TKI治疗转移性肾细胞癌伴横纹肌样分化与伴肉瘤样分化的疗效比较

目的:比较酪氨酸激酶抑制剂(TKI)治疗转移性肾细胞癌伴横纹肌样分化(mRCC-R)与伴肉瘤样分化(mRCC-S)的疗效。方法:回顾性分析天津医科大学肿瘤医院2016年2月至2018年12月采用TKI治疗的5例mRCC-R和9例mRCC-S患者的临床资料。mRCC-R患者5例,男3例,女2例;年龄(60.2±7.1)岁...     

Prediction of early progression of metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitor

Background:There are various alternative first-line therapeutic options besides tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma (mRCC). To inform therapeutic decision-making for such patients, this study aimed to identify predictive factors for resistance to TKI.Materials and methods:A total of 239 cases of mRCC patients who received first-line TKI therapy were retrospectively studied. Patients with a radiologic diagnosis of progressive disease within 3 months after initiating therapy were classified as primary refractory cases; the others were classified as non-primary refractory cases. The association between primary refractory cases and age, gender, pathology findings, serum c-reactive protein (CRP) level, metastatic organ status, and 6 parameters defined by the International Metastatic Renal Cell Carcinoma Database Consortium were analyzed.Results:Of 239 cases, 32 (13.3%) received a radiologic diagnosis of progressive disease within 3 months after initiating therapy. The rates of sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, presence of liver metastasis, anemia, and time from diagnosis to treatment interval of less than a year were significantly higher in the primary refractory group. Multivariate analysis showed that sarcomatoid differentiation, hypercalcemia, a serum CRP level of 0.3 mg/dL or higher, and liver metastasis were independently associated with primary refractory disease. A risk-stratified model based upon the number of patients with these factors indicated rates of primary refractory disease of 4.0%, 10.1%, and 45.0% for patients with 0, 1, and 2 or more factors, respectively.Conclusions:Sarcomatoid differentiation, hypercalcemia, an elevated serum CRP level, and presence of liver metastasis were associated with primary refractory disease in mRCC patients receiving first-line TKI therapy. These results provide clinicians with useful information when selecting a first-line therapeutic option for mRCC patients.     

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.     

Time to progression after first-line tyrosine kinase inhibitor predicts survival in patients with metastatic renal cell carcinoma receiving second-line molecular-targeted therapy

Objectives

The effect of response to first-line tyrosine kinase inhibitor (TKI) therapy on second-line survival in patients with metastatic renal cell carcinoma who receive second-line molecular-targeted therapy (mTT) after first-line failure remains unclear.

Prolonged use of the tyrosine kinase inhibitor in a peritoneal dialysis patient with metastatic renal cell carcinoma: possible beneficial effects on peritoneal membrane and peritonitis rates

Increased submesothelial collagen deposition, loss of mesothelial cells and increased peritoneal vascularization of peritoneal membrane with vasculopathy leads to peritoneal fibrosis in a patient on long-term peritoneal dialysis (PD). This vascular proliferation within the peritoneum is associated with an increased expression of vascular endothelial growth factor (VEGF), which in turn leads to functional loss or deterioration of the peritoneal membrane over time. Vascular endothelial growth factor inhibitors may slow or even prevent vascular proliferation and subsequent loss of membrane function in peritoneal dialysis patient. We have observed the anti-VGEF effects of a tyrosine kinase inhibitor, sunitinib maleate, in a patient who was on this medication for renal cell carcinoma with extensive abdominal metastasis. The patient had also been on PD for 26 months at the time of the study. In this patient, the tyrosine kinase inhibitor helped to stabilize the abdominal metastasis as well as the thickness of the peritoneal membrane. The D/P creatinine ratio also remained stable. These observations suggest that this tyrosine kinase inhibitor may have prevented peritoneal membrane angiogenesis. We also observed that the patient did not have any further episode of peritonitis from gut-derived organisms, suggesting that stabilization of the intestinal metastasis prevented the transmural migration of bacteria from the gut, thereby preventing peritonitis.     

Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors

Background

The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined.

Objective

To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment.

Design, setting, and participants

Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres.

Intervention

Sequence of systemic targeted treatment with sunitinib (n = 85) or sorafenib (n = 23) followed by EV (n = 62) or another rTKI (n = 46; sorafenib, n = 35; sunitinib, n = 11).

Measurements

We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS).

Results and limitations

Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8–5.4) for EV and 4.0 mo (3.2–4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9–52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6–39.5; p = 0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15–3.62; p = 0.015) and OS (HR: 6.54; 95% CI, 3.01–14.20; p < 0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors.

Conclusions

The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.     

Tumor type M2 pyruvate kinase expression in metastatic renal cell carcinoma

The M2 isoenzyme of pyruvate kinase (M2-PK) is specifically expressed in tumor cells (TuM2-PK) and has been detected in the peripheral blood of patients with renal cell carcinoma (RCC). TuM2-PK is not useful as a biological marker in localized RCC. We analysed TuM2-PK in 68 patients with metastatic RCC after initial surgery and prior to or during chemoimmunotherapy of metastases. In 50 patients, the levels of TuM2-PK were measured during chemoimmunotherapy with interleukin-2, interferon-2a and 5-fluorouracil for up to 8 months and were correlated to response as assessed by radiological imaging techniques. TuM2-PK was quantified with a commercially available enzyme linked immunosorbent assay kit using a cut off of 15 kU/l. In 48 of 68 patients (71%), TuM2-PK was elevated above the cut-off. TuM2-PK was significantly higher in G3 tumors than in G2 tumors. In 34 of 50 patients (68%) undergoing chemoimmunotherapy, a positive correlation between TuM2-PK values and response to treatment was observed. Based on these data, we would not recommend the routine clinical use of TuM2-PK in metastatic RCC at this point.     

Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not significantly alter plasma concentrations. In this retrospective study we define the safety and efficacy of tyrosine kinase inhibitors in patients with metastatic RCC (mRCC) and end‐stage renal disease requiring haemodialysis. Even though the retrospective nature of this survey and the relatively small sample size represent major limitations, these data indicate that treatment with sunitinib and sorafenib in this cohort of patients is feasible with no unexpected toxicity and good efficacy, results similar to those in the general population of patients with mRCC.

OBJECTIVE

• ? To investigate the safety and efficacy of tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) and end‐stage renal disease requiring haemodialysis (HD).

PATIENTS AND METHODS

• ? Between July 2006 and December 2010, 24 patients undergoing HD were treated with sunitinib and/or sorafenib for mRCC in 14 Italian institutions.
• ? We retrospectively reviewed the medical records of these patients to evaluate the administered doses of TKIs, treatment‐related toxicities and the clinical response to therapy.

RESULTS

• ? Sunitinib was administered at 50 mg daily for 4–6 weeks in six patients, 37.5 mg daily for 4–6 weeks in seven patients (one patient subsequently increased the dose to 50 mg daily), 25 mg daily for 4–6 weeks in two patients and 12.5 mg daily for 4–6 weeks in one patient. Among the eight patients treated with sorafenib, four patients received 800 mg daily (400 mg every 12 h), three patients 400 mg daily and one patient 200 mg daily with a continuous schedule.
• ? The estimated median progression‐free and overall survival periods of this cohort of patients were 10.3 months and 22.6 months, respectively.
• ? With regard to tolerability and safety, no unexpected adverse events were registered and no grade 4 haematological or non‐haematological toxicities were reported.

CONCLUSIONS

• ? Sunitinib and sorafenib treatment is not contraindicated in patients with mRCC undergoing HD.
• ? The outcome of this patient population is similar to that observed in patients with normal renal function treated with TKIs.
• ? These results merit further confirmation by a larger prospective trial.

     

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.     

Enhancement of Siglec-8 expression predicts adverse prognosis in patients with clear cell renal cell carcinoma

Purpose

Sialic acid-binding immunoglobulin-like lectins (siglecs) family has important functions in tumor progression. The purpose of our study is to figure out the correlation between the expression level of Siglec-8 and prognosis of patients with clear cell renal cell carcinoma (ccRCC), and then to predict the overall survival (OS) via a novel nomogram.

Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: A registry-based analysis

ObjectivesThe aim of the present study was to describe the efficacy and safety of everolimus in the treatment of metastatic renal cell carcinoma (mRCC) after administration of 1 vs. 2 prior tyrosine kinase inhibitors (TKIs).Patients and methodsA national renal information system database was used as the data source for the retrospective study. There were 483 patients who received everolimus as the second (n = 350) or the third (n = 112) targeted agent following TKIs.ResultsMedian progression-free survival (PFS) from the start of everolimus in the second or the third line of targeted therapy was 6.1 months for both subgroups (P = 0.863). Median total PFS from the start of the first targeted agent to progression on the third targeted agent for patients receiving 3 lines of therapy with TKI-TKI-everolimus (n = 112) and TKI-everolimus-TKI (n = 27) sequences was 28.3 months vs. 31.3 months, respectively (P = 0.16), and there was no significant difference in overall survival. PFS on everolimus was associated with PFS on previous TKIs in patients receiving 1 but not 2 previous TKIs. Only 13% of 352 patients starting targeted therapy for mRCC in 2010 had received 3 sequential targeted agents by the data cutoff in March 2013.ConclusionPFS on everolimus correlated with PFS on TKIs in patients pretreated with 1 but not 2 TKIs. Everolimus can be deferred to the third line without loss of efficacy or increased toxicity. However, only a minority of patients with mRCC starting targeted treatment can be expected to receive third-line therapy.     

Immune checkpoint inhibitors further aggravate proteinuria in patients with metastatic renal cell carcinoma after long-term targeted therapy

BackgroundIncreasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosine-kinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria’s and renal function’s condition since the administration of PD-1 inhibitor.MethodsTo assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%).ResultsOf the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m² to 66.75 mL/min/1.73 m² after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent’s survival (P<0.001).ConclusionsTargeted therapy was associated with an increase in proteinuria level and a decrease in eGFR in patients with mRCC. The administration of PD-1 inhibitor contributed to exacerbation in proteinuria, but no significant difference in a decrease of eGFR was observed.     

Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma

Background

In patients with metastatic renal cell carcinoma (mRCC), the timing of systemic targeted therapy in relation to cytoreductive nephrectomy (CN) is under investigation.

Objective

To evaluate postoperative complications after the use of presurgical targeted therapy prior to CN.

Design, setting, and participants

A retrospective review of all patients who underwent a CN at The University of Texas M.D. Anderson Cancer Center from 2004 to 2010 was performed. Inclusion in this study required documented evidence of mRCC, with treatment incorporating CN.

Interventions

Patients receiving presurgical systemic targeted therapy prior to CN were compared to those undergoing immediate CN.

Measurements

Complications were assessed using the modified Clavien system for a period of 12 mo postoperatively.

Results and limitations

Presurgical therapy was administered to 70 patients prior to CN (presurgical), while 103 patients had an immediate CN (immediate). A total of 232 complications occurred in 57% of patients (99 of 173). Use of presurgical systemic targeted therapy was predictive of having a complication > 90 d postoperatively (p = 0.002) and having multiple complications (p = 0.013), and it was predictive of having a wound complication (p < 0.001). Despite these specific complications, presurgical systemic targeted therapy was not associated with an increased overall complication risk on univariable or multivariate analysis (p = 0.064 and p = 0.237) and was not predictive for severe (Clavien ≥3) complications (p = 0.625). This study is limited by its retrospective nature. As is inherent to any retrospective study reporting on complications, we are limited by reporting bias and the potential for misclassification of specific complications.

Conclusions

Despite an increased risk for specific wound-related complications, overall surgical complications and the risk of severe complications (Clavien ≥3) are not greater after presurgical targeted therapy in comparison to upfront cytoreductive surgery.     

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.     

Recent advances in the treatment of metastatic renal cell carcinoma

In the past 5 years, the treatment of patients with metastatic renal cell carcinoma has changed dramatically from being largely cytokine‐based with the emergence of targeted therapy. Following the elucidation of various molecular pathways in renal cell carcinoma, targeted agents (particularly vascular endothelial growth factor‐targeting antiangiogenic agents) now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma and the outcome of treatment has improved. However, many tumors eventually develop resistance to targeted therapy due to secondary mutation of the target protein or compensatory changes within the target pathway that bypass the site of inhibition. On the other hand, there are new forms of immunotherapy that hold the promise of improving the outcome for patients with metastatic renal cell carcinoma. In this article, we describe some of these new therapies, including the anti‐vascular endothelial growth factor monoclonal antibody bevacizumab, several receptor tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, and tivozanib), the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and new immunotherapy modalities, such as anti‐cytotoxic T‐lymphocyte‐associated antigen 4 antibody and anti‐programmed cell death 1/programmed cell death‐ligand 1 antibody. We also discuss their role in the current management of patients with metastatic renal cell carcinoma.     

Overall survival in patients with metastatic renal cell carcinoma and clinical N1 disease undergoing cytoreductive nephrectomy and lymph node dissection

Background

Patients with metastatic renal cell carcinoma (mRCC) have limited treatment options. Cytoreductive nephrectomy (CN) in select patients has been associated with improved survival. We aim to assess the survival in patients with mRCC and cN1 disease who underwent CN with and without lymph node dissection (LND).

Surgical considerations for patients with metastatic renal cell carcinoma

Among patients with renal cell carcinoma (RCC), 25–30% present with metastatic disease at the time of initial diagnosis. Despite the ever-increasing array of treatment options available for these patients, surgery remains one of the cornerstones of therapy. Proper patient selection for cytoreductive surgery is paramount to its effective use in the management of patients with metastatic RCC despite the decrease in reported morbidity rates. We explore the evolving role cytoreductive surgery in metastatic RCC spanning the immunotherapy era to the targeted therapy era. Despite significant advances in the management of patients with metastatic RCC, further evidence on the definitive role of cytoreductive surgery in the targeted therapy era is awaited through large randomized trials.