The impact of cytoreductive nephrectomy on survival outcomes in patients treated with tyrosine kinase inhibitors for metastatic renal cell carcinoma in a real-world cohort

BackgroundTyrosine kinase inhibitor therapy (TKI) has changed the treatment paradigm of metastatic renal cell carcinoma (mRCC). The recent CARMENA and SURTIME trials challenged the role of the cytoreductive nephrectomy (CN).ObjectiveTo assess the impact of CN prior to TKI therapy in patients with mRCC in a real-world setting.MethodsOverall, 262 consecutive patients with mRCC were treated with CN plus TKI or TKI only at our institution between 2000 and 2016. Patients with prior immunotherapy or metastasectomy were excluded. Multiple imputation and inverse probability of treatment weighting (IPTW) were performed to account for missing values and imbalances between the treatment groups, respectively. Unadjusted and adjusted Kaplan-Meier estimates were used to determine differences in progression-free (PFS), overall (OS), and cancer-specific survival (CSS).ResultsOverall, 104 (40%) patients received CN before TKI treatment. Most frequent first line therapy was Sunitinib (66%), followed by Sorafenib (20%) and Pazopanib (10%). After adjustment with IPTW, there was no difference in PFS, CSS, and OS (all P > 0.05) between the treatment groups. In subgroup analyses, CSS was improved when CN was performed in patients with sarcomatoid features and clear cell histology (P = 0.04 and P = 0.03) and PFS was improved in patients with clear cell histology when CN was performed [0.04]). CN did not improve OS in any subgroup analysis.ConclusionThe role of CN remains controversial. We found no difference in survival outcomes between patients treated with and without CN before TKI therapy. However, CN was associated with improved survival in specific patient subgroups. Tailored, individualized treatment is key to further improve oncological outcomes for mRCC.     

肿瘤肾脏切除在转移性肾细胞癌治疗中的意义

转移性肾细胞癌的治疗是肾癌治疗的难点。以往认为转移性肾细胞癌切除肿瘤原发灶是没有意义的。但随着肾癌免疫治疗和靶向治疗的发展,越来越多的证据证明肿瘤肾脏切除在转移性肾细胞癌的治疗中有着重要意义。本文通过复习相关文献对肿瘤肾脏切除术在转移性肾细胞癌治疗中的意义作简单介绍。     

A population-based competing-risks analysis of survival after nephrectomy for renal cell carcinoma

ObjectivesVariability in survival after surgical treatment is observed in patients with renal cell carcinoma (RCC), thereby affirming the heterogeneity of the disease. The aim of our study was to provide a clinically relevant and detailed assessment of survival following surgical excision in patients with RCC of all stages according to age, stage, and grade.Materials and methodsA retrospective population-based analysis of 42,090 patients in the United States who were treated with partial nephrectomy (PN) or radical nephrectomy (RN) for RCC of all stages between the years 1988 and 2008 was performed. Competing-risks Poisson regression analyses focusing on cancer-specific mortality (CSM) or other-cause mortality (OCM) were executed. Stratification was performed according to age groups (≤59, 60–69, 70–79, and ≥80 y), the American Joint Committee on Cancer stage (I, II, III, and IV), and the Fuhrman grade (I–II and III–IV).ResultsIncreasing stage was associated with higher CSM rates (from 2%–9% to 54%–79% for stage I and IV), regardless of age. Similarly, high tumor grade was associated with higher CSM rates (from 2%–64% to 6%–79% for low and high grade). However, OCM was nonnegligible amongst persons aged 70 to 79 years (11%–24%) and ≥80 years (17%–44%), regardless of stage and grade. In subanalyses focusing on stage I RCC, CSM (3%–10%) rates were slightly higher for RN-treated patients, regardless of age and grade. However, in individuals aged 70 to 79 years with high-grade RCC, OCM rates were slightly higher for PN relative to RN (25.5% vs. 23.5%). In those aged ≥80 years, OCM rates were higher for PN compared with RN, both for low-grade (39.4% vs. 32.7%) and high-grade disease (52.0% vs. 42.8%).ConclusionsTumor grade and American Joint Committee on Cancer stage represent important prognostic factors for the prediction of CSM, despite adjustment for patient age. However, OCM rates were nonnegligible in elderly individuals (≥70 y) with low-grade and stage I to III RCC.     

Normalization of C-reactive protein levels following cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors is associated with improved overall survival

Introduction and objectives

Pretreated C-reactive protein (CRP) has been suggested as one of the most important prognostic factors for metastatic renal cell carcinoma (mRCC). The aim of this study was to investigate the prognostic impact of the change in CRP level before and after cytoreductive nephrectomy (CN) in patients with mRCC treated with tyrosine kinase inhibitor.

Sequential mTOR inhibitor treatment with temsirolimus in metastatic renal cell carcinoma following failure of VEGF receptor tyrosine kinase inhibitors

Purpose

Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy.

Methods

Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed.

Results

Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1–10.4) and 18.0 months (12.6–23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13).

Conclusions

Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.     

The role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma

Cytoreductive nephrectomy can be an important and effective component of a multidisciplinary treatment approach to metastatic renal cell carcinoma in carefully selected patients. The results of retrospective single institution series and randomized multicenter phase III trials suggest that removal of the primary tumor, even in the setting of metastatic disease, can significantly prolong survival and delay time to progression. It may also enhance the response to systemic therapy in the postoperative period. When employing initial cytoreductive nephrectomy as part of an overall treatment approach, careful patient selection is critical to success. A poor performance status (ECOG performance status less than 1), significant comorbidities that make surgical intervention high risk, or high-volume metastatic disease, and the presence of brain, liver, or bone metastases, or of atypical (sarcomatoid) histology have all been shown to be associated with an extremely poor prognosis. Patients exhibiting these clinical phenotypes should not be considered for initial cytoreductive nephrectomy as part of their treatment paradigm. Instead, they should receive some form of upfront systemic therapy (immunotherapy or novel therapy) and then be considered for delayed nephrectomy as part of a surgical consolidation approach after an interval of treatment if their disease kinetics demonstrate stable or regressing disease in response to systemic therapy. Patients who do not demonstrate these poor prognostic features should be considered for upfront cytoreductive nephrectomy as part of their overall treatment approach because of the potential it offers for palliation from local tumor symptoms, a delay in the time to disease progression, an improved response to systemic therapy, and improved overall survival.     

Role of nephrectomy in metastatic renal cell carcinoma

Metastatic kidney cancer is still a devastating disease but it represents a very heterogeneous situation. Some patients will have a median survival limited to some months, while others will live several years. If the initial diagnosis of kidney cancer at metastatic stage is quite uncommon, it raises the question of whether or not performing initial nephrectomy. The point was long debated as it was suggested that initial nephrectomy could result in a spontaneous metastase regression and protect against local complications (hematuria, local pain,...). Today, nephrectomy must not be systematic, as effective alternative treatments are often available. Furthermore spontaneous postoperative metastasis regression is unusual. Two recent prospective randomized trials clarified the impact of initial nephrectomy. It is now accepted that initial surgery prior to systemic immunotherapy results in 30% survival benefit. However this procedure should only be considered for highly selected cases: patients in otherwise good condition (ECOG 0-1), macroscopically complete local resection, no supra-hepatic caval thrombus, and patients suitable for systemic immunotherapy treatment. Several questions remain unanswered, such as lymph node dissection to be performed, and its real survival impact. Furthermore the definition of "suitable" patients for immunotherapy has to be clarified, based on the recent results from the Percy Quatro study. It would probably be more effective to consider only patients with an expected good survival benefit using immunotherapy, such as those classified as "good prognosis" based on the CRECY criteria. Finally the development of new drugs, targeting mainly the angiogenic pathway may lead to different future indications in this setting.     

Prognostic significance of pseudocapsule status in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors

BackgroundWe sought to determine whether pseudocapsule (PS) features have prognostic implications in patients with metastatic renal cell carcinoma (mRCC).MethodsWe retrospectively reviewed 231 patients diagnosed with mRCC and treated with tyrosine kinase inhibitors; 188 patients with data available regarding the tumor-parenchyma interfacial PS of the primary tumor were enrolled for analysis. PS status was evaluated as intact (grade 0), merely involved (grade 1), penetrated (grade 2), and absent (grade 3). We applied the Kaplan-Meier method and Cox regression model to assess the survival impact.ResultsOf the 188 patients, 19 (10.1%), 61 (32.4%), 96 (51.1%) and 12 (6.4%) had grade 0, 1, 2 and 3 PS, respectively. PS status was significantly associated with histology (P=0.0206), venous tumor embolus (P=0.0511), microvascular invasion (P=0.0108) and microsatellite formation (P=0.0097). Patients without a PS had the worst overall survival (OS), with a 3-year OS rate of 12.7%, whereas the OS rates for grades 0, 1 and 2 were 78.8%, 50.8% and 43.6%, respectively. Adjusted by other variables, grade 3 and grade 2 PS gave rise to a much higher risk of death across the cohort [hazard ratio (HR) =5.217, P=0.0182; HR =3.765, P=0.0281, respectively]. Sarcomatoid change was also an independent factor for OS (HR =2.932, P=0.0075). In contrast, microsatellite formation was not associated with survival in the cohort.ConclusionsPS status has prognostic implications for OS in metastatic renal cancer. The absence of the PS and sarcomatoid change are two pathological features related to an extremely poor prognosis.     

Trends in usage of cytoreductive partial nephrectomy and effect on overall survival in patients with metastatic renal cell carcinoma

Purpose

Cytoreductive radical nephrectomy (cRN) improves survival in select patients with metastatic renal cell carcinoma (mRCC). It is unclear, however, whether cytoreductive partial nephrectomy (cPN) compromises oncologic efficacy. We evaluated trends in utilization of cPN and compared overall survival (OS) in patients who underwent cRN or cPN for mRCC.

CXCR1 expression predicts benefit from tyrosine kinase inhibitors therapy in patients with metastatic renal cell carcinoma

Purpose

CXCR1 signaling promotes tumor progression in various cancers, and clinical trial has proved efficacy of CXCR1 inhibitor in metastatic breast cancer. Therefore, we investigated the prognostic value of CXCR1 in patients with metastatic renal cell carcinoma (mRCC) receiving tyrosine kinase inhibitors (TKIs) therapy.

Impact of smoking status on survival after cytoreductive nephrectomy for metastatic renal cell carcinoma

Objective

To assess the association of smoking status with standard clinicopathological features and overall survival (OS) in a large multi-institutional cohort of patients with metastatic renal cell carcinoma (mRCC) treated with cytoreductive nephrectomy (CNT).

Methods

A total of 613 patients with mRCC treated with CNT in US and Europe institutions between 1990 and 2013 were included. Smoking history comprised smoking status, smoking duration in years, number of cigarettes per day and years since smoking cessation. Cumulative smoking exposure was categorized as light short term, heavy long term and moderate. Association between smoking history and OS was assessed by Cox regression logistic analysis.

Results

One hundred and seventy-one patients (27.9 %) never smoked, 193 (31.5 %) were former smokers and 249 (40.6 %) were current smokers. Smoking status was associated with a higher number of metastases (p < 0.001) and an abnormal preoperative corrected calcium level (p = 0.01). Median follow-up was 16 (IQR 7–24) months. Current smokers had a shorter OS than never and former smokers (log rank, p = 0.004). Smoking status was significantly associated with OS in univariable analysis (HR 1.45; 95 % CI 1.16–1.82; p < 0.001), and in multivariable analysis that adjusted for established prognostic factors (HR 1.46; 95 % CI 1.16–1.84; p = 0.002). Daily consumption of more than 20 cigarettes, more than 20 years of smoking exposure and heavy long exposure were all independent prognosticators of worse OS.

Conclusions

Current smoking and a higher cumulative smoking exposure are associated with a higher risk of death in patients with mRCC treated with CNT. Even at this stage, smoking negatively affects kidney cancer outcomes.

     

Embolization and subsequent nephrectomy in metastatic renal cell carcinoma

Summary Twenty-five patients with primary metastatic adenocarcinoma renis were treated by embolization and delayed nephrectomy. The objective of the study was to examine whether the natural history of the disease is influenced by this combined treatment. Most patients (19/25) had measurable metastatic lesions. No patient received additional therapy unless progression occurred. Embolization was mainly performed with Gelfoam and Gianturco coils. Complete remission of metastases was observed in 1 patient (still in remission after 36 months); stable disease in 6 patients (lasting between 14 and 31 months). Eighteen patients died after a median survival of 5.7 months (range 14 days to 11 months). No major complication related to the embolization procedure occurred. Angio-infarction followed by nephrectomy cannot be recommended for widespread use in patients with primary metastatic kidney carcinoma. The procedure may be tested in controlled clinical trials together with other treatment protocols, such as immunotherapy, infarction with radioactive particles, or chemoembolization. These approaches are experimental and therefore limited to institutions with sufficient experience.     

Delayed nephrectomy has comparable long-term overall survival to immediate nephrectomy for cT1a renal cell carcinoma: A population-based analysis

ObjectivesEarly surgical resection remains the recommended treatment option for most small renal mass (≤4 cm). We examined the long-term overall survival (OS) of patients managed with delayed and immediate nephrectomy of cT1a renal cancer.Patient and methodsWe utilized the National Cancer Database (2005–2010) to identify 14,677 patients (immediate nephrectomy: 14,050 patients vs. late nephrectomy: 627 patients) aged <70 years with Charlson Comorbidity Index 0 and cT1aN0M0 renal cell carcinoma. Immediate nephrectomy and late nephrectomy were defined as nephrectomy performed <30 days and >180 days from diagnosis, respectively. Inverse probability of treatment weighting–adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare OS of patients in the 2 treatment arms. Influence of patient age and Charlson Comorbidity Index on treatment effect was tested by interactions. Sensitivity analysis was performed to explore the outcome of delaying nephrectomy for >12 months.ResultsMedian patient age was 55 years with a median follow-up of 82.5 months. Inverse probability of treatment weighting-adjusted Kaplan-Meier curves suggest no significant difference between treatment arms (immediate nephrectomy [<30 days] vs. delayed nephrectomy [>180 days]) (Hazard ratio 0.96; 95% confidence interval 0.73–1.26; P = 0.77). This outcome was consistent between all patients regardless of age (P = 0.48). Sensitivity analysis reports no difference in OS even if nephrectomy was delayed by >12 months (P = 0.60).ConclusionsWe report that delayed and immediate nephrectomy for cT1a renal cell carcinoma confers comparable long-term OS. These findings suggest that a period of observation of between 6 and 12 months is safe to allow identification of renal masses, which will benefit from surgical resection.     

Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis

Background

To date, few data are available about the sequential use of the tyrosine kinase inhibitors (TKI) sorafenib and sunitinib in metastatic renal cell carcinoma (mRCC).

Objective

To investigate the effectiveness of the use of sunitinib after progression under sorafenib in mRCC.

Design, setting, and participants

A retrospective analysis of 30 patients with progressive mRCC, treated with sorafenib between May 2005 and February 2008. When radiologic progression was diagnosed, treatment was switched to sunitinib and continued until a further tumour progression occurred.

Measurements

Radiologic evaluation of the treatment results was performed every 3 mo according to the criteria for Response Evaluation Criteria in Solid Tumors (RECIST). Adverse effects and therapeutic abnormalities (eg, dose reduction) were documented during regular visits.

Results and limitations

Of the patients, 50% benefited from the secondary use of sunitinib. In detail, a radiologically confirmed new disease stabilisation or partial response was observed in seven and eight patients, respectively. Median progression-free survival was 8.7 mo and 10.3 mo under sorafenib and sunitinib, respectively. Overall, the median time from the initialisation of the first TKI until progression under therapy with the second TKI was 17.3 mo.To our knowledge, this is the second largest study reporting results of sequential therapy from sorafenib followed by sunitinib. However, the number of patients is still not extensive enough to settle this important question conclusively.

Conclusions

This study supports the hypothesis that sequential TKI therapy with the sorafenib followed by sunitinib has clinical validity in some patients with advanced renal cell carcinoma when progressive disease occurs under the initial TKI therapy.