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The Extent of Lymph Node Dissection in Patients with Localised Prostate Cancer: Debate Continues
european urology 51 (2007) 1472–1474
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial –
referring to the article published on pp. 1573–1581 of this issue
The Extent of Lymph Node Dissection in Patients with Localised Prostate Cancer: Debate Continues Levent Tu¨rkeri * Marmara University School of Medicine, Department of Urology, Istanbul, Turkey
The extent of lymph node dissection during radical prostatectomy has been a source of recent controversy. Introduction of prostate-specific antigen (PSA) into clinical practice resulted in a stage shift along with a decreasing incidence of lymph node metastasis in patients with prostate cancer [1]. A recent analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry clearly identified changing patterns of lymph node dissection during the last decade, including omission of the procedure at the time of radical prostatectomy in low- and medium-risk patients [2]. Although the rate of positive nodes is generally very low in this category of patients, it may be due, at least in part, to the surgical technique. The study by Allaf et al in a similar patient population revealed a positive lymph node rate of 3.2% with extended lymph node dissection compared to 1.1% with a more limited technique [3]. Consequently, the issue of the extent of node dissection has two important factors for clinical relevance. First of all, a more accurate staging of disease allows better identification of patients who may benefit from adjuvant therapy when instituted early as shown by a randomised clinical trial [4]. Second, excision of low-volume or limited lymph node metastases may transform the procedure into a potentially curative one, as reported recently from Europe [5]. However, controversy still continues because two recent studies indicated that the extent of lymph node dissection does not affect outcome, albeit the
analyses were based mainly on data from limited lymphadenectomy [1,6]. In a study by Heidenreich et al, without any significant differences in age, preoperative PSA, or mean biopsy Gleason score, 26.2% and 12% of the patients who underwent extended pelvic and standard lymphadenectomy had metastases, respectively [7], indicating the superiority of the former in accurate staging. The incidence of lymph node metastases was 56.3% in patients with a high Gleason score (>7) and PSA > 10 ng/ml, in contrast to 2% in patients with serum PSA < 10.5 ng/ml. Positive lymph nodes were outside the regions of standard pelvic lymphadenectomy in 42% of the samples. Therefore, the authors suggested that all patients with unfavourable preoperative prognostic factors should undergo extended lymph node dissection. Similar findings were observed in a study by Bader et al in which positive lymph nodes were identified in 25% of the patients with clinically localised prostate cancer after extended dissection [5]. Although omission of lymph node dissection in low-risk patients appeared to gain acceptance in the urologic community [2], data from the literature indicates the presence of a small but significant risk of lymph node metastases even in patients with a clinically low-risk profile. Lymph node metastases were found in 12% of patients with a preoperative PSA level of <10 ng/ml in a recent clinical series [8]. In fact, the incidence of positive lymph nodes was
DOI of original article: 10.1016/j.eururo.2007.01.108 * Marmara University Hospital, Tophanelioglu cad. No. 13–15, Altunizade 34662, Istanbul, Turkey. Tel. +90 216 325 2052; Fax: +90 216 325 8579. E-mail address: [email protected] (L. Tu¨rkeri). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.02.040
european urology 51 (2007) 1472–1474
10% in patients with a PSA < 10 ng/ml and cytologic grade 1 or 2. Even in patients with a PSA level of <4 ng/ml, lymph node metastases were identified in 10% of the cases by extended dissection in this study. The role of lymphadenectomy on disease-specific and overall survival in patients with metastatic lymph nodes is also controversial at present. In contrast to two recent studies, where no effect of the extent of lymphadenectomy was observed in prostate cancer outcome [1,6], in a retrospective analysis of 4000 patients operated on by two surgeons [3], overall 5-yr biochemical progression-free survival for patients with node-positive disease who underwent extended dissection was 34.4% compared to 16.5% with limited technique ( p = 0.07). After further stratification of patients according to the percentage of positive lymph nodes, limited disease was associated with a significantly higher 5-yr progression-free survival in the extended lymph node dissection group (42% and 10%, respectively; p = 0.01). In support of these findings, Bader et al identified the number of lymph node metastases as the only variable significantly affecting the progression and cancer-specific survival by multivariate Cox proportional hazards analysis of their data [5]. After a median follow-up of 45 mo, 92% of the patients with only one positive lymph node were alive compared to 67.4% of the patients with two or more positive nodes. These findings supported results of previous retrospective studies, which indicated that survival could be related to the number of lymph node metastases and that radical prostatectomy can be curative at least in some of these patients. Thus, data from clinical series makes it almost impossible to draw a line below which lymphadenectomy does not contribute either to accurate staging or the disease outcome. Therefore, proper preoperative identification of patients with possible lymph node involvement appears to make a difference and efforts for better prediction have already been undertaken. Subsequently, in 2006, a nomogram was developed based on clinical parameters that predicted metastatic spread to the lymph nodes in extended lymphadenectomy specimens with an accuracy rate of 76% [9]. In this issue of European Urology, Briganti et al report on further refinement of their previous nomogram with an enhanced ability to accurately predict lymph node involvement by using, for the first time, the percentage of positive biopsy cores in addition to other readily available clinical variables such as Gleason score, clinical stage, and PSA level [10]. The importance of this study stems from the selection of a cohort of 278 patients who
1473
underwent a careful extendend lymphadenectomy at the time of radical prostatectomy. Obviously, this is a prerequisite for valid scientific conclusions, which was lacking in studies analysing data from limited lymphadenectomy series. Detailed analysis in this study indicated the percentage of positive biopsy cores as the most informative individual and multivariate predictor of lymph node metastases in men who underwent extended pelvic lymph node dissection and had the greatest effect in improving the combined multivariate predictive accuracy of Gleason score, clinical stage, and PSA, up to 81%. One should be aware of the fact that even with the most recent evidence in the literature, it is still possible to miss 20% of the cases with lymph node involvement if extended dissection is omitted. Nevertheless, this study clearly demonstrates the potential for refining our ability to better predict patients who may need more extensive dissection, while sparing the rest. This study also underlines the insufficient nature of particular biopsy parameters for the exact prediction and the need for more novel markers. Although studies of this kind are a step further towards selection of the scale of lymph node dissection, they are still not perfect and the issue of prognostic relevance of the extent of lymphadenectomy in terms of disease-free and overall survival still continues to be a dilemma. This issue, most probably, will not be resolved until a welldesigned, prospective, randomised clinical trial is performed with the above-mentioned parameters as the trial end points. References [1] DiMarco DS, Zincke H, Sebo TJ, Slezak J, Bergstralh EJ, Blute ML. The extent of lymphadenectomy for pTXNO prostate cancer does not affect prostate cancer outcome in the prostate specific antigen era. J Urol 2005;173: 1121–5. [2] Kawakami J, Meng MV, Sadetsky N, Latini DM, Duchane J, Carroll PR. Changing patterns of pelvic lymphadenectomy for prostate cancer: results from CaPSURE. J Urol 2006;176: 1382–6. [3] Allaf ME, Palapattu GS, Trock BJ, Carter HB, Walsh PC. Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. J Urol 2004;172:1840–4. [4] Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781–8. [5] Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph
1474
european urology 51 (2007) 1472–1474
nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169:849–54. [6] Berglund RK, Sadetsky N, DuChane J, Carroll PR, Klein EA. Limited pelvic lymph node dissection at the time of radical prostatectomy does not affect 5-year failure rates for low, intermediate and high risk prostate cancer: results from CaPSURE. J Urol 2007;177:526–9, discussion 529–30. [7] Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167:1681–6. [8] Burkhard FC, Bader P, Schneider E, Markwalder R, Studer UE. Reliability of preoperative values to determine the
need for lymphadenectomy in patients with prostate cancer and meticulous lymph node dissection. Eur Urol 2002;42:84–90, discussion 90–2. [9] Briganti A, Chun FK-H, Salonia A, et al. Validation of a nomogram predicting the probability of lymph node invasion among patients undergoing radical prostatectomy and an extended pelvic lymphadenectomy. Eur Urol 2006;49:1019–26, discussion 1026–7. [10] Briganti A, Karakiewicz PI, Chun FK-H, et al. Percentage of positive biopsy cores can improve the ability to predict lymph node invasion in patients undergoing radical prostatectomy and extended pelvic lymph node dissection. Eur Urol 2007;51:1573–81.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial –
referring to the article published on pp. 1573–1581 of this issue
The Extent of Lymph Node Dissection in Patients with Localised Prostate Cancer: Debate Continues Levent Tu¨rkeri * Marmara University School of Medicine, Department of Urology, Istanbul, Turkey
The extent of lymph node dissection during radical prostatectomy has been a source of recent controversy. Introduction of prostate-specific antigen (PSA) into clinical practice resulted in a stage shift along with a decreasing incidence of lymph node metastasis in patients with prostate cancer [1]. A recent analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry clearly identified changing patterns of lymph node dissection during the last decade, including omission of the procedure at the time of radical prostatectomy in low- and medium-risk patients [2]. Although the rate of positive nodes is generally very low in this category of patients, it may be due, at least in part, to the surgical technique. The study by Allaf et al in a similar patient population revealed a positive lymph node rate of 3.2% with extended lymph node dissection compared to 1.1% with a more limited technique [3]. Consequently, the issue of the extent of node dissection has two important factors for clinical relevance. First of all, a more accurate staging of disease allows better identification of patients who may benefit from adjuvant therapy when instituted early as shown by a randomised clinical trial [4]. Second, excision of low-volume or limited lymph node metastases may transform the procedure into a potentially curative one, as reported recently from Europe [5]. However, controversy still continues because two recent studies indicated that the extent of lymph node dissection does not affect outcome, albeit the
analyses were based mainly on data from limited lymphadenectomy [1,6]. In a study by Heidenreich et al, without any significant differences in age, preoperative PSA, or mean biopsy Gleason score, 26.2% and 12% of the patients who underwent extended pelvic and standard lymphadenectomy had metastases, respectively [7], indicating the superiority of the former in accurate staging. The incidence of lymph node metastases was 56.3% in patients with a high Gleason score (>7) and PSA > 10 ng/ml, in contrast to 2% in patients with serum PSA < 10.5 ng/ml. Positive lymph nodes were outside the regions of standard pelvic lymphadenectomy in 42% of the samples. Therefore, the authors suggested that all patients with unfavourable preoperative prognostic factors should undergo extended lymph node dissection. Similar findings were observed in a study by Bader et al in which positive lymph nodes were identified in 25% of the patients with clinically localised prostate cancer after extended dissection [5]. Although omission of lymph node dissection in low-risk patients appeared to gain acceptance in the urologic community [2], data from the literature indicates the presence of a small but significant risk of lymph node metastases even in patients with a clinically low-risk profile. Lymph node metastases were found in 12% of patients with a preoperative PSA level of <10 ng/ml in a recent clinical series [8]. In fact, the incidence of positive lymph nodes was
DOI of original article: 10.1016/j.eururo.2007.01.108 * Marmara University Hospital, Tophanelioglu cad. No. 13–15, Altunizade 34662, Istanbul, Turkey. Tel. +90 216 325 2052; Fax: +90 216 325 8579. E-mail address: [email protected] (L. Tu¨rkeri). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.02.040
european urology 51 (2007) 1472–1474
10% in patients with a PSA < 10 ng/ml and cytologic grade 1 or 2. Even in patients with a PSA level of <4 ng/ml, lymph node metastases were identified in 10% of the cases by extended dissection in this study. The role of lymphadenectomy on disease-specific and overall survival in patients with metastatic lymph nodes is also controversial at present. In contrast to two recent studies, where no effect of the extent of lymphadenectomy was observed in prostate cancer outcome [1,6], in a retrospective analysis of 4000 patients operated on by two surgeons [3], overall 5-yr biochemical progression-free survival for patients with node-positive disease who underwent extended dissection was 34.4% compared to 16.5% with limited technique ( p = 0.07). After further stratification of patients according to the percentage of positive lymph nodes, limited disease was associated with a significantly higher 5-yr progression-free survival in the extended lymph node dissection group (42% and 10%, respectively; p = 0.01). In support of these findings, Bader et al identified the number of lymph node metastases as the only variable significantly affecting the progression and cancer-specific survival by multivariate Cox proportional hazards analysis of their data [5]. After a median follow-up of 45 mo, 92% of the patients with only one positive lymph node were alive compared to 67.4% of the patients with two or more positive nodes. These findings supported results of previous retrospective studies, which indicated that survival could be related to the number of lymph node metastases and that radical prostatectomy can be curative at least in some of these patients. Thus, data from clinical series makes it almost impossible to draw a line below which lymphadenectomy does not contribute either to accurate staging or the disease outcome. Therefore, proper preoperative identification of patients with possible lymph node involvement appears to make a difference and efforts for better prediction have already been undertaken. Subsequently, in 2006, a nomogram was developed based on clinical parameters that predicted metastatic spread to the lymph nodes in extended lymphadenectomy specimens with an accuracy rate of 76% [9]. In this issue of European Urology, Briganti et al report on further refinement of their previous nomogram with an enhanced ability to accurately predict lymph node involvement by using, for the first time, the percentage of positive biopsy cores in addition to other readily available clinical variables such as Gleason score, clinical stage, and PSA level [10]. The importance of this study stems from the selection of a cohort of 278 patients who
1473
underwent a careful extendend lymphadenectomy at the time of radical prostatectomy. Obviously, this is a prerequisite for valid scientific conclusions, which was lacking in studies analysing data from limited lymphadenectomy series. Detailed analysis in this study indicated the percentage of positive biopsy cores as the most informative individual and multivariate predictor of lymph node metastases in men who underwent extended pelvic lymph node dissection and had the greatest effect in improving the combined multivariate predictive accuracy of Gleason score, clinical stage, and PSA, up to 81%. One should be aware of the fact that even with the most recent evidence in the literature, it is still possible to miss 20% of the cases with lymph node involvement if extended dissection is omitted. Nevertheless, this study clearly demonstrates the potential for refining our ability to better predict patients who may need more extensive dissection, while sparing the rest. This study also underlines the insufficient nature of particular biopsy parameters for the exact prediction and the need for more novel markers. Although studies of this kind are a step further towards selection of the scale of lymph node dissection, they are still not perfect and the issue of prognostic relevance of the extent of lymphadenectomy in terms of disease-free and overall survival still continues to be a dilemma. This issue, most probably, will not be resolved until a welldesigned, prospective, randomised clinical trial is performed with the above-mentioned parameters as the trial end points. References [1] DiMarco DS, Zincke H, Sebo TJ, Slezak J, Bergstralh EJ, Blute ML. The extent of lymphadenectomy for pTXNO prostate cancer does not affect prostate cancer outcome in the prostate specific antigen era. J Urol 2005;173: 1121–5. [2] Kawakami J, Meng MV, Sadetsky N, Latini DM, Duchane J, Carroll PR. Changing patterns of pelvic lymphadenectomy for prostate cancer: results from CaPSURE. J Urol 2006;176: 1382–6. [3] Allaf ME, Palapattu GS, Trock BJ, Carter HB, Walsh PC. Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. J Urol 2004;172:1840–4. [4] Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781–8. [5] Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph
1474
european urology 51 (2007) 1472–1474
nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169:849–54. [6] Berglund RK, Sadetsky N, DuChane J, Carroll PR, Klein EA. Limited pelvic lymph node dissection at the time of radical prostatectomy does not affect 5-year failure rates for low, intermediate and high risk prostate cancer: results from CaPSURE. J Urol 2007;177:526–9, discussion 529–30. [7] Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167:1681–6. [8] Burkhard FC, Bader P, Schneider E, Markwalder R, Studer UE. Reliability of preoperative values to determine the
need for lymphadenectomy in patients with prostate cancer and meticulous lymph node dissection. Eur Urol 2002;42:84–90, discussion 90–2. [9] Briganti A, Chun FK-H, Salonia A, et al. Validation of a nomogram predicting the probability of lymph node invasion among patients undergoing radical prostatectomy and an extended pelvic lymphadenectomy. Eur Urol 2006;49:1019–26, discussion 1026–7. [10] Briganti A, Karakiewicz PI, Chun FK-H, et al. Percentage of positive biopsy cores can improve the ability to predict lymph node invasion in patients undergoing radical prostatectomy and extended pelvic lymph node dissection. Eur Urol 2007;51:1573–81.