Debulking surgery in the setting of very high-risk prostate cancer scenarios
Paolo Gontero, University of Turin, Urologia 1, A.O.U. San Giovanni Battista, C.so Bramante 88/90, 10126, Turin, Italy. e-mail: firstname.lastname@example.org
According to the recent European Association of Urology (EAU) guidelines, radical prostatectomy (RP) is considered an optional treatment for selected patients with low-volume high-risk localized prostate cancer (PCa). High-risk disease is usually defined as clinical stage ≥ T3 and/or a PSA level > 20 ng/mL and/or Gleason score (GS) of 8–10 . Patients diagnosed with high-risk PCa are at increased risk of PSA failure, metastatic progression and cancer-specific death. For this reason, historically, this subgroup of patients has not been viewed as the better candidate for RP and, despite the paucity of evidence in support of any other treatment option, only about 36% of high-risk cases have been initially treated with RP . Nevertheless, not all high-risk patients have a uniformly poor prognosis after RP : many cases are still organ-confined and others will experience long-term biochemical recurrence-free survival . Remarkable long-term survival rates have been reported in locally advanced PCa treated with RP [4–9] and similar findings have emerged in large series with PSA > 20 ng/mL, even for values exceeding 100 ng/mL [10–14]. Intriguing surgical outcomes have been found even in cases of node-positive (N+) PCa  and it has been hypothesized that removing the prostate in patients with metastatic PCa might improve the tumour sensitivity to systemic treatment . Furthermore, salvage RP has become the most effective second local treatment with curative intent in the setting of radioresistant PCa, with high oncological efficacy and acceptable morbidity in well-selected patients [17–29]. Initial reports on the role of surgery in the setting of nodal recurrences after primary therapy have been reported [30–32]. It has also been speculated that debulking RP might prove active in hormone-refractory PCa with no evidence of systemic disease by ablating hormone-refractory cell clones. The aim of this review is to conduct a critical analysis of the available literature on the feasibility of debulking surgery in all these advanced PCa scenarios.
PATIENTS AND METHODS
A literature search was conducted according to current methodological recommendations for systematic reviews . The PubMed and Embase databases were searched using various combinations of the following keywords: radical prostatectomy, surgery, high-risk, high PSA, radiorecurrent, hormone-refractory, metastatic prostate cancer, salvage. Further results were found using the reference list of key articles. Identified articles were examined by the authors (M.O., P.G.), and the most relevant were selected. With the term ‘very high-risk prostate cancer’ we indicated a clinical disease beyond the common definition of high-risk PCa, i.e. any clinical stage > T3, N0 or N+, any PSA level > 50 ng/mL and any recurrent disease after primary treatment. Original articles, reviews and selected peer-reviewed abstracts addressing surgical therapy for these disease features were retained.
RESULTS AND DISCUSSION
RADICAL PROSTATECTOMY IN LOCALIZED PCA WITH VERY HIGH PSA LEVEL
According to the D'Amico classification , patients with PSA level ≥ 20 ng/mL at the time of PCa diagnosis represent a high-risk group, even in localized disease. These patients are suspected to harbour locally advanced tumours or occult metastases and therefore are considered to have a poorer prognosis than those with lower PSA levels [11,16,35], and indeed a higher risk of recurrence , progression and cancer-specific mortality has been reported . The question is whether a PSA upper limit exists to discourage surgery. A PSA level > 100 ng/mL has long been considered the single most important indicator of bone metastatic disease . On the other hand, high PSA alone might not necessarily reflect the burden of cancer but also underlying benign conditions such as BPH or inflammation . Furthermore, the application of Partin tables proved inadequate in staging prediction for PSA values > 20 ng/mL , which is reflected in the high percentage of organ-confined tumours (30.6% , 20.8% ) and lymph-node negative disease (85.5% , 75.2% ). Recently, several studies addressed the role of RP in cases of raised PSA, demonstrating remarkable long-term survival [3,10–13,39]. Zwergel et al.  reported the results of RP in patients with PSA level >20 ng/mL and found disease-specific survival rates of 93%, 83% and 71% at 5, 10 and 15 years, respectively. In 2008, Inman et al.  described the outcomes of RP with multimodal adjuvant therapy in a cohort of patients with PSA level ≥ 50 ng/mL and no clinical evidence of systemic disease. Progression-free survival rates at 10 years were 83% and 74% for PSA in the ranges 50–99 and ≥100 ng/mL, respectively, while 10-year cancer-specific survival (CSS) was 87% for the whole group. These findings were confirmed by Gontero et al.  in a large retrospective, multicentre European study on 712 patients with RP with a baseline PSA level > 20 ng/mL. The 10-year CSS (90.9% for PSA level 20–50 ng/mL, 85.4% for PSA level 50–99 ng/mL and 79.8% for PSA level ≥ 100 ng/mL), while showing significant reduction with increasing PSA value intervals, remained relatively high, even for PSA levels > 100 ng/mL. A recent analysis on outcome predictors of RP in patients with PSA level > 20 ng/mL concluded that a raised PSA alone is not sufficient to define a patient as at high risk . RP could represent a potential treatment option even for selected patients with very high PSA values, namely those with a prostatic involvement not fixed to surrounding organs, a good performance status and no evidence of bone or visceral metastatic spread .
DEBULKING SURGERY IN PCA WITH NODAL METASTASES
Involvement of regional lymph nodes in PCa is regarded as a poor prognostic factor, indicating systemic disease with limited long-term survival. The recurrence rate in these patients is very high and the CSS is significantly reduced compared with patients without metastases . Therefore, patients with nodal metastases are not considered surgical candidates and are usually treated with hormonal therapy and/or radiotherapy (RT) . Most urologists will abort surgery if nodal involvement is detected. Nevertheless, recent studies reported excellent cancer-specific outcomes in patients with histologically proven nodal metastases submitted to RP, with or without immediate adjuvant therapy [15,37,42,43]. Bader et al.  showed that there is heterogeneity within the group of patients with N+ PCa, indicating a favourable course in those with minimal metastatic disease. Meticulous pelvic lymph node dissection was suggested to have a positive impact on disease progression and long-term disease-free survival. In 2006, Messing et al.  showed that early androgen deprivation therapy (ADT) benefits N+ patients who have undergone prostatectomy and lymphadenectomy, achieving a 10-year CSS > 80%. These findings were confirmed by Da Pozzo et al. , who demonstrated excellent long-term outcome for patients with N+ PCa treated with surgery plus adjuvant RT and hormone treatments. In their series of 250 patients, CSS rates at 5 and 10 years were 89% and 80%, respectively. More recently, Engel et al.  showed a dramatic improvement in CSS and overall survival (OS) in favour of completed RP vs abandoned RP in patients who were found intraoperatively to be N+. Relative survival rates (an estimate of CSS) of patients at 5 and 10 years were 95% and 86%, respectively, with RP and 70% and 40%, with aborted RP. These recent findings suggest that at least some N+ patients do not have a systemic disease and that they might benefit from the surgical removal of the lymph nodes involved. It has been recently demonstrated that patients with up to two positive nodes experience excellent CSS, significantly higher than those with > two positive nodes . In light of this, RP with lymphadenectomy is progressively achieving a place in the complex scenario of N+ PCa. An accurate selection of the patient is essential, bearing in mind that higher nodal burden, extranodal tumour extension and less differentiated histology are factors associated with an adverse outcome, regardless of treatment .
IS THERE A RATIONALE FOR SURGERY IN METASTATIC PCA?
If patients with N+ PCa are not considered the best candidates for surgery, RP is not even considered an option in treating metastatic PCa. Nonetheless, recent data have suggested that removal of the primary tumour could enhance cancer control and survival in some patients [16,46]. Laboratory experiments have shown that Copenhagen rats implanted with human PCa always develop lung metastases. Those in which the implanted tumour was removed lived longer and with few lung colonies . Furthermore, several retrospective studies revealed that patients with metastatic PCa who had undergone previous RP had a better response to androgen ablation and better survival than those with an untreated prostate [48,49]. These intriguing data raise the possibility that removing the prostate in patients with metastatic PCa might result in a more complete and more durable response to adjuvant hormonal treatment, with an ultimate impact on survival . Further studies are surely needed to assess the real impact of surgery in this setting, and to explore every possibility to further improve survival of patients with metastatic PCa.
NODAL RECURRENCES AFTER PREVIOUS DEFINITIVE PCA TREATMENT
After RP, up to 40% of patients develop a biochemical recurrence (BCR) , which can be associated with local or systemic recurrence of PCa. Traditional imaging studies such as bone scintigraphy or CT to detect the site of recurrence are not useful unless PSA level is >20 ng/mL or unless PSA velocity is >2 ng/mL per year . [11C]Choline positron emission tomography (PET)/CT has demonstrated interesting results in terms of sensitivity and specificity for detecting nodal metastases after RP . In light of the excellent CSS rates obtained in patients with histologically proven nodal metastases submitted to RP [15,37,42,43], it could be hypothesized that at least some N+ patients do not harbour a systemic disease and that they might benefit from salvage lymphadenectomy in terms of delayed tumour progression. Only a few studies report the results of salvage lymphadenectomy in patients with [11C]Choline PET/CT evidence of nodal recurrence after primary therapy [31,32,51] and the results are conflicting. In 2008, Rinnab et al.  reported the outcomes of 15 patients with BCR associated with [11C]Choline PET/CT evidence of nodal recurrence who underwent pelvic/retroperitoneal lymph node dissection. Only one of 15 patients achieved a postoperative PSA nadir <0.1 ng/mL. At a mean follow-up of 13.7 months, only one patient had a stable PSA level of 0.5 ng/mL, while three developed bone metastases. In 2010, Winter et al.  described the results of salvage lymphadenectomy performed on six patients with BCR after RP. Three out of six showed a complete permanent PSA remission after a median follow-up of 19.7 months. Finally, in 2010 Suardi et al.  reported the results of a prospective study on 49 patients with PCa previously treated with RP who presented with a postoperative BCR and nodal pathological uptake at [11C]Choline PET/CT scan, who were submitted to pelvic/retroperitoneal lymph node dissection. One month after surgery, 61.2% of the patients had PSA level < 0.2 ng/mL. One- and 2-year biochemical progression-free survival (BFS) rates in these patients were 81.8% and 41.7%, respectively. According to these studies, [11C]Choline PET/CT scan is an effective technique for restaging patients with BCR after primary treatment of PCa, considering that it cannot be generally recommended for PSA values <1 ng/mL. A recent study, however, questioned the effectiveness of [11C]Choline PET/CT scan for nodal staging before RP, showing a sensitivity of only 9.4% for lymph node status, with 7.9% of correctly recognized cases. The high number of false negatives would reflect the deficiency of this technique in detecting micrometastasis and also some cases of macrometastasis, at least before RP . On the other hand, the effectiveness of the salvage surgery is questioned by the fact that only a minority of patients showed a durable PSA remission. Suardi et al.  concluded that, due to the low amount of evidence, salvage lymph node dissection should not be considered a treatment option outside of clinical trials. Whether debulking surgery in this clinical situation might account for a better response to salvage therapies and/or a survival advantages in the long term remains to be elucidated.
SALVAGE SURGERY FOR RADIORECURRENT PCA
According to the Surveillance Epidemiology and End Results database, ≈ one-third of patients with PCa are initially treated with RT, either external beam RT (EBRT) or brachytherapy . However, up to 50% of these patients will experience biochemical progression within 5 years . The Phoenix definition of post-RT BCR (PSA increase >2 ng/mL above the post-radiation nadir) is currently well recognized . If left untreated, patients with biochemical relapse will develop distant metastases within 3–5 years . Currently, many of these cases are treated with ADT, which is of palliative benefit only. However, depending on the initial tumour stage, a lot of these patients initially harbour local persistence as the only site of recurrence  and they might benefit from local salvage therapy. A positive prostate biopsy is recommended to confirm the diagnosis, bearing in mind that biopsies performed earlier than 18 months after RT could detect regressing cancer and should not prompt salvage therapy . Traditional imaging studies must be performed to exclude possible sites of distant metastases, but they are of scarce utility unless PSA level is >20 ng/mL . Recently, [11C]Choline PET/CT has demonstrated a high sensitivity in identifying local recurrences, although it was not able to detect microscopic lymph node metastases . Once the local recurrence has been confirmed, salvage RP is the most effective and durable treatment option [17–29], with 5-year progression-free survival and 10-year CSS rates reported to be up to 66%  and 83% , respectively. Table 1 shows the oncological and functional outcomes of the main studies related to salvage RP. Despite the high oncological efficacy shown in the recent series, this procedure carries a higher risk of complication than primary RP, due to the tissue effects of radiation that lead to fibrosis, poor tissue vascularization and obliteration of anatomical planes for dissection. In particular, the risk of urinary incontinence is higher, due to the sphincteric deficiency secondary to radiation-induced fibrosis. However, improvement in surgical experience and in RT techniques has led to improved functional outcomes with fewer side-effects . A recent study has demonstrated a perioperative complication rate less than 10%, and a continence rate 1 year after surgery of 80% . Regarding sexual function, selected patients can recover functional erections when nerve-sparing techniques are used. It was recently reported that 40% of post-RT patients with normal erectile function were able to have sexual intercourse with the use of oral medication after salvage RP . However, vascular damage induced by RT make erectile dysfunction frequent, even when excellent nerve-sparing RP are performed. Furthermore, a high rate of extraprostatic extension (>50%) and of lymph node-positive disease make a radiorecurrent PCa a high-risk prostate cancer where a nerve-sparing procedure should have little role. Patient selection is essential: the optimal candidates are motivated patients with isolated recurrence and a life expectancy of more than 10 years, counselled on the higher complication rate and the higher risk of incontinence. The most favourable group has been identified as patients with a PSA level < 4 ng/mL and a post-RT prostate biopsy GS ≤ 7 . According to Stephenson et al. , ideal candidates for salvage RP should have a postradiotherapy PSA level < 10 ng/mL, cT3a or less, and the absence of regional or distant metastases by preoperative imaging studies. Earlier detection of RT failure and prompt indication to salvage surgery could result in a larger proportion of patients with still localized disease and improved treatment outcomes. Recently, several studies assessed the feasibility of the laparoscopic [24–26] and robot-assisted [27–29] salvage RP, with encouraging results in terms of oncological and early functional outcomes. Although RP is the most established procedure with long-term survival benefit, nowadays salvage cryotherapy appears as an appealing, less-invasive alternative, recognized by 2008 AUA Best Practice Consensus Statement as an established treatment option for radiorecurrent organ-confined PCa . Salvage cryoablation showed acceptable oncological outcomes and morbidity in comparison with salvage RP, with the caveat that long-term follow-up is needed to confirm these results. However, a recent retrospective study found that younger patients should consider salvage RP because it can offer superior progression-free survival in comparison with cryotherapy .
Table 1. Oncological and functional outcomes of salvage RP for radiorecurrent PCa
|Open salvage prostatectomy|
|Chade et al., 2011 ||404||41||EBRT, brachytherapy||Extraprostatic extension – 45%; N+– 16%; PSM – 25%||10-year BPFS – 37%; 10-year MFS – 77%; 10-year CSS – 83%||NR|
|Heidenreich et al., 2010 ||55||28||EBRT, brachytherapy||Organ-confined – 72.7%; locally advanced – 27.3%; N+– 20%; PSM – 12.7%||NR||Transfusion rates – 4.5%; rectal injury – 2%; 1-year urinary incontinence – 19%|
|Sanderson et al., 2006 ||51||62.4||EBRT, interstitial RT, cryotherapy, proton beam RT||Organ-confined – 25%; locally advanced – 59%; N+– 16%; PSM – 36%||5-year PFS – 47%; 5-year OS – 65%; 10-year OS – 85%||Rectal injury – 2%; bladder neck contracture – 41%; artificial urinary sphincter – 45%|
|Ward et al., 2005 ||136||40||EBRT, interstitial RT||Extraprostatic extension – 74%; PSM – 31%;||10-year PFS – 60%; 10-year CSS – 77%||Rectal injury – 4%; urinary incontinence – 48%; bladder neck contracture – 22%|
|Bianco et al., 2005 ||100||48||EBRT, brachytherapy||Extraprostatic extension – 23%; PSM – 21%; N+– 9%||5-year PFS – 55%; 10-year CSS – 73%; 15-year CSS – 60%||NR|
|Stephenson et al., 2004 ||60||50||EBRT, interstitial RT||Extraprostatic extension – 50%; PSM – 10%; N+– 12%||5-year PFS – 66%;||Transfusion rates – 29%; rectal injury – 2%; 5-year urinary incontinence – 32%; anastomotic stricture – 32%|
|Gheiler et al., 1998 ||30||58||EBRT, brachytherapy||Extraprostatic extension – 46.7%||36-month BPFS – 50%||Rectal injury – 3%; 36-month urinary incontinence – 50%|
|Laparoscopic salvage prostatectomy|
|Ahallal, 2010 ||15||NR||EBRT, brachytherapy, cryotherapy||Extraprostatic extension – 60%; PSM – 13.3%; N+– 13.3%||8-month BPFS – 73.3||Rectal injury – 66.6%; urinary incontinence – 53.3%|
|Nunez-Mora, 2009 ||9||NR||EBRT, brachytherapy||Extraprostatic extension – 55%||1-year BPFS – 77.7%||Transfusion rates – 0%; rectal injury – 0%; urinary incontinence – 33%|
|PSM – 22%|| || || || || || |
|Stolzenburg, 2007 ||9||17.1||EBRT, brachytherapy, HIFU||Extraprostatic extension – 44.4%; PSM – 22.2%||1-year BPFS – 88.9%||Urinary incontinence – 22.2%|
|Robotic-assisted salvage prostatectomy|
|Eandi et al., 2010 ||18||79||EBRT, brachytherapy, proton beam therapy||Extraprostatic extension – 50%; PSM – 28%||18 month BPFS – 67%||Rectal injury – 0%; 18-month urinary incontinence – 66%|
|Boris et al., 2008 ||11||53.2||EBRT, brachytherapy, IMRT||Extraprostatic extension – 72.7%; PSM – 27.2%||20-month BPFS – 72.7%||2-month urinary incontinence – 20%|
|Kaouk et al., 2007 ||4||NR||EBRT, brachytherapy||Extraprostatic extension – 75%; PSM – 50%||NR||Rectal injury – 0%; 1-month urinary incontinence – 25%|
DEBULKING SURGERY FOR HORMONE-REFRACTORY PCA (HRPC)
To our knowledge, there are no published studies regarding debulking surgery in HRPC without evidence of systemic disease after previous radiotherapy. Surgery could prove active in HRPC by ablating hormone-refractory cell clones, leading to restoration of hormone sensitivity. We conducted a prospective, multicentre study to assess the feasibility of debulking prostatectomy in ‘limited’ HRPC in patients with previous RT. The study was conducted in good clinical practice and received institutional board approval (trial protocol no. 00039866, A.O.U. S.Giovanni Battista, Turin, Italy). We enrolled 10 HRPC patients with previous RT and no evidence of extra-nodal disease at bone scan or PET/CT (i.e. no evidence of disease beyond the retroperitoneal lymph-nodes) and a PSA doubling time (PSA-DT) >6 months . All patients underwent debulking RP with extended lymphadenectomy. PSA level < 0.2 ng/mL was achieved by seven of 10 patients after 1 month and by three of 10 patients after 6 months notwithstanding suspension of hormone therapy. At a mean follow-up of 27 months, five patients died of disease, two had hormone-refractory disease and three had no evidence of disease, without restarting hormonal therapy. Significant morbidity was recorded: two patients had rectal injury that required permanent colostomy, and two needed ileal urinary conduit for untreatable bladder neck contracture. Urinary continence was achieved in 40% of cases. Further studies are needed to assess the feasibility of debulking surgery in this setting.
In recent years, debulking surgery has achieved an important role in several aggressive PCa scenarios. RP achieved excellent survival rates in high-risk PCa, even in patients with very high PSA levels, meaning that this latter condition does not always reflect systemic disease. The completion of RP with lymphadenectomy might give a survival benefit in patients who were found intraoperatively to be N+. By contrast, surgery of isolated nodal recurrences after previous radical therapy has shown little benefit according to the few available series, pointing out that this treatment option should be further explored only within clinical trials. Salvage RP was confirmed to be the most effective treatment option after RT failure, with increased functional outcomes and decreased side-effects in the most recent series. To optimize the oncological outcomes, the surgery should be carried out via an extrafascial approach and with an extended pelvic lymph node dissection. To date, there has been no evidence supporting the efficacy of debulking surgery in metastatic PCa or in HRPC disease.