed by the transurethral resection of the bladder tumor (TUR-Bt), with or without adjuvant intravesical treatment with chemotherapy or bacille Calmetté-Guerin, and thus the bladder can be preserved. The clinical course of the superficial disease is favorable with 5-year cause-specific survival higher than 95%. However, the invasive disease found in one-third of patients with bladder cancer usually has an unfavorable clinical course with a 5-year survival of 50–60%. Thus, treatment of the invasive disease remains a challenge for us (2).
The standard treatment for invasive bladder cancer is radical cystectomy with lymphadenectomy. This treatment is indicated for patients who have a clinically invasive disease but not pelvic lymph node or distant metastases. However, there are several pitfalls in this standard management of the disease. First, not all patients are indicated for radical cystectomy with lymphadenectomy followed by urinary diversion or reconstruction because of the invasive nature of surgery. Surgery is generally contraindicated for some patients with medical complications such as cardiovascular disease. More importantly, there is a group of patients who do not achieve full benefit from surgery alone. Many studies have been performed to decide whether treatments in addition to surgery alone provide a better clinical course or survival for such patients. Unfortunately, there is still little clinical evidence that clearly demonstrates clinical benefit of treatments added to surgery, since either the numbers of patients in past studies were small or the studies were retrospective. Recently, however, the efficacy of neoadjuvant chemotherapy prior to radical cystectomy was demonstrated by both an excellent clinical randomized study that recruited many participants and a meta-analysis (3,4). Many more clinical trials are now under way which will evaluate the efficacy of current modalities of treatment.
We overview in this review what we have learned from past and present studies on this invasive disease and consider the future of its treatment.
The grading and staging system of the disease in this article is based on the General Rules for Clinical and Pathological Studies on Bladder Cancer based on the TNM Classification of Malignant Tumours (Fifth edition) (5), unless otherwise indicated.
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DILEMMA IN CLINICAL STAGING AND LACK OF SERUM MARKERS IN INVASIVE BLADDER CANCER |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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TUR-Bt is the standard procedure to detect invasion of cancer cells into the muscle layer of the bladder. Invasive bladder cancer can be verified by TUR-Bt only when its specimens contain the bladder muscle tissue. Thus, resection must be deep enough to obtain muscle tissue, otherwise, the extent of bladder cancer cannot be accurately known. In addition, even when the specimens contain bladder muscle tissue, damage caused by the resection itself does not always allow surgical pathologists to stage them accurately. Indeed, understaging of TUR specimens can often occur in patients with clinically non-muscle invasive disease who undergo radical cystectomy (6). This is particularly common in T1 G3 disease (7). Deep resection of all visible tumors in the bladder is a cornerstone for diagnosis and treatment of invasive bladder cancer.
Computed tomography (CT) and/or magnetic resonance imaging (MRI) are widely used modalities for staging of invasive bladder cancer. However, they do not necessarily allow us to achieve accurate staging of the disease. In particular, an early muscle-invasive disease cannot be distinguished from a superficial one by CT or MRI (8). For this purpose, TUR-Bt is still the most reliable method for staging. When patients have a tumor large enough to be detected by CT or MRI, however, staging of the disease becomes more reliable. Barentsz et al. (9) showed that the accuracy of CT ranged from 40 to 92% (mean, 74%) and that MRI accuracy was 10–30% higher than CT. In terms of imaging diagnosis of lymph node metastasis, both imaging modalities achieve similar accuracy. However, minimal disease of the node, which is found in 10–30% of invasive disease depending on the extent of the primary lesion, cannot be accurately detected by CT or MRI, because their false negative rates are as high as 40% (10). Even positron emission tomography achieves only a 67% detection rate of node disease (10). Thus, at this time, urologists should integrate all information available from clinical and TUR-Bt-findings, and those obtained from imaging diagnosis, to determine the clinical stage of patients with the disease.
It is unfortunate that bladder cancer does not have a ‘serum marker’ that can reflect the clinical course of patients and monitor the response to treatment, like prostate-specific antigen for prostate cancer. Efforts so far have been mainly towards developing methods for detecting new lesions in the bladder rather than monitoring the response to treatment or the clinical course. We now have various methods that can be used for screening high-risk patients with superficial disease or for detecting early recurrence of the disease in the bladder. Indeed, markers for urine protein and chromosomal or gene alterations have become available (8,11). In addition, various oncogenes, tumor-suppressor genes, microvessel density and angiogenic inhibitors are available as tissue markers (12). Although these markers potentially allow us to retrospectively stratify patients with invasive disease who are likely to respond to a specific treatment such as chemotherapy, they cannot be used as convenient serum markers reflecting disease status at a given time. Thus, what we really need in the treatment of invasive bladder cancer is a serum marker on which we can rely for determining the treatment policy.
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RADICAL CYSTECTOMY WITH LYMPHADENECTOMY AS THE GOLD STANDARD FOR TREATMENT OF INVASIVE BLADDER CANCER |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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Radical Cystectomy With or Without Urethrectomy
Radical cystectomy is the gold standard for treatment of invasive bladder cancer. This procedure includes bilateral pelvic lymphadenectomy in addition to removal of the bladder, seminal vesicles and prostate with perivesical fat in male patients. In female patients, the bladder with perivesical fat, urethra, anterior wall of the vagina, uterus and ovary are removed together with lymphadenectomy. Many studies have reported that favorable long-term survival is achieved for patients with pathologically organ-confined disease (13–18). Five-year overall survival rates by pathologic stage after radical cystectomy are summarized in Table 1. Although the rate for patients with organ-confined disease (pT2N0) is higher than 60%, it decreases to 30–50% in those with locally advanced diseases (pT3N0 and pT4N0) or lymph node involvement. Thus, the curability of bladder cancer by radical cystectomy primarily depends on the pathologic stage of the primary tumor and pathological status of the lymph nodes. Indeed, Dalbagni et al. (14) reported that only the pT stage and previous chemotherapy were significant factors for disease-specific survival in Cox’s proportional hazards analysis, and the survival prognosis for non-organ-confined disease was significantly worse than that for organ-confined disease. Involvement of the prostatic stroma has a significant effect on survival, but prostatic ductal or urethral involvement does not (19,20). Esrig et al. (20) reported that 5-year overall survival rates of patients with urethral tumors, ductal involvement and stromal invasion were 74%, 67% and 36%, respectively.
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When radical cystectomy is attempted, urethrectomy is indicated only for male patients with urethral involvement of the disease. Thus, recurrence of the disease in the urethra is always considered whenever the urethra is left intact. The incidence of recurrence in the retained male urethra ranges from 4 to 14% (21,22). Urethral washing cytology has been recommended for early detection of recurrence in the urethra. Indeed, the procedure has high sensitivity and specificity in detecting early disease (23). However, a recent study raised a question about the procedure as a routine test, since early detection of the urethral disease may not guarantee patients a favorable survival outcome (24). The aggressive biological nature of bladder cancer generally affects survival more strongly than urethral recurrence. This issue should be confirmed by studying a larger number of patients.
Interestingly, the rate of urethral recurrence in patients who underwent orthotopic neobladder construction was reported to range between 2 and 6% (22,25,26), which was lower than the rate for those with cutaneous urinary diversion (27). In other words, urine flow potentially contributes to prevention of recurrence in the urethra. However, diffuse carcinoma in situ (CIS) extending to the prostatic urethra is a sign of high risk for synchronous anterior urethral involvement (28). Therefore, prophylactic urethrectomy is recommended for patients with this risk factor, and an orthotopic neobladder is basically contraindicated for such patients.
In female patients, radical cystourethrectomy has been the standard procedure. Coloby et al. (29) reported that 6% of female patients who underwent radical cystourethrectomy had urethral involvement. All of them had grade 3 disease with adjacent CIS, located in the bladder neck. In a study by Stenzl et al. (30), urethral involvement was found in 2% of female patients with bladder cancer (including superficial disease), and a risk factor for the involvement was simultaneous disease in the bladder neck. Thus, they recommended that most of the urethra should be left intact for orthotopic urinary diversion when patients did not have any cancerous changes or atypia in the bladder neck in transurethral biopsy before cystectomy or frozen sections of the distal end of the urethra at cystectomy. To date, however, there has been no report of urethral recurrence after orthotopic neobladder construction in women (31).
Radical cystectomy with lymphadenectomy is indicated for patients with clinical stages T2-4N0M0. When patients clinically have node metastasis in the pelvis or distant metastasis, they are believed not to benefit from this treatment alone. However, symptoms caused by locally advanced disease such as gross hematuria, difficulty on urination, urgency and pain on urination often cause conspicuous deterioration of the quality of life (QOL) of patients. Palliative cystectomy is an optional treatment for a relief of those symptoms, since palliative urinary diversion alone does not always improve patients’ QOL (32,33). Indeed, even in our small series of such patients, some had the chance to benefit from cystectomy in terms of maintenance of their QOL and survival, although the selection of candidates for the treatment was biased (34).
Pelvic Lymphadenectomy
Pelvic lymphadenectomy is an integral part of treatment for patients with invasive bladder cancer. It provides accurate extension and staging of the disease, information that is valuable for prediction of the clinical course. Indeed, as shown in Table 1, the disease status of pelvic lymph nodes is surely one of the critical determinants for survival. Lymphadenectomy is believed to have a therapeutic role as well for a very limited burden of node metastasis in some patients, depending on the extent of node dissection. This issue will be discussed later.
Before reviewing staging and the therapeutic role of lymphadenectomy, we will discuss how extensive lymphadenectomy should be. Unfortunately, there is no consensus on the extent of lymphadenectomy. Limited pelvic lymphadenectomy consists of node dissection in the areas of the external iliac artery and vein, the internal iliac artery and vein and the obturator nerve on both sides (Fig. 1). It removes all lymph nodes that are regarded as the ‘regional lymph nodes’ of bladder cancer defined by the TNM classification. The conventional or extended type is defined as that removing the bilateral common iliac lymph nodes as well as regional lymph nodes. There are some differences in the dissection areas for conventional or extended lymphadenectomy according to the studies (35–37). For example, Bochner et al. (35) defined conventional (or standard) lymphadenectomy as removal of the distal common iliac (or the mid-common iliac) nodes together with the regional lymph nodes. Poulsen et al. (36) regarded lymphadenectomy as the ‘extended type’, when they removed the common iliac lymph nodes together with the regional lymph nodes. However, in another study, removal of lymph nodes above the level of the aortic bifurcation and those located in the presacral area together with the regional lymph nodes was included in ‘extended lymphadenectomy’ (37). Thus, we should be careful in interpreting results for extended lymphadenectomy when this may represent a different area of dissection in each study.
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Although lymphadenectomy is included in the surgical procedure for radical cystectomy, there is some controversy over whether limited or extended lymphadenectomy should be performed. The guidelines on bladder cancer of the European Association of Urology recommend limited lymphadenectomy, although they refer to recent studies that show the benefit of the extended type (38). This is partly because lymph node metastases are found more frequently in the regional lymph nodes than in the common iliac or presacral ones, and also metastasis beyond the regional lymph nodes is regarded as disseminated disease. The lack of an established adjuvant chemotherapy for patients who are node positive is another explanation for the limited type to be recommended.
As for staging and prognostic indicators, extensive lymphadenectomy retrieving 16 lymph nodes or more was reported to detect a higher proportion of pathologically proven node metastases in those with pT3 and pT4 cancer, although this was not the case in those with pT2 or less (39). Poulsen et al. (36) compared the incidence of lymph node metastasis in limited lymphadenectomy with that in the extended type. They found that the incidence was higher in patients with the extended type, although it was more prominent when the disease was pathologically confined to the bladder or was less extensive. How many lymph nodes should be retrieved by lymphadenectomy for accurate diagnosis of node metastasis? In the study by Poulsen et al. (36), extended lymphadenectomy retrieved a larger number of lymph nodes than the limited type. The extended lymphadenectomy recovered 23–25 nodes, ranging from 9 to 67, and the limited type recovered 5–14, with a range of 5–30. A postmortem study suggested that removal of approximately 20 nodes may be the reference number of nodes for retrieval by limited pelvic lymphadenectomy (40). It can be expected that node metastasis will be found more frequently with an increase in the number of nodes retrieved. According to the study of Leissner et al. (39), 60% of node-positive patients had, at most, 15 nodes retrieved. To detect more than 80% of patients who are node positive, at most 23 nodes should be removed (39). A similar number of nodes, around 20, was also reported to detect 80% of node-positive patients (41).
It is well known that the number of positive nodes strongly affects the survival of patients with invasive disease who undergo radical cystectomy with pelvic lymphadenectomy. Indeed, two recent large series clearly confirmed this (42,43). Stein et al. (42) showed that patients with eight positive nodes or less had a clearly better prognosis than those with more than eight. Frank et al. (43) also reported that the number of positive nodes was a significant prognostic parameter. In their study, patients with more than five positive nodes had a significantly worse prognosis than those with five or less. Since the number of positive nodes may depend on the number of lymph nodes removed by lymphadenectomy, the absolute number does not necessarily indicate an accurate prognosis. Thus, the concept of the ratio of positive nodes per total number of nodes removed or the positive-lymph node density was introduced and this ratio has been reported to be more predictive of the prognosis of patients in two studies (41,42). These studies demonstrated that patients with a ratio of 20% or greater definitely had a lower survival rate than those with ratios less than 20%. While the ratio of 20% remains to be confirmed by future studies, it can be applicable in the clinical setting, in particular in the case of limited lymphadenectomy, which recovers a smaller number of nodes than the extended type.
Finally, there is still the question of whether the number of lymph nodes retrieved affects the prognosis of the patient. In other words, does retrieval of a greater number of lymph nodes achieve a more favorable clinical outcome?
There are few studies that compare survival of patients who received extended lymphadenectomy with that of those who received regional or limited lymphadenectomy. The study of Poulsen et al. (36) showed that patients with disease confined to the bladder wall and negative nodes achieved a higher survival rate when the limit of lymphadenectomy was extended (Table 2). Unfortunately, it was not a randomized study, and it used historical controls, so it may not be possible to extrapolate their conclusion. However, several recent studies have emphasized the survival benefit of extended lymphadenectomy. Leissner et al. (39) reported that patients who had 16 or more lymph nodes removed by extended lymphadenectomy achieved cancer-specific and disease-free survivals significantly higher than those who had 15 or less removed. Even when patients were subcategorized according to several pathological stages, significantly higher disease-free survival was confirmed. Similar results were reported in other studies, all of which suggested that the number of lymph nodes recovered by lymphadenectomy and thorough pathological study of them affected the outcomes of patients (44,45). Interestingly, using the Cox proportional hazards model, Herr (46) indicated that the number of lymph nodes examined was one of the significant risk factors for both survival and local recurrence in node-negative patients. Even in node-positive patients, the number of lymph nodes retrieved similarly affected these outcomes. Finally, based on personal and others’ experience, Herr (47) suggested that complete lymphadenectomy along with securing a wider margin around the bladder and more thorough examination of surgical specimens by pathologists contributed to improvement of outcomes in patients with invasive bladder cancer.
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Although recent studies have suggested that extended lymphadenectomy may be more beneficial than the limited type for staging accuracy and survival benefit, as indicated earlier, this issue remains to be determined in a prospective, randomized study.
Local Recurrence
Local recurrence of cancer in the pelvis after definitive surgical treatment for patients with invasive disease is a greatly frustrating problem both for patients and physicians. Its development potentially compromises not only survival but also the QOL of patients. Local recurrence may not produce any symptomatic findings in the early stage but eventually causes bowel obstruction and pain due to involvement of various nerves, both of which strongly affect the QOL of patients. For physicians, that there is no effective treatment for such lesions is a devastating problem. Before the era of modern imaging diagnosis, many small lesions recurring in the pelvis were not precisely detected if they did not produce specific signs and symptoms. However, the current use of CT allows us to more frequently detect even small lesions of recurrence in the pelvis. Accurate diagnosis and specific treatment of such lesions is a matter for debate in daily practice, in particular when they are not associated with distant metastasis.
A recent study indicated that local recurrence was much more frequent than previously believed (48). Recurrence with or without concurrent distant metastasis was found in 5–20% of patients who received radical surgery, depending on their clinical and pathological features (49). In patients with pT3 or pT4 disease, the rate of local recurrence or systemic recurrence was reported to be around 30% (50). Although pathological stage and lymph node status were suggested to be risk factors for local recurrence, recent studies indicate that it may be avoided by meticulous radical cystectomy and extended lymphadenectomy (44,51).
Once local recurrence develops, its clinical course is generally pessimistic. Westney et al. (52) reported that the survival interval from diagnosis of local recurrence was less than one year with treatments currently available. Unfortunately, there have been no studies suggesting any specific treatments that can clearly reduce the rate of local recurrence after cystectomy. Whether or not neoadjuvant and adjuvant chemotherapy regimens currently available and newly developing are effective for reduction of the rate remains to be determined.
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BENEFITS AND PITFALLS OF CHEMOTHERAPY ADJUNCTIVE TO RADICAL CYSTECTOMY FOR INVASIVE BLADDER CANCER |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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Adjuvant and Neoadjuvant Chemotherapy
As indicated earlier, radical cystectomy with lymphadenectomy alone cannot achieve satisfactory survival for patients with pT3, pT4 and node-positive disease. Patients with such diseases need additional treatments for improvement of their survival. Preoperative irradiation, which was tried in the early 1980s, finally turned out not to have advantage for survival in a randomized study conducted by the Southwest Oncology Group (SWOG) (53,54). Since then, along with progress in clinical efficacy of cisplatin-based combination chemotherapy for metastatic bladder cancer, many chemotherapeutic regimens have been studied for this purpose. Unfortunately, until very recently, only non-conclusive results were reported. In addition, the timing of chemotherapy adjunctive to cystectomy, neoadjuvant or adjuvant, has not been established.
Adjuvant and neoadjuvant chemotherapies have their own advantages and disadvantages (55). The advantages of adjuvant chemotherapy consist of accurate stage diagnosis, more appropriate selection of patients based on pathologically identified risk factors for recurrence, and no delays in performing cystectomy. On the other hand, its disadvantages include the lack of a marker lesion for assessment of the response to chemotherapy, no chance to preserve the bladder, relative delay for treatment of micrometastases and difficulties in giving chemotherapy with a planned dose intensity and treatment cycle. In the daily clinical setting, many patients seem to receive adjuvant chemotherapy when the disease pathologically extends beyond the bladder or have margin-positive status of the cystectomy specimen. However, no published studies have proved any definite benefit of adjuvant chemotherapy for long-term disease-free and overall survivals, although several investigators have conducted randomized trials (56–59). Currently, the adjuvant phase II and III protocols using newly developed drugs and their combinations are under investigation (Table 3) (60).
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Advantages of neoadjuvant chemotherapy include information about the response to chemotherapy that may predict future clinical course, possible treatment of micrometastases without delay and potential preservation of the bladder if the disease responds well to chemotherapy (55). Another advantage is that patients may better tolerate chemotherapy in a neoadjuvant setting than in an adjuvant one.
Disadvantages of neoadjuvant chemotherapy are the negative sides of each advantage of adjuvant chemotherapy, which include less accurate staging of the primary tumor, no identifiable pathological risk factors and unavoidable chemotherapy not beneficial for patients with a low risk for recurrence.
As with adjuvant chemotherapy, many randomized trials of neoadjuvant chemotherapy have been conducted over the last 10 years to determine whether the chemotherapy improved survival (3,61–65). Unfortunately, there have been no reports that clearly demonstrate any survival benefit of chemotherapy in the neoadjuvant setting before the study conducted by the SWOG (Table 4). The group reported in 2003 that three cycles of MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) neoadjuvant chemotherapy followed by radical cystectomy provided patients with invasive disease a median interval of survival longer than that with cystectomy alone (3). Even when patients were stratified according to age and stage, the survival benefit was predominant in those who received neoadjuvant chemotherapy. The study concluded that neoadjuvant chemotherapy can be offered to patients with invasive disease who need radical cystectomy. Hopefully, there will be additional successful trails that support the results of the SWOG.
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The predominant benefit of neoadjuvant chemotherapy before radical cystectomy is supported by a recent meta-analysis summing up 11 randomized, potentially eligible studies of neoadjuvant chemotherapy (4). This analysis, including survival data for a total of 2492 patients, showed a 9% relative reduction in the risk of death with neoadjuvant chemotherapy. Furthermore, the platinum-based chemotherapy in the neoadjuvant setting achieved significantly improved overall survival that was characterized by a 13% relative reduction in risk of death, 5% absolute benefit at 5 years and improvement of overall survival from 45% to 50%. The author concluded that the platinum-based combination chemotherapy showed a significant survival benefit although platinum alone did not contribute to improved survival of patients. In Japan, a randomized phase III study of two cycles of MVAC neoadjuvant chemotherapy followed by radical cystectomy, compared with cystectomy alone for T2-T4aN0M0 bladder cancer is being conducted by the Japan Clinical Oncology Group.
Currently, the SWOG is conducting a phase II study of neoadjuvant chemotherapy consisting of gemcitabine, paclitaxel and carboplatin followed by observation or immediate cystectomy in patients with stage II or III transitional cell cancer of the urothelium (SWOG-S0219) (60). The aim of this study is to evaluate the effectiveness of the new combination chemotherapy.
More Effective Regimens of Chemotherapy in Adjuvant and Neoadjuvant Settings
At this moment, there are no adjuvant and neoadjuvant chemotherapy regimens more effective than MVAC, although several clinical trials with new agents are being carried out. Even for patients with advanced or metastatic disease, MVAC is still the standard regimen. Indeed, among many combination chemotherapy regimens that were studied, MVAC (66) and CMV (cisplatin, methotrexate and vinblastine) (67) achieved the highest overall response and CR rates. Randomized trials for metastatic urothelial cancer showed that MVAC was superior to the single agent cisplatin (68,69) and CISCA (cisplatin, cyclophosphamide and doxorubicin) (70). There is no randomized trial comparing MVAC with CMV. Although MVAC is one of the most effective chemotherapy regimens for advanced or metastatic diseases, it is associated with substantial toxicity, including leucopenia, culture-negative fever at the time of granulocytopenia, mucositis and renal failure (54). Furthermore, an escalated dosage of MVAC was associated with significant toxicity but had no apparent benefit over standard MVAC with regard to the complete response rate and survival (71). Interestingly, a combination of methotrexate, epirubicin and cisplatin was reported to achieve a response rate comparable to MVAC in patients with metastatic urothelial cancer but had milder intensity and less frequent toxicity (72). Unfortunately, the survival benefit was not reported.
New regimens using new chemotherapeutic agents have recently been studied for locally advanced or metastatic disease. Bellmunt et al. (73) demonstrated that a combination of cisplatin, paclitaxel and gemcitabine achieved 28% complete and 50% partial response rates for patients with previously untreated, locally advanced or metastatic urothelial cancer. In this phase II trial, the main nonhematologic toxicity was grade 2 and grade 3 asthenia, found in 37% and 8% of patients, respectively. Grade 3/4 neutropenia was found in 55% of patients and thrombocytopenia with the same grades occurred in 22%. Overall, febrile neutropenia was seen in 22% of patients, and one toxic death occurred because of neutropenic sepsis. A similar combination of paclitaxel, carboplatin and gemcitabine also achieved a favorable result with 32% complete and 36% partial responses (74). The incidence of side effects was comparable to that reported by Bellmunt et al. (73). Febrile neutropenia was observed in 1.4% and no patients died of drug-related toxicity. In the study of Meluch et al. (75), 47% of patients who were previously treated with platinum-based chemotherapy responded to combination therapy using paclitaxel and gemcitabine. The side effects in their study consisted of grade 3/4 leukopenia (46%), thrombocytopenia (13%) and anemia (28%). One of 54 patients died of treatment-related sepis.
Finally, von der Maase et al. (76) reported a randomized study of gemcitabine plus cisplatin (GC) versus MVAC, which demonstrated that GC provided response and survival rates similar to MVAC and less intensive toxicity than MVAC. However, Cohen and Rothman (77) criticized the result reported by von der Maase who recommended GC instead of MVAC for advanced or metastatic urothelial cancer. Thus, a further large scale study will be needed to confirm the current results (78). Another recent multicenter, randomized phase III study consisting of more than 200 patients with inoperable or metastatic urothelial cancer reported that MVAC was significantly superior to a combination of docetaxel and cisplatin (DC) in terms of median time to progression and median survival (79). Although MVAC produced hematologic toxicity more frequently than DC, support with granulocyte-colony stimulating factor reduced its frequency when compared with that of MVAC without such support in previous studies.
Thus, several new agents or their combinations may be promising in the treatment of patients with advanced or metastatic disease because of their less toxic nature. This may be advantageous when a regimen with a combination of several agents is used in the adjuvant or neoadjuvant setting. However, at this moment, we have no chemotherapy regimen that clearly exceeds the clinical efficacy of MVAC. In addition, no advantage has been proved in the adjuvant or neoadjuvant setting.
Currently, various phase II and III trials of chemotherapies using paclitaxel and/or gemcitabine are in progress (Table 5) (54,55,80). Their objective is to find the most effective and least toxic combination for patients with advanced or metastatic disease and also for those with neoadjuvant or adjuvant chemotherapy. It is also valuable to evaluate other anti-cancer drugs such as gefitinib, irinotecan or bortezomib, although the long-term results of such studies have not been disclosed to date. The efficacy of the drugs is being studied in phase II trials (60).
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BLADDER PRESERVATION IN THE TREATMENT OF INVASIVE BLADDER CANCER |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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Bladder-sparing strategy is basically considered when patients are poor risks for radical cystectomy. However, a recent trend is for the treatment to be indicated also when it seemingly controls invasive disease without compromising the ‘cure’ of the disease. Needless to say, the QOL of the patient with the bladder preserved is definitely better since urinary diversion is avoided. However, it is of concern that a later tumor developing in the preserved bladder may increase the risk of cancer uncontrollable by treatment modalities currently available (81).
While superficial bladder cancer can be completely resected by TUR-Bt, a well-defined and non-penetrating tumor is also resectable even in muscle-invasive disease. Herr (82) reported a 5-year survival of 70% in treatment of T2 bladder cancer with TUR-Bt. The 10-year disease-specific survival rate of patients who received TUR-Bt as definitive treatment for cancer of this stage was reported to be 76% and the bladder preservation rate 57% (83). In contrast, Roosen et al. (84) reported a 5-year survival of <30% in patients with T2 cancers who were treated with TUR-Bt. Solsona et al. (85) found that 41% of patients treated with radical TUR-Bt for invasive disease were alive with bladder preservation in a follow-up at 5 years and 22% of those at 10 years. Thus, TUR-Bt alone for muscle-invasive disease is controversial. However, when TUR-Bt is combined with other modalities, it may achieve more favorable results, which will be discussed later.
External-beam radiation therapy (XRT) is planned for patients with high risks who are not good candidates for radical cystectomy, since its curative capability has not been clearly proved (81). The radiosensitivity of transitional cell carcinoma is low and XRT alone offers local control inferior to that obtained with cystectomy (81,86). XRT as a single-modality therapy is not usually recommended in the USA or Japan, partly because of control of bleeding, and relief of pain, bladder irritability and urinary frequency are crucial for patients with invasive bladder cancer. Systemic chemotherapy alone has the same efficacy as XRT (87). Scattoni et al. (88) reported that only half of clinical complete responders achieved a pathological complete response. Another monotherapy for bladder-sparing treatment of invasive disease is intra-arterial chemotherapy in which a larger dose of chemotherapeutic agents may be delivered to the tumor with less toxicity (2). Unfortunately, the pathological complete response rate, which is mandatory for bladder preservation, was reported to be less than 50% (89,90). Thus, it is clear that every monotherapy fails as an appropriate single treatment modality for bladder preservation in patients with invasive disease.
This situation has led to the next stage where combination treatments consisting of TUR-Bt, XRT and systemic chemotherapy have been tried, and are seemingly more effective in selected patients (Table 6) (91–98). A combination of intra-arterial chemotherapy with concurrent XRT demonstrated good local control (95–98). The main purpose of their combination is to increase radiosensitivity by chemotherapeutic agents. Furthermore, systemic chemotherapy in combination can eradicate occult metastases that have already developed in as many as 50% of T2-3 patients who have T2-3 disease at the initial presentation (99). In most studies, however, radical cystectomy was performed even when the initial bladder sparing treatment produced a complete response. In other words, survival data were based on patients who were treated not by bladder-sparing treatment alone but by protocol treatment including cystectomy. In addition, in studies with long-term outcomes, 30–60% of complete responders eventually developed new tumors in the bladder even if the patients underwent combination treatment with bladder preservation (91,93,100). Patients might not have died of this new cancer, because they would not have developed it if the bladder had been removed initially (101).
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Nevertheless, the results of a recent large, long-term study by Rödel et al. (94) are intriguing. It included almost 400 patients with high-risk T1 and invasive disease, and followed-up those surviving for more than 5 years (Table 6). They reported that TUR-Bt followed by chemotherapy with XRT or XRT alone achieved a 72% complete response rate and 42% 10-year disease-specific survival, and that the bladder could be preserved in more than 80% of survivors. In addition, chemotherapy with XRT produced more favorable results than XRT alone. Based on the results of this study together with those of other studies, Gospodarowicz (102) commented that ‘these results certainly offer hope and indeed opportunity for bladder preservation in a significant proportion of patients who currently undergo cystectomy’. However, it should be cautioned that not all invasive diseases are indicated for bladder preservation. Indeed, Rödel et al. (94) stated that ‘ideal candidates for this treatment were patients with early-stage and unifocal tumors in whom a microscopically or at least visibly complete TUR-Bt was accomplished’. Thus, appropriate selection of patients and confirmation of complete TUR are crucial for applying this treatment modality.
Unfortunately, to date, there have been no randomized studies that directly compare radical cystectomy with bladder-sparing treatment. A current pilot phase I/II study at the University of Michigan of concurrent gemcitabine and radiotherapy after aggressive TUR has shown good patient tolerance, preserved bladder function and favorable results (101). Furthermore, phase III randomized studies of radical radiotherapy with or without carbogen and niaciamide, and standard volume radiotherapy versus reduced volume radiotherapy with or without synchronous fluorouracil and mitomycin in patients with locally advanced bladder cancer have been initiated in the UK (60).
At present, although some patients with invasive disease can be managed with bladder-sparing treatment, the indication for the treatment may be limited to those with favorable clinical and pathological features. In addition, once the initial bladder-sparing treatment fails, immediate radical surgery is mandatory.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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In summary, radical cystectomy is still the most effective and reliable treatment for invasive bladder cancer. Neoadjuvant chemotherapy may contribute to improvement of survival of patients with organ-confined and locally advanced disease, but more clinical studies are necessary to confirm this. Although new chemotherapeutic regimens and new methods of cancer therapy are expected to be more effective and less toxic than MVAC, there are no such regimens at this time. Various clinical studies are under way, and will give us valuable information in the near future. Bladder preservation should be basically indicated when poor general condition does not allow cystectomy in patients with invasive disease. Some, but not all, patients with invasive disease may be managed with bladder-sparing treatment when they have favorable clinical and pathological features and the bladder tumor can be completely resected.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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The authors thank Dr Tadao Kakizoe, Editor-in-Chief and the staff of JJCO for giving us the opportunity to review this important issue and contribute to the journal. This article was partly supported by a Grant-in-Aid of Clinical Research For Evidence-based Medicine by the Ministry of Health, Labor and Welfare of Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Taiji Tsukamoto, Department of Urology, Sapporo Medical University School of Medicine, Minami 1-Jo, Nishi 16-chome, Chuo-Ku, Sapporo 060-8543, Japan. E-mail: taijit{at}sapmed.ac.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONDILEMMA IN CLINICAL STAGING...RADICAL CYSTECTOMY WITH...BENEFITS AND PITFALLS OF...BLADDER PRESERVATION IN THE...CONCLUSIONSAcknowledgmentsREFERENCES |
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1 Kakizoe T, Yamaguchi N, Mitsuhashi F, Koshiji M, Oshima A, Ohtaka M. Cancer Statistics in Japan – 2001. Tokyo: Foundation for Promotion of Cancer Research, 2001, p. 38.
2 Schoenberg M. Management of invasive and metastatic bladder cancer. In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr, editors: Campbell’s Urology, 8th edn. Philadelphia: WB Saunders Co, 2002, pp 2803–17.
3 Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–66.
4 Advanced bladder cancer (ABC) meta-analysis collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361:1927–34.[CrossRef][Web of Science][Medline]
5 The Japanese Urological Association and Japanese Society of Pathology. The General Rules for Clinical and Pathological Studies on Bladder Cancer, 3rd edn. Tokyo: Kaneharashuppan, 2001.
6 Soloway MS, Soffer M, Vaidya A. Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol 2002;167:1573–83.[CrossRef][Web of Science][Medline]
7 van der Meijden A, Sylvester R, Collette L, Bono A, Kate FT. The role and impact of pathology review on stage and grade assessment of stages Ta and T1 bladder tumors: a combined analysis of 5 European Organization for Research and Treatment of Cancer Trials. J Urol 2000;164:1533–7.[CrossRef][Web of Science][Medline]
8 Jichlinski P. New diagnostic strategies in the detection and staging of bladder cancer. Curr Opin Urol 2003;13:351–5.[CrossRef][Web of Science][Medline]
9 Barentsz JO, Witjes A, Ruijs JHJ. What is new in bladder cancer imaging. Urol Clin N Am 1997;24:583–602.[CrossRef][Web of Science][Medline]
10 Shvarts O, Han KR, Seltzer M, Pantuck AJ, Belldegrun AS. Positron emission tomography in urologic oncology. Cancer Control 2002;9:335–42.[Medline]
11 Shigyo M, Sugano K, Tobisu K, Tsukamoto T, Sekiya T, Kakizoe T. Molecular followup of newly diagnosed bladder cancer using urine samples. J Urol 2001;166:1280–5.[CrossRef][Web of Science][Medline]
12 Quek ML, Quinn DI, Daneshmad S, Stein JP. Molecular prognostication in bladder cancer – a current perspective. Eur J Cancer 2003;39:1501–10.[CrossRef][Web of Science][Medline]
13 Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, et al. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999;161:1494–7.[CrossRef][Web of Science][Medline]
14 Dalbagni G, Genega E, Hashibe M, Zhang Z, Russo P, Herr H, et al. Cystectomy for bladder cancer: a contemporary series. J Urol 2001;165:1111–6.[Web of Science][Medline]
15 Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, Boyd S, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666–75.
16 Madersbacher S, Hochreiter W, Burkhard F, Thalmann GN, Danuser H, Markwalder R, et al. Radical cystectomy for bladder cancer today – a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21:690–6.
17 Nishiyama H, Habuchi T, Watanabe J, Teramukai S, Tada H, Ono Y, et al. Clinical outcome of a large-scale multi-institutional retrospective study for locally advanced bladder cancer: a survey including 1131 patients treated during 1990–2000 in Japan. Eur Urol 2004;45:176–81.[CrossRef][Web of Science][Medline]
18 Takahashi A, Tsukamoto T, Tobisu K, Shinohara N, Satoh K, Tomita Y, et al. Radical cystectomy for invasive bladder cancer: results of multi-institutional pooled analysis. Jpn J Clin Oncol 2004;34:14–9.
19 Skinner DG, Stein JP, Lieskovsky G, Skinner EC, Boyd SD, Figueroa A, et al. 25-year experience in the management of invasive bladder cancer by radical cystectomy. Eur Urol 1998;33(Suppl 4):25–6.
20 Esrig D, Freeman JA, Elmajian DA, Stein JP, Chen S, Groshen S, et al. Transitional cell carcinoma involving the prostate with a proposed staging classification for stromal invasion. J Urol 1996;156:1071–6.[CrossRef][Web of Science][Medline]
21 Erckert M, Stenzl A, Falk M, Bartsch G. Incidence of urethral tumor involvement in 910 men with bladder cancer. World J Urol 1996;14:3–8.[CrossRef][Web of Science][Medline]
22 Kakizoe T, Tobisu K. Transitional cell carcinoma of the urethra in men and women associated with bladder cancer. Jpn J Clin Oncol 1998;28:357–9.
23 Hickey DP, Soloway MS, Murphy WM. Selective urethrectomy following cystoprostatectomy for bladder cancer. J Urol 1986;136:828–30.[Web of Science][Medline]
24 Lin DW, Herr HW, Dalbagni G. Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol 2003;169:961–3.[CrossRef][Web of Science][Medline]
25 Hautmann RE, Miller K, Steiner U, Wenderroth U. The ileal neobladder: 6 years of experience with more than 200 patients. J Urol 1993;150:40–5.[Web of Science][Medline]
26 Studer UE, Danuser H, Merz VW, Springer JP, Zingg EJ. Experience in 100 patients with an ileal low pressure bladder substitute combined with an afferent tubular isoperistaltic segment. J Urol 1995;154:49–56.[CrossRef][Web of Science][Medline]
27 Freeman J, Tarter TA, Esrig D, Stein JP, Elmajian DA, Chen SC, et al. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996;156:1615–9.[CrossRef][Web of Science][Medline]
28 Tobisu K, Kanai Y, Sakamoto M, Fujimoto H, Doi N, Horie S, et al. Involvement of the anterior urethra in male patients with transitional cell carcinoma of the bladder undergoing radical cystectomy with simultaneous urethrectomy. Jpn J Clin Oncol 1997;27:406–9.
29 Coloby PJ, Kakizoe T, Tobisu K, Sakamoto M. Urethral involvement in female bladder cancer patients: mapping of 47 consecutive cysto-urethrectomy specimens. J Urol 1994;152:1438–42.[Web of Science][Medline]
30 Stenzl A, Draxl H, Posch B, Colleselli M, Falk M, Bartsch G. The risk of urethral tumors in female bladder cancer: Can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol 1995;153:950–5.[CrossRef][Web of Science][Medline]
31 Stein JP, Ginsberg DA, Skinner DG. Indications and technique of the orthotopic neobladder in women. Urol Clin North Am 2002;29:725–34.[CrossRef][Web of Science][Medline]
32 Shekarriz B, Pontes JE. Management of poor risk patients with muscle-invasive transitional cell carcinoma of the bladder. AUA Update Series 2001;20:90–5.
33 Shekarriz B, Shekarriz H, Upadhyay J, Banerjee M, Becker H, Pontes JE, et al. Outcome of palliative urinary diversion in the treatment of advanced malignancies. Cancer 1999;85:998–1003.[CrossRef][Web of Science][Medline]
34 Nishiyama N, Masumori N, Satoh E, Takahashi A, Itoh N, Tsukamoto T. Role of cystectomy for patients with invasive bladder cancer having metastasis. Hinyoki Geka 2003;16:1195–9 (in Japanese).
35 Bochner BH, Herr HW, Reuter VE. Impact of separate versus en block pelvic lymph node dissection on the number of lymph nodes retrieved in cystectomy specimens. J Urol 2001;169:2295–6.[CrossRef]
36 Poulsen AL, Horn T, Steven K. Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998;160:2015–20.[CrossRef][Web of Science][Medline]
37 Leissner J, Ghoneim MA, Abol-Enein H, Thuroff JW, Franzaring L, Fisch M, et al. Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004;171:139–44.[CrossRef][Web of Science][Medline]
38 Oosterlinck W, Lobel B, Jakse G, Malmstrom P-U, Stockle M, Sternberg C. Guidelines on bladder cancer. European Association of Urology Guidelines. Arnhem (the Netherlands): European Association of Urology, 2001, p.12.
39 Leissner L, Hohenfellner R, Thuroff JW, Wolf HK. Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int 2000;85:817–23.[CrossRef][Web of Science][Medline]
40 Weingarter K, Ramaswamy A, Bittinger A, Gerharz EW, Voge D, Riedmiller H. Anatomical basis for pelvic lymphadenectomy in prostate cancer: results of an autopsy study and implications for the clinic. J Urol 1996;156:1969–71.[CrossRef][Web of Science][Medline]
41 Herr HW. Superiority of ratio based lymph node staging for bladder cancer. J Urol 2003;169:943–5.[CrossRef][Web of Science][Medline]
42 Stein JP, Cai J, Groshen S, Skinner DG. Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en block pelvic lymphadenectomy: the concept of lymph node density. J Urol 2003;170:35–41.[CrossRef][Web of Science][Medline]
43 Frank I, Cheville JC, Blute ML, Lohse CM, Nehra A, Weaver AL, et al. Transitional cell carcinoma of the urinary bladder with regional lymph node involvement treated by cystectomy. Cancer 2003;97:2425–31.[CrossRef][Web of Science][Medline]
44 Herr HW, Bochner BH, Dalbagni G, Donat M, Reuter VE, Bajorin DF. Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 2002;167:1295–8.[CrossRef][Web of Science][Medline]
45 Konety BR, Joslyn SA, O’Donnel MA. Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer; analysis of data from the Surveillance, Epidemiology, and End Results Program data base. J Urol 2003;169:946–50.[CrossRef][Web of Science][Medline]
46 Herr HW. Extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. Urology 2003;61:105–8.[CrossRef][Web of Science][Medline]
47 Herr HW. Surgical factors in bladder cancer: more (nodes) + more (pathology) = less (mortality). BJU Int 2003;92:187–8.[CrossRef][Web of Science][Medline]
48 Cole CJ, Pollack A, Zangers GK, Dinney CP, Swanson DA, von Eschenbach AC. Local control of muscle-invasive bladder cancer: preoperative radiotherapy versus cystectomy alone. Int J Radiat Oncol Biol Phys 1995;32:331–40.[CrossRef][Web of Science][Medline]
49 Bochner BH, Montie JE, Lee CT. Follow-up strategies and management of recurrence in urologic oncology bladder cancer: invasive bladder cancer. Urol Clin N Am 2003;30:777–89.[CrossRef][Web of Science][Medline]
50 Schuster TG, Smith DC, Montie JE. Pelvic recurrences post cystectomy: current treatment strategies. Sem Urol Oncol 2001;19:45–50.[Medline]
51 Thalman GN, Fleishman A, Mills RD, Burkhard FC, Markwalder R, Studer UE. Lymphadenectomy in bladder cancer. EAU Update Series 2003;1:100–7.[CrossRef]
52 Westney OL, Pister LL, Pettaway CA, Tu S-M, Pollack A, Dinney CPN. Presentation, methods of diagnosis and therapy for pelvic recurrence following radical cystectomy for transitional cell carcinoma of the bladder. J Urol 1998;159:792–5.[CrossRef][Web of Science][Medline]
53 Smith JA Jr, Crawford ED, Paradelo JC, Blumenstein B, Herschman BR, Grossman HB, et al. Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol 1997;157:805–8.[CrossRef][Web of Science][Medline]
54 Crawford ED, Wood DP, Petrylak DP, Scott J, Coltman CA Jr, Raghaven D. Southwest Oncology Group studies in bladder cancer. Cancer 2003;97(Suppl 8):2099–108.[CrossRef]
55 Juffs HG, Moore MJ, Tannock F. The role of systemic chemotherapy in the management of muscle-invasive bladder cancer. Lancet Oncol 2002;3:738–47.[CrossRef][Web of Science][Medline]
56 Skinner DG, Daniels JR, Russell CA, Lieskovsky G, Boyd SD, Nichols P, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991;145:459–64.[Web of Science][Medline]
57 Studer UE, Bacchi M, Biedermann C, Jaeger P, Kraft R, Mazzucchelli L, et al. Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994;152:81–4.[Web of Science][Medline]
58 Stockle M, Wellek S, Meyenburg W, Voges GE, Fischer U, Gertenbach U, et al. Radical cystectomy with or without adjuvant polychemotherapy for non-organ-confined transitional cell carcinoma of the urinary bladder: prognostic impact of lymph node involvement. Urology 1996;48:868–75.[CrossRef][Web of Science][Medline]
59 Freiha F, Reese J, Torti FM. A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996;155:495–500.[CrossRef][Web of Science][Medline]
60 National Cancer Institute, Bethesda, MD, USA. 2003. http://www.nci.nih.gov/search/clinical_trials/results_clinicaltrials.aspx, accessed October 2003.
61 Martinez-Pineiro JA, Martin GM, Arocena F, Flores N, Roncero CR, Portillo JA, et al. Neoadjuvant cisplatin chemotherapy before radical cystectomy in invasive transitional cell carcinoma of the bladder: a prospective randomized phase III study. J Urol 1995;153:964–73.[CrossRef][Web of Science][Medline]
62 Malmström PU, Rintala E, Wahlqvist R, Hellström P, Hellsten S, Hannisdal E. Five-year follow-up of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996;155:1903–6.[CrossRef][Web of Science][Medline]
63 Bassi P, Pagano F, Pappagallo G, Cosciani S, Lembo A, Anselmo G, et al. Neoadjuvant M-VAC chemotherapy of invasive bladder cancer: the G.U.O.N.E. multicenter phase II trial. Eur Urol 1998;33(Suppl 1):142.[CrossRef]
64 International collaboration of trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party, EORTC Genito-Urinary Group, Australian Bladder Cancer Study Group, National Cancer Institute of Canada Clinical Trials Group, Finnbladder Norwegian Bladder Cancer Study Group and Club Urologico Espanol de Tratamiento Oncologico (CUETO) group. Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomized control trial. Lancet 1999;354:533–40.[CrossRef][Web of Science][Medline]
65 Sherif A, Rintala E, Mestad O, Nilsson J, Holmberg L, Nilsson S, et al. Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer. Nordic Cystectomy Trial 2. Scand J Urol Nephrol 2002;6:419–25.
66 Sternberg CN, Yogoda HI, Watson RC, Herr HW, et al. Methotrexate, vinblastine, doxorubicin and cisplatin for advanced transitional cell carcinoma of the uroepithelium; efficacy and patterns of response and relapse. Cancer 1989;64:2448–58.[CrossRef][Web of Science][Medline]
67 Harker WG, Meyers FJ, Freiha FS, Palmer JM, Shortliffe LD, Hannigan JF, et al. Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract. A Northern California Oncology Group study. J Clin Oncol 1985;3:1463–70.
68 Loehrer PJ Sr, Einhorn LH, Elson PJ, Crawford ED, Kuebler P, Tannock I, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992;10:1066–73.[Abstract]
69 Saxman SB, Propert KJ, Einhorn LH, Crawford ED, Tannock I, Raghavan D, et al. Long-term follow-up of a phase III intergroup study of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1997;15:2564–9.
70 Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with advanced metastatic urothelial tumors. J Clin Oncol 1990;8:1050–5.[Abstract]
71 Loehrer PJ Sr, Elson P, Dreicer R, Hahn R, Nichols CR, Williams R, et al. Escalated dosages of methotrexate, vinblastine, doxorubicin, and cisplatin plus recombinant human granulocyte colony-stimulating factor in advanced urothelial carcinoma: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1994;12:483–8.[Abstract]
72 Kuroda M, Kotake T, Akaza H, Hinotsu S, Kakizoe T, and the Japanese Urothelial Cancer Research Group. Efficacy of dose-intensified MEC (methotrexate, epirubicin and cisplatin) chemotherapy for advanced urothelial carcinoma: a prospective randomized trial comparing MEC and M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin). Jpn J Clin Oncol 1998;28:497–506.
73 Bellmunt J, Guillem V, Paz-Ares L, Gonzalez-Larriba JL, Carles J, Batiste-Alentorn E, et al. Phase I-II study of paclitaxel, cisplatin and gemcitabine in advanced transitional cell carcinoma of the urothelium. J Clin Oncol 2000;18:3247–55.
74 Hussain M, Vaishampayan U, Du W, Redman B, Smith DC. Combination paclitaxel, carboplatin, and gemcitabine is an active treatment for advanced urothelial cancer. J Clin Oncol 2001;19:2527–33.
75 Meluch AA, Greco FA, Burris HA 3rd, O’Rourke T, Ortega G, Steis RG, et al. Paclitaxel and gemcitabine chemotherapy for advanced transitional cell carcinoma of the urothelial tract: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2001;15:3018–24.
76 von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatinum in advanced or metastatic bladder cancer: results of a large randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;17:3068–77.
77 Cohen MH, Rothmann M. Correspondence: Gemcitabine and cisplatin for advanced, metastatic bladder cancer. J Clin Oncol 2001;19:1229–31.
78 Hussain SA, James ND. The systemic treatment of advanced and metastatic bladder cancer. Lancet Oncol 2003;4:489–97.[CrossRef][Web of Science][Medline]
79 Bamias A, Aravantionos G, Deliveliotis C, Bafaloukos D, Kalofomos C, Xiros N, et al. Docetaxel and cisplatin with granulocyte-colony stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. J Clin Oncol 2004;22:220–8.
80 de Wit R. Overview of bladder cancer trials in the European Organization for Research and Treatment. Cancer 2003;97(Suppl 8):2120–6.
81 Montie JE. Against bladder sparing: surgery. J Urol 1999;162:452–7.[CrossRef][Web of Science][Medline]
82 Herr HW. Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol 1987;138:1162–3.[Web of Science][Medline]
83 Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89–93.
84 Roosen JU, Geertsen U, Hahn H, Jorgen J, Weinreich J, Nissen HM. Invasive, high grade transitional cell carcinoma of the bladder treated with transurethral resection – a survival analysis focusing on TUR as monotherapy. Scand J Urol Nephrol 1997;31:39–42.[Web of Science][Medline]
85 Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Calabuig C. Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term follow-up of a prospective study. J Urol 1998;159:95–9.[CrossRef][Web of Science][Medline]
86 Gospodarowicz MK, Warde PR. A critical review of the role of definitive radiation therapy in bladder cancer. Semin Urol 1993;4:214–26.
87 Angulo JC, Sanchez-Chapado M, Lopez JI, Flores N. Primary cisplatin, methotrexate and vinblastine aiming at bladder preservation in invasive bladder cancer: multivariate analysis on prognostic factors. J Urol 1996;155:1897–1902.[CrossRef][Web of Science][Medline]
88 Scattoni V, Da Pozzo L, Nava L, Broglia L, Galli L, Torelli T, et al. Five-year results of neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy plus radical cystectomy in locally advanced bladder cancer. Eur Urol 1995;28:102–7.[Web of Science][Medline]
89 Galetti TP, Pontes JE, Montie J, Medendorp SV, Bukowski R. Neoadjuvant intra-arterial chemotherapy in the treatment of advanced transitional cell carcinoma of the bladder: results and followup. J Urol 1989;142:1211–5.[Web of Science][Medline]
90 Jacobs SC, Menashe DS, Mewissen MW, Lipchik EO. Intraarterial cisplatin infusion in the management of transitional cell carcinoma of the bladder. Cancer 1989;64:388–91.[CrossRef][Web of Science][Medline]
91 Tester W, Caplan R, Heaney J, Venner P, Whittington R, Byhardt R, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14:119–26.[Abstract]
92 Kachnic LA, Kaufman DS, Heney NM, Althausen AF, Griffin PP, Zietman AL, et al. Bladder preservation by combined modality therapy for invasive bladder cancer. J Clin Oncol 1997;15:1022–9.
93 Shipley WU, Winter KA, Kaufman DS, Lee WR, Heney NM, Tester WR, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998;16:3576–83.[Abstract]
94 Rödel C, Gerhard G, Grabenbauer GG, Kühn R, Papadopoulos T, Dunst J, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002;20:3061–71.
95 Mokarim A, Uetani M, Hayashi N, Sakamoto I, Minami K, Ogawa Y, et al. Combined intraarterial chemotherapy and radiotherapy in the treatment of bladder carcinoma. Cancer 1997;80:1776–85.[CrossRef][Web of Science][Medline]
96 Sumiyoshi Y, Hashine K, Karashima T, Kasahara K, Inoue Y. Preliminary results of bladder preservation by concurrent intraarterial chemotherapy and radiotherapy for muscle-invasive bladder cancer. Int J Urol 1998;5:225–9.[Medline]
97 Miyanaga N, Akaza H, Okumura T, Sekido N, Kawai K, Shimazui T, et al. A bladder preservation regimen using intra-arterial chemotherapy and radiotherapy for invasive bladder cancer: a prospective pilot study. Int J Urol 2000;7:41–8.[CrossRef][Web of Science][Medline]
98 Tsukamoto S, Ishikawa S, Tsutsumi M, Nakajima K, Sugahara S. An organ-sparing treatment using combined intra-arterial chemotherapy and radiotherapy for muscle-invading bladder carcinoma. Scand J Urol Nephrol 2002;36:339–43.[CrossRef][Web of Science][Medline]
99 Kuczyk M, Turkeri L, Hammerer P, Ravery V. Is there a role for bladder preserving strategies in the treatment of muscle-invasive bladder cancer? Eur Urol 2003;44:57–64.[CrossRef][Web of Science][Medline]
100 Shipley WU, Kaufman DS, Zehr NM, Heney NM, Lane SC, Thakral HK, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology 2002;60:62–8.[Web of Science][Medline]
101 Montie JE. Editorial comment. Urology 2002;60:67.[Web of Science][Medline]
102 Gospodarowicz M. Radiotherapy and organ preservation in bladder cancer: are we ignoring the evidence? J Clin Oncol 2002;20:3048–50.
Received March 10, 2004; accepted March 22, 2004
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