Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category

Background

We hypothesized that changes in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic category at start of second-line therapy (2L) for metastatic renal cell carcinoma (mRCC) might predict response.

Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium

BackgroundThe role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear.ObjectiveTo evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy.Design, setting, and participantsUsing the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy.Outcome measurements and statistical analysisOverall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors.Results and limitationsWe identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor–treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41–0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67–0.78, p < 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study.ConclusionsUpfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors.Patient summaryBefore effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors.     

Cytoreductive Nephrectomy in Patients with Synchronous Metastases from Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Background

The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted therapy.

Objective

To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies.

Design, setting, and participants

Retrospective data from patients with synchronous mRCC (n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not.

Outcome measurements and statistical analysis

OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria.

Results and limitations

Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo (p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively.

Conclusions

CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials.

Patient summary

We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.     

Metastatic Renal Cell Carcinoma: Recent Advances in the Targeted Therapy Era

Context

The treatment of metastatic renal cell carcinoma (mRCC) has recently evolved from being predominantly cytokine based to being grounded in the use of targeted agents.

Objective

To analyse current evidence on the medical management of mRCC.

Evidence acquisition

The PubMed and Medline databases were searched for articles published as of 15 July 2009. Only articles published in English were considered. The search terms were metastatic renal cell cancer, targeted therapy, and immunotherapy. Proceedings from the 2000–2009 conferences of the American Society of Clinical Oncology, the American Urological Association, and the European Association of Urology were also searched for relevant abstracts.

Evidence synthesis

Sunitinib has recently emerged as a front-line standard of care in mRCC. Temsirolimus is considered a first-line therapy for patients with poor risk features. Bevacizumab/interferon is likely to be the next U.S. Food and Drug Administration–approved first-line treatment. The use of sorafenib has moved toward second-line and later therapy. Everolimus was the first agent to show clinical benefit post–tyrosine kinase inhibitor failure in a phase 3 study and is considered the standard of care in this setting. Temsirolimus provided benefit to patients with non–clear-cell histology. In preliminary results, a favourable risk–benefit ratio has been shown with pazopanib and axitinib as first- and second-line treatment. Until combination therapy is clearly shown to be superior to monotherapy, it should be used in the context of a clinical trial. Deciding which is the best sequence to use in mRCC patients remains up to the best judgement of the treating physician. Cytoreductive nephrectomy in the presence of metastatic disease is often indicated as part of an integrated management strategy.

Conclusions

Given considerable advances in understanding the biology of mRCC, several new drugs have recently been developed, offering an increasing number of treatment options. A treatment algorithm based on the best available evidence so far can be therefore postulated, though it continues to evolve as data from ongoing trials become available.     

Pancreatic Resection for Metastatic Renal Cell Carcinoma: Presentation,Treatment, and Outcome

Background: The diverse natural history of renal cell carcinoma (RCC) includes metastases to the pancreas, a very unusual site for distant spread of other cancers. Considering the relatively indolent behavior of some cases of metastatic RCC, pancreatic resection is offered to select patients.Methods: We reviewed the records of patients at three affiliated university hospital centers who had prior nephrectomy for RCC and subsequent pancreatic resection of metastases.Results: Fourteen patients—9 women and 5 men with a median age of 63.8 years—underwent a total of 15 pancreatic resections for metastatic RCC. Nine (64%) had solitary metastases. The median interval from nephrectomy to diagnosis of pancreatic metastases was 83 months. The median size of metastases was 4.6 cm. There was one perioperative death. Pancreatic recurrence occurred in five patients (36%), and one patient underwent repeat resection. At a median follow-up of 32 months, seven patients (50%) are alive without evidence of disease, and four patients (28%) are alive with recurrent disease.Conclusions: Resection of pancreatic metastases from RCC is associated with long-term survival and should be considered for patients in whom complete resection is possible.     

Successful Sorafenib Treatment for Metastatic Renal Cell Carcinoma in a Case with Chronic Renal Failure

Treatment options for patients with end-stage renal disease (ESRD) and metastatic renal cell carcinoma (mRCC) are limited. We report the case of a 69-yr-old male who was treated with sorafenib after failure of immunotherapy. The treatment has resulted in remission with stable disease for 13 mo so far. Sorafenib seems to be a safe treatment option for patients with ESRD and mRCC, but further studies are required.     

Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

Background

The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).

Objective

To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy.

Design, setting, and participants

We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC.

Outcome measurements and statistical analysis

We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression.

Results and limitations

The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p < 0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p = 0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22–1.62) for BMs, 1.42 (95% CI, 1.17–1.73) for LMs, and 1.82 (95% CI, 1.47–2.26) for both BMs and LMs compared with other metastatic sites (p < 0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p < 0.0001). Data in this analysis were collected retrospectively.

Conclusions

The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.     

Metastatic Biliary Polypoid Thrombus from Renal Cell Carcinoma: Report of a Case

We report an extremely rare case of metastatic biliary polypoid thrombus with hepatic metastases from renal cell carcinoma. A 74-year-old man was admitted with a low-grade fever and obstruction of the left hepatic duct. He had undergone left nephrectomy 17 years previously due to a diagnosis of renal cell carcinoma. A preoperative diagnosis of left hepatic duct carcinoma was made, and a left lobectomy and left caudate lobectomy with right biliary anastomosis of jejunal loop were performed. The resected specimen showed a polypoid mass in the left hepatic duct with metastases in the caudate lobe, and a histological examination revealed both tumors to be clear cell-type renal cell carcinoma. The mechanism of biliary metastatic thrombus formation was speculated to be as follows: caudate lobe metastases invade the adjacent bile ducts, and a tumor fragment in the bile duct then becomes implanted in the intraluminal left hepatic duct, thus leading to the growth of the biliary polypoid thrombus. Received: April 16, 2001 / Accepted: November 20, 2001     

Renal Cell Carcinoma Metastatic to the Duodenum: Treatment by Classic Pancreaticoduodenectomy and Review of the Literature

Renal cell cancer (RCC) most commonly metastasizes to the lungs, bones, liver, renal fossa, and brain, although metastases can occur elsewhere. RCC metastatic to the duodenum is especially rare, with only a small number of cases reported in the literature. Herein, we describe a case of an 86-year-old woman with a history of RCC treated by radical nephrectomy 13 years previously. The patient presented with duodenal obstruction and anemia from a solitary duodenal mass invading into the pancreas and was treated via classic pancreaticoduodenectomy. Preoperative imaging and intra-operative assessment showed no evidence of other disease. Pathology confirmed metastatic RCC without lymph node involvement. Our case report and review of the English language literature underscore the rarity of this entity and support aggressive surgical treatment in such patients. Presented as a poster at the 41st Annual Meeting of the Pancreas Club, May 20th, 2007, Washington DC.     

Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma

Context

The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) in the targeted therapy (TT) era is controversial.

Prognosis of Japanese Metastatic Renal Cell Carcinoma Patients in the Cytokine Era: A Cooperative Group Report of 1463 Patients

Background

Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients.

Objectives

We aimed to investigate the prognosis of Japanese patients and their prognostic factors.

Design, setting, and participants

The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002.

Measurements

The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features.

Results and limitations

The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival.

Conclusions

The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.     

己糖激酶1在肾癌中的异常表达

目的探讨己糖激酶1(hexokinase 1,HK1)基因在人肾癌和癌旁组织中差异表达。方法提取47例肾癌及其癌旁组织的RNA和蛋白,荧光定量实时聚合酶链反应(real-time quantitative polymerase chain reaction,QPCR)检测HK1的表达水平,应用免疫组化方法检测HK1蛋白在肾癌及相应癌旁组织的表达情况。结果癌组织△CT值为4.43±1.54,癌旁组织的△CT值为5.59±1.70,二者有统计学差异(t=-4.97,P=0.00)。37例(78.7%,37/47)肾癌组织样本中HK1表达量高于癌旁组织。免疫组化结果显示,HK1蛋白表达于胞浆内,在肾癌组织中的表达量明显高于相应的正常组织。结论 HK1高表达于肾癌组织,可能在肿瘤发生发展的过程中发挥重要作用,该基因有望成为指导肾癌诊断及治疗的新靶点。     

The Management of Spinal Metastases from Renal Cell Carcinoma

INTRODUCTION

Osseous metastases occur in 50% of patients with renal cell carcinoma; of these, 15% occur in the spine. The treatment options for spinal metastases secondary to renal cell carcinoma are limited. This paper considers the current management options available for spinal metastases secondary to renal cell carcinoma.

PATIENTS AND METHODS

A review of four patients with spinal metastases secondary to renal cell carcinoma.

RESULTS

The presentation of four cases highlighting the current management options for spinal metastases secondary to renal cell carcinoma.

CONCLUSIONS

Historically, spinal metastases from renal cell carcinoma have been poorly managed; however, as the treatment of the primary disease improves, better treatment of the secondary disease is needed. Cement augmentation, used alone for prophylactic stabilisation or in conjunction with a posterior decompression and fixation, provides a useful addition in the management of these patients optimising their chance to remain ambulant, continent, and pain-free.     

Retrospective Comparison of Triple-sequence Therapies in Metastatic Renal Cell Carcinoma

Background

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

Objective

To describe the efficacy and toxicity of the most common sequences of targeted therapy, namely, receptor tyrosine kinase inhibitor (rTKI) and mammalian target of rapamycin inhibitor (mTORi), in different sequences after failure of vascular endothelial growth factor signaling inhibition (VEGFi) in first-line therapy.

Design, setting and participants

Retrospective study of 103 patients receiving VEGFi-rTKI-mTORi (n = 62) or VEGFi-mTORi-rTKI (n = 41) at two German academic centers.

Intervention

Sequence of systemic targeted treatment.

Outcome measurements and statistical analysis

Response was assessed using Response Evaluation Criteria in Solid Tumors 1.0 and toxicity was measured using the Common Terminology Criteria for Adverse Events 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Predictors of survival were analyzed using Cox regression.

Results and limitations

Sequence groups did not significantly differ by patient characteristics and response rate following first VEGFi failure. Median PFS for second-line therapy was 4.6 mo (95% confidence interval [CI], 3.8–5.4), 4.1 mo (95% CI, 3.4–4.9) for rTKI treatment, and 5.4 mo (95% CI, 2.7–8.1) for mTORi treatment (p = 0.400). No differences in PFS were observed among third-line therapy groups (3.6 mo for mTORi; 3.7 mo for rTKI). Treatment duration following first VEGFi failure (combined second- and third-line PFS) was 10.0 mo for VEGFi-rTKI-mTORi and 12.2 mo for VEGFi-mTORi-rTKI (p = 0.103). No significant differences in OS were observed among sequence groups (33.7 mo [95% CI, 30.4–37.1] for VEGFi-rTKI-mTORi; 38.7 mo [95% CI, 24.4–52.9] for VEGFi-mTORi-rTKI). Primary resistance on first-line therapy was an independent predictor of OS, but type of sequence was not. Limitations are the retrospective design and limited numbers of cases.

Conclusions

The sequence therapies VEGFi-mTORi-rTKI and VEGFi-rTKI-mTORi with the currently available agents appear to be equally efficacious in terms of PFS, OS, and response rate, with no apparent beneficial effect with an early use of mTORi.     

Survival Outcome and Treatment Response of Patients with Late Relapse from Renal Cell Carcinoma in the Era of Targeted Therapy

Background

A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≥5 yr after initial nephrectomy.

Objective

To characterize the clinical outcome of patients with late recurrence beyond 5 yr.

Design, setting, and participants

Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr.

Outcome measurements and statistical analysis

Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses.

Results and limitations

Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5–35 yr) after 5 yr. LRs presented with younger age (p < 0.0001), fewer with sarcomatoid features (p < 0.0001), more clear cell histology (p = 0.001), and lower Fuhrman grade (p < 0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p = 0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p = 0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p = 0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols.

Conclusions

A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.