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Originally published as JCO Early Release 10.1200/JCO.2004.03.936 on June 15 2004 © 2004 American Society of Clinical Oncology.
Does the Who and How of Surgery in Bladder Cancer Matter?University of Washington, Seattle, WA Surgery continues to have an important, if not predominant, role in the management, economics, and curability of human solid tumors. Yet two questions that continually challenge all those who think about the role of surgery are: does the profile of the performing surgeon, in terms of experience and didactic focus and training, influence overall results? And, by extension, does the extent of surgical resection of the primary tumor and the regional lymph nodes influence disease outcome? With regard to the surgeon profile, there is growing evidence—both outside and inside oncology—that surgical experience (eg, the number of cases performed per year) is an important, though not the only, determinant of surgical excellence. By inference, procedures in institutions with large volumes, such as academic centers, also seem to convey an advantage.1-3 A problem with comparing these findings in assessing cancer control, as opposed to cardiac, orthopedic, or plastic surgery, may be the unfounded assumption that the overriding factors in outcomes from cancer surgery are dependent on the disease rather than the quality of treatment. Thus, the second question is the hardest to address: does the quality of surgery influence cancer outcome? Certainly, there is increasing evidence, both in the laboratory and in some clinical settings, that local excision, regardless of how well done, is merely a debulking or staging maneuver. Disease outcome then becomes more a factor of preordained systemic factors, such as the character and volume of circulating cancer cells and presence and location of micrometastases.4-6 Yet there remains compelling evidence that so-called "Halstedian" surgical techniques, such as wide local resections and meticulous removal of regional lymph nodes, do matter. For example, in colon cancer, the survival for a Dukes' C lesion (positive mesenteric lymph nodes) is as high as 40% with surgery alone.7 In urologic cancers, significant numbers of men with penile and testicular cancers who have positive regional lymph nodes are cured with surgery alone,8,9 though the same cannot now be proven in renal or prostate neoplasms. In bladder cancer, the article by Herr et al10 in this issue adds to several past studies specifically addressing the importance of surgical technique on bladder cancer outcome. For example, earlier literature suggested that the survival after cystectomy in patients with positive nodes was less than 15%,11 but more recent series have shown that the survival is now up to 35%.12 While some of this change can be ascribed to stage migration, there is suggestive evidence that surgical technique is also a factor. More recently, several groups—including Dr Herr's at Memorial Sloan-Kettering—have shown that the number of lymph nodes removed and examined influences outcome, not only in those with positive nodes but also those with negative nodes.13,14 The problem with those studies was that they were from single academic institutions where the surgery was performed by a limited number of surgeons. Herr et al partially overcome this objection in their study. They used the data from the recently reported15 randomized cooperative group trial (SWOG 8710, INT-0080) of cystectomy, with or without neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy, and analyzed measures of surgical quality, which they correctly assumed would vary widely among the 109 participating institutions. Specifically, in the 268-patient data set, they analyzed the influence of the following surgical factors on survival and local recurrence: surgical margin status, extent of node dissection as evidenced by type of dissection and number of nodes found pathologically, whether the surgeon was a general urologist or a specialist trained in urologic oncology, and whether the surgery was done at an academic or community center. The findings of this analysis were interesting from several viewpoints. For example, they found that whether the patient received neoadjuvant chemotherapy did not significantly alter these surgical factors. This comes as no surprise, because although this cooperative study did show a survival advantage for neoadjuvant chemotherapy,15 other studies and opinions make this conclusion controversial.16 More importantly, with multivariate modeling adjusting for well-known risk factors influencing survival or local recurrence, such as pathologic stage, grade, and age, the most important negative factors were whether the surgical margins were positive and whether fewer than 10 lymph nodes were removed. In other analyses, the authors present some evidence that the number of nodes removed influenced survival even if the nodes were negative for cancer. Since both margin status and number of nodes were independent predictors of survival and local recurrence in multivariate models, the authors conclude that the quality of the surgery has a significant impact on bladder cancer outcomes. The authors then logically extended their inquiries to discover whether these surgical quality factors were related to the type of surgeon and institution. Thus, in another, admittedly less robust analysis, they found that surgeons specifically trained in urologic oncology were more likely to achieve negative margins and remove more than ten lymph nodes than were general urologists. Predictably, the analyses also revealed that these desirable surgical outcomes were more likely achieved in academic medical centers, because those surgeons who carry the imprimatur as genitourinary oncologic surgeons currently mostly practice in such centers. These analyses, of course, merit a variety of reservations that Herr and associates nicely address. For example, these are secondary analyses of a prospective trial, and the techniques for bladder and lymph node removal were not specifically mandated. Also, the study lasted more than a decade, during which time surgical techniques may have changed. However, in our opinion, the greatest uncertainly to the conclusions is the influence of pathologic examination. One might argue that all the results are due to stage migration because of the variability of pathologic scrutiny. There is no doubt that the number of nodes found in a surgical specimen is influenced by the diligence and technique of the examining pathologist. For example, we believe one can identify more nodes (and presumably more positive nodes) with increasingly meticulous gross dissection, including fat clearance of the material, more step-sectioning and microscopic scrutiny, broadening the criteria of a lymph node to include small aggregations of lymphatic material, and even immunohistochemical staining.17 However, these maneuvers can quickly exceed the usual practicalities of time and expense, unless driven by other factors. Thus, pathologists associated with urologic surgical oncologists and academic medical centers might detect more nodes and possibly more positive margins, independent of surgical technique. Yet other findings in this article and other reported studies14,18 suggest that the number of nodes removed or the positive surgical margin rates are not primarily related to pathologic examination. At the least, these results should prompt additional new studies and specific analyses of surgical factors in ongoing trials. At the risk of appearing self-serving, we believe that the article by Herr et al adds importantly to the increasingly mounting evidence that the extent of local excision and regional lymphadenectomy in bladder cancer and probably many (but not all) solid tumors significantly influences local recurrence and survival. This article also reinforces the qualified notion that the surgeon's specific training in a particular oncologic area (eg, enhanced training of urologists in genitourinary oncology) is important for optimal cancer management and, by implication, so is the performance of the surgery at academic and high-volume institutions where most of the specifically trained urologic surgical oncologists work and are presumably challenged to continued excellence by irreverent trainees. The label "qualified" is necessary here because the excellence that a surgeon brings to bear on results is influenced by many other factors aside from subspecialty training or institution, and many so-called general urologists, both in and out of academia, become excellent urologic oncologic surgeons by virtue of experience, training, and talent. The findings of this article are specifically important to several groups. To patients and their primary physicians, these results might modify lines of referral. To the medical oncologist deciding about follow-up care, including adjuvant therapies, the surgeon and maybe where the surgery was performed could influence decisions beyond the pathology report. To the hospital and department administrators, the credentials of the surgeon, the standardization of the pathology examination, and better benchmarks of surgical outcome might deserve increased attention. To the cancer investigator focusing on metastasis, this article could influence the debate about the importance of persistent local disease on metastatic processes and disease outcomes. To those who design and run multi-institutional trials where surgery is involved, more attention to surgical technique and surgeon identity is now warranted. The American College of Surgeons Oncology Group is a relatively new national cooperative-trial group organized to design and perform surgically orientated cancer trials, and it has made great progress in defining and practicing surgical quality control.19 But we believe the Herr et al article should have the greatest impact on those who influence surgical specialty and sub-specialty training and cancer practice. If who does the surgery and how it is done greatly influences solid tumor outcomes, then several areas related to surgical training and practice need improvement. For example, multimodality care is a necessity in many solid-tumor situations. An oncologic surgeon needs to be an integral part of such management teams and should earn the appreciation of their associates not only for their technical skills but for their cognitive wisdom. In our opinion, this association should not just be theoretical but grounded in time and space. Thus, one should strive for multidisciplinary clinics where, at a minimum, surgeons, medical and radiation oncologists, pathologists, and radiologists see patients or patient materials at the same time and in the same place. This is being accomplished despite the difficult logistics of special equipment (radiation or imaging units) and facilities (outpatient chemotherapy or surgical suites) and the special time demands on the surgeon in the operative suite. Finally, subspecialty training and verification of surgeons dedicated to oncology needs greater attention. Surgical oncology fellowships need to be established, expanded, promulgated, standardized and verified. Participants in surgical oncology societies need to document their excellence, not just their membership. With regard to genitourinary cancer, including bladder cancer, the Society of Urological Oncology has made significant strides toward these goals.20 There are many formidable problems impeding such goals. For example, at the national level the "if" and "how" of surgical oncology subspecialty accreditation and certification require difficult choices by surgical specialty organizations.21 At the local level, there are many challenges related to facility, personnel, time, and finance issues. Yet the paper by Herr et al adds further impetus to a mandate that these problems must be addressed and solved if we are to achieve better contemporary care and future prospects for the solid tumor patient. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES 1. Shahian DM: Improving cardiac surgery quality-volume, outcome, progress. JAMA 291:246-248, 2003
2. Begg CB, Cramer LD, Hoskins WJ, et al: Impact of hospital volume on operative mortality for major cancer surgery. JAMA 280:1747-1751, 1998
3. Begg CB, Riedel ER, Bach PB, et al: Variations in morbidity after radical prostatectomy. N Engl J Med: 346:1138-1144, 2002 4. Fisher B: The evolution of paradigms for the management of breast cancer: A personal perspective. Cancer 52:2371-2383, 1992
5. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002
6. Pantel K, Cote RJ, Fodstad O: Detection and clinical importance of micrometastatic disease. J Natl Cancer Inst 91:1113-1124, 1999 7. Cohen AM, Tremiterra S, Candela F, et al: Prognosis of node-positive colon cancer. Cancer 67:1859-1861, 1991[CrossRef][Medline] 8. Srinivas V, Morse MJ, Herr HW, et al: Penile cancer: Relation of extent of nodal metastasis to survival. J Urol 137:880-882, 1987[Medline] 9. Donohue JP, Thornhill JA, Foster RS, et al: The role of retroperitoneal lymphadenectomy in clinical stage B testis cancer: The Indiana University experience (1965-1989). J Urol 153:85-89, 1995[CrossRef][Medline]
10. Herr HW, Faulkner JR, Grossman HB, et al: Surgical factors impact bladder cancer outcomes: A cooperative group report. J Clin Oncol 22:2781-2789, 2004 11. Soloway MS, Lopez AE, Patel J, et al: Results of radical cystectomy for transitional cell carcinoma of the bladder and the effect of chemotherapy. Cancer 73:1926-1931, 1994[Medline]
12. 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 13. Leissner J, Hohenfellner R, Thuroff JW, et al: Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder: Significance for staging and prognosis. BJU Int 85:817-821, 2000[CrossRef][Medline] 14. 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]
15. 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 16. Kim H, Steinberg GD: The current status of bladder preservation in the treatment of muscle invasive bladder cancer. J Urol 164:627-632, 2000[Medline]
17. Le Voyer TE, Sigurdson ER, Hanlon AL: Colon cancer survival is associated with increasing number of lymph nodes analyzed: A secondary survey of intergroup trial INT-0089. J Clin Oncol: 21:2912-2919, 2003 18. Herr HW: Extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. Urol 61:105-108, 2003 19. American College of Surgeons Oncology Group Web site: http://www.acosog.org 20. Society of Urologic Oncology Web site: http://www.societyofurologiconcology.org 21. Lange PH: Urology in the 21st century: Futuristic musings. Urol 61:681-684, 2003
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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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