CIK细胞治疗转移性肾癌48例的疗效预测因素分析

目的：探讨细胞因子诱导的杀伤细胞（cytokine-induced killer cells, CIK）治疗转移性肾癌（metastatic renal cell carcino?ma,MRCC）的疗效及预后预测因素。方法：48例MRCC患者,采用CIK细胞治疗,所有患者均接受至少2个周期的治疗。治疗后定期复查进行疗效评价,并将无进展生存期 （progression-free survival,PFS）与临床特征、生化参数等因素进行相关性分析,疗效相关性采用Kaplan-Meier法及Cox回归分析分别进行单因素及多因素分析。用中位数检验法进行不同脏器转移组之间中位PFS的比较。结果：48例患者中,PR 2例,SD 30例,PD 16例。PR+SD占66.7%。中位PFS为7个月。多因素分析提示脏器转移数目、血小板（platelet, PLT）计数与PFS明显相关（P值分别为0.034、 0.046）。对33例仅有单个脏器转移的病例进行的分层分析表明转移部位对CIK治疗疗效的影响可能不大。结论：CIK细胞是治疗MRCC的一种安全、有效的治疗方法。脏器转移数目和PLT计数是其疗效的独立预测因素,提示脏器转移数目>1和PLT升高的患者预后差。     

Second-Line Treatment Outcomes After First-Line Sunitinib Therapy in Metastatic Renal Cell Carcinoma

This study was conducted to evaluate the treatment outcomes associated with common second-line targeted therapies given after first-line sunitinib for metastatic renal cell carcinoma (mRCC). The sample comprised patients with mRCC (n = 257) who were receiving second-line everolimus, sorafenib, or temsirolimus between April 1, 2008, and February 29, 2011, after first-line sunitinib treatment. The patients were followed-up from the start of second-line treatment until treatment failure (defined as advancement to a third-line therapy or to mortality) or the last observation in the medical and pharmacy databases. Treatment failure was observed in 38.5% (n = 99) of cases: 20.2% of patients (n = 52) advanced a line of treatment; and 18.3% of patients (n = 47) died. Kaplan-Meier analysis indicated a statistical difference in time to treatment failure among the 3 second-line targeted therapies (log-rank test, P = .045). The estimated 1-year cumulative probabilities of treatment failure were 49.9% for everolimus, 68.4% for sorafenib, and 71.4% for temsirolimus. In a multivariate Cox proportional hazards model, a higher adjusted risk of treatment failure vs. everolimus was observed for both temsirolimus (hazard ratio [HR] 2.05 [95% CI, 1.26-3.35]; P = .004) and sorafenib (HR 1.77 [95% CI, 1.02-3.07]; P = .043). The results of this real-world data analysis suggest that the risk of second-line treatment failure after first-line sunitinib was significantly higher with temsirolimus and sorafenib compared with everolimus.     

Surgical Treatment of Metastatic Renal Cell Carcinoma

The survivals of 174 patients who underwent nephrectomy forrenal cell carcinoma were analyzed to evaluate the influenceof the surgical treatment of metastases on their prognosis.For 34 of the 174 patients, surgical resections of the metastaseswere performed concurrently with nephrectomy. For 38 patients,44 surgical resections of metastases were performed in the follow-upperiod after nephrectomy. Apparently curative resections ofmetastases, at the time of nephrectomy or after nephrectomy,were significantly correlated with good survivals after surgery,irrespective of the number of metastatic foci. Aggressive surgicaltreatment was beneficial in patients with a longer tumor-freeperiod after nephrectomy or with stable disease for about sixmonths after surgical treatment, although this might simplybe a reflection of a longer natural disease course in this specificgroup of patients.     

Current Treatment Considerations in Metastatic Renal Cell Carcinoma

OPINION STATEMENT: In general, debulking neprhectomy is still considered for metastatic RCC patients with primary tumor in place, assuming good performance status. Initial systemic therapy should consider high-dose IL-2 for the highly select patient. One reason for initial consideration of this therapy is the less certain risk/benefit profile if employed after targeted therapy. Notably, due to its potential toxicity and emergence of new effective and more tolerable drugs, IL-2 has become a less favorable and subsequently a less utilized therapeutic tool in the current era. Otherwise, VEGF-targeted therapy is the treatment of choice, preferably on a clinical trial. Off trial, sunitinib has long been favored but pazopanib is gaining more use for tolerance pending the comparative trial. Continued VEGF targeting is favored by these authors given the underlying biology of RCC and the prospective clinical data, noting no direct comparison of mTOR and VEGF agents has yet occurred. Maintaining patient dose is critical and requires optimal supportive care and appreciation/early intervention for toxicity. Predictive biomarkers are desperately needed, and enrollment on clinical trials remains a priority to optimize patient outcome.     

Patients with Metastatic Renal Cell Carcinoma with Long-Term Disease-Free Survival After Treatment with Sunitinib and Resection of Residual Metastases

A complete response (CR) to therapy in patients with metastatic renal cell carcinoma (RCC) is rare but has been achieved in a minority of patients using high-dose interleukin-2. Surgical CR after partial response to immunotherapy in metastatic RCC has been anecdotally reported, although the low overall response rate to cytokines precludes this procedure in the majority of patients. Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor with antiangiogenic and antitumor activity. Clinical efficacy has been demonstrated, with high objective response rates observed in a variety of solid tumor types, including RCC. Herein, we report 2 cases of patients with cytokine-refractory metastatic RCC who received sunitinib and achieved sufficient decrease in tumor burden to permit subsequent surgical resection, resulting in long-term CR.     

Sarcomatoid Renal Cell Carcinoma: Clinical Outcome and Survival After Treatment With Sunitinib

BackgroundRenal tumors with sarcomatoid changes are aggressive malignancies with poor prognosis. Immunotherapy and chemotherapy have provided little benefit. The efficacy of treatments targeting the vascular endothelial growth factor pathway is unclear because of the lack of clinical trial data and the small number of published series.Patients and MethodsWe reviewed the clinical records of 23 consecutive patients with advanced sarcomatoid renal cell carcinoma who were treated with sunitinib in our center. Overall survival (OS), progression-free survival, and response rate were evaluated. We also studied the effect on clinical outcome of performance status, prognostic risk group, and proportion of sarcomatoid component.ResultsMedian OS was 15.7 months (95% confidence interval [CI], 5.0-21.2). Median progression-free survival was 5.7 months (95% CI, 3.2-12.6). Seven patients (30%) had an objective response, 5 patients (22%) had stable disease, and 11 (48%) had progressive disease. The median survival of the 13 (56.5%) patients with performance status of 0 to 1 was 20.9 months (95% CI, 9.7-63.3) whereas the medial survival of the 10 (43.5%) patients with performance status of 2 to 3 was 5.0 months (95% CI, 1.1-16.5). Objective responses were observed only among the 13 (56.5%) patients with performance status of 0 to 1. Heng prognostic risk group and percentage of sarcomatoid component did not influence outcome.ConclusionSunitinib shows efficacy in advanced renal tumors with sarcomatoid differentiation particularly in patients with good performance status. Appropriate patient selection and risk-directed treatment remains essential in this aggressive disease.     

Clinical Relevance of Gene Copy Number Variation in Metastatic Clear Cell Renal Cell Carcinoma

Background

Gene copy number variations (CNVs) have been reported to be frequent in renal cell carcinoma (RCC), with potential prognostic value for some. However, their clinical utility, especially to guide treatment of metastatic disease remains to be established. Our objectives were to assess CNVs on a panel of selected genes and determine their clinical relevance in patients who underwent treatment of metastatic RCC.

Contemporary Cytoreductive Nephrectomy Provides Survival Benefit in Clear-cell Metastatic Renal Cell Carcinoma

IntroductionA recent randomized trial questioned the role of cytoreductive nephrectomy in clear-cell metastatic renal cell carcinoma (ccmRCC). We reassessed the effect of cytoreductive nephrectomy on survival in a contemporary population-based ccmRCC cohort.Patients and MethodsWithin the Surveillance, Epidemiology, and End Results database (2010-2015), we focused on patients with ccmRCC. The primary endpoint consisted of overall mortality. Univariable and multivariable Cox regression models were applied in the overall cohort and in patients who underwent targeted therapy. Sensitivity analyses included 1:1 propensity score matching, 3- and 6-month landmark analyses, incremental survival benefit analyses, and metastases number and location-based stratifications.ResultsOf 4062 patients with ccmRCC, 2241 (55.1%) received targeted therapy; cytoreductive nephrectomy was performed in 2226 (54.8%) patients and 1168 (52.1%) patients in the overall and targeted therapy cohorts, respectively. Cytoreductive nephrectomy was associated with lower overall mortality in the overall cohort (median survival, 30 vs. 9 months; hazard ratio [HR], 0.43; P < .001), as well as in the targeted therapy cohort (median survival, 28 vs. 12 months; HR, 0.49; P < .001). In sensitivity analyses, cytoreductive nephrectomy was associated with lower overall mortality after 1:1 propensity score-matching (HR, 0.49; P < .001), in 3- and 6-month landmark analyses (HR, 0.49; P < .001 and HR, 0.51; P < .001, respectively), in metastases number and location-based stratifications, except for exclusive liver metastases, as well as in all incremental benefit analyses.ConclusionCytoreductive nephrectomy is associated with better survival in patients with ccmRCC, including those exposed to targeted therapy, after adjustment for multiple potential confounders.     

Effect of Switching Systemic Treatment After Stereotactic Radiosurgery for Oligoprogressive,Metastatic Renal Cell Carcinoma

Background

We assessed the clinical outcomes of patients with oligoprogressive renal cell carcinoma (mRCC) treated with stereotactic radiosurgery (SRS), stratified by changing or continuing systemic treatment.

Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC Registry

BackgroundTreatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group.MethodsMulticenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group.ResultsFour hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P = .012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR = 1.72, P = .002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR = 0.56, P = .005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P = .003) and intermediate-risk (26.3 vs. 20.1, P = .038), but not high-risk (P = .911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P = .004) but not intermediate- (P = .06) and high-risk (P = .595) groups.ConclusionsMetastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances.     

Fibroblast Growth Factor Receptor-2 Polymorphism rs2981582 is Correlated With Progression-free Survival and Overall Survival in Patients With Metastatic Clear-cell Renal Cell Carcinoma Treated With Sunitinib

Background

There are no validated markers that predict response or resistance in patients with metastatic clear-cell renal cell carcinoma (mccRCC) treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors such as sunitinib and pazopanib. Recently, single nucleotide polymorphism (SNP) rs2981582 in Fibroblast Growth Factor Receptor 2 (FGFR2) was found to be associated with clinical outcome in patients with mccRCC treated with pazopanib and sunitinib. We aimed to validate these findings in patients treated with sunitinib.

Five-Year Survival in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma Treated With Axitinib

BackgroundIn a phase II study of axitinib for cytokine-refractory metastatic renal cell carcinoma, median overall survival (OS) was 29.9 months (95% CI, 20.3 to not estimable months).Patients and MethodsLong-term survival data were collected retrospectively from 52 patients with cytokine-refractory metastatic renal cell carcinoma who received axitinib in a completed phase II study (protocol 1), 11 of whom enrolled in a continuing access protocol (protocol 2), for the current observational study (protocol 3). In a post hoc analysis, the patients were grouped into quartiles based on cycle 1 day 1, 1- to 2-hour post-dose axitinib plasma levels to explore the impact of drug exposure on efficacy.ResultsThe 5-year survival rate was 20.6% (95% CI, 10.9%-32.4%), with a median follow-up of 5.9 years. Frequent all-grade adverse events were fatigue (n = 38; 73.1%), diarrhea (n = 34; 65.4%), hypertension (n = 33; 63.5%), and nausea (n = 33; 63.5%). Quartile 3 patients (axitinib level, 45.2-56.4 ng/mL; n = 12) had the best clinical outcome: objective response rate 82%, median progression-free survival (PFS) 28.3 months, and median OS that was not reached after 5 years.ConclusionsAxitinib was well tolerated and provided an estimated 5-year survival rate of 20.6% for cytokine-refractory metastatic renal cell carcinoma. Exploratory analyses showed numerically higher objective response rate and longer OS and PFS in patients who achieved post–first-dose axitinib plasma concentrations within a specific range.     

Activity of Systemic Treatments After Cabozantinib Failure in Advanced Metastatic Renal Cell Carcinoma

BackgroundCabozantinib, a potent multityrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated.Materials and MethodsWe conducted a retrospective study on patients receiving systemic treatment after cabozantinib failure in heavily pretreated patient with mRCC. We assessed Time to Treatment Failure (TTF), OS and objective response rate (ORR).ResultsAmong 150 patients treated with cabozantinib in our institution, 56 (37.3%) received subsequent systemic therapy and were eligible for the analysis. IMDC prognostic group was good, intermediate and poor in 11 (19.6%), 24 (42.9%) and 11 (19.6%) patients, respectively. Cabozantinib was administered mainly as a second (41.1%), or third (33.9%) line treatment. axitinib or immune-checkpoint inhibitors were the subsequent treatment in 18 (34.8%) patients for each everolimus (n:16, 28.6%), other angiogenesis inhibitors (n:4, 7.1%) TTF and OS from subsequent systemic therapy after cabozantinib failure were 2.8 months (95%CI 1.9-3.7) and 7.7 months (95%CI 4.4-10.8), respectively. ORR was 8.7% and 2 patients with axitinib and 2 patients treated with Immune checkpoint inhibitors achieved a partial response.ConclusionOverall, activity of systemic therapies after cabozantinib was limited.     

Novel Predictive Models of Early Death Less Than 1 Year in Patients With Metastatic Renal Cell Carcinoma After Treatment With First-line Tyrosine Kinase Inhibitors

BackgroundWe aimed to develop a modified International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model that can predict early death less than 1 year in patients with metastatic renal cell carcinoma (mRCC) after receiving first-line tyrosine kinase inhibitors (TKIs).Patients and MethodsWe retrospectively reviewed records of patients with mRCC treated with first-line TKIs at our institution between 2007 and 2012. The primary endpoint was the rate of early death within 1 year after first-line TKI administration. We determined statistically significant factors predicting early death by performing multiple logistic regression. The modified IMDC model 1 was developed using new variables in addition to the risk criteria of the IMDC model, and model 2 was developed using new variables irrespective of the risk classification of IMDC model.ResultsEarly mortality within 1 year of first-line TKI treatment was 19.7% (n = 98) in 462 patients. Although the C-index of the IMDC model for early death was 0.655, the C-index of model 1, which includes 5 variables (previous nephrectomy, body mass index, multiple metastases, previous metastasectomy, and serum albumin level) in addition to the Heng criteria, was 0.823. The C-index of model 2, which includes 7 variables (hemoglobin, neutrophil level, and the 5 variables of model 1) was 0.822. Of note, there was no significant difference in net reclassification index between the 2 models.ConclusionThis is the first study suggesting novel prediction models for early death less than 1 year in patients with mRCC treated with first-line TKI.     

Quality of Life and Targeted Treatment for Metastatic Renal Cell Carcinoma

The results of quality of life analyses from a randomized, placebo-controlled phase III trial of everolimus for metastatic renal cell carcinoma patients progressing after treatment with sunitinib or sorafenib are reviewed.In a recent issue of The Oncologist, Beaumont and colleagues reported on quality of life analyses [1] from their pivotal, randomized, placebo-controlled, phase III trial of everolimus for metastatic renal cell carcinoma progressing after treatment with sunitinib and/or sorafenib [2]. They reported that disease-related symptoms were similar for participants allocated to the everolimus group and participants allocated to the placebo group, but that physical functioning and global quality of life deteriorated somewhat quicker in those allocated everolimus. They conclude that the “delay in tumor progression demonstrated by everolimus is associated with minimal impact on symptoms, physical functioning or quality of life.”These conclusions may seem disappointingly negative for those accustomed to seeing symptoms of metastatic cancer improve with effective treatment. They warrant closer scrutiny and highlight three important questions for clinicians considering the results of quality of life analyses in cancer clinical trials: who was asked about their quality of life, what were they asked, and when were they asked it?Most participants had good functional status, negligible symptoms, and reasonable quality of life at baseline. Karnofsky performance status scores were 90 or 100 in about 65% of participants, and none were <70. Mean scores at baseline were about 28 for symptoms (on a scale of 0 = worst to 36 = best) [3], 75 for physical function, and 60 for global quality of life (both on scales of 0 = worst to 100 = best) [4].Participants were asked questions about symptoms, physical function, and global quality of life. The specific symptoms were selected because they were “predominantly attributable to kidney cancer itself,” including pain, fatigue, shortness of breath, fevers, weight loss, coughing, and blood in the urine [3]. However, all but the first and last of these symptoms are listed as common adverse effects of everolimus. Physical function ratings assessed trouble doing strenuous activities and walking, restriction to a bed or chair, and needing help with activities of daily living [4]. Global quality of life comprised single items rating “overall health” and “overall quality of life” [4]. Given the participants'' characteristics, it is no surprise that their baseline ratings on these aspects were generally high and fell slowly over time.Participants rated their quality of life from randomization until objective tumor progression. Imaging was repeated every 8 weeks, or earlier if progression was suspected, so progression was likely to be documented before participants developed troublesome cancer-related symptoms. At each time point, the results reflect the quality of life of participants who had not yet progressed and were well enough to complete questionnaires. Participants allocated to the placebo group progressed about three times faster than participants allocated to everolimus (hazard ratio for progression, 0.31) [2], so at each successive assessment, there were progressively more participants remaining on everolimus than on placebo. So by 8 months, for example, the quality of life results tell us that the remaining 4% of participants allocated placebo (six of 139) had a somewhat better physical function and global quality of life than the remaining 20% of participants allocated everolimus (54 of 277).The authors confirmed that the missing quality of life ratings were likely to be systematically worse than those that were completed, and used modern statistical methods to account for these missing data. Although it is clear that missing data will make the results in both treatment groups look better than they really are, there is no satisfactory way to determine how missing data alter the result we are really interested in: the estimated difference between the two groups.The investigators should be congratulated for carefully collecting and analyzing quality of life data from a rigorous, pivotal, placebo-controlled trial addressing an important question. Their findings reassure us that the adverse effects of everolimus on symptoms and quality of life are probably relatively modest for relatively well people having second-line treatment for metastatic kidney cancer. Unfortunately, however, for most people considering this treatment, the results tell us little about its net effect on the quality of their remaining lives.     

On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study

BackgroundPreliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis.Patients and MethodsFrom January 2006 through December 2015, we retrospectively analyzed data of 145 patients with metastatic renal cell carcinoma treated with sunitinib as a first-line therapy in 7 different Italian oncology departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia, and anemia were evaluated. Overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox regression model was performed.ResultsWe evaluated 145 patients (92 males; median age, 70 years); 105 (62.4%) patients experienced at least 1 toxicity: 66 (45.5%) patients developed hypothyroidism, 41 (28.3%) thrombocytopenia, 39 (26.9%) hypertension that required medical therapy, 22 (15.2%) anemia, and 11 (7.6%) neutropenia. The median PFS of patients who developed hypertension was 12 months (95% confidence interval [CI], 9-21 months) versus 9 months (95% CI, 7-12 months) in patients who did not develop toxicity; the median OS was 36 months (95% CI, 22 months to not reached) versus 26 months (95% CI, 18-34 months). For neutropenia, the median PFS was 17.5 months (95% CI, 9-65 months) versus 10 months (95% CI, 8-12 months); the median OS was 23 months (95% CI, 13 months to not reached) versus 28 months (95% CI, 22-35 months). At univariate and multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression (hazard ratio, 0.47; 95% CI, 0.28-0.78 and hazard ratio, 0.26; 95% CI, 0.09-0.76, respectively).ConclusionsMany patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.     

PD-L1 Assay Concordance in Metastatic Renal Cell Carcinoma and Metastatic Urothelial Carcinoma

BackgroundImmune checkpoint inhibitors are now standard of care for many patients with metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC). Given real-world limitations in programmed death-ligand 1 (PD-L1) testing, concordance studies between PD-L1 assays are needed. We undertook comparisons of Dako 28-8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC.Patients and MethodsThirty-two patients with mRCC and 18 patients with mUC who had received immune checkpoint inhibitor therapy were identified. Formalin-fixed paraffin-embedded tumor samples for patients with mRCC were evaluated with Dako 28-8 and Ventana SP142 PD-L1 immunohistochemistry assays. For patients with mUC, formalin-fixed paraffin-embedded tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 immunohistochemistry assays.ResultsThe majority (29/32; 91%) of mRCC cases were concordant between assays. The majority (17/18; 94%) of mUC cases were also concordant between assays.ConclusionsThere was strong concordance between PD-L1 assays chosen for comparison in both mRCC and mUC, with similar performance characteristics. One limitation is the small number of cases in this study; larger comparison studies are needed for this biomarker in mRCC and mUC.     

Modern Therapeutic Approaches in Metastatic Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most deadly urological malignancy with only 62% of all patients surviving 5 years in all stages. Approximately 20–30% present initially with metastatic disease as well as 20–40% of patients who will develop systemic spread after surgery. New insights in angiogenesis lead to the development of new drugs directed against receptors and downstream signaling molecules of angiogenetic regulation mechanisms. The results of clinical trials with these drugs will lead to a change of paradigm in the systemic treatment of RCC patients. Specially Sutent, Sorafenib and Temsirolimus proved efficacy in metastatic disease and should be added substantially to the therapeutic armamentarium when surgery of the primary or metastases is impossible.