The purpose of the present study was to examine retrospectively the contribution of 18Fluorodeoxyglucose positron emission tomography computed tomography (18FDG-PET/CT) to the evaluation of response to first-line gemcitabine plus cisplatin-based chemotherapy in patients with metastatic bladder cancer.

To evaluate the response to Gemcitabine plus Cisplatin -based chemotherapy using 18FDG-PET/CT imaging in patients with metastatic bladder cancer.

Between July 2007 and April 2019, 79 patients underwent 18FDG-PET/CT imaging with the diagnosis of Metastatic Bladder Carcinoma (M-BCa). A total of 42 patients (38 male, 4 female) were included in the study, and all had been administered Gemcitabine plus Cisplatin-based chemotherapy. After completion of the therapy, the patients underwent a repeat 18FDG-PET/CT scan and the results were compared with the PET/CT findings before chemotherapy according to European Organisation for the Research and treatment of cancer criteria. Mean age was 66.1 years and standard deviation was 10.7 years (range: 41-84 years).

Of the patients, seven (16.6%) were in complete remission, 17 (40.5%) were in partial remission, six (14.3%) had a stable disease, and 12 (28.6%) had a progressive disease. The overall response rate was 57.1 percent.

18FDG-PET/CT can be considered as a successful imaging tool in evaluating response to first-line chemotherapy for metastatic bladder cancer. Anatomical and functional data obtained from PET/CT scans may be useful in the planning of secondline and thirdline chemotherapy.

Upper tract urothelial carcinoma (UTUC) accounts for 5% of urothelial carcinomas (UCs), the estimated annual incidence being 1-2 cases per 100,000 inhabitants. Similarly to bladder UC, divergent differentiations and histologic variants confer an adverse risk factor in comparison with pure UTUC. Molecular and genomic characterization studies on UTUC have shown changes occurring at differing frequencies from bladder cancer, with unique molecular and clinical subtypes, potentially with different responses to treatment. Systemic chemotherapy is the standard approach for patients with inoperable locally advanced or metastatic UCs. Although initial response rates are high, the median survival with combination chemotherapy is about 15 months. In first-line chemotherapy several cisplatin-based regimens have been proposed. For patients with advanced UC who progress to first-line treatment, the only product licensed in Europe is vinflunine, a third-generation, semisynthetic, vinca alkaloid. Better response rates (15-60%), with higher toxicity rates and no overall survival (OS) benefit, are generally achieved in multidrug combinations, which often include taxanes and gemcitabine. The US FDA has recently approved five agents targeting the programmed death-1 and programmed death ligand-1 pathway as a second-line therapy in patients with locally advanced or metastatic UC with disease progression during or following platinum-containing chemotherapy. Potential therapeutic targets are present in 69% of tumours analyzed. Specific molecular alterations include those involved in the RTK/Ras/PI(3)K, cell-cycle regulation and chromatin-remodeling pathways, many of them have either targeted therapies approved or under investigation. Angiogenic agents, anti-epidermal growth factor receptor therapy, phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathway inhibitors and immunotherapeutic drugs are being successfully investigated.

The combination of gemcitabine plus cisplatin (GC) is a standard regimen in patients with locally advanced or metastatic urothelial cancer. A phase I/II study suggested that a three-drug regimen that included paclitaxel had greater antitumor activity and might improve survival.

We conducted a randomized phase III study to compare paclitaxel/cisplatin/gemcitabine (PCG) with GC in patients with locally advanced or metastatic urothelial carcinoma. Primary outcome was overall survival (OS). Secondary outcomes were progression-free survival (PFS), overall response rate, and toxicity.

From 2001 to 2004, 626 patients were randomly assigned; 312 patients were assigned to PCG, and 314 patients were assigned to GC. After a median follow-up of 4.6 years, the median OS was 15.8 months on PCG versus 12.7 months on GC (hazard ratio [HR], 0.85; P = .075). OS in the subgroup of all eligible patients was significantly longer on PCG (3.2 months; HR, 0.82; P = .03), as was the case in patients with bladder primary tumors. PFS was not significantly longer on PCG (HR, 0.87; P = .11). Overall response rate was 55.5% on PCG and 43.6% on GC (P = .0031). Both treatments were well tolerated, with more thrombocytopenia and bleeding on GC than PCG (11.4% v 6.8%, respectively; P = .05) and more febrile neutropenia on PCG than GC (13.2% v 4.3%, respectively; P < .001).

The addition of paclitaxel to GC provides a higher response rate and a 3.1-month survival benefit that did not reach statistical significance. Novel approaches will be required to obtain major improvements in survival of incurable urothelial cancer.

Urothelial cancer is among the most chemotherapy-sensitive neoplasms of all the solid tumors. However, for the majority of patients with advanced disease, response durations with conventional treatment are relatively short. Second-line systemic treatment regimens are associated with modest response rates and poor outcomes. Trials in both the first- and second-line settings have demonstrated that a ceiling in efficacy has likely been reached with cytotoxic drugs, particularly in unselected patient populations. Promising areas of investigation include integrating predictive biomarkers to optimize patient selection for specific therapies, disrupting driving oncogenomic mutations, and associated signaling pathways and cotargeting both tumor and the immune system or tumor stroma. In addition, expanded sources of evidence generation are of interest in an effort to refine treatment for the general population of patients with advanced urothelial cancer, not only those who meet the narrow eligibility criteria used in most clinical trials.

Urothelial carcinoma is one of the leading causes of death in Europe and the United States. Despite its chemosensitivity, median overall survival for advanced disease is still nearly 1 year. Most second-line chemotherapeutic agents tested have been disappointing. Thus, new treatment strategies are clearly needed. This review focuses on emerging therapies in urothelial carcinoma. Results from recent clinical trials, investigating the activity of new generation cytostatic agents, as well as results from studies assessing the toxicity and efficacy of novel targeted therapies, are discussed. In this setting, anti-epidermal growth factor receptor, angiogenesis, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors account for the majority of phase I and II trials.

The purpose of this article is to provide updated recommendations for the diagnosis and treatment of muscle- invasive and metastatic bladder cancer. The diagnosis of muscle-invasive bladder cancer is made by transurethral resection and following histopathologic evaluation. Invasive bladder cancer should be staged according to the UICC system. Patients with confirmed muscle-invasive bladder cancer should be staged by computed tomography scans of the chest, abdomen and pelvis. Radical cystectomy is the treatment of choice for both sexes and lymph node dissection should be an integral part of cystectomy. In muscle- invasive bladder cancer (cT2-4aN0M0) patients with good performance status (PS 0-1) and correct renal function, neoadjuvant chemotherapy should be recommended. Adjuvant chemotherapy is widely used in high-risk patients with pathologic stage T3 or T4 and/or positive nodes and within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well informed and compliant patients for whom cystectomy is not considered for clinical or personal reasons. In metastatic disease, the first-line treatment for patients is cisplatin-containing combination chemotherapy. Recently, vinflunine has been approved in Europe for second-line treatment and is an option for second-line therapy in patients progressing to first-line platinum-based chemotherapy.

Urothelial cell carcinoma of the upper urinary tract (UUT-UCC) is a rare, aggressive urologic cancer with a propensity for multifocality, local recurrence, and metastasis. This review highlights the main chemotherapy regimens available for UUT-UCCs based on the recent literature.

Data on urothelial malignancies and UUT-UCCs management in the literature were searched using MEDLINE and by matching the following key words: urinary tract cancer; urothelial carcinomas; upper urinary tract; carcinoma; transitional cell; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; neoadjuvant treatment; recurrence; risk factors; and survival.

No evidence level 1 information from prospective randomized trials was available. Because of its many similarities with bladder urothelial carcinomas, chemotherapy with a cisplatin-containing regimen is often proposed in patients with metastatic or locally advanced disease. Most teams have proposed a neoadjuvant or an adjuvant treatment based either on the combination of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) or on gemcitabine/cisplatin (GC). These regimens have been shown to prolong survival moderately. All recent studies have included limited numbers of patients and have reported poor patient outcomes after both neoadjuvant and adjuvant chemotherapy. Regarding metastatic UUT-UCCs, vinflunine has demonstrated moderate activity in these patients with a manageable toxicity. Interestingly, specific molecular markers [microsatellite instability (MSI), E-cadherin, HIF-1α, and RNA levels of the telomerase gene] can provide useful information that can help diagnose and determine patient prognosis in patients with UUT-UCC.

Chemotherapy with a cisplatin-containing regimen is often proposed in patients with metastatic or locally advanced disease. However, there is no strong evidence that chemotherapy is effective due to the rarity of the disease and the lack of data in the current literature. Thus, physicians must take into account the specific clinical characteristics of each individual patient with regard to renal function, medical comorbidities, tumor location, grade, and stage, and molecular marker status when determining the optimal treatment regimen for their patients. The ongoing identification of the oncologic mechanisms of this type of cancer might pave the way for the development of specific treatments that are targeted to the characteristics of each patient's tumor in the future.

Advanced bladder cancer is a disease with a high recurrence rate and metastatic capacity exhibiting a poor outcome. The pathologic stage and nodal involvement are independent prognostic factors for survival after cystectomy, and in locally advanced or metastatic disease, the performance status and the presence of visceral metastases have been correlated with treatment outcome. The regimen methotrexate-vinblastine-adriamycin-cisplatin (MVAC) has been the treatment of choice for decades and later the combination of cisplatin with gemcitabine became also the new standard of care, by demonstrating a more favorable toxicity profile. Also, carboplatin-gemcitabine and taxanes have been useful alternatives for patients unfit for cisplatin-based treatment. Additionally, the evaluation of certain chemotherapeutic agents has produced promising results in the second-line setting. Lastly, the past decade has provided information on the molecular mechanism of bladder cancer offering a personalized approach and optimizing the management of the disease.

In Japan, until now, the treatment of bladder cancer has been based on guidelines from overseas. The problem with this practice is that the options recommended in overseas guidelines are not necessarily suitable for Japanese clinical practice. A relatively large number of clinical trials have been conducted in Japan in the field of bladder cancer, and the Japanese Urological Association (JUA) considered it appropriate to formulate their own guidelines. These Guidelines present an overview of bladder cancer at each clinical stage, followed by clinical questions that address problems frequently faced in everyday clinical practice. In this English translation of a shortened version of the original Guidelines, we have abridged each overview, summarized each clinical question and its answer, and only included the references we considered of particular importance.

Advanced urothelial cancer remains a very serious disease. The mainstray of patients' care is systemic chemotherapy. In the last three decades, most of the progress resulted in limiting the toxicity of treatments either by using granulocytic growth factors or by using drug combinations which proved to be less toxic than that described previously. However, very little changed in terms of efficacy, median overall survival remaining in the range of 14 months. One step forward consisted in definishing subgroups of patients, according to prognostic factors. This takes a particular importance at a time when a new drug, vinflunine succeeded in showing a survival advantage as a second line chemotherapy versus best supportive care alone in these patients. Further improvement is expected from a better knowledge of tumor biology, which may allow targeted therapies to be beneficial for these patients.

There is no standard treatment for patients with advanced urothelial cancer who are ineligible ("unfit") for cisplatin-based chemotherapy (CHT). To compare the activity and safety of two CHT combinations in this patient group, a randomized phase II/III trial was conducted by the EORTC (European Organisation for Research and Treatment of Cancer). We report here the phase II results of the study.

CHT-naïve patients with measurable disease and impaired renal function (30 mL/min < glomerular filtration rate [GFR] < 60 mL/min) and/or performance status (PS) 2 were randomly assigned to receive either GC (gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin area under the serum concentration-time curve [AUC] 4.5) for 21 days or M-CAVI (methotrexate 30 mg/m(2) on days 1, 15, and 22; carboplatin AUC 4.5 on day 1; and vinblastine 3 mg/m(2) on days 1, 15, and 22) for 28 days. End points of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups.

Three of 178 patients who were ineligible or did not start treatment were excluded. SAT was reported in 13.6% of patients on GC and in 23% on M-CAVI. Overall response rates were 42% (37 of 88) for GC and 30% (26 of 87) for M-CAVI. Patients with PS 2 and GFR less than 60 mL/min and patients in Bajorin risk group 2 showed a response rate of only 26% and 20% and an SAT rate of 26% and 25%, respectively.

Both combinations are active in this group of unfit patients. However, patients with PS 2 and GFR less than 60 mL/min do not benefit from combination CHT. Alternative treatment modalities should be sought in this subgroup of poor-risk patients.

Sequential chemotherapy with doxorubicin and gemcitabine (AG) followed by ifosfamide, paclitaxel, and cisplatin (ITP) was previously demonstrated to be well tolerated in patients with advanced transitional cell carcinoma (TCC). This study sought to evaluate the efficacy and to additionally define toxicity.

Sixty patients with advanced TCC received AG every 2 weeks for five or six cycles followed by ITP every 21 days for four cycles. Granulocyte colony-stimulating factor was given between cycles.

Myelosuppression was seen with 68% of patients who experienced grades 3 to 4 neutropenia and with 25% who experienced febrile neutropenia. Grade 3 or greater nonhematologic toxicities were infrequent. Forty (73%) of 55 evaluable patients (95% CI, 59% to 84%) demonstrated a major response (complete, n = 19; partial, n = 21) and had a median response duration of 11.3 months (range, 1.7 to >or= 105.6 months). Twenty-seven (79%) of 34 patients with locally advanced disease (ie, T4, N0, M0) or with regional lymph node involvement (ie, T3-4, N1, M0) and 10 (56%) of 18 patients with distant metastases achieved a major response. The median progression-free survival was 12.1 months (95% CI, 9.0 to 14.8 months), and the median overall survival was 16.4 months (95% CI, 14.0 to 22.5 months). At a median follow-up of 76.4 months, seven (11.7%) patients remain alive, and all were disease free.

AG plus ITP is an active regimen in previously untreated patients with advanced TCC; however, it is associated with toxicity and does not clearly offer a benefit compared with other nonsequential, cisplatin-based regimens.

Conventional front-line platinum-based combination chemotherapy yields high response rates but suboptimal long-term outcomes for advanced transitional cell carcinoma. Salvage therapy is an unmet need with disappointing outcomes. The emergence of novel biologic agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biologic agents are reviewed.

This review summarizes the results of first-line and second-line systemic chemotherapy for advanced urothelial carcinoma as well as data from adjuvant and neoadjuvant trials for locally advanced bladder cancer. Whereas conventional systemic chemotherapy prevailed for over two decades, targeted therapeutics have been introduced to treat urothelial cancer during recent years. As in other tumor entities, molecular profiling will presumably emerge in the future as a means to tailor individual therapy.

Conventional first-line platinum-based combination chemotherapy with gemcitabine/cisplatin and standard or dose-dense methotrexate, vinblastine, doxorubicin and cisplatin yields high response rates but suboptimal long-term outcomes for advanced urothelial cancer. Salvage therapy is an unmet need, with disappointing outcomes. The emergence of novel biological agents offers the promise of improved outcomes. Neoadjuvant therapy preceding cystectomy for muscle-invasive bladder cancer provides an important paradigm and an interesting approach in developing novel agents. Patients who are not candidates for cisplatin require special attention. A multidisciplinary approach and collaboration among laboratory scientists, oncologists, urologists and radiation oncologists is necessary to make therapeutic advances. Recent and ongoing trials of novel chemotherapeutic and biological agents are reviewed.