Volume 51, Issue 4, Pages 922-930 (April 2007)
1. Introduction:
Radical prostatectomy is still a controversial issue in the management of locally advanced prostate cancer [1].
Those who oppose a surgical approach claim the lack of benefit if complete excision is not accomplished [2], the absence of a long-term survival benefit [3], and also the fear of an increased surgery-related morbidity [4]. By contrast the group coordinated by Ward and Zinke [5] at the Mayo Clinic has long been advocating radical prostatectomy as the first line treatment in T3 disease and has shown that the procedure, with or without adjuvant treatment, has minimal morbidity and excellent cancer-specific survival rates.
Radiation and hormonal therapy have been the preferred treatment modalities for locally advanced disease [6], [7]. However, some concerns have been raised about the use of radiotherapy alone in view of the fairly high rate of posttreatment-positive biopsies [8] and the increased risk of metastatic dissemination in cases of persistence of local disease [9]. Combined hormone therapy and radiation treatment seems to improve local and distant disease control only in patients with bulky prostate cancer with a low Gleason score, whereas there does not appear to be a significant advantage for high Gleason score disease [10]. Another possible advantage of debulking surgery for locally advanced disease would be to prevent the complications related to local cancer progression: up to now the 10-yr data of high-dose radiotherapy are not mature enough to demonstrate if advances in radiation technology have improved local disease control [11].
Previous prospective studies of the surgical treatment of non–organ-confined prostate cancer included selected series of patients with a limited clinical T3 disease [12], [13], a clinical N0 disease at computed tomography (CT) scan [14], or the absence of nodal extension in intraoperative frozen sections [15]. In our study we report the morbidity and survival data of a consecutive series of patients undergoing radical retropubic prostatectomy for advanced prostate cancer of any clinical T≥3, N0–N1, any N1 or M1a, or non-bone metastatic disease by a single surgeon (B.F.). A consecutive series of radical prostatectomies performed by the same operator during the same period for clinically organ-confined disease served as a control group for the comparison of morbidity and survival.
2. Methods
Since 1998, more extensive criteria for performing radical retropubic prostatectomy have been adopted at our institution. All patients with biopsy-proven prostate cancer with any Gleason score, any initial prostate-specific antigen (PSA) value, and any clinical stage were considered eligible for radical retropubic prostatectomy as the first-line treatment option, provided there was no evidence of extranodal metastases. Previous hormone therapy did not contraindicate surgery if the pretreatment staging showed no bone or other extranodal metastases. Candidates for surgery had to be below 75 yr of age, and have low comorbidities and a good performance status (0–1). Staging investigations included digital rectal examination (DRE) and transrectal ultrasound (TRUS) in all cases. According to the 2002 TNM staging system [16], an unequivocal palpable induration extending beyond the prostatic capsule on one or both prostatic lobes defined a clinical stage T3a disease and was taken as the minimal requirement for the clinical diagnosis of a locally invasive disease. Any suspicion of seminal vesicle invasion on DRE or TRUS was categorised as T3b. A bone scan was performed if the PSA was >20ng/ml or the biopsy Gleason score was ≥8 [17]. On the basis of our previous observations (unpublished data), we adopted a PSA threshold of 40ng/ml, a Gleason score ≥8, and the presence of a bulky palpable tumour on DRE as indications for an abdominal and pelvic CT. A cT4 disease was diagnosed when CT showed tumour extending to the bladder neck, ureteral orifices, or pelvic sidewalls, whereas any regional or extraregional node enlargement >2cm was taken as highly suggestive of clinical N1 or M1a disease, respectively.
A lymphadenectomy limited to the obturator fossa was performed according to the risk categorized by the Partin tables [18] in clinically organ-confined diseases, assuming a risk of lymph nodes involvement not greater than 5% to avoid the procedure. In all cases of clinical T≥3 and/or in any N1 disease, lymphadenectomy also included the external and internal iliac nodes [19], [20]. An extensive periaortic and pericaval lymph node dissection was carried out only when the CT scan suggested retroperitoneal nodes involvement (clinical M1a disease stage). In patients with clinical T≥3 disease, the following technical aspects were carefully considered when removing the prostate: (1) transection of the urethra a few millimetres distal to the apex; (2) wide excision of both neurovascular bundles; (3) development of the posterior plane between the posterior Denonvilliers layer and the rectum to maintain both sheets of that fascia attached to the prostatic specimen; and (4) resection of the bladder neck [21].
All patients were followed up with PSA measurements every 3 mo. Adjuvant treatment based on regional guidelines (unpublished data) was planned by a multidisciplinary oncology group. In general, any pT3b/T4N0 or any positive surgical margin in pathologic specimens received adjuvant radiotherapy on the prostatic bed. Limited N1 disease (i.e., microscopic nodal involvement) received adjuvant hormone therapy with the possibility of stopping treatment after 2 yr in the presence of undetectable PSA. Bulky nodal involvement and any rising PSA or PSA not falling <1ng/ml after adjuvant radiotherapy was an indication for permanent hormone therapy. At 1-yr follow-up, patients were asked to rate their perception of urine continence into “none,” “mild,” and “severe,” and to report the number of pads used daily. On the basis of these two subjectively reported parameters, continence was categorized into “none” (self-reported and no pads), “mild” (self-reported and/or one pad per day), or “severe” (self-reported and/or two pads/day).
Between March 1998 and February 2003, 350 consecutive patients meeting our inclusion criteria underwent radical retropubic prostatectomy at our institution. Of these, 282 had an organ-confined disease on preoperative staging, whereas 68 had clinically advanced M0 prostate cancer. Only patients operated on by a senior expert surgeon (B.F.) who performed the majority of procedures for clinical T3 or more diseases (51 of 68) and 152 of 282 radical prostatectomies for organ-confined disease in the same time period were considered in the current study. A referee pathologist reviewed all 203 study pathologic specimens.
The primary study endpoints were (1) the comparative results of intraoperative and postoperative complication rates for the advanced and the organ-confined prostate cancers, and (2) the overall and cancer-specific survival at the median follow-up available for the advanced prostate cancer group. Comparative data on survival, disease-free status (defined as the presence of undetectable PSA with or without hormone therapy or PSA <0.5ng/ml after adjuvant radiotherapy), and progression rate (defined as any rising PSA on two consecutive measurements with or without local or systemic progression at last follow-up) among the two disease groups constituted a secondary endpoint.
Statistical analysis was conducted using the Student t test for the comparison of variables between the two groups and the Kaplan-Meier method to generate the survival curves for the locally advanced and the organ-confined prostate cancer groups.
3. Results
3.1. Comparative morbidity data
Table 1 reports the preoperative characteristics of the patients with clinically organ-confined and advanced prostatic disease. In the latter group, eight patients had a preoperative PSA ≥100. Comparative data on morbidity for the two groups of patients are reported in Table 2. The percentage of patients requiring transfusion was significantly higher in the advanced disease group, whereas the clinically organ-confined group had a significantly higher number of mean blood units transfused per patient. Operative time was significantly longer in the group of advanced prostatic cases. Three patients from this group had a lymphadenectomy extended to the retroperitoneum, and three additional patients required reimplantation of one ureter at the time of surgery (in two cases for hydronephrosis, in one case for inadvertent intraoperative injury). The rate of clinically relevant lymphoceles was four times higher in the advanced disease series. Ultrasound-guided percutaneous aspiration was successfully adopted in all cases. There was a tendency, which was not statistically significant, towards a longer hospital stay for the advanced disease group. Twelve organ-confined and three advanced disease patients were lost to follow-up. As shown in Table 2, there was no significant difference in the 1-yr continence rate and the various degrees of stress incontinence between the two groups. Bladder neck stricture occurred more often in the advanced disease group, but the difference was not statistically significant. Table 3 reports the pathologic staging as well as the rate, extension (focal or diffuse) and location of positive surgical margins for the two groups. The rate of positive surgical margins was nearly three times higher in the clinically advanced group compared with the organ-confined series.
3.2. Comparative oncologic outcome
At a median follow-up of 47.6 mo, only 5 of the 48 evaluable patients in the advanced disease group had not received any adjuvant treatment. Eight had undergone adjuvant radiotherapy only, 8 received temporary hormone treatment (bicalutamide 150mg daily for 2 yr), 15 required hormone therapy at some stage after radiotherapy, and 27 were on permanent hormone treatment (luteinising hormone-releasing hormone analogue or complete androgen blockage) at the time of last follow-up. The Kaplan-Meier estimate of overall survival at 7 yr was 76.7%. Of the 10 deaths, 5 were due to prostate cancer, giving a cancer-specific survival of 90.2%. Three of the 5 deaths for prostate cancer occurred in the three patients with an intraoperative M1a disease.
Thirty-four of the 140 (24%) evaluable patients in the localised disease group received adjuvant treatment at a median follow-up of 51.6 mo. This treatment consisted of radiotherapy alone (N=9), temporary antiandrogen treatment (N=9), and a combination of radiotherapy and hormone treatment (N=7). Twelve patients were on permanent hormone treatment at the time of last follow-up. Twelve patients died during the follow-up, giving a 7 yr estimate of overall survival of 88.4% and cancer-specific survival of 99.3% (only one death due to prostate cancer), significantly higher than that reported for the locally advanced disease group (p=0.009 and p=0.005, respectively). Fig. 1 shows the Kaplan-Meier curves comparing overall survival for both disease groups.
Fig. 1. Kaplan-Meier curves comparing overall survival for the clinically advanced group (blue line) and the clinically organ-confined group (orange line) up to 7 yr of follow-up. Gehan generalized test (also called generalized Wilcoxon statistic) showed a statistically significant difference (p<0.01).
Clinical progression occurred in 12 of 38 survivors in the advanced disease group and in 10 of 128 patients alive in the organ-confined group. The type of clinical progression for both groups is shown in Table 4.
The overall disease-free rate was 68% (26 of 38 patients) for the locally advanced group and 92% (118 of 128 patients) for the organ-confined group. In Table 5, disease-free patients for both groups are categorized according to the type of adjuvant treatment received.
| |
|
|
 |
Type of adjuvant treatment |
Clinically advanced disease (N=26) |
Clinically organ-confined disease (N=118) |
|
|
NED* |
3 |
93 |
|
|
NED after RT† |
6 |
8 |
|
|
NED after HT‡ |
6 |
8 |
|
|
NED under HT§ |
11 |
9 |
|
| |
|
|
|
* No evidence of disease (PSA <0.2ng/ml) without adjuvant treatment.
† No evidence of disease after adjuvant radiotherapy (PSA <0.5ng/ml).
‡ No evidence of disease after stopping adjuvant hormone therapy (at least 1 year beforehand).
§ No evidence of disease under hormone treatment (hormone sensitive prostate cancer). |
4. Discussion
The optimal treatment strategy for T3 prostate cancer has not been defined yet. So far, radical prostatectomy has been considered mainly for selected patients with locally advanced prostate cancer. In the series reported by Van den Ouden et al. [15], 83 clinically T3 prostate cancers with negative lymph node metastases on intraoperative frozen sections received surgery. The authors reported a 10-yr cancer-specific survival of 76% for low-grade tumours and 65% for high-grade tumours, and found that the former performed well without the need for adjuvant treatment. Favourable results after radical prostatectomy were reported on a large series of 812 patients treated at the Mayo Clinic for a limited clinical T3 disease [5]. Even though 60% of patients needed adjuvant treatment, the overall 10-yr prostate cancer–specific survival was 70%. In our study, radical prostatectomy was offered to a consecutive series of patients with locally advanced prostate cancer of any clinical T extension up to the M1 disease stage. To our knowledge a protocol with such extensive indications for radical surgery in prostate cancer (i.e., the presence of extranodal metastatic disease as the only exclusion criteria) has not been previously reported.
The perception of an increased technical difficulty and a higher morbidity rate has been a major source of concern in proposing surgery for locally advanced prostate cancer [4]. When compared with the series of clinically organ-confined disease treated by radical prostatectomy performed by the same surgeon in the same period, both intraoperative and postoperative complications in the advanced prostate cancer group were limited. The need to perform a lymphadenectomy, which always extended beyond the obturator fossa and, in three patients, up to the retroperitoneum, may easily account for the longer operative time as well as for the significantly higher incidence of lymphoceles in comparison with the organ-confined group. There was a tendency in the advanced group towards a higher rate of bladder neck stricture than in the organ-confined series. It is possible that either local recurrence or more extensive use of adjuvant radiotherapy in the locally advanced group may have had an impact on these results. Of note, the rate and degree of incontinence in the advanced disease group paralleled that seen in patients with clinical T2 prostate cancer.
Our results in terms of cancer-specific survival and progression-free probabilities for the clinically organ-confined group were remarkably similar to recent data from major institutions [22]. As far as the locally advanced group, oncologic outcome was significantly worse than in the organ-confined series in terms of both overall and cancer-specific survival. A comparison with a previous series of T3 prostate cancer treated with radical prostatectomy is hampered above all by the more advanced baseline disease stage as a result of our extensive inclusion criteria, which is documented by a lower rate of pathologic organ-confined disease (5%) and a higher baseline PSA value than that reported in other studies [12], [15]. In addition, comparisons of various clinical studies are biased by substantial differences in the type and indication for adjuvant treatment. The decision to administer immediate adjuvant treatment to the majority of our patients represents a limitation of the current study in that we were not able to report the curative rate of surgery alone. Only 5 of the 48 evaluable patients had not received any adjuvant treatment during the follow-up. Furthermore, among the 15 patients who were disease-free under no treatment at last follow-up, 12 had been previously treated with either radiotherapy or temporary hormone therapy. With these caveats, our survival and progression free rates fared well in comparison with the series reported by Van den Ouden et al. [15] and the Mayo Clinic [5] in which more favourable disease patients were recruited.
Recently the results of a large randomised clinical trial recommended a combination of 3 yr of androgen suppression with external irradiation as a possible standard of treatment for locally advanced prostate cancer [7]. Interestingly enough, the 7-yr estimated survival observed in our series (76.7%) at a median follow-up of 47.6 mo is similar to that reported by Bolla et al. in 1997 [6] at a median follow-up of 45 mo. Again, a comparison of the two trials is difficult for a number of reasons, including the potential staging errors and different selection criteria. Taking into account the inclusion of 9% of clinical T1 and T2 prostate cancer and the lower rate of clinical N+ disease in the Bolla et al. studies [6], [7], we think our results may be viewed as promising because they are likely to have been obtained from a more advanced prostate cancer series. Nonetheless, on the basis of a randomised comparative trial, any comment on the survival advantage of either of the two treatment modalities in locally advanced prostate cancer remains merely speculative.
Another argument in favour of surgery for locally advanced prostate cancer is the potential to reduce the morbidity related to local disease progression. A report of 120 patients with localized prostate cancer who received radiotherapy only and subsequently underwent prostate biopsies revealed positive biopsy rates of 65% at 2 yr [8]. With new understandings in the interpretation of postradiation prostate rebiopsies, these figures have improved [23] but still show that the rate of residual tumour following radiotherapy is consistent. In the Bolla et al. study [7] local progression, defined as recurrence of a palpable tumour after initial regression, had been reported in 17% of patients in the radiotherapy-only arm. Although these figures are likely to be improved by increasing doses of radiation with modern technologies and by the standard use of combination hormone therapy with radiotherapy [11], in situ tumour progression may result in local complications such us bladder outlet obstruction and hydronephrosis. Notably, these aspects are often overlooked in the recent radiotherapy trials [6], [7]. In our series, a local recurrence was documented in four patients, but it had not lead to any significant local complication at the last follow-up. Another potential advantage of surgery is that it allows a more precise definition of the pathologic disease stage, a knowledge that may turn out to be useful in the future for patients’ selection for systemic chemotherapy trials.
There appears to be an emerging role for surgery in advanced prostate cancers with the belief that radical prostatectomy followed by adjuvant radiotherapy and/or hormone therapy may provide a survival advantage over the more commonly used combination of androgen suppression and external irradiation [6], [7] although randomised comparative trials are currently unavailable. A recent secondary analysis [24] of a large series of patients with metastatic prostate cancer receiving hormone ablation treatment in a Southwest Oncology Group trial has shown that men who had previously undergone radical prostatectomy had a significant survival advantage. This indirect observation generates the hypothesis that radical prostatectomy for advanced prostate cancer, even when not completely extirpative, may have a positive impact on cancer aggressiveness. The 90% cancer-specific survival at 5 yr observed in our series provides additional support for this belief. Larger prospective studies are needed to better clarify the advantages of surgery in different subgroups of advanced prostate cancers, particularly those with clinical disease extension to the retroperitoneum. The observation that all three patients from our series with M1 disease were dead at a median follow-up of 21 mo makes the role of surgery for this disease stage questionable.
5. Conclusions
Our results show that radical prostatectomy proved to be technically feasible in a consecutive series of unselected non-bone metastatic advanced prostate cancers. The intraoperative and postoperative complication profile did not differ significantly from that observed in clinically organ-confined disease. Initial survival data suggest the potential role of surgery as an essential part of the multimodal approach to treating advanced prostate cancer.
Editorial Comment
The treatment of patients with local or locally advanced prostate cancer is under constant discussion. Currently, the treatment of almost all stages of prostate cancer is being debated. Conducting well-designed prospective studies can only solve the controversies within these treatment modalities. It is clear that these studies are lacking. It is questionable if we will ever have answers on, for example, the place of watchful waiting in local prostate cancers or if the treatment of the prostate organ is useful in patients with advanced prostate cancer. We, therefore, need more tools to improve the individualisation of the treatment of patients with prostate cancer.
The current study is an example of a single surgeon experienced in rating advanced-stage prostate cancer with intent-to-cure radical prostatectomy. First, the perioperative outcomes compared to patients with more favourable clinical characteristics treated surgically at the same institution during the same time period are presented. Because it is a nonrandomised study, the groups are unbalanced. Second, a separate unadjusted survival analysis was performed outside the context of the study design. The authors report that despite longer operative times, high rates of blood transfusion, lymphocele, and ureteral injuries requiring intraoperative reconstruction, and longer hospital stays, radical surgery was relatively well tolerated in the advanced cancer group. In the survival analysis, they report a 5-yr estimated overall survival of approximately 79% and a cause-specific survival of 90%. Although it is difficult to judge, it can reflect the outcome of patients with really local disease.
Several questions can still be asked. It seems clear that the majority of patients with advanced-stage disease received some form of adjuvant systemic treatment, most typically androgen-deprivation therapy. This means that it comes down to a multimodality treatment in which surgery is only part of the treatment. This also means that it should be investigated if surgery itself really gives additional effect on survival in this multimodality approach. Moreover, the question of adequate staging arises. This aspect needs more attention because a significant number of patients with cT3 prostate cancer are overstaged (pT2) in the current era of prostate-specific antigen testing. Pathologic grade, ploidy, and margin status are all significant predictors of outcome after surgery. Investigations on these aspects have been done in retrospective analysis and once again lack prospective randomised data [1].
If one focuses on the main issue in this manuscript it is concluded that surgery in advanced local disease is feasible but is associated with a higher complication rate compared to those with more favourable cancers. Moreover, it is clear that patients with advanced disease treated surgically will have adverse pathologic features requiring adjuvant therapy in a multimodality treatment approach. This approach should be investigated in well-conducted clinical trials so that ultimately we may better define how this group of challenging patients should best be treated. It is up to the urology community to start these studies.
Reference
[1] Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int. 2005;95:751–756.
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