Roberto Bertini

Positive Surgical Margin Appears to Have Negligible Impact on Survival of Renal Cell Carcinomas Treated by Nephron-Sparing Surgery

BACKGROUND The occurrence of positive surgical margins (PSMs) after partial nephrectomy (PN) is rare, and little is known about their natural history. OBJECTIVE To identify predictive factors of cancer recurrence and related death in patients having a PSM following PN. DESIGN, SETTING, AND PARTICIPANTS Some 111 patients with a PSM were identified from a multicentre retrospective survey and were compared with 664 negative surgical margin (NSM) patients. A second cohort of NSM patients was created by matching NSM to PSM for indication, tumour size, and tumour grade. MEASUREMENTS PSM and NSM patients were compared using student t tests and chi-square tests on independent samples. A Cox proportional hazards regression model was used to test the independent effects of clinical and pathologic variables on survival. RESULTS AND LIMITATIONS Mean age at diagnosis was 61+/-12.5 yr. Mean tumour size was 3.5+/-2 cm. Imperative indications accounted for 39% (43 of 111) of the cases. Some 18 patients (16%) underwent a second surgery (partial or total nephrectomy). With a mean follow-up of 37 mo, 11 patients (10%) had recurrences and 12 patients (11%) died, including 6 patients (5.4%) who died of cancer progression. Some 91% (10 of 11) of the patients who had recurrences and 83% of the patients (10 of 12) who died belonged to the group with imperative surgical indications. Rates of recurrence-free survival, of cancer-specific survival, and of overall survival were the same among NSM patients and PSM patients. The multivariable Cox model showed that the two variables that could predict recurrence were the indication (p=0.017) and tumour location (p=0.02). No other variable, including PSM status, had any effect on recurrence. None of the studied parameters had any effect on the rate of cancer-specific survival. CONCLUSIONS PSM status occurs more frequently in cases in which surgery is imperative and is associated with an increased risk of recurrence, but PSM status does not appear to influence cancer-specific survival. Additional follow-up is needed.

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.

Impact of Lymph Node Dissection on Cancer Specific Survival in Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy

PURPOSE We examined the impact of lymphadenectomy on the clinical outcomes of patients with upper tract urothelial cancer treated with radical nephroureterectomy. MATERIALS AND METHODS Data were collected on 1,130 consecutive patients with pT1-4 upper tract urothelial cancer treated with radical nephroureterectomy at 13 centers worldwide. Patients were grouped according to nodal status (pN0 vs pNx vs pN+). The choice to perform lymphadenectomy was determined by the treating surgeon. All pathology slides were reevaluated by dedicated genitourinary pathologists. Univariable and multivariable Cox regression models measured the association of nodal status (pN0 vs pNx vs pN+) with cancer specific survival. RESULTS Overall 412 patients (36.5%) had pN0 disease, 578 had pNx disease (51.1%) and 140 had pN+ disease (12.4%). The 5-year cancer specific survival estimate was lower in patients with pN+ compared to those with pNx disease (35% vs 69%, p <0.001), which in turn was lower than that in those with pN0 disease (69% vs 77%, p = 0.024). In the subgroup of patients with pT1 disease (345) cancer specific survival rates were not different in those with pN0 and pNx. In pT2-4 cases (813) cancer specific survival estimates were lowest in pN+, intermediate in pNx and highest in pN0 (33% vs 58% vs 70%, p = 0.017). When adjusted for the effects of standard clinicopathological features pN+ was an independent predictor of cancer specific survival (p <0.001). pNx was significantly associated with worse prognosis than pN0 in pT2-4 upper tract urothelial cancer only. CONCLUSIONS Nodal status is a significant predictor of cancer specific survival in upper tract urothelial cancer. pNx is significantly associated with a worse prognosis than pN0 in pT2-4 tumors. Patients expected to have pT2-4 disease should undergo lymphadenectomy to improve staging and thereby help guide decision making regarding adjuvant chemotherapy.

Validation of the 2009 TNM Version in a Large Multi-Institutional Cohort of Patients Treated for Renal Cell Carcinoma: Are Further Improvements Needed?

BACKGROUND A new edition of the TNM was recently released that includes modifications for the staging system of kidney cancers. Specifically, T2 cancers were subclassified into T2a and T2b (< or =10 cm vs >10 cm), tumors with renal vein involvement or perinephric fat involvement were classified as T3a cancers, and those with adrenal involvement were classified as T4 cancers. OBJECTIVE Our aim was to validate the recently released edition of the TNM staging system for primary tumor classification in kidney cancer. DESIGN, SETTING, AND PARTICIPANTS Our multicenter retrospective study consisted of 5339 patients treated in 16 academic Italian centers. INTERVENTION Patients underwent either radical or partial nephrectomy. MEASUREMENTS Univariable and multivariable Cox regression models addressed cancer-specific survival (CSS) after surgery. RESULTS AND LIMITATIONS In the study, 1897 patients (35.5%) were classified as pT1a, 1453 (27%) as pT1b, 437 (8%) as pT2a, 153 (3%) as pT2b, 1059 (20%) as pT3a, 117 (2%) as pT3b, 26 (0.5%) as pT3c, and 197 (4%) as pT4. At a median follow-up of 42 mo, 786 (15%) had died of disease. In univariable analysis, patients with pT2b and pT3a tumors had similar CSS, as did patients with pT3c and pT4 tumors. Moreover, both pT3a and pT3b stages included patients with heterogeneous outcomes. In multivariable analysis, the novel classification of the primary tumor was a powerful independent predictor of CSS (p for trend <0.0001). However, the substratification of pT1 tumors did not retain an independent predictive role. The major limitations of the study are retrospective design, lack of central pathologic review, and the small number of patients included in some substages. CONCLUSIONS The recently released seventh edition of the primary tumor staging system for kidney tumors is a powerful predictor of CSS. However, some of the substages identified by the classification have overlapping prognoses, and other substages include patients with heterogeneous outcomes. The few modifications included in this edition may have not resolved the most critical issues in the previous version.

Long-term Outcomes of Salvage Lymph Node Dissection for Clinically Recurrent Prostate Cancer: Results of a Single-institution Series with a Minimum Follow-up of 5 Years

BACKGROUND Prostate cancer (PCa) patients with lymph node recurrence after radical prostatectomy (RP) are usually managed with androgen-deprivation therapy. Despite the absence of prospective randomized studies, salvage lymph node dissection (LND) has been proposed as an alternative treatment option. OBJECTIVE To examine long-term outcomes of salvage LND in patients with nodal recurrent PCa documented by 11C-choline positron emission tomography/computed tomography (PET/CT) scan. DESIGN, SETTING, AND PARTICIPANTS Overall, 59 patients affected by biochemical recurrence (BCR) with 11C-choline PET/CT scan with pathologic activity treated between 2002 and 2008 were included. INTERVENTION Pelvic and/or retroperitoneal salvage LND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES Biochemical response (BR) was defined as prostate-specific antigen (PSA) <0.2 ng/ml at 40 d after surgery. BCR for those who achieved BR was defined as a PSA >0.2 ng/ml. Clinical recurrence (CR) was defined as a positive PET/CT scan after salvage LND in the presence of a rising PSA. Kaplan-Meier curves assessed time to BCR, CR, and cancer-specific mortality (CSM). Cox regression analyses were fitted to assess predictors of CR. RESULTS AND LIMITATIONS Median follow-up after salvage LND was 81.1 mo. Overall, 35 patients (59.3%) achieved BR. The 8-yr BCR-free survival rate in patients with complete BR was 23%. Overall, the 8-yr CR- and CSM-free survival rates were 38% and 81%, respectively. In multivariable analyses evaluating preoperative variables, PSA at salvage LND represented the only predictor of CR (p=0.03). When postoperative variables were considered, BR and the presence of retroperitoneal lymph node metastases were significantly associated with the risk of CR (all p ≤ 0.04). Our study is limited by the lack of a control group. CONCLUSIONS Salvage LND may represent a therapeutic option for patients with BCR after RP and nodal pathologic uptake at 11C-choline PET/CT scan. Although most patients progressed to BCR after salvage LND, roughly 40% of them experienced CR-free survival. PATIENT SUMMARY Salvage lymph node dissection may represent a therapeutic option for selected patients with nodal recurrence after radical prostatectomy. Roughly 40% of men did not show any further clinical recurrence at long-term follow-up after surgery.

Prognostic Impact of the 2009 UICC/AJCC TNM Staging System for Renal Cell Carcinoma with Venous Extension

BACKGROUND The prognostic significance of venous involvement and tumour thrombus level in renal cell carcinoma (RCC) remains highly controversial. In 2010, the American Joint Committee on Cancer (AJCC) and the Union International Centre le Cancer (UICC) revised the RCC staging system (7th edition) based on tumour thrombus level, differentiating the T stage of tumours limited to renal-vein-only involvement. OBJECTIVE We aimed to evaluate the impact of tumour thrombus extension in a multi-institutional cohort of patients. DESIGN, SETTING, AND PARTICIPANTS An international consortium of 11 institutions was established to retrospectively review a combined cohort of 1215 patients undergoing radical nephrectomy and tumour thrombectomy for RCC, including 585 patients with inferior vena cava (IVC) involvement or higher. MEASUREMENTS Predictive factors of survival, including histology, tumour thrombus level, nodal status, Fuhrman grade, and tumour size, were analysed. RESULTS AND LIMITATIONS A total of 1122 patients with complete data were reviewed. The median follow-up for all patients was 24.7 mo, with a median survival of 33.8 mo. The 5-yr survival was 43.2% (renal vein involvement), 37% (IVC below the diaphragm), and 22% with caval involvement above the diaphragm. On multivariate analysis, tumour size (hazard ratio [HR]: 1.64 [range: 1.03-2.59]; p=0.036), Fuhrman grade (HR: 2.26 [range: 1.65-3.1]; p=0.000), nodal metastasis (HR: 1.32 [range: 1.09-1.67]; p=0.005), and tumour thrombus level (HR: 2.10 [range: 1.53-3.0]; p=0.00) correlated independently with survival. CONCLUSIONS Based on analysis of the largest known cohort of patients with RCC along with IVC and atrial thrombus involvement, tumour thrombus level is an independent predictor of survival. Our findings support the changes to the latest AJCC/UICC staging system.

The extent of lymphadenectomy seems to be associated with better survival in patients with nonmetastatic upper-tract urothelial carcinoma: how many lymph nodes should be removed?

BACKGROUND The role and extent of lymphadenectomy in patients with upper-tract urothelial carcinoma (UTUC) is debated. OBJECTIVE To establish whether the number of lymph nodes (LNs) removed might be associated with better cause-specific survival in patients with UTUC. DESIGN, SETTING, AND PARTICIPANTS The study included 552 consecutive patients who underwent radical nephroureterectomy (RNU) and lymphadenectomy between 1992 and 2006. INTERVENTION Patients were treated with RNU and lymphadenectomy. MEASUREMENTS Univariable and multivariable Cox proportional hazards regression models addressed the association between the number of LNs removed and cause-specific mortality (CSM). The number of LNs removed was coded as a cubic spline to allow for nonlinear effects. Finally, the most informative cut-off for the number of removed LNs was identified. RESULTS AND LIMITATIONS In the entire population, the number of LNs removed was not associated with CSM in univariable (hazard ratio [HR]: 0.99; p=0.16) or in multivariable (HR: 0.97; p=0.12) analyses. In contrast, in the subgroup of pN0 patients (n=412), the number of LNs removed achieved the independent predictor status of CSM (HR: 0.93; p=0.02). Eight LNs removed was the most informative cut-off in predicting CSM (HR: 0.42; p=0.004). The inclusion of the variable defining dichotomously the number of removed LNs (< 8 vs > or = 8) in the base model (age, Eastern Cooperative Oncology Group performance status, pathologic stage, grade, architecture, and lymphovascular invasion) significantly increased the accuracy in predicting CSM (+1.7%; p<0.001). CONCLUSIONS The extension of the lymphadenectomy in pN0 UTUC patients seems to be associated with CSM. Longer survival was observed in patients in whom at least eight LNs had been removed.

Prognostic Value of Lymph Node Dissection in Patients with Muscle-Invasive Transitional Cell Carcinoma of the Upper Urinary Tract

OBJECTIVES To analyze the prognostic role of lymphadenectomy (LND) in patients with muscle-invasive transitional cell carcinoma (TCC) of the upper urinary tract (UUT) managed with radical surgery. METHODS From 1986 to 2003, 132 consecutive patients with muscle-invasive TCC of the UUT underwent radical surgery. LND was performed in 95 cases. Patients were stratified according to the presence of LND and lymph node (LN) status. Univariable and multivariable Cox regression models determined the effect of age, pT, grade, nodal status (pN), number of LNs removed, year of surgery, and postoperative chemotherapy on disease-free survival (DFS) and cancer-specific survival (CSS) in the overall population and in patients who underwent LND. RESULTS The actuarial 5-yr CSS in pNx patients was significantly worse than in pN0 patients (48% vs. 73%, p=0.001) and comparable to pN+ outcome (48% vs. 39%, p=0.476). In the entire population, multivariable Cox regression analyses indicated that pT and pN status were independent predictors of DFS (p=0.04, hazard ratio [HR]=1.82 and p<0.01, HR=1.34, respectively) and CSS (p<0.01, HR=2.42 and p=0.04, HR=1.32, respectively). In patients who underwent LND, the number of LNs removed was an independent predictor of DFS (p=0.03, HR=0.928) and of CSS (p=0.007, HR=0.903). The extent of LND again resulted in an independent predictor either of DFS or CSS (p=0.04, HR=0.904 and p=0.01, HR=0.867, respectively) in the subgroup of pN0 patients. CONCLUSIONS LND emerged as a strong independent predictor of DFS and CSS in patients surgically managed for a muscle-invasive TCC of the UUT.

Simple Enucleation is Equivalent to Traditional Partial Nephrectomy for Renal Cell Carcinoma: Results of a Nonrandomized, Retrospective, Comparative Study

PURPOSE The excision of the renal tumor with a substantial margin of healthy parenchyma is considered the gold standard technique for partial nephrectomy. However, simple enucleation showed excellent results in some retrospective series. We compared the oncologic outcomes after standard partial nephrectomy and simple enucleation. MATERIALS AND METHODS We retrospectively analyzed 982 patients who underwent standard partial nephrectomy and 537 who had simple enucleation for localized renal cell carcinoma at 16 academic centers between 1997 and 2007. Local recurrence, cancer specific survival and progression-free survival were the main outcomes of this study. The Kaplan-Meier method was used to calculate survival functions and differences were assessed with the log rank statistic. Univariable and multivariable Cox regression models addressed progression-free survival and cancer specific survival. RESULTS Median followup of the patients undergoing traditional partial nephrectomy and simple enucleation was 51 ± 37.8 and 54.4 ± 36 months, respectively (p = 0.08). The 5 and 10-year progression-free survival estimates were 88.9 and 82% after standard partial nephrectomy, and 91.4% and 90.8% after simple enucleation (p = 0.09). The 5 and 10-year cancer specific survival estimates were 93.9% and 91.6% after standard partial nephrectomy, and 94.3% and 93.2% after simple enucleation (p = 0.94). On multivariable analysis the adopted nephron sparing surgery technique was not an independent predictor of progression-free survival (HR 0.8, p = 0.55) and cancer specific survival (HR 0.7, p = 0.53) when adjusted for the effect of the other covariates. CONCLUSIONS To our knowledge this is the first multicenter, comparative study showing oncologic equivalence of standard partial nephrectomy and simple enucleation.

A Preoperative Prognostic Model for Patients Treated with Nephrectomy for Renal Cell Carcinoma

BACKGROUND Currently two pretreatment prognostic models with limited accuracy (65-67%) can be used to predict survival in patients with localized renal cell carcinoma (RCC). OBJECTIVE We set out to develop a more accurate pretreatment model for predicting RCC-specific mortality after nephrectomy for all stages of RCC. DESIGN, SETTING, AND PARTICIPANTS The data originated from a series of prospectively recorded contemporary cases of patients treated with radical or partial nephrectomy between 1984 and 2006. Model development was performed using data from 2474 patients from five centers and external validation was performed using data from 1972 patients from seven centers. MEASUREMENTS The probability of RCC-specific mortality was modeled using Cox regression. The significance of the predictors was confirmed using competing risks analyses, which account for mortality from other causes. RESULTS AND LIMITATIONS Median follow-up in patients who did not die of RCC-specific causes was 4.2 yr and 3.5 yr in the development and validation cohorts, respectively. The freedom from cancer-specific mortality rates in the nomogram development cohort were 75.4% at 5 yr after nephrectomy and 68.3% at 10 yr after nephrectomy. All variables except gender achieved independent predictor status. In the external validation cohort the nomogram predictions were 88.1% accurate at 1 yr, 86.8% accurate at 2 yr, 86.8% accurate at 5 yr, and 84.2% accurate at 10 yr. CONCLUSIONS Our model substantially exceeds the accuracy of the existing pretreatment models. Consequently, the proposed nomogram-based predictions may be used as benchmark data for pretreatment decision making in patients with various stages of RCC.