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Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study.

ABSTRACT: BACKGROUND:Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We also evaluated the feasibility of contrast-enhanced ultrasound (D-CEUS) as a predictor of early tumour response to famitinib and to correlate functional parameters with clinical efficacy. METHODS:The trial was conducted in subjects with stage III or IVa-b NPC using a 3?+?3 design of escalating famitinib doses. Briefly, subjects received 2 weeks of famitinib monotherapy followed by 7 weeks of famitinib plus CCRT. D-CEUS of the neck lymph nodes was performed at day 0, 8 and 15 after famitinib was administered before starting concurrent chemoradiotherapy. End points included safety, tolerability and anti-tumour activity. RESULTS:Twenty patients were enrolled (six each for 12.5, 16.5 and 20 mg and two for 25 mg). Two patients in the 25 mg cohort developed dose-limiting toxicities, including grade 4 thrombocytopenia and grade 3 hypertension. The most common grade 3/4 adverse events were leukopenia, neutropenia and radiation mucositis. D-CEUS tests showed that more than 60% of patients achieved a perfusion parameter response after 2 weeks taking famitinib alone, and the parameter response was associated with disease improvement. In the famitinib monotherapy stage, three patients (15%) showed partial responses. The complete response rate was 65% at the completion of treatment and 95% 3 months after the treatment ended. After a median follow-up of 44 months, the 3-year progression-free survival (PFS) and distant metastasis-free survival were 70% and 75%, respectively. Subjects with a decrease of perfusion parameter response, such as peak intensity decreased at least 30% after 1 week of famitinib treatment, had higher 3-year PFS (90.9% vs. 44.4%, 95% CI 73.7%-100% vs. 11.9%-76.9%, P?

SUBMITTER: Chen Q

PROVIDER: S-EPMC6235389 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study.

Chen Qiuyan Q Tang Linquan L Liu Na N Han Feng F Guo Ling L Guo Shanshan S Wang Jianwei J Liu Huai H Ye Yanfang Y Zhang Lu L Liu Liting L Wang Pan P Li Yingqin Y He Qingmei Q Yang Xiaoqun X Tang Qingnan Q Li Yang Y Liang YuJing Y Sun XueSong X Xie Chuanmiao C Mo Yunxian Y Guo Ying Y Sun Rui R Mo Haoyuan H Cao Kajia K Guo Xiang X Zeng Musheng M Mai Haiqiang H Ma Jun J Ma Jun J

Cancer communications (London, England) 20181101 1

<h4>Background</h4>Famitinib is a tyrosine kinase inhibitor against multiple targets, including vascular endothelial growth factor receptor 2/3, platelet-derived growth factor receptor, and stem cell factor receptor (c-kit). Previous studies have demonstrated anti-tumour activities of famitinib against a wide variety of advanced-stage solid cancers. We aimed to determine the safety and efficacy of famitinib with concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopha ...[more]

PMID: 30382933

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Project description:PurposeThis large population-based analysis aims to investigate whether the additional induction chemotherapy to concurrent chemoradiotherapy improved overall survival (OS) and disease-free survival (DFS) for locoregionally advanced nasopharyngeal carcinoma (LRANPC).Patients and methodsThe study group comprised 3,980 patients who were treated either with IC+CCRT (1,888 patients) or CCRT alone (2,092 patients) between January 1998 and June 2013. Survival outcomes were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods. Primary outcome variables included OS and DFS.ResultsKaplan-Meier analysis showed that CCRT and IC+CCRT were of similar benefit to OS (P=0.099), whereas there was a marginal benefit of CCRT to DFS (P=0.063) in the overall cohort, which showed no differences between the two treatment regimens using multivariate Cox analysis and propensity score. Interestingly, for patients with 2D radiationtherapy (2DRT), CCRT had OS and DFS benefits for stage III, with 5-year and 10-year OS for CCRT vs IC+CCRT being 88% and 75% vs 81% and 67%, respectively (P=0.002); 5-year and 10-year DFS for CCRT vs IC+CCRT being 84% and 74% vs 76% and 66%, respectively (P=0.002). In contrast, IC + CCRT had OS and DFS benefits for stage IVa-b, with 5-year and 10-year OS for CCRT vs IC+CCRT being 71% and 55% vs 76% and 60%, respectively (P=0.037, HR=0.786); 5-year and 10-year DFS for CCRT vs IC+CCRT were 64% and 50% vs 69% and 58%, respectively (P=0.038, HR=0.801). No difference was found in intensity-modulated radiotherapy (IMRT) subgroup.ConclusionOur study indicates that CCRT and IC+CCRT may have similar OS and DFS benefits for overall LRANPC. Stage-specific chemoradiotherapy may be administered based on the greatest benefit of IC+CCRT for stage IVa-b patients and CCRT alone for stage III patients received 2DRT. The optimal chemotherapy pattern in combination with IMRT needs further investigation.Trial registration ClinicalTrials.gov ID: NCT02604472.

Project description:The objective of this study was to evaluate the prognostic value of the cumulative cisplatin dose (CCD) for long-term survival outcomes after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC).Patients were included in an open-label phase III multicenter randomized controlled trial performed at seven institutions in China, and the 298 patients receiving CCRT only were assessed. Patient survival between different CCD groups were compared.Median CCD for the 298 patients was 240 mg/m2 (range, 40-320 mg/m2); 113 (37.9%) patients received a CCD of <240 (?200) mg/m2, and 185 (62.1%) received a CCD of ?240 mg/m2. For CCD of ?240 mg/m2 vs. <240 mg/m2, the estimated 5-year overall survival, disease-free survival, locoregional relapse-free survival, and distant metastasis-free survival rates were 83.2% vs. 76.2% (p = .403), 73.5% vs. 67.8% (p = .461), 90.4% vs. 86.8% (p = .551), and 82.6% vs. 79.7% (p = .632), respectively. Multivariate analysis demonstrated that CCD (240 mg/m2) was not an independent prognostic factor in either the entire cohort or stage III/IV subgroup.A CCD of ?240 mg/m2 was not an independent prognostic factor in patients with locoregionally advanced NPC at high risk of distant metastasis, and 200 mg/m2 cisplatin may be adequate to achieve a survival benefit.The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based concurrent chemoradiotherapy (CCRT), and the cisplatin is delivered every 3 weeks (100 mg/m2) for three cycles. However, the prognostic value of cumulative cisplatin dose (CCD) delivered during CCRT is controversial. The present study investigated the prognostic value of CCD and demonstrated that a CCD of 200 mg/m2 during CCRT is adequate to achieve satisfactory survival outcomes for patients with locoregionally advanced NPC. This finding is of great importance to clinicians because it could allow patients to avoid excessive treatment and toxicities.

Project description:BACKGROUND:Promising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy (CCRT) were reported in head and neck cancer. In addition, the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma (NPC) was verified. However, CCRT with docetaxel for locoregionally advanced NPC are not well studied. This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC. METHODS:Clinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel (15 mg/m2) or tri-weekly cisplatin (80-100 mg/m2) were reviewed. Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics. Adverse events and survival were compared between the two groups. RESULTS:A total of 962 patients were included as the whole cohort, and 448 patients were matched and were regarded as the matched cohort. The median follow-up duration was 48 months for the whole cohort. The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole (hazard ratio [HR] = 0.37, 95% confidence interval [CI] 0.19-0.72, P = 0.030) and matched cohorts (HR = 0.33, 95% CI 0.14-0.79, P = 0.023). However, no significant differences were observed in overall survival, local recurrence-free survival, and distant metastasis-free survival between the two groups in both cohorts. Significantly higher rates of grade 3 radiodermatitis (6.7% vs. 1.8%, P = 0.001), mucositis (74.5% vs. 37.9%, P < 0.001), and leucopenia (2.2% vs. 11.6%, P < 0.001) were observed in the docetaxel group, but any grade of renal injury (1.8% vs. 15.1%, P < 0.001), vomiting (18.8% vs. 88.3%, P < 0.001), and ALT elevation (19.2% vs. 31.3%, P = 0.027) were more common in the cisplatin group. CONCLUSIONS:CCRT with weekly low-dose docetaxel is an effective and tolerable therapeutic regimen for locally advanced NPC. It provides a survival benefit mainly by improving the control of regional lymph node metastases, especially for patients with low pretreatment EBV DNA levels.

Dataset Information

Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study.

Publications

Famitinib in combination with concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 1, open-label, dose-escalation Study.

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