Association between treatment effects on disease progression end points and overall survival in clinical studies of patients with metastatic renal cell carcinoma.
ABSTRACT: BACKGROUND: The relationship between progression-free survival and time to progression (PFS/TTP) and overall survival (OS) has been demonstrated in a variety of solid tumours but not in metastatic renal cell carcinoma (mRCC). METHODS: A systematic literature search was conducted to identify controlled trials of cytokine or targeted therapies for mRCC reporting information on treatment effects on PFS/TTP and OS for one or more comparison. The associations between treatment effects on PFS/TTP and OS were analysed using linear regression. RESULTS: Thirty-one studies representing 10943 patients, 75 treatment groups, and 41 comparisons were identified. The correlation coefficient between the negative log of the hazard ratio (HR) for PFS/TTP (-ln HR(PFS/TTP)) vs the negative log of the HR for OS (-ln HR(OS)) was 0.80 (P<0.0001). In linear regression, the coefficient on -ln HR(PFS/TTP) vs -ln HR(OS) was 0.64 (95% confidence interval (CI): 0.470.81; R(2)=0.63), suggesting each 10% relative risk reduction (RRR) for PFS/TTP was associated with a 6% RRR for OS. A 1-month gain in median PFS/TTP was associated with a 1.17-month gain in median OS (95% CI: 0.59,1.76; R(2)=0.28). CONCLUSION: In trials of treatments for mRCC, treatment effects on PFS/TTP are strongly associated with treatment effects on OS.
Project description:This study evaluated the effects of metastasectomy on overall survival (OS) and progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC) according to metastatic organs. The medical records (2005-2017) of 273 patients with mRCC were analyzed retrospectively to evaluate OS and PFS according to metastatic organs and their metastasectomy states. The Cox proportional hazard model was used to determine the prognostic significance of metastasectomy. The Kaplan-Meier curve and log-rank test were used to compare groups with different modalities and metastatic organs at a statistical significance of p < 0.05. The overall median age was 57 years; 175 (64.3%) and 83 (30.4%) patients received cytoreductive nephrectomy and metastasectomy, respectively. The metastasectomy group was significantly younger and had a lower clinical T stage with significantly better PFS/OS (20.2/32.0 vs. 9.7/12.8 months) than that in the non-metastasectomy group (N = 190, p < 0.05). Liver with lung metastases were the worst metastatic combination for survivals in which liver metastasis was the only significant unfavorable risk factor for both PFS (HR 1.67) and OS (HR 1.74) (p < 0.05). Multivariable analysis confirmed that metastasectomy was a significant favorable risk factor for PFS (HR 0.70) and OS (HR 0.56) (p < 0.05) along with non-clear cell type (HR 0.61 for PFS), whereas the nuclear grade and poor Heng risk group were unfavorable risk factors (HR > 2.0) for both PFS and OS (p < 0.05). Metastasectomy and the affected metastatic organs significantly influenced prognostic survival in mRCC.
Project description:The aim of the present study was to investigate the association between clinical parameters and the overall survival (OS) of Japanese patients with metastatic renal cell carcinoma (mRCC). The medical records of 59 consecutive mRCC patients receiving molecular-targeted therapy were retrospectively assessed. Kaplan-Meier and log-rank analyses were used to evaluate the progression-free survival (PFS) and OS, and a multivariate Cox proportional hazard model was used to analyze the clinical parameters for their prognostic relevance. The median OS for all patients was 23.7 months [95% confidence interval (CI): 17.9-30 months], and the median OS stratified by the Memorial Sloan Kettering Cancer Center risk classification was 28.5, 20.9 and 8.1 months for the favorable-, intermediate- and poor-risk groups, respectively (P=0.137; degree of freedom: 2). Univariate analyses identified prior nephrectomy, number of metastatic sites, anemia, best response to first-line treatment and PFS with first-line treatment as prognostic variables. Multivariate analyses identified number of metastatic sites [2: hazard ratio (HR)=3.351, 95% CI: 1.460-8.201, P=0.004; ≥3: HR=6.397, 95% CI: 1.939-20.209, P=0.003], time from diagnosis to therapy (≥1 year: HR=0.334, 95% CI: 0.137-0.755, P=0.008), PFS with first-line treatment (≥5.1 months: HR=0.353, 95% CI: 0.156-0.766, P=0.008) and number of lines of molecular-targeted agents (≥3: HR=0.248, 95% CI: 0.091-0.664, P=0.006) as independent prognostic factors. The results indicated that the PFS of first-line treatment may be a meaningful intermediate endpoint for OS in patients with mRCC who received treatment with molecular-targeted therapy.
Project description:Purpose:This study aimed to compare progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) in Heng intermediate-risk patients with metastatic renal cell carcinoma (mRCC) treated with first-line immunotherapy (IT) or targeted therapy (TT). Materials and Methods:From 2000 to 2017, a total of 186 intermediate-risk mRCC patients treated with first-line IT (n=64, 34.4%) or TT (n=122, 65.6%) were retrospectively evaluated for PFS, OS, and CSS using the Kaplan-Meier method with log-rank test and Cox proportional hazards models for their risk factors with a p-value for significance of <0.05. Results:During a median 5.08-month of systemic treatment and 92.22 months of follow-up, the median PFS, OS, and CSS were 5.16, 18.44, and 19.04 months, respectively. The comparison of baseline characteristics between the two groups showed a significantly higher rate of T3-4 stages, a lower rate of high nuclear grades, shorter follow-up, longer treatment durations, lesser rates of cytoreductive nephrectomy, a lower objective response rate, and no cases of complete response in the TT group compared with the IT group (p<0.05). The survival comparisons between the two groups showed that PFS was significantly different, whereas OS and CSS were not significantly different. The multivariate analyses showed that synchronous metastatic type(hazard ratio [HR], 2.285), IT (HR, 1.746), and treatment-free interval <1 year (HR, 1.926) were significant factors for PFS, whereas none of the risk factors were significant for OS or CSS. Conclusions:TT significantly prolonged PFS compared with IT, whereas long-term survival was not significantly different in intermediate-risk mRCC patients.
Project description:We retrospectively analyzed sunitinib outcome as a function of age in metastatic renal cell carcinoma (mRCC) patients.Data were pooled from 1059 patients in six trials. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were compared by log-rank test between patients aged <70 (n=857; 81%) and ≥70 (n=202; 19%) years.In first-line patients, median PFS was comparable in younger and older patients, 9.9 vs 11.0 months, respectively (HR, 0.89; 95% CI: 0.73-1.09; P=0.2629), as was median OS, 23.6 vs 25.6 months (HR, 0.93; 95% CI: 0.74-1.18; P=0.5442). Similarly, in cytokine-refractory patients, median PFS was 8.1 vs 8.4 months (HR, 0.79; 95% CI: 0.49-1.28; P=0.3350), while median OS was 20.2 vs 15.8 months (HR, 1.14; 95% CI: 0.73-1.79; P=0.5657). Some treatment-emergent adverse events were significantly less common in younger vs older patients, including fatigue (60% vs 69%), cough (20% vs 29%), peripheral edema (17% vs 27%), anemia (18% vs 25%), decreased appetite (13% vs 29%), and thrombocytopenia (16% vs 25%; all P<0.05). Hand-foot syndrome was more common in younger patients (32% vs 24%).Advanced age should not be a deterrent to sunitinib therapy and elderly patients may achieve additional clinical benefit.
Project description:The first-line therapy in metastatic renal cell carcinoma (mRCC), sunitinib, exhibits an objective response rate of approximately 30%. Therapeutic alternatives such as other tyrosine kinase inhibitors, VEGF inhibitors, or mTOR inhibitors emphasize the clinical need to predict the patient's response to sunitinib therapy before treatment initiation. In this study, we evaluated the prognostic value of pretreatment portal venous phase contrast-enhanced computed tomography (CECT) mean tumor density on overall survival (OS), progression-free survival (PFS), and tumor growth in 63 sunitinib-treated mRCC patients. Higher pretreatment CECT tumor density was associated with longer PFS and OS [hazard ratio (HR)=0.968, P=.002, and HR=0.956, P=.001, respectively], and CECT density was inversely correlated with tumor growth (P=.010). Receiver operating characteristic analysis identified two CECT density cut-off values (63.67 HU, sensitivity 0.704, specificity 0.694; and 68.67 HU, sensitivity 0.593, specificity 0.806) which yielded subpopulations with significantly different PFS and OS (P<.001). Pretreatment CECT is therefore a promising noninvasive strategy for response prediction in sunitinib-treated mRCC patients, identifying patients who will derive maximum therapeutic benefit.
Project description:BACKGROUND:Biomarkers to guide treatment in metastatic renal-cell carcinoma (mRCC) are lacking. We aimed to investigate the association between pretreatment neutrophil-to-lymphocyte ratio (NLR) and outcome of patients with mRCC receiving nivolumab. PATIENTS AND METHODS:Through retrospective chart review, we identified 38 patients with mRCC treated with standard-of-care nivolumab between 2015 and 2016 at Winship Cancer Institute of Emory University. NLR was determined from complete blood count collected before starting treatment, and imaging was performed to assess progression. The NLR cutoff value of 5.5 was determined by log-rank test, and the univariate association with overall survival (OS) or progression-free survival (PFS) was assessed by the Cox proportional hazard model and Kaplan-Meier method. RESULTS:The 38 patients had a median age of 69 years. The PFS and OS for all patients at 12 months was 54% and 69%, respectively. The median PFS was 2.6 months in the high NLR group but not reached in the low NLR group. Low NLR was strongly associated with increased PFS with hazard ratio of 0.20 (95% confidence interval, 0.07-0.64; P = .006). The median OS was 2.7 months in the high NLR group but not reached in the low NLR group. Low NLR was significantly associated with a prolonged OS with hazard ratio of 0.06 (95% confidence interval, 0.01-0.55; P = .012). CONCLUSION:Pretreatment NLR < 5.5 is associated with superior PFS and OS. NLR is a biomarker that can inform prognosis for patients with mRCC and should be further validated in larger cohorts and in prospective studies.
Project description:OBJECTIVE:This study aimed to determine the prognostic factors of progression-free survival (PFS) and overall survival (OS) in non-nephrectomized patients with synchronous metastatic renal cell carcinoma (mRCC) receiving first-line vascular endothelial growth factor (VEGF)-targeted therapy or immunotherapy. METHODS:Of 70 patients, 57 (81.4%) were treated with targeted therapy, including 5 (7.1%) with previous immunotherapy and 13 (18.6%) with immunotherapy only. The medical records of patients were retrospectively reviewed and analyzed to determine factors of PFS and OS using the Cox proportional hazards model with a statistical significance p-value <0.05. RESULTS:The median treatment and follow-up periods were 3.9 and 30.9 months, respectively. Disease progression was reported in 90.0% of patients, with an objective response rate and clinical benefit rate of 26.1% and 76.8%, respectively. The lung (77.1%) was the most common site of metastasis. Multivariable analysis showed that poor Heng risk (hazard ratio [HR]: 2.37) and liver metastasis (HR: 2.34) were significant prognostic factors for PFS, and female sex (HR: 2.13), poor Heng risk (HR: 3.14), and liver metastasis (HR: 2.78) were significant prognostic factors for OS (p < 0.05). A subset analysis of risk factors among patients without previous history of immunotherapy also showed poor Heng risk (HR 2.92 and HR 4.24 for PFS) and liver metastasis (HR 2.87 and HR 4.81 for OS) as significant factors for both PFS and OS (p<0.05). CONCLUSION:Poor Heng risk, sex, and liver metastasis were associated with survival outcomes after first-line systemic therapy in patients with non-nephrectomized synchronous mRCC.
Project description:BACKGROUND:The RAISE phase III clinical trial demonstrated that ramucirumab + FOLFIRI improved overall survival (OS) [hazard ratio (HR) = 0.844, P = 0.0219] and progression-free survival (PFS) (HR = 0.793, P < 0.0005) compared with placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients previously treated with first-line bevacizumab, oxaliplatin, and a fluoropyrimidine. Since some patient or disease characteristics could be associated with differential efficacy or safety, prespecified subgroup analyses were undertaken. This report focuses on three of the most relevant ones: KRAS status (wild-type versus mutant), age (<65 versus ?65 years), and time to progression (TTP) on first-line therapy (<6 versus ?6 months). PATIENTS AND METHODS:OS and PFS were evaluated by the Kaplan-Meier analysis, with HR determined by the Cox proportional hazards model. Treatment-by-subgroup interaction was tested to determine whether treatment effect was consistent between subgroup pairs. RESULTS:Patients with both wild-type and mutant KRAS benefited from ramucirumab + FOLFIRI treatment over placebo + FOLFIRI (interaction P = 0.526); although numerically, wild-type KRAS patients benefited more (wild-type KRAS: median OS = 14.4 versus 11.9 months, HR = 0.82, P = 0.049; mutant KRAS: median OS = 12.7 versus 11.3 months, HR = 0.89, P = 0.263). Patients with both longer and shorter first-line TTP benefited from ramucirumab (interaction P = 0.9434), although TTP <6 months was associated with poorer OS (TTP ?6 months: median OS = 14.3 versus 12.5 months, HR = 0.86, P = 0.061; TTP <6 months: median OS = 10.4 versus 8.0 months, HR = 0.86, P = 0.276). The subgroups of patients ?65 versus <65 years also derived a similar ramucirumab survival benefit (interaction P = 0.9521) (?65 years: median OS = 13.8 versus 11.7 months, HR = 0.85, P = 0.156; <65 years: median OS = 13.1 versus 11.9 months, HR = 0.86, P = 0.098). The safety profile of ramucirumab + FOLFIRI was similar across subgroups. CONCLUSIONS:These analyses revealed similar efficacy and safety among patient subgroups with differing KRAS mutation status, longer or shorter first-line TTP, and age. Ramucirumab is a beneficial addition to second-line FOLFIRI treatment for a wide range of patients with mCRC. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01183780.
Project description:Purpose: Sorafenib and sunitinib are extensively used as first-line medications for metastatic renal cell carcinoma (mRCC). This meta-analysis was conducted to assess the antitumor efficacy, toxicity, and costs of the two drugs among mRCC patients. Materials and methods: PubMed, ScienceDirect, Scopus, Web of Science, Ovid MEDLINE, the Cochrane Library, Embase, and Google Scholar were searched for eligible articles. The endpoints consisted of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), adverse effects (AEs), and per-patient-per-month (PPPM) costs. Results: We included 14 studies with 2,925 patients. Both drugs were valid for treating mRCC with equivalent PFS [hazard ratio (HR) = 0.98, 95% confidence interval (CI): 0.88-1.10, P = 0.74] and disease control rates [DCRs; risk ratio (RR) = 1.03, 95% CI: 0.98-1.08, P = 0.28], but sunitinib had a better OS (HR = 1.10, 95% CI: 1.01-1.20, P = 0.04) and higher ORR (HR = 0.66, 95% CI: 0.45-0.97, P = 0.03) than sorafenib. Furthermore, sunitinib induced more incidences of severe hematologic AEs (anemia, neutropenia, and thrombocytopenia) and stomatitis/mucositis than sorafenib. In the subanalysis, Asian patients treated with sorafenib reported a longer PFS than those treated with sunitinib (HR = 0.87, 95% CI: 0.83-0.90, P = 0.01), and European patients treated with sunitinib had a longer OS than those treated with sorafenib (HR = 1.17, 95% CI: 1.01-1.30, P = 0.04). Moreover, the pooled results of the high-quality studies reported a higher ORR with sunitinib than with sorafenib, and medium-quality studies showed a longer OS with sunitinib than with sorafenib. Conclusions: Sunitinib has more benefits (longer OS and better ORR) than sorafenib as a first-line therapy for mRCC. However, sunitinib has higher toxicity than sorafenib. Sorafenib might be more suitable than sunitinib among Asian patients, and sunitinib might be superior to sorafenib in European patients. Nevertheless, more large-scale, high-quality studies are required.
Project description:BACKGROUND:Sunitinib and pazopanib are extensively used as first-line treatment of metastatic renal cell carcinoma (mRCC). We performed this meta-analysis to assess the anti-tumor effectiveness, toxicity, and total costs of the two drugs among patients with mRCC/advanced RCC (aRCC). MATERIALS AND METHODS:PubMed, ScienceDirect, Scopus, Web of Science, Ovid MEDLINE, the Cochrane Library, Embase, and Google Scholar were searched to obtain eligible articles. The endpoints included progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and per-patient-per-month (PPPM) costs. RESULTS:We included 14 medium- to high-quality studies. Both drugs were valid for mRCC/aRCC, with equivalent PFS (hazard ratio (HR) =1.06, 95% confidence interval [CI]: 0.98-1.15, P = 0.13), OS (HR = 0.92, 95% CI: 0.79-1.07, P = 0.29), objective response rate (ORR, risk ratio (RR) =1.03, 95% CI: 0.93-1.13, p = 0.58), and disease control rate (DCR, RR = 1.03, 95% CI: 0.94-1.22, P = 0.54). Sunitinib had more dosage reductions and higher PPPM (weighted mean difference = - 1.50 thousand US dollars, 95% CI: - 2.27 to - 0.72, P = 0.0002). Furthermore, more incidences of severe fatigue, thrombocytopenia, and neutropenia were recorded for sunitinib, but pazopanib had more liver toxicity. In subgroup analysis, studies from the US reported longer OS (HR = 0.86, 95% CI: 0.77-0.95, P = 0.004) and higher ORR (RR = 1.24, 95% CI: 1.03-1.51, P = 0.03). CONCLUSIONS:Pazopanib provides equivalent anti-tumor effectiveness and lower PPPM as compared with sunitinib for mRCC/aRCC. Great care should be given to pazopanib-treated patients with abnormal liver function. Nevertheless, more large-scale, high-quality studies are required.