Lymph Node Dissection in Patients With Kidney Cancer: When Is It Indicated?

POINT-COUNTERPOINT Lymph Node Dissection in Patients With Kidney Cancer: When Is It Indicated? Ganesh S. Palapattu, MD, Hyung L. Kim, MD, Arie S. Belldegrun, MD, FACS Division of Urologic Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA It is necessary to consider the potential risks and benefits of performing a lymph node dissection (LND) at the time of radical nephrectomy. LND may lead to more accurate staging, a decrease in local recurrence, and an increase in survival for patients with metastatic disease limited to the resected lymph nodes. However, there are risks associated with the treatment that must be considered. The advantages of LND vary among patients, depending on the location and extent of disease progression. For patients with stage T3 or T4 disease, we recommend a limited LND. Patients with T3 or T4 disease with grossly positive nodes with or without hematogenous metastasis should undergo a more extensive LND. [Rev Urol. 2003;5(3):196–199] © 2003 MedReviews, LLC Key words: Lymph node dissection • Nephrectomy • Kidney cancer • Lymphadenectomy ecent advances in the treatment options available to patients with kidney cancer have once again called into question the importance of performing a lymph node dissection (LND) at the time of radical nephrectomy. Before a clear recommendation can be made, we must be able to justify the risks as well as demonstrate a significant benefit from this intervention. R 196 VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY Lymph Node Dissection in Kidney Cancer What Are the Potential Benefits? There are several potential benefits to performing a retroperitoneal LND at the time of nephrectomy. An LND may lead to more accurate staging. The more extensive dissection of perinephric tissue necessitated by an LND may decrease the risk of positive margins and, thus, lead to a lower risk of local recurrence. Finally, an LND may cure a select group of patients with metastatic disease limited to the resected nodes and, thus, lead to improved survival. More Accurate Staging? The extent of the disease, as defined by tumor stage, is one of the most significant predictors of survival in patients with renal cell carcinoma. Our tive imaging are more likely to undergo an LND and have lymph node involvement. In a subset analysis of patients with clinically organconfined disease, patients with fewer than 13 recovered nodes had a 3.4% risk of being identified as node positive, and patients with 13 or more recovered nodes had a 10.5% risk of being identified as node positive.3 Nodal involvement has important clinical implications. Patients with nodal disease are at higher risk for disease recurrence and should be considered for clinical trials of adjuvant therapy.4 Furthermore, in designing clinical trials that include nephrectomy, the surgical treatment should be standardized; either LND is performed in all patients or in no Lymph node metastasis has long been known to be a poor prognostic factor in kidney cancer. group, as well as others, has developed a prognostic system to identify patients at risk for disease recurrence or progression that incorporates many clinicopathologic variables, including lymph node status.1 Lymph node metastasis has long been known to be a poor prognostic factor in kidney cancer. Lymph node status is an important prognostic factor even in the presence of distant hematogenous metastasis; we have recently shown that the number of different organ systems involved is of greater prognostic significance than the specific site of metastasis.2 In a recent study of more than 700 patients, Terrone and colleagues3 demonstrated that the number of lymph nodes recovered during a nephrectomy directly correlates with the likelihood of being staged as node positive. This relationship is unlikely to simply reflect the fact that patients with lymphadenopathy on preopera- patients. If LND is performed, a uniform template should be used by all participating surgeons. This will ensure consistent staging of disease and facilitate interpretation of patient outcomes. Decreased Risk of Local Recurrence? The current retrospective data suggest that there is a decrease in local recurrence after nephrectomy plus LND (2.5%-8%) versus nephrectomy alone (11%).5-7 However, these studies were performed before the widespread use of modern imaging technology. In many of these patients, disease was likely understaged preoperatively. In our experience at UCLA, the local recurrence rate is significantly lower among patients clinically staged with helical computed tomography scans: patients who did not undergo a formal retroperitoneal LND had a 2.8% local recurrence rate (unpublished data). Given such a low recurrence rate, there is little room for improvement, and it is unlikely that an extensive nodal dissection will significantly improve outcome. Improved Survival? Several studies have indicated that there might be a survival advantage to performing an LND at the time of nephrectomy. Peters and Brown8 performed a retrospective study of 356 patients that demonstrated a 5-year survival advantage for patients with Robson stage C tumors who received an LND at the time of nephrectomy compared with those who did not (44% vs 26%, respectively). Of interest, this study did not show an overall 5-year survival advantage for Robson stage A and B patients in whom LND was performed. However, Herrlinger and colleagues9 published a retrospective review of 511 patients that revealed a 5-year survival advantage for patients with Robson stage I-III tumors who had lymphadenectomy performed at the time of nephrectomy (ie, 66% vs 58%). Other retrospective studies did not demonstrate a survival advantage in patients treated with LND.10-12 For example, Schafhauser and colleagues10 compared survival among 3 groups of patients treated with nephrectomy: those treated with extensive lymphadenectomy, those receiving lymphadenectomy for gross nodal disease only, and those receiving no LND. After adjusting for age, at both 5 and 10 years, there was no significant survival advantage for any particular group. All of these studies are extremely difficult to interpret, given the confounding nature of their designs. All were nonrandomized and retrospective. The only prospective, randomized, controlled study to address this question (EORTC 30881) is still maturing.13 In this study, 772 patients with clinically localized disease were ran- VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY 197 Lymph Node Dissection in Kidney Cancer continued domized to nephrectomy with or without a standardized LND. We will have to await the completion of this study before passing judgment on the issue of survival impact with lymphadenectomy. There is reasonable evidence, however, to suggest that patients with metastasis and grossly positive lymph nodes who receive a nephrectomy plus lymphadenectomy have a prolonged survival after immunotherapy with IL-2 compared with patients who receive a nephrectomy and immunotherapy only.4 Patients with complete responses to immunotherapy have the best chance of long-term survival. We have noted that bulky lymphadenopathy almost never responds to immunotherapy. Therefore, surgical removal offers the best hope for achieving a complete response. What Are the Risks? There are certainly potential benefits to performing an LND. However, all potential benefits must be weighed against the risks associated with the treatment. The main risks associated with LND are bleeding, persistent lymph leakage, and damage to surrounding tissues. In patients without radiographic evidence of nodal metastasis, the morbidity associated with a radical nephrectomy plus lymphadenectomy versus a radical nephrectomy alone is minimal. Indeed, the only prospective ran- Table 1 LND Recommendations in Patients With Kidney Cancer Diffuse Metastasis Stages Clinical Nodes T1/T2 No No LND No LND Yes Extensive LND Regional/gross LND No Limited LND No LND Yes Extensive/gross LND Regional/gross LND T3/T4 No Yes LND, lymph node dissection. domized trial addressing this issue has found no significant increase in morbidity with addition of lymphadenectomy.13 What Do We Do? The low incidence (approximately 5%) of lymph node metastasis in patients with T1 and T2 tumors precludes a broad recommendation that these patients undergo routine lymphadenectomy in the absence of grossly positive nodes. However, in patients with gross nodal disease, we would advocate lymphadenectomy when achievable—even in the presence of distant metastasis. This is based on the rationale that in doing so we are obtaining more prognostic information and possibly performing a cytoreductive procedure. The type of LND that we recommend depends on the extent of the disease (Table 1). The extensive LND extends from the crus of the ipsilateral diaphragm superiorly to the medial border of the contralateral great vessel (including interaortocaval) medially to the bifurcation of the ipsilateral great vessel inferiorly. For patients with stage T3 or T4 disease, the incidence of occult lymph node metastasis is approximately 20%. Therefore, we would recommend a more limited LND in these patients, even with apparently clinically localized disease. Given the low morbidity of a limited LND in these patients, we believe the additional pathologic information garnered from this procedure may be of some value. We suggest a dissection that begins at the level of the renal hilum superiorly to the anterior, posterior, and lateral aspects of the ipsilateral great vessel down to the level of the infe- Main Points • Lymph node dissection (LND) may lead to more accurate staging and may decrease the risk of positive margins, leading to a lower risk of local recurrence. LND may also cure patients with metastatic disease limited to the resected nodes. • The main risks of LND are bleeding, persistent lymph leakage, and damage to surrounding tissues. • The type of LND recommended by physicians depends on the extent of the disease. • We believe that, for patients in whom post-nephrectomy immunotherapy is considered, grossly positive nodes should be removed when possible. • We are beginning to understand that each patient may in fact need a distinct combination of therapies based on several histopathologic, clinical, and molecular variables. 198 VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY Lymph Node Dissection in Kidney Cancer in all cases was to cure. Today, with modern immunotherapy, the outcomes for patients with advanced kidney cancer are improved and the focus of surgery has slightly shifted to include cytoreductive approaches. 3. Today, with modern immunotherapy, the outcomes for patients with advanced kidney cancer are improved and the focus of surgery has slightly shifted to include cytoreductive approaches. 6. rior mesenteric artery. Patients with T3 or T4 disease with grossly positive nodes with or without metastasis should receive a gross lymphadenectomy with a regional (peri-hilar nodes) or extensive LND, respective- 4. 5. 7. 8. ly (see Table 1). We believe that, for patients in whom post-nephrectomy immunotherapy is considered, grossly positive nodes should be removed when possible. As integrated staging systems are becoming more sophisticated, so are treatment strategies for patients with kidney cancer. We are beginning to understand that each patient may in fact need a distinct combination of therapies based on several histopathologic, clinical, and molecular variables. In the past, adjuvant therapies for kidney cancer had extremely poor results, so the goal of surgery Until large, multicenter, prospective, randomized trials are completed, we may never know for certain the answers to such questions as the efficacy of lymphadenectomy in patients with kidney cancer. Pending these studies, we should continue to formulate rational treatment plans. 2. 10. 11. 12. References 1. 9. Zisman A, Pantuck AJ, Dorey F, et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol. 2001;19:1649–1657. Han KR, Pantuck AJ, Bui M, et al. Number of metastatic sites rather than location dictates overall survival of patients with node-negative metastatic renal cell carcinoma. Urology. 2003;61:314–319. 13. Terrone C, Guercio S, De Luca S, et al. The number of lymph nodes examined and staging accuracy in renal cell carcinoma. BJU Int. 2003;91:37–40. Pantuck AJ, Zisman A, Dorey F, et al. Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol. 2003;169:2076–2083. Phillips E, Messing E. Role of lymphadenectomy in the treatment of renal cell carcinoma. Urology. 1993;41:9–15. Giuliani L, Martorana C, Giberti C, et al. Results of radical nephrectomy with extensive lymphadenectomy for renal cell carcinoma. J Urol. 1983;130:664–668. Skinner DG, Vermillion CD, Anderson W. The surgical management of renal cell carcinoma. J Urol. 1969;101:297. Peters PC, Brown GL. The role of lymphadenectomy in the management of renal cell carcinoma. Urol Clin North Am. 1980;7:705–709. Herrlinger A, Schrott KM, Schott G, Sigel A. What are the benefits of extended dissection of the regional renal lymph nodes in the therapy of renal cell carcinoma. J Urol. 1991;146:1224–1227. Schafhauser W, Ebert A, Brod J, et al. Lymph node involvement in renal cell carcinoma and survival chance by systematic lymphadenectomy. Anticancer Res. 1999;19:1573–1578. Siminovitch JP, Montie JE, Straffon RA. Lymphadenectomy in renal adenocarcinoma. J Urol. 1982;127:1090. Minervini A, Lilas L, Morelli C, et al. Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery? BJU Int. 2001;88:169–172. Blom JH, Van Poppel H, Marechal JM, et al. Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol. 1999;36:570–575. VOL. 5 NO. 3 2003 REVIEWS IN UROLOGY 199