Table 1.
Select clinical trials with reported outcomes
| Phase | n | % UCB | % UTUC | Arm A | Arm B | Median survival (A vs. B; months) | p value | Notes | Reference |
|---|---|---|---|---|---|---|---|---|---|
| First-line therapy for cisplatin-eligible patients | |||||||||
| II | 133 | 75 | 17 | MVAC | - | 13.3 | - | [3] | |
| III | 269 | 87 | NR | MVAC | Cisplatin | 12.5 versus 8.2 | 0.002 | [4] | |
| III | 263 | 85 | 13 | DD-MVAC + G-CSF | MVAC | 15.1 versus 14.9 | – | 5-year survival was significantly higher with DD-MVAC + G-CSF at 21.8 versus 13.5 % with MVAC. | [5,6] |
| III | 405 | 100 | 0 | GC | MVAC | 13.8 versus 14.8 | 0.75 | [7] | |
| III | 85 | NR | NR | Paclitaxel + carboplatin | MVAC | 13.8 versus 15.4 | 0.65 | [8] | |
| III | 220 | 84 | 16 | Docetaxel + cisplatin | DD-MVAC + G-CSF | 9.3 versus 14.2 | 0.026 | Survival difference was nonsignificant after adjusting for prognostic factors (p = 0.089). | [9] |
| III | 130 | 83 | 13 | Dose-dense GC + G-CSF | DD-MVAC + G-CSF | 18.0 versus 19.0 | 0.98 | [10] | |
| III | 626 | 82 | 13 | PGC | GC | 15.8 versus 12.7 | 0.075 | [11] | |
| II | 63 | 83 | 18 | Sunitinib + GC | - | 12 | - | [12] | |
| II | 98 | 70 | 30 | Sorafenib + GC | Placebo + GC | 11.3 versus 10.6 | 0.66 | [13] | |
| First-line therapy for cisplatin-ineligible patients | |||||||||
| II/III | 238 | 74 | 22 | Carbo/gem | M-CAVI | 9.3 versus 8.1 | 0.64 | Criteria: (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] |
| II | 51 | 61 | 39 | Bevacizumab + carbo/gem | – | 13.9 | – | Criteria: (1) KPS 60–70 %; (2) CrCl < 60 ml/min; (3) visceral metastasis; and/or (4) solitary kidney. | [17] |
| I/II | 32 | 100 | 0 | Split-dose cisplatin (day 1 and 8) + gemcitabine (21-day cycle) | - | 16 | - | Criteria: (1) WHO PS 0–2 and (b) GFR > 40 ml/min. | [18] |
| - | 38 | 97 | 0 | Split-dose cisplatin (day 1 and 15) + gemcitabine (28-day cycle) | - | 8.5 | - | Criterion: CrCl between 35 and 59 ml/min. | [19] |
| II | 69 | 52 | 46 | Vinfìunine + gemcitabine | Vinfìunine + carboplatin | 14.0 versus 12.8 | 0.86 | Criteria: (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 | |||||||||
| III | 370 | NR | NR | Vinfìunine + BSC | BSC | 6.9 versus 4.6 | 0.287 | Significant after adjusting for “eligible” patients. | [21] |
| II | 47 | NR | NR | Pemetrexed | - | 9.6 | - | [22] | |
| II | 31 | 94 | 6 | Paclitaxel | - | 7.2 | - | [23] | |
| II | 30 | 83 | 17 | Docetaxel | - | 9 | - | [24] | |
| II | 148 | NR | NR | Ramucirumab + docetaxel | Docetaxel | 10.4 versus 9.2 | 0.201 | Median PFS: 5.4 months with arm A versus 2.8 months with arm B (p = 0.0002). Trial included a third arm, icru- cumab + docetaxel, which did not improve PFS. |
[25] |
| Immunotherapy | |||||||||
| Ib | 33 | NR | NR | Pembrolizumab | - | 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] |
| Ib | 44 | NR | NR | Avelumab | - | NR | - | Studied as second-line therapy. ORR was 15.9 % overall and 40 % in PD-Ll-positive tumors. |
[39] |
| II | 316 | 74 | 21 | Atezolizumab | - | 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] |
BSC best supportive care, Carbo/gem carboplatin plus gemcitabine, CrCl creatinine clearance, DD-MVAC dose-dense methotrexate, vinblastine, doxorubicin, plus cisplatin, G-CSF granulocyte- colony stimulating factor, GC gemcitabine plus cisplatin, GFR glomerular filtration rate, IC immune cell PD-L1 expression grade, KPS Kamofsky performance status, M-CAVI methotrexate, carboplatin, plus vinblastine, MVAC methotrexate, vinblastine, doxorubicin, plus cisplatin, NR not reported, NYHA New York Heart Association, ORR objective response rate, PGC paclitaxel, gemcitabine plus cisplatin, PFS progression-free survival, PS performance status, UC urothelial carcinoma, UCB urothelial carcinoma of the bladder, UTUC upper tract urothelial carcinoma, WHO World Health Organization