Prospective randomized double‐blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO‐AB 31/05)

Abstract

Objective To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine‐kinase inhibitor, compared with chemotherapy alone as first‐line treatment in advanced urothelial cancer. Patients and Methods The study was a randomized phase II trial. Its primary aim was to show an improvement in progression‐free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double‐blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3–21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. Results Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand‐foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. Conclusion Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS.

Risk of treatment-related mortality with sorafenib in cancer patients: a meta-analysis of 20 randomly controlled trials

“…Baseline characteristics of all included studies are listed in Table 1. Underlying malignancies for these trials included RCC [5,16,18,22,24] (five trials), HCC [7,13,17] (three), NSCLC [8][9][10]12] (four), breast cancer [11,14,19] (three), melanoma [6,15] (two), thyroid cancer [21] (one), urothelial cancer [23] (one) and CRC [20] (one); The starting dose and schedule of sorafenib was based on the US Food and Drug Administration guideline (400 mg, orally, twice daily) in each study.…”

“…Sorafenib is a new targeted oral tumor treatment that inhibits a variety of intercellular and cell-surface kinases, including RAF kinase, VEGF receptor-2 and -3 [2][3][4], platelet-derived growth factor receptor beta, KIT and PLT-3. Sorafenib has been tested in randomized controlled trials (RCTs) for patients who have hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small-cell lung cancer (NSCLC), melanoma, colorectal cancer (CRC), breast cancer, urothelial cancer and thyroid cancer [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Fatal adverse events (FAEs) are defined as deaths that are usually secondary to drug use.…”

Molecular biology and targeted therapies for urothelial carcinoma

“…A randomized phase II study evaluated the efficacy of CG with or without sorafenib in 98 patients with advanced UC in the first-line setting. The addition of sorafenib did not show any benefit in terms of ORR (52.5% vs 47%), PFS (6.3 vs 6.1 months), or OS (11.3 vs 10.6 months), compared with CG alone [98].…”

Vinflunine and bladder cancer: present and future indications

“…Phase I and II studies have examined the impact of anti-EGFR drugs on advanced UC. 23 On the basis of these findings, a phase I trial assessing the combination of VFL and erlotinib has been designed. The trial has enrolled patients with advanced tumors, among which UC.…”