舒尼替尼治疗转移性肾癌的初步评价

目的 评价舒尼替尼治疗转移性肾癌的疗效和安全性. 方法转移性肾癌患者31例.男23例,女8例.中位年龄55(25～75)岁.31例中行原发肿瘤切除30例,仅行活检术1例,病理证实为肾细胞癌,并至少有1处可测量的转移病灶.初始患者均口服舒尼替尼50 mg/d,用药4周、间歇2周为1个周期,每2个周期行CT扫描以评价疗效. 结果全组可评价疗效24例,无完全缓解病例,部分缓解5例、疾病稳定15例、疾病进展4例,其中死亡1例.中断治疗4例,其中因高龄、全身情况差、不能耐受服药1例,因经济困难停药2例,因肝功能损害停药1例.3例因治疗时间短而未评价.全组客观反应率21%(5/24),疾病控制率83%(20/24),中位无疾病进展生存时间11个月,1年无进展生存率80%.常见不良反应是手足皮肤反应、腹泻、食欲差、口腔炎、出血倾向和血液学毒性,分别通过外敷、口服药物和补液治疗得到及制. 结论舒尼替尼对转移性肾癌的病情控制有显著效果,也存在一定不良反应,通过及时干预和处理,患者大多可以耐受其不良反应.     

舒尼替尼治疗肾透明细胞癌的临床研究

目的 探讨舒尼替尼治疗肾透明细胞癌的疗效和安全性. 方法 我院2008年4月至2009年10月采用舒尼替尼治疗的肾透明细胞癌患者15例,男11例,女4例.年龄26 ～ 74岁,平均55岁.T3～T4期13例,其中8例曾行肾癌根治术,5例行肾活检术,病理诊断均为肾透明细胞癌.另2例为孤立肾肾癌T1a期合并肾功能不全,活检病理诊断为肾透明细胞癌.1例既往有高血压病史,单药控制血压＜140/90 mm Hg(1 mm Hg=0.133 kPa).肿瘤最大径(9.5 ±3.3)cm,可评估转移灶包括腹膜后淋巴结(6例)、纵隔淋巴结(3例)、脑(2例)、肺(6例)、骨(2例)及肝脏(2例).采用舒尼替尼50 mg,每天1次,用药4周、停药2周的方案.每个治疗周期开始前采用RECIST疗效评价标准对本组患者进行临床评估.观察并记录肿瘤变化情况、不良反应以及生存期等数据. 结果 本组用药时间1.5 ～15.0个月(中位时间6.0个月),最短为1个周期,最长10个周期.其中部分缓解7例,疾病稳定7例,疾病进展1例.治疗的客观反应率为46.7％ (7/15),疾病控制率为93.3％(14/15).6个月无进展生存率为93.3％(14/15),中位无进展生存时间12个月,治疗后肾肿瘤最大径(8.7±4.0)cm.1例既往有高血压病史者,第二周期血压＞ 160/105 mm Hg,降压药加量并调整为两联后血压控制良好;1例治疗前无高血压病史者,第三周期出现血压＞ 150/100 mm Hg,使用降压药后血压控制良好.此2例治疗后肿瘤最大径分别从4.2 cm和3.2 cm减小至2.0 cm和1.3 cm.本组1/2级不良反应:皮肤发黄及黄色汗液12例(80％),乏力12例(80％),甲状腺功能低下4例(26.7％),胆红素升高和三酰甘油升高各有7例(46.7％);3/4级不良反应4例,其中因突发血小板减少,出现消化道出血1例;严重乏力、恶心、呕吐合并严重手足皮肤反应3例. 结论 舒尼替尼治疗肾透明细胞癌效果良好,患者耐受性较好,安全性高.     

舒尼替尼治疗转移性肾癌的预后因素分析

目的 探讨影响舒尼替尼治疗转移性肾癌的预后因素. 方法 回顾性分析2008年5月至2012年12月82例接受舒尼替尼治疗的转移性肾癌患者的临床资料,男60例,女22例.年龄29～ 82岁,平均(56.1±11.3)岁.52例有血尿、腰痛、肿块等临床症状.肿瘤大小2.0～18.0 cm,平均(8.0±3.0) cm.肾肿瘤位于左侧41例,右侧37例,双侧4例.69例接受了肾切除术,13例未行肾切除术者行穿刺活检获得病理.病理诊断为透明细胞癌75例,乳头状癌、嫌色细胞癌、肉瘤样癌各2例,集合管癌1例.转移部位包括肺50例、肝11例、骨14例、胰腺3例、后腹膜淋巴结31例.美国东部肿瘤协作组(eastern cooperative oncology group,ECOG)评分1～2分52例,≥3分30例.Hb平均(132±24) g/L,治疗开始时59例低于正常值.碱性磷酸酶平均(90±65) U/L,治疗开始时9例异常.乳酸脱氢酶平均(168±114) U/L,治疗开始时6例异常者.WBC平均为(6.4±2.0)×109/L,治疗开始时2例异常.MSKCC风险模型高危组14例,中危组68例.74例在确诊1年内、8例在确诊1年后接受舒尼替尼治疗,59例治疗首月相对剂量密度≥50％.采用Kaplan-Meier生存分析法计算患者的生存率,log-rank检验生存率差异,应用Cox比例回归风险模型分析影响预后的因素. 结果 本组82例的总生存期为2.8264.1个月,平均(21.6±14.1)个月.Kaplan-Meier生存分析结果显示,1年存活率为71％,2年存活率为64％,3年存活率为58％.单因素分析结果显示ECOG评分≥2分(P=0.005)、初次就诊时有临床症状(P=0.031)、未行患肾切除术(P=0.012)、转移部位数目≥2个(P=0.015)、靶向治疗开始时的Hb值(P=0.005)、靶向治疗开始时的碱性磷酸酶值(P=0.007)、MSKCC评分≥3分(P=0.000)、肝转移(P=0.000)、骨转移(P=0.000)、舒尼替尼首月相对剂量密度＜50％(P=0.000)等10项因素对转移性肾癌的预后有影响.Cox多因素分析结果显示ECOG评分≥2分(P=0.136)、初诊时无临床症状(P=0.801)、靶向治疗开始时碱性磷酸酶值＜126 U/L(P=0.618)、无骨转移(P=0.068)、无胰腺转移(P=0.265)等是对预后有益的因素;舒尼替尼首月相对剂量密度≥50％(P=0.000)是影响转移性肾癌预后的独立因素. 结论 靶向药物可使影响转移性肾癌预后的因素发生一定变化.舒尼替尼首月相对剂量密度≥50％是影响转移性肾癌预后的独立因素.     

Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with downsizing to reconsider cytoreductive surgery

Objective  To evaluate neoadjuvant sunitinib in patients with synchronous metastatic renal cell cancer (mRCC) to downsize surgically complex tumours and reconsider cytoreductive surgery. Patients and methods  Retrospective analysis of ten consecutive mRCC patients treated with sunitinib in an expanded access program who presented with surgically complex primary tumours or bulky locoregional metastases. Surgery-limiting tumour sites (SLTSs) were defined as primary or retroperitoneal lesions with direct invasion of adjacent organs or encasement of vital structures on imaging. Patients received sunitinib 50 mg/day for 4 weeks on and 2 weeks off to be followed by cytoreductive surgery after downsizing and individual reassessment. Response was measured according to Response Evaluation Criteria in Solid Tumours (RECIST). Results  Six out of ten SLTSs revealed a reduction of tumour size with a median of 14% according to RECIST. None of the ten SLTSs had a partial response (PR), whilst at distant metastatic sites one complete remission and two PRs occurred. Downsizing of SLTSs appeared most prominent in the first 2–4 months, which resulted in reconsidering cytoreductive nephrectomy in three patients. These three tumours invaded the liver on imaging and were reduced by 11, 18 and 20%. Conclusions  In this patient group with mRCC and surgically complex primary tumours or locoregional metastases, downsizing of SLTSs by neoadjuvant sunitinib was limited. Cytoreductive surgery was reconsidered in three patients. Given the overall reduction in tumour burden by sunitinib alone, further investigation to define the role of cytoreductive surgery is warranted.     

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment

Introduction

The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib.

Early experience with sunitinib, combined with docetaxel, in patients with metastatic breast cancer

Sunitinib malate (SUTENT^®) is an oral, multitargeted tyrosine kinase inhibitor that blocks several pathways central to angiogenesis and tumor cell proliferation and migration, including vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). Sunitinib has demonstrated clinical activity as a single agent in patients with metastatic breast cancer and it is hypothesized that enhanced clinical benefit may be derived by combining sunitinib with chemotherapy or other targeted agents. The current report describes four patients with advanced/metastatic breast cancer who experienced clinically meaningful responses following treatment with sunitinib in combination with docetaxel.     

Third-line sorafenib after sequential therapy with sunitinib and mTOR inhibitors in metastatic renal cell carcinoma

Background

Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined.

Objective

To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective.

Design, setting, and participants

One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib–everolimus or temsirolimus–sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment.

Measurements

PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS).

Results and limitations

Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3–6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6–10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data.

Conclusions

Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.     

Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: Correlation with dynamic microbubble ultrasound data and review of the literature

BackgroundIncreased sunitinib exposure (area under the curve) is associated with better outcome in metastatic renal cell cancer. Recommendations for dose modification do not take this into account. A treatment strategy, based on individual patient toxicity, was developed to maximize dose and minimize time without therapy for patients who could not tolerate the standard sunitinib schedule of 50 mg given for 28 days with a 14-day break (50 mg, 28/14).MethodsA single-center retrospective review was conducted on patients with metastatic renal cell cancer treated from October 2005 to March 2010. Dose/schedule modifications (DSM) were done to keep toxicity (hematological, fatigue, skin, and gastrointestinal) at≤grade 2. DSM-1 was 50 mg, 14 days on/7 days off with individualized increases in days on treatment. DSM-2 was 50 mg, 7 days on/7 days off with individualized increase in days on treatment. DSM-3 was 37.5 mg with individualized 7-day breaks. DSM-4 was 25 mg with individualized 7-day breaks. Multivariable analysis was performed for outcome as a function of patient and treatment variables.ResultsOverall, 172 patients were included in the analysis. Most patients had clear cell histology (79.1%) with sunitinib given as a first-line therapy in 59%. The DSM-1 and 2 and DSM-3 and 4 groups had a progression-free survival (PFS) (10.9–11.9 mo) and overall survival (OS) (23.4–24.5 mo) that was significantly better than the PFS (5.3 mo; P<0.001) and OS (14.4 mo; P = 0.03 and 0.003) for the standard schedule (50 mg, 28/14). DCE-US in a subset of patients showed that maximum antiangiogenic activity was achieved after 14 days on therapy.ConclusionsIndividualized sunitinib scheduling based on toxicity may improve PFS and OS. This hypothesis is supported by several other respective data that are reviewed. A confirmatory prospective trial is ongoing.     

Early primary tumor size reduction is an independent predictor of improved overall survival in metastatic renal cell carcinoma patients treated with sunitinib

Background

In metastatic renal cell carcinoma (mRCC) patients treated with targeted agents and their primary tumor (PT) in situ, early PT decrease in size correlates with improved overall PT response, but the effect on overall survival (OS) is unknown.

Objective

To evaluate whether early PT size reduction is associated with improved OS in patients with mRCC undergoing treatment with sunitinib.

Design, setting, and participants

We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between January 2004 and December 2009 without prior systemic treatment who received sunitinib with their PT in situ.

Measurements

Two independent reviewers measured the diameter of the PT and metastatic disease at baseline and subsequent scans to assess response. Early minor response was defined as ≥10% decrease within 60 d of treatment initiation. Univariate and multivariate analyses were used to calculate a hazard ratio (HR) corresponding to the risk of death based on clinical and pathologic factors as well as PT response.

Results and limitations

We identified 75 consecutive patients with a median follow-up of 15 mo. All patients were intermediate or poor risk by common risk stratification systems. Median initial PT diameter was 9.7 cm. Median maximum PT size reduction was −10.2% overall and −36.4% in patients who had early minor PT response.Median OS for patients without minor PT response, with minor PT response after 60 d, and with early minor PT response was 10.3, 16.5, and 30.2 mo, respectively. On multivariate analysis, early minor response was an independent predictor of improved OS (HR: 0.26; p = 0.031). Other significant predictors included venous thrombus, multiple bone metastases, lactate dehydrogenase above the upper limit of normal, symptoms at presentation, and more than two metastatic sites.

Conclusions

Early minor PT response is associated with improved OS. Future studies should evaluate this prognostic factor to identify patients with prolonged OS.     

Clinical efficacy and prognostic factors for overall survival in Japanese patients with metastatic renal cell cancer treated with sunitinib

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? A randomized prospective phase III clinical trial for systemic treatment‐naïve metastatic renal cell cancer (RCC) patients demonstrated the superiority of sunitinib over interferon with an acceptable safety profile. However, a commonly asked question is whether patients with RCC in clinical trials are representative of those with this disease being seen in ordinary clinical practice. To our knowledge, this is the first report of sunitinib for the Japanese patients with metastatic RCC in ordinary clinical practice. The estimated median PFS and OS in this study were 9.3 and 32.2 months, respectively. The application of the MSKCC model distinctly separated OS curves (P < 0.001), suggesting that MSKCC prognostic factors might be still valid to predict survival in metastatic RCC in the era of molecular targeted therapy.

OBJECTIVES

• ? To report the treatment efficacy and safety profile of sunitinib for patients with metastatic renal cell carcinoma (RCC) in ordinary clinical practice.
• ? In addition, to investigate the prognostic clinicopathological factors in these patients.

PATIENTS AND METHODS

• ? The present study consisted of native Japanese patients with metastatic RCC, comprising 29 pretreated and 34 systemic treatment‐naïve patients.
• ? Univariate and multivariate analyses were performed by the log‐rank test and the Cox proportional hazards model, respectively.

RESULTS

• ? Estimated median progression‐free survival and overall survival (OS) were 9.3 months (95% confidence interval, CI, 5.0–13.7) and 32.2 months (95% CI, 24.4–40.0), respectively.
• ? Among the patients pretreated before sunitinib, two patients were treated with initialized systemic therapy with sorafenib and the remaining 27 were initialized with interferon‐α.
• ? The OS from the initial systemic therapy of the patients in pretreated groups was 79.6 months (95% CI, 14.6–144.5).
• ? The application of the Memorial Sloan‐Kettering Cancer Center model distinctly separated the OS curves (P < 0.001).
• ? The most common grade 3 adverse events were fatigue (53%), thrombocytopaenia (48%), hand‐foot syndrome (16%), anaemia (20%), hypertension (10%) and leucopaenia (9%), although these events were manageable and reversible.

CONCLUSIONS

• ? Sunitinib has a favourable efficacy/safety profile for Japanese metastatic RCC patients in clinical practice.
• ? The estimated median OS was >2 years with acceptable tolerability.
• ? The median OS from the initial systemic therapy of the pretreated patients was >6 years.
• ? Memorial Sloan‐Kettering Cancer Center prognostic factors still appear to be valid for predicting survival in metastatic RCC in the era of molecular targeted therapy.

     

Reprint of: Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: Correlation with dynamic microbubble ultrasound data and review of the literature

BackgroundIncreased sunitinib exposure (area under the curve) is associated with better outcome in metastatic renal cell cancer. Recommendations for dose modification do not take this into account. A treatment strategy, based on individual patient toxicity, was developed to maximize dose and minimize time without therapy for patients who could not tolerate the standard sunitinib schedule of 50 mg given for 28 days with a 14-day break (50 mg, 28/14).MethodsA single-center retrospective review was conducted on patients with metastatic renal cell cancer treated from October 2005 to March 2010. Dose/schedule modifications (DSM) were done to keep toxicity (hematological, fatigue, skin, and gastrointestinal) at≤grade 2. DSM-1 was 50 mg, 14 days on/7 days off with individualized increases in days on treatment. DSM-2 was 50 mg, 7 days on/7 days off with individualized increase in days on treatment. DSM-3 was 37.5 mg with individualized 7-day breaks. DSM-4 was 25 mg with individualized 7-day breaks. Multivariable analysis was performed for outcome as a function of patient and treatment variables.ResultsOverall, 172 patients were included in the analysis. Most patients had clear cell histology (79.1%) with sunitinib given as a first-line therapy in 59%. The DSM-1 and 2 and DSM-3 and 4 groups had a progression-free survival (PFS) (10.9–11.9 mo) and overall survival (OS) (23.4–24.5 mo) that was significantly better than the PFS (5.3 mo; P<0.001) and OS (14.4 mo; P = 0.03 and 0.003) for the standard schedule (50 mg, 28/14). DCE-US in a subset of patients showed that maximum antiangiogenic activity was achieved after 14 days on therapy.ConclusionsIndividualized sunitinib scheduling based on toxicity may improve PFS and OS. This hypothesis is supported by several other respective data that are reviewed. A confirmatory prospective trial is ongoing.     

Expression of tyrosine kinase receptor AXL is associated with worse outcome of metastatic renal cell carcinomas treated with sunitinib

Background

Renal cell carcinoma (RCC) represents 2%–3% of all cancers of the Western countries. Currently, sunitinib, a receptor tyrosine kinase inhibitor, particularly of PDGF and VEGF receptors, is the first-line therapy for metastatic RCC (mRCC), with significant improvement in clinical outcome. However, there is a lack of predictive biomarkers of sunitinib response. Recently, others and our group suggested that the receptor tyrosine kinase AXL may modify the response to sunitinib.

Dynamic outcome prediction in patients with clear cell renal cell carcinoma treated with radical nephrectomy: the D-SSIGN score

PURPOSE: To date all prediction models for patients with renal cell carcinoma have estimated outcome in static fashion starting from the date of surgery only. We created a dynamic outcome prediction model for continual surveillance that accounts for the disease-free interval following surgery. MATERIALS AND METHODS: We identified 1,560 patients treated with radical nephrectomy for pM0 clear cell renal cell carcinoma between 1970 and 1999. The previously published stage, size, grade and necrosis score was used to stratify patients according to the risk of death from renal cell carcinoma. Cancer specific survival rates were calculated using the Kaplan-Meier method at surgery and at various disease-free intervals following surgery. RESULTS: At last followup 461 of the 1,560 patients had died of renal cell carcinoma at a median of 3.1 years following surgery. Median followup in patients still alive was 11.2 years. Patient outcome improved as the disease-free interval following surgery increased. For example, patients with a stage, size, grade and necrosis score of 5 had an estimated 5-year cancer specific survival rate of 69.6% at surgery. However, those who survived without disease for 1, 2 and 3 years following surgery had adjusted estimated 5-year cancer specific survival rates of 81.9%, 91.9% and 93.2%, respectively. Patients with a stage, size, grade and necrosis score of 7 had a 5-year cancer specific survival rate of 44.9% at surgery, which increased to 63.3%, 71.0% and 72.8% after 1 to 3 years of disease-free followup, respectively. CONCLUSIONS: Within each stage, size, grade and necrosis score cancer specific survival rates increase as the disease-free interval following surgery increases. We present a dynamic outcome prediction model that allows clinicians to continually adjust surveillance as the disease-free interval increases.     

Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma

Objective

To identify factors that can be used to identify metastatic clear cell RCC patients more likely to benefit from sequential sunitinib.

Patients and methods

We identified patients who failed sorafenib or bevacizumab and subsequently received sunitinib. We looked at objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) to sunitinib in relation to baseline clinical variables.

Results

Seventy-one patients received sunitinib sequential therapy. Median duration of follow-up after starting sunitinib was 9.3 months. Median PFS was 5.8 months; median OS was not reached. Significantly higher ORR was seen in patients with normal hemoglobin (25.6%) [defined as >12 gm/dl for female; >13 gm/dl for male]. In addition, a shorter PFS for patients with low hemoglobin, and patients with time from diagnosis to first treatment ≤1 year was found. There was a shorter OS for patients ≥60 years old, with brain metastasis, low hemoglobin, and time from diagnosis to treatment ≤1 year. There was no difference in ORR, PFS, or OS in patients who started sunitinib after or within a 30-day period.

Conclusions

Metastatic clear-cell RCC patients with anemia have less clinical benefit from sequential sunitinib after failure of bevacizumab or sorafenib. Other factors associated with poor outcome include brain metastases, older age, and <1 year between diagnosis and first treatment. Importantly, no difference in outcomes was observed if sequential therapy was initiated within or after 30 days. External validation and prospective evaluation are needed to confirm these findings.     

高危肾细胞癌术后舒尼替尼辅助治疗的效果观察

目的 评价高危肾细胞癌术后舒尼替尼辅助治疗的疗效与安全性. 方法 接受根治性肾切除术的肾癌患者60例,均经病理检查确诊为肾透明细胞癌.术后1个月开始口服舒尼替尼50 mg(用4周停2周方案)或37.5 mg每日连续给药的方案治疗,共3个周期. 结果 60例患者均可耐受舒尼替尼治疗,无因不良反应而中止治疗者.不良反应多为1～2度.其中中性粒细胞减少56.7％,其次为血小板减少53.3％、白细胞减少48.3％、手足综合征46.7％和高血压36.7％.3 ～4度不良反应血小板减少发生率为25.0％,其次为中性粒细胞减少(15.0％)、手足综合征(11.7％)、白细胞减少(8.3％).大多数不良反应于治疗后1～2个周期内发生,并于治疗停止后1个月左右减轻,无不可逆的不良反应发生.截至2012年4月5日,除1例死于与疾病无关的脑血管意外外,余59例未出现复发,6个月和9个月的无疾病复发生存率100％. 结论 高危肾癌患者术后舒尼替尼辅助治疗的骨髓抑制发生率少于晚期肾癌患者,但仍需较长期的进一步数据来证实.     

舒尼替尼一线治疗转移性肾癌初探

目的 观察舒尼替尼一线治疗转移性肾癌的疗效及安全性.方法 对经病理确诊的46例转移性肾透明细胞癌患者给予舒尼替尼治疗,50 mg,每天1次,服用4周,休息2周,6周为1个周期.2个周期评价疗效,有效或病情稳定者继续口服舒尼替尼治疗.结果 46例患者中病情部分缓解(PR)15例(32.6%),病情稳定(SD)25例(54.3%),疾病进展(PD)6例(13.1%);全组有效率32.6%(95%CI:19.1%～46.1%),疾病控制率86.9%,中位无进展生存期11个月,1年生存率65.2%,中位总生存期尚未达到.主要不良反应:疲乏33例(71.7%)、皮肤黄染29例(63.0%)、食欲减退28例(60.9%)、手足皮肤反应26例(56.5%)、口腔黏膜炎25例(54.3%)、高血压19例(41.3%)、颜面水肿18例(39.1%)、腹泻17例(37.0%)、出血17例(37.0%)、恶心15例(32.6%)等;血液学毒性方面:白细胞减少32例(69.6%)、中性粒细胞减少30例(65.2%)、血小板减少28例(60.9%)、贫血21例(45.7%),3～4级严重不良反应主要为血小板减少[15例(32.6%)].结论 舒尼替尼一线治疗转移性肾癌疗效显著,不良反应多为轻中度,3～4级血小板减少应引起重视.

Abstract：

Objective To evaluate the efficacy and safety of sunitinib as first line treatment in patients with metastatic renal cell carcinoma (RCC). Methods This study included 46 Chinese patients who were diagnosed with metastatic RCC after radical nephrectomy. The patients received oral sunitinib (50 mg once daily on a 4 weeks on, 2 weeks off) on a 6 weeks cycle dose schedule until disease progression or intolerable toxicities occurred. Results The overall objective response rate was 32.6% (95% confidence interval [CI, 19.1% to 46. 1%]), and the disease control rate was 86.9%,with complete response (CR) 0 (0%), partial responses (PRs) 15 (32.6%), stable disease (SD) 25(54.3 %), and progression disease (PD) 6 ( 13. 1%). The median progression-free survival was 11 months, and the 1-year survival rate was 65.2%, while the median overall survival (mOS) has not been reached. The main adverse events included fatigue 33 (71.7%), skin discoloration 29 (63.0 %),anorexia 28 (60.9%), hand-foot syndrome 26 (56.5%), oral mucositis 25 (54.3%), hypertension 19 (41.3%), facial edema 18 (39.1%), diarrhea 17 (37.0%), hemorrhage 17 (37.0%), nausea 15 (32.6%), and hematological toxicity: leukopenia 32 (69.6%), neutropenia 30 (65.2%), thrombocytopenia 28 (60.9%), anemia 21 (45.7%). Most of grade 3/4 serious adverse events were thrombocytopenia in 15 (32. 6%) patients. Conclusions Sunitinib has a prominent effect in metastatic renal cell cancer in a Chinese population with mostly mild to moderate adverse reactions. More attention should be paid to grade 3/4 adverse reaction of thrombocytopenia.     

Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma

ObjectiveTo determine whether presurgical sunitinib reduces primary renal cell carcinoma (RCC) size and facilitates partial nephrectomy (PN).MethodsData from potential candidates for PN treated with sunitinib with primary RCC in situ were reviewed retrospectively. Primary outcome was reduction in tumor bidirectional area.ResultsIncluded were 72 potential candidates for PN who received sunitinib before definitive renal surgery on 78 kidneys. Median primary tumor size was 7.2 cm (interquartile range [IQR]: 5.3–8.7 cm) before and 5.3 cm (IQR: 4.1–7.5 cm) after sunitinib treatment (P<0.0001), resulting in 32% reduction in tumor bidirectional area (IQR: 14%–46%). Downsizing occurred in 65 tumors (83%), with 15 partial responses (19%). Tumor complexity per R.E.N.A.L. score was reduced in 59%, with median posttreatment score of 9 (IQR: 8–10). Predictors of lesser tumor downsizing included clinical evidence of lymph node metastases (P<0.0001), non–clear cell histology (P = 0.0017), and higher nuclear grade (P = 0.023). Surgery was performed for 68 tumors (87%) and was not delayed in any patient owing to sunitinib toxicity. Grade≥3 surgical complications occurred in 5 patients (7%). PN was performed for 49 kidneys (63%) after sunitinib, including 76% of patients without and 41% with metastatic disease (P = 0.0026). PN was completed in 100%, 86%, 65%, and 60% of localized cT1a, cT1b, cT2, and cT3 tumors, respectively.ConclusionPresurgical sunitinib leads to modest tumor reduction in most primary RCC, and many patients can be subsequently treated with PN with acceptable morbidity and preserved renal function. A randomized trial is required to definitively determine whether presurgical therapy enhances feasibility of PN.     

The role of initial immunotherapy as selection for nephrectomy in patients with metastatic renal cell carcinoma and the primary tumor in situ

OBJECTIVE: A prospective pilot study in patients with metastatic renal cell cancer and the primary in situ to assess the feasibility of immunotherapy prior to nephrectomy and to evaluate the rationale for a future randomized trial to define the role of response to upfront immunotherapy as selection for cytoreductive surgery. PATIENTS AND METHODS: Sixteen patients with synchronous multiple metastases were treated with the primary tumor in place and were evaluated with regard to age, sex, sites of extrarenal disease, morbidity, response, nephrectomy rate, time to progression and overall survival. Immunotherapy consisted of 2 courses low-dose IL-2 4MIU/m(2), subcutaneous GM-CSF 2.5 microg/kg and interferon-alpha (IFN-alpha) 5MU flat on day 1-13 and 22-34. Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by a third and fourth course. RESULTS: No response was seen in the primary tumors. With regard to extrarenal sites SD was noted in nine cases, PR in two and progressive disease (PD) in five. Eleven patients underwent nephrectomy. No surgical complete response (CR) could be achieved. All patients with PD died after a median overall survival of 3 months versus 11.5 months (range 4-22) in those who underwent nephrectomy. Four patients are still alive at 10, 12, 18 and 19 months. Median duration of response was 6 months (range 2-10). One patient with SD following nephrectomy developed CR after two additional cycles, which is currently maintained for >10 months. CONCLUSIONS: Absence of progression at metastatic sites following immunotherapy may be used as a selection for nephrectomy in this selected group. Non-responding patients can be spared from surgery. A randomized study is needed to assess the timing of nephrectomy in combination with immunotherapy with regard to morbidity, overall survival and quality of life.     

Prognostic effect of preoperative serum albumin to globulin ratio in patients treated with cytoreductive nephrectomy for metastatic renal cell carcinoma

BackgroundAccurate identification of ideal candidates for cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is an unmet need. We tested the association between preoperative value of systemic albumin to globulin ratio (AGR) and overall survival (OS) as well as cancer-specific survival (CSS) in mRCC patients treated with CN.MethodsmRCC patients treated with CN were included. The overall population was therefore divided into two AGR groups using cut-off of 1.43 (low, <1.43 vs. high, ≥1.43). Univariable and multivariable Cox regression analyses tested the association between AGR and OS as well as CSS. The discrimination of the model was evaluated with the Harrel’s concordance index (C-index). The clinical value of the AGR was evaluated with decision curve analysis (DCA).ResultsAmong 613 mRCC patients, 159 (26%) patients had an AGR <1.43. Median follow-up was 31 (IQR: 16–58) months. On univariable analysis, low preoperative serum AGR was significantly associated with both OS (HR: 1.55, 95% CI: 1.26–1.89, P<0.001) and CSS (HR: 1.55, 95% CI: 1.27–1.90, P<0.001). On multivariable analysis, AGR <1.43 was associated with worse OS (HR: 1.51, 95% CI: 1.23–1.85, P<0.001) and CSS (HR: 1.52, 95% CI: 1.24–1.86, P<0.001). The addition of AGR only minimally improved the discrimination of a base model that included established clinicopathologic features (C-index=0.640 vs. C-index=0.629). On DCA, the inclusion of AGR marginally improved the net benefit of the prognostic model. Low AGR remained independently associated with OS and CSS in the IMDC intermediate risk group (HR: 1.52, 95% CI: 1.16–1.99, P=0.002).ConclusionsIn our study, low AGR before CN was associated with worse OS and CSS, particularly in intermediate risk patients.