Methotrexate, Vinblastine, Adriamycin And Cisplatin Research Articles

Abstract 4558: A triterpenoid derivative has strong antitumor activities in gemcitabine-resistant advanced bladder cancer models and promotes immune cell infiltration in a high grade murine syngeneic model

Abstract Bladder cancer (BC) presents a formidable challenge in treatment and patient survival, requiring particular attention to advanced stages, such as muscle-invasive stage (MIBC), due to its potential for rapid progression and substantial impact on patient morbidity and mortality. The five-year survival rate for MIBC is a meager 30%, which drops further down to 8% once tumors metastasize. Advanced bladder cancers (High grade T1) are treated with intravesical therapy with Gemcitabine and Cisplatin (G+C) combination and Stage T2 are treated neoadjuvant with G+C and cystectomy, thereby decreasing the quality of life for patients with BC. Furthermore, tumors progress beyond responding to other chemotherapy regimens such as dose-dense treatment with Methotrexate +Vinblastine + Adriamycin and Cis-platin (MVAC), all of which will further decrease the quality of life with persistent adverse toxicity. Our laboratory has developed a novel compound derived from the pentacyclic triterpenoid, Ursolic acid, termed N-methyl piperazine conjugated-Ursolic acid, or UA4, and have demonstrated its antitumor activities against both Gem-Sensitive (Gem-S) and Gem-Resistant (Gem-R) human advanced BC cell lines, T24 and 5637. We tested the combination of Gem, UA4 and Gem + UA4 in a murine non-MIBC model (MB49) to investigate the role of immune cell infiltration during tumor development and treatment response. UA4 treatment was equally effective in chemo-sensitive and chemo-resistant cell lines at dosages between 4-5µM. Previous in vitro mechanistic studies on UA4 and UA4+Gem combination treatments revealed cell death occurred through apoptosis and autophagy, along with a highly selective form of mitochondrial-mediated autophagy (mitophagy). These findings were confirmed with transmission electron microscopy ultrastructural analysis, cell cycle phase analyses, excess, changes in mitochondrial membrane potential and reactive oxygen species measurements. Gem-S and Gem-R xenografts in athymic mice further supported UA4’s efficacy in vivo, demonstrating a significant reduction in both tumor weight and volume following oral gavage (100mg/kg), with mice exhibiting no signs of systemic toxicity. Combination treatment with UA4 and Gem synergistically increased antiproliferative activity. MB49 syngeneic mice model further supported UA4 as an effective therapy, and immunofluorescence assays with immune-related markers, suggested an anti-inflammatory effect in vivo. Overall, we demonstrate UA4 has a potential to be used as an efficacious, non-toxic compound for further adjuvant use in clinical settings. Citation Format: Juliette Rose Seremak, Kunj Bihari Gupta, Siva S. Panda, Bal L. Lokeshwar. A triterpenoid derivative has strong antitumor activities in gemcitabine-resistant advanced bladder cancer models and promotes immune cell infiltration in a high grade murine syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4558.

The Impact of an Enrolment in Clinical Trial on Tolerance and Pathological Response for Patients Treated by Neoadjuvant MVAC Against an Invasive Bladder Cancer. A Retrospective Comparative Study

IntroductionMVAC (Methotrexate, Vinblastine, Adriamycin, and Cisplatin) neoadjuvant chemotherapy a standard treatment for invasive bladder cancer is associated with mainly haematological toxicities. Randomized clinical trials remain a gold standard for treatment outcomes and efficacy assessment. Patients enrolled in clinical trials are selected and tend to benefit from a stricter follow-up unlike everyday clinical practice patients. Conversely, real-life observational studies better define the effectiveness of treatments in clinical routine practice. The aim of this study is to analyse the impact of clinical trial monitoring on MVAC-related toxicities. Material and MethodsPatients with an infiltrative localized bladder cancer treated by MVAC neoadjuvant chemotherapy between 2013 and 2019 were enrolled, and divided into 2 groups: patients included in a clinical trial namely “VESPER study” during their treatment and patients treated in clinical routine practice. ResultsOut of 59 patients were enrolled in this retrospective study, 13 patients were included in a clinical trial. Clinical characteristics were similar between the 2 groups. Comorbidities were more frequent in the nonclinical trial group (NCTG). Completed 6 cures treatment proportion was higher in the clinical trial group (CTG) (69.2% vs. 50%). Yet, in this group, patients had more doses reduction (38.5% vs. 19.6%). The proportion of complete pathologic response was higher in patients enrolled in clinical trial (53.8% vs. 39.1%). Statistically, the expected stricter monitoring due to clinical trial enrolment had no impact on the complete pathologic response and clinically relevant toxicities. DiscussionWhen compared to conventional clinical practice, clinical trial enrolment induced no significant difference on the pathologic complete response or toxicity rate. Further large prospective studies are needed to confirm these data.

Defects in DNA repair genes and long-term survival in cisplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC).

4536 Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in MIBC, only a subset of patients have pathologic complete response (pT0) at cystectomy. ATM, RB1 and FANCC mutations have shown correlation with pT0 to cisplatin-based NAC, as previously published. We now report updated OS and disease specific survival (DSS) from two phase II trials using these gene alterations as biomarkers. Methods: Patients with stage T2-T4 (N0 or N1) MIBC were enrolled in phase II trials of dose-dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin; NCT01031420) or GC (gemcitabine and cisplatin; NCT01611662). Patients were treated with NAC with plan for curative cystectomy. DNA from pretreatment tumor tissue was sequenced for coding exons of 287 cancer-related genes and analyzed for mutations. Survival in patients with one or more mutations in ATM, RB1, or FANCC genes was compared to those without mutations. Results: Of 58 pts treated, 38% (22/58 pts) had relevant mutations in the combined group of MVAC (13/34 pts) and GC (9/24 pts) trials. At a median follow-up of 56 months and minimum follow up of 16 months, patients with mutations had statistically significantly greater OS (p = 0.0043) and DSS (p = 0.0015). Median OS/DSS was not reached for patients with a mutation in any group. At 5 years post treatment, OS/DSS were greater in mutated vs non-mutated patients in all groups (see table). Conclusions: Long-term follow up reveals that previously reported improved responses to cisplatin-based NAC associated with mutations in ATM, RB1 and FANCC also confer a clinically meaningful and statistically significant survival benefit in these patients. These alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients most likely to benefit from NAC prior to radical cystectomy. [Table: see text]

Neoadjuvant chemotherapy with gemcitabine and cisplatin for muscle-invasive bladder cancer: multicenter retrospective study.

The aim of this study was to evaluate the efficacy of neoadjuvant gemcitabine and cisplatin (GC) therapy for muscle-invasive bladder cancer (MIBC). We retrospectively evaluated patients who underwent neoadjuvant GC therapy followed by radical cystectomy from April 2009 through December 2015 in the Sapporo Medical University Urologic Consortium. The efficacy of neoadjuvant chemotherapy (NAC) was assessed based on the pathological T0 (pT0) rate in radical cystectomy specimens, and the recurrence-free survival, cause-specific survival and overall survival (OS) rates. To compare the oncological benefit of NC with GC to that of the methotrexate, vinblastine, adriamycin and cisplatin (MVAC) regimen, we also utilized historical clinical data of patients who were treated with MVAC as NAC followed by radical cystectomy in our institute from 1986 through 2010. Fifty-eight patients receiving neoadjuvant GC therapy and 74 receiving neoadjuvant MVAC were included. The pT0 achieving rates were comparable between the two groups (20.7% vs. 18.9%, P = 0.83). Neoadjuvant GC was associated with a better 2-year OS rate than neoadjuvant MVAC for clinical T2 disease (95.2% vs. 70.8%, P = 0.036). In contrast, in patients with clinical T3 or more advanced disease, neoadjuvant MVAC provided more pT0 (20.0% vs. 5.6%, P = 0.07) and better 2-year OS than neoadjuvant GC (71.1% vs. 55.0%, P = 0.142), although the difference did not reach statistical significance. Neoadjuvant GC had no inferiority in oncological outcomes to MVAC for MIBC.

Abstract SY36-01: Optimizing neoadjuvant therapy prior to surgery: Biomarker and target discovery

Abstract SY36-01: Optimizing neoadjuvant therapy prior to surgery: Biomarker and target discovery

Co-administration of dexamethasone increases severity and accelerates onset day of neutropenia in bladder cancer patients on methotrexate, vinblastine, adriamycin and cisplatin chemotherapy: a retrospective cohort study

BackgroundBladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia.MethodsThis was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (−)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia.ResultsEpisodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (−), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 ± 1.0) was significantly accelerated compared to the Dex (−) group (17.7 ± 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3–223.1).ConclusionsCo-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy.

Palliative Chemotherapy for Bladder Cancer: Treatment Delivery and Outcomes in the General Population.

Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines because of the results achieved in clinical trials. However, real-world treatment and outcomes have not been well described. We report the treatment delivery and survival associated with palliative chemotherapy in routine clinical practice. The population-based Ontario Cancer Registry was linked to electronic records of treatment to identify all patients with bladder cancer treated with palliative chemotherapy in Ontario during 1994 to 2008. Treatment regimens were identified for those cases treated at regional cancer centers. Overall survival (OS) and cancer-specific survival (CSS) were determined from the start of palliative chemotherapy. A Cox proportional hazards model was used to identify the factors associated with OS and CSS. The palliative chemotherapy regimen was identified for 710 patients with bladder cancer in Ontario during 1994 to 2008. Gemcitabine-cisplatin (Gem-Cis) was delivered to 37% (261 of 710), gemcitabine-carboplatin (Gem-Carbo) to 14% (96 of 710), and MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin) to 8% (56 of 710). Other regimens were delivered to 42% of cases. The proportion of cases treated with Gem-Cis increased during the study period: 3% in 1994 to 1999, 32% in 2000 to 2003, and 52% in 2004 to 2008 (P< .001). The median survival and 5-year OS by regimen was 10 months and 16% for Gem-Cis, 7 months and 6% for Gem-Carbo, and 10 months and 13% for MVAC, respectively. Multivariate analysis controlling for age and comorbidity demonstrated improved survival for Gem-Cis and MVAC compared with Gem-Carbo (hazard ratio, 1.53; 95% confidence interval, 1.19-1.98). The median survival associated with palliative chemotherapy for bladder cancer in routine practice is slightly inferior to the outcomes reported in clinical trials. However, consistent with the clinical trial results, a proportion of patients treated with palliative chemotherapy will achieve long-term survival. Gem-Carbo is associated with inferior survival compared with Gem-Cis and MVAC in routine practice.

Abstract 449: Targeted proteomic analysis for personalized treatment of muscle invasive bladder cancer

Abstract Background: Standard treatment for muscle-invasive bladder cancer (MIBC) includes chemotherapy with either gemcitabine-cisplatin (GC) or methotrexate, vinblastine, adriamycin and cisplatin (MVAC). These regimens have similar clinical complete response rates of approximately 30%. While no targeted treatment has been approved for bladder cancer, clinical trials have identified biochemical markers that predict the chemoresponsiveness of MIBC tumors to specific chemotherapeutic agents. For example, patients with high hENT1 and low RRM1 expression responded better to GC-based chemotherapy than their counterparts, and HER2 overexpression predicted resistance to cisplatin-based therapy. To quantify targets that are known indicators of tumor behavior, we used targeted proteomic analysis to assess 30 different protein biomarkers in formalin-fixed paraffin-embedded (FFPE) MIBC tumor tissue. Methods: Twelve FFPE MIBC tissue blocks were obtained and a pathologist marked a minimum 8mm2 of tumor area from 1 or 2 slides. Following laser microdissection of the marked areas, proteins were extracted using the Liquid-Tissue® process and subjected to selected reaction monitoring mass spectrometry to quantify the amounts of 30 different targeted proteins in each patient sample. Results: Of the 12 patient samples, 7 (58%) expressed high levels of hENT1 and 11 (92%) expressed low levels of RRM1, indicating that gemcitabine-based therapy would be an appropriate choice. A single patient expressed high levels of RRM1, an indication for non-gemcitabine based therapy. All 12 patients expressed TUBB3, a marker of resistance to taxane (vinblastine) and 10 patients (83%) lacked expression of FR-alpha, a marker of sensitivity to methotrexate. The majority of patients expressed a marker of sensitivity to anthracycline (TOPO2A) and did not express a resistance biomarker for platinum therapy (ERCC1). Of 3 patients whose tumors expressed HER2, 2 had overexpression (&amp;gt;750 amol/ug) and would thus be eligible for HER2 basket trials. Further, multiplex-targeted proteomics discovered patients expressing FGFR1 (17%), cMET (33%), Axl (17%) and IDO1 (25%), which would make them eligible for clinical trials of targeted or immunotherapies. Conclusion: MIBC is heterogeneous and expresses a wide range of proteins. Yet, it continues to be treated with only 2 chemotherapeutic regimens. Multiplexed proteomics is currently being used in clinical practice to inform personalized patient care decisions with identification and the relative quantities of actionable proteins known to predict tumor behavior. Citation Format: Fabiola Cecchi, Sheeno Thyparambil, Adele Blackler, Todd Hembrough, Shahrooz Rabizadeh, Patrick Soon-Shiong, Henry Frierson, Daniel Theodorescu. Targeted proteomic analysis for personalized treatment of muscle invasive bladder cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 449.

Predicting the response of patients with advanced urothelial cancer to methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) after the failure of gemcitabine and platinum (GP).

BackgroundPlatinum-based systemic chemotherapy is the treatment of choice for patients with advanced urothelial carcinoma (UC). Although no chemotherapeutic regimen is established as a second-line therapy, recent studies reported that methotrexate, vinblastine, Adriamycin and cisplatin (MVAC) elicited a significant response in patients who failed gemcitabine and platinum (GP) chemotherapy. We investigated the clinical factors useful for predicting a favourable response to MVAC in UC patients who failed GP.MethodsForty-five patients with advanced UC who received second-line MVAC chemotherapy after failure with first-line GP chemotherapy were enrolled in this study. Univariate and multivariate analyses based on Cox’s regression were performed to identify independent prognostic factors for progression-free survival (PFS) after second-line MVAC chemotherapy.ResultsThe median follow-up period after the first MVAC administration was 10.0 months. The median PFS and overall survival (OS) were 6.5 months (95 % confidence interval [CI]: 5.1–7.9) and 14.5 months (95 % CI, 7.4–21.4), respectively. The overall response rate was 57.8 %. The response to first-line GP chemotherapy (hazard ratio [HR], 2.500; p = 0.012) and patient age (HR, 1.047; p = 0.033) were predictors of PFS after MVAC chemotherapy.ConclusionsThe response to first-line GP chemotherapy and age were independent predictors of PFS in patients who received second-line MVAC chemotherapy. This report is the first to describe independent predictors of PFS after MVAC chemotherapy.

Chimiothérapie néoadjuvante dans le cancer de vessie infiltrant le muscle : complications et conséquences sur la réalisation de la cystectomie

The fear of the deterioration of the patient's condition related to the toxicity of neoadjuvant chemotherapy is a barrier to its development. This multicenter retrospective study aims to present the secondary effects of neoadjuvant chemotherapy and its impact on the achievement of cystectomy. Patients with urothelial carcinoma classified cT2to cT4a N0M0were included. Chemotherapy with 6cycles of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) followed by a cysto-prostatectomy or anterior pelvectomy was scheduled. A total 32patients were included. Six cycles of neoadjuvant chemotherapy were performed in all 11patients. Shutdown causes were toxicity in 85% of cases. Cystectomy was performed in 86.6% of patients. Surgery was not performed in 6patients. The reasons were the alteration of the general condition in 2cases, 2patients had advanced cancers diagnosed intraoperatively, and 2refused surgery. Complications of grades 3and 4according to the classification of Clavien and Dindo had occurred respectively in 15.3% and 11.5%. This study reports results close to what is found in the literature on the effects of neoadjuvant chemotherapy on achieving cystectomy, but it has some limitations: the retrospective analysis of data on surgery and the lack of control group. In addition, the short follow-up does not yet allow to know the long-term oncological results. This study supports the fact that the toxicity of neoadjuvant chemotherapy does not seem to cause a significant risk of non-completion of cystectomy. 4.

Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up

Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and follow-up

Prerandomization factors and utilization of neoadjuvant chemotherapy in a clinical trial of extended versus standard pelvic lymphadenectomy at the time of radical cystectomy for bladder cancer.

295 Background: Despite level I evidence supporting the use of cisplatin-based NAC, this practice has not been widely adopted. We assessed contemporary utilization of NAC within the context of an ongoing prospective clinical trial (SWOG S-1011; NCT01224665) in order to identify clinical and/or demographic factors that are associated with receipt of NAC. Methods: S1011 tests the hypothesis that an extended pelvic lymphadenectomy (PLND) is associated with a 10-12% improvement in recurrence-free survival compared to a standard PLND among patients with clinical stage T2-4aN0-2M0 urothelial cell carcinoma of the bladder. Patients are registered prior to RC and are randomized intra-operatively to extended vs. standard PLND. Receipt of NAC, including type and duration are is a stratification factor and prospectively recorded at registration. We evaluated the association of pre-randomization factors, including age, gender, clinical stage, performance status, and institution with the receipt of NAC. Results: 243 patients have been registered as of 9/18/2013 and 229 randomized. Among randomized patients, 119 (52%) received NAC, including 97 (82%) treated with cisplatin-based NAC. The most common NAC regimens, Gem-Cis (gemcitabine-cisplatin) and MVAC (methotrexate, vinblastine, adriamycin, and cisplatin), were administered to 58 and 35 patients, respectively. 63% (40/64) of patients with cT3-4a disease received NAC vs. 48% (79/165) with cT2. There was no association of age, gender, race, ethnicity or PS with receipt of NAC. Among 8 institutions with at least 10 patients registered, the range of utilization of neoadjuvant chemotherapy received was 7% to 83%. Reason for not giving NAC is recorded at time of registration and a detailed analysis will be presented. Conclusions: Interim analysis of S1011, a prospective surgical trial, reveals the highest rate of integration of NAC with RC to date and reflects a considerable change in evidence based practice patterns. The institutional variation in utilization of NAC warrants further exploration of factors influencing delivery of care. Clinical trial information: NCT01224665.

Effects of neoadjuvant chemotherapy on the prognostic mortality risk of invasive transitional bladder cancer: a meta-analysis

To systematically assess the effects of neoadjuvant chemotherapy on the prognostic risk of invasive transitional bladder cancer. All known randomized controlled trials (RCTs) on neoadjuvant chemotherapy in the treatment of invasive transitional bladder cancer, published from the date of database building to September 2012, were retrieved from such databanks as Pubmed, CBMdisc, Embase and Cochrane. The data on 5-year survival rate of included studies were extracted for further heterogeneity exploration, subgroup analysis and statistical pooling with the RevMan 5.10 software. Fourteen subjects involving 2072 cases and 2086 controls were published from 1991 to 2012. The overall odds ratio of survival suggested a 21% relative reduction in mortality risk for neoadjuvant chemotherapy compared to that on control (OR = 0.79, 95%CI:0.70-0.90). In subgroup analysis according to different neoadjuvant chemotherapies, MCV (methotrexate, cisplatin and vinblastine) and MVAC (methotrexate, vinblastine, adriamycin and cisplatin) chemotherapies showed significant benefit to overall survival with 28% and 25% reduction in risk of death respectively (OR = 0.72,95%CI:0.60-0.86, OR = 0.75,95%CI:0.59-0.96) . However, no significant difference existed in effects between C (cisplatin) chemotherapy, CM (cisplatin and methotrexate) chemotherapy and CD (cisplatin and docetaxel) chemotherapy and controls. In subgroup analysis according to local treatment of cystectomy or radiotherapy after neoadjuvant chemotherapy, the patients with cystectomy showed significant benefits in overall survival with 25% reduction in risk of death (OR = 0.75, 95%CI:0.65-0.87). However, the patients with radiotherapy or radiotherapy plus cystectomy showed no significant benefits in overall survival. MCV and MVAC neoadjuvant chemotherapies improve survival among patients with bladder cancer. And neoadjuvant chemotherapy has better long-term survival after cystectomy.

Two cases of plasmacytoid variant of urothelial carcinoma of urinary bladder: systemic chemotherapy might be of benefit

We report two cases of the plasmacytoid variant of urothelial carcinoma of urinary bladder in which systemic chemotherapy was effective. In the first case, a 76-year-old man presented with dysphasia. Magnetic resonance imaging (MRI) and computed tomography revealed a brain tumor and a bladder tumor. Resection of the brain tumor and transurethral resection of the bladder tumor were performed. The pathological diagnosis was plasmacytoid variant of urothelial carcinoma of urinary bladder with brain metastasis (pT1N0M1). Three cycles of adjuvant MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) chemotherapy were performed. He has no evidence of recurrence 96 months after resection of brain metastasis. In the second case, a 76-year-old man presented with hematuria. MRI revealed a bladder tumor with abdominal wall invasion, and a transurethral biopsy was performed. The pathological diagnosis was plasmacytoid variant of urothelial carcinoma of urinary bladder (cT4bN0M0). After three cycles of neoadjuvant GC (gemcitabine and cisplatin) chemotherapy, MRI demonstrated a complete response. Radical cystectomy was performed, and the pathological diagnosis was pT0pN0. Although there was no evidence of recurrence 9 months after radical cystectomy, he died from other causes. Our two cases suggest that systemic chemotherapy might be effective for the plasmacytoid variant of urothelial carcinoma.

A phase I study of personalized peptide vaccination for advanced urothelial carcinoma patients who failed treatment with methotrexate, vinblastine, adriamycin and cisplatin

• To investigate the safety and immune responses of 12 consecutive weeks of once-weekly personalized peptide vaccine (PPV) administration in patients with advanced urothelial carcinoma (UC) for whom therapy with methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has failed. • A phase I trial was designed. Ten patients with MVAC-refractory advanced or metastatic UC were treated with weekly personalized peptide vaccine 12 times using positive peptides chosen from 14 and 16 peptides in patients with human leucocyte antigens A24 and A2, respectively. • Peptide-specific cytotoxic T lymphocyte precursor analysis by interferon-γ production and peptide-reactive immunoglobulin G (IgG) using an enzyme-linked immunosorbent assay was monitored during the treatment. • The peptide vaccination was safe and well tolerated with no major adverse effects. Increased cytotoxic T lymphocyte response and the anti-peptide IgG titre were revealed by the post-vaccination sera in eight patients. • Clinical responses were as follows: one complete response, one partial response, two stable disease and six progressive disease. • Median progression-free survival and overall survival were 3.0 and 8.9 months, respectively. In the four responders, median progression-free survival and overall survival were 21 and 24 months, respectively. • This phase I study showed the safety of and boosted immune responses in response to PPV for advanced UC. • The potential efficacy of 12 consecutive weekly vaccinations with PPV in patients with advanced UC merits further investigation based on these findings.

Respuesta a la quimioterapia adyuvante post-cistectomía en pacientes con tumor de vejiga infiltrante: Análisis de 397 casos

To define the usefulness of adjuvant chemo-therapy in patients with pT2, pN0, pT3-4, pN0 and pN+ disease. Retrospective analysis of 397 patients with transitional bladder cancer who underwent radical cys-tectomy between 1986 and 2005. Adjuvant chemo-therapy was administered to 40.2% of patients. Three cycles of adjuvant MVAC (methotrexate, vinblastine, adriamycin and cisplatin) were given. In patients with pT3, pN0 (p=0.04) and/or N+ stages (p=0.001), adjuvant chemotherapy significantly improved cancer-specific survival, which did not occur in pT2N0 (p=0.9) and pT4, pN0 (p=0.6) patients. In the univariate analysis, adjuvant chemotherapy was significantly associated with a lower cancer-specific survival rate (RR 1.452 95% CI: 1.028- 2.057 p= 0.03), while the multivariate analysis showed a trend (RR: 0.651 95% CI 0.398-1.065, p=0.08) towards a decrease in cancer-specific mortality. Although adjuvant chemotherapy was not shown to improve survival in patients with pT0-2, pN0 and pT4, pN0 disease, it did increase survival in those with extravesical disease, pathological state T3, pN0 and/or pN+. Considering its tendency to improve cancer-specific survival, adjuvant chemotherapy may be considered as a "protective factor" (RR=0.651, p=0.08).

Pleural Metastasis in a Patient With Bladder Cancer

A 49-year-old, heavy-smoker presented with macroscopic hematuria. Diagnostic work-up disclosed a bladder tumor. Transurethral resection of the bladder revealed a muscle-invasive bladder cancer. Initial work-up failed to demonstrate metastatic spread. The patient had a cystoprostatectomy with pelvic lymphadenectomy. The pathology (Figs 1 and 2) revealed a sarcomatoid variant of urothelial carcinoma with undifferentiated spindle cell neoplasm and chondrosarcomatous heterologous elements staged pT3pN0M0 according to the WHO Classification. The patient refused adjuvant treatment. Three months later, he developed left pleural effusion. Chest x-rays showed thickened pleura with pleural effusion (Fig 3). The patient underwent symptomatic pleurodesis. Pleural biopsy showed the same histological pattern as for initial tumor. Chest computed tomography examination after pleurodesis revealed thickening of the pleura associated with heterologous calcifications and multiple lung metastases (Fig 4). The patient had evidence of disease progression after two cycles of MVAC (methotrexate, vinblastine, adriamycin and cisplatin) regimen. Second-line treatment with gemcitabine and cisplatin resulted in disease stabilization for 4 months. The thickening of the pleura increased on chest computed tomography (Fig 5). The patient died 12 months after initial diagnosis. This report describes an unusual metastasis to the pleura in a patient with urothelial cancer. Only a few cases have been reported in the literature. Moreover, the radiological presentation of the secondary tumor, with heterologous calcifications due to the chondrosarcomatous component, is unusual. The radiological differential diagnoses are sarcomatous tumor, calcifications due to pleurodesis, or pleural mesothelioma, which is rare. Sarcomatoid carcinoma of the urinary bladder represents only 0.3% of all histological types. The sarcomatoid variant of urothelial carcinoma corresponds to all biphasic malignant neoplasms exhibiting morphologic and/or immunohistochemical evidence of epithelial and mesenchymal differentiation (with presence or absence of heterologous elements acknowledged at diagnosis). This tumor variant is highly aggressive and has a poor prognosis. Nodal and distant organ metastases at diagnosis are common, and 70% of patients die of cancer at 1 to 48 months (mean, 17 months). The outcome of our patient was fatal within 12 months of diagnosis.

Systemic chemotherapy options for metastatic bladder cancer

Systemic chemotherapy has reached a therapeutic plateau in the treatment of transitional cell carcinomas of the urothelium. Since the advent of the combination of methotrexate, vinblastine, adriamycin and cisplatin (MVAC) in the 1980s, no chemotherapy regimen has been proven to be superior to this therapy. Only one regimen, a combination of gemcitabine and cisplatin, has been equivalent. With a similar response rate and survival, plus the benefit of an improved toxicity profile, the gemcitabine cisplatin combination has largely supplanted MVAC in physician’s practices. Although a recent dose-intense version of MVAC has shown an improved toxicity profile compared with traditional MVAC, it is clear that, for many patients, a full-dose cisplatin-based chemotherapy regimen may not be a tolerable option. Tobacco use, which is a common risk factor predisposing for the development of transitional cell carcinoma, may also cause morbidities that preclude treatment with aggressive combination therapy. Therefore, there is a clear need for regimens with improved toxicity, especially for the frequently frail or elderly patient population with poor renal function. There is an additional unmet requirement in rare bladder tumors, for which treatment has traditionally been based upon anecdotal evidence, limited by small patient numbers. Currently, there is newfound hope for all bladder cancer patients, with investigators studying new combinations and novel treatment paradigms, with recent studies focusing on frail, or ‘cisplatin-unfit’, patients and additional studies in the setting of rare small cell or urachal carcinoma patients.

Chemotherapy in Locally Advanced and Metastatic Bladder Cancer

The gold standard for the treatment of metastatic urothelial cancer over the past 15 years was a regimen including MVAC (methotrexate, vinblastine, adriamycin and cisplatin). It was demonstrated that this systemic approach revealed a significantly higher clinical efficacy when compared with different forms of combination chemotherapy, resulting in promising response and complete remission rates of up to 50% and 25%, respectively. Although it became evident that mainly patients with complete remissions reveal a favourable clinical prognosis, this advantage regarding overall survival becomes undetectable after 5 years of follow-up. Given that 25% of patients experience a complete tumor remission that persists for more than 3 years in about 50% of cases, a long lasting therapy-induced clinical benefit can be expected in only about 13% of patients. Therefore, the median long-term survival of patients with metastatic bladder cancer is roughly one year. Due to the observation that locally advanced tumors reveal a higher risk for the development of regional lymph node metastases already present at the time of surgery and that up to 50% of patients develop systemic tumor progression even following an aggressive local treatment, it has been postulated that an early chemotherapeutical treatment, either as neoadjuvant or adjuvant therapy in addition to local radiation or radical cystectomy, might improve the clinical prognosis of the patients due to an eradication of low-volume metastatic deposits. The present review tries to elucidate the clinical benefit that has been suggested to result from the latter treatment option. In addition, the role of new cytotoxic drugs like gemcitabine and paclitaxel during the therapy of metastatic urothelial cancer even in patients with significant comorbidity like impaired renal function as well as the impact on the patients’ clinical prognosis that might be derived from molecular targeting is discussed.

Gemcitabine in transitional cell carcinoma of the urothelium

Gemcitabine has become one of the key drugs in the treatment of patients with locally advanced and metastatic transitional cell carcinoma of the urothelium. The overall response rate for single-agent gemcitabine is 25% with a complete response rate of 9% and toxicity is mild-to-modest. The overall response rate for gemcitabine combined with cisplatin (GC) in Phase II studies is 47% with a complete response rate of 18% and a median survival ranging from 12.5 to 14.3 months. A randomized Phase III study comparing GC and methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has demonstrated similar efficacy with respect to response, time-to-progression and overall survival, whereas GC is associated with less toxicity than MVAC. Thus, GC is now considered a standard of care for patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine together with one of the taxanes with or without cisplatin.