Adjuvante autologe Tumorvakzine beim Nierenzellkarzinom

Background

Organ-confined renal cell carcinoma (RCC) is associated with tumour progression after surgical therapy in approximately 30% of cases. However, of all recently available adjuvant treatment options, only the autologous tumour cell lysate vaccination therapy (Reniale) has been able to demonstrate a significant positive impact on progression-free survival in a phase III trial. Nevertheless, this therapeutic option has not yet been established as a standard adjuvant treatment.

Materials and methods

Between August 1993 and December 1996, a total of 1,267 patients who underwent radical tumour nephrectomy at 84 German centres received Reniale outside a controlled trial. Of these patients, 692 presented at stage pT2–3, pNx-2, M0 (based on the 4th version of TNM classification). These patients were matched with a cohort of 861 patients not receiving any adjuvant treatment who underwent surgical therapy for RCC in a 15-year period in the Carl-Thiem-Klinikum in Cottbus, Germany. Matching criteria included age, gender, pT stage, pN stage, grading, histological cell type, and UICC stage. This resulted in 495 matched pairs (study group n=990) that were comparable regarding demographic and tumour-specific criteria. Statistical analyses included univariate and multivariate analyses of overall survival (OS). Median follow-up time of all patients still alive at the end of the trial (n=667) was 11 years.

Results

In the vaccine group, OS after 5 and 10 years was 80.6% and 68.9%, respectively, whereas control patients had an OS of 79.2% and 62.1%, respectively (p=0.066). The 5-year OS of patients with pT3 RCC was 71.3% after vaccination therapy and 65.4% for control patients. After 10 years, 53.6% of the patients in the vaccine group and 36.2% in the control group were still alive (p=0.022). Median survival of patients with pT3 RCC was 81 months (SD 7.8) in the control group. This period was not achieved in the vaccine group. Multivariate Cox analysis revealed a significant positive impact of Reniale on OS among the whole study group [hazard ratio (HR) 1.28, p=0.030]. The analysis of patient subgroups showed a significant positive influence of Reniale for patients presenting with pT3 tumours (HR 1.67, p=0.001).

Conclusion

Adjuvant postsurgical treatment with Reniale in patients presenting with stage pT3 RCC results in a significant enhancement of OS and should be considered especially in this group of patients. Further clinical trials integrating the recent TNM classification and comprising different risk constellations should follow in order to ultimately assess the value of adjuvant treatment with vaccination immunotherapy.     

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.     

Growth kinetics of renal masses: analysis of a prospective cohort of patients undergoing active surveillance

Background

Active surveillance (AS) represents a treatment option for renal masses in patients who are not surgical candidates either because of existing comorbidities or patient choice. Among renal masses undergoing AS, some grow rapidly and require treatment or progress to metastatic disease. Patient and tumour characteristics related to this more aggressive behaviour have been poorly studied.

Objective

To report the analysis of a multi-institutional cohort of patients undergoing AS for small renal masses.

Design, setting, and participants

This prospective study included 82 patients with 84 renal masses who underwent AS in three Canadian institutions between July 2001 and June 2009.

Intervention

All patients underwent AS for renal masses presumed to be renal cell carcinoma (RCC) as based on diagnostic imaging.

Measurements

Age, sex, symptoms at presentation, maximum diameter at diagnosis (cm), tumour location (central/peripheral), degree of endophytic component (1–100%), and tumour consistency (solid/cystic) were used to develop a predictive model of the tumour growth rate using binary recursive partitioning analysis with a repeated measures outcome.

Results and limitations

With a median follow-up of 36 mo (range: 6–96), the mean annual renal mass growth rate for the entire cohort was 0.25 cm/yr (standard deviation [SD]: 0.49 cm/yr). Only one patient (1.2%) developed metastatic RCC. Amongst all variables, maximum diameter at diagnosis was the only predictor of tumour growth rate, and two distinct growth rates were identified. Masses that are ≥2.45 cm in largest diameter at diagnosis grow faster than smaller masses. This series was limited by its moderate sample size, although it is the largest published prospective series to date.

Conclusions

We confirm that most renal masses grow slowly and carry a low metastatic potential. Tumour size is a predictor of tumour growth rate, with renal masses <2.45 cm growing more slowly than masses >2.45 cm.     

Radiofrequency ablation versus partial nephrectomy in patients with solitary clinical T1a renal cell carcinoma: comparable oncologic outcomes at a minimum of 5 years of follow-up

Background

Long-term comparative outcomes for radiofrequency ablation (RFA) versus partial nephrectomy (PN) for the primary treatment of clinical T1a renal cell carcinoma (RCC) have not previously been reported.

Objective

Report comparative 5-yr oncologic outcomes for RFA versus PN in patients with clinical T1a RCC.

Design, setting, and participants

Observational single-institution cohort study, involving consecutive patients with a solitary histologically confirmed T1a RCC treated by RFA or PN and followed for a minimum of 5 yr. Those presenting with synchronous multiple, metachronous, bilateral, and/or metastatic disease, a history of hereditary RCC syndromes, a family history of RCC, and with post-treatment follow-up <5 yr were excluded from analysis.

Measurements

The Kaplan-Meier method was used to determine 5-yr overall survival (OS), cancer-specific survival (CSS), local recurrence-free survival (local RFS), overall disease-free survival (DFS), and metastasis-free survival (MFS) for RFA versus PN. Survival curves were compared using the log-rank test. A p value ≤0.05 was considered statistically significant.

Results and limitations

A total of 37 patients in each group met the selection criteria. The RFA cohort was significantly older and had more advanced comorbidities, but other patient characteristics were similar. For RFA versus PN, median follow-up was 6.5 yr (interquartile range [IQR]: 5.8–7.1) versus 6.1 yr (IQR: 5.4–7.3) (p = 0.68), respectively. The 5-yr OS was 97.2% versus 100% (p = 0.31), CSS was 97.2% versus 100% (p = 0.31), DFS was 89.2% versus 89.2% (p = 0.78), local RFS was 91.7% versus 94.6% (p = 0.96), and MFS was 97.2% versus 91.8% (p = 0.35), respectively. Study limitations are retrospective data analysis, loss to follow-up, limited statistical power, and limited generalizability of our data.

Conclusions

In appropriately selected patients, RFA is an effective minimally invasive therapy for the treatment of cT1a RCC, yielding comparable long-term oncologic outcomes to nephron-sparing surgery.     

Predictive Factors for Ipsilateral Recurrence After Nephron-sparing Surgery in Renal Cell Carcinoma

Background

Ipsilateral recurrence after nephron-sparing surgery (NSS) is rare, and little is known about its specific determinants.

Objective

To determine clinical or pathologic features associated with ipsilateral recurrence after NSS performed for renal cell carcinoma (RCC).

Design, setting, and participants

We analysed 809 NSS procedures performed at eight academic institutions for sporadic RCCs retrospectively.

Measurements

Age, gender, indication, tumour bilaterality, tumour size, tumour location, TNM stage, Fuhrman grade, histologic subtype, and presence of positive surgical margins (PSMs) were assessed as predictors for recurrence in univariate and multivariate analysis by using a Cox proportional hazards regression model.

Results and limitations

Among 809 NSS procedures with a median follow-up of 27 (1–252) mo, 26 ipsilateral recurrences (3.2%) occurred at a median time of 27 (14.5–38.2) mo. In univariate analysis, the following variables were significantly associated with recurrence: pT3a stage (p = 0.0489), imperative indication (p < 0.01), tumour bilaterality (p < 0.01), tumour size >4 cm (p < 0.01), Fuhrman grade III or IV (p = 0.0185), and PSM (p < 0.01). In multivariate analysis, tumour bilaterality, tumour size >4 cm, and presence of PSM remained independent predictive factors for RCC ipsilateral recurrence. Hazard ratios (HR) were 6.31, 4.57, and 11.5 for tumour bilaterality, tumour size >4 cm, and PSM status, respectively. The main limitations of this study included its retrospective nature and a short follow-up.

Conclusions

RCC ipsilateral recurrence risk after NSS is significantly associated with tumour size >4 cm, tumour bilaterality (synchronous or asynchronous), and PSM. Careful follow-up should be advised in patients presenting with such characteristics.     

Is There a Need to Further Subclassify pT2 Renal Cell Cancers as Implemented by the Revised 7th TNM Version?

Background

The recently modified TNM classification of renal cell carcinoma (RCC) (7th edition) has implemented a subdivision of pT2 tumours into stage pT2a (>7 or ≤10 cm) versus pT2b disease (>10 cm).

Objective

Our aim was to evaluate whether this subdivision of pT2 RCC is justified due to a clinical prognosis divergence between the two groups (pT2a vs pT2b)

Design, setting, and participants

In total, 5122 patients were subjected to either radical nephrectomy or nephron-sparing surgery at three centres in Germany (University Hospitals of Hannover, Homburg/Saar, and Marburg). Patients were reclassified into stage pT2a and pT2b according to the maximum tumour diameter as suggested by the 7th revised version of the TNM classification system.

Measurements

The t test and Fisher exact test were applied to evaluate the comparability of the two groups (pT2a vs pT2b) regarding several additional patients’ and tumour-specific characteristics of known prognostic relevance for RCC. Univariable (Kaplan-Meier analysis) and multivariable statistical analyses (Cox proportional hazards regression model) were applied to identify a possible difference between the two groups (pT2a vs pT2b) regarding cancer-specific survival (CSS).

Results and limitations

Applying the new TNM classification, 579 previously pT2-staged patients were divided into 445 (76.9%) with pT2a and 134 (23.1%) with pT2b tumours. Kaplan-Meier curves revealed no significant difference in CSS between pT2a and pT2b patients; 5-yr CSS was 79.0% and 74.1%, respectively (p = 0.38). When applying multivariable analysis, unlike tumour grade and N/M status, pT2 subclassification failed to independently predict survival in RCC patients.

Conclusions

The new subclassification of pT2 RCC into two different subgroups as suggested by the latest modification of the TNM system does not yield additional/prognostic information.     

Positive surgical margins after nephron-sparing surgery

Context

Little is known on the natural history of positive surgical margins (PSMs) in partial nephrectomy (PN). Accumulating data suggest that secondary nephrectomy might not be necessary in all patients with PSMs after PN.

Objective

Provide an overview on incidence and risk factors for PSMs after partial nephrectomy and on the rate of local and distant disease recurrence related to PSMs. We also provide recommendations on how to avoid and how to treat PSMs after PN.

Evidence acquisition

A nonsystematic literature research was based on Medline, Scopus, and Web of Science queries on these keywords: nephron-sparing surgery, partial nephrectomy/ies, and margin. Only human studies (original research) published in English were included.

Evidence synthesis

PSMs are present in 0–7% of patients after open PN, in 0.7–4% after laparoscopic PN, and in 3.9–5.7% after robot-assisted PN. The thickness of healthy parenchyma surrounding the tumour is irrelevant as long as complete tumour removal is achieved. The coincidence of a highly malignant tumour and PSM increases the risk of local recurrence. Intermediate follow-up data indicate that the vast majority of patients with PSMs will not experience local or distant tumour recurrence. Frozen-section analysis for evaluation of resection margins during PN is of minor clinical significance, as the surgeon's gross assessment of macroscopically negative margins provides reliable results.

Conclusions

PSMs in PN are rare. As indicated by intermediate follow-up data, the majority of patients with PSMs after PN remain without disease recurrence, and a surveillance strategy seems preferable to surgical reintervention.     

Inflammatory Protein Serum Amyloid A1 Marks a Subset of Conventional Renal Cell Carcinomas with Fatal Outcome

Background

Conventional renal cell carcinoma (RCC) is the most common renal cancer. As the metastatic conventional RCC is practically incurable, there is a need for markers to estimate the tumour aggressiveness.

Objective

To identify and characterise new marker(s) associated with the poor prognosis of conventional RCC.

Design, Setting, and Participants

RNA from 24 conventional RCCs was analysed for global gene expression by Affymetrix U133 Plus 2.0 arrays. Tissue microarrays containing 224 renal tumours including 87 conventional RCCs were used for immunohistochemistry. Cell lines HD2, HD48, HA344 and HA465 established in our laboratory were used for invasion assay and zymography.

Measurements

Serum amyloid A 1 (SAA1) was found to be upregulated in conventional RCCs and it has been analysed by quantitative RT-PCR and immunohistochemistry on TMAs to establish the correlation between SAA1 protein expression and patient survival by uni and multivariate analysis. The effect of SAA1 on tumour cell behaviour in vitro has also been examined by invasion assay and zymography.

Results and Limitations

SAA1 RNA is expressed in conventional RCC samples of patients with poor prognosis. Immunohistochemistry of 72 conventional RCCs with a 5 yr follow up showed a correlation between SAA1 expression and the clinical outcome of disease. Stimulation of conventional RCC cell lines with recombinant SAA1 increased the expression of metalloproteinase (MMP)-9 and the invasive potential of tumour cells. Limitation of the study is a relatively small number (72) of patients having follow up.

Conclusion

SAA1 seems to be a useful marker to estimate the prognosis of conventional RCCs.     

Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: results of a matched analysis

Background

Previous prospective randomised trials have shown a positive impact of adjuvant radiation therapy (RT) in patients with locally advanced prostate cancer. However, none of these trials included patients with lymph node invasion (LNI).

Objective

The aim of this study was to assess the impact of combination adjuvant hormonal therapy (HT) and RT on the survival of patients with prostate cancer and histologically documented lymph node metastases (pN+).

Design, setting, and participants

Data on 703 consecutive patients with LNI treated with radical prostatectomy, pelvic lymph node dissection, and adjuvant treatments between September 1986 and November 2002 at two large academic institutions were reviewed.

Measurements

For study purposes, patients treated with adjuvant HT plus RT and patients treated with adjuvant HT alone were matched for age at surgery, pathologic T stage and Gleason score, number of nodes removed, surgical margin status, and length of follow-up. Differences in cancer-specific survival (CSS) and overall survival (OS) were compared using the Kaplan-Meier method and life table analyses.

Results and limitations

Following the matching process, 117 pT2–4 pN1 patients of 171 (68.4%) treated with adjuvant HT plus RT (group 1) were compared with 247 pT2–4 pN1 patients of 532 (46.4%) receiving adjuvant HT alone (group 2). After matching, the two groups of patients were comparable in terms of pre- and postoperative characteristics (all p ≥ 0.07). Mean follow-up was 100.8 mo (median: 95.1 mo; range: 3.5–229.3 mo). Overall, prostate CSS and OS rates at 5, 8, and 10 yr were 90%, 82%, and 75%, and 85%, 70%, and 60%, respectively. Patients treated with adjuvant RT plus HT had significantly higher CSS and OS rates compared with patients treated with HT alone at 5, 8, and 10 yr after surgery (95%, 91%, and 86% vs 88%, 78%, and 70%, and 90%, 84%, and 74% vs 82%, 65%, and 55%, respectively; p = 0.004 and p < 0.001, respectively). Similarly, higher survival rates associated with the combination of HT plus RT were found when patients were stratified according to the extent of nodal invasion (namely, two or fewer vs more than two positive nodes; all p ≤ 0.006). Lack of standardised HT and RT protocols represents the main limitations of our retrospective study.

Conclusions

Adjuvant RT plus HT significantly improved CSS and OS of pT2–4 pN1 patients, regardless of the extent of nodal invasion. These results reinforce the need for a multimodal approach in the treatment of node-positive prostate cancer.     

Novel Immunotherapeutic Strategies in Development for Renal Cell Carcinoma

Context

The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase.

Objective

To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm.

Evidence acquisition

A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy.

Evidence synthesis

Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon-α were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host–tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies.

Conclusions

It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy.     

A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma

Background

Nephron-sparing surgery (NSS) can safely be performed with slightly higher complication rates than radical nephrectomy (RN), but proof of oncologic effectiveness is lacking.

Objective

To compare overall survival (OS) and time to progression.

Design, setting, and participants

From March 1992 to January 2003, when the study was prematurely closed because of poor accrual, 541 patients with small (≤5 cm), solitary, T1–T2 N0 M0 (Union Internationale Contre le Cancer [UICC] 1978) tumours suspicious for renal cell carcinoma (RCC) and a normal contralateral kidney were randomised to NSS or RN in European Organisation for Research and Treatment of Cancer Genito-Urinary Group (EORTC-GU) noninferiority phase 3 trial 30904.

Intervention

Patients were randomised to NSS (n = 268) or RN (n = 273) together with limited lymph node dissection (LND).

Measurements

Time to event end points was compared with log-rank test results.

Results and limitations

Median follow-up was 9.3 yr. The intention-to-treat (ITT) analysis showed 10-yr OS rates of 81.1% for RN and 75.7% for NSS. With a hazard ratio (HR) of 1.50 (95% confidence interval [CI], 1.03–2.16), the test for noninferiority is not significant (p = 0.77), and test for superiority is significant (p = 0.03). In RCC patients and clinically and pathologically eligible patients, the difference is less pronounced (HR = 1.43 and HR = 1.34, respectively), and the superiority test is no longer significant (p = 0.07 and p = 0.17, respectively). Only 12 of 117 deaths were the result of renal cancer (four RN and eight NSS). Twenty-one patients progressed (9 after RN and 12 after NSS). Quality of life and renal function outcomes have not been addressed.

Conclusions

Both methods provide excellent oncologic results. In the ITT population, NSS seems to be significantly less effective than RN in terms of OS. However, in the targeted population of RCC patients, the trend in favour of RN is no longer significant. The small number of progressions and deaths from renal cancer cannot explain any possible OS differences between treatment types.     

Prognostic Value of Capsular Invasion for Localized Clear-Cell Renal Cell Carcinoma

Background

The impact of capsular invasion on the survival of patients undergoing surgery for renal cell carcinoma (RCC) has attracted little attention in the literature and remains controversial.

Objectives

To evaluate the value of capsular invasion, without perirenal fat invasion, on the prognosis of patients with localized clear-cell RCC.

Design, setting, and participants

Between 1984 and 2007, we retrospectively reviewed the records of 317 consecutive patients with localized clear-cell RCC (pT1–T2N0M0) who underwent radical nephrectomy or nephron-sparing surgery at our institution. Overall, 299 patients were eligible for the study. We analyzed clinical (presentation and body mass index [BMI]) and pathologic (tumor size, Fuhrman nuclear grade, collecting system invasion, microvascular invasion, and capsular involvement) parameters.

Measurements

Recurrence-free survival (RFS) and cancer-specific survival (CSS) were investigated using the Kaplan-Meier method, and the Cox regression model was used to determine the significant prognostic factors based on multivariate analysis.

Results and limitations

Renal capsular invasion was observed in 106 of 299 patients (35.5%). Capsular invasion had a statistically significant association with age, symptomatic presentation, tumor diameter, pathologic stage, collecting system invasion, and microvascular invasion. The mean follow-up was 60.5 mo (range: 1–249). The 5-yr RFS and CSS rates for tumors with capsular invasion were significantly lower compared with rates for tumors without invasion (77.7% vs 92.3% and 85.5% vs 95.7%, respectively; p = 0.0004). Multivariate analysis showed that BMI (hazard ratio [HR] = 0.19), stage (HR = 2.45), and capsular invasion (HR = 3.36) were independent prognostic factors of disease recurrence. With respect to CSS, BMI (HR = 0.20), tumor size (HR = 1.13), and capsular invasion (HR = 4.03) were the factors related to death. Nevertheless, we recognize that these findings may be limited by the study's retrospective, single-institution design.

Conclusions

Our findings suggest that capsular invasion is associated with poor survival in patients with localized clear-cell RCC.     

Chronic kidney disease after nephrectomy in patients with small renal masses: a retrospective observational analysis

Context

Chronic kidney disease (CKD) is a worldwide health threat associated with increased cardiovascular disease and mortality.

Objective

To examine postoperative CKD in patients with small renal masses (SRMs) treated with partial nephrectomy (PN) or radical nephrectomy (RN).

Design, setting, and participants

A US National Cancer Institute Surveillance Epidemiology and End Results (SEER)–Medicare-linked retrospective cohort of 4633 T1aN0M0 renal cell carcinoma (RCC) patients who underwent PN or RN.

Outcome measurements and statistical analysis

The primary outcome of interest was the onset of CKD stage ≥3. Secondary end points comprised acute renal failure (ARF), chronic renal insufficiency (CRI), anemia in CKD, and end-stage renal disease (ESRD). Kaplan-Meier and Cox regression analyses were performed.

Results and limitations

Postpropensity matching resulted in 840 RN and PN patients. In multivariable analyses, RN patients were 1.9-, 1.4-, 1.8-, and 1.8-fold more likely to have an occurrence of CKD, ARF, CRI, and anemia in CKD, respectively (all p ≤ 0.004). The risk of ESRD between treatment groups failed to achieve statistical significance (p = 0.06).

Conclusions

PN is associated with more favorable postoperative renal function outcomes relative to RN in the setting of SRMs.     

Adjuvant therapy for locally advanced renal cell carcinoma: A meta-analysis and systematic review

Objectives

Many adjuvant therapies have been widely used in an attempt to reduce the local recurrence or distant metastasis of locally advanced renal cell carcinoma (RCC) after surgical resection. However, the benefits of adjuvant therapy remain controversial. Thus, we performed this study to analyze the role and safety of adjuvant therapy in renal cancer setting.

A non-cancer-related survival benefit is associated with partial nephrectomy

Background

Partial nephrectomy (PN) may better protect against other-cause mortality (OCM) when compared with radical nephrectomy (RN) in patients with localized renal cell carcinoma (RCC).

Objective

Test the effect of treatment type on OCM.

Design, setting, and participants

Using the Surveillance Epidemiology and End Results–Medicare-linked database, 4956 RN patients (82%) and 1068 PN patients (18%) with T1a RCC were identified (1988–2005).

Measurements

To adjust for inherent differences between treatment types, we relied on propensity-matched analyses. One-to-one matching was performed according to age, sex, race, baseline Charlson comorbidity index (CCI), baseline diagnosis of hypercalcemia and hyperlipidemia, socioeconomic status (SES), population density, tumor size, and year of surgery. The 2- and 5-yr OCM rates were computed using cumulative incidence. Univariable and multivariable competing-risks regression analyses for prediction of OCM were performed according to treatment type. Adjustment was made for cancer-specific mortality (CSM), patient age, CCI, sex, race, SES, tumor grade, and year of surgery.

Results and limitations

Following propensity-based matching, 1068 RN patients were matched with 1068 PN patients. The 2- and 5-yr OCM rates after nephrectomy were 5.0% and 16.0% for PN versus 6.9% and 18.1% for RN, respectively. In the postpropensity multivariable analyses, patients who underwent PN were significantly less likely to die of OCM compared with their RN-treated counterparts (hazard ratio [HR]: 0.83; 95% confidence interval, 0.69–0.98; p = 0.04). Increasing age (HR: 1.08, p < 0.001), higher CCI (HR: 1.14, p < 0.001), female gender (HR: 0.79, p = 0.02), baseline hypercalcemia (HR: 2.05, p = 0.03), baseline hyperlipidemia (HR: 0.73, p = 0.003), and year of surgery (HR: 0.95, p = 0.003) were independent predictors of OCM.

Conclusions

Compared with PN-treated patients, RN-treated patients are more likely to die of OCM after surgery, even after adjusting for CSM, as well as baseline CCI. Consequently, PN should be offered whenever technically feasible.     

Long-Term Follow-up of Patients with Prostate Cancer and Nodal Metastases Treated by Pelvic Lymphadenectomy and Radical Prostatectomy: The Positive Impact of Adjuvant Radiotherapy

Background

Recent large, prospective, randomised studies have demonstrated that adjuvant radiotherapy (RT) is a safe and effective procedure for preventing disease recurrence in locally advanced prostate cancer (PCa) patients. However, no study has ever tested the role of adjuvant RT in node-positive patients after radical prostatectomy (RP).

Objective

We hypothesised that adjuvant RT with early hormone therapy (HT) might improve long-term outcomes of patients with PCa and nodal metastases treated with RP and extended pelvic lymph node dissection (ePLND).

Design, setting, and participants

This retrospective study included 250 consecutive patients with pathologic lymph node invasion. We assessed factors predicting long-term biochemical recurrence (BCR)–free and cancer-specific survival (CSS) in node-positive PCa patients treated with RP, ePLND, and adjuvant treatments between 1988 and 2002 in a tertiary academic centre.

Intervention

All patients received adjuvant treatments according to the treating physician after detailed patient information: 129 patients (51.6%) were treated with a combination of RT and HT, while 121 patients (48.4%) received adjuvant HT alone.

Measurements

BCR-free survival and CSS in patients with node-positive PCa.

Results and limitations

Mean follow-up was 95.9 mo (median: 91.2). BCR-free survival and CSS rates at 5, 8, and 10 yr were 72%, 61%, 53% and 89%, 83%, 80%, respectively. In multivariable Cox regression models, adjuvant RT and the number of positive nodes were independent predictors of BCR-free survival (p = 0.002 and p = 0.003, respectively) as well as of CSS (p = 0.009 and p = 0.01, respectively). Moreover, there was significant gain in predictive accuracy when adjuvant RT was included in multivariable models predicting BCR-free survival and CSS (gain: 3.3% and 3%, respectively; all p < 0.001).

Conclusions

Our data showed excellent long-term outcome for node-positive PCa patients treated with radical surgery plus adjuvant treatments. This study is the first to report a significant protective role for adjuvant RT in BCR-free survival and CSS of node-positive patients.     

Technique of Laparoscopic-Endoscopic Single-Site Surgery Radical Nephrectomy

Background

Laparoscopic-endoscopic single-site surgery (LESS) represents the closest surgical technique to scar-free surgery.

Objective

To assess the feasibility of LESS radical nephrectomy (LESS-RN).

Design, setting, and participants

Ten patients with body mass index (BMI) ≤30 underwent LESS-RN for renal tumour by two experienced laparoscopists.

Surgical procedure

TriPort (Olympus Winter &; Ibe, Hamburg, Germany) was inserted through a transumbilical incision. A combination of standard laparoscopic instruments and flexible grasper and scissors was used. A 5-mm 30° camera was also used. The standard laparoscopic transperitoneal nephrectomy technique was performed.

Measurements

Patient demographics, operative details, and final pathology were prospectively recorded. Postoperative evaluation of pain and use of analgesic medication were recorded.

Results and limitations

Ten cases were successfully accomplished (two right-sided tumours and eight left-sided tumours; tumour diameter ranges: 4–8 cm). The mean patient age was 63.5 yr (22–77 yr), and median BMI was 23.56 (18.2–26.6). The mean operative time was 146.4 min (120–180 min), and the mean blood loss was 202 ml (50–900 ml). Pathological examination observed organ-confined T1 renal cell carcinoma in nine cases and pT3b tumour in one case. One bleeding complication occurred. Limitations regarding the intraoperative instrument ergonomics and the requirement for ambidexterity of the surgeon were noted.

Conclusions

LESS-RN proved to be safe and feasible. Further clinical investigation in comparison to the established techniques should take place to evaluate the outcome of LESS-RN.     

Prognostic and Therapeutic Impact of the Histopathologic Definition of Parenchymal Epithelial Renal Tumors

Context

In the last few years, the treatment of renal cell carcinoma (RCC) has progressed significantly, and some histopathologic issues have become important for selection and follow-up after medical and surgical therapies.

Objective

The aim of this collaborative article is to review the most recent literature on the role of traditional histopathologic features obtained from renal core biopsy or nephrectomy specimens in the management of confined, locally advanced, and metastatic RCC.

Evidence acquisition

A nonsystematic review of the literature was performed in April 2010 using the Medline database. Multiple free-text searches were performed for the following items: renal cell carcinoma, clear cell, papillary, chromophobe, histologic* subtype*, histotype*, nuclear grade*, necrosis, sarcomatoid differentiation, biopsy, molecular marker*, and cytogenetic marker*. A total of 2369 records were retrieved from Medline, and 263 full-text studies were considered and partially included in the present review. A panel of experts reached consensus on the main subheadings of this paper.

Evidence synthesis

Core needle biopsies can provide important information that is useful to avoid the overtreatment of benign tumors and to help plan watchful waiting or minimally invasive treatments in selected patients. Tumor histotype is fundamental in the pathologic report. In the context of integrated prognostic systems, the combination of the most important clinical and pathologic factors (TNM stage, Fuhrman nuclear grade, presence of necrosis, microvascular invasion, and sarcomatoid dedifferentiation) allows us to reach a high prognostic accuracy. These models can be used to select patients suitable for adjuvant protocols, to design an appropriate follow-up schedule, and to provide careful patient counseling. Molecular and cytogenetic markers should be further evaluated.

Conclusions

The histopathologic definition of parenchymal epithelial renal tumors is fundamental to plan the management and follow-up of patients with locally confined, locally advanced, and metastatic RCC.     

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.     

Reassessing the Current UICC/AJCC TNM Staging for Renal Cell Carcinoma

Context

The outcome prediction for renal cell cancer (RCC) remains controversial, and although many parameters have been tested for prognostic significance, only a few have achieved widespread acceptance in clinical practice. The TNM staging system defines local extension of the primary tumour (T), involvement of regional lymph nodes (N), and presence of distant metastases (M).

Objective

This review focuses on reassessing the current TNM staging system for RCC.

Evidence acquisition

A literature search in English was performed using the National Library of Medicine database and the following keywords: renal cell cancer, kidney neoplasm, and staging. We scrutinized 1952 references, and 62 were selected for review based on their pertinence, study size, and overall contribution to the field.

Evidence synthesis

The prognostic significance of tumour size for localized RCC has been investigated in a large number of studies. As a consequence, many modifications of the TNM staging system were primarily made to the size cut points between stage I and II tumours. The latest three revisions of the TNM system are systematically reviewed. For the heterogeneous group of locally advanced RCCs, involving different anatomic structures surrounding the kidney, the situation is still the subject of controversial scientific dispute. In detail, perirenal fat invasion, direct infiltration of the ipsilateral adrenal gland, invasion of the urinary collecting system, infiltration of renal sinus fat, and vena cava and renal vein thrombosis are disputed. Finally, staging of lymph node metastases and distant metastatic disease is discussed.

Conclusions

Special emphasis should be put on renal sinus invasion for stage evaluation. Retrospective studies relying on material collected at a time when no emphasis was placed on adequate sampling of the renal sinus should be treated with caution. In view of new treatment opportunities, the current TNM staging system of RCC and any other staging system must be dynamic.