BACKGROUND: 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. METHODS: The original stratification, which was developed using a single-institution series, produced 3 subgroups with significantly different LF risk based on pathologic tumor (pT) classification and the number of lymph nodes identified. This model was then applied to patients in Southwest Oncology Group (SWOG) 8710, a randomized trial of RC with or without chemotherapy. LF was defined as any pelvic failure before or within 3 months of distant failure. RESULTS: Patients in the development cohort and the SWOG cohort had significantly different baseline characteristics. The original risk model was not fully validated in the SWOG cohort, because lymph node yield was not as strongly associated with LF as in the development cohort. Regression analysis indicated that margin status could improve the model. A revised stratification using pT classification, margin status, and the number of lymph nodes identified produced 3 subgroups with significantly different LF risk in both cohorts: low risk (pT2), intermediate risk (pT3 with negative margins AND 10 lymph nodes identified), and high risk (pT3 with positive margins OR <10 lymph nodes identified) with 5-year LF rates of 8%, 20%, and 41%, respectively, in the SWOG cohort and 8%, 19%, and 41%, respectively, in the development cohort. CONCLUSIONS: A model incorporating pT classification, margin status, and the number of lymph nodes identified stratified LF risk in 2 different RC populations and may inform the design of future trials. Cancer 2014;120:1272-80. V C 2014 American Cancer Society.KEYWORDS: bladder cancer, urothelial cancer, local failure, adjuvant radiation. INTRODUCTIONPatients with muscle-invasive bladder cancer who undergo radical cystectomy plus bilateral pelvic lymphadenopathy (RC) with or without the receipt of perioperative chemotherapy have an estimated 5-year overall survival rate of approximately 50%.1 Although considerable attention has been given to the problem of distant relapse after RC, approximately 33% of patients with pT3 tumors develop a recurrence within the pelvis, either as isolated locoregional failures (LF) or cosynchronous with distant metastases.2 Several organizations are now considering clinical trials to assess the impact of radiation therapy (RT) after RC. However, criteria for the selection and stratification of patients most likely to benefit from adjuvant RT in these trials have not been clearly defined. A LF risk-stratification model derived from a single-institution experience has recently been published but not externally validated. 3 The purpose of this study was to assess the validity of this LF stratification model within the Southwest Oncology Group (SWOG) 8710 datab...
Background Risk stratification is a major challenge in bladder cancer (BC), and a biomarker is needed. Multiple studies report the neutrophil-to-lymphocyte ratio (NLR) as a promising candidate; however, these analyses have methodological limitations. Therefore, we performed a category B biomarker study. We tested whether NLR is prognostic for overall survival (OS) after curative treatment or predictive for the benefit from neoadjuvant chemotherapy (NAC). Methods We performed a secondary analysis of SWOG 8710—a randomized, phase III trial that assessed cystectomy ± NAC in 317 patients with muscle-invasive BC. We calculated NLR from prospectively collected complete blood counts. We identified 230 patients for the prognostic analysis and 263 for the predictive analysis. We evaluated NLR using proportional hazards models including pre-specified factors (age, gender, T-stage, lymphovascular invasion, treatment arm). Results With a median follow-up of 18.6 years, there were 172 and 205 deaths in the prognostic and predictive cohorts, respectively. On multivariable analysis, NLR was not prognostic for OS (HR 1.04, 95%CI [0.98–1.11], P=0.24). Furthermore, NLR did not predict for the OS benefit from NAC (HR 1.01, 95%CI [0.90 – 1.14], P=0.86). Factors associated with worse OS were older age (HR 1.05, 95%CI [1.04–1.07], P<0.001) and surgery without NAC (HR 1.39, 95%CI [1.03–1.88], P=0.03). Conclusion This is the first analysis of NLR in BC to use prospectively collected clinical trial data. In contrast to previous studies, it suggests NLR is neither a prognostic nor predictive biomarker for OS in muscle-invasive BC. Trial Registration clinicaltrials.gov Identifier NCT02756637 https://clinicaltrials.gov/show/NCT02756637
Purpose/Objectives To inform prospective trials of adjuvant radiation therapy (adj-RT) for bladder cancer after radical cystectomy, a local-regional 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 impact the stratification model’s 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 due to early disease progression, death, or loss to follow-up shortly after cystectomy; bias due to different statistical methodologies 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 +/− 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. Using more stringent inclusion criteria, 26 SWOG patients (10%) and 60 (14%) from the single-institution cohort were excluded. Analysis of the remaining patients confirmed 3 subgroups with significantly different LF risk with 3-year rates of 7%, 17%, and 36%, respectively (p<0.01), 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 model’s LF estimates.
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.
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.
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