Sarcomatoid renal cell carcinoma: Biology and treatment advances

Sarcomatoid transformation in renal cell carcinoma, so called sacromatoid RCC (sRCC), is associated with an aggressive behavior and a poor prognosis. Current therapeutic approaches are largely ineffective. Recent studies looking into the genomic and molecular characterization of sRCCs have provided insights into the biology and pathogenesis of this entity. These advances in molecular signatures may help development of effective treatment strategies. We herein present a review of recent developments in the pathology, biology, and treatment modalities in sRCC.     

后腹腔镜根治性肾切除术治疗局限性肾癌

目的总结后腹腔镜根治性肾切除术治疗局限性肾癌的经验。方法2003年10月至2007年10月共对67例局限性肾癌患者施行后腹腔镜下根治性肾切除术，区域性淋巴结清扫，其中男44例，女23例；年龄25～78岁，平均年龄50．3岁。术后定期行血生化及影像学随访。结果本组手术平均时间176min，术中平均出血量70ml，术后平均住院时间8．5d。术中腹膜损伤2例，胸膜损伤1例，下腔静脉属支损伤2例，无一例中转开放手术。随访3～51个月。3年癌症相关生存率为96．4％。结论掌握术中常见并发症预防和处理方法、减少术中周围组织损伤是后腹腔镜肾癌根治术达到“微创”目标的关键。     

Prognostic value of multifocality on progression and survival in localized renal cell carcinoma

OBJECTIVE: Incidence of multifocality in Renal Cell Carcinoma (RCC) is estimated at between 5 and 25%. Multifocality has been largely studied because of the growing interest in conservative surgery which is a risk of local recurrence. The aim of this study is to evaluate the relationship between multifocality and other prognostic parameters and whether it is an independent prognostic factor. MATERIAL AND METHODS: From 1980 to 1990, 255 patients (median age: 60.9 years) were treated by radical nephrectomy for pT1 to pT3b N0M0 RCC. The median follow-up time was 183 months. Multifocality was defined as the existence of at least one other tumoral localization, macroscopically and microscopically diagnosed as renal cell carcinoma, in the same kidney. Studied parameters were: age, sex, side, size, stage, Fuhrman's grade, capsular invasion, renal vein involvement and microvascular invasion. Survival was assessed with Kaplan-Meier and Cox models. RESULTS: 37 cases of multifocal RCC were diagnosed (14.5%). There was only a significant correlation with stage (p=0.002) and with capsular invasion (p=0.002). No other factor was correlated with multifocality. It had no influence on the risk of metastatic progression, overall or specific survival. CONCLUSION: There is a significant correlation between capsular invasion and multifocality that has to be considered before proposing conservative surgery for a localized RCC. Multifocality has no influence on survival or metastatic progression in case of radical nephrectomy.     

The independent oncological role for cytoreductive nephrectomy in metastatic renal cell carcinoma: Prognostic features in the era of targeted therapies

Objectives

To describe the effects of cytoreductive nephrectomy (CN) on the natural course of metastatic renal cell carcinoma (mRCC). CN appears to stabilize metastatic lesions in mRCC in a subgroup of patients and we hypothesize that systemic treatment might be deferred in these patients with stable disease after CN.

Interferon alpha 2b as medical selection for nephrectomy in patients with synchronous metastatic renal cell carcinoma: a consecutive study

OBJECTIVE: Up to 25% of the patients with synchronous metastatic renal cell carcinoma (mRCC) treated with nephrectomy and interferon alpha-2b (IFN-alpha) will progress rapidly at metastatic sites and undergo needless surgery for an asymptomatic primary. We reversed the timing of surgery and immunotherapy and evaluated the role of initial IFN-alpha as selection for nephrectomy. PATIENTS AND METHODS: Sixteen patients with mRCC and the primary in-situ received initial IFN-alpha for 8 weeks (2 weeks 5x3x10(6)IU/wk; 2 weeks 5x6x10(6)IU/wk; 2 weeks 5x9x10(6)IU/wk and 2 weeks 3x9x10(6)IU/wk). Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by IFN-alpha maintenance at 3x9x10(6)IU/wk. Patients were evaluated with regard to age, sex, metastatic sites, morbidity, response, nephrectomy rate, time to progression and survival. RESULTS: Thirteen patients received 2 months of preoperative IFN-alpha; 3 stopped during the 2 months period due to progressive disease (PD). Eight patients developed either a PR (n=3) or SD (n=5) at metastatic sites and underwent nephrectomy. Survival at 1 year is 50% (4/8 patients). Median progression-free survival was 6 months (3-17 months).Two of the 3 patients with PR developed a CR after 2 months maintenance following surgery. Eight patients with PD did not undergo surgery and had a median survival of 4 months (range 1-8 months). CONCLUSIONS: Absence of progression at metastatic sites following IFN-alpha with the primary tumor in place may be used as selection for nephrectomy in patients with an intermediate prognosis. Currently, a randomized study is underway to assess the role of initial versus delayed nephrectomy in combination with IFN-alpha with regard to morbidity and survival.     

ICUD-EAU International Consultation on Kidney Cancer 2010: treatment of metastatic disease

Context

Until the development of novel targeted agents directed against angiogenesis and tumour growth, few treatment options have been available for the treatment of metastatic renal-cell carcinoma (mRCC).

Objective

This review discusses current targeted therapies for mRCC and provides consensus statements regarding treatment algorithms.

Evidence acquisition

Medical literature was retrieved from PubMed up to April 2011. Additional relevant articles and abstract reviews were included from the bibliographies of the retrieved literature.

Evidence synthesis

Targeted treatment for mRCC can be categorized for the following patient groups: previously untreated patients, those refractory to immunotherapy, and those refractory to vascular endothelial growth factor (VEGF)-targeted therapy. Sunitinib and bevacizumab combined with interferon alpha are generally considered first-line treatment options in patients with favourable or intermediate prognoses. Temsirolimus is considered a first-line treatment option for poor-risk patients. Either sorafenib or sunitinib may be valid second-line treatments for patients who have failed prior cytokine-based therapies. For patients refractory to treatment with VEGF-targeted therapy, everolimus is now recommended. Pazopanib is a new treatment option in the first- and second-line setting (after cytokine failure). Sequential and combination approaches, and the roles of nephrectomy and tumour metastasectomy will also be discussed.

Conclusions

Increasing clinical evidence is clarifying appropriate first- and second-line treatments with targeted agents for patients with mRCC. Based on phase 2 and 3 trials, a sequential approach is most promising, while combination therapy is still investigational. The role of nephrectomy in mRCC is being evaluated in ongoing phase 3 clinical trials.     

The role of initial immunotherapy as selection for nephrectomy in patients with metastatic renal cell carcinoma and the primary tumor in situ

OBJECTIVE: A prospective pilot study in patients with metastatic renal cell cancer and the primary in situ to assess the feasibility of immunotherapy prior to nephrectomy and to evaluate the rationale for a future randomized trial to define the role of response to upfront immunotherapy as selection for cytoreductive surgery. PATIENTS AND METHODS: Sixteen patients with synchronous multiple metastases were treated with the primary tumor in place and were evaluated with regard to age, sex, sites of extrarenal disease, morbidity, response, nephrectomy rate, time to progression and overall survival. Immunotherapy consisted of 2 courses low-dose IL-2 4MIU/m(2), subcutaneous GM-CSF 2.5 microg/kg and interferon-alpha (IFN-alpha) 5MU flat on day 1-13 and 22-34. Patients with either partial remission (PR) or stable disease (SD) underwent nephrectomy followed by a third and fourth course. RESULTS: No response was seen in the primary tumors. With regard to extrarenal sites SD was noted in nine cases, PR in two and progressive disease (PD) in five. Eleven patients underwent nephrectomy. No surgical complete response (CR) could be achieved. All patients with PD died after a median overall survival of 3 months versus 11.5 months (range 4-22) in those who underwent nephrectomy. Four patients are still alive at 10, 12, 18 and 19 months. Median duration of response was 6 months (range 2-10). One patient with SD following nephrectomy developed CR after two additional cycles, which is currently maintained for >10 months. CONCLUSIONS: Absence of progression at metastatic sites following immunotherapy may be used as a selection for nephrectomy in this selected group. Non-responding patients can be spared from surgery. A randomized study is needed to assess the timing of nephrectomy in combination with immunotherapy with regard to morbidity, overall survival and quality of life.     

Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma

Background

Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity.

Objective

The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC.

Design, setting, and participants

We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials.

Outcome measurements and statistical analysis

Statistical analyses were performed using Cox regression and the Kaplan-Meier method.

Results and limitations

We identified 2749 patients treated with sunitinib (n = 1059), sorafenib (n = 355), axitinib (n = 359), temsirolimus (n = 208), temsirolimus plus interferon-α (IFN-α) (n = 208), or IFN-α (n = 560), with 28% (n = 781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p < 0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p < 0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p = 0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p = 0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p = 0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p < 0.0001). Data were analyzed retrospectively.

Conclusions

We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity.

Patient summary

In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.     

Clinically nonmetastatic renal cell carcinoma with sarcomatoid dedifferentiation: Natural history and outcomes after surgical resection with curative intent

PurposeRenal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease.Patients and methodsAn institutional review board–approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses.ResultsOS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size.ConclusionsLong-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted.     

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.

Comparison of four early posttherapy imaging changes (EPTIC; RECIST 1.0, tumor shrinkage, computed tomography tumor density, Choi criteria) in assessing outcome to vascular endothelial growth factor-targeted therapy in patients with advanced renal cell carcinoma

Background

Vascular endothelial growth factor (VEGF)-targeted therapy has become standard treatment for patients with metastatic renal cell cancer (mRCC). Since these therapies can induce tumor necrosis and minimal tumor shrinkage, Response Evaluation Criteria in Solid Tumors (RECIST) may not be optimal for predicting clinical outcome.

Objective

To systematically determine the optimal early posttherapy imaging changes (EPTIC) to separate responders and nonresponders at the first posttreatment follow-up computed tomography (CT).

Design, setting, and participants

Seventy mRCC patients with 155 target lesions treated with first-line sunitinib, sorafenib, or bevacizumab at academic medical centers underwent contrast-enhanced thoracic and abdominal CT at baseline and first follow-up after therapy initiation (median: 78 d after therapy initiation; range: 31–223 d).

Measurements

Evaluations were performed according to (1) RECIST 1.0; (2) Choi criteria; (3) tumor shrinkage (TS) of ≥10% decrease in sum of the longest unidimensional diameter (SLD); and (4) 15% or 20% decrease in mean CT tumor density. Correlation with time to treatment failure (TTF) and overall survival (OS) were compared and stratified by response to each of the radiologic criteria.

Results and limitations

Eleven patients were considered responders by RECIST 1.0; 49 based on Choi criteria; 31 patients had ≥10% decrease in the SLD; and 36 and 32 patients had ≥15% and ≥20% decrease, respectively, in mean tumor density on CT. Only the threshold of 10% decrease in the SLD was statistically significant in predicting TTF (10.4 vs 5.1 mo; p = 0.02) and OS (32.5 vs 15.8 mo; p = 0.002). Receiver operating characteristic analysis yielded a 10% decrease in SLD as the optimal size change threshold for responders. The retrospective nature of the study and measurements by a single oncoradiologist are inherent limitations.

Conclusions

In the retrospectively analyzed study population of mRCC patients receiving VEGF-targeted agents, a 10% reduction in the SLD on the first follow-up CT was an optimal early predictor of outcome.     

Renal cell carcinoma (RCC) and telomerase activity: relationship to stage

Limited information is available on the correlation of telomerase activity and the clinical and pathological characteristics, in patients with renal cell carcinoma (RCC). Telomerase repeat amplification protocol (TRAP) was used to measure telomerase activity in frozen RCC specimens from partial/radical nephrectomies performed between 1987 and 1991. Presence of tumor tissue was verified by a pathologist using hematoxylin and eosin stained sections. RNA was measured to ensure the presence of intact protein necessary for telomerase expression. Data on demographics, tumor type, and stage at presentation, local recurrence, distant metastasis, disease-free survival (DFS), and overall survival (OS) was collected, and telomerase activity was correlated with each of these variables. Forty-nine of 67 patients (73%) were telomerase positive (+ve). Gender and stage were the only variables that appeared to be associated with telomerase positivity. Tumors were telomerase +ve in 12/21 females (57 %) vs. 37/46 males (80%) (P = 0.07). Tumors were telomerase +ve in 85% of Stage IV, 76% of Stage III, and 70% of Stage I/II patients (P = 0.12). Five-year survival was 0% for Stage IV, 57% for Stage III, and 77% for Stage I/II patients (P < 0.001), DFS 54% for stage III and 84% for Stage I/II patients (P = 0.05). Telomerase activity, however, was not related to survival in either univariate or multivariate analysis. In patients with telomerase +ve tumors 5-year survival was 55%, and with telomerase −ve tumors 58% (P = 0.56). Stage was the only variable associated with OS or DFS in clear cell RCC patients. In patients with advanced disease, there is a high incidence of telomerase positivity was found, within this limited sample, however, no correlation with survival was found.     

Effect of median household income on surgical approach and survival in renal cell carcinoma

Purpose

We sought to determine whether median household income (MHI) independently predicts surgical approach (partial vs. radical nephrectomy) and survival in patients with renal cell carcinoma.

Cell-based vaccines for renal cell carcinoma: genetically-engineered tumor cells and monocyte-derived dendritic cells

Initial vaccine developments for renal cell carcinoma (RCC) have concentrated on cell-based approaches in which tumor cells themselves provide mixtures of unknown tumor-associated antigens as immunizing agents. Antigens derived from autologous tumors can direct responses to molecular composites characteristic of individual tumors, whereas antigens derived from allogeneic tumor cells must be commonly shared by RCC. Three types of cell-based vaccine for RCC have been investigated: isolated tumor cell suspensions, gene modified tumor cells and dendritic cells (DCs) expressing RCC-associated antigens. Approaches using genetic modification of autologous RCC have included ex vivo modification of tumor cells or modification of tumors in vivo. We have used gene-modification of allogeneic tumor cell lines to create generic RCC vaccines. More recently, emphasis has shifted to the use of DCs as cell-based vaccines for RCC. DCs have moved to a position of central interest because of their excellent stimulatory capacity, combined with their ability to process and present antigens to both naive CD4 and CD8 cells. The long impasse in identifying molecular targets for specific immunotherapy of RCC is now rapidly being overcome through the use of tools and information emerging from human genome research. Identification of candidate molecules expressed by RCC using cDNA arrays, combined with protein arrays and identification of peptides presented by MHC molecules, allow specific vaccines to be tailored to the antigenic profile of individual tumors, providing the basis for development of patient-specific vaccines.B. Frankenberger and S. Regn made equal contributions to these studies     

A stage-for-stage and grade-for-grade analysis of cancer-specific mortality rates in renal cell carcinoma according to age: a competing-risks regression analysis

Background

The association of advanced age and cancer control outcomes shows discordant findings.

Objective

To evaluate the effect of age on cancer control outcomes in a large population-based cohort of patients diagnosed with renal cell carcinoma (RCC) of all stages.

Design, setting, and participants

Using the Surveillance Epidemiology and End Results database, 36 333 patients with RCC were identified. The population was stratified according to age: < 50, 50–59, 60–69, 70–79, and ≥80 yr. The effect of age on cancer control outcomes was evaluated using competing-risks regression models. Analyses were repeated stage for stage and grade for grade.

Measurements

Cancer-specific mortality (CSM) was measured.

Results and limitations

Age categories 50–59, 60–69, 70–79, and ≥80 yr respectively portended a 1.4-, 1.5-, 1.6-, and 1.9-fold higher risk of CSM than age category <50 yr (all p < 0.001). The effect of advanced age was particularly detrimental in patients with stage I disease: 1.8-, 2.3-, 3.2-, and 3.8-fold higher CSM risk for the same age groups, respectively (all p < 0.001). The effect of age on CSM was at its peak in patients with stage I, low-grade RCC (1.6-, 2.2-, 3.6-, and 4.3-fold, respectively; all p < 0.001) and remained elevated in stage I, high-grade RCC (2.2-, 2.6-, 2.4-, and 3.0-fold higher, respectively; all p < 0.05). Conversely, its effect was virtually absent in patients with stage II–IV RCC.

Conclusions

Our data suggest that stage I RCC may behave in a more aggressive fashion in elderly patients. Further studies are required to confirm the current findings.     

Preoperative nutritional status is an important predictor of survival in patients undergoing surgery for renal cell carcinoma

Background

The role of malnutrition has not been well studied in patients undergoing surgery for renal cell carcinoma (RCC).

Objective

Our aim was to evaluate whether nutritional deficiency (ND) is an important determinant of survival following surgery for RCC.

Design, setting, and participants

A total of 369 consecutive patients underwent surgery for locoregional RCC from 2003 to 2008. ND was defined as meeting one of the following criteria: body mass index <18.5 kg/m², albumin <3.5 g/dl, or preoperative weight loss ≥5% of body weight.

Intervention

All patients underwent radical or partial nephrectomy.

Measurements

Primary outcomes were overall and disease-specific mortality. Covariates included age, Charlson comorbidity index (CCI), preoperative anemia, tumor stage, Fuhrman grade, and lymph node status. Multivariate analysis was performed using a Cox proportional hazards model. Mortality rates were estimated using the Kaplan-Meier product-limit method.

Results and limitations

Eighty-five patients (23%) were categorized as ND. Three-year overall and disease-specific survival were 58.5% and 80.4% in the ND cohort compared with 85.4% and 94.7% in controls, respectively (p < 0.001). ND remained a significant predictor of overall mortality (hazard ratio [HR]: 2.41, 95% confidence interval [CI], 1.40–4.18) and disease-specific mortality (HR: 2.76; 95% CI, 1.17–6.50) after correcting for age, CCI, preoperative anemia, stage, grade, and nodal status. This study is limited by its retrospective nature.

Conclusions

ND is associated with higher mortality in patients undergoing surgery for locoregional RCC, independent of key clinical and pathologic factors. Given this mortality risk, it may be important to address nutritional status preoperatively and counsel patients appropriately.     

后腹腔镜肾癌根治术的临床应用研究

目的：评价后腹腔镜肾癌根治性切除术与开放性肾癌根治性切除术的临床效果。方法：回顺性分析和比较后腹腔镜肾癌根治性切除术(Retroperitoneal laparoscopic radical nephrectomy,RLRN)34例(A组)与开放性肾癌根治性切除术(Open radical nephrectomy,ORN)33例(B组),比较两种方法的手术时间、术中出血、术后引流、术后最早下床活动时间、肠功能恢复情况、术后住院时间、术后镇痛剂使用量、术中术后输血、血浆量、术后随访时间及手术效果。结果：A组中1例因最初对解剖结构难于辨认,无法分离肾前筋膜至肾门而改行开放手术,1例因损伤精索静脉出血难以控制而改行开放手术,1例因肾周脂肪过多,无法将肾脏掀起显露肾蒂而行开放手术,31例手术成功。B组手术均获成功,1例术后2个月因大面积脑出血死亡,余均无瘤生存。比较两组术中出血、术后引流、术后最早下床活动时间、肠功能恢复情况、术后住院时间、术后镇痛剂使用量、术中术后输血、血浆量差异有统计学意义(P＜0．01),而肿瘤大小、手术时间、随访时间差异无统计学意义(P＞0．05)。结论：与传统的开放性肾癌根治性切除术相比,后腹腔镜肾癌根治性切除术虽然技术难度大,但其具有微创、痛苦小、恢复快、并发症少等优点,对T_1N_0M_0和T_1N_0M_0期肿瘤控制,临床疗效相同。     

21例囊性肾癌的诊治和随访结果分析

目的：增加对囊性。肾癌真实发病率和生物学行为的认识，提高术前诊断准确性。方法：回顾性分析1997年5月～2007年5月收治的所有。肾癌中存在囊性成分病例的临床特点、影像学表现、手术治疗方式的选择、病理特点以及随访的情况。结果：以囊性成分所占体积不少于肿瘤总体的75％为入选标准，筛选出21例囊性肾癌（22个病灶，其中病例17为双侧病变），占所有肾癌总数（312例）的6．7％，患者平均年龄为47．3岁（30岁到77岁）．4处病灶行。肾部分切除术（18．2％）．18处病灶行肾癌根治术（81．8％）；按病理分期T1期16例（76．2％），T2期5例（23．8％），T3期1例（4．8％）；按Bosniak分类，Ⅱ类4例（18．2％），Ⅲ类12例（54．5％），IV类6例（27．3％）。术后随访平均39．0个月（2～110个月，中位数33个月），除1例因术后心脏合并症死亡外，余20例（95．2％）均生存，没有肿瘤复发和转移。结论：囊性肾癌是一种少见的临床病理亚型，Bosniak分类能在一定程度上提高术前诊断的准确性，手术切除特别是保留肾单位手术能有效地治疗囊性肾癌，临床预后很好。     

Renal cell carcinoma with giant common bile duct stone: A feasible surgical approach

A 65-year-old man who presented with right renal mass and a giant CBD stone. The patient was managed with right radical nephrectomy and choledocotomy. Both the lesions of two different systems could be easily accessed via a subcostal incision in the same sitting.