Sorafenib in combination with gemcitabine plus cisplatin chemotherapy in metastatic renal collecting duct carcinoma: A prospective, multicentre, single-arm, phase 2 study.

BACKGROUND: Collecting duct carcinoma (CDC) is a rare type of renal cancer with a poor prognosis. As there are no standard guidelines for the management of metastatic CDC (mCDC), we evaluated the efficacy and safety of combined therapies of sorafenib, gemcitabine, plus cisplatin in patients with mCDC. MATERIALS AND METHODS: A prospective, multicentre, single-arm, open-label, phase 2 trial (ClinicalTrials.gov identifier NCT01762150) that enrolled 26 mCDC patients with no prior systemic chemotherapy. Patients were treated with sorafenib (400 mg orally, twice daily) combined with chemotherapy (gemcitabine 1000 mg/m2, intravenously for 30-60 min on days 1 and 8, plus cisplatin 25 mg/m2, intravenously on days 1-3, repeated every 28 days for 4 cycles), until disease progression, unacceptable toxicity, or study discontinuation for any other reason. The primary end-points were progression-free survival (PFS) and 6-month PFS rate. RESULTS: The 6-month PFS rate was 65%, and the median PFS was 8.8 months (95% confidence interval [CI]: 6.7-10.9) with a median overall survival of about 12.5 months (95% CI: 9.6-15.4). The objective response rate was 30.8%, and the disease control rate was 84.6%. The treatment was generally well tolerated. Major grade 3/4 toxicities included leucopenia (26.9%), thrombocytopenia (23.1%), anaemia (11.5%) and palmar-plantar erythrodysesthesia (7.7%). CONCLUSIONS: Though the combination of sorafenib and chemotherapy demonstrated a similar outcome as that of the previously reported regimens in patients with mCDC, this combination may be a suitable option for patients who have low Eastern Cooperative Oncology Group performance status or less metastatic sites.

Nanosecond Pulsed Electric Fields Enhance the Anti-tumour Effects of the mTOR Inhibitor Everolimus against Melanoma.

The PI3K/mTOR/AKT pathway is activated in most melanomas, but mTOR inhibitors used singly have limited activity against advanced melanomas. The application of nanosecond pulsed electric fields (nsPEFs) is a promising cancer therapy approach. In this study, we evaluated the synergistic anti-tumour efficacy of the mTOR inhibitor everolimus in conjunction with nsPEFs against melanoma. The combined treatment of nsPEFs and everolimus gradually decreased cell growth concurrent with nsPEF intensity. nsPEFs alone or combined with everolimus could promote melanoma cell apoptosis, accompanied with a loss in cellular mitochondrial membrane potential and an increase in Ca2+ levels. In vivo experiments showed that a combination of the mTOR inhibitor everolimus and nsPEFs improved the inhibitory effect, and all skin lesions caused by nsPEFs healed in 1 week without any observed adverse effect. Combination treatment induced caspase-dependent apoptosis through the upregulation of the pro-apoptotic factor Bax and downregulation of the anti-apoptotic factor Bcl-2. Everolimus and nsPEFs synergistically inhibited angiogenesis by decreasing the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and CD34. Our findings indicate that nsPEFs in combination with an mTOR inhibitor can be used as a potential treatment approach for advanced melanoma.

Efficacy and safety of sorafenib versus sunitinib as first-line treatment in patients with metastatic renal cell carcinoma: largest single-center retrospective analysis.

We conducted this largest, single-center, retrospective study to determine the efficacy of sorafenib versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) in Chinese patients to validate the potential data on direct comparison of the efficacy of first-line treatment with sorafenib and sunitinib in the treatment of mRCC. From November 2006 to March 2015, we reviewed medical records from Peking University Cancer Hospital and found 169 patients receiving sorafenib (400 mg orally BID continuously in a 4-week cycle) and 165 patients receiving sunitinib (50 mg orally daily in a 6-week cycle; 4/2 schedule) as the first-line targeted therapy. Median follow-up was 23.0 months. In sorafenib and sunitinib groups, there is no significant difference in progression-free survival (PFS) (9.0 months [95%CI:8.00-12.00] vs 11.0 months [95%CI:9.00-14.00], respectively; P=0.6289) and overall survival (OS) (28.0 months [95%CI:24.00-34.00] vs 28.0 months [95% CI:19.00-33.00], respectively; P=0.979). Subgroup analysis based on Karnofsky performance status (KPS), pathological type, Memorial Sloan Kettering Cancer Center score, and metastasis was also conducted. Multivariate analysis revealed that sorafenib treated patients had superior efficacy in patients with a KPS of <90 and significantly better PFS (hazard ratio: 0.460 [95% CI:0.222-0.954]). Most common adverse events were hand-foot skin reaction and thrombocytopenia which were manageable. Overall, no significant differences were seen between sorafenib and sunitinib in the treatment of advanced renal cancer. However, fewer toxicities associated with sorafenib and superior efficacy in subgroups (non-clear cell carcinoma and KPS <90) indicates sorafenib as an effective first-line treatment agent in patients with mRCC.

[Phase II clinical trial of sorafenib plus local chemotherapy in the treatment of metastatic renal cell carcinoma with pleural effusion].

OBJECTIVE: To evaluate the safety and efficacy of sorafenib plus cisplatin in the treatment of metastatic renal cell carcinoma (mRCC) with pleural effusion. METHODS: A total of 30 patients with mRCC (clear cell carcinoma) with pleural effusion from April 2009 to January 2011 were recruited. All received sorafenib 400 mg twice daily. And 11 patients in chemotherapy group received sorafenib plus local chemotherapeutic perfusion of cisplatin 40 mg weekly for 2 weeks while another 19 patients in control group received sorafenib alone. RESULTS: The response rate of pleural effusion was 10/11 for chemotherapy group versus 3/19 for control group (χ(2) = 13.097, P < 0.01). Followed up to April 30(th), 2011, 5 of 11 patients in chemotherapy group and 10 of 19 patients in control group died. Among those on sorafenib, the median overall survival time was 22 months (95%CI: 2.12 - 41.88) for local chemotherapy versus 9 months (95%CI: 8.20 - 9.80) without local therapy (P = 0.04). The most common events in local chemotherapy group were I-II thoracic pain, nausea and vomiting. And the incidence rates were 8/11 and 9/11 versus 4/19 and 3/19 respectively (P < 0.01). The main laboratory abnormalities were similar in two groups. CONCLUSION: The regimen of sorafenib plus pleural cavity perfusion of cisplatin is both effective and safe in the treatment of mRCC with pleural effusion. It may control local symptoms and achieve a better overall survival.