Systematic classification and prediction of complications after nephrectomy in patients with metastatic renal cell carcinoma (RCC)

Study Type – Harm (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Radical nephrectomy for patients with metastatic renal cell carcinoma results in greater rates of morbidity than for those with less advanced disease. This study systematically characterizes complications associated with nephrectomy for metastatic RCC and identifies patient and disease characteristics that are associated with a greater risk of developing complications. Overall complications were relatively frequent, but major complications (grade 3 or greater) were rare. Increasing age and worsening performance status were associated with increased probability of complications. When complications were sustained, patients were less likely to receive systemic therapy in a timely fashion. These observations may influence the timing or patient selection for surgery or systemic therapy.

OBJECTIVE

• ? To evaluate and identify factors predictive for morbidity after radical nephrectomy in patients with metastatic renal cell carcinoma (mRCC).

PATIENTS AND METHODS

• ? We identified patients with mRCC who underwent nephrectomy at Memorial Sloan‐Kettering Cancer Center (MSKCC) between 1989 and 2009.
• ? Postoperative complications were characterised using a modified version of the Clavien‐Dindo classification system.
• ? Patient and disease characteristics, including a previously validated MSKCC risk‐stratification system using calcium, haemoglobin (Hb), lactate dehydrogenase, and Karnofsky Performance Status (KPS), were evaluated as predictors of postoperative complications using univariate and multivariable logistic regression models.
• ? The area under the receiver operating characteristic curve (AUC) was calculated for each model to assess predictive accuracy and corrected for overfit using 10‐fold cross validation.

RESULTS

• ? Over the study period, 195 patients with mRCC underwent nephrectomy; 53 (27%) developed grade ≥2 complications within 8 weeks of surgery.
• ? Pulmonary, thromboembolic events and anaemia requiring transfusion were the most common types of complications after nephrectomy in the metastatic setting.
• ? In univariate analysis, age, low albumin, low KPS, high corrected serum calcium, low serum Hb, and unfavourable MSKCC risk score were predictive of complications.
• ? Patients who sustained postoperative complications were less likely to receive systemic therapy within 56 days (odds ratio [OR] 0.32; 95% confidence interval [CI] 0.12–0.86; P= 0.024).
• ? A multivariable model containing KPS (OR 14.5; 95%CI 4.34–48.6; P < 0.001) and age (OR 1.04; 95%CI 1.01–1.08; P= 0.014) showed the greatest predictive accuracy (corrected AUC 0.72; 95%CI 0.63–0.80) for postoperative complications.

CONCLUSIONS

• ? Postoperative complications after radical nephrectomy in the setting of mRCC are common and occur frequently in older patients and those with worse KPS.
• ? These complications are important because they may delay or deny receipt of subsequent systemic therapy.

     

Laparoscopic high-intensity focused ultrasound for renal tumours: a proof of concept study

Study Type – Therapy (case series)
Level of Evidence What’s known on the subject? and What does the study add? Renal cancer is increasingly diagnosed when tumours are small and asymptomatic, during routine abdominal imaging. Whilst surgery is an effective and potentially curative option, it carries a significant risk of complications. Recent work suggests that thermally ablative therapies (RFA, cryotherapy, HIFU) may be suitable minimally invasive treatment options in selected patients. The success of extracorporeal HIFU has been limited by the abdominal wall and rib‐cage limiting energy delivery. For this study, a purpose‐built laparoscopic HIFU probe was designed to allow direct application of the transducer to the tumour surface, thus facilitating tumour destruction. Successful and accurate tumour destruction was demonstrated, paving the way for further clinical trials, subject to device modifications.

OBJECTIVE

• ? To test and establish clinical proof of concept for a laparoscopic high‐intensity focused ultrasound (HIFU) device that facilitates delivery of ultrasound by direct application of a probe to the tumour surface.

PATIENTS AND METHODS

• ? Twelve patients with renal tumours were treated with laparoscopic HIFU using a newly designed probe inserted via an 18‐mm laparoscopic port.
• ? HIFU treatment was targeted at a pre‐defined proportion of the tumour and immediate laparoscopic partial or radical nephrectomy was then performed.

RESULTS

• ? No tumour ablation was seen in the first five patients which made modifications in the treatment protocol necessary. After this, definite histological evidence of ablation was seen in the remaining seven patients.
• ? The ablated zones were within the targeted area in all patients and no intra‐lesional skipping was seen.
• ? Subcapsular skipping was seen at the probe–tumour interface in two patients with viable tumour cells seen at microscopy.
• ? One patient did not undergo surgical extirpation; subsequent biopsy revealed no viable tumour cells.
• ? There were no intraoperative or postoperative complications directly related to HIFU therapy and patients have reached a mean (range) follow‐up of 15 (8–24) months with no evidence of metastatic disease or late complications.

CONCLUSIONS

• ? Tumour ablation with laparoscopic HIFU is feasible.
• ? Homogenous ablation can be achieved with no vital tissue within the targeted zone.
• ? The technique is associated with low morbidity and may have a role in the definitive management of small tumours.

     

Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma

Study Type – Prognosis (cohort series) Level of Evidence 2b What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status.

OBJECTIVE

• ? To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression‐free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC).

PATIENTS AND METHODS

• ? A homogenous group of patients with mRCC enrolled in second‐line trials post‐cytokine treatment were selected for the present analysis.
• ? The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB.
• ? The PFS and OS rates were estimated using the Kaplan–Meier method and compared across the groups using the log‐rank test.
• ? The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment.

RESULTS

• ? A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow‐up was 80.1 month.
• ? TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,.
• ? Each 1‐cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02–1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03–1.08; P < 0.001).

CONCLUSIONS

• ? TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC.
• ? We report for the first time the independent prognostic role of baseline TB in multivariate analysis.
• ? We believe that this information could be translated into clinical practice.

     

Transrectal ultrasonography-guided biopsy does not reliably identify dominant cancer location in men with low-risk prostate cancer

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? The widespread use of serum PSA testing followed by TRUS‐guided biopsy have resulted in profound prostate cancer stage migration with many patients presenting with focal rather than multifocal disease. There is increasing interest in the use of focal rather than whole‐gland treatment. However, current biopsy schemes may still miss cancer or, even when cancer is identified, its extent or grade might not be accurately characterized. In order for focal therapy to be effective, the area of highest tumour volume and/or grade needs to localized accurately. The aim of this study was to assess how well biopsy, as currently performed, locates the focus of highest prostate cancer volume and/or grade.

OBJECTIVE

• ? To evaluate the ability of transrectal ultrasonography (TRUS)‐guided extended core biopsy to identify the dominant tumour accurately in men with early stage prostate cancer.

PATIENTS AND METHODS

• ? Patients with early stage, low‐risk prostate cancer who subsequently underwent radical prostatectomy (RP) and had complete surgical specimens were identified.
• ? Re‐review was performed by a single uropathologist using ImageJ software to identify tumour location, dominant grade (DG) and dominant volume (DV).
• ? Pathology findings were then compared with biopsy results.

RESULTS

• ? A total of 51 men with early stage, low‐risk prostate cancer, who had undergone RP, had complete specimens for review and a median of 15 biopsy cores taken for diagnosis and grading.
• ? Sixteen men had a single diagnostic biopsy, 21 had one repeat biopsy, and 14 had two or more repeat biopsies.
• ? Compared with surgical findings, biopsy correctly identified the sextant with the largest tumour volume in 55% (95% CI 0.5–0.6) of specimens and the highest grade in 37% (95 CI 0.3–0.5).
• ? No demographic or clinical factors were significantly associated with identification of DG. Interval between last biopsy and RP, total tissue length taken and total length of tumour identified were significantly associated with correct identification of DV.

CONCLUSIONS

• ? Our findings show that TRUS‐guided biopsy detects and localizes DV better than it does DG.
• ? Even with an extended scheme, TRUS‐guided biopsy does not reliably identify dominant cancer location in this low‐risk cohort of men with early stage prostate cancer.
• ? TRUS‐guided biopsy may perform better in similar men with low stage, but higher volume disease.

     

The role of transrectal saturation biopsy in tumour localization: pathological correlation after retropubic radical prostatectomy and implication for focal ablative therapy

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What’s known on the subject? and What does the study add? The traditional transrectal sextant and extended biopsy schemes demonstrated low accuracy in predicting unilateral prostate cancer on radical prostatectomy specimens. We examined the accuracy of an initial saturation biopsy (24‐core) to predict unilateral prostate cancer on radical prostatectomy specimens.

OBJECTIVE

• ? To evaluate the accuracy of an initial 24‐core prostate biopsy scheme (PBx24) in predicting unilateral prostate cancer (PCa) in radical prostatectomy (RP) specimens.

PATIENTS AND METHODS

• ? Between 2005 and 2008, 203 consecutive patients underwent PBx24 followed by RP for PCa. The area under the curve (AUC) was used to evaluate the accuracy of unilateral PCa on PBx24 to predict unilateral PCa in RP specimens.
• ? The positive predictive value (PPV) and negative predictive value (NPV) were also calculated. Moreover, in patients with unilateral PCa on biopsy, univariable and multivariable logistic regression analyses tested the relationship between the presence of unilateral PCa in an RP specimen and the variables: age, prostate‐specific antigen (PSA), total prostate volume, clinical stage, primary Gleason grade, secondary Gleason grade and the number of positive cores.

RESULTS

• ? PCa cores were unilateral in 115 patients (56.7%) on biopsy. Of those, only 26 (22.6%) had unilateral PCa in the RP specimen (AUC, 72.9%; PPV, 22.6%; NPV, 98.8%). In patients with clinically low‐risk tumours, only 17 of 63 (27%) had a unilateral PCa on PBx24 and in the RP specimen (AUC, 59.1%; PPV, 27.0%; NPV, 100.0%).
• ? None of the examined variables was an independent predictor of the presence of unilateral PCa in the RP specimen (all P > 0.05).

CONCLUSIONS

• ? Initial PBx24 is not sufficiently accurate to be dependable as a method of predicting tumour laterality in RP specimens. Therefore, the use of PBx24 to guide hemi‐ablation therapy of PCa may lead to mistreatment in a considerable proportion of patients.
• ? Moreover, none of the routinely available clinical and pathological characteristics appears to improve the ability of unilateral PCa on biopsy to predict unilateral PCa in the RP specimen.

     

Prediction of outcomes after radical prostatectomy in patients diagnosed with prostate cancer of biopsy Gleason score ≥ 8 via contemporary multi (≥ 12)-core prostate biopsy

Study Type – Prognostic (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Currently, controversy continues with regards to the efficacy of performing radical prostatectomy (RP) and the potential predictor of outcome after surgery in patients with prostate cancers of higher biopsy Gleason score. Among contemporary patients with biopsy Gleason score ≥8 who underwent RP alone, patients with pathologically organ‐confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ‐confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥8.

OBJECTIVE

• ? To investigate the outcome of patients who underwent radical prostatectomy (RP) for prostate cancer of biopsy Gleason score ≥ 8 diagnosed via contemporary prostate biopsy.

PATIENTS AND METHODS

• ? We reviewed records of 151 patients who underwent RP for prostate cancer of biopsy Gleason score ≥ 8 detected via multi (≥12)‐core prostate biopsy without any neoadjuvant or adjuvant treatment.
• ? Preoperative predictors of pathologically organ‐confined disease along with biochemical recurrence‐free survival were analyzed via multivariate logistic regression and Cox proportional hazards model.

RESULTS

• ? For 151 total subjects, 5‐year estimated biochemical recurrence‐free survival rate was 41.0%. Patients with pathologically organ‐confined disease were observed to have much higher 5‐year biochemical recurrence‐free survival rate than those otherwise (72.1 vs 31.5%, P < 0.001).
• ? Serum PSA level (P= 0.031) and maximum tumour length in a biopsy core (P= 0.005) were observed to be significant preoperative predictors of having pathologically organ‐confined disease.
• ? As for biochemical recurrence‐free survival following RP, serum PSA (P= 0.023), biopsy Gleason score (P= 0.032), and percent of total tumour length in biopsy cores (P < 0.001) were observed be significant preoperative predictors on multivariate analysis.

CONCLUSION

• ? Among contemporary patients with biopsy Gleason score ≥ 8 who underwent RP alone, patients with pathologically organ‐confined disease demonstrated significantly better biochemical outcome than others. Serum PSA level and maximum tumour length in a biopsy core, independent predictors of organ‐confined disease, would be useful in the selection of candidates for RP among patients presenting with biopsy Gleason score ≥ 8.

     

Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours

Study Type – Diagnostic (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The Gleason score of prostate cancer is frequently underestimated at the time of diagnostic biopsy, although the contribution of sampling error to its incidence is unknown. We show that under‐graded tumours are significantly smaller that tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.

OBJECTIVE

• ? To determine the influence of tumour and prostate gland volumes on the underestimation of prostate cancer Gleason score in diagnostic core biopsies.

PATIENTS AND METHODS

• ? Patients undergoing radical prostatectomy with matched diagnostic biopsies were identified from a prospectively recorded database.
• ? Tumour volumes were measured in serial whole‐mount sections with image analysis software as part of routine histological assessment.
• ? Differences in various metrics of tumour and prostate volume between upgraded tumours and tumours concordant for the lower or higher grade were analysed.

RESULTS

• ? In all, 684 consecutive patients with Gleason score 6 or 7 prostate cancer on diagnostic biopsy were identified.
• ? Of 298 patients diagnosed with Gleason 6 tumour on biopsy, 201 (67.4%) were upgraded to Gleason 7 or higher on final pathology. Similarly, of 262 patients diagnosed with Gleason 3 + 4 = 7 prostate cancer on initial biopsy, 60 (22.9%) were upgraded to Gleason score 4 + 3 = 7 or higher.
• ? Tumours upgraded from Gleason 6 to 7 had a significantly lower index tumour volume (1.73 vs 2 mL, P= 0.029), higher calculated prostate volume (41.6 vs 39 mL, P= 0.017) and lower relative percentage of tumour to benign glandular tissue (4.3% vs 5.9%, P= 0.001) than tumours concordant for the higher grade.
• ? Similarly, tumours that were Gleason score 3 + 4 on biopsy and upgraded on final pathology to 4 + 3 were significantly smaller as measured by both total tumour volume (2.3 vs 3.3 mL, P= 0.005) and index tumour volume (2.2 vs 3, P= 0.027) and occupied a smaller percentage of the gland volume (6.3% vs 8.9%, P= 0.017) compared with tumours concordant for the higher grade.
• ? On multivariate analysis, lower prostate weight (hazard ratio 0.97, 95% confidence interval 0.96–0.99, P < 0.001) and larger total tumour volume (hazard ratio 1.87, 95% confidence interval 1.4–2.6, P < 0.001) independently predicted an upgrade in Gleason score from 6 to 7. In tumours upgraded from biopsy Gleason 3 + 4, only higher index tumour volume (hazard ratio 3.1, 95% confidence interval 1.01–9.3, P= 0.048) was a significant predictor of upgrading on multivariate analysis.

CONCLUSIONS

• ? Under‐graded tumours are significantly smaller than tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.
• ? Surrogate measures of tumour volume may predict those at greatest risk of Gleason score upgrade.

     

A biopsy simulation study to assess the accuracy of several transrectal ultrasonography (TRUS)-biopsy strategies compared with template prostate mapping biopsies in patients who have undergone radical prostatectomy

Study Type – Diagnostic (validating cohort) Level of Evidence 1b What's known on the subject? and What does the study add? Transrectal ultrasonography (TRUS)‐guided biopsies can miss prostate cancer and misclassify risk in a diagnostic setting; the exact extent to which it does so in a repeat biopsy strategy in men with low–intermediate risk prostate cancer is unknown. A simulation study of different biopsy strategies showed that repeat 12‐core TRUS biopsy performs poorly. Adding anterior sampling improves on this but the highest accuracy is achieved using transperineal template prostate mapping using a 5 mm sampling frame.

OBJECTIVE

• ? To determine the effectiveness of two sampling strategies; repeat transrectal ultrasonography (TRUS)‐biopsy and transperineal template prostate mapping (TPM) to detect and exclude lesions of ≥0.2 mL or ≥0.5 mL using computer simulation on reconstructed three‐dimensional (3‐D) computer models of radical whole‐mount specimens.

PATIENTS AND METHODS

• ? Computer simulation on reconstructed 3‐D computer models of radical whole‐mount specimens was used to evaluate the performance characteristics of repeat TRUS‐biopsy and TPM to detect and exclude lesions of ≥0.2 mL or ≥0.5 mL.
• ? In all, 107 consecutive cases were analysed (1999–2001) with simulations repeated 500 times for each biopsy strategy.
• ? TPM and five different TRUS‐biopsy strategies were simulated; the latter involved a standard 12‐core sampling and incorporated variable amounts of error, as well as the addition of anterior cores.
• ? Sensitivity, specificity, negative and positive predictive values for detection of lesions with a volume of ≥0.2 mL or ≥0.5 mL were calculated.

RESULTS

• ? The mean (sd ) age and PSA concentration were 61 (6.4) years and 8.5 (5.9) ng/mL, respectively.In all, 53% (57/107) had low–intermediate risk disease.
• ? In all, 665 foci were reconstructed; there were 149 foci ≥0.2 mL and 97 ≥ 0.5 mL in the full cohort and 68 ≥ 0.2 mL and 43 ≥ 0.5 mL in the low–intermediate risk group.
• ? Overall, TPM accuracy (area under the receiver operating curve, AUC) was ≈0.90 compared with AUC 0.70–0.80 for TRUS‐biopsy.
• ? In addition, at best, TRUS‐biopsy missed 30–40% of lesions of ≥0.2 mL and ≥0.5 mL whilst TPM missed 5% of such lesions.

CONCLUSION

• ? TPM under simulation conditions appears the most effective re‐classification strategy, although augmented TRUS‐biopsy techniques are better than standard TRUS‐biopsy.

     

The role of transperineal template prostate biopsies in restaging men with prostate cancer managed by active surveillance

Study Type – Diagnostic (exploratory cohort) Level of Evidence 3b What's known on the subject? and What does the study add? The optimal method of active surveillance in prostate cancer remains unknown. This study is one of the first to report on the role of transperineal template prostate biopsies in active surveillance. It demonstrates that around one third of men are reclassified with more significant prostate cancer at an early stage in their management. This is a higher proportion than reported in contemporary cancers using standard transrectal biopsies for restaging.

OBJECTIVE

• ? To evaluate the role of transperineal template prostate biopsies in men on active surveillance.

PATIENTS AND METHODS

• ? In all, 101 men on active surveillance for prostate cancer underwent restaging transperineal template prostate biopsies at a single centre.
• ? Criteria for active surveillance were ≤75 years, Gleason ≤3+3, prostate‐specific antigen (PSA) ≤15 ng/mL, clinical stage T1–2a and ≤50% ultrasound‐guided transrectal biopsy cores positive for cancer with ≤10 mm of disease in a single core.
• ? The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed.
• ? The role of PSA and PSA kinetics were studied.

RESULTS

• ? In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies.
• ? Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under‐sampled by transrectal biopsies.
• ? In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance 38% had more significant disease.
• ? There was no correlation with PSA velocity or PSA doubling time.
• ? In total, 33% of men stopped active surveillance and had radical treatment.

CONCLUSIONS

• ? Around one‐third of men had more significant prostate cancer on transperineal template biopsies.
• ? This probably reflects under‐sampling by initial transrectal biopsies rather than disease progression.

     

Use of tyrosine kinase inhibitors in patients with metastatic kidney cancer receiving haemodialysis: a retrospective Italian survey

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sunitinib and sorafenib are orally administered multikinase inhibitors approved for the treatment of advanced RCC. The limited pharmacokinetics data on sunitinib and sorafenib suggest that haemodialysis does not significantly alter plasma concentrations. In this retrospective study we define the safety and efficacy of tyrosine kinase inhibitors in patients with metastatic RCC (mRCC) and end‐stage renal disease requiring haemodialysis. Even though the retrospective nature of this survey and the relatively small sample size represent major limitations, these data indicate that treatment with sunitinib and sorafenib in this cohort of patients is feasible with no unexpected toxicity and good efficacy, results similar to those in the general population of patients with mRCC.

OBJECTIVE

• ? To investigate the safety and efficacy of tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) and end‐stage renal disease requiring haemodialysis (HD).

PATIENTS AND METHODS

• ? Between July 2006 and December 2010, 24 patients undergoing HD were treated with sunitinib and/or sorafenib for mRCC in 14 Italian institutions.
• ? We retrospectively reviewed the medical records of these patients to evaluate the administered doses of TKIs, treatment‐related toxicities and the clinical response to therapy.

RESULTS

• ? Sunitinib was administered at 50 mg daily for 4–6 weeks in six patients, 37.5 mg daily for 4–6 weeks in seven patients (one patient subsequently increased the dose to 50 mg daily), 25 mg daily for 4–6 weeks in two patients and 12.5 mg daily for 4–6 weeks in one patient. Among the eight patients treated with sorafenib, four patients received 800 mg daily (400 mg every 12 h), three patients 400 mg daily and one patient 200 mg daily with a continuous schedule.
• ? The estimated median progression‐free and overall survival periods of this cohort of patients were 10.3 months and 22.6 months, respectively.
• ? With regard to tolerability and safety, no unexpected adverse events were registered and no grade 4 haematological or non‐haematological toxicities were reported.

CONCLUSIONS

• ? Sunitinib and sorafenib treatment is not contraindicated in patients with mRCC undergoing HD.
• ? The outcome of this patient population is similar to that observed in patients with normal renal function treated with TKIs.
• ? These results merit further confirmation by a larger prospective trial.

     

Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies

Study Type – Diagnostic (exploratory cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Hypermethylation of genes such as glutathione‐S‐transferase P1 (GSTP1) and adenomatous polyposis coli (APC) occurs with high frequency in prostate tumour tissue but is much less common in the benign prostate; however, the potential value of gene methylation biomarkers as an adjunct to biopsy histopathology has had little study. When measured in histologically benign prostate biopsy tissue, APC gene hypermethylation was found to have high negative predictive value and high sensitivity. GSTP1 hypermethylation was found to have lower performance than APC.

OBJECTIVE

• ? To evaluate the performance of DNA methylation biomarkers in the setting of repeat biopsy in men with an initially negative prostate biopsy but a high index of suspicion for missed prostate cancer.

PATIENTS AND METHODS

• ? We prospectively evaluated 86 men with an initial histologically negative prostate biopsy and high‐risk features.
• ? All men underwent repeat 12‐core ultrasonography‐guided biopsy.
• ? DNA methylation of glutathione‐S‐transferase P1 (GSTP1) and adenomatous polyposis coli (APC) was determined using tissue from the initially negative biopsy and compared with histology of the repeat biopsy.
• ? The primary outcome was the relative negative predictive value (NPV) of APC compared with GSTP1, and its 95% confidence interval (CI).

RESULTS

• ? On repeat biopsy, 21/86 (24%) men had prostate cancer.
• ? APC and GSTP1 methylation ratios below the threshold (predicting no cancer) produced a NPV of 0.96 and 0.80, respectively. The relative NPV was 1.2 (95% CI: 1.06–1.36), indicating APC has significantly higher NPV.
• ? Methylation ratios above the threshold yielded a sensitivity of 0.95 for APC and 0.43 for GSTP1.
• ? Combining both methylation markers produced a performance similar to that of APC alone.
• ? APC methylation patterns were consistent with a possible field effect or occurrence early in carcinogenesis.

CONCLUSIONS

• ? APC methylation provided a very high NPV with a low percentage of false‐negatives, in the first prospective study to evaluate performance of DNA methylation markers in a clinical cohort of men undergoing repeat biopsy.
• ? The potential of APC methylation to reduce unnecessary repeat biopsies warrants validation in a larger prospective cohort.

     

Survival after partial and radical nephrectomy for the treatment of stage T1bN0M0 renal cell carcinoma (RCC) in the USA: a propensity scoring approach

Study Type – Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Partial nephrectomy has become the standard of care for T1a renal tumours, and the application of nephron‐sparing techniques has increasingly been expanded to patients with localized T1b cancers. However, the relative efficacy of partial versus radical nephrectomy for these medium‐sized tumours has yet to be definitively established. This study employs a propensity scoring approach within a large US population‐based cohort to determine that no survival differences exist among patients with T1b renal tumours undergoing partial versus radical nephrectomy.

OBJECTIVES

• ? To compare survival after partial nephrectomy (PN) vs radical nephrectomy (RN) among patients with stage TIb renal cell carcinoma (RCC) using a propensity scoring approach.
• ? Propensity score analysis is a statistical methodology that controls for non‐random assignment of patients in observational studies.

PATIENTS AND METHODS

• ? Using the Surveillance, Epidemiology, and End Results registry, 11 256 cases of RCCs of 4–7 cm that underwent PN or RN between 1998 and 2007 were identified.
• ? Propensity score analysis was used to adjust for potential differences in baseline characteristics between patients in the two treatment groups.
• ? Overall survival (OS) and cancer‐specific survival (CSS) of patients undergoing PN vs RN was compared in stratified and adjusted analysis, controlling for propensity scores.

RESULTS

• ? In all, 1047 (9.3%) patients underwent PN. For the entire cohort, no difference in survival was found in patients treated with PN as compared with RN, as shown by the adjusted hazard ratio (HR) for OS (1.10; 95% confidence interval [CI]: 0.91–1.36) and renal‐CSS (HR 0.91; 95% CI: 0.65–1.27).
• ? When the cohort was stratified by tumour size and age, no difference in survival was identified between the groups.

CONCLUSIONS

• ? Even when stratified by tumour size and age, a survival difference between PN and RN in a propensity‐adjusted cohort of patients with T1b RCC could not be confirmed.
• ? If validated in prospective studies, PN may become the preferred treatment for T1b renal tumours in centres experienced with nephron‐sparing surgery.

     

Prognostic significance of preoperative kidney volume for predicting renal function in renal cell carcinoma patients receiving a radical or partial nephrectomy

Study Type – Prognosis (case series) Level of Evidence 4 What's known on the subject? and What does the study add? At present, many studies have been executed to identify predictors for chronic kidney disease or renal insufficiency after radical nephrectomy or partial nephrectomy. We examined whether preoperative kidney volume is a predictor for renal function after radical or partial nephrectomies in RCC patients. To our knowledge, this is the first study to report on the relationship between preoperative kidney volume and changes in renal function in RCC patients who underwent radical nephrectomy or partial nephrectomy performed by one surgeon.

OBJECTIVE

• ? To investigate whether preoperative kidney volume is a prognostic factor for predicting the postoperative glomerular filtration rate (GFR) in renal cell carcinoma (RCC) patients.

PATIENTS AND METHODS

• ? We included 133 patients who underwent radical (n= 83) or partial (n= 50) nephrectomy for RCC.
• ? Kidney parenchymal volume was measured using personal computer‐based software and GFR was estimated before and after surgery at 6 and 12 months.
• ? We evaluated the change in kidney volume after radical and partial nephrectomy and used regression analysis to identify predictors of lower post‐surgical GFR at 12 months.

RESULTS

• ? The mean volume of the normal side kidney for the radical nephrectomy group increased from 142.4 mL to 166.0 mL (17.2%) and 171.5 mL (21.2%) after surgery at 6 and 12 months, respectively.
• ? In the partial nephrectomy group, the volume of the normal side kidney increased from 127.2 mL to 138.8 mL (9.1%) and 140.6 mL (10.9%) after surgery at 6 and 12 months, respectively.
• ? The volume of the operated side kidney decreased from 128.5 mL to 102.3 mL (20.1%) and 101.8 (20.6%) after surgery at 6 and 12 months, respectively.
• ? In the radical nephrectomy group, older age (P < 0.001), preoperative volume of the normal kidney (P= 0.022) and preoperative GFR for the normal side kidney (P= 0.045) were significant predictors of lower post‐surgical GFR at 12 months.
• ? In the partial nephrectomy group, older age (P= 0.001) and preoperative volume for both kidneys (P= 0.037) were significant predictors of lower post‐surgical GFR at 12 months.

CONCLUSION

• ? Preoperative kidney volume is an independent predictor of GFR in RCC patients who underwent radical or partial nephrectomy.

     

Predictors of early mortality after radical nephrectomy with renal vein or inferior vena cava thrombectomy – a population‐based study

Study Type – Prognosis (cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Surgical volume has been well established as a predictor of outcomes for several complex surgical procedures, yet few studies have evaluated this relationship with regards to radical nephrectomy with either renal vein or inferior vena cava thrombectomy. In addition, most published literature consists of single‐institution series from centres of excellence. We performed a population‐level analysis and identified surgeon volume as a significant predictor of short‐term mortality for this procedure. Such findings have potential implications regarding future policy and regionalization of care.

OBJECTIVE

• ? To study the short‐term mortality associated with radical nephrectomy with renal vein or inferior vena cava thrombectomy and the variables associated with this adverse outcome.

METHODS

• ? Using the Ontario Cancer Registry, we identified 433 patients in the province of Ontario, Canada undergoing radical nephrectomy with venous thrombectomy between 1995 and 2004.
• ? We determined mortality rates at postoperative days 30 and 90.
• ? Other variables analysed include pathological tumour characteristics, surgeon graduation year, hospital/surgeon academic status, surgery year and hospital/surgeon volume.
• ? We used multivariable logistic regression to assess outcomes.

RESULTS

• ? Overall mortality was 2.8% (30‐day) and 5.8% (90‐day).
• ? Surgeons performing a single nephrectomy with venous thrombectomy performed 14% of the cases and had the highest 30‐day (6.7%) and 90‐day (10%) mortality. The mortality rate for surgeons performing more than one surgery was 2.1% (30‐day) and 5.1% (90‐day).
• ? In recent years, this procedure was performed more commonly by the highest volume surgeons – 67% of cases in 2004 vs 40% in 1995.
• ? Significant predictors of 30‐day mortality included procedure year and low surgeon volume.
• ? Significant predictors of 90‐day mortality included procedure year, low surgeon volume, left‐sided tumour and increasing hospital volume.

CONCLUSIONS

• ? For radical nephrectomy with venous thrombectomy, surgeon volume predicts short‐term mortality, emphasizing the importance of experience in patient outcome.
• ? Despite a shift towards high‐volume surgeons, 13.8% of cases continued to be performed by low‐volume providers.
• ? If these results are confirmed in other jurisdictions, radical nephrectomy with venous thrombectomy should be regionalized and performed by surgeons who manage these cases regularly.

     

Tumour size, tumour complexity, and surgical approach are associated with nephrectomy type in small renal cortical tumours treated electively

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Although the benefits of nephron‐sparing renal cortical tumour treatments are now widely accepted and have robust data supporting their oncological efficacy, safety, and positive effect on medium‐ and long‐term renal function, the decision to perform partial nephrectomy (PN) remains a complex interaction between several competing factors. Various patient factors, e.g. comorbid conditions, age, body habitus, patient preference, etc. may effect this decision. Then there are the preferences of the surgeon him‐ or herself, including faculty with different operative techniques and surgical approaches, which may lead to one treatment decision over another. Finally, the anatomy of the tumour itself, i.e. the complexity of the tumour within the kidney and anatomical relationships within the organ, is intuitively critical to a surgeon's assessment of resectability. There is very little published data indicating which of the multitude of clinical variables have the greatest impact on the decision to perform PN. Most previous investigations into the subject have focused on either imperative or relative indications for PN (i.e. solitary kidney, bilateral renal masses, and multifocal tumours) or have used maximal tumour diameter (i.e. tumour size) alone in their assessment of the clinical variables associated with PN use.

OBJECTIVE

• ? To identify preoperative variables associated with choice of partial nephrectomy (PN) vs radical nephrectomy (RN).

PATIENTS AND METHODS

• ? Between January 2004 and June 2008, 203 patients were treated for clinical T1a renal cortical tumours. Of these, 154 (75.8%) had all data available and form the analytic cohort.
• ? Patients were categorized into two groups, PN and RN, based on preoperative treatment plan.
• ? Patient‐, procedure‐, and tumour‐related variables, together with tumour complexity (based on the R.E.N.A.L Nephrometry Score [RENAL‐NS]) were evaluated for their association with planned PN vs RN.

RESULTS

• ? PN was planned in 120/154 patients (77.9%).
• ? Minimally invasive surgical approaches were planned in 66/154 cases overall (42.9%) and in 40/120 PN cases (33.3%).
• ? On univariate analysis, lower American Society of Anesthesiologists (ASA) score, planned open approach, smaller tumour size, left‐sided tumour, and lower RENAL‐NS were associated with planned PN.
• ? On multivariate analysis three factors remained independently associated with PN: tumour size (each 1 cm decrease in tumour size odds ratio [OR] 2.2, 95% confidence interval [CI] 1.2–4.0, P= 0.011), tumour complexity quantified by RENAL‐NS (each 1 point decrease OR 2.4, 95% CI 1.5–3.7, P < 0.001), and planned open surgical approach (OR 7.3, 95% CI 2.2–25, P= 0.001).

CONCLUSIONS

• ? The decision to perform elective PN is based primarily on tumour anatomical features but is also associated with surgical approach.
• ? The RENAL‐NS accurately predicts nephrectomy type in clinical T1a renal cortical tumours.

     

Does repeat biopsy affect the prognosis of patients with prostate cancer treated with radical prostatectomy? Analysis by the number of cores taken at initial biopsy

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? To date, studies to evaluate clinical significance of prostate cancer detected on repeat biopsy in patients who underwent radical prostatectomy have yielded inconsistent results. The present study confirms that prostate cancer diagnosed after repeat biopsies is related to better pathological outcomes after radical prostatectomy, but not predictive of biochemical recurrence. Additionally, we find that the number of cores taken at initial biopsy do not affect the association between the number of previous biopsies and the prognosis.

OBJECTIVE

• ? To determine whether repeat prostate biopsies are associated with more favourable prognoses compared with diagnosis at initial biopsy in patients who undergo radical prostatectomy for prostate cancer and to determine if this association is affected by the number of cores taken at initial biopsy.

PATIENTS AND METHODS

• ? We reviewed 1147 patients with prostate cancer from 1991 to 2008.
• ? Patients were stratified into two groups by the number of biopsies before diagnosis (initial biopsy vs repeat biopsy: at least two biopsies).
• ? The effects of several variables on pathological outcomes and biochemical recurrence‐free and systemic progression‐free survivals were assessed.

RESULTS

• ? Of the 1147 patients, 1064 (92.8%) were diagnosed with cancer at first biopsy and 83 (7.2%) at repeat biopsy.
• ? Compared with patients diagnosed at initial biopsy, those diagnosed at repeat biopsies were more likely to have a lower clinical stage (cT1c: 79.5% vs 55.5%, P < 0.001) and organ‐confined tumours (78.3% vs 61.3%, P= 0.003), but there was no significant difference in initial biopsy core number (8.3 vs 8.7, P= 0.373).
• ? Five‐year biochemical recurrence‐free and progression‐free survival rates did not show significant differences between the two groups (88.8% vs 82.2%, P= 0.078; 100.0% vs 96.5%, P= 0.105, respectively), and these results were not affected by the number of cores taken at initial biopsy.

CONCLUSIONS

• ? Although prostate cancer diagnosed after repeat biopsies was related to better pathological outcomes after radical prostatectomy, the number of previous biopsies did not predict disease recurrence.
• ? Moreover, the number of cores taken at initial biopsy did not affect these associations.

     

Laparoscopic partial nephrectomy for multiple tumours: feasibility and analysis of peri-operative outcomes

Study Type – Therapy (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? Laparoscopic nephron‐sparing procedures have been increasingly utilized. However, in the presence of multiple tumours the procedure choice is usually shifted to radical nephrectomy. In view of favourable perioperative outcomes, the benefits of minimally‐invasive, nephron‐sparing surgery in experienced hands could be safely extended to patients presenting with multiple ipsilateral renal masses.

OBJECTIVE

• ? To describe our experience with laparoscopic partial nephrectomy (LPN) for multiple kidney tumours and compare the outcomes with LPN performed for single masses.

PATIENTS AND METHODS

• ? Retrospective analysis of medical records of patients undergoing LPN at our institution between 2005 and 2009 was performed.
• ? The cohort was divided in two groups based on tumour focality: group 1, LPN for a single tumour (n= 99) and group 2, LPN for multiple ipsilateral tumours (n= 12).
• ? The groups were compared with regards to demographic and peri‐operative variables.

RESULTS

• ? Demographic variables were not different between the groups. Median dominant tumour size was 3.1 cm (interquartile range [IQR] 2.4–4.0) and 4.0 cm (2.3–5.9) in groups 1 and 2, respectively.
• ? Median secondary tumour size in group 2 was 1.0 cm (1.0–1.8).
• ? Operative times were longer in group 2 compared with group 1 (220 vs 160 min, P= 0.009).
• ? Warm ischaemia times (WIT) (23 vs 22 min) and estimated blood loss (EBL) (100 vs 85 mL) were similar.

CONCLUSIONS

• ? LPN is a viable option for the treatment of multiple ipsilateral renal tumours.
• ? Peri‐operative outcomes are similar to standard LPN with the exception of longer operative time.
• ? In experienced hands, the advantages of minimally invasive surgery may be extended to select patients with ipsilateral multifocal renal tumours.

     

Phase II escalation study of sorafenib in patients with metastatic renal cell carcinoma who have been previously treated with anti-angiogenic treatment

Study Type – Therapy (individual cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Sorafenib is an oral receptor tyrosine kinase inhibitor that inhibits RAF serine/threonine kinases and receptor tyrosine kinases (vascular endothelial growth factor receptors 1, 2, 3 and platelet‐derived growth factor‐beta, Flt‐3 and c‐kit) that are implicated in tumourigenesis and tumour progression. Sorafenib is approved for the treatment of advanced renal cell cancer. B‐RAF mutations (V600E and K601E) may be interesting negative predictive markers in metastatic kidney cancer patients treated with Sorafenib. Larger trials are needed to validate this hypothesis and should include B‐RAF molecular analysis for better patient selection.

OBJECTIVE

• ? To assess both clinical and biological efficacy and toxicity of sorafenib in patients with metastatic renal cell carcinoma (mRCC) previously treated with an anti‐angiogenic vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor.

METHODS

• ? Sorafenib is an orally active multikinase inhibitor approved for the treatment of mRCC.
• ? Drug‐focused translational research on tissues (i.e. B‐RAF) and plasma (VEGFR‐α, circulating endothelial cells, endothelial progenitor cells) was performed to define biological predictive and prognostic markers and their related kinetics.
• ? Patients with mRCC pretreated with an anti‐angiogenic treatment, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2 and adequate organ function were eligible.
• ? Patients received sorafenib 400 mg twice a day continuously in 4‐week cycles. Patients with no progressive disease at 12 weeks continued to receive sorafenib at the standard dose, whereas progressing patients received an increased dose (600 mg twice a day) with early disease restaging after 4 weeks. Patients who progressed at 600 mg twice a day went off study. Efficacy (overall tumour control) was assessed by Response Evaluation Criteria in Solid Tumors.

RESULTS

• ? In all, 19 patients were entered. The baseline characteristics were as follows: ECOG PS 0–1 94.8%; median (range) age 62 (41–81) years; nephrectomy 100%; surgery for metastatic disease 26.4%; clear cell 79.1%; papillary cell 15.7%; sarcomatoid/high grade 5.2%; two or more metastatic sites 84%.
• ? Overall, 11 patients (58%) had disease control at 6 months without significant correlation between response to prior therapy and hypertension. Progression‐free survival (PFS) of 8.3 months was observed.
• ? Of six patients for whom the dose was escalated due to early progression, three benefitted with PFS of >3 months. Three (15.7%) of 19 patients had a V600E mutation and one had a K601E mutation; PFS appeared to be substantially shorter in these patients compared with 15 patients with wild‐type B‐RAF (2.5 vs 9.1 month, P < 0.05).
• ? The most common toxicity (National Cancer Institute Common Toxicity Criteria, NCIC 3.0, all patients) was grade ≥1 diarrhoea and grade 2–3 hand–foot syndrome in 11 patients. Grade 3 mucositis was observed in one patient.

CONCLUSIONS

• ? Sorafenib at doses of 400–600 mg twice a day continuously results in acceptable and well tolerated salvage treatment after VEGFR tyrosine kinase inhibitor failure.
• ? In progressive patients, treatment with a higher dose could be a valid option and B‐RAF mutations may be an interesting predictive marker to be studied in a larger randomized trial.

     

Partial nephrectomy in two patients with known T3a tumours involving the renal vein

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Although nephron‐sparing surgery (NSS) has became accepted therapy for T1 tumours, radical nephrectony is considered the best therapy for T3a tumours involving the renal vein. NSS can be considered in T3a or greater tumours if imperative indications exist, such as bilateral disease or solitary kidney. However, there is little published data on the characteristics of these patients, the impact of surgery on their renal function, and long‐term oncologic outcomes. This study profiles single‐institution experience with nephron‐sparing surgery for known T3a tumours involving the renal vein, including patient characteristics, tumour characteristics, preoperative and follow‐up imaging, preoperative and follow‐up estimated glomerular filtration rate, length of temporary postoperative haemodialysis, and oncologic outcome. Additionally, we compare this to other published data on nephron‐sparing surgery for similar tumors.

OBJECTIVE

• ? To present two patients with T3a tumours involving the renal vein who underwent nephron‐sparing surgery (NSS) for imperative reasons.

PATIENTS AND METHODS

• ? Retrospective chart review of patients who underwent NSS for renal cell carcinoma (RCC) with known renal vein tumour thrombus (RVTT).
• ? Both patients underwent open partial nephrectomy and renal vein thrombectomy of a solitary kidney.
• ? Primary outcomes of the study include radiographic evidence of recurrence, haemodialysis requirement and estimated glomerular filtration rate (eGFR) before and after surgery.

RESULTS

• ? Patient 1 is 24 months from NSS and has no evidence of recurrence based on CT scan. His final pathology revealed a 9‐cm, T3a, clear cell, Fuhrman grade II carcinoma. He spent 42 days on haemodialysis and is now off all dialysis. His preoperative and most recent eGFR are 48 and 23 mL/min/1.73 m² based on the Modification of Diet in Renal Disease (MDRD) equation and 69.4 and 29.8 mL/min by the Cockcroft–Gault equation.
• ? Patient 2 is 9 months from NSS and has no evidence of recurrence based on CT scan. Her final pathology revealed a 6‐cm, T3a, clear cell, Fuhrman grade II–III carcinoma. She spent 30 days on haemodialysis and is now off all dialysis. Her preoperative and most recent eGFR are 58 and 30 mL/min/1.73 m² based on the MDRD equation and 62.2 and 32.8 mL/min by the Cockcroft–Gault equation.

CONCLUSION

• ? Based on our review, preservation of renal function and favourable oncological outcome can be accomplished with NSS in patients with known stage T3a RCC with RVTT and should be considered in carefully selected patients.