World J Urol (2002) 20: 175–182 DOI 10.1007/s00345-002-0277-0
T O P I C P A PE R
Samira Syed Æ Geoffrey R. Weiss
Management of locally advanced bladder cancer: early vs deferred chemotherapy
Published online: 19 June 2002 Ó Springer-Verlag 2002
Abstract Locally advanced bladder cancer is associated with a high risk of local recurrence and distant metastases. Clinical and pathologic variables have been useful in predicting outcome in patients with muscle-invasive bladder cancer. Recently, a number of molecular prognostic markers have been identified that help predict tumor aggressiveness, response to chemotherapy, and survival. Transitional cell carcinoma is a chemosensitive tumor. The early use of chemotherapy to reduce the risk of recurrence and improve survival has been the focus of many randomized clinical trials. Unfortunately, the majority of studies have failed to show a survival advantage for chemotherapy-treated patients. Well-designed prospective trials that target high-risk patients, defined by clinical, pathological, and molecular features, and incorporate new more tolerable chemotherapeutic agents are needed to clarify the benefit of early chemotherapy. Keywords Bladder cancer Æ Transitional cell carcinoma Æ Prognostic factors Æ Chemotherapy
Bladder cancer is the second most common genitourinary malignancy. Transitional cell carcinoma (TCC) comprises nearly 90% of primary bladder tumors [23]. While the majority of bladder tumors are superficial,
S. Syed Æ G.R. Weiss (&) The University of Texas Health Science Center at San Antonio, South Texas Veterans Health Care System, San Antonio, TX E-mail: geoff
[email protected] Tel.: 001-210-6175120 Fax: 001-210-9493292 G.R. Weiss Division of Medical Oncology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284–6200, USA
about 20%–40% either present with or develop invasive disease. Such tumors are usually high grade and originate in the bladder mucosa, progressively invading the lamina propria, muscularis propria, perivesical fat, and contiguous pelvic structures with increasing incidence of lymph node involvement as progression occurs [23]. Radical cystectomy has emerged as an effective local therapy for high-grade, muscle-invasive bladder cancer [6, 61]. This procedure includes removal of the bladder and prostate in men and the uterus and anterior vaginal wall in women. Bilateral pelvic lymph node dissection and some form of lower urinary tract reconstruction are also performed. While this procedure is still associated with considerable morbidity and has an impact on both urinary and sexual functions, it provides the surest means of eliminating the cancer. It also provides an accurate evaluation of the primary bladder tumor, as well as regional lymph nodes. Despite complete removal of the tumor by radical cystectomy, up to 50% of patients with invasive bladder cancer progress within the first two years following cystectomy, developing local recurrence or distant metastases [23]. The risk of progression is dependent upon several prognostic factors, including tumor stage, grade, and certain molecular prognostic markers. In recent years, the standards of care for muscle-invasive disease have been evolving, with an emphasis on combined-modality approaches. Numerous clinical trials have been performed in invasive bladder cancer exploring the role of both neoadjuvant [1, 3, 8, 10, 14, 24, 32, 33, 35, 42, 45, 54, 63, 71] and adjuvant chemotherapy [14, 19, 29, 55, 65, 67, 72]. However, a clear consensus has not emerged from these studies. The optimal goals of treatment of invasive bladder cancer are long-term survival, prevention of pelvic recurrence or distant metastases, and preserving quality of life. Since the benefits of early chemotherapy are not proven, perhaps a more effective development strategy might be conducting clinical trials in patients who have specific high-risk factors for developing metastatic disease and in whom treatment effects can be discerned rapidly. This article reviews some of the
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prognostic markers of aggressive disease and the debate on early chemotherapy versus chemotherapy at first relapse for patients with TCC of the bladder.
Prognostic factors for transitional cell carcinoma Clearly, predictive factors that stratify patients into different prognostic groups are needed in order to better select patients for early chemotherapy and to allow comparison of treatment outcomes among different institutions. Several studies have examined the prognostic significance of clinical and pathologic variables on survival in patients treated by radical cystectomy for bladder cancer [6, 12, 48, 49, 57, 61, 66]. Histological grade is an established prognostic factor. However, it is more important for superficial tumors because almost all invasive neoplasms are of high grade. Like grade, the growth fraction of a tumor is also an important prognostic feature. Two immunohistochemical markers of cellular proliferation are Ki-67 and proliferating cell nuclear antigen. Increased expression of these antigens is associated with an increased propensity for tumor progression and metastases [18, 60]. These markers may supplement the use of grade and stage in assessing bladder tumor aggressiveness and metastatic potential. Pathologic stage is clearly relevant in predicting survival after cystectomy. In various series, tumor size measured from gross and frozen section examination of cystectomy specimens, margin status, extravesical involvement, and lymph node metastases proved to be important pathologic factors in predicting cancer specific survival [6, 13, 48, 49, 57, 61, 66]. In one study, among patients with muscle invasive transitional cell carcinoma, those with organ confined disease (
the presence of extravesical extension and lymph node metastases in patients with TCC [51]. Uroplakins, which are specific differentiation products of terminally differentiated superficial urothelial cells, are almost always expressed to some degree in urothelial cancers. In one study [51], after patients with TCC had undergone radical cystectomy, biopsies from the external surface of the bladder and from the largest lymph node were obtained. RT-PCR analysis for UP II mRNA was performed on these specimens. Among the pathologically node-negative cancers perivesical tissue was positive by RT-PCR in 54% and lymph nodes were positive in 25% of cases. All patients with pathologically positive nodes in the series also had positive UP II signals in the lymph node samples. The RT-PCR analysis for UP II mRNA, allowed the detection of perivesical extension and lymph node metastases not appreciated by conventional histology. While the results are preliminary, such molecular approaches may prove useful in the future for identifying patients at high risk for relapse following cystectomy. There is mounting evidence suggesting that individual or several combined molecular events may be sufficient to predict which local cancers are likely to metastasize and which metastatic cancers may be more or less likely to respond to systemic chemotherapy. Fundamental cell cycle regulators p53 and retinoblastoma (Rb) tumor suppressors appear to be particularly important in bladder cancer. Mutations in the p53 gene are the most common genetic defect in bladder cancer and p53 expression, as determined by immunohistochemical analysis, has been extensively evaluated as a prognostic factor for bladder cancer progression [16, 20, 46, 52, 56, 75]. This tumor suppressor gene located on chromosome 17 is involved in the regulation of the cell cycle. When DNA is damaged, wild type p53 protein prevents the propagation of the DNA defect. Additionally, p53 induces apoptosis. Mutations within the p53 gene result in an abnormal and usually dysfunctional protein product with a prolonged half-life that accumulates in the nucleus [56, 75]. Currently, the presence of mutant p53 expression in greater than 10% of cells is considered abnormal. In general, the altered expression of p53 correlates with advanced tumor stage and grade [56]. Several retrospective studies have evaluated p53 expression in patients with superficial bladder cancer undergoing transurethral resection [47, 52, 56]. These studies indicate that increased staining is a significant negative predictor for survival. Abnormal p53 expression has also been examined in patients with muscleinvasive bladder cancer undergoing radical cystectomy. In one large retrospective study [16], nuclear accumulation of p53 (greater than 10%) was an independent predictor of disease progression in a multivariate analysis of p53 status, histological grade, and pathologic stage. There is conflicting data regarding the role of p53 mutations and resistance to chemotherapy [12, 26, 46]. This issue remains unsettled at present and studies are underway to clarify the importance of p53 in determining the response to chemotherapy [56].
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An important target of p53 is p21, which exerts a negative effect on the regulation of the cell cycle as a cyclin-dependant kinase inhibitor. Alterations in p53 that result in decreased p21 expression can lead to upregulated cell growth [56, 60, 75]. Stein et al. [59], evaluated p21 expression by immunohistochemical techniques in bladder tumors from 101 patients who were post-cystectomy. The tumors evaluated were all positive for the p53 mutation. The patients whose tumors were p21 negative while expressing mutant p53 had a significantly greater probability of disease recurrence and lower overall survival, compared to patients whose tumors maintained expression of p21. Another tumor suppressor gene of prognostic importance in bladder cancer is the retinoblastoma (Rb) gene. Similar to p53, altered Rb expression has been associated with advanced tumor stage and high histological grade [25, 60, 73]. In one series, Cordon-Cardo et al. reported that patients with muscle-invasive bladder tumors who had altered Rb immunoexpression had a statistically significant shorter 5-year survival (p<.001) than those with normal Rb protein expression [9]. The interaction between p53 and Rb is also important. Abnormalities in both proteins seem to have an additive prognostic effect [11, 17, 56, 60]. In one series of patients with muscle-invasive bladder cancer undergoing cystectomy, those with simultaneous alterations in p53 and Rb had a significantly greater rate of recurrence compared to the patients with normal p53 and Rb staining [11]. Studies have demonstrated that the Bcl-2 gene, which protects against apoptosis, is overexpressed in bladder cancer. A consensus seems to be emerging that Bcl-2 expression is a marker of disease with poor prognosis, more likely to progress [7, 75]. In one series reported by Kong et al. [28], overexpression of Bcl-2 and p53 were independent prognostic factors for the survival of patients with muscle-invasive bladder cancer. The interaction between Bcl-2 and its other family members, including Bax and Bcl-XL, seems also to be important biologically in bladder cancer [7, 74, 75]. In this multigene family, some members block cell death (Bcl-2 and Bcl-XL) where as others promote apoptosis (Bax). In one study, Gazzaniga et al. [21], evaluated the expression of Bcl-2 and Bax in bladder tumors using RT-PCR analysis. Bcl-2 expression was increased in high-stage tumors, whereas the reverse was true for Bax expression. In another report [74], while Bcl-2 or Bax expression individually had no effect on relapse after intravesical mitomycin C, a Bcl-2:Bax ratio of >1 was associated with a greater recurrence rate in the first year after treatment. It has been proposed that the ratio of Bcl2:Bax and other anti-apoptotic members of the Bcl-2 family govern the relative sensitivity of cellular response to apoptotic stimuli [74]. These genes may influence chemotherapy-induced apoptosis and regulate resistance to chemotherapy. If Bcl-2 confers a poor prognosis by inducing chemotherapy resistance, then knowing the Bcl-2 status of a tumor may help direct the treatment
approach of TCC of the bladder. Tumors that are Bcl-2 positive would be less likely to benefit from neoadjuvant chemotherapy but may be candidates for novel therapies, such as Bcl-2 antisense therapy aimed at reversing the effects of this particular molecular aberration. Altered expression of E-cadherin has also been studied as an independent prognostic variable for carcinoma in situ and muscle-invasive TCC [5, 53, 60]. In order to metastasize, cancer cells must detach from their original site, a process that requires the disruption of normal cell-cell adhesion in epithelial tissue. E-cadherin, expressed in epithelial tissue and found on the plasma membrane of transitional cells, is a mediator of calcium dependent cell-cell adhesion. Loss of functional E-cadherin expression has been frequently observed in bladder cancer and seems to be an integral part of neoplastic progression. In patients with carcinoma in-situ, abnormal E-cadherin expression has been independently associated with disease recurrence, progression, and bladder cancer specific death [53]. Abnormal E-cadherin expression seems to be a useful marker to identify patients with carcinoma in-situ who may benefit from early cystectomy. In muscle-invasive TCC, aberrant expression of E-cadherin is an independent predictor of disease progression following cystectomy, suggesting that these tumors may be biologically more aggressive [5]. Another important predictor of recurrence and metastases in patients with bladder cancer is angiogenesis factor expression [27, 60]. It is known that angiogenesis is critical for tumor growth and metastases. A balance between proangiogenic and antiangiogenic signals regulates the process. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are proangiogenic factors that have been identified in the tissue, serum, and urine of patients with bladder cancer and correlate with disease recurrence. Interleukin 8 (IL8) has also been shown to be proangiogenic and to promote the invasion and metastasis of human TCC [27]. The immunohistochemical expression of epidermal growth factor receptor (EGF-R) may be an early event in bladder cancer tumorigenesis and may also have prognostic significance [38, 43, 44]. This transmembrane glycoprotein is activated by the binding of epidermal growth factor (EGF) or transforming growth factor a (TGF-a) to its external domain. This activation results in the phosphorylation of intracellular tyrosine kinases by the cytoplasmic portion of EGF-R and subsequent cellular proliferation, transformation, and division. EGF-R expression has been correlated with a higher rate of recurrence and increased rate of progression in superficial bladder tumors [38, 43, 60]. In summary, there are several molecular prognostic markers that have been examined in retrospective studies that can be correlated with biological behavior of bladder cancer. Prospective studies need to confirm whether these variables should direct the clinical management of patients with transitional cell carcinoma. It is
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noteworthy that specific small molecule therapeutic agents targeted to some of these markers are in clinical development.
Adjuvant chemotherapy for transitional cell carcinoma of the bladder Local and distant failure after cystectomy is still a distressing problem in the manage of patients with TCC. Many investigators have attempted to improve the outcome of high-risk patients by the early introduction of chemotherapy either before or after surgery. In prospective phase II trials, combination chemotherapy, largely with cisplatin-based regimens, induces objective response rates in up to 50% of patients with metastatic disease (Table 1). Given the responsiveness of TCC to chemotherapy, early administration of combination chemotherapy following definitive local therapy to reduce the risk of local recurrence and distant metastases seems logical. If chemotherapy is administered as adjuvant therapy, then patients are accurately staged, and there is no delay in definitive local treatment. Removal of the bladder reduces the risk of new tumor formation and eliminates the need for repeated cystoscopy to detect recurrent disease. The disadvantage of this approach is that tumor response to chemotherapy cannot be assessed. In addition, many patients, due to post-operative morbidity, are unable to receive the planned chemotherapy. Randomized trials have demonstrated the superiority of M-VAC (methotrexate, vinblastine, adriamycin, and cisplatin) to single-agent cisplatin in metastatic TCC [23, 30]. This regimen, which has become the standard of care for the treatment of advanced bladder cancer over the years, is associated with significant toxicity [64]. Recently, combinations of cisplatin and gemcitabine [70], cisplatin and paclitaxel [15, 41], cisplatin and docetaxel [50], carboplatin and paclitaxel [69], and gemcitabine and paclitaxel [34, 37] have been studied in metastatic TCC with the aim of improving the efficacy, as well as the tolerability of chemotherapy. Gemcitabine, a nucleoside analogue, has demonstrated significant activity as a single agent in bladder cancer [31, 40, 58]. The combination of gemcitabine and cisplatin has been compared to M-VAC for patients with advanced bladder cancer in a phase III randomized trial. Table 1. Combination chemotherapy for transitional cell carcinoma of the bladder. NR not reported; mths months
The results demonstrated that response rate, time to progression, and survival with the gemcitabine and cisplatin combination were similar to M-VAC but the safety profile and tolerability were improved with gemcitabine and cisplatin [70]. Paclitaxel and docetaxel have also shown significant activity in bladder cancer and have been combined with other active agents, including carboplatin, cisplatin, gemcitabine and ifosfamide, for metastatic disease with encouraging results [2, 4, 15, 36, 37, 41, 50, 68, 69]. In phase II studies, non-cisplatin combinations are also being studied for patients with metastatic TCC [34, 37, 68, 69]. These regimens are likely to prove especially useful in patients with renal impairment, where administration of cisplatin may be problematic. While newer combinations have been examined for metastatic disease, the regimens used in adjuvant chemotherapy trials to date have been cisplatin-based. The benefit of adjuvant chemotherapy after radical cystectomy has been assessed in four randomized trials [19, 55, 65, 67]. The first study reported by Skinner et al. [55] randomized high-risk patients (T3, T4, or pelvic lymph-node involvement), to either observation or adjuvant chemotherapy after radical cystectomy. The chemotherapy – usually cisplatin, cyclophosphamide, and doxorubicin – was given for four cycles. Patients receiving adjuvant chemotherapy had a statistically significant improvement in disease-free survival and overall survival when compared to the observation arm. This study has been criticized for the statistical methodology used, for its small sample size, and for the use of nonstandardized chemotherapy. In addition, many of the enrolled patients did not receive the therapy to which they were assigned. Subset analysis showed that the survival advantage was confined mainly to patients with negative lymph nodes or with only one positive lymph node. In a second trial reported by Stockle et al. [65], similar problems of study design and chemotherapy administration occurred. In this study, patients with locally advanced (T3, T4 and/or N1, N2) were randomly assigned to receive three cycles of MVAC or MVEC (methotrexate, vinblastine, epirubicin, and cisplatin) versus observation. This study was closed early because of an interim analysis of 49 patients showing a significant relapse-free survival advantage in the chemotherapy arm.
Regimen
Agents
Patients (n)
Response rate
Median survival Reference
MVAC
Methotrexate/vinblastine Adriamycin/cisplatin Gemcitabine/cisplatin Cisplatin/paclitaxel Cisplatin/docetaxel Carboplatin/paclitaxel Gemcitabine/paclitaxel Ifosfamide/paclitaxel Cisplatin Gemcitabine/paclitaxel/ Carboplatin
269
39%
12.5 mths
30
203 20 25 33 50 44
49% 63% 60% 50% 54% 68%
13.8 mths NR 13.6 mths 8.5 mths 15 mths 18 mths
70 15 50 69 37 36
23
58%
NR
68
GC
ITP
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Patients in the cystectomy-alone group had a worse than expected outcome. In addition, there was some question as to whether these patients received any chemotherapy at relapse, a factor that may have adversely effected overall survival in the control arm of the study. A third study by Freiha et al. [19] included 50 patients who were randomized to receive CMV (cisplatin, methotrexate, and vinblastine) chemotherapy or were observed after cystectomy. With a median follow up of 5 years, the adjuvant chemotherapy group demonstrated a significant improvement in disease-free survival but there was no statistically significant difference in overall survival. The authors postulated that the lack of difference in overall survival between the two study arms may have been because patients in the observation arm received effective chemotherapy at relapse. Lastly, Struder et al. [67] compared single-agent cisplatin to observation in 72 patients with T2-T4 transitional cell carcinoma who were post-cystectomy. There was no significant difference in relapse-free or overall survival between the two arms. This study was also comprised of a small number of patients and many had organ-favorable disease (55% with organ-confined disease and only 10% with lymph node involvement). Collectively, these trials fail to definitely prove that adjuvant chemotherapy provides a survival benefit in muscle-invasive bladder cancer and the trials have several flaws, which make interpretation of the results a matter of debate. With the lack of a clear survival advantage, it is hard to justify this approach in all patients. Deferred chemotherapy offered at the time of clinical relapse may spare those patients cured by surgery alone the morbidity associated with chemotherapy. There are several ongoing trials studying the merits of early chemotherapy post-cystectomy. Some of these studies are incorporating newer agents, such as gemcitabine and paclitaxel [29, 63, 72]. These combinations may be better Table 2. Randomized trials of neoadjuvant chemotherapy for transitional cell carcinoma of the bladder. EORTC European Organization for the Research and Treatment of Cancer; MRC Medical Research Council; GUONE Gruppo Uro-Oncologico del Nord-Est; CUETO Club Urologico Espanol de Tratamiento Oncologico; RTOG Radiation Therapy Oncology Group; SWOG South West Oncology Group; GISTV Gruppo Italiano per la
tolerated and possibly more efficacious in preventing relapse and improving overall survival. An approach – utilizing molecular prognostic markers in addition to clinical-pathological parameters – to determine the patients best suited for early is also under way [56, 63, 72]. One study initiated by investigators at the University of Southern California [56] randomizes patients with organ-confined bladder cancer and p53 alterations to three cycles of MVAC versus observation after cystectomy. In addition to assessing the benefit of adjuvant chemotherapy, this trial will compare recurrence-free and overall survival between patients with the p53 mutation and those with wild type p53. It will also examine whether cell cycle regulatory proteins, such as p53 and Rb, predict response to chemotherapy.
Neoadjuvant chemotherapy for transitional cell carcinoma of the bladder Neoadjuvant chemotherapy has been used for locally advanced TCC with the aim of downstaging the primary tumor and treating possible micrometastases. Neoadjuvant chemotherapy allows an accurate assessment of the tumor’s sensitivity to chemotherapy, and many also argue that chemotherapy administered prior to definitive local treatment is better tolerated. Despite the theoretical advantages cited for this approach, the routine use of neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer remains controversial. There have been several randomized clinical trials investigating the benefit of neoadjuvant chemotherapy (Table 2) [1, 3, 8, 10, 14, 24, 32, 33, 35, 42, 45, 54, 62, 63, 71]. In general, these studies have been small and have failed to show an overall survival advantage. Many of the trials have used radiotherapy (RT) as the local definitive treatment rather than cystectomy [24, 54, 71]. There is no reason to Studio dei Tumori della Vescica; NCIC National Cancer Institute of Canada; CMV cisplatin, methotrexate and vinblastine; CarboMV carboplatin, methotrexate and vinblastine; MVAC methotrexate, vinblastine, doxorubicin and cisplatin; MVEC methotrexate, vinblastine, epirubicin and cisplatin; 5FU 5-fluorouracil; RT radiation therapy
Trial organization
Patients (n)
Neoadjuvant arm
Standard arm
Reference
EORTC/MRC Abol-Enein et al. Australia / UK Italy GUONE Nordic I
976 194 255 206 325
RT or cystectomy Cystectomy RT Cystectomy RT/cystectomy
24 1 71 3 32
Nordic II
317
Cystectomy
33
Spain CUETO RTOG SWOG Italy GISTV Canada NCIC
122 123 317 171 99 104
Cystectomy RT/cisplatin Cystectomy Cystectomy RT or pre-op RT and cystectomy Cystectomy
35 54 42 10 8
Italy Genoa
CMV/RT or cystectomy CarboMV/cystectomy Cisplatin/RT MVAC/cystectomy Cisplatin/doxorubicin/ RT/cystectomy Methotrexate/ cisplatin Cystectomy Cisplatin/cystectomy CMV/ RT/cisplatin MVAC/cystectomy MVEC/cystectomy Cisplatin/RT or pre-op RT and cystectomy Cisplatin/5FU RT/Cystectomy
45
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expect that the benefit from chemotherapy would differ based on the local treatment (RT versus surgery). One of the largest randomized studies is that reported by the Medical Research Council (MRC) and European Organization for Research and Treatment of Cancer (EORTC) [24]. In this trial of 976 patients, neoadjuvant CMV chemotherapy, followed by cystectomy or RT, was compared to immediate cystectomy or RT. An 8% difference in time to progression in treated patients and a 5.5% difference in absolute 3-year survival was seen (HR= 0.85, 95% CI 0.71–1.02). The median survival for the chemotherapy group was 44 months and 37.5 months for the surgery or RT alone group. This difference of 6.5 months with a two-sided P-value of .075 was not statistically significant. More recently, the results of the Intergroup Study 0080, coordinated by the Southwest Oncology Group (SWOG), were reported [42]. This study was designed to detect a difference in overall survival between neoadjuvant chemotherapy and cystectomy versus cystectomy alone. In this trial, 317 patients with T2-T4a, N0 TCC were randomized to receive three cycles of MVAC prior to cystectomy vs cystectomy alone. Grade 4 toxicities occurred in 37% of patients receiving chemotherapy, although there were no chemotherapy-associated deaths. At the time of surgery, 38% of the MVAC-treated patients had a pathological complete remission. 5-year survival in the MVAC arm was significantly superior to survival in the cystectomy alone arm (57% vs 42%, P=.04), with estimated median survivals of 6.2 years and 3.8 years respectively. There has been some criticism of this trial due to its statistical design and the long duration (11 years) taken to accrue patients. The study was planned for one-sided testing, suggesting that it was designed to test not for a difference but only an improvement in survival with chemotherapy. In addition, since most clinical trials are designed for two-sided significance, a comparison of this study to others is also difficult because of differences in statistical design. Sternberg et al. [63] recently summarized information from all relevant randomized trials of neoadjuvant chemotherapy in the form of a meta-analysis. They found that more favorable results were seen with cisplatin combinations compared to single-agent cisplatin. However, when all the trials are combined, a hazard ratio of 0.9 (CI 0.81–1.00) is observed. This borderline result raises some doubt about the magnitude of benefit from neoadjuvant chemotherapy. Finally, while many investigators support the idea of early chemotherapy, the preferred sequence (neoadjuvant vs adjuvant) is also not clearly defined. Millikan et al. [39], have examined the importance of the timing of chemotherapy with respect to surgery in a recent study of 140 patients. In this trial, patients with locally advanced TCC were randomly assigned to receive either two courses of neoadjuvant MVAC followed by surgery plus three additional cycles of chemotherapy or to have initial cystectomy followed by five cycles of adjuvant chemotherapy. The investigators found no significant
difference in outcome between the two groups. Of the patients, 58% remained disease-free with a median follow up of 6.8 years. The authors argue in favor of early chemotherapy since the expected survival of the highrisk group of patients they treated would have been 20%–30%. However, no preferred sequence was demonstrated in this study. In conclusion, there is no doubt that the recurrence rate after cystectomy for locally advanced TCC of the bladder is disappointingly high and that there is an urgent need to improve the outcome of these patients. Well-designed, multi-center, prospective trials investigating neoadjuvant and adjuvant chemotherapy for TCC are needed. Such clinical trials should incorporate less toxic non-cisplatin regimens and investigate novel therapies targeting the molecular aberrations present in these tumors. High-risk patients need to be identified using prognostic markers (clinical, pathological, and molecular) and such patients should be the focus of further clinical trials. The available data provide enticing evidence that early chemotherapy (adjuvant or neoadjuvant) for patients with organ-confined TCC may be beneficial. Because the intent of early intervention is to cure, the application of systemic therapy at relapse may be conceptually and biologically too late to affect the optimum result. With the emergence of a variety of small molecule anticancer agents targeted to the epithelial growth factor receptor family, to downstream signal transduction molecules, and to other effectors of cell growth, malignant differentiation, and antiapoptosis, the next decade of clinical trials in bladder cancer promises to offer unmatched opportunities to alter and reverse the natural history of this malignancy.
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