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Importance of Node Dissection in Relation to Neoadjuvant and Adjuvant Therapy JN04X_Jrnl_41011Bochn.qxd 11/7/06 11:56 AM Page 1019 1019 Original Article Importance of Node Dissection in Relation to Neoadjuvant and Adjuvant Therapy William C. Huang, MD, and Bernard H. Bochner, MD, New York, New York Key Words opment of regional lymph node (LN) involvement, dis- Bladder cancer, pelvic lymph node dissection, lymphadenectomy, tant disseminated disease, and death.2,3 chemotherapy Radical cystectomy with pelvic lymphadenectomy (RC/PLND) is currently the gold standard treatment for Abstract managing localized and regionally advanced invasive Since the advent of effective chemotherapeutic regimens for treat- bladder cancer. Although RC/PLND cures most patients ing transitional cell carcinoma, multimodal therapy has become part with organ-confined disease, the risk for recurrence after of the contemporary management of patients with muscle-invasive bladder cancer. However, radical cystectomy with pelvic lym- surgery significantly increases for tumors extending beyond phadenectomy remains the cornerstone of treatment for patients the confines of the bladder or involving the regional with localized and regionally advanced muscle-invasive disease. The pelvic LNs.4–6 The incidence of node-positive bladder effectiveness of chemotherapy models in bladder cancer can de- cancer in contemporary surgical series is relatively high, pend greatly on the quality of surgery. Unfortunately, without suf- with approximately 25% of patients who undergo ficient level I data, the boundaries of lymphadenectomy and the RC/PLND showing pathologic evidence of LN metasta- diagnostic and therapeutic ramifications of variations in the pelvic 1,5–8 lymph node dissection remain undetermined. This article examines sis. Autopsy studies and clinical observations have the role of pelvic lymph node dissection during perioperative documented that the risk for nodal or distant metastatic chemotherapy and discusses the current challenges in establishing disease directly correlates with the depth of invasion of standards for lymphadenectomy in patients undergoing treatment the primary tumor within the bladder.2,3,9 Regional LN for muscle-invasive bladder cancer. (JNCCN 2006;4:1019–1026) involvement has been identified in 6% to 19% of pa- tients with organ-confined, invasive bladder cancer and Muscle-invasive transitional cell carcinoma (TCC) of in 30% to 75% of patients with extravesical or locally the bladder is a potentially lethal epithelial malignancy advanced primary tumors.5,10,11 The presence of LN in- characterized by the ability to invade, locally progress, volvement is a poor prognostic characteristic associated and subsequently metastasize. Of the 63,000 annual new with a high risk for disease recurrence and reduced over- diagnoses of bladder cancer in the United States, 90% all survival.4–6,12 Data from a large consortium of centers are of TCC histology, with roughly one fourth of patients of excellence (The International Bladder Cancer presenting with muscle invasive disease.1 Patients with Nomogram Consortium) on more than 9000 patients muscle invasive TCC account for most of the 12,500 treated with RC/PLND document that those with organ- bladder cancer–related deaths each year,1 because the confined, LN-negative tumors have a 5-year survival rate depth of invasion is strongly associated with the devel- of approximately 80% compared with 30% for patients with involved regional LNs.12 From the Department of Urology, Memorial Sloan-Kettering Cancer Chemotherapy and Bladder Cancer Center, New York, New York. Submitted July 31, 2006; accepted for publication August 7, 2006. Because of the poor prognosis associated with dissemi- The authors received funding from an NIH T32 Research Training nated TCC, a great deal of effort has gone into develop- Grant (WCH) and The Allbritton Foundation (BHB). ing effective systemic treatments for advanced disease. Correspondence: Bernard H. Bochner, MD, Department of Urology, Memorial Sloan-Kettering Cancer Center, 353 East 68th Street, New TCC is a chemotherapy-sensitive neoplasm, with cisplatin York, NY 10021. E-mail: [email protected] emerging as the most effective systemic agent.13 Although © Journal of the National Comprehensive Cancer Network | Volume 4 Number 10 | November 2006 JN04X_Jrnl_41011Bochn.qxd 11/7/06 11:56 AM Page 1020 1020 Original Article Huang and Bochner limited responses were initially observed with cisplatin viding excellent rates of local control and long-term as a single agent,14 results from clinical trials incorpo- survival, particularly in patients with localized dis- rating cisplatin into a multiagent drug regimen showed ease.12 With significant reductions in treatment- improved response proportions. In the late 1980s, in- related morbidity and mortality and the advent of vestigators at Memorial Sloan-Kettering Cancer orthotopic bladder substitution techniques, the pop- Center (MSKCC) reported that 69% (± 10%) of pa- ularity of RC has increased. Although wide excision tients with metastatic bladder cancer treated with a of the bladder and the perivesical tissues is recognized combination of methotrexate, vinblastine, doxoru- as an essential component of the surgical management bicin, and cisplatin (MVAC) experienced complete or of invasive bladder cancer, mounting data also sup- partial responses.15 Multiple randomized control tri- port a critical role for PLND in optimizing surgical als then compared MVAC with single-agent cisplatin outcomes. and other multiagent platinum-containing regi- The importance of controlling the regional lym- mens,16,17 showing its superiority, and established it as phatics became apparent soon after the earliest cys- the standard for patients with metastatic bladder can- tectomy series reported unacceptably high local cer. Unfortunately, MVAC is associated with consid- recurrence rates. The initial techniques used for sur- erable toxicities, including granulocytopenia, renal gical extirpation of the bladder made little attempt to toxicity, and peripheral neuropathy.15–17 completely excise the perivesical tissues or control the To lessen the morbidity associated with treatment, regional pelvic LNs. Poor local tumor control and dis- alternative regimens were evaluated, including the mal long-term survival observed in historical series doublet of gemcitabine and cisplatin (GC). In a phase led to the development of more radical surgical tech- III randomized, multicenter trial, the combination of niques, which were largely based on autopsy studies and GC resulted in equivalent response and survival rates clinical observations published from the 1930s through compared with MVAC in patients with metastatic the 1950s.2,3,9,26 Based on an understanding of the path- TCC. However, patients treated with GC experienced ways of invasive bladder cancer progression and the re- significantly lower rates of granulocytopenia, neu- lationship between the depth of invasion of the 18 tropenic fever, and sepsis. Based on the similar re- primary tumor and the development of regionally sponse rates and lower toxicity profile, GC has emerged metastatic disease, procedures were adopted that in- as the preferred regimen for patients undergoing sys- corporated a thorough PLND at bladder removal. temic chemotherapy for TCC. Reports then emerged documenting the ability of RC Because of the significant risk for distant failure in and PLND to reduce the risk for local recurrence and patients undergoing cystectomy for locally advanced improve overall survival.3,26,27 or regionally metastatic disease, strategies to incor- Over the next 30 years, RC/PLND became pop- porate effective systemic chemotherapy in the peri- ular, and reported outcomes confirmed that the addi- operative period have been completed. Multiple trials tion of a thorough PLND could be performed safely evaluating both neoadjuvant and adjuvant chemother- with improvements in outcomes.28,29 Unlike the poor apy have documented a survival benefit in patients initial outcomes that patients with surgically treated, undergoing chemotherapy in conjunction with node-positive bladder cancer experienced, contem- 19–25 RC/PLND. Regardless of the chemotherapeutic porary series show that approximately one third of all approach, RC/PLND continues to be the cornerstone node-positive patients can be rendered disease-free of the overall treatment plan. This article focuses on when treated with RC and a thorough PLND.5,6,29 the role of surgery, specifically PLND, in the multi- Despite the consensus among urologic surgeons modal management of high-risk bladder cancer and that a PLND should be performed at cystectomy, discusses the problems associated with establishing controversy remains as to the optimal extent of PLND contemporary standards for PLND. required for the most favorable outcome. No clear guidelines exist regarding the boundaries of Role of Surgery in Muscle-Invasive lymphadenectomy or the critical number of nodes that Bladder Cancer should be removed during RC/PLND to ensure ade- RC has long been considered the most effective local quate staging and provide maximum therapeutic ben- treatment for muscle-invasive bladder cancer, pro- efit. Without a universally accepted standard, © Journal of the National Comprehensive Cancer Network | Volume 4 Number 10 | November 2006 JN04X_Jrnl_41011Bochn.qxd 11/7/06 11:56 AM Page 1021 Original Article 1021 Node Dissection in Neoadjuvant and Adjuvant Therapy significant variations in the quality of RC/PLND have been noted in most published series and data obtained from general
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