The impact of tumor burden characteristics in patients with metastatic renal cell carcinoma treated with sunitinib

BACKGROUND:

An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor‐targeted therapy.

METHODS:

Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re‐reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST).

RESULTS:

A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1‐27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm‐42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression‐free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs >12; P < .001) were found to be significant predictors of survival after PD.

CONCLUSIONS:

The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib. Cancer 2011. © 2010 American Cancer Society.     

Prognostic nomogram for sunitinib in patients with metastatic renal cell carcinoma

BACKGROUND.

In a randomized, phase 3 trial, sunitinib demonstrated superior efficacy over interferon‐alfa as first‐line therapy in patients with metastatic clear‐cell renal cell carcinoma (RCC). On the basis of outcome data from that trial, the authors developed a nomogram for predicting the probability of 12‐month progression‐free survival for patients who received sunitinib therapy.

METHODS.

Three‐hundred seventy‐five patients who received sunitinib in the phase 3 trial were the subject of the current analysis. Nomogram pretreatment predictor variables included corrected serum calcium levels, the number of metastatic sites, hemoglobin levels, prior nephrectomy, the presence of lung and liver metastases, thrombocytosis, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, and serum levels of alkaline phosphatase and lactate dehydrogenase. Investigator‐assessed progression‐free survival was the predicted outcome endpoint. Internal validation of the nomogram consisted of quantification of the discrimination with the concordance index and assessment of calibration.

RESULTS.

One‐hundred seventy‐four of 375 patients (46%) who received sunitinib achieved an objective response, and the median progression‐free survival was 10.8 months (95% confidence interval, 10.6‐12.6 months). A nomogram for predicting the probability of 12‐month progression‐free survival for patients who received sunitinib therapy was constructed on the basis of a Cox regression model from 11 parameters that were determined before treatment. The concordance index was 0.633.

CONCLUSIONS.

A nomogram was developed from pretreatment clinical features to predict the probability of achieving 12‐month progression‐free survival with sunitinib therapy for metastatic clear‐cell RCC. The authors concluded that independent validation of the nomogram and additional studies to identify tumor‐specific prognostic factors are warranted. Cancer 2008. © 2008 American Cancer Society.     

Current status of studies on targeted therapy for renal cell carcinoma

Renal cell carcinoma (RCC) is regarded as one of the most refractory malignancies. A further study of the molecular mechanism of RCC formation has led to a series of successful examples for treatment of patients with advanced RCC. Over the past 20 years, a nonspecific immunotherapy, with cytokines, has been employed as the gold standard for therapy of metastatic RCC. However, with scientific development and clinical testing of new drugs, targeted molecular cancer therapy has become a focus of interest. At the same time, with a better understanding of RCC,the treatment method has converged on anti-vascular endothelial growth factor (VEGF) and related molecular-targeted pathways.A large amount of research and numerous clinical trials have demonstrated the clinical efficacy of the targeted molecular therapies in patients with metastatic RCC. For example sorafenib and sunitinib were approved, in 2005 and 2006 respectively, by the U.S. FDA for treating advanced RCC. In this report, issues such as the importance of VEGF in RCC and the studies of bevacizumab,sunitinib and sorafenib in treating metastatic RCC etc., are reviewed.     

Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma

Background:

Prognostic factors for progression-free survival (PFS), overall survival (OS), and long-term OS (⩾30 months) were investigated in sunitinib-treated patients with metastatic renal cell carcinoma (RCC).

Methods:

Data were pooled from 1059 patients in six trials. Baseline variables, including ethnicity, were analysed for prognostic significance by Cox proportional-hazards model.

Results:

Median PFS and OS were 9.7 and 23.4 months, respectively. Multivariate analysis of PFS and OS identified independent predictors, including ethnic origin, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, prior cytokine use, haemoglobin, lactate dehydrogenase, corrected calcium, neutrophils, platelets, and bone metastases (OS only). Characteristics of long-term survivors (n=215, 20%) differed from those of non-long-term survivors; independent predictors of long-term OS included ethnic origin, bone metastases, and corrected calcium. There were no differences in PFS (10.5 vs 7.2 months; P=0.1006) or OS (23.8 vs 21.4 months; P=0.2135) in white vs Asian patients; however, there were significant differences in PFS (10.5 vs 5.7 months; P<0.001) and OS (23.8 vs 17.4 months; P=0.0319) in white vs non-white, non-Asian patients.

Conclusion:

These analyses identified risk factors to survival with sunitinib, including potential ethnic-based differences, and validated risk factors previously reported in advanced RCC.     

A population‐based study evaluating the impact of sunitinib on overall survival in the treatment of patients with metastatic renal cell cancer

BACKGROUND:

Sunitinib has replaced interferon (IFN) as a first‐line standard of care in the treatment of metastatic renal cell carcinoma (RCC). This study aimed to determine overall survival and to confirm effectiveness in a population that includes poor prognosis patients.

METHODS:

Data were collected on all patients identified by the BC Cancer Registry with metastatic RCC who were treated with IFN or sunitinib. The IFN group consisted of patients who received IFN between January 2000 and October 2005, and the sunitinib group included patients treated with first‐line sunitinib from October 2005 to September 2007.

RESULTS:

There were 131 and 69 patients in the IFN and sunitinib groups, respectively. The median follow‐up of those still alive was 12.6 months. The median age (62 vs 63 years; P = .41), Memorial Sloan Kettering Cancer Center (MSKCC) prognostic criteria (poor in 19% vs 30%; P = .41), and proportion with >1 metastasis (53% vs 62%; P = .21) were similar between the IFN and sunitinib groups, respectively. The median survival of the IFN and sunitinib groups was 8.7 and 17.3 months, respectively (log‐rank P = .004). The median survival of patients with favorable, intermediate, and poor MSKCC prognostic profiles in the IFN group was 22.9, 8.7, and 4.1 months, respectively (P < .001), whereas in the sunitinib group it was not reached, 16.8, and 10.7 months, respectively (P = .006). The hazard ratio of death after adjusting for MSKCC criteria was 0.49 (95% confidence interval, 0.31‐0.76; P = .001).

CONCLUSIONS:

The introduction of first‐line sunitinib was associated with a doubling of overall survival compared with patients treated with IFN alone. This benefit extended to patients with poor MSKCC prognostic profiles. Cancer 2009. © 2009 American Cancer Society.     

转移性肾细胞癌分子靶向治疗进展

肾细胞癌是我国泌尿生殖系统最常见的肿瘤之一。约30%的肾细胞癌患者在就诊时或手术后可能出现转移,预后差。转移性肾细胞癌对放疗与化疗均不敏感。转移性肾癌的分子靶向治疗已经取得了显著进展。现将最新的相关进展进行总结。     

Molecularly targeted therapy in renal cell carcinoma

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.     

Adjuvant therapy in renal cell carcinoma

Localized renal cell carcinoma (RCC) has an associated risk of recurrence after nephrectomy. Several clinical risk models attempt to predict oncologic outcomes based on clinical and pathologic features. In addition, novel gene signatures have been developed to refine risk prediction based on tumor biology. Systemic therapies targeting angiogenic pathways that are effective in metastatic RCC failed to show an improvement in overall survival in the adjuvant setting. Immune checkpoint inhibitors have shown significant antitumor activity with prolonged and durable responses in metastatic RCC, which led to an interest in evaluating these agents in the adjuvant setting. In this review, clinical risk-predictive models, novel gene signatures, major clinical trials completed in the adjuvant setting, ongoing immune checkpoint inhibitor trials, and the perspective of adjuvant treatment in RCC are discussed.     

Clinical factors associated with outcome in patients with metastatic clear-cell renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy

BACKGROUND: Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care for patients with metastatic renal cell carcinoma (RCC). The identification of patients who are more likely to benefit from these agents is warranted. METHODS: In total, 120 patients with metastatic clear-cell RCC received bevacizumab, sorafenib, sunitinib, or axitinib on 1 of 9 prospective clinical trials at the Cleveland Clinic. Clinical features associated with outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and to form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation. RESULTS: The overall median PFS was 13.8 months, and the objective response according to the Response Criteria in Solid Tumors was 34%. Multivariate analysis identified time from diagnosis to current treatment <2 years; baseline platelet and neutrophil counts >300 K/microL and >4.5 K/microL, respectively; baseline corrected serum calcium <8.5 mg/dL or >10 mg/dL; and initial Eastern Cooperative Oncology Group performance status >0 as independent, adverse prognostic factors (PF) for PFS. Three prognostic subgroups were formed based on the number of adverse prognostic factors present. The median PFS in patients with 0 or 1 adverse prognostic factor was 20.1 months compared with 13 months in patients with 2 adverse prognostic factors and 3.9 months in patients with >2 adverse prognostic factors. CONCLUSIONS: Five independent prognostic factors for predicting PFS were identified and were used to categorize patients with metastatic RCC who received VEGF-targeted therapies into 3 risk groups. These prognostic factors can be incorporated into patient care and clinical trials that use such novel, VEGF-targeted agents.     

Optimizing treatment for metastatic renal cell carcinoma

With the advent of targeted antiangiogenic therapies for renal cell carcinoma (RCC), the prognosis for patients with locally advanced or metastatic disease has significantly improved. Indeed, the results of several randomized clinical trials have demonstrated that targeted therapies, such as tyrosine kinase inhibitors (TKIs), provide superior efficacy and tolerability compared with traditional cytokine-based treatments. However, TKI therapy is still associated with significant toxicities related to off-target inhibition that are detrimental to patient quality of life. The results of ongoing head-to-head trials will determine how these agents compare with each other in terms of efficacy, and whether TKIs that interact with fewer off-target kinases have improved tolerability profiles. Furthermore, examining how these agents could be integrated with surgery to provide a multimodal approach to the treatment of metastatic RCC could further improve the outlook for RCC patients.     

Progression-free and overall survival in patients with relapsed/refractory germ cell tumors treated with single-agent chemotherapy: endpoints for clinical trial design

BACKGROUND:

Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents.

METHODS:

The characteristics and outcome of refractory GCT patients enrolled in 7 single‐agent phase 2 trials conducted at Memorial Sloan‐Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all‐transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression‐free survival (PFS), and overall survival (OS).

RESULTS:

Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty‐six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8‐1.3) and 4.7 months (95% CI, 3.5‐6.4), respectively. Eighty‐six of the 90 patients have died. The 12‐ and 16‐week PFS rates were 9% (95% CI, 3‐15%) and 6% (95% CI, 1%‐11%), respectively.

CONCLUSIONS:

Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve‐week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials. Cancer 2012;. © 2011 American Cancer Society.     

Hypertension management in patients with renal cell cancer treated with anti-angiogenic agents

Inhibitors of the vascular endothelial growth factor (vegf-is) signalling pathway have fundamentally changed the treatment of metastatic renal cell carcinoma (mrcc). Hypertension is one of the most common side effects of vegf-is and has been reported with almost every vegf-i used for treatment to date. The exact mechanism of vegf-i-induced hypertension appears complex and multifactorial, and it remains to be fully explained. No randomized clinical trials are available to guide the management of hypertension during vegf-i treatment in mrcc patients. The guiding principles suggested here summarize the consensus of opinions on the diagnosis and management of vegf-i-induced hypertension during treatment of mrcc obtained from an expert working group composed of 4 Canadian medical oncologists and 5 Canadian hypertension specialists. The Canadian Hypertension Education Program guidelines, available literature, and expert opinion were used to develop the guiding principles.     

Progression-free survival and one-year milestone survival as surrogates for overall survival in previously treated advanced non-small cell lung cancer

The advent of immunotherapy leads to greater availability of effective subsequent treatments and extended survival in previously treated advanced non-small cell lung cancer (NSCLC), complicating the evaluation of overall survival (OS) in second-line NSCLC trials. Here, we aimed to assess the surrogacy of progression-free survival (PFS) and milestone survival for OS in second-line NSCLC trials investigating chemotherapy, targeted therapy and immunotherapy, respectively. We systemically searched for active-controlled, second-line NSCLC trials. The milestone time point was set at one-year based on pre-analysis. A two-stage meta-analytic validation model was adopted to assess associations between surrogate endpoint (SE) and OS and associations between treatment effects on SE and OS. Treatment effects on SE and OS were expressed as PFS hazard ratios (HR_PFS), 1 yr-milestone ratio (Ratio_1y-SUR) and HR_OS. Subgroup analyses stratified by treatment types and trial publication years evaluated the surrogacy in different clinical contexts. The study included 50 trials with 22,804 patients. One-year survival strongly correlated with OS (R²[95% confidence interval]: one-year survival -median OS = 0.707 [0.704–0.708]; Ratio_1y-SUR-HR_OS = 0.829 [0.828–0.831]). No correlation was established between PFS and OS (median PFS-median OS = 0.100 [0.098–0.101]; HR_PFS-HR_OS = 0.064 [0.059–0.069]), except in immunotherapy subgroup (HR_PFS-HR_OS = 0.835 [0.791–0.918]). In subgroup analyses, surrogacy of one-year survival persisted in different clinical contexts, and the disassociation between PFS and OS persisted in recent trials. One-year milestone survival showed strong surrogacy for OS in second-line NSCLC trials. Although no association was identified between PFS and OS, the strong HR_PFS-HR_OS correlation in immunotherapy trials indicates the potential of PFS as a SE in NSCLC trials involving immunotherapies.     

Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome

BACKGROUND:

The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)‐targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long‐term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time.

METHODS:

A retrospective study of patients with mRCC who initiated VEGF‐targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave‐Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)‐defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression‐free survival (PFS), measured as the time from discontinuation of therapy to RECIST‐defined PD.

RESULTS:

Forty patients were identified. After a median follow‐up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4‐27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19‐5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04‐0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model.

CONCLUSIONS:

A select subset of mRCC patients achieving stable disease or better on VEGF‐targeted therapy can be observed off all therapy. Further prospective investigation is warranted. Cancer 2011. © 2011 American Cancer Society.     

转移性肾癌术前D-二聚体对靶向治疗的预测意义

目的：回顾性分析减瘤性肾切除术（cytoreductive nephrectomy ,CN）术前各项临床指标对于联合靶向治疗的转移性肾癌（metastatic renal cell carcinoma,mRCC）患者预后的影响。方法：收集1996年1 月至2015年6 月40例天津医科大学肿瘤医院行CN且术后1 年内行靶向药物治疗mRCC 患者的临床病理学资料,采用Kaplan-Meier 法进行单因素分析,Cox 回归模型进行多因素分析。结果：单因素生存分析结果显示,碱性磷酸酶、血小板与淋巴细胞比值（platelet lymphocyte ratio ,PLR ）、中性粒细胞与淋巴细胞比值（neutrophil lymphocyte ratio ,NLR ）、D-二聚体、T 分期、肿瘤转移器官数目、MSKCC危险模型评分均为影响患者总生存期（overall survival,OS ）的危险因素（P < 0.005）,其中碱性磷酸酶、PLR 、NLR 、D-二聚体、肿瘤转移器官数目、MSKCC危险模型评分为影响无进展生存期（progression-free survival,PFS）的危险因素（P < 0.005）。 Cox 回归模型多因素分析结果显示,D-二聚体（P =0.033）是影响患者OS、PFS 的独立因素,同时碱性磷酸酶（P = 0.045）、MSKCC危险模型评分（P = 0.003）也是影响PFS 的独立因素。结论：术前D-二聚体水平是行CN联合靶向治疗mRCC 患者的独立预后危险因素。     

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma

BackgroundTo determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study.MethodsThe relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan–Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test.ResultsIn the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P < 0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan–Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P < 0.0001).ConclusionsA positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.