Review Article Radical Prostatectomy for Locally Advanced Prostate Cancer: Current Status Eliney F. Faria, Brian F. Chapin, Roberto L. Muller, Roberto D. Machado, Rodolfo B. Reis, and Surena F. Matin In the past, prostate cancer (PC) could only be detected clinically, and delayed diagnosis of locally advanced or metastatic disease at presentation was common. Prostate-specific antigen testing and magnetic resonance imaging led to PC detection in a much earlier stage. However, controversy about the best treatment for locally advanced PC remains. Recent refinements in surgery and radiation therapy have improved outcomes, but no comparative study has yet conclusively determined superiority of one option over the other. In this review, we present the most recent evidence about the role of radical prostatectomy for locally advanced PC treatment from a surgeon’s perspective. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
U
ntil the 1990s, locally advanced prostate cancer (LAPC), defined as tumor-nodes-metastasis category cT3, could only be staged with a digital rectal examination. In the last 2 decades, prostatespecific antigen (PSA) testing, newer imaging methods such as magnetic resonance imaging (MRI), the periodic refinement of the Gleason score,1 and other tools to improve risk stratification have aided clinicians to better evaluate patients with prostate cancer (PC) and to design more individualized treatment plans. These new technologies were quickly incorporated in the widespread use of PC screening and have resulted in a known stage migration in PC, possibly affecting the extent in which LAPC is currently diagnosed compared with that decades ago. This “earlier” identification of LAPC may alter treatment strategies in the modern PC era. Currently, 5%-15% of new cases are diagnosed as LAPC.2 In some areas from developing countries, the incidence of LAPC can be as high as 26.5% among unscreened men vs 6.0% of men who participate in screening programs.3 Although the optimal treatment approach for these patients remains uncertain, there is a tendency for LAPC patients who are healthy, younger, and have low-volume tumors to receive radical surgical treatment.4 In this
Eliney F. Faria and Brian F. Chapin both share first-author status. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Surgical Uro-Oncology Department, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil; the Division of Surgery, Department of Urology, University of Texas, MD Anderson Cancer Center, Houston, TX; and the Urology Department, Sao Paulo University (Ribeirao Preto), Ribeirao Preto, Sao Paulo, Brazil Address correspondence to: Eliney F. Faria, M.D., Ph.D., Surgical Uro-Oncology Department, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, Doutor Paulo Prata, Barretos, Sao Paulo 14784-400, Brazil. E-mail: elineyferreirafaria@ yahoo.com.br Submitted: January 5, 2015, accepted (with revisions): March 16, 2015
ª 2015 Elsevier Inc. All Rights Reserved
review, we present the most recent evidence about the role of radical prostatectomy (RP) and its multiple aspects for LAPC treatment.
METHODS We conducted a review of the literature within the MEDLINE electronic database published through December 2014. We identified all relevant studies using various combinations of the search terms “locally advanced,” “high-risk,” “surgery,” and “prostate cancer.” We expanded the search using the “related articles” function and by examining the references identified in some relevant electronically abstracted studies. Articles were screened based on titles and abstracts and were limited to the English language. Final selection was based on a full review of the article.
Right Definition of LAPC and Its Implications for Treatment Choices Occasionally, there is some confusion among clinicians between LAPC and high-risk disease according to the most popular risk stratification classification for PC (D’Amico). Classically, in LAPC, there is evidence of extracapsular extension (categorized as cT3a by 2007 tumor-nodes-metastasis classification), seminal vesicle invasion (SVI, cT3b), and/or invasion of adjacent organs (cT4) in physical examination or radiographic studies but no distant metastasis. By definition, the D’Amico classification in based on PSA values, digital rectal examination, and biopsy Gleason score obtained before surgery. Thus, all LAPC cases are categorized as “high risk” according to the D’Amico classification,5 whereas the opposite is not true; a patient with organ-confined PC may be stratified as high risk by D’Amico classification owing to a Gleason score 8 or a PSA level >20 ng/mL. The fact that there is no complete overlap between LAPC and high-risk PC based on D’Amico classification may be challenging for clinicians when communicating or making clinical decisions about these patients. http://dx.doi.org/10.1016/j.urology.2015.03.012 0090-4295/15
1
An important consideration in LAPC management is the odds of pathologic downstaging. Van Poppel et al6 reported that 43.8% of patients who had been previously staged as T3 actually had organ-confined tumors in the European Organization for Research and Treatment of Cancer (EORTC-30001) study. Those results confirmed a prior study from Mayo Clinic, wherein 27% of men with LAPC were subsequently downstaged to pathologic T2 after RP.7 Collectively, these results indicate that a substantial amount of men classified as LAPC have actually organ-confined disease; therefore, they would be candidates to standard surgical treatment with RP similar to men with early PC. Despite a significant proportion of LAPC patients have actually less-invasive disease found out at surgical specimen, estimates about the overall indication of RP for LAPC patients suggest that these rates are fairly low. Using data from Surveillance, Epidemiology and End Results (SEER) database, a large registry in the United States of patients >65 years of age, Denberg et al8 analyzed trends in LAPC treatment and have shown the proportion of patients receiving aggressive treatment increased by 11% (58.4%-69.4%). However, that occurred with a 20% increase indication to external beam radiation therapy (RT) (40.3%-60.2%) but a decline by half in RP (18.1%-9.3%). Therefore, indication for RT was 6.5 times more common than RP for LAPC patients. Younger age was the strongest predictor of receiving RP rather than RT.8 LAPC is a complex entity with many issues: one is the clinical relevance and the best treatment approach for men with solitary occult or overt positive lymph node (PLN) in pelvic region. As many as 25%-30% of clinical LAPC may be diagnosed with PLN, with careful pathologic examination after RP.7 Although these patients are currently staged by American Joint Committee on Cancer (AJCC) guidelines as stage IV (similar to patients with bone metastasis), their clinical outcomes are apparently far better than average stage IV PC patients. For patients with PLN treated with RP without androgen deprivation treatment (ADT), the 5and 10-year probability of freedom from biochemical recurrence (BCR) of was found to be 35% and 28%, respectively; the 5- and 10-year overall survival (OS) was 91% and 60%, respectively, and the 5- and 10-year cancer-specific survival (CSS) was 94% and 72%, respectively, based on a recent study.9 Another issue is the management for clinically staged regional node positive patients (cN1) or those with pelvic lymph nodes with an anterior posterior diameter of >1 cm by computed tomography (CT) imaging. Currently, no prospective trials have compared treatments for this population and with the majority of them ending up receiving external RT plus ADT per National Comprehensive Cancer Network (NCCN)10 and European Association of Urology (EAU) guidelines.11
LAPC Staging for Surgeons Imaging tests are considered important tools for more precise LAPC staging and treatment guidance, although there is still debate in the literature regarding how accurate these methods are. To exclude distant metastases, NCCN and EAU guidelines recommend bone scan and abdominal or pelvic CT imaging as part of the initial workup. The optimal use of imaging is yet unknown, as different methods can result in slight stage discrepancies and distinct treatment recommendations.12 The available options are constantly advancing with regard to both research and practice. Imaging information is extremely important when balancing the extent of surgical resection with the functional aspects of 2
potency and continence. Each method, including transrectal ultrasound, CT, and MRI, has advantages and disadvantages. Of these, MRI appears to be superior for defining the location, size, and extent of prostate disease, as well as defining the presence, location, and extent of extracapsular extension.13 Additionally, research is ongoing to assess if methods such as spectroscopy and multiparametric evaluation could enhance MRI yield. Finally, positron emission tomography (PET) technology is still an experimental but a promising tool, as some evidence suggests that 18F-NaF has been shown to improve sensitivity and specificity14 and radiolabeled choline may be useful to detect recurrent and metastatic disease earlier compared with traditional imaging.15
Nomograms Because PC behavior is heterogeneous, nomograms incorporating relevant clinical and laboratorial variables can aid in counseling patients, individualizing treatments, and estimating risk of recurrence or survival, among other uses. Currently, several nomograms are available16 online in the World Wide Web (see URL www.mskcc.org/prostate/nomograms for a collection of some) or in smartphone applications. These computer technologies aided the incorporation of those nomograms in clinical practice, although it is very important to the clinician to understand their limitations and judge when it is appropriate to use them. One particular nomogram that is worth mentioning for selecting high-risk PC patients for surgery is the Briganti’s nomogram based on 1366 patients who underwent surgery at 8 European centers between 1987 and 2009.17 The accuracy for predicting specimen-confined PC among high-risk PC was 72% in the original population and 64% in an external validation data set.18
Oncologic Aspects of Surgery Treatment goals in LAPC are to cure the disease, improve local control, metastasis free, and CSS rates while maintaining the best possible quality of life. If observed alone, LAPC progress systemically and locally over a 36-month period in 100% and 87% of cases, respectively.19 Delayed treatment with noncurative intent may be an option in patients with very limited life expectancy, although a Swedish study suggested that even for older patients, LAPC accounts for a significant cause of deaths, and thus, this population is commonly undertreated.20 Regarding cancer control with RP alone, Mitchell et al reported in a study with 20 years of follow-up of 843 LAPC patients local recurrence-free survival, metastasis-free survival, and CSS of 76%, 72%, and 81%, respectively.21 Also favoring sustained cancer control with surgery alone for LAPC is the observation that in a large long-term study, CSS after surgery for LAPC was similar compared with T2 stage at 5- and 10-years of follow-up, with more significant differences detected only at the 15-years time point (79% vs 92% for T3 vs T2).7 Nonetheless, the long-term results for surgery in LAPC are sometimes hard to ascertain given the fact that many patients receive multimodal treatments, which include adjuvant or salvage RT and/or ADT in a nonuniform fashion.7 Still, the results so far suggest that RP as a single modality therapy for high-risk PC may be effective in the long term for 50%-65% of patients.
What Is the “Gold Standard” Treatment?
There is no consensus about “the” best treatment for LAPC patients for some reasons. One is that, as mentioned previously, UROLOGY
-
(-), 2015
monotherapy is often insufficient for a significant amount of them, which require multimodality to improve oncologic results.4 Also, randomized prospective studies comparing treatments for LAPC are still scarce, limiting direct comparisons between surgery and other options. Nevertheless, we can surmise that RP may be beneficial to aggressive PC based on the results from the Scandinavian Prostate Cancer Group 4 trial, which enrolled patients with localized PC (ie, cT2 or less). In this study, surgery seemed to be unequivocally of benefit for patients who have a Gleason score 8 and are 2300 high-risk patients (including LAPC) show patients initially treated with RP had lower risk of metastasis (P
U
ntil the 1990s, locally advanced prostate cancer (LAPC), defined as tumor-nodes-metastasis category cT3, could only be staged with a digital rectal examination. In the last 2 decades, prostatespecific antigen (PSA) testing, newer imaging methods such as magnetic resonance imaging (MRI), the periodic refinement of the Gleason score,1 and other tools to improve risk stratification have aided clinicians to better evaluate patients with prostate cancer (PC) and to design more individualized treatment plans. These new technologies were quickly incorporated in the widespread use of PC screening and have resulted in a known stage migration in PC, possibly affecting the extent in which LAPC is currently diagnosed compared with that decades ago. This “earlier” identification of LAPC may alter treatment strategies in the modern PC era. Currently, 5%-15% of new cases are diagnosed as LAPC.2 In some areas from developing countries, the incidence of LAPC can be as high as 26.5% among unscreened men vs 6.0% of men who participate in screening programs.3 Although the optimal treatment approach for these patients remains uncertain, there is a tendency for LAPC patients who are healthy, younger, and have low-volume tumors to receive radical surgical treatment.4 In this
Eliney F. Faria and Brian F. Chapin both share first-author status. Financial Disclosure: The authors declare that they have no relevant financial interests. From the Surgical Uro-Oncology Department, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil; the Division of Surgery, Department of Urology, University of Texas, MD Anderson Cancer Center, Houston, TX; and the Urology Department, Sao Paulo University (Ribeirao Preto), Ribeirao Preto, Sao Paulo, Brazil Address correspondence to: Eliney F. Faria, M.D., Ph.D., Surgical Uro-Oncology Department, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, Doutor Paulo Prata, Barretos, Sao Paulo 14784-400, Brazil. E-mail: elineyferreirafaria@ yahoo.com.br Submitted: January 5, 2015, accepted (with revisions): March 16, 2015
ª 2015 Elsevier Inc. All Rights Reserved
review, we present the most recent evidence about the role of radical prostatectomy (RP) and its multiple aspects for LAPC treatment.
METHODS We conducted a review of the literature within the MEDLINE electronic database published through December 2014. We identified all relevant studies using various combinations of the search terms “locally advanced,” “high-risk,” “surgery,” and “prostate cancer.” We expanded the search using the “related articles” function and by examining the references identified in some relevant electronically abstracted studies. Articles were screened based on titles and abstracts and were limited to the English language. Final selection was based on a full review of the article.
Right Definition of LAPC and Its Implications for Treatment Choices Occasionally, there is some confusion among clinicians between LAPC and high-risk disease according to the most popular risk stratification classification for PC (D’Amico). Classically, in LAPC, there is evidence of extracapsular extension (categorized as cT3a by 2007 tumor-nodes-metastasis classification), seminal vesicle invasion (SVI, cT3b), and/or invasion of adjacent organs (cT4) in physical examination or radiographic studies but no distant metastasis. By definition, the D’Amico classification in based on PSA values, digital rectal examination, and biopsy Gleason score obtained before surgery. Thus, all LAPC cases are categorized as “high risk” according to the D’Amico classification,5 whereas the opposite is not true; a patient with organ-confined PC may be stratified as high risk by D’Amico classification owing to a Gleason score 8 or a PSA level >20 ng/mL. The fact that there is no complete overlap between LAPC and high-risk PC based on D’Amico classification may be challenging for clinicians when communicating or making clinical decisions about these patients. http://dx.doi.org/10.1016/j.urology.2015.03.012 0090-4295/15
1
An important consideration in LAPC management is the odds of pathologic downstaging. Van Poppel et al6 reported that 43.8% of patients who had been previously staged as T3 actually had organ-confined tumors in the European Organization for Research and Treatment of Cancer (EORTC-30001) study. Those results confirmed a prior study from Mayo Clinic, wherein 27% of men with LAPC were subsequently downstaged to pathologic T2 after RP.7 Collectively, these results indicate that a substantial amount of men classified as LAPC have actually organ-confined disease; therefore, they would be candidates to standard surgical treatment with RP similar to men with early PC. Despite a significant proportion of LAPC patients have actually less-invasive disease found out at surgical specimen, estimates about the overall indication of RP for LAPC patients suggest that these rates are fairly low. Using data from Surveillance, Epidemiology and End Results (SEER) database, a large registry in the United States of patients >65 years of age, Denberg et al8 analyzed trends in LAPC treatment and have shown the proportion of patients receiving aggressive treatment increased by 11% (58.4%-69.4%). However, that occurred with a 20% increase indication to external beam radiation therapy (RT) (40.3%-60.2%) but a decline by half in RP (18.1%-9.3%). Therefore, indication for RT was 6.5 times more common than RP for LAPC patients. Younger age was the strongest predictor of receiving RP rather than RT.8 LAPC is a complex entity with many issues: one is the clinical relevance and the best treatment approach for men with solitary occult or overt positive lymph node (PLN) in pelvic region. As many as 25%-30% of clinical LAPC may be diagnosed with PLN, with careful pathologic examination after RP.7 Although these patients are currently staged by American Joint Committee on Cancer (AJCC) guidelines as stage IV (similar to patients with bone metastasis), their clinical outcomes are apparently far better than average stage IV PC patients. For patients with PLN treated with RP without androgen deprivation treatment (ADT), the 5and 10-year probability of freedom from biochemical recurrence (BCR) of was found to be 35% and 28%, respectively; the 5- and 10-year overall survival (OS) was 91% and 60%, respectively, and the 5- and 10-year cancer-specific survival (CSS) was 94% and 72%, respectively, based on a recent study.9 Another issue is the management for clinically staged regional node positive patients (cN1) or those with pelvic lymph nodes with an anterior posterior diameter of >1 cm by computed tomography (CT) imaging. Currently, no prospective trials have compared treatments for this population and with the majority of them ending up receiving external RT plus ADT per National Comprehensive Cancer Network (NCCN)10 and European Association of Urology (EAU) guidelines.11
LAPC Staging for Surgeons Imaging tests are considered important tools for more precise LAPC staging and treatment guidance, although there is still debate in the literature regarding how accurate these methods are. To exclude distant metastases, NCCN and EAU guidelines recommend bone scan and abdominal or pelvic CT imaging as part of the initial workup. The optimal use of imaging is yet unknown, as different methods can result in slight stage discrepancies and distinct treatment recommendations.12 The available options are constantly advancing with regard to both research and practice. Imaging information is extremely important when balancing the extent of surgical resection with the functional aspects of 2
potency and continence. Each method, including transrectal ultrasound, CT, and MRI, has advantages and disadvantages. Of these, MRI appears to be superior for defining the location, size, and extent of prostate disease, as well as defining the presence, location, and extent of extracapsular extension.13 Additionally, research is ongoing to assess if methods such as spectroscopy and multiparametric evaluation could enhance MRI yield. Finally, positron emission tomography (PET) technology is still an experimental but a promising tool, as some evidence suggests that 18F-NaF has been shown to improve sensitivity and specificity14 and radiolabeled choline may be useful to detect recurrent and metastatic disease earlier compared with traditional imaging.15
Nomograms Because PC behavior is heterogeneous, nomograms incorporating relevant clinical and laboratorial variables can aid in counseling patients, individualizing treatments, and estimating risk of recurrence or survival, among other uses. Currently, several nomograms are available16 online in the World Wide Web (see URL www.mskcc.org/prostate/nomograms for a collection of some) or in smartphone applications. These computer technologies aided the incorporation of those nomograms in clinical practice, although it is very important to the clinician to understand their limitations and judge when it is appropriate to use them. One particular nomogram that is worth mentioning for selecting high-risk PC patients for surgery is the Briganti’s nomogram based on 1366 patients who underwent surgery at 8 European centers between 1987 and 2009.17 The accuracy for predicting specimen-confined PC among high-risk PC was 72% in the original population and 64% in an external validation data set.18
Oncologic Aspects of Surgery Treatment goals in LAPC are to cure the disease, improve local control, metastasis free, and CSS rates while maintaining the best possible quality of life. If observed alone, LAPC progress systemically and locally over a 36-month period in 100% and 87% of cases, respectively.19 Delayed treatment with noncurative intent may be an option in patients with very limited life expectancy, although a Swedish study suggested that even for older patients, LAPC accounts for a significant cause of deaths, and thus, this population is commonly undertreated.20 Regarding cancer control with RP alone, Mitchell et al reported in a study with 20 years of follow-up of 843 LAPC patients local recurrence-free survival, metastasis-free survival, and CSS of 76%, 72%, and 81%, respectively.21 Also favoring sustained cancer control with surgery alone for LAPC is the observation that in a large long-term study, CSS after surgery for LAPC was similar compared with T2 stage at 5- and 10-years of follow-up, with more significant differences detected only at the 15-years time point (79% vs 92% for T3 vs T2).7 Nonetheless, the long-term results for surgery in LAPC are sometimes hard to ascertain given the fact that many patients receive multimodal treatments, which include adjuvant or salvage RT and/or ADT in a nonuniform fashion.7 Still, the results so far suggest that RP as a single modality therapy for high-risk PC may be effective in the long term for 50%-65% of patients.
What Is the “Gold Standard” Treatment?
There is no consensus about “the” best treatment for LAPC patients for some reasons. One is that, as mentioned previously, UROLOGY
-
(-), 2015
monotherapy is often insufficient for a significant amount of them, which require multimodality to improve oncologic results.4 Also, randomized prospective studies comparing treatments for LAPC are still scarce, limiting direct comparisons between surgery and other options. Nevertheless, we can surmise that RP may be beneficial to aggressive PC based on the results from the Scandinavian Prostate Cancer Group 4 trial, which enrolled patients with localized PC (ie, cT2 or less). In this study, surgery seemed to be unequivocally of benefit for patients who have a Gleason score 8 and are 2300 high-risk patients (including LAPC) show patients initially treated with RP had lower risk of metastasis (P
