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Originally published as JCO Early Release 10.1200/JCO.2004.11.024 on June 15 2004 © 2004 American Society of Clinical Oncology. Surgical Factors Influence Bladder Cancer Outcomes: A Cooperative Group ReportFrom the Memorial Sloan-Kettering Cancer Center, New York, NY; Southwest Oncology Group Statistical Center, Seattle, WA; University of Texas M.D. Anderson Cancer Center, Houston; University of Texas, San Antonio, TX; Salick Health Care, Los Angeles; University of California, Davis, CA; University of Colorado, Denver, CO Address reprint requests to Southwest Oncology Group (SWOG-8710), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217; e-mail: bgranados{at}swog.org
PURPOSE: A randomized, cooperative group trial (Southwest Oncology Group 8710, Intergroup 0080) reported that neoadjuvant chemotherapy improved the survival of patients with locally advanced bladder cancer who were treated with radical cystectomy. We evaluated whether surgical factors from patients enrolled onto the study predicted bladder cancer outcomes. PATIENTS AND METHODS: Surgical and tumor factors were recorded from surgical and pathologic reports from 268 patients with muscle-invasive bladder cancer who received radical cystectomy. Cystectomies were performed by 106 surgeons in 109 institutions. Half of the patients received neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. Variables were tested in univariate and multivariate analyses for associations with postcystectomy survival (PCS) and local recurrence (LR) in all patients receiving cystectomy.
RESULTS: Five-year PCS and LR rates were 54% and 15%, respectively. A multivariate model adjusted for MVAC (P = .97), age (P = .03), pathologic stage (P = .0002), and node status (P = .04) showed that surgical variables associated with longer PCS were negative margins (v positive; hazard ratio [HR], 0.37; P = .0007), and CONCLUSION: Surgical factors influence bladder cancer outcomes after cystectomy, after adjustment for pathologic factors and neoadjuvant chemotherapy usage.
Radical cystectomy (RC) with a pelvic lymphadenectomy provides excellent local control and long-term survival of muscle-invasive bladder cancer. The curative intent of radical surgery is to remove all cancer in the bladder, pelvis, and regional lymph nodes. Contemporary cystectomy series with 10-year follow-up show that surgery cures the majority of patients with muscle-invasive tumors that are confined to the bladder (pathologic [P] stage pT2), about half with extravesical disease (stage pT3-4), and a significant minority with positive (N+) pelvic lymph nodes.1,2 Surgery also provides important pathologic information to identify patients who are likely to develop recurrent disease. A large proportion of patients eventually die of bladder cancer owing to unrecognized and untreated nodal or distant metastasis present at the time of surgery. This has led to attempts to improve the survival of patients with locally advanced bladder cancer by integrating systemic chemotherapy with RC. A randomized Intergroup trial conducted by the Southwest Oncology Group (SWOG 8710, INT-0080) reported that neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy improved the survival of patients with muscle-invasive bladder cancer treated by cystectomy.3 Half of the patients were randomly assigned to receive three cycles of the standardized MVAC regimen. All patients enrolled onto the study agreed to undergo an RC and a bilateral pelvic lymph node dissection (PLND). Surgery was performed by many different surgeons in multiple institutions located throughout the United States. Although the techniques of RC and PLND are well described, there are no currently accepted standards measuring the quality of surgery performed. Given that the quality of RC and extent of PLND might vary among surgeons, we evaluated the impact of surgical variables on bladder cancer outcomes among all patients enrolled onto this randomized, cooperative group trial who underwent a cystectomy. Our aim was to investigate associations of surgical factors with postcystectomy survival and local recurrence in patients receiving cystectomy on the SWOG 8710 trial, and to assess whether these associations depend on the assigned treatment received.
Eligibility criteria for the SWOG 8710 trial was a muscle-invasive (clinical stage T2-T4a, N0, M0) bladder cancer and a candidate for RC; no prior pelvic radiation; adequate renal, hepatic, and hematologic function; and a SWOG performance status of 0 or 1. Patients were randomly assigned to receive either RC alone or three cycles of MVAC followed by RC. A total of 317 patients were accrued over an 11-year period (1987 to 1998). Of these, 307 patients (97%) had complete records available for review. Thirty-nine patients (13%) with available records did not have a cystectomy (13 refused, 22 had RC aborted because of unresectable tumor or positive nodes, and four experienced tumor progression while receiving MVAC). Of the 268 patients who had a cystectomy, nine had surgery performed outside of protocol. All patients that received cystectomy and had available records (n = 268) were used in the following supplemental analysis. All patients were to be observed until death. Median follow-up time postcystectomy for those patients alive at last contact was 8.9 years, and 96% of all patients had known survival status at 5 years.
Biologic and surgical variables were retrieved from the original operative and pathology reports and reviewed by the first author. Patient, tumor, and surgical variables analyzed included age at surgery (< 65 v Prescribed surgery consisted of an RC (removal of the bladder and adjacent organs with a margin of perivesical adipose tissue within the muscular-skeletal boundaries of the pelvis) and a bilateral PLND. The extent of PLND was recorded directly from the operative report, independent from the number of nodes examined. A standard PLND included the distal common iliac, external iliac, obturator, and hypogastric nodes. A limited PLND included only nodes sampled medial to the external iliac vein and obturator nodes. If no lymph node dissection was dictated by the surgeon and no nodes were found in the specimen by the pathologist, the patient was recorded as having received no PLND and was classified as node-negative. This occurred in 18 patients (7%). We also recorded node counts according to how the surgeon submitted the nodes to pathology (separate or en bloc with the cystectomy specimen).
Statistical Analysis
Our aim was to identify variables univariately associated with the outcomes and then test whether the variables related to surgery were important predictors of outcome after adjusting for other patient, disease, and treatment-related variables. Cox proportional hazards regression was used to test for surgical predictors of postcystectomy survival. Multivariate proportional hazards models were adjusted for treatment, age, pathologic stage, and node status. Logistic regression was used to test for surgical predictors of local recurrence. Multivariate logistic regression models for local recurrence were adjusted for treatment, pathologic stage, and node status. All proportional hazards models and logistic regression models were fit with the use of the PHREG and LOGISTIC procedures, respectively, in the SAS software package (SAS/STAT User's Guide, version 8, 1999; SAS Institute Inc, Cary, NC). The Wald All variables had complete records except margin status, which was missing for 26 patients. Any model including margin status used only the 242 patients with complete records. Survival curves and point estimates were based on Kaplan-Meier estimates generated using the LIFETEST procedure in SAS software. All statistical tests were two sided and P values were considered significant if less than .05. Analysis of the data was performed by the SWOG Statistical Center and approved by the Institutional Review Board at Memorial Sloan-Kettering Cancer Center (New York, NY).
Table 1 lists characteristics and surgical and pathologic variables for all patients. Half of the patients received MVAC chemotherapy before cystectomy. The patients were well balanced between treatment arms of the study relative to the variables shown in Table 1, except for pathologic stage and node status. Patients receiving neoadjuvant MVAC had more organ-confined tumors (tumor downstaging; P = .001 from  2 test) and fewer positive nodes (P = .04) than patients who had surgery alone.
Twenty-four patients (9%) had no node dissection, 98 patients (37%) had a limited node sampling, and 146 patients (54%) had a standard bilateral PLND. The median number of nodes removed from all patients was 10 (range, zero to 54 nodes). Twenty-four percent of the patients had zero to four nodes removed, 25% had five to nine nodes, 25% had 10 to 15 nodes, and 26% had more than 15 nodes removed. The median number of nodes after none, limited, or standard PLND was zero, seven (range, zero to 16), and 15 (range, one to 54), respectively. Node status was positive for 55 patients (21%). Of the 242 patients with status of surgical margins reported, 25 (10%) had positive margins. Local recurrence occurred in 41 (15%) of the 268 patients after cystectomy and was balanced between treatment arms. Study patients were operated on by 106 different surgeons in 109 institutions. Fourteen surgeons performed five or more cystectomies on this study and 92 did fewer than five operations. All but one of the high-volume surgeons were urologic oncologists. Of the 109 institutions represented, 50 were community hospitals (n = 84 patients), 36 were academic medical centers (n = 137 patients), and 23 were VA/military hospitals (n = 47 patients), of which half had academic affiliations. Of the 268 cystectomies, 115 were performed by urologic oncologists and 153 were performed by general urologists. The type of surgeons handling patients was dependent on the type of institution. Ninety percent of patients who had surgery at academic institutions were operated on by urologic oncologists, whereas urologic oncologists were only responsible for 9% of patients who received surgery at VA/military and community institutions combined.
Urinary Diversion
Postcystectomy Survival
As shown in Table 2, the 5-year survival rate after RC and no node dissection was 33% (median, 2.4 years), 46% after a limited dissection (median, 4.2 years), and 60% with a standard dissection (median, 7.2 years). Figure 1 shows survival curves by fewer than versus greater than or equal to the median number of 10 nodes removed for patients receiving cystectomy. Among 138 patients who had 10 or more nodes removed, the probability of survival 5 years after cystectomy was 61% (median survival time, 7.7 years), compared with 44% for the 130 patients (median survival time, 3.8 years) having fewer than 10 nodes removed (P = .0007). Figure 2 suggests that the survival advantage conferred by removing 10 or more nodes was retained in both node-negative and node-positive patients. Among 213 node-negative patients, 5-year survival for the group with  10 versus fewer than 10 nodes removed was 69% and 52%, respectively (median survival not reached and 5.3 years, respectively). Among the 42 node-positive patients, 5-year survival for those with 10 versus fewer than 10 nodes removed was 34% and 9%, respectively (median, 2.3 and 1.2 years, respectively). The comparisons of survival among node groups in Figures 1 and 2 are mainly for visualization purposes and do not provide an adequate assessment because other potentially confounding covariates such as disease status cannot be adjusted for using this type of univariate analysis.
Table 3 lists results of a proportional hazards regression analysis used to test for surgical predictors of postcystectomy survival after adjusting for other covariates. In this multivariate model adjusted for treatment, age, pathologic stage, and node status, surgical predictors of longer postcystectomy survival were negative surgical margins (P = .0007) and 10 nodes removed (P = .0001). The adjusted hazard ratio for death for patients with positive surgical margins relative to negative was 2.7 (95% CI, 1.5 to 4.9), and that for patients with fewer than 10 relative to 10 nodes removed was 2.0 (95% CI, 1.4 to 2.8). Type of surgeon and type of institution (academic v other) were not significant (P > .05) and were removed from the model. Tests for interactions between treatment and margin status, and treatment and nodes removed in the multivariate model were not significant (P > .21 for each test), suggesting that the associations of margins and nodes examined with survival did not depend on whether MVAC was received.
The PLND variable was not significant (P = .15) when substituted for the node count variable in the model shown in Table 3. PLND and the number of nodes (by quartiles) were closely correlated (data not shown), although there was overlap among PLND categories. Type of PLND was a coarse categorization of the actual number of nodes removed, suggesting that node counts are a more accurate measure of the extent of the lymph node dissection.
Local Recurrence
Associations Among Surgical Factors and Other Covariates Surgical margins and number of nodes removed were the strongest surgical predictors of survival and local recurrence. These two surgical factors also were associated with each other. Positive surgical margins were associated with fewer nodes removed (P = .01 from 2 test); 17 (68%) of the 25 patients with positive margins had less than 10 nodes removed. These two surgical factors were also correlated with other variables. Table 5 lists univariate associations of number of nodes removed and surgical margin status with the other patient variables. Univariate predictors (P < .05) of less than 10 nodes removed were urologists and nonacademic institutions. Predictors of no or limited PLND (v standard) were the same as those for less than 10 nodes removed (data not shown). Univariate predictors of positive margins were older patients, more advanced pT stages, positive node status, surgery by urologists, and surgery at nonacademic institutions.
It was of interest to investigate whether the type of surgeon or type of institution (academic v other) was an important predictor of margin status or nodes removed after adjusting for patient characteristics and extent of disease. Although these are crude representations, one would expect the institution and surgeon variables to provide some surrogate measure of the knowledge base of the surgeons and the practice standards held by institutions. The high correlation between these two variables makes separating the individual importance of either difficult, so separate adjusted models were fit for each. A multivariate logistic regression model using margin status as the response and adjusting for treatment, pT stage, node status, and age found type of surgeon (general urologist) to be an important predictor of positive margin status (P = .0004). The same model found that type of institution (nonacademic) predicted positive margins (P = .009) when substituted for type of surgeon. Likewise, a multivariate logistic regression using number of nodes removed (< 10 v 10) as the response and adjusting for treatment, pT stage, node status, and age found that type of surgeon (general urologist) predicted removal of less than 10 nodes (P < .0001). Type of institution (nonacademic) predicted removal of less than 10 nodes (P = .0001) when substituted for type of surgeon in that model. These investigations are purely exploratory and causal relationships should not be drawn, but they do suggest that much of the variability in quality of surgery can be explained by characteristics of the surgeon or institution, even after patient characteristics and extent of disease are accounted for.
The primary question asked by the SWOG-Intergroup study was whether neoadjuvant MVAC chemotherapy improves the survival of patients with locally advanced bladder cancer. Although MVAC improved survival compared with cystectomy alone, the primary aim of the trial focused on the chemotherapy question. The surgeon and surgical variability were not considered as risk factors predictive of bladder cancer outcomes. The cooperative group mechanism ensures a large participation of diverse community and academic hospitals and surgeons, including possible variations in the quality of RC as it is currently practiced in the United States. We sought to evaluate whether surgery influences bladder cancer outcomes among all patients receiving RC on the SWOG trial. We found substantial variability in how cystectomy was performed, especially in the extent of PLND, and that surgical factors play a significant role in determining the outcome of patients with locally advanced bladder cancer who are treated by RC, whether or not they receive neoadjuvant chemotherapy. Patients who underwent an RC and a standard template PLND, achieved a negative surgical margin, and had more lymph nodes removed had superior postcystectomy survival than patients who had less favorable surgical features. Urologic oncologists achieved better long-term survival and fewer local recurrences among their patients than did general urologists. A positive surgical margin, regardless of node status or total number of nodes removed, was associated with a local recurrence and death as a result of bladder cancer. The 5-year survival rate for patients having RC and no, limited, or standard lymph node dissection was 33%, 46%, and 60%, respectively. The 5-year survival rate for patients with fewer than 10 nodes removed was 44% compared with 61% for patients with more than 10 nodes examined. Local recurrences occurred in only 6% of patients after RC and a standard pelvic node dissection removing more than 10 nodes, compared with 25% after a limited node dissection with fewer than 10 nodes. Half the patients who had no node dissection had a local recurrence. The importance of locoregional control is emphasized by the fact that 91% of the 41 patients who had a local recurrence died as a result of bladder cancer, including all 25 patients who had positive surgical margins. The fact that both surgical margins and number of nodes were independent predictors of postcystectomy survival and local recurrence in multivariate models suggests that the quality of surgery significantly influences bladder cancer outcomes. Single-institution cystectomy series have shown for both node-negative and node-positive patients with invasive bladder cancer that overall survival improves with an increasing number of lymph nodes examined.4,5 A recent analysis of 1,923 patients obtained from the Surveillance, Epidemiology, and End Results program cancer registry showed improved postcystectomy survival with a more comprehensive lymph node dissection.6 The extent of lymphadenectomy also was relevant to survival in patients with locally advanced disease who received chemotherapy, suggesting that maximum surgical debulking of the primary tumor and regional lymph nodes is an essential part of combined therapy. The Surveillance, Epidemiology, and End Results data suggest that excision of a predetermined minimum number of nodes (10 to 14) should be used as a surrogate measure of the quality of lymphadenectomy or pathologic examination on which to base accurate staging of node status and to optimize therapeutic benefit of RC. Our study has limitations. It represents a secondary analysis of a prospective trial. The associations we found could be considered suggestive but no causal inferences should be drawn. Other variables that were not measured might have contributed to the observed associations between surgical variables and bladder cancer outcomes. The patients were operated on over a decade, and it is possible that unmeasured surgical practices have improved over time. However, it is unlikely that patient selection, surgical techniques, or the surrogate markers (surgical margins and number of nodes) defining surgical variability changed significantly during the years of the study. Why some surgeons elected to do no or a limited node sampling rather than a complete PLND was not clear from the operative records. One reason might be that the protocol did not mandate specific limits of the pelvic node dissection. Patient age and assigned treatment group were not contributing factors given that equal numbers of older patients in each arm had no or a limited node dissection. The most likely reason was experience of the individual surgeon. Sixty-two percent of general urologists performed a limited or no node dissection compared with 23% of urologic oncologists (P < .001). Largely ignored in our analysis is the influence of the pathologist, whose technique and diligence in examining the cystectomy specimen and searching for nodes may vary. Although practice guidelines for examining and reporting of cystectomy and lymph node specimens are available,7,8 quality assurance of recommended pathology protocols has not been verified and none has been standardized or validated. For example, the minimum number of nodes required to label a patient as node-negative has not been determined reliably. This fact alone is critical to the medical oncologist who must decide which patients are at high risk for tumor recurrence, which patients to treat with chemotherapy, and how to evaluate the results of treatment. We found that although all pathology reports described the pathologic stage of cancer, in some cases other variables were poorly documented in the records. Margin status was not mentioned in 26 patients (10%), and number of nodes was not reported in another 18 patients (7%). Only 1% to 2% of pathology reports from academic medical centers failed to report margins or nodes compared with 15% and 21% from community or VA/military hospitals, respectively. The surgeon can aid the pathologist by submitting nodes separately rather than en bloc with the bladder. We found that the median number of nodes recovered in separate node packets was 12 (range, one to 54) compared with only four (range, zero to 12) in en bloc specimens. When improved survival correlates with increasing numbers of lymph nodes reported by the pathologist, three factors are potentially involved: a diminished risk of local and regional recurrence may result from a complete pelvic lymphadenectomy, which yields more lymph nodes in the specimen; the surgeon who performs a more complete node dissection may secure wider margins around the bladder and adjacent organs; or a more thorough examination of the specimen by the pathologist may result in more accurate staging. Although we cannot assign a mechanism for the improved outcome with increased node count, other studies suggest that variations in the number of nodes identified per specimen are not related specifically to pathologic examination but to variations in the extent of the lymphadenectomy.4,9 Our data show that reduced local recurrence and better survival were associated with negative surgical margins and higher node counts. These two significant surgical variables are interrelated and depend on the experience of the surgeon and thoroughness of the PLND. The data emerging from collective studies is that the quality of RC is critical to outcome. Our findings raise larger questions worthy of additional investigation, especially in an era of combined-modality therapy for invasive bladder cancer. We demonstrate substantial variability in the type of surgical resection performed and hence the number of lymph nodes removed. The technique and the diligence of the pathologist also may vary. The result is that tumors may be understaged or overtreated, directly influencing a patient's duration and quality of survival. Does removing more nodes influence survival or is it merely better staging and a way of identifying candidates for chemotherapy? The fact that patients who had limited sampling of nodes fared worse than similarly staged patients who had more complete clearing of regional nodes suggests (but does not prove) that lymphadenectomy might have therapeutic benefit. If RC and pelvic node dissection are based on anatomic guidelines, why is there substantial variability among individual surgeons regarding margin status and number of lymph nodes retrieved? Is there adequate communication between the surgeon and the pathologist? Is the retrieval of a small number of lymph nodes an indication for adjuvant chemotherapy? These and other questions can be answered by prospective trials in which surgical resection of invasive bladder cancer is founded on accepted anatomic boundaries, well-defined margins, and verifiably complete lymph node templates of dissection. The need to secure and retain local and regional control of invasive bladder cancers, even extravesical tumors with positive nodes, will assume increasing importance as systemic therapy improves and reduces deaths from distant metastases. Accepted surgical standards for RC with PLND and pathologic assessment of cystectomy specimens should be established and prospectively validated. Given that nodes are related to both margins and outcome, a minimum number should be agreed on as a proxy measure of the quality of surgery. This is important not only for individual patient management but also for the design and evaluation of adjuvant and neoadjuvant chemotherapy studies in bladder cancer. Improving the general quality of surgery may even prove to be as important as or more important than anticipated improvements in chemotherapy regimens. Our study shows that improved postcystectomy survival and reduced local recurrence are associated with negative surgical margins and more lymph nodes removed. Surgical variables influence bladder cancer outcomes, with or without neoadjuvant chemotherapy, emphasizing that quality assurance of RC and pelvic lymphadenectomy should be factored in combined-modality clinical trials of invasive bladder cancer.
The authors indicated no potential conflicts of interest.
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Bethesda, MD: CA32102, CA38926, and CA42777. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, June 2, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: Long-term results in 1,054 patients. J Clin Oncol 19:666-675, 2001
2. Madersbacher S, Hochreiter W, Burkhard F, et al: Radical cystectomy for bladder cancer: A homogeneous series with neoadjuvant therapy. J Clin Oncol 21:690-696, 2003
3. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003 4. Leissner J, Hohenfellner R, Thuroff JW, et al: Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: Significance for staging and prognosis. BMJ Int 85:817-821, 2000 5. Herr HW, Bochner BH, Dalbagni G, et al: Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 167:1295-1298, 2002[CrossRef][Medline] 6. Konety BR, Joslyn SA, O'Donnell MA: Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: Analysis of data from the Surveillance, Epidemiology and End Results program data base. J Urol 169:946-950, 2003[CrossRef][Medline] 7. Murphy WM, Crissman JD, Johansson SL, et al: Recommendations for the reporting of urinary bladder specimens containing bladder neoplasms. Am J Clin Pathol 106:568-570, 1996[Medline] 8. Hammond EH, Henson DE, for members of College of American Pathologists: Practice protocol for the examination of specimens removed from patients with carcinoma of the urinary bladder. Arch Pathol Lab Med 120:1103-1110, 1996[Medline] 9. Herr HW: Extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. Urology 61:105-108, 2003[CrossRef][Medline] Submitted November 5, 2003; accepted May 4, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
