Harras B. Zaid

Identification of Site-specific Recurrence Following Primary Radiation Therapy for Prostate Cancer Using C-11 Choline Positron Emission Tomography/Computed Tomography: A Nomogram for Predicting Extrapelvic Disease

BACKGROUND Management of recurrent prostate cancer (CaP) after radiotherapy (RT) is dependent on accurate localization of the site of recurrent disease. OBJECTIVE To describe the anatomic patterns and clinical features associated with CaP recurrence following RT identified on advanced imaging. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of 184 patients with a rising prostate-specific antigen (PSA) after RT for CaP. INTERVENTION C-11 choline positron emission tomography/computed tomography (CholPET). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Recurrence patterns were classified as pelvic soft tissue only (as a surrogate for potentially salvageable disease) versus any extrapelvic disease, and clinical features were compared between patterns. Multivariable logistic regression was used to generate a predictive nomogram for extrapelvic recurrence. Discrimination was assessed with a c-index. RESULTS AND LIMITATIONS Recurrence site was identified in 161 (87%) patients, with 95 (59%) sites histologically confirmed. Factors associated with the detection of recurrence included the difference between PSA nadir and PSA at CholPET (odds ratio: 1.30, p<0.01) and National Comprehensive Cancer Network high-risk classification (odds ratio: 10.83, p=0.03). One hundred (54.3%) patients recurred in the pelvic soft tissue only, while 61 (33%) had extrapelvic recurrence. Of 21 patients who underwent CholPET prior to meeting the Phoenix criteria of biochemical failure, 15 (71%) had recurrence identified on CholPET with 11 localized to the pelvis. On multivariable analysis, the difference between PSA nadir and PSA at CholPET, time from RT, and National Comprehensive Cancer Network risk group were predictive of recurrence outside of the pelvis, and a nomogram was generated with a c-index of 0.79. CONCLUSIONS CholPET identified the site of recurrence in 87% of patients with a rising PSA after RT; most commonly within the pelvis in potentially salvageable locations. A predictive nomogram was generated, and pending external validation, this may aid in assessing the risk of disease beyond the pelvis. These findings underscore the importance of advanced imaging when considering management strategies for patients with a rising PSA following primary RT. PATIENT SUMMARY We identified anatomic patterns of recurrence in patients with a rising prostate-specific antigen after radiotherapy using C-11 choline positron emission tomography/computed tomography. Most recurrences were localized to the pelvis and we were able to generate a tool to aid in disease localization prior to evaluation with advanced imaging.

Contemporary Mapping of Post-Prostatectomy Prostate Cancer Relapse with 11C-Choline Positron Emission Tomography and Multiparametric Magnetic Resonance Imaging

Purpose: We identify sites and patterns of cancer recurrence in patients with post‐prostatectomy biochemical relapse using 11C‐choline positron emission tomography/computerized tomography and endorectal coil multiparametric magnetic resonance imaging. Materials and Methods: Between January 2008 and June 2015, 2,466 men underwent choline positron emission tomography for suspected prostate cancer relapse at our institution. Of these men 202 did not receive hormone or radiation therapy, underwent imaging with choline positron emission tomography and multiparametric magnetic resonance imaging, and were found to have disease recurrence. Overall patterns of recurrence were described, and factors associated with local only recurrence were evaluated using univariable and multivariable logistic regression. Results: Median prostate specific antigen at positive scan was 2.3 ng/ml (IQR 1.4–5.5) with a median time from prostate specific antigen relapse to lesion visualization of 15 months (IQR 4.8–34.2). Of these 202 men 68 (33%) exhibited local only, 45 (22%) local plus metastatic and 89 (45%) metastatic only relapse. Pelvic node only relapse was observed in 39 (19%) men. Median prostate specific antigen at positive imaging for patients with local only, metastatic only and local plus metastatic relapse was 2.3, 2.7 and 2.2 ng/ml (p=0.46), with a median interval from biochemical recurrence to positive scan of 33.5, 7.0 and 15.0 months, respectively (p <0.001). On multivariable analysis time from biochemical recurrence to positive imaging was independently associated with local only recurrence (OR 1.10 for every 6‐month increase, p=0.012). Conclusions: Combined choline positron emission tomography and multiparametric magnetic resonance imaging evaluation of biochemical recurrence after prostatectomy reveals an anatomically diverse pattern of recurrence. These findings have implications for optimizing the salvage treatment of patients with prostate cancer with relapse following surgery.

Outcomes Following Complete Surgical Metastasectomy for Patients with Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

Purpose: The benefit of complete surgical metastasectomy for patients with metastatic renal cell carcinoma remains controversial due to limited outcome data. We performed a systematic review and meta‐analysis to determine whether complete surgical metastasectomy confers a survival benefit compared to incomplete or no metastasectomy for patients with metastatic renal cell carcinoma. Materials and Methods: Ovid Embase®, MEDLINE®, Cochrane and Scopus® databases were searched for studies evaluating complete surgical metastasectomy for metastatic renal cell carcinoma through January 19, 2016. Only comparative studies reporting adjusted hazard ratios (aHRs) for all cause mortality of incomplete surgical metastasectomy vs complete surgical metastasectomy were included in the analysis. Generic inverse variance with random effects models was used to determine the pooled aHR. Risk of bias was assessed with the Newcastle‐Ottawa Scale. Results: Eight published cohort studies with a low or moderate potential for bias were included in the final analysis. The studies reported on a total of 2,267 patients (958 undergoing complete surgical metastasectomy and 1,309 incomplete surgical metastasectomy). Median overall survival ranged between 36.5 and 142 months for those undergoing complete surgical metastasectomy, compared to 8.4 to 27 months for incomplete surgical metastasectomy. Complete surgical metastasectomy was associated with a reduced risk of all cause mortality compared with incomplete surgical metastasectomy (pooled aHR 2.37, 95% CI 2.03–2.87, p <0.001), with low heterogeneity (I2 = 0%). Complete surgical metastasectomy remained independently associated with a reduction in mortality across a priori subgroup and sensitivity analyses, and regardless of whether we adjusted for performance status. Conclusions: Complete surgical metastasectomy for metastatic renal cell carcinoma is associated with improved survival compared with incomplete surgical metastasectomy based on meta‐analysis of observational data. Consideration should be given to performing complete surgical metastasectomy, when technically feasible, in patients with metastatic renal cell carcinoma who are surgical candidates.

Application of the Stage, Size, Grade, and Necrosis (SSIGN) Score for Clear Cell Renal Cell Carcinoma in Contemporary Patients

BACKGROUND The tumor stage, size, grade, and necrosis (SSIGN) score was originally defined using patients treated with radical nephrectomy (RN) between 1970 and 1998 for clear cell renal cell carcinoma (ccRCC), excluding patients treated with partial nephrectomy (PN). OBJECTIVE To characterize the original SSIGN score cohort with longer follow-up and evaluate a contemporary series of patients treated with RN and PN. DESIGN, SETTING, AND PARTICIPANTS Retrospective single-institution review of 3600 consecutive surgically treated ccRCC patients grouped into three cohorts: original RN, contemporary (1999-2010) RN, and contemporary PN. INTERVENTION RN or PN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The association of the SSIGN score with risk of death from RCC was assessed using a Cox proportional hazards regression model, and predictive ability was summarized with a C-index. RESULTS AND LIMITATIONS The SSIGN scores differed significantly between the original RN, contemporary RN, and contemporary PN cohorts (p<0.001), with SSIGN ≥4 in 53.5%, 62.7%, and 4.7%, respectively (p<0.001). The median durations of follow-up for these groups were 20.1, 9.2, and 7.6 yr, respectively. Each increase in the SSIGN score was predictive of death from RCC (hazard ratios [HRs]: 1.41 for original RN, 1.37 for contemporary RN, and 1.70 for contemporary PN; all p<0.001). The C-indexes for these models were 0.82, 0.84, and 0.82 for original RN, contemporary RN, and contemporary PN, respectively. After accounting for an era-specific improvement in survival among RN patients (HR: 0.53 for contemporary vs original RN; p<0.001), the SSIGN score remained predictive of death from RCC (HR: 1.40; p<0.001). CONCLUSIONS The SSIGN score remains a useful prediction tool for patients undergoing RN with 20-yr follow-up. When applied to contemporary RN and PN patients, the score retained strong predictive ability. These results should assist in patient counseling and help guide surveillance for ccRCC patients treated with RN or PN. PATIENT SUMMARY We evaluated the validity of a previously described tool to predict survival following surgery in contemporary patients with kidney cancer. We found that this tool remains valid even when extended to patients significantly different than were initially used to create the tool.

Characterization of perioperative infection risk among patients undergoing radical cystectomy: Results from the national surgical quality improvement program.

OBJECTIVES To evaluate the incidence, risk factors, and timing of infections following radical cystectomy (RC). METHODS The American College of Surgeons National Surgical Quality Improvement Project database was queried to identify patients undergoing RC for bladder cancer from 2006 to 2013. Characteristics including year of surgery, age, sex body mass index, diabetes, smoking, renal function, steroid usage, preoperative albumin, preoperative hematocrit, perioperative blood transfusion (PBT), and operative time were assessed for association with the risk of infection within 30 days of RC using multivariable logistic regression. RESULTS A total of 3,187 patients who had undergone RC were identified, of whom 766 (24.0%) were diagnosed with a postoperative infection, at a median of 13 days (interquartile ranges 8-19) after RC. Infections included surgical site infection (SSI) (404; 12.7%), sepsis/septic shock (405; 12.7%), and urinary tract infection (UTI) (309; 9.7%). On multivariable analysis, body mass index≥30kg/m2 (odds ratios [OR] = 1.52; P<0.01), receipt of a PBT (OR = 1.27; P<0.01), and operative time≥480 minutes (OR = 1.72; P<0.01) were significantly associated with the risk of infection. When the outcomes of UTI, SSI, and sepsis were analyzed separately, operative time≥480 minutes remained independently associated with increased infection risk in each model (OR = 2.11 for UTI, OR = 1.63 for SSI, and OR = 1.80 for sepsis/septic shock; all P<0.05), whereas PBT was associated with SSI and sepsis/septic shock (OR = 1.33 and OR = 1.29, respectively; both P< 0.05). CONCLUSIONS Approximately 25% of patients undergoing RC experience an infection within 30 days of surgery. Several potentially modifiable risk factors for infection were identified, specifically PBT and prolonged operative time, which may represent opportunities for future care improvement.

Predicting Oncologic Outcomes in Renal Cell Carcinoma After Surgery

BACKGROUND Predicting oncologic outcomes is important for patient counseling, clinical trial design, and biomarker study testing. OBJECTIVE To develop prognostic models for progression-free (PFS) and cancer-specific survival (CSS) in patients with clear cell renal cell carcinoma (ccRCC), papillary RCC (papRCC), and chromophobe RCC (chrRCC). DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort review of the Mayo Clinic Nephrectomy registry from 1980 to 2010, for patients with nonmetastatic ccRCC, papRCC, and chrRCC. INTERVENTION Partial or radical nephrectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PFS and CSS from date of surgery. Multivariable Cox proportional hazards regression was used to develop parsimonious models based on clinicopathologic features to predict oncologic outcomes and were evaluated with c-indexes. Models were converted into risk scores/groupings and used to predict PFS and CSS rates after accounting for competing risks. RESULTS AND LIMITATIONS A total of 3633 patients were identified, of whom 2726 (75%) had ccRCC, 607 (17%) had papRCC, and 222 (6%) had chrRCC. Models were generated for each histologic subtype and a risk score/grouping was developed for each subtype and outcome (PFS/CSS). For PFS, the c-indexes were 0.83, 0.77, and 0.78 for ccRCC, papRCC, and chrRCC, respectively. For CSS, c-indexes were 0.86 and 0.83 for ccRCC and papRCC. Due to only 22 deaths from RCC, we did not assess a multivariable model for chrRCC. Limitations include the single institution study, lack of external validation, and its retrospective nature. CONCLUSIONS Using a large institutional experience, we generated specific prognostic models for oncologic outcomes in ccRCC, papRCC, and chrRCC that rely on features previously shown-and validated-to be associated with survival. These updated models should inform patient prognosis, biomarker design, and clinical trial enrollment. PATIENT SUMMARY We identified routinely available clinical and pathologic features that can accurately predict progression and death from renal cell carcinoma following surgery. These updated models should inform patient prognosis, biomarker design, and clinical trial enrollment.

Evaluation of beta-blockers and survival among hypertensive patients with renal cell carcinoma

OBJECTIVES Beta-blocker use is associated with improved survival for multiple nonurologic malignancies. Our objective was to evaluate the association between beta-blocker use and survival among surgically managed hypertensive patients with clear-cell renal cell carcinoma (ccRCC). METHODS Hypertensive patients with ccRCC treated with either radical or partial nephrectomy between 2000 and 2010 were identified from our Nephrectomy Registry. Beta-blocker use within 90 days before surgery was identified. The associations between beta-blocker use and risk of disease progression, death from renal cell carcinoma (RCC), and all-cause mortality were assessed using Cox proportional hazards regression models. RESULTS In total, 913 hypertensive patients were identified who underwent either partial or radical nephrectomy for ccRCC. Of these, 104 (11%) had documented beta-blocker use within 90 days before surgery. At last follow-up (median 8.2y among survivors), 258 patients showed progression (median 1.6y following surgery), and 369 patients had died (median 4.1y following surgery), including 138 who died of RCC. After adjusting for PROG (progression-free survival) and SSIGN (cancer-specific survival) scores, beta-blocker use was not significantly associated with the risk of disease progression (hazard ratio [HR] = 0.94; 95% CI: 0.61-1.47; P = 0.80) or the risk of death from RCC (HR = 0.74; 95% CI: 0.38-1.41; P = 0.35). Similarly, on multivariable analysis adjusting for clinicopathologic features, there was not a significant association between beta-blocker use and the risk of all-cause mortality (HR = 0.83; 95% CI: 0.59-1.16; P = 0.27). CONCLUSIONS Beta-blocker use for hypertension within 90 days before surgery was not associated with the risk of progression, death from RCC, or death from any cause.

Patient factors associated with 30-day complications after partial nephrectomy: A contemporary update

INTRODUCTION Patient-level factors associated with perioperative complications after partial nephrectomy (PN) have not been well described in a contemporary series. METHODS Single-institution retrospective study evaluating patients undergoing open, laparoscopic, and robotic PN between 2001 and 2012. Univariable and multivariable logistic regression models were evaluated to assess factors associated with complications within 30 days of surgery. RESULTS We identified 1,763 patients who underwent 1,773 PNs between 2001 and 2012. From 2001 to 2006, 766 PNs were performed (85% open, 15% laparoscopic, and<1% robotic); in contrast, from 2007 to 2012, 1,007 PNs were performed (75% open, 8% laparoscopic, and 17% robotic); P<0.001. Overall, 241 (14%) PNs resulted in an early surgical complication. Patients undergoing a minimally invasive approach had smaller tumors (P<0.001), were less likely to have a solitary kidney (P<0.001), and had a lower Charlson score (P = 0.004). On multivariable analysis, factors independently associated with an increased risk of any complication included male sex (odds ratio [OR] = 1.40), solitary kidney (OR = 1.71), estimated glomerular filtration rate (OR = 2.89 for estimated glomerular filtration rate<30), Charlson score (OR = 1.97 for Charlson score≥3), and tumor size (OR = 1.12 for each 1-cm increase in tumor size); meanwhile, laparoscopic and robotic approaches were associated with a lower risk for complication (OR = 0.017 and 0.016, respectively), all P< 0.05. CONCLUSION Several patient-level factors are associated with 30-day complications after PN, regardless of surgical approach. These data may inform counseling before PN, including potential identification and selection of high-risk surgical candidates for percutaneous ablative approaches.

Long-Term Renal Function Recovery following Radical Nephrectomy for Kidney Cancer: Results from a Multicenter Confirmatory Study

Purpose: We sought to confirm the findings from a previous single institution study of 572 patients from Memorial Sloan Kettering Cancer Center in which we found that 49% of patients recovered to the preoperative estimated glomerular filtration rate within 2 years following radical nephrectomy for renal cell carcinoma. Materials and Methods: A multicenter retrospective study was performed in 1,928 patients using data contributed from 3 independent centers. The outcome of interest was postoperative recovery to the preoperative estimated glomerular filtration rate. Data were analyzed using cumulative incidence and competing risks regression with death from any cause treated as a competing event. Results: This study demonstrated that 45% of patients had recovered to the preoperative estimated glomerular filtration rate by 2 years following radical nephrectomy. Furthermore, this study confirmed that recovery of renal function differed according to preoperative renal function such that patients with a lower preoperative estimated glomerular filtration rate had an increased chance of recovery. This study also suggested that larger tumor size and female gender were significantly associated with an increased chance of renal function recovery. Conclusions: In this multicenter retrospective study we confirmed that in the long term a large proportion of patients recover to preoperative renal function following radical nephrectomy for kidney tumors. Recovery is more likely among those with a lower preoperative estimated glomerular filtration rate.

A House Divided: The Irradiation Versus Prostatectomy Debate Continues

We read with interest the recent Red Journal article “Radical Prostatectomy Versus Radiation and Androgen Deprivation Therapy for Clinically Localized Prostate Cancer: How Good Is the Evidence?” by Roach et al (1). This was a thoughtful and critical analysis of the complex literature relating to irradiation versus prostatectomy in men with localized prostate cancer. Overall, the authors assigned low reliability scores to many of the studies evaluated, citing an inadequate (or unreported) duration of androgen deprivation therapy (ADT) with radiation therapy for intermediateor high-risk disease, unadjusted survival metrics, or incomplete reporting of patient or disease features. They concluded that many published studies are not adequate to answer the question of whether prostatectomy or radiation therapy is preferred. In contrast, a systematic review and meta-analysis conducted by Wallis et al (2) in 2016 on this same subject included only those studies (19 total) that reported adjusted hazard ratios for overall survival or cancer-specific survival, thereby (at least partly) accounting for differences in baseline disease characteristics and patient comorbidity. The meta-analysis suggested that pooled adjusted hazard ratios for overall mortality and cancerspecific mortality were 1.63 and 2.08, respectively (both P<.05), favoring surgery over irradiation. These 2 articles are just a pair among many that highlight the discordant literature on the subject of “best” treatment of localized prostate cancer. It is especially challenging to evaluate retrospective institutional and registry-based studies with all their inherent flaws including