Vaccine Therapy in Patients with Renal Cell Carcinoma

Context

Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans. Although immunotherapy is currently much less used than in the past, it remains an important option that warrants further exploration.

Objective

To examine the current status of vaccine therapy for RCC and to provide information on relevant clinical studies.

Evidence acquisition

We reviewed recent literature on Medline (2003–2008, using the keywords renal cell carcinoma, cancer vaccines, active immunotherapy, and dendritic cells). Subsequent references were identified from reference list of retrieved articles. Quality assessment included prospective phase 1–3 trials and critical evaluations with low numbers of patients.

Evidence synthesis

Therapeutic vaccines can be divided in autologous tumour cell–based vaccines, genetically modified tumour cell–based and dendritic cell (DC)–based vaccines, and peptide-based vaccines. To date, only two randomised, adjuvant, phase 3 studies investigating RCC vaccines have been published. Autologous tumour cell vaccine (Reniale) improved the 5-yr progression-free survival (PFS) for high-risk nonmetastatic RCC patients at all tumour stages when administered after nephrectomy. The benefit was clearer in the T3 group. A per-protocol analysis revealed a statistically significant PFS and overall survival (OS) in favour of the vaccine. Autologous tumour-derived heat shock protein peptide complex (HSPPC-96; vitespen) could not significantly improve recurrence-free survival in RCC patients at high risk for recurrence after nephrectomy, but did so in intermediate risk patients. DC vaccination in metastatic RCC (mRCC) patients is safe and can induce antigen-specific immune response and obtain tumour regression in a subset of patients.

Conclusions

RCC vaccines have much less toxicity than other current therapies and remain an important area for further research. Reniale has shown significant benefit as an adjuvant RCC vaccine. Vitespen seems promising as an adjuvant treatment in earlier stage disease. A possible area of research is the use of RCC vaccines with immune-enhancing or antiangiogenic agents in the adjuvant setting.     

Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.     

Survival and Impact of Clinical Prognostic Factors in Surgically Treated Metastatic Renal Cell Carcinoma

Background

The survival impact of metastasectomy for metastatic renal cell carcinoma (mRCC) is still an active research field, particularly in the multimodal/targeted therapy era.

Objective

To determine the survival impact of clinical prognostic factors and their application to stratification of patients according to their prognosis so clinicians may be aided in their management of mRCC.

Design, setting, and participants

Retrospective, bi-institutional cohort study of 109 consecutive patients (71 male and 38 female; median age: 62 yr (range: 25–82 yr) with renal cell carcinoma (RCC) who underwent partial or radical nephrectomy and at least one metastasectomy for mRCC.

Intervention

Metastasis resection from various anatomic sites with the aim of completely removing detected lesions.

Outcome measurements and statistical analysis

Univariable and multivariable Cox regression models were used to analyse the impact of clinical prognostic factors on cancer-specific survival (CSS). Kaplan-Meier analysis with the log-rank test was used to compare CSS. Receiver operating characteristic (ROC) analysis was performed to test accuracy of prognostic groups. The α error for statistical significance was set at 0.05.

Results and limitations

Multivariable analysis revealed that primary tumour T stage ≥3 (hazard ratio [HR]: 2.8; p < 0.01), primary tumour Fuhrman grade ≥3 (HR: 2.3; p < 0.03), nonpulmonary metastases (HR: 3.1; p < 0.03), disease-free interval ≤12 mo (HR: 2.3; p < 0.058), and multiorgan metastases (HR: 2.5; p < 0.04) were independent pretreatment prognostic factors. Leuven-Udine (LU) prognostic groups based on these covariates were created and analysed with Kaplan-Meier and log-rank tests. The 2- and 5-yr CSS were significantly different; the respective group A CSS rates were 95.8% and 83.1%; group B, 89.9% and 56.4%; group C, 65.6% and 32.6%; and group D, 24.7% and 0% (p < 0.0001). ROC analysis on the accuracy of prognostic grouping revealed respective areas under the curve of 0.87 and 0.88 at 2 and 5 yr. Main limitations to present study are the retrospective design and the presence of different metastasis sites.

Conclusions

LU prognostic groups could be considered an accurate clinical tool to stratify patients according to prognosis and aid clinicians in the management of mRCC.     

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.     

Expression of tyrosine kinase receptor AXL is associated with worse outcome of metastatic renal cell carcinomas treated with sunitinib

Background

Renal cell carcinoma (RCC) represents 2%–3% of all cancers of the Western countries. Currently, sunitinib, a receptor tyrosine kinase inhibitor, particularly of PDGF and VEGF receptors, is the first-line therapy for metastatic RCC (mRCC), with significant improvement in clinical outcome. However, there is a lack of predictive biomarkers of sunitinib response. Recently, others and our group suggested that the receptor tyrosine kinase AXL may modify the response to sunitinib.

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.     

Carbonic Anhydrase IX in Renal Cell Carcinoma: Implications for Prognosis,Diagnosis, and Therapy

Context

The clinical management of patients with renal cell carcinoma (RCC) remains difficult, and the development of new diagnostic, prognostic, and therapeutic tools is still required.

Objective

To review the current knowledge on the RCC-associated antigen carbonic anhydrase IX (CAIX) and provide evidence for how this antigen may aid in the clinical management of RCC.

Evidence acquisition

Clinical papers describing diagnostic, prognostic, and/or therapeutic applications of CAIX in RCC were selected from the Pubmed database. The search was manually augmented by reviewing the reference lists of articles.

Evidence synthesis

Expression of CAIX is regulated by the Von Hippel Lindau (VHL) protein (pVHL). Because of the invariable VHL mutational loss in clear-cell RCC (ccRCC) patients, CAIX expression is ubiquitous in ccRCC. Determination of CAIX expression in nephrectomy specimens of RCC patients improves prognostic accuracy; high CAIX expression appears to correlate with a favourable prognosis and a greater likelihood of response to systemic treatment for metastatic disease. Therefore, CAIX expression might be used to stratify metastatic ccRCC (mRCC) patients for systemic treatment. When incorporated into the RCC nomogram, CAIX expression seems to improve diagnostic accuracy for primary RCC as well as mRCC patients, but further evidence is required. Clinical studies with the CAIX-specific monoclonal antibody (mAb) cG250 have provided unequivocal evidence that ccRCC lesions can be imaged with radiolabeled cG250. Results are awaited of a large, randomised trial that aims to establish the value of cG250 imaging for primary RCC. The outcome of another large, placebo-controlled study is awaited to establish the usefulness of CAIX-targeted therapy in the adjuvant setting. Therapeutic trials with high-dose radiolabeled cG250 and CAIX-loaded dendritic cells in mRCC patients are still in phase 1 or 2.

Conclusions

CAIX improves diagnostic accuracy and is an attractive target for imaging of and therapy for ccRCC.     

A preoperative prognostic model for patients treated with nephrectomy for renal cell carcinoma

Background

Currently two pretreatment prognostic models with limited accuracy (65–67%) can be used to predict survival in patients with localized renal cell carcinoma (RCC).

Objective

We set out to develop a more accurate pretreatment model for predicting RCC-specific mortality after nephrectomy for all stages of RCC.

Design, setting, and participants

The data originated from a series of prospectively recorded contemporary cases of patients treated with radical or partial nephrectomy between 1984 and 2006. Model development was performed using data from 2474 patients from five centers and external validation was performed using data from 1972 patients from seven centers.

Measurements

The probability of RCC-specific mortality was modeled using Cox regression. The significance of the predictors was confirmed using competing risks analyses, which account for mortality from other causes.

Results and limitations

Median follow-up in patients who did not die of RCC-specific causes was 4.2 yr and 3.5 yr in the development and validation cohorts, respectively. The freedom from cancer-specific mortality rates in the nomogram development cohort were 75.4% at 5 yr after nephrectomy and 68.3% at 10 yr after nephrectomy. All variables except gender achieved independent predictor status. In the external validation cohort the nomogram predictions were 88.1% accurate at 1 yr, 86.8% accurate at 2 yr, 86.8% accurate at 5 yr, and 84.2% accurate at 10 yr.

Conclusions

Our model substantially exceeds the accuracy of the existing pretreatment models. Consequently, the proposed nomogram-based predictions may be used as benchmark data for pretreatment decision making in patients with various stages of RCC.     

Predicting Occult Multifocality of Renal Cell Carcinoma

Background

Multifocal renal cell carcinoma (RCC) has been reported in up to 25% of all radical nephrectomy specimens. Modern imaging tends to underestimate the rate of multifocality. Recognition of multifocality before treatment may guide physicians and patients to the type of intervention and tailor long-term follow-up.

Objective

Our aim was to develop and assess preoperative nomograms to predict occult multifocal RCC.

Design, setting, and participants

We evaluated 560 consecutive patients undergoing radical nephrectomy for clinically localized suspected sporadic RCC between 2000 and 2008 in a tertiary center. Clinically manifest multifocal lesions were excluded. Logistic regression models were used to assess the potential risk factors of occult multifocality with and without pathologic variables that may be available with preoperative biopsy. Nomograms were developed and assessed for diagnostic properties.

Interventions

All patients underwent radical nephrectomy.

Measurements

Assessments of risk factors for occult multifocal RCC were obtained using regression models and nomograms.

Results and limitations

The incidence of occult multifocality was 7.9%. Significantly associated predictors of multifocality were male gender, family history of malignancy other than RCC, radiographic size of the lesion, histologic subtype other than clear cell, and Fuhrman grade IV. The two designed nomograms had 0.75 and 0.82 concordance indices, respectively.

Conclusions

Our data suggest that occult multifocal RCC is more frequently associated with small (2–4 cm) renal lesions. Male gender, family history of kidney cancer, histologic subtype, and grade are strongly associated with an increased risk of occult multifocal RCC. The developed nomograms had good predictive accuracy that was enhanced when combined with pathologic variables.     

Lymph node dissection at the time of radical nephrectomy for high-risk clear cell renal cell carcinoma: indications and recommendations for surgical templates

Background

Observational studies suggest a proportion of patients with lymph node metastases will benefit from lymph node dissection (LND) at the time of nephrectomy for clear cell renal cell carcinoma (RCC).

Objective

Our aim was to report the performance of five previously identified high-risk pathologic features assessed by intraoperative examination on prediction of lymph node metastases and propose a template for LND based on locations of lymph node involvement.

Design, setting, and participants

The study included a historical cohort of consecutive patients from a single institution who received LND in conjunction with nephrectomy for high-risk clear cell RCC between 2002 and 2006.

Interventions

All patients underwent nephrectomy and LND.

Measurements

Patients were considered high risk for nodal metastasis if two or more of the following features were identified during intraoperative pathologic assessment of the primary tumor: nuclear grade 3 or 4, sarcomatoid component, tumor size ≥10 cm, tumor stage pT3 or pT4, or coagulative tumor necrosis. Based on these features, LND was performed at the time of nephrectomy, and the numbers and sites of regional lymph node metastasis were recorded for each patient.

Results and limitations

Of the 169 high-risk patients, 64 (38%) had lymph node metastases. All patients with nodal metastases had nodal involvement within the primary lymphatic sites of each kidney prior to involvement of the nodes overlying the contralateral great vessel. A limitation of the study is the lack of a standardized LND performed throughout the study period.

Conclusions

Pathologic features of renal tumors are associated with the risk of regional lymph node metastases and lymph node metastases that appear to progress though the primary lymphatic drainage of each kidney. Based on these findings we recommend that when performing LND the lymph nodes from the ipsilateral great vessel and the interaortocaval region be removed from the crus of the diaphragm to the common iliac artery.     

Long-term Survival in Patients Undergoing Radical Nephrectomy and Inferior Vena Cava Thrombectomy: Single-Center Experience

Background

Renal cell carcinoma (RCC) with a tumor thrombus extension into the inferior vena cava (IVC) demands aggressive surgical management.

Objective

To evaluate the long-term survival in patients undergoing radical nephrectomy and IVC thrombectomy.

Design, setting, and participants

We performed a retrospective analysis of 87 patients undergoing surgery between 1997 and 2008. The patients were grouped according to the extent of tumor thrombus, with level I involving the IVC at the level of the renal vein, level II being infrahepatic IVC, level III being intrahepatic IVC, and level IV being suprahepatic IVC or right atrium. Relevant clinical and pathologic data were analyzed.

Measurements

Disease-free survival (DFS) and disease-specific survival (DSS) were studied.

Results and limitations

The median follow-up was 22 mo, and 19, 14, 40, and 14 patients had level I, II, III, and IV IVC thrombus, respectively. Among patients with M0 disease, 22 developed metastases. The 5-yr DFS was 64% for all levels and 74%, 69.5%, 59.5%, and 58% for levels I, II, III, and IV, respectively. Of the level I group, 16% of patients died of disease compared to 57% of the level IV group. The 5-yr DSS for all levels was 46% and 71%, 48%, 40%, and 35% for levels I, II, III, and IV, respectively. Patients with level IV thrombus had a significantly lower 5-yr DSS compared to level I (p = 0.03). However, when analyzed in two groups—supradiaphragmatic and infradiaphragmatic—there was no significant difference in DSS (P = 0.14). On univariate analysis, metastasis at presentation, non–clear-cell histology, lymph node metastases, and higher nuclear grade were statistically significant prognostic factors influencing DSS. Only higher nuclear grade (p = 0.03), metastasis at presentation (p < 0.01), and non–clear-cell histology (p = 0.03) were independent prognostic factors on multivariate analysis.

Conclusions

Radical nephrectomy and IVC thrombectomy offer reasonable long-term survival. The level of tumor thrombus is not an independent prognostic factor. Distant metastasis at presentation, higher nuclear grade, and non–clear-clear cell histology are significant prognostic factors influencing DSS.     

Primary tumor response to targeted agents in patients with metastatic renal cell carcinoma

Background

The recent development of multiple targeted agents for metastatic renal cell carcinoma (mRCC) has changed the treatment paradigm; hence the benefit and optimal timing of cytoreductive nephrectomy is being reevaluated.

Objective

To determine primary tumor response to treatment with targeted agents in patients with mRCC.

Design, setting, and participants

We reviewed the clinical and radiographic data of all mRCC patients seen at our institution between November 2004 and December 2009 without prior systemic treatment who received targeted therapy with their primary tumor in situ.

Measurements

Two independent reviewers measured the diameter of primary and metastatic tumors at baseline and subsequent scans, using Response Evaluation Criteria Solid Tumors (RECIST) v.1.1 to assess disease response.

Results and limitations

We identified 168 consecutive patients with a median 15 mo of follow-up and a median maximum tumor diameter of 9.6 cm. Median maximum primary tumor response was −7.1% (interquartile range: −14.0 to −0.1).A total of 61 patients had multiple studies available for evaluation. In 43 patients with <10% decrease in primary tumor within in the first 60 d, median maximum response was −7.2% at 154 d versus −24.5% maximum response at 174.5 d for 18 patients with ≥10% decrease in primary tumor during the initial 60 d.

Conclusions

Decrease in primary tumor diameter >30% while on targeted therapy for mRCC is rare, with most patients demonstrating minimal or no decrease in primary tumor diameter. Early response predicts a better overall primary tumor response.     

Can Tyrosine Kinase Inhibitors be Discontinued in Patients with Metastatic Renal Cell Carcinoma and a Complete Response to Treatment? A Multicentre,Retrospective Analysis

Background

Discontinuation of treatment with tyrosine kinase inhibitors (TKIs) and readministration in case of recurrence could improve quality of life (QoL) and reduce treatment costs for patients with metastatic renal cell carcinoma (mRCC) in which a complete remission (CR) is achieved by medical treatment alone or with additional resection of residual metastases.

Objective

To evaluate whether TKIs can be discontinued in these selected patients with mRCC.

Design, setting, and participants

A retrospective analysis of medical records and imaging studies was performed on all patients with mRCC treated with TKIs (n = 266) in five institutions. Patients with a CR under TKI treatment alone or with additional metastasectomy of residual disease following a partial response (PR), in which TKIs were discontinued, were included in the analysis. Outcome criteria analysed were time to recurrence of previous metastases, occurrence of new metastases, symptomatic progression, improvement of adverse events, and response to reexposure to TKIs.

Interventions

Sunitinib 50 mg/day for 4 wk on and 2 wk off, sorafenib 800 mg/day.

Measurements

Response according to Response Evaluation Criteria in Solid Tumours (RECIST).

Results and limitations

We identified 12 cases: 5 CRs with sunitinib, 1 CR with sorafenib, and 6 surgical CRs with sunitinib followed by residual metastasectomy. Side-effects subsided in all patients off treatment. At a median follow-up of 8.5 mo (range: 4–25) from TKI discontinuation, 7 of 12 patients remained without recurrence and 5 had recurrent disease, with new metastases in 3 cases. Median time to progression was 6 mo (range: 3–8). Readministration of TKI was effective in all cases. The study is limited by small numbers and retrospective design.

Conclusions

Discontinuation of TKI in patients with mRCC and CR carries the risk of progression with new metastases and potential complications. Further investigation in a larger cohort of patients is warranted before such an approach can be regarded as safe.     

Surgery for Metastatic Urothelial Carcinoma with Curative Intent: The German Experience (AUO AB 30/05)

Background

Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients.

Objective

We report the combined experience and outcome of patients undergoing resection of UCM gained at 15 uro-oncologic centers in Germany.

Design, setting, and participants

Retrospective survey of 44 patients with distant UCM of the bladder or upper urinary tract who underwent complete resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008.

Intervention

Resected metastatic sites were the following: retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). Systemic chemotherapy was administered in 35 of 44 patients (79.5%) before and/or after UCM surgery.

Measurements

Overall, cancer-specific and progression-free survival from time of diagnosis and metastasectomy of UCM.

Results and limitations

Median survival from initial diagnosis of UCM and subsequent resection was as follows: overall survival, 35 mo and 27 mo; cancer-specific survival, 38 mo and 34 mo; and progression-free survival, 19 mo and 15 mo. Overall 5-yr survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up of 8 mo. Seven patients without disease progression survived for >2 yr and remained free from tumor progression at a median follow-up of 63 mo. No significant prognostic factors could be determined due to the limited patient number.

Conclusions

Long-term cancer control and possible cure can be achieved in a subgroup of patients following surgical removal of UCM. Metastasectomy in patients with disseminated UCM remains investigational and should only be offered to those with limited disease as a combined-modality approach with systemic chemotherapy.     

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.     

Metastasectomy of neuroendocrine tumors in patients with multiple endocrine neoplasia type 1

Background

Neuroendocrine (NE) tumors commonly afflict patients with multiple endocrine neoplasia type 1 (MEN1). It is thought that patients with MEN1 have improved survival compared with individuals with analogous lesions. The role of metastasectomy of NE tumors in MEN1 patients is not clearly defined.

Methods

A review of MEN1 patients undergoing surgery for NE tumors from 1994 to 2010 at a single tertiary care center was performed. Tumor function, the extent of metastasis, R0 resection, and survival were analyzed.

Results

We identified 30 patients who underwent resection including synchronous and metachronous metastasectomy. Synchronous metastases were identified in 19 patients (63%), whereas 11 (37%) had metachronous disease. R0 resection was achieved in 93% of patients. Estimated 10-year survival is 86.4% (95% confidence interval, 60% to 100%) with no factors predictive of overall survival. The disease-free interval at 1, 5, and 10 years was 89%, 50%, and 19%, respectively, with recurrence occurring at a median of 5.4 years (95% confidence interval, 77.7% to 100%). Synchronous metastasis (P = .0072; hazard ratio [HR], 3.4) and nonfunctioning tumors (P = .014; HR, 3.3) were more likely to recur, whereas age (P = .09; HR, 1.5), gender (P = .49; HR, 1.3), and the site of metastasis (P = .81; HR, 1.1) did not influence recurrence.

Discussion

Patients with MEN1 benefit from resection of metastatic NE disease. Despite a high recurrence rate, survival and disease-free interval is favorable vs patients without MEN1.     

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.     

Laparoscopic and Open Partial Nephrectomy: A Matched-Pair Comparison of 200 Patients

Background

Laparoscopy is currently challenging the role of the open approach for nephron-sparing surgery (NSS), yet comparative studies on this issue are scant.

Objective

To compare surgical, oncologic, and functional outcomes after laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN).

Design, setting, and participants

We undertook matched-pair (age, sex, tumour size) analysis of patients who underwent elective NSS for renal masses either by laparoscopic (Klagenfurt) or open (Vienna) access.

Measurements

Surgical data, complications, histologic and oncologic data, and short- and long-term renal function of the open and laparoscopic groups were compared.

Results and limitations

In total, 200 patients matched for age, sex, and tumour size entered the study after either LPN or OPN and were followed for a mean of 3.6 yr. Surgical, ischemia, and hospitalisation times were shorter in the LPN group (p < 0.001). Blood loss and complication rates were comparable in both groups. Malignant tumours were pT1 stage renal-cell cancer only in both groups. The positive surgical margin (PSM) rate was 4% after LPN and 2% after OPN (p = 0.5); positive margins were not a risk factor for disease recurrence. Kaplan-Meier estimates of 5-yr local recurrence-free survival (RFS) were 97% after LPN and 98% after OPN (p = 0.8); the respective numbers for distant free survival were 99% and 96% (p = 0.2). Five-year overall survival (OS) for patients with pT1 stage renal cell carcinoma (RCC) was 96% after LPN and 85% after OPN. The decline in glomerular filtration rate at the last available follow-up (LPN: 10.9%; OPN: 10.6%) was similar in both groups (p = 0.8). We recognise the retrospective nature, limited follow-up, and sample size as shortcomings of this study.

Conclusions

In experienced hands, LPN provides similar results compared to open surgery. PSM rates were comparable after LPN and OPN. Current experience questions the indication of secondary nephrectomy in these patients.     

A Proposal for Reclassification of the Fuhrman Grading System in Patients with Clear Cell Renal Cell Carcinoma

Background

The conventional Fuhrman grading system, which categorizes renal cell carcinoma (RCC) with grades I, II, III, and IV, is the most widely used predictor assessment of RCC cancer-specific mortality (CSM).

Objectives

The aim of this study was to test the prognostic ability of simplified Fuhrman grading schemes (FGSs) that rely on two- or three-tiered classifications.

Design, setting, and participants

The current study addressed a population of 14 064 patients with clear cell RCC who were treated with partial or radical nephrectomy between 1988–2004, within nine Surveillance, Epidemiology, and End Results (SEER) cancer registries.

Measurements

Univariable and multivariable analyses as well as prognostic accuracy analyses were performed for various FGSs to test their ability to predict CSM rates. The conventional four-tiered FGS was compared to a modified two-tiered FGS in which grades I and II and grades III and IV were combined. A second simplified three-tiered FGS in which grades I and II were combined but grades III and IV were kept separate was also tested.

Results and limitations

The overall 5-yr CSM-free rate was 81.5%. All three FGSs achieved independent predictor status in multivariable analyses. Prognostic accuracy of multivariable models that relied on various FGSs was 83.6% for the modified two-tiered FGS and 83.8% for both the conventional four-tiered and the modified three-tiered FGS.

Conclusions

Our findings indicate that the simplified FGSs perform equally as well as the conventional four-tiered FGS. The use of simplified grading schemes may represent an advantage for pathologists as well as for clinicians caring for patients with RCC.