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Management of PSA failure following radical radiotherapy for cancer of the prostate

Presented at the XXXVII Annual Scientific Congress of the Polish Urological Association, Warsaw, Poland, June 21-23,200t


Carcinoma of the prostate (CaP) is the most common malignancy in American males, with 17.1% lifetime probability of developing this disease (1). Management of patients with CaP in the United States is a success story in oncology. Over the past 25 years, there has been a sharp increase in the 5−year survival rates. It was 69% in 1977 and it increased to 100% in 2002 (Table 1) (1). This improvement was driven by multiple factors, which included our better understanding of the disease process and its risk factors, better ability to define anatomic extent of the tumor, an ability to diagnose the majority (91%) of patients with localized tumors at presentation and a major evolution of surgical and radiotherapy techniques. Additionally, there has been generally a well−integrated multidisciplinary approach to the management of CaP with an active participation of urologists, radiation oncologists, radiologists, pathologists and appropriately trained nursing staff. All of the above facilitated the improvement of the patient survival and the quality of life.

Fotografia 1


Radiotherapy (RT) is a well−established and widely accepted curative treatment modality for selected patients with localized (CaP). RT treatment outcomes have substantially improved over the past two decades and became similar to those obtained with contemporary radical prostatectomy (RP) (2−7). Contemporary RT utilizes 3−D conformal or intensity modulated radiation therapy (IMRT). RT treatment planning and delivery represent a complex process which extensively utilizes imaging and computers as well as highly trained radiation oncologists, technical and nursing staff. Accuracy of treatment planning and delivery is of critical importance as the treatment outcome depends on it. Radiation dose and schedules are designed based on patient risk factors. Generally, patients with favorable prognosis receive at least 70 Gy and those in intermediate and unfavorable risks groups receive up to 81Gy. RT is given at 1.8−2.0 Gy daily over a period of 7 to over 8 weeks. Patient quality of life during the treatment course is reasonably good with a minor toxicity common (40%) but easy to control and major toxicity rare (<3%).

Tabela 1
5-Year overall survival USA 1996-2002 (1)

In a report from Memorial Sloan−Kettering Cancer Center in New York on IMRT treated patients with localized CaP, the 8−year actuarial PSA relapse free survival for the favorable, intermediate and unfavorable groups was 85, 76 and 72%, respectively (2). The 8−year cause specific survival for the above risk groups was 100%, 96% and 84%, respectively. This report is representative of other published studies from large American university centers.

Biochemical relapse

Unfortunately, the above excellent 5 or 8−year overall and disease free survival does not address well the existence of late (10 years) PSA relapse, which has been well documented in RT and RP series. The reported 10−year incidence of PSA relapse is extremely variable and ranges from a low of 15% to a high of over 60% (2, 5−12). The well known factors adversely affecting prognosis, among others, include tumor stage, Gleason's score, pre−treatment PSA, radiation dose and technique, PSA nadir following RT and its timing, PSA doubling time, etc. The unfortunate aspect of many published reports is a paucity of data on these important risk factors to allow the reader to understand the outcome data. This is also true for many reports of RP series. An additional problem is represented by multiple definitions of PSA failure making interpretation of reported data difficult. In January 2005, the Second Consensus Conference of Radiation Therapy Oncology Group (RTOG) and American Society of Therapeutic Radiology and Oncology (ASTRO) revised the prior ASTRO definition of post RT PSA failure (13). The following recommendations were made: 1. a rise by 2ng/ml or more above PSA nadir defines PSA failure 2. the date of failure is the date of a report rather than to backdate. A strict adherence to the above definitions was strongly recommended by the Consensus Conference panel of experts. The appearance of PSA failure in RT treated patients is a major event. It may lead to a local recurrence causing all well known management problems resulting in a sharp decrease in quality of life. Local recurrence is initially asymptomatic with subsequent pelvic and systemic symptoms and signs of recurrence being common. About 50% of patients with clinical recurrence die within 10 years. PSA failure predicts well (75%) positive prostatic biopsy and predicts in 50% of patients clinical recurrence within 1 to 4 years. On the other hand, a not elevated PSA is associated with < 5% incidence of clinical recurrence. Additionally, PSA failure may lead to development of metastasis leading to patient death. Prior to any management decision following a diagnosis of PSA failure, other relevant factors need to be carefully considered. These include, among others: clinical and pathological stage, pre−RT PSA and its velocity, the duration from completion of RT to PSA relapse (with those >2 years from RT having a better prognosis), PSA nadir (nPSA), and PSA doubling time (PSA−DT). Patients with PSA−DT>10 months were well documented to have a better prognosis than those with a shorter PSA−DT. Patients with Gleason's score GS>7 have a poor prognosis compared with those of GS 5−6. The importance of nPSA was well investigated in a multi−institutional study of 4,839 RT treated patients between 1986 and 1995 (12). In a multivariate analysis, times to nPSA and nPSA were found to be predictive of PSA failure and clinical failure as well as predictive of metastatic disease, which was true in all risk categories. Higher RT doses were predictive of lower nPSA, longer time to nPSA and improved incidence of PSA free survival.

Salvage therapy

Once a diagnosis of biochemical failure has been made and multiple risk factors carefully evaluated, a search to identify likely site(s) of possible clinical recurrence can be initiated. Patients with early postradiation PSA failure (within 1 year), rapid PSA−DT (<10 months) have >50% probability of developing metastatic disease at 5 years (14, 15). Detailed history and physical examination are frequently very helpful in making a diagnosis of a local and/or distant recurrence. Careful assessment of risk factors and the use of appropriate imaging to include TRUS can also help to identify the site of local or distant recurrence. If a local (pelvic) recurrence is suspected based on the above measures, a TRUS or computerized tomography assisted needle biopsy may histologically confirm a recurrence and allow for further histological studies to identify important risk factors. Evaluation of any therapeutic intervention has to be based on numerous patient and tumor related factors. It is of major importance to consider the treatment of a patient with PSA relapse as opposed to a treatment program designed for an elevated PSA in the absence of other considerations. An additional important and relevant factor in this complex process includes the lack of effective curative therapy in the overwhelming (90%) majority of patients (16, 17). Patient must be informed in detail on all of the available treatment options, including watchful waiting. The likely treatment outcome needs to be presented as well as a likely impact of the proposed treatment on the patient's quality of life. Prior to an application of potentially curative therapy, major effort needs to be made to precisely define local recurrence and exclude a possibility of metastatic disease. It is of relevance at this time to quote Dr. Willet F. Whitmore, Jr. of Memorial Sloan−Kettering Cancer Center in New York who made the following statements more than 20 years ago: „Is cure possible? Is cure necessary? Is cure possible only when it is necessary?” (16). It is believed that we should be guided in our decision making process by the above important and relevant statements.


Surgery remains the most effective salvage therapy for patients with radio recurrent CaP. Surgical treatment options include salvage RP, laparoscopic prostatectomy and cryosurgery.

Salvage RP

The aim of the salvage procedure, consisting of RP or cystoprostatectomy, is a total resection of entire known tumor in the pelvis. Salvage RP has been reported infrequently since the late 1970's when Willet Whitmore reported treatment outcomes following salvage RP (18). Treatment outcomes in that report were not very good and the incidence of surgical complications was high. Following this report, urologists were reluctant to perform salvage RP due to a well known problem of defining a local recurrence and fear of severe treatment toxicity (19). In the past 15 years, there has been an increase in the number of published reports on this subject. There was a sharp decrease, reported by most investigators from large university centers in the incidence of surgical complications and mortality. Appropriate patient selection and experience of a surgeon represent a key to a successful outcome following a salvage procedure. Patients selected for salvage of post−radiation failure are expected to meet the following criteria: 1. confirmation of local recurrence by biopsy 2. no seminal vesicle involvement 3. no positive pelvic lymph nodes 4. no metastatic disease 5. patient's good performance status with a projected survival = 10 years 6. treatment should be undertaken in a major urologic center with appropriate surgical expertise.

In the three published studies from Mayo Clinic, University of Southern California (USC) and Baylor University consisting of a total of 120 patients, a sharp decrease in the incidence of surgical complications and mortality was demonstrated (19). The problem, however, was a low (27%) incidence of histologically confirmed organ confined disease (Table 2). The presence of a recurrent tumor outside of the prostate makes a cure following the salvage procedure unlikely.

Tabela 2
Pathological finding after salvage RP (19)

A recent USC report is of interest to consider (16). Between 1983 and 2002, in a total of 2,739 patients, RP was performed including 51 (1.9%) salvage RP's for a biopsy confirmed post−radiotherapy failure. Median follow−up from a completion of RT to salvage RP was 5.2 years and median follow−up from the salvage procedure was 7.2 years. No hormonal therapy was given in this group of 51 patients. The 5−year progression−free survival (PFS) was 47% and median PFS survival was 4.8 years. There was a strong correlation between pathological stage and PFS. It was 100% for pT2, 35% for pT3 and 0% for pTxN(+), p<0.001. PSA = 5 ng/ml was predictive of organ confined disease and PFS, p< 0.001. There was no post surgical mortality with the incidence of important surgical complications of <3%. Bladder neck contracture was noted in 41% within a median of 10 months of surgery. Of the 21 patients so affected, only 1 was not successfully treated for this complication. Overall, there was an excellent quality of life outcome with a frequent use of penile prosthesis and artificial sphincter inserted during the salvage procedure. Similar excellent outcomes of salvage RP were reported by other investigators (15, 17, 19, 20−22).

Salvage Laparoscopic Prostatectomy

Laparoscopic surgery appears as an interesting salvage treatment modality in the management of patients with post−radiotherapy PSA failure. Very little published data is available for a review. The only reported study consisted of 7 patients treated in Institut Montsouris of Universite Pierre et Marie Curie in Paris, France (23). The procedure was reported to be safe and feasible. Treatment outcome is difficult to evaluate due to a very limited follow−up.


Multiple studies have been reported on the use of cryosurgery in patients presenting with PSA failure following radiotherapy (19). In three published studies on 140 patients the treatment tolerance was good. A single mortality was noted. Longer follow−up is required for the evaluation of treatment results.


Salvage brachytherapy in patients with PSA failure following external beam radiotherapy appears to have relatively limited usefulness. An interesting study on salvage brachytherapy was recently reported from Mayo Clinic (24). A total of 17 biopsy confirmed patients with post radiotherapy local recurrence and a median PSA of 4.7 ng/ml received a 3−month course of androgen deprivation therapy followed by ultrasound guided brachytherapy. A median follow−up was 44 months and the actuarial 4−year biochemical control rate was 75%. Significant GU (Grade 3+4) toxicity was reported in 8 (47%) patients, while 6 (35%) had Grade 2+3 GI toxicity. It is apparent that salvage brachytherapy needs further refinement in order to reduce the incidence of treatment toxicity.

Deep hyperthermia−RT combination

Highly selected patients with proven local recurrence following a course of external beam irradiation may be considered for deep regional hyperthermia in combination with a short (about 40 Gy) course of focused external beam radiotherapy. A report of Phase I study from USC on the treatment of 20 locally advanced patients with local recurrence following definitive external beam radiotherapy is of interest (25). These 20 patients were defined as end−stage loco−regional disease not suitable for other forms of salvage therapy. Complete response was obtained in 4 (20%), and partial response in 4 (20%) of these patients. A total of 15 (75%) patients experienced major and long−lasting improvement in the quality of life. The 3− and 5−year actuarial survival was 82%. This treatment combination needs to be re−evaluated in view of major technological improvements of hyperthermia techniques and instrumentation.

Palliative therapy

An overwhelming (about 90%) majority of patients, who demonstrate PSA failure following definitive external beam irradiation, are not suitable candidates to be considered for potentially curative local therapy. The most effective therapy for patients with recurrent advanced loco−regional or metastatic disease is hormonal therapy (HT) (26). The problem is that virtually all patients receiving HT sooner or later become refractory to this treatment. Additionally, patients show frequent treatment toxicity which sharply reduces their quality of life. The issue of the timing of initiating HT in patients with PSA failure remains controversial. The treatment decision needs to be carefully considered and its impact clearly discussed with patients. It is of particular relevance and importance in a majority of PSA relapse patients who remain asymptomatic sometimes for a very long period of time. A therapeutic intervention, which is palliative in nature in this large group of patients, is rather difficult. At USC, in those who are not suitable candidates for curative therapy, we discuss in great detail with each patient his PSA increase and its implications on longevity and the quality of life. Patients remain in our follow−up clinic for an indefinite period of time and are seen as frequently as necessary. HT is typically recommended if PSA exceeds 20 ng/ml, there is a rapid PSA−DT or patient becomes symptomatic due to his progressive cancer.


It is apparent that efficacy of salvage RP has substantially improved over the past two decades. The incidence of important treatment toxicity is low and mortality is much less than 1%. There are two important remaining problems in salvage RP. First relates to a very small (<5%) number of patients who can be accepted for this salvage therapy. Second problem to a limited patient access, due to the need for the treatment to be given in a major properly equipped and staffed medical center. Laparoscopic prostatectomy, cryosurgery and brachytherapy represent emerging salvage therapies, which require more studies to establish their indications in patients with PSA relapse following definitive RT. Major research efforts need to be directed towards the establishment of effective therapy for the 90% of patients who at the present time do not qualify for curative therapy.