阿昔替尼与索拉非尼一线治疗晚期肾癌的临床疗效

目的:比较阿昔替尼与索拉非尼一线治疗晚期肾癌的临床疗效,探讨分子靶向药物阿昔替尼能否作为一线治疗晚期肾癌的优选药物.方法:选取海口市人民医院肿瘤科60例晚期肾癌患者,以数字表法随机分为试验组和对照组,每组30例.实验组给予阿昔替尼,对照组给予索拉非尼治疗,比较两组患者的DCR、ORR、PFS、OS及不良反应的差异.结果:两组患者均能完成试验并进行结果评价.试验组和对照组的DCR分别为83.33％和80.00％、ORR分别为20.00％和20.00％,差异均无统计学意义(P＞0.05);试验组和对照组的中位PFS分别为12.8个月和10.1个月,差异有统计学意义(P＜0.05);中位OS分别为22.2个月和22.8个月,差异无统计学意义(P＞0.05).两组患者不良反应发生率相近,差异无统计学意义(P＞0.05),主要表现在高血压、全身反应、手足皮肤综合征、消化道反应、肝功能损害,未见严重不良反应.结论:分子靶向药物阿昔替尼较索拉非尼一线治疗晚期肾癌更能延长患者中位PFS,两药治疗后患者的DCR、ORR、OS及不良反应相似,阿昔替尼可以作为一线治疗晚期肾癌的优选.     

Long-lasting successful cerebral response with sorafenib in advanced renal cell carcinoma

We report the case of a 75-year old woman who received sorafenib (Nexavar), Bayer Pharmaceuticals Corporation, West Haven, CT) for a CNS relapse of clear cell renal cell carcinoma. After four months of sorafenib treatment, a brain magnetic resonance imaging showed 95%-volumetric regression of cerebral metastasis. To the best of our knowledge, this is the first almost complete resolution of brain metastases in renal cell carcinoma treated with sorafenib that has been described.     

A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma

There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand–foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC.     

索拉非尼治疗转移性肾癌的疗效与安全性观察

目的:评估63例转移性肾细胞癌（metastatic renal cell carcinoma,mRCC）患者服用索拉非尼的疗效及安全性。方法:前瞻性观察2010年6月至2018年6月就诊于西安交通大学第一附属医院肿瘤内科及中华慈善总会索拉非尼援助赠药项目mRCC患者共计71例,其中63例可评价疗效及安全性。使用SPSS 18.0 软件进行K-M单因素生存分析,所得阳性因素导入COX回归模型进行多因素分析,明确影响索拉非尼治疗mRCC疗效的因素。结果:63例可评价mRCC患者中,无CR患者,PR 18例,SD 22例,PD 23例,ORR为28.57%（18/63）,DCR为63.49%（40/63）;中位PFS为14月（3~51月）,中位OS为29月（6~69月）;所有不良反应均可控或随剂量减少而降低。索拉非尼作为mRCC一线治疗者39例,二线及以上治疗者24例。一线和二线及以上治疗的ORR及DCR均无统计学差异,且中位PFS分别为24月（4~51月）和13月（3~42月）（P=0.021）。COX回归分析示,索拉菲尼是否为一线治疗是影响PFS的独立危险因素（P=0.030）。结论:索拉非尼治疗mRCC疗效确切,不良反应较少,并且是否为一线治疗是影响患者中位PFS的独立预测因素。     

Sequential therapy with sorafenib and sunitinib in renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are small‐molecule tyrosine kinase inhibitors (TKI) with antitumor activity in advanced renal cell carcinoma. A retrospective study was conducted to assess the response of renal cell carcinoma to sequential treatment with these two agents.

METHODS:

Tumor response was evaluated by using Response Evaluation Criteria In Solid Tumors (RECIST) criteria in patients failing first‐line therapy with either sunitinib or sorafenib and subsequently receiving second‐line therapy with the other TKI agent.

RESULTS:

Twenty‐nine patients received sorafenib followed by sunitinib (Group A), and 20 patients received sunitinib followed by sorafenib (Group B). TKI drugs were terminated in 6 (12%) patients in Group A and 4 (8%) in Group B because of toxicity. Median duration of stable disease for Groups A and B was 20 and 9.5 weeks, respectively. Median time from starting first TKI to disease progression after second TKI (time to progression) in Groups A and B was 78 and 37 weeks, respectively. Multivariate analysis revealed that Group B had a shorter time to progression than Group A (risk ratio [RR] 3.0; P = .016). Median overall survival was 102 and 45 weeks in Groups A and B, respectively (P = .061).

CONCLUSIONS:

The longer duration of disease control in patients who received sorafenib followed by sunitinib warrants further investigation. Cancer 2009. © 2008 American Cancer Society.     

Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib.

BACKGROUND: Sorafenib is an orally bioavailable vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity in metastatic renal cell carcinoma (RCC). Sunitinib, also a VEGFR inhibitor, induces biochemical hypothyroidism in 85% of metastatic RCC patients, the majority of whom have signs or symptoms of hypothyroidism. Hence, the incidence of thyroid function test (TFT) abnormalities in patients with metastatic RCC receiving sorafenib was investigated. PATIENTS AND METHODS: Sixty-eight patients with metastatic RCC were treated with sorafenib at the Cleveland Clinic Taussig Cancer Center, and 39 patients had TFTs available. RESULTS: Eight patients (21%) had thyroid dysfunction possibly caused by sorafenib [seven hypothyroidism (18%) and one hyperthyroidism (3%)] and eight additional patients (21%) had findings compatible with nonthyroidal illness. Only two patients had clinical signs and symptoms secondary to thyroid dysfunction and received thyroid hormone replacement. CONCLUSIONS: In summary, clinically significant TFT abnormalities were not common in patients treated with sorafenib, and replacement therapy was rarely indicated. TFTs should be measured before sorafenib therapy in RCC patients and subsequently only if clinically indicated.     

Pituitary metastasis from a renal cell carcinoma progressed after sorafenib treatment

Pituitary metastasis from renal cell carcinoma is rare and has never been reported for renal cell carcinoma primarily treated with sorafenib. Herein, we present a case of an advanced clear-cell renal cell carcinoma in which pituitary metastasis progressed but extracerebral metastases showed partial response to sorafenib treatment.     

舒尼替尼与索拉非尼交替应用治疗肾癌1例并文献复习

目的:探讨舒尼替尼与索拉非尼交替应用治疗转移性肾癌的疗效。方法:报道舒尼替尼与索拉非尼交替应用治疗转移性肾癌1例并结合文献讨论。结果:该患者一线舒尼替尼治疗疾病进展时间（TTP）为6个月。二线索拉非尼治疗TTP为5个月。二线治疗失败后改变舒尼替尼给药方式（37.5mg 每日1次,连续口服）继续治疗,三线TTP为8个月。结论:患者一线应用舒尼替尼和二线应用索拉非尼的治疗疗效与文献报道相符。二线治疗失败后改变舒尼替尼给药方式继续治疗仍获得较好的疗效。     

Nutlin‐3 enhances sorafenib efficacy in renal cell carcinoma

The renal cell carcinoma (RCC) is one of the top 10 cancers in USA. The renal tumors are highly angiogenic and are resistant to conventional interventions, particularly radiotherapy. The advent of multi‐specific tyrosine kinase inhibitor sorafenib has improved the progression‐free survival in RCC, but overall survival in recurrent and metastatic RCC is still a concern that has lead to characterization of combinatorial regimens. Hence, we studied the effect of combination of nutlin‐3, an MDM2 inhibitor, which increases p53 levels, and sorafenib in RCC. Sorafenib along with nutlin‐3 synergistically inhibited the cell survival and enhanced caspase‐3 cleavage leading to apoptosis in RCC. Nutlin‐3 and sorafenib were more effective in reducing the migration of RCC, in combination than as single agents. Sorafenib and nutlin‐3 decreased the phosphorylation of vascular endothelial growth factor receptor‐2 (VEGFR‐2) and ERK along with inducing p53 activity. The sorafenib and nutlin‐3 co‐treatment lead to enhanced levels of p53, p‐p53, and increase in the levels of p53 pro‐apoptotic effector PUMA, Bax, and decrease in the anti‐apoptotic Bcl‐2 levels. Importantly, our studies revealed that sorafenib alone can activate p53 in a concentration dependent manner. Thus, co‐treatment of nutlin‐3 with sorafenib leads to increased half‐life of p53, which in turn can be activated by sorafenib, to induce downstream pro‐apoptotic and anti‐proliferative effects. This is the first report showing the synergistic effect of sorafenib and nutlin‐3 while providing a strong clinical‐translational rationale for further testing of sorafenib and nutlin‐3 combinatorial regimen in human RCC. © 2011 Wiley Periodicals, Inc.     

Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial

Background:

Preclinical investigations support combining sorafenib with IL-2 in the treatment of metastatic renal cell carcinoma (mRCC).

Methods:

In this open-label, phase II study, 128 patients with mRCC were randomised to receive oral sorafenib, 400 mg twice daily, plus subcutaneous IL-2, 4.5 million international units (MIU) five times per week for 6 in every 8 weeks, or sorafenib alone. After enrolment of the first 40 patients, IL-2 dose was reduced to improve the tolerability.

Results:

After a median follow-up of 27 months, median progression-free survival (PFS) was 33 weeks with sorafenib plus IL-2, and 30 weeks with sorafenib alone (P=0.109). For patients receiving the initial higher dose of IL-2, median PFS was 43 weeks vs 31 weeks for those receiving the lower dose. The most common adverse events were asthenia, hand–foot syndrome, hypertension, and diarrhoea. Grade 3–4 adverse events were reported for 38 and 25% of patients receiving combination and single-agent treatment, respectively.

Conclusion:

The combination of sorafenib and IL-2 did not demonstrate improved efficacy vs sorafenib alone. Improvements in PFS appeared greater in patients receiving higher-dose IL-2.     

Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial

Background:

In the AXIS trial, axitinib prolonged progression-free survival (PFS) vs sorafenib in patients with advanced renal cell carcinoma (RCC) previously treated with sunitinib or cytokines.

Methods:

In post hoc analyses, patients were grouped by objective response to prior therapy (yes vs no), prior therapy duration (< vs ⩾median), and tumour burden (baseline sum of the longest diameter < vs ⩾median). PFS and overall survival (OS), and safety by type and duration of prior therapy were evaluated.

Results:

Response to prior therapy did not influence outcome with second-line axitinib or sorafenib. PFS was significantly longer in axitinib-treated patients who received longer prior cytokine treatment and sorafenib-treated patients with smaller tumour burden following sunitinib. Overall survival with the second-line therapy was longer in patients who received longer duration of prior therapy, although not significant in the sunitinib-to-axitinib sequence subgroup; OS was also longer in patients with smaller tumour burden, but not significant in the cytokine-to-axitinib sequence subgroup. Safety profiles differed modestly by type and duration of prior therapy.

Conclusions:

AXIS data suggest that longer duration of the first-line therapy generally yields better outcome with the second-line therapy and that lack of response to first-line therapy does not preclude positive clinical outcomes with a second-line vascular endothelial growth factor-targeted agent in patients with advanced RCC.     

索拉非尼治疗转移性肾癌疗效与不良反应的关系

目的:探索索拉非尼在治疗转移性肾细胞癌（mRCC）患者中的不良反应与疗效之间的关系。方法:回顾性研究西京医院接受索拉非尼治疗的mRCC患者63例,利用卡方检验分析肿瘤控制率与不良反应的发生频率和严重程度的相关性,利用Kaplan-Meier方法分析16种不良反应,筛选出与患者PFS,OS相关的不良反应,将P＜0.05变量纳入多变量Cox比例风险回归模型进行进一步的多因素分析,确定独立预后因素。结果:63例接受索拉非尼治疗的患者中,完全缓解2例（3.2％）,部分缓解16例（25.4％）,疾病稳定37例（58.7％）,疾病进展8例（12.7％）。中位PFS为12.0个月,中位OS为24.0个月。卡方检验结果示肿瘤控制率与不良反应的发生频率和严重程度相关（均P＜0.05）。多变量分析显示,更好的PFS的独立预后因素包括腹泻（OR 0.255,95％CI 0.130~0.500,P=0.000）和皮疹（OR 0.235,95％CI 0.114~0.482,P=0.000）。OS的独立预后因素包括腹泻（OR 0.454,95％CI 0.246~0.839,P=0.012）,皮疹（OR 0.405,95％CI 0.211~0.776,P=0.006）和高血压（OR 0.373,95％CI 0.177~0.784,P=0.009）。结论:索拉非尼治疗mRCC患者的疗效与不良反应的发生频率和严重程度呈正相关。皮疹和腹泻是影响PFS的独立保护因素,皮疹,腹泻和高血压是影响OS的独立保护因素。这一结论仍需大量前瞻性研究证实。     

Clusterin inhibition using OGX-011 synergistically enhances antitumour activity of sorafenib in a human renal cell carcinoma model

Background:

The objective of this study was to investigate whether the therapeutic activity of sorafenib could be enhanced by combining with OGX-011, an antisense oligodeoxynucleotide (ODN) targeting clusterin, in renal cell carcinoma (RCC).

Methods:

We investigated the effects of combined treatment with OGX-011 and sorafenib on a human RCC ACHN model both in vitro and in vivo.

Results:

Although clusterin expression was increased by sorafenib, additional treatment of ACHN with OGX-011 significantly blocked the upregulation of clusterin induced by sorafenib. Despite the lack of a significant effect on the growth of ACHN, OGX-011 synergistically enhanced the sensitivity to sorafenib, reducing the IC₅₀ by >50%. Apoptotic changes were intensively detected in ACHN after combined treatment with OGX-011 and a sublethal dose of sorafenib, but not either agent alone. Furthermore, this combined treatment resulted in the marked downregulation of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN compared with treatment with either agent alone. In vivo systemic administration of OGX-011 plus sorafenib significantly decreased the ACHN tumour volume compared with control ODN plus sorafenib.

Conclusion:

Combined use with OGX-011 may be useful in enhancing the cytotoxic effect of sorafenib on RCC by inducing apoptosis and inactivating major signal transduction pathways.     

Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America

BACKGROUND:

The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval.

METHODS:

In this nonrandomized, open‐label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months.

RESULTS:

The most common grade ≥2 drug‐related adverse events were hand‐foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression‐free survival in the extension population was 36 weeks (95% confidence interval [CI], 33‐45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46‐52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups.

CONCLUSIONS:

Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020). Cancer 2010. © 2010 American Cancer Society.     

Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma

OBJECTIVE: Sorafenib (Nexavar) is an oral multi-kinase inhibitor that targets tumor growth and angiogenesis. This phase II study investigated efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma (RCC). METHODS: Nonrandomized, open-label study in Japanese patients with metastatic renal cell carcinoma who had received nephrectomy and failed >/=1 cytokine-containing therapy. The primary endpoint was response rate. Patients received sorafenib 400 mg twice daily (b.i.d.) on a continuous dosing schedule. RESULTS: A total of 129 patients (median age 63 years) were valid for intention-to-treat analyses. Confirmed partial responses were observed in 16 (12.4%) patients, and investigators assessed that 19 (14.7%) of the patients achieved a partial response. Stable disease was reported in 93 (72.1%) patients, and 103 (80.5%) patients had tumor shrinkage. Median progression-free survival was 224 days and the 25th percentile of overall survival was estimated at 288 days. The most frequently occurring drug-related adverse events (any grade) were elevated lipase (56%), hand-foot skin reaction (55%), alopecia (39%), increased amylase (38%), rash/desquamation (37%), and diarrhea (34%). A total of 14 (10.7%) patients had serious sorafenib-related adverse events, including one adverse event of worst grade 5 (dyspnea occurred 35 days after the last dose of study medication). The C(trough,steady state) values in RCC patients (n = 63) receiving sorafenib 400 mg b.i.d. were similar to those obtained from a Japanese phase I study involving patients with mixed solid tumors. CONCLUSION: Sorafenib showed encouraging efficacy and was well tolerated in Japanese patients with metastatic RCC.     

Role of sorafenib in renal cell carcinoma: focus on elderly patients

Mounting evidence suggests that, in order to optimize therapeutic benefits, it is important to consider the range of parameters and characteristics relevant to each individual patient. Of note, the six targeted therapies currently approved for the treatment of advanced/metastatic renal cell carcinoma have not been evaluated in all relevant settings and in all prognostic groups. Among different agents currently licensed for the treatment of renal cell carcinoma, sorafenib was the first therapy to show improvements in progression-free survival and overal survival in Phase III trials. This article will discuss the current role of sorafenib in the treatment of elderly patients with renal cell carcinoma.     

New drug therapies for advanced renal cell carcinoma

The incidence of renal cell cancer is increasing and surgery is the only curative treatment for patients presenting with localized disease at diagnosis. The treatment of metastatic renal cell cancer is palliative and, until recently, immunotherapy has been the standard treatment approach with response rates between 10 and 20%. An increase in the appreciation of the biology of this disease has resulted in a number of new ‘targeted’ therapies being developed. Most notable is the introduction of tyrosine kinase inhibitors with significant activity in both treatment-naive and cytokine-refractory renal cell cancer. Drugs targeting angiogenic pathways also appear promising. These agents are being rapidly introduced into clinical practice, but further studies are needed to establish their optimal place in the management of renal cell cancer and, in particular, the role of combination and/or sequential therapy.     

Hypothyroidism in patients with renal cell carcinoma

BACKGROUND:

Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC.

METHODS:

Eighty‐seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid‐stimulating hormone (TSH), tri‐iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 μM/mL) with normal T3 and T4 levels.

RESULTS:

Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14‐0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014).

CONCLUSIONS:

The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered. Cancer 2011. © 2010 American Cancer Society.