Clinical Nodal Staging Scores for Bladder Cancer: A Proposal for Preoperative Risk Assessment

EUROPEAN UROLOGY 61 (2012) 237 242 available at www.sciencedirect.com journal homepage: www.europeanurology.com Platinum Priority Bladder Cancer Editorial by Alexandre R. Zlotta on pp. 243 244 of this issue Clinical Nodal Staging Scores for Bladder Cancer: A Proposal for Preoperative Risk Assessment Shahrokh F. Shariat a,1, *, Behfar Ehdaie a,1, Michael Rink a,b, Eugene K. Cha a, Robert S. Svatek c, Thomas F. Chromecki a,d, Harun Fajkovic a,e, Giacomo Novara f, Scott G. David a, Siamak Daneshmand g, Yves Fradet h, Yair Lotan i, Arthur I. Sagalowsky i, Thomas Clozel a, Patrick J. Bastian j, Wassim Kassouf k, Hans-Martin Fritsche l, Maximilian Burger l, Jonathan I. Izawa m, Derya Tilki j, Firas Abdollah n, Felix K. Chun b, Guru Sonpavde o, Pierre I. Karakiewicz n, Douglas S. Scherr a, Mithat Gonen p a Weill Cornell Medical College, New York, NY, USA; b University Medical Center Hamburg-Eppendorf, Hamburg, Germany; c University of Texas San Antonio, San Antonio, TX, USA; d Medical University of Graz, Graz, Austria; e St. Poelten General Hospital, St. Poelten, Austria; f University of Padua, Padua, Italy; g University of Southern California, Los Angeles, CA, USA; h Laval University, Québec City, Québec, Canada; i University of Texas Southwestern Medical Center, Dallas, TX, USA; j Ludwig-Maximilians-Universität München, Klinikum Grosshadern, Munich, Germany; k McGill University Health Centre, Montréal, Québec, Canada; l Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany; m University of Western Ontario, London, Ontario, Canada; n University of Montréal, Montréal, Québec, Canada; o Baylor College of Medicine, Houston, TX, USA; p Memorial Sloan-Kettering Cancer Center, New York, NY, USA Article info Article history: Accepted October 12, 2011 Published online ahead of print on October 21, 2011 Keywords: Lymph node Radical cystectomy Prognosis Bladder cancer Urothelial carcinoma Survival Abstract Background: Radical cystectomy (RC) with pelvic lymph node dissection (LND) is the standard of care for refractory non-muscle-invasive and muscle-invasive bladder cancer. Although consensus exists on the need for LND, its extent is still debated. Objective: To develop a model that allows preoperative determination of the minimum number of lymph nodes (LNs) needed to be removed at RC to ensure true nodal status. Design, setting, and participants: We analyzed data from 4335 patients treated with RC and pelvic LND without neoadjuvant chemotherapy at 12 academic centers located in the United States, Canada, and Europe. Measurements: We estimated the sensitivity of pathologic nodal staging using a betabinomial model and developed clinical (preoperative) nodal staging scores (cnss), which represent the probability that a patient has LN metastasis as a function of the number of examined nodes. Results and limitations: The probability of missing a positive LN decreased with an increasing number of nodes examined (52% if 3 nodes were examined, 40% if 5 were examined, and 26% if 10 were examined). A cnss of 90% was achieved by examining 6 nodes for clinical Ta-Tis tumors, 9 nodes for ct1 tumors, and 25 nodes for ct2 tumors. In contrast, examination of 25 nodes provided only 77% cnss for ct3-t4 tumors. The study is limited due to its retrospective design, its multicenter nature, and a lack of preoperative staging parameters. Conclusions: Every patient treated with RC for bladder cancer needs an LND to ensure accurate nodal staging. The minimum number of examined LNs for adequate staging depends preoperatively on the clinical T stage. Predictive tools can give a preoperative estimation of the likelihood of nodal metastasis and thereby allow tailored decisionmaking regarding the extent of LND at RC. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. 1 Both authors contributed equally to the manuscript. * Corresponding author. Brady Urologic Health Center, Weill Cornell Medical College, 525 East 68th St., Box 94, Starr 900, New York, NY 10065, USA. E-mail address: sfshariat@gmail.com (S.F. Shariat). 0302-2838/$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2011.10.011

238 EUROPEAN UROLOGY 61 (2012) 237 242 1. Introduction Radical cystectomy (RC) with bilateral pelvic lymph node dissection (LND) is the standard of care for refractory non-muscle-invasive and muscle-invasive bladder cancer. Despite advancements in surgical technique, imaging, perioperative management, and chemotherapy, approximately 50% of patients develop metastases and die from their disease [1 3]. Lymph node (LN) positivity is a critical factor for disease-specific survival and a primary determinant of therapeutic course following surgery. Multiinstitutional series of patients treated with RC have shown that approximately 80% of patients with pathologic nodepositive disease experience disease recurrence, compared with 30% of patients with extravesical disease and pathologically negative LN [4 6]. Several studies have found that in addition to nodal status, the extent of LND (defined by number of nodes removed, the number of positive nodes detected, and LN density) can have prognostic and therapeutic implications [7 9]. In an effort to reduce understaging and maximize survival, many studies have tried to establish a minimum number of LNs needed to be taken at time of RC [10 12]. While a minimum number of LNs needed to be removed has been proposed, the survival probability continues to improve with increasing number of LNs removed [7 13]. The discrepancy between studies in the number of LNs needed to be removed may be due to extent of dissection, pathologic factors (ie, the manner in which specimens are submitted or interpreted by pathologists), and variability in patients pelvic anatomy [14]. The difference in disease severity between study populations likely also contributed to the discrepancies. Indeed, the rate of LN metastasis increases from a low of 5 10% in non-muscle-invasive bladder tumors (pt0, pta, ptis, pt1) to 15 20% in superficial muscle-invasive tumors (pt2a), to 25 30% in deep muscleinvasive tumors, and to >40% in extravesical tumors (pt3-4) [1 3,5,6,15]. We hypothesized that the number of LNs needed to be removed to ensure accurate nodal staging could be predicted based on clinical (preoperative) tumor stage. Recently, Gonen et al. used a beta-binomial model to estimate the probability that a colorectal cancer patient is correctly staged as node negative [16]. Using a similar approach, we developed a model that uses the clinical (preoperative tumor stage) to determine the number of nodes needed to be removed at RC to determine the true nodal status. 2. Methods 2.1. Patient selection and data collection Prior to analysis, the database was frozen and the final data set was produced. A total of 12 academic centers worldwide provided data. This study comprised 4335 patients who underwent RC with bilateral pelvic LND between 1980 and 2008. No patient received preoperative radiotherapy or chemotherapy. No patient had distant metastatic disease at the time of RC. 2.2. Pathologic evaluation All surgical specimens were processed according to standard pathologic procedures as discussed by Shariat et al. [5]. Genitourinary pathologists assigned pathologic stage, which was reassigned according to the 2002 American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging system. All lymphoid tissue removed was submitted for histologic examination. The extent of LND was at the surgeon s discretion. Extended LND was not routinely performed. Clinical stage was assigned based on the information from the pathologic evaluation of the transurethral resection (TUR) specimen, bimanual examination, and imaging study results. 2.3. Statistical analysis The method we followed is identical to an earlier work on colon cancer [16]. Briefly, we were concerned with the probability of incorrect nodal staging as a function of the number of examined nodes. The true nodal status is unascertainable, but information from node-positive patients can used to determine if the number of nodes examined and the number of these that are negative are sufficient to classify a patient as node negative. Consider a patient with a large number of examined nodes and small, positive k, wherek is the number of positive nodes from patients with node involvement: If fewer nodes were examined, there would be a chance that this patient would be incorrectly deemed node negative. Conversely, for a patient with a small number of examined nodes and large k, itisunlikelythatnodaldiseasewouldhavebeen missed, even though fewer nodes were examined. Hence, the data from node-positive patients were used to interpret the data for the nodenegative patients. The probability that a node-negative patient has nodal disease can be computed using the following algorithm: Compute the probability of missing a positive node, compute the prevalence, and compute the nodal staging score from sensitivity and prevalence. 2.3.1. Probability of missing a positive node The probability of missing a positive node (1, the sensitivity) is inherent to the process of pathologic detection and, as such, depends on the number of examined nodes but not on patient characteristics. We used a beta-binomial model for this purpose, allowing for heterogeneity in the intensity of nodal spread across patients. Two key assumptions underlie this step: (1) There are no false positives (if the specimen contains a positive node, it will be correctly identified by the pathologist), and (2) sensitivity is the same for node-positive and node-negative patients. These assumptions may not be completely tenable, but we find them to be sufficient approximations to our biologic understanding of nodal spread and clinical practice of nodal staging. This was an institutional review board approved study, with all participating sites providing the necessary institutional data-sharing agreements prior to initiation. A computerized databank was generated for data transfer. After combining the data sets, reports were generated for each variable to identify data inconsistencies and other data integrity problems. Through regular communication with all sites, resolution of all identified anomalies was achieved before analysis. 2.3.2. Estimation of prevalence of nodal disease The observed prevalence was an underestimate and needed to be adjusted for false negatives. This was done in two steps. The first step invokes Assumption 1 and estimates #FN k as a function of k: ½ #FN k ¼ 1 PðFN kþš#tp k PðFN k Þ

EUROPEAN UROLOGY 61 (2012) 237 242 239 Table 1 Characteristics of the 4335 patients treated with radical cystectomy with pelvic lymphadenectomy Patients, no. Patients, % Clinical T stage Ta 138 3.2 Tis 316 7.3 T1 1114 25.7 T2 2450 56.5 T3-T4 317 7.3 Pathologic T stage T0-Ta-Tis 774 17.9 T1 585 13.5 T2 1042 24.0 T3-T4 1934 44.6 Pathologic N stage Negative 3216 74.2 Positive 1119 25.8 Median Range Age, yr 67 23 93 Examined nodes, no. 18 1 136 Removed nodes in patients with positive nodes, no. 18 1 136 Positive nodes in patients with positive nodes, no. 2 1 93 In this step, #TP k is the number of true positives for a given k. Since prevalence is not a function of k, the second step obtains the adjusted prevalence by averaging over k: P kð Prev ¼ FN k þ TP k Þ P kð FN k þ TP k þ TN k Þ Estimation of prevalence was stratified by T stage for clinical (preoperative) nodal staging scores (cnss), but this is not explicitly noted in the above formula to avoid cumbersome notation. 2.3.3. Nodal staging score Adequate staging was assessed by computing NSS, the probability that a pathologically node-negative patient is indeed free of nodal disease: 1 Prev NSS ¼ 1 Prev þ ½PrevPðFN k ÞŠ 2.3.4. Confidence intervals The precision of the reported estimates was assessed by creating 2000 bootstrap samples from the entire data set and replicating the estimation process [17]. We formed 95% confidence intervals (CIs) using this bootstrap estimate of the corresponding sampling distributions. [(Fig._1)TD$FIG] Analyses were performed with SPSS 17 (IBM Corp., Armonk, NY, USA). 3. Results Table 1 shows the descriptive characteristics of the patients. The median number of removed LNs was 18 (quartiles: 11 31) and 74.2% of the patients were deemed node negative. LN metastases were present in 32 of 774 (4.1%) pt0/ta/tis patients, 40 of 585 (6.8%) pt1 patients, 188 of 1042 (18.0%) pt2 patients, and 859 of 1934 (44.4%) pt3-4 patients. Using our model, the beta-binomial parameters a and b were estimated to be 0.194 (95% CI, 0.189 0.199) and 0.306 (95% CI, 0.301 0.311). The resulting probability of missing nodal disease (1 the sensitivity) as a function of the number of LN examined is plotted in Figure 1. As expected, the probability of missing nodal disease decreased as the number of nodes examined increased (Table 2): If only a single node was examined in all patients, 76% of nodal disease would be missed. Even with 11 nodes examined (observed median), 24% of the nodepositive patients would be incorrectly staged. Sensitivity of nodal staging exceeded 80% only when 15 nodes were examined. The clinical nodal staging score is presented in Table 3 and Figure 2. For Ta-Tis tumors, six examined nodes provide 90% confidence that the patient was, indeed, node negative. For the same level of confidence, one would need 9 nodes for T1, and 25 for T2 tumors. Even with 30 examined nodes, the probability of incorrect nodal staging remains 20%. Bootstrap CIs for all the estimates reported in Table 2 and Table 3 are all within 1% (in absolute terms) of the estimates (data not shown). Table 2 Probability of missing nodal disease for selected values of examined nodes in 4335 patients treated with radical cystectomy with pelvic lymphadenectomy Nodes examined, no. 1 3 5 8 10 15 20 25 Fig. 1 Probability of missing nodal disease as a function of nodes examined in 4335 patients who were treated with radical cystectomy with pelvic lymphadenectomy. Probability of missing nodal disease, % 76 52 40 30 26 19 15 13

240 EUROPEAN UROLOGY 61 (2012) 237 242 Table 3 Clinical nodal staging score for selected values of numbers of nodes examined in 4335 patients who were treated with radical cystectomy with pelvic lymphadenectomy * Nodes examined, no. 2 5 8 10 15 20 25 30 Tumor stage, % Ta-Tis 84.3 89.2 91.7 92.8 94.5 95.6 96.3 96.8 T1 80.8 86.6 89.6 91.0 93.1 94.4 95.3 95.9 T2 65.7 74.7 79.8 82.1 86.0 88.5 90.2 91.4 T3-T4 45.4 52.0 59.2 62.8 69.4 73.9 77.1 79.7 * This score can be used to find the probability of having nodal disease despite a pathologic N0 classification. The number corresponding to patient s T stage and the number of examined nodes is the percent probability of patient having node-negative disease. [(Fig._2)TD$FIG] Fig. 2 Sensitivity of the pathologic evaluation of nodal disease stratified by clinical tumor stage in 4335 patients who were treated with radical cystectomy with pelvic lymphadenectomy. Vertical axis is the probability of missing nodal disease (1 sensitivity) and horizontal axis is the number of examined nodes. 4. Discussion Researchers have tried to identify the minimum necessary number of LNs needed to be removed at RC. However, the analysis of a large tertiary care center s database revealed that the probability of survival continues to rise as the number of LNs removed increases and that no minimum number of LNs can be determined [12]. One potential limitation of that and previous studies is that they did not adjust for clinical factors. To address this need, the primary aim of our study was to assess whether every patient needs the same extent of LND, and if not, whether we could identify a minimal number of LN needed based on clinical tumor stage. We found that the number of LNs needed to be removed varies largely among patients according to their tumor stage. However, in accordance with previous studies, we found that every patient treated with RC for bladder cancer, even those with cta-tis, needs an LND to ensure accurate nodal staging. On the other hand, even an extended LND does not ensure 100% accuracy with regard to nodal status. Indeed, different studies have shown 8% extrapelvic skip lesions above the aortic bifurcation, although these skip lesions have not been reported exclusively above the extended LND template [8,18]. However, not all patients benefit from an extended LND. Furthermore, extended LND may incur morbidity. Therefore, an estimation of the minimum number of LNs needed to be removed to ensure detection of possible cancer-burdened LNs could help establish an individualized risk-based determination of the extent of LND each patient should undergo. We found that clinical tumor stage is a powerful predictor of the number of LNs needed to be removed to ascertain LN status. In patients with clinical Ta-Tis disease, at least six LNs need to be removed to achieve 90% confidence that the patient is node negative. Up to 6% of patients with refractory ctis treated with RC harbor LN metastasis [19]. Moreover, 71% and 32 48% of patients with cta and ctis, respectively, are upstaged at RC to pathologic T1 or higher [20,21]. One potential reason for this relatively high range of discrepancy between clinical and pathologic stage could be the lack of routine restaging TUR and currently inadequate imaging technology [22]. While one cannot extrapolate from the number of LNs removed to the surgical template, an LND limited to the true pelvis or even to the obturator fossa in patients with cta-tis seems adequate. Conversely, in patients with ct1, at least 10 LNs need to be removed to ensure 90% probability of ascertaining true nodal status. In ct2 bladder cancer patients, removal of 25 LNs results in a >90% probability of ascertaining true nodal status. In ct3-4 bladder cancer, the 90% probability is not reached, with an asymptotic approach to a maximum 80% probability of detecting a positive LN. One possible reason for this is the higher likelihood of skip lesions outside of the regular template in patients with locally advanced tumor stage [23]. Taking these data together, it seems that a safe approach would be to recommend an extended LND in patients with stage ct1 and higher bladder cancer. In patients with ct3-4 bladder cancer, one has to realize that even with an extended LND, there is the probability of missing 20% of LN metastasis. This further reinforces the need of multimodal therapy in patients with pt2 or greater disease. We developed a simple probabilistic model to predict the number of LNs needed to be removed as a function of clinical determinants of stage, including pathologic examination of the TUR specimen, bimanual examination, and imaging studies. Generally, the extent of LND is performed based on the surgeon s intuitive experience integrating his beliefs and patient factors such as health status and tumor features. Our model is a simple tool that could guide preoperative clinical decision-making regarding the extent

EUROPEAN UROLOGY 61 (2012) 237 242 241 of LND. Performing an extended LND in all patients would result in overtreatment of many patients, with resulting side effects and cost. While an extended pelvic LND is not associated with increased morbidity compared with a limited LND in experienced hands, the risk of longer operative time and associated complications needs to be determined for each individual patient [8,24]. In contrast, removing too few LNs may result in inaccurate staging and possibly inferior survival [8,9,25,26]. However, neither intuition nor nomograms [6] can give a personalized risk/ benefit analysis integrating threshold probabilities based on individual preferences. Our tool may enable the physician and the patient to engage in shared decision making and determine risks by incorporating the risk of missing a positive node compared with the risk/benefit of an extended LND. Therefore, our cnss can be incorporated to individualize treatment and demonstrates the incremental improvement of nodal stage accuracy with each individual node resected. Nevertheless, our study has some limitations. First and foremost are limitations inherent to its retrospective design and multicenter nature, as well as the lack of routine repeat TUR [27], failure to control for the quality of the TUR [28], and failure to control for other preoperative prognostic factors, such as lymphovascular invasion [29]. Other limitations include the variability in preoperative imaging and pathologic evaluation, as well as differences in treatment decisions and surgical technique. Newer imaging techniques such as positron emission tomography/ computer tomography and magnetic resonance imaging with ultrasmall superparamagnetic iron oxide may allow better decision making about the extent of LND [30]. In addition, the number of LNs removed is not only a factor of the extent of LND but also is dependent on the pathologic evaluation and inherent differences between patients. Moreover, the number of LNs removed is not an exact surrogate for the extent of LND. Central pathology review was not performed, which might have an undefined impact, given differences in the rigor used by different pathologists to identify LNs. Conversely, our data reflect a real-world multicenter experience and pathologic examination was performed by genitourinary pathologists in major academic centers. Our study did not examine the differential impact of the extent of LND on long-term outcomes; two randomized trials are comparing a standard with extended extent of LND and may shed more light on this issue. Finally, the location of LNs is important. Removing nodes from an area of high likelihood of malignancy may be more valuable than removing nodes less likely to be involved with cancer [23]. 5. Conclusions We found that the risk of LN metastases and the number of LNs needed to be removed to ensure true node-negative status increases with advancing clinical stage. There is no one-size-fits-all for LND in patients treated with RC for bladder cancer. While all patients need an LND, a limited LND seems sufficient in patients with cta-tis, while an extended LND should be recommended for those with ct1 and higher stage. In patients with ct3-4, even an extended LND still misses about 20% of LN metastasis. We developed a simple cnss to aid preoperative clinical decision making about the extent of LND in patients for whom RC for bladder cancer is planned. After validation, such a tool could help physicians decide treatment strategies prior to RC and tailor the extent of LND at RC. Author contributions: Shahrokh F. Shariat had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Shariat, Ehdaie, Gonen. Acquisition of data: Svatek, Novara, Lotan, Sagalowsky, Fradet, Kassouf, Fritsche, Bastian, Burger, Izawa, Tilki, Abdollah, Scherr, Shariat. Analysis and interpretation of data: Shariat, Gonen. Drafting of the manuscript: Shariat, Ehdaie, Rink, Cha. Critical revision of the manuscript for important intellectual content: Shariat, Ehdaie, Rink, Cha, Svatek, Chromecki, Fajkovic, Novara, David, Daneshmand, Fradet, Lotan, Sagalowsky, Clozel, Bastian, Kassouf, Fritsche, Burger, Izawa, Tilki, Abdollah, Chun, Sonpavde, Karakiewicz, Scherr, Gonen. Statistical analysis: Shariat, Gonen. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Gonen, Shariat. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: M. Burger has consulted and lectured for Astellas Pharma, GE Healthcare, and Photocure ASA. Funding/Support and role of the sponsor: None. References [1] Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer today a homogeneous series without neoadjuvant therapy. J Clin Oncol 2003;21:690 6. [2] Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. J Urol 2006;176:2414 22, discussion 2422. 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