Presented at the XXXVII Annual ScientificCongressofthePolishUrologicalAssociation, Warsaw, Poland, June 21-23, 2007

Summary

In the past decade major progress has been made in the management of patients with CaP. Most patients are now diagnosed with tumor clinically confined to the capsule and yet about50%of patients treated with RP are found to have pT3N0 disease or have a relapse at 10 years post treatment. Adjuvant pelvic RT after RP showed in randomized and non-randomized trials to be an important and effective treatment in reducing the incidence of local recurrence and improving DFS. To date, it has not demonstrated a significant improvement in overall survival. More prospective randomized trials with longer follow-up are needed to provide this most important answer. At the present time there is no effective therapy for patients with seminal vesicle involvement (pT3b) and /or GS 7-10. These patients should be targeted for trials including adjuvant RT and some form of systemic management.

Introduction

The reported 5-year overall survival in patients treated for loco-regional adenocarcinoma of the prostate (CaP) in the United States has been excellent (1). Substantially lower overall survival rates have been reported from the European Community. Radical prostatectomy (RP) is a well-established and effectivecurative treatment modality for selected patients with capsule confined CaP. In a reported study, which is representative of out comes published by other large university centers, RP alone was used in the treatment of 1,000 patients with T1 and T2 cancer (2). The10-year freedom from progression was75% and the10-year freedom from metastasis was 84% (2). The long-termoutcomes of RP in patients with cT3 disease, as expected, were substantially lower with 50% or more demonstrating a PSA and/or clinical recurrence at 10 years post treatment (3). Based on the above treatment outcomes, many physicians and surgeons consider RP as the "gold standard" therapy for selected patients with CaP.

A controversy exists, however, with some investigators believing that RP should be superseded by watchful waiting particularly in patients with T1 and T2 tumor as well as those >65 years of age. This opinion is primarily based on the reported Scandinavian experience of a prospective randomized trial in T1 and T2 patients (4, 5). During a 10-year period, 695 T1 and T2 patients were randomly assigned to watchful waiting group or to RP (4). There was no significant difference between the two groups in overall survival. RP, however, significantly reduceddisease-specific mortality and reduced the incidence of metastatic disease. The important quality of life parameters were studied in each patient group. While the endpoints as expected were different in each group, there was no significant difference in the incidence of state of well being or overall quality of life of RP patients or those assigned to watchful waiting (5).

The out comes of the above randomized trial are of major importance but one also needs to review a recent American report, which comes to a different conclusion(6). Between 1991 and 1999, a total of 44,630 65-80 year old men were diagnosed with organ confined tumors. The study patient shadwell-or moderately- well differentiated cancer and had to survive >1 year following diagnosis. The duration of this study was 12 years. A total of 32,022 patients within 6 months of diagnosis were treated with RP or radiotherapy (RT). No therapy was accepted or offered in 12,608 patients who were assigned to the observation (watchful waiting) group. These patients had similar characteristics and risk factors as those assigned to the treatment group. The treatment group patients had significantly better 5- and 10-year survival than those in the observation group. Thirty seven percent of the patients died in the observation group vs. 23.8% in the treatment group. Important tumor related prognostic factors as well as those pertaining to patient general health issues were carefully adjusted. Treatment benefit was apparent in all patient subgroups examined including those between 75 and 80 years of age. In spite of the large size of this study, state-of-the-art statistical analyses and an appropriately long follow-up, it suffers from the usual problems associated with a non-randomized trial. Acknowledging the above limitations, the important findings of this study can not be ignored by uro-oncologists. The outcomes of this study as well as the outcomes of the Swedish randomized trial should be presented to CaP patients as an important part of their informed consent.

Risk Factors

In spite of major improvements in imaging modalities, accurate preoperative staging remains an elusive goal. Thereasonfortheabove problem relates to the natural history of CaP with the presence of frequent microscopic tumor extension outside of the confines of the prostate. Microscopic disease can only be recognized by careful histological examination of the resected RP specimen. Our inability to accurately stage the disease process in up to 50% of patients makes planning of therapeutic intervention difficult(7-14). The understanding of multiple important risk factors prior to RP, intra-operative and postoperative findings predicting local recurrence (LR), biochemical relapse (BCR) and the probability of metastasis is very helpful in predicting pathological stage and eventually treatment outcomes. Similarly, the knowledge of factors adversely affecting prognosis at the time of BCR is also of major importance. In practice, the application of a well known nomogram recommended by Allan Partin helps to predict pathologic stage (15). The above nomogram utilizes a logistic regression of the three important parameters: Gleason’s score, preoperative PSA and clinical stage.
Careful analysis of the above listed and other adverse prognostic factors helps the clinician to select appropriate postoperative loco-regional or systemic therapy. Additionally, a prospective recognition of risks factors for loco-regional recurrence or BCR allows for a planned application of a limited postoperative pelvic irradiation which is the most effective therapy to eliminate or sharply reduce these risks. Table 1 shows widely recognized risk factors for the treatment of loco-regional or BCR failure.

Indications for Postoperative RT

Postoperative RT plays a major role in carefully selected patients following RP. Each of the listed conditions requires different RT techniques and doses and a selection of different anatomical sites to be treated with radiotherapy, which is also given at different times after RP.There are the following indications for RT in a number of distinctly different conditions:

• Adjuvant RT is primarily considered in those at high risk for recurrence with pT3N0 and positive surgical margin patients who are presumed to have microscopic residual tumor and have an undetectable PSA level following prostatectomy;
• Salvage RT in those who demonstrate a postoperative BCR and are suspected or proven to have tumor recurrence in the prostatic fossa;
• Gross tumor recurrence in the prostatic fossa, which frequently is a cause of distressing signs and symptoms;
• Postoperative RT for symptomatic metastasis.

Adjuvant RT

Adjuvant RT has been utilized since the early 1960’s. Many thousands of patients received this treatment following RP in an attempt to reduce the incidence of local recurrence and/or BCR. The incidence of BCR and or clinical relapse at 10 years following RP is about 25% in T1 and T2 patients, while it is well over 50% in those with T3 disease (2, 3, 12, 14). Unfortunately, the data generated from many dozens of published reports on the treatment outcomes is very difficult to interpret. The treatment indications for adjuvant RT have been very poorly defined and frequently included patients with elevated PSA and gross pelvic recurrence in addition to those with high probability for recurrence with undetectable PSA. Similarly, the timing of RT administration was variable as well as the RT doses and schedules. Most of the published reports on adjuvant RT presented retrospective analyses of small series of patients from single institutions with a limited follow up.

There are two additional important complicating factors in the use of adjuvant RT: 1. Fifty percent or more of the treated patients with high risk for failure are needlessly treated since at the present time there is no diagnostic method to objectively identify those with microscopic residual disease; and 2. Based on a classic study of 1,997 RP’s from John’s Hopkins, even among the patients who demonstrate PSA relapse at a median follow up of 8 years, about one-third is expected to develop metastatic disease and 50% of those are expected to die within 5 years (16). Ultimately, the experience of a uro-oncologist in the evaluation of important preoperative and postoperative risk factors would allow for optimal selection of patients for adjuvant RT.

Most of the published reports clearly demonstrated benefits of adjuvant RT in terms of a reduction in the expected incidence of local recurrence or BCR (8, 9, 10, 17, 18, 19). A published study to be noted is from Duke University reporting on 46 T3/4 patients treated with adjuvant RT of a total of 159 RP’s (18). RT was given to the whole pelvis (45-50Gy) and 10-15Gy boost to the prostatic fossa. All 159 patients were followed for a median period of 10 years. There was no statistically significant difference in the 10- and 15-year incidence of overall and disease-free survival and the incidence of metastatic disease between the two treatment groups. Important difference was noted in the incidence of local control. The 10-and15-year incidence of local control was 92 and 82%, respectively, for the adjuvant RT group and it was 60 and 53%, respectively, for the RP alone group, p=0.002.

The largest single institution experience with adjuvant RT was reported by the group from USC (11, 12). This study considerably evolved during its 25-year duration. Initially, all pT3N0 patients were selected for adjuvant RT. During a preliminary analyses of treatment outcomes prior to the activation of a prospective trial in the early 1980s, patients with GS<6 were excluded from postoperative therapy, since there was no local failure in this group. Theotherstudyparametersremainedverystablethroughout the trial duration with none of the patients receiving any form of hormone therapy, only two surgeons performing RP and one radiation oncologist directing RT dose, schedules and techniques.

Between 1976 and 1998, a total of 1,976 patients were treated at USC with RP for organ confined disease. Following RP,423(21%) were found to have pT3N0 tumor and received planned adjuvant RT (12). Of these 423 patients, 100 (24%) had GS 8-10, 151 (33%) had GS 7 and 127 (30%) had tumor involvement of seminal vesicles. All of the above groups represented patients with a very high probability of a relapse. RT was given within 42 to 90 days of RP and was directed to the prostatic fossa and its immediate vicinity using four portals and a dose of 45 Gy for pT3a and 54 Gy for pT3b and GS 7-10 patients. The 5- and 10-year overall and DFS was 92 and 73%, respectively, and 69 and 51%, respectively. In multivariate analysis, GS was the most important predictor for overall survival (p=0.00005) while GS and pStage were independently predictive of DFS (p=0.00007). The worst prognosis was found in patients with GS 7-10 and seminal vesicle invasion who had 5.3 times greater risk of tumor recurrence than those with pT3aN0, GS 2-6 tumors. Basically, patients with GS 7-10 had >80%, 10-year probability of BCR and/or clinical relapse. Preoperative PSA >25ng/ml was also an important predictor of a relapse, (p=0.03). A total of 13 (3%) patients developed local recurrence and 30 (7%) metastatic disease. The treatment program was well to lerated by the study patients with no Grade 3, 4 or late toxicity. Acute toxicity was common but of no clinical significance.The treatment program did not substantially impair patient quality of life during RT or following RT course. The out comes of this study were viewed as very good resulting in a 3% incidence of local failure where the expectation based on patient profile was about 30% incidence of local recurrence.

A companion to the above study was a report comparing treatment outcomes in 199 lower risk pT3N0 patients treated with RP alone vs. 423 high risk pT3N0 patients treated with RP followed by adjuvant RT (11). Adjuvant RT helped to reduce the incidence of local recurrence and improved DFS when compared with RP alone treated patients.

A number of investigators have reported on the status of surgical margins, which represented an important and independent prognostic factor for recurrence of disease in RP treated CaP patients (19-21). In addition, the use of adjuvant RT lowers the probability of relapse in this patient group. At USC we assessed the role of margins status on the recurrence and survival experience in 622 pT3N0 patients treated by either surgery alone or surgery plus adjuvant radiation therapy (Petrovich-unpublished data) . There were 89 of the 199 patients with positive surgical margins in pT3N0, RP alone treated patients and 287 of the 423 pT3N0, RP+RT patients. There was no significant differencein the 5- and 10-year overall, DFS and freedom from clinical recurrence (FFCR) in patients with negative surgical margins in either treatment group. Likewise, the above parameters showed no significant difference among margin positive and negativep T3aN0 patients. The2-and5-year over all, DFS and FFCR in pT3bN0, positive surgical margins tumors was better in patients receiving adjuvant RT than in those treated with RP alone, p=0.001. In multivariate analysis, the effect of adjuvant RT persisted and continued to be a significant predictor of DFS and treatment failure. The rate of failure in RP+RT patients was about one half that in the RP alone group. Cox model demonstrated pStage to be the most important factor influencing DFS,p=0.002 followed by the status of surgical margins, p=0.03. No other factors were significant predictors of DFS. This study clearly demonstrated adjuvant RT eliminating the adverse effect of positive surgical margins in our high risk pT3N0 patients.

Tabela 1	Common risk factors in patients treated with RP

Tabela 2	Probability of metastasis in PSA relapse (25)

Tabela 3	Probability of metastasis in PSA relapse (25)

It is of interest to compare the USC published reports with the other similar publications in the literature. The USC patients received planned adjuvant RT within 90 days of RP to a small volume which included the prostatic fossa and its immediate vicinity and the RT of 45-54 Gy. Most other studies reported variable time for treatment administration, which was up to 5 months following RP and RT given to whole pelvis for at least two-thirds of the treatment course. RT dose in USC studies was at least 20% lower than that reported in other trials, yet the USC treatment outcomes were as good or better than those in other published reports. Likewise, USC treatment toxicity was much lower than that of other reports.
In the past few years there has been a major progress in the fieldof adjuvant RT. Thefirstreportsofprospectiverandomizedtrials conducted in the United States and in Europe have been published in the literature (22-23).

The American multi-institutional prospective randomized study enrolled a total of 425 patients between 1988 and 1997 (22). All study patients underwent RP and had pT3N0 disease and/or positive surgical margins. Unfortunately, an undetectable PSA level was not required for the study entry. A relatively large (30%) group had detectable post operative PSA level indicating an incomplete resection. Such patients should not be entered into an adjuvant RT trial but should instead be treated with salvage RT. Adjuvant RT (60-64 Gy) was given to 214 patients while 211 were randomly assigned to the watchful waiting group. A median follow up was 10.6 years. There was no significant difference between the two groups in overall and metastasis-free survival but there was a significant difference in PSA-free survival with a median to PSA failure of 10.3 years in RT group vs. 3.1 years in the observation group, p<0.001). Similarly, there was a better recurrence- free survival in RT as compared to the control group, p=0.001. Toxicity was noted in 23.8% of RT patients and in 11.9% of the observation patients. Rectal toxicity was 3.3% in the former and 0% in the latter while urethral stricture was 17.8 vs. 9.5%.

EORTC prospective randomized trial between 1999-2001, accrued 1,005 patients who have undergone RP and had pT3N0 disease or positive surgical margins (23). Adjuvant RT (60 Gy) was given to 502 patients while 503 were assigned to the watchful waiting group. The median follow up was 5years. The5-yearPSA progression-free survival was 74% for the former and 53% for the latter group, p<0.0001. RT group had a significantly better clinical disease-free survival (p=0.0009) and the incidence of loco-regional relapse (p=0.0009). The incidence of severe treatment toxicity was low and similar to that of the American study.

Salvage Radiotherapy

Following RP, patients who show persistent PSA elevation or develop postoperative PSA failure after a period of an undetectable level may be considered for salvage RT. In such patients a reasonable effort should be made to exclude the presence of meta stasis. The presence of biopsy proven or suspected local recurrence in the pelvis is also necessary. A substantial amount of reliable information on the presence of local recurrence can be obtained by careful history, physical examination with DRE, TRUS and assessment of important prognostic parameters. The successful outcome of this process requires considerable experience. This helps to limit the number of various tests, which may be of a limited value in a given patient. Diagnosis of loco-regional recurrence still remains an art in addition to a body of appropriate scientific data and the ability to interpret such.

PSA failure was recently defined by the AUAP anelas>0.2ng/mllevel determined on two separate occasions (24). Important parameters predicting failure have already been discussed and are summarized in Table 1. In recent years, the importance of PSA-DT combined with GS was clearly demonstrated by John’s Hopkins investigators in a study of 3,263 patients treated with RP (25). Basically, PSA-DT in BCR patients with GS 8-10 demonstrates a very aggressive disease with metastatic disease being very likely (Table 2 and 3). A rapid (<3 months) PSA-DT in patient with recent (<1 year) RP and GS 8-10 may help to make a decision to with hold salvage RT. On the other hand, patients who demonstrate a slow (>12 months) PSA-DT with the first PSA rise diagnosed several years after RP may also be considered to with hold salvage RT and follow carefully the progress of disease. Therapeuticinterventionsometimesbecomesnecessaryif PSA-DT increases or there is other evidence of progressive disease.

AfteradecisionhasbeenmadetoadministersalvageRT,patients usually receive to the prostate bed about 64 Gy given at 2.0 daily fractions. Thistreatmentisusuallywelltoleratedbypatients with moderate or severe gastrointestinal or GU toxicity being uncommon (about 3%). Numerous studies have been published by single institutions presenting outcomes of salvage RT. Due to the apparent differencesinpatientselectionprocessand small number of patients involved in a given report, the interpretation of the data is difficult.Ina reviewofseveralreports,the incidence of PSA normalization following its elevation ranged from a low of 30% to high of 80% (26). It is apparent that this PSA response decreases with the increase in the duration of follow-up (27). Other published reports presented essentially similar data (28-31).

The USC experience consisted of 63RP patients who developed post operative PSA relapse. Of these 63 patients, 54 (86%) were asymptomatic while 9 presented with a non specific irritative or obstructive signs and symptoms. Median time from RP to relapse was 2 years and median PSA was 2.2 ng/ml with PSA-DT of 12 months. Median time from RT salvage was 5 years. RT was given with 3-D conformal technique and a median dose of 64 Gy. Undetectable PSA was obtained in 40 (63%) patients. Time to response ranged from 2-12 months with a median of 3 months. Freedom from progression at 3- and 5 years was 63 and 55%, respectively. In 23 failures, 10 had initial PSA decrease, 8 developed distant metastasis and 5 had local failure. A total of 5 patients died of CaP. GS 7-10 and pT3b disease were good predictors of failure. Treatment was well tolerated with none developing Grade 3 or 4 toxicity.

Gross Tumor Recurrence in the Pelvis

Gross tumor recurrence in the pelvis in patients following RP presents a difficult management problem. Patients frequently have well known distressing signs and symptoms of a recurrent pelvic tumor. RT alone is only of a palliative value since local tissue tolerance following RP does not permit to deliver much higher than 50 Gy radiation dose. Each patient’s treatment program needs to be individually designed. The use of hormonal therapy to reduce tumor volume prior to RT and following radiotherapy is of value. A combination of deep regional hyperthermia with RT has been reported to be of a major benefit in some USC studies (32). New treatment strategies need to be developed to improve the management of these difficult patients.

Palliative RT

RT is a treatment of choice in patients who develop focal and symptomatic metastasis. Usual presentation is pain due to tumor invasion of a skeletal structure such as the spine. A short course of limited volume RT is very effective(>70%) and a well to lerated treatment. The patient needs to be rapidly referred for such a palliative therapy in order to prevent the occurrence of spinal compression syndrome.

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