Methotrexate, Vinblastine, Doxorubicin, Cisplatin Research Articles

Systemic therapy for bladder cancer - a medical oncologist's perspective.

Advanced bladder cancer, both muscle-invasive localized disease and metastatic disease, is managed with systemic chemotherapy. Cisplatin-based multi-agent chemotherapy remains the cornerstone for systemic therapy. MVAC (methotrexate-vinblastine-doxorubicin-cisplatin) has been most rigorously studied, both neoadjuvantly and for palliation of metastatic disease. For metastatic disease, cisplatin-gemcitabine (GC) has compared favorably to MVAC due to improved tolerability with similar efficacy. GC has been adopted as standard therapy. Neoadjuvant chemotherapy for muscle-invasive bladder cancer improves survival among those patients eligible to receive cisplatin. Adjuvant chemotherapy is difficult to administer effectively given morbidity of radical cystectomy, and studies have shown mixed results about its benefit. Non-cisplatin regimens have been investigated but remain experimental and reserved for those not candidates for cisplatin in the metastatic setting. While multiple agents have been studied after metastatic disease progression after cisplatin-based therapy, there remain no FDA-approved therapies for the second line. Future trials with anti-VEGF therapy and immunotherapy are actively being investigated. This review examines the systemic therapy available to oncologists with current evidence and future directions.

MP55-08 PATHOLOGIC RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN A MULTICENTRE COHORT OF PATIENTS WITH MUSCLE INVASIVE BLADDER CANCER.

Homayoun Zargar*, Vancouver, Canada; Adrian S. Fairey, Los Angles, CA; Laura Mertens, Amsterdam, Netherlands; Patrick N. Espiritu, Tampa, FL; Colin P. Dinney, Houston, TX; Laura-Maria Krabbe, Dallas, TX; Michael S. Cookson, Nashville, TN; Nils E. Jacobsen, Edmunton, Canada; Jeffrey S. Montgomery, Ann Arbor, MI; Nilay Gandhi, Baltimore, MD; Joshua Griffin, Kansas city, KS; Evan Y. Yu, Seattle, WA; Nikhil Vasdev, Newcastle Upon Tyne, United Kingdom; Nicholas J. Campain, Exeter, United Kingdom; Evanguelos Xylinas, New York, NY; Simon Horenblas, Amsterdam, Netherlands; David Youssef, Vancouver, Canada; Wassim Kassouf, Montreal, Canada; Shahrokh F. Shariat, Vienna, Austria; Jonathan J. Aning, Exeter, United Kingdom; Jonathan L. Wright, Seattle, WA; Andrew C. Thorpe, Newcastle Upon Tyne, United Kingdom; Jeff M. Holzbeierlein, Kansas city, KS; Trinity J. Bivalacqua, Baltimore, MD; Todd M. Morgan, Ann Arbor, MI; Scott North, Edmunton, Canada; Daniel A. Barocas, Nashville, TN; Yair Lotan, Dallas, TX; Jay B. Shah, Houston, TX; Philippe E. Spiess, Tampa, FL; B.W. van Rhijn, Amsterdam, Netherlands; Siamak Daneshmand, Los Angles, CA; Peter.C. Black, Vancouver, Canada

Long-Term Efficacy and Safety Outcomes of Modified (Simplified) MVAC (Methotrexate/Vinblastine/Doxorubicin/Cisplatin) as Frontline Therapy for Unresectable or Metastatic Urothelial Cancer

BackgroundThe classic MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) regimen was the first recognized option for untreated patients with locally advanced or metastatic urothelial cancer (UC). Modifying MVAC by reducing side effects may have the potential to improve efficacy. Patients and MethodsChanges to classic MVAC were provided at the authors' institution: (1) deletion of day 22 and administration of 25 mg/m2 cisplatin on days 2 to 5 (modified [m]MVAC); (2) deletion of day 22 only (simplified [s]MVAC1); and (3) deletion of days 15 and 22 in a 3-week schedule (sMVAC2). A total of 4 to 6 cycles were provided. Multivariate analysis was undertaken for recognized clinical variables. ResultsFor the period from September 1986 to May 2012, 157 patients were identified (25 with mMVAC, 72 with sMVAC1, and 60 with sMVAC2). Overall, 43.9% had a Memorial Sloan-Kettering Cancer Center score of 1 or 2, with differences across series (P = .002). Altogether, 65.8% attained a complete (19.1%) or partial response (46.7%), and 24.3% a stable disease, with no difference across regimens. After a median follow-up of 87 months (interquartile range, 37-161), median progression-free survival was 10.2 months (95% CI, 8.4-10.8), and median overall survival (OS) was 19.5 months (95% CI, 16.3-24.1). Responses were mainly seen in nodal metastases or soft tissue relapse (odds ratio, 2.48; 95% CI, 1.12-5.54). Only visceral (hazard ratio [HR], 2.42; 95% CI, 1.37-4.30) and nodal metastases/local relapse (HR, 1.70; 95% CI, 1.07-2.69) were independently associated with OS. Grade 3 or 4 toxicities were similar across regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. Two treatment-related deaths occurred. ConclusionSimplifying MVAC may result in improved efficacy and reduced toxicity. The combined results of the original and modified MVAC regimens encourage a reappraisal of the frontline management of advanced UC.

Management of Renal Collecting Duct Carcinoma: A Systematic Review and the McMaster Experience

Collecting duct carcinoma (cdc) is a rare, aggressive form of renal carcinoma that presents at an advanced stage and has a poor prognosis. Little is known concerning the optimal management of cdc. We present the results of a systematic review addressing the management of cdc and the McMaster University cdc series. The medline, Cochrane Library, and embase databases and conference proceedings were searched to identify studies relating to the management of cdc. Included studies reported on a minimum of 10 subjects receiving a single intervention. Series in which an evaluation of therapeutic effectiveness was not possible were excluded. The McMaster University (Hamilton, Ontario) series of 6 cases of cdc were retrospectively reviewed. We identified 3 studies relevant to the management of cdc that included a total of 72 patients. A gemcitabine-cisplatin or -carboplatin regimen resulted in a 26% objective response rate in 23 patients with metastatic cdc. Two additional studies indicated that 49 patients treated with immunotherapy achieved no response. In the McMaster series, cytoreductive nephrectomy was performed in 4 of 6 patients. In 2 patients, mvac therapy (methotrexate-vinblastine-doxorubicin-cisplatin) achieved no response. No significant therapeutic complications occurred, but survival was poor (median: 11 months; range: 10-33 months). Our review and clinical experience suggest that the current standard of care for metastatic cdc is a gemcitabine-cisplatin regimen.

Neoadjuvant chemotherapy with gemcitabine/cisplatin vs. methotrexate/vinblastine/doxorubicin/cisplatin for muscle-invasive urothelial carcinoma of the bladder: A retrospective analysis from the University of Southern California

ObjectivesWe evaluated pathologic and survival outcomes of GC (gemcitabine/cisplatin) and methotrexate/vinblastine/doxorubicin/cisplatin (M-VAC) neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC). Materials and methodsA retrospective analysis of prospectively collected data on 116 patients who received NAC (GC: n = 58; M-VAC: n = 58) before radical cystectomy and superextended pelvic lymph node dissection for clinical stage T2-4N0M0 bladder cancer was performed. The outcomes were complete response rate (CRR; pT0N0), partial response rate (PRR; pT0N0, pTaN0, pT1N0, or pTisN0), overall mortality (OM), and recurrence. The Kaplan-Meier method and multivariable Cox regression analysis were used to analyze OM. The cumulative incidence method and Fine and Gray's competing risk regression analysis were used to analyze recurrence. ResultsThe median follow-up duration was 2.1 years for the GC group and 7.4 years for the M-VAC group (P < 0.001). There were no statistically significant differences between the GC and M-VAC groups with regard to CRR (27.3% vs. 17.1%, P = 0.419) or PRR (45.5% vs. 37.1%, P = 0.498). The predicted 5-year freedom from OM rate (P = 0.634) and cumulative incidence of recurrence rate (P = 0.891) did not differ between the GC and M-VAC groups. Multivariable analysis showed that there was no independent association between type of NAC and OM (P = 0.721) or recurrence (P = 0.065). ConclusionsPathologic and survival outcomes did not differ in patients who received GC and M-VAC NAC. These data support the use of the GC regimen in the neoadjuvant setting.

Bladder Cancer Pharmacogenomics: Recent Insights and Future Perspectives

PharmacogenomicsVol. 13, No. 14 EditorialBladder cancer pharmacogenomics: recent insights and future perspectivesPeter H O’DonnellPeter H O’DonnellDepartment of Medicine & Section of Hematology/Oncology, Committee on Clinical Pharmacology & Pharmacogenomics, & Center for Personalized Therapeutics, The University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA. Search for more papers by this authorEmail the corresponding author at podonnel@medicine.bsd.uchicago.eduPublished Online:13 Nov 2012https://doi.org/10.2217/pgs.12.145AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail View articleKeywords: biomarkersbladder cancerpharmacogeneticspharmacogenomicsurothelial cancerReferences1 American Cancer Society. Cancer Facts & Figures 2010. American Cancer Society, GA, USA, 4, 10, 21 (2010).Google Scholar2 Grossman HB, Natale RB, Tangen CM et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N. Engl. J. Med.349,859–866 (2003).Crossref, Medline, CAS, Google Scholar3 von der Maase H, Hansen SW, Roberts JT et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, Phase III study. J. Clin. Oncol.18,3068–3077 (2000).Crossref, Medline, CAS, Google Scholar4 Stadler WM, Lerner SP, Groshen S et al. Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J. Clin. Oncol.29,3443–3449 (2011).Crossref, Medline, CAS, Google Scholar5 Rosenberg CL. Polysomy 17 and HER-2 amplification: true, true, and unrelated. J. Clin. Oncol.26,4856–4858 (2008).Crossref, Medline, Google Scholar6 Gossage L, Madhusudan S. 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Validation study of the prediction system for clinical response of M-VAC neoadjuvant chemotherapy. Cancer Sci.98,113–117 (2007).Crossref, Medline, CAS, Google Scholar11 Takata R, Obara W, Fujioka T. Study of the prediction system for clinical response to M-VAC neoadjuvant chemotherapy for bladder cancer. Aktuelle Urol.41(Suppl. 1),S41–S45 (2010).Crossref, Medline, Google Scholar12 Lee JK, Havaleshko DM, Cho H et al. A strategy for predicting the chemosensitivity of human cancers and its application to drug discovery. Proc. Natl Acad. Sci. USA104,13086–13091 (2007).Crossref, Medline, CAS, Google Scholar13 Havaleshko DM, Cho H, Conaway M et al. Prediction of drug combination chemosensitivity in human bladder cancer. Mol. Cancer Ther.6,578–586 (2007).Crossref, Medline, CAS, Google Scholar14 Williams PD, Cheon S, Havaleshko DM et al. Concordant gene expression signatures predict clinical outcomes of cancer patients undergoing systemic therapy. Cancer Res.69,8302–8309 (2009).Crossref, Medline, CAS, Google Scholar15 Griffiths G, Hall R, Sylvester R et al. International Phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J. Clin. Oncol.29,2171–2177 (2011).Crossref, Medline, CAS, Google Scholar16 Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur. Urol.48,202–205 (2005).Crossref, Medline, Google Scholar17 David KA, Milowsky MI, Ritchey J et al. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J. Urol.178,451–454 (2007).Crossref, Medline, Google Scholar18 Raj GV, Karavadia S, Schlomer B et al. Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer. Cancer117,276–282 (2011).Crossref, Medline, CAS, Google Scholar19 O’Donnell PH, Ratain MJ. Germline pharmacogenomics in oncology: decoding the patient for targeting therapy. Mol. Oncol.6,251–259 (2012).Crossref, Medline, Google Scholar101 National Cancer Institute. Organ Specific Workshops. http://trp.cancer.gov/information_for_public/organ_specific.htmGoogle Scholar102 Genetic Determinants of Response to Neoadjuvant Cisplatin-based Chemotherapy in Urothelial Cancer. http://www.clinicaltrials.gov/ct2/show/NCT01206426Google ScholarFiguresReferencesRelatedDetailsCited ByClinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial CancerClinical Genitourinary Cancer, Vol. 14, No. 6Diagnostic Microdosing Approach to Study Gemcitabine Resistance10 October 2016 | Chemical Research in Toxicology, Vol. 29, No. 11Pharmacogenomics in bladder cancerUrologic Oncology: Seminars and Original Investigations, Vol. 32, No. 1 Vol. 13, No. 14 Follow us on social media for the latest updates Metrics Downloaded 195 times History Published online 13 November 2012 Published in print November 2012 Information© Future Medicine LtdKeywordsbiomarkersbladder cancerpharmacogeneticspharmacogenomicsurothelial cancerFinancial & competing interests disclosureThe author has received funding from the NIH K12 CA139160 and The Cancer Research Foundation. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

Neoadjuvant chemotherapy for muscle-invasive bladder cancer at the University of Southern California.

301 Background: There is a paucity of data on neoadjuvant GC (gemcitabine, cisplatin) chemotherapy in patients with muscle-invasive bladder cancer (MIBC). Our aim was to compare pathologic and survival outcomes of neoadjuvant GC and M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) chemotherapy in patients with MIBC. Methods: A retrospective analysis of prospectively collected data from the University of Southern California (USC) Bladder Cancer Database was performed. Between 1985 and 2011, 116 patients received neoadjuvant chemotherapy prior to radical cystectomy and extended pelvic lymph node dissection for clinical stage T2-T4N0M0 bladder cancer. The outcomes were pathologic complete response (pT0N0), pathologic tumor downstaging (pT0N0, pTaN0, pT1N0, or pTisN0), overall survival (OS), and recurrence-free survival (RFS). The Kaplan-Meier method and Cox proportional regression models were used to analyze survival data. Results: The median follow-up duration was 4.5 years (range, 0 to 19.8 years). Fifty-eight patients each received GC and M-VAC chemotherapy. There were no statistically significant differences between the GC and M-VAC groups with regard to pathologic complete response (27.3% versus 17.1%, p=0.419) or pathologic tumor downstaging (45.5% versus 37.1%, p=0.498). The predicted 5-year OS (29% versus 38%, Log rank p=0.634) and RFS (36% versus 35%, Log-rank p=0.891) rates did not differ between the GC and M-VAC groups. However, in a subset of 37 patients with pathologic lymph node positive disease, the predicted 1-year RFS rate differed between the GC and M-VAC groups (0% versus 32%, log rank p=0.019). Multivariable analysis showed a trend toward an independent association between type of neoadjuvant chemotherapy and RFS (GC versus M-VAC: HR 1.64, 95% CI 0.93 to 2.89, p=0.089). Conclusions: Pathologic complete response, pathologic tumor downstaging, and survival did not differ in patients who received neoadjuvant GC and M-VAC chemotherapy. However, GC was associated with poorer RFS in a subset of patients with pathologic lymph node positive disease. Randomized controlled trials comparing neoadjuvant chemotherapy regimens are urgently needed.

Gemcitabine chemotherapy for the treatment of metastatic bladder carcinoma

• To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer. • The Medical Literature Analysis and Retrieval System Onlinedatabase (MEDLINE), the Excerpta Medicadatabase (EMBASE), the Cumulative Index to Nursing and Allied Health Literature database(CIHNAL), the Cochrane database of randomized trials, the Literatura Latino-Americana e do Caribe emCiências da Saúdedatabase (LILACS), and Web of Science were searched to identify trials of gemcitabine for metastatic bladder cancer. Also searched were international guidelines on metastatic prostate cancer, trial registries, and recent systematic reviews. Data on trial design, survival, tumour response and toxicity outcomes were extracted from relevant studies. • This review identified six randomized trials of combined chemotherapy with gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer. • One trial compared gemcitabine plus cisplatin (GCis) with methotrexate/vinblastine/doxorubicin/cisplatin(MVAC) and found no difference in overall survival (OS; hazard ratio 1.09) but a better safety profile with GCis, which was suggested as the treatment of choice. • A second trial evaluated GCis against gemcitabine plus carboplatin (GCarbo) and reported similar median OS (12.8 vs 9.8 months), disease progression (8.3 vs 7.3 months) and tumour response rates (66% vs 56%) for the two patient groups. • A third trial compared GCis with GCis plus paclitaxel (GCisPac) and showed no significant difference in median OS (12.3 vs 15.3 months) and response rates (44% vs 43%) but greater toxicity with GCisPac. • A fourth trial assessed GCarbo against methotrexate plus carboplatin plus vinblastine in patients unfit for cisplatin-based chemotherapy and found similar tumour response rates for each regime (38% vs 20%) but the triplet regime was more toxic. • Two other randomized studies compared a 2-weekly maintenance regime of gemcitabine plus paclitaxel with a 3-weelky regime given for a maximum of six cycles and found that the maintenance schedule did not confer any additional survival benefit. • In all, 53 observational studies of gemcitabine chemotherapy were identified that varied considerably in the drug combinations used and schedules. Overall response rates (17-78%) and median OS (6.4-24.0 months) were variable with no combination being clearly superior. • Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer. • GCis may be considered an alternative regime to MVAC. • GCarbo should be considered for patients unfit for cisplatin-based therapy.

Combination therapy consisting of gemcitabine, carboplatin, and docetaxel as an active treatment for advanced urothelial carcinoma

To evaluate the efficacy and toxicity of a combination chemotherapy consisting of gemcitabine, carboplatin, and docetaxel (GCD) in patients with advanced urothelial carcinoma (UC) as a phase II trial. Patients with metastatic or locally advanced unresectable UC were eligible for this trial. All enrolled patients were considered to be "unfit" for cisplatin-based chemotherapy, or to have methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)-refractory UC. The chemotherapy regimen consisted of gemcitabine 1000mg/m(2) on days 1 and 8, and carboplatin (with a target area under the curve of 5) and docetaxel 70mg/m(2) on day 1; this was repeated every 21days. Thirty-five patients were enrolled, with a median age of 68years. A total of 89 cycles were administered (median, 2 cycles). Major toxicities were Grade 3/4 neutropenia in 28 (80.0%) patients and Grade 3/4 thrombocytopenia in 18 (51.5%). An objective response rate (ORR) was 11 of 21 patients (52.4%), including a complete response in 1 (4.8%). The median overall survival (OS) was 13.1months (1-year survival rate, 60%) and the median progression-free survival (PFS) was 5.0months. Among 16 patients who had previously received MVAC, the ORR, the median PFS, the median OS and 1-year survival rate was 56.3%, 5.0months, 12.6months and 54%, respectively. GCD chemotherapy is active and well tolerated as a first- or second-line therapy for patients with advanced UC. Response rate, duration and survival did not differ between those with and without a history of MVAC treatment.

Meta-analysis of randomized trials comparing cisplatin versus carboplatin-based regimens for the first-line therapy of metastatic transitional cell carcinoma of the urothelium (TCCU).

247 Background: Cisplatin-based chemotherapy is the first-line treatment standard for metastatic TCCU, although carboplatin is substituted for cisplatin-ineligibility, tolerability, and ease of administration. Since definitive data comparing cisplatin- versus carboplatin-based chemotherapy are lacking, a meta-analysis of published randomized trials was performed. Methods: PubMed was searched for articles published in the English language from 1966 until 2010 and abstracts presented at the American Society of Clinical Oncology Annual Meeting between 2000 and 2010 were searched to identify relevant trials. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in cisplatin-eligible patients with metastatic TCCU. Individual patient data were not available and progression and survival data were inconsistently reported. Therefore, the analysis focused on overall (OR) and complete response (CR). The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RR). Results: A total of 286 patients with metastatic TCCU from 4 randomized trials (3 phase II and 1 phase III trial) were included. Chemotherapy regimens included MVEC (methotrexate, vinblastine, epirubicin, cisplatin) vs. MVECa (methotrexate, vinblastine, epirubicin, carboplatin), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) vs. MCAVI (methotrexate, carboplatin, vinblastine), MVAC vs. paclitaxel plus carboplatin, and gemcitabine plus cisplatin vs. gemcitabine plus carboplatin. Cisplatin-based chemotherapy was associated with a significant improvement in the likelihood of CR (RR=3.973 [95%CI: 1.562 – 10.110], p =0.004) and OR (RR=1.336 [95%CI: 1.043 – 1.712], p=0.025). Conclusions: Cisplatin-based as compared with carboplatin-based combination chemotherapy significantly increases the likelihoods of both OR and CR, in patients with metastatic TCCU. In the absence of definitive phase 3 trials, these results support cisplatin-based regimens as the preferred first-line treatment for cisplatin-eligible patients with metastatic TCCU. No significant financial relationships to disclose.

Tolerability of neoadjuvant chemotherapy with gemcitabine plus cisplatin in elderly (older than age 65) patients (pts) with muscle-invasive urothelial cancer.

296 Background: Urothelial cancer (UC) is a common tumor with a peak in the seventh decade. Locally advanced disease has a significant risk for developing metastases. Neoadjuvant, platinum-containing, combination chemotherapy improves survival over radical cystectomy (RC). Chemotherapy with gemcitabine plus cisplatin (GC) shows equivalent efficacy with less toxicity to methotrexate-vinblastine-doxorubicin- cisplatin (MVAC) in metastatic setting. Methods: We prospectively evaluated 23 elderly pts (8 female, 15 male) with a median age of 72 years, WHO performance status 0/1, with muscle invasive UC who received neoadjuvant GC (gemcitabine 1,000 mg/m2 days 1, 8, 15 and cisplatin 70 mg/m2, day 2 q28) for 3 cycles between 2006 and 2010 prior to RC. Assessments included toxicity of GC, pathologic response, progression free survival (PFS) and overall survival (OS). Results: 21 (91.3%) out of 23 pts finished intended chemotherapy. Two refused chemotherapy due to personal reasons. According to CTCAE guidelines 43.5% developed grade 3 hematologic toxicities; 13% developed grade 4 thrombopenia. Grade 3 non-hematologic toxicities included nausea in 2 patients. In 2 (8.7%) pts grade 4 thromboembolic events occurred. There was no treatment related febrile neutropenia or death. 15 (71.4%) of the pts underwent RC. 5 (23.8%) pts refused RC due to personal reasons. 1 of them agreed second look TURB. 1 patient underwent palliative radiotherapy due to progression of disease. Out of the 16 pts 43.75% achieved pathological response (18.75% pT0 stage and 25% pT1 stage). 56.25% had muscle invasive UC. 18.75% of them nodal positive disease. All 7 pts achieving &lt; pT2 pathologic stage remained progression-free at a median follow up of 16 months. Pts &gt; pT2 stage had a median PFS of 14 months. Median OS was not reached yet. Conclusions: Neoadjuvant GC is a well tolerated regiment in elderly pts and it seems to be less toxic than MVAC. Prophylactic anticoagulation during treatment should be considered. Although pathologic response is lower than in previously published retrospective data we recommend neoadjuvant treatment with GC in elderly pts. [Table: see text]

Efficacy of methotrexate/vinblastine/doxorubicin/cisplatin combination in gemcitabine-pretreated patients with advanced urothelial cancer: a retrospective analysis

ObjectiveSecond-line treatment options in advanced urothelial cancer are limited. We investigated the efficacy of a methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) combination after failure of gemcitabine/platinum chemotherapy.Patients and methodsTwenty-five patients with advanced urothelial cancer, who received second-line MVAC after first-line gemcitabine/cisplatin (n = 9) or gemcitabine/carboplatin (n = 16), were included in this retrospective analysis.ResultsTwenty-two patients (88%) relapsed within 6 months after first-line treatment. Following MVAC, there were 5 (20%) objective responses. Median follow-up was 20.2 months. Median progression-free survival (PFS) was 3.8 months (95% CI: 2.3–5.2), and median overall survival (OS) was 9 months (95% CI: 6.6–11.4). Eastern Cooperative Oncology Group performance status 0.1 versus 2 was associated with longer PFS (5 months versus 3.3 months, P = 0.049). Response or stabilization of disease during second-line chemotherapy predicted for a significantly longer PFS and OS (7.4 versus 3.5, P = 0.005; 15.5 versus 7, P = 0.046).ConclusionsSecond-line MVAC chemotherapy may result in prolonged survival in some patients with refractory disease. Further research in this field is necessary.

Critical evaluation of vinflunine in the treatment of refractory metastatic urothelial carcinoma

Urothelial carcinoma (UC) accounts for 5% to 10% of malignancies in men in Europe and the United States. For locally advanced or metastatic disease, there are two standard firstline chemotherapy regimens: MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) and gemcitabine/cisplatin. For refractory disease, there is currently no standard treatment. Vinflunine, a second-generation Vinca alkaloid, is the first chemotherapeutic agent to be evaluated in a large UC second-line population. This review discusses the pre-clinical and clinical data published, and compares vinflunine to alternative single agents and combination regimens tested in this setting. Based on the results of the phase II and III clinical trials, there appears to be sufficient evidence to support the use of vinflunine in the second-line setting.

Chemotherapy for bladder cancer: A United Kingdom practice survey

16078 Background: Chemotherapy has an established role in the treatment of locally advanced (LABC) and metastatic bladder cancer (MBC). Chemotherapy regimens vary, in particular, there is no agreed standard of care for second line treatment of metastatic disease. To aid future study design, we conducted a current practice survey. Methods: A written questionnaire was mailed to 110 UK urological oncologists requesting anonymous replies in pre-paid envelopes. Results: Of the 61 questionnaires returned, 8 denied treating bladder cancer. These were excluded from further analyses. In first line MBC, 45/53 [85%] preferred gemcitabine/cisplatin (GC), with considerable variation in schedule. Methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) was the next preferred regimen (7/53[13%]). In patients unsuitable for cisplatin, 39/51 [76%] reported using gemcitabine/carboplatin (GCarbo). Other options were gemcitabine alone (5/51[10%]) and methotrexate/carboplatin/vinblastine (CMV) (2/51[4%]). In second line MBC, 10/43 [23%] respondents reported using GC, 7/43 [16%] used GCarbo, 6/43 [14%] used paclitaxel/carboplatin (PC) and 6/43 [14%] used MVAC. In the absence of formulary restrictions, 16/34 [47%] clinicians would choose paclitaxel alone or in combination with platinum as their preferred choice of second line regimen. 25/26 [96%] clinicians reported 3 weekly PC as an acceptable control arm for a randomised controlled trial of second line chemotherapy. The most popular neoadjuvant regimen for LABC was GC (42/49[86%]). 4/49 [8%] of clinicians used MVAC based regimens. In the adjuvant setting, 29/34 [85%] clinicians chose GC and the remainder CMV or MVAC. Conclusions: In UK clinical practice, chemotherapy treatment of bladder cancer is largely uniform. Standard of care for neoadjuvant, adjuvant and 1st line for MBC consists of gemcitabine/platinum doublet. Second line treatment of MBC, however, is more variable and this is an area which needs further clinical study. These data will inform the design of future trials in treatment of MBC. No significant financial relationships to disclose.

Modern chemotherapy of invasive bladder cancer

to identify the place and role of modern chemotherapy in invasive bladder cancer. overview of the important data of papers presented in the last three years. Cisplatin-based chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (M-VAC) or gemcitabine-cisplatin (GC) is the standard treatment and prolongs survival in metastatic disease. The paclitaxel-gemcitabine-cisplatin (TGC) protocol did not change standard therapy. Neoadjuvant chemotherapy before cystectomy for T2-3 disease provides a survival benefit compared with surgery alone. Adjuvant chemotherapy is less compelling, however, it is used in case of locally advanced, extravesical and/or lymph node-positive disease. The identification of patient's risk factors helps the decision of individual treatment strategy. Better understanding of molecular mechanisms and carcinogenetic pathways of bladder cancer and combination of old and new drugs with targeted therapy may increase the effectiveness of treatment in bladder cancer.

Efficacy of neo-adjuvant gemcitabine plus cisplatin (GC) in muscle-invasive urothelial cancer (UC)

5077 Background: Neoadjuvant chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) plus radical cystectomy (RC) improves survival over cystectomy alone in urothelial cancer (UC); survival is greatest for patients achieving either pT0 or = pT1 after chemotherapy. GC is less toxic and achieves a similar response and survival to MVAC in metastatic UC, but is untested as neoadjuvant therapy. This study compared GC-induced pathological response in the bladder to that seen with neoadjuvant MVAC in an historic control series (1983–88) at our center (JCO 12:1394, 1994). Methods: We retrospectively reviewed records from muscle-invasive UC patients who received neoadjuvant chemotherapy from 11/2000 to 5/2006; 43 received GC (planned 4 cycles) followed by RC. Post-chemotherapy pathologic response was compared to neoadjuvant MVAC pts (planned 4 cycles) but whose post-chemotherapy surgery varied by surgeon’s discretion. 34 of 111 MVAC patients underwent post-chemotherapy RC and an additional 21 patients underwent partial cystectomy (PC). Pathologic outcomes of the GC cohort were compared to MVAC patients that underwent either RC (n=34) or to either RC or PC (n=55). IRB approval was obtained. Results: Baseline characteristics and treatment results were similar for both groups. The median time from start of GC chemotherapy to RC was 141 days (IQ range 123–155). Start of MVAC to RC (n=34) was 95 days (IQ range 76–163) and to either RC or PC (n=55) was 119 days (IQ range 89–175). Achieving = pT1 was similar for GC (15/43; 35%, 95% CI 21–51%) and MVAC followed by RC (6/34; 18%, 95% CI 7–35) or MVAC followed by either RC or PC (20/55; 36%, 95% CI 24–50). Achieving pT0 for GC patients (11/43; 26%, 95% CI 14–41) was also similar to MVAC plus RC (5/34; 15%, 95% CI 5–31) and MVAC plus either RC or PC (15/55; 27%, 95% CI 16–41). Conclusions: Neoadjuvant GC is similar to MVAC in both pathologic response in the bladder and time to cystectomy. The efficacy and tolerance of neoadjuvant GC warrants further study to assess overall survival. No significant financial relationships to disclose.

Therapy of metastatic bladder carcinoma

The methotrexate, vinblastine, doxorubicin, cisplatin (M-VAC) regimen has been considered as standard treatment of metastatic bladder carcinoma till recent years. The superiority of M-VAC both to cisplatin alone and to another cisplatin combination regimen has been demonstrated in randomized studies. During the last years, the use of gemcitabine in metastatic bladder carcinoma has considerably increased, mainly in combination with cisplatin (CG). A phase III trial comparing M-VAC and CG demonstrated similar activity and less toxicity for CG, which has now become the new standard of care for patients with metastatic bladder carcinoma. The substitution of cisplatin with carboplatin, the combination of platinum and taxanes, and the addition of a third drug to basal CG combination represent possible ways to improve outcome. Among the novel cytotoxic compounds, pemetrexed has raised interest, since a phase II second-line study showed a 28% response rate with a manageable toxicity profile. Vinflunine is a novel antitubulin agent with a relevant clinical activity in pretreated metastatic bladder carcinoma (18% response rate, 6.6 months median survival). Novel biologic compounds (in particular drugs targeting epidermal growth factor receptor) are being tested in metastatic bladder carcinoma also and much effort is being pursued in understanding the determinants of tumor response. Crucial mutations to which the tumor becomes addicted have to be discovered so that more effective and specific drugs or combinations can be delivered.

Long-Term Survival Results of a Randomized Trial Comparing Gemcitabine Plus Cisplatin, With Methotrexate, Vinblastine, Doxorubicin, Plus Cisplatin in Patients With Bladder Cancer

To compare long-term survival in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium treated with gemcitabine/cisplatin (GC) or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC). Efficacy data from a large randomized phase III study of GC versus MVAC were updated. Time-to-event analyses were performed on the observed distributions of overall and progression-free survival. A total of 405 patients were randomly assigned: 203 to the GC arm and 202 to the MVAC arm. At the time of analysis, 347 patients had died (GC arm, 176 patients; MVAC arm, 171 patients). Overall survival was similar in both arms (hazard ratio [HR], 1.09; 95% CI, 0.88 to 1.34; P = .66) with a median survival of 14.0 months for GC and 15.2 months for MVAC. The 5-year overall survival rates were 13.0% and 15.3%, respectively (P = .53). The median progression-free survival was 7.7 months for GC and 8.3 months for MVAC, with an HR of 1.09. The 5-year progression-free survival rates were 9.8% and 11.3%, respectively (P = .63). Significant prognostic factors favoring overall survival included performance score (> 70), TNM staging (M0 v M1), low/normal alkaline phosphatase level, number of disease sites (<or= three), and the absence of visceral metastases. By adjusting for these prognostic factors, the HR was 0.99 for overall survival and 1.01 for progression-free survival. The 5-year overall survival rates for patients with and without visceral metastases were 6.8% and 20.9%, respectively. Long-term overall and progression-free survival after treatment with GC or MVAC are similar. These results strengthen the role of GC as a standard of care in patients with locally advanced or metastatic TCC.

The outcome of elderly patients with advanced urothelial carcinoma after platinum-based combination chemotherapy

BackgroundThe majority of patients with advanced urothelial cancer are elderly, but data regarding this specific age group are limited. We compared the tolerability and efficacy of first-line platinum (cisplatin or carboplatin)-based chemotherapy in elderly patients (≥70 years) with those in younger patients. Patients and methodsA total of 381 patients with advanced urothelial carcinoma received CIMV (cisplatin, ifosphamide, methotrexate, vinblastine) (n=32), MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) (n=105), DC (docetaxel, cisplatin) (n=174), CaG (carboplatin, gemcitabine) (n=64) or other regimes (n=6) and were included in this analysis. ResultsA total of 116 patients were ≥70 years. Elderly patients experienced more frequent neutropenia grade 3/4 (55% versus 37%, P=0.087) and renal toxicity (28% versus 10%, P=0.033) among patients treated with CIMV/MVAC, and neutropenic infections (4% versus 0%, P=0.019) among patients treated with DC. Median survival did not differ significantly between elderly and younger patients (9.3 versus 10.5 months, P=0.16). Eastern Cooperative Oncology Group performance status (PS) and haemoglobin were independently associated with prognosis. Patients with PS <2 and haemoglobin ≥10g/dl had a median survival of 14 months as opposed to 5 months for patients with PS ≥2 or haemoglobin <10g/dl (P <0.001). ConclusionElderly patients with advanced urothelial cancer tolerate platinum-based chemotherapy well and derive the same benefit as their younger counterparts.

Current and future perspectives in advanced bladder cancer: Is there a new standard?

The methotrexate/vinblastine/doxorubicin/cisplatin (MVAC) regimen has been the standard treatment in patients with locally advanced and metastatic urothelial cancer for the past 15 years. The minimal or moderate survival benefit-depending on prognostic features-and the severe toxicity associated with the MVAC regimen have made the search for new drugs and drug combinations of utmost importance to increase efficacy and/or decrease toxicity. In this respect, the taxanes and gemcitabine are promising new drugs. Paclitaxel and docetaxel as single agents have yielded overall response rates of 7% to 56%, depending on whether the patients have received prior chemotherapy for metastatic disease. The combination of paclitaxel and cisplatin has been explored in three studies with a total of 104 evaluable patients, a pooled overall response (OR) rate of 61%, and a complete response (CR) rate of 20%. There are two studies of docetaxel and cisplatin with a total of 91 evaluable patients, an OR rate of 54%, and a CR rate of 16%. The OR rate for paclitaxel and carboplatin in six studies was 43%, with a CR rate of 13%; however, the reported median survival was only 8.5 to 9.5 months. The OR rate for single-agent gemcitabine based on five studies was 26%, with a CR rate of 9%, which was apparently independent of whether the patients had received prior chemotherapy. The OR rate for gemcitabine and cisplatin in four phase II studies ranged from 41% to 57%, with a CR rate of 15% to 22% and a median survival of 12.5 to 14.3 months. Based on the encouraging results for the combination of gemcitabine and cisplatin (GC), a randomized phase III trial comparing GC and MVAC was begun in late 1996. This study of 405 randomized patients showed that the two regimens were associated with similar response rates, time to progression, and overall survival, whereas GC was associated with less toxicity than MVAC. On the basis of this superior risk–benefit ratio, the GC regimen should be favored as a new standard treatment in patients with locally advanced and metastatic urothelial cancer. Other promising combinations include gemcitabine and paclitaxel, with or without cisplatin, and the combination of ifosfamide, paclitaxel, and cisplatin. The triple combination of gemcitabine, paclitaxel, and cisplatin has yielded an OR rate of 78%, a CR rate of 28%, and a median survival of 24 months. An international phase III trial comparing this triple combination with GC in patients with locally advanced and metastatic urothelial cancer has now been initiated. Semin Oncol 29 (suppl 3):3-14. Copyright 2002, Elsevier Science (USA). All rights reserved.