Timing Of Cytoreductive Nephrectomy Research Articles

Multicenter randomized trial of deferred cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma receiving checkpoint inhibitors: the NORDIC-SUN-Trial

BackgroundPrimary tumor removal by cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma patients has been investigated in the context of various treatment regimens. Two randomized controlled trials investigated the role and timing of cytoreductive nephrectomy in the era of targeted therapy and demonstrated that upfront nephrectomy should no longer be performed when patients require systemic therapy. Superiority of checkpoint immunotherapy agents has led to a paradigm change from targeted therapies to immunotherapy-based first-line treatment in patients with primary metastatic disease; thus, deferred cytoreductive nephrectomy needs to be verified in the immunotherapy setting. Furthermore, a need exists for personalizing treatment choices for the individual patient to avoid unnecessary overtreatment.Methods/designTo explore the impact of cytoreductive nephrectomy in this patient group receiving checkpoint immunotherapy, we initiated a randomized, controlled trial comparing deferred cytoreductive nephrectomy with no surgery. The trial integrates a comprehensive translational research program with specimen sampling for biomarker analysis.DiscussionThe trial aims to show that deferred cytoreductive nephrectomy improves overall survival in patients with synchronous metastatic renal cell carcinoma, and furthermore, to identify relevant biomarkers for personalized renal cancer management.Trial registrationClinicalTrials.gov NCT03977571 June 6, 2019.

Cytoreductive nephrectomy for metastatic renal cell carcinoma, the ultimate urologic 'Choosing Wisely' campaign: a narrative review.

In the early 2000s, cytoreductive nephrectomy in addition to systemic cytokines became standard of care for treating metastatic renal cell carcinoma. Since that time, the development of novel systemic targeted therapies and immuno-oncologic agents have challenged the utility of cytoreductive nephrectomy in clinical practice. In 2019, the controversial CARMENA study was published, providing the first level one evidence suggesting that cytoreductive nephrectomy combined with targeted therapy yielded no survival advantage over targeted therapy alone in intermediate and poor risk metastatic renal cell carcinoma patients. Later that year, the SURTIME trial demonstrated that patients undergoing targeted therapy with delayed nephrectomy maintained a survival advantage over those that underwent upfront cytoreductive nephrectomy followed by targeted therapy. Both of these studies underscored the importance of patient selection and timing of cytoreductive nephrectomy and systemic therapy. As new immuno-oncologic agents are trialed, particularly in combination, the role of cytoreductive nephrectomy will continue to be questioned. In this narrative review, we discuss the evolution of the role of cytoreductive nephrectomy in treating metastatic renal cell carcinoma through the context of the ever-changing landscape of targeted therapies and immuno-oncologic agents. We assess the evidence for cytoreductive nephrectomy with respect to patient factors, timing of surgery, and combination with other therapies.

Can I Get a Multidisciplinary Consult, Please? Systemic Immunotherapy and the Timing of Cytoreductive Nephrectomy

Patient selection is critical to determine who benefits from initial cytoreductive nephrectomy and who benefits from initial systemic treatment. Cytoreductive nephrectomy can no longer be considered a one-size-fits-all approach. Multidisciplinary evaluation is key.

The role and timing of cytoreductive nephrectomy in the immunotherapy era

The role and timing of cytoreductive nephrectomy in the immunotherapy era require further investigation. Extrapolation of data from the cytokine era that demonstrated an overall survival benefit of cytoreductive nephrectomy suggest that similar results might emerge from future trials using immunotherapy agents.

Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions

Major strides have been made in the treatment of kidney cancer in the last several years with checkpoint immunotherapies and novel targeted agents. This manuscript will review current treatment strategies for metastatic renal cell carcinoma and will discuss future directions. Most recently, several new drugs including nivolumab, cabozantinib, and a combination of lenvatinib and everolimus have demonstrated acceptable toxicity and significantly improved overall survival, but evidence-based guidelines for sequencing of the approved treatment options and treatment selection based on biomarkers are still missing. Despite the significant progress, many questions still remain unanswered. Several ongoing clinical trials are evaluating sequencing, timing of cytoreductive nephrectomy, combinations of immunotherapies and targeted therapies as well as selection of the best systemic treatment. Personalized treatment based on tumor profiling is one of the brightest spots on the horizon.

Cytoreductive Surgery in the Management of Renal Tumours: Rationale, Current Evidence and Future Perspectives.

Renal cell carcinoma accounts for 3% of adult solid malignant tumours. Approximately 25% of the patients present with metastatic disease at presentation. In the era of immunotherapy (interferon alpha-2b and interleukin-2), studies showed significant survival benefit with cytoreductive nephrectomy (CRN) followed by interferon alpha-2b than interferon alpha 2-b alone. Introduction of targeted therapies (vascular endothelial growth factor receptor-tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors) in 2005 generated a great interest in the management of metastatic renal cell carcinoma (mRCC) as these drugs exhibited tumour shrinkage in the primary tumour as well as in the metastatic site/s. Though there is no level 1 evidence, many studies have shown the usefulness of cytoreductive nephrectomy along with targeted therapy as against to targeted therapy alone. This review is aimed at the rationale behind the cytoreductive nephrectomy in mRCC, the current evidence and what is in store for the future. A detailed search on the management of mRCC was carried out on MEDLINE, Embase, CANCERLIT and Cochrane Library databases using the key words "cytoreductive nephrectomy", "immunotherapy" and "targeted therapy" since 1980 till 2015. Original articles, review articles, monograms, book chapters on metastatic renal cancer and textbooks on urologic oncology, oncology and urology were reviewed. Various international guidelines on this issue were also studied. An identical search was performed using the American Society of Clinical Oncology Abstract database. Trials in the progress or recently completed that were relevant to this paper were identified through clinicaltrials.gov. The latest information for new articles ahead of publication was last accessed in November 2015. CRN has remained an integral part to the management of metastatic renal cell carcinoma mainly for the patients with good performance status, life expectancy of more than 12months and in the absence of adverse prognostic factors. It had shown measurable survival benefit in the era of immunotherapy (CRN + immunotherapy vs. immunotherapy alone). In the era of targeted therapy, many studies have shown significant survival benefit with CRN + targeted therapy. However, there is no clear level 1 evidence to support this. The ongoing trials (CARMENA and European Organisation for Research and Treatment of Cancer SURTIME) would perhaps guide us in the way in which we should manage mRCC disease in the future. Maybe we may find some answers on the issues of the effectiveness of targeted therapy, the timing of CRN and sequencing these treatment arms once the results of these ongoing and future trials are through.

Cytoreductive nephrectomy and its role in the present-day period of targeted therapy

The beneficial effect of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma in the immunotherapy era was based on two prospective randomized trials. Unfortunately, such evidence does not yet exist in the present-day period of targeted therapy. Despite this, cytoreductive nephrectomy remains integral in the multimodal management of patients with metastatic renal cell carcinoma. Multiple retrospective studies as well as data from prospective studies examining targeted therapy support the continued use of cytoreductive nephrectomy in the properly selected patient. Ongoing studies will hopefully fine-tune the role and timing of cytoreductive nephrectomy in the context of targeted therapy.

Using presurgical sunitinib to select patients with newly diagnosed metastatic clear cell renal cell carcinoma for cytoreductive nephrectomy: A phase II study.

371^ Background: Timing of cytoreductive nephrectomy (CN) is still a matter of debate in mRCC. This study was designed to test the hypothesis that lead-in treatment with sunitinib (Su) selects patients (pts) most likely to benefit from nephrectomy, and can aid in assessing determinants of response and resistance. Methods: Pts with biopsy proven, newly diagnosed clear cell mRCC with measurable disease, performance status of 0/1, and resectable primary tumor were eligible. Pts received one cycle of sunitinib 50mg PO QD on a 28 day on/14 day off cycle, were restaged, and if stable/responding underwent nephrectomy between day 7 and 21 of second cycle of Su. If disease remained stable on postop scans, pts continued Su. Mutations in a 200 gene cancer gene panel as well as copy number variation were used to correlate molecular changes with clinical outcome. Results: 50 pts were enrolled: 36 (72%) were male and 38 (76%) Caucasian, Median age 61 years (range: 43–84). 44 had intermediate MSKCC score and 6 were poor risk. 45 pts (90%) were evaluable. No drug-related perioperative complications were noted. A total of 9 (18%) pts did not have nephrectomy: 6 because of progression, 2 because of drug related toxicity, and one who required emergency surgery during the first cycle for bowel obstruction. Median primary tumor shrinkage after 1 cycle was 4 percent (range -18 to +11%). 4 (8%) pts were found to have nonclear cell pathology at nephrectomy (2 sarcomatoid, 1 papillary, 1 unclassified). Among the 45 evaluable pts, the median PFS was 8.7 months (95% CI: 5.8 – 37.3 months). 24 (53%) pts came off for progressive disease, and five (11%) pts came off for toxicity. With a median follow-up time of 27.3 months, median OS was 32.2 months (95% CI: 17.2 – Not estimable). To date, 20 (40%) pts have died. Copy number and genomic data analysis are underway, and will be presented and correlated with clinical outcome. Conclusions: Pretreatment with Su safely triaged mRCC pts into nephrectomy versus nonnephrectomy groups, with acceptable efficacy and OS. Ongoing studies will define molecular characteristics defining subgroups most likely to benefit from Su. Clinical trial information: NCT00715442.

Reply

Our study affirms the role of cytoreductive nephrectomy (CRN) in the setting of multimodal treatment of metastatic renal cell carcinoma (mRCC) in the targeted-therapy era. Indeed, although complete resection of metastatic disease at presentation may still represent the best approach in selected patients, 1 Alt A.L. Boorjian S.A. Lohse C.M. et al. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011; 117: 2873-2882 Crossref PubMed Scopus (290) Google Scholar our study lends further support to a strategy that incorporates an up-front antiangiogenic challenge to patients with mRCC who are not amenable to a combination of CRN and complete metastectomy, the benefit of which is to avoid unnecessary surgery in patients with progressive metastatic disease. 2 Wood C.G. Margulis V. Neoadjuvant (presurgical) therapy for renal cell carcinoma: a new treatment paradigm for locally advanced and metastatic disease. Cancer. 2009; 115: 2355-2360 Crossref PubMed Scopus (57) Google Scholar This strategy is not without risk however, and the significant degree of toxicity associated with targeted agents, the potential for treatment-related delays and surgical morbidity, and the paucity 3 Hellenthal J. Underwood W. Penetrante R. et al. Prospective clinical trial of preoperative sunitinib in patients with renal cell carcinoma. J Urol. 2010; 184: 859-864 Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar of high-level evidence supporting the approach are legitimate concerns. We look forward to the results of ongoing randomized trials being conducted by European Organisation for Research and Treatment of Cancer and the Assistance Publique-Hôpitaux de Paris, which should provide further insight regarding timing of CRN and systemic therapy, 4 Haanen JBAG, Bex A. European Organization for Research and Treatment of Cancer - EORTC. Randomized phase III trial comparing immediate versus deferred nephrectomy in patients with synchronous metastatic renal cell carcinoma. NLM Identifier: NCT01099423. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Available at: http://clinicaltrials.gov/ct2/show/NCT01099423. Accessed July 22, 2012. Google Scholar , 5 Mejean A. Assistance Publique - Hôpitaux de Paris; Pfizer. Clinical Trial to Assess the Importance of Nephrectomy (CARMENA). NLM Identifier: NCT00930033. ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Available at: http://clinicaltrials.gov/ct2/show/NCT00930033. Accessed July 22, 2012. Google Scholar and we call for further randomized prospective investigation to evaluate the role of CRN and optimal agents(s) for primary targeted therapy for mRCC. Editorial CommentUrologyVol. 81Issue 4PreviewThis retrospective outcome analysis in a relatively small cohort of patients shows that patients with metastatic clear cell renal cell carcinoma (RCC), treated with neoadjuvant sunitinib tyrosine kinase inhibitor (TKI) therapy, followed by cytoreductive nephrectomy (CRN), fared significantly better than those treated with by CRN, followed by adjuvant TKI therapy, whereas patients who received TKI without CRN had a very grim outcome. Specifically, they observed that responders to neoadjuvant TKI therapy who underwent CRN had better disease-specific survival and overall survival than patients who underwent CRN, followed by adjuvant TKI therapy. Full-Text PDF

1760 IMPACT OF CARDIOPULMONARY BY-PASS IN CANCER-SPECIFIC SURVIVAL IN PATIENTS WITH RENAL CELL CARCINOMA AND LEVEL III/IV THROMBUS. INTERNATIONAL RENAL CELL-CARCINOMA-VENOUS THROMBUS CONSORTIUM

ent between group 1 and group 2 (19.7 vs 24.5 months). Statistically significant predictors of death included presence of sarcomatoid features(HR 2.4: 95%CI 1.5–3.8), pathologic T and N stage (HR 2.0: CI 1.1–3.7 and 2.4: CI 1.6–3.6), and having a post-operative complication (HR 2.2:CI 1.5–3.2). Pre-surgical STT was not a significant predictor of death on univariate or multivariate analysis (p 0.88 and p 0.20). CONCLUSIONS: There was no significant difference in overall survival in patients receiving presurgical STT followed by CRN compared to patients treated with immediate CRN. Larger prospective studies are necessary to answer the question of the need for and the most appropriate timing of cytoreductive nephrectomy in patients with metastatic RCC.

Novel Targeted therapy for advanced renal carcinoma: trials in progress

Better understanding of renal cell carcinoma biology has led to a new era of targeted therapy in the management of metastatic renal cell carcinoma. This review provides an updated survey of the recently reported and ongoing clinical trials that will help to further define the role of these novel drugs in the treatment of renal cell carcinoma. Treatment of metastatic renal cell carcinoma has dramatically changed in the past few years. Sunitinib, sorafenib, bevacizumab with interferon-alpha, pazopanib, temsirolimus, and everolimus have improved clinical outcomes in randomized phase III clinical trials by inhibiting vascular endothelial growth factors, other tyrosine kinases, the mammalian target of rapamycin pathway, and other related pathways. Combinations and sequences of these agents are being evaluated. Other novel agents are in clinical development, some of which target novel pathways. Ongoing trials should help to define the exact role and timing of cytoreductive nephrectomy in metastatic or locally advanced renal cell carcinoma as well as the option for adjuvant treatments after surgery.

Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma

Cytoreductive nephrectomy prior to cytokine therapy has a well-established role in the treatment of appropriately selected patients with metastatic renal cell carcinoma (RCC). Recent use of novel molecular targeted agents in the management of metastatic RCC has challenged the current dogma of treatment with regards to the necessity, patient selection for and timing of cytoreductive nephrectomy. Current evidence suggests that cytoreductive nephrectomy still plays an integral part in the multimodal paradigm of management for metastatic RCC. This review highlights the role of cytoreductive nephrectomy, and discusses controversial issues surrounding cytoreductive nephrectomy in the treatment of metastatic RCC, in the context of immunotherapy and also in the new era of targeted therapy. It also gives updates on the changing concepts of surgical approaches to cytoreductive nephrectomy in metastatic RCC.

Presurgical bevacizumab in patients with metastatic clear cell renal cell carcinoma: A phase II study

5104 Background: The increasing use of targeted therapies in metastatic renal cell carcinoma (mRCC) has raised questions about the timing of cytoreductive nephrectomy. We initiated a phase II trial to evaluate the safety and efficacy of presurgical bevacizumab (bev) in newly diagnosed patients (pts) with mRCC, with the hope of improving clinical outcomes and to obtain tissue for correlative studies. Methods: Pts with conventional-type mRCC with PS 0/1, resectable primary tumor and no brain metastasis received bev 10 mg/kg iv q2wks (plus erlotinib 150 mg daily for the first 25 pts) for 8 wks, followed 4 weeks later by cytoreductive nephrectomy. Primary endpoints: progression free survival (PFS) and safety. Secondary endpoints: response rate (RR), overall survival (OS) and correlative studies. Responding or stable pts resumed bev 4 weeks postoperatively. Response was defined by RECIST. PFS was measured from registration to date of progressive disease (PD) or death from any cause. Overall survival (OS) was m...

Should radical nephrectomy be performed in the face of surgically incurable disease?

The role of cytoreductive nephrectomy in the management of metastatic renal cancer remains controversial. Recent trials, like SWOG 8949 have suggested the usefulness of this approach at least in selected patients with good performance status and other favorable indicators. The timing of cytoreductive nephrectomy has also been controversial and remains so to this time. Commentary An estimated 30,000 new cases of renal cell carcinoma (RCC) are detected annually in the U.S. In approximately one-third of these cases, metastatic disease is diagnosed at presentation. Multi-modality treatment combines biologic response modifier (BRM) therapy with surgery in an attempt to improve survival with either form of treatment alone. The optimal timing of surgery relative to BRM therapy continues to be debated. Prior to the advent of multi-modality therapy, there were relatively few indications for nephrectomy in patients with metastatic RCC. The incidence of spontaneous regression of metastatic RCC following removal of the primary tumor is only 1–4% and, therefore, nephrectomy on this basis is not justified. There is a palliative role for nephrectomy in selected patients with metastatic RCC who are experiencing severe disability from associated local symptoms; however, some patients in this category can be managed with percutaneous renal angioinfarction. A small subset of patients with a solitary metastasis may benefit from nephrectomy and resection of the metastatic lesion based on reported 5-year survival rates of up to 30–35%. There has been controversy concerning the appropriate timing of adjuvant or cytoreductive nephrectomy in the multi-modality approach to treatment of metastatic RCC. Many protocols have involved preliminary removal of the primary tumor before the administration of BRM therapy. The rationale for this has been to enhance response rates to BRM therapy by reducing tumor volume and, in some cases, to provide immunoreactive cells for treatment. A drawback of this approach was that many patients underwent nephrectomy without subsequently receiving BRM therapy due to postoperative morbidity/mortality or rapid tumor progression. This prompted interest in an alternative approach of delayed adjuvant nephrectomy wherein BRM therapy was administered initially and nephrectomy was subsequently performed only in those patients who demonstrated a response to systemic therapy. The relative merits of initial versus delayed adjuvant nephrectomy in conjunction with BRM therapy for metastatic RCC have recently been clarified through two phase III prospective multicenter clinical trials conducted in Europe (EORTC) and the United States (SWOG). The results of both of these carefully done studies have indicated improved survival with initial nephrectomy followed by BRM therapy. The latter comprised interferon monotherapy in both studies, which opens the studies to criticism, however the essential observation of extended survival with preliminary nephrectomy appears to be valid. On this basis, there is now objective evidence to suggest that initial cytoreductive nephrectomy is the preferred approach in patients with metastatic RCC who are candidates for multi-modality therapy. The most appropriate candidates for such therapy remain patients with good performance status and low-volume (preferably pulmonary) metastatic disease. The ability to perform cytoreductive nephrectomy laparoscopically in some of these patients, with reduced morbidity, is a further development that has strengthened the argument in favor of initial nephrectomy. Andrew C. Novick, M.D.

Should radical nephrectomy be performed in the face of surgically incurable disease?

The role of cytoreductive nephrectomy in the management of metastatic renal cancer remains controversial. Recent trials, like SWOG 8949 have suggested the usefulness of this approach at least in selected patients with good performance status and other favorable indicators. The timing of cytoreductive nephrectomy has also been controversial and remains so to this time.