Review of Current Neoadjuvant and Adjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

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1 available at journal homepage: Review of Current Neoadjuvant and Adjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Nadine Houédé a,b, *, Philippe Pourquier b, Philippe Beuzeboc c a Department of Medical Oncology, CRLCC Institut Bergonié, Bordeaux, France b INSERM U916 and University of Bordeaux, Bordeaux, France c Department of Medical Oncology, CRLCC Institut Curie, Paris, France Article info Keywords: Chemotherapy Bladder Neoadjuvant Adjuvant Abstract Context: There are >8000 cases of bladder cancer per year in France, and 30% are muscle invasive. Despite an aggressive initial treatment, only 60% of patients with T2 tumours, 50% with T3a, and 15% with T3b stage tumours will be alive at 5 yr. Objective: To address the role of chemotherapy in urothelial tumours of the bladder. Evidence acquisition: Published randomised trials of chemotherapy in urothelial tumours of the bladder in both neoadjuvant and adjuvant settings from 1980 and 2010 and corresponding meta-analyses were included in this review. Evidence synthesis: In the neoadjuvant setting, a meta-analysis of individual data from 3005 patients included in 11 randomised neoadjuvant chemotherapy trials for localised muscle-invasive bladder cancers demonstrated an absolute survival benefit of 5% at 5 yr with cisplatin-based combination chemotherapy. Despite these results, neoadjuvant chemotherapy is very rarely proposed for this indication. Comparative trials undertaken in the adjuvant setting have been limited by major methodological weaknesses (eg, very low statistical power and unwarranted early trial interruptions) preventing definitive conclusions. In a meta-analysis based on individual data from 491 patients, a 25% reduction in death risk was observed for an absolute gain of 9% at 3 yr. However, the small number of patients included and the heterogeneity of the chemotherapy protocols used limit the validity of these analyses. Conclusions: Given this uncertainty, chemotherapy should be offered early and proposed as a reasonable option for patients for tumours with extravesical extension or with nodal involvement detected postoperatively. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Institut Bergonié, Department of Medical Oncology, 229 cours de l Argonne Bordeaux Cedex, France. Tel. +33 (0) ; Fax: +33 (0) address: houede@bergonie.org (N. Houédé). 1. Introduction The poor prognostic rate and high death rate for muscleinvasive urothelial tumours (only 60% of patients with T2, 50% with T3a, or 15% with T3b tumours will be alive at 5 yr) mean that to improve outcomes, more than just surgery is required to treat these tumours Objectives of neoadjuvant treatment Neoadjuvant chemotherapy is a systemic medical treatment performed before locoregional treatment, chosen for operable tumours. This treatment has multiple objectives: (1) to eradicate micrometastases and to prevent tumoural cells that are circulating at the time of surgery from settling, /$ see front matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eursup

2 [()TD$FIG] e21 (2) to reduce tumour size and to allow preservation of the organ (if a pt0 is obtained) where possible, and (3) to increase survival duration. Neoadjuvant chemotherapy treatment offers several advantages: Toxicity is often much less significant than in a metastatic situation for patients in a better general state of health, and, in particular, it enables the chemosensitivity of the tumour to be tested in vivo [1]. The risks involved are the possibility of a deleterious effect if the patient does not respond because surgery is delayed while the treatment is administered. This is especially true if the delay between diagnosis and surgery is >12 wk [2,3] or if toxicity is too high. An alternative is to offer adjuvant therapy Objectives of adjuvant treatment The objectives of adjuvant treatment are to supplement a surgical intervention that was not microscopically complete and to increase the duration of survival. Compared with neoadjuvant chemotherapy, the adjuvant setting can offer several advantages: The treatment decision is based on a precise classification of the stage of the disease, there is minimal residual disease, and the curative surgery is not delayed. However, it also presents potential inconveniences such as significant physical and psychological consequences of a cystectomy, more difficult tolerance of chemotherapy, and postoperative alteration of renal function. 2. Evidence acquisition A systematic review of the Medline database, restricted to articles published in English from 1980 to the present, was undertaken to find relevant papers on neoadjuvant and adjuvant chemotherapy in urothelial tumours of the bladder. 3. Evidence synthesis 3.1. Principal results in the neoadjuvant setting The use of neoadjuvant chemotherapy has been detailed in several clinical trials. The largest trial, published in 1999 and undertaken by the European Organisation for Research and Treatment of Cancer (EORTC) and the Medical Research Council, included 976 patients treated with a cisplatin, methotrexate, and vinblastine (CMV) type of chemotherapy [4]. Locoregional treatment included cystectomy or radiotherapy. With a long follow-up, the study demonstrated a significant advantage for the chemotherapy-receiving group with a survival increase of 5.5% (results presented at American Society of Clinical Oncology [ASCO] 2002). The pt0 rate was 32% for patients who received a cystectomy (57%). In another trial by the Southwest Oncology Group that compared three cycles of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) with local treatment from the outset, 298 patients were included, and a median survival of 77 mo was found in the neoadjuvant chemotherapy group compared with 46 mo in the surgery-only Fig. 1 Global survival (extract from the ABC Meta-analysis Collaboration [6]). CT = chemotherapy. group. The pt0 rate after chemotherapy was 38% (compared with 15%) [5]. A meta-analysis of individual data from 11 trials and >3000 T2 T4a patients participating in a trial comparing cisplatin-based chemotherapy (alone or in association) versus local treatment from the outset (surgery or radiotherapy) was published in A statistically significant survival benefit of 5% at 5 yr was observed (hazard ratio [HR]: 0.86; 95% confidence interval [CI], ; p = 0.003) (Fig. 1) [6] with a reduction in the risk of death of 14% and an increase in specific survival of 9% New agents in neoadjuvant treatment Many agents are developed in therapeutic trials in advanced-stage bladder cancer, including inhibitors of vascular endothelial growth factor and endothelial growth factor receptors. Several of these agents are being trialled in the neoadjuvant setting as a short treatment administered after biopsy and before cystectomy with a pharmacodynamic objective. At this stage, not one of these agents, used alone or in association, has proven its superiority over MVAC (Table 1) Neoadjuvant chemotherapy and bladder preservation After transurethral bladder resection, 15% of patients are pt0 on the cystectomy specimen that was removed. This rate increases to between 35% and 45% after neoadjuvant chemotherapy [6,7]. Unfortunately, the absence of residual tumour does not mean the patient has been cured of all disease. Patient survival after resection alone has not yet been compared in a randomised trial with survival after cystectomy. Several factors are favourable indications for bladder preservation: clinical stage, tumour size (<3 5 cm), absence of hydronephrosis, absence of a palpable mass, and the existence of a unifocal lesion. Several trials [8 12] have endeavoured to evaluate neoadjuvant chemotherapy associated with radiotherapy alone or combined with chemotherapy [12] in complete

3 e22 Table 1 Trials evaluating neoadjuvant chemotherapy registered on Clinicaltrials.gov Trial Agents Objective Phase 2, MSKCC (recruiting) GC plus sunitinib Efficacy/toxicity Phase 2, MD Anderson Cancer Center (active) MVAC plus bevacizumab Efficacy/toxicity Phase 2, Lilly (completed) GC Efficacy/toxicity Phase 2, Celldex Therapeutics (recruiting) GC plus CD1307 Efficacy/toxicity Phase 2, University of Michigan (recruiting) Carboplatin gemcitabine plus ABI 007 Efficacy/toxicity Phase 2, Fox Chase Cancer Center (recruiting) Dose-dense MVAC Efficacy Phase 2, NCI (active) GC plus bevacizumab Efficacy/toxicity MSKCC = Memorial Sloan-Kettering Cancer Centre; GC = gemcitabine-cisplatin; MVAC = methotrexate, vinblastine, adriamycin, and cisplatin; NCI = National Cancer Institute. histologic response situations. Global survival varied in these series from 48% to 63% at 5 yr. The proportion of bladders left in place at 5 yr is >40% [7,13,14]. Neoadjuvant chemotherapy could also be used in combination with a high-quality transurethral bladder resection to preserve the bladders of patients showing complete histologic responses [15]. A national Ministry of Health research project is underway in France (N. Mottet) to evaluate the rate of bladder preservation at 5 yr. The protocol neoadjuvant chemotherapy is dose-dense MVAC Principal results in the adjuvant setting Scientific results of phase 3 studies are without a doubt in favour of neoadjuvant chemotherapy versus adjuvant chemotherapy. All clinical trials in adjuvant therapy have had major methodological problems and have been limited by low accrual and experimental groups using inappropriate chemotherapy (Table 2). A 2005 meta-analysis based on individual data from 491 patients included in six trials found a 25% reduction in the risk of death for an absolute gain of 9% at 3 yr [16]. However, the small number of patients included clearly limits the usefulness of these analyses, and the statistical power was insufficient to provide a recommendation with an adequate level of statistical certainty. It was concluded that only a trial recruiting >1000 patients would have the necessary power to demonstrate the benefits of adjuvant chemotherapy. This was the subject of the EORTC trial, an international trial comparing immediate or delayed until Table 2 List of randomised trials published comparing adjuvant chemotherapy and a control group Author Year Protocol CT, n No CT, n Logothetis 1988 CISCA Skinner 1991 CAP Stoeckle 1992 MVAC/MVEC Studer 1994 CDDP Bono 1995 CM Freiha 1996 CMV Otto 2001 MVEC CISCA = cisplatin, cyclophosphamide, and adriamycin; CAP = cyclophosphamide, adriamycin, and cisplatin; MVAC/MVEC = methotrexate, vinblastine, adriamycin, and cisplatin/methotrexate, vinblastine, epirubicin, and cisplatin; CDDP = cisplatin; CM = cisplatin and methotrexate; CMV = cisplatin, methotrexate, and vinblastine; CT = chemotherapy. appearance of metastases the administration of a MVACtype chemotherapy, dose-dense MVAC, or gemcitabine and cisplatin (GC). It was planned to include 1350 patients to demonstrate a survival gain of 7% at 5 yr in favour of adjuvant chemotherapy with 80% statistical power. The trial was closed prematurely due to low accrual. The results of two other trials that were not completed have also been reported recently. The Italian phase 3 study comparing immediate with delayed delivery of adjuvant chemotherapy by GC was closed early due to low accrual. At ASCO 2008, Cognetti reported the results of this study, which aimed to include 610 patients to detect a 10% reduction in global survival at 5 yr (25% reduction in HR) [17]. In total, 194 patients were randomised. With a median follow-up of 27 mo, no differences in terms of recurrencefree survival ( p = 0.58) or global survival ( p = 0.10) were observed. The Spanish GEICAM study evaluated the benefits of four cycles of the paclitaxel, gemcitabine, and cisplatin (PGC) combination (paclitaxel l80 mg/m 2 days 1 and 8 plus gemcitabine 1000 mg/m 2 days 1 and 8 plus cisplatin 70 mg/m 2 day 1, every 21 d) compared with observation in a population of patients at high risk of recurrence (pt3 4 and/or N+), performance status (PS) of 0 1 with creatinine clearance >50 ml/min [18]. The main objective was a 15% improvement in global survival (from 50% to 65%), requiring 340 patients. The study opened in July 2000 and was closed prematurely in July 2007 due to low accrual. Data from the 142 patients randomised with a median follow-up of 30 mo show a significant improvement in survival (45 of 74 patients died in the observation group vs 24 of 68 in the PGC group) with a median not reached on one side (61% of survivors at 5 yr) and 26 mo for the control group (31% of survivors at 5 yr; HR: 0.44; p < ). Time to progression and specific survival were also greater in the PGC group (HR: 0.38; p < ; and HR: 0.37; p < , respectively). The early closure of this trial and the small number of patients included must nevertheless be kept in mind when interpreting these positive results. A future meta-analysis of adjuvant trials incorporating this study as well as those of Cognetti et al and the EORTC is under way How to select patients for neoadjuvant chemotherapy The beneficial effects found in the meta-analysis do not identify a specific subgroup of patients based on age,

4 e23 gender, clinical staging T or N, or PS as benefitting more from treatment. Nevertheless, this meta-analysis demonstrated a small but certain advantage for cisplatin-based combination chemotherapy but not for platinum monotherapy for a selected patient population corresponding to the inclusion criteria of these trials, that is, having a T2 T4a N0 tumour, in good general health (PS 0 1), with good renal function (creatinine clearance >50 ml/min), and age < 70 yr. These criteria cover approximately 50% of our patients How to select patients for adjuvant chemotherapy Due to a high curability rate of pt2n0 patients by surgery alone, with an expected absolute gain in global survival around 5%, and chemotherapy morbidity (in particular for the MVAC protocol), most American and European groups limit chemotherapy indications to stages pt3 and for N+ tumours [19] N+ patients The extremely poor prognosis provides good justification for adjuvant chemotherapy [20]. Extension into perivesical fat also enables the identification of pt3 patients that may benefit from adjuvant chemotherapy. In the absence of lymph node invasion, macroscopic extension into the perivesical fat (pt3b) is associated with poor a prognosis compared with pt3a patients. Tilki et al [21] reviewed 2605 patients treated by radical cystectomy without chemotherapy or preoperative radiotherapy in six international centres. Eight hundred and eight tumours (31%) were pt3: 310 pt3a (38.4%), 498 pt3b (61.6%), and 352 (43.6%) N+. With a median follow-up of 45 mo, the recurrence-free survival rates at 5 yr for pt3a and pt3b (43.8% and 41.4%) and the specific survival rates at 5 yr (48.6% and 46.8%, respectively) were identical in the two groups. For N patients, a pt3b stage was associated with a higher recurrence rate at 5 yr (60.7% vs 47.9%; p = 0.020) and a lower specific survival rate (64.4% vs 55%; p = 0.048) What type of chemotherapy? Studies undertaken over the years with different chemotherapy combinations (MVAC, methotrexate, vinblastine, epirubicin, and cisplatin [MVEC], CMV, cisplatin-methotrexate [CM], GC, etc) have demonstrated the feasibility of perioperative chemotherapy. In 2006, Flechon et al [22] published the results of a Groupe d Etude des Tumeurs Uro-Génitales trial with a combination of four cycles of gemcitabine (1250 mg/m 2 days 1 and 8) and cisplatin (70 mg/m 2 day 1) every 21 d, indicating good dose intensity compliance (96% for cisplatin and 88% for gemcitabine) with acceptable toxicity and with no toxicity-related deaths. The cooperative Hellenic Cooperative Oncology Group [23] reported results after four cycles of paclitaxel (175 mg/ m 2 ) and carboplatin (area under the curve: 5) for 92 patients with tumours with extravesical extension pt3b (95%) or N+ (40%). Tolerance was acceptable with grade 3/4 neutropaenia and febrile neutropaenia rates of 19% and 7%, respectively. Sixty-two percent received the total planned dose. Global, specific, and recurrence-free survival rates at 5 yr appear low at 28.9% (95% CI, ], 36.6% (95% CI, ), and 29% (95% CI, ), respectively. However, no formal conclusions can be drawn from this study, and this combination is not indicated in practice. A German randomised study [24] compared two methods of chemotherapy in the adjuvant setting. This multicentre phase 3 study (AUO-AB 05/95) randomised 327 patients into three cycles of CM (cisplatin: 70 mg/m 2 ; methotrexate: 40 mg/m 2 days 8 and 15) every 21 d and three cycles of MVEC (methotrexate: 30 mg/m 2 days 1, 15, and 22; vinblastine: 3 mg/m 2 days 2, 15, and 22; epirubicin: 45 mg/m 2 day 2; cisplatin: 70 mg/m 2 day 2) every 28 d. The progression-free, specific, and global survivals for CM versus MVEC were, respectively, 43.3% 4.6% versus 48.8% 4.5%, 52% 4.6% versus 52.3% 4.8%, and 46.1% 4.3% versus 45.1% 4.6%. It was concluded that the CM protocol could not be considered inferior to the MVEC protocol Adjuvant or neoadjuvant? Only one study has compared different perioperative chemotherapies. A randomised MD Anderson trial [25] compared outcomes after cystectomy plus adjuvant MVAC with pre- and postoperative MVAC. One hundred and forty T3 or T4 patients were included (70 patients: five cycles MVAC plus cystectomy and clearance; 70 patients: either two neoadjuvant cycles plus three adjuvant or five adjuvant cycles). No differences were found between the groups. In intention-to-treat analyses, 81 patients (58%) were in remission with a median follow-up of 6.8 yr. Again, the study design and small number of inclusions prevent us from concluding the equivalence of outcomes after neoadjuvant or adjuvant treatment. 4. Conclusions In this age that requires scientific proof to validate treatment choices, neoadjuvant chemotherapy followed by a cystoprostatectomy with extended lymph node clearance should be considered the standard for the treatment of muscleinvasive operable bladder tumours [26] for patients in good general health with sufficient renal function to allow them to receive a cisplatin-based first chemotherapy without compromising the cystectomy. The meta-analysis of randomised trials shows clearly a long-term survival benefit as early as the T2 clinical stage and increasing for the T3b stage. In the European Association of Urology recommendations, updated in 2009 [27], an adjuvant chemotherapy is recommended only as part of a therapeutic trial. Despite the results of randomised trials and expert recommendations regarding neoadjuvant chemotherapy, the data from the American National Cancer Data Base [28] show that only 11.6% of patients receive perioperative chemotherapy and that it is most often adjuvant (10.4% vs 1.2% neoadjuvant). These data reflecting current practices

5 e24 highlight the vast and incomprehensible gap between recommendations and practice. They illustrate the efforts that still need to be made with only a small proportion of patients being referred initially to an oncologist. The generalisation of multidisciplinary meetings should assist in establishing improved indications. A certain number of questions remain unanswered. One, the choice of the reference chemotherapy: Only the MVAC and CMV protocols have been evaluated in a neoadjuvant setting. The GC is a less toxic protocol with a retrospective analysis demonstrating histologic response rates similar to those published with MVAC. However, its efficacy remains to be evaluated in a prospective trial. Two, which tumours? Translational genomic and proteomic research with these tumours aiming to predict treatment response offers promising results [29]. Agroup of 14 genes could separate patients into two groups as responders or nonresponders to neoadjuvant MVAC. This profile was demonstrated in a sample of 27 patients with positive predication of 93% for the responders and 100% for the nonresponders, and it was validated in a second group of 22 patients [30]. BRCA1 also appears implicated in theresponsetochemotherapy[31]. Inananalysisof57 patients, the median survival of 39 patients expressing BRC1 weakly or moderately was 168 mo with a chemotherapy response rate of 66%, whereas the 18 patients expressing BRC1 strongly had a median survival of 34 mo and a chemotherapy response rate of 22% with no clinical characteristics influencing survival. These different results led to the idea that in a few years a fully selective treatment could be offered to patients based on their genomic profile [32]. Conflicts of interest The authors have nothing to disclose. Funding support None. Acknowledgements The authors thank Pippa McKelvie for English medical editorial assistance. References [1] Teramukai S, Nishiyama H, Matsui Y, Ogawa O, Fukushima M. 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