Pretreatment Tables Predicting Pathologic Stage of Locally Advanced Prostate Cancer

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.

The best management of locally advanced prostate cancer (PCa) is a challenging problem. In the absence of randomized trials comparing different treatment modalities (ie, surgery, radiation therapy [RT], androgen-deprivation therapy, or a combination), it is very difficult to counsel patients properly on the optimal treatment strategy. For patients with localized PCa, radical prostatectomy (RP) is considered an ideal therapy [1] . However, several studies have shown that RP as the initial treatment may also show acceptable long-term outcomes in patients with locally advanced PCa [2], [3], [4], [5], [6], [7], [8], [9], and [10]. This may be partly due to the fact that a significant portion (13–27%) of cT3a tumors are overstaged and are actually T2 at RP [5], [6], [8], and [11]. In contrast, a number of cT3a tumors are understaged and invade the seminal vesicles (pT3b) or neighboring organs (pT4). As expected, the outcome of RP for pT2 and pT3a tumors is significantly better than for pT3b and pT4 tumors [5], [8], [12], and [13]. International guidelines support the addition of an extended pelvic lymph node dissection (ePLND) to RP in locally advanced PCa because the risk of finding positive lymph nodes (LNs) at surgery is considerable [1] and [14].

Although a number of patients with cT3a need adjuvant or salvage RT or hormonal therapy, a non-negligible proportion may be treated with surgery alone and will not need any further therapy, thereby sparing them from associated morbidity. The problem remains how to best select those patients suitable for RP. The Partin tables, using combinations of preoperative serum prostate-specific antigen (PSA) level, biopsy Gleason score (GS), and clinical stage, are widely used to predict final pathologic stage after RP for men with clinically localized PCa (T1c–T2c) [15] and [16]. However, despite the fact that such tables would also be of high value for men with locally advanced PCa, regrettably only one published paper provides a single-center nonvalidated pretreatment prediction table [11] .

In the present study, we constructed and validated a pretreatment table for predicting the final histopathology and the presence of positive LNs after RP for locally advanced PCa (cT3a), based on a retrospective analysis of a large multicenter European database. This could aid physicians in making treatment decisions for patients with cT3a PCa in daily clinical practice.

Patients with clinical stage T3a disease constitute a high-risk PCa group, recognized by clinical guidelines [1] and [14]. Despite an extensive practice of PSA screening and early detection of PCa, a fair proportion of patients still present with locally advanced disease. In the screening arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC), published in 2012, 8.6% and 1.2% of the patients had clinical stage T3 and T4 tumors, respectively; those numbers were 15.9% and 3.6% in the control arm [18] . Moreover, 76.8% of the “escapes,” that is, men who developed metastasis and/or died from PCa despite screening, in the Rotterdam arm of the ERSPC were patients with high-risk PCa (defined as clinical stage ≥T3, or PSA >20 ng/mL, or GS ≥8). More specifically, 51.2% of the escapes had clinical stage T3 or T4 disease [19] .

The optimal management of patients with locally advanced PCa continues to be debated. Although surgical treatment has traditionally been discouraged secondary to an increased risk of PSM, SVI, and LN metastases, studies indicate that surgery may have a place in the management of T3a PCa [2], [3], [4], [5], [6], [7], [8], and [12]. Currently, RP, combined with ePLND, is a valid strategy accepted by international guidelines [1] and [14]. The 5- and 10-yr overall survival rates after RP for cT3a PCa have been reported to range from 75% to 97.6% and 60% to 94.8%, respectively. In addition, 5- and 10-yr PCa-specific survival rates ranged from 85% to 100% and from 57% to 92%, respectively [2], [3], [4], [5], and [11].

Pathologic stage has been reported to be an important factor influencing outcomes after RP. In the update of the SPCG-4 study on radical prostatectomy versus watchful waiting, extracapsular tumor growth was associated with a sevenfold increase in the risk of death from PCa when compared with those without extracapsular growth (relative risk: 6.92; 95% confidence interval, 2.6–18.4) [20] . Likewise, in retrospective analyses of patients who underwent surgery for clinical stage T3 PCa, the outcome after RP in patients with pT2 PCa was also shown to be better than those with pT3 PCa [5], [8], and [12]. About 13–27% of cT3 PCa patients are actually overstaged and have pathologically organ-confined disease at RP [2], [3], [4], [5], [6], [7], and [8]. However, patients with SVI or extensive ECE might less likely benefit from RP alone [13] . A total of 6–68% of cT3a patients are understaged and in reality have pathologically confirmed SVI or adjacent organ invasion [11] .

From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is key because studies in high-volume referral centers have shown an “inverse” stage migration toward more aggressive PCa [21] and [22]. Thus the ability to predict the final pathologic stage of a patient with cT3a PCa may substantially influence treatment decisions in daily clinical practice. For example, patients with pT2 disease at final pathology might be cured by surgery alone. However, patients with ECE, SVI, and PSMs might benefit from a multimodal approach. In this context, randomized controlled trials reported that the administration of adjuvant RT improved the 10-yr biochemical-free survival rates [23] . However, because additional treatments are not devoid of short- and long-term side effects, the identification of patients who might benefit from multimodal therapy can be useful during preoperative patient counseling about possible treatment options and expectations.

Not only the primary tumor pathologic stage, but also the presence of positive LNs has an important effect on the outcome of RP [2], [5], and [8]. For this reason, a high possibility of positive LNs will have an impact on the extent of surgery that should be performed, whether a PLND is indicated and to what extent [1] and [14]. Ample evidence is available to recommend an ePLND in men presenting with cT3 disease. A few publications have proposed pretreatment nomograms for accurate prediction of the presence of positive LNs after ePLND [24] and [25]. Unfortunately, the population of patients with locally advanced disease was largely underrepresented in those studies, thus questioning the applicability of the nomograms in this particular patient group. In these studies including mostly patients with cT1–2 PCa, the percentage of patients with positive LNs was in the range of 8%; the incidence of positive LNs in men with cT3a PCa has been reported to range from 8% to 49% [2], [3], [4], [5], [6], [7], [8], [11], and [12]. In the present study, this was 25.8%. A better prediction of risk of positive LNs in patients with locally advanced PCa would thus provide additional information to guide surgical practice as well as radiation fields for those men opting for this treatment. In our analyses, the predicted probability of positive LNs after surgery was 45% in patients with a GS ≤6 and high PSA levels receiving an ePLND. Although these findings might suggest a potential aggressiveness for low-grade diseases, they should be interpreted with caution. We should underline that recent series report that upgrading was experienced in up to 45% of patients presenting with biopsy GS 6 at diagnosis [26] .

We present tables predicting primary tumor pathologic outcomes and presence of positive LNs after RP for patients with cT3a PCa based on pretreatment PSA levels and biopsy GS. We opted to construct these as “look-up” tables instead of a nomogram because for many, tables are more user friendly and perhaps easier to apply in clinical practice and would provide a welcome addition to the existing Partin tables for localized disease. The main effects of biopsy GS and pretreatment PSA were significant in the model, and the validation procedure showed that the model has good predictive ability. This table can be considered in the prediction of pathologic outcomes at RP for patients with cT3a PCa, which can help urologists counsel RP patients preoperatively and can also benefit radiation oncology in regard to treatment field planning. The risk of positive LNs also increases with preoperative PSA levels and biopsy GS. Validation using the split-sample approach also showed excellent predictive power of the model.

Our study is limited by the fact that the patients were included from several centers over a relatively long period (1987–2010). Over time, improvements have been achieved in both diagnostic and surgical techniques potentially leading to different outcomes in particular subgroups of patients. Interpretative changes to the Gleason grading system might have potentially changed the pattern of grade distribution over time [27] . However, the results of our analyses were also confirmed when evaluating only patients diagnosed in most recent years. Clinical stage was determined by DRE alone, and this assessment may vary from one physician to another. However, all the patients included in our analyses were carefully evaluated by board-certified urologists at referral tertiary centers. Also, the lack of data on preoperative imaging in our multi-institutional database prevented us from addressing the impact of imaging techniques such as CT and MRI on the assessment of clinical stage. Although the number of biopsy cores taken, the percentage of positive cores, and tumor volume per core might be associated with the risk of adverse features at final pathology [28], [29], and [30], our preoperative model did not include these covariates. A potential selection bias may have been introduced in our study, selecting the “more favorable” among cT3 cancers because our patient population consisted of patients treated initially with RP. Therefore, these tables might be applicable only to patients who are candidates for surgery. Only the PSA prior to RP was analyzed, limiting our ability to assess PSA kinetics and its potential prediction application to this patient group. No standardized PLND template was applied, and the mean of 11.5 nodes removed per patient lies below the LN count threshold for optimal pelvic LN staging. Abdollah et al. demonstrated that to achieve a correct LN staging in 90% of cases, an ePLND should contain at least 20 LNs [31] . However, according to the same authors, a mean of 11.5 LNs still achieves 75% correct staging. Thus underestimation of our table is thought to be limited. We tried to circumvent this limitation by performing a separated analysis only in patients undergoing ePLND. Central pathology review was not available, potentially limiting the generalizability of the results. Nevertheless, dedicated uropathologists from tertiary referral centers assessed all biopsies and resection specimens, thus limiting bias. Finally, the tables were constructed with European patients, and these results might not be applicable to other patient populations. For all the reasons just cited, the tables still need to be externally validated, even though an internal split-sample validation was applied.

Notwithstanding the limitations, our study has important strengths. First, a high number of patients were included compared with previous studies, leading to robust statistical outcomes. Second, in contrast to previous studies, our study reports for the first time an analysis strictly focusing on patients with cT3a PCa. In those patients, the need for substratification is high due to the substantial heterogeneity in outcomes published. Former pretreatment tables or nomograms included only a small minority of cT3a patients, severely limiting the reliability of predictions for this specific population [15] and [32]. One other pretreatment table had already focused on cT3a PCa. However, the table was based on a single-center series of only 200 patients, and no predictions on the risk of LN invasion were provided [11] .

Clearly, a fair proportion of patients with cT3a will have favorable pathologic outcomes, especially in the presence of more favorable PSA and biopsy GS. Those patients may be ideal candidates for surgery as a monotherapy. On this note, a former analysis from the European Multicenter High-Risk Prostate Cancer Clinical and Translational Research Group has shown patients with specimen-confined PCa (ie, pT2–3a, node negative, margin negative) to have exceptionally good outcomes following RP only [33] . The benefits of these tables extend beyond urologists’ exclusive use. As noted previously, this information may prove to be equally useful for radiation oncologists in treatment planning.