28 %, 0.050). exploration. UCBUTUCvaluewith MVAC.[5,6]?III4051000GCMVAC13.8 versus 14.80.75[7]?III85NRNRPaclitaxel + carboplatinMVAC13.8 versus 15.40.65[8]?III2208416Docetaxel + cisplatinDD-MVAC + G-CSF9.3 versus 14.20.026Survival difference was nonsignificant after adjusting for prognostic factors (0.089).[9]?III1308313Dose-dense GC + G-CSFDD-MVAC + G-CSF18.0 versus 19.00.98[10]?III6268213PGCGC15.8 versus 12.70.075[11]?II638318Sunitinib + GC-12-[12]?II987030Sorafenib + GCPlacebo + GC11.3 versus 10.60.66[13]First-line therapy for cisplatin-ineligible patients?II/III2387422Carbo/gemM-CAVI9.3 versus 8.10.64Criteria: (1) GFR 60 but 30 ml/mi; and/or (2) PS of 2.Severe acute toxicity was 9.3 in GC versus 21.2 % in M-CAVI.[16]?II516139Bevacizumab + carbo/gemC13.9CCriteria: (1) KPS 60C70 %; (2) CrCl 60 ml/min; (3) visceral metastasis; and/or (4) solitary kidney.[17]?I/II321000Split-dose cisplatin (day 1 and 8) + gemcitabine (21-day cycle)-16-Criteria: (1) WHO PS 0C2 and (b) GFR 40 ml/min.[18]?-38970Split-dose cisplatin (day 1 and 15) + gemcitabine (28-day cycle)-8.5-Criterion: CrCl between 35 and 59 ml/min.[19]?II695246Vinfunine + gemcitabineVinfunine + carboplatin14.0 versus 12.80.86Criteria: (1) ECOG PS 0 or 1 and (2) cisplatin-ineligible. defined as calculated CrCl 60 but 30 mL/min and/or NYHA class II/III heart failure.[20]Second-line therapy?III370NRNRVinfunine + BSCBSC6.9 versus 4.60.287Significant after adjusting for eligible patients.[21]?II47NRNRPemetrexed-9.6-[22]?II31946Paclitaxel-7.2-[23]?II308317Docetaxel-9-[24]?II148NRNRRamucirumab + docetaxelDocetaxel10.4 versus 9.20.201Median PFS: 5.4 months with arm Y16 A versus 2.8 months with arm B (0.0002).Trial included a third arm, icru- cumab Rabbit Polyclonal to HSP90A + docetaxel, which did not improve PFS.[25]Immunotherapy?Ib33NRNRPembrolizumab-NR-Criteria: (1) tumors on immuno- histochemistry showed 1 PD-Ll-positive cells in tumor nests or a PD-Ll-positive band in stroma and (2) recurrent or persistent metastatic UC.ORR was 25 12-month PFS was 19%.[38]?Ib44NRNRAvelumab-NR-Studied as second-line therapy.ORR was 15.9 % overall and 40 in PD-Ll-positive tumors.[39]?II3167421Atezolizumab-7.9-Criteria: (1) cisplatin-ineligible and chemo-naive or (2) cisplatin- refractory.ORR for the IC2/3, IC1/2/3, and overall cohort were 26, 18, and 15 %, respectively. Median survival for the IC2/3, IC1/2/3, and overall cohorts were 11.4, 8.8, and 7.9 months, respectively.[34] Open in a separate window best supportive care, carboplatin plus gemcitabine, creatinine Y16 clearance, dose-dense methotrexate, vinblastine, doxorubicin, plus cisplatin, granulocyte- colony stimulating factor, gemcitabine plus cisplatin, glomerular filtration rate, immune cell PD-L1 expression grade, Kamofsky performance status, methotrexate, carboplatin, plus vinblastine, methotrexate, vinblastine, doxorubicin, plus cisplatin, not reported, New York Heart Association, objective response rate, paclitaxel, gemcitabine plus cisplatin, progression-free survival, performance status, urothelial carcinoma, urothelial carcinoma of the bladder, upper tract urothelial carcinoma, World Health Organization Table 2 Planned, ongoing, and completed trials incorporating targeted or immune therapy (if applicable)identifierataxia telangiectasia and Rad3 related, best supportive care, cyclin-dependent kinase 4, cyclin-dependent kinase 6, cisplatin-eligible, cisplatin-ineligible, cytotoxic T lymphocyte-associated protein 4, epidermal growth factor receptor, fibroblast growth factor receptor, fibroblast growth factor receptor 3, farnesyltransferase, gemcitabine plus cisplatin, histone deacetylase, human epidermal growth factor receptor 1, human epidermal growth factor receptor 2, heat shock protein 27, mechanistic target of rapamycin, programmed death 1, programmed death ligand 1, phosphoinositide 3-kinase, rearranged during transfection, Recepteur dOrigine Nantais, soluble ephrin type-B receptor 4-human serum albumin, vascular endothelial growth factor, vascular endothelial growth factor receptor 2 Results First-line chemotherapy in cisplatin-eligible patients Similar to patients with UCB, the first-line treatment for Y16 metastatic UTUC is cisplatin-based combination chemotherapy; however, an initial determination must be made regarding fitness for cisplatin. Using a consensus definition, patients meeting any of the following criteria are considered unfit for cisplatin: (1) World Health Organization (WHO) or Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or Karnofsky performance status (KPS) 60C70 %; (2) creatinine clearance (CrCl) 60 mL/min; (3) grade 2 hearing loss; (4) grade 2 peripheral neuropathy; and (5) New York Heart Association (NYHA) class III heart failure [2]. For cis-platin-eligible patients, three standard regimens may be considered for the first-line treatment of metastatic UTUC: methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC); dose-dense MVAC (DD-MVAC); and gemcitabine plus cisplatin (GC). MVAC became the first primary regimen for metastatic UC after demonstrating a median survival of 13 months in spite of significant toxicity including myelosuppression, mucositis, and drug-related mortality in 3C4 % of patients [3, 4]. The introduction of granulocyte colony-stimulating factor (G-CSF) decreased the incidence of myelosuppression and mucositis. DD-MVAC with G-CSF support as compared to MVAC demonstrated similar survival outcomes.

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