Kai Tucker

Optimizing bladder cancer locoregional failure risk stratification after radical cystectomy using SWOG 8710.

Clinical trials of radiation after radical cystectomy (RC) and chemotherapy for bladder cancer are in development, but inclusion and stratification factors have not been clearly established. In this study, the authors evaluated and refined a published risk stratification for locoregional failure (LF) by applying it to a multicenter patient cohort.

Bladder Cancer Patterns of Pelvic Failure: Implications for Adjuvant Radiation Therapy

PURPOSE Local-regional failures (LFs) after cystectomy with or without chemotherapy are common in locally advanced disease. Adjuvant radiation therapy (RT) could reduce LFs, but toxicity has discouraged its use. Modern RT techniques with improved normal tissue sparing have rekindled interest but require knowledge of pelvic failure patterns to design treatment volumes. METHODS AND MATERIALS Five-year LF rates after radical cystectomy plus pelvic node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 urothelial bladder carcinoma patients. The impact of pathologic stage, margin status, nodal involvement, and extent of node dissection on failure patterns was assessed using competing risk analysis. We calculated the percentage of patients whose sites of LF would have been completely encompassed within various hypothetical clinical target volumes (CTVs) for postoperative radiation. RESULTS Compared with stage ≤pT2, stage ≥pT3 patients had higher 5-year LF rates in virtually all pelvic sites. Among stage ≥pT3 patients, margin status significantly altered the failure pattern whereas extent of node dissection and nodal positivity did not. In stage ≥pT3 patients with negative margins, failure occurred predominantly in the iliac/obturator nodes and uncommonly in the cystectomy bed and/or presacral nodes. Of these patients in whom failure subsequently occurred, 76% would have had all LF sites encompassed within CTVs covering only the iliac/obturator nodes. In stage ≥pT3 with positive margins, cystectomy bed and/or presacral nodal failures increased significantly. Only 57% of such patients had all LF sites within CTVs limited to the iliac/obturator nodes, but including the cystectomy bed and presacral nodes in the CTV when margins were positive increased the percentage of LFs encompassed to 91%. CONCLUSIONS Patterns of failure within the pelvis are summarized to facilitate design of adjuvant RT protocols. These data suggest that RT should target at least the iliac/obturator nodes in stage ≥pT3 with negative margins; coverage of the presacral nodes and cystectomy bed may be necessary for stage ≥pT3 with positive margins.

Occult Pelvic Lymph Node Involvement in Bladder Cancer: Implications for Definitive Radiation

PURPOSE To inform radiation treatment planning for clinically staged, node-negative bladder cancer patients by identifying clinical factors associated with the presence and location of occult pathologic pelvic lymph nodes. METHODS AND MATERIALS The records of patients with clinically staged T1-T4N0 urothelial carcinoma of the bladder undergoing radical cystectomy and pelvic lymphadenectomy at a single institution were reviewed. Logistic regression was used to evaluate associations between preoperative clinical variables and occult pathologic pelvic or common iliac lymph nodes. Percentages of patient with involved lymph node regions entirely encompassed within whole bladder (perivesicular nodal region), small pelvic (perivesicular, obturator, internal iliac, and external iliac nodal regions), and extended pelvic clinical target volume (CTV) (small pelvic CTV plus common iliac regions) were calculated. RESULTS Among 315 eligible patients, 81 (26%) were found to have involved pelvic lymph nodes at the time of surgery, with 38 (12%) having involved common iliac lymph nodes. Risk of occult pathologically involved lymph nodes did not vary with clinical T stage. On multivariate analysis, the presence of lymphovascular invasion (LVI) on preoperative biopsy was significantly associated with occult pelvic nodal involvement (odds ratio 3.740, 95% confidence interval 1.865-7.499, P<.001) and marginally associated with occult common iliac nodal involvement (odds ratio 2.307, 95% confidence interval 0.978-5.441, P=.056). The percentages of patients with involved lymph node regions entirely encompassed by whole bladder, small pelvic, and extended pelvic CTVs varied with clinical risk factors, ranging from 85.4%, 95.1%, and 100% in non-muscle-invasive patients to 44.7%, 71.1%, and 94.8% in patients with muscle-invasive disease and biopsy LVI. CONCLUSIONS Occult pelvic lymph node rates are substantial for all clinical subgroups, especially patients with LVI on biopsy. Extended coverage of pelvic lymph nodes up to the level of the common iliac nodes may be warranted in subsets of patients.

Neutrophil-to-lymphocyte ratio as a bladder cancer biomarker: Assessing prognostic and predictive value in SWOG 8710

Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies have reported the neutrophil‐to‐lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, the authors performed a category B biomarker study to test whether NLR is prognostic for overall survival (OS) after curative treatment or is predictive for the survival benefit from neoadjuvant chemotherapy (NAC).

Validating a Local Failure Risk Stratification for Use in Prospective Studies of Adjuvant Radiation Therapy for Bladder Cancer

PURPOSE To inform prospective trials of adjuvant radiation therapy (adj-RT) for bladder cancer after radical cystectomy, a locoregional failure (LF) risk stratification was proposed. This stratification was developed and validated using surgical databases that may not reflect the outcomes expected in prospective trials. Our purpose was to assess sources of bias that may affect the stratification models validity or alter the LF risk estimates for each subgroup: time bias due to evolving surgical techniques; trial accrual bias due to inclusion of patients who would be ineligible for adj-RT trials because of early disease progression, death, or loss to follow-up shortly after cystectomy; bias due to different statistical methods to estimate LF; and subgrouping bias due to different definitions of the LF subgroups. METHODS AND MATERIALS The LF risk stratification was developed using a single-institution cohort (n=442, 1990-2008) and the multi-institutional SWOG 8710 cohort (n=264, 1987-1998) treated with radical cystectomy with or without chemotherapy. We evaluated the sensitivity of the stratification to sources of bias using Fine-Gray regression and Kaplan-Meier analyses. RESULTS Year of radical cystectomy was not associated with LF risk on univariate or multivariate analysis after controlling for risk group. By use of more stringent inclusion criteria, 26 SWOG patients (10%) and 60 patients from the single-institution cohort (14%) were excluded. Analysis of the remaining patients confirmed 3 subgroups with significantly different LF risks with 3-year rates of 7%, 17%, and 36%, respectively (P<.01), nearly identical to the rates without correcting for trial accrual bias. Kaplan-Meier techniques estimated higher subgroup LF rates than competing risk analysis. The subgroup definitions used in the NRG-GU001 adj-RT trial were validated. CONCLUSIONS These sources of bias did not invalidate the LF risk stratification or substantially change the models LF estimates.

1628 RISK STRATIFICATION FOR LOCAL-REGIONAL FAILURE AFTER CYSTECTOMY

INTRODUCTION AND OBJECTIVES: Poor nutrition status is associated with adverse outcome after radical cystectomy. Use of validated nutrition screening tools has not been advocated in a prospective fashion. We attempted to prospectively evaluate nutritional status and identify associated risks in patients undergoing Robot-Assisted Radical Cystectomy (RARC) using the Nutrition Risk Screening 2002 (NRS 2002); a validated assessment tool. We also examined nutrition-related biochemical indices and body composition percentage in this patient population over one year period. METHODS: All consecutive patients undergoing RARC at Roswell Park cancer Institute during year 2011 were offered to enroll in this prospective study. Using the NRS 2002, patients are scored for nutrition risk at baseline and are categorized as at nutrition risk or not at risk. A tanita scale is used to measure body composition. Surgical complications after surgery and laboratory values (hemoglobin, hematocrit, albumin, and total leukocytic count “TLC”) were also collected at 2 weeks, 3, 6 and 12-month intervals. RESULTS: 33 patients are currently enrolled in the study. Mean age and body mass index (BMI) are 71 years and 27.5 kg (SD: / 0.9) respectively. NRS 2002 identified 73% of the cohort to be at nutrition risk and at baseline, 46% of the cohort already had mild to severe deficits in nutritional status. In comparison to patients not at risk, those at risk were older (p .01), and had unintentional weight loss prior to surgery (p .047). Length of stay was higher in those at risk (12 days vs. 9 days) (p 0.47).Decreasing trends for weight, BMI, body composition and hemoglobin from baseline through one year post-op were present in the at risk group.(Table). CONCLUSIONS: Patients undergoing RARC present with nutritional deficiency and report unintentional weight loss indicating poor nutrition status. Patients at nutrition risk based on the NRS 2002 continue to have weight loss and worsening nutritional status during their postoperative course. Preoperative 2 WEEK 3 MONTH 6 MONTH 1 YEAR

Bladder cancer patterns of pelvic failure: Implications for adjuvant radiation therapy.

293 Background: Local-regional recurrences (LF) after radical cystectomy with or without chemotherapy are common in patients with locally advanced disease. Adjuvant radiation (RT) could reduce LF, but toxicity discouraged its use. Modern RT with reduced morbidity has rekindled interest but requires knowledge of pelvic failure patterns to design appropriate clinical target volumes. METHODS 5-yr LF rates after radical cystectomy plus pelvic lymph node dissection with or without chemotherapy were determined for 8 pelvic sites among 442 patients with urothelial carcinoma of the bladder. The impact on the pattern of failure of pathologic stage, margin status, nodal involvement, and extent of node dissection was assessed using competing risk statistical methods. The percentage of patients whose sites of LF would be completely encompassed within various hypothetical clinical target volumes for post-operative radiation were calculated. RESULTS Stage pT3-4 patients had higher 5-yr LF rates in virtually all pelvic sites compared to pT0-2 patients. Among pT3-4 patients, margin status significantly altered the pattern of failure while extent of node dissection and pathologic nodal involvement did not. Stage pT3-4 patients with negative margins failed predominantly in the iliac/obturator nodes. Failures in the cystectomy bed and presacral region were significantly higher in pT3-4 patients with positive rather than negative margins. 76% of pT3-4 patients with negative margins who failed would have had all sites of LF included within clinical target volumes encompassing the iliac/obturator nodes, but only 57% of pT3-4 patients with positive margins would have their LF sites covered by such target volumes. Including the cystectomy bed and presacral region in the clinical target volume when margins were positive increased the percentage of encompassed failures to 91%. CONCLUSIONS In adjuvant RT protocols, the obturator and iliac regions should be targeted in pT3-4 tumors with negative margins; coverage of presacral region and cystectomy bed is advised for pT3-4 with positive margins.

A novel risk stratification to predict local-regional failures in urothelial carcinoma of the bladder after radical cystectomy.

262 Background: Invasive urothelial bladder carcinoma is typically treated with radical cystectomy (RC) plus pelvic lymph node dissection (PLND) +/- chemotherapy. Local-regional failures (LF) following cystectomy are a significant problem. Adjuvant radiation therapy (RT) could potentially reduce LF but currently has no defined role because of previously reported morbidity. Modern RT techniques with improved normal tissue sparing have rekindled interest in adjuvant RT. Stratifying patients by differing LF risk could facilitate selection for adjuvant RT. METHODS From 1990-2008, 442 patients with urothelial bladder carcinoma were prospectively followed at the University of Pennsylvania after RC+PLND +/- chemotherapy with routine pelvic CT or MRI. Univariate and multivariate competing risk analyses identified subgroups with differing LF risk. RESULTS On univariate analysis, stage pT3-4, total nodes removed (<10 vs. ≥10), positive margins, positive nodes, hydronephrosis, lymphovascular invasion, and mixed histology were significant predictors of LF, while use of chemotherapy, number of positive nodes, surgical diversion type, age, gender, race, smoking history and BMI were not. Node density was a marginal predictor of LF. On multivariate analysis, only stage ≥pT3-4 and nodes removed (<10) were significant independent predictors of LF with hazard ratios of 3.17 and 2.37 respectively (p<0.01). Analysis identified 3 patient subgroups with significantly different LF risk: low-risk (pT0-2), intermediate-risk (pT3-4, ≥10 nodes), and high-risk (pT3-4, <10 nodes) with 5-year LF rates of 8%, 23%, and 42% (p <0.01). CONCLUSIONS This study of local-regional recurrence risk factors after RC is based on the largest reported, prospectively maintained patient database with routine follow-up pelvic CT surveillance. LF after RC varies significantly among different subgroups. This risk stratification model could facilitate selection for future adjuvant radiotherapy trials.