analyses relied on T stage, Fuhrman grade and presence of enm. Data were analysed using univariable, multivariable and stratified analyses.

Transcription

1 BJU INTERNATIONAL Urological Oncology EFFECT OF EXCLUSIVE DAL METASTASES ON CSS OF PATIENTS WITH RCC DIFFERS WITH T STAGE CAPITANIO et al. BJUI BJU INTERNATIONAL Stage-specific effect of nodal metastases on survival in patients with non-metastatic renal cell carcinoma Umberto Capitanio 1, Claudio Jeldres 1, Jean-Jacques Patard 2, Paul Perrotte 3, Laurent Zini 1, Alexandre de La Taille 4, Vincenzo Ficarra 5, Luca Cindolo 6, Karim Bensalah 2, Walter Artibani 7, Jacques Tostain 8, Antoine Valeri 9, Richard Zigeuner 10, Arnaud Méjean 10, Jean Luc Descotes 11, Eric Lechevallier 12, Peter F. Mulders 13, Herve Lang 13, Didier Jacqmin 14 and Pierre I. Karakiewicz 1,3 1 Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada, 2 Department of Urology, Rennes University Hospital, Rennes, France, 3 University of Montreal, Montreal, Quebec, Canada, 4 CHU Henri Mondor, Creteil, France, 5 University of Padua, Padua, 6 G. Rummo Hospital, Benevento, Italy, 7 St-Etienne University Hospital, St-Etienne, 8 Brest University Hospital, Brest, France, 9 Graz Medical University, Graz, Austria, 10 Necker Medical School, Paris, 11 Grenoble University Hospital, Grenoble, 12 Marseille University Hospital, Marseille, France, 13 Nijmegen University Hospital, the Netherlands, and 14 Strasbourg University Hospital, Strasbourg, France Accepted for publication 18 June 2008 Study Type Prognosis (retrospective cohort study) Level of Evidence 2b OBJECTIVE To quantify the survival disadvantage related to the presence of exclusive nodal metastases (enm) in patients with otherwise non-metastatic (M0) renal cell carcinoma (RCC). PATIENTS AND METHODS Data were retrieved from 12 institutional databases and yielded 3507 patients with T1-3N1-2M0 RCC treated with partial or radical nephrectomy. Cox regression analyses relied on T stage, Fuhrman grade and presence of enm. Data were analysed using univariable, multivariable and stratified analyses. RESULTS Overall 165 (4.7%) patients had enm; of 2023 patients of stage T1, 23 (1.1%) had enm, vs 20 of 448 (4.5%) for T2 and 122 of 993 (12.3%) for T3. In univariable analyses the presence of enm increased the rate of cancer specific mortality (CSM) by 7.1 times. After adjusting for T stage and Fuhrman grade, in all patients enm increased the rate of CSM by 3.2 times. In stratified analyses adjusted for Fuhrman grade, the increase in CSM related to the presence of enm was 28.9, 4.3 and 2.5 times (all P < 01) for stages T1, T2 and T3, respectively. CONCLUSIONS From the prognostic perspective, staging lymphadenectomy appears of most value in patients with T1-2 RCC, but the low prevalence of enm questions the practical applicability of nodal staging in those patients. Conversely, in patients with T3 RCC, the prevalence and the prognostic impact of enm might make a staging lymphadenectomy worthwhile. KEYWORDS renal cell carcinoma, radical nephrectomy, lymph node invasion, cause-specific survival INTRODUCTION The presence of nodal metastases is associated with a poor prognosis in patients with RCC but no distant metastases [1 8]. However, to date it is not known to what extent nodal metastases worsen cancerspecific survival (CSS) in such patients. Some of the difficulties relate to the clinical staging of lymph node metastases [9,10]. In many instances grossly enlarged lymph nodes will be benign. Conversely, in other instances, unenlarged lymph nodes might contain neoplastic cells. Therefore, nodal staging has so far been limited to surgical staging [11 13] in patients with suspected but unconfirmed lymph node metastases [12]. Our objective was to quantify the prevalence and the detriment to CSS associated with the presence of nodal metastases in all nonmetastatic patients with RCC, and in a stagespecific fashion for various T substages (T1 vs T2 vs T3). PATIENTS AND METHODS Data were retrieved from institutional databases for 3507 consecutive patients with RCC, who were treated with partial or radical 2008 BJU INTERNATIONAL 103, doi: /j x x 33

2 CAPITANIO ET AL. nephrectomy at one of 12 participating institutions between 1984 and 2001 (Table 1). Patients were staged before surgery with CT of the abdomen and pelvis, chest CT or radiography, serum electrolytes, and liver function tests. Tumours were classified according to the 2002 TNM staging system and according to Fuhrman grade [14]. All stages were reclassified according to the 2002 version of the Unione Internationale Contre le Cancer staging system manual [14]. The presence of nodal metastases was defined according to lymphadenectomy findings. Patients with no nodal metastases were classified as N0, vs N1 for patients with one positive lymph node vs N2 for patients with more than one positive lymph node. In all cases a hilar lymphadenectomy was performed and included all lymph nodes on the ipsilateral side of the great vessels. At several centres, on the basis of surgeon preference, more extensive lymphadenectomies that included interaortocaval lymph nodes were performed. The number of nodes removed, the number of metastatic nodes, and other specific details of the extent, technique and pathological handling of the lymphadenectomy specimens were not prospectively collected at all centres. Therefore these details could not be incorporated in the analyses. Nonetheless, in all cases the presence of nodal metastases was pathologically confirmed. Absence of distant metastases was confirmed on the basis of radiographic findings in all patients. The follow-up comprised one baseline visit after surgery and then at least every 6 months for 2 years. Subsequently, the minimum follow-up consisted of annual visits. At each visit, a CT of the chest or chest radiography accompanied CT of the abdomen. The cause of death was either obtained from the medical chart and recorded prospectively, or was obtained from the death certificate retrospectively. RCC-specific mortality included deaths that were directly attributable to kidney cancer. Kaplan-Meier plots were used to explore the effect of exclusive nodal metastases (enm) and other variables on CSS, and life-table analyses were used for actuarial survival predictions. Univariable and multivariable Cox regression analyses were used to assess the effect of enm on CSS. In multivariable analyses, covariates consisted of T stage, Fuhrman grade and the presence of enm. The analyses were restricted to patients with clear TABLE 1 The clinical characteristics of the 3507 patients with T1 43N1 2M0 RCC stratified according to lymph node status (pn0 vs pn1-2) Variable Overall Lymph node status pn0 pn1 2 P N (%) or mean (median, range) Total n 3507 (100) 3342 (95.3) 165 (4.7) Age, years 60.9 (62, 10 93) 60.9 (62, 10 93) 62.3 (65, 14 85) Gender 9 Male 2315 (66.0) 119 (72.1) 2196 (65.7) Female 1192 (34.0) 1146 (34.3) 46 (27.9) T stage <01 T1a 1145 (32.6) 1137 (34.0) 8 (4.8) T1b 901 (25.7) 886 (26.5) 15 (9.1) T2 468 (13.3) 448 (13.4) 20 (12.1) T3 993 (28.3) 871 (26.1) 122 (73.9) Tumour size, cm 6.0 ( 22) 5.8 ( 22) 8.8 (2.5 18) <01 Furhman grade <01 Low (1 2) 2414 (68.8) 2367 (7) 47 (28.5) High (3 4) 1093 (31.2) 996 (39.5) 118 (71.5) cell, papillary and chromophobe RCC variants. As these RCC subtypes do not have differential effects on CSS [15], we did not include histological subtypes in the multivariable analyses. Age and gender were also omitted, as they have no established independent prognostic value [16]. The same consideration was applied to Eastern Cooperative Oncology Group performance status and symptom classification [16]. Fuhrman grade was coded as either low (I II) or high (III IV) grade, according to the previously validated prognostic groupings [17] that dichotomized Fuhrman grade between low and high. The univariable and multivariable analyses were applied to all 3507 patients with T1-3N1-2M0 RCC. Subsequently, we subdivided the population into three groups that consisted of T1N0-2, T2N0-2 and T3N0-2 patients. In all analyses, adjustment was made for Fuhrman grade. The effect of T and N stage was controlled for by restriction in the three subset analyses. In all analyses the main variable of interest consisted of the nodal stage defined as N0 vs N1-2. All statistical tests were two-sided with a significance level set at 5. RESULTS Table 1 shows the clinical characteristics of all patients and for the two subsets stratified according to lymph node status (pn0 vs pn1-2). Overall, 165 patients had enm (4.7%); only 21 (%) were N2, and thus we did not analyse the effect of N1 vs N2 stage on CSS. The N1 and N2 stages were grouped as nodepositive patients. Of T1 patients, 23 (1.1%) had enm, vs 20 (2.3%) for T2 and 122 (12.3%) for T3. In all patients the median survival was not reached. At 1, 2, 5 and 10 years the CSS was, respectively, 97%, 93%, 86% and 78%. After stratifying for the presence of enm, the 1-, 2-, 5- and 10-year CSS rates were, respectively, 97%, 94%, 87% and 81% for patients with no enm vs 72%, 51%, 38% and 29% for patients with enm (log rank P < 01). The median survival was again not reached in patients with no enm, vs 24 months in patients with enm. In univariable analyses that focused on all patients the presence of enm increased the rate of cancer-specific mortality (CSM) by 7.1 times (P < 01; Fig. 1A). After adjusting for T stage and Fuhrman grade, the rate of CSM remained 3.2 times higher in patients with enm (P < 01). The analyses were repeated for each of the T subgroups (Fig. 1B D); for patients with T1 the 1-, 2-, 5- and 10-year CSS rates were 99%, 98%, 95% and 91%. When data were stratified according to the presence of the enm, the 1-, 2- and 5-year survival for patients with no enm was 99%, 98% and 96%, but was 81%, 56% and 41% (and 28% at BJU INTERNATIONAL

3 EFFECT OF EXCLUSIVE DAL METASTASES ON CSS OF PATIENTS WITH RCC DIFFERS WITH T STAGE FIG. 1. Kaplan-Meier survival curves depicting the cause-specific survival of overall population (A), T1 patients (B), T2 (C) and T3 (D) stratified according to presence of enm. A 0.9 Log Rank < HR C Log Rank < 01 HR years) for patients with enm (log rank P < 01). The median survival was not reached for patients with no enm but it was 35 months for patients with enm. In univariable analyses (Table 2) the presence of enm increased the risk of cancer-specific mortality by 27.6 times and by 28.9 times after adjusting for Fuhrman grade (both P < 01). B D Log Rank < 01 HR Log Rank < 01 HR patients with enm (log rank P < 01). The median survival was not reached for patients with no enm but it was 24 months for those with enm. In univariable analyses (Table 2), the presence of enm increased the risk of CSM by 2.9 times and remained 2.7 times higher after adjusting for Fuhrman grade (both P < 01). RCC, with an intermediate effect for patients with T2-3 RCC. Although the effect of enm increased with decreasing stage, the prevalence of enm directly increased with increasing T stage. For example, the rate of enm was 1.1% in patients with T1, vs 12.3% in those with T3. These findings imply that the presence of enm undermines CSS in stages T1 3. However, the likelihood of finding positive nodes is extremely low in those patients in whom the prognosis will be most affected by positive nodes, i.e. in pt1 2 RCC. The dichotomy between prevalence and prognostic significance poses a clinical dilemma, i.e. is it worthwhile to stage patients with a very low prevalence of nodal metastases (1.1%) even if the presence of enm increases the risk of CSM by 28.9 times? In our opinion the answer is no. Possibly, the advent of informative biomarkers capable of discriminating between positive and negative lymph nodes might assist clinicians to more accurately identify patients at high risk of enm. At present, a nomogram devised to identify such patients is 78.4% accurate [9]. However, a 22% misclassification rate associated with this nomogram might discourage some clinicians from applying it in clinical practice. Moreover, the nomogram might be <80% accurate in patients with pt1a disease, in whom the rate of nodal metastases (%) is even lower than the 2% found in the entire cohort of T1-2 patients [9]. For patients with T2 the 1-, 2-, 5- and 10-year CSS was 98%, 93%, 84% and 76%. When data were stratified according to the presence of the enm, the 1-, 2-, 5- and 10-year CSS for patients with no enm was 98%, 94%, 84% and 73%, vs 73%, 46%, 46% and 46% for patients with enm (log rank P < 01). The median survival was not reached for patients with no enm but it was 22 months for patients with enm. In univariable analyses (Table 2), the presence of enm increased the risk of CSM by 4.7 times and remained 4.3 times higher after adjusting for Fuhrman grade (both P < 01). For patients with T3 the 1-, 2-, 5- and 10-year CSS was 91%, 82%, 67% and 54%. When data were stratified according to the presence of the enm, the 1-, 2-, 5- and 10-year CSS for patients with no enm was 92%, 85%, 70% and 57%, vs 70%, 51%, 37% and 29% for DISCUSSION Available data on the effect of enm on the natural history of treated RCC are scarce [12,18 21]. For example, two large series addressing cancer control outcomes after nephrectomy for patients with enm included 211 patients [18,19]. The paucity of outcomes makes it difficult to ascertain the importance of enm and the effect on CSM. We examined the effect of enm in patients with nonmetastatic RCC, as the potential detrimental effect of enm might have a profound influence on the treated natural history of RCC. Specifically, we attempted to quantify the prevalence and the effect of enm on CSS for specific stages. Our analyses relied on one of the largest multi-institutional European cohorts, and showed that the effect of enm depends on T stage. Overall, enm have the strongest impact on CSS of patients with T1 Conversely, is it of value to stage patients with pt3 RCC, in whom the rate of nodal metastases is substantially higher (12.3%) but in whom the CSM is only increased by 2.5 times, if nodal metastases are found? The answer to this question is not clear. The only randomized clinical trial of lymphadenectomy showed no survival benefit [11]. Furthermore, there are no data indicating that the use of targeted therapies in an adjuvant setting might improve CSS [22 28], e.g. if lymph nodes are involved. Therefore, the choice of performing a lymphadenectomy might be based on the feasibility and potential morbidity of lymphadenectomy, where the putative benefit is carefully weighed against risks. Notably, a hilar lymphadenectomy dissection, as reported by Blom et al. [11], is not associated with greater morbidity than no lymphadenectomy. However, the morbidity might substantially increase if bulky inter BJU INTERNATIONAL 35

4 CAPITANIO ET AL. TABLE 2 Univariable (UVA) and multivariable (MVA) Cox regression models predicting the rate of CSM in all 3507 patients and in the subgroups of those with T1 (2046), T2 (468) and T3 (993) RCC Hazard ratio; P All patients T1 T2 T3 Variable UVA MVA UVA MVA UVA MVA UVA MVA T stage T1 ; <01 ; <01 T2 vs T1 3.0; <01 2.5; <01 T3 vs T1 7.1; <01 4.1; <01 N stage N1 vs N0 7.1; <01 3.2; < ; < ; <01 4.7; <01 4.3; <01 2.8; <01 2.5; <01 Fuhrman grade High vs low 4.3; <01 2.1; <01 2.5; <01 2.7; <01 1.5; 9 1.3; 2.7; <01 2.5; <01 aortocaval lymph nodes are completely resected [11] Taken together, our findings indicate that the presence of enm has the strongest effect on CSS in a very small subset of patients (pt1-2). Unfortunately, due to the low prevalence of enm in this patient subgroup, an extended lymphadenectomy cannot be suggested. The present study has several weaknesses. First, our analyses are based on hilar lymph node dissections (LNDs). Hilar lymph nodes do not represent a sentinel landing zone for RCC. Lymph node metastases might be situated in the inter-aortocaval region and on the contralateral aspect of the great vessels. There might also be skip areas, so that hilar nodes might be exempt from metastases but inter-aortocaval or contralateral nodes might be involved. Therefore, our study needs to be interpreted as an assessment of the detriment in CSS secondary to the presence of invasion of hilar lymph nodes. Despite the limitation in the extent of LND, the resection of hilar nodes still represents the standard of care, when a LND is performed for RCC [12,29]. More extensive LNDs are not recommended [6,12,20]. The inclusion of data from several institutions might also be considered as a weakness. Multi-institutional data with no central pathology review tend to introduce interobserver biases [30]. Additional differences might be introduced by the variability in surgical technique or extent of LND at participating centres. The small sample size might represent another limitation, but patients with enm are relatively rare, and it is difficult to include many such patients. Our data do not allow us to assess the effect of the extent of LND or the density of positive nodes. Similarly, we have no detail on pathological specimen handling or evaluation. In addition, we do not have all the information on adjuvant and/or salvage treatment regimens of the included patients. Some received adjuvant immunotherapy, while others received immunotherapy at relapse. Some were treated with experimental chemotherapy, while others received only the best supportive care. Nonetheless, our survival findings might have been contaminated by the effect of immunotherapy in some individuals. In conclusion, the presence of enm undermines the CSS of patients with RCC. However, due to the very low prevalence it appears highly impractical to undertake a thorough lymphadenectomy in low-stage patients, despite the prognostic effect of nodal metastases being very important. Therefore, from a practical perspective a staging lymphadenectomy only appears warranted in the group of patients with T3 in whom the prevalence and the prognostic implications are not negligible. In neither category does a staging lymphadenectomy appear to be clearly warranted. ACKWLEDGEMENTS Dr Pierre I. Karakiewicz is partly supported by the University of Montreal Urology Associates, Fonds de la Recherche en Santé du Québec, the University of Montreal Department of Surgery and the University of Montreal Foundation. CONFLICT OF INTEREST None declared. REFERENCES 1 Antonelli A, Cozzoli A, Zani D et al. The follow-up management of nonmetastatic renal cell carcinoma: definition of a surveillance protocol. BJU Int 2007; 99: Klatte T, Wunderlich H, Patard JJ et al. Clinicopathological features and prognosis of synchronous bilateral renal cell carcinoma: an international multicentre experience. BJU Int 2007; 100: Verhoest G, Veillard D, Guille F et al. Relationship between age at diagnosis and clinicopathologic features of renal cell carcinoma. Eur Urol 2007; 51: Terrone C, Cracco C, Porpiglia F et al. Reassessing the current TNM lymph node staging for renal cell carcinoma. Eur Urol 2006; 49: Patard JJ. Prognostic and biological significance of lymph node spreading in renal cell carcinoma. Eur Urol 2006; 49: Ficarra V, Novara G, Iafrate M et al. Proposal for reclassification of the TNM staging system in patients with locally advanced (pt3 4) renal cell carcinoma according to the cancer-related outcome. Eur Urol 2007; 51: Margulis V, Tamboli P, Jacobsohn KM, Swanson DA, Wood CG. Oncological efficacy and safety of nephron-sparing surgery for selected patients with locally advanced renal cell carcinoma. BJU Int 2007; 100: Bandi G, Christian MW, Hedican SP, Moon TD, Nakada SY. Oncological outcomes of hand-assisted laparoscopic radical nephrectomy for clinically BJU INTERNATIONAL

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