Chemotherapy For Urothelial Cancer Research Articles

Choline-phosphate cytidylyltransferase-α as a possible predictor of survival and response to cisplatin neoadjuvant chemotherapy in urothelial cancer of the bladder

Objectives: The aim of this study was to test choline-phosphate cytidylyltransferase-α (CCT-α) protein as a biomarker for neoadjuvant cisplatin chemotherapy response in a bladder tumor setting.Materials and methods: A total of 238 patients with T2–T4 bladder cancer enrolled into two prior randomized trials comparing neoadjuvant cisplatin-based chemotherapy (NAC) plus cystectomy with cystectomy only (no-NAC) were used as discovery and validation cohorts. Protein expression was determined with immunohistochemistry and assessed with Histo (H)-scoring.Results: In the discovery cohort, comprising 61 patients, the survival ratio after NAC treatment for CCT-α-negative patients was significantly increased (p = 0.001) while there was no survival advantage in the CCT-α-positive patient group. Similarly, in the validation cohort with 177 patients, NAC treatment improved survival only in the CCT-α-negative group (p = 0.006). Although there was a tendency for a good NAC response with negative CCT-α status, the interaction variable between biomarker and treatment was not significant (p = 0.24). In the cystectomy-only group, patients with positive CCT-α expression had a better survival than CCT-α-negative patients. This prognostic effect of CCT-α expression remained significant after adjusting for well-known prognostic factors in a multivariate analysis. In a pooled database of both patient data sets, multivariate analyses showed CCT-α status as an independent factor for overall survival (p = 0.018; hazard ratio = 1.80, 95% confidence interval 1.11–2.93).Conclusion: CCT-α status was not predictive of outcome of NAC response; however, in the control group with cystectomy only it was found to have prognostic value.

Current status of systemic chemotherapy for octogenarians with advanced urothelial cancer in Japan: a Japanese multi-institutional study (CURE study).

The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80years. Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80years was reviewed before and after 2008 and compared with 315 young patients. There were only 7 (4.6%) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12%) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5%) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis. Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.

The expression of ERCC1 and BRCA1 predicts prognosis of platinum-based chemotherapy in urothelial cancer.

ObjectiveTo investigate the expression and clinical significance of ERCC1 and BRCA1 genes in urothelial cancer patients.MethodsForty-two urothelial cancer patients who did not receive platinum-based chemotherapy during January 2009 to May 2013 were enrolled. The expression levels of ERCC1 and BRCA1 were determined by immunohistochemistry and the median survival time (MST) for these patients was calculated.ResultsERCC1-positive patients who received oxaliplatin-based chemotherapy had a shorter MST than ERCC1-negative patients (P<0.05), whereas there is no difference of MST between BRCA1-positive and -negative patients. Furthermore, MST in ERCC1 and BRCA1 double-positive patients was shorter than ERCC1 and BRCA1 double-negative patients (P<0.05). The positive expression of ERCC1 had a significant positive correlation with BRCA1 (r=0.313, P=0.044).ConclusionThe expression level of ERCC1 may be used as a prognostic marker for urothelial cancer patients who received postoperative adjuvant chemotherapy.

High throughput screening to assess urothelial cancer lines and their metastatic derivatives for assessing changes in sensitivity in therapeutics.

407 Background: Chemotherapy for urothelial cancer (UC) is less effective in patients with large volume metastatic disease, likely due to acquired driver mutations. Driver mutation may lead to differences in sensitivity between primary cell lines and metastatic clones. Quantitative high throughput screening (qHTS) assesses large drug libraries to evaluate in vitro effectiveness. We utilized this modality to compare effectiveness of cell inhibition in two bladder cancer cell lines with their metastatic lines. Methods: We screened T24 and UMUC-3 bladder cancer cell lines against 1,912 oncology-focused drugs using a 48 hr cell proliferation assay with an ATP-based readout (CellTiterGlo), and determined the activity and potency of the compounds in a dose response manner. We compared the results of their activity with known metastatic lines for reach of these primary lines: T24T, SLT3 and FL3 for T24 and LUL2 UMUC3 and UMUC3-luc (LUC3). We identified candidate drugs based on two parameters: 1) more than 70% inhibition at 48 hours and 2) a curve class of -1.1 or -1.2 indicating curve class with good fit (r2 &gt; 0.9). We used a custom capture next generation DNA sequencing chip for exonic regions of 229 known cancer related genes to compare primary and metastatic tumor cell lines. Results: The qHTS compounds, are demonstrated in figure 1a for T24 cell lines and figure 1b for UMUC cell lines. Amongst 1912 drugs tested, only 141 (7.4%) met inclusion criteria for T24. However, only 79 of these drugs (56%) met criteria for all cell lines derived from T24. 160 (8.4%) compounds were found to be active in the UMUC line. Only 32 (20%) of the UMUC3 detected compounds remained active in all UMUC3 derived cell lines. Genomic comparison between cell lines identified several mutations which were found only in the derived cell lines (RAC1 and CDH1 in UMUC3) and (AR, CDK12, GATA1, GUCY1A2 in T24). Conclusions: qHTS of a library of potential therapeutic interventions can produce a list of targets and therapies for bladder cancer. This data reinforces the differences between primary and metastatic tumors as compounds identified active in the primary cell lines were inactive in known metastatic cancer cell lines .

Recommendations for the Use of White Blood Cell Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update.

Purpose To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSFs). Methods The American Society of Clinical Oncology convened an Update Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014. Guideline recommendations were based on the review of the evidence by the Update Committee. Results Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz, moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma, and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high–dose-intensity chemotherapy in urothelial cancer. The Update Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults. Recommendations Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% or higher and no other equally effective and safe regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on the basis of age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. Dose-dense regimens that require CSFs should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, include the prompt administration of CSFs. J Clin Oncol 33:3199-3212. © 2015 by American Society of Clinical Oncology

Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update.

To update the 2006 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSFs). The American Society of Clinical Oncology convened an Update Committee and conducted a systematic review of randomized clinical trials, meta-analyses, and systematic reviews from October 2005 through September 2014. Guideline recommendations were based on the review of the evidence by the Update Committee. Changes to previous recommendations include the addition of tbo-filgrastim and filgrastim-sndz, moderation of the recommendation regarding routine use of CSFs in older patients with diffuse aggressive lymphoma, and addition of recommendations against routine dose-dense chemotherapy in lymphoma and in favor of high-dose-intensity chemotherapy in urothelial cancer. The Update Committee did not address recommendations regarding use of CSFs in acute myeloid leukemia or myelodysplastic syndromes in adults. Prophylactic use of CSFs to reduce the risk of febrile neutropenia is warranted when the risk of febrile neutropenia is approximately 20% or higher and no other equally effective and safe regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of febrile neutropenia in patients who are at high risk on the basis of age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. Dose-dense regimens that require CSFs should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Current recommendations for the management of patients exposed to lethal doses of total-body radiotherapy, but not doses high enough to lead to certain death as a result of injury to other organs, include the prompt administration of CSFs.

Towards effective adjuvant treatment for urothelial cancer

Data for the efficacy of adjuvant chemotherapy in urothelial cancer comes from prematurely closed trials with poor accrual that have not yielded definitive conclusions about benefit. Yet, the potential activity reported in these trials has been promising enough to encourage investigators to pursue assessment of this treatment. In The Lancet Oncology, Cora Sternberg and colleagues1 report the results of the EORTC 30994 trial, which compared immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with urothelial carcinoma of the bladder.

Prediction of pathologic complete response to neoadjuvant chemotherapy in urothelial cancer by genetic determinants of platinum sensitivity.

290 Background: Despite level 1 evidence demonstrating survival benefit for cisplatin-based neoadjuvant chemotherapy in urothelial cancer, its utilization remains low, likely due to the modest benefit and potentially significant toxicities. To improve selection of patients (pts) most likely to benefit, we evaluated the association of pharmacogenomic markers of cisplatin sensitivity with neoadjuvant therapy outcome. Methods: Pts receiving standard neoadjuvant cisplatin-based chemotherapy for muscle-invasive disease were recruited to provide a germline DNA sample. Nine single nucleotide polymorphisms (SNPs) selected for their associations with platinum sensitivity in various clinical and pre-clinical studies were tested for association with complete pathologic response (pT0) rate at cystectomy. Results: Sixty-three Caucasian pts were analyzed (median age=64; 67% male; all bladder primary and cN0). The overall pT0 rate was 27%; 52% were &lt;pT2. Using a multivariate, recessive genetic model, rs244898 in RARS (odds ratio [OR] 6.8 [95% CI 1.6-32.6], P=0.01) and rs7937567 in GALNTL4 (OR 5.2 [95% CI 1.1-26.2], P=0.03) were associated with likelihood of achieving pT0. For each SNP, pts carrying the favorable genotype achieved pT0 in &gt;58% of cases. Demonstrating the apparent independent nature of the two SNPs, pts carrying either favorable genotype had pT0 OR=8.5 (95% CI 2.5-31.8, P=0.0008). The combined effect of detecting both SNPs was most informative, as 2/3 pts with both favorable genotypes achieved pT0 (67%), compared to 9/15 pts with one favorable genotype (60%), and only 6/43 lacking both favorable genotypes (14%). The negative predictive value considering both SNPs was 86%. Conclusions: Two germline SNPs having prior evidence of governing platinum sensitivity in pre-clinical and clinical models were demonstrated to confer strong associations with complete response to cisplatin-based neoadjuvant chemotherapy. Validation testing in an independent, multi-institutional cohort of urothelial cancer pts is underway. If reproducible, these SNPs deserve consideration as predictive clinical biomarkers to inform the use of neoadjuvant chemotherapy in this disease.

Complete remission of pulmonary metastases of Bellini duct carcinoma with cisplatin, gemcitabine and bevacizumab.

SummaryBackground:Bellini carcinomas, rare tumors of kidney, are aggressive and have a poor prognosis. For these cancers, there is no standard treatment regimen and chemotherapy for urothelial cancer is usually used.Case Report:In a 44-year-old man with hematuria, a tumor was diagnosed in the right kidney. After radical nephrectomy, pathologic analysis revealed Bellini carcinoma, staged pT3apN0, Fuhrman grade 3. Secondary pulmonary lesions occur one year later. Chemotherapy (gemcitabine, cisplatin and bevacizumab) was started and after 2 cycles of chemotherapy, Thoracic CT scans showed good response to treatment, with almost complete regression of the pulmonary lesions. After the third cycle of chemotherapy, maintenance treatment with bevacizumab continued. Fifteen months after diagnosing pulmonary metastases, hilar adenopathies progressed slightly and cisplatin-gemcitabine was started again leading to a partial response after five courses. Approximately 2 years after the diagnosis of lung metastases, the patient presented a second relapse, so carboplatin-gemcitabine was started, while bevacizumab was continued. 24 months after the diagnosis of lung metastases, the patient was still alive with controlled disease.Conclusions:In view of our findings, a prospective multicenter trial with cisplatin, gemcitabine and bevacizumab in patients with metastatic collecting duct carcinoma is planned.

1148 RETICULOCALBIN-1 DOWN-REGULATION AS A POSSIBLE PREDICTOR OF CISPLATIN RESISTANCE IN UROTHELIAL CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 20101148 RETICULOCALBIN-1 DOWN-REGULATION AS A POSSIBLE PREDICTOR OF CISPLATIN RESISTANCE IN UROTHELIAL CANCER Masaaki Tachibana, Yoshio Ohno, Masahiko Kuroda, Ayako Tanaka, Kenji Shimodaira, Jun Nakashima, Takashi Hirano, and Norihiko Ikeda Masaaki TachibanaMasaaki Tachibana More articles by this author , Yoshio OhnoYoshio Ohno More articles by this author , Masahiko KurodaMasahiko Kuroda More articles by this author , Ayako TanakaAyako Tanaka More articles by this author , Kenji ShimodairaKenji Shimodaira More articles by this author , Jun NakashimaJun Nakashima More articles by this author , Takashi HiranoTakashi Hirano More articles by this author , and Norihiko IkedaNorihiko Ikeda More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.647AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Cisplatin is a main chemotherapeutic agent for urothelial cancer. Urothelial cancer patients treated with cisplatin-based chemotherapy often develop cisplatin resistance and, consequently, cancer recurrence. Therefore, elucidation of the mechanisms underlying cisplatin-resistance is crucial for efficient cancer chemotherapy. Proteomic analysis of cisplatin-resistant lung cancer cell lines identified reticulocalbin-1 as one of the proteins associated with cisplatin resistance. The purpose of this study is to evaluate significance of reticulocalbin-1 in urothelial cancer. METHODS Cisplatin-resistant sublines were established from the urothelial cancer cell lines KU-1, KU-7, and KU-19-19 by repeated subcultures with increasing cisplatin concentrations. Cell cycle analysis was performed by flow cytometry, and cisplatin cytotoxicity was determined with the Alamar Blue cytotoxicity assay. Reticulocalbin-1 expression was analyzed by real-time reverse transcriptase PCR and western blot. Surgically resected urothelial cancer specimens were immunohistochemically analyzed for reticulocalbin-1 to determine its association with response to cisplatin-based chemotherapy. Reticulocalbin-1 immunostaining was determined by the percentage of reticulocalbin-1-positive cells: weak staining, ≤25% of the tumor cells were positive for reticulocalbin-1; moderate, ≤50%; strong, >90%. RESULTS Cell growth inhibition was 2.5-fold greater in cisplatin-resistant sublines than in the parental cell lines. The S-phase fraction showed a significant increase. Reticulocalbin-1 was down-regulated in all three cisplatin-resistant cell lines as compared with their parent cell lines on both mRNA and protein levels. In immunohistochemical analysis, reticulocalbin-1 was expressed in normal urothelial epithelium. Fifteen tumors were strongly positive for reticulocalbin-1; 18, moderately positive; 20, weakly positive. Seventy-five percent (15/20) of patients with weak positive primary cancer did not respond to the chemotherapy. CONCLUSIONS Reticulocalbin-1 expression may be a marker for response to cisplatin-based chemotherapy in urothelial cancer. Tokyo, Japan© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e444 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masaaki Tachibana More articles by this author Yoshio Ohno More articles by this author Masahiko Kuroda More articles by this author Ayako Tanaka More articles by this author Kenji Shimodaira More articles by this author Jun Nakashima More articles by this author Takashi Hirano More articles by this author Norihiko Ikeda More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Immunohistochemical Differentiation of High-grade Prostate Carcinoma From Urothelial Carcinoma

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial markers were relatively specific with only a few prostate cancers showing scattered (<or=2%) weak-moderate positive cells. In summary, PSA can be used as the first screening marker for differentiating high-grade prostate adenocarcinoma from high-grade urothelial carcinoma. Immunohistochemistry for P501S, PSMA, NKX3.1, and pPSA are useful when high-grade prostate cancer is suspected based on the morphology or clinical findings, yet shows negative or equivocal PSA staining. HMWCK and p63 are superior to the novel markers thrombomodulin and S100P.

Major response and clinical benefit following third-line treatment for Bellini duct carcinoma

Bellini duct carcinoma accounts for 1-3% of all renal carcinomas and is characterized by an aggressive course and extremely poor prognosis. Conventional treatment for renal-cell carcinoma seems to be ineffective. Since the histology of Bellini duct carcinoma is similar to urothelial carcinoma, chemotherapy for urothelial cancer might be more promising than conventional treatment. We present a patient with renal carcinoma of the left kidney who underwent laparoscopic extrafascial nephrectomy and adrenalectomy. Histopathologic work-up showed Bellini duct carcinoma (pT3a, NX, G3, R0 and M0). Eight months after surgery, disease progression was observed with local recurrence, multiple pulmonal lesions, para-aortic and aortocaval lymphadenopathies and a solitary bone lesion. First-line treatment with interferon-alpha and interleukin-2, as well as second-line treatment with thalidomide, were ineffective. Disease progressed rapidly and the patient experienced a dramatic reduction in performance status and quality of life. Six courses of chemotherapy with cisplatin and gemcitabine were given, a treatment reported to be highly active in urothelial cancer. The treatment was well tolerated, with thrombopenia WHO grade II, anemia WHO grade I and nausea/vomitus WHO grade II being the most severe side effects. Follow-up computer tomography revealed partial remission with 50-100% response at the different sites of metastasis. This response was accompanied by a dramatic improvement in performance status (from an initial 60% to 100% Karnofsky index) and quality of life. The combination of cisplatin and gemcitabine was highly active in this patient with metastatic Bellini duct carcinoma, even given as third-line treatment. This regimen fulfils all criteria for palliative treatment, as our patient showed an impressive improvement in WHO performance status and therefore in quality of life. Histopathologic characteristics should be a major criterion for treatment strategy in renal carcinoma, particularly in Bellini duct carcinoma.

Chemotherapy for Urothelial Cancer

Chemotherapy for Urothelial Cancer