Current status of cytoreductive nephrectomy in metastatic renal cell carcinoma

The incidence of metastatic renal cell carcinoma (mRCC) continues to rise. While treatment options have increased dramatically in the last few years, few patients achieve a cure. The standard of care for mRCC in cytokine-eligible candidates is nephrectomy followed by high-dose IL-2. High-dose IL-2 can induce durable complete remissions, but only select patients can enjoy its benefits owing to toxicities. While not curative, the newer targeted therapies offer a broader patient population the chance for treatment response and prolonged survival. This review highlights the historical background of cytoreductive nephrectomy in mRCC, discusses the available treatment options and considers alternative treatment paradigms, such as the integration of the targeted agents with nephrectomy and the use of systemic therapy as medical selection for determining appropriate nephrectomy candidates.     

Selecting patients for cytoreductive nephrectomy in advanced renal cell carcinoma: who and when

Renal cell carcinoma presents with metastatic disease in approximately 30% of patients at the time of diagnosis. Cytoreductive nephrectomy (CN) of the primary tumor in the face of metastatic disease is part of a multimodality approach including systemic therapy that is based on evidence from randomized trials in the cytokine era. Data from the pretargeted therapy era showed that CN had a clear role in metastatic renal cell carcinoma, increasing life expectancy by approximately 6 months. The substantial improvement in outcomes reported for targeted therapy has challenged the previous role of CN. However, despite the absence of data from Phase III trials, available evidence suggests that some patients may benefit substantially from CN in the era of targeted therapy. This review summarizes current arguments for CN and how to best select patients for surgery. Ongoing trials are key in generating evidence towards a personalized approach to debulking nephrectomy.     

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。     

The use of cytoreductive nephrectomy in patients with renal cell carcinoma

Introduction: The systemic options for managing metastatic renal cell carcinoma (mRCC) have expanded considerably over the past decade. Initially limited to cytokines, clinicians may now choose from several classes of targeted therapies and, most recently, immune checkpoint inhibitors.

Areas covered: In this review, we discuss the role and timing of cytoreductive nephrectomy (CN) and its evolution starting with cytokines, and then alongside the emergence of targeted therapy and novel immunotherapy with immune checkpoint inhibitors. Patient selection remains the most critical determinant in offering CN, and the anticipated survival benefits of CN must be weighed against the surgical morbidity and potential delay to receipt of systemic therapies.

Expert opinion: Proper patient selection is key for decision-making in mRCC. Prospective data is urgently needed to define the role of CN in the contemporary immunotherapy era, with greater personalization of prognostic models.     

减瘤手术联合靶向治疗在转移性肾癌合并下腔静脉癌栓治疗中的临床价值

目的:探讨减瘤手术联合靶向治疗转移性肾癌(metastatic renal cell carcinoma,mRCC)合并下腔静脉癌栓患者的安全性和有效性。方法:回顾性分析2011年11月至2019年02月收治的13例mRCC合并下腔静脉癌栓患者的临床资料,根据有无靶向治疗分为靶向组和非靶向组。靶向组8例,男7例,女1例,平均年龄(48.38±13.92)岁,肿瘤位于左侧5例,右侧3例,平均直径(9.93±5.37)cm。非靶向组5例,男4例,女1例,平均年龄(60.60±5.37)岁,肿瘤位于左侧1例,右侧4例,平均直径(11.24±2.76)cm。结果:术后病理:靶向组透明细胞癌6例,乳头状肾细胞癌和肉瘤样癌各1例,术后TNM分期T3bN1M0和T4N1M1各1例,T3aN1M1 3例,T3bN1M1 3例。非靶向组透明细胞癌2例,Xp11.2易位/TFE3基因融合相关性肾癌、乳头状肾细胞癌和低分化癌各1例,术后TNM分期T3bN1M1和T3cN1M1各1例,T4N1M1 3例。所有患者获随访4～47个月,中位随访时间27个月。靶向组和非靶向组中位无进展生存期分别为6.5个月和2个月,半年、1年无进展生存率分别为50.00%(4/8)、37.50%(3/8)和40.00%(2/5)、20.00%(1/5),两组对比无统计学差异(HR=0.46,95%CI:0.13~1.70,P=0.125 9)。靶向组和非靶向组中位总生存期分别为41个月和8个月,1年和2年总存活率分别为100.00%(8/8)、87.50%(7/8)和20.00%(1/5)、20.00%(1/5),两组对比统计学差异显著(HR=0.17,95%CI:0.03~0.99,P=0.000 5)。结论:减瘤手术治疗mRCC并下腔静脉癌栓患者安全有效,术后进行靶向治疗可显著延长患者总生存期。     

Cytoreductive nephron-sparing surgery does not appear to undermine disease-specific survival in patients with metastatic renal cell carcinoma

BACKGROUND: The role of nephron-sparing surgery (NSS) showed promise in patients with metastatic renal cell carcinoma (MRCC). The disease-specific survival of patients with MRCC was compared according to the type of surgery, NSS (N=45) versus radical nephrectomy (RN) (N=732), in unmatched and matched analyses. METHODS: Kaplan-Meier, life tables, log-rank test, and univariate as well as multivariate Cox regression analyses addressed disease-specific survival of NSS versus RN patients. Subsequently, up to 4 RN cases were matched with each NSS case for TNM stage, Fuhrman grade, and histology. Then, disease-specific survival differences were tested with the log-rank statistic. Finally, the sample size necessary to achieve 80% power in survival analyses between the 2 groups (NSS vs RN) was calculated. RESULTS: Of 45 NSS cases, 38 were matched with 99 of 732 RN cases. First, in multivariate unmatched analyses RN predisposes to 1.7-fold higher RCC-specific mortality rate; second, in matched analyses RN predisposes to 1.5-fold higher RCC-specific mortality rate; and third, both analyses failed to demonstrate statistically significant differences. Based on these findings it could be postulated that until further data become available, NSS does not appear to undermine RCC-specific survival in carefully selected patients with MRCC. The power analyses demonstrated that at least 146, 48, and 76 observations per arm are necessary at 1, 2, and 3 years, respectively, to confirm survival equivalence. CONCLUSIONS: Although the data were limited in size and completeness, they may indicate that RCC-specific survival may not be undermined if NSS is performed in properly selected cases.     

Nephrectomy for metastatic renal cell carcinoma: A component of systemic treatment regimens

New immunotherapeutic and chemotherapeutic regimens have altered the medical approach to metastatic renal cell carcinoma (RCC). Surgery for metastatic RCC needs to be reappraised in the context of these developments. We retrospectively examined the course of 25 patients with metastatic RCC who underwent nephrectomy or resection of renal fossa recurrences as an adjunct to intended systemic therapy. Four patients (16%) had complications and there was no perioperative mortality. Of 23 patients who had surgery first, 17 received subsequent systemic therapy and 2 experienced a response. Two patients underwent nephrectomy after achieving a partial response with systemic therapy. Overall, 3 patients (12%) are alive without detectable disease, 8 (32%) are alive with disease, and 14 (56%) are dead of disease, with a median survival of 23.5 months. Nephrectomy for metastatic renal cell carcinoma may be associated with less morbidity and mortality than previously reported. When initial nephrectomy is performed, most patients go on to receive systemic therapy. Within the context of a systemic treatment regimen, nephrectomy continues to play a role in the management of selected patients with metastatic RCC. © Wiley-Liss, Inc.     

Cytoreductive Nephrectomy Following Immunotherapy-Base Treatment in Metastatic Renal Cell Carcinoma: A Case Series and Review of Current Literature

The role and timing of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving immunotherapy-based regimens is unclear. However, the ability to achieve a complete response for metastatic renal cell carcinoma likely requires a nephrectomy at some point during treatment. Here we present a case series of three patients with metastatic clear-cell renal-cell carcinoma who received front-line immunotherapy-based treatment and subsequently underwent a cytoreductive nephrectomy. All three patients had a complete response to therapy and have subsequently remained off systemic therapy for a median of 531 days (range, 476–602). We also review the limited literature in this setting and highlight ongoing clinical trials. Although the role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma receiving immunotherapy-based treatment is uncertain, a subset of patients will benefit from either an immediate or deferred cytoreductive nephrectomy. Ongoing trials are underway to further determine how to incorporate cytoreductive nephrectomy into the treatment paradigm for patients with metastatic renal cell carcinoma.     

Radical versus partial nephrectomy for T1 non-clear cell renal cell carcinoma

IntroductionNephron-sparing surgery is the recommended surgical management of T1 renal cell carcinoma (RCC). However, non-clear cell RCC (nccRCC) is heterogeneous and included many histological types. Therefore, the present study was performed to compare radical nephrectomy (RN) versus partial nephrectomy (PN) in nccRCC.Materials and methodsWithin the Surveillance, Epidemiology, and End Results registry (2000–2019), the patients with nccRCC were identified. Kaplan-Meier survival curve and the log-rank test were conducted. Univariate analysis and multivariate Cox regression analysis were performed to explore the prognostic factors.ResultsA total of 7575 patients with nccRCC were included, of which papillary RCC (n = 5219) is the major histology. Kaplan-Meier plots and log-rank tests showed that nccRCC patients who underwent RN had significantly worse overall survival (OS) and cancer-specific survival (CSS) than those who received PN (all P < 0.05). Multivariate analysis also revealed that RN was significantly associated with poor OS and CSS in nccRCC patients. Stratified by histological types, the multivariate analysis also revealed that RN was significantly associated with poor OS in papillary and chromophobe (all P < 0.05). Besides, the multivariable analysis indicated that RN was associated with poor CSS in papillary RCC (P < 0.05). For other histology, the patients who received RN had a comparable survival to those who received PN.ConclusionFor patients with T1 nccRCC, our findings revealed that PN was not inferior to RN in OS and CSS. PN may be also the preferred option for T1 nccRCC, but more prospective studies are required to validate this finding.     

Multimodality treatment paradigms for renal cell carcinoma: surgery versus targeted agents

For decades, advanced renal cancer was almost resistant to systemic therapy. Only a few patients with metastatic disease derived clinical benefit from immunotherapy after nephrectomy. Recent advances in understanding the molecular biology of advanced and metastatic renal cancer led to the development of several targeted agents that showed impressive anti-tumor efficacy and prolongation of progression-free survival. The integration of these drugs into clinical practice did not only revolutionize the management of renal cancer, but also created controversy about the necessity, patient selection for and timing of the extirpation of the primary tumor, as well as metastasectomy. Data from ongoing preclinical investigations, including basic science and translational research, are presented and carried forward into multimodal considerations to optimize clinical efficacy of concomitant surgical treatments in the era of targeted agents. In addition to these analyses, this article highlights available clinical data regarding the disputable importance of surgical treatment approaches and explores the need of multimodality treatment paradigms within interdisciplinary decision making.     

肾癌根治术后生物化疗的临床观察

目的：探讨生物化疗在肾癌根治术后的治疗作用。方法：对69例行肾癌根治术后的患者按治疗方法分为A、B两组，A组术后用α-干扰素和5-氟尿嘧啶，B组用白细胞介素-2、α-干扰素和5-氟尿嘧啶联合治疗。比较两组术后生存率。结果：通过随访比较，两组早期（Ⅰ—Ⅱ期）肾癌根治术后患者1年-3年生存率差异无显著性（P〉0．05），晚期（Ⅲ期）肾癌根治术后患者3年生存率差异有显著性（P〈0．05）。所有患者没有发生严重毒副反应。结论：白细胞介素-2、α-干扰素联合5-氟尿嘧啶对晚期肾癌有效，疗效优于仅用α-干扰素和5-氟尿嘧啶。     

The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

Background: Renal cell carcinoma with sarcomatoid dedifferentiation represents a rare histological entity characterized by aggressive behavior, limited efficacy of tyrosine kinase inhibitors or mTOR inhibitors, and poor outcome. The immune checkpoint inhibitor therapy regimen combining ipilimumab with nivolumab represents a new standard of care for this patient population due to a hitherto unprecedented response rate and overall survival. On the other hand, the role of cytoreductive nephrectomy in metastatic renal cell carcinoma, in particular, with sarcomatoid histology, remains controversial. Patient and Methods: In the present case series, we report six patients with locally advanced or synchronous metastatic sarcomatoid renal cell carcinoma and intermediate or poor International Metastatic RCC Database Consortium (IMDC) risk score, five of whom were successfully subjected to cytoreductive nephrectomy. Results: All six patients received the combination regimen of ipilimumab with nivolumab. Five of these patients underwent upfront cytoreductive nephrectomy followed by systemic treatment without any significant delay, with a durable treatment outcome. Notably, two patients with poor prognostic features achieved a long-term major partial response to therapy. We also performed a review of the literature on optimal treatment strategies for patients with sarcomatoid renal cell carcinoma. Conclusion: Herein, we highlight the feasibility of performing cytoreductive nephrectomy in patients with intermediate/poor prognosis metastatic renal cell carcinoma with sarcomatoid dedifferentiation followed by immunotherapy with ipilimumab and nivolumab. To enhance the chances of immunotherapy success, cytoreductive nephrectomy should also be considered for patients presenting with a disease with adverse prognostic parameters.     

后腹腔镜肾部分切除术治疗T1a期肾癌

目的：探讨后腹腔镜肾部分切除术治疗T1a期肾癌的临床价值.方法：回顾性分析2011年9月至2012年12月16例采用后腹腔镜肾部分切除术治疗的T1a期肾癌患者的临床资料,评价手术方法的优点和缺点.结果：16例手术均顺利完成,无中转开放手术者.手术时间为100-155min.16例均单纯阻断肾动脉,热缺血时间为20-30min.术中失血量120-260ml.术后镇痛药用量6-40mg（相当于硫酸吗啡量）;引流管留置时间2-3d,进食时间18-36h,住院天数7-12d.无术后出血、感染、漏尿等并发症.术后病理检查均为肾透明细胞癌,切缘均为阴性.随访1-16个月均健在,肿瘤无局部复发、转移.随访期间患者肾功能均正常.结论：后腹腔镜肾部分切除术治疗T1a期肾癌安全可行,具有创伤小、恢复快等优点,但远期疗效需进一步观察.     

Cytoreductive nephrectomy in metastatic renal cell carcinoma

Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6-12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.     

转移性肾细胞癌生物治疗的现状及展望

由于肾细胞癌（renal cell carcinoma, RCC）的内在抵抗性,使得其对放、化疗均不敏感,生物治疗成为转移性肾细胞癌（metastatic renal cell carcinoma, mRCC）患者唯一的选择。随着对RCC的进一步了解,小分子靶向药物治疗已逐步取代了以往的细胞因子疗法。近年来,新型免疫疗法成为RCC生物治疗研究的热点;小分子靶向药物治疗和新型免疫疗法在RCC治疗中显示出极大的优势,提高了患者的生存时间和生活质量,但是反应率低、耐药、副反应等问题也随之出现。为RCC患者提供个体化治疗,让患者从治疗中得到更大的益处是临床工作者努力的目标。     

Multimodality treatment of metastatic renal cell carcinoma

The treatment of choice for nondisseminated disease is surgery. However, the 5-year survival rates for all stages do not exceed 60%, even in contemporary series. Further improvement will most likely have to await the development of a more effective systemic therapy and the application of combined treatment modalities to counter the relatively high number of patients presenting with advanced stages. Treatment options in metastatic disease include nephrectomy, sometimes in combination with metastasectomy in selected cases, alone or cytoreductive surgery followed by immunotherapy. Alternatively, one may initially apply immunotherapy and perform adjuvant nephrectomy in the case of a response, or proceed to immunotherapy as a monotherapy. Nevertheless, long-term survival ranges from merely 5 to 10% depending strongly on patient selection criteria. Concepts and progress in this field appear to be of major interest for modern uro-oncologists following the advent of immunotherapeutic strategies that require a surgical intervention at some stage of the treatment cascade.     

转移性肾癌靶向治疗和免疫治疗的现状与进展

近年来,转移性肾癌的治疗方式从细胞因子药物的治疗,到现在的针对血管生成、哺乳动物的雷帕霉素途径、免疫应答的药物的应用发生了巨大的变化。尽管耐药仍然是一个巨大的挑战,但通过对这些药物的应用及药物联合应用,转移性肾癌的治疗疗效得到大大的提高。目前新的治疗方法正在迅速发展,治疗前景一片大好。     

Sunitinib in metastatic renal cell carcinoma patients with brain metastases

BACKGROUND:

In a broad patient population with metastatic renal cell carcinoma (RCC), enrolled in an open‐label, expanded access program (EAP), the safety profile of sunitinib was manageable, and efficacy results were encouraging. Here, the authors report results for patients with baseline brain metastases participating in this global EAP.

METHODS:

Previously treated and treatment‐naive metastatic RCC patients ≥18 years received sunitinib 50 mg orally, once daily, on Schedule 4/2. Safety was assessed regularly, tumor measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention‐to‐treat (ITT) population, consisting of all patients who received ≥1 dose of sunitinib.

RESULTS:

As of December 2007, 4564 patients had enrolled in 52 countries. Of these enrollees, 4371 were included in the modified ITT population, of whom 321 (7%) had baseline brain metastases and had received a median of 3 treatment cycles (range 1‐25). Reasons for their discontinuation included lack of efficacy (32%) and adverse events (8%). The most common grade 3‐4 treatment‐related adverse events were fatigue and asthenia (both 7%), thrombocytopenia (6%), and neutropenia (5%), the incidence of which were comparable to that for the overall EAP population. Of 213 evaluable patients, 26 (12%) had an objective response. Median progression‐free survival and overall survival were 5.6 months (95% CI, 5.2‐6.1) and 9.2 months (95% CI, 7.8‐10.9), respectively.

CONCLUSIONS:

In patients with brain metastases from RCC, the safety profile of sunitinib was comparable to that in the general metastatic RCC population, and sunitinib showed evidence of antitumor activity. Cancer 2011. © 2010 American Cancer Society.